International Journal of Translational Medicine doi: 10.3390/ijtm6010011

Authors: Sonia Fernández-Cañabate Asunción Díaz-Serrano Álvaro Corral-Alaejos

Background: Mitotane is the cornerstone adjuvant and palliative treatment for adrenocortical carcinoma (ACC), requiring strict therapeutic drug monitoring (TDM) due to its narrow therapeutic window and high inter- and intra-individual pharmacokinetic variability. As a highly lipophilic compound, mitotane may be influenced by plasma lipid levels; however, current TDM protocols do not systematically incorporate lipid profile assessment. We report a case illustrating the clinical impact of hypertriglyceridemia on measured mitotane plasma concentrations. Methods: We retrospectively analyzed clinical, biochemical, and pharmacokinetic data from a patient with metastatic ACC treated with oral mitotane. Plasma mitotane concentrations were correlated with triglyceride and cholesterol levels using Spearman’s rank correlation analysis. Results: A 50-year-old male with metastatic ACC experienced abrupt fluctuations in mitotane plasma concentrations despite stable dosing. Supratherapeutic mitotane levels coincided with episodes of marked hypertriglyceridemia. A significant positive correlation was observed between triglyceride levels and plasma mitotane concentrations (ρ = 0.802, p < 0.001), as well as with total cholesterol (ρ = 0.658, p < 0.001). Conclusions: This case highlights a clinically relevant interaction between triglyceride levels and measured mitotane concentrations. Incorporating routine lipid profile assessment into mitotane TDM protocols may improve interpretation of plasma levels and therapeutic decision-making. Prospective studies are warranted to validate these findings and refine monitoring strategies.

International Journal of Translational Medicine doi: 10.3390/ijtm6010010

Authors: Andrés Soto-Rodríguez Luis Felipe Deliyore-Vega Marcelo González-Kitzing Paula María Muñoz-Araya Juan Antonio Valverde-Espinoza Victor Urzola-Herrera Vincent Giampapa José Rafael Rojas-Solano

Background: Chronic shoulder pain is a frequent musculoskeletal complaint that significantly affects function, productivity, and quality of life. Mesenchymal stem cell (MSC)-based therapies have emerged as a potential regenerative option due to their anti-inflammatory and tissue-repair properties. This study aims to evaluate the safety and short-term effectiveness of intra-articular injections of umbilical cord-derived MSCs (UC-MSCs) in patients with chronic shoulder pain. Methods: A retrospective pragmatic observational study was conducted at the Regenerative Medicine Institute in Costa Rica. Medical records were reviewed to extract clinical, sociodemographic, and treatment-related variables. The primary outcome was functional improvement measured with the American Shoulder and Elbow Surgeons (ASES) score. Changes between baseline and the 3-month follow-up were analyzed using paired tests, effect size calculations, and regression models to explore predictors of treatment response. Results: Twenty patients met the inclusion criteria. A significant improvement in shoulder function was observed, with a mean ASES increase of 17.17 points, exceeding the minimum clinically important difference of 12. Sixty percent of patients achieved clinically meaningful improvement. Effect size estimates indicated a large magnitude of change. Regression analyses showed that baseline ASES predicted follow-up scores, while higher UC-MSC doses were associated with greater functional improvement. No adverse events were documented during the study period. Conclusions: The study shows that UC-MSC therapy is a safe, minimally invasive, and clinically beneficial option for chronic shoulder pain. These findings support the therapeutic potential of MSCs and highlight the need for larger controlled studies to validate long-term efficacy and optimize treatment protocols.

International Journal of Translational Medicine doi: 10.3390/ijtm6010009

Authors: Martin Tobi Fadi Antaki Mark F. Cotton Mary P. Moyer Martin H. Bluth Noreen F. Rossi Mike Lawson James S. Hatfield Suzanne Fligiel Benita McVicker

Introduction: Early HIV replication in the gastrointestinal tract plays an important role in HIV pathogenesis. We have followed the onset of the acquired immune deficiency disease (AIDS) pandemic and human immunodeficiency virus (HIV) infection from its recognition in the US. Patients and Methods: We followed 34 adult HIV positive Veterans on cART comparing colon Innate Immune System (InImS) expression of a Paneth cell product (p87; the denominator) and blood ferritin (the numerator) to derive the FERAD ratio, and p87 expression by immunohistochemistry available in some of our HIV patients and compare the expression to 2252 without HIV. Stool and colonoscopically obtained tissue specimens were run in a p87 ELISA and immunohistochemistry for both fixed and native antigens, using the Adnab-9 antibody. Results: There were no significant differences in demographics aside from lower BMI in HIV patients (24.93 ± 6.30 vs. 28.0 ± 6.13 kg/m2) p < 0.0001. Native p87 antigen was elevated in HIV patients compared to controls in the ascending, transverse, and descending colon (0.794 ± 0.890 vs. 0.170 ± 0.201 respectively; p < 0.000004; 1.062 ± 0.730 vs. 0.202 ± 0.377 respectively; p < 0.000003; and 0.611 ± 0.182 vs. 0.174 ± 0.251 respectively; p < 0.0009), respectively; and Helicobacter pylori (H. pylori) detection was higher in HIV patients (84.6% vs. 36%; p < 0.0002). We also ran these assays in cancer patients for comparison. Conclusions: Colonic inflammation as expressed by p87, a Paneth cell product, is significantly elevated in HIV patients and likely represents continued HIV activity leading to inflammation.

International Journal of Translational Medicine doi: 10.3390/ijtm6010008

Authors: Arianna Racca Francesco Ciabattoni Enrico Alleva Daniela Santucci

Zebrafish (ZF) have gained increasing attention in developmental neuroscience due to their experimental tractability, favorable ethical profile, and translational value. However, the expanding use of the ZF model has also highlighted the need to consider species-specific differences in relation to early social and emotional development. This review adopts a comparative and ethological perspective to examine early social interactions in ZF and mammals, integrating evidence from non-altricial vertebrates and teleost species with parental care (cichlids). Selected illustrative ZF papers were discussed, while Cichlids fish were chosen as a complementary, translationally consistent subject for developmental behavioral studies. The analysis focuses on developmental stages that are relevant for behavioral phenotyping in models of neuropsychiatric conditions. Zebrafish offer multiple methodological advantages, including suitability for high-throughput experimentation and substantial genetic and neurobiological homologies with humans. Nevertheless, the absence of mother–offspring bonding limits the modeling of neurodevelopmental processes shaped by early caregiving, such as imprinting and reciprocal regulatory interactions, instead observed in cichlids. Accumulating evidence indicates that early interactions among age-matched ZF are measurable, developmentally regulated, and sensitive to environmental and experimental manipulations. Within a comparative approach, these early conspecific interactions could be analogs of early social bonding observed in altricial mammals. Rather than representing a critical limitation, such species-specific features can inform the investigation of fundamental mechanisms of social development and support the complementary use of ZF and mammalian models. A contextualized and integrative approach may therefore enhance the translational relevance of ZF-based research, particularly for the study of neurodevelopmental disorders involving early social dysfunction.

International Journal of Translational Medicine doi: 10.3390/ijtm6010007

Authors: Robert M. Trout Amit Narawane Christian Viehland Vahid Ownagh Mark Draelos Al-Hafeez Dhalla Anthony N. Kuo Cynthia A. Toth

Background: Scattering of the sclera limits optical coherence tomography (OCT) imaging of deeper targets including lesions, malignancies, and other surgical targets. While existing applications of fluorescein dye are currently focused on fluorescence properties for tissue labeling, the absorption characteristics of the dye also hold potential for scleral tissue clearing. Methods: Fluorescein is investigated here to gauge the potential impact of its optical clearing on intrasurgical OCT guidance. Fluorescein was applied topically to ex vivo porcine and human eye models. OCT imaging was conducted over time to assess the increases in imaging depth due to fluorescein clearing. High-speed microscope-integrated OCT was used during pilot trabeculectomy surgery on cleared eye models to assess clearing applications in a surgical context. Results: The OCT depth of imaging increased with fluorescein concentration and application time. The effect saturates at a near-20% concentration with 50 min of application time, with a maximum signal increase of +15 dB. Reversal of the effect was observed following 10 min of rinsing. Conclusions: High-concentration fluorescein dye has novel applications as an optical clearing agent, increasing the OCT imaging depth through highly scattering biological tissue. These properties can be leveraged for improved image guidance in surgical contexts.

International Journal of Translational Medicine doi: 10.3390/ijtm6010006

Authors: Anh Nguyen Molly Lausten Bruce M. Boman

Oncofetal reprogramming has recently emerged as a critical concept in translational cancer research, particularly for its role in driving therapeutic resistance across a variety of malignancies. This biological process refers to a pattern of gene expression that is restricted to embryogenesis, but becomes expressed again in a subpopulation of cancer cells. These genes are typically suppressed after embryogenesis, and their aberrant re-expression in tumors endows cancer cells with stem-like properties and enhanced adaptability. The goal of this review is the following: (i) comprehensively examine the multifaceted nature of oncofetal reprogramming; (ii) elucidate its underlying molecular mechanisms, including its regulators and effectors; and (iii) evaluate its consequences for the therapeutic response in different cancer types. We comprehensively integrate the latest findings from colorectal, breast, lung, liver, and other cancers to provide a detailed understanding of how oncofetal programs interfere with tumor response to treatment. Among the candidates, YAP1 and AP-1 have emerged as central transcriptional drivers of this reprogramming process, especially in colorectal and breast cancers. We also explore the distinct expression patterns of oncofetal genes across different tumor types and how these patterns correlate with treatment outcomes and patient survival. Lastly, we propose a dual-targeting therapeutic strategy that simultaneously targets both cancer stem cells and oncofetal-reprogrammed populations as a more effective approach to overcome resistance and limit recurrence.

International Journal of Translational Medicine doi: 10.3390/ijtm6010005

Authors: Juan Fernández-Cadena Edwin W. Naylor Heidi Reinhard Arindam Bhattacharjee

Background: We describe the post-mortem analysis of a CARD11 variant allele, p.Ser995Leu, identified in fraternal twins who died in early infancy with no identifiable cause of death. CARD11 variants through varied inheritance models can alter immune function through loss- or gain-of-function mechanisms, involving distinct protein domains; yet the significance of GUK domain variants remains poorly characterized. Twin autopsies showed non-specific findings, such as pulmonary macrophage accumulation and splenic white pulp expansion, but without infection or structural abnormalities. Methods: Whole-exome sequencing, performed as part of molecular autopsies, identified the shared CARD11 p.Ser995Leu variant, previously classified as a variant of uncertain significance (VUS). We assessed evolutionary conservation across CARD family proteins and species and predicted functional impact using in silico tools, which estimate the likelihood that a variant is deleterious. AlphaFold-based structural modeling emphasized qualitative biophysical assessment. Using epidemiological data, population allele frequency, and Bayesian ACMG variant classification, we assessed competing hypotheses under an autosomal dominant model. Results: The p.Ser995Leu substitution affects a conserved, surface-exposed β-sheet within the GUK domain. While CADD scores exceeded 20, other predictive algorithms offered only partial support of pathogenicity. Structural modeling suggested a potential GUK domain destabilization. Integrating genetic, pathologic, immunologic, and probabilistic modeling, we propose a biologically plausible model in which the variant, like other GUK variants, may alter NF-κB or other signaling pathways and is likely pathogenic. Conclusions: While the CARD11 p.Ser995Leu variant’s contribution to disease is uncertain without functional validation or parental testing, and phenotypic findings are non-specific, the presence of an ultra-rare GUK domain variant in both twins, combined with in silico and statistical modeling, supports its interpretation as likely pathogenic or high risk. The results highlight the challenges of data-limited post-mortem variant interpretation.

International Journal of Translational Medicine doi: 10.3390/ijtm6010004

Authors: Fiona Jaederlund Ka Wei Katty Joo Hu Claudio Karsulovic Lia Hojman

Idiopathic inflammatory myopathies (IIM) comprise a heterogeneous group of autoimmune disorders with variable systemic involvement. Among them, dermatomyositis (DM) is the subtype with the most extensive biomarker characterization due to its defined immunopathology and frequent association with interstitial lung disease (ILD). This narrative review summarizes studies retrieved from PubMed, Scopus, and Web of Science up to March 2025, focusing on non-autoantibody biomarkers in DM. Reported categories include soluble proteins, cytokines, chemokines, muscle-specific microRNAs, and transcriptomic signatures reflecting interferon activation, tissue injury, and fibrotic remodeling. Among the most validated molecules, interferon-stimulated genes, ferritin, KL-6, SP-D, and CXCL10 demonstrate diagnostic and prognostic value, particularly in anti-MDA5-positive DM, where they support early identification of patients at risk for rapidly progressive ILD. However, despite increasing evidence, most biomarkers lack disease specificity, standardized cutoffs, and multicenter validation, while molecular assays remain confined to specialized laboratories. Clinically accessible markers such as ferritin, KL-6, and CXCL10 currently offer the highest translational potential. Nevertheless, the heterogeneity of study designs and analytical methods continues to limit comparability and routine clinical integration. Future research should prioritize the validation of composite biomarker panels through standardized, multicentric studies to enhance diagnostic precision and enable precision medicine approaches in DM and related inflammatory myopathies.

International Journal of Translational Medicine doi: 10.3390/ijtm6010003

Authors: Jamal Nasser Saleh Al-Maamari Junaidi Khotib Mahardian Rahmadi Yusuf Alif Pratama Nadia Ahmed Nasser Hosrom

Background/Objectives: GATA-binding protein 3 (GATA-3) is a crucial transcription factor that drives type 2 immune responses, and it is actively involved in allergic conditions such as asthma, allergic rhinitis (AR), and atopic dermatitis (AD). However, the molecular mechanisms GATA-3 uses to modulate immune responses and its potential therapeutic targeting are not fully understood. This systematic review aimed to summarize studies on the role of GATA-3 in immune responses, particularly in allergic diseases, and evaluate GATA-3’s potential as a therapeutic target. Methods: We searched PubMed, Scopus, Web of Science, Cochrane, and Science Direct for studies published before April 2025. Articles were sifted through using predefined criteria, and risk of bias was measured with RoB 2 for clinical trials and SYRCLE for animal models and in vitro studies; evidence was graded using the GRADE system. Results: Twenty-nine eligible studies reported that GATA-3 is a key regulator of Th2 and ILC2 differentiation, promoting the production of IL-4, IL-5, and IL-13. Animal models and in vitro studies demonstrated its role in exacerbating allergic inflammation and highlighted the promise of targeting strategies such as DNAzymes and nanocapsules. Clinical trials showed that targeting GATA-3, particularly with DNAzymes, can reduce allergic responses in asthma. Conclusions: GATA-3’s role in driving allergic inflammation through Th2 and ILC2 pathways suggests it as a promising therapeutic target. Understanding its broader regulatory mechanisms is imperative for designing effective GATA-3 targeting-based therapies.

International Journal of Translational Medicine doi: 10.3390/ijtm6010002

Authors: Christian J. Wiedermann Arian Zaboli Gianni Turcato

Background/Objective: Early hemodynamic instability in sepsis arises from endothelial dysfunction and vasoplegia before capillary leakage and organ failure occur. Albumin administration guided by serum concentration or shock criteria has not improved outcomes. This review synthesized evidence supporting an early, physiology-guided framework for albumin and norepinephrine use in pre-δ vasoplegic sepsis. Methods: A narrative synthesis of experimental and clinical studies examined endothelial injury, sepsis phenotypes, hemodynamic monitoring, biochemical markers, and intravascular albumin mass. Evidence from phenotype cohorts was integrated to construct a physiology-based therapeutic framework. Results: The δ phenotype consistently emerged as a vasoplegic, hyperinflammatory endotype with hypoalbuminemia, elevated lactate, and the highest mortality. Studies showed 20–25% of patients with community-acquired sepsis exhibit early vasoplegia, with low systemic vascular resistance and high cardiac output. Mass-balance analyses showed intravascular albumin mass declines early in sepsis, correlate inversely with fluid balance, and predict mortality. These findings suggest early low-dose norepinephrine may stabilize perfusion pressure, while albumin use should follow intravascular albumin mass trajectories. A dynamic exclusion concept proposes withholding albumin during capillary leak and reintroducing it when intravascular albumin mass stabilizes. Conclusions: Albumin therapy in sepsis should shift from late concentration-based to early physiology-guided endothelial protection. Monitoring intravascular albumin mass, lactate, and fluid balance may guide targeted norepinephrine and albumin use before δ-type endothelial failure occurs. This framework needs phenotype-stratified validation.

International Journal of Translational Medicine doi: 10.3390/ijtm6010001

Authors: Aigerim Tanyrbergenova Zhandos Burkitbayev Asel Zhumabekova Daulet Marat Damesh Orazbayeva Bekkozha Yeskendirov Dinara Zharlyganova

Background: Takotsubo cardiomyopathy (TTC), also known as stress-induced cardiomyopathy, is an acute but reversible form of left ventricular dysfunction, most commonly triggered by physical or emotional stress. Although well documented in cardiology practice, its occurrence following hepatobiliary surgery is rarely reported. Case presentation: We describe the case of a 67-year-old woman with a history of arterial hypertension and prior cholecystectomy who was admitted for elective hepatobiliary surgery due to choledocholithiasis complicated by a liver abscess. She underwent laparotomy with choledocholithotomy, hepaticojejunostomy, and abdominal drainage. The postoperative course was complicated by intra-abdominal bleeding, requiring reoperation, and subsequent intestinal leakage, necessitating a second re-laparotomy. On the tenth postoperative day after the second surgery, she developed chest discomfort and dyspnea upon minimal exertion. Electrocardiography revealed T-wave inversions in leads V3–V6, while echocardiography demonstrated a reduced ejection fraction of 45% with apical akinesis. Plasma levels of N-terminal pro-B-type natriuretic peptide (NT–proBNP) were elevated, whereas troponin remained within normal limits. Coronary angiography excluded obstructive coronary artery disease, and ventriculography confirmed apical ballooning consistent with Takotsubo cardiomyopathy. Conclusions: This case highlights Takotsubo cardiomyopathy as a rare but important postoperative complication of major hepatobiliary surgery. Awareness of this condition in surgical patients presenting with acute chest symptoms is essential, as timely recognition and differentiation from acute coronary syndrome directly influence management and prognosis.

International Journal of Translational Medicine doi: 10.3390/ijtm5040058

Authors: Mariana Godinho Lara Marques Nuno Vale

Background/Objectives: Understanding the pharmacokinetics (PK) of antiepileptic and anti-inflammatory drugs under different physiological conditions is essential for optimizing therapy. Phenytoin, a widely used antiepileptic, and indomethacin, a nonsteroidal anti-inflammatory drug, are frequently prescribed in women of reproductive age. This study aimed to evaluate the influence of age, pregnancy, and dosing regimens on the PK of both drugs, as well as to investigate potential drug–drug interactions (DDIs). Methods: PK parameters of phenytoin and indomethacin were systematically analyzed in women aged 20–45 years under non-pregnant and pregnant conditions. Different dosing regimens were compared, and coadministration studies were conducted to assess DDI. Results: Phenytoin demonstrated stable absorption and bioavailability across ages and during pregnancy. Single daily dosing (300 mg once daily) yielded slightly higher peak concentration (Cmax) values, while fractionated dosing (100 mg q8h) produced significantly higher drug exposure (AUC) and absorption fraction, particularly with prolonged administration, reflecting saturable metabolism. During pregnancy, systemic exposure (Cmax and AUC) was modestly reduced, while absorption and distribution remained unchanged. Indomethacin showed minimal age-related variability and linear pharmacokinetics across dosing regimens. In pregnancy, exposure was reduced (lower Cmax and AUC) with delayed Tmax, indicating slower absorption. Importantly, no PK DDI was observed, as indomethacin parameters remained unchanged except for Tmax, which was lower in the interaction scenario compared with baseline, suggesting a faster absorption rate without affecting overall exposure or peak concentration in the presence of phenytoin. Conclusions: Phenytoin and indomethacin exhibit stable and predictable PK across ages and during pregnancy, with dose-dependent characteristics that align with their known metabolic profiles. The absence of clinically relevant DDI supports their safe concomitant use. These findings provide preliminary reassuring evidence for clinicians and contribute to a better understanding of their pharmacological behavior in diverse patient populations.

International Journal of Translational Medicine doi: 10.3390/ijtm5040057

Authors: Takuya Miyano Tsuyoshi Mikkaichi

Background: Autism spectrum disorder (ASD) is a complex and heterogeneous neurodevelopmental disorder. This study aims to demonstrate the potential of comprehensive polygenic scores (PGSs) as clinical biomarkers for stratifying individuals with ASD and for advancing the understanding of ASD’s heterogeneous etiology. Methods: We calculated 2602 PGSs—representing all publicly available, license-cleared PGSs in the PGS Catalog—for 75 individuals with ASD by utilizing the database of the Tohoku Medical Megabank Birth and Three-generation cohort study. Results: Unsupervised clustering revealed three ASD subgroups. We identified twenty PGSs with the most significant differences among these subgroups as distinctive PGSs for each subgroup. PGS set enrichment analysis associated these distinctive PGSs with different traits in each subgroup: high-density lipoprotein cholesterol measurements, urea measurement, and body mass index. Furthermore, distinctive PGSs indicated consistent genetic predisposition directions: lower high-density lipoprotein cholesterol levels in subgroup 1, higher urea levels in subgroup 2, and lower body mass index in subgroup 3. Conclusions: Comprehensive PGSs extending beyond psychiatry-related traits represent promising clinical biomarkers for identifying ASD subgroups with different genetic predispositions. Such stratification may enhance understanding of heterogenous genetic backgrounds and targeted drug development.

International Journal of Translational Medicine doi: 10.3390/ijtm5040056

Authors: Nikitas G. Liolitsas Evangelia Pantazaka Evangelia Papadimitriou

G protein-coupled receptors (GPCRs) are the largest family of diverse receptors in eukaryotic organisms, playing a critical role in modulating human physiology. It therefore comes as no surprise that about 36% of all currently available drugs target this superfamily. When an agonist binds to a GPCR, it induces conformational changes in the receptor that allow it to interact with intracellular proteins. This interaction triggers downstream signaling cascades that alter the cell’s activity. GPCR signaling is complex, as GPCRs transmit signals through coupling with G proteins, arrestins, and numerous other intracellular effectors. Different ligands, receptor subtypes, and cellular environments can result in the activation of distinct signaling pathways. Biased signaling through GPCRs has emerged as a frontier area in pharmacological research efforts towards designing targeted therapeutic interventions and enhancing drug efficacy and safety. This review presents the types of bias associated with GPCRs and the mechanisms underlying biased signaling. Examples of biased ligands and their therapeutic implications will be discussed. In addition, the inherent challenges in measuring signaling bias, and especially the translational gap between in vitro and in vivo assays and clinical outcomes, will be outlined.

International Journal of Translational Medicine doi: 10.3390/ijtm5040055

Authors: Julia Groszewska Michał Romaniuk Ewa Małecka-Wojciesko

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with poor survival even after surgical resection. Clinical stages include resectable (R-PDAC), borderline resectable (BR-PDAC), locally advanced, and metastatic disease. Neoadjuvant therapy (NAT)—chemotherapy or chemoradiotherapy before surgery—has emerged as a promising strategy to improve outcomes by increasing margin-negative resection rates and enhancing overall survival. For R-PDAC, surgery followed by adjuvant chemotherapy remains the standard, but NAT may be considered in high-risk patients, such as those with severe pain, elevated CA 19-9, or large tumors. For BR-PDAC, NAT is the primary approach, significantly increasing R0 resection rates and prolonging survival. Common regimens include mFOLFIRINOX and gemcitabine-based combinations. NAT also carries risks, including disease progression during therapy, loss of resectability, and uncertainty in evaluating response. Current tools, such as imaging and CA 19-9, offer limited predictive value. The role of NAT in R-PDAC remains under debate, while its benefits in BR-PDAC are more established. This review summarizes current evidence and guidelines on NAT in PDAC, with a focus on treatment strategies, patient selection, and emerging approaches.

International Journal of Translational Medicine doi: 10.3390/ijtm5040054

Authors: Maxwell A. Barffour Mustafa Gandhi Harleen Chela Serena Crawford Zguri Liridon Kwame Frimpong Elizabeth Karanja Kevin Luton Emily Reznicek Hayford Frimpong Emily Bosak Yezaz A. Ghouri

Background: Terminal ileum inflammation and surgical resections impair absorption of vitamin B12 and D in patients with Crohn’s disease (CD) and Ulcerative Colitis (UC). We assessed differences in subclinical deficiencies of vitamin B12 (<350 pg/mL) or D (<50 nmol/L), by lesion localization (namely non-ileal CD, ileal CD, and UC) and surgical resection status (namely no resection, non-ileal small bowel resections, ileocecal resections, and colonic resections) in CD and UC patients. Methods: We analyzed data from 571 patients (17–93 years), with UC (51%) and CD (49%, including 47 non-ileal (8%), 244 ileal-CD (46%)) managed at the University of Missouri Health Care System (Jan 2017–April 2022). Results: Prevalence of vitamin B12 and vitamin D deficiencies was 19% and 83%, respectively. Prevalence of resection was 26%, including 5% with non-ileal small bowel resections, 11% with ileocecal resections, and 10% with colonic resections. CD with ileal involvement was associated with a 3-fold elevated risk of B12 deficiency (p = 0.004), but not vitamin D. Ileocecal resections were associated with a >3-fold increase in both B12 deficiency (OR = 3.53, p = 0.001) and D deficiency (OR = 3.35, p = 0.044). Conclusions: CD patients with ileal involvement and ileocecal resections have an elevated risk of vitamin B12 and D deficiency, and may benefit from adjunctive supplementation.

International Journal of Translational Medicine doi: 10.3390/ijtm5040053

Authors: Carlo Ferrari Jacopo Crippa Paola Floris Davide Vailati Benedetta Basta Roberto Santalucia Salvatore Barbaro Carmelo Magistro

Background: Neuraxial anesthesia (NA) is increasingly utilized across various surgical specialties, particularly for abdominal procedures, making it a potential alternative to general anesthesia (GA). Methods: This narrative review was conducted following the PRISMA guidelines for systematic reviews to report on the application of NA worldwide and across various surgical fields. Results: The findings indicate that while NA is gaining popularity, its adoption varies significantly by procedure type and specialty. Evidence supporting its use in major abdominal surgeries remains limited, with most studies focusing on pelvic and minor procedures. The emerging concept of awake surgery under NA shows promising potential, as preliminary data suggest benefits in reducing perioperative morbidity and enhancing recovery. Despite these advancements, gaps in the literature highlight the need for further high-quality trials to establish NA as a safe and routine alternative to GA. Conclusions: NA is increasingly explored across different surgical specialties as a feasible and effective option for abdominal procedures. However, despite this growing interest, solid evidence supporting its use in major abdominal surgery remains limited.

International Journal of Translational Medicine doi: 10.3390/ijtm5040052

Authors: Federica Palacino Paolo Manganotti Alberto Benussi

Frontotemporal lobar degeneration (FTLD) represents a heterogeneous group of neurodegenerative disorders with overlapping clinical, pathological, and genetic characteristics. Increasing evidence indicates that disease mechanisms begin decades before the appearance of clinical symptoms, highlighting the importance of identifying preclinical and prodromal stages. This review provides a comprehensive synthesis of current knowledge on the complexity of FTLD, emphasizing early detection and intervention strategies. It integrates findings from neuropathological, neuroimaging, fluid biomarker, genetic, and clinical studies in both familial and sporadic forms, with particular attention to gene-specific trajectories, biomarker evolution, and emerging therapeutic approaches targeting presymptomatic and prodromal phases. Recent advances in biomarker discovery and neuroimaging are enabling earlier diagnosis and intervention, offering the potential to delay phenoconversion and preserve brain function.

International Journal of Translational Medicine doi: 10.3390/ijtm5040051

Authors: Mateusz Zajączkowski Łukasz Klasa Olga Milczarek Stanisław Kwiatkowski

Background: Cerebrospinal fluid (CSF) shunting remains a crucial intervention in the treatment of paediatric hydrocephalus. Overdrainage syndrome is a well-recognised but potentially severe complication, in which hyperostosis cranii ex vacuo—diffuse thickening of the cranial bones—emerges as an adaptive response to chronic intracranial hypotension. Currently, no established diagnostic criteria exist to reliably identify and classify this phenomenon, nor are there defined strategies to prevent associated complications of reduced intracranial compliance. Objective: This study aimed to characterise the morphoradiological and clinical phenotype of hyperostosis cranii ex vacuo in paediatric patients with long-term shunt dependency and to propose its classification as a fifth subtype of CSF overdrainage syndrome with direct implications for long-term neurosurgical care. Methods: A retrospective observational study was conducted on nine paediatric patients with radiologically confirmed diffuse calvarial thickening secondary to surgical treatment of hydrocephalus. Quantitative morphometric analysis of frontal, parietal, and occipital bones, sella turcica dimensions, and dural enhancement was performed using high-resolution neuroimaging. Clinical records were reviewed for hydrocephalus aetiology, shunt revision history, and neurological impairment. Results: All patients exhibited a mean two-fold increase in age-adjusted calvarial thickness. Premature craniosynostosis was identified in 33.3% of cases. Diffuse pachymeningeal enhancement was noted in all patients with contrast-enhanced imaging. Neurological comorbidities included epilepsy, spastic paraparesis, and features of Chiari type I malformation. Conclusions: Hyperostosis cranii ex vacuo represents a distinct and underrecognised consequence of chronic CSF overdrainage. We propose preliminary diagnostic criteria and a structured management pathway—from radiological recognition through ICP assessment to tiered surgical intervention. Formal recognition of this entity as a fifth subtype of CSF overdrainage syndrome may enhance early diagnosis, improve risk stratification, and guide long-term surveillance of shunted children.

International Journal of Translational Medicine doi: 10.3390/ijtm5040050

Authors: Mateus Blasques Frade Paola Critelli Eleonora Trifiletti Giuseppe Ripepi Antonio Pontoriero

Background: Radiation therapy is a key treatment modality for brain metastases. While providing a treatment alternative, post-treatment imaging often presents diagnostic challenges, particularly in distinguishing tumor recurrence from radiation-induced changes such as necrosis. Advanced imaging techniques and artificial intelligence (AI)-based radiomic analyses emerge as alternatives to help lesion characterization. The objective of this study was to assess the capacity of machine learning algorithms to distinguish between brain metastases recurrence and radiation necrosis. Methods: The research was conducted in two phases and used publicly available MRI data from patients treated with Gamma Knife radiosurgery. In the first phase, 30 cases of local recurrence of brain metastases and 30 cases of radiation-induced necrosis were considered. Image segmentation and radiomic feature extraction were performed on these data using MatRadiomics_1_5_3, a MATLAB-based framework integrating PyRadiomics. Features were then selected using point-biserial correlation. In the second phase, a classification was performed using a Support Vector Machine model with repeated stratified cross-validation settings. Results: The results achieved an accuracy on the test set of 83% for distinguishing metastases from necrosis. Conclusions: The results of this feasibility study demonstrate the potential of radiomics and AI to improve diagnostic accuracy and personalized care in neuro-oncology.

International Journal of Translational Medicine doi: 10.3390/ijtm5040049

Authors: Alessio Danilo Inchingolo Angelo Michele Inchingolo Claudia Ciocia Francesca Calò Sara Savastano Francesco Inchingolo Andrea Palermo Giuseppe Giudice Daniela Di Venere Grazia Marinelli Gianna Dipalma

Background: Mandibular advancement devices (MADs) are widely used for mild-to-moderate obstructive sleep apnea (OSA). We aimed to synthesize recent evidence on their clinical effectiveness and tolerability. Methods: A systematic review was conducted. Ten studies were included, evaluating MAD therapy in adults with mild-to-moderate OSA. The review reported on standard outcomes, including the apnea-hypopnea index (AHI), oxygenation, daytime sleepiness (Epworth Sleepiness Scale, ESS), quality of life, adherence, and adverse events. Risk of bias was also assessed. Results: Across the included studies, MADs consistently reduced AHI from baseline and improved ESS and/or snoring. In head-to-head comparisons, MADs generally yielded smaller reductions in AHI than CPAP but achieved comparable improvements in symptoms and quality of life, with higher nightly adherence. Reported adverse effects were mostly mild and transient. Conclusions: MAD therapy is an effective and generally well-tolerated option for adults with mild-to-moderate OSA and for the patients intolerant to CPAP, although average AHI reduction is smaller than with CPAP. Given the low certainty and heterogeneity of current evidence, high-quality randomized trials with objective adherence tracking and standardized titration are needed.

International Journal of Translational Medicine doi: 10.3390/ijtm5040048

Authors: Meyrem Osum Louai Alsaloumi Rasime Kalkan

Background/Objectives: Gliomas are the most common tumours of the central nervous system (CNS), classified into grades I to IV based on their malignancy. Genetic and epigenetic alterations play a crucial role in glioma progression. DNA methyltransferases (DNMTs) are vital enzymes responsible for DNA methylation, with DNMT1 and DNMT3 catalysing the addition of a methyl group to the 5-carbon of cytosine in CpG dinucleotides. Targeting DNMTs with DNA methyltransferase inhibitors (DNMTi) has become a promising therapeutic approach in tumour treatment. In this study, in silico screening tools were employed to evaluate potential inhibitors of DNMT1, DNMT3A, and DNMT3B for the treatment of glioblastoma multiforme (GBM). Methods: The Gene2Drug platform was used to screen compounds and rank them based on their capacity to dysregulate DNMT genes. PRISM viability assays were performed on 68 cell lines, and DepMap data were analyzed to assess the antitumor activities of these compounds and their target genes. Candidate drug similarity was evaluated using DSEA, and compounds with p < 1 × 10−3 were considered statistically significant. Gene-compound interactions for DNMT1, DNMT3A, and DNMT3B were confirmed using Expression Public 24Q2, while Prism Repositioning Public data were analyzed via DepMap. Results: Glioblastoma cell lines showed sensitivity to compounds including droperidol, demeclocycline, benzthiazide, ozagrel, pizotifen, tracazolate, norcyclobenzaprine, monocrotaline, dydrogesterone, 6-benzylaminopurine, and nifedipine. SwissTargetPrediction was utilised to identify alternative molecular targets for selected compounds, revealing high-probability matches for droperidol, pizotifen, tracazolate, monocrotaline, dydrogesterone, and nifedipine. Conclusions: Integrating computational approaches with biological insights and conducting tissue-specific and experimental validations may significantly enhance the development of DNMT-targeted therapies for gliomas.

International Journal of Translational Medicine doi: 10.3390/ijtm5040047

Authors: Nigara Yerkhojayeva Nazira Zharkinbekova Sovet Azhayev Ainash Oshibayeva Gulnaz Nuskabayeva Rauan Kaiyrzhanov

Background: Rare pediatric neurological diseases (RPND) often remain undiagnosed for years, creating prolonged and costly diagnostic odysseys. Combining Human Phenotype Ontology (HPO)-based deep phenotyping with exome sequencing (ES) and reverse phenotyping offers the potential to improve diagnostic yield, accelerate diagnosis, and support sustainable healthcare in resource-limited settings. Objectives: To evaluate the diagnostic yield and clinical impact of an integrated approach combining deep phenotyping, ES, and reverse phenotyping in children with suspected RPNDs. Methods: In this multicenter observational study, eighty-one children from eleven hospitals in South Kazakhstan were recruited via the Central Asian and Transcaucasian Rare Pediatric Neurological Diseases Consortium. All patients underwent standardized HPO-based phenotyping and ES, with variant interpretation following ACMG guidelines. Reverse phenotyping and interdisciplinary discussions were used to refine clinical interpretation. Results: A molecular diagnosis was established in 34 of 81 patients (42%) based on pathogenic or likely pathogenic variants. Variants of uncertain significance (VUS) were identified in an additional 9 patients (11%), but were reported separately and not included in the diagnostic yield. Reverse phenotyping clarified or expanded clinical features in one-third of genetically diagnosed cases and provided supportive evidence in most VUS cases, although their classification remained unchanged. Conclusions: Integrating deep phenotyping, ES, and reverse phenotyping substantially improved diagnostic outcomes and shortened the diagnostic odyssey. This model reduces unnecessary procedures, minimizes delays, and provides a scalable framework for advancing equitable access to genomic diagnostics in resource-constrained healthcare systems.

International Journal of Translational Medicine doi: 10.3390/ijtm5040046

Authors: Pol Molina Perelló Montse Puntes Rodríguez Jimena Coimbra Hurtado Maite Garrido Sánchez Marta Castillo Ocaña David Martínez Bonifacio Lydia Carrera Marcolin Jordi Cuñé Castellana Rosa Antonijoan Arbós

Background/Objectives: Diamine oxidase (DAO) enzyme metabolizes dietary histamine in the gastrointestinal tract. DAO deficiency can lead to histamine intolerance (HIT), manifesting as migraines, gastrointestinal disturbances, and allergic reactions. DAO supplementation has been shown to enhance histamine breakdown, alleviating these symptoms. This randomized, double-blind, single ascending dose (SAD) Phase I clinical trial aimed to evaluate the safety and tolerability of escalating doses of DAO supplementation in healthy volunteers. Methods: Thirty participants were randomly assigned to receive single doses of 42 mg, 84 mg, or 210 mg of DAO extract (adiDAO® Veg) or placebo under fasting conditions. Vital signs, laboratory parameters, and adverse events (AEs) were monitored. Results: No serious adverse events or clinically significant changes in vital signs, ECGs, or laboratory parameters were observed. Conclusions: This trial confirms the safety and tolerability of high-dose DAO supplementation. Future studies are recommended to explore the effects of chronic high-dose administration and alternative dosage forms to improve convenience.

International Journal of Translational Medicine doi: 10.3390/ijtm5040045

Authors: Maja Bürdek Petra U. Prinz Kathrin Mutze Miriam Bosch Stefanie Tippmer Andrea Coluccio Christiane Geiger Snigdha Majumder Giulia Longinotti Dolores J. Schendel

Background/Objectives: Whilst adoptive cell therapy (ACT) using chimeric antigen receptor-engineered T (CAR-T) cells represents an efficient approach for the treatment of patients suffering from several hematological malignancies, solid tumors have been shown to be far more challenging to tackle, mainly due to the hostile tumor microenvironment that inhibits optimal T cell functionality. As proven by the broad clinical success of immune checkpoint inhibitors, blocking the interaction of programmed cell death ligand 1 (PD-L1) expressed on tumor cells and the checkpoint receptor programmed cell death 1 (PD-1) expressed on activated T cells allows an intrinsic T cell-mediated anti-tumor response to be unleashed. We developed a cellular product (MDG1015) consisting of New York esophageal squamous cell carcinoma-1 (NY-ESO-1)/L antigen family member 1a (LAGE-1a)-specific CD8+ T cell receptor-transduced (TCR-)T cells co-expressing the costimulatory switch protein (CSP) PD1-41BB, which turns an inhibitory signal mediated by the PD-1:PD-L1 axis into positive T cell costimulation. Methods: In vitro co-cultures of MDG1015 and PD-L1-positive or -negative target cells were used to analyze TCR-T cell functionality, such as TCR-T (poly-)cytokine release, the killing of target cells, and TCR-T proliferation. The safety of MDG1015 was evaluated via different panels of antigen-negative cell lines or primary cells expressing or lacking PD-L1. Results: Preclinical analyses demonstrated TCR-gated activation of the CSP, leading to enhanced functionality of MDG1015 against antigen-expressing, PD-L1-positive tumor cells without any impact on antigen-negative target cells. Conclusions: The favorable, preclinical functionality and safety profile qualifies MDG1015 as a promising cellular therapy for explorative clinical testing in hard-to-treat solid tumor indications.

International Journal of Translational Medicine doi: 10.3390/ijtm5040044

Authors: Pietro Pozzessere Roberto Lovero Corrado Crocetta Najada Firza Vincenzo Brescia Angela Pia Cazzolla Mario Dioguardi Francesco Testa Marica Colella Luigi Santacroce

Background: It is estimated that most patients with severe sepsis are admitted through the emergency department. Early identification and subsequent early appropriate therapy remain cornerstones of sepsis management. Early recognition of sepsis in the emergency department (ED) is crucial. The National Early Warning Score 2 (NEWS2) has shown limitations in prognostic accuracy. We aimed to develop and evaluate a prognostic model combining NEWS2 with triage data to predict 28- and 90-day mortality in adult patients with bacterial sepsis. Methods: We conducted a retrospective cohort study of 557 patients admitted to the ED with suspected bacterial infection between March 2017 and September 2019. Candidate predictors included triage variables (vital signs, comorbidities, blood gas data) and clinical scores (NEWS2, SOFA, qSOFA, APACHE2, and SIRS). Outcomes were 28- and 90-day mortality. Logit analysis was used to develop prognostic models, with assessment of discrimination and calibration. Results: Overall mortality was 24.6% at 28 days and 36.4% at 90 days. Models combining NEWS2, age, and lactates outperformed NEWS2 alone (28-day: 73.8% vs. 69%; 90-day: 71.6% vs. 67%). Including terminal status further improved accuracy. Finally, this paper proposes new criteria for the early identification of patients with sepsis in triage, with positive outcomes. Conclusions: Combining NEWS2 with age and lactates enhances prognostic accuracy at triage. This model may inform improved sepsis management.

International Journal of Translational Medicine doi: 10.3390/ijtm5030043

Authors: Leidivan Sousa Da Cunha Isabelle Magalhães Farias Beatriz Maria Dias Nogueira Caio Bezerra Machado Flávia Melo Cunha De Pinho Pessoa Deivide De Sousa Oliveira Guilherme Passos de Morais André Pontes Thé Patrícia Maria Pontes Thé Manoel Odorico De Moraes Filho Maria Elisabete Amaral De Moraes Caroline Aquino Moreira-Nunes

The JAK2V617F mutation is a major molecular factor in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and has been increasingly associated with clonal progression to acute myeloid leukemia (AML), resulting in a poorer prognosis and resistance to conventional therapies. This study integrates a comprehensive literature review with bioinformatic approaches to investigate the potential inhibitory activity of Epigallocatechin Gallate (EGCG), a green tea polyphenol widely recognized for its antioxidant and anticancer properties, on the JAK2V617F mutation. Clinical data from case reports demonstrated heterogeneity in disease progression and frequent therapeutic failures. Molecular docking analysis using the Janus Kinase 2 (JAK2) protein structure (PDB ID: 6D2I) identified a high-affinity binding pocket for EGCG near the V617F mutation site. EGCG exhibited strong binding affinity (−9.2 kcal/mol), forming key interactions with residues Lys581, Ile559, and Leu680, suggesting allosteric modulation of the JH2 pseudokinase domain. To validate our docking protocol, redocking of the known inhibitor AT9283 yielded a favorable Root Mean Square Deviation (RMSD) 2.683 Å and binding energy (−8.3 kcal/mol), confirming the reliability of our approach. Notably, EGCG demonstrated superior binding affinity compared to AT9283 and targets a distinct allosteric site, highlighting its unique mechanism of action and potential as a selective allosteric inhibitor. These findings position EGCG as a promising candidate for future preclinical evaluation, offering a novel strategy to overcome therapy resistance in JAK2V617F-driven malignancies.

International Journal of Translational Medicine doi: 10.3390/ijtm5030042

Authors: Ezek Mathew Nathan Jones Katherine Hernandez Sterling B. Ortega Rob Dickerman

Background/Objectives: Traumatic brain injury (TBI) remains the most common cause of morbidity and mortality in adolescents and adults. Although numerous animal and human studies have demonstrated the beneficial effects of branched-chain amino acids (BCAA) treatment on various models of brain injury, the optimal concentration and mechanism of action have not been elucidated. Methods: Based on our prior work, we hypothesized that a 2:1:1 ratio of BCAAs promotes neuronal regrowth and repair. Using in vitro mixed cortical cultures (composed of CNS cells, including neuronal and glial cells), we recapitulated the mechanical damage induced by TBI using the scratch assay model. We evaluated various concentrations of BCAA to promote the regrowth of CNS cells after mechanical damage. Results: A 2:1:1 ratio of leucine: isoleucine: valine was observed to yield superior regrowth rates at the 48 h time point across various concentrations when compared to a 1:1:1 ratio and even a 4:1:1 ratio. In addition, both 2:1:1 and 4:1:1 ratios offered multiple instances of accelerated regrowth, where less than 5% of the wound remained unhealed. Conclusions: The importance of leucine ratios in the context of BCAA treatment for TBI was demonstrated by the superior CNS cell regrowth offered by the 2:1:1 ratio.

International Journal of Translational Medicine doi: 10.3390/ijtm5030041

Authors: Hans Christian Wulf Anne L. Christiansen Ida M. Heerfordt

Background/Objectives: Patients with erythropoietic protoporphyria (EPP) have a decreased activity of the ferrochelatase enzyme which converts protoporphyrin IX (PpIX) into heme, causing PpIX to accumulate in erythrocytes. The ensuing release of PpIX to the skin when exposed to visible light causes a phototoxic reaction with severe pain, erythema, and edema. Erythrocyte PpIX levels in adult EPP patients are rather stable and largely unaffected by pharmaceutical treatments. It is important to be aware of drugs causing an increase in PpIX as this may increase the risk of liver toxicity. Method: The patient had blood samples taken regularly for analyses of PpIX, znPpIX, ALT, ALP, iron, leucocytes, C-reactive protein, and hemoglobin before, during, and after treatment with teriflunomide. Additionally, we tested if teriflunomide increased PpIX in vitro. Results: A female EPP patient was treated for 7 years with teriflunomide for multiple sclerosis attacks. During treatment, her natural PpIX level increased from about 30 µmol/L to about 200 µmol/L, without significant simultaneous changes in hemoglobin, iron levels, alanine transaminase (ALT), or alkaline phosphatase (ALP). The patient experienced no increase in photosensitivity. In vitro addition of teriflunomide did not affect PpIX levels. Discussion: In patients with lead intoxication, the release of PpIX from erythrocytes is very slow. The increase in PpIX during treatment with teriflunomide compared to periods with no medication could be caused by a similar slow PpIX release from the erythrocytes. This theory is supported by the patient’s unchanged light sensitivity and stable levels of hemoglobin, iron, and liver enzymes.

International Journal of Translational Medicine doi: 10.3390/ijtm5030040

Authors: Albrecht Blosse Markus Pirlich Andreas Dietz Christin Möser Katrin Arnold Jessica Freitag Thomas Neumuth David M. Smith Hans Kubitschke Maximilian Gaenzle

Head and neck squamous cell carcinomas (HNSCCs) are the seventh most common form of cancer worldwide, typically characterized by high mortality and significant morbidity, including pain and speech and swallowing disorders. Complete tumor tissue resection, the common first line of therapy, remains a surgical challenge with room for improvements. Because tumor cells express highly specific surface molecules serving as receptors for ligands, specific targeting ligands can be conjugated to fluorescent molecules in order to better visualize tumor borders. Targeted fluorescence-guided surgery (T-FGS) as well as tumor-targeted and near-infrared (NIR) fluorescence imaging are emerging techniques for real-time intraoperative cancer imaging. Targeting agents include nanodots or fluorophores, which have been conjugated to specific ligands like antibodies, peptides, or other synthetic moieties. This article surveys tumor-targeted ligands in recent and current preclinical studies and clinical trials related to HNSCC, highlighting common NIRF dyes used for molecular imaging and their physical properties, working concentrations, and associated risks. Smaller ligands, nanodots, dual-modality NIR dyes, and activatable agents can enhance tumor-targeting processes, resulting in faster, more penetrable, and clearer imaging, which could lead to improved clinical applications and better tumor removal rates in the future.

International Journal of Translational Medicine doi: 10.3390/ijtm5030039

Authors: Valeria Carcia Alessandro Vincenzo De Salve Chiara Nonno Maria Felice Brizzi

Coronary artery disease (CAD) is a leading cause of death worldwide, encompassing a broad spectrum of pathological conditions ranging from chronic to acute coronary syndromes. It underlies complex biological mechanisms, among which an emerging role is played by extracellular vesicles (EVs). EVs are non-replicable cell-derived particles enclosed by lipid bilayers acting as mediators of cellular interactions. In the past two decades, there has been a growing interest in EVs as potential diagnostic, prognostic and therapeutic tools in cardiovascular disease. We reviewed the most recent studies on circulating EVs in CAD with a particular focus on their role in biomarker discovery. Our aim was to evaluate the feasibility of translating these findings into routine clinical practice. To this end, we underlie the development and application of integrated indicators, referred to as “Bioscores”, which combine clinical, laboratory, and molecular data to enhance diagnostic and prognostic accuracy. We briefly discuss the opportunity and pitfalls related to the emerging use of Machine Learning (ML) algorithms. Moreover, we highlight that further investigation of mechanistic pathways is required beyond the initially predicted associations generated by in silico studies. Finally, we analyzed the key limitations, challenges, and unmet needs in the field, including small and unrepresentative sample sizes, a lack of external validation, overlapping and often contradictory effects on targeted pathways, difficulties in standardizing EV isolation and characterization methods, as well as concerns regarding affordability and clinical reliability.

International Journal of Translational Medicine doi: 10.3390/ijtm5030038

Authors: Michał Mazur Agnieszka Malik Monika Pytka Joanna Popiołek-Kalisz

This review focuses specifically on pediatric patients with cystic fibrosis. Cystic fibrosis (CF) is a serious inherited disease that affects the respiratory and gastrointestinal systems in children and adolescents, causing chronic inflammation, infections, and impaired nutrient absorption. A key component of patient care is monitoring nutritional status, particularly based on BMI, which correlates with lung function and life expectancy. This paper presents the latest guidelines for dietary therapy, including a high-calorie and fat-rich diet supported by pancreatic enzymes, as well as the importance of vitamin and mineral supplementation in the context of CF pathophysiology. The role of modern therapies that modulate CFTR function to improve patients’ quality of life and support antimicrobial therapy is discussed. Particular attention is paid to the role of the gut microbiota and the potential for its modulation by probiotics, highlighting their potential to alleviate inflammation and support the immune system. The conclusions underscore the need for a comprehensive, individualized approach to diagnosis and therapy, which is crucial for improving the quality of life and health prognosis of children with CF. New visual tools and a clinical case study enhance the practical applicability of current recommendations, while emerging areas such as microbiome-targeted interventions and treatment inequalities are also addressed.

International Journal of Translational Medicine doi: 10.3390/ijtm5030037

Authors: Joseph S. D’Arrigo

Apolipoprotein A-I (apoA-I)-coated nanoemulsion particles target scavenger receptors. Adsorbed apoA-I (from the bloodstream) mediates/facilitates this targeted molecular contact, which is followed by receptor-mediated endocytosis and subsequent transcytosis of these same nanoemulsion (nanocarrier) particles across the blood–brain barrier (BBB). When the right drugs are added in advance to these high-density lipoprotein (HDL)-like nanocarriers, multifunctional combination treatment is achieved. This medication penetrates the BBB and targets particular cell-surface scavenger receptors, mainly class B type I (SR-BI). As a result, these (drug-carrying) nanoemulsions may find application in the biomedical therapy of complex medical disorders, such as dementia, as well as some aspects of aging. According to recent research, sustained inflammatory stimulation in the gut, such as via serum amyloid A (SAA), may cause the release of proinflammatory cytokines. Thus, using this “HDL-like” nanoemulsion vehicle to target drugs early (or even proactively) toward a major SAA receptor (like SR-BI), which is implicated in SAA-mediated cell-signaling processes that lead to aging and/or cognitive decline (and eventually Alzheimer’s disease or dementia), may be a useful preventive and therapeutic strategy.

International Journal of Translational Medicine doi: 10.3390/ijtm5030036

Authors: M. Kristen Hall Cody J. Hatchett Haris A. Khan Hannah Lewis Ruth A. Schwalbe

Background/Objectives: Perturbation in terminal N-glycan processing is a feature of congenital disorders of glycosylation and neurological disorders. Since treatment options are limited, N-glycans are plausible therapeutic targets. Here, we investigated the consequences of substituting complex/hybrid with oligomannose types of N-glycans on nervous and musculature systems, employing mgat1a and mgat1b mutant zebrafish models. Methods: CRISPR Cas9 technology was employed to engineer the mgat1a zebrafish model. The N-glycan populations in Wt AB, mgat1a−/− and mgat1b−/− zebrafish were characterized via lectin blotting. Motor and sensory functions were measured by tail-coiling and touch-evoked response assays in embryos and larvae. Swimming locomotion and anxiety-like behavior were characterized in adult Wt AB, and mutant zebrafish using motility and novel tank dive assays. Results: The mgat1a−/− model had increased oligomannosylated proteins compared to Wt AB in embryos and dissected brain, spinal cord, skeletal muscle, heart, swim bladder, and skin from adults, supporting a global knockdown of GnT-I activity. Higher levels were also observed in mgat1a−/− relative to mgat1b−/−, except in the brain. Band patterns for oligomannosylated proteins were different between all three zebrafish lines. The mgat1−/− embryos and larvae had deficient motor and sensory functions which persisted into adulthood, with a higher deficiency in mgat1b−/−. Anxiety-like behavior was decreased and increased in adult mgat1a−/− and mgat1b−/−, respectively, compared to Wt AB. Conclusions: Taken together, this study revealed that aberrant terminal N-glycan processing impacts brain, spinal and muscle control, and hence will enhance our understanding of the vital role of complex/hybrid N-glycans in nervous system health.

International Journal of Translational Medicine doi: 10.3390/ijtm5030035

Authors: Harbinder Singh

High-mobility group box 1 (HMGB1) is a nuclear protein that can interact with a transmembrane cell surface receptor for advanced glycation end products (RAGEs) and mediates the inflammatory pathways that lead to various pathological conditions like cancer, diabetes, cardiovascular diseases, and neurodegenerative disorders. Blocking the HMGB1/RAGE axis using various small synthetic or natural molecules has been proven to be an effective therapeutic approach to treating these inflammatory conditions. However, the low water solubility of these pharmacoactive molecules limits their clinical use. Pharmaceutically active molecules with low solubility and bioavailability in vivo convey a higher risk of failure for drug development and drug innovation. The pharmacokinetic and pharmacodynamics parameters of these compounds are majorly affected by their solubility. Enhancement of the bioavailability and solubility of drugs is a significant challenge in the area of pharmaceutical formulations. This review mainly describes various technologies utilized to improve the bioavailability of synthetic or natural molecules which have been particularly used in various inflammatory conditions acting specifically through the HMGB1/RAGE pathway.

International Journal of Translational Medicine doi: 10.3390/ijtm5030034

Authors: Yasmin Azizbayli Amanda Tatler Victoria James Adam Watkins Lucy C. Fairclough

Objectives: Parental exposure to tobacco smoke is a significant public health concern, with over 1.1 billion smokers worldwide. The aim of this systematic review was to evaluate the impact of maternal, paternal, and dual-parental cigarette smoke exposure on offspring reproductive health. Methods: Original human clinical and animal research studies were included; titles and abstracts were manually scanned for relevance to the effect of parental smoking on offspring reproductive outcomes (Date of search:18/03/2025). Results: This systematic review incorporates 30 studies identified from three databases (PubMed, Web of Science, and Scopus). The results indicate that male offspring exhibit reduced spermatogenic capacity, characterized by decreased testicular size, lower sperm count, and impaired hormonal biosynthesis, with reductions of 30–40% in sperm production. Dual-parental smoking exacerbates these effects, with sperm counts averaging 85 million per ml in human male offspring from dual-smoking households, compared to 111 million per ml in single-smoking households. Animal studies provide mechanistic insights, revealing reduced testis weight in nicotine-exposed male rats and increased oxidative stress in offspring. Conclusions: This review highlights the dose-dependent and sex-specific effects of smoking on the fertility of offspring and underscores the need for standardized protocols to enhance the consistency and comparability of future research in both human and animal studies.

International Journal of Translational Medicine doi: 10.3390/ijtm5030033

Authors: Catherine R. Lewis Yazan Samhouri Christopher Sherry Neda Dadgar Moses S. Raj Patrick L. Wagner

Gastrointestinal (GI) malignancies are diverse and particularly challenging in terms of current immunotherapy but hold great opportunity for impact given that they constitute the highest cancer incidence and mortality rates worldwide. Traditional treatment options for solid GI malignancies include surgical intervention, chemotherapy, radiation, or a combination of these treatments. Emerging modalities within immunotherapy are anticipated to extend the results with conventional therapy by stimulating the patient’s own intrinsic potential for tumor-specific immunologic rejection. Combination regimens of chemotherapy and tumor-infiltrating lymphocyte (TIL) therapy in advanced colorectal cancer and pancreatic cancer, autologous monocyte therapy in advanced gastric cancer, and CAR-T therapy trained against GI-selective tumor antigens such as carcinoembryonic antigen are currently being studied. Clinical trials are underway to study the combination of various chemotherapeutic agents along with immunotherapy in the management of cholangiocarcinoma, hepatocellular carcinoma, and esophageal cancer. Alternative therapies are needed based on the tumor immune microenvironment, which can lead to a personalized approach to treatment. In this review, we discuss the current status of various modalities of immunotherapy in common GI malignancies, along with their mechanisms of immune activation and cancer suppression. We will also discuss the use of immunotherapy in less common solid GI malignancies and touch on recent advancements and clinical trials.

International Journal of Translational Medicine doi: 10.3390/ijtm5030032

Authors: Piotr Wańczura Wiktoria Mytych Dorota Bartusik-Aebisher Dawid Leksa Adrian Truszkiewicz David Aebisher

Background: Singlet oxygen (1O2) generation in biological samples remains a significant challenge. Studying the mechanism of 1O2 action during photodynamic therapy (PDT) in atherosclerotic plaques in vitro represents an innovative cardiological approach. Atherosclerosis, a chronic and progressive disease, is characterized by plaque buildup inside arterial walls. Objectives: This study focused on the use of spin–lattice (T1) and spin–spin (T2) relaxation times measured by Magnetic Resonance Imaging (MRI) before and after the administration of indocyanine green-mediated PDT (ICG-PDT). Methods: To enhance visualization of morphological changes in atherosclerotic plaques, the clinically approved MRI contrast agent Gadovist was utilized. A total of 12 atherosclerotic plaque samples were collected from six patients undergoing endarterectomy. The generation of 1O2 in these plaques was assessed using quantitative MRI measurements and microscopic imaging, which visualized structural changes induced by PDT. Results: This research explores the potential of T1 and T2 relaxation times as indicators of PDT efficacy, while Gadovist helped provide evidence of 1O2 diffusion within the samples. Conclusions: Considering advancements in modern treatment, PDT may offer a novel approach for targeting atherosclerosis.

International Journal of Translational Medicine doi: 10.3390/ijtm5030031

Authors: Guillermo de Jesús Aguirre-Vera Luisa Montufar María Fernanda Tejada-Pineda María Paula Fernandez Gomez Andres Alvarez-Pinzon José E. Valerio Eder Luna-Ceron

Epilepsy remains a major therapeutic challenge, with approximately one-third of patients experiencing drug-resistant epilepsy (DRE) despite the availability of multiple antiseizure medications (ASMs). This review aims to evaluate emerging ASMs—cenobamate, fenfluramine, ganaxolone, ezogabine (retigabine), and perampanel—with a focus on their mechanisms of action, pharmacological profiles, and potential role in precision medicine. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science to identify preclinical and clinical studies evaluating the pharmacodynamics, pharmacokinetics, efficacy, and safety of the selected ASMs. Relevant trials, reviews, and mechanistic studies were reviewed to synthesize the current understanding of their application in DRE and specific epilepsy syndromes. Each ASM demonstrated unique mechanisms targeting hyperexcitability, including the modulation of γ-aminobutyric acid receptor A (GABA-A) receptors, sodium and potassium channels, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptors), and serotonin systems. These mechanisms correspond with specific pathophysiological features in syndromes such as Dravet and Lennox–Gastaut. Evidence from clinical trials supports their use as adjunctive therapies with generally favorable tolerability, though adverse events and variable efficacy profiles were noted. The mechanistic diversity of these emerging ASMs supports their value in personalized epilepsy management, particularly in treatment-resistant cases. While the promise of precision medicine is evident, further studies are required to address challenges related to long-term safety, cost, and equitable access.

International Journal of Translational Medicine doi: 10.3390/ijtm5030030

Authors: Opeyemi. O. Deji-Oloruntoba James Onoruoiza Balogun Taiwo. O. Elufioye Simeon Okechukwu Ajakwe

Hyperuricemia, defined as elevated serum uric acid (SUA) levels (>6.8 mg/dL), is traditionally linked to gout and nephrolithiasis but is increasingly implicated in insulin resistance (IR) and type 2 diabetes mellitus (T2DM). Epidemiological studies, such as NHANES, suggest hyperuricemia increases the risk of T2DM by 1.6 to 2.5 times. Mechanistically, uric acid promotes IR via oxidative stress, chronic inflammation, endothelial dysfunction, and adipocyte dysregulation. Despite growing evidence, significant gaps remain in understanding these pathways, with existing studies often limited by observational designs and short intervention durations. A bibliographic analysis of studies from 2004–2024 using Web of Science and VOSviewer highlights a growing focus on hyperuricemia’s interplay with inflammation, oxidative stress, and metabolic disorders. However, inconsistencies in therapeutic outcomes and limited exploration of causality underscore the need for further research. We also explored the importance of gender stratification and the limitations of the binary model for the relationship between hyperuricemia and insulin resistance. This review emphasizes the importance of addressing these gaps to optimize hyperuricemia management as a potential strategy for diabetes prevention and metabolic health improvement.

International Journal of Translational Medicine doi: 10.3390/ijtm5030029

Authors: Ravinder K. Bahia Kyle Heemskerk Samir Assaf Orsolya Cseh Xiaoguang Hao Rozina Hassam Panagiotis Prinos H. Artee Luchman Samuel Weiss

Background: Protein arginine methyltransferase 3 (PRMT3), a type I family PRMT, regulates the activity of downstream substrates by catalyzing the asymmetric dimethylation of arginine residues. While PRMT3 activity has been reported to be deregulated in many cancers, including glioblastoma (GBM), the underlying signalling mechanisms that contribute to disease progression are largely unknown. Methods: We tested the efficacy of a PRMT3 chemical probe, SGC707, in a cohort of GBM patient-derived primary and recurrent brain tumour stem cell (BTSC) lines. RNA-sequencing, CRISPR-cas9 knockout, and inducible overexpression methods were used to investigate the molecular mechanisms regulated by the aberrant activity of PRMT3 in different BTSC lines. Results: We show that expression of the tumour suppressor protein 4.1B, a negative regulator of PRMT3, predicts the response of GBM BTSCs to the PRMT3 chemical probe, SGC707. Furthermore, PRMT3 modulates the stability and subcellular localization of the downstream effector, UHRF1, a member of the DNA methylation complex. These findings suggest that UHRF1 and DNMT1 may suppress the expression of 4.1B through the increased promoter methylation of EPB4.1L3. Intriguingly, the inducible overexpression of EPB4.1L3 in the BT248EPB4.1L3low BTSC line mimicked the effects of the pharmacologic and genetic inhibition of PRMT3. In contrast, knockout of EPB4.1L3 in BT143EPB4.1L3high cells reduced the interactions between PRMT3 and 4.1B proteins, resulting in increased sensitivity of knockout cells to SGC707 treatment. Conclusions: These findings show that 4.1B, PRMT3, and UHRF1/DNMT1 function together to promote BTSC growth. Thus, targeting PRMT3 or UHRF1/DNMT1, especially in tumours with low endogenous 4.1B protein, may have high therapeutic relevance.

International Journal of Translational Medicine doi: 10.3390/ijtm5030028

Authors: Zahra Naderiyan Alireza Shoari

Cancer continues to be a leading cause of global mortality, necessitating innovative therapeutic strategies to address its complexity and heterogeneity. Protein engineering has emerged as a transformative approach in developing cancer biotherapeutics, enabling the creation of highly specific, potent, and adaptable treatments. This paper provides a comprehensive review of the state-of-the-art in protein engineering, highlighting key techniques such as directed evolution, rational design, and hybrid approaches that underpin the development of monoclonal antibodies, bispecific antibodies, and novel fusion proteins. Case studies of FDA-approved therapies, including engineered monoclonal antibodies like trastuzumab and bispecific T-cell engagers such as blinatumomab, are discussed to illustrate the impact of these advancements. Furthermore, emerging trends, including AI-driven protein design and synthetic biology applications, are explored alongside their potential to revolutionize future cancer treatments. Challenges such as immunogenicity, stability, and scalability are critically evaluated, offering insights into potential solutions and future research directions. By synthesizing advancements in protein science and oncology, this paper aims to guide researchers and clinicians in harnessing the full potential of engineered proteins for cancer therapy.

International Journal of Translational Medicine doi: 10.3390/ijtm5030027

Authors: Trang T. T. Nguyen Eunhee Yi Christian E. Badr

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, characterized by a dismal prognosis and limited therapeutic options. Its highly invasive nature and pronounced intratumoral heterogeneity underscores the urgent need for innovative and targeted therapeutic strategies. One promising approach is synthetic lethality, which exploits cancer-specific genetic vulnerabilities to selectively eliminate tumor cells. A well-characterized example involves the deletion of methylthioadenosine phosphorylase (MTAP), commonly observed in GBM and other malignancies. This review focuses on synthetic lethality targeting protein arginine methyltransferase 5 (PRMT5) in MTAP-deleted GBM. Loss of MTAP leads to the accumulation of methylthioadenosine (MTA), a metabolite that partially inhibits PRMT5, thereby creating a selective vulnerability to PRMT5 inhibition which is used to inhibit the residual function of PRMT5. We critically evaluate preclinical and clinical data on both first- and second-generation PRMT5 inhibitors, with particular emphasis on MTA-cooperative compounds that selectively exploit MTAP deficiency. Despite promising anti-tumor activity in vitro, the clinical efficacy of PRMT5 inhibitors is often limited by the tumor microenvironment, particularly the impact of non-malignant cells that attenuate drug activity. Finally, we explore rational combination strategies that integrate PRMT5 inhibition with existing therapies to enhance clinical outcomes in GBM.

International Journal of Translational Medicine doi: 10.3390/ijtm5030026

Authors: Preyangsee Dutta Dwaipayan Saha Atanu Giri Aseem Rai Bhatnagar Abhijit Chakraborty

Background: Gastric cancer is a leading cause of cancer-related mortality worldwide, with approximately one million new cases diagnosed annually. While Helicobacter pylori infection remains a primary etiological factor, mounting evidence implicates obesity and lipid metabolic dysregulation, particularly in hypercholesterolemia, as emerging drivers of gastric tumorigenesis. This study investigates the molecular intersections between gastric cancer, obesity, and hypercholesterolemia through a comprehensive multi-omics and systems biology approach. Methods: We conducted integrative transcriptomic analysis of gastric adenocarcinoma using The Cancer Genome Atlas (TCGA) RNA-sequencing dataset (n = 623, 8863 genes), matched with standardized clinical metadata (n = 413). Differential gene expression between survival groups was assessed using Welch’s t-test with Benjamini–Hochberg correction (FDR < 0.05, |log2FC| ≥ 1). High-confidence gene sets for obesity (n = 128) and hypercholesterolemia (n = 97) were curated from the OMIM, STRING (confidence ≥ 0.7), and KEGG databases using hierarchical evidence-based prioritization. Overlapping gene signatures were identified, followed by pathway enrichment via Enrichr (KEGG 2021 Human) and protein–protein interaction (PPI) analysis using STRING v11.5 and Cytoscape v3.9.0. CD36’s prognostic value was evaluated via Kaplan–Meier and log-rank testing alongside clinicopathological correlations. Results: We identified 36 genes shared between obesity and gastric cancer, and 31 genes shared between hypercholesterolemia and gastric cancer. CD36 emerged as the only gene intersecting all three conditions, marking it as a unique molecular integrator. Enrichment analyses implicated dysregulated fatty acid uptake, adipocytokine signaling, cholesterol metabolism, and NF-κB-mediated inflammation as key pathways. Elevated CD36 expression was significantly correlated with higher tumor stage (p = 0.016), reduced overall survival (p = 0.001), and race-specific expression differences (p = 0.007). No sex-based differences in CD36 expression or survival were observed. Conclusions: CD36 is a central metabolic–oncogenic node linking obesity, hypercholesterolemia, and gastric cancer. It functions as both a mechanistic driver of tumor progression and a clinically actionable biomarker, particularly in metabolically comorbid patients. These findings provide a rationale for targeting CD36-driven pathways as part of a precision oncology strategy and highlight the need to incorporate metabolic profiling into gastric cancer risk assessment and treatment paradigms.

International Journal of Translational Medicine doi: 10.3390/ijtm5030025

Authors: Ana Kasirer-Friede

Historically, pharmacological interventions aimed at platelets have targeted their canonical hemostatic and thrombotic roles. The therapeutic vision, however, has minimally embraced alternate mechanisms by which anucleate platelets, their parent cells, megakaryocytes, and cellular derivatives may be utilized to yield novel and effective therapies. Platelets contain storage granules rich in a wide variety of proteins, chemicals, growth factors, and lipid particles that can modulate the fate and activity of diverse cell types, and impact diseases not previously thought to have a platelet component. In this article, we will address unconventional platelet contributions to health and disease development. Recent studies indicate extensive platelet roles in neurodegeneration, insulin secretion, and bone marrow fibrosis, along with a recognition of platelets as immune cells in their own right, partially based on the presence of surface MHC, Toll-like receptors, and stored immunomodulatory molecules. Recent technological advances have produced iPS-derived gene-editable megakaryocytes (MKs) that have been differentiated to clinical-grade platelets for transfusion; however, such successes are still rare. Continued improvements in the standardization of cell isolation, iPS differentiation protocols, technology for the utilization of platelet derivatives, and platelet Omics will expand our understanding of underlying platelet and MK heterogeneity and direct novel therapeutic applications. Furthermore, additional roles for these cells as microniche sensors that monitor systemic pathology by endocytosing shed particles as they circulate through the vasculature will be explored. Taken together, novel insights into the many exciting potential uses of platelets outside of their canonical roles are on the horizon, and continued amelioration of existing protocols and enhanced understanding of communication pathways between platelets and specific cells will help expand opportunities for platelet-related clinical trials to yield improved health outcomes.

International Journal of Translational Medicine doi: 10.3390/ijtm5020024

Authors: Anirudh Bhimavarapu Hana Mucevic Sadiq Rahman Amruta Desai

Neuropathic pain has emerged as a significant concern for patients dealing with persistent post-COVID-19 symptoms. Small fiber neuropathy (SFN) has been identified as a potential underlying mechanism contributing to long-term pain in these patients. Despite an increasing body of evidence associating post-COVID-19 SFN with immune dysregulation and neuroinflammation, the exact pathophysiology and optimal treatment remains unclear. This review aims to explore the pathophysiology, diagnosis, proposed mechanisms, and treatment of post-COVID-19 SFN. A comprehensive literature review was conducted, examining studies on SFN, as well as SFN in the context of COVID-19, including clinical manifestations, diagnostic criteria, and potential treatment modalities. Evidence was gathered from case studies, observational reports, and clinical trials addressing post-COVID-19 neuropathy and SFN. SFN in long COVID presents a heterogeneous range of sensory and autonomic symptoms. Diagnosis relies on clinical evaluation, quantitative sensory testing, and confirmatory skin biopsy. Proposed mechanisms include autoimmune dysregulation, molecular mimicry, direct viral invasion of neural structures, and inflammatory responses. Pharmacological treatments—such as gabapentin, antidepressants, and corticosteroids—have demonstrated symptom relief, while immunomodulatory therapies show promise in immune-mediated cases. Non-pharmacological strategies warrant further investigation. Post-COVID-19 SFN represents a complex and multifactorial condition requiring a multidisciplinary approach to diagnosis and management. While merging evidence supports immune-mediated pathogenesis, further research is needed to establish definitive mechanisms and optimize targeted therapeutic strategies. Continued investigation into post-COVID-19 SFN will be crucial in addressing the long-term neurological sequelae of SARS-CoV-2 infection.

International Journal of Translational Medicine doi: 10.3390/ijtm5020023

Authors: Kaitlyn P. White Susan Hewlings Corey Bryant Megan Moseley Christopher R. D’Adamo Christopher S. Colwell Jeff Chen Emily K. Pauli

Background/Objectives: Anxiety and stress are interrelated and connected to reduced health-related quality of life. Botanicals such as Apocynum venetum L. (A. venetum) have been shown to improve health outcomes. No human studies have been conducted in a diverse large group of healthy adults in the US. The purpose of this randomized, double-blind, placebo-controlled study was to evaluate the effects of Venetron® Rafuma (A. venetum leaf extract) on self-reported anxiety levels and overall health outcomes compared to placebo. Methods: Healthy adults (N = 476) seeking improvement in self-reported anxiety and stress were randomly assigned to receive 50 mg of A. venetum (n = 234) or placebo (n = 242) for 6 weeks. Feelings of anxiety were assessed at baseline and weekly using Patient-Reported Outcomes Measurement Information System (PROMIS™) Anxiety 8A. Perceived stress, sleep quality, and cognitive function were evaluated at baseline and weekly using validated assessments. A linear mixed-effects regression model was used to compare the change in health outcome scores between active and placebo groups. Results: A total of 370 participants completed at least one additional assessment and were included in the analysis: 179 in the active arm and 191 in the placebo arm. There was a significant difference between the groups in the rate of improvement in perceived stress and sleep disturbance. The active group was significantly more likely to experience a Minimal Clinically Important Difference (MCID) in their perceived stress and marginally significantly more likely to experience an MCID in their feelings of anxiety. Participants who reported experiencing side effects did not significantly differ between arms. Conclusions: Venetron® may be safe and effective therapy for stress and sleep disturbance among those suffering from feelings of anxiety.

International Journal of Translational Medicine doi: 10.3390/ijtm5020022

Authors: Francesca K. Martino Chiara Ciotti Anna Basso Ruggero Zanella Lucia F. Stefanelli Dorella Del Prete Federico Nalesso

Background/Objectives: Phosphate level is a critical factor in the health of dialysis patients, as it is linked to cardiovascular risk. In peritoneal dialysis (PD), phosphate removal is related to residual kidney function, dietary intervention, and the ability of the visceral peritoneum to transport phosphate. The role of dialysis prescriptions in phosphate management is not sufficiently enhanced. Standardizing a phosphate removal propensity marker could optimize the peritoneal dialytic program. Our preliminary report aims to evaluate a simple model of phosphate handling and to assess which marker during the peritoneal equilibration test (PET) could better describe the propensity of phosphate removal through the peritoneal membrane. Methods: We hypothesized a simple two-compartment model to describe phosphate removal driven by diffusion. We performed an explorer study on 10 PD patients to assess the reliability of the two-compartment model. In each patient, we evaluated the basal condition and performed a PET with 2 L of 3.86% glucose exchange to assess phosphate handling. We collected blood and peritoneal effluent samples at the beginning of the test (t0), after 1 h (t1), and after 4 h (t4). We proposed and examined the following biomarkers: the ratio between dialysis effluent phosphate and plasma at t4 (PHO-D/P4); the difference between dialysis effluent phosphate at t0 and t4 (PHOΔd0-d4); and phosphate permeability–area product at t4 (PHO-PxA4). Results: 9 men and one woman with a mean age of 58.7 ± 16.7 years and a mean dialysis vintage of 25 ± 18.3 months were enrolled. The PHO-D/P4 mean was 0.68 ± 0.18, the PHO-Δd0-d4 median was 0.89 mmol/L [0.7–1.19], and the PHO-PxA4 mean was 1.7 ± 0.85. PHO-D/P4was significantly related to creatinine D/P4 (beta 1.49, p < 0.001), PHO-Δd0-d4 was significantly influenced by plasma phosphate at t0 (beta 0.56, p < 0.001), and the PHO-PxA4 was significantly influenced by ultrafiltration (beta 0.003, p < 0.001). Conclusions: In our two-compartment model, we observed the independence of the PHO-D/P4marker, which could serve as a potential marker for standardizing phosphate handling. However, PHO-Δd0-d4 and PHO-PxA4 normalized by plasma phosphate at t0 and ultrafiltration rate were able to reserve a potential good performance as markers in phosphate handling standardization.

International Journal of Translational Medicine doi: 10.3390/ijtm5020021

Authors: Liqing He Vatsalya Vatsalya Raobo Xu Xinmin Yin Xipeng Ma Seongho Kim Eugene G. Mueller Wenke Feng Craig J. McClain Xiang Zhang

Background/Aims: We explored the possibility of using urine polar metabolites as non-invasive biomarkers of alcohol-associated liver disease (ALD) for early-stage diagnosis and severity assessment, as well as the possible changes in metabolic pathways in ALD patients. Methods: Polar metabolites were extracted with 80% methanol, and parallel 2DLC-MS was used for polar metabolite quantification. Results: Data from untargeted metabolomics showed that 194 metabolites were significantly changed in patients, and three metabolites can differentiate healthy controls (HC), non-severe ALD, and severe alcohol-associated hepatitis (severe AH) with high accuracy (0.92–0.97). Pathway analysis showed that arginine biosynthesis and histidine metabolism pathways were among the pathways containing the metabolites that were most altered in the urine of patients. Metabolites in the urea cycle, histidine catabolism, and histidine dipeptides pathways were notably increased in the urine of ALD patients, but none of the metabolites in these two pathways can simultaneously differentiate patients from healthy volunteers and non-severe ALD from severe AH. As the top differentiated pathways, the alterations of arginine biosynthesis and histidine metabolism indicate their importance in the metabolic dysfunction of ALD. Conclusions: Our results show that the abundance changes of specific metabolites can differentiate the disease severity of ALD, showing the potential of urine polar metabolites as non-invasive biomarkers for early-stage diagnosis and disease severity assessment of ALD.

International Journal of Translational Medicine doi: 10.3390/ijtm5020020

Authors: Andrea Elmelid Amra Osmancevic Martin Gillstedt Mikael Alsterholm

In the original publication [...]

International Journal of Translational Medicine doi: 10.3390/ijtm5020019

Authors: Fabrizio Belleggia Luca Signorini Mirko Martelli Marco Gargari

Background/Objectives: Guided bone regeneration (GBR) is a regenerative technique used to treat maxillary osseous defects to enable implant placement for prosthetic rehabilitation. It is generally performed with the use of barrier membranes and bone substitute materials of human or animal origin. Here, we report the clinical and histological outcomes of a horizontal GBR, treated using only synthetic biomaterials. Methods: A graft of nanocrystalline hydroxyapatite (NH) embedded in a silica gel matrix was used to fill a horizontal bone defect. The graft was covered with a titanium-reinforced dense polytetrafluoroethylene (TR-dPTFE) membrane, and primary closure was completed and maintained for 10 months. Then, the site was re-opened for membrane removal and implant insertion. During implant bed preparation, a bone biopsy was obtained for histological evaluation. A metal–ceramic crown was fitted, and the 5-year follow-up after prosthetic loading showed clinical and radiographically healthy tissues. Results: Histological examination revealed good integration of the biomaterial into the surrounding tissues, which were composed of lamellar bone trabeculae and connective tissue. New bone formation occurred not only around the NH granules but even inside the porous amorphous particles. Conclusions: The combination of NH and the TR-dPTFE membrane produced good clinical and histological results, which remained stable for 5 years.

International Journal of Translational Medicine doi: 10.3390/ijtm5020018

Authors: Tanvir Ahmed Akhi Nath Nusrat Jahan Aakanksha Khadka Jaimala Kishore Ashley Farokhrouz Rodney G. Bowden

Introduction: Dyslipidemia, characterized by abnormal blood lipid levels, is a key risk factor for cardiovascular disease. Socioeconomic status can play a role in the development of chronic disease, including as an influence on risk factors for chronic diseases such as cardiovascular disease. Methods: This study analyzes the relationship between socioeconomic status and dyslipidemia using a population-based cross-sectional survey (NHANES 2017–2020 data). A cohort of 5862 adults was examined, focusing on socioeconomic factors (income, education, occupation) and their association with lipid profiles while controlling for sociodemographic, lifestyle, and medical variables, contributing to understanding how health disparities may affect chronic disease outcomes. Results: Low socioeconomic status was consistently associated with higher dyslipidemia risk, while high socioeconomic status demonstrated a modest protective effect. Age, BMI, hypertension, and diabetes were key predictors, highlighting the need for targeted interventions. Conclusions: This study underscores the critical role of socioeconomic status in dyslipidemia risk. Low socioeconomic status consistently increased the odds of dyslipidemia. While high socioeconomic status demonstrated some protective effects, these were diminished when accounting for lifestyle and clinical factors, highlighting the complex interplay of socioeconomic status and health behaviors.

International Journal of Translational Medicine doi: 10.3390/ijtm5020017

Authors: Yu Kuramasu Yu Suzuki Daisuke Akaneya Yoshikazu Okuma Yuta Tsujimoto Daisuke Ishizawa Kazunori Moriya Parichart Hongsing Mohan Amarasiri Cameron Hurst Paul G. Higgins Kenji Shibuya Anthony Kicic Yoshitaka Shimotai Hiroshi Hamamoto Dhammika Leshan Wannigama Shuichi Abe

Background: Active nasal surveillance culture (ANSC) is recognized to enable rapid detection of antibiotic-resistant bacteria in the intensive care unit (ICU), which can contribute to the prevention of Ventilator-associated pneumonia (VAP). This study aims to evaluate the usefulness of ANSC in assessing the development of VAP in ICU patients. Methods: Patients admitted to the Yamagata Prefectural Central Hospital ICU from January 2017 to 2018 (Term 1) or January 2020 to December 2021 (Term 2) and underwent invasive mechanical ventilation supports were eligible for this study. Nasal swab samples were collected from the patients upon their admission to the ICU. The diagnosis of VAP was made according to the criteria set by the Centers for Disease Control and Prevention. Results: A total of 467 patients (156 women) in term 1, and 312 patients (113 women) in term 2 were enrolled. The incidence of VAP in term 2 was higher than in term 1 (7.1% vs. 12.8%, respectively). ANSC isolated several causative pathogens from the patients on admission who later developed VAP. Haemophilus influenza, Streptococcus pneumoniae, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa had a 100% match rate with the sputum culture, indicating a perfect relation between ANSC results and sputum culture in VAP (+) cases. Conclusions: The isolation of high-risk bacterial species by ANSC could foresee the development of VAP in ICU patients and efficiently prevent VAP in critically ill patients.

International Journal of Translational Medicine doi: 10.3390/ijtm5020016

Authors: Abdulatif Al Haj Kamila Ćwikłowska Antonina Joanna Mazur Beate Brand-Saberi Ewald Hannappel Hans Georg Mannherz

Background/Objectives: Tumor cell migration depends on the actin cytoskeleton modified by actin-binding proteins (ABPs). Overexpression of cofilin or thymosin beta4 (Tß4) has been correlated with an increase or decrease in their migratory activity, respectively. Methods: Immunostaining of tumor cells and transfection with EGFP-tagged cofilin or bicistronic vectors leading to independent expression of EGFP and Tß4. Determination of cell migration by transwell or agarose drop assay. Results: We modulated by transfection the intracellular concentrations of cofilin and Tß4 of two colon (3LNLN and EB3) and one breast carcinoma (MDA-MB-231) cell line and analyzed their migratory activity. Increasing wild-type cofilin did not alter their migratory activity, whereas the constitutively active S3A–cofilin mutant elevated migration. Transfection leading to an up- or downregulation of Tß4 showed that MDA-MB-231 and 3LNLN cells responded with a decrease or increase in migration, respectively. Exposure of MDA-MB-231 and 3LNLN cells to increasing concentrations of extracellular Tβ4 (or His-tagged Tß4) induced a biphasic response of migration, being highest around 0.24 µM and decreased at higher extracellular Tß4. Immunostaining of 3LNLN cells exposed to 0.24 µM extracellular His-tagged Tß4 with anti-His antibody indicated its uptake co-localizing with integrin-linked kinase at cell attachment points. Furthermore, the exposure to 0.24 µM His-tagged Tß4 led to increased phosphorylation of AKT1/2 and secretion of matrix metalloproteases. These effects and tumor cell migration were abrogated after exposure of 3LNLN cells to 2.8 µM His-Tß4, also inducing apoptosis in a number of cells. Conclusions: Tumor cell migration can be inhibited by high extracellular Tß4.

International Journal of Translational Medicine doi: 10.3390/ijtm5020015

Authors: Kathleen Nicholls Andrea Wise David Elliot Menno ter Huurne Maria Fuller Sharon Ricardo

Background: Fabry disease (FD) results from pathogenic GLA variants, causing lysosomal α-galactosidase A (α-GalA) deficiency and sphingolipid ceramide trihexoside (Gb3 or THC) accumulation. Disease phenotype varies widely but cardiomyopathy is commonly life-limiting. As a multisystemic disorder, FD initiates at the cellular level; however, the mechanism/s underlying Gb3-induced cell dysfunction remains largely unknown. This study established an in vitro mutation-specific model of Fabry cardiomyopathy using human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes to explore underlying cell pathology. Methods: Skin biopsies from consenting Fabry patients and normal control subjects were reprogrammed to iPSCs then differentiated into cardiomyocytes. The GLA mutations in Fabry cell lines were corrected using CRISP-Cas9. Phenotypic characteristics, α-Gal A activity, Gb3 accumulation, functional status, and lipid analysis were assessed. Cardiomyocytes derived from two patients with severe clinical phenotype and genotypes, GLAc.851T>C, GLAc.1193_1196del, and their respective corrected lines, GLAcorr c.851T>C, GLAcorr c.1193_1196del, were selected for further studies. Results: Cardiomyocytes derived from individuals with FD iPSCs exhibited stable expression of cardiomyocyte markers and spontaneous contraction, morphological features of FD, reduced α-Gal A activity, and accumulation of Gb3. Lipidomic profiling revealed differences in the Gb3 isoform profile between the control and FD patient iPSC-derived cardiomyocytes. Contraction strength was unchanged but relaxation after contraction was delayed, mimicking the diastolic dysfunction typical of Fabry cardiomyopathy. Conclusions: iPSC-derived cardiomyocytes provide a useful model to explore aspects of Fabry cardiomyopathy, including disruptions in sphingolipid pathways, proteomics, and multigene expression that together link genotype to phenotype. The platform potentially offers broad applicability across many genetic diseases and offers the prospect of testing and implementation of individualised therapies.

International Journal of Translational Medicine doi: 10.3390/ijtm5020014

Authors: Yan Li Qiong Zhang Shelly Cook

Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer-related mortality worldwide, with prognosis significantly deteriorating at advanced stages. While current diagnostic methods, such as colonoscopy and tissue biopsy, are widely employed in clinical practice, they are invasive, expensive, and limited in assessing tumor heterogeneity and monitoring disease processes, including therapy response. Therefore, early and accurate detection, coupled with minimal invasion and cost-effective strategies, are critical for improving patient outcomes. Liquid biopsy has emerged as a promising, minimally invasive alternative, enabling the detection of tumor-derived components. This approach is increasingly utilized in clinical settings. The current key liquid biopsy modalities in CRC include circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and RNA-based biomarkers such as long non-coding RNAs (lncRNAs), microRNAs(miRNAs), and circular RNAs (circRNAs), and tumor-educated platelets (TEPs). These methods provide valuable insights into genetic and epigenetic tumor alterations, and serve as indicators for early detection, treatment monitoring, and recurrence prediction. However, challenges such as assay standardization and variability in sensitivity persist. This review delves into the clinical applications of liquid biopsy in CRC management, highlighting the transformative roles of ctDNA, CTCs, and non-coding RNAs, TEPs in early detection, prognostic assessment, and personalized therapy. In addition, it addresses current limitations and explores potential advancements to facilitate their integration into routine clinical practice.

International Journal of Translational Medicine doi: 10.3390/ijtm5020013

Authors: Hanano Takahashi Yukito Sashide Mamoru Takeda

Background and Objectives: Docosahexaenoic acid (DHA) has been shown to modulate various voltage-gated ion channels and both excitatory and inhibitory synapses. Nonetheless, its exact effect on nociceptive signaling in the trigeminal system has yet to be elucidated. The purpose of the current investigation was to assess if acute DHA given intravenously to rats diminished the excitability of wide dynamic range spinal trigeminal nucleus caudalis (SpVc) neurons in response to mechanical stimulation in vivo. Methods: Single-unit extracellular activity was recorded from SpVc neurons in response to mechanical stimulation of the whisker pad in anesthetized rats. Responses to both non-noxious and noxious mechanical stimuli were analyzed in the present study. Results: The mean firing frequency of SpVc wide dynamic range neurons in response to both non-noxious and noxious mechanical stimuli was significantly dose-dependently inhibited by DHA, and the effect was seen within 5 min. After approximately 20 min, the inhibiting effects dissipated. Conclusions: These results suggest that, in the absence of inflammatory or neuropathic pain, the acute intravenous administration of DHA reduces the activity of trigeminal sensory neurons, including those responsible for pain, indicating that DHA could be utilized as an adjunct and alternative therapeutic agent for managing trigeminal nociceptive pain, including hyperalgesia.

International Journal of Translational Medicine doi: 10.3390/ijtm5010012

Authors: Izumi Yamamoto Kazuyo Igawa Natsuko Kondo Yoshinori Sakurai Atsushi Fujimura Kiyofumi Takabatake Peng Huang Hiroyuki Michiue Soichiro Ibaragi Kenji Izumi

Background/Objectives: Cancer-associated fibroblasts (CAFs), which are an important component of the tumor microenvironment, have been reported to have an adverse effect on conventional radiotherapy. This study aims to elucidate the effects of CAFs in boron neutron capture therapy (BNCT) using a three-dimensional (3D) oral cancer model. Methods: Three-dimensional cancer models were fabricated using patient-derived CAFs or patient-derived normal oral fibroblasts (NOFs) and a human oral squamous cell carcinoma cell line. Each 3D cancer model was performed with either a conventional X-ray treatment or BNCT and additionally analyzed histomorphologically. Results: The 3D oral cancer-CAFs model demonstrated a greater depth of cancer cell invasion than the 3D oral cancer-NOFs model. Radiation therapy for the 3D oral cancer models indicated a trend for decreasing cancer cell invasion and cell number with dose dependence in both X-ray and BNCT. In comparison with X-rays, BNCT showed a consistent increase in the number of NOFs and a significant reduction in the number of CAFs. Conclusions: BNCT for the 3D oral cancer model was shown to be effective against cancer cells and CAFs but not against NOFs, indicating its usefulness as a minimally invasive treatment for advanced cancer. Furthermore, it is indicated that the 3D oral cancer-CAFs model is a valuable tool to evaluate cancer treatment and research, particularly in high-grade malignant tumors with invasion.

International Journal of Translational Medicine doi: 10.3390/ijtm5010011

Authors: Francesca Lucca Sonia Volpi Mirco Ros Benedetta Fabrizzi Ilaria Meneghelli Marica Bordicchia Francesca Buniotto Alessia Lancini Cecilia Brignole Francesca Pauro Valentino Bezzerri Marco Cipolli

Background: Cystic Fibrosis is an inherited disorder caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene, encoding a chloride and bicarbonate channel widely expressed in epithelia. Loss of CFTR function leads to dehydration of the epithelium surface with thicker mucus secretions from tissues. The lungs, pancreas, liver, intestines, and sweat glands are the most common affected organs. However, pulmonary disease remains the main cause of morbidity and mortality. Fortunately, elexacaftor/tezacaftor/ivacaftor (ETI) therapy is showing unprecedented clinical benefits in patients with Cystic Fibrosis (CF) carrying at least one F508del mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. However, almost 35% of the CF population living in the Mediterranean area still lacks effective CFTR modulator therapies because of the elevated incidence of patients with (pw)CF harboring CFTR rare mutations (RMs), different from F508del. Methods: Twenty-three pwCF harboring RM including the N1303K underwent off-label ETI treatment for 6-12 months. Respiratory function in terms of FEV1 and FVC was measured after 3, 6, and 12 months of treatment. In addition, we analyzed sweat chloride concentration, body mass index (BMI), and quality of life before and after treatment. Possible adverse effects were recorded. Results: All patients included in this off-label program displayed a substantial improvement in respiratory function. In particular, patients carrying the N1303K mutation showed an improvement in FEV1 and FVC similar to that observed in subjects harboring the F508del mutation, although sweat chloride concentration was not significantly decreased. No severe adverse effect was reported. Conclusions: This study strengthens the clinical efficacy of ETI in pwCF harboring the N1303K and other CFTR rare variants. Since these CFTR RMs have not been approved for ETI therapy in Europe, this study may promote the inclusion of these variants in the list of CFTR mutations responsive to ETI.

International Journal of Translational Medicine doi: 10.3390/ijtm5010010

Authors: David Pakeliani Giuseppe Indelicato Liborio Ferrante Maurizio Finocchiaro

Background: The spontaneous rupture of the internal iliac artery (IIA) is an exceedingly rare vascular event, typically associated with congenital anomalies or degenerative conditions. This report details an unprecedented case of isolated IIA rupture in an elderly patient with evidence of plaque rupture but devoid of congenital vascular pathology. Case Presentation: An 81-year-old Caucasian male presented to the Emergency Department following a syncopal episode and acute right iliac fossa pain. His significant medical history was atrial fibrillation managed with anticoagulation (Apixaban), non-insulin-dependent diabetes mellitus, and recent hospitalization for multidrug-resistant Klebsiella pneumoniae pneumonia. Initial imaging with contrast-enhanced computed tomography revealed an aneurysmatic dilatation of the right IIA, indicative of rupture. An endovascular repair was performed, employing a combination of stent grafts to achieve proximal and distal sealing and to restore vascular continuity. Outcome: The patient exhibited hemodynamic stability throughout the perioperative period and was transferred to the general ward postoperatively. However, he suffered a recurrent rupture on the 30th postoperative day, prompting a second endovascular intervention to extend the graft landing zone into the common iliac artery. Intraoperative findings confirmed localized plaque rupture as the underlying trigger for the initial vessel rupture. He ultimately achieved clinical stability and was discharged on the 35th postoperative day. Discussion: This case illustrates the critical importance of recognizing spontaneous IIA rupture as a potential complication in elderly patients, particularly in the context of recent severe infections. While the relationship between the rupture and the Klebsiella pneumoniae infection remains speculative, this report underscores the necessity of further research into the role of infectious processes in vascular integrity and susceptibility to rupture. Conclusions: The successful management of this rare and complex vascular emergency using endovascular techniques underscores the evolving landscape of minimally invasive interventions. This case contributes to the limited existing literature on spontaneous IIA rupture and highlights the need for increased clinical vigilance regarding atypical presentations in similar patient populations.

International Journal of Translational Medicine doi: 10.3390/ijtm5010009

Authors: Enrique Soltero-Mariscal Prasanna Sengodan Aisha Siraj Adnan Yousaf Dennis Super Marc S. Penn Sanjay Gandhi Ashish Aneja

Background: Biomarkers have emerged as a cost-effective tool to risk stratify patients presenting to the emergency department with chest pain. The measurement of serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and myeloperoxidase (MPO) may improve the identification of patients who are more likely to have abnormal stress test results and require revascularization. Methods: In this prospective observational study, we evaluated the use of NT-proBNP and MPO in predicting abnormal stress testing results and revascularization in patients presenting to the ED with chest pain and an intermediate TIMI risk score. The serum levels of NT-proBNP and MPO were obtained at enrollment. Stress testing or coronary angiography was performed at the discretion of the treating physician. Clinical outcomes were followed at index hospitalization, 6 months, and 1 year. Results: A total of 485 patients were enrolled. NT-proBNP had a fair ability to predict abnormal stress testing results (AUC 0.69, p < 0.001). Based on the Mann–Whitney U test, there was a detectable difference in the median serum levels of both biomarkers among patients who did not undergo revascularization compared to patients who did undergo revascularization (NT-proBNP 70.5 vs. 250, p < 0.001, MPO 341 vs. 471, p < 0.001). NT-proBNP and MPO revealed a meaningful ability to predict revascularization in all patients (NT-proBNP AUC = 0.725, p < 0.001, MPO AUC = 0.653 p < 0.001). Conclusion: Elevated serum NT-proBNP was a fair predictor of abnormal stress test results. Furthermore, higher serum NT-proBNP and MPO levels were associated with revascularization events up to 1-year follow-up and were found to be meaningful predictors of coronary revascularization.

International Journal of Translational Medicine doi: 10.3390/ijtm5010008

Authors: Brian K. Foutch Molly R. Wilson Allison Kramer Lourdes Fortepiani

(1) Background/Objectives: This pilot study aims to address the research gap on the interplay between ocular and systemic parameters as well as sex hormones in men. (2) Methods: We measured intraocular pressure (IOP), central corneal thickness (CCT), and macular thickness (CMT) in nine healthy male volunteers. These measures, along with blood glucose; blood pressure; and sex steroid hormones (testosterone, estrogen, and progesterone), were measured twice for each subject. Linear regression was used to determine the individual effects of these measures as well as self-reported age, height, and weight. (3) Results: Height, weight, systolic blood pressure, blood glucose, and estrogen significantly predicted IOP and CMT. CCT models were more limited, with systolic blood pressure and estrogen as the most significant predictors. (4) Conclusions: Our findings suggest that height, weight, blood pressure, and estrogen levels have the most substantial impact on ocular measurements. Testosterone levels were strongly associated with systemic health markers, a common result in the literature. However, ours appears to be the first study demonstrating estrogen’s effects on ocular structure or physiology in men. As many of our comparisons were statistically underpowered, future research with larger populations is needed to confirm these relationships and elucidate underlying mechanisms.

International Journal of Translational Medicine doi: 10.3390/ijtm5010007

Authors: Samuel Dinerman Yan Shu

Metabolic dysfunction-associated steatohepatitis (MASH) is rapidly becoming a leading cause of hepatocellular carcinoma and end-stage liver transplantation. Characterized by hepatic steatosis, lobular inflammation, and hepatocyte ballooning, there is a dire need to develop therapeutic strategies to mitigate MASH alongside the subsequent fibrosis and cirrhosis. For years, therapeutic development for the treatment of MASH had been considered a graveyard, with various pharmacotherapies failing to achieve clinical efficacy. However, the recent Food and Drug Administration (FDA) approval of Madrigal Pharmaceuticals’ Resmetirom in the United States provides a positive step in the collective effort to eradicate MASH. Granted, with much about Resmetirom’s long-term efficacy and safety still to be determined and with the multi-factorial nature of MASH pathogenesis, continuing to evaluate alternative therapeutic options remains in the best interest of the field. Currently, therapeutics previously approved for other ailments, alongside novel therapeutics developed specifically for the treatment of MASH, are being evaluated in late-phase clinical trials. However, considering the complex nature of the disease and varying clinical outcomes to assess treatment efficacy, achieving regulatory approval as a MASH therapeutic continues to be a rigorous endeavor. In this review, we summarize notable therapeutics of various mechanistic backgrounds having achieved, or actively undergoing, late-phase clinical trials for the treatment of MASH and offer our perspectives on anti-MASH therapeutic development.

International Journal of Translational Medicine doi: 10.3390/ijtm5010006

Authors: Raghavendra Sashi Krishna Nagampalli Gangadhar P. Vadla Eswar Kumar Nadendla

The ATP-binding cassette (ABC) transporter superfamily, one of the largest membrane protein families, plays a crucial role in multidrug resistance (MDR) in cancer by mediating the efflux of various chemotherapeutic agents, thereby lowering their intracellular concentrations and diminishing therapeutic effectiveness. Beyond drug efflux, these transporters are also involved in vital biological processes, such as signal transduction in cancer. Over the past few decades, extensive structural and functional research has provided valuable insights into ABC transporters’ broad substrate specificity and transport mechanisms, leading to promising strategies for overcoming MDR. This review will provide a structural understanding of the interactions between ABC transporters and inhibitors to develop novel cancer therapeutics. Additionally, we focus on methods such as irradiation-based immune therapies, thermal therapies, nanomedicine, CRISPR-Cas, and natural therapies that can genetically modify ABC transporters to reduce their expression or reverse the drug efflux ability. Knowledge gained from these approaches can then be translated into the development of new cancer therapeutics that can combat chemotherapy resistance.

International Journal of Translational Medicine doi: 10.3390/ijtm5010005

Authors: Sukho Lee Hyun Chul Jung Michael Sargent Minsoo Kang

Background: This study aimed to investigate the acute effects of wild ginseng extract (Panax ginseng C.A. Meyer) on exercise performance, cognitive function, and fatigue recovery. Methods: Twelve healthy male participants were randomly assigned to receive either wild ginseng extract (WG) or a placebo prior to exercise trials, utilizing a double-blind, placebo-controlled cross-over design. The exercise protocol included 30 min cycling exercises followed by a 10-mile time trial, during which muscular power, strength, endurance, cognitive function, and fatigue were assessed. Additionally, biomarkers such as glucose, interleukin-6 (IL-6), myoglobin, total antioxidant capacity (TAC), and cortisol were measured. Repeated measures ANOVAs were used to analyze the effects of acute WG intake on the dependent variables. Results: In the placebo condition, both peak and mean power levels significantly decreased over time (p = 0.039 and p = 0.028, respectively), whereas no such decline was observed in the WG condition (p > 0.05). Furthermore, average reaction time (ART) was significantly delayed over time in the placebo trial (p = 0.005), while ART remained stable in the WG trial (p = 0.051). A significant increase in TAC was observed across time in the WG trial (p = 0.036), but no change was found in the placebo trial (p = 0.326). Cortisol levels significantly decreased over time in the WG trial (p = 0.001), while no change was observed in the placebo trial (p = 0.141). No significant differences were found for other variables between the WG and placebo trials (p > 0.05). Conclusions: The acute supplementation with WG positively influenced exercise performance by maintaining muscular power, reducing reaction time delay, and enhancing antioxidant capacity and cortisol regulation. These findings suggest that WG may be a promising ergogenic aid for improving exercise performance and recovery. NCT06679725 (ClinicalTrials.gov).

International Journal of Translational Medicine doi: 10.3390/ijtm5010004

Authors: Margarita Elloso Maria Fernanda Hutter Nicklas Jeschke Graham Rix Yufei Chen Alisa Douglas Marc G. Jeschke

Pigs are important translational research models for wound healing due to their skin, which is similar to human skin in terms of anatomy and physiology. Porcine wound models have been developed and used for years to study wound healing and evaluate various therapeutic agents. However, the study of porcine wound healing is multilayered as it involves not just the complex biological processes of wound healing but also cost, animal housing, handling, staff experience, and challenges such as procedural risks and human resources. In this review article, we discuss the various challenges of the model. Investigators using pig models should be well informed of the challenges of the porcine wound model to prevent possible problems and complications.

International Journal of Translational Medicine doi: 10.3390/ijtm5010003

Authors: Antonio Doronzo Giovanni Musci Gennaro Gadaleta-Caldarola Maria Chiara Sergi

Background: Salivary gland tumors are relatively rare neoplasms, comprising approximately 3–6% of all head and neck tumors. Parotid gland carcinoma (PGC) represents approximately 70–80% of all salivary gland malignancies. Treatment strategies depend on tumor histology, stage, and molecular characteristics, with surgical resection and adjuvant radiotherapy being the mainstays of treatment for localized disease. Conversely, in advanced stages, therapeutic approaches, including chemotherapy and targeted agents, are more challenging. Methods: We present a case report of a 60-year-old patient with hepatic and nodal metastases of parotid gland carcinoma HER2+ who received dual blockade with Pertuzumab and trastuzumab (PH) with addition of Docetaxel, with the aim of highlighting the management and treatment outcomes. Results: Our patient received 4 cycles of chemotherapy and PH with near-complete response. After lymph node dissection (level I–IV) with primitive tumor resection and radiosurgery on the residual liver metastases, currently she continues treatment as maintenance. Conclusions: Based on the patient’s overall condition and response to current treatment, the oncology team ought to consider further targeted therapies, radiotherapy, or surgery as future therapeutic options.

International Journal of Translational Medicine doi: 10.3390/ijtm5010002

Authors: Elina Gianzina Christos K. Yiannakopoulos Georgios Kalinterakis Spilios Delis Efstathios Chronopoulos

Background: There has been a growing interest in using inertial sensors to explore the temporal aspects of the Timed Up and Go (TUG) test. The current study aimed to analyze the spatiotemporal parameters and phases of the TUG test in patients with knee osteoarthritis (KOA) and compare the results with those of non-arthritic individuals. Methods: This study included 20 patients with KOA and 60 non-arthritic individuals aged 65 to 84 years. All participants performed the TUG test, and 17 spatiotemporal parameters and phase data were collected wirelessly using the BTS G-Walk inertial sensor. Results: Significant mobility impairments were observed in KOA patients, including slower gait speed, impaired sit-to-stand transitions, and reduced turning efficiency. These findings highlight functional deficits in individuals with KOA compared to their non-arthritic counterparts. Conclusions: The results emphasize the need for targeted physiotherapy interventions, such as quadriceps strengthening, balance training, and gait retraining, to address these deficits. However, the study is limited by its small sample size, gender imbalance, and limited validation of the BTS G-Walk device. Future research should include larger, more balanced cohorts, validate sensor reliability, and conduct longitudinal studies. Despite these limitations, the findings align with previous research and underscore the potential of inertial sensors in tailoring rehabilitation strategies and monitoring progress in KOA patients.

International Journal of Translational Medicine doi: 10.3390/ijtm5010001

Authors: Yina Wang Liangyou Rui

NF-κB-inducing kinase (NIK) is primarily recognized for its role as the apical kinase that activates non-canonical NF-κB signaling and its involvement in immune system regulation. NIK is crucial for maintaining cellular health by regulating fundamental processes such as differentiation, growth, and survival. Emerging evidence suggests that dysregulated expression or function of NIK in non-lymphoid cells is a key factor in cancer progression. While NIK deficiency causes severe immune dysfunction, its overexpression or excessive activation is linked to inflammatory diseases, metabolic disorders, and cancer development. The development of small molecule inhibitors targeting NIK has sparked optimism for clinical intervention, positioning NIK as a promising druggable mediator for cancer. The ongoing progress in creating novel small molecule NIK inhibitors offers new opportunities for testing NIK-targeted cancer therapies, potentially advancing the clinical application of NIK-based cancer treatments.

International Journal of Translational Medicine doi: 10.3390/ijtm4040053

Authors: Mei-Yu Chen Cheng-Yu Chi Chiau-Wei Zheng Chen-Hung Wang Ing-Ming Chiu

The failure of endogenous repair mechanisms is a key characteristic of neurological diseases, leading to the inability to restore damaged nerves and resulting in functional impairments. Since the endogenously regenerative capacity of damaged nerves is limited, the enhancement of regenerative potential of quiescent neural stem cells (NSCs) presents as a therapeutic option for neural diseases. Our previous studies have shown exciting progress in treating sciatic nerve injury in mice and rats using NSCs in conjunction with neurotrophic factors such as fibroblast growth factor 1 (FGF1). Additionally, a recently discovered neurotrophic factor, IL12p80, has shown significant therapeutic effects in sciatic nerve injury repair via myelinating oligodendrocytes. IL12p80 induces oligodendrocyte differentiation from NSCs through phosphorylation of Stat3. Therefore, it might be possible to alleviate the myelination defects of oligodendrocytes in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and even schizophrenia through the administration of IL12p80. These applications could shed light on IL12p80 and FGF1, not only in damaged nerve repair, but also in rectifying the oligodendrocytes’ defects in neurodegenerative diseases, such as ALS and MS. Finally, the synergistic effects of neurogenesis-induced FGF1 and myelination-induced IL12 might be able to supplant the need of NSCs for nerve repair and neuroregeneration.

International Journal of Translational Medicine doi: 10.3390/ijtm4040052

Authors: Lucy C. Taylor Gertrude Arthur Marcella de Carvalho Cruz David E. Stec Olufunto O. Badmus

Sex differences are a complex and crucial variable in developing and progressing metabolic and cardiovascular disease pathophysiology and clinical outcomes. The female sex, compared to the male sex, is protected from metabolic disturbances and their resulting cardiovascular events. However, the peculiar life phases associated with females, such as puberty, pregnancy, and premenopausal and menopausal stages, are all associated with different risks for the development of cardiovascular disease (CVD). Metabolic dysfunction-associated steatotic liver disease (MASLD), a condition of hepatic steatosis, and at least one feature of metabolic syndrome is associated with an increased risk of cardiovascular events. The risk of MASLD and its progression to the development of CVD differs between men and women. Differences in several factors, including formyl peptide receptor (FPR) 2, adipose tissue distribution, liver pyruvate kinase (LPK), and ketone body production, may underlie the sex differences in the risk of development of MASLD-induced CVD. Understanding the specific risk factors involved in the development and progression of MASLD between the sexes is crucial. This knowledge will provide important insights into the mechanisms responsible for its cardiovascular complications and can potentially lead to therapeutics targeted explicitly for each sex, offering new hope in the fight against MASLD-induced CVD.

International Journal of Translational Medicine doi: 10.3390/ijtm4040051

Authors: Nafisa Nawar Tamzi Md Motiur Rahman Subhadeep Das

The increase in cancer incidence in recent years necessitates urgent exploration of novel and alternative sources of natural bioactives for targeted cancer therapy. Approximately 75% of the Earth’s surface is covered by oceans, which are thought to harbor untapped physiologically active compounds with potential efficacy against cancer. Recently, a growing focus has been on isolating and investigating novel bioactive compounds derived from marine sources. Bioactive metabolites with diverse chemical structures, isolated from various marine species such as algae, mollusks, and actinomycetes, demonstrate potential efficacy against a wide range of cancers. To our knowledge, this is one of the articles that has reviewed recent papers on the application of marine-derived bioactives in targeted cancer therapy. This study aims to showcase some of the most current developments in targeted cancer therapy with various bioactives that have been identified from marine sources.

International Journal of Translational Medicine doi: 10.3390/ijtm4040050

Authors: Martin Tobi Harvinder Talwar Noreen F. Rossi Warren Lockette Benita McVicker

Cancer discovery is directed at the identification of a specific cancer type which allows for specific therapeutic interventions. Background/Objectives: Recently, similar immune checkpoint therapeutics have been applied with success across several cancer types, opening the field for other immune disruptive interventions that have practical applications. Methods: We have discovered an innate immune system (InImS) biomarker that allows for the characterization of allied cancer subtypes and outliers that might aid with diagnosis, treatment, and prognostication. Results: These InImS biomarkers are related to PD-L1 treatment outcomes and can be potentially manipulated by dietary means. Conclusions: The FERAD (ferritin–fecal p87) and absolute neutrophil/lymphocyte (aNLR) ratios are two such InImS biomarkers and we show herein, that they allow for the discovery of diagnosis and prognostication patterns, as demonstrated by this study.

International Journal of Translational Medicine doi: 10.3390/ijtm4040049

Authors: Renhao Lu

Background: Organ-on-a-chip models have emerged as transformative tools in ophthalmology, offering physiologically relevant platforms for studying ocular diseases and testing therapeutic interventions. These microfluidic devices replicate human eye tissue architecture, addressing limitations of traditional in vitro and animal models. Methods: A narrative review of recent advancements in organ-on-a-chip technology was conducted, focusing on models simulating ocular structures like the retina and cornea and their applications in studying diseases such as dry eye disease (DED), age-related macular degeneration (AMD), and glaucoma. Results: Advanced organ-on-a-chip models successfully mimic key ocular features, providing insights into disease mechanisms and therapeutic responses. Innovations in microengineering and cellular integration have enhanced these platforms’ translational potential, though challenges like scalability and regulatory validation persist. Conclusions: Organ-on-a-chip models are poised to enhance preclinical research and clinical applications in ophthalmology. Addressing scalability and regulatory hurdles will be key to unlocking their full potential in drug discovery and disease modeling.

International Journal of Translational Medicine doi: 10.3390/ijtm4040048

Authors: Ayla Kyler Núñez Claudia Marcela Arenas-Gómez Belfran Alcides Carbonell Medina

Sirtuins are a family of lysine deacetylases that regulate cellular homeostasis and energy sensing. Regeneration is the process that restores structural and functional homeostasis at the cellular, tissue, organ, and appendage levels. Several cellular processes, such as epithelial–mesenchymal transition (EMT), proliferation, migration, and differentiation, contribute to restoration after an injury. This review highlights the role of sirtuins in tissue, organ, and anatomical structure regeneration, showing how sirtuins modulate signalling pathways by deacetylating targets such as transcription factors. Furthermore, understanding the role of this protein family could help elucidate the molecular and cellular mechanisms underlying tissue regeneration, which may hold significant potential for fields such as regenerative medicine. The review compiles evidence suggesting that sirtuins are emerging factors in the regeneration of various organs (e.g., skin, liver, heart) and tissues (e.g., bone, muscle, cornea, spinal cord).

International Journal of Translational Medicine doi: 10.3390/ijtm4040047

Authors: Vincentius J. Suhardi Anastasia Oktarina Benjamin F. Ricciardi Mathias P. G. Bostrom Xu Yang

Background: Active recruitment of osteogenic cells by secreted signaling factors, such as stromal-cell-derived factor 1 (SDF-1), has recently been proposed as a novel strategy to enhance osseointegration. However, the intrinsic importance of the SDF-1/C-X-C chemokine receptor type 4 (CXCR4) axis in promoting osseointegration is unknown. To study the role of SDF-1/CXCR4 in osseointegration, we blocked the SDF-1/CXCR4 pathway in a murine tibial implant model through repeated administrations of an antibody against SDF-1. Methods: Using our previously described murine tibial implant model (N = 24), mice were randomized into an anti-SDF-1 group and a control group (N = 12/group). Intraperitoneal injections of CXCL12/SDF-1 monoclonal antibody (84 µg/mouse) or mouse IgG1 isotype were administered on days 2, 4, 7, 10, 13, 16, 19, 22, and 25 post-surgery. Mice were euthanized 4 weeks post-surgery. Peri-implant bone mass and architecture were determined through microcomputed tomography (µ-CT). Bone implant strength was detected through implant pull-out testing. Results: Inhibition of the SDF-1/CXCR4 pathway significantly reduced host bone–implant interface strength but did not significantly change the cancellous architecture surrounding the implant. Conclusion: SDF-1/CXCR4 is an important pathway to achieve maximum implant osseointegration. However, inhibition of the pathway did not completely eliminate osseointegration.

International Journal of Translational Medicine doi: 10.3390/ijtm4040046

Authors: Arghavan Ashja Ardalan Ghazaleh Khalili-Tanha Alireza Shoari

Lung cancer is a leading cause of cancer-related mortality worldwide, characterized by its aggressive nature and poor prognosis. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, play a pivotal role in the progression of lung cancer. They contribute to tumor invasion, metastasis, angiogenesis, and the modulation of the tumor microenvironment by degrading extracellular matrix components and regulating various cellular signaling pathways. Elevated levels of specific MMPs, such as MMP-2, MMP-9, and MMP-14, have been associated with advanced disease stages and reduced survival rates. As such, MMPs have emerged as valuable biomarkers for the diagnosis, prognosis, and prediction of treatment responses in lung cancer. This review aims to provide a comprehensive overview of the current understanding of MMPs in lung cancer, highlighting their diagnostic and prognostic significance, as well as their potential as therapeutic targets. Despite the initial setbacks in developing broad-spectrum MMP inhibitors, recent advancements have spurred interest in more selective inhibitors that minimize off-target effects and enhance therapeutic efficacy. Furthermore, combining MMP-targeted therapies with conventional treatments, such as chemotherapy and immunotherapy, holds promise for improving clinical outcomes. Future research directions include exploring novel MMP inhibitors, understanding the regulatory mechanisms of MMP activity, and integrating MMP biomarkers into personalized medicine approaches. As the field progresses, targeting MMPs may offer new therapeutic avenues and improve the prognosis for lung cancer patients, making this a promising area of investigation.

International Journal of Translational Medicine doi: 10.3390/ijtm4040045

Authors: Giulia Airò Virginia Agnetti Fabiana Pratticò Marianna Peroni Simona Bui Giovanni Mura Maria Urbanowicz-Nijaki Eleonora Lai Marco Puzzoni Fabiana Contu Nerina Denaro Mario Scartozzi Cinzia Solinas Chiara Tommasi

The aggressive nature of gastric cancer often leads to late diagnosis and poor prognosis. Chemotherapy and the more recently added immunotherapy remain key treatments for this disease. Several studies have focused on identifying tissue biomarkers with prognostic and/or predictive roles and therefore the therapeutic options are rapidly growing. In this narrative review, we summarize the major tissue biomarkers routinely assessed in clinical practice. In addition, we focus on new evidence about emerging tissue biomarkers that could have a predictive role in future therapeutic approaches and also on the potential role of liquid biopsy in this neoplasm.

International Journal of Translational Medicine doi: 10.3390/ijtm4040044

Authors: Álvaro Corral Alaejos Jose Jiménez Casaus Ángel López Delgado Aranzazu Zarzuelo Castañeda

Background: Invasive aspergillosis (IA) is an opportunistic infection that affects immunocompromised patients. While voriconazole is commonly used for IA treatment, it presents the risk of drug interactions, particularly in patients on polytherapy. Isavuconazole may serve as a safer alternative with fewer interactions. However, the use of isavuconazole is typically limited to the parenteral route for patients without access to the enteral route, due to recommendations against tablet handling for enteral administration. The objective of this study was to evaluate the suitability of isavuconazole administration via an enteral tube, by therapeutic drug monitoring of isavuconazole plasma concentrations. Methods: This case study examines a patient with diffuse large B-cell lymphoma who was diagnosed with IA and treated with isavuconazole via an enteral tube. Therapeutic pharmacokinetic monitoring of isavuconazole plasma concentrations was performed to assess the feasibility and safety of enteral administration. Results: The results show that isavuconazole concentrations were maintained within the therapeutic range when administered via an enteral tube. No significant deviations in plasma concentration were noted during the monitoring period. Conclusions: Administering isavuconazole through an enteral tube is a safe and viable alternative for patients that are unable to receive the drug via the oral route. Therapeutic monitoring of plasma concentrations is recommended to ensure proper dosing and efficacy.

International Journal of Translational Medicine doi: 10.3390/ijtm4040043

Authors: Salvatore Rossi Arcangelo Fargnoli Daniele Di Natale Gianmarco Dalla Zanna Antonio Funcis Federica Re Vincenza Gragnaniello Elena Verrecchia Alberto Burlina Elisabetta Tabolacci Gabriella Silvestri

Background: Fabry Disease (FD) is an X-linked lysosomal disease, in which, unlike other X-linked disorders, most female carriers manifest signs or symptoms for unknown reasons. Objectives: Herein, we aimed to test the potential role of X-chromosome inactivation (XCI) in leukocytes as a prognostic biomarker of disease in FD female carriers. Moreover, we explored if levels of X-inactive-specific transcript (Xist), a long non-coding RNA driving XCI, were detectable in the leukocytes of FD female carriers. Methods: We tested the XCI pattern in leukocytes on 33 consecutive females carrying pathogenic GLA variants. Disease severity was defined using the Mainz Severity Score Index (MSSI). Xist levels in leukocytes were assessed by real-time PCR and compared to the levels of 22 controls. Results: XCI was obtained for 31 female patients, finding 16 skewed (51.6%) individuals. Global MSSI did not differ in skewed vs. non-skewed FD carriers. In skewed FD females, the renal function and mean cardiologic MSSI subscore were significantly worse, and systemic arterial hypertension was more frequent. Xist levels detected in leukocytes were similar between female patients and controls, and did not differ by phenotype or XCI status. Conclusions: A skewed XCI pattern in leukocytes may represent a prognostic biomarker of worse renal and cardiac outcomes in female FD carriers.

International Journal of Translational Medicine doi: 10.3390/ijtm4040042

Authors: Kyle Paulk Lee E. Neilson

Background: Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by motor impairments, cognitive decline, and affective changes. Beyond the well-described motor symptoms, neuropsychiatric symptoms play a crucial role in PD disability burden. Novelty seeking, a trait extensively studied within various models of personality, may influence the manifestation of these non-motor symptoms. Methods: A narrative review of articles determined relevant by the author(s) was undertaken. Results: The literature indicates that PD patients typically exhibit low novelty seeking initially. However, dopaminergic therapies can increase novelty-seeking behaviors, sometimes leading to impulse control disorders (ICD). Studies using the Temperament and Character Inventory (TCI) suggest a complex interplay between disease state, medication, and baseline personality, which is not fully elucidated. High novelty seeking scores predict a higher risk of ICDs, yet they also correlate with a more benign clinical phenotype and improved quality of life post-DBS surgery. Conclusions: Novelty seeking is a significant trait in PD, influencing non-motor symptoms and treatment responses. Understanding its neurobiological basis and clinical implications could lead to better diagnostic and therapeutic strategies through the use of objective, practical tools for disease monitoring, individualized therapy, and pharmacological development.

International Journal of Translational Medicine doi: 10.3390/ijtm4040041

Authors: Kazumasa Osawa Saya Taharaguti Chiaki Ito Tadashi Takino Katsuro Hagiwara

Objectives: Various measures have been attempted to prevent infectious diseases in calves, such as environmental improvement and vaccine administration. Probiotics are commonly used to improve the body condition of newborn calves and prevent disease. In our previous research, Lactiplantibacillus plantarum RGU-LP1 (LP1) suppressed the expression of inflammatory cytokines in PBMCs of cattle fed it in the diet. In this study, we evaluated the effect of LP1 on the weights and number of treatments of the calves. Methods: Twenty-six one-week-old Holstein bull calves were divided into two groups (thirteen each), the LP1 group (LP1-treated) and the CN group (no LP1 fed), and tested as follows. The LP1 group was fed lyophilized LP1 (109 CFU/head/day) in milk replacer for 40 days. The CN group was fed the same diet only. Calves were followed for 63 days. The average treatment costs for the LP1 during the period were recorded. Feces and blood were collected from each calf during this period. Feces were examined for gut microbiota, and blood for immune assay and cytokine gene expression. Results: The LP1-treated group showed a decrease in disease incidence and an increase in body weights compared to controls. The average treatment cost during the observation period was significantly reduced compared to the CN group. The expression of TGFβ and IL10, inhibitory cytokines of inflammation, was significantly increased. The simultaneous expression of this set of inhibitory molecules resulted in low serum IL1β levels during the growth period. Conclusions: The Th1-type cytokine IFNγ was also significantly increased in LP1-treated calves. By reducing the amount of disease treatments and increasing dairy gain, LP1 is effective in preventing infectious diseases in calves. In addition, the increase in IFNγ by LP1 indicates improved Th1-type immunity in calves. These results show that LP1 has effects on the regulated inflammatory response and growth of calves.

International Journal of Translational Medicine doi: 10.3390/ijtm4030040

Authors: Peilin Zhang Omid Bakhtar Chris Wixom Brian Cox John Lee Saha Sadeghi Aidan Clement Lana Kabakibi Madeleine Schwab

Background: The effect of gender dimorphism and marital status on colorectal cancer mortality have been previously documented, but the relationship between these factors and DNA mismatch repair protein (MMRP) expression status is unknown. Methods: Colectomy specimens were reviewed retrospectively for patients between 2018 and 2023, with demographics including race/ethnicity, gender, marital status, faith, body mass index, pathologic staging, and MMRP expression status. Statistical analyses were performed by using baseline characteristics tables and various programs in the R package. Results: A total 1018 colectomies were reviewed, and the tumor stages were significantly higher in the right colon (stage 3 and 4) than in the left colon and rectosigmoid colon (p < 0.01). Marital status was significantly associated with patients’ gender, age, tumor size, and tumor stages (all p < 0.01). MMRP status was available in 775 cases, with 139 (17.9%) MMRP-deficient and 636 (82%) MMRP-proficient. MMRP deficiency was significantly associated with older female patients, larger tumor sizes, higher tumor stages, higher histologic grades, and was more common in the right colon (all p < 0.01). In addition, MMRP deficiency was statistically associated with a higher percentage of divorced and widowed patients (p < 0.01). Multivariate linear regression analysis revealed a persistent association of MMRP deficiency with tumor size, tumor grade, tumor stage, and nodal metastasis, but the associations with gender and marital status no longer existed. Conclusions: The differences in prevalence of CRC by gender and marital status and tumor MMRP status illustrate the importance of these factors on tumor stages and nodal metastasis but these associations are more complex with other confounding factors.

International Journal of Translational Medicine doi: 10.3390/ijtm4030039

Authors: Tomoyuki Abe Kazuhiro Endo Yutaka Hanazono Eiji Kobayashi

Imaging technologies are used to observe the morphology and function of various organs in the body and have become indispensable in a multitude of fields, ranging from basic research to clinical medicine. The luminescence technology based on the luciferin–luciferase reaction has been used in many research fields as an imaging technique, enabling quantitative analysis and detection at high sensitivity. Specifically in gene therapy and cell therapy, it has been developed as an in vivo bioimaging technique mainly for small animal models because of its non-invasive and time-sequential analysis. Currently, translational research using this luminescence imaging technology in pigs for clinical applications is ongoing. In this review, we discuss the progress of these technologies and issues for their clinical application, focusing on pigs, by comparing conventional imaging techniques, including fluorescent probes, with luminescence imaging techniques.

International Journal of Translational Medicine doi: 10.3390/ijtm4030038

Authors: Stephen C. Bondy

A novel means of applying radiotherapy in cancer treatment is the application of a radiation dose at a very high intensity for a very short time in FLASH radiotherapy (FLASH-RT). This technique involves the exposure of tumors to >40 Gy/s, usually for less than one second. Studies conducted in cell and preclinical models suggest that FLASH-RT seems less damaging to normal tissues from adverse effects relative to the same overall dose of radiation administered in conventional therapy (CONV-RT), which involves the administration of lower levels of radiation repeated intermittently over a protracted period. In contrast, the susceptibility of tumor tissues to FLASH-RT is not diminished relative to CONV-RT. Within solid tumors, both modes of dispensation of radiation produce an equivalent degree of cell damage. The differential treatment between normal and malignant material has been found in isolated tissues, animal studies and, more recently, in clinical trials. However, the classic radiation concept is that high-energy linear transfer radiation (LET) is more damaging than the equivalent total dose of low LET. Thus, the susceptibility of cells should be greater after short-term exposure to high LET. This article discusses the potential reasons that may account for this discrepancy. While the relative protection given to untransformed tissues by FLASH-RT relative to tumor tissue is a major step forward in radiation therapy for cancer, the processes that lie behind this phenomenon are incompletely understood and are considered here.

International Journal of Translational Medicine doi: 10.3390/ijtm4030037

Authors: Koen J. van Aerde Gerben Ferwerda Agnieszka Smolinska Edward Dompeling Jolt Roukema

Background: In recent years, cystic fibrosis transmembrane regulator (CFTR) modulating therapy has made it possible to treat the underlying pathophysiological defect in children with cystic fibrosis (CF). Response to therapy varies among patients. We investigated the immune responses and exhaled breath profile changes after the initiation of CFTR modulator therapy to explore their potential as markers of therapy response. Methods: We performed a prospective, longitudinal proof-of-principle study, investigating immune responses and exhaled breath volatile organic component (VOC) profiles prior to and during the initiation of therapy with Lumacaftor/Ivacaftor in a cohort of 17 patients with CF aged 2 to 6 years old. Response to therapy was assessed based on clinical markers and the decrease in sweat chloride. Whole blood stimulation assays were performed at t = 0, 6 and 18 weeks, while VOC analysis was performed at t = 0 and 18 weeks. Results: A pattern of immune reconstitution was found in the first 4 months of therapy. The same pattern was found in responders and non-responders. Exhaled breath VOC profiles were significantly affected by therapy. A trend toward a significant difference was found between responders and non-responders. Conclusions: Pediatric CF patients show a pattern of immune reconstitution after the initiation of CFTR modulating therapy. We hypothesize that this could be explained by the need for a pro-inflammatory profile for a more effective clearance of latent airway pathogens in the initial phase. The exhaled breath profile also clearly changes after the initiation of therapy, indicating the therapy’s influence on airway inflammation and oxidative stress; thus, it might predict the response to therapy.

International Journal of Translational Medicine doi: 10.3390/ijtm4030036

Authors: Amruta Desai Shruti Parikh Sergio Bergese

The prevalence of patients on buprenorphine therapy presenting for elective surgery has increased. Buprenorphine is a widely used medication for the management of patients with chronic pain. It is also used as maintenance therapy for patients with a history of opioid use disorder (OUD). Due to the lack of a standardized protocol for managing patients on buprenorphine perioperatively, we performed a retrospective analysis to compare pain score outcomes and postoperative opiate requirements between patients who continued buprenorphine versus patients who discontinued buprenorphine. We identified 35 patients: 11 continued buprenorphine and 24 discontinued buprenorphine. The average Post-Anesthesia Care Unit (PACU) pain score was 5.59 for those who continued buprenorphine and 7.54 for those who discontinued preoperative buprenorphine (p value 0.0339). The average postoperative morphine milligram equivalent (MME) use was 86.13 for those who continued preoperative buprenorphine and 107.70 for those who discontinued buprenorphine (p value 0.6439). The results from our study correlate with several previous studies, which showed lower PACU pain scores in patients who continued buprenorphine. There is a benefit of decreased postoperative pain when preoperative buprenorphine is continued, and a decreased possibility for relapse in those with a history of OUD.

International Journal of Translational Medicine doi: 10.3390/ijtm4030035

Authors: Adam P. Burch M. Kristen Hall Debra Wease Ruth A. Schwalbe

Aberrant N-glycosylation has been associated with progression of the pediatric cancer neuroblastoma (NB) but remains understudied. Here we investigated oligomannose N-glycans in NB by genetic editing of MGAT1 in a human NB cell line, BE(2)-C, called BE(2)-C(MGAT1−/−). Lectin binding studies confirmed that BE(2)-C(MGAT1−/−) had decreased complex and increased oligomannose N-glycans. The relevance of 2D and 3D cell cultures was demonstrated for cell morphology, cell proliferation, and cell invasion, thereby highlighting the necessity for 3D cell culture in investigating cancerous properties. Western blotting revealed that oligomannosylated EGFR had increased autophosphorylation. Proliferation was decreased in BE(2)-C(MGAT1−/−) using 2D and 3D cultures, but both cell lines had similar proliferation rates using 3D cultures without serum. Upon EGF treatment, BE(2)-C(MGAT1−/−), but not BE(2)-C, showed increased proliferation, and furthermore, the mutant proliferated much faster than BE(2)-C under 3D conditions. Cell spheroid invasiveness was greatly increased in BE(2)-C(MGAT1−/−) compared with BE(2)-C. Moreover, invasiveness was reduced in both cell lines with either EGF or RhoA activator treatment, regardless of the N-glycan population. Thus, this study further extends our earlier findings that oligomannose N-glycans enhance NB cell invasiveness, and that EGF stimulation of oligomannosylated EGFR greatly enhances cell proliferation rates, underlining the role of oligomannose N-glycans in the promotion of NB.

International Journal of Translational Medicine doi: 10.3390/ijtm4030034

Authors: Piotr Wańczura David Aebisher Dawid Leksa Wiktoria Mytych Klaudia Dynarowicz Angelika Myśliwiec Natalia Leksa Adrian Truszkiewicz Dorota Bartusik-Aebisher

Atherosclerosis, marked by plaque accumulation within arteries, results from lipid dysregulation, inflammation, and vascular remodeling. Plaque composition, including lipid-rich cores and fibrous caps, determines stability and vulnerability. Photodynamic therapy (PDT) has emerged as a promising treatment, leveraging photosensitizers to induce localized cytotoxicity upon light activation. PDT targets plaque components selectively, reducing burden and inflammation. Challenges remain in optimizing PDT parameters and translating preclinical success to clinical efficacy. Nonetheless, PDT offers a minimally invasive strategy for atherosclerosis management, promising personalized interventions for cardiovascular health. The objective of the current study was to present the findings from quantitative non-contrast MRI of atherosclerosis post-PDT by assessing relaxation times. The study aimed to utilize and optimize a 1.5T MRI system. Clinical scanners were used for MRI examinations. The research involved analyzing T1 and T2 relaxation times. Following treatment of the samples with Rose Bengal and exposure to pure oxygen, PDT irradiation was administered. The results indicated that the therapy impacted the crus, evidenced by a significant decrease in relaxation times in the MRI data.

International Journal of Translational Medicine doi: 10.3390/ijtm4030033

Authors: Jari Intra Sara Pezzatti Rinaldo Brivio Monica Carpenedo Rita Romano Nadia Spinoni Marco Casati

Immunoglobulin D (IgD) myeloma represents an uncommon subtype of multiple myeloma (MM), accounting for 1–2% of cases. Subjects affected by IgD MM have been demonstrated to have an inferior outcome and survival compared to those with other MM subtypes. A retrospective study was conducted on 15 patients (9 males and 6 females) diagnosed from 2008 to 2022 with IgD MM, in order to investigate the clinical and biochemical features at the moment of diagnosis, cytogenetic alterations, and survival times. The median age was 69 years, and higher frequencies of bone lesions, renal impairments, Bence–Jones proteinuria, and increased serum LDH were observed. Serum calcium levels were in the reference ranges. In the assessment of protein electrophoresis patterns, nine patients had a serum monoclonal protein that was not detectable. A cytogenetic analysis via fluorescence in situ demonstrated that the most common abnormalities were the deletion of 13q and IGH rearrangements. Patients treated with new chemotherapeutic drugs (immunomodulators, proteasome inhibitors), with or without autologous stem cell transplantation presented a higher median survival. The fundamental role of the laboratory in monoclonal IgD detection and the monitoring and studying of IgD MM cases enhances the knowledge of this disease, thus improving patient outcomes.

International Journal of Translational Medicine doi: 10.3390/ijtm4030032

Authors: Abenaya Muralidharan Christopher D. Bauer Claire G. Nissen St Patrick Reid Jill A. Poole Todd A. Wyatt

SARS-CoV-2, the causative agent of the COVID-19 pandemic, has had a global impact, affecting millions over the last three years. Pre-existing lung diseases adversely affect the prognosis of infected COVID-19 patients, and agricultural workers routinely exposed to inhalable organic dusts have substantial increased risk for developing chronic lung diseases. In previous studies, we characterized the protein kinase C (PKC)-dependent airway inflammation mediated by organic dust extract (ODE) derived from dust collected from swine confinement facilities in in vitro and in vivo models. Here, we studied the effect of ODE on SARS-CoV-2 pseudoviral infection in mice and human bronchial epithelial cells (BEAS-2B). In wild-type (WT) and transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor (SARS-CoV-2 entry receptor), ODE increased ACE2 shedding by ADAM-17 in the lungs. After repeated ODE treatments, the increased soluble ACE2 correlated to higher pseudovirus titer in the mouse lungs. In the human bronchial epithelial cells, ODE augmented PKCα activity in WT cells, and membrane ACE2 expression was diminished in PKCα-dominant negative cells. Unlike in the mice, increasing membrane ACE2 levels by treating with PKCα or ADAM-17 inhibitors and a low dose of ODE enhanced pseudoviral entry in vitro. Following viral entry, IL-8 secretion by the cells was diminished in a PKCα- and ADAM-17-independent manner. Together, the complex mechanisms involved in the synergistic effects of agricultural dust and SARS-CoV-2 highlight the importance of studying dust-mediated changes to immunity against circulating pathogens.

International Journal of Translational Medicine doi: 10.3390/ijtm4030031

Authors: Tihomir Zh. Todorov Roger Schibli Martin Béhé Jürgen Grünberg

Cancer stem cells (CSCs) are a dynamic population of tumor cells characterized by long-term self-renewal, high tumorigenicity, resistance to conventional therapies such as radio- and chemotherapy, and capacity to recapitulate the tumor heterogeneity. Similar to other tumor cells, CSCs need to carry critical mutations and epigenetic changes to acquire their aberrant phenotype. Confirmed in various hematologic and solid malignancies, the critical need to deepen our understanding of CSC biology, including identification of CSC biomarkers, and develop novel CSC-targeted therapies has been clearly recognized. Here, we review the L1 cell adhesion molecule (L1CAM) as a CSC-associated biomarker in ovarian cancer. Furthermore, we inform on the promising potential of anti-L1CAM radioimmunotherapy with 161Tb as a novel CSC-targeted therapeutic approach to overcome CSC radioresistance in comparison to 177Lu.

International Journal of Translational Medicine doi: 10.3390/ijtm4030030

Authors: Leonardo Massoni

It is well known that mental illness is often the result of genetic susceptibility combined with environmental factors. In this context, it is useful to consider the role that changes in DNA expression, known as epigenetic, can play in the development and progression of psychiatric disorders. Accordingly, psychotherapy, a form of pharmacological strategy that often targets dysfunctional emotions and behaviors, may also improve the symptoms of mental illness via epigenetic changes. This article reviews the current literature on epigenetic changes induced by psychotherapy in psychiatric disorders, pointing out encouraging findings for borderline personality disorder (BPD), post-traumatic stress disorder (PTSD), anxiety disorders and obsessive–compulsive disorder (OCD). It focuses on genes that are more commonly associated with epigenetic changes and paves the way for further research.

International Journal of Translational Medicine doi: 10.3390/ijtm4030029

Authors: Tsuyoshi Takara Rei Takara Aya Kobayashi Hina Shirakata Shinobu Ambai Yusei Shinohara Yoshihiro Uto

Many anti-tumor effects of group-specific component-derived macrophage-activating factors (GcMAFs) have been reported; however, the specific mechanisms remain unclear. Controlling tumor-associated macrophages (TAMs) in the tumor microenvironment is essential for cancer treatment. This study assessed the role of GcMAF in macrophage activation, elucidated the mechanisms by which it exerts its anti-tumor effects, and determined its effects on TAMs in the tumor microenvironment. GcMAF-stimulated RAW264.7 macrophages and EMT6 breast tumor cells were co-cultured in a 0.4 µm pore cell culture insert, and gene and protein expression and cell viability were evaluated. DNA microarray analysis of GcMAF-stimulated RAW264.7 cells was conducted. The induction of M2 RAW264.7 cells by interleukin (IL)-4 and IL-13 was analyzed. GcMAF stimulation increased the tumor necrosis factor-α and inducible nitric oxide synthase mRNA and protein levels in RAW264.7 cells but decreased the viability of co-cultured EMT6 cells. Although the details of the receptor or signal pathway of GcMAF are still unclear, these results were confirmed in the M2 RAW264.7 cells, suggesting that GcMAF exerts anti-tumor effects by inducing the differentiation of macrophages into the M1 type and reprogramming M2 macrophages to the M1 type. The anti-tumor activity of GcMAF via M2-to-M1 macrophage reprogramming could aid in developing novel cancer immunotherapies.

International Journal of Translational Medicine doi: 10.3390/ijtm4030028

Authors: Hiroshi Kobayashi Shogo Imanaka Sho Matsubara Hiroshi Shigetomi Chiharu Yoshimoto

Background: Tissue factor pathway inhibitors (TFPI1 and TFPI2) are ubiquitously distributed in humans and exhibit inhibitory activity against serine proteinases. TFPI1 inhibits the tissue factor (TF)-dependent extrinsic coagulation pathway, while TFPI2 modulates extracellular matrix remodeling. TFPI2 has been reported to be an epigenetically silenced tumor suppressor and independent prognostic factor in various human cancers. However, elevated serum levels of TFPI2 have been observed in ovarian and endometrial cancers compared to healthy controls, with increased levels correlating with poor prognosis in endometrial cancer. This raises the question of why the tumor suppressor TFPI2 is elevated in the blood of patients with gynecological cancers and is associated with adverse outcomes. Methods: A comprehensive literature search was performed in PubMed and Google Scholar without time restriction. Results: TFPI2 gene expression may be influenced by both cancer cell-specific gene expression profiles (e.g., oncogenic signaling pathways) and epigenetic modifications (e.g., DNA methylation, histone modifications, and non-coding RNAs). Although TFPI2 generally exhibits an anti-invasion effect in most human cancers, it has been reported to have a paradoxical pro-invasive effect in certain cancers. TFPI2 facilitates cancer invasion through aberrant alternative splicing or through a pathophysiological process known as angiotropism or vasculogenic mimicry. The overproduction of TFPI2 in the tumor microenvironment may reinforce the extracellular matrix, thereby enhancing tumor cell adhesion and invasion. Conclusion: This review summarizes the current understanding of the seemingly contradictory functions of TFPI2 in human malignancies, primarily focusing on the mechanisms regulating its expression and function, and discusses future prospects for translational research.

International Journal of Translational Medicine doi: 10.3390/ijtm4030027

Authors: Charisse Y. J. Kuo Ilva D. Rupenthal Rinki Murphy Odunayo O. Mugisho

While existing local therapies partially restore vision loss from diabetic retinopathy (DR), there is currently no reliable treatment to prevent the onset or stop the progression of the disease. This review seeks to explore the inflammatory molecular mechanisms underpinning DR pathogenesis, which have not been targeted by current interventions. Specifically, this review explores the role of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) protein 3 (NLRP3) inflammasome in DR onset and progression. Evidence through clinical trials has begun to note that specific drugs (fenofibrate, metformin) appear effective in slowing DR progression independent of lipid or glucose-lowering, respectively, suggesting that other mechanisms are at play. Novel therapeutics that inhibit the activation of the NLRP3 inflammasome pathway may provide a novel treatment for halting DR progression.

International Journal of Translational Medicine doi: 10.3390/ijtm4030026

Authors: Zachary Lee Divya Mohanraj Abraham Sachs Madhavi Kambam Sandra DiBrito

Gastric gastrointestinal stromal tumors (GIST) are rare, neuroectodermal tumors primarily residing in the stomach with characteristic genetic mutations. They are often identified using ultrasound and cross-sectional imaging, or they are noted during endoscopy. Localized gastric GISTs are commonly treated with surgical resection, with the possible use of neoadjuvant or adjuvant medical therapies as they are considered to have malignant potential. The use of tyrosine kinase inhibitors (TKI) such as imatinib has been shown to successfully reduce pre-operative tumor burden, recurrence, and disease progression. Surgical resection considerations vary depending on tumor size, location, and malignant potential. Neoadjuvant and adjuvant TKI therapy dosing varies in response to the type of GIST mutation present and greatly influences prognosis. Novel cooperative minimally invasive surgical techniques and targeted therapies are currently in development to address challenges in GIST treatment for tumors in challenging locations or with significant potential for progression. The management of localized gastric GISTs continues to rapidly evolve; each case should be managed individually, where care is taken in considering details, including tumor location, tumor size, and the molecular genetic profile, before embarking on a course of treatment.

International Journal of Translational Medicine doi: 10.3390/ijtm4020025

Authors: Jari Intra Alice Biffi Francesca Basta Cristina Delfini Nicoletta Novati Elisa Zucchetti Fabrizio Luppi Marco Casati

Hypersensitivity pneumonitis (HP) represents the third common interstitial lung disease caused by an exaggerated immune response following the inhalation of organic and/or chemical environmental antigens. The aim of this study was to determine the cut-off values of specific IgG antibodies (named precipitins) and their association with clinical data in the diagnosis of HP. In this 10-year retrospective study, the IgG concentrations against six antigens, Penicillium chrysogenum/notatum, Aspergillus fumigatus, Alternaria alternata, Aspergillus niger, Micropolyspora faeni, and pigeon droppings, were retrieved. The controlled group was made of 1516 healthy subjects without diagnosis of lung pathologies, while the case group consisted of 54 individuals affected by HP. Considering all six IgG antibodies together and the 97.5% percentiles determined in the control group, 30 of 54 subjects (56%) had one or more positive precipitins. In these patients, the major frequencies found were IgG antibodies against pigeon droppings, followed by Penicillium chrysogenum/notatum and Aspergillus niger. Although the sensitivity of serum precipitins depends on the population enrolled and the method used, the cut-off values determined in this study can be a valuable tool for clinicians in the diagnosis of HP, in eliminating the antigens responsible from the environment, and in establishing more specific IgG panels.

International Journal of Translational Medicine doi: 10.3390/ijtm4020024

Authors: Tanvir Ahmed Rodney G. Bowden

High-density lipoprotein cholesterol (HDL) has long been regarded as a protective factor against cardiovascular disease (CVD). However, recent research challenges this notion, suggesting that HDL functionality rather than its quantity may be a more accurate predictor of CVD risk. While epidemiological studies have traditionally found that higher HDL levels are associated with reduced CVD risk, intervention trials aiming to elevate HDL levels have yielded inconsistent results. Moreover, observational studies have reported that unusually high HDL levels are associated with increased mortality rates. These discrepancies underscore the complexity of the role of HDL in CVD. Reverse cholesterol transport, facilitated by HDL, plays a crucial role in preventing atherosclerosis by removing cholesterol from peripheral tissues. Additionally, HDL exhibits anti-inflammatory properties by inhibiting endothelial adhesion molecules and suppressing pro-inflammatory cytokines. Recent studies have highlighted the importance of HDL particle number, size, and functionality in assessing CVD risk. For instance, increased HDL particle number and larger particle size have been associated with reduced CVD risk, independent of HDL cholesterol levels. Furthermore, HDL’s cholesterol efflux capacity has emerged as a promising biomarker for predicting CVD risk, with higher efflux capacity correlating with lower CVD incidence and mortality. This article reviews the latest findings regarding the role of HDL in CVD risk assessment, emphasizing the need to focus on HDL quantity and HDL quality.

International Journal of Translational Medicine doi: 10.3390/ijtm4020023

Authors: Lizbeth A. Ramirez-Guzman Wenjing Huang John J. Cole Heather G. Jørgensen

Tyrosine kinase inhibitors (TKIs), such as imatinib (IM), increase the survival of chronic myeloid leukemia (CML) patients but do not eradicate the disease as leukemia stem cells (LSCs) with primitive and quiescent signatures persist after TKI monotherapy, driving disease relapse. Using single-cell publicly available transcriptomic data, we investigated potentially tractable vulnerabilities in this persistent CML LSC population. GAS2 is significantly upregulated when comparing LSCs from CML patients in remission to normal hematopoietic stem cells (HSCs). A topoisomerase IIβ inhibitor, XK469, was proposed to be repurposed as a candidate small-molecule inhibitor of GAS2, and its effect was investigated in cell line models in combination with IM in vitro. Alone, XK469 could induce cell cycle arrest/differentiation in CML cells and reduce cell viability. In combination with IM, XK469 significantly increased CML cell apoptosis and reduced CML cell clonogenic capacity. These results suggest that GAS2 is a targetable vulnerability in CML LSCs and that using XK469 in combination with TKI potentiates the sensitivity of CML cells to IM.