Int. J. Transl. Med., Volume 5, Issue 4 (December 2025) – 14 articles

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article