Therapeutics doi: 10.3390/therapeutics3020012

Authors: Francisco Alfredo Call-Orellana Juan Pablo Zuluaga-Garcia Maria Alejandra Sierra Mariana Zuluaga-Garcia Esteban Ramirez-Ferrer Alejandro Bugarini

Spinal cord hemangioblastomas are rare, benign, and highly vascular tumors that occur sporadically or in association with von Hippel–Lindau disease. Despite their histological benignity, they often cause significant morbidity due to progressive neurological deficits, syrinx formation, and recurrence in the von Hippel-Lindau population. We performed a comprehensive review of the literature by searching PubMed, EMBASE, and Scopus for studies published in English on spinal cord hemangioblastomas. Eligible studies included original research, case series, and case reports with explicit clinical outcomes or management strategies for pathologically or radiographically confirmed SCHb. Gross total resection is feasible in most cases, leading to durable tumor control and favorable neurological outcomes. Preoperative embolization has been employed selectively to reduce intraoperative bleeding. Radiotherapy, particularly stereotactic radiosurgery, has shown promising local control for surgically inaccessible or recurrent lesions, while conventional external beam approaches provide less consistent results. Anti-angiogenic agents have demonstrated anecdotal benefit, and the HIF-2α inhibitor belzutifan represents the first systemic therapy approved by the FDA for VHL-associated hemangioblastomas. The management of SCHb requires an individualized, multimodal strategy. Microsurgery remains the cornerstone of treatment; radiotherapy and pharmacotherapy are valuable adjuncts for specific clinical scenarios. Further prospective studies are needed to optimize patient selection and integration of these therapies.

Therapeutics doi: 10.3390/therapeutics3020010

Authors: Katherine Estephani Contreras Zapata Nadia Ximena Cruz Hidalgo Nicole Constanza Villalobos González Alejandro Rubio-Zarapuz Vicente Javier Clemente-Suárez Isidro Miguel Martín Pérez Sebastián Eustaquio Martín Pérez

Background/Objectives: Children at cardiovascular risk require effective non-pharmacological strategies to improve cardiometabolic health. This study aimed to evaluate the effectiveness of physical activity and lifestyle-based interventions on blood pressure and related cardiovascular risk markers in children and adolescents. Materials and Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines and registered in PROSPERO (CRD42025644256). Searches were performed in MEDLINE (PubMed), SPORTDiscus (EBSCO), and the Cochrane Library from January 2015 to March 2025. Methodological quality and risk of bias were evaluated using the PEDro scale, RoB 2.0, and GRADE. Results: Twenty-nine studies were included, showing overall high methodological quality. Pooled analyses showed a statistically significant reduction in systolic blood pressure (SMD = −0.35; 95% CI: −0.40 to −0.31; p < 0.00001, I2 = 83%). Diastolic blood pressure also showed a small but statistically significant reduction (SMD = −0.06; 95% CI: −0.11 to −0.01; p = 0.01; I2 = 93%), equivalent to an estimated decrease of about 1 mmHg. Fasting insulin levels were significantly reduced (SMD = −0.92; 95% CI: −1.27 to −0.56; p < 0.00001), suggesting improvements in metabolic regulation despite considerable heterogeneity (I2 = 95%). In contrast, pooled effects for body fat percentage (%) (SMD = 0.11; 95% CI: −0.10 to 0.32; p = 0.31) and BMI z-score (standardized units) (SMD = 0.13; 95% CI: −0.04 to 0.31; p = 0.14) were not statistically significant, with very high between-study variability. Conclusions: Multicomponent interventions integrating physical activity with lifestyle modification appear effective in reducing systolic and diastolic blood pressure and improving insulin sensitivity in children and adolescents at elevated cardiovascular risk. Although the magnitude of blood pressure reductions is modest, even small decreases at the population level may contribute to meaningful long-term cardiovascular risk reductions.

Therapeutics doi: 10.3390/therapeutics3020011

Authors: Elisabetta Ricottini Nicolò Graziano Ciavaroli Anna Di Cristo Antonio Emanuele Lentini Teresa Trunfio Luca D’Antonio Fabio Mangiacapra Annunziata Nusca Valeria Cammalleri Rosetta Melfi Nino Cocco Paolo Gallo Raffaele Rinaldi Annamaria Tavernese Francesco Piccirillo Martina Gelfusa Giorgio Antonelli Laura Gatto Saverio Muscoli Gian Paolo Ussia

Extensive evidence now confirms Lipoprotein(a) [Lp(a)] as a causal, independent risk factor for atherosclerotic cardiovascular disease. Elevated Lp(a) levels are detected in approximately 20% of the global population, positioning it as a major contributor to residual cardiovascular risk. Circulating Lp(a) levels are determined predominantly by genetic factors, so they are largely unresponsive to lifestyle modifications or conventional lipid-lowering therapies. Therefore, multiple international guidelines now endorse a one-time, lifetime measurement of Lp(a), as lowering Lp(a) concentrations is expected to have a positive impact on the reduction of cardiovascular risk. Currently, the therapeutic landscape of Lp(a) lowering drugs is rapidly evolving. Some RNA-based therapies (antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs)) have been demonstrated to reduce plasma Lp(a) concentrations by up to 98% in early-phase clinical trials. The efficacy and safety of these compounds are currently being evaluated in large-scale cardiovascular outcome trials. The results of these studies will be critical in validating the “Lp(a) hypothesis”: specific reduction of Lp(a) levels can lead to a measurable decrease in cardiovascular events. The purpose of this narrative review is to examine and discuss the available evidence on the role of Lp(a) as a risk factor and pharmacological target to provide a practical tool for decision-making in clinical practice.

Therapeutics doi: 10.3390/therapeutics3020009

Authors: Samuel Okurut David B. Meya

Cryptococcal meningitis occurs in 62% of persons with HIV-associated meningitis, making Cryptococcus an important cause of meningitis among adults with advanced HIV disease in regions with elevated prevalence of HIV. Despite efforts to advance treatment, the in-hospital death rate of 19% remains unprecedentedly high. Aggregate published clinical trial data evaluating cryptococcosis treatment with survival as the primary endpoint show a significant reduction in the proportion of survivors from diagnosis to 88.5% at 2 weeks of treatment and further to 74% survival at 10 weeks of follow-up (p = 0.001). Disease complications concomitant with unveiling symptoms and reoccurrence of fungal infections, deferment in treatment, and high prevalence of other comorbidities increase the risk of individuals succumbing to cryptococcal meningitis. Among clinical trials of cryptococcal meningitis, the World Health Organization-recommended standard of care was used to randomize participants to the control trial arm. The proportion of participants surviving in the trial was not statistically different between trial randomization arms. In summary, high in-hospital death rates and continued participants’ deterioration post-hospital discharge are challenges for evidence-based new therapies seeking to improve outcomes.

Therapeutics doi: 10.3390/therapeutics3010008

Authors: Nicholas Chin Joel Kallarackal Jomana Shenouda Adrianne Pan Lilia Correa-Selm

Background/Objectives: Pyoderma gangrenosum (PG) is a rapidly progressive, ulcerating condition that can cause large, painful lesions when uncontrolled. There is currently no standard of care treatment for severe PG ulcers refractory to systemic treatment. The present study aims to characterize the outcomes of placental allografts in treating severe PG lesions. Methods: A single institution retrospective chart review was conducted at the University of South Florida affiliated sites examining PG patients that received placental allograft treatment. Results: The review returned five patients with clinically diagnosed or biopsy-proven PG treated with placental allograft. In all five patients, application of placental allograft resulted in varying degrees of short-term (<1 month) improvement. Near-complete resolution was observed in one patient. Out of the 20 total allografts placed between the 5 patients, only one had an adverse event of infection within one week of placement. Grafts were otherwise very well tolerated by all patients. Conclusions: Placental allografts show promising adjunctive therapeutic potential for severe PG lesions with preliminary findings showing good viability and safety profiles. Future prospective controlled studies should be performed to further examine the viability of this adjunctive treatment in this disease.

Therapeutics doi: 10.3390/therapeutics3010007

Authors: Renato M. Rodrigues Bárbara Matos Vera Miranda-Gonçalves Carmen Jerónimo Margarida Fardilha

Introduction: Radioresistance in prostate cancer (PCa) poses a major therapeutic challenge. Galectin-3 (Gal-3) is overexpressed in aggressive PCa and may contribute to resistance mechanisms. This study evaluated the role of Gal-3 in radioresistance and assessed the effect of its pharmacological inhibition using GB1107. Methods: Parental (22RV1-P) and radioresistant (22RV1-RR) PCa cell lines were treated with GB1107. Western blotting assessed Gal-3 and Protein Phosphatase 1 alpha (PP1α) expression. Cell viability (PrestoBlue™), migration (wound assay), and clonogenic survival post-irradiation were evaluated. Statistical significance was set at p < 0.05. Results: Gal-3 was significantly upregulated in 22RV1-RR cells (p = 0.0237). GB1107 reduced viability and impaired migration in both cell lines. Radiosensitisation was observed in 22RV1-P cells (p < 0.0001) but was not significant in 22RV1-RR cells (p = 0.1258). A non-significant increase in PP1α expression was detected in RR cells. Conclusion: Gal-3 contributes to radioresistance. Further studies are needed to clarify the role of PP1α and optimise Gal-3-targeted strategies.

Therapeutics doi: 10.3390/therapeutics3010006

Authors: Gianluca Mondillo Alessandra Perrotta Mariapia Masino Simone Colosimo Vittoria Frattolillo Fabio Giovanni Abbate

Artificial Intelligence (AI) and Precision Medicine are increasingly influencing pediatric pharmacotherapy, where age-dependent pharmacokinetic variability demands highly individualized therapeutic strategies. This review examines current applications of AI in pediatric precision medicine and evaluates their clinical relevance and translational challenges. Recent evidence shows substantial progress across multiple domains. In pharmacogenomics, predictive models have reached R2 = 0.95 for drug exposure. Tools for adverse drug reaction detection report sensitivities of 81.5% and specificities of 79.5%. Clinical decision support systems for pediatric epilepsy have achieved diagnostic accuracies of 93.4%. Real-world implementations have been associated with a 75% reduction in prescription distribution errors and a 65% improvement in adverse drug reaction detection. Despite these advances, clinical translation remains limited: only 0.38% of pediatric AI models progress to testing in real patients, and 77% of published studies carry a high risk of bias. These gaps highlight the need for rigorous validation, improved data quality, and careful consideration of ethical and algorithmic constraints. Overall, AI has the potential to shift pediatric pharmacotherapy from empirically driven decisions toward predictive, precision-based approaches. Achieving this goal will require well-designed pediatric studies and sustained interdisciplinary collaboration to ensure safe and effective integration into clinical practice.

Therapeutics doi: 10.3390/therapeutics3010005

Authors: Ayooluwa Ilesanmi Casey Stevens-Washington Shelby Jones Karina Alarcon Anush Aryal Panneerdoss Subbarayalu Terry J. Shackleford Davida Crossley Benjamin C. Onyeagucha

Background: The signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) is a secretory protein that plays a role in cancer, cardiovascular, and immune disorders. SCUBE1, SCUBE2, and SCUBE3 belong to the SCUBE family. They contain multiple copies of EGF-like repeats at the amino acid terminal, a spacer region, three cysteine-rich motifs, and a CUB domain at the carboxyl terminus. The SCUBE family members are multifunctional proteins that act primarily as extracellular ligands or co-receptors in various cells. Methods: In this study, we examined the expression pattern and role of SCUBE3 in various cancers, as well as other diseases such as cardiovascular disease and immune disorders, and its impact on growth and development. Results: SCUBE3 expression is upregulated and secreted by the cells of lung cancer, hepatocellular carcinoma (HCC), melanoma, osteosarcoma, ovarian cancer, glioma, and breast cancer. Extracellular SCUBE3 protein often binds to TGFβRII or acts as a co-receptor for TGFβ and BMP2/BMP4 in regulating cellular signaling. Through the TGFβRII signaling, SCUBE3 activities promote tumor growth, metastasis, invasion, angiogenesis, and poor clinical outcomes. Conversely, in renal cell carcinoma, SCUBE3 expression suppresses growth. Altered SCUBE3 activity is associated with cardiovascular diseases, immune disorders, and hair growth. Conclusions: The review presents mechanistic evidence that SCUBE3 plays a crucial regulatory role in multiple cancers and other diseases. The evidence suggests the SCUBE3 protein could serve as a potential molecular target for various diseases and highlights its usefulness as a minimally invasive diagnostic marker, as it is a secreted protein.

Therapeutics doi: 10.3390/therapeutics3010004

Authors: Vincenzo Bassi Valentina Apuzzi Ciro Salzano Olimpia Fattoruso

Background: Hyponatremia (serum sodium levels below 135 mEq/L) is the most prevalent electrolyte imbalance, with the syndrome of inappropriate antidiuresis (SIAD) being the most common cause among inpatients. Fluid restriction is the primary treatment for SIAD, yet its efficacy is inconsistent. A novel therapeutic approach involves the use of oral vaptans, such as tolvaptan (TLV), which are non-peptide antagonists of arginine vasopressin receptors. The recommended daily dose of TLV is 15 mg; however, the risk of overcorrection and osmotic demyelination syndrome must be considered. Methods: Consequently, a more cautious approach involving a 7.5 mg dose of TLV was studied in SIAD patients to determine its safety and efficacy compared with a 15 mg dose. Results: The findings of our investigation show that the results obtained from the two doses are highly similar. However, it is important to note that the risk of overcorrection was lower in the 7.5 mg TLV group than in the 15 mg group. Furthermore, a more gradual increase in serum Na was observed in the 7.5 mg group than in the 15 mg group after the most critical first 24 h. Conclusions: TLV therapy can be initiated with a 7.5 mg dose, with serum sodium levels monitored at 12 and 24 h to confirm or adjust the TLV dose as required.

Therapeutics doi: 10.3390/therapeutics3010003

Authors: Anna Christakou Ioannis Kyrosis Konstantinos Michopoulos Ioannis Fytanidis Ioannis Siakabenis

Background/Objectives: Pes planus is characterized by loss of medial longitudinal foot arch, resulting potentially in dysfunction in balance. Chronic ankle instability (CAI) is related to sensorimotor control deficits. Both of these two musculoskeletal disorders have a diminishing effect on joint proprioception. The present study examined the impact of flatfoot on balance in individuals with CAI. Methods: A total of 28 students (15 men, 13 women; 18–23 years, M = 20.46, SD = 1.07) were assigned to CAI with pes planus (n = 15) or CAI only (n = 13). Balance was assessed using the Y-balance test (YBT) and modified star excursion balance test (mSEBT) in three directions (anterior, posteromedial, and posterolateral), alongside the Cumberland ankle instability tool (CAIT). Group differences were analyzed with independent t tests or Mann–Whitney U tests (α = 0.05). Results: The findings of the study did not show statistically significant differences between the two groups in the balance variable [mSEBT/anterior left foot (t = 0.239, p = 0.865); mSEBT/posteromedial left foot (t = −0.048, p = 0.562); mSEBT/posterolateral left foot (t = 0.164, p = 0.258); mSEBT/anterior right foot (t = −0.433, p = 0.748); mSEBT/posteromedial right foot (t = 0.745, p = 0.606); mSEBT/posterolateral right foot (t = 0.263, p = 0.680); YBT/anterior left foot (U = 96.00, p = 0.93); YBT/posteromedial left foot (U = 94.50, p = 0.87); YBT/posterolateral left foot (U = 96.00, p = 0.93); YBT/anterior right foot (U = 95.50, p = 0.92); YBT/posterolateral right foot (U = 82.50, p = 0.45)]. However, a trend towards significance was found as patients with flatfeet had a weaker performance in balance tests [posteromedial direction of the YBT for the right foot (U = 70.00, p = 0.12)]. Conclusions: Although pes planus did not seem to affect the balance ability of individuals with CAI, future studies should confirm the relationship of pes planus and CAI with a larger group, including variables such as ankle range of motion, muscle strength, and functional activity level. A better understanding of the above relationship may lead to more precise diagnostic processes and more efficient therapies in CAI.

Therapeutics doi: 10.3390/therapeutics3010002

Authors: Alexander Grieme Yizhong Wu Kalee Moore Manuel Garza Eric R. Smith Erica Yatsynovich Thomas J. Egeland Rajesh Shah

Alcohol-associated liver disease, particularly severe alcoholic-associated hepatitis (AH), remains a major cause of morbidity and mortality worldwide. Conventional treatments, including corticosteroids, offer limited short-term benefit and are contraindicated in many patients, necessitating exploration of alternative therapies. Fecal microbiota transplant (FMT) has emerged as a novel therapeutic intervention, targeting the gut–liver axis that is disrupted in AH. This review synthesizes the current literature on FMT in the management of alcohol-induced liver injury, examining its pathophysiological basis, clinical efficacy, and implementation challenges. Dysbiosis and increased gut permeability in patients with alcohol use disorder contribute to systemic endotoxemia and hepatic inflammation. FMT aims to restore microbiota diversity and gut barrier integrity, mitigating the progression of liver injury. Some clinical trials have demonstrated encouraging survival benefits and modulation of gut microbiota composition in patients with severe AH. These studies report improved one-year survival rates and reductions in pathogenic bacterial taxa following FMT. However, the field remains nascent, with unresolved questions regarding optimal donor selection, sample preparation, administration routes, and long-term safety. Despite limited large-scale randomized data, FMT shows potential as an adjunct or alternative to existing therapies. Continued research is needed to establish standardized protocols and fully elucidate its role in the treatment algorithm for AH. Given the high mortality associated with untreated severe AH and limitations of current therapies, FMT represents a promising frontier in the management of alcohol-associated liver disease.

Therapeutics doi: 10.3390/therapeutics3010001

Authors: Dimitrios Stasinopoulos

Electrophysical Agents (EPAs) are commonly used in physical therapy to treat musculoskeletal and orthopedic conditions [...]

Therapeutics doi: 10.3390/therapeutics2040021

Authors: Amber D. Fraley Joshua Eudy Daniel T. Anderson

Background: Combination therapy for Enterococcus faecalis was established in the 1940s due to high rates of treatment failure, especially for infective endocarditis (IE). However, during this period antimicrobials were limited, optimal dosing was unknown, and development of resistance was rapid. Today, nearly 80 years later, combination therapy is still the standard practice for IE caused by E. faecalis despite improvements in antimicrobial availability, activity, and evidence-based, optimized antimicrobial dosing. These treatment decisions are guided by in vitro synergy principles and are frequently extrapolated to E. faecalis bloodstream infections (BSI) without IE. The paucity of clinical data to support this practice, paired with the known risks from unnecessary antibiotic exposure, makes further research and clinical guidance necessary. Methods: This single-center retrospective observational study of hospitalized adult patients with E. faecalis BSI treated with combination therapy aimed to describe treatment approaches and outcome data. Results: Between 1 January 2017, and 30 September 2024, 358 patients were screened, and 54 met study inclusion criteria. IE was present in 53.7% of patients, and 25.9% met the composite outcome (30-day mortality, 60-day hospital readmission, and/or 60-day recurrence). Adverse events were noted in 5.6% of patients. Conclusions: Observational data from this review supports the hypothesis that guideline recommendations for the use of combination therapy in E. faecalis IE are occasionally extrapolated to patients without IE. Given the in vitro and dated observational data used as the basis for these recommendations and the risks associated with unnecessary antibiotic exposure, more extensive, prospective, interventional studies are needed to address this dogmatic practice surrounding a high-morbidity, high-mortality disease state.

Therapeutics doi: 10.3390/therapeutics2040020

Authors: Calvin Diep Daniella Veloria Amy Kloosterboer

Background/Objectives: Our objective was to describe the safety and efficacy of enteral droxidopa, a norepinephrine prodrug, for intravenous (IV) vasopressor weaning in intensive care unit (ICU) patients. Methods: This was a single-center, retrospective descriptive study of adult ICU patients. Patients who received ≥ 4 consecutive doses of droxidopa for IV vasopressor weaning were included. The cessation of the IV vasopressor without re-initiation within 72 h of droxidopa initiation was the primary outcome. The adverse events assessed included hypotension, hypertension, and arrhythmias. Results: Forty-six patients were included, with a median age of 61. Forty-two patients (91%) were on midodrine at the time of droxidopa initiation. The median daily midodrine dose was 80 mg. The median time from ICU admission to droxidopa initiation was 17 days. Patients were on a median of one IV vasopressor at the time of droxidopa initiation, with norepinephrine as the most common agent (50%). The median initial daily droxidopa dose was 300 mg, with a median maximum daily dose of 900 mg. Vasopressor support was discontinued within 72 h of droxidopa initiation in 46% of patients, with a median time to IV vasopressor cessation of 3.3 days. There were no incidences of hypotension, hypertension, arrhythmias, or ICU readmissions related to droxidopa. Droxidopa was continued upon discharge in 29% of patients. Conclusions: Droxidopa may be a safe and effective option to facilitate the weaning of IV vasopressor support in patients who are refractory or intolerant to midodrine. Larger prospective studies are needed to confirm these findings.

Therapeutics doi: 10.3390/therapeutics2040019

Authors: Antonios Tsartsarakis Eleftheria Tampouratzi Christos Moulias Konstantinos Sfaelos Vassilis Aletras

Background: Psoriasis has a huge impact on a patient’s life. Treatment dissatisfaction and non-adherence are common among patients with psoriasis, partly due to discordance between individual preferences and recommended treatments. The modern strategy for psoriasis should be focused on human-centric treatment that recognizes the needs and preferences of patients with a goal for safe, effective, quality and acceptable health services for a lifetime. The aim of this analysis was to capture patients’ preferences with moderate-to-severe psoriasis regarding various treatment attributes. Methods: A specialized questionnaire containing four attributes with three levels, each, was used, followed by an orthogonal plan based on conjoint analysis. Nine combinations of therapeutic scenarios were produced as a result, to investigate participants’ preferences. Respondents were asked to rank alternatives from best to worst. Results: The risk of developing pneumonia or other serious infections within a decade seems to be higher in patients with an implied assigned value of 37. The second attribute was the type and frequency of the administration with a value of 27, followed by the treatment effectiveness with great improvement of body surface with a value of 25. The lowest utility (11) was the sustainability of early remission of psoriasis. Conclusions: Psoriasis patients want safe, effective and easy to administer treatments.

Therapeutics doi: 10.3390/therapeutics2040018

Authors: Viviana Cortiana Harshal Chorya Rabab Hunaid Abbas Jade Gambill Adhith Theyver Chandler H. Park Yan Leyfman

Hematopoietic stem cell (HSC) therapy remains essential in treating blood disorders, autoimmune diseases, neurodegenerative conditions, and cancers. Despite its potential, challenges arise from the inherent heterogeneity of HSCs and the complexity of their regulatory niche. Recent advancements in single-cell RNA sequencing and chromatin accessibility sequencing have provided deeper insights into HSC markers and chromatin dynamics, highlighting the intricate balance between intrinsic and extrinsic regulatory mechanisms. Zebrafish models have emerged as valuable tools in HSC research, particularly through live imaging and cellular barcoding techniques. These models have allowed us to describe critical interactions between HSCs and embryonic macrophages, involving reactive oxygen species and calreticulin signaling. These are essential for ensuring HSC quality and proper differentiation, with implications for improving HSC transplant outcomes. Furthermore, the review examines clonal hematopoiesis, with a focus on mutations in epigenetic regulators such as DNMT3A, TET2, and ASXL1, which elevate the risk of myelodysplastic syndromes and acute myeloid leukemia. Emerging technologies, including in vivo cellular barcoding and CRISPR-Cas9 gene editing, are being investigated to enhance clonal diversity and target specific mutations, offering potential strategies to mitigate these risks. Additionally, macrophages play a pivotal role in maintaining HSC clonality and ensuring niche localization. Interactions mediated by factors such as VCAM-1 and CXCL12/CXCR4 signaling are crucial for HSC homing and the stress response, opening new therapeutic avenues for enhancing HSC transplantation success and addressing clonal hematopoiesis. This review synthesizes findings from zebrafish models, cutting-edge sequencing technologies, and novel therapeutic strategies, offering a comprehensive framework for advancing HSC biology and improving clinical outcomes in stem cell therapy and the treatment of hematologic diseases.

Therapeutics doi: 10.3390/therapeutics2040017

Authors: Raquel Sanabrias Fernández de Sevilla Sarela García-Masedo Fernández Rosalía Laporta Hernández Myriam Aguilar Pérez Christian García Fadul María Teresa Lázaro Carrasco de la Fuente Enrique Rodríguez Rubio Amelia Sánchez Guerrero Carlos Almonacid Sánchez María Piedad Ussetti Gil

Background/Objectives: Cytomegalovirus (CMV) infection is a frequent complication after lung transplantation, especially in high-risk donor-positive/recipient-negative (D+/R−) patients. CMV-specific hyperimmunoglobulin (CMV-HIG), administered either with antivirals or as monotherapy, may be beneficial for preventing or treating CMV infection in selected clinical scenarios. This study evaluated CMV-HIG indications and their impact on clinical outcomes in our lung transplant unit. Methods: We retrospectively analyzed adult lung transplant recipients (2010–2023) who received ≥2 doses of CMV-HIG for universal prophylaxis, monotherapy prophylaxis, preemptive therapy, or treatment of invasive disease. Results: CMV-HIG was administered to 204 out of 336 recipients (61%). CMV-HIG was well tolerated, with no treatment-related adverse events. Indications were preemptive therapy (63%), universal prophylaxis (24%), monotherapy prophylaxis (7%), and treatment of invasive disease (6%). CMV-HIG was well tolerated, with no treatment-related adverse events. No patients developed invasive disease during combination prophylaxis or preemptive treatment. The combination treatment of patients with invasive disease was also effective, and no cases of VGC resistance were detected. CMV-HIG monoprophylaxis has allowed us to delay or prevent viral replication in recipients who developed VGC side effects. Rates of acute rejection, Chronic Lung Allograft Dysfunction (CLAD), and overall survival were similar across CMV risk groups. Conclusions: Our results showed that the combined use of CMV-HIG and antiviral agents is effective in preventing CMV infection and disease in high-risk lung transplant recipients. This combination is also useful in treating invasive disease and preventing VGC resistance. Additionally, CMV-HIG monoprohylaxis can delay or prevent viral replication in recipients experiencing VGC-related side effects. These findings support the use of CMV-HIG in selected clinical settings, although prospective studies are needed to define its potential benefits within the current therapeutic armamentarium.

Therapeutics doi: 10.3390/therapeutics2040016

Authors: Paula Simon-Silva Rocio del Castillo-Acuña Jonathan Saavedra-Bejarano Angeles Sanchez-Galvez Antonio Lazo-Prados Manuel Luis Blanco-Villar

Background/Objectives: Biochemical recurrence (BCR) occurs in 15–40% of men within five years of radical prostatectomy (RP), presenting a major challenge for long-term disease control. While salvage radiotherapy (SRT) and androgen deprivation therapy (ADT) are established post-RP interventions, the optimal integration of ADT with SRT—regarding timing, duration, and patient selection—remains unclear. We aimed to synthesize current clinical evidence on the efficacy and safety of combining ADT with SRT in patients experiencing BCR after RP. Methods: A narrative review was conducted, encompassing retrospective cohort studies, prospective randomized controlled trials (notably RTOG 9601, GETUG-AFU 16, RADICALS-HD, and SPPORT), and meta-analyses. Studies were selected based on relevance to combined ADT + SRT versus SRT alone, with outcomes of interest including biochemical progression-free survival (bPFS), metastasis-free survival (MFS), and overall survival (OS). Trial characteristics, ADT duration (short-term [4–6 months] versus long-term [≥24 months]), radiation scheme, and prostate specific antigen (PSA) thresholds at SRT initiation were extracted and compared. Results: The combination of ADT and SRT represents a promising strategy for the treatment of prostate cancer with BCR after RP. Current evidence supports its benefit in terms of disease control and survival, particularly in high-risk patients. Conclusions: Differences in inclusion criteria, ADT duration, and the heterogeneous quality of the available studies limit the formulation of universal recommendations. Well-designed prospective trials are needed to optimize therapeutic approaches and personalize treatment based on each patient’s risk profile.

Therapeutics doi: 10.3390/therapeutics2030015

Authors: Namrata Khurana Hogyoung Kim Talal Khan Shohreh Kahhal Amar Bukvic Asim B. Abdel-Mageed Debasis Mondal Suresh C. Sikka

Background: The outgrowth of castration-resistant prostate cancer (CRPC) dictates patient morbidity and mortality. Recurrence of prostate cancer (PC) following androgen-deprivation therapy (ADT) often occurs due to constitutively active androgen receptor (AR) splice variants (AR-Vs), primarily AR-V7. Therefore, safe and effective therapies enabling the suppression of both full-length AR (AR-FL) and AR-Vs are urgently needed. The natural compound dimethyl sulfoxide (DMSO) has negligible cytotoxicity at concentrations below 5% and has anticancer potential. DMSO has been broadly used in biomedical research as a solvent for pharmaceuticals, as a cryoprotectant for cells, and as a topical treatment to suppress pain and inflammation. We investigated the effect of low-dose DMSO on AR expression, cell viability, and metastatic ability in PC cell lines expressing both AR-FL and AR-V7 (e.g., 22Rv1) and those expressing only AR-FL (e.g., C4-2B). Methods: MTT cell viability assays were performed to measure DMSO-induced cytotoxicity. Wound-healing assays were conducted to monitor the effect of DMSO on the migratory phenotype of cancer cells. Western blot analyses were performed to study the efficacy of DMSO in suppressing the protein levels of AR-FL and AR-V7, and expression of heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) was measured as a possible mechanism. Results: At concentrations of 0.1–1% (v/v), DMSO treatment showed minimal cytotoxicity, whereas the highest concentration used (2.5%) showed approximately 20% cytotoxicity at 96 h. Interestingly, however, DMSO treatment at concentrations of 1.0 and 2.5% significantly inhibited the migration of PC cells. Treatment with DMSO led to a dose-dependent inhibition of both AR-FL and AR-V7. Notably, in 22Rv1 cells, DMSO potently downregulated the expression of hnRNPH1, a splicing factor often associated with AR expression and signaling. Conclusions: Our findings suggest that low concentrations of DMSO may have potential as an effective anticancer agent, both at the initial and later stages when PC cells become castration resistant.

Therapeutics doi: 10.3390/therapeutics2030014

Authors: Chrishaun Alexander Akeem Henry Derek Nuamah Joshua Lewis Bryce Gantt Kelsey M Green Malory Alexis Oyetokunbo Ibidapo-Obe

Background/Objectives: Gender-affirming surgery (GAS) is associated with improved mental health outcomes in transgender and gender-diverse (TGD) individuals. However, TGD populations experience disproportionately high rates of substance use disorders (SUDs), which are established risk factors for surgical complications. Despite this, the relationship between preoperative SUDs and postoperative outcomes following GAS has not been studied. Our objective was to evaluate how specific SUD subtypes, including tobacco, alcohol, and cannabis, impact short- and medium-term postoperative complications following GAS. Methods: A retrospective cohort study was conducted using the TriNetX Research Network, which includes de-identified electronic health records from over 100 million U.S. patients. Adults with documented gender dysphoria who underwent GAS between April 2015 and April 2025 were included. Patients were divided into four groups: no SUD, tobacco use, alcohol use, and cannabis use. Propensity score matching was used to control for demographic variables. Postoperative complications were assessed at 30 days and 6 months. Results: Alcohol use was significantly associated with increased rates of delayed wound healing, wound dehiscence, gastrointestinal symptoms, and postoperative pain at both 30 days and 6 months. Cannabis use was linked to higher rates of wound dehiscence, infections, GI symptoms, and pain. Tobacco use showed the broadest impact, significantly associated with nearly all complications measured except pain at 30 days. These associations persisted at six months. Conclusions: This is the first study to quantify the relationship between substance use and GAS outcomes. Preoperative use of tobacco, alcohol, and cannabis was independently associated with increased postoperative complications. These findings underscore the need for systematic preoperative screening and the development of SUD-specific perioperative care pathways to improve outcomes and advance equity in surgical care for TGD patients.

Therapeutics doi: 10.3390/therapeutics2030013

Authors: Isidro Miguel Martín Pérez David Alejandro Parra Castillo Carlos Pastor Ruiz de la Fuente Sebastián Eustaquio Martín Pérez

Background: Multiple Chemical Sensitivity (MCS) is a complex, disabling condition marked by non-specific symptoms in response to low-level chemical exposures. It often leads to substantial impairments in quality of life, psychological health, and daily functioning. Although non-pharmacological approaches—such as lifestyle and psychological interventions—are widely used, their clinical effectiveness remains unclear. Objective: We aim to evaluate the effectiveness of lifestyle-based approaches in improving clinical and psychosocial outcomes in adults with Multiple Chemical Sensitivity. Methods: A systematic review was conducted in accordance with PRISMA guidelines (PROSPERO: CRD420251013537). Literature searches were carried out in MEDLINE (PubMed), CINAHL, Google Scholar, and ResearchGate between March and April 2025. Eligible studies included adults (≥18 years) with a confirmed diagnosis of MCS and reported outcomes such as perceived stress, anxiety, depressive symptoms, or quality of life. Methodological quality and risk of bias were independently assessed using the PEDro scale, NIH Quality Assessment Tool, CEBMa checklist, and Cochrane RoB 2.0. Results: Twelve studies (N = 378) met the inclusion criteria. Cognitive and behavioral therapies demonstrated the most consistent evidence of efficacy, with reductions in symptom severity, maladaptive cognitive patterns, and functional limitations. Mindfulness-based stress reduction showed favorable outcomes, while other mindfulness-based interventions yielded mixed results. Exposure-based therapies contributed to increased chemical tolerance and reduced avoidance behavior. Electromagnetic and biomedical approaches demonstrated preliminary but limited effectiveness. Aromatherapy was well tolerated and perceived as relaxing, though its clinical impact was modest. Conclusions: Cognitive and behavioral therapies appear to be most effective among lifestyle-based interventions for MCS/IEI. However, study heterogeneity limits the generalizability of findings, underscoring the need for more rigorous research.

Therapeutics doi: 10.3390/therapeutics2030012

Authors: Luigi Bonavina Guglielmo Trovato Rosario Caruso Prisco Piscitelli Alberto Aiolfi Rosario Squatrito Roberto Penagini Davide Bona Giovanni Dapri Jerome R. Lechien

Background and Aims: Gastroesophageal reflux disease (GERD) is the most common esophageal disorder worldwide and a progressive condition leading to Barrett’s esophagus and adenocarcinoma. Continuous medical therapy with proton pump inhibitors fails to restore the antireflux barrier and is unable to relieve symptoms in up to 40% of patients. A tailored and standardized antireflux surgical procedure may increase cure rates and meet patient expectations. Methods and Results: Antireflux surgery aims to reestablish the natural antireflux barrier, which includes the diaphragmatic crura, the lower esophageal sphincter (LES), and the angle of His along with the gastroesophageal flap valve. For decades, the Nissen total fundoplication has been the primary procedure and remains the gold standard for surgical treatment. Alternatives such as Toupet partial fundoplication, Dor partial fundoplication, and the magnetic sphincter augmentation (LINX™) procedure have been developed to mitigate side effects like dysphagia, gas-bloat syndrome, and the inability to belch or vomit. Recent clinical findings regarding a novel procedure, RefluxStop™, indicate that restoring the gastroesophageal flap valve, in conjunction with anterior fundoplication and a silicone device for stabilizing the LES beneath the diaphragm, can achieve lasting reflux control and enhance patient-reported outcomes. Conclusions: The planning of healthcare services and actionable strategies to improve equity and quality of treatment is critical to address the global burden of GERD. Modern laparoscopic surgery for GERD is safe and effective and should be performed in centers offering a complete diagnostic pathway and specific surgical techniques tailored to the individual GERD phenotype. Shared decision-making between the surgeon and the patient is essential for the choice of operation. A personalized approach can offer clinical benefits over total fundoplication and improve patient-reported outcomes.

Therapeutics doi: 10.3390/therapeutics2030011

Authors: Jordann Lewis Basil Yaseen Haodi Wu Anita Saraf

Background: Human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) allow for high-throughput evaluation of cardiomyocyte (CM) physiology in health and disease. While multimodality testing provides a large breadth of information related to electrophysiology, contractility, and intracellular signaling in small populations of iPSC-CMs, current technologies for analyzing these parameters are expensive and resource-intensive. Methods: We have designed a novel 2D/3D hybrid organoid system that can harness optical imaging techniques to assess electromechanical properties and calcium dynamics across CMs in a high-throughput manner. We validated our methods using a doxorubicin-based system, as the drug has well-characterized cardiotoxic, pro-arrhythmic effects. Results: This novel hybrid system provides the functional benefit of 3D organoids while minimizing optical interference from multilayered cellular systems through our cell-culture techniques that propagate organoids outwards into 2D iPSC-CM sheets. The organoids recapitulate contractile forces that are more robust in 3D structures and connectivity, while 2D CMs facilitate analysis at an individual cellular level, which recreated numerous doxorubicin-induced electrophysiologic and propagation abnormalities. Conclusions: Thus, we have developed a novel 2D/3D hybrid organoid model that employs an integrated optical analysis platform to provide a reliable high-throughput method for studying cardiotoxicity, providing valuable data on calcium, contractility, and signal propagation.

Therapeutics doi: 10.3390/therapeutics2030010

Authors: Mahmoud Singer David K. Imagawa Michael Alexander Nadine Abi-Jaoudeh

Animal models are indispensable in biomedical research, offering critical insights into disease mechanisms and therapeutic strategies. However, existing models often inadequately replicate human pathophysiology, leading to discrepancies between preclinical and clinical outcomes. Despite their contributions, many models exhibit significant limitations, especially concerning cancer and infectious diseases. Inaccurate modeling of human biological responses can result in failed clinical trials, escalated research costs, and delays in developing effective treatments. The golden hamster (Mesocricetus auratus) has emerged as a viable model, particularly in cancer and infectious disease research. Sharing physiological and immunological profiles similar to humans, the golden hamster offers distinct advantages over other rodent models, such as mice and rats. This review explores the benefits of using golden hamsters in cancer research, highlighting their contributions to scientific advancements while also addressing the limitations due to incomplete immunological and molecular knowledge about this species.

Therapeutics doi: 10.3390/therapeutics2020009

Authors: Alessandra Pagano Matilde Bruni Laura Tavanti Francesco Pistelli Davide Chimera Laura Carrozzi Alessandro Celi Roberta Pancani

Background: Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are chronic conditions often accompanied by a prothrombotic state. Antifibrotic therapies, including nintedanib and pirfenidone, have demonstrated efficacy in slowing disease progression. Despite the known interactions between coagulation pathways and fibrotic processes, there is a lack of data in the literature on the safety of the concomitant use of anticoagulants and antifibrotics. Objectives: This study aimed to evaluate the safety and clinical impact of combining antifibrotics and anticoagulants in patients with IPF or PPF. A single-center, retrospective study was conducted on 137 patients diagnosed with IPF or PPF, 25 of whom were on concurrent anticoagulant therapy (AC+). Baseline demographics, pulmonary function tests (PFTs), bleeding risk scores (HAS-BLED, RIETE), and clinical outcomes were analyzed over a 12-month follow-up period. Methods: Statistical analyses included t-tests, χ2 tests, Kaplan–Meier survival analysis, and multivariate logistic regression. Results: Two clinically relevant bleeding events were observed, with one in the AC+ group. No major bleeding episodes occurred in either group. Baseline forced vital capacity (FVC) was lower in the AC+ group (73.4 ± 16.9% vs. 83.0 ± 21.9%; p = 0.04), but no significant differences were observed in FVC, forced expiratory volume (FEV1), or diffusing capacity for carbon monoxide (DLCO) at 6 and 12 months. Survival rates and radiological progression were comparable between groups. Multivariate analysis revealed that DLCO was an independent predictor of mortality (HR 0.84; p = 0.005), while anticoagulant use was not. Conclusions: The concomitant use of antifibrotics and anticoagulants appears safe, with no significant increase in bleeding risk or adverse effects on disease progression. Future prospective studies are required to confirm these findings and explore the long-term impact of this therapeutic combination.

Therapeutics doi: 10.3390/therapeutics2020008

Authors: Diane N. Gutgsell Randolph E. Regal

Venous thromboembolic events (VTEs), especially in the form of portal vein thrombosis (PVT), are common complications of cirrhosis and are associated with significant morbidity. These patients can also be easily tipped toward bleeding because of deficiencies in procoagulant factors and pharmacokinetic and pharmacodynamic changes that occur during disease progression. Therefore, the understanding of how to use pharmacotherapy to treat VTE is a key to success in achieving VTE resolution without potentiating adverse bleeding events (AEs). Based on a review of the literature and the authors’ clinical experience, it was determined that unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux, argatroban, warfarin, and direct oral anticoagulants all have evidence of use in patients with cirrhosis and VTE. However, the available literature is mostly limited to retrospective studies and case reports. There appears to be a paucity of prospective, randomized trials that compare the available pharmacotherapy at typical and adjusted doses. Overall, the decision as to the choice of agent and dose prescribed for anticoagulant therapy should include assessment on clot burden, bleeding risk, drug-drug/disease interactions, and the risk of presence of AEs.

Therapeutics doi: 10.3390/therapeutics2020007

Authors: Danilo Giffoni de Mello Morais Mata Tatianny P. Araujo Vargas Carlos Amir Carmona Abdullah Al-Humiqani Sara Gehlaut Alia Thawer Maria Romero Mark K. Doherty Ines B. Menjak

Background: In metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation, osimertinib is the cornerstone treatment able to prolong overall survival (OS). Evidence around osimertinib being effective in leptomeningeal metastasis (LM) is scarce. Methods: We conducted a retrospective cohort study of patients with metastatic NSCLC-EGFR mutation treated with osimertinib at Sunnybrook Hospital. Results: We identified a total of 56 patients. Of these, 45 (79.4%) were never smokers, 53 (94.6%) had adenocarcinoma histology, and 26 (46.42%) had either the EGFR exon 21-L858R mutation or exon 19 deletion. The estimated median OS was 51 months (43.5–58.5). All eight patients with LM died during the study period. From the time of NSCLC diagnosis, the OS of patients without LM was 53 months (95% CI 47.2–58.7), and with LM was 21 months (95% CI 3.0–39), p = 0.001. However, the median OS from LM diagnosis was 2 months (95% CI, 1.0–26). Conclusions: In our population of patients with metastatic NSCLC-EGFR mutation who received osimertinib, there was a significant reduction in life expectancy in the group with LM. Patients who had advanced stage at diagnosis and were more likely to develop LM exhibited poorer survival compared to those who had early-stage cancer at diagnosis and developed metastases later on.

Therapeutics doi: 10.3390/therapeutics2020006

Authors: Tibor Attila Rauch Annamaria Marton Tamás Solymosi Hristos Glavinas Csaba Vizler

Background/Objectives: The epigenetic drug 5-azacytidine (AzaC) is being used for the treatment of myeloproliferative diseases. It has multiple immunomodulating activities: it enhances the activity of Treg cells and suppresses effector T cell proliferation and function. Our aim was to repurpose AzaC for the treatment of multiple sclerosis (MS). AzaC treatment of myelodysplastic syndrome often improves the autoimmune disorders accompanying it. Another epigenetic drug, decytabin, was effective in EAE, suggesting that AzaC might behave similarly. Earlier, we found that AzaC improves aggrecan-induced arthritis in mice, further supporting our hypothesis. Methods: AzaC was tested in an animal model of MS: MOG35–55-induced experimental allergic encephalomyelitis (EAE) in B6 mice. In addition to AzaC, its ester, prodrug triacetyl-5-azacytidine (TAC), reported earlier to exhibit improved stability and oral bioavailability, was also tested. Results: In our proof-of-concept experiment, i.p. administered AzaC ameliorated EAE. Then, we demonstrated that oral TAC is as effective as the positive comparator fingolimod. Next, we demonstrated that sub-optimal doses of oral TAC and fingolimod positively synergize. Importantly, the myelosuppression induced by TAC was not worse than that of the gold-standard fingolimod. Conclusions: Ours is the first study reporting the therapeutic activity of oral TAC. Both AzaC and TAC were effective in EAE; therefore, they can be proposed for the treatment of remitting–relapsing MS and possibly other autoimmune diseases. In addition, combination treatment with TAC and fingolimod might allow for lower individual drug doses, thus offering an alternative when side effects limit the use of current multiple sclerosis drugs.

Therapeutics doi: 10.3390/therapeutics2010005

Authors: Simge Karagil Aleksandra Szczesnowska Natalia Haddad Sara Magura Gamaethige Ellen Coakley Nabila Dawood Vernard J. Rama James Barker Moses K. Langat Huda Morgan Nadine Wehida Ahmed Elbediwy

Plant extracts are increasingly becoming an answer to expensive, high-dose, synthesized chemotherapy, with milder side effects and easier accessibility. Many botanical plants contain active ingredients, such as terpenoids and alkaloids, which may combat cancer; however, studies need to be performed to test whether they are solely effective enough and whether the extracted compounds are selective for the tumor itself. Many chemotherapy drugs were initially of botanical origin, such as vincristine from Catharanthus roseus and paclitaxel from the Taxus baccata tree. The objective of this review is to assess the mechanisms of herbal therapeutics in their role against malignancy. Ajwa, curcumin, ginseng, lycopene, and ursolic acid were all respectively evaluated in the paper for their prevalent properties, their method of extraction, notable usage in medicine, which pathways they activate, and whether the transductions can disrupt cancer formation or proliferation. The findings from the review demonstrated that all the therapeutics exhibited pro-apoptotic behavior, Ajwa and curcumin exerted cell cycle arrest upon neoplasms, and Ajwa, curcumin, and lycopene showed anti-metastatic behavior. Most extracts were tested on colorectal cancer, and the pathways most commonly applied were through BAX/Bcl2 and endoproteases, such as caspase-3 and caspase-9, indicating predominantly mitochondrial apoptosis. In addition, cell cycle arrest was noted to occur during the G2/M phase via Wnt/β-catenin in both curcumin and ginseng, independently of the Wnt/β-catenin pathway in Ajwa constituents, reducing cell viability. All of these studies were demonstrated in vitro within varieties of single cell cultures, which did not take into account bioavailability nor properly demonstrate the tumor microenvironment, which may not yield the same results in vivo. Clinical trials need to be undergone to appropriately test effective dosages, as if a compound is strongly pro-apoptotic, it may not be selective just to tumor cells but also to healthy cells, which may impair their functions.

Therapeutics doi: 10.3390/therapeutics2010004

Authors: Michaela Mastrud Kirsten Juhl Lindsey Dahl Shabbir Haiderbhai Peyton Lahr Gunjan Manocha Abbigail Olson Jennifer Raum David Theige Ryan McGrath

Background: Handgrip strength (HGS) is strongly recommended for use in clinical settings because it is a convenient assessment of muscle strength and a robust prognostic indicator of health. However, it may lack use in clinical settings, and may not be well understood by healthcare providers and patients. We sought to determine the healthcare provider and patient perceptions of HGS in an internal medicine resident clinic. Methods: Healthcare providers were presented with didactic sessions for HGS and engaged in routine follow-up meetings. HGS was measured on eligible older adult patients during an approximately 9-month phased study period. Both healthcare providers and patients were asked to complete a questionnaire with 10-point Likert scale response items regarding their experiences with HGS. Results were presented as descriptive. Results: Overall, patients had a positive perception of HGS, as they understood HGS instructions (score: 9.8 ± 0.7), their results (score: 9.5 ± 1.3), and found value in HGS for their health (score: 8.4 ± 2.3). However, healthcare providers were generally neutral about HGS, such that at study end HGS was viewed as moderately valuable for their practice (score: 6.0 ± 2.1) and patients (score: 6.0 ± 2.1). Conclusions: Overall, patients had a positive perception of HGS, but healthcare providers were neutral. Our findings should be used to guide HGS for possible implementation and quality management in appropriate healthcare settings.

Therapeutics doi: 10.3390/therapeutics2010003

Authors: Darian Peters Jacob Kalathoor Courtney Phillips Belma Andric Lea Sacca

Background/Objectives: This scoping review aims to identify the diverse existing tools applicable for the measurement of SUD outcomes, examining and comparing their item characteristics, benefits, limitations, cost effectiveness, and overall utility. This study provides recommendations on the next steps toward the design and dissemination of a unified version of a standard SUD outcome measurement tool. Methods: Using PRISMA-ScR guidelines, the databases PubMed and Embase, as well as the grey literature, were searched for existing SUD outcome measurement tools. Additionally, references and information on tools were found via the Addictions Drug and Alcohol Institute Library at the University of Washington. Tools were examined based on their characteristics, benefits, limitations, and overall utility. Results: Thirteen tools met the analysis requirements and were analyzed, revealing great variance. The domains covered by each tool is categorized for comparison among other tools, showing strong focus over some domains more than others. Additionally, great variance in characteristics such as the number of questions, question structure, time required for completion, and scoring were seen. Sources for each of these tools’ development were seen to reveal the unique origination of each, as well as their intended utility. Conclusions: Our analysis highlights the importance of considering certain characteristics when selecting measurement instruments, emphasizing the need for clear and concise questions to enhance levels of adherence and interpretation. The current lack of standardization among SUD measurement tools in assessing new and existing SUD treatment modalities has hindered progress in the field, compromising the quality of care delivered.

Therapeutics doi: 10.3390/therapeutics2010002

Authors: Sharon Koorse Germans Christine Wamsley Kahlow Weina Chen Franklin Fuda

Background: Plasma cell myeloma is an incurable malignancy of clonal plasma cells. Recent success in immunotherapeutic strategies has altered the landscape of myeloma treatment. Daratumumab is an anti-CD38 IgG kappa monoclonal antibody that has shown great efficacy in the treatment of myeloma. However, Daratumumab brought with it new challenges in post-therapeutic laboratory assessment, including therapeutic antibody interference with serum protein electrophoresis and serum immunofixation electrophoresis assays. In this study, we highlight the interference identified in post-therapeutic flow cytometry analysis related to bound Daratumumab on normal hematopoietic cells. We also highlight the methods of detection of residual plasma cell neoplasm, post-Daratumumab therapy.: A total of 28 patients with refractory plasma cell myeloma who received Daratumumab (2016–2018) were included in this study. Flow cytometry was performed using 4- or 10-color antibody panels (BD FASC Canto) and analyzed by cluster analysis (Cytopaint Classic software) using four tube panels including VS38c for measurable residual disease (MRD) testing. Pretreatment and post-Daratumumab follow-up bone marrow flow cytometry samples were analyzed. In addition, 10 multiple myeloma patient samples were reflexed to multi-epitope CD38 analysis by flow cytometric analysis of post-Daratumumab residual disease. When discussing CD38 expression, we will refer to CD38 as being detected by conventional reagents. Results: All post-Daratumumab-treated cases (100%) showed negative staining for CD38 using conventional reagents on all plasma cells in the specimens. MRD testing successfully identified small clonal plasma cell populations using VS38C and multi-epitope CD38 (meCD38) antibodies, despite the absence of demonstrable CD38 expression. Additionally, all cases exhibited weak kappa light chain staining on hematogones, attributed to the binding of Daratumumab kappa monoclonal antibody. This interaction can create the appearance of a CD10+ monotypic B-cell population. We also noted diminished CD38 staining on myeloblasts, resulting in an atypical CD34/CD38 staining pattern. This alteration could potentially be misinterpreted as indicative of a myelodysplastic neoplasm (MDS). Furthermore, decreased staining of CD38 was noted on T cells, natural killer (NK) cells, basophils, monocytes, and plasmacytoid dendritic cells. Conclusions: With the emergence of successfully targeted immunotherapies, such as anti-CD38 antibodies, it is important to understand and correctly interpret variations in flow cytometry that may arise from the therapy. Hematogones exhibit high-intensity levels of CD38 expression; thus, Daratumumab binds to them, creating the appearance of kappa expression on all hematogones. Stage I/early stage II hematogones normally lack surface immunoglobulin light chain expression, but in the presence of Daratumumab, they appear to be a CD10(+) monotypic population of B cells. The misinterpretation of these normal cells as a CD10(+) B-cell clone can lead to inaccurate assessment, unnecessary bone marrow immunohistochemical evaluation, and unwarranted anxiety. Additionally, artefacts on various other hematopoietic cells can result in inaccurate assessments of immunophenotypic aberrancy due to binding of the drug. This may lead to the false interpretation of a secondary/therapy-related myeloid neoplasm. This study highlights in detail the interferences that must be considered when assessing residual disease in the era of targeted drug therapies.

Therapeutics doi: 10.3390/therapeutics2010001

Authors: Justin N. Durland Frank Hoyland John Elliott Epps Mathew J. Gregoski Jacqueline Angles Gregory R. Jackson

Background: Past studies have found mixed benefits to treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) in heart failure (HF) patients. Here we evaluate the effect of OSA treatment in symptomatic HF patients who received an inpatient sleep study. Methods: We performed a retrospective observational review of 6-month outcomes in 109 hospitalized HF patients with newly diagnosed OSA who followed up to initiate PAP therapy (N = 48) or never started PAP (N = 61). Primary outcomes were cardiovascular readmissions and all-cause mortality. Results: Patients who started PAP overall had worse apnea–hypopnea index (AHI) compared to those who did not (AHI 49.4 vs. 31.3). There were significantly fewer deaths in the “PAP” group versus the “non-PAP” group: 2% versus 15% (p = 0.04). We then sub-analyzed our population based on strict CPAP adherence, defined as ≥4 PAP hours per night and at least ≥70% of nights used. Twenty-eight out of 48 PAP patients met adherence criteria. The “Adherent” group (N = 28) had notable PAP use of 6.3 h per night (interquartile range 5–7.7 h/night). In comparison to the “Non-Adherent or Never Started PAP” group (N = 81), the Adherent group had no observed deaths and significantly fewer first-time readmissions: 11% versus 33% (p = 0.026). Conclusions: Despite worse baseline OSA in our PAP population, we found an association between PAP compliance and improved cardiovascular outcomes. Future research should investigate dose–response relationships between PAP use and HF outcomes. There are important limitations to our study.

Therapeutics doi: 10.3390/therapeutics1020011

Authors: Rasaq Akinsola Kumaran Narayanan

Bacterial vectors for biomolecule delivery to targeted organelles, facilitating temporary or continuous protein production, have emerged as a promising approach for treating acquired and inherited diseases. This method offers a selective cancer eradication and targeting strategy with minimal side effects. Bacterial vectors provide an alternative to viral gene delivery, given their capacity to deliver large genetic materials while inducing minimal immunogenicity and cytotoxicity. Bacteria such as Bifidobacterium, Salmonella, Clostridium, and Streptococcus have demonstrated potential for tumor-targeted biomolecule delivery or serve as oncolytic bacteria. These vectors have also been used to transfer and amplify genes encoding biomolecules such as pro-drug-converting enzymes, toxins, angiogenesis inhibitors, and cytokines. The microenvironment of necrotic tumors offers a unique opportunity for targeted therapy with the non-pathogenic anaerobic bacterium. For example, Clostridium sporogenes can germinate selectively in the necrotic regions upon injection as endospores, which helps to enhance the specificity of Clostridium sporogenes, resulting in tumor-specific colonization. Also, E. coli and Salmonella sp. can be capacitated with a hypoxic sensing promotor gene for specificity delivery into the core region of solid tumors. The uniqueness of the tumor microenvironment, including hypoxia, immunosuppression, metabolite deficiency or enrichment, and necrosis, selectively enables bacteria in the tumor. Combining traditional cancer therapy with bacterial therapy will significantly complement and cover the limitations of other treatments. This review provides an overview of the use of the bacteria vector in cancer therapy, discussing strategies to maximize delivery efficiency and address potential challenges. In this review, we discuss the potential of bacteria vectors as anti-cancer therapeutics while focusing on therapeutic delivery strategies. We highlight the complementary use of bacteria therapy with other cancer therapies and the mechanism of bacteria cancer immunotherapy with limitations and perspectives for future use.

Therapeutics doi: 10.3390/therapeutics1020010

Authors: Wassim Khalil Roula Khalil Alexandre Meynard Alexandre Perani Elodie Chaudruc Mathilde Duchesne Karine Durand François Caire Henri Salle

Background: Schwannomas, predominantly benign nerve sheath tumors, are typically found within the intradural extramedullary space of the spinal cord with potential extradural expansion. Other typical localizations are the upper limbs and neck area. Pure epaxial paraspinal schwannomas are very rare, often asymptomatic, and predominantly occur in the thoracic region, with only a handful of cases reported globally. The range of differential diagnoses for paraspinal lesions is extensive, emphasizing the importance of accurate diagnosis to ensure optimal therapy and avoid unnecessary treatments. Method: We conducted a systematic literature review searching for published recommendations for paraspinal lesion management in addition to examining the case of a 49-year-old male patient who presented with a history of persistent back pain. A thorough medical history and physical examination were followed by ultrasound and MRI, revealing a well-defined paravertebral mass spanning from T7 to T9. A secure ultrasound-guided biopsy was performed, leading to a preliminary diagnosis of paraspinal schwannoma. Subsequently, complete surgical resection was performed. Results: pathological reports confirmed the initial diagnosis of paraspinal schwannoma. Further investigation using FMI and RNA sequencing did not detect any specific genetic anomalies aside from an NF2 gene mutation. A follow-up MRI conducted six months later showed no signs of recurrence. Conclusions: The broad spectrum of differential diagnoses for paraspinal lesions necessitates a multidisciplinary approach to ensure accurate diagnosis and tailored treatment. This approach involves meticulous imaging interpretation followed by a secure biopsy procedure to obtain preliminary pathology results, ultimately leading to the implementation of the most suitable surgical treatment.

Therapeutics doi: 10.3390/therapeutics1020009

Authors: Katja Seipel Lynn Benninger Ulrike Bacher Thomas Pabst

Background/Objectives: Mantle cell lymphoma (MCL) represents a rare B-cell lymphoma subtype with rather high relapse rates. Somatic mutations in the PPM1D gene were shown to be associated with adverse outcomes in patients with diffuse large B-cell lymphoma (DLBCL) who received CD19 CAR-T-cell therapy with tisa-cel, which may also apply to mantle cell lymphoma receiving brexu-cel CAR-T-cells. Methods: In this study, we determined the prevalence of PPM1D mutations in peripheral blood cells of MCL patients before CAR-T-cell infusion and analyzed the impact of low-frequency PPM1D mutations on efficacy and safety aspects of brexu-cel CAR-T-cell treatment in the first 16 r/r MCL patients enrolled at Inselspital Bern. Results: The prevalence of low-frequency PPM1D gene mutations was 25%, with variant allele frequencies (VAF) of 0.011 to 0.099. Clinical response was analyzed in the PPM1D mutated (PPM1Dmut) vs. PPM1D wild-type (PPM1Dwt) groups with median progression-free survival of 1 versus 32 months (p = 0.07) and median overall survival of 1.5 vs. 27 months (p = 0.001). Conclusions: Our data suggest that low-frequency PPM1D gene mutations in peripheral blood cells may predict inferior outcomes in patients with mantle cell lymphoma treated with CAR-T-cell therapy.

Therapeutics doi: 10.3390/therapeutics1020008

Authors: Naiya Patel Seyed M. Karimi Bert Little Michael Egger Demetra Antimisiaris

Background/Objectives: Directed acyclic graphs (DAGs) inform the epidemiologic statistical modeling confounders to determine close to true causal relationships in a study context. They inform the inclusion of the predictive model variables that affect the causal relationship. Non-small cell lung cancer (NSCLC) is frequently diagnosed, aggressive, and the second leading cause of cancer deaths in the United States. Determining factors affecting both the guideline-concordant treatment receipt and survival outcomes for early-stage lung cancer will help inform future statistical models aiming to achieve a close to true causal relationship. Methods: Peer-reviewed original research published during 2002–2023 was identified through PubMed, Embase, Web of Sciences, Clinical trials registry, and the gray literature. DAGitty version 3.1, an online software program, developed implied DAGs and integrated DAG graphics. The evidence synthesis for constructing directed acyclic graphs (ESC-DAGs) protocol was utilized to guide DAG development. The conceptual models utilized were Andersen and Aday for factors affecting treatment receipt and Shi and Steven for survival outcome factors. Results: A total of 36 studies were included in the DAG synthesis out of 9421 retrieved across databases. Eight studies served in the synthesis of treatment receipt DAG, while 28 studies were used for the survival outcomes DAG. There were 10 causal paths and 13 covariates for treatment receipt and 2 causal pathways and 32 covariates for survival outcomes. Conclusions: There are very few studies reporting on factors affecting early-stage NSCLC guideline-concordant care receipt compared to factors affecting its survival outcomes in the past two decades of original research. Future investigations can utilize data extracted in the current study to develop a meta-analysis informing effect size.

Therapeutics doi: 10.3390/therapeutics1020007

Authors: Taylor Powell Cameron Robicheaux Rhian Germany Gauri Mankekar

Objective(s): The objective of this study was to report our experience with a series of patients with temporal bone fractures from 2019 to 2023 and to evaluate the dilemmas in diagnosing the extent of their ontological injuries through a narrative review of the literature focusing on the classifications of temporal bone fractures. Methods: Data were collected retrospectively from the electronic medical records of patients who presented to the emergency department and were diagnosed with temporal bone fractures using computed tomograms of the head and temporal bone between September 2019 and March 2023. A total of 117 patients were included in the study. Demographic data, fracture classification, mechanism of injury, and presence and/or repair of cerebrospinal fluid (CSF) leak, facial nerve injury (both immediate and delayed), and hearing loss (both immediate and delayed) were also recorded. Results: In total, 49.5% of our cohort were between the ages of 19 and 39, and the majority (66%) were males. The primary cause of the trauma was falls in 41% of patients, followed by motor vehicle accidents (29%), and 70% had a Glasgow Coma Score (GCS) between 13 and 15 at presentation. In total, 92.3% of temporal bone fractures did not involve the otic capsule, and 79.3% were longitudinal fractures. In total, 89% of the CSF leaks were seen in patients with longitudinal fractures. Similarly, 70% of facial nerve deficits were seen in patients with longitudinal and otic capsule-sparing fractures. Conclusion: Diagnosis of facial asymmetry and hearing loss in patients with TBFs can be challenging in acute care settings but was less challenging in our cohort due to patients presenting with good GCSs. Dilemmas in clinical evaluation in the acute care setting are due to poor GCSs, heterogeneity of documentation of injuries, and classification of TBFs. Implementation of universal protocols with homogeneity in the documentation and classification of temporal bone fractures may help improve patient care and prediction of outcomes.

Therapeutics doi: 10.3390/therapeutics1010006

Authors: Tyler Chinedu Chinyere Ikeotunye Royal Chinyere

Atrial fibrillation (AF) in the setting of heart failure (HF) with preserved ejection fraction (HFpEF) is a prevalent comorbidity and is enabled by adverse left atrial (LA) remodeling, dilation, and scar tissue formation. These changes are facilitated by poor left ventricular compliance. A growing body of clinical evidence and medical guidelines suggest that managing atrial tachyrhythms with catheter ablation (CA) is paramount to treating concomitant HF. This recommendation is complicated in that thermal CA modalities, namely radiofrequency ablation and cryoablation, are both therapeutic via inducing additional scar tissue. AF treatment with thermal CA may compound the atrial scar burden for patients who already have extensive scars secondary to HFpEF. Therefore, thermal CA could act as “gasoline” to the slowly burning “fire” within the LA, increasing the rate of AF recurrence. Pulsed-field ablation (PFA), which utilizes high-voltage irreversible electroporation, is a non-thermal CA technique that is capable of disrupting reentrant microcircuits and arrhythmogenic foci without inducing significant scar burden. PFA has the potential to mitigate the strong fibrosis response to thermal CA that predisposes to AF by serving as “water” rather than “gasoline”. Thus, PFA may increase the efficacy and durability of CA for AF in HFpEF, and subsequently, may decrease the risk of procedural complications from repeat CAs. In this article, we provide a summary of the clinical concepts underlying HFpEF and AF and then summarize the data to date on the potential of PFA being a superior CA technique for AF in the setting of comorbid HFpEF.

Therapeutics doi: 10.3390/therapeutics1010005

Authors: Natasha Venugopal Hyma V. Polimera Jessica Santucci Erik Washburn Elizabeth Federici

Background: Complement-mediated hemolytic uremic syndrome (CM-HUS), formerly known as atypical HUS, is a rare but potentially fatal thrombotic microangiopathy (TMA) characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and acute kidney injury. It is primarily caused by complement dysregulation. The condition can progress to end-stage renal disease (ESRD), often necessitating kidney transplant. In rare instances, it can develop in post-renal-transplant patients. Methods: Here, we present the cases of two patients with ESRD status post kidney transplant who presented with thrombocytopenia, anemia, and acute kidney injury. In both cases, work-up was suggestive of CM-HUS, and stabilization was achieved with eculizumab. Discussion: The pathogenesis of CM-HUS involves dysregulation of the complement system, and complement inhibitors such as eculizumab can be used for initial management and relapse. The relapse rate following eculizumab treatment can range from 20 to 67%. Patients with a history of kidney transplant are more prone to relapse than those with native kidneys. Re-treatment with complement inhibitors has proven effective in managing relapses, and long-term continuation of complement inhibitor medications is recommended to prevent recurrence. Conclusions: CM-HUS is rare, especially in post-transplant patients, and can be potentially fatal. It is crucial for clinicians to recognize and treat this condition promptly. Management often involves complement inhibitors. The risk of relapse is particularly high in patients with a history of kidney transplant, but long-term continuation of these medications can prevent relapse.

Therapeutics doi: 10.3390/therapeutics1010004

Authors: Eugene Annor Harishankar Gopakumar Ishaan Vohra Srinivas R. Puli

Background: Endoscopic retrograde cholangiopancreatography (ERCP) is preferred for biliary drainage in malignant distal biliary obstruction (MDBO). Endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) is considered a rescue therapy for failed ERCP. This study aims to evaluate the safety and efficacy of this technique as the primary modality for MDBO biliary drainage. Methods: An electronic database search was conducted following PRISMA guidelines to identify studies on EUS-CDS for primary biliary drainage in MDBO. A meta-analysis was performed using random and fixed effects models. Results: We extracted data from 10 eligible studies comprising 519 patients. The mean age for the study was 70 years ± SD 2.66. The pooled technical success rate was 92.36% (95% CI = 88.39–95.56), and the clinical success rate was 88.91% (95% CI = 85.22–92.13). The pooled stent dysfunction rate was 13.66% (95% CI = 7.47–21.35), and the reintervention rate was 15.91% (95% CI = 11.00–21.54) of patients. The mean stent patency duration was 229.20 days ± SD 113.9. The total pooled adverse events rate was 17.50% (95% CI = 12.90–22.64), and 9.03% (95% CI = 4.43–15.05) was considered moderate to severe. Procedure-related pancreatitis had a pooled rate of 0%. The pooled adverse event rate of acute cholangitis was 6.84% (95% CI = 3.69–10.88), and for acute cholecystitis it was 2.61% (95% CI = 1.06–4.83). Conclusions: EUS-CDS demonstrates favorable outcomes when used as a primary approach in MDBO. With a long stent patency duration and no procedure-related acute pancreatitis, it may be considered the primary technique when expertise is available.

Therapeutics doi: 10.3390/therapeutics1010003

Authors: Arman Romiani Daniella Pettersson Nishte Rassol Klara Simonsson Hana Bakr Dan E. Lind Anikó Kovács Johan Spetz Ruth H. Palmer Bengt Hallberg Khalil Helou Eva Forssell-Aronsson

Background/Objectives: Neuroblastoma (NB) is a childhood cancer with heterogeneous characteristics, posing challenges to effective treatment. NBs express somatostatin receptors that facilitate the use of somatostatin analogs (SSTAs) as tumor-seeking agents for diagnosis and therapy. High-risk (HR) NBs often have gain-of-function mutations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK). Despite intensive multimodal treatment, survival rates remain below 40% for children with HR-NB. The aim of this work was to investigate the combined effect of the SSTA 177Lu-octreotide with the ALK inhibitor lorlatinib. Methods: Mice bearing human HR-NB CLB-BAR tumors were treated with lorlatinib, 177Lu-octreotide, and a combination of these pharmaceuticals or saline (control). Tumor volume was monitored and tumor samples were evaluated for cleaved caspase-3 and expression of 84 human genes involved in apoptosis. Results: Combination treatment with 177Lu-octreotide and lorlatinib demonstrated synergistic antitumor effects. An increased number of cleaved caspase 3-positive cells was observed in tumors from mice treated with 177Lu-octreotide alone and in combination with lorlatinib. Modulation of Bcl-2 family gene expression was observed only in the presence of both 177Lu-octreotide and lorlatinib, with BID down-regulated and HRK up-regulated on days 2 and 7, respectively. Conclusions: The data suggest that ALK signaling pathway inhibition may contribute to radiosensitization in radionuclide therapy with 177Lu-octreotide and could improve treatment outcomes in patients with HR-NB.

Therapeutics doi: 10.3390/therapeutics1010002

Authors: Nejat Düzgüneş

It is an honor to serve as the founding Editor-in-Chief of the open access journal Therapeutics [...]

Therapeutics doi: 10.3390/therapeutics1010001

Authors: Shu-Kun Lin

We are publishing volume 11 of Medicines in 2024 [...]