Pegmolesatide ameliorates indoxyl sulfate-induced cardiomyocyte hypertrophy through modulating the EPOR-CD131-dependent JAK2/STAT3 signaling pathway.

Glucose metabolism reprogramming in gastric cancer: Implications for tumor.

Exploring the context-dependent role of miR-744 as a prognostic, diagnostic, and therapeutic biomarker across different cancer types.

Encapsulated cells as an enzyme replacement therapy for metachromatic leukodystrophy.

Early clinical experience with the use of chimeric antigen receptor (CAR) T-cell therapies for patients with acute myeloid leukemia (AML) has been beset by high rates of toxicities and low rates of response. We convened an international workshop with the goal of bringing investigators in the field of AML-directed CAR T-cell therapy together to facilitate discussion of challenges and to brainstorm potential solutions. Based on discussions at the workshop, it was evident that (1) treating and targeting AML with CAR T cells is associated with unique clinical challenges, and (2) variability in clinical trial design, definitions of toxicities, correlative data collection, and reporting methods hinders the field's ability to compare study outcomes and to develop best practices. Further, details of fundamental CAR T-cell attributes and key correlates of efficacy and toxicity were not uniformly reported in published studies, limiting understanding of barriers to success. These observations led to a concerted team effort in which experts in basic/translational science and clinical investigation from pediatric and adult centers worked together to streamline key attributes of clinical trial design and reporting. Consensus criteria were discussed and agreed upon, leading to the creation of a white paper. These guidelines aim to bolster the overall quality of AML-directed CAR T-cell research, allow for comparisons across trials, and inform the next phase of development of AML-directed CAR T-cell therapies that we hope will improve patient outcomes.

BACKGROUND Pulmonary arterial hypertension (PAH) is a debilitating and progressive pulmonary pathology that often leads to death. Guidelines recommend the use of palliative care (PC) early in the treatment course to ease the burden of symptoms; however, uptake remains low. AIM To evaluate barriers to PC uptake and determine its association with mortality in patients with PAH. METHODS All studies discussing PC in PAH were selected in our review and analysis. Clinical and cross-sectional studies were included. Barriers were described in a qualitative fashion. A random-effects meta-analysis was also conducted, in which the odds ratio for mortality was pooled and reported, along with 95% confidence intervals. RESULTS A total of 19 studies were included in the review. The most common barriers identified included feeling like the patients were “not sick enough”, belief that PC is only appropriate for end-of-life care, belief that it would burden family members, and general feelings of hopelessness. Physicians identified structural causes, such as a lack of funding and low levels of PC-related knowledge, as barriers to recommending PC. The meta-analysis showed no statistically significant difference in mortality across four included studies (Log odds ratio = 0.89, 95% confidence intervals: -3.06-1.28). Heterogeneity was high (I 2 = 80.32%). CONCLUSION Uptake of PC in PAH is low due to patient and physician-level barriers, which can be overcome with systematic PC integration. Long-term studies are also needed to investigate the impact of PC on outcomes in PAH, as the current limited data show no significant difference.

BACKGROUND Administration of thrombolytics for acute ischemic stroke (AIS) via telemedicine has expanded in recent years at institutions without on-site neurology specialists. This helped to improve the care of stroke patients in rural areas. However, it is uncertain if telemedicine-administered thrombolytics is as safe and effective as in-person evaluation by neurology specialists. AIM The authors conducted a meta-analysis evaluating stroke metrics, safety and outcomes of telemedicine compared to in-person evaluation by neurologist specialist in AIS patients receiving intravenous thrombolytics. METHODS PubMed, EMBASE, and Cochrane were searched for randomized clinical trials and observational cohort studies. The Mantel-Haenszel method or inverse variance, as applicable, were applied to calculate an overall effect estimate for each outcome by combining specific risk ratio (RR) or standardized mean difference (SMD). Risk of bias was analyzed using the Newcastle-Ottawa Scale. Primary outcome examined was door-to-needle time (DTN). Secondary outcomes were symptomatic intracranial hemorrhage (sICH), mortality, and mRS ≤ 2. RESULTS Eleven retrospective cohort studies involving 2350 patients were included in the analysis. Of those, 34% (n = 794) received thrombolytics via telemedicine. Telemedicine was associated with a significantly longer mean DTN compared to in-person evaluation [SMD: 0.72 minutes; 95% confidence interval (CI) 0.22-1.22; P < 0.01], a similar rate of sICH [3.9% vs 4.2%; Odds ratio (OR): 0.75; 95%CI 0.42-1.37; P = 0.35], similar rate of mortality (13.2% vs 14.7%; OR: 0.87; 95%CI 0.47-1.63; P = 0.67), and comparable rate of favorable short-term functional outcome (46.8% vs 50.7%; OR: 0.79; 95%CI 0.41-1.53; P = 0.48). Risk of bias was low to moderate for each outcome. CONCLUSION The available literature suggests that telemedicine is associated with longer DTN compared to in-person evaluation. This difference in stroke metric does not affect safety or outcome. Further studies are needed to understand and address the underlying factors of the longer DTN time.

Autism is a heterogeneous condition with a rising prevalence and demand for specialized care. Autistic children are more likely than neurotypical peers to experience co-occurring conditions (CCs), including medical, psychiatric, and behavioral issues, highlighting the urgent need for autism-competent healthcare providers in general healthcare. This review aims to equip primary care providers (PCPs) with a concise summary of common CCs and strategies for effective identification. A panel of experts with extensive experience in caring for autistic children collaboratively summarized key literature, research evidence, and existing clinical trial outcomes, supplementing their clinical expertise. Autistic children consistently show higher rates of both medical and mental health issues. Despite greater healthcare utilization, many autistic individuals report unmet needs. CCs can impair behavior, functioning, and well-being, but are often treatable when recognized early. Timely identification and management of medical and psychiatric CCs are critical for improving outcomes for autistic children and their families. This evidence-based review supports PCPs in enhancing their knowledge, fostering early recognition, and delivering comprehensive, responsive care.

BACKGROUND Critically ill patients often present on admission or develop acute respiratory failure requiring intubation and application of positive pressure ventilation during their hospital stay. AIM To investigate and identify the epidemiological data, parameters associated with respiratory settings or the mechanics, and values related to arterial blood gases (ABGs) that are associated with outcomes in critically ill patients. METHODS A retrospective analysis of 131 patients [mean age, 67.3 years; mean acute physiology and chronic health evaluation (APACHE) score, 21.4] with acute respiratory failure requiring invasive mechanical ventilation was performed. The parameters that were statistically analyzed included demographic data, the presence of comorbidities, the presence of coronavirus disease 19 (COVID-19), the respiratory rate (RR), peak airway pressure (Ppeak), minute ventilation (MV), positive end-expiratory pressure, and the values related to ABGs. In order to facilitate the statistical analysis, patients were evaluated and compared in groups: Survivors (n = 41) vs non-survivors (n = 90) and patients without acute kidney injury (AKI) (n = 60) vs patients with AKI (n = 71). Four endpoints were studied: Mortality, length of stay, duration of mechanical ventilation, and AKI. Group comparisons were performed using the following statistical tests: The χ 2 test with Yates’ correction, Fisher’s exact test, the Mann-Whitney U test, and Spearman’s rank correlation analysis. Binary logistic regression analysis conducted after the univariate statistical tests facilitated the investigation of the independent predictors of mortality and AKI. A two-sided P value of less than 0.05 was considered the threshold of statistical significance. RESULTS Non-survivors presented statistically significant differences in terms of being older in age, the presence of comorbidities, elevated APACHE score, medical (vs surgical) reasons for admission, presence of COVID-19, lower pH at ABGs, lower values of the oxygenation ratio (arterial oxygen partial pressure to the fraction of inspired oxygen) and arterial oxygen partial pressure, and elevated values of Ppeak, positive end-expiratory pressure, RR, arterial carbon dioxide partial pressure, and MV. The factors identified as independent predictors of mortality were the presence of comorbidities, APACHE score, COVID-19 status, arterial carbon dioxide partial pressure, Ppeak, RR, and MV. COVID-19 presence and elevated values of RR and Ppeak were positively correlated with the other three endpoints (length of stay, the duration of mechanical ventilation in survivors, and the occurrence of AKI in the entire study population) that were studied. The other parameters exhibited a variable (either positive/negative, or no) correlation to the four endpoints under investigation. CONCLUSION Among all investigated outcome measures, COVID-19, Ppeak, and RR were strongly associated with all the endpoints studied, suggesting that proper interventions involving the modifiable respiratory parameters Ppeak and RR could improve the overall outcome in these patients. A novel finding of this study was the relationship between RR and AKI, which is worthy of further investigation. Future studies may explore the clinical interpretation of these findings to improve outcomes in critically ill patients with acute respiratory failure.

N-of-1 trials offer a unique and rigorous methodology for evaluating individualized treatment responses, particularly within the context of personalized medicine. This article provides a comprehensive explanation of the conceptual and methodological underpinnings of N-of-1 trials, with particular emphasis on statistical techniques and considerations critical for their design and analysis. Existing guidelines for planning and conducting these studies are summarized, along with a discussion of the practical and theoretical challenges to their implementation in clinical practice. We provide an overview for clinicians and researchers who may be unfamiliar with the design. As most of the existing guidance has focused on design and implementation considerations, we expand on the statistical analysis. We aim to support researchers and methodologists in understanding and advancing the methodological toolkit necessary for high-quality N-of-1 research.

Adoptive immunotherapy with third-party virus-specific T lymphocytes (VSTs) is effective against refractory viral infections. However, its long-term efficacy and persistence must be enhanced. T memory stem cells (TSCMs) with superior self-renewal and multilineage differentiation potential may enhance VSTs durability, although their antiviral capacity is underexplored. Cytomegalovirus (CMV)-and Epstein-Barr virus (EBV)-specific T cells are enriched with CD8⁺ TSCM through cytokine and peptide stimulation. Comprehensive preclinical evaluations show that purified TSCM-VSTs exhibit reduced exhaustion, enhanced expansion, and stronger antiviral activity than central or effector memory VSTs (TCM or TEM). Transcriptomic and epigenetic analyses show significant enrichment of the MAPK and Wnt signaling pathways, consistent with stem-like characteristics. In a murine model, CD8⁺ TSCM VSTs provide more effective protection against Raji-pp65 tumors than TCM or TEM VSTs. In a phase I clinical trial, 10 patients with refractory CMV or EBV infections post-transplant who received third-party, off-the-shelf TSCM-enriched VSTs show a 100% overall response rate and 70% complete response, with persistence up to 12 weeks and no severe adverse events. These findings support TSCM-enriched VSTs as a potent, scalable antiviral immunotherapy and highlight TSCM proportion as a critical determinant of VSTs efficacy.

Chemotherapy remains one of the principal treatment strategies in cancer treatment, is widely used but often limited by the development of chemoresistance and adverse side effects. This study aimed to develop highly effective chemotherapeutic agents with minimal or no adverse effects, specifically focusing on synthesizing a diisothiocyanatozinc(II) complex, [Zn(LCX)(NCS)₂], and evaluating its antineoplastic efficacy and host toxicity. The compound's in vitro anticancer activity was assessed against MCF7 cells using cell growth inhibition, apoptotic morphological observation, and gene expression analysis. In vivo antitumor properties of the compound were assayed in Swiss albino mice bearing EAC cells by monitoring key parameters such as tumor burden, survival rate, tumor cell proliferation, and hematological profiles. Toxicity was evaluated through biochemical, hematological, and histological assessments in mice. The compound demonstrated dose-dependent growth (11-85%) inhibition at 20-500µg/mL doses against MCF7 cells. Compound-treated cells showed apoptotic body formation under fluorescent and phase-contrast microscopes. Notably, mRNA expressions of proapoptotic genes such as p53, Bax, PARP1, Caspase-3, -8, -9, etc., were upregulated while anti-apoptotic genes such as Bcl2 were downregulated in compound-treated cells. Also, the compound showed 83% and 86% inhibition of tumor cell proliferation at doses of 100 and 200µg/kg/day, respectively, compared to the control group of EAC-bearing mice (p < 0.001). Mice treated with 200µg/kg/day showed a 60.3% increase in mean survival time compared to untreated controls (p < 0.001). Hematological parameters (RBC, WBC, hemoglobin), which were significantly reduced in EAC-bearing control mice, were restored to near-normal levels in treated mice. Transient alterations in hematological and biochemical parameters (serum glucose, cholesterol, creatinine, SGOT, SGPT) were observed during treatment; however, they normalized post-treatment, indicating minimal host toxicity. The compound also demonstrated a low LC50 value (7.734µg/mL) in the brine shrimp lethality bioassay, further confirming its pharmacological potential. The [Zn(LCX)(NCS)₂] complex demonstrated potent anticancer activity, followed by induction of apoptosis with minor host toxicity, positioning it as a viable option for advancement as an efficient chemotherapeutic agent. However, more research and clinical studies with animal and human models are needed to further develop the compound as a chemotherapeutic agent.

Personalized cancer vaccines represent a revolutionary frontier in oncology, harnessing the unique genetic and molecular profile of individual tumors to elicit targeted immune responses. This review provides a comprehensive overview of the current landscape and future perspectives of neoantigen-based personalized cancer vaccines, encompassing peptide, mRNA, DNA, autologous dendritic cell, and viral or bacterial vector platforms. We further discuss the integration of immune adjuvants, delivery systems, and combinational strategies, particularly with immune checkpoint inhibitions, to overcome tumor-induced immune exhaustion and improve therapeutic efficacy. Despite significant clinical progress over the past decade in this space, major challenges remain in immunogenic neoantigens prediction, streamlining individualized vaccine manufacturing, and optimization of combinational regimens to maximize durable antitumor responses. By reviewing recent preclinical and clinical studies on neoantigen-based cancer vaccines, this review highlights key advances, identifies persistent translational bottlenecks, and underscores the need for biomarker-guided mechanistically informed trials to fully unleash the clinical potential of neoantigen-based personalized cancer vaccines in the era of precision immuno-oncology.

Objectives: Hepatic arteries (HA) are an important source of blood supply to the liver and the biliary system. The HA is associated with anatomical variations that have implications for surgical procedures. The purpose of this study is to identify the HA variations on computed tomographic angiography imaging in patients presenting to a single tertiary care centre in Sri Lanka. The reported incidence of variations in the hepatic arterial anatomy varies from 20.0 % to 49.0%.Methods: This is a cross-sectional descriptive study. Patients undergoing computed tomographic scan (CT) of the abdomen with CT angiogram were included in this study. Data on the patient's age, gender, details on branching pattern variations of the HA were obtained. Incomplete records, images with artefacts, patients with pathologies distorting the hepatic arterial anatomy and the patients who have undergone previous interventions near the area of study were excluded from the analysis. HA variations were classified according to the Michael classification system. 100 images were included in the analysis.Results: There were 63 [63.0%] males and 37 [37.0%] females. The mean age was 49.8 years (17-100). 74 (74.0%) had type I (normal pattern) anatomy. HA variations were found in 26 (26.0%) images. The commonest variation observed was an accessory LHA in 12 (12.0%) followed by a replaced LHA in 7 (07.0%). The variations occurred in 7 females (7/37 - 18.9%) and 19 males (19/63 - 30.2%) however, this difference was not statistically significant (p-0.3168).Conclusions: This CTA-based study gives insight into the hepatic artery variations in the study population. This is likely to be the case with the Sri Lankan population. A countrywide study from multiple centres with a larger sample size is needed to know the actual pattern in Sri Lanka.

De novo malignancy is a significant complication following kidney transplantation, attributed to prolonged immunosuppression. This study evaluates the incidence, risk factors, and clinical outcomes of de novo malignancies in kidney transplant recipients. A retrospective cohort analysis was conducted on 1200 kidney transplant recipients between 2016 and 2023. Patients were categorized based on the presence or absence of de novo malignancies. Statistical analyses were performed to identify risk factors, including age, sex, comorbidities, and immunosuppressive regimens. Patient and graft survival were assessed using Kaplan-Meier analysis and the log-rank test. Among the study population, 43 patients (3.6%) developed de novo malignancies. The most frequent malignancy types were non-melanoma skin cancers (27.9%) and post-transplant lymphoproliferative disorders (18.6%). Patients with malignancies exhibited a lower three-year survival rate (83.7%) compared to those without malignancies (91.4%), though the difference was not statistically significant (p=0.067). Graft survival at three years was slightly lower in the malignancy group (84.0% vs. 88.7%, p=0.146). Older recipient age was identified as a significant risk factor (hazard ratio=1.03 per year, p=0.025). De novo malignancy remains a concern in kidney transplant recipients, particularly among older patients. Regular screening protocols, lifestyle interventions, and individualized immunosuppressive regimens are essential to mitigate risk and improve outcomes.

This review examines the role of indoxyl sulfate, a gut-derived uremic toxin, in the development of anemia in chronic kidney disease. It dissects the cellular and biochemical mechanisms through which indoxyl sulfate suppresses erythropoietin production, disrupts iron metabolism, and promotes oxidative stress and inflammation. Indoxyl sulfate interferes directly with the hypoxia-inducible factor pathway, thereby reducing the transcriptional activation of erythropoietin. In parallel, indoxyl sulfate-induced oxidative stress damages red blood cells and accelerates premature cell death, while its stimulation of pro-inflammatory pathways further downregulates erythroid progenitor cell function. Therapeutic strategies such as dietary protein modulation, gut microbiota interventions, oral adsorbents, and enhanced dialysis modalities have shown promise in lowering indoxyl sulfate levels and, consequently, improving erythropoietin responsiveness and iron homeostasis in chronic kidney disease patients. The review synthesizes evidence from clinical and experimental studies that position indoxyl sulfate as a central yet underappreciated mediator of anemia in chronic kidney disease. Indoxyl sulfate establishes a vicious cycle that exacerbates anemia and contributes to erytropoiesis-stimulating agent hyporesponsiveness. The article advocates for targeted interventions aimed at reducing indoxyl sulfate burden, which could transform anemia management in chronic kidney disease and pave the way for personalized treatment strategies.

Background Ribociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, occupies a pivotal role in the clinical management of metastatic breast cancer, with its hematologic and gastrointestinal toxicities well-established. However, cutaneous adverse reactions induced by this agent—among which vitiligo is particularly prominent—are extremely rare. Herein, we report a case of vitiligo-like lesions induced by ribociclib, aiming to elucidate this underrecognized drug-adverse reaction association and conduct an in-depth analysis of its potential immune-mediated mechanism. Case summary A 59-year-old woman with ER/PR (90% strong+), HER2-negative metastatic breast cancer developed pruritic hypopigmented patches on her forearms 16 months after initiating ribociclib/letrozole. Dermoscopy revealed complete pigment loss, peripheral hyperpigmentation, and telangiectasia. Wood’s lamp examination demonstrated bright blue-white fluorescence, confirming non-segmental vitiligo. No personal/family history of autoimmunity was noted. Topical 0.1% mometasone cream and 0.1% tacrolimus ointment were initiated, with stabilization of existing lesions and no new depigmentation at 2-month follow-up. Ribociclib was maintained due to ongoing tumor control. Conclusions HR-positive metastatic breast cancer patients using ribociclib may develop vitiligo, with individual differences (e.g., over one-year incubation as in this case). Combined with prior reports, it suggests a link between ribociclib and vitiligo. Further clinical observations and studies are needed to confirm causality, and pre-use risk explanations to patients are advisable.

Magnesium supplementation is regularly given to acutely ill patients with serum levels below the standard reference range, primarily for the prevention of tachyarrhythmias, such as atrial fibrillation. The evidence for this practice and the specific treatment thresholds used is limited. Conventional observational studies of this question are at risk of confounding by indication and other biases. To determine whether giving magnesium supplementation to patients with hypomagnesemia, as defined by a given institution's usual treatment cutoff, reduces adverse clinical outcome using a quasi-experimental study design that plausibly allows for causal inference. This nonrandomized clinical trial of intensive care unit (ICU) patients undergoing serum magnesium testing was conducted in 93 ICUs across the US and Europe between 2003 and 2022. A fuzzy regression discontinuity design was used, in which individuals just either side of the eligibility cutoff for magnesium supplementation were compared with regard to the study outcomes. This comparison was performed across a range of treatment cutoffs in current use, ranging from 1.6 mg/dL to 2.0 mg/dL. Data were analyzed from August to October 2025. Magnesium supplementation. The primary outcome was ventricular or supraventricular tachyarrhythmia in the 24 hours after magnesium testing. Secondary outcomes were the occurrence of hypotension or death. A total of 478 901 twenty-four-hour treatment windows from 171 727 ICU admissions were included in the study. A total of 72 767 admitted patients (42.4%) were female, 98 960 (57.6%) were male, and the mean (SD) age of the cohort was 63 (16) years. There was no evidence of an effect of magnesium supplementation on the occurrence of tachyarrhythmia, with a risk difference of 0.1% (95% CI, -4.2 to 6.9). This was true across all the cutoff levels evaluated. There was similarly no association with the occurrence of hypotension (risk difference, 1.2%; 95% CI, -0.9 to 17.7) or death (risk difference, 1.4%; 95% CI, -0.6 to 5.3). In this nonrandomized clinical trial, routine supplementation of magnesium with currently used doses and treatment thresholds was not associated with beneficial effects for individuals with serum magnesium values close to those cutoffs.

Background The risk-to-benefit ratio of using combined oral contraceptive pills (COCPs) and/or metformin for comprehensive management of polycystic ovary syndrome (PCOS) in women with obesity is unclear. As there is a lack of robust evidence on the impact of these first-line medications on cardiovascular disease (CVD) risk, we compared the effect of COCPs, metformin or both on prevalence of metabolic syndrome (MetS) in participants with hyperandrogenic PCOS and hypothesized that COCPs would increase prevalence of MetS while metformin would decrease prevalence of MetS. Methods and findings We conducted a multicenter, double-blind, double-dummy, randomized trial (COMET-PCOS) in participants between ages ≥18 and ≤40 years and body mass index (BMI) ≥25 kg/m 2 and ≤ 48 kg/m 2 with hyperandrogenic PCOS (defined by the Rotterdam criteria). Participants were randomized 1:1:1 to 24 weeks of low-dose COCPs (20 μg ethinyl estradiol/0.15 mg desogestrol), metforminXR (2,000 mg), or both (Combined). The primary outcome, assessed by intention-to-treat analysis, was the effect of the different treatment groups on the prevalence of MetS at the end of study. The analytical model included site, race, and the presence or absence of MetS at the screening visit as covariates. The secondary outcomes included changes in each component of MetS (TG, HDL-C, BP, WC, and fasting glucose levels) over the study period. Of the 240 participants randomly assigned, 20 out of 79 in the COCP group, 16 out of 81 in the metformin group, and 17 out of 80 in the combined group dropped out of the study. A total of 169 participants (70.4%) completed the trial between January 2018 and June 2023 (mean age: 29.5 years; mean BMI: 35.6 kg/m 2 ; 70% were White and 23% were Black). The overall prevalence of MetS was 31% at baseline and comparable across groups. At the end of the study, the prevalence of MetS was 26.2% (17/65) in the metformin group, 28.6% (17/59) in the Combined group, and 28.8% (17/59) in COCP group with no significant difference in trend of MetS prevalence between groups (adjusted p = 0.26). Waist circumference (mean change (MC) −2.23 cm; 95% CI [−3.98, −0.49]; p = 0.01), BMI (MC −0.49 kg/m 2 ; 95% CI [−0.88, −0.10[; p = 0.01), and android fat mass measured by DXA (MC −167 g; 95% CI [−264, −71[; p &lt; 0.001) decreased in the COCP group over the study period whilst there was no statistically significant changes in these parameters in the metformin only group when compared to baseline.. In the metformin and Combined groups, the majority of participants (&gt;64%) reported diarrhea, while 24.1% in the COCP group reported uterine bleeding. The main methodologic limitation of the study is the potential lack of power to detect differences in secondary outcomes. Conclusions In participants with hyperandrogenic PCOS and overweight/obesity, low-dose COCPs effectively managed PCOS symptoms without increasing prevalence of MetS. Our findings challenge the current practice of using metformin alone or with COCPs for lowering cardiometabolic risk. Trial registration ClinicalTrials.Gov Identifier: NCT03229057.

Improving actigraphy adherence among clinical trial participants with a real-time data-driven workflow