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PubMed2026

Harnessing Endogenous Plasticity Rather than Reprogramming of Mature Cells Will Advance Regenerative Medicine, Cancer Treatment and Rejuvenation.

The successful culture of human embryonic stem (hES) cells from inner cell mass cells of blastocyst stage 'spare' embryos in 1998, followed by induced pluripotent stem (iPS) cells in 2006, which allowed somatic cells to be reprogrammed to pluripotency using the Yamanaka factors, transformed regenerative biology and inspired extensive global efforts towards developing pluripotent stem cell-based applications. However, hES and iPS cells, as well as organoids generated from them, largely retain fetal-like characteristics, which limits their relevance for clinical translation. Concurrently, the prevailing assumption published in leading journals that adult tissues lack endogenous stem cells has led to the belief that mature cells dedifferentiate and reprogram during in vivo regeneration upon chronic injury, and that the appearance of embryonic/fetal markers in diabetes, heart failure, cancer, and many other chronic disease states reflects dedifferentiation of mature cells. We suggest that the prevailing concepts of dedifferentiation and reprogramming, both in vitro and in vivo, require careful re-evaluation. Adult somatic cells possibly do not truly dedifferentiate, neither in vitro nor in vivo. Instead, tissue-resident, pluripotent, very small embryonic-like stem cells (VSELs) in multiple organs account for the observed biology. In vitro "reprogramming" responses to Yamanaka factors likely reflect selective activation and expansion of VSELs/early progenitors rather than the dedifferentiation/ reprogramming of mature adult somatic cells. Likewise, the embryonic/fetal-like signatures reported in multiple disease states including cancer reflect expansion of immature tissue-specific progenitors that arise from VSELs but fail to differentiate normally due to a damaged microenvironment in vivo. Therapeutic strategies involving transplantation of MSCs, MUSE cells, or their secreted exosomes improve disease outcomes, possibly by restoring the damaged niche that supports functional tissue repair by VSELs. Although direct evidence to support this is lacking at present, recognising the central role of VSELs/progenitors and their niche in maintaining tissue homeostasis in vivo could resolve existing roadblocks and guide more effective endogenous regenerative therapies for diseased tissues and age-related dysfunctions.

Humans↗

PubMed2026

Molecular Landscape and Advanced Diagnostic Technologies for BRAF Mutations in Cancer: From Quantitative PCR and ddPCR to CRISPR-Based Platforms.

BRAF mutations are key oncogenic alterations across multiple malignancies, including melanoma, thyroid carcinoma, colorectal cancer, non-small cell lung cancer, glioma, and hairy cell leukemia. The most prevalent variant, BRAF-V600E, induces constitutive activation of the MAPK signaling pathway, promoting tumor progression and influencing therapeutic responsiveness. Accurate detection of BRAF alterations is therefore essential for molecular classification, prognostic assessment, treatment selection, and resistance surveillance. This review summarizes the molecular heterogeneity of BRAF mutations and critically evaluates current diagnostic methodologies. Conventional approaches such as allele-specific PCR and Sanger sequencing are compared with advanced quantitative platforms, including high-resolution melting analysis, droplet digital PCR, and next-generation sequencing, with emphasis on analytical sensitivity, mutation coverage, and clinical applicability. Emerging technologies such as CRISPR-based assays, rolling circle amplification systems, and nanoparticle-based biosensors and point-of-care diagnostic platforms are also discussed for their potential to enhance ultra-sensitive detection, particularly in liquid biopsy settings. These emerging tools are highlighted for their potential to enable ultra-sensitive, rapid, and decentralized mutation detection, particularly in liquid biopsy settings. Key challenges, including intratumoral heterogeneity, low allele-frequency variants, FFPE-associated artifacts, and clonal evolution under therapeutic pressure, are examined within a translational framework. In addition, we examine critical barriers to clinical implementation, including standardization, cost, and global accessibility of molecular diagnostics, and outline potential solutions through scalable technologies and decentralized testing strategies. We propose that optimal BRAF testing requires a mutation subclass-informed and clinically integrated strategy combining comprehensive baseline profiling with longitudinal molecular monitoring. Future diagnostic paradigms will likely integrate multi-omics data and artificial intelligence (AI)-assisted interpretation to refine precision oncology implementation. Looking forward, we propose that optimal BRAF testing will require integration of multi-omics profiling with AI-assisted interpretation, enabling automated variant classification, real-time clinical decision support, and improved prediction of therapeutic response and resistance.

Humans↗

PubMed2026

Effects of Transcranial Direct Current Stimulation and Individualized Physical Therapy on Pain and Function in Individuals With Chronic Knee Pain: A Pilot Study.

BACKGROUND AND PURPOSE: Noninvasive brain stimulation is a promising neuromodulatory intervention for chronic pain. This study aimed to determine the impact that transcranial direct current stimulation (tDCS) in combination with individualized physical therapy (PT) has on pain and function in individuals with chronic knee pain. METHODS: This study was a preliminary pragmatic, triple-blinded, randomized, and sham-controlled clinical trial performed in an outpatient orthopedic physical therapy clinic. Participants participated in 5 sessions of active or sham tDCS followed by individualized PT intervention. Pain outcomes included the Numeric Pain Rating Scale, Movement-Evoked Pain, pressure pain thresholds (PPT), and the Central Sensitization Inventory. Functional outcomes included the 2-minute walk test, 5-time sit-to-stand test, quadriceps strength, knee range of motion, Patient Specific Functional Scale, and the Lower Extremity Functional Scale. RESULTS: Thirty participants with chronic knee pain completed the study. There were no significant differences observed for primary patient-centered pain and functional outcomes. For secondary outcomes, the active tDCS group had a significant effect (p < 0.05) on percent change in lateral joint line PPT and a significant multivariate effect of group on PPT change scores for 3-site and 5-site clusters (p < 0.05). Exploratory responder analyses demonstrated that the active tDCS group was 12.8 times more likely to achieve the minimum detectable change in quadriceps strength improvement compared with the sham tDCS group (p < 0.05). DISCUSSION: There were no significant between-group differences for primary pain and functional outcomes. However, the active tDCS group showed improvements in pain sensitivity, as measured by PPT, and quadriceps strength, which were superior to those seen in the sham tDCS group. These preliminary findings provide insight into possible mechanisms of tDCS in addressing pain as opposed to efficacy. Given that there were no clear between-group differences in patient-centered outcomes, there is insufficient evidence for routine tDCS use for chronic knee pain. TRIAL REGISTRATION: NCT06132412.

Humans↗

PubMed2026

Pre-transport dietary chitosan improves the physiological robustness of juvenile largemouth bass (Micropterus salmoides) by modulating antioxidant and inflammatory responses.

The acute stress caused by long-distance transport can lead to oxidative damage, immune dysfunction, and health deterioration in fish. This study evaluated dietary chitosan as a pre-transport nutritional strategy for juvenile largemouth bass (Micropterus salmoides). Five experimental diets contained chitosan at 0, 2.5, 5.0, 7.5, or 10.0 g/kg, designated as p0, p25, p50, p75, and p100, respectively, for 56 d. The effects of dietary chitosan were evaluated using growth performance, feed utilization, digestive function, antioxidant capacity, nonspecific immunity, and resistance to Aeromonas hydrophila infection. Then, fish from the p0 and p50 groups underwent a 12-h transport stress test, with samples collected before, during, and 7 d after transport. Dietary chitosan improved most of these parameters. Among the treatment groups, p50 and p75 showed the best overall performance. The dose-response analysis further indicated that the appropriate dietary inclusion range was 5.0-7.5 g/kg. Under transport stress, fish in the p50 group exhibited more stable antioxidant enzyme responses and lower lipid peroxidation, as indicated by reduced MDA levels. Consistent with these enzyme responses, antioxidant-related genes remained relatively stable. At the same time, expression patterns related to the Nrf2-Keap1 and NF-κB signaling pathways suggested that 5.0 g/kg chitosan alleviated transport-induced oxidative damage and inflammation. Dietary chitosan also attenuated pro-inflammatory gene induction and altered the temporal expression patterns of anti-inflammatory genes. Overall, 5.0-7.5 g/kg dietary chitosan is suitable for juvenile largemouth bass, and 5.0 g/kg may serve as an effective pre-transport dietary inclusion level.

Animals↗

PubMed2026

The Impact of Chatbot Type and Normative Messaging on Chatbot Usage Intention Based on the Health Technology Acceptance Model: Randomized Controlled Trial.

BACKGROUND: Digital health tools, such as health chatbots, may improve access to scalable health support, but adoption remains inconsistent. Existing models do not fully integrate technology acceptance factors with health motivation factors relevant to digital health use. OBJECTIVE: This study proposed and tested the health technology acceptance model and examined whether normative message framing and chatbot type were associated with health motivation, technology acceptance, and intention to use a health chatbot. METHODS: In October 2025, we conducted a 4 × 2 between-participants online experiment with 1000 US adults recruited from a nationally representative YouGov panel. Participants were randomized to 1 of 8 conditions varying norm message type (self-oriented, peer-oriented, expert-oriented, or family-oriented) and chatbot type (AI-powered or rule-based) in a cancer prevention and genetic risk information scenario. Outcomes included descriptive norms, injunctive norms, perceived susceptibility, perceived severity, perceived benefits, self-efficacy, perceived ease of use, trust, privacy concerns, and usage intention. Data were analyzed using a multivariate ANOVA with Bonferroni-adjusted post hoc tests and multiple linear regression. RESULTS: Peer-oriented and family-oriented messages produced higher usage intention than expert-oriented messages, and peer-oriented messages also increased descriptive norms, injunctive norms, self-efficacy, and trust. AI-powered chatbots were associated with higher usage intention (P=.02) and greater trust (P=.008) than rule-based chatbots. In regression analyses, the model explained 50.8% of the variance in usage intention. Usage intention was positively associated with descriptive norms (β=0.087; P=.003), injunctive norms (β=0.078; P=.009), perceived susceptibility (β=0.051; P=.03), perceived benefits (β=0.253; P<.001), and trust (β=0.33; P<.001), and negatively associated with perceived severity (β=-0.047; P=.049) and privacy concerns (β=-0.11; P<.001). Perceived ease of use and self-efficacy were not significant predictors. CONCLUSIONS: The health technology acceptance model was a useful framework for explaining the intention to use a health chatbot by combining technology acceptance and health motivation constructs. Both social design features and chatbot design features shaped adoption-related beliefs, with peer-oriented and family-oriented framing and AI-powered chatbots showing particular promise. Trust and privacy concerns remained central determinants of intended use.

Humans↗

PubMed2026

High-dose radiotherapy in patients with high-risk prostate cancers treated with long-term androgen deprivation therapy (GETUG AFU 18): a randomised, phase 3 trial.

BACKGROUND: For patients with high-risk prostate cancer, the role of dose-escalated radiotherapy in combination with long-term androgen deprivation treatment (ADT) is controversial, without any demonstrated benefit on cancer-specific or overall survival. We aimed to evaluate the effect of a 10 Gy dose increase, from 70 Gy to 80 Gy, on progression-free survival in men with high-risk prostate cancer. METHODS: In this multicentre, open-label, randomised, phase 3 trial, we enrolled patients with high-risk prostate cancer, defined as prostate-specific antigen of 20 ng/mL or more, Gleason score of at least 8, or clinical stage T3-T4, from 25 centres in France. Participants were randomly assigned (1:1) by minimisation, stratified by centre and previous pelvic lymph node dissection, to receive prostate-targeted dose-escalated external beam radiotherapy (80 Gy; 2 Gy per fraction for 8 weeks) or standard-dose external beam radiotherapy (70 Gy; 2 Gy per fraction for 7 weeks), combined with long-term ADT. Neither the participants nor the investigators were masked to the allocated treatment. The primary endpoint was 5-year progression-free survival defined as the time from randomisation to first biochemical (defined as prostate-specific antigen >nadir plus 2 ng/mL) or clinical (ie, local, regional, or metastatic) disease progression, analysed in the intention-to-treat population, with 197 events required. 5-year progression-free survival was the prespecified endpoint, and 10-year progression-free survival was additionally reported (post hoc) in view of the low number of events at 5 years. The trial is registered at ClinicalTrials.gov, NCT00967863, and is complete. FINDINGS: Between April 6, 2009, and Jan 24, 2013, 505 patients with high-risk prostate cancer were enrolled; 250 were assigned to receive dose-escalated radiotherapy (80 Gy) and 255 to receive standard dose radiotherapy (70 Gy). All participants were male and ethnicity data were not collected. At a median follow-up of 9·5 years (IQR 8·5-10·3), 5-year progression-free survival was 91·4% (95% CI 87·0-94·4) in the dose-escalation group versus 88·1% (83·2-91·6) in the control group, and 10-year progression-free survival was 83·6% (77·8-88·0) versus 72·2% (65·3-78·0; stratified HR 0·56, 95% CI 0·40-0·78, p<0·0001). Grade 3 or worse adverse events assessed at 6 months (acute toxicity) were observed in 60 (24%) of patients in the dose-escalation group and 62 (25%) in the control group. The most frequent grade 3 or worse adverse events were sexual disorders (28 [11%] in the dose-escalation group vs 20 [8%] in the control group) and bladder or urethra disorders (12 [5%] vs 19 [8%]). Adverse events assessed at 5 years (late toxicity) occurred in 118 (70%) of 168 in the dose-escalation group and 122 (73%) of 168 in the control group; grade 3 or worse late toxicities occurred in 19 (8%) participants in the dose-escalated radiotherapy group versus 17 (7%) participants in the control group. The most common late grade 3 adverse event was bladder or urethra disorders (seven [4%] vs three [2%], respectively). Serious adverse events occurred in nine (4%) patients in the dose escalation group and nine (4%) in the control group; none were considered to be treatment related. There were no treatment-related deaths. INTERPRETATION: For patients with high-risk prostate cancer, radiotherapy at a total dose of 80 Gy, in combination with long-term ADT, improved progression-free survival and could be a potential option in this situation. However, given the low number of events, further research is needed to consolidate and confirm the benefit in dose-escalation in prostate cancer-specific survival and overall survival. FUNDING: French National Cancer Institute and AstraZeneca.

Aged↗

PubMed2026

Distinct functions of mammalian RAD51 paralogs in genome maintenance.

RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) are evolutionarily conserved essential proteins for cell survival and genome maintenance. RAD51 paralogs were originally identified to play a role in homologous recombination-mediated repair of DNA double-strand breaks (DSBs). However, investigations over the last decade have uncovered new roles of RAD51 paralogs beyond DSB repair in replication stress responses, including replication fork progression, fork stability, and its restart. Recent structural studies have not only uncovered the molecular architecture of previously known RAD51 paralog complexes but also identified novel paralog complex assemblies, providing mechanistic insights into their various genome-maintenance functions. Additionally, a role for RAD51 paralogs in resolving R-loops has been identified, and studies with cancer-associated variants suggest that RAD51 paralogs are potential determinants of cancer susceptibility and therapeutic responses. In the present review, we highlight the recently deciphered structures and novel functions of RAD51 paralog complexes and discuss the clinical and therapeutic implications.

Rad51 Recombinase↗

PubMed2026

Biomarker Analysis from Patients with Metastatic PDAC Treated with TGFβ Antibody NIS793 plus Abraxane + Gemcitabine versus Abraxane + Gemcitabine Alone in a Phase II, Open-Label, Randomized Study.

PURPOSE: Transforming growth factor β (TGFβ) plays a dual role in cancer, acting as a tumor suppressor early in the disease but promoting progression and immune evasion when dysregulated. In pancreatic ductal adenocarcinoma (PDAC), TGFβ-driven desmoplasia fosters chemoresistance and immunosuppression, limiting therapeutic efficacy. NIS793, a fully human mAb targeting TGFβ, demonstrated antifibrotic and immunomodulatory activity in preclinical models and early-phase trials. PATIENTS AND METHODS: We conducted a randomized, open-label, phase II study in treatment-naïve patients with metastatic PDAC (mPDAC) to evaluate NIS793 ± spartalizumab (anti-PD-1) combined with nab-paclitaxel (or Abraxane)/gemcitabine (ABRA/GEM) versus ABRA/GEM alone. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), safety, pharmacokinetics, and biomarker analyses. Exploratory assessments included paired tumor RNA sequencing, cell-free DNA profiling, and plasma proteomics. RESULTS: NIS793 demonstrated target engagement and suppression of TGFβ signaling, confirmed by transcriptomic and proteomic analyses. Stromal remodeling was evident, with significant downregulation of cancer-associated fibroblast markers (Acta2, Fap) and collagen-related signatures. Despite proof of mechanism, clinical efficacy was not observed: Median PFS and OS were comparable or numerically worse in the NIS793 arm versus control (HR for OS in NIS793 + ABRA/GEM vs. ABRA/GEM: 1.32; 95% confidence interval, 0.84-2.07). The safety profile was manageable, with no unexpected toxicities. Biomarker data revealed increased expression of neutrophil-related genes after treatment, suggesting potential induction of tumor-promoting inflammation. CONCLUSIONS: NIS793 effectively inhibited TGFβ signaling and led to stromal remodeling but failed to improve outcomes in mPDAC. These findings highlight the complexity of TGFβ biology and caution against its blockade in combination with chemotherapy for PDAC. Future strategies should consider context-dependent effects of TGFβ inhibition.

Humans↗

PubMed2026

Safety Profile of the Non-steroidal Anti-inflammatory Drug Celecoxib in the Short-Term Management of Acute Non-cancer Pain: A Systematic Review with Meta-analysis of Randomised Controlled Trials.

OBJECTIVE: To summarise the literature regarding the safety of short-term use of the non-steroidal anti-inflammatory drug (NSAID) celecoxib. STUDY DESIGN: Systematic review with meta-analysis of randomised trials. Participants comprised individuals of all ages with acute non-cancer pain. Interventions included celecoxib at 200-400 mg/day for up to 10 days. The comparators were placebo, other NSAIDs (including cyclooxygenase-2 [COX-2] inhibitors and non-selective NSAIDS [nsNSAIDS]), or opioids. DATA SOURCES: Five databases were searched from inception to April 2025: Embase, Web of Science, MEDLINE, Cochrane Central Register of Controlled Trials, and Scopus. Additionally, a registry was searched: ClinicalTrials.gov. DATA SYNTHESIS: Meta-analyses using Mantel-Haenszel and random-effects model were used to calculate risk ratios (RRs) and 95% confidence intervals (CIs) for severe cardiovascular, respiratory, and gastrointestinal adverse events and secondary outcomes. The Cochrane Risk of Bias Tool for randomised trials (RoB-2) was used to assess bias risk. The Grading of Recommendation Assessment, Development and Evaluation (GRADE) was conducted to assess the certainty of evidence of each reported outcome. RESULTS: Title/abstract and full text screening comprised 3976 and 273 studies, respectively. Fifty studies were included with 10,693 participants. The RRs for adverse events were no different between celecoxib and placebo for severe events (3 studies) (RR 0.44 [95% CI 0.10-2.03]), cardiovascular (3 studies) (RR 0.84 [95% CI 0.24-2.92]), respiratory (4 studies) (RR 1.23 [95% CI 0.29-5.26]), and gastrointestinal events (33 studies) (RR 0.96 [95% CI 0.64-1.43]). There was no difference between celecoxib and NSAIDS for gastrointestinal adverse events, RR 0.89 (95% CI 0.68-1.17). Celecoxib had a lower risk compared to opioids for gastrointestinal events, RR 0.34 (95% CI 0.14-0.86), and showed a lower risk of nausea compared with placebo, RR 0.75 (95% CI 0.60-0.93), and nsNSAIDS, RR 0.80 (95% CI 0.64-0.99). Most studies had some risk of bias concerns, and the overall certainty of evidence for most outcomes was very low. Celecoxib appears to be safe for acute non-cancer pain when compared to placebo, NSAIDS, and opioids. It had a lower risk compared to opioids for gastrointestinal adverse events in general, nausea and vomiting, as well as a lower risk for nausea adverse events when compared to placebo and nsNSAIDS. REGISTRATION: PROSPERO-CRD42025642152.

Journal Article↗

PubMed2025

The Association Between Child Maltreatment and Quality of Life: A Systematic Review and Meta-Analysis.

The association between child maltreatment (CM) and quality of life (QoL) has been widely examined in the past decade. In this study, we estimated the association between CM and QoL using a systematic review and meta-analysis. Articles were searched up to May 15, 2024, in both English databases (Web of Science, EMBASE, CINAHL, PsycINFO & PsycArticles, MEDLINE, Cochrane Library, PubMed, and Scopus) and Chinese databases (CNKI, Weipu, and Wanfang). The meta-analysis was performed by a random-effects model, using 43 studies comprising 130,884 participants. This study demonstrated that general CM had an adverse impact on QoL and its sub-dimensions, including physical, mental, psychosocial, and environmental QoL. Further analysis showed that the subtypes of CM also had negative impacts on the dimensions of QoL, except for mental QoL. Emotional maltreatment had stronger negative associations with QoL than other subtypes of CM, while neglect received relatively less attention. In addition, the association between CM and QoL was moderated by region, gender ratio, and measurement methods. The findings of this study suggest that CM is negatively associated with QoL. Future studies need to investigate the impact of neglect on QoL and develop tailored programs to improve the QoL of people who have suffered from CM.

Humans↗

PubMed2026

Dosimetric Parameters of the Heart and Its Substructures in Predicting Cardiac Events or Survival in Patients With Lung Cancer After Radiation Therapy: A Systematic Review and Meta-analysis.

The predictive value of radiation dose to the whole heart (WH) and cardiac substructures (CS) for cardiac events (CEs) and survival in patients with lung cancer remains uncertain. The goal of this study was to conduct a systematic review and meta-analysis to provide an evidence-based estimate of the relationship between these associations. A systematic meta-analysis was performed following PRISMA guidelines. Risk of bias was assessed using the JBI Critical Appraisal Checklist for Case Series. Outcomes were classified into major adverse cardiac events (MACE), arrhythmias, pericardial effusion, and survival. Depending on heterogeneity, random- or fixed-effects models were applied to calculate pooled hazard ratios (HRs) for univariable and multivariable analyses. A total of 80 studies, including 21,645 patients, were analyzed. Of these, 25 studies reported CEs, and 69 reported survival outcomes. Among 91 WH and 215 CS parameters evaluated, several showed significant associations. Key findings from our meta-analysis include: (1) left anterior descending (LAD) V15 was significantly associated with MACE. The mean heart dose (MHD), as well as ventricle and LAD doses, were significantly associated with ischemic events. (2) Multiple CS parameters were associated with different arrhythmia subtypes. (3) MHD, heart V5/V35/V55 and pericardial doses were significantly associated with pericardial effusion. (4) MHD was significantly associated with survival; CS parameters also showed predictive value, and especially, heart base dose being the most significant. (5) We also identified several thresholds with potential predictive values, such as LAD V15 <10% for MACE, left pulmonary vein (LPV) V55 <2%, and right pulmonary vein (RPV) V10 <54% for atrial fibrillation (AF), right atrium (RA) V60 <0.03 cc for non-AF supraventricular tachyarrhythmia, and left main artery (LMA) V10 ≥1 cc for bradyarrhythmia. This study identified 130 WH and CS dosimetric parameters associated with CEs and 131 with survival outcomes. These findings enhance our understanding of radiation-induced heart injury mechanisms and provide guidance for potential protective and intervention strategies.

Humans↗

PubMed2025

Systematic meta-analysis of the toxicities and side effects of the targeted drug lenvatinib.

BACKGROUND: Lenvatinib, an effective targeted drug for various cancers, has clinical medication safety concerns due to its toxicities and side effects. OBJECTIVE: This study evaluated lenvatinib-induced any adverse events (any AEs) and nine aspects: vascular toxicities related to the circulatory system (vascular toxicities, blood system, and heart), toxicities of the skin and its appendages (skin/subcutaneous tissue and taste system), toxicities of the respiratory system (respiratory, thoracic, and mediastinal and respiratory tract), toxicities of the nervous system (nervous system and general), toxicities of the digestive system (gastrointestinal and liver), toxicities of the urinary system, toxicities of the endocrine and metabolic system (endocrine and metabolism/nutrition), toxicities of the musculoskeletal system, and other severe toxicities. Toxicities and side effects were stratified by severity into any and ≥3 grades for analysis. PATIENTS/MATERIALS AND METHODS: Multiple databases were searched for lenvatinib cancer clinical studies (cohort studies and randomized controlled trials) from inception to December 31, 2024; toxicity and side effect data were extracted and analyzed. RESULTS: Nine high-quality studies were included, showing that lenvatinib is effective in cancers but has notable toxicities. Taking hypertension as an example, for any grade, the risk ratio (RR) was 2.34 with a 95% confidence interval (CI) of [2.09, 2.62], a Z-value of 14.74, and a P-value <0.00001; for grade ≥3, the RR was 2.60 with a 95% CI of [2.21, 3.06], a Z-value of 11.44, and a P-value <0.00001. CONCLUSION: Lenvatinib is effective for cancer but toxic, and this study supports its rational clinical use.

Humans↗

PubMed2026

Ribosomal protein S3: a critical regulator of human disease mechanisms.

Ribosomal protein S3 (RPS3) is an essential structural component of the 40S ribosomal subunit, yet growing evidence highlights crucial extraribosomal roles in genome maintenance, cell-cycle control, and immune signaling. Dysregulation of RPS3 contributes to diverse human disorders, including cancer, inflammatory diseases, neurodegeneration, and resistance to antimicrobial and anticancer therapies. As a cofactor of NF-κB and a participant in DNA damage responses, RPS3 occupies a node that integrates stress signaling with transcriptional reprogramming, enabling both protective and pathological outcomes. The present review critically evaluates mechanistic insights into RPS3 biology, emphasizing recent findings that delineate its context-dependent effects, discrepancies across models, and remaining gaps that restrict translational applications. Understanding these complexities is essential to assess RPS3's potential as a biomarker and therapeutic target.

Humans↗

PubMed2026

The effect of monetary versus point-based rewards on effort-cost decision making in individuals at clinical high risk for psychosis.

OBJECTIVE: The dissemination of inexpensive computerized behavioral tasks indexing amotivation may enhance the assessment of clinical high risk (CHR) across settings. However, the impact of varying reward value in such tasks is unclear. If point-based rewards engage participants, this could improve the scalability of computerized assessments. We tested how point-based rewards versus money impacted effort-cost decision-making in CHR individuals. We further assessed how negative symptom severity and household income interacted with reward-type to impact behavior. METHODS: Participants completed the Effort Expenditure for Reward Task (EEfRT). Participants were randomly assigned to receive either money or points for their performance during the EEfRT. Data from a large sample of CHR (N = 233) individuals and healthy controls (HC; N = 157) were collected. RESULTS: Across diagnostic groups, we observed heightened effort expenditure when money was used as a reward (b = 0.13, p = 0.018). We did not find an interaction of CHR status (b = 0.07, p = 0.845) or negative symptoms (b = 0.01, p = 0.429) with reward-type. Within CHR individuals, heightened negative symptom severity was associated with reduced expended effort (b = -0.03, p = 0.016), regardless of reward type. In an exploratory analysis, we found that individuals in the money condition with relatively high household income expended less effort during high reward, high probability trials (b = -0.24, p = 0.046). CONCLUSIONS: Across CHR and HC individuals, individuals pursuing money expended greater effort. While we did not find a group by reward type interaction, CHR individuals with heightened negative symptom severity expended less effort across trials, replicating prior work. Present findings support further study of point-based rewards in tasks indexing amotivation.

Humans↗

PubMed2026

Artificial intelligence in genitourinary oncology: publication trends and systematic review.

OBJECTIVE: To conduct an analysis of publication trends and a systematic review of randomized controlled trials (RCTs) to characterize the current state of artificial intelligence (AI) use in genitourinary (GU) oncology, as AI has emerged as a transformative tool in healthcare with potential applications in diagnostics, treatment planning, and prognostication. METHODS: We searched the Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE; Ovid), and Cumulative Index to Nursing and Allied Health Literature (CINAHL) Ultimate for studies related to AI and GU oncology, excluding non-English papers, non-human studies, review articles, and articles using AI solely for manuscript writing. Publication trends were analysed from 2013 to 2023 and categorized by study design and cancer type. RCTs were evaluated through systematic review using Covidence (Veritas Health Innovation Ltd, Melbourne, Victoria, Australia) for screening and data extraction. Two reviewers independently assessed all studies, with risk of bias (RoB) evaluated using the Cochrane RoB 2.0 tool. RESULTS: Of 2409 articles identified, 1220 met inclusion criteria. These included 962 retrospective articles, 175 prospective studies, 79 studies with combined retrospective/prospective methods, and four RCTs. Studies most commonly addressed prostate (n = 923), renal (n = 274), and urothelial (n = 194) cancers. Publications grew from 14 in 2013 to 362 in 2023, with substantial acceleration in 2019. Four RCTs were identified - one in urothelial cancer and three in prostate cancer. Two RCTs evaluated AI-based diagnostics, demonstrating improved performance over conventional methods; the remaining two RCTs evaluated AI in prognostication and treatment planning, showing improved gains in imaging interpretation and operational efficiency. RoB varied across studies, primarily related to randomisation and deviations from intended interventions. CONCLUSIONS: Artificial intelligence research in GU oncology has grown, although high-level evidence from RCTs remains limited. Existing trials underscore AI's promise in diagnostics, prognostication, and treatment planning, and the rapidly evolving nature of this field warrants continued prospective investigation.

Humans↗

PubMed2026

A novel neoadjuvant immunotherapy confers improved overall survival in oral cancer patients with low tumor PD-L1 expression The IT-MATTERS Clinical trial - Prognostic role of tumor PD-L1 expression.

OBJECTIVE: Five-year overall survival (OS) remains < 50% for patients with resectable, locally advanced (LA) primary oral squamous cell carcinoma (OSCC) and soft palate, receiving current standard of care (SOC). The aim of our study was to examine neoadjuvant Leukocyte Interleukin Injection (LI) with CIZ (intravenous low dose cyclophosphamide, indomethacin and zinc multivitamins) effect on OS, in low-risk (LR) OSCC patients. PATIENTS AND METHODS: In a randomized, controlled Phase 3 trial, treatment-naïve locally advanced patients, with stage III/IVa OSCC and soft-palate cancer, had surgical tumor samples assessed for pre-defined thresholds of PD-L1 tumor proportion score (TPS). OS was analyzed using proportional hazard models for LI + CIZ + SOC vs SOC, in the intention-to-treat (ITT) population. RESULTS: OS was superior in low risk (LR) patients receiving LI + CIZ + SOC compared to SOC; OS advantage hazard ratio (HR) 0.64, p = 0.0569 (without selecting for N0, PD-L1 TPS < 10%), and the Kaplan-Meier (K-M) lifetable achieved significance (log rank p = 0.0340) favoring LI + CIZ + SOC vs SOC. Applying the selection criteria (cN0 and TPS < 10%) to ITT, OS reached HR 0.34p = 0.0012, Kaplan-Meier log rank p = 0.0015. The ITT LR cohort (cN0 and TPS < 10%) achieved a HR 0.26 (p = 0.0023), Kaplan-Meier log rank p = 0.0013, supported by progression free survival (PFS) HR 0.43, p = 0.0178, Kaplan-Meier log rank p = 0.0431, with 32% absolute survival advantage over control at 60 months. CONCLUSIONS: Significant OS prolongation was observed in ITT population for LI + CIZ + SOC vs SOC, in LR and in ITT LR cN0, PD-L1TPS < 10% cohort having locally advanced squamous cell carcinoma tumors in oral cavity/soft-palate. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01265849; EudraCT (Identifier: 2010-019952-35).

Humans↗

PubMed2026

Functions of tandem-repeat galectins and domain coordination governs galectin-4 activity in grass carp (Ctenopharyngodon idella).

Galectins are β-galactoside-binding lectins that play essential roles in innate immunity. Among them, tandem-repeat galectins (TrGals), typically composed of two distinct carbohydrate-recognition domains (CRDs) connected by a linker peptide, are well established as key regulators of pathogen recognition and host defense in mammals. However, their structural diversity and immunological functions in teleost fish remain poorly understood. In this study, five TrGals (Gal-4, Gal-8a, Gal-8b, Gal-9, and Gal-9like) were identified in grass carp. Sequence and structural analysis revealed that Gal-8a/b, Gal-9, and Gal-9like possess the canonical two-CRD architecture, whereas Gal-4 uniquely contains four highly similar tandem-repeat domains. All five TrGals were broadly expressed across examined tissues, with predominant expression in the liver. Upon Aeromonas hydrophila infection, Gal-4, Gal-8a, Gal-8b, and Gal-9 were rapidly up-regulated at early time points (3-6 h). To elucidate the functional significance of CRD number, recombinant full-length CiGal-4 (CiGal4-full) and three truncated variants containing one, two, or three CRDs (CiGal4-1CRD, CiGal4-2CRD, and CiGal4-3CRD) were generated and systematically characterized. All recombinant proteins contained the conserved β-sheet structure typical of galectin CRDs. Functional assays revealed that CiGal4-full displayed the strongest growth-inhibitory activity against all tested bacteria, whereas CiGal4-1CRD showed the weakest effect. Notably, CiGal4-2CRD exhibited the most potent bactericidal activity, surpassing the full-length protein, while CiGal4-3CRD showed no further enhancement. CiGal4-full and CiGal4-2CRD showed superior carbohydrate-binding activities compared with the other variants. Collectively, these results reveal that CRD copy number alone does not linearly determine galectin function. Instead, domain organization and conformational coordination are critical for optimizing antimicrobial activity. This study provides new insights into the structure-function relationships and evolutionary diversification of galectins in teleosts and highlights their potential as novel antimicrobial and immunomodulatory agents in aquaculture.

Animals↗

PubMed2026

HPV circulating tumor DNA as a potential prognostic and predictive biomarker in head and neck squamous cell carcinoma: a systematic review.

PURPOSE: Human papillomavirus circulating tumor DNA (HPVctDNA) has emerged as a promising prognostic biomarker in HPV-related head and neck squamous cell carcinoma (HNSCC). This systematic review aimed to synthesize current evidence on the diagnostic accuracy and prognostic value of HPVctDNA in HNSCC management. MATERIAL/METHODS: We systematically reviewed a PubMed-indexed database of studies published between January 2012 and September 2025. Eligible studies were assessed for design, primary tumor site and stage, treatment modality, HPVctDNA detection method, diagnostic accuracy (sensitivity and specificity), and reported clinical endpoints. Descriptive syntheses were performed; sensitivity and specificity were standardized to proportions and summarized as median values per group. RESULTS: A total of 60 studies, including 8,234 patients were analyzed, of which 41 (68.3%) focused exclusively on oropharyngeal squamous cell carcinoma (OPSCC) and 17 (28.3%) included mixed HPV-related HNSCC subsites and HPV-positive cancers of unknown primary. The median follow-up across the included studies was 23 months. Among the included studies, 19 were retrospective (31.7%) and 33 were prospective (55.0%), with a small proportion of cross-sectional and randomized clinical trials. Overall, 40 (66.7%) evaluated the role of HPVctDNA in a curative setting. Plasma was the most common sample type, analyzed in 55 studies (91.7%), while 5 studies also included saliva. Detection methods varied: 40 employed droplet digital PCR (ddPCR), 16 used quantitative PCR (qPCR) and 4 applied NGS-based assays. Most of these studies (38, 63.3%) evaluated the prognostic utility of HPVctDNA, while only 4 (6.7%) assessed HPVctDNA in a screening or diagnostic setting. Regarding diagnostic accuracy, the median sensitivity across evaluable studies was 91.1%, while the median specificity was 99.4%. In OPSCC-only cohorts, the median sensitivity and specificity were 89.4% and 99.4%, respectively. Dynamic changes in HPVctDNA levels during or after treatment were consistently associated with outcomes: clearance or sustained negativity correlated with higher response rates, improved progression-free survival and overall survival, while persistent positivity or increasing levels predicted disease progression and recurrence. CONCLUSIONS: HPVctDNA demonstrates high diagnostic and prognostic accuracy in HPV-related HNSCC, especially OPSCC, supporting its use for prognosis, treatment monitoring and early detection of recurrence. However, prospective interventional studies are still required to demonstrate that HPVctDNA-guided treatment decisions improve clinical outcomes before routine implementation.

Humans↗