Highly effective second-line treatments for hepatocellular carcinoma remain an unmet need. The GOING investigator-initiated Phase I/IIa trial evaluated regorafenib plus nivolumab (add-on) in patients who progressed on sorafenib (Cohort-A) or discontinued atezolizumab-bevacizumab (Cohort-B). Patients received regorafenib for two 28-day cycles, adding nivolumab in cycle 3, until unacceptable adverse events, symptomatic progression, withdrawal or death. Primary endpoint was safety. Secondary endpoints included overall survival, time to progression, post-progression survival, objective response rate and incidence of new-extrahepatic-spread. Of 85 patients screened, 67 were enrolled (75.5% BCLC-C). All experienced adverse events and 9% led to discontinuation. Severe treatment-related adverse events occurred in 28.4% overall, 32.1% in Cohort-A, and 14.3% in Cohort-B. Median overall survival was 20.0 (95% CI 11-37) months, with 40.6% survival at 36 months. In Cohort-A, median overall survival was 25 (95% CI 14-39) months with 45% survival at 36 months, while Cohort-B median overall survival was 8 (95% CI 4-NE) months with 28.6% survival at 24 months. Objective response rate was 16.4%; median time to progression and post-progression survival were 5 (95% CI 4-9) months and 14 (95% CI 8-33) months. Intrahepatic growth was the most common progression pattern, followed by new-extrahepatic-spread. The add-on strategy of regorafenib plus nivolumab in second-line had manageable safety and significant clinical activity with a noteworthy median overall survival of 20 months. Among those progressing on sorafenib, 45% were alive at 3 years. These findings support further evaluation with mechanism-guided trials after progression on immunotherapy. EudraCT number: 2019-003108-10; https://www.clinicaltrialsregister.eu.

Integration of various sources of information for prediction of disease progression is an unmet need in glaucoma diagnostics. We designed a deep learning-based prognostic model incorporating clinical and structural data for forecasting functional glaucoma progression and compared its performance to clinicians. Retrospective, comparative cohort study of prognostic accuracy. We included 1599 eyes (908 patients) with definite or suspected glaucoma with ≥5 24-2 visual fields (VF) and 3 or more years of follow-up. VF mean deviation (MD) rates of change were estimated with linear regression. Sequential MD rates of change were estimated with each series spanning only 5 years of follow-up. VF progression was declared when four sequential statistically significant negative MD slopes were observed, and slope for the entire follow-up was significant. A convolutional neural network pretrained on ImageNet was designed to predict VF progression using baseline clinical and demographic data, disc photographs, and optical coherence tomography-derived global and sectoral retinal nerve fiber layer and macular thickness measurements. In addition, average intraocular pressure and treatment information during follow-up were put into the model. The same data for a subset of patients was provided to two clinicians to independently predict future progression. The model was validated on a separate cohort of eyes in which optical coherence tomography imaging was done with a different device (291 eyes). Model's area under receiver operating characteristic curves (AUC), accuracy, and area under the precision and recall curves. Average (SD) baseline MD and number of VF exams were -3.5 (4.9) dB and 10.1 (4.7). 399 eyes (25%) deteriorated. The best-performing model incorporated baseline disc photographs, and retinal nerve fiber layer and macular thickness: AUC, 0.839 (0.771-0.906), accuracy, 76.0% (62.0%-85.0%), and area under the precision and recall curves, 0.558 (0.385-0.733). Deep learning model significantly outperformed clinical graders (AUC : 0.629 [0.531-0738], P < .001 and 0.680 [0.584-0.776], P = .001, for grader one and two, respectively). Model performance was similar on the validation cohort (AUC: 0.754 [0.671-0.837], and accuracy: 77% [71%-82%], respectively, P = .122). The model performed well when predicting fast-progression, defined as MD rate <-1.0 dB/y (AUC: 0.869 [0.792-0.947]). Our newly designed deep learning model can combine baseline demographic and clinical data with widely available structural measurements and provide clinically relevant information for the prediction of glaucoma progression.

Personalizing radiotherapy dose in breast cancer remains a major unmet need, as current treatment paradigms rely on uniform prescriptions that overlook interpatient variability in intrinsic radiosensitivity. Over the past decade, transcriptome-based biomarkers such as the Radiosensitivity Index (RSI) and its radiobiological extension, the Genomic-Adjusted Radiation Dose (GARD), have emerged as promising tools capable of quantifying this biological heterogeneity and linking it to expected therapeutic effectiveness. Retrospective clinical studies across diverse breast cancer cohorts have consistently demonstrated that RSI and GARD correlate with locoregional control, identify radioresistant subgroups that may benefit from dose escalation, and reveal radiosensitive tumors for which de-escalation may be safely explored. These findings challenge the assumption that radiation response is uniform within histological or molecular subtypes and highlight the opportunity for biologically tailored dosing. Yet despite early evidence, translation into clinical practice remains limited. Key barriers include the absence of prospective validation, heterogeneous analytic pipelines for RNA sequencing and RSI computation, uncertainty regarding optimal biomarker timing in the neoadjuvant era, and sensitivity of bulk transcriptomic assays to spatial and microenvironmental heterogeneity. Addressing these challenges will require standardization, consensus on clinically meaningful GARD thresholds, and coordinated international efforts to define methodological and regulatory pathways. Emerging approaches in radiomics, digital pathology, and multimodal artificial intelligence may further refine radiosensitivity assessment and reduce reliance on invasive sampling. As the field progresses, genomic personalization of radiotherapy has the potential to transform breast cancer management by replacing one-size-fits-all prescriptions with biologically informed dose adaptation aimed at maximizing tumor control while minimizing toxicity.

Epstein-Barr virus-positive post-transplant lymphoproliferative disorder (EBV + PTLD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-SCT). Given evolving transplantation practices, updated data are needed. Multicenter analysis of PTLD epidemiology, clinical characteristics, and outcomes in Spain. Retrospective study across 17 Spanish transplant centers including all proven/probable EBV+ PTLD cases after allo-SCT from January 2000 to June 2023. Among 14.568 allo-SCTs, 170 PTLD cases were identified (1.2%) peaking in 2010-2017 (2.0%), versus 0.9% in 2000-2009 and 0.7% in 2018-2023. Median onset was 91 days; 75% occurred within 6 months. Proven cases comprised 67%, mostly diffuse large B-cell lymphoma. Advanced stage occurred in 67%, extranodal disease in 22%. Rituximab ± immunosuppression reduction (ISR) was given to 80%, yielding a 62.4% response rate. Responders had superior survival (2-year OS 73.4% vs. 10.7%). EBV-specific cellular therapies were infrequently used. Median follow-up was 97.8 months; 5-year OS 39.6%, with PTLD causing 49% of deaths. Severe hypoalbuminemia, lack of ISR, and rituximab refractoriness predicted worse survival. EBV + PTLD frequency has declined in Spain. Prognosis remains poor for rituximab non-responders, highlighting limited access to EBV-specific cellular therapies as an unmet need.

Ophiopogonis japonicus polysaccharide inhibits oxidative stress in hepatocytes by promoting Runx3 in nonalcoholic fatty liver disease.

Mechanistic insights and therapeutic interventions of mitochondrial quality control in chemotherapy-related cognitive impairment.

Ultra-thin elastin-based membranes as an innovative dressing to enhance skin wound healing.

Therapeutics and vaccines involving mRNA have shown significant progress over the last five years. These lipid nanoparticle-based formulations introduce substantial analytical complexity, as multiple Quality Attributes (QAs) must be monitored to ensure product efficacy, stability, and safety. Encapsulation efficiency (EE) and mRNA integrity are particularly critical, yet current analytical approaches often require separate assays, challenging sample handling, and limited selectivity toward free versus encapsulated species. Therefore, new chromatographic methods capable of resolving these species and supporting multi-payload formulations remain a major unmet need. To rapidly obtain multiple QAs for mRNA-LNP formulations, we present an optimized two-dimensional liquid chromatography (2D-LC) workflow combining anion-exchange chromatography (AEX) in the first dimension (1D) and ion-pair reversed-phase liquid chromatography (IP-RPLC) in the second dimension (2D). The 1D-AEX evaluated encapsulation efficiency of mRNA within lipid nanoparticles based on the mRNA ratio of intact and disrupted drug products, while 2D-IP-RPLC assessed integrity profiles and mRNA-lipid adducts. Attention was paid to the 2D optimization to eliminate solvent incompatibilities and ensure efficient transfer between dimensions. This approach enables simultaneous determination of EE, mRNA integrity, mRNA-lipid adducts, and transcript ratios in multi-payload mRNA-LNP formulations. It also provides chromatographic assessment of free mRNA integrity within formulations. This method furthermore enables the characterization of additional species and confirms the presence of surface-associated mRNA. The workflow demonstrates good selectivity and applicability to both mono- and multi-payload mRNA-LNP products. Overall, the developed 2D-LC platform is a powerful analytical tool for comprehensive mRNA-LNP characterization. By enabling simultaneous assessment of several critical QAs, including EE, integrity, transcript ratios, and mRNA-lipid adducts, it streamlines analytical workflows and reduces reliance on multiple independent assays. This approach provides mechanistic insight into LNP structure, including detection of surface-associated RNA species, and establishes an innovative tool to support formulation development, process optimization, drug products release, and stability studies for next-generation mRNA vaccines and therapeutics.

Discovery of novel indole derivatives as LRH-1 antagonists for the treatment of castration resistant prostate cancer.

Oral disorders are among the most prevalent diseases globally, yet their burden in Southeast Asia remains poorly characterized. Understanding regional patterns is critical for health planning and prevention. We analysed data from the Global Burden of Disease 2021 study to assess the prevalence, incidence, and disability-adjusted life years of oral disorders across the 10 Association of Southeast Asian Nations (ASEAN) member states from 1990 to 2021. Indicators were age-standardized and analysed by sex, age, country, and socio-demographic index. Oral disorders accounted for nearly half of all-cause prevalence and around 1% of total disease burden in 2021. From 1990 to 2021, prevalent cases rose by over 50% and incident cases by more than 30%, while age-standardized rates showed slight declines. Population growth and ageing were the primary drivers of these increases. Caries of permanent teeth contributed the largest share, followed by periodontal disease and edentulism. Higher socio-demographic index correlated with lower overall burden but a higher proportion of periodontal disease. These findings indicate that oral health remains a major source of morbidity across ASEAN despite modest epidemiologic improvement. Demographic pressures continue to offset gains from prevention and care. Expanding prevention and primary oral healthcare - including sugar reduction, fluoridation, and sealant or varnish programs - could substantially reduce disability and unmet need. Routine regional surveillance using harmonized indicators is essential to guide equitable policy and investment within the post-2025 ASEAN health agenda.

Mitigating loss of lean muscle in GLP-1 and dual GLP-1/GIP agonists: Pipeline opportunities and limitations.

PKM2 from hyperactive neuron aggravate lung injury post-stroke by promoting FOXO3A/TXNIP mitochondria translocation in mice.

Neveskin from Ferula samarcandica exerts anti-gastric cancer effects via the Hippo-YAP signaling pathway.

Respiratory syncytial virus (RSV) is the leading cause of respiratory infections in infants, young children, and elderly people worldwide. Developing a safe and broadly effective vaccine remains a critical and unmet public health need. This study comparatively evaluated the immunogenicity and protective efficacy of respiratory syncytial virus (RSV) mRNA vaccines expressing a modified G protein extracellular domain (Gecto), delivered via either lipid nanoparticle (LNP) or lipid-polymer hybrid (LPP) platforms. Both RSV Gecto-mRNA elicited robust humoral and cellular immunity in mice. Although the humoral immunity in both groups showed a Th2 bias, the advantage of the LNP platform lies in its ability to simultaneously trigger potent humoral and Th1-type cellular immunity. Comparing the two groups, The LNP group elicited a stronger Th1-biased cellular response, manifested by high expression of cytokines such as IL-2 and TNF-α in CD4+T cells, and the production of higher neutralizing antibody titers against A/B subtypes of RSV strains than the LPP group,which elicited slightly higher Th2 bias IgG antibody titers. Viral challenge confirmed that both groups provided effective cross-protection against RSV A2 and B9320, significantly reducing lung viral load and histopathology, with comparable protective efficacy.These findings demonstrate that both platforms enabled robust delivery of the RSV Gecto-mRNA vaccine and generated cross-protective immunity, albeit with divergent response characteristics. These results inform the selection of RSV vaccine delivery platforms aimed at distinct immune correlates of protection.

Cognitive impairments and negative symptoms (NS) represent an unmet therapeutic need in psychotic disorders. Both NS and cognitive impairments, are key predictors of functioning. Both also appear during the illness prodrome, highlighting their relevance to the etiology of psychosis. Cross-sectional and longitudinal links between NS and cognition have been established, suggesting a common underlying foundation. Thus, investigating the relationship between cognition and NS is particularly relevant, especially given the clinical fluctuations seen in the early stages of psychosis and the marked cognitive deficits present throughout the illness. The following study aims to investigate the longitudinal relationship between NS and cognition and whether, over the first two years following psychosis onset, 1) NS influences cognition, 2) cognition influences NS, or 3) the relationship is bidirectional. We used data from the Recovery After an Initial Schizophrenia Episode Early Treatment Program (2010-2014). Participants underwent early treatment intervention, with assessments at baseline, 12, and 24months using the Brief Assessment of Cognition in Schizophrenia and the Positive and Negative Syndrome Scale (n=404). Random intercept cross-lagged panel models, which consider the temporal sequence of effects, were created to model the relationship between cognition and NS through the three timepoints over two years. We found a unidirectional relationship- declines in cognitive function predicted increased NS severity, while NS did not predict future cognitive function. This suggests that cognitive deficits may contribute to the development or exacerbation of NS. These findings underscore the role of cognition on NS trajectories and open new avenues for early psychosis treatments.

A meta-analysis of the intervention effect of cognitive behavioral therapy on adult ADHD.

Pimicotinib versus placebo for tenosynovial giant cell tumour (MANEUVER): an international, randomised, placebo-controlled, phase 3 trial.

Objective Suicidal ideation and planning affect ∼10.6 million and 3.1 million adults in the United States annually, respectively, with sexual minority individuals experiencing disproportionately higher rates. Despite greater mental health service utilization, sexual minority individuals experience greater unmet need due to additional barriers to care, including stigma and a lack of practitioner cultural competency, compared to heterosexual individuals. Unmet need for mental health services is a known risk factor for suicidal ideation, planning, and attempts, and may contribute to disparities in suicidality between heterosexual and sexual minority individuals. The current study aims to explore how unmet need and service utilization interact with sexual orientation in relation to past-year suicidal ideation and planning. Method Using a cross-sectional nationally representative sample of 41,806 respondents, the current study used logistic regression to examine past-year suicidal ideation and planning in relation to sexual orientation, unmet need, reasons for unmet need, service utilization, and the interactions between sexual orientation and both unmet need and service utilization. Results Results indicated that sexual minority status, unmet need, and service utilization were independently associated with higher odds of suicidal ideation and planning. Interaction analyses revealed that sexual minority individuals were more likely than heterosexual individuals to report suicidal ideation and planning among those with unmet need or service utilization. Conclusions These findings suggest that factors beyond service access, such as stigma, may contribute to suicidal outcomes among sexual minority individuals, highlighting the need for tailored interventions addressing their specific barriers.

Depression in both bipolar and major depressive disorder remains a major unmet need due to treatment resistance to the existing treatments. Emerging evidence implicates the renin-angiotensin system in regulating the cellular stress response relevant to depression, suggesting it as a novel therapeutic target for depression. Candesartan, a common hypertension medication, decreases neuroinflammation, oxidative and nitrosative pathway activation, and neurotrophic signalling of angiotensin II by predominantly blocking the angiotensin II type 1 receptors (AT1R). Given AT1R-induced activities are implicated in the pathophysiology of bipolar and major depressive disorder and with supportive pharmacoepidemiology data, candesartan may represent a novel antidepressant strategy. The CADET Trials are 2 parallel 16-week double-blind randomized placebo-controlled trials of adjunctive candesartan (or placebo) for the treatment of bipolar depression (CADET-BD) and major depressive disorder (CADET-UD). Each trial aims to recruit 240 adult participants. The primary outcome is the between-group (ie, intervention vs. placebo) differential change from baseline to week 16 in depression symptoms as measured by the Montgomery Åsberg Depression Rating Scale. Secondary outcomes measure depression, mania, anxiety, quality of life, cost-effectiveness, functioning, substance use, cognition, and biological markers. Findings are not yet available as the trial is ongoing. The CADET Trials examine the efficacy of candesartan in reducing depressive symptoms in both unipolar and bipolar depression, and whether its effects are mediated through the renin-angiotensin system. Candesartan is affordable, accessible, and well-tolerated. If effective, it could quickly be adopted into clinical practice as a new adjunctive medication for the treatment of these disorders.

Constipation affects about 25% of the general population, with higher prevalence in elderly people. Many of the products used for the treatment of constipation, laxatives and drugs with this indication have undesirable effects such as dehydration, electrolyte disturbances and diarrhea or side effects that, in frail patients with comorbidities, such as the elderly, can have clinically significant consequences. For these reasons, the treatment of chronic constipation constitutes, especially in the elderly patient, a partial unmet medical need. This interventional, single-arm pilot study evaluated efficacy and safety of a probiotic-prebiotic combination in elderly patients with chronic constipation. The probiotics included Lactobacillus rhamnosus, Lactobacillus paracasei, Bifidobacterium animalis ssp. lactis, and Bifidobacterium breve. Treatment lasted 28 consecutive days. Fifty elderly patients (average age 65.3 years) with chronic constipation participated. At baseline, 72% of patients reported ≤2 complete spontaneous bowel movements (CSBM) per week. After the treatment, 36% of patients reported ≤2 CSBMs/week (P=0.023), 64% experienced improvement of 1-4 CSBMs/week. Quality of Life (QoL) related to abdominal pain, bloating, and constipation improved. No adverse events were reported. This real-world study suggests that probiotic-prebiotic combinations can rapidly improve bowel transit and constipation symptoms, potentially reducing dependence on laxatives and enemas while improving QoL. A longer-term randomized controlled trial is needed to confirm these findings.