Vitamin B3 (Niacinamide)

Chronic pruritus is a distressing condition associated with various dermatological and systemic diseases, significantly impairing patients' quality of life. While conventional treatments such as antihistamines and corticosteroids offer relief, their efficacy varies, and long-term use may lead to adverse effects. Emerging evidence suggests that certain vitamins, including vitamin D, vitamin E, vitamin B12, and niacinamide (B3), may play a role in alleviating pruritus through their anti-inflammatory, immune-regulatory, and skin barrier-enhancing properties. However, the effectiveness of these vitamins in managing chronic pruritus remains unclear. This meta-analysis aims to update and expand the evaluation of vitamin supplementation in reducing pruritus severity across different underlying conditions, extending the scope beyond vitamin D to include vitamins B and E. A comprehensive search was performed across PubMed, Embase, Web of Science, and Cochrane Library databases up to January 2025 to identify randomized controlled trials (RCTs) evaluating the effects of vitamin supplementation on chronic pruritus. A total of 21 RCTs (n = 1723) were included in the meta-analysis. Compared to placebo, vitamin supplementation demonstrated a significant reduction in pruritus severity (Standardized Mean Difference [SMD]: -0.578, 95% CI: -0.736 to -0.419, p = 0.000; I2 = 53.630, p = 0.003). Subgroup analysis revealed that topical vitamin B12 and vitamin D3 showed the most pronounced antipruritic effects, particularly in patients with atopic dermatitis and chronic kidney disease-associated pruritus. Sensitivity analysis confirmed the robustness of the findings; however, potential publication bias was suggested by Egger's regression test (p = 0.00979), indicating that the overall effect may be influenced by small-study effects or underreporting of negative results. This meta-analysis indicates that vitamin B, D, and E supplementation may serve as effective adjunct therapies for managing chronic pruritus. However, the variability among the included studies highlights the necessity for well-structured, long-term RCTs to determine the ideal dosage, treatment duration, and target pati

INTRODUCTION: Sarcopenia is associated with the loss of skeletal muscle function and mass. Nicotinamide precursors, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), have received attention for their potential to improve NAD+ levels and mitigate age-related sarcopenia in preliminary models, though evidence on their effects in older adults remains inconclusive. METHODS: We searched PubMed, Cochrane Library, Web of Science, and Scopus to identify randomized controlled trials (RCTs), comparing NR or NMN vs. placebo. A random-effects meta-analysis was employed to determine their impact on measures of sarcopenia such as skeletal muscle index (SMI), handgrip strength (HGS) and gait speed. A narrative synthesis was used for 5-time chair stand test (5CST), short physical performance battery (SPPB), timed-up-and-go (TUG), 6-min walking distance (6MWD), leg and chest press 80% 1RM (repetition maximum) and thigh muscle mass. RESULTS: Included participants had a mean age range from 60.9 to 83 years. NMN supplementation showed no significant effects on SMI (n = 3; mean difference (MD): -0.42, 95% confidence interval (CI): -0.99 - 0.14, I2 = 63%, p = 0.14), HGS (One study estimating left grip; n = 5; MD: 0.61, 95%CI: -0.89 - 2.10, I2 = 0%, p = 0.42; One study estimating right grip; n = 5; MD: 0.45, 95%CI: -1.06 - 1.96, I2 = 0%, p = 0.56), gait speed (n = 4; MD: -0.01, 95%CI: -0.08 - 0.06, I2 = 0%, p = 0.79), or 5CST (n = 2; MD: -0.21, 95%CI: -0.70 - 0.29, I2 = 11%, p = 0.41). Additionally, our narrative synthesis showed that NMN did not improve knee extension strength, SPPB, or thigh muscle mass. NR supplementation was associated with a longer 6MWD among individuals with peripheral artery disease. However, lower scores in the SPPB and slower 5CST were observed in those with mild cognitive impairment. CONCLUSIONS: Current evidence does not support NMN and NR supplementation for preserving muscle mass and function in adults with mean age of over 60 years. Future research should explore supplementation dosage, NAD+ baseline deficiency, and combined interventions. © 2025 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodic

BACKGROUND: Nicotinamide is the active form of vitamin B3 (niacin) obtained through endogenous synthesis, mainly through tryptophan metabolism and dietary supplements, fish, meats, grains, and dairy products. It participates in cellular energy metabolism and modulates multiple cellular survival and death pathways. Nicotinamide has been widely studied as a safe chemopreventive agent that reduces actinic keratosis (AKs) and non-melanoma skin cancers (NMSC). METHODS: We used the Medline, EMBASE, PubMed, and Cochrane databases to search the concepts "nicotinamide", "chemoprevention", and "skin cancer" up to August 2023. Three independent authors screened titles and abstracts for intervention and study design before searching full texts for eligibility criteria. The primary outcome was the impact of oral nicotinamide on the incidence of NMSC in high-risk patients. We also conducted a systematic search to identify relevant epidemiological studies published evaluating dietary niacin intake and the risk of NMSC. RESULTS: Two hundred and twenty-five studies were reviewed, and four met the inclusion criteria. There was no association between NAM consumption and risk for squamous cell carcinoma (SCC) (rate ratio (RR) 0.81, 95% CI 0.48-1.37; I2 = 0%), basal cell carcinoma (BCC) (RR 0.88, 95% CI 0.50-1.55; I2 = 63%), and NMSC (RR 0.82, 95% CI 0.61-1.12; I2 = 63%). Adverse events were rare and acceptable, allowing optimal compliance of patients to the treatment. We found only one article evaluating the association between niacin dietary intake and NMSC risk, supporting a potential beneficial role of niacin intake concerning SCC but not BCC or melanoma. CONCLUSIONS: The present meta-analysis shows, by pooling immunocompetent and immunosuppressed patients, that there is insufficient evidence that oral nicotinamide therapy significantly reduces the number of keratinocyte cancers.

OBJECTIVE: Sorafenib, an oral vascular endothelial growth factor receptor tyrosine-kinase inhibitor, has become a cornerstone in the treatment of various malignancies. However, concerns have arisen regarding the risk of hemorrhage with sorafenib use. Nevertheless, the contribution of sorafenib to hemorrhage and the underlying risk factors remains unclear. MATERIALS AND METHODS: We performed a meta-analysis to determine the incidence and risk of hemorrhage associated with sorafenib treatment. Multiple databases were searched to identify relevant studies. The analysis included randomized controlled trials (RCTs) that directly compared cancer patients treated with or without sorafenib. Statistical analyses were conducted to determine the overall incidence, relative risks (RRs), and 95% confidence intervals (CIs) using fixed- or random-effect models. RESULTS: Ten RCTs involving 4720 patients were included in the analysis. Overall, the incidence rates of all- and high-grade hemorrhage in patients receiving sorafenib were 9.89% (95% CI: 8.73-11.18%) and 2.86% (95% CI: 2.25-3.63%), respectively. Sorafenib treatment increased the risk of all-grade hemorrhage in patients compared to control treatment (RR: 1.99; 95% CI: 1.59-2.49; P < 0.00001), but did not increase the incidence of high-grade hemorrhage (RR: 1.42; 95% CI: 0.95-2.12; P = 0.09). Subgroup analysis showed no significant increase in the risk of hemorrhage between patients with various malignancies or concurrent treatment. No evidence of publication bias was observed. CONCLUSION: In patients with malignancy, sorafenib treatment combined with standard treatment significantly increases the risk of low-grade hemorrhagic events.

CONTEXT: Nicotinic acid and nicotinamide are soluble compounds of the vitamin B group, widely used to regulate the lipid profile in hyperlipidemic individuals. Higher doses of nicotinic acid are associated with adverse effects, especially flushing. A unique tolerable upper intake level (UL) of nicotinic acid has not been defined. OBJECTIVE: This meta-analysis aims to evaluate adverse effects and their incidence after supplementation with different doses of nicotinic acid and nicotinamide, comparing results with current ULs in Europe and the United States. DATA SOURCES: PubMed was searched for articles providing detailed information about nicotinic acid or nicotinamide supplementation and related outcomes. STUDY SELECTION: A total of 2670 citations were selected for screening. Two primary outcomes were considered: occurrence of adverse effects following nicotinic acid or nicotinamide supplementation, and dose at which adverse effects occurred. DATA EXTRACTION: Details on study population, type and duration of treatment, dosage of vitamins, association with lipid-influencing drugs, length of follow-up, and incidence and type of adverse events were extracted. RESULTS: After screening, 47 articles involving 11 741 individuals were included. Meta-analysis was based on estimation of benchmark doses for the probability of adverse effects after supplementation. In individuals with dyslipidemia or cardiovascular disease, nicotinic acid monotherapy seems to be protective against any adverse effects considered, as adverse events occurred at doses above those used with other treatments. In healthy individuals treated with nicotinic acid alone, major adverse effects occurred at doses below 1000 mg/d. CONCLUSIONS: Results may indicate a high degree of conservativeness in the UL of nicotinic acid, fixed at 35 mg/d in United States and 10 mg/d in Europe. Reconsideration of the UL of nicotinic acid for nutritional supplements, possibly differentiating between ULs in healthy and unhealthy individuals, may be warranted. © The Author(s) 2017. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-

BACKGROUND: Friedreich's ataxia is a rare, chronic, progressive, neurodegenerative condition affecting multiple organ systems, including neurological, musculoskeletal, cardiac, and endocrine systems, and is marked by low cardiopulmonary fitness. We tested the effect of exercise and NAD+ precursor supplementation with nicotinamide riboside, which have each shown benefits in animal and early clinical studies, on cardiopulmonary fitness in individuals with Friedreich's ataxia. METHODS: This 12-week, outpatient, phase 2, single-site (Children's Hospital of Philadelphia, Philadelphia, PA, USA), randomised, 2 × 2 factorial clinical trial recruited individuals aged 10-40 years with an ejection fraction of 45% or greater who were able to exercise. A computer-generated randomisation sequence was developed by the trial statistician. Random allocation was age-stratified (<18 years vs ≥18 years) to one of four groups: placebo and no exercise with attention control (weekly phone calls; henceforth placebo only), nicotinamide riboside and no exercise with attention control (henceforth nicotinamide riboside only), placebo and exercise (exercise only), and nicotinamide riboside and exercise (combination therapy). Individualised exercise plans were developed by the exercise physiologist (three aerobic and two resistance training sessions weekly), performed at the individual's home, and overseen remotely (telephone check-ins by the physiologist). Weight-based dosing of nicotinamide riboside or placebo was 300 mg (1 capsule) for weights of 24 kg up to 48 kg, 600 mg (2 capsules) for weight 48 kg up to 72 kg, and 900 mg (3 capsules) for weights of over 72 kg. The primary outcome was change in peak VO2 (L/min) during cardiopulmonary exercise testing at 12 weeks versus baseline, and the effect of treatment group was assessed in a statistical model accounting for age (stratification variable), sex, and baseline peak VO2. Stage 1 analysis tested the difference between each active treatment versus the control group, and stage 2 analysis (if combination therapy was effective) tested the difference between combination treatment and exercise alone; family-wise type 1 error was maintained <0·

Nicotinamide adenine dinucleotide (NAD(H)) and its phosphorylated form NADP(H) are vitamin B3-derived redox cofactors essential for numerous metabolic reactions and protein modifications. Various health conditions are associated with disturbances in NAD+ homeostasis. To restore NAD+ levels, the main biosynthetic pathways have been targeted, with nicotinamide (Nam), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) being the most prominent boosters. However, while many preclinical studies have examined the effects of these precursors, a direct comparison in humans is lacking, and recent rodent research suggests that the NAD+-boosting effects of NR and NMN may depend on their microbial conversion to nicotinic acid (NA), a mechanism not yet confirmed in humans. Here we show in a randomized, open-label, placebo-controlled study in 65 healthy participants that 14 days of supplementation with NR and NMN, but not Nam, comparably increases circulatory NAD+ concentrations in healthy adults. Unlike the chronic effect, only Nam acutely and transiently affects the whole-blood NAD+ metabolome. Using ex vivo fermentation with human microbiota, we identify that NR and NMN give rise to NA and specifically enhance microbial growth and metabolism. We further demonstrate ex vivo in whole blood that NA is a potent NAD+ booster, while NMN, NR and Nam are not. Ultimately, we propose a gut-dependent model for the modes of action of the three NAD+ precursors with NR and NMN elevating circulatory NAD+ via the Preiss-Handler pathway, while rapidly absorbed Nam acutely affects NAD+ levels via the salvage pathway. Overall, these results indicate a dual effect of NR and NMN and their microbially produced metabolite NA: a sustained increase in systemic NAD+ levels and a potent modulator of gut health. ClinicalTrials.gov identifier: NCT05517122 . © 2026. The Author(s).

AIM: Evaluation of the efficacy of Cytoflavin in the correction of mild cognitive disorders in patients with chronic brucellosis. MATERIALS AND METHODS: A total of 40 patients with inactive forms of chronic brucellosis who sought medical care were examined, including 17 men (42.5%) and 23 women (57.5%), with an average age of 46.4±3.7 years. In Group 1 patients received intravenous infusions of Cytoflavin for 10 days as a neuroprotector, and in Group 2 - "active placebo" (100 ml of 0.9% sodium chloride solution). STUDY DESIGN: open-label, randomized, comparative, random sampling. RESULTS: It has been established that inactive forms of chronic brucellosis are accompanied by damage to the nervous system with the development of mild (predementia) cognitive impairment and deterioration in quality of life. In the group of patients receiving Cytoflavin, there was a statistically significant decrease in the severity of neurological deficit, a significant increase in the total score of the MoCA test, and a statistically significant improvement in the indicators of both physical and psychological health components according to the scales of the SF-36 questionnaire. No side effects were recorded during the use of Cytoflavin in the patients of the study group, which indicates good tolerability of the drug. CONCLUSION: The prescription of a course of infusion neuroprotective therapy with Cytoflavin contributes to a significant clinical improvement in patients with inactive chronic brucellosis with significant positive dynamics of cognitive functioning parameters assessed using MoCA testing and health indicators according to the SF-36 questionnaire. Publisher: Цель. Оценить эффективность препарата Цитофлавин в коррекции легких когнитивных расстройств у пациентов с хроническим бруцеллезом (ХБ). Материалы и методы. Обследованы 40 пациентов с неактивными формами ХБ, обратившихся за медицинской помощью, из них 17 (42,5%) – мужчины, 23 (57,5%) – женщины, средний возраст которых составил 46,4±3,7 года. Все пациенты с их согласия проконсультированы психиатром. После выявления нейрокогнитивных сдвигов и диагностирования «легких когнитивных расстройств в связи с другими вирусными и

BACKGROUND AND AIMS: Recent preclinical studies have shown that nicotinamide adenine dinucleotide (NAD+) plays a critical role in molecular mechanisms of axon degeneration, and reductions in NAD+ levels are associated with axonal degeneration. Nicotinamide riboside (NR) is a safe and widely available pyridine-nucleoside form of vitamin B3 and is an NAD+ precursor. METHODS: To investigate if oral supplementation of synthetic NR can act as a therapeutic agent to prevent degeneration of small somatic sensory axons innervating the skin or promote regeneration of these same fibers in humans, we utilized a validated experimental model of cutaneous nerve degeneration and regeneration and conducted a placebo-controlled, double-blinded Phase 2 study. RESULTS: NR supplementation did not result in elevation of plasma NAD+ levels but resulted in a small increase in NAD+ in the skin samples. NR supplementation did not prevent capsaicin-induced degeneration of the epidermal sensory nerve fibers, and there was no difference in the amount of epidermal reinnervation at the 90-day visit. Although there was a small but statistically significant increase in the number of epidermal sensory nerve fibers at the 60-day visit, these results are preliminary and will need to be validated in larger studies. INTERPRETATION: At present oral NR supplementation, at the doses used in this study, cannot be recommended to prevent neuropathy or to improve nerve regeneration. © 2026 Peripheral Nerve Society.

INTRODUCTION AND OBJECTIVES: Dermocosmetics have proven their benefit in acne management. However, only very few studies investigated their efficacy kinetics. This study assessed the efficacy kinetics of a dermocosmetic cream (DC) containing Punica granatum Pericarp extract, Salicylic acid, Niacinamide, Zinc gluconate, and Aqua Posae Filiformis in subjects with acne. MATERIAL AND METHODS: 16 subjects (14 women, 2 men; mean age 29.4 ± 7.7 years; phototype II and III) with mild to moderate acne participated in a randomized, intra-individual, split-face study for 15 days. Hemi-faces randomly received DC or remained untreated. Assessments included lesion counts, acne severity, and local tolerance; subjects also rated the perceived benefit of the DC. Efficacy was also evaluated using standardized multi-modality full-face imaging and a mobile connected imaging system. RESULTS: The inflammatory lesion count significantly (p ≤ 0.05) decreased with DC at Day 8 and Day 15; a significant decrease of the non-inflammatory lesion count was observed at Day 15 (p < 0.01). The total lesion count had significantly (p ≤ 0.05) decreased with DC at Day 8 and Day 15. Between-side differences were significant (all p ≤ 0.05) for all lesion types at D15. Local tolerance was good. Most subjects considered that their skin appearance and the visibility of acne lesions had improved. CONCLUSION: This exploratory study provides strong evidence on the efficacy kinetics of a DC cream in acne management in subjects with fair skin tones. It shows that early, daily and specific treatment with a targeted DC significantly improves all acne lesions type, as well as acne severity as soon as 15 days. © 2026 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.

Comment in Blood. 2026 Mar 26;147(13):1384-1386. doi: 10.1182/blood.2025032327. Many patients receiving frontline tyrosine kinase inhibitors (TKIs) for chronic-phase chronic myeloid leukemia (CML-CP) experience inadequate disease control and/or adverse events (AEs) that impair quality of life. Treatments offering optimal efficacy, safety, and tolerability will support long-term therapy. In the primary analysis from the ASC4FIRST trial, a phase 3 randomized trial comparing asciminib with investigator-selected TKIs (IS-TKIs) in newly diagnosed CML-CP, asciminib demonstrated superior efficacy vs all IS-TKIs and vs imatinib in the imatinib stratum, meeting both primary objectives. In the secondary analysis (2.2 years' median follow-up), major molecular response (MMR) rate at week 96 was 74.1% with asciminib vs 52.0% with IS-TKIs (treatment difference, 22.4% [95% confidence interval (CI), 13.6-31.3]; 1-sided P< .001) and 76.2% with asciminib vs 47.1% with imatinib in the imatinib stratum (treatment difference, 29.7% [95% CI, 17.6-41.8]; 1-sided P< .001), meeting both key secondary objectives. MMR rate was 72.0% with asciminib vs 56.9% with second-generation (2G) TKIs (treatment difference, 15.1% [95% CI, 2.3-28.0]; 1-sided P< .05), suggesting possible clinical benefit, although the study was not designed to formally confirm statistical significance for this secondary end point. Safety/tolerability remained favorable with asciminib vs IS-TKIs. Dose reductions and interruptions, respectively, occurred with asciminib (18.5%; 46.5%), imatinib (23.2%; 47.5%), and 2G TKIs (54.9%; 63.7%). The hazard ratio for time to discontinuation of treatment due to AEs for asciminib vs 2G TKIs was 0.46 (95% CI, 0.215-0.997). With longer follow-up, asciminib continued to demonstrate a favorable benefit-risk profile over IS-TKIs and imatinib, supporting its potential as a treatment option for newly diagnosed CML-CP. This trial was registered at www.clinicaltrials.gov as NCT04971226. © 2026 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, n

BACKGROUND: Current methods to evaluate therapeutic response in patients with hepatocellular carcinoma (HCC) rely on tumor size and density, which do not always correlate well with survival. We used pretreatment clinical and radiomics variables to predict overall survival (OS) in the randomized phase III CALGB 80802 (Alliance) trial, investigating the efficacy of sorafenib + doxorubicin versus sorafenib alone. MATERIALS AND METHODS: Using machine learning, we analyzed baseline and first follow-up computed tomography (CT) images and associated clinical metadata from patients imaged in February 2010-May 2015, up to November 2015 with follow-up. Adult patients with HCC (n = 129) were randomly assigned to training (n = 92) and validation (n = 37) sets. We assessed the performance of a signature combining CT imaging features and clinical variables using hazard ratios to estimate OS after week 10 (first follow-up). RESULTS: Most patients were male (86.6%) and had bilirubin <2 mg/dl (98.4%), albumin >3.5 g/dl (69.0%), and moderately differentiated HCC (34.1%). Median (interquartile range) age: 58 years (63-71 years), alpha-fetoprotein (AFP): 2.5 ng/ml (26-282 ng/ml), international normalized ratio: 1 (1.1-1.2), Child-Pugh score: 5 (5-6). The highest-performing parsimonious training set signature combined clinical and radiomics features at baseline and week 10. In the validation set, the hazard ratio was 2398 (95% confidence interval 121-47 371) (P < 0.001). The signature's variables, ranked by importance, included baseline clinical features [albumin (1), AFP (2), Child-Pugh (4)], baseline radiomics features [component 17 (3), component 1 (5), component 9 (7), tumor volume (8)], and week 10 radiomics features [delta tumor volume (6)]. CONCLUSION: OS can be accurately predicted in patients with HCC receiving sorafenib by combining certain radiomics features with clinical metadata, centered primarily on baseline characteristics.

Melasma is a common hyperpigmentary skin disorder. Because of its high prevalence and serious complications, including negative psychiatric effects, early diagnosis and treatment would be essential. This randomized, double-blind, case-controlled clinical trial compared the efficacy of niosomal tranexamic acid (TXA) 2%/niacinamide (NCA) 2% cream and conventional TXA 5%/NCA 4% cream with topical hydroquinone (HQ) 4% cream as a gold standard in melasma patients. A total of 99 patients were randomly assigned to three groups: Group A received niosomal TXA/NCA cream, Group B received conventional TXA/NCA cream, and Group C received HQ cream for three months. Each patient attended five dermatologist visits to evaluate clinical efficacy. All treatment groups showed a considerable reduction in melanin index and modified melasma area and severity index (mMASI) scores, as well as a notable improvement in patients' quality of life. Although both niosomal TXA/NCA cream and conventional TXA/NCA cream were as effective as HQ cream in management of melasma, adverse reactions and relapse were observed in HQ group. Niosomal or conventional TXA/NCA creams are as effective as HQ 4% cream and due to less serious adverse reactions they would be better choices than HQ-containing preparations in hyperpigmentary disorders. Clinical Trial Registration No.: IRCT20220609055116N1 (Approval date: 07/23/2023). © 2025. The Author(s).

BACKGROUND: Minimally-to-moderately invasive facial rejuvenation procedures, such as chemical peels, hyaluronic acid (HA) injections and fractional lasers, yield visible improvements in skin texture, tone and wrinkles; their long-term benefits can be optimized through a targeted anti-aging skincare regimen. AIMS: This controlled study aimed to evaluate the tolerability and efficacy of a cream containing three evidence-based active ingredients (retinaldehyde, niacinamide and haritaki fruit extract) to support and maintain the benefits of minimally to moderately invasive facial rejuvenation procedures. METHODS: A monocentric, controlled, randomized, split-face study was conducted over a three-month period in subjects who had undergone one type of rejuvenation procedure, with assessments beginning after re-epidermization. Subjects were instructed to apply the test product on the randomized hemiface once daily. RESULTS: This comparative controlled study, conducted under close dermatological supervision in 66 subjects who had undergone either chemical peels, HA injections, or fractional laser (n = 22 per group), demonstrated that the cream significantly improved multiple signs of aging. Throughout the entire study, compliance was very good. At 1 month (M1), wrinkles were significantly reduced, and the skin was significantly firmer and plumper, with improved texture. Skin tone homogeneity and radiance were significantly enhanced as of M1 (and M2 for skin smoothness) versus the control hemiface. CONCLUSION: Regular application of the study product, which contains retinaldehyde, niacinamide, and haritaki fruit extract, yielded significantly visible anti-aging results already at 1 month compared with the control, with very good skin tolerance. It can be used to maximize and maintain the benefits of rejuvenation procedures and promote long-term skin health. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06942403. © 2025 Pierre Fabre Dermo‐Cosmetique & Personal Care. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.

BACKGROUND: The phase 3 CARES-310 trial showed significant improvements in progression-free survival (primary analysis) and overall survival (interim analysis) with the anti-PD-1 antibody camrelizumab plus the oral vascular endothelial growth factor receptor 2 inhibitor rivoceranib versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Here, we present the final analysis of overall survival, and updated data on progression-free survival, secondary efficacy endpoints, and safety. METHODS: This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions. Eligible patients were aged 18 years or older, with unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Participants were randomly assigned (1:1) using a centralised interactive response system to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. The study is complete and was registered with ClinicalTrials.gov, NCT03764293. FINDINGS: Between June 28, 2019, and March 24, 2021, 543 patients (457 [84%] males; 450 [83%] were Asian) were randomly assigned to receive camrelizumab-rivoceranib (n=272) or sorafenib (n=271). At final analysis on June 14, 2023, the median follow-up was 22·1 months (IQR 11·9-30·3) in the camrelizumab-rivoceranib group and 14·9 months (7·2-28·3) in the sorafenib group. Median overall survival was 23·8 months (95% CI 20·6-27·2) with camrelizumab-rivoceranib and 15·2 months (13·2-18·5) with sorafenib (hazard ratio [HR] 0·64 [95% CI 0·52-0·79]; one-sided p<0·0001). Median progression-free survival was 5·6 months (95% CI 5·5-7·4) with camrelizumab-rivoceranib and 3·7 months (3·1-3·7) with

Ferroptosis, a newly identified form of regulated cell death driven by iron-dependent lipid peroxidation, has emerged as a promising therapeutic strategy for triple-negative breast cancer (TNBC) due to the heightened susceptibility of TNBC cells to this form of cell death. Nonetheless, the unique hypoxic and acidic tumor microenvironment confers resistance to ferroptosis, which limits the clinical efficacy of single-agent ferroptosis inducers. To overcome this, we developed a synergistically enhancing ferroptosis nanomedicine named sorafenib (SOR)-quercetin (QUE) nanoparticles (SQ NPs) by co-assembling SOR, QUE, and polyvinylpyrrolidone K30 (PVP K30). In this system, SOR facilitates ferroptosis by downregulating the expression of glutathione peroxidase 4 (GPX4). Simultaneously, QUE mitigates the hypoxic tumor microenvironment by suppressing the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and hexokinase Ⅱ (HK-Ⅱ), thereby inhibiting glycolysis, reducing LA production, and impeding GSH synthesis. This multifaceted approach culminates in enhanced ferroptosis in TNBC cells. In vivo studies on antitumor and antimetastatic effects have demonstrated the superior therapeutic efficacy and metastasis-inhibiting capabilities of SQ NPs in the context of TNBC. This report highlights the therapeutic potential of QUE in synergy with SOR under hypoxic conditions, offering a novel strategic approach for the treatment of TNBC.

BACKGROUND: Colorectal cancer (CRC) is among the most prevalent malignancies globally, with its incidence continuing to rise in recent years. Sorafenib, a multi-kinase inhibitor, has shown therapeutic effects in advanced CRC. Usenamine A (UD32-3), a natural compound, is isolated from lichens. However, anti-tumor activity of UD32-3 in CRC and its biological functions in anti-CRC activity of sorafenib remain unknown. PURPOSE: This study aims to elucidate the mechanism underlying anti-CRC effects of UD32-3 and its potential to enhance the therapeutic efficacy of sorafenib. STUDY DESIGN AND METHODS: Immunofluorescence assays were employed to investigate reactive oxygen species (ROS) and autophagy levels. Gene knockdown or overexpression was performed using Lipofectamine 3000 reagent, and relative gene and protein expression levels were evaluated by quantitative real-time PCR (qRT-PCR) and Western blot analyses. Molecular docking analysis was performed to investigate the interaction between UD32-3 and superoxide dismutase 2 (SOD2). Mouse xenograft models were employed to evaluate the effects of combination therapy with UD32-3 and sorafenib. RESULTS: UD32-3 exerts anti-CRC activity by inducing ROS-mediated autophagy and inhibiting YAP pathway through targeting SOD2. Knocking down SOD2 sufficiently induced ROS generation and autophagy, and inhibited the YAP pathway, thereby enhancing the anti-CRC activity of UD32-3. Conversely, overexpression of SOD2 yielded opposite results, attenuating these effects. Combined treatment with UD32-3 and sorafenib exerted synergistic anti-tumor activities by activating autophagy and inhibiting YAP signaling pathway. Additionally, YAP inhibitor strengthened anti-CRC activity of UD32-3 and sorafenib by inhibiting SOD2 expression, suggesting autophagy-mediated negative feedback loop between SOD2 and YAP. CONCLUSIONS: UD32-3 has significant druggable potential, and combination treatment of UD32-3 and sorafenib may serve as an effective therapeutic strategy for patients with certain CRC.

Triple-negative breast cancer (TNBC), lacking effective therapeutic targets, is highly aggressive, prone to metastasis, and associated with poor prognosis, highlighting the necessity for innovative therapeutic strategies. Ferroptosis, an emerging form of iron-dependent programmed cell death, presents a promising treatment approach. However, its effectiveness is often hindered by adaptive resistance within the tumor microenvironment and inefficient drug delivery. To address these limitations, the glutathione (GSH)-responsive disulfide linker (-SS-) was utilized to engineer rhein (Rhe, chemotherapeutic agent) and ferrocene (Fc, ferroptosis booster) into the self-assembling small-molecule prodrug RSSF. Sorafenib (SOR), a ferroptosis inducer, was stably loaded into RSSF via a simple nanoprecipitation method, yielding the newly nanoprodrug designated as SOR@RSSF nanoparticles (NPs) for the combination therapy of TNBC. SOR@RSSF NPs exhibit markedly enhanced cellular uptake and enable the highly specific and synchronous release of Rhe, Fc, and SOR in response to intracellular GSH levels. Notably, Fc efficiently generates hydroxyl radicals (•OH) through the Fenton reaction, thereby inducing pronounced oxidative stress, while SOR concurrently impaired the cellular ferroptosis defense machinery. Combined with the chemotherapeutic activity of Rhe, the resulting lipid peroxide (LPO) accumulation and GSH depletion synergistically trigger both ferroptosis and apoptosis selectively in tumor cells. In a 4T1 tumor-bearing mouse model, SOR@RSSF NPs significantly inhibited tumor progression while maintaining a favorable biosafety profile. Overall, this study presents a promising ferroptosis-sensitizing strategy using a nanoprodrug delivery system for combination therapy against TNBC.

Hepatocellular carcinoma (HCC), which makes up about 90% of liver cancer, is the third leading cause of cancer-related death. Recent studies suggest that metabolites derived from the gut microbiome may offer new therapeutic opportunities for HCC. In this study, we explored whether microbial metabolites could enhance the effectiveness of sorafenib, a first-line multi-kinase inhibitor used in advanced HCC. Through a screen of a microbiome metabolite library, we identified spermine and sphingosine as potential candidates that boosted anticancer effects of sorafenib in HepG2, Huh7, and SK-Hep-1 cells. These metabolites worked synergistically with sorafenib to suppress tumor growth in cultured HCC cells, patients-derived HCC organoids, and a xenograft mouse model. Mechanistically, spermine triggered cell cycle arrest at the S phase, while sphingosine and sorafenib induced G1 arrest, contributing to an increased sub-G1 population and apoptosis when combined. Notably, sorafenib treatment led to the downregulation of SMOX (a key catabolic enzyme for spermine), as well as SPHK1 and CERS1 (critical enzymes involved in sphingosine metabolism), whose high expression levels are associated with poorer survival outcomes in liver cancer patients according to TCGA data. A 16S rRNA sequencing analysis revealed that combination of sorafenib with spermine or sphingosine alters the gut microbiome, increasing the relative abundance of Faecalibaculum, inversely correlated with tumor sizes in a xenograft mouse model. Therefore, we propose that combining sorafenib with spermine or sphingosine could enhance its anti-HCC effects by promoting apoptosis and reducing the expression of metabolic enzymes. Moreover, Faecalibaculum may serve as a potential microbiome-based prognostic marker for HCC. © The author(s).

BACKGROUND: Over-reliance on and excessive use of pesticides for pest management have led to various side effects, including the rapid development of pesticide resistance. The abundant reactive species present in plasma-activated water (PAW) make it a potential alternative to pesticides for controlling crop pests. Whether PAW can truly replace pesticides or significantly reduce their usage depends on its efficacy when applied in the same manner as pesticides. RESULTS: A foliar spray bioassay that simulates the field application of pesticides was established to estimate the direct toxicity of PAW to two insecticide-susceptible and two resistant strains of cotton aphids in the presence and absence of imidacloprid or flonicamid. Spraying PAW alone only caused mortality of about 20-30% against the four cotton aphid strains, significantly lower than the effects of imidacloprid LC25 dose and flonicamid LC25 dose to the four strains. Spraying a mixture of PAW and imidacloprid at LC25 dose or flonicamid at LC25 dose resulted in significantly higher mortality rates against the four strains compared to the two insecticides diluted with pure water. Relative to pure water control, PAW and its mixtures with imidacloprid LC25 dose or flonicamid LC25 dose displayed no adverse effects on chlorophyll content and the photosynthetic parameters of cotton seedlings. CONCLUSION: The data obtained indicate that PAW has the potential to serve as a plant-safe synergist for enhancing the insecticidal efficacy of imidacloprid and flonicamid against both insecticide-susceptible and -resistant cotton aphids. © 2026 Society of Chemical Industry. © 2026 Society of Chemical Industry.

OBJECTIVE: Niacinamide is a well-established ingredient known for reducing hyperpigmentation by inhibiting melanosome transfer from melanocytes to keratinocytes. This study aimed to explore the potential synergistic effects of niacinamide and low pH in melanogenesis pathways and their impact on skin hyperpigmentation in clinical trials. METHODS: In vitro experiments were conducted using human melanocyte and/or keratinocyte cultures to investigate the effects of niacinamide at varying pH levels (neutral pH 7 and low pH 2.5-4). Melanin synthesis, melanocyte dendricity, melanosome transfer and melanosome degradation were assessed. Transcriptome analysis was performed to identify gene expression changes in human melanocytes. Additionally, vehicle-controlled facial clinical trials were conducted among Caucasian and Chinese females to evaluate the effects of niacinamide formulations at neutral and low pH. RESULTS: Niacinamide in neutral pH solutions and simple low pH solutions (without niacinamide) did not inhibit melanin synthesis or melanocyte dendricity, as expected. However, niacinamide in low pH solutions significantly inhibited both, indicating a synergistic interaction. Enhanced suppression of melanosome transfer and degradation was also observed, although these effects appeared to be additive to the effects of neutral pH niacinamide. Transcriptome analysis revealed downregulation of genes and pathways associated with melanogenic cytokine signalling, melanin biosynthesis, melanocyte dendricity and melanosome transfer for niacinamide in low pH formulation, but not niacinamide in neutral pH or simple low pH formulations (without niacinamide), further supporting the synergistic effect. A 4-week clinical trial among Caucasian females using 2% niacinamide formulation at pH 2.5 revealed a marked reduction in the appearance of facial spots compared to 2% niacinamide neutral pH or vehicle formulations. Similarly, an 8-week clinical trial conducted with Chinese females using 5% niacinamide formulation at pH 4 demonstrated significantly greater efficacy in both facial spot reduction and skin brightening in appearance than neutral pH niacinamide and vehicle formulations.

8. Int J Cosmet Sci. 2026 Apr;48(2):445-455. doi: 10.1111/ics.70044. Epub 2025 Nov 30. Synergistic effects of niacinamide and low pH on melanin synthesis, melanocyte function and hyperpigmentation: In vitro and clinical insights. Hakozaki T(1), Laughlin T(1), Zhao W(1), Deng G(2), Wang J(1), Mou

Combination therapy in cancer treatment offers significant potential to overcome drug resistance, enhance efficacy, reduce toxicity, and expand drug indications. sorafenib, an FDA-approved multi-targeted kinase inhibitor, has demonstrated effectiveness across various cancers but currently lacks approved combination therapies. Recently, we identified LZX-2-73 as a promising drug candidate with potent anticancer activity, targeting the nuclear protein 1 (NUPR1), an emerging and promising target in cancer therapy. In this study, we report that the combination of the NUPR1 inhibitor LZX-2-73 with sorafenib produces strong synergistic anticancer effects in various cancer cell lines as well as in primary pancreatic ductal adenocarcinoma (PDAC) organoids. This combination significantly enhanced lactate dehydrogenase (LDH) release and caspase 3/7 activity, markedly induced ROS accumulation, reduced the reduced/oxidized glutathione ratio, and increased the accumulation of malondialdehyde (MDA) and lipid hydroperoxides. Collectively, the combination of LZX-2-73 and sorafenib led to a substantial increase in cell death due to massive oxidative stress. Additionally, in a pancreatic cancer xenograft mouse model, the combination of LZX-2-73 and sorafenib exhibited a synergistic anticancer effect, effectively inhibiting tumor growth. In summary, this study provides valuable insights into enhancing the anticancer activity of NUPR1 inhibitors through combination with sorafenib, offering a promising new avenue for cancer therapy and opening new indications. © 2025. The Author(s).

The macrofungus Sanghuangporus vaninii has been used in traditional medicine and diets for over 2000 years. In this study, a novel water-soluble polysaccharide (SVP-1) was extracted and purified from S. vaninii. SVP-1 has an average molecular weight of 186.6 kDa and comprises glucose, mannose, and galactose. GC-MS and NMR results revealed its backbone structure as →6)-β-D-Glcp-(1→3)-α-L-Manp-(1→6)-β-D-Glcp-(1→3)-β-D-Glcp-(1→, with branches at α-L-Manp-(1→ and β-D-Galp-(1→. Pharmacological experiments demonstrated that SVP-1 exhibits certain anti-hepatocellular carcinoma efficacy. When combined with sorafenib, it enhances sorafenib's anti-hepatocellular carcinoma activity and reduces its side effects-specifically, significantly decreasing HepG2 cell viability and inhibiting their proliferation and migration. Animal experiments showed that co-administration of SVP-1 and sorafenib strengthens sorafenib's inhibitory effect on the expression of VEGFR1/2/3 and RAS/RAF/ERK proteins in mouse tumor tissues, thereby achieving anti-hepatocellular carcinoma effects by enhancing inhibition of tumor tissue angiogenesis and tumor cell proliferation. Transcriptomics results indicated that SVP-1 promotes natural killer (NK) cells to release large amounts of TNF-α/GM-CSF/IFN-γ, exerting a tumor cell-killing effect.

β3-adrenergic receptors (β3-ARs) are increasingly recognized as modulators of tumor progression and treatment resistance across multiple cancer types. SR59230A, a β3-AR antagonist, has shown preclinical antitumor activity through mechanisms involving mitochondrial reactivation, reactive oxygen species (ROS) production, and antiangiogenic effects. Based on this premise, this study aimed to investigate the in vitro synergistic effects of SR59230A combined with standard chemotherapeutics or targeted therapies in various human cancer cell lines (glioblastoma, melanoma, triple-negative breast cancer, and anaplastic thyroid carcinoma) and endothelial cells (HUVECs). Cells were treated with SR59230A alone or in fixed-ratio combinations with temozolomide, paclitaxel, vemurafenib, lenvatinib, or sorafenib. Drug interactions were quantified using the Chou-Talalay method and validated with the Loewe additivity model. SR59230A exhibited dose-dependent antiproliferative activity, particularly in HUVECs and thyroid carcinoma cells. Synergistic effects were observed in all models, with the strongest synergy in A-2058 melanoma cells (SR59230A + vemurafenib), MDA-MB-231 breast cancer and 8505C thyroid carcinoma cells (SR59230A + paclitaxel), U-87 glioblastoma cells (SR59230A + temozolomide), and HUVECs (SR59230A + lenvatinib or sorafenib). Dose reduction index (DRI) values confirmed the potential to lower cytotoxic drug doses while preserving efficacy. These findings suggest that SR59230A may enhance the efficacy of conventional and targeted anticancer agents through multimodal mechanisms. The consistent synergistic effects across diverse tumor types support further investigation into the role of SR59230A, including its effects on β3-AR, as a promising strategy to overcome resistance and optimize cancer therapy. © 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

INTRODUCTION: The phase III ASC4FIRST study (NCT04971226) demonstrated superior efficacy and favorable safety and tolerability for asciminib against investigator-selected tyrosine kinase inhibitors (IS-TKI) in newly diagnosed chronic myeloid leukemia (CML). Results of a subgroup analysis in Japanese patients are presented here. METHODS: Adult patients were randomized 1:1 to asciminib or IS-TKI following stratification by European Treatment and Outcome Study long-term survival risk score and prerandomization-selected TKI (imatinib and second-generation [2G] TKI strata). At week 48, major molecular response (MMR) rate in all patients and imatinib stratum (primary endpoints) were assessed along with MR4.0, MR4.5, and safety (cutoff: November 28, 2023). RESULTS: In Japanese patients (asciminib, n = 21; IS-TKI, n = 17 [imatinib/2G TKI, n = 8/9]), the MMR rate was higher with asciminib (81.0%) than IS-TKI (47.1%), and versus imatinib (asciminib: 100%; imatinib: 25.0% [imatinib stratum]). More patients on asciminib than IS-TKI achieved MR4.0 (57.1% vs. 11.8%) and MR4.5 (28.6% vs. 5.9%). Fewer grade ≥ 3 adverse events (AEs; 42.9%, 50.0%, and 55.6%) and AEs leading to treatment discontinuation (0%, 37.5%, and 11.1%) occurred with asciminib than imatinib or 2G TKI. CONCLUSION: Outcomes in Japanese patients were consistent with the ASC4FIRST overall population. Asciminib may be a therapy of choice for Japanese patients with CML. © 2025. The Author(s).

BACKGROUND: Immunotherapy combinations have revolutionised the therapeutic landscape of advanced hepatocellular carcinoma (HCC), but not all yield a significant overall survival benefit, underscoring the need for novel effective agents. Anlotinib plus penpulimab has demonstrated encouraging activity and safety in a phase 2 study. In this phase 3 trial, we aimed to assess whether the combination of anlotinib plus penpulimab improved survival versus sorafenib in patients with unresectable HCC. METHODS: APOLLO was a multicentre, open-label, parallel-controlled, randomised, phase 3 trial conducted at 79 centres in China. Patients aged 18-75 years with unresectable HCC, no previous systemic therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were randomly assigned (2:1) to anlotinib (10 mg orally once daily on days 1-14) plus penpulimab (200 mg intravenously on day 1), or sorafenib (400 mg orally twice daily) every 3 weeks. Randomisation was done centrally using block randomisation with a fixed block size of 3 and stratified by the presence of macrovascular invasion or extrahepatic metastasis, α-fetoprotein concentration, and ECOG performance status. Sex (male or female) and ethnicity (Chinese or other) were self-reported. The co-primary endpoints were progression-free survival assessed by masked independent review committee and overall survival in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of the study drug and had at least one recorded safety assessment. Final progression-free survival and second interim overall survival analyses are presented. This trial is registered at ClinicalTrials.gov, NCT04344158, and follow-up is ongoing. FINDINGS: From Aug 11, 2020, to June 20, 2023, 940 patients were screened for inclusion in the trial, 291 were excluded, and 649 were randomly assigned to an intervention (433 were assigned to the anlotinib plus penpulimab group and 216 were assigned to the sorafenib group. 551 (85%) of the 649 patients were male and 98 (15%) were female. All patients were Chinese with a median age of 57 years (IQR 50-65). For the final analysis of progression

BACKGROUND: The original population pharmacokinetics (popPK) model for asciminib in patients with chronic myeloid leukemia in chronic phase (CML-CP) was refined to address drug development needs in support of drug submission, namely, attainment of target drug exposure in specific patient populations, populating individual daily exposures for exposure-response analyses of key efficacy and safety endpoints, confirmation of comparability in exposure between 40 mg b.i.d. and 80 mg q.d., and assessment of ethnic insensitivity. METHODS: Participants from two organ dysfunction studies, patients with CML in blast and acute phases and acute lymphoblastic leukemia and patients from a phase III efficacy study in newly diagnosed Ph + CML-CP, and data from a dedicated phase II study in the Chinese patients previously treated with at least two prior tyrosine kinase inhibitors, and a phase IIIb study comparing two dose regimens of asciminib (40 mg b.i.d. and 80 mg q.d.) were included in the revised popPK model. Covariates evaluated were line of therapy, baseline renal and hepatic functions, Chinese or Japanese ethnicity. RESULTS: The apparent clearance and steady-state volume of distribution of asciminib were 6.84 L/h and 110 L, respectively, for a typical individual of 70 kg weight and 90 mL/min absolute glomerular filtration rate. Both the 40 mg b.i.d. and 80 mg q.d. resulted in a steady-state daily AUC of 12,600 ng.h/mL, and there was no difference between lines of therapy. Effects of renal or hepatic impairment on clearance were not clinically relevant. Chinese and Japanese exhibited similar PK as that of the global population. CONCLUSIONS: The 40 mg b.i.d. and 80 mg q.d. regimens are comparable in their daily exposure, supporting the use of the two dosing regimens in newly diagnosed and previously treated CML-CP patients. The PK of asciminib is insensitive to ethnic differences and no dose adjustment is required for severe renal and hepatic impaired patients. © 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Despite advances in the treatment of hepatocellular carcinoma (HCC) over the last few decades, treatment opportunities for patients with HCC remain limited. HCC is the most common form of liver cancer, accounting for approximately 90% of all cases worldwide. Moreover, apart from the current pharmacological interventions, hepatic resection and liver transplantation are the mainstay curative approaches for patients with HCC. This systematic review included phase I, II, III, and IV clinical trials (CTs) and randomized controlled trials (RCTs) on current treatments for patients with HCC in Asian populations (2013-2023). A total of 427 articles were screened, and 184 non-duplicate publications were identified. After screening the titles and abstracts, 96 publications were excluded, and another 28 were excluded after full-text screening. The remaining 60 eligible RCTs/CTs were finally included. A total of 60 clinical trials fulfilled our inclusion criteria with 36 drugs used as monotherapy or combination therapy for HCC. Most studies used sorafenib alone or in combination with any of the treatment regimens. Lenvatinib or atezolizumab with bevacizumab was used for HCC after initial sorafenib treatment. Eighteen studies compared the efficacy of sorafenib with that of other drugs, including lenvatinib, cabozantinib, tepotinib, tigatuzumab, linifanib, erlotinib, resminostat, brivanib, tislelizumab, selumetinib, and refametinib. This study provides comprehensive insights into effective treatment interventions for HCC in Asian populations. The overall assessment indicates that sorafenib, used alone or in combination with atezolizumab and bevacizumab, has been the first treatment choice in the past decade to achieve better outcomes in patients with HCC in Asian populations.

Comment in Hepatobiliary Surg Nutr. 2025 Dec 1;14(6):1023-1027. doi: 10.21037/hbsn-2025-517. BACKGROUND & AIMS: In the global, phase III HIMALAYA study in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) improved overall survival (OS) vs. sorafenib; durvalumab was non-inferior to sorafenib. HBV is the predominant HCC aetiology in most of Asia vs. HCV or non-viral aetiologies in Western countries and Japan. This analysis evaluated safety and efficacy outcomes for STRIDE and durvalumab monotherapy vs. sorafenib, in HIMALAYA participants enrolled in Asia, excluding Japan. METHODS: In HIMALAYA, participants were randomised to STRIDE, durvalumab, or sorafenib. The Asian subgroup in this analysis included participants enrolled in Hong Kong, India, South Korea, Taiwan, Thailand, and Vietnam. OS, objective response rate (ORR; per RECIST, version 1.1), and safety were assessed in the Asian subgroup and in an exploratory subgroup of participants in Hong Kong and Taiwan. RESULTS: The Asian subgroup included 479 participants randomised to STRIDE (n = 156), durvalumab (n = 167), or sorafenib (n = 156). OS was improved for STRIDE vs. sorafenib (hazard ratio [HR] 0.68; 95% CI 0.52-0.89). The OS HR for durvalumab vs. sorafenib was 0.83 (95% CI 0.64-1.06). In Hong Kong and Taiwan (n = 141), OS HRs for STRIDE vs. sorafenib and durvalumab vs. sorafenib were 0.44 (95% CI 0.26-0.77) and 0.64 (95% CI 0.37-1.08), respectively. In the Asian subgroup, ORR (including unconfirmed responses) was numerically higher for STRIDE (28.2%) and durvalumab (18.6%) vs. sorafenib (9.0%), and Grade 3/4 treatment-related adverse events were numerically lower for STRIDE (19.9%) and durvalumab (13.3%) vs. sorafenib (30.5%). CONCLUSIONS: STRIDE improved outcomes vs. sorafenib in the Asian subgroup. These results support the benefits of STRIDE for participants with uHCC globally, including in the Asia-Pacific region. CLINICAL TRIAL NUMBER: NCT03298451. IMPACT AND IMPLICATIONS: The global, phase III HIMALAYA study found that the STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen improved overall survival (OS), including long-term OS vs. so

Purpose To perform a systematic review and meta-analysis of liver background uptake across four prostate-specific membrane antigen (PSMA)-targeting PET radiotracers (fluorine 18 [18F]-piflufolastat, gallium 68 [68Ga]-PSMA-11, 18F-flotufolastat, and 18F-PSMA-1007) and evaluate the potential impact on patient selection for PSMA-targeted therapy. Materials and Methods A comprehensive literat

Renal carcinoma ranks among the most lethal cancers, primarily attributed to its atypical symptoms and high metastatic potential. The metabolism of nicotinamide (NAM) plays a significant role in the progression of various tumors. However, investigations into the impact of the NAM metabolism-related signature (NMRS) in kidney renal clear cell carcinoma (KIRC) remain insufficient. Clinical and RNA sequencing data (RNA-seq) from 541 KIRC tissues and 72 adjacent normal tissues were extracted from TCGA. NAM metabolism-related genes (NMRGs) were identified through the Molecular Signatures Database. Cox regression analyses (univariate/multivariate) were conducted to develop NMRS. Time-dependent ROC curve analysis showed that this method had good accuracy in predicting 1-year (AUC = 0.691), 3-year (AUC = 0.749), and 5-year (AUC = 0.764) survival. The Receiver Operating Characteristic (ROC) curve from the external RECA-EU dataset (AUC = 0.682) highlights the accurate prognostic assessment of the NMRS. Overall survi

Cisplatin remains a widely used anticancer agent; however, its effectiveness can be influenced by systemic toxicity, resistance mechanisms, and interactions with exogenous compounds. Nicotinamide (vitamin B3), an NAD+ precursor and a commonly used dietary supplement, is involved in cellular metabolism, redox homeostasis, and DNA repair pathways, which ma

Nicotinamide (NAM), the amide form of vitamin B3, has gained increasing attention in dermatology due to its potential role in both skin aging and non-melanoma skin cancer (NMSC) prevention. This review summarizes the biological rationale and current clinical evidence supporting the use of NAM and other NAD+ precursors in photoaging and cutaneous carcinogenesis. Chronic ultraviolet exposure induces DNA damage, oxidative stress, inflammation, immune dysregulation, and extracellular matrix remodeling, linking photoaged skin to increased susceptibility to actinic keratoses (AKs), squamous cell carcinoma (SCCs), and basal cell carcinoma (BCCs). Through the NAD+ salvage pathway, NAM contributes to the maintenance of i

Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy characterized by poor prognosis and limited therapeutic response. Cancer stem cells (CSCs) contribute to tumor progression, therapeutic resistance, and tumor recurrence. Among transcriptional regulators potentially involved in these processes, Specificity Protein 1 (SP1) has emerged as a candidate integrator of oncogenic and epigenetic signaling networks. However, its contribution to CSC-associated phenotypes and drug resistance in HCC remains incompletely defined. In this study, we combined transcriptomic analyses of TCGA datasets with functional experiments in HCC cell lines (Huh7 and HepG2). SP1-associated transcriptional programs were targeted pharmacologically using mithramycin A (MIT-A) and genetically using siRNA-mediated knockdown. The ef

Targeted therapies have broadened the treatment landscape for colorectal cancer (CRC), highlighting the need for rational combination strategies. Although sorafenib and GW5074 show therapeutic promise and lidocaine may sensitise cancer cells to treatment, the mechanisms underlying these combinations remain poorly understood. Here, we systematically evaluated the effects of combining lidocaine with sorafenib and/or GW5074 in CRC cell lines. Combination index analysis showed that sorafenib increased responsiveness to GW5074 by 19.5- and 1.7 × 107-fold in HT29 and SW480 cells, respectively, while lidocaine enhanced this response by 45- and 3 × 107-fold. Ropivacaine, bupivacaine, and levobupivacaine also showed synergistic interactions with GW5074 by 14- and 1.03 × 107-fold, 15.1- and 6.5 × 106-fold, and 33.6- and 3.8 × 107-fold in HT29 a

Alpha fetoprotein (AFP) regulates glucose metabolism reprogramming (GMR) related to drug resistance of hepatocellular carcinoma (HCC) and remains unclear. This study explores the effect of AFP regulating GMR (Glucose metabolic reprogramming) on the tolerance of HCC cells to sorafenib. Thirty clinical liver cancer samples and multi-omics databases were collected; the expression of AFP, GMR-related proteins, pyruvate kinase M2 (PKM2), and the PI3K/AKT signalling pathway-associated proteins were assessed using immunohistochemistry (IHC) or Western blotting. MTT, cloning assays, flow cytometry, and TUNEL were performed to evaluate the effects of AFP on HCC resistance to sorafenib. Alterations in glucose consumption, lactate dehydrogenase activity, and AT

BACKGROUND: Lung adenocarcinoma (LUAD) is a prevalent and lethal malignancy. The three-dimensional (3D) chromatin architecture significantly influences tumor progression, yet the contribution of 3D chromatin structure-related genes (3DCRGs) in LUAD remains unclear. This study was designed to explore the role of 3DCRGs in postoperative recurrence of early-stage LUAD, response to Sorafenib therapy in advanced LUAD, tumor progression, and the regulation of the tumor microenvironment (TME). METHODS: Based on prior studies of chromatin 3D architecture, we curated 49 3DCRGs. Differential expression analysis in the TCGA-LUAD cohort identified 21 3D differentially expressed genes (3DDEGs) between tumor and adjacent normal tissues. Seven GEO datasets (GSE31210, GSE30219, GSE33072, GSE27389, GSE115002, GSE83836 and GSE31428) were used to screen key genes associated with early recurrence, Sorafenib response, and LUAD stage progression through integrated machine learning approaches, and the selected genes were validated in independent datasets. TME characteristics in high-risk early-stage LUAD patients were assessed using IOBR 2.0. Single-cell transcriptomic analysis (GSE200972) was utilized to identify cell populations enriched with the core genes, while spatial transcriptomics was employed to validate their spatial localization. Virtual single-gene perturbation analysis was performed using scTenifoldKnk to assess the functional convergence of core 3DCRGs in tumor proliferating cells. RESULTS: We identified 21 3DDEGs (|log2FC|≥ 0.5, q < 0.05). Machine-learning integration consistently highlighted SMC3, RAD21, FOXM1, MYBL2, and MTA3 as key regulators in postoperative recurrence in early-stage LUAD, response to Sorafenib treatment in advanced LUAD, and tumor progression across different stages of LUAD. Models constructed using these genes demonstrated robust performance and were validated in independent cohorts. IOBR analysis revealed that patients with high recurrence risk exhibited co-activation of glycolysis and oxidative phosphorylation, along with significantly increased infiltration of myeloid-derived suppressor cells (MDSCs) (P = 0.0001). Single-cell transcriptomic an

BACKGROUND: Hepatocellular carcinoma (HCC) arising from non-alcoholic steatohepatitis (NASH) represents a growing clinical challenge with limited therapeutic options. Despite known antioxidant and immunomodulatory properties, the role of beta-glucan in NASH-associated HCC remains insufficiently explored. METHODS: HCC was experimentally induced in rats via a single intraperitoneal (i.p.) injection of diethylnitrosamine (DEN; 200 mg/kg), followed by repeated intraperitoneal administrations of thioacetamide (TAA; 300 mg/kg) thrice weekly for four weeks. Upon establishment of hepatic tumors, beta-glucan was administered orally (p.o.) at doses of 25, 50, and 75 mg/kg/day for eight consecutive weeks. Sorafenib (30 mg/kg/day; p.o.) was used as the reference standard. Key parameters, including serum biochemical markers, oxidative stress indicators, insulin-like growth factor-1 (IGF-1) levels, and histopathological alterations, were evaluated to assess therapeutic efficacy. RESULTS: Administration of hi

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pleiotropic transcription factor essential for cellular defense. Extensive research has demonstrated its oncogenic role, positioning Nrf2 as a promising target for cancer therapy. However, achieving tumor-specific Nrf2 inhibition remains a challenge. Herein, we report the discovery of 13, a biased inhibitor of Kelch-like ECH-associated protein 1-phosphorylated p62 (Keap1-p-p62) interaction, as a selective and effective Nrf2 inhibitor. In fluorescence polarization assays, 13 showed potent Keap1-p-p62 inhibitory activity (IC50 = 0.11 μM) and high selectivity over the inhibition of Keap1-Nrf2 interaction. Notably, 13 specifically inhibited Nrf2 activity in p62 aberrant hepatocellular carcinoma (HCC) cells b

Colorectal cancer (CRC) is a third leading cause of death and is often recognised by a higher mutation burden. The standard clinical regimen for CRC chiefly focuses on targeting a single-cell death mechanism, which encounters constraints such as resistance, chronic toxicity, and suboptimal efficacy. Thus, triggering a hybrid cell death mechanism that acts through distinct pathways offers a promising avenue in CRC management. The present investigation explores the combined therapy of Sorafenib (SOR) and Atorvastatin (ATST) to induce a dual cell death mechanism, specifically ferroptosis and classic apoptosis, in colon cancer cells. The combination of ATST + SOR at a 1:1 ratio showed a combination index value of < 1 and a dose reduction index > 1 in

Pharmacophore hybridization is a well-established strategy for developing novel anticancer agents with improved biological profiles. In this study, a new series of (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide derivatives has been rationally designed by hybridizing key structural features of sorafenib with cinnamide pharmacophores and subsequently synthesized. The antiproliferative activities of the synthesized compounds were evaluated against a panel of human cancer cell lines, including A549 (lung), DU-145 (prostate), SKOV3 (ovarian), and HepG2 (liver), along with non-cancerous Hek293T cells. In comparison with the standard drug sorafenib, most of the (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamides demonstrated significant antiproliferative activity, with specificity toward the HepG2 (liver cancer) cell line, and no effect on the noncancerous cells (Hek293T). Among them, compound 5f, the derivative containing a trifluoromethyl-substituted cinnamoyl moiety was identified as the lead candidate, exhibiting an IC50 of 5.3 µM towards HepG2 (liver) cancer cells, comparable to the reference drug sorafenib. Enzyme inhibition studies showed that compound 5f inhibited both b-Raf and VEGFR-2 with IC50 values of 1.45 and 0.37 µM, respectively. Furthermore, compound 5f suppressed angiogenesis in vitro and in vivo, as evidenced by the tube formation assay using HUVECs and in transgenic zebrafish Tg(fli1a:EGFP) models, respectively. Mechanistic studies indicated that compound 5f induced apoptosis in HepG2 cells through mitochondrial membrane depolarization and increased ROS generation. Molecular docking studies supported experimental findings and showed that 5f can interact with catalytically active residues via hydrogen-bonding interactions. Overall, these results highlight the potential of compound 5f as a promising dual target therapeutic lead with dual direct anticancer and antiangiogenic properties.

Cannabis-derived compounds are increasingly used as adjuncts in cancer therapy due to their reported antiproliferative and pro-apoptotic effects. However, potential drug-herb interactions with standard anticancer agents-namely sorafenib-remain unclear. This study investigated the interaction between cannabis and sorafenib, together with transcriptomic alterations in human hepatoma HepG2 cells. Cell viability was assessed using the MTT assay, and drug interactions were evaluated using the Combenefit program. RNA sequencing was performed to characterize gene expression changes across treatment groups. Combination analysis demonstrated concentration-dependent synergistic effects at intermediate doses. Transcriptomic profiling revealed that the combination treatment induced a broader and more distinct set

Targeting ferroptosis, a form of regulated cell death, holds potential for improving treatment efficacy in a range of cancers including hepatocellular carcinoma (HCC). The selenoprotein glutathione peroxidase 4 (GPX4) plays a crucial role in suppressing ferroptosis by converting toxic phospholipid hydroperoxides into non-toxic lipid alcohols, yet the mechanisms regulating its synthesis remain poorly understood. This study identifies SHIELD (suppressor of hypoxia-induced lipid peroxidation and death), a long noncoding RNA (lncRNA) and direct HIF-1α target, as a regulator of ferroptosis in HCC. SHIELD inhibits ferroptosis by interacting with the RNA-binding protein GRSF1, which forms a ternary complex with GPX4 5'-UTR to enhance GPX4 mRNA translation and expression. Furthermore, targeting SHIELD with antisense oligonucleotides (ASOs) in combination with sorafenib significantly reduced tumor growth in patient-derived xenograft models. This discovery paves the way for improving the efficacy of tyrosine kinase inhibitors in HCC, which addresses the challenge of therapeutic resistance.

PURPOSE OF REVIEW: Hepatocellular carcinoma (HCC) ranks among the most prevalent solid malignancies worldwide. A substantial proportion of patients are diagnosed at advanced stages, making systemic therapies the primary treatment option. In recent years, treatment strategies have shifted from single-agent targeted therapies, such as sorafenib and lenvatinib, to combination regimens incorporating immune checkpoint inhibitors, with or without antiangiogenic agents. This evolving treatment paradigm has led to an increasing number of patients receiving second-line and subsequent therapies. However, clinical guidelines for treatment selection remain lacking. RECENT FINDINGS: Currently, available salvage therapies include various molecularly targeted agents, immune checkpoint inhibitors, and combination regimens. Nonetheless, evidence supporting their efficacy and patient selection for specific strateg

PURPOSE: Sorafenib remains a systemic treatment option for advanced hepatocellular carcinoma (HCC), but its clinical efficacy is limited by rapid development of adaptive cellular responses that promote cell survival and phenotypic plasticity. Store-operated calcium entry (SOCE) is a key regulator of intracellular calcium signaling and has been implicated in proliferation, apoptosis, migration, and epithelial-mesenchymal plasticity in cancer. This study investigated the association between SOCE and early adaptive responses to sorafenib in Huh7 HCC cells. METHODS: Huh7 cells were treated with sorafenib, the SOCE inhibitor SKF-96365, or their combination. Functional effects were evaluated using real-time proliferation assays, intracellular calcium measurements, apoptosis analysis, and wound-healing assays. Findings were complemented by integrated bioinformatic analyses of TCG

Liver fibrosis, a major cause of morbidity in chronic liver diseases, lacks effective therapies. Activated hepatic stellate cells (HSCs) are a promising therapeutic target for liver fibrosis, as their transformation into myofibroblasts drives disease progression by excessively depositing an extracellular matrix. Despite its antifibrotic potential, sorafenib faces clinical challenges due to poor aqueous solubility and lack of HSC specificity. To overcome these challenges, we developed IGFIIR aptamer-functio

OBJECTIVES: Prostate-specific membrane antigen positron emission tomography (PSMA-PET) is a sensitive imaging modality for detecting recurrent prostate cancer following definitive local therapy. However, evidence on 18F-labeled PSMA tracers in Japanese patients with biochemical recurrence (BCR) remains limited. The aim of this study was to examine the recurrence site distribution by [18F]PSMA-1007 PET in patients with BCR and identify factors associated with metastatic disease. METHODS: We retrospectively analyzed 129 patients with prostate cancer who developed BCR after definitive local therapy and underwent [18F]PSMA-1007 PET. The primary endpoint was the distribution of recurrence sites detected by PSMA-PET. Secondary endpoints included clinicopathological factors associated with metastatic disease. Exploratory endpoints involved outcomes of lesion-directed therapy following PSMA-PET. RESULTS: PSMA-PET identified recurrent lesions in 83% (n = 107), including local recurrence in 40% (n = 51), lymph node metastasis in 43% (n = 55), and bone metastasis in 26% (n = 33); sites were not mutually exclusive. Metastatic lesions were detectable even at low prostate-specific antigen (PSA) levels (≤ 1.0 ng/mL). In multivariate analysis, Grade Group ≥ 4 was independently associated with metastatic disease (odds ratio [OR], 2.65; 95% confidence interval [CI], 1.06-6.77), whereas a PSA doubling time ≥ 8.7 months was independently associated with a lower likelihood of metastasis (OR, 0.12; 95% CI, 0.05-0.27). Among 55 patients who underwent lesion-directed therapy, PSA declines ≥ 90% were observed in 60% of cases. CONCLUSIONS: In this Japanese cohort with BCR, [18F]PSMA-1007 PET delineated recurrence patterns and identified clinicopathological factors associated with metastatic disease. PSMA-PET may provide clinically relevant information to support individualized salvage treatment strategies. © 2026 The Author(s). International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Urological Association.

Benign prostatic hyperplasia mainly arises within the para-urethral transition zone and is rarely seen in the peripheral zone. We describe MRI and 18 F-PSMA-1007 PET/CT findings in a patient with a large benign hyperplastic nodule in the peripheral zone. The benign prostatic hyperplastic nodule appeared as a well-defined mass with heterogeneous signal intensity at T2-weighted images and increased 18 F-PSMA-1007 with SUV max of 7.3. This case indicates that a large benign prostatic hyperplastic nodule can arise from the peripheral zone and shows increased 18 F-PSMA-1007 uptake mimicking prostate cancer.

BACKGROUND: Finotonlimab combined with bevacizumab demonstrated superior progression-free survival and overall survival compared with sorafenib in patients with unresectable hepatocellular carcinoma. However, its economic value in different healthcare systems has not been fully characterized. This study evaluated the cost-effectiveness of finotonlimab plus bevacizumab from the perspectives of U.S. payers and the Chinese healthcare system. A Markov state-transition model was constructed using clinical efficacy data from a phase 3 randomized controlled trial. METHODS: Health state utilities were obtained directly from trial data, and cost inputs were derived from published sources and country-specific charge databases. The outcomes included quality-adjusted life years (QALYs), incremental cost-effectiveness ra

This study aimed to develop and validate a predictive model for biochemical recurrence (BCR) after radical prostatectomy in patients with prostate cancer, incorporating clinical, pathological, inflammatory, and 18F-PSMA-1007 positron emission tomography/computed tomography (PET/CT) imaging parameters. This retrospective study included 240 patients with histopathologically confirmed prostate adenocarcinoma who underwent radical prostatectomy between June 2022 and July 2025. BCR was defined as a postoperative serum prostate-specific antigen (≥0.2 ng/mL). Preoperative clinical variables, systemic immune-inflammation index (SII), PET/CT lesion status, and maximum standardized uptake value (SUVmax) were collected along with postoperative pathological staging. Patients were divided into BCR (n = 64) and non-BCR (n = 176) groups. Univariate and multivariate logistic regression analyses identified independent predictors of BCR. A multivariable predictive model was developed and internally validated using a 70/30 training-validation split. Model

Hepatocellular carcinoma (HCC) imposes a substantial health burden in China. Finotonlimab plus bevacizumab recently prolonged progression-free survival (PFS) and overall survival (OS) vs. sorafenib, but its economic value remains unknown. Here we evaluated the cost-effectiveness of finotonlimab plus bevacizumab vs. sorafenib from the Chinese healthcare system perspective. Parametric survival models were fitted to extrapolate PFS and OS. Total costs, life-years (LYs), quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), incremental net monetary benefit (INMB), and incremental net health benefit (INHB) were estimated at a willingness-to-pay (WTP) threshold of $27,906 per QALY. Uncertainty

Sorafenib resistance remains a major challenge in the treatment of hepatocellular carcinoma (HCC). Through an in vivo CRISPR/Cas9 screen, we identified protein SUMOylation as a key pathway enriched in sorafenib-resistant HCC tumors. SUMO1 expression was significantly upregulated in resistant tumors and cell lines, and its modulation directly influenced sorafenib sensitivity both in vitro and in vivo. Proteomic analysis revealed that SUMO1 overexpression enhanced glycolysis, and metabolic assays confirmed increased extracellular acidification rate (ECAR) and decreased oxygen consumption rate (OCR) in SUMO1-high cells. We further identified PKM2 as a key SUMOylation target, mediated by the E3 ligase TRIM28. The SUMOylation of PKM2 increased its enzymatic activity, promoted aerobic glycolysis, and conferred sorafenib resistance. The inhibition of PKM2 with Compound 3k reversed glycolytic flux and restored sorafenib sensitivity. Clinically, SUMOylated PKM2 was highly expressed in HCC tumors and was associated with the expression of markers of glycolysis and sorafenib resistance in HCC. Our study revealed a novel SUMO1-PKM2 axis that drives glycolysis and sorafenib resistance in HCC, suggesting a potential therapeutic target for overcoming drug resistance.

Hepatocellular carcinoma (HCC) features a high mortality burden worldwide, highlighting the need for improved therapeutic strategies. Caffeine (CAF), a widely consumed bioactive compound, has been reported to exert chemopreventive effects in HCC, but its interaction with standard therapies remains poorly explored. We investigated whether CAF enhances the antitumor effects of sorafenib (SOR) chemotherapy in preclinical HCC models. C3H/HeJ mice were submitted to diethylnitrosamine (DEN)-induced hepatocarcinogenesis and treated with CAF (50 mg/kg), SOR (30 mg/kg), or their combination for 3 weeks. C3A+LX2 spheroids and transwell co-cultures were also exposed to CAF, SOR, or their combination at 1/5 or 1/10 of the half-maximal effective concentration. The combination of CAF and SOR produced a synergistic reduction in tumor sphe

BACKGROUND: Acquired resistance to sorafenib remains a major obstacle to effectively treating advanced hepatocellular carcinoma (HCC). Ferroptosis has emerged as a key mechanism influencing therapeutic response. EGF-containing fibulin extracellular matrix protein 1 (EFEMP1) contributes to sorafenib resistance in HCC cells by regulating ferroptosis, but its upstream regulatory mechanisms remain elusive. METHODS: Potential E3 ligases for EFEMP1 were screened using the UbiBrowser database. Protein interactions were validated by co-immunoprecipitation. The effects of SMAD ubiquitination regulatory factor 1 (SMURF1) and EFEMP1 on sorafenib sensitivity were assessed via IC50, colony formation, apoptosis, and migration/invasion assays. Assessment of ferroptosis was based on measuring levels of ROS, MDA, and iron, along with the expression of SLC7A11 and GPX4. The in vivo efficacy was demonstrated employing a xenograft mouse model. RESULTS: SMURF1 could bind to and ubiquitinate EFEMP1, promoting its proteasomal degradation. Overexpression of SMURF1 in sorafenib-resistant HCC cells decreased EFEMP1 protein stability, reversed drug resistance, and suppressed malignant phenotypes, but these effects were rescued following EFEMP1 upregulation. Mechanistically, SMURF1-mediated EFEMP1 degradation activated ferroptosis, evidenced by increased ROS/MDA/iron and decreased SLC7A11/GPX4, which was also reversed by EFEMP1. In vivo, SMURF1 overexpression synergized with sorafenib to inhibit tumor growth, which was again reversed by EFEMP1. CONCLUSION: This study demonstrates a novel SMURF1-EFEMP1-ferroptosis regulatory axis, wherein SMURF1 overcomes sorafenib resistance by ubiquitinating and degrading EFEMP1 to relieve its inhibition on ferroptosis. Targeting this axis presents a promising strategy for combating acquired resistance in HCC.

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a central role in tumor angiogenesis and remains a well-established therapeutic target in cancer treatment. In this study, twenty-six benzimidazole-based derivatives (3a-k, 5a-d, 8a-g, and 10a-d) were rationally designed to incorporate the essential structural and pharmacophoric features required for effective VEGFR-2 inhibition, followed by their synthesis and biological evaluation. In vitro kinase assays demonstrated that the synthesized derivatives inhibited VEGFR-2 with IC50 values ranging from 0.061 to 1.895 µM. Based on their enzymatic potency, the most active compounds (3

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common causes of death around the world, and it is commonly diagnosed late, so systemic chemotherapy is commonly used. Lysosomal sequestration of chemotherapy drugs such as sorafenib [1] decreases the effective concentration of chemotherapy at the target sites and leads to chemoresistance, also chemoresistance may arise from autophagy activation. We aimed to find a new therapeutic regimen for HCC through enhancing the chemosensitivity of SB by combining it with the lysosomotropic drug

BACKGROUND: Drug resistance is a constantly evolving challenge. The allosteric inhibitor asciminib is a novel therapy for chronic myelogenous leukemia (CML) that targets the myristoyl pocket of the BCR::ABL1 kinase. While it can overcome resistance to active-site inhibitors like imatinib, new resistance mutations to asciminib are emerging. The complete landscape of these mutations, particularly those outside the kinase domain or those arising from epistatic interactions between mutations, are not well understood. METHODS: This study employed a dual functional genomics approach in CML cell line models. A high-throughput adenosine base editing (ABE) screen was used to identify broad hotspots of asciminib resistance across the entire BCR::ABL1 protein. Deep mutational

Ferroptosis, an iron-dependent form of regulated cell death, plays a pivotal role in hepatocellular carcinoma (HCC) progression and is now recognized as a key mechanism underlying the antitumor activity of sorafenib. Src homology and collagen protein 4 (SHC4), an adaptor protein implicated in oncogenic signaling and tumor progression, has recently emerged as a potential regulator in multiple cancers; however, its involvement in ferroptosis and sorafenib response remains unclear. Our preliminary data showed that sorafenib treatment alters SHC4 expression in both clinical tissues and HCC cell models, suggesting a possible connection between SHC4 and ferroptotic susceptibility. These findings prompted us to investigate whether SHC4 modulates ferroptosis and contributes to sorafenib resistance. Here, we found that SHC4 decreased the anti-tumor activity of sorafenib by reducing ferroptosis both in vitro and in vivo. SHC4 diminished ROS and MDA production, lowered intracellular iron levels, enhanced GSH levels, and regulated the expression of Nrf2, xCT, and GPX4 proteins associated with antioxidant stress. In addition, SHC4 interacts with the 383-522 fragment of NCOA4, thereby blocking the association between NCOA4 and FTH1. This interference reduces the lysosomal degradation of FTH1, leading to decreased intracellular Fe2+ levels and ultimately suppressing ferroptosis. Clinically, the concurrent overexpression of SHC4 and FTH1 has been identified as a potential prognostic marker for poor outcomes in patients with hepatocellular carcinoma. Collectively, our study demonstrates the pivotal role of SHC4 in regulating ferroptosis in hepatocellular carcinoma and highlights its potential as a novel therapeutic target for overcoming sorafenib resistance.

Ferroptosis, an iron‑dependent form of non‑apoptotic cell death, is a potential target for cancer therapy. Sorafenib, a molecular targeted agent for renal cell carcinoma (RCC), is involved in ferroptosis induction. Chronic stress, mediated by catecholamines via β2‑adrenergic receptors (ADRB2), promotes cancer progression, yet its influence on drug resistance and ferroptosis remains elusive. To investigate ADRB expression in RCC, immunohistochemistry of surgical specimens was performed and assessed ADRB mRNA and protein levels were assessed by RT‑qPCR and western blotting in RCC cell lines. To determine whether β‑adrenergic signaling modulates sorafenib sensitivity, we used ADRB2‑expresing ACHN cells and conducted MTS cell viability assays following β‑adrenergic agonist isoproterenol (ISO) stimulation, ADRB2 knockdown by siRNA, as well as a restraint‑stress

BACKGROUND: Oral nicotinamide has been proposed as a chemoprevention strategy to reduce new keratinocyte carcinomas in people with a history of skin cancer, but its effect may differ between immunocompetent patients and transplant recipients. OBJECTIVE: To evaluate the effectiveness and safety of oral nicotinamide for the secondary prevention of cutaneous squamous cell carcinoma and other keratinocyte carcinoma-related outcomes in adults with a history of skin cancer. METHODS: We conducted a systematic review following PRISMA 2020. We searched PubMed/MEDLINE, Embase, and LILACS through the Virtual Health Library

Postoperative cognitive dysfunction (POCD) is common after anesthesia and surgery in older adults, yet no targeted therapy exists, and the mechanism linking volatile anesthetic exposure to circadian dysregulation in the aged hippocampus is undefined. Here we show that RAF manipulation bidirectionally alters CLOCK protein levels in HT22 hippocampal neurons, and that RAF-MAPK-MSK1 protein abundance is inversely related to CLOCK levels in the aged hippocampus after desflurane exposure. Aged C57BL/6 mice (18 months, both sexes) were exposed to 2% desfl

The present study explores the potential of sorafenib (SOR) and atorvastatin (ATST) to induce a ferroptosis and apoptosis-based hybrid cell death mechanism. The synergistic ATST + SOR combination was delivered through Glutamine-tagged PLGA nanoparticles (ATST + SOR/G-PLGA NPs) to promote intratumoral specificity. The formulation was optimized using DesignExpert® software by adopting Box-Behnken design (BBD). The optimized ATST + SOR/G-PLGA NPs had a spherical particle size of ~ 178.3 ± 12.6 nm, a PDI of 0.151 ± 0.08, and a Z-potential of -24.8 ± 5.8 mV. The formulation revealed a biphasic sustained release with higher release at acidic pH. In-vitro biological assessment showed a dose-de

The tumor microenvironment (TME) is characterized by heightened metabolic activity, dysfunctional vasculature, and chronic inflammation. Together, these features create an ecosystem that supports tumor progression. This review examines how nicotinamide (NAM) metabolism, mediated through its key enzymes Nicotinamide phosphoribosyl transferase (NAMPT) and Nicotinamide N‑methyltransferase (NNMT), may contribute to malignant remodeling of the TME at three interconnected levels: (1) fueling the hypermetabolic state of cancer cells and contributing to TME acidification; (2) modulating tumor angiogenesis; and (3) establishing and sustaining an immunosuppressive, chronic inflammatory milieu. Building on this framework, we further discuss the therapeutic potential of targeting NAM metabolism-such as via NAM supplementation or inhibition of NAMPT/NNMT-while also addressing challenges like metabolic plasticity. Future research should aim to unravel the d

Hepatocellular carcinoma (HCC) is a major contributor to cancer-related mortality worldwide and is closely linked to oxidative stress and progressive hepatic dysfunction. This study investigated the effects of plumbagin on antioxidant defense systems and hepatic function markers in an N-nitrosodiethylamine-thioacetamide (NDEA-TAA)-induced experimental model of HCC and compared its efficacy with that of sorafenib. Male Wistar rats were assigned to five groups: normal control, plumbagin-only, HCC control, HCC treated with plumbagin, and HCC treated with sorafenib. Hepatocarcinogenesis was induced using NDEA-TAA, after which antioxidant parameters including reduced glutathione (GSH), glutathione-S-transferase (GST), glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD)

BACKGROUND: Nance-Horan syndrome-like protein 3 (NHSL3) has been implicated in hepatocellular carcinoma (HCC) progression, but its role in sorafenib response and related growth and motility phenotypes remains unclear. In this study, we examined NHSL3 loss in Huh-7 cells and selected phenotypes in Hep3B cells. METHODS AND RESULTS: NHSL3 knockout clones were generated in both cell lines by paired Cas9 nickase editing. Data were obtained from three independent biological experiments. In Huh-7 cells, NHSL3 loss increased sorafenib sensitivity, lowering the 24 h half-maximal inhibitory concentration from 13.4 µM to 5.8 µM. NHSL3 loss was associated with G1 enrichment, reduced S-phase fraction, and impa

Vascular endothelial growth factor receptor-2 (VEGFR-2) is a vital mediator of angiogenesis. Therefore, VEGFR-2 inhibition is considered a promising therapeutic target to combat cancer. In the present study, a series of 22 imidazo[4,5-b]pyridine-acrylonitrile-based derivatives was designed and synthesized. All compounds were evaluated for their VEGFR-2 inhibitory activity. Seven of the tested compounds showed high inhibitory activity against VEGFR-2 with IC50 (0.029-0.087 µM) compared to reference drug sorafenib IC50 = 0.091 µM. Four of these derivatives were selected for in vitro cytotoxic activity against breast cancer (MCF-7) and hepatocellular (HepG2) carcinoma cell lines, showing IC50 (0.073-0.196 µM) and (0.20-0.21 µM), respectively, relative to sorafenib IC50 0.16 and 0.19 µM, respectively. Compound 2f exhibiting a supe

Cancer cells must deal with excessive reactive oxygen species (ROS) to survive severe hypoxia and anticancer therapy; however, anti-ROS mechanisms other than the well-known NFE2L2/NRF2 signaling pathway are poorly recognized. Here, we report a ROS scavenging mechanism mediated by HIF1α-KLF4-induced hemoglobin extraerythrocytically expressed in hepatocellular carcinoma (HCC). We found that the ROS pathway was aberrantly activated in HCC and was associated with hemoglobin upregulation, which independently predicts poor outcomes. Network analysis further identified heme binding as the top ROS-associated functional module, suggesting a previously unrecognized role of hemoglobin in maintaining redox homeostasis in HCC. Hemoglobin expression in cancer cells is transcriptionally controlled by HIF1α via KLF4 but not HIF2α or the recently identified KDM5A-KLF1 signaling. The upregulated hemoglobin counteracts the detrimental effects of oxidative stress by scavenging ROS, promoting sorafenib resistance, which could be effectively reversed by interfering with hemoglobin expression, leading to tumor suppression. Both in vitro and in vivo experiments consistently supported the functional importance of hemoglobin in regulating oxidative stress adaptation and therapeutic response. Overall, a previously unrecognized mechanism was identified for cancer cell survival under oxidative stress, where HIF1α-KLF4 signaling induces hemoglobin to scavenge ROS produced during hypoxia and anticancer therapy, providing a promising target of synthetic lethality for cancer therapeutics. © 2026. The Author(s).

BACKGROUND: Hepatic stellate cells (HSCs) are major regulators of the hepatocellular carcinoma (HCC) tumor microenvironment, contributing to extracellular matrix remodeling, tumor progression, and therapeutic resistance. Although three-dimensional (3D) coculture spheroid models better represent tumor-stroma interactions than conventional monocultures, the impact of HSCs on spheroid architecture and function remains incompletely characterized. This study investigated how HSCs influence the structural and functional properties of a 3D HCC model. METHODS AND RESULTS: Spheroids were produced using HepG2 cells, LX-2 cells (HSCs), or a 1:1 coculture system (CCS) and characterized over 96 h. Morphometric analysis demonstrated that CCS spheroids exhibited reduced area and perimeter together with increased circularity and normalized solidity, indicating enhanced structural organization and compaction. Scanning electron microscopy (SEM) confirmed distinct ultrastructural organization among the spheroid models. Flow cytometry revealed fewer membrane-compromised cells in CCS spheroids than in HepG2 spheroids. Although the percentage of active caspase-3-positive cells was unchanged, active caspase-3 fluorescence intensity was lower in both HepG2-like and LX-2-like populations. CCS spheroids showed higher collagen type I alpha-1-associated fluorescence, predominantly in the α-SMA-positive compartment, consistent with a stromal collagen-producing phenotype. Biochemical analyses revealed distinct extracellular lactate profiles. Extracellular LDH activity was lower in CCS spheroids than in HepG2 spheroids, although normalized LDH release did not differ between these groups. Functionally, CCS spheroids displayed reduced sorafenib sensitivity, with an IC30 approximately 3-fold higher than HepG2 monoculture. CONCLUSIONS: LX-2 incorporation was associated with greater spheroid organization, increased collagen type I-related expression, altered cell-death and extracellular metabolic profiles, and reduced sorafenib sensitivity, supporting the value of HepG2/LX-2 coculture spheroids for studying selected tumor-stromal interactions. © 2026. The Author(s).

OBJECTIVE: To assess the cost-effectiveness of tremelimumab plus durvalumab [the Single Tremelimumab Regular Interval Durvalumab (STRIDE) regimen] versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma in China using 5-year follow-up data from the HIMALAYA trial. METHODS: A three-state partitioned survival model comprising progression-free survival, progressed disease, and death was developed from the perspective of the Chinese healthcare system. Individual patient data were reconstructed from the published Kaplan-Meier curves from the HIMALAYA trial and used to estimate and extrapolate progression-free and overall survival. The model used 28-day cycles, a 10-year base-case time horizon, and an annual discount rate of 4.5%. Only direct medical costs were included and expressed in 2025 United States dollars. The

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death, and systemic therapy with sorafenib is limited by primary and acquired resistance. Copper is now recognized both as a growth-promoting cofactor in HCC and as the trigger of cuproptosis, a copper-dependent form of regulated cell death executed through ferredoxin-1 (FDX1)-mediated reduction of Cu2+, aggregation of lipoylated tricarboxylic acid (TCA) cycle proteins such as dihydrolipoamide S-acetyltransferase (DLAT), loss of Fe-S cluster proteins and proteotoxic mitochondrial stress. This review is deliberately restricted to a single mechanistic axis - copper handling, cuproptosis competence and sorafenib response in HCC - and grades the evidence supporting it. We distinguish direct experimental demonstrations of cuproptosis from copper overload, oxidative stress and mitochondria

79. J Am Acad Dermatol. 2026 Sep 7:S0190-9622(26)03468-7. doi: 10.1016/j.jaad.2026.05.146. Online ahead of print. Comment on "Decreased risk of cardiovascular disease in dermatology patients taking niacinamide: A TriNetX cohort study". Li C(1), Pan L(2). Author information: (1)Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany. (2)Department of Plastic and Hand Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany. Electronic address: [email protected]. DOI: 10.1016/j.jaad.2026.05.146 PMID: 42705349 Conflict of interest statement: Conflicts of interest None disclosed.

Despite considerable advances in cancer therapy, the intrinsic heterogeneity of malignant cells continues to compromise therapeutic efficacy with conventional monotherapies, driving the need for combination treatments to achieve more durable and complete responses. The limited efficacy of conventional chemotherapy is largely attributable to the immunosuppressive tumor micr

Molecular-targeted therapies require biomarker-driven evaluation to optimize precision oncology strategies; however, translational models integrating clinical outcomes with mechanistic biomarkers are limited. Canine urothelial carcinoma shares molecular features with human muscle-invasive bladder cancer, including activation of VEGFR signaling, providing a valuable comparative oncology platform. Sorafenib is a multi-kinase inhibitor targeting VEGFRs, PDGFRβ, BRAF, and related pathways, but its therapeutic mechanisms and clinical benefit in uroth

There is a critical need for tailored photoprotection in skin of color (SOC) populations. SOC has higher eumelanin-to-phenomelanin ratios, more mature melanosomes, and enhanced DNA repair capacity compared with lighter skin. The quantity and distribution of melanin in darker skin provide natural photoprotection. This leads to a misconception that SOC populations are inherently protected from all photodamage and serves as a barrier to proper photoprotection for these populations. Although the skin cancer incidence is lower in dark skin, mortality is higher, perhaps as a result of late diagnosis or misdiagnosis. These populations are