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关键词： omeprazole   PPI   ileostomy   stoma   high-output stoma   colorectal surgery  

摘要： Introduction: High-output stoma (HOS) is a frequent and morbid complication following ileostomy formation. Proton pump inhibitors (PPIs) may reduce intestinal secretions, but no randomized trial has yet tested whether intensified intravenous omeprazole treatment prevents or mitigates early postoperative HOS. We aim to determine whether intensified PPI dosing reduces early postoperative ileostomy output compared with standard dosing. Methods and Analysis: STOP-HOS-1 is a randomized, parallel-group, open-label, superiority trial conducted at two academic centers in Poland. The target sample size is 100 adults undergoing the formation of a loop or end ileostomy. Participants will be randomized 1:1 to receive either: intensified omeprazole group-80 mg IV loading dose, followed by 40 mg IV twice daily through postoperative day (POD) 10, or standard omeprazole group-40 mg IV once daily through POD 10. The primary outcome is mean ileostomy output (mL/24 h) across POD 1-3. A >= 250 mL/day reduction is prespecified as clinically meaningful. Key secondary outcomes include: incidence of HOS (>= 1000 mL/day for >= 3 consecutive days or >= 1400 mL on any single day), time to output stabilization (<1400 mL/day for 3 consecutive days), dehydration-related complications (hyponatremia, hypokalemia, acute kidney injury), length of hospital stay and 30-day readmission rate. The primary analysis will follow the intention-to-treat principle. One interim safety analysis is planned after enrollment of the first 20 patients. Discussion: Although PPIs are commonly used to reduce ileostomy output, high-quality evidence in the early postoperative setting is lacking. STOP-HOS-1 targets the critical period when output is most variable, and complications are most frequent, using a pragmatic randomized design and an objective, clinically meaningful primary endpoint. Conclusions: STOP-HOS-1 will provide the first randomized evidence on whether intensified postoperative PPI therapy reduces early il

摘要： BBP-398 is a selective allosteric SHP2 inhibitor designed to inhibit mitogen-activated protein kinase (MAPK) pathway-driven tumors. We performed the first-in-human phase 1 trial described herein to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of BBP-398 in patients with advanced solid tumors harboring MAPK pathway mutations. Once-daily BBP-398 was administered at 350-550 mg in the dose-escalation phase (1a; n = 35) followed by a dose-expansion phase (1b; n = 37). The study endpoints were dose-limiting toxicities, treatment-emergent adverse events, pharmacokinetics, target engagement, disease control rate, progression-free survival, and overall survival. In phase 1a, 26% of the 23 evaluable patients had stable disease, with a median progression-free survival duration of 1.8 months (range, 1.7-4.1 months). In phase 1b, 30% of the 27 evaluable patients had stable disease (31% at 350 mg, 27% at 450 mg), with median progression-free survival of 2.2 months and 1.9 months at 350 mg and 450 mg, respectively. We halted dose escalation at 550 mg owing to an increased rate of thrombocytopenia and edema. At daily doses of up to 450 mg, BBP-398 exhibited an acceptable safety profile and produced disease stabilization in nearly 30% of heavily pretreated patients.

摘要： In this longitudinal study, 37 patients with severe alcohol use disorder (SAUD) were tested at the beginning (T1) and end (T2) of supervised detoxification to explore the evolution of and relationship between systemic inflammation, volumetric changes for brain grey matter (GM) and choroid plexus (ChP), and clinical symptoms. At T1, patients exhibited high levels of anxiety, depression, and craving, and had elevated plasmatic pro-inflammatory cytokines, indicating low-grade systemic inflammation. Monocyte chemoattractant protein-1 (CCL2) (MCP-1) levels correlated positively with ChP volume and severity of withdrawal symptoms, while macrophage inflammatory protein-1 beta (CCL4) (MIP-1β) also correlated with ChP volume, together suggesting an acute immune response at T1, and underscoring the ChP as a potential neuroimmune biomarker to be further evaluated in future studies. During three weeks’ abstinence, Interleukin-8 (IL-8), MIP-1β, and MCP-1 levels decreased, although MIP-1β did not return to control levels, and tumor necrosis factor-alpha (TNF-α) showed no significant reduction. Volumetric MRI analyses suggested two concurrent trajectories during detoxification. First, an overall “recovery-driven” pattern of rapidly increasing GM volume in widespread forebrain regions with parallel declines in ventricle size and craving. Second, GM in limbic cortical areas, temporal and inferior frontal cortex showed no significant volumetric gain. However, these regional volumes correlated significantly with declining MCP-1, indicative of a “deflation”, potentially related to declining microglial activation. These findings highlight the role of inflammatory processes in shaping early neuroplastic changes during detoxification and point to a central role of MCP-1 in inflammation-driven morphometric changes.

摘要： The myocardial infarction-associated transcript (MIAT), a conserved long noncoding RNA, is upregulated in failing human and murine hearts. We previously demonstrated that systemic or cardiomyocyte (CM)-restricted ablation of MIAT in mice attenuated maladaptive cardiac remodeling following myocardial infarction by suppressing the expression of proapoptotic and profibrotic genes. Despite growing evidence from human and rodent studies implicating MIAT in heart failure, the upstream regulatory pathways controlling its expression remain poorly defined. We hypothesized that MIAT is regulated either by β-arrestin1-mediated β-adrenergic receptor protective signaling or by the transcription factor BTB domain and CNC homolog 2 (BACH2), which is downregulated in failing human and murine hearts. In this study, we show that treatment with the β-blocker carvedilol downregulates cardiac MIAT via β-adrenergic receptor/β-arrestin1 signaling and concurrently upregulates BACH2. Mechanistically, our co-immunoprecipitation and electrophoretic mobility shift assays reveal that BACH2 forms a nuclear complex with β-arrestin1 and binds to conserved elements within the MIAT promoter. Using primary adult human cardiac fibroblasts (CFs) as well as human and rodent CMs, we further show that BACH2 represses profibrotic and proapoptotic MIAT expression, thereby inhibiting CF activation and CM apoptosis. Together, these findings identify a novel regulatory axis involving β-adrenergic receptor/β-arrestin1 signaling, BACH2, and MIAT, highlighting its critical role in maladaptive cardiac remodeling.

关键词： BLMP equation   breather   kink soliton   elastic interaction   resonant interaction  

摘要： In this paper, by using the Hirota bilinear method, we investigate elastic and resonant interactional solutions for the (2+1)-dimensional Boiti-Leon-Manna-Pempinelli (BLMP) equation, which is a fundamental model equation governing diverse nonlinear phenomena in fluid dynamics, plasma physics, nonlinear optics and so on. The introduced logarithmic transformation with a function of y facilitates the creation of more intricate and adaptable solution frameworks. We study three different cases of soliton interactions: the interactions between one breather and one kink soliton, the interactions between one breather and two kink solitons, and the interactions between two breathers. Through comprehensive asymptotic analysis and graphical representations, we elucidate the dynamic characteristics and fundamental properties of these nonlinear wave solutions. These solutions could uncover some novel nonlinear interactional patterns and shed light on the theoretical comprehension for the localized wave dynamics in higher-dimensional nonlinear systems.

关键词： HER2-positive gastric cancer   neoadjuvant therapy   disitamab vedotin (RC48)   adebrelimab   apatinib  

摘要： Background: Gastric cancer is the fifth most common malignancy worldwide and a major cause of cancer-related mortality, with over 750,000 deaths annually. Neoadjuvant chemotherapy remains the standard treatment for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, but recent evidence suggests that incorporating immunotherapy could offer synergistic effects. However, clinical benefits are limited in patients with low HER2 expression or programmed death-ligand 1 (PD-L1) levels due to primary or acquired resistance. To address this, we are conducting a prospective study to evaluate the efficacy and safety of a four-drug neoadjuvant regimen combining RC48 [a HER2-targeted antibody-drug conjugate (ADC)], adebrelimab (a PD-L1 inhibitor), apatinib (a VEGFR2 inhibitor), and S-1 (an oral fluoropyrimidine) in patients with locally advanced HER2-positive gastric cancer.
Methods: The DAWN trial is a prospective, open-label, phase II clinical trial designed to enroll 32 treatment-na & iuml;ve patients with resectable, locally advanced HER2-positive gastric adenocarcinoma. Eligible patients will receive 3-4 cycles of neoadjuvant therapy, with each cycle lasting 21 days. The treatment regimen includes: RC48: 2.5 mg/kg, intravenous (iv), day 1, every 3 weeks (q3w). Adebrelimab: 1,200 mg, iv, day 1, q3w. S-1: For patients with a body surface area (BSA) <= 1.5 m2, 50 mg orally, twice daily (bid), days 1-14, q3w;for BSA >1.5 m2, 60 mg orally, bid, days 1-14, q3w. Apatinib: 250 mg orally, once daily (qd), q3w. The primary endpoint is the pathological complete response (pCR) rate. Secondary endpoints include major pathological response (MPR) rate, R0 resection rate, disease-free survival (DFS), overall survival (OS), and safety. All patients must provide written informed consent before enrollment. The study protocol was approved by the independent ethics committee at each participating institution.
Discussion: Previous preclinical and clinical studies

关键词： Physical capacity   Frailty   Survival   Muscle strength  

摘要： Methods Adult patients referred for physical function evaluation by physio-or occupational therapists were evaluated with the Cumulated Ambulation Score (CAS) for basic mobility, 30sec-Sit-To-Stand-test (30s-STS) for muscle strength and function in lower extremities, and handgrip strength (HGS) as a proxy for general muscle strength. Results were categorized as normal (mean+/-1SD) or reduced (<-1SD) according to Danish sex-and age-decade reference values. The day of the first CAS assessment was used as an index for 1-year mortality in Cox regression analysis adjusted for age, sex, and multimorbidity (M3-index >1 point). Results A total of 5062 unselected patients with a mean +/- SD age of 74.5 +/- 13.9 years (54% women), were evaluated with CAS in an acute (n = 337), surgical (n = 1671) or medical (n = 3054) ward. Of these, the 30s-STS was assessed in 85% (n = 4309) and HGS in 51% (n = 2580) patients, respectively. One-year mortality was 19.3%. The adjusted hazard ratio for 1-year mortality in patients with reduced CAS-mobility (57%), reduced 30s-STS (93%), and reduced HGS (44%) was 1.98 (95%CI, 1.71-2.29), 3.57 (2.21-5.78), and 2.06 (1.66-2.56), respectively, versus those with a normal physical function in respective tests. Correspondingly, hazard ratios for patients >= 85 years of age (n = 1185) were 2.02, 3.34 and 1.98. Conclusions In older medical and surgical hospitalised patients with reduced physical function (CAS, 30s-STS or HGS) 1-year mortality was markedly increased. This simple test battery is rapid and low-cost and can easily be implemented in other hospitals, acute care facilities, and across sectors. [GRAPHICS]

关键词： Type 1 diabetes mellitus   Mesenchymal stem cells   Clinical trials  

摘要： Type 1 diabetes mellitus (T1DM) is an autoimmune disease that targets pancreatic beta cells, causing insulin deficiency and hyperglycemia. Unfortunately, till now, no conclusive treatment has been established for the entire treatment of T1DM. Today, Mesenchymal stem cells (MSCs) are widely used in regenerative medicine. MSCs have several advantages, including easy access, strong proliferation ability, differentiation power, minimal risk of tumorigenesis, and low risk of immunogenicity. However, there have been few clinical trials using MSC implants to treat T1DM. In this paper, we look at clinical trials using MSCs to treat T1DM and analyze the benefits and limitations of this approach. To collect crucial data, a comprehensive search was undertaken on articles published between 2015 and 2024. The search involved PubMed, Google Scholar, Embase, CINAHL, PsycInfo, and Cochrane databases. All MeSH words related to mesenchymal stem cells, clinical trials, and type 1 diabetes mellitus were searched. Relevant studies with full access, authored in English from 2015 to 2024, were selected. Ultimately, eleven papers that met the predetermined criteria underwent a comprehensive analysis. This systematic review reveals that MSC treatment is an acceptable treatment option for T1DM, with a positive safety profile observed in the evaluated research. The analyzed findings suggest potential benefits in sustaining beta-cell function and modifying the immunological response, which could lead to a decrease in insulin requirement. However, it remains to be proven as an alternative for insulin administration, and more detailed clinical research is necessary to verify its enduring effectiveness and reliability.

关键词： enzyme replacement therapy   Gaucher disease   lysosomal disorder  

摘要： Objective: To compare the efficacy and safety of extended interval (Q3-4W) enzyme replacement therapy (ERT) versus standard biweekly (Q2W) ERT in clinically stable type 1 Gaucher disease (GD) patients. Methods: We emulated a target trial with a sequential trial design, using data from the French Gaucher Disease Registry. Eligible patients were treated for >= 2 years biweekly without clinical events. Every 3 months, switchers to Q3-4W were matched to Q2W patients by age, sex, referral center follow-up, disease history (bone events, anemia, thrombocytopenia, splenectomy, and hepatosplenomegaly), and dose of ERT. The primary outcome was a composite of GD-related events (bone events, anemia, and thrombocytopenia). A 10% non-inferiority margin was prespecified. Secondary outcomes were biomarker changes and economic analyses. Results: Among 280 eligible GD patients, 63 switched to Q3-4W and were matched to a total of 215 Q2W patients, followed for an average of 6.3 years. No significant difference in the risk of clinical events was observed between groups (hazard ratio: 0.98 [95% confidence intervals (CI): 0.54-1.51]). During follow-up, absolute risk difference remained below the 10% non-inferiority threshold at all timepoints. Biomarkers remained stable or slightly decreased in the Q3-4W group. The dosing interval extension led to an average reduction of 55 infusions per patient, corresponding to approximately & euro;450,000 saved per patient over 6 years. Conclusion: In stable GD1 patients, extending ERT administration to every 3-4 weeks was non-inferior to the standard biweekly regimen, supporting personalized spacing strategies that may improve quality of life and reduce healthcare costs.

关键词： triptolide   Galectin-1   ferroptosis   oral squamous cell carcinoma   GPX4  

摘要： Background: Oral squamous cell carcinoma (OSCC) remains clinically challenging, particularly in advanced disease, where treatment resistance limits therapeutic outcomes. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a potential anticancer vulnerability. Galectin-1 (Gal-1/LGALS1), a beta-galactoside-binding lectin frequently overexpressed in OSCC, is associated with tumor progression and unfavorable prognosis;however, its involvement in ferroptosis regulation remains incompletely understood. Methods: To investigate whether Triptolide (TPL) influences ferroptosis-associated responses through Gal-1 modulation, OSCC cell lines (SAS and HSC-3) were treated with TPL and analyzed for cell viability, lipid reactive oxygen species (ROS) accumulation, and glutathione peroxidase 4 (GPX4) expression. Publicly available The Cancer Genome Atlas (TCGA) datasets were examined to evaluate Gal-1 expression patterns and survival associations. An OSCC xenograft mouse model was further used to assess the antitumor effects of TPL and changes in ferroptosis-related markers in vivo. Results: TPL treatment reduced cell viability and increased lipid ROS accumulation in OSCC cells, accompanied by downregulation of GPX4 expression. Gal-1 expression was also decreased following TPL exposure in vitro and in xenograft tumors. Analysis of TCGA data revealed that elevated Gal-1 expression was significantly associated with poorer overall survival in OSCC patients. Conclusions: These findings indicate that TPL induces ferroptosis-associated responses in OSCC and suggest that this effect is partly mediated through modulation of Gal-1 expression. Gal-1 may represent a clinically relevant factor influencing ferroptosis susceptibility, and targeting this pathway warrants further investigation as a potential therapeutic strategy for OSCC.