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关键词： Gastric cancer   Fibrotic TME   CAF   FZD1   SLIT2  

摘要： BackgroundA fibrotic tumor microenvironment (TME) promotes tumor progression by the interactions between tumor cells and cancer-associated fibroblasts (CAFs) in the extracellular matrix (ECM), which enhance tumor cell survival and growth, and by suppressing antitumor immunity. However, how characteristic gene expression and amplification in cancer cells drive the formation of a fibrotic TME in patients with gastric cancer (GC) is *** performed genomic and transcriptomic analyses via datasets from The Cancer Genome Atlas and the Asian Cancer Research Group to identify amplified and overexpressed genes associated with the presence of a fibrotic TME in tumors. Syngeneic mouse models of GC and multiplexed immunohistochemistry (IHC) were used to validate the findings of the transcriptomic analysis and investigate the underlying *** Frizzled class receptor 1 (FZD1) gene was frequently amplified and highly expressed in GC patients with fibrotic tumors, and FZD1 expression was related to a poor prognosis. The overexpression of Fzd1 in murine GC tumor cells was significantly associated with enhanced tumor fibrosis and growth and reduced infiltration of CD3+ lymphocytes and CD8+ T cells into tumors. SLIT2 secretion was increased in Fzd1-overexpressing tumor cells via the canonical WNT-beta-catenin pathway, and SLIT2 activated CAFs to produce more ECM through the SLIT2-ROBO1 *** study highlights the potential of FZD1 as a biomarker for predicting fibrotic status in patients with GC and the SLIT2-ROBO1 axis as a therapeutic target to reverse a fibrotic and immunosuppressive TME.

关键词： GLP-1 receptor agonists   Peripheral artery disease   Major adverse limb events (MALE)   Type 2 diabetes mellitus   Peripheral revascularization  

摘要： IntroductionGLP-1 receptor agonists (GLP-1 RAs) are hypothesized to reduce peripheral arterial disease (PAD) complications through mechanisms, including enhanced cardiac function, improved cardiovascular risk factors and inflammation, and local vascular effects such as angiogenesis. We assessed the effectiveness of GLP-1 RAs in lowering the risk of major adverse limb events (MALE) among individuals with diabetes and diagnosed *** was a meta-analysis of a structured search of MEDLINE, PubMed, and SCOPUS databases until 16 June 2025. Eligibility criteria were randomized controlled trials of GLP-1 RAs reporting major adverse limb events from PAD. We identified five articles published up to June 2025 that met the inclusion and exclusion criteria. Study selection, data extraction, and quality assessment were carried out by two reviewers working independently and in duplicate, to assess eligibility and risk of bias, and extract data from eligible studies. Random-effects models were used to pool estimates across the included studies. Meta-analyses were performed using *** studies were included in the meta-analysis, comprising 25,067 patients in total. There were 433 revascularization events. Compared with the control group, the overall log odds ratio for revascularization with GLP-1 RA treatment was 0.87 (95% confidence interval [CI]: 0.73, 1.05;p = 0.13). Two of the studies reported amputation rates (comprising 224 events), with an overall log odds ratio of 0.82 (95% CI: 0.53, 1.27;p = 0.37) for GLP-1 RA *** this meta-analysis of randomized trials, GLP-1 RAs were not associated with statistically significant differences in revascularization or amputation outcomes in individuals with diabetes and PAD.

关键词： alpha-1-acid glycoprotein   clozapine   C-reactive protein   inflammation   therapeutic drug monitoring  

摘要： Several publications have reported elevated clozapine concentrations in patients experiencing infections or inflammatory reactions. Proposed mechanisms include increased levels of pro-inflammatory cytokines that may inhibit clozapine metabolism and enhanced binding of clozapine to the acute phase protein alpha-1-acid glycoprotein (AGP). We collected serum samples sent to our routine laboratory over a 15-month period for the analysis of clozapine. In the 1106 eligible samples, we measured AGP and C-reactive protein (CRP) levels. By using a linear mixed effects regression model, we found a clear association between higher AGP and CRP levels and higher dose-adjusted clozapine concentrations. As an example, an increase in the CRP level from 5 to 60 mg/L or an increase in the AGP level from 0.5 to 1.5 g/L would be expected to cause a more than twofold increase in the clozapine concentration. Our findings support and extend previous case reports and studies, suggesting that increased AGP levels during inflammatory states may play a significant role in the rise of clozapine plasma concentrations observed during illness. We propose that in addition to the clozapine concentration, CRP levels and clinical signs of adverse effects and toxicity should be closely monitored in patients with infectious or inflammatory diseases.

关键词： Alzheimer's disease   backward digit span test   Boston process approach   digital assessment of cognition   episodic memory   executive control   mild cognitive impairment   Philadelphia (repeatable) verbal learning test  

摘要： Background: In prior research, the Digital Assessment of Cognition (DAC), a brief digitally administered neuropsychological protocol that assesses verbal episodic memory, verbal working memory, and language, has been used to classify a small sample of memory clinic patients (n = 77) into four meaningful clinical groups. Objective: The current research sought to extend these findings with a considerably larger sample. Methods: The DAC was administered to 179 ambulatory care/memory clinic patients (45.30% female;91.10% Caucasian). A comprehensive analysis of DAC core outcome measures and behavior reflecting process/errors was undertaken. Traditional paper/pencil assessment was also obtained. Using Jak, Bondi criteria (2009), paper/pencil test results classified patients into five groups: cognitively unimpaired (CU;n = 74), subtle cognitive impairment (SCI;n = 21), amnestic mild cognitive impairment (aMCI;n = 21), combined dysexecutive/mixed MCI (dys/mxMCI;n = 22), and mild dementia (n = 41). Results: The aMCI group presented with many of the classic features consistent with amnesia, i.e., rapid forgetting, reduced free recall clustering, and profligate responding to recognition foils. Latency for correct recognition responding was slower for aMCI compared to the CU group and appears to be associated with a neurocognitive network measuring both memory and language-related operations. SCI and dys/mxMCI groups tended to produce more perseverations on working memory test trials;and produced lower scores on DAC executive outcome measures that assessed auditory span and semantic fluency. Conclusions: These findings support the criterion and construct validity of the DAC. When brought to scale the DAC could be an effective tool to assess for emergent MCI and dementia syndromes.

关键词： Übergewicht   Adipositas   Diabetes mellitus Typ 2   GLP   1   Rezeptor   Agonisten   Inkretine   Co   Agonisten   overweight   obesity   diabetes mellitus type 2   GLP   1 receptor agonists   inkretins   coagonists  

摘要： Obesity is currently considered as adiposity based chronic disease with BMI as therapeutic target for prevention of obesity associated complications. For treatment of obesity, a stepwise approach is recommended including multifactorial basal therapy with nutrition counseling, exercise training and behavior modification. Further steps comprise adjuvant pharmacological treatment and bariatric surgery. With the development of incretin based medications that activate GLP-1 and GIP receptors for increase in satiety, an impressive improvement in effectivity of obesity medications is observed. Licensed substances in Germany include the GLP-1 receptor agonists liraglutide and semaglutide, and the GLP-1/GIP receptor coagonist tirzepatide. Trial data reveal weight losses of on average 7.5 kg after 160 weeks for liraglutide, up to 17.4 kg after 68 weeks for semaglutide, and up to 22.5 kg after 72 weeks for tirzepatide. In addition, semaglutide demonstrated positive results in cardiovascular outcome trials. The weight reducing effects of incretin based substances are close to those achieved by bariatric interventions, therefore closing the gap between lifestyle intervention and bariatric surgery.

关键词： CKD   diabetes   kidney failure  

摘要： Key PointsCompared with glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors were associated with a lower risk of kidney failure among individuals with type 2 *** of combination SGLT2 inhibitor and glucagon-like peptide-1 receptor agonist was infrequent but associated with lower kidney failure risk in high-risk *** should prioritize SGLT2 inhibitors in patients with type 2 diabetes to prevent progression to kidney *** relative effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for kidney protection, both individually and in combination, is incompletely understood. We sought to compare associations of GLP-1 receptor agonists, SGLT2 inhibitors, and both medications in combination with incident kidney failure among individuals with type 2 *** conducted a target trial emulation study with new user, active comparator design using deidentified electronic health records data from Optum Labs Data Warehouse. We included adults with type 2 diabetes who were prescribed a GLP-1 receptor agonist, SGLT2 inhibitor, or both between January 1, 2015, and June 29, 2024. We estimated the association of medication class with incident kidney failure using inverse probability of treatment weighted Cox proportional hazards regression models in both intention-to-treat and as-treated *** were 504,151 individuals with 2965 kidney failure events during a median 2.35 (interquartile range 1.09-4.32) years of follow-up. Average prescription duration was 0.69 years for GLP-1 receptor agonists, 0.62 years for SGLT2 inhibitors, and 0.44 years for combination therapy. In the intention-to-treat analysis, compared with GLP-1 receptor agonists, the risk of kidney failure was significantly lower with SGLT2 inhibitors (hazard ratio [HR], 0.82;95% confidence interval [CI], 0.73 to 0.91) but no different with combinat

关键词： Plant remains   Fermented beverages   Feasting   Long distance trading   Agro-pastoralist societies   Northwest Argentina  

摘要： In this article we discuss the historical landscapes of agro-pastoralist societies that inhabited the Puna high elevation desert of northwest Argentina from 1,600 to 1,000 bp, based on our research on exceptionally well preserved macro-remain assemblages from Alero 1, a small rock shelter within the Punta de la Pe & ntilde;a 9 archaeological site, Antofagasta de la Sierra. A deposit of plant remains was found there, dated between 1,507 and 1,176 cal bp, primarily consisting of Neltuma spp. (Fabaceae, Caesalpinioideae) and Geoffroea decorticans (Fabaceae, Faboideae) fruit and pod remains. The homogeneity and concentration of the remains at approximately 2,700 per L of sediment in this deposit, along with its date range, represent continuing family ceremonies at the site, in which food and fermented beverages were shared, made from pods and fruits which had been brought from the Monte region where they grew. Based on these findings, we propose the existence of a periodic and recurrent movement of people, probably facilitated by family social networks, between the high Puna desert and the mid-altitude valleys about 100 km away where Monte woods grew, and Neltuma (algarrobo) and Geoffroea (cha & ntilde;ar) pods and fruits could be gathered for these ceremonial practices.

关键词： Optical coherence tomography angiography   pachychoroid neovasculopathy   macular neovascularization   swept-source OCT   imaging protocols   anastomoses  

摘要： Purpose To compare the effectiveness of 3 x 3 mm versus 6 x 6 mm swept source optical coherence tomography angiography (SS-OCTA) scan patterns in detecting and characterizing pachychoroid-associated macular neovascularization (MNV).Methods We retrospectively analyzed 79 eyes from 79 treatment-na & iuml;ve patients with pachychoroid-associated MNV using SS-OCTA. Both 3 x 3 mm and 6 x 6 mm scans were obtained on the same day. Two masked graders independently evaluated neovascular network area and presence of *** Mean lesion areas were significantly larger in 6 x 6 mm scans compared to 3 x 3 mm scans (0.869 +/- 0.868 mm(2) vs 0.699 +/- 0.697 mm(2);p = 0.005). However, analysis of anastomoses revealed superior detection with 3 x 3 mm scans, with 12 eyes (15.2%) showing anastomoses only in 3 x 3 mm scans compared to 4 eyes (5.1%) visible only in 6 x 6 mm scans (p = 0.021). Interobserver agreement was excellent for area measurements (ICC = 0.92).Conclusions While 6 x 6 mm SS-OCTA scans demonstrate larger overall neovascular area measurements, the 3 x 3 mm scan pattern provides superior visualization of anastomoses and fine vascular details in pachychoroid-associated MNV. These findings suggest that 3 x 3 mm scans should be considered the preferred protocol for detailed evaluation of these lesions.