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关键词： atopic dermatitis   cytokine   neurogenic inflammation   neuropeptide   skin organ culture  

摘要： Background Atopic dermatitis (AD) is a common, relapsing inflammatory skin disease driven by an immune imbalance, microbial dysbiosis, and skin barrier impairment, culminating in (neurogenic) inflammation and itch. We hypothesized that the neuropeptide and pruritogen endothelin-1 (ET-1) contributes to AD pathology by impeding skin barrier formation via its cognate receptor ETAR and TRPA1, a cation channel involved in neurogenic inflammation, pain, and *** We utilized differentiated human keratinocytes and ex vivo human skin organ cultures in vitro to evaluate the impact of ET-1 on human skin barrier function. ET-1 effects were assessed at the RNA level by RT-qPCR and at the protein level by quantitative immunofluorescence microscopy. Barrier integrity was monitored using real-time cell analysis and transwell permeability *** ET-1 markedly reduced cell resistance in differentiated keratinocytes, an effect abrogated by the ETAR antagonist bosentan. ET-1 significantly decreased expression of skin differentiation markers filaggrin and loricrin, and tight junction proteins occludin, claudin-1, and claudin-4, at mRNA and protein levels. ETAR-specific siRNA in combination with ET-1, rescued ET-1-mediated downregulation of filaggrin. Furthermore, TRPA1 antagonist HC-030031 abrogated the impairing effect of ET-1 on the skin barrier. We observed increased inflammatory responses of ET-1-stimulated keratinocytes, suggesting that the ET-1-initiated barrier disruption could be mediated by IL-6 and IL-1 beta and induced by *** Our findings suggest that a neurogenic inflammation axis ET-1/ETAR/TRPA1 contributes to skin barrier impairment in AD by repressing differentiation markers and tight junction proteins. Additionally, we demonstrate ETAR-blockage as a rational therapeutic modality for patients with AD.

关键词： laminectomy   substance abuse   complications   alcohol   nicotine   opioids   elective surgery  

摘要： Study Design Retrospective cohort study.
Objectives To assess the effect of alcohol, nicotine, and opioid use history on 90 day and 1 year postoperative complications after elective laminectomy.
Methods Using the TriNetX Database (2004-2025), adult patients undergoing elective laminectomy were divided into cohorts with a history of alcohol, nicotine, or opioid abuse/dependence, matched 1:1 with controls (age, sex, race, body mass index, comorbidities). Exclusions included malignancy, preceding trauma, and prior complications. Outcomes included the development of acute kidney failure, sepsis, emergency department visits, deep vein thrombosis, myocardial infarction, pulmonary embolism, pneumonia, stroke, and mortality at 90 days and 1 year.
Results Matched cohorts comprised 4053 alcohol, 22 469 nicotine, and 2724 opioid patients, each with controls. Alcohol abuse was significantly associated with increased odds of death, DVT, MI, pneumonia, sepsis, and stroke following elective laminectomy at 90 days, and with acute renal failure, PE, pneumonia, stroke, sepsis, DVT, and death at 1 year (P < 0.05). Nicotine dependence significantly elevated the risk of death, MI, pneumonia, and sepsis at 90 days, and at 1 year, remained associated with increased odds of acute renal failure, stroke, ED visits, MI, pneumonia, sepsis, and death (P < 0.05). Opioid abuse was significantly linked to higher risks of DVT, MI, pneumonia, sepsis, stroke, and death at 90 days, with persistent 1-year risks for acute renal failure, MI, pneumonia, sepsis, and death (P < 0.05).
Conclusions Alcohol, nicotine, and opioid use significantly heighten postoperative complications after laminectomy, underscoring the need for preoperative risk evaluation and tailored interventions.

关键词： Cardiovascular disease   Cardiovascular-kidney-metabolic syndrome   Chronic kidney disease   Glucagon-like peptide-1 (GLP-1) receptor agonists   Kuwait   Obesity   Semaglutide   Type 2 diabetes  

摘要： Obesity, type 2 diabetes (T2D), cardiovascular disease (CVD), and chronic kidney disease (CKD) are overlapping conditions that drive premature morbidity and mortality worldwide. Care remains siloed and reactive despite shared risk factors and strong evidence for early intervention. To support integrated disease management, the American Heart Association (AHA) recently introduced the concept of cardiovascular-kidney-metabolic (CKM) syndrome, recognizing the bidirectional links between metabolic, kidney, and cardiovascular health. Kuwait faces one of the highest burdens of CKM-related diseases globally. Three-quarters of adults are overweight or have obesity, and 28% have diabetes, both of which are leading causes of mortality and health system strain. Yet multidisciplinary care remains limited, and innovative pharmacotherapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), are underused. A panel of Kuwaiti endocrinologists, cardiologists, and nephrologists convened to assess barriers to optimal CKM care and define practical recommendations. Discussions focused on current gaps in screening, care coordination, provider education, and access to therapies. Evidence on GLP-1 RAs was reviewed, considering the demonstrated benefits for weight loss, glycemic control, cardiovascular outcomes, and CKD progression. The expert group agreed that multidisciplinary, risk-stratified, and patient-centered approaches are urgently needed. Recommendations include earlier screening and diagnosis, improved integration across specialties, healthcare provider upskilling, public awareness campaigns, and broader access to GLP-1 RAs. Semaglutide was highlighted as a clinically valuable option owing to its broad efficacy and safety profile. Adopting a CKM care model tailored to Kuwait's specific challenges, with appropriate use of GLP-1 RAs, can reduce disease burden, improve outcomes, and increase healthcare system efficiency. The local implementation of evidence-based, cros

关键词： Bioinformatics   Gene expression   Hepatic stellate cell   Liver fibrosis   Neuraminidase  

摘要： Objective(s): Liver fibrosis is an abnormal wound-healing response. Neuraminidase 1 (NEU1) is a sialidase that has been reported to be involved in the development of cancers and metabolic diseases. However, the role of NEU1 in liver fibrosis remains unreported. This study explored the potential role of NEU1 in liver fibrosis. Materials and Methods: Liver fibrosis was induced in C57BL/6J mice by using carbon tetrachloride (CCl4) and thioacetamide (TAA). The CCl(4 )group was established by intraperitoneal injection of CCl4 (1.0 & micro;l/g body weight, 1:4 dilution in olive oil) twice weekly for six weeks. In the TAA group, mice were provided drinking TAA water at 300 mg/l for 12 weeks. The expression of NEU1, Collagen-1, alpha-SMA and TIMP1 was detected by western blotting. The expression of NEU1 was measured by immunohistochemistry. Bioinformatics analysis was performed to explore the correlation between NEU1 and liver fibrosis in the GSE84044 dataset. Western blot analyses were performed to investigate the molecular mechanisms of NEU1 in hepatic stellate cells (HSCs). Results: NEU1 expression was up-regulated in liver fibrosis tissues compared with normal liver tissues. The level of NEU1 was positively correlated with liver fibrosis in Chronic Hepatitis B (CHB) patients according to bioinformatics analysis. NEU1 levels were increased after stimulation with TGF beta in vitro. Knocking down NEU1 decreased the activation of HSCs by suppressing TGF-beta/Smad3 signaling. Conclusion: This study showed that NEU1 plays a crucial role in activating HSCs via TGF-beta/Smad3 signaling. Therefore, it may be a potential therapeutic target for liver fibrosis.

关键词： antagonist   GIP receptor   glucose-dependent insulinotropic polypeptide   hypoglycaemia   type 1 diabetes  

摘要： Aims: In type 1 diabetes, glucose-dependent insulinotropic polypeptide (GIP) increases glucagon secretion during low plasma glucose and improves time in the glycaemic range during daytime. To explore the glucose-stabilising potential of GIP in type 1 diabetes, we evaluated the effects of exogenous and endogenous GIP on plasma glucose excursions in a setting of excess prandial insulin and physical activity after meal ingestion. Materials and Methods: In a randomised, placebo-controlled, double-blind crossover design, 12 men with type 1 diabetes underwent three separate study days involving a 4.5-h continuous intravenous infusion of GIP, the GIP receptor antagonist GIP(3-30)NH2, and placebo, respectively, during which ingestion of a standardised mixed meal with subcutaneous injection of excess prandial insulin (125% of normal dose) was followed by 30 min of intermediate resistance bicycling (to increase the risk of postprandial hypoglycaemia). Results: The GIP infusion did not protect against hypoglycaemia, but compared to GIP(3-30)NH2 infusion, it attenuated postprandial maximum plasma glucose by 1.5 +/- 0.5 mmol/L (mean +/- standard error of the mean) (p = 0.048). GIP(3-30)NH2 did not exacerbate glucose excursions or risk of hypoglycaemia compared with placebo. The amount of glucose infused to avoid plasma glucose <2.5 mmol/L was similar on all three study days. No differences were found in C-peptide, insulin or glucagon levels. Conclusion: GIP did not prevent hypoglycaemia following excess prandial insulin and physical activity after meal ingestion in males with type 1 diabetes, but it reduced peak postprandial plasma glucose compared to GIP(3-30)NH2.

关键词： NCI Awardee Skills Development Consortium   NASDC   Skills Development   NCI-funded Junior Investigators   Evaluation   Mentorship   Leadership   Resilience   Cell and Gene Therapy   Immuno-Oncology   Health Disparities   Program Evaluation  

摘要： The pilot National Cancer Institute (NCI) Awardee Skills Development Consortium (NASDC) was designed and funded by the NCI in 2019 to support a group of multi-institutional educational projects to help early-career NCI grantees remain academically competitive. Retention and academic competitiveness of early-career awardees are critical for advancing cancer research;therefore, NASDC sought to develop the next generation of leaders to meet the nation's biomedical, behavioral, and clinical cancer research needs. NASDC comprised a group of institutions supported through cooperative agreement awards issued by the NCI, including a U24 coordinating center (U24CC) to support logistics and evaluations and four institutional awardees to deliver evidence-based scientific and educational content (UE5 awards for research education projects [UE5]). The U24CC managed applications, conducted course evaluations, and facilitated the consortium's administrative structure. The consortium infrastructure consisted of a Governance Steering Committee with five working groups to manage the projects. A web portal was developed to help recruit eligible applicants to attend the courses. Each course was delivered five to six times over 3 years, and an evaluation system was implemented to assess outcomes within courses and across courses and cohorts. Originally intended to be in-person short courses, the COVID pandemic forced the projects to adapt to virtual platforms. NASDC aimed to build a stable pool of leading cancer researchers. NASDC successfully supported junior faculty NCI grantees by delivering evidence-based educational content, despite the COVID-19 pandemic. The intent of the program was implemented smoothly, and courses were delivered effectively. Although NCI did not reissue the program in 2021 for budgetary reasons, some of these courses are now funded by an R25 mechanism. This is the first in a series of papers detailing this program's outcomes.

关键词： 1,2-propanediol   carbon nanotubes   glycerol hydrogenolysis   heterogeneous catalysis   structure-activity-selectivity-relationship  

摘要： Multiwall carbon nanotube (NC7000) supported mono-, bi-, and trimetallic catalysts were synthesized and tested in a multi-batch reactor setup supported by data-driven modeling for the chemical hydrogenolysis of glycerol to 1,2-Propanediol (1,2-PDO) at 220 degrees C under 30 bar hydrogen pressure in aqueous solution. ICP-OES, N-2-physisorption, scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive x-ray spectroscopy (EDX), powder x-ray diffraction (XRD) and x-ray photoelectron spectroscopy (XPS) were used to investigate the physico-chemical properties of the synthesized catalysts. Interesting structure-activity-selectivity correlations could be deduced from the different metal ratios and combinations. While Ru was by far the most active monometallic species (X = 100%), followed by Pt (X = 80%) and Ir (X = 65%), it suffered from a very low 1,2-PDO selectivity (S < 10%). Combining Ru with the more selective transition-metals RuX2 (X = Fe, Co, or Ni) maintained the high activity (X > 95%) but only moderately increased 1,2-PDO selectivity (S = 20%-30%). Interestingly, combining Ru with Cu in a bimetallic RuCu2 catalyst slightly decreased activity (X = 81%) but drastically improved 1,2-PDO selectivity (S = 58%). Moreover, a trimetallic combination of RuMCu2 (M = Pt, Pd, Ir) did not further increase activity (X = 50%-70%) but could push 1,2-PDO selectivity up to 79% for the trimetallic RuIrCu2 catalyst. Most prominently, a final metal ratio variation for the RuCux catalyst was derived with the help of the data-driven models producing the most promising RuCu3/NC7000) catalyst combining both high activity (X = 78%) with a very high 1,2-PDO selectivity (S = 79%) resulting in the highest 1,2-PDO yield of 58% in a nearly closed carbon balance (C > 95%). This lays the foundation for implementing this highly active and selective catalyst in a future SMART reactor for glycerol valorization.