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Aims: To investigate the impact of Metabolic–Bariatric surgery (MBS) on pancreatic cancer (PCa) risk in individuals with obesity based on type 2 diabetes(T2D) status. Materials and Methods: We conducted a systematic review and meta‐analysis following the Preferred Reporting Items for Systematic Reviews and Meta‐analysis guidelines (PROSPERO: CRD42022367749). The primary outcomes were the PCa incidence rates in participants with or without T2D who underwent MBS compared with the control (non‐MBS) group. Subgroup analyses based on the MBS types were performed and a random‐effects model was employed. Sensitivity analysis was conducted by applying the leave‐one‐out meta‐analysis technique and excluding studies with a short follow‐up. Heterogeneity was evaluated using the I2 index and Cochran's Q test. Publication bias was assessed with Egger's test and the risk of bias was assessed with the Cochrane Risk‐of‐Bias tool. Results: Twelve studies, with 3,711,243 participants, were included. PCa risk was lower in the MBS group for both T2D and the overall population than in the non‐MBS group (RR = 0.46, 95% CI: 0.30–0.71 and RR = 0.21; 95% CI: 0.07–0.57, respectively), with consistent findings after excluding studies with < 3‐year follow‐up. A favourable impact was also observed in individuals without T2D (RR = 0.56, 95% CI: 0.41–0.78). When comparing the types of MBS versus control, a significant difference was observed for sleeve gastrectomy (SG) (RR = 0.24; 95% CI, 0.12–0.46 for SG and RR = 0.52; 95% CI, 0.25–1.09 for Roux‐En‐Y bypass). Egger's test showed no indication of publication bias (p = 0.417). Conclusions: MBS is associated with reduced PCa risk regardless of T2D, with a more pronounced effect in T2D patients. Additional research is needed to investigate the impact of MBS types on PCa. [ABSTRACT FROM AUTHOR]

Research on lean, energy-deficient athletic and military cohorts has broadened the concept of the Female Athlete Triad into the Relative Energy Deficiency in Sport (REDs) syndrome. REDs represents a spectrum of abnormalities induced by low energy availability (LEA), which serves as the underlying cause of all symptoms described within the REDs concept, affecting exercising populations of either biological sex. Both short- and long-term LEA, in conjunction with other moderating factors, may produce a multitude of maladaptive changes that impair various physiological systems and adversely affect health, well-being, and sport performance. Consequently, the comprehensive definition of REDs encompasses a broad spectrum of physiological sequelae and adverse clinical outcomes related to LEA, such as neuroendocrine, bone, immune, and hematological effects, ultimately resulting in compromised health and performance. In this review, we discuss the pathophysiology of REDs and associated disorders. We briefly examine current treatment recommendations for REDs, primarily focusing on nonpharmacological, behavioral, and lifestyle modifications that target its underlying cause-energy deficit. We also discuss treatment approaches aimed at managing symptoms, such as menstrual dysfunction and bone stress injuries, and explore potential novel treatments that target the underlying physiology, emphasizing the roles of leptin and the activin-follistatin-inhibin axis, the roles of which remain to be fully elucidated, in the pathophysiology and management of REDs. In the near future, novel therapies leveraging our emerging understanding of molecules and physiological axes underlying energy availability or lack thereof may restore LEA-related abnormalities, thus preventing and/or treating REDs-related health complications, such as stress fractures, and improving performance. [ABSTRACT FROM AUTHOR]

Severe insulin resistance syndromes are a heterogeneous group of rare disorders characterized by profound insulin resistance, substantial metabolic abnormalities, and a variety of clinical manifestations and complications. The etiology of these syndromes may be hereditary or acquired, due to defects in insulin potency and action, cellular responsiveness to insulin, and/or aberrations in adipose tissue function or development. Over the past decades, advances in medical technology, particularly in genomic technologies and genetic analyses, have provided insights into the underlying pathophysiological pathways and facilitated the more precise identification of several of these conditions. However, the exact cellular and molecular mechanisms of insulin resistance have not yet been fully elucidated for all syndromes. Moreover, in clinical practice, many of the syndromes are often misdiagnosed or underdiagnosed. The majority of these disorders associate with an increased risk of severe complications and mortality; thus, early identification and personalized clinical management are of the essence. This Review aims to categorize severe insulin resistance syndromes by disease process, including insulin receptor defects, signaling defects, and lipodystrophies. We also highlight several complex syndromes and emphasize the need to identify patients, investigate underlying disease mechanisms, and develop specific treatment regimens., Introduction This Review, inspired by the 100th anniversary of insulin's discovery, focuses on severe insulin resistance syndromes, which constitute only the tip of the iceberg of a wide variety of [...]

Recent insights into the pathophysiologic underlying mechanisms of obesity have led to the discovery of several promising drug targets and novel therapeutic strategies to address the global obesity epidemic and its comorbidities. Current pharmacologic options for obesity management are largely limited in number and of modest efficacy/safety profile. Therefore, the need for safe and more efficacious new agents is urgent. Drugs that are currently under investigation modulate targets across a broad range of systems and tissues, including the central nervous system, gastrointestinal hormones, adipose tissue, kidney, liver, and skeletal muscle. Beyond pharmacotherapeutics, other potential antiobesity strategies are being explored, including novel drug delivery systems, vaccines, modulation of the gut microbiome, and gene therapy. The present review summarizes the pathophysiology of energy homeostasis and highlights pathways being explored in the effort to develop novel antiobesity medications and interventions but does not cover devices and bariatric methods. Emerging pharmacologic agents and alternative approaches targeting these pathways and relevant research in both animals and humans are presented in detail. Special emphasis is given to treatment options at the end of the development pipeline and closer to the clinic (ie, compounds that have a higher chance to be added to our therapeutic armamentarium in the near future). Ultimately, advancements in our understanding of the pathophysiology and interindividual variation of obesity may lead to multimodal and personalized approaches to obesity treatment that will result in safe, effective, and sustainable weight loss until the root causes of the problem are identified and addressed. [ABSTRACT FROM AUTHOR]

Pre-B-cell leukaemia (PBX) is a transcription factor family ( PBX1, PBX2, PBX3 and PBX4 ) that regulates important cellular functions and has been identified to be involved in human cancers. This study aimed to explore the expression of PBX genes and their clinical significance in colorectal cancer (CRC). We analysed the differential expression of PBX genes in CRC vs. normal tissue, using the Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/) and ONCOMINE platform (https://www.oncomine.org/). The UALCAN (http://ualcan.path.uab.edu/) interactive OMICS web-server was used to evaluate the epigenetic regulation of PBX genes via their promoter methylation status. We found that only PBX4 was upregulated whereas PBX1 and PBX3 were downregulated (644 tumour vs. 51 normal samples) (P<0.001). The methylation status of PBX4 promoter appeared to be decreased (P=1.4e-07) whereas the methylation status of PBX1 and PBX3 promoters was increased (P=3.8e-04 and P=3.2e-07, respectively) in cancer vs. normal samples. To determine the prognostic value of PBXs , we conducted a Kaplan-Meier survival analysis and multivariable COX regression. We observed that high PBX4 expression was associated with increased risk for a worse overall survival (OS) in the TCGA CRC patient cohort (n=639), (HR 1.46, 95% CI 1.14-1.88, P=0.003) adjusted for age, gender, tumour location and metastases. We conducted in vitro gene expression modulation experiments to investigate the impact of PBX4 overexpression in CRC cell (HCT116) growth. Additionally, we evaluated the RNA expression of epithelial-mesenchymal transition (EMT) and angiogenesis markers. In vitro studies showed that PBX4 overexpression increased CRC cell proliferation (P<0.001) and upregulated the expression of EMT markers VIM, CDH1, CDH2, ZEB1, SNAI1 (P<0.05) and angiomarker VEGFA (P<0.0001). Lastly, through the Cistrome data browser (http://dbtoolkit.cistrome.org/) we investigated putative transcriptional regulators and we performed gene set enrichment analysis in Enrichr server (https://maayanlab.cloud/Enrichr/) to identify related biological processes. Nineteen factors were identified to be putative regulators of PBX4 and gene set enrichment analysis showed that biological processes related to cell cycle and cell proliferation were enriched (GO:0051726: CDK8, JUN, JUND , and IRF1 , P=0.001). In conclusion, our study identified PBX4 as a potential novel oncopromoter in CRC and its overexpression was found to be associated with increased risk for worse survival rate., Competing Interests: None., (AJCR Copyright © 2022.)