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INTRODUCTION:Growing gastrointestinal cancers in the United States necessitate further research due to substantial health care and economic impacts. The aim of this study was to analyze trends and future projections for 5 major gastrointestinal cancers (colorectal, pancreatic, liver, stomach, and esophageal).METHODS:Data were sourced from the Surveillance, Epidemiology, and End Results database; National Center for Health Statistics; and Global Burden of Diseases databases. An age-period-cohort model using the Bayesian Information Criterion method was applied to project incidence and mortality rates to 2040.RESULTS:Men consistently exhibited higher incidence and mortality rates across all gastrointestinal cancers, with significant variation across the 51 US states. From 2000 to 2020, colorectal cancer incidence and mortality rates declined across all racial groups, except for the incidence rates of American Indian and Alaska Native (AIAN) men, Hispanic men, and Hispanic women, which remained stable. Pancreatic cancer incidence increased across all groups except for AIAN men, while mortality rates rose only for White men and Hispanic women. Liver cancer incidence rose among AIAN men and White, AIAN, and Hispanic women, while mortality rates declined for most groups. Stomach cancer incidence and mortality either declined or stabilized, and esophageal cancer rates showed a general decline. By 2040, increases in incidence and mortality are projected for most gastrointestinal cancers, particularly in men.DISCUSSION:Despite varied trends over the past 2 decades, an overall increase in gastrointestinal cancer incidence and mortality rates is anticipated in the next 20 years in the United States, underscoring the need for effective prevention and intervention strategies.

INTRODUCTION:Cyclic vomiting syndrome (CVS) imposes a substantial burden, but epidemiological data are scarce. This study aimed to estimate the incidence and prevalence of CVS, comorbid conditions, and treatment patterns, using administrative databases in the United States.METHODS:This cross-sectional study used claims data from Merative MarketScan Commercial/Medicare Supplemental and Medicaid databases in all health care settings. Incidence and prevalence rates for 2019 were calculated and stratified by age, sex, region, and race/ethnicity. Patient characteristics were reported among newly diagnosed patients with CVS (i.e., no documented claims for CVS before 2019). CVS was defined as having 1+ inpatient and/or 2+ outpatient CVS claims that were 7+ days apart.RESULTS:The estimated prevalence of CVS was 16.7 (Commercial/Medicare) and 42.9 (Medicaid) per 100,000 individuals. The incidence of CVS was estimated to be 10.6 (Commercial/Medicare) and 26.6 (Medicaid) per 100,000 individuals. Both prevalence and incidence rates were higher among female individuals (for both Commercial/Medicare and Medicaid). Comorbid conditions were common and included abdominal pain (56%-64%), anxiety (32%-39%), depression (26%-34%), cardiac conditions (39%-42%), and gastroesophageal reflux disease (30%-40%). Despite a diagnosis of CVS, only 32%-35% had prescriptions for prophylactic treatment and 47%-55% for acute treatment within the first 30-day period following diagnosis.DISCUSSION:This study provides the first population-level estimates of CVS incidence and prevalence in the United States. Comorbid conditions are common, and most patients with CVS do not receive adequate treatment. These findings underscore the need for improving disease awareness and developing better screening strategies and effective treatments.

INTRODUCTION:We describe female authorship trends in gastroenterology (GI) randomized controlled trial literature as a novel focus on gender bias in academic GI.METHODS:Using a systematic PubMed search, we extracted GI randomized controlled trial reports published from 2011 to 2022. We describe time trends in proportions of females among first and last authors overall and within GI subspecialties and high-impact journals.RESULTS:The proportion of females increased from 25.4% to 36.8% and from 14.3% to 24.8% among first and last authors, respectively. Smaller increases in female authorship occurred in most subgroups, although there were proportionately fewer females among authors in high-impact journals and advanced therapeutic endoscopy publications.DISCUSSION:Over the past decade, female authorship in GI RCT reports has increased. However, female representation, particularly among senior authors and in high-impact journals, remains significantly lower. Despite recent improvements, female still constitutes a minority of the authors of original GI RCTs.

INTRODUCTION:Bile acid diarrhea (BAD) is an underrecognized and socially debilitating disease caused by high concentrations of bile acids in the colon. Bile acids directly and indirectly promote carcinogenesis. In this article, we investigated whether individuals with BAD have an increased risk of gastrointestinal (GI) cancers.METHODS:By using the Danish health registries, adult individuals with BAD were identified by International Classification of Diseases 10th revision code K90.8 or referral to the diagnostic ⁷⁵selenium-homotaurocholic acid test followed by prescription of a bile acid sequestrant within 365 days (n = 5,245). Age- and sex-matched individuals without BAD were included for comparison (n = 52,450). We analyzed the cumulative incidence of GI cancers after BAD diagnosis and the odds ratios (ORs) of GI cancer 8 and 15 years before BAD diagnosis/matching.RESULTS:Cumulative incidence of GI cancer 6 years after BAD diagnosis/matching was 1.6% in the BAD group and 1.1% in controls (P = 0.01). The ORs of total GI cancer 8 and 15 years before BAD diagnosis were 6.16 (5.08-7.48) and 5.19 (4.28-6.29), respectively. Furthermore, 47 individuals with BAD (0.9%) and 250 (0.5%) controls died of GI cancer.DISCUSSION:This nationwide cohort study indicates an association between BAD and GI cancers. We found both a higher incidence of GI cancer after BAD diagnosis compared with controls and increased OR of GI cancer before BAD diagnosis. Bearing in mind the underdiagnosis of BAD, the delay of BAD diagnosis, and the carcinogenic effect of bile acids, these findings warrant further investigations of the risk of GI cancer in individuals with BAD.

G-protein-coupled receptors (GPCRs) are the largest superfamily of transmembrane proteins and the targets of over 30% of currently marketed pharmaceuticals. Although several structures have been solved for GPCR–G protein complexes, few are in a lipid membrane environment. Here, we report cryo-EM structures of complexes of neurotensin, neurotensin receptor 1 and Gα i1 β 1 γ 1 in two conformational states, resolved to resolutions of 4.1 and 4.2 Å. The structures, determined in a lipid bilayer without any stabilizing antibodies or nanobodies, reveal an extended network of protein–protein interactions at the GPCR–G protein interface as compared to structures obtained in detergent micelles. The findings show that the lipid membrane modulates the structure and dynamics of complex formation and provide a molecular explanation for the stronger interaction between GPCRs and G proteins in lipid bilayers. We propose an allosteric mechanism for GDP release, providing new insights into the activation of G proteins for downstream signaling. Structures of GPCR neurotensin receptor 1 (NTSR1) in complex with neurotensin and Gα i1 β 1 γ 1 in a lipid bilayer environment and without stabilizing antibodies reveal extensive interactions at the GPCR–G protein interface.

Background Prehabilitation has emerged as a strategy to prepare patients for elective abdominal cancer surgery with documented improvements in postoperative outcomes. The aim of this study was to assess the evidence for prehabilitation interventions of relevance to the older adult. Methods Systematic searches were conducted using MEDLINE, Web of Science, Scopus, CINAHL and PsychINFO. Studies of preoperative intervention (prehabilitation) in patients undergoing abdominal cancer surgery reporting postoperative outcomes were included. Age limits were not set as preliminary searches revealed this would be too restrictive. Articles were screened and selected based on PRISMA guidelines, and assessment of bias was performed. Qualitative, quantitative and meta‐analyses of data were conducted as appropriate. Results Thirty‐three studies (3962 patients) were included. Interventions included exercise, nutrition, psychological input, comprehensive geriatric assessment and optimization, smoking cessation and multimodal (two or more interventions). Nine studies purposely selected high‐risk, frail or older patients. Thirty studies were at moderate or high risk of bias. Ten studies individually reported benefits in complication rates, with meta‐analyses for overall complications demonstrating significant benefit: multimodal (risk difference −0·1 (95 per cent c.i. −0·18 to −0·02); P = 0·01, I2 = 18 per cent) and nutrition (risk difference −0·18 (−0·26 to −0·10); P < 0·001, I2 = 0 per cent). Seven studies reported reductions in length of hospital stay, with no differences on meta‐analysis. Conclusion The conclusions of this review are limited by the quality of the included studies, and the heterogeneity of interventions and outcome measures reported. Exercise, nutritional and multimodal prehabilitation may reduce morbidity after abdominal surgery, but data specific to older patients are sparse. Antecedentes La pre‐habilitación ha surgido como una estrategia para preparar a los pacientes para la cirugía electiva del cáncer abdominal con mejoras documentadas en los resultados postoperatorios. El objetivo de este estudio fue evaluar la evidencia sobre las intervenciones de pre‐habilitación relevantes en adultos de edad avanzada. Métodos Se realizaron búsquedas sistemáticas utilizando MEDLINE, Web of Science, Scopus, CINAHL y PsychINFO. Registro PROSPERO: CRD42019120381. Se incluyeron estudios de intervención preoperatoria (pre‐habilitación) en pacientes sometidos a cirugía oncológica abdominal que describiesen resultados postoperatorios. No se fijaron límites en la edad dado que las búsquedas preliminares revelaron que ello sería demasiado restrictivo. Los artículos fueron examinados y seleccionados en base a las guías PRISMA y se realizó una evaluación del sesgo. Se llevó a cabo un análisis cualitativo, cuantitativo y metaanálisis de los datos según fuese apropiado. Resultados Se incluyeron 33 estudios (3.962 patients). Las intervenciones incluyeron ejercicio, nutrición, intervención psicológica, evaluación geriátrica global y optimización, abandono del tabaquismo y multimodal (dos o más intervenciones). Nueve estudios seleccionaron expresamente una población de pacientes de elevado riesgo, frágiles o de edad avanzada. Treinta estudios presentaban un riesgo moderado/alto de sesgo. Diez estudios describieron de forma individual beneficios en las tasas de complicaciones con metaanálisis para las complicaciones globales demostrando un beneficio significativo: multimodal (diferencia de riesgo ‐0,1 (i.c. del 95% −0,18 a −0,02); P = 0,01, I2 = 18%) e intervención nutricional (diferencia de riesgo −0,18 (i.c. del 95% −0,26 a −0,10); P < 0,001, I2 = 0%). Siete estudios describieron reducciones en la duración de la estancia hospitalaria, sin diferencias en el metaanálisis. Conclusión Las conclusiones de esta revisión están limitadas por la calidad de los estudios incluidos, heterogeneidad de las intervenciones y descripción de las medidas de resultados. Las intervenciones de pre‐habilitación de ejercicio, nutricionales y multimodales puede reducir la morbilidad tras cirugía abdominal, pero los datos concretos en pacientes de edad avanzada son escasos. This systematic review and meta‐analysis suggests that multimodal and nutrition‐alone prehabilitation interventions may reduce postoperative complications and length of hospital stay. More high‐quality research is needed specifically on prehabilitation for older patients. Use multimodal prehabilitation to reduce morbidity

While androgens may function via nuclear androgen receptor (nAR) to increase bladder cancer (BCa) progression, the impact of androgens on muscle invasive BCa, which contains nearly 80% nAR-negative cells, remains unclear. To dissect the androgens potential impacts on these nAR-negative muscle invasive BCa, we first found that the androgens, dihydrotestosterone (DHT) might function via a novel membrane AR (mAR-SLC39A9) to increase nAR-negative BCa cell migration and invasion. Mechanism dissection revealed that DHT/mAR-SLC39A9 might function by altering Gαi protein-mediated MAPK/MMP9 intracellular signaling to increase nAR-negative BCa cell migration and invasion. Preclinical studies using multiple in vitro nAR-negative BCa cell lines and an in vivo mouse model all demonstrated that targeting this newly identified DHT/mAR-SLC39A9/Gαi/MAPK/MMP9 signaling with small molecules mAR-SLC39A9-shRNA or Gαi-shRNA, and not the classic antiandrogens including enzalutamide, bicalutamide, or hydroxyflutamide, could suppress nAR-negative BCa cell invasion. Results from human clinical samples surveys also indicated the positive correlation of this newly identified DHT/mAR signaling with BCa progression and prognosis. Together, these results suggest that androgens may not only function via the classic nAR to increase the nAR-positive BCa cell invasion, they may also function via this newly identified mAR-SLC39A9 to increase the nAR-negative/mAR-positive BCa cell invasion.

BackgroundA GI hospitalist (GIH) is a physician who practices in the inpatient setting performing consultations and endoscopic procedures. Obscure small bowel bleeding is a common inpatient diagnosis that is difficult to manage and associated with longer hospitalizations. Having an onsite GIH physician with expertise in video capsule endoscopy (VCE) and double-balloon enteroscopy (DBE) has the potential to improve patient outcomes.AimsThis study will be the first to explore how implementing a GIH model and providing a GIH with training in DBE can affect the outcomes of patients with small bowel pathology.MethodsWe performed a retrospective study of patients who received an inpatient DBE at an academic medical center before and after initiation of a GIH model and credentialing of a GIH in DBE. We compared outcomes, including procedure volumes, diagnostic and therapeutic yields, procedure duration, time to procedure, and length of stay.ResultsThere was a 46.5% increase in the number of DBEs performed by the GIH. The diagnostic yield increased from 56.3 to 74.0% (OR 2.2, 95% CI 1.2–4.2), and the proportion of DBEs with a therapeutic intervention increased from 38.0 to 65.4% (OR 3.1, 95% CI 1.4–7.0). The total procedure time increased from 77.8 to 96.4 min (p < 0.05) with a GIH.ConclusionHaving a GIH perform inpatient DBEs was associated with an increased number of procedures, duration of procedures, diagnostic yield, and therapeutic interventions. The onsite presence of a GIH with competency in DBE improves the care of hospitalized patients with small bowel pathology.

Asymmetric cell divisions allow stem cells to balance proliferation and differentiation. During embryogenesis, murine epidermis expands rapidly from a single layer of unspecified basal layer progenitors to a stratified, differentiated epithelium. Morphogenesis involves perpendicular (asymmetric) divisions and the spindle orientation protein LGN, but little is known about how the apical localization of LGN is regulated. Here, we combine conventional genetics and lentiviral-mediated in vivo RNAi to explore the functions of the LGN-interacting proteins Par3, mInsc and Gα i3 . Whereas loss of each gene alone leads to randomized division angles, combined loss of Gnai3 and mInsc causes a phenotype of mostly planar divisions, akin to loss of LGN . These findings lend experimental support for the hitherto untested model that Par3–mInsc and Gα i3 act cooperatively to polarize LGN and promote perpendicular divisions. Finally, we uncover a developmental switch between delamination-driven early stratification and spindle-orientation-dependent differentiation that occurs around E15, revealing a two-step mechanism underlying epidermal maturation. During embryogenesis, the single layer of mouse epidermal progenitors becomes a stratified and differentiated epithelium. Fuchs and colleagues show that the polarity proteins Par3–mInsc and Gα i3 act cooperatively to polarize LGN and promote perpendicular divisions to induce stratification.

Gastric cancer (GC) is one of the leading causes of human mortality around the world. We have previously shown that Gαi1 (the inhibitory subunit 1 of the heterotrimeric guanine nucleotide-binding protein) recruitment to ligand-activated receptor tyrosine kinases (RTKs) is essential for signaling. Testing its role in GC cancer-promoting functions, we found that Gαi1 is upregulated in human GC, correlating with poor overall survival. In established and primary human GC cells, Gαi1 shRNA (small hairpin RNA) or knockout produced significant anti-GC cell activity, proliferation and migration was inhibited, and apoptosis was activated. Conversely, ectopic Gαi1 overexpression promoted proliferation and migration of GC cells in vitro. By examining the tumor-suppressive miRNA microRNA-200a (miR-200a), we found that miR-200a directly silenced Gαi1 to induce anti-GC cell activity. The expression of miR-200a was downregulated in human GC, correlating with upregulation of a novel miR-200a-targeting long non-coding RNA (LncRNA), PINK1 (PTEN Induced Kinase 1)-AS. RNA immunoprecipitation, RNA-pull down, and RNA fluorescence in situ hybridization assays confirmed that PINK1-AS directly binds to miR-200a. Silencing PINK1-AS in GC cells led to miR-200a accumulation, Gαi1 downregulation, and inhibition of GC cell progression in vitro, whereas PINK1-AS upregulation produced the converse results. Significantly, anti-GC cell activity induced by PINK1-AS shRNA was ameliorated by the expression of miR-200a antisense or the 3ʹ-UTR (untranslated region)-depleted Gαi1. In vivo, the growth of subcutaneous MGC-803 xenografts in nude mice was inhibited by PINK1-AS shRNA, but accelerated by PINK1-AS overexpression. Patient-derived GC xenograft growth in nude mice was largely inhibited after intratumoral injection of PINK1-AS shRNA lentivirus. In conclusion, PINK1-AS promotes Gαi1-driven GC progression by sponging miR-200a.