Loss of STIM2, but not of STIM1, drives colorectal cancer metastasis through metabolic reprogramming and the ATF4 ER stress pathway.

The large amounts of calcium (Ca) stored in the endoplasmic reticulum (ER) and the controlled release of this Ca store into the cytosol regulate many cellular functions, and altered ER Ca homeostasis induces ER stress. Stromal-interacting molecules 1 and 2 (STIM1/2) are homologous ER-resident Ca sensors that synergistically activate cytosolic Ca influx through Orai channels to promote Ca-dependent changes in gene expression and ER Ca refilling. Here, we demonstrated that reduced abundance of STIM2, but not that of STIM1, was associated with poor prognosis in colorectal cancer (CRC).

Apixaban Versus Enoxaparin for Venous Thromboembolism Prophylaxis in Colorectal Surgery.

Introduction: Guidelines recommend postoperative venous thromboembolism (VTE) prophylaxis in colorectal cancer patients, as well as others at high risk of VTE. However, compliance, especially with injectable prophylaxis strategies remains challenging for patients and providers. Here, we evaluate the efficacy of apixaban versus enoxaparin in patients undergoing colorectal surgery (CRS) for postoperative VTE prophylaxis.

Twenty Years of Disease-Modifying Anti-IBD Drug Use Preceding Colectomy for Refractory IBD-Associated Colitis.

Background: Disease-modifying anti-IBD drugs such as infliximab have altered the treatment of IBD. Despite the increasing availability of disease-modifying anti-IBD drugs, many individuals with IBD still require surgical resection, and the role of disease-modifying anti-IBD drugs in delaying colectomy is limited.

Objective: To assess use patterns of disease-modifying anti-IBD drug use preceding colectomy for refractory IBD.

Low Rates of Short-Term Anastomotic Complications After Kono-S versus Side-to-Side Stapled Anastomosis.

Introduction: The Kono-S (KS) anastomosis for Crohn's disease (CD) is associated with improved endoscopic and clinical long-term outcomes. Ileocolonic anastomoses in CD are associated with an unacceptable anastomotic complication rate - up to 40%. Investigation of short-term benefits of KS is thus warranted.

Cystathionine Gamma-Lyase Regulates TNF-α-Mediated Injury Response in Human Colonic Epithelial Cells and Colonoids.

Cystathionine gamma-lyase (CSE) and TNF-α are now recognized as key regulators of intestinal homeostasis, inflammation, and wound healing. In colonic epithelial cells, both molecules have been shown to influence a variety of biological processes, but the specific interactions between intracellular signaling pathways regulated by CSE and TNF-α are poorly understood. In the present study, we investigated these interactions in normal colonocytes and an organoid model of the healthy human colon using CSE-specific pharmacological inhibitors and siRNA-mediated transient gene silencing in analytical and functional assays in vitro.

Identification of differentially expressed genes and splicing events in early-onset colorectal cancer.

Background: The incidence of colorectal cancer (CRC) has been steadily increasing in younger individuals over the past several decades for reasons that are incompletely defined. Identifying differences in gene expression profiles, or transcriptomes, in early-onset colorectal cancer (EOCRC, < 50 years old) patients versus later-onset colorectal cancer (LOCRC, > 50 years old) patients is one approach to understanding molecular and genetic features that distinguish EOCRC.

Methods: We performed RNA-sequencing (RNA-seq) to characterize the transcriptomes of patient-matched tumors and adjacent, uninvolved (normal) colonic segments from EOCRC (n=21) and LOCRC (n=22) patients.

Loss of STIM2 in colorectal cancer drives growth and metastasis through metabolic reprogramming and PERK-ATF4 endoplasmic reticulum stress pathway.

The endoplasmic reticulum (ER) stores large amounts of calcium (Ca), and the controlled release of ER Ca regulates a myriad of cellular functions. Although altered ER Ca homeostasis is known to induce ER stress, the mechanisms by which ER Ca imbalance activate ER stress pathways are poorly understood. Stromal-interacting molecules STIM1 and STIM2 are two structurally homologous ER-resident Ca sensors that synergistically regulate Ca influx into the cytosol through Orai Ca channels for subsequent signaling to transcription and ER Ca refilling.

Disease Severity Impairs Generation of Intestinal Organoid Cultures From Inflammatory Bowel Disease Patients.

Introduction: Chronic inflammation of the intestinal epithelium is an underlying cause of the two main types of inflammatory bowel disease (IBD), ulcerative colitis (UC), and Crohn's disease (CD). Ex vivo organoids derived from the intestinal epithelium are a useful model to study IBD. Whether such cultures can be established from surgically resected diseased IBD intestinal tissues has not been fully explored.

Control of Paneth cell function by HuR regulates gut mucosal growth by altering stem cell activity.

Rapid self-renewal of the intestinal epithelium requires the activity of intestinal stem cells (ISCs) that are intermingled with Paneth cells (PCs) at the crypt base. PCs provide multiple secreted and surface-bound niche signals and play an important role in the regulation of ISC proliferation. Here, we show that control of PC function by RNA-binding protein HuR via mitochondria affects intestinal mucosal growth by altering ISC activity.

Creating a Surgical Biobank: The Hershey Medical Center Experience.

Background: Tissue harvesting at the time of surgery offers surgeons and scientists a unique opportunity to discover and better understand disease pathophysiology. Tissue biobanking presents challenges in patient consents, specimen collection, preparation, and storage, but the potential for scientific discovery justifies the effort. Although the number of tissue biobanks is increasing worldwide, information regarding necessary infrastructure, process flow, and management of expected obstacles is lacking.

The Microbiome of Complicated Diverticulitis: An Imbalance of Sulfur-Metabolizing Bacteria.

Background: The progression to acute diverticulitis from the relatively benign condition of colonic diverticulosis is not well characterized. A smaller subset may even develop complicated (perforated) diverticulitis resulting in sepsis and/or death. Characterizing the differences between recurrent, uncomplicated diverticulitis, and the more virulent, complicated diverticulitis is necessary to guide clinical decision-making.

TCF7L1 Regulates Expression in Colorectal Cancer Cells.

Mutations in components of the Wnt/β-catenin signaling pathway drive colorectal cancer (CRC), in part, by deregulating expression of genes controlled by the T-cell factor (TCF) family of transcription factors. TCFs contain a conserved DNA binding domain that mediates association with TCF binding elements (TBEs) within Wnt-responsive DNA elements (WREs). Intestinal stem cell marker, leucine-rich-repeat containing G-protein-coupled receptor 5 (LGR5), is a Wnt target gene that has been implicated in CRC stem cell plasticity.

Transcriptome Analyses Identify Deregulated in Early Onset Colorectal Cancer.

Despite a global decrease in colorectal cancer (CRC) incidence, the prevalence of early-onset colorectal cancer (EOCRC), or those occurring in individuals before the age of 50, has steadily increased over the past several decades. When compared to later onset colorectal cancer (LOCRC) in individuals over 50, our understanding of the genetic and molecular underpinnings of EOCRCs is limited. Here, we conducted transcriptomic analyses of patient-matched normal colonic segments and tumors to identify gene expression programs involved in carcinogenesis.

Th17 Cell-Derived Amphiregulin Promotes Colitis-Associated Intestinal Fibrosis Through Activation of mTOR and MEK in Intestinal Myofibroblasts.

Background & Aims: Intestinal fibrosis is a significant complication of Crohn's disease (CD). Gut microbiota reactive Th17 cells are crucial in the pathogenesis of CD; however, how Th17 cells induce intestinal fibrosis is still not completely understood.

Methods: In this study, T-cell transfer model with wild-type (WT) and Areg Th17 cells and dextran sulfate sodium (DSS)-induced chronic colitis model in WT and Areg mice were used.

Characteristics and Outcomes of Right- Versus Left-Sided Early-Onset Colorectal Cancer.

Background: Early-onset colorectal cancers are increasing in incidence. Studies reported more left-sided cancers in patients aged <50 years. Some advocate for screening via flexible sigmoidoscopy at age 40 years.

Stoma-less IPAA Is Not Associated With Increased Anastomotic Leak Rate or Long-term Pouch Failure in Patients With Ulcerative Colitis.

Background: There is debate regarding the utility of diverting loop ileostomy with IPAA construction in patients requiring colectomy for ulcerative colitis.

Objective: This study aimed to determine whether the omission of diverting loop ileostomy at the time of IPAA construction increases the risk of complications.

Design: This was a retrospective study.

Special Considerations of Anastomotic Leaks in Crohn's Disease.

Rates of anastomotic leak following intestinal resections in the setting of inflammatory bowel disease are significantly influenced by clinical characteristics. While the literature can be contradictory due to significant heterogeneity in the published data, several common themes appear to consistently arise. With respect to Crohn's disease, low serum albumin, preoperative abscess, reoperative abdominal surgery, and steroid use are associated with an increased risk of postoperative intra-abdominal septic complications.

CD163L1CXCL10 Macrophages are Enriched Within Colonic Lamina Propria of Diverticulitis Patients.

Background: Inflammation of diverticula, which are outpouchings of the colonic bowl wall, causes diverticulitis. Severe cases of diverticulitis require surgical intervention. Through RNA-seq analysis of intestinal tissues, we previously found that the innate immune response was deregulated in surgical diverticulitis patients.

COLQ and ARHGAP15 are Associated with Diverticular Disease and are Expressed in the Colon.

Background: Diverticular disease is a common but poorly understood disease of the gastrointestinal tract. Recent studies have identified several single nucleotide polymorphisms (SNPs) that are associated with diverticular disease.

Materials And Methods: The genotypes of three SNPs (rs4662344 in ARHGAP15, rs7609897 in COLQ, and rs67153654 in FAM155A) were identified by Taqman assay in 204 patients with diverticular disease.

Impairment of Tissue-Resident Mesenchymal Stem Cells in Chronic Ulcerative Colitis and Crohn's Disease.

Background And Aims: Little is known about the presence and function of tissue-resident mesenchymal stem cells [MtSCs] within the gastrointestinal mucosa in health and inflammatory bowel disease [IBD]. The contribution of MtSCs to the generation of inflammatory fibroblasts during IBD is also poorly understood. We hypothesized that IBD-MtSCs are impaired and contribute to the generation of the pathological myofibroblasts in IBD.

Dichotomous role of the human mitochondrial Na/Ca2/Li exchanger NCLX in colorectal cancer growth and metastasis.

Despite the established role of mitochondria in cancer, the mechanisms by which mitochondrial Ca (mtCa) regulates tumorigenesis remain incompletely understood. The crucial role of mtCa in tumorigenesis is highlighted by altered expression of proteins mediating mtCa uptake and extrusion in cancer. Here, we demonstrate decreased expression of the mitochondrial Na/Ca/Li exchanger NCLX () in human colorectal tumors and its association with advanced-stage disease in patients.

Transcriptomic analysis of ileal tissue from Crohn's disease patients identifies extracellular matrix genes that distinguish individuals by age at diagnosis.

Crohn's disease (CD) is a debilitating gastrointestinal (GI) disorder that can impact the entirety of the GI tract. While substantial progress has been made in the medical management of CD, it remains incurable, frequently relapses, and is a significant financial and medical burden. The pathophysiology of CD is not well understood, but it is thought to arise in genetically susceptible individuals upon an environmental insult.

Clinical and Genetic Factors Associated With Complications After Crohn's Ileocolectomy.

Background: Ileocolectomy is the most common surgery performed for Crohn's disease, and postoperative complications occur frequently. There has been minimal evaluation of complications after ileocolectomy as a function of both clinical and genetic factors.

Objective: The purpose of this study was to evaluate both genetic and clinical factors associated with complications after Crohn's ileocolectomy.

The Impact of Preoperative Anti-TNFα Therapy on Postoperative Outcomes Following Ileocolectomy in Crohn's Disease.

Background: Controversy remains regarding the impact of anti-TNFα agents on postoperative outcomes in Crohn's disease.

Methods: Patients (≥ 18 years) with Crohn's disease (ICD-9, 555.0-555.