Management of Patients With Acute Lower Gastrointestinal Bleeding: An Updated ACG Guideline.

Acute lower gastrointestinal bleeding (LGIB) is a common reason for hospitalization in the United States and is associated with significant utilization of hospital resources, as well as considerable morbidity and mortality. These revised guidelines implement the Grading of Recommendations, Assessment, Development, and Evaluation methodology to propose recommendations for the use of risk stratification tools, thresholds for red blood cell transfusion, reversal agents for patients on anticoagulants, diagnostic testing including colonoscopy and computed tomography angiography (CTA), endoscopic therapeutic options, and management of antithrombotic medications after hospital discharge. Important changes since the previous iteration of this guideline include recommendations for the use of risk stratification tools to identify patients with LGIB at low risk of a hospital-based intervention, the role for reversal agents in patients with life-threatening LGIB on vitamin K antagonists and direct oral anticoagulants, the increasing role for CTA in patients with severe LGIB, and the management of patients who have a positive CTA. We recommend that most patients requiring inpatient colonoscopy undergo a nonurgent colonoscopy because performing an urgent colonoscopy within 24 hours of presentation has not been shown to improve important clinical outcomes such as rebleeding. Finally, we provide updated recommendations regarding resumption of antiplatelet and anticoagulant medications after cessation of LGIB.

Two Cases of Biphasic Synovial Sarcoma With Expression of PAX8 and ER: A Diagnostic Pitfall.

Synovial sarcoma (SS) is a high-grade malignant neoplasm frequently arising in the deep soft tissue of the lower and upper extremities of young adults. Primary SS in the pelvis is extremely rare with scattered case reports. It often causes a diagnostic challenge in small biopsy and/or with aberrant expression of immunohistochemical markers. Here, we report 2 unusual cases of SS in the pelvis. Microscopically both cases present with biphasic morphology including spindle and epithelioid cells. In addition, the tumor cells in both cases expressed PAX8 and estrogen receptor. PAX8 is a transcription factor usually expressed in tumors of thyroid gland, kidney, and Müllerian system origin. The expression of PAX8 especially with co-expression of estrogen receptor can be misleading and result in a diagnosis of Müllerian tumors in female patients with pelvic masses. The diagnosis of SS for both cases was confirmed either with the fluorescence in situ hybridization or reverse transcription polymerase chain reaction showing a SS18 (SYT) (18q11) gene rearrangement. It is imperative to include SS in the differential diagnosis for malignant neoplasms exhibiting monotonous spindle cells (monophasic SS) and biphasic mixed monotonous spindle and epithelioid tumor cells in female patients with a pelvic mass. Molecular study for SS18 translocation is essential for the diagnosis in such cases.

Idiopathic myointimal hyperplasia of the mesenteric veins: A systematic review and individual patient data regression analysis.

BACKGROUND AND AIM: Idiopathic myointimal hyperplasia of the mesenteric veins (IMHMV) is an uncommon cause of colonic ischemia for which surgical treatment is typically curative. We describe clinical, radiologic, and endoscopic findings in IMHMV patients to provide clinicians with a framework for pre-surgical identification of this rare disease. METHODS: We performed a systematic review of seven databases for IMHMV cases and identified additional cases from Yale New Haven Hospital records. To identify features specifically associated with colonic ischemia due to IMHMV, we performed multivariate logistic regression analysis incorporating data from a large cohort of patients with biopsy-proven ischemic colitis. RESULTS: A total of 124 patients with IMHMV were identified (80% male, mean age 53 years, 56% Caucasian). Presenting symptoms were most commonly abdominal pain (86%) and diarrhea (68%). The most affected areas were the sigmoid colon (91%) and rectum (61%). Complications associated with diagnostic delay occurred in 29% of patients. Radiologic vascular abnormalities including non-opacification of the inferior mesenteric vein were observed in 35% of patients. Of the patients, 97% underwent curative surgical resection. Compared with non-IMHMV colonic ischemia, IMHMV was significantly associated with younger age, male sex, absence of rectal bleeding on presentation, rectal involvement, and mucosal ulcerations on endoscopy. CONCLUSION: IMHMV is a rare, underreported cause of colonic ischemia that predominantly involves the rectosigmoid. Our findings suggest younger age, rectal involvement, and absence of rectal bleeding as clinical features to help identify select patients presenting with colonic ischemia as having higher likelihood of IMHMV and therefore consideration of upfront surgical management.

A National Survey of the Infrastructure and Scope of Practice for Gastroenterology Hospitalists.

BACKGROUND: Hospital-based specialty-trained physicians have become more prevalent with emerging data suggesting benefit in consult and procedure volume, reduced complication rates, and increased practice productivity. Interest in gastroenterology (GI) hospitalist programs has increased in recent years. However, little is known regarding the types of GI hospitalist models that currently exist. AIMS: To characterize the infrastructure of GI hospitalist models across the USA. METHODS: A 50-question survey was distributed to the GI Hospitalist Special Interest Group of the American Society for Gastrointestinal Endoscopy. Information on demographics, hospital infrastructure, and compensation were collected. RESULTS: 31 of 33 (94%) GI hospitalists completed the questionnaire. Respondents were mostly male (65%), white (48%) or Asian (42%). Most GI hospitalists spent at least half of their clinical time dedicated to the inpatient consultation service (73%), during which they had no other clinical duties. Most services had endoscopy suites with dedicated inpatient endoscopy rooms (66%), over 4 h allotted for procedures (83%), and were available on weekends (62%). Over half of GI hospitalists reported having outpatient duties, the most common being performance of direct access endoscopy (69%). Outside of clinical responsibilities, GI hospitalists were most frequently involved in clinical education or fellowship program leadership (48%). Most GI hospitalists were salaried with an incentive-based bonus based on work relative value units. CONCLUSION: GI hospitalist programs are varied throughout the USA but key commonalities exist between most programs.

A strategy to improve the solubility and bioavailability of the insoluble drug piperlongumine through albumin nanoparticles.

Piperlongumine (PL) is a biologically active alkaloid derived from peppers, has significant cytotoxic effects on cancer with no cytotoxicity. This study used NabTM technology to prepare PL albumin nanoparticles (PL-BSA-NPs) to improve water solubility and bioavailability. We carried out a pharmacological evaluation of the PL-BSA-NPs. The morphological profile of the PL-BSA-NPs was relatively uniform, with an average particle size of approximately 210 nm, with drug load of 2.1% and encapsulation rate of 87.6%. PL-BSA-NPs were stable for 4 weeks when stored at 4°C. In vitro release behavior of the PL-BSA-NPs showed a sustained release, with a cumulative release of 67.24% in approximately 24 hours. The pharmacokinetic properties of PL-BSA-NPs were shown that PL-BSA-NPs could maintain a certain level of blood drug concentration for a long time, thus demonstrating the sustained release and increased bioavailability of PL. Finally, we investigated the in vitro antitumor activity of the PL-BSA-NPs and found that PL can significantly inhibit HepG2 cell proliferation, and that PL-BSA-NPs enhanced the inhibitory effect of PL on this proliferative effect. Thus, we concluded that PL can destroy liver cancer cells by increasing ROS levels. These results suggested that PL-BSA-NPs show promising potential as a targeted anti-tumor drug.

Validation of the Adapted Clavien-Dindo in Trauma (ACDiT) Classifications in Medical and Surgical Management of Acute Diverticulitis.

OBJECTIVES: To validate the adapted Clavien-Dindo in trauma (ACDiT) tool as a novel outcome measure for patients with acute diverticulitis managed both operatively and nonoperatively. BACKGROUND: Complications following diverticulitis are difficult to classify because no traditional tools address patients managed both operatively and nonoperatively. The ACDiT grading system-graded from 0 to 5b-is applied in this manner but has not yet been validated for this patient group. METHODS: We performed a 5-year observational study of patients with acute diverticulitis at a safety-net hospital. Baseline demographics and hospitalization data were collected. ACDiT scores were assigned, and validation was undertaken by comparing scores with hospital-free days, and verifying that higher scores were associated with known risk factors for poor outcomes. Inverse probability weighted propensity scores were assigned for surgical management, and inverse probability weighted regression analysis was used to determine factors associated with ACDiT ≥ grade 2. RESULTS: Of 260 patients, 188 (72%) were managed nonoperatively. Eighty (31%) developed a complication; 73 (91%) were grades 1 to 3b. Higher grades correlated inversely with hospital-free days (rs = -0.67, P < 0.0001) for all patients and for nonoperative (rs = -0.63, P < 0.0001) and operative (rs = -0.62, P < 0.0001) patients. Hinchey 2 to 3 and initial operative management had higher odds of having a complication of ACDiT ≥ grade 2. CONCLUSION: The ACDiT tool was successfully applied to acute diverticulitis patients managed operatively and nonoperatively, is associated with known risk factors for adverse outcomes. ACDiT may be considered a meaningful outcome measure for comparing strategies for acute diverticulitis.

Gastric Bezoar: Retrieve it, Leave it, or Disbelieve it?

OBJECTIVES: To determine the demographics, potential risk factors, endoscopic interventions and outcomes relating to gastric bezoars in pediatric patients; and comparing results with previously published literature. METHODS: Retrospective series by chart review of patients identified by International Classification of Diseases-9 codes 938 and 935, using the following Medical Subject Headings: 1, term bezoar; 2, Keywords gastric bezoar∗ or gastric foreign body∗. RESULTS: Thirty pediatric patients between ages of 2 to 18 years were found with gastric bezoars, with a female predominance. Majority had a phytobezoar. Six patients were diagnosed with dysautonomia, implying possible role of autonomic dysfunction contributing to abnormal gastric retention. Frequent symptoms included abdominal pain, nausea and vomiting, a decrease in appetite, and unintentional weight loss. A higher prevalence of underlying gastrointestinal disorders was found in those with bezoars. Nuclear medicine gastric emptying scan performed in 13 children was significantly abnormal in only 4 of these children. Most patients were treated with endoscopic removal of the bezoar. Endoscopic removal was accomplished by Roth net, generally requiring multiple passes. At follow-up, most of the children had improvement of symptoms, with bezoar recurrence in 1 patient. CONCLUSIONS: This is to our knowledge the largest series of gastric bezoars in pediatrics. On the basis of our review, phytobezoars may be under-reported in pediatrics. Bezoars should be considered in children presenting with chronic abdominal pain, nausea, and vomiting; even in developmentally normal children and those with normal gastric emptying. We suggest that dysautonomia and underlying gastrointestinal disorders may be potential risk factors.

Gastrointestinal Bleeding in Patients With Coronavirus Disease 2019: A Matched Case-Control Study.

INTRODUCTION: Although current literature has addressed gastrointestinal presentations including nausea, vomiting, diarrhea, abnormal liver chemistries, and hyperlipasemia as possible coronavirus disease 2019 (COVID-19) manifestations, the risk and type of gastrointestinal bleeding (GIB) in this population is not well characterized. METHODS: This is a matched case-control (1:2) study with 41 cases of GIB (31 upper and 10 lower) in patients with COVID-19 and 82 matched controls of patients with COVID-19 without GIB. The primary objective was to characterize bleeding etiologies, and our secondary aim was to discuss outcomes and therapeutic approaches. RESULTS: There was no difference in the presenting symptoms of the cases and controls, and no difference in severity of COVID-19 manifestations (P > 0.05) was observed. Ten (32%) patients with upper GIB underwent esophagogastroduodenoscopy and 5 (50%) patients with lower GIBs underwent flexible sigmoidoscopy or colonoscopy. The most common upper and lower GIB etiologies were gastric or duodenal ulcers (80%) and rectal ulcers related to rectal tubes (60%), respectively. Four of the esophagogastroduodenoscopies resulted in therapeutic interventions, and the 3 patients with rectal ulcers were referred to colorectal surgery for rectal packing. Successful hemostasis was achieved in all 7 cases that required interventions. Transfusion requirements between patients who underwent endoscopic therapy and those who were conservatively managed were not significantly different. Anticoagulation and rectal tube usage trended toward being a risk factor for GIB, although it did not reach statistical significance. DISCUSSION: In COVID-19 patients with GIB, compared with matched controls of COVID-19 patients without GIB, there seemed to be no difference in initial presenting symptoms. Of those with upper and lower GIB, the most common etiology was peptic ulcer disease and rectal ulcers from rectal tubes, respectively. Conservative management seems to be a reasonable initial approach in managing these complex cases, but larger studies are needed to guide management.

Design, synthesis, and biological activity of a novel series of benzofuran derivatives against oestrogen receptor-dependent breast cancer cell lines.

A docking study of a novel series of benzofuran derivatives with ERα was conducted. In this study, we report the synthesis of a novel series of benzofuran derivatives and evaluation of their anticancer activity in vitro against MCF-7 human breast cancer cells, as well as their potential toxicity to ER-independent MDA-MB-231 breast cancer cells, human renal epithelial HEK-293 cells, and human immortal keratinocytes (HaCaT cells) by using the MTT colorimetric assay. The screening results indicated that the target compounds exhibited anti-breast cancer activity. The target compound 2-benzoyl-3-methyl-6-[2-(morpholin-4-yl)ethoxy]benzofuran hydrochloride (4e) exhibited excellent activity against anti-oestrogen receptor-dependent breast cancer cells and low toxicity. The preliminary structure-activity relationships of the target benzofuran derivatives have been summarised. In conclusion, the novel benzofuran scaffold may be a promising lead for the development of potential oestrogen receptor inhibitors.

To Scope or Not to Scope? The Safety of Upper Endoscopy in the Setting of Pulmonary Embolism.

OBJECTIVES: We aimed to describe the frequency of upper endoscopy and associated outcomes in subjects hospitalized with upper GI bleeding (UGIB) and pulmonary embolism (PE). METHODS: We performed a cross-sectional study using the Nationwide Inpatient Sample from 2007 to 2014. The association between upper endoscopy and in-hospital mortality was evaluated using propensity score matching. RESULTS: A total of 44,412 subjects had a coexistent PE and UGIB. 63.5% had an inpatient upper endoscopy with a lower likelihood of in-hospital death and a shorter length of stay. CONCLUSIONS: A substantial proportion of inpatients with PE and UGIB undergo endoscopy with a relatively lowmortality rate.

Discovery of 4,5-Dihydro-1H-thieno[2',3':2,3]thiepino [4,5-c]pyrazole-3-carboxamide Derivatives as the Potential Epidermal Growth Factor Receptors for Tyrosine Kinase Inhibitors.

The epidermal growth factor receptors (EGFRs), in which overexpression (known as upregulation) or overactivity have been associated with a number of cancers, has become an attractive molecular target for the treatment of selective cancers. We report here the design and synthesis of a novel series of 4,5-dihydro-1H-thieno [2',3':2,3]thiepino[4,5-c]pyrazole-3-carboxamide derivatives and the screening for their inhibitory activity on the EGFR high-expressing human A549 cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). A Docking simulation was performed to fit compound 6g and gifitinib into the EGFR to determine the probable binding models, and the binding sites and modes conformation of 6g and gifitinib were exactly similar, the two compounds were stabilized by hydrogen bond interactions with MET769. Combining with the biological activity evaluation, compound 6g demonstrated the most potent inhibitory activity (IC50 = 9.68 ± 1.95 µmol·L⁻1 for A549). Conclusively, 4,5-dihydro-1H-thieno[2',3':2,3]thiepino[4,5-c]pyrazole-3-carboxamide derivatives as the EGFR tyrosine kinase inhibitors were discovered, and could be used as potential lead compounds against cancer cells.

Discovery of a Novel HIV-1 Integrase/p75 Interacting Inhibitor by Docking Screening, Biochemical Assay, and in Vitro Studies.

Protein-protein interaction between lens epithelium-derived growth factor (LEDGF/p75) and HIV-1 integrase becomes an attractive target for anti-HIV drug development. The blockade of this interaction by small molecules could potentially inhibit HIV-1 replication. These small molecules are termed as LEDGINs; and several newly identified LEDGINs have been reported to significantly reduce HIV-1 replication. Through this project, we have finished the docking screening of the Maybridge database against the p75 binding site of HIV-1 integrase using both DOCK and Autodock Vina software. Finally, we have successfully identified a novel scaffold LEDGINs inhibitor DW-D-5. Its antiviral activities and anticatalytic activity of HIV-1 integrase are similar to other LEDGINs under development. We demonstrated that the combination of DW-D-5 and FDA approved anti-HIV drugs resulted in additive inhibitory effects on HIV-1 replication, indicating that DW-D-5 could be an important component of combination pills for clinic use in HIV treatment.

MiR-25 suppresses 3T3-L1 adipogenesis by directly targeting KLF4 and C/EBPα.

In the past decade, miRNA emerges as a vital player in orchestrating gene regulation and maintaining cellular homeostasis. It is well documented that miRNA influences a variety of biological events, including embryogenesis, cell fate decision, and cellular differentiation. Adipogenesis is an organized process of cellular differentiation by which pre-adipocytes differentiate towards mature adipocytes. It has been shown that adipogenesis is tightly modulated by a number of transcription factors such as PPARγ, KLF4, and C/EBPα. However, the molecular mechanisms underlying the missing link between miRNA and adipogenesis-related transcription factors remain elusive. In this study, we unveiled that miR-25, a member of miR-106b-25 cluster, was remarkably downregulated during 3T3-L1 adipogenesis. Restored expression of miR-25 significantly impaired 3T3-L1 adipogenesis and downregulated the expression of serial adipogenesis-related genes. Further experiments presented that ectopic expression of miR-25 did not affect cell proliferation and cell cycle progression. Finally, KLF4 and C/EBPα, two key regulators of adipocyte differentiation, were experimentally identified as bona fide targets for miR-25. These data indicate that miR-25 is a novel negative regulator of adipocyte differentiation and it suppressed 3T3-L1 adipogenesis by targeting KLF4 and C/EBPα, which provides novel insights into the molecular mechanism of miRNA-mediated cellular differentiation.

Miltirone Is a Dual Inhibitor of P-Glycoprotein and Cell Growth in Doxorubicin-Resistant HepG2 Cells.

Miltirone (1), an abietane-type diterpene quinone isolated from Salvia miltiorrhiza, possesses anticancer activity in p-glycoprotein (P-gp)-overexpressing human cancer cells. Results of the current study suggest a dual effect of miltirone on P-gp inhibition and apoptotic induction in a human hepatoma HepG2 cell line and its P-gp-overexpressing doxorubicin-resistant counterpart (R-HepG2). Miltirone (1) elicited a concentration-dependent cytotoxicity, with a similar potency (EC50 ≈ 7-12 µM), in HepG2 and R-HepG2 cells. Miltirone (1) (1.56-6.25 µM) produced synergistic effects on doxorubicin (DOX)-induced growth inhibition of R-HepG2 (synergism: 0.3 < combination index < 0.5). Molecular docking studies illustrated that miltirone (1) interacted with the active site of P-gp with a higher binding affinity than DOX, suggesting that it was a P-gp inhibitor. Flow cytometric analysis confirmed miltirone (1) as a competitive inhibitor of P-gp. At non-necrotic concentrations (1.56-25 µM), miltirone (1) activated caspase-dependent apoptotic pathways and triggered the generation of reactive oxygen species (ROS) and ROS-mediated mitogen-activated protein kinase (MAPK) signaling pathways (e.g., p38 MAPK, stress-activated protein kinase/c-Jun N-terminal kinase, and extracellular regulated kinase 1/2) in both HepG2 and R-HepG2 cells. Thus, we conclude that miltirone (1) is a dual inhibitor of P-gp and cell growth in human drug-resistant hepatoma cells.

Antiviral activities of whey proteins.

Milk contains an array of proteins with useful bioactivities. Many milk proteins encompassing native or chemically modified casein, lactoferrin, alpha-lactalbumin, and beta-lactoglobulin demonstrated antiviral activities. Casein and alpha-lactalbumin gained anti-HIV activity after modification with 3-hydroxyphthalic anhydride. Many milk proteins inhibited HIV reverse transcriptase. Bovine glycolactin, angiogenin-1, lactogenin, casein, alpha-lactalbumin, beta-lactoglobulin, bovine lactoferrampin, and human lactoferrampin inhibited HIV-1 protease and integrase. Several mammalian lactoferrins prevented hepatitis C infection. Lactoferrin, methylated alpha-lactalbumin and methylated beta-lactoglobulin inhibited human cytomegalovirus. Chemically modified alpha-lactalbumin, beta-lactoglobulin and lysozyme, lactoferrin and lactoferricin, methylated alpha-lactalbumin, methylated and ethylated beta-lactoglobulins inhibited HSV. Chemically modified bovine beta-lactoglobulin had antihuman papillomavirus activity. Beta-lactoglobulin, lactoferrin, esterified beta-lactoglobulin, and esterified lactoferrindisplayed anti-avian influenza A (H5N1) activity. Lactoferrin inhibited respiratory syncytial virus, hepatitis B virus, adenovirus, poliovirus, hantavirus, sindbis virus, semliki forest virus, echovirus, and enterovirus. Milk mucin, apolactoferrin, Fe(3+)-lactoferrin, beta-lactoglobulin, human lactadherin, bovine IgG, and bovine kappa-casein demonstrated antihuman rotavirus activity.

Discovery of FDA-approved drugs as inhibitors of fatty acid binding protein 4 using molecular docking screening.

We first identified fluorescein, ketazolam, antrafenine, darifenacin, fosaprepitant, paliperidone, risperidone, pimozide, trovafloxacin, and levofloxacin as inhibitors of fatty acid binding protein 4 using molecular docking screening from FDA-approved drugs. Subsequently, the biochemical characterizations showed that levofloxacin directly inhibited FABP4 activity in both the in vitro ligand displacement assay and cell-based function assay. Furthermore, levofloxacin did not induce adipogenesis in adipocytes, which is the major adverse effect of FABP4 inhibitors.

Identification of miRNAs that specifically target tumor suppressive KLF6-FL rather than oncogenic KLF6-SV1 isoform.

The Krüppel like factor 6 (KLF6) gene encodes multiple protein isoforms derived from alternative mRNA splicing, most of which are intimately involved in hepatocarcinogenesis and tumor progression. Recent bioinformatics analysis shows that alternative mRNA splicing of the KLF6 gene produces around 16 alternatively spliced variants with divergent or even opposing functions. Intriguingly, the full-length KLF6 (KLF6-FL) is a tumor suppressor gene frequently inactivated in liver cancer, whereas KLF6 splice variant 1 (KLF6-SV1) is an oncogenic isoform with antagonistic function against KLF6-FL. Compelling evidence indicates that miRNA, the small endogenous non-coding RNA (ncRNA), acts as a vital player in modulating a variety of cellular biological processes through targeting different mRNA regions of protein-coding genes. To identify the potential miRNAs specifically targeting KLF6-FL, we utilized bioinformatics analysis in combination with the luciferase reporter assays and screened out two miRNAs, namely miR-210 and miR-1301, specifically targeted the tumor suppressive KLF6-FL rather than the oncogenic KLF6-SV1. Our in vitro experiments demonstrated that stable expression of KLF6-FL inhibited cell proliferation, migration and angiogenesis while overexpression of miR-1301 promoted cell migration and angiogenesis. Further experiments demonstrated that miR-1301 was highly expressed in liver cancer cell lines as well as clinical specimens and we also identified the potential methylation and histone acetylation for miR-1301 gene. To sum up, our findings unveiled a novel molecular mechanism that specific miRNAs promoted tumorigenesis by targeting the tumor suppressive isoform KLF6-FL rather than its oncogenic isoform KLF6-SV1.