The BTG2-PRMT1 module limits pre-B cell expansion by regulating the CDK4-Cyclin-D3 complex.

Developing pre-B cells in the bone marrow alternate between proliferation and differentiation phases. We found that protein arginine methyl transferase 1 (PRMT1) and B cell translocation gene 2 (BTG2) are critical components of the pre-B cell differentiation program. The BTG2-PRMT1 module induced a cell-cycle arrest of pre-B cells that was accompanied by re-expression of Rag1 and Rag2 and the onset of immunoglobulin light chain gene rearrangements. We found that PRMT1 methylated cyclin-dependent kinase 4 (CDK4), thereby preventing the formation of a CDK4-Cyclin-D3 complex and cell cycle progression. Moreover, BTG2 in concert with PRMT1 efficiently blocked the proliferation of BCR-ABL1-transformed pre-B cells in vitro and in vivo. Our results identify a key molecular mechanism by which the BTG2-PRMT1 module regulates pre-B cell differentiation and inhibits pre-B cell leukemogenesis.

The role of family history in predicting germline pathogenic variant carriers who develop pancreatic cancer: Results of a multicenter collaboration.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) surveillance is recommended for some individuals with a pathogenic or likely pathogenic variant (PV/LPV) in a PDAC susceptibility gene; the recommendation is often dependent on family history of PDAC. This study aimed to describe PDAC family history in individuals with PDAC who underwent genetic testing to determine the appropriateness of including a family history requirement in these recommendations. METHODS: Individuals with PDAC with a germline heterozygous PV/LPV in ATM, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PALB2, or PMS2 (PV/LPV carriers) were assessed for family history of PDAC in first-degree relatives (FDRs) or second-degree relatives (SDRs) from nine institutions. A control group of individuals with PDAC without a germline PV/LPV was also assessed. RESULTS: The study included 196 PV/LPV carriers and 1184 controls. In the PV/LPV carriers, 25.5% had an affected FDR and/or SDR compared to 16.9% in the control group (p = .004). PV/LPV carriers were more likely to have an affected FDR compared to the controls (p = .003) but there was no statistical difference when assessing only affected SDRs (p = .344). CONCLUSIONS: Most PV/LPV carriers who developed PDAC did not have a close family history of PDAC and would not have met most current professional societies' recommendations for consideration of PDAC surveillance before diagnosis. However, PV/LPV carriers were significantly more likely to have a family history of PDAC, particularly an affected FDR. These findings support family history as a risk modifier in PV/LPV carriers, and highlight the need to identify other risk factors.

Starvation increases susceptibility to bacterial infection and promotes systemic pathogen proliferation in Drosophila melanogaster females.

Defense against pathogens and parasites requires substantial investment of energy and resources on part of the host. This makes the host immune function dependent on availability and accessibility of resources. A resource deprived host is therefore expected to be more susceptible to infections, although empirical results do not always align with this prediction. Limiting host access to resources can additionally impact within-host pathogen numbers, either directly by altering the amount of resources available to the pathogens for proliferation or indirectly by altering the efficiency of the host immune system. We tested for the effects of host starvation (complete deprivation of resources) on susceptibility to bacterial pathogens, and within-host pathogen proliferation, in Drosophila melanogaster females. Our results show that starvation increases post-infection mortality of the host, but in a pathogen-specific manner. This increase in mortality is always accompanied by increased within-host pathogen proliferation. We therefore propose that starvation compromises host resistance to bacterial infections in Drosophila melanogaster females thereby increasing susceptibility to infections.

Land use and land cover dynamics in the Upper Ganga Riverine Wetland: unraveling ecosystem services over two decades.

Anthropogenic activities have drastically transformed natural landscapes, profoundly impacting land use and land cover (LULC) and, consequently, the provision and functionality of ecosystem service values (ESVs). Evaluating the changes in LULC and their influence on ESVs is imperative to protect ecologically fragile ecosystems from degradation. This study focuses on a highly sensitive Upper Ganga riverine wetland in India, covering Hapur, Amroha, Bulandshahr, and Sambhal districts, which is well-known for its significant endemic flora and fauna. The study analyzes the subtle variability in ecosystem services offered by the various LULC biomes, including riverine wetland, built-up, cropland, forest, sandbar, and unused land. LULC classification is carried out using Landsat satellite imagery 5 and 8 for the years 2000, 2010, and 2020, using the random forest method. The spatiotemporal changing pattern of ESVs is assessed utilizing the value transfer method with two distinct value coefficients: global value coefficients (C14) for a worldwide perspective and modified local value coefficients X08 for a more specific local context. The results show a significant increase in built-up and unused land, with a corresponding decrease in wetlands and forests from 2000 to 2020. The combined ESVs for all the districts are worth US $5072 million (C14) and US $2139 million (X08) in the year 2000, which declined to US $4510 million (C14) and US $1770 million (X08) in the year 2020. The sensitivity analysis reveals that the coefficient of sensitivity (CS) is below one for all biomes, suggesting the robustness of the employed value coefficients in estimating ESVs. Moreover, the analysis identifies cropland, followed by forests and wetlands, as the LULC biomes most responsive to changes. This research provides crucial insights to stakeholders and policymakers for developing sustainable land management practices aimed at enhancing the ecological worth of the Upper Ganga Riverine Wetland.

Incidence and risk factors for recurrence of ampullary adenomas after endoscopic papillectomy: Comparative analysis of familial adenomatous polyposis and sporadic ampullary adenomas in an international multicenter cohort.

OBJECTIVES: Endoscopic papillectomy (EP) is a minimally invasive therapy for the management of ampullary adenomas (AA). We conducted this multicenter study to assess the incidence of and factors related to the recurrence of AA after EP in patients with familial adenomatous polyposis (FAP) compared to sporadic AA. METHODS: We included patients who underwent EP for AA at 10 tertiary hospitals. Adenomatous tissue at the resection site at the time of surveillance endoscopies was considered recurrent disease. RESULTS: In all, 257 patients, 100 (38.9%) with FAP and 157 (61%) patients with sporadic AA, were included. Over a median of 31 (range, 11-61) months, recurrence occurred in 48/100 (48%) of patients with FAP and 58/157 (36.9%) with sporadic AA (P = 0.07). Two (2%) FAP patients and 10 (6.3%) patients with sporadic AA underwent surgery for recurrence. On multivariable regression analysis, the recurrence in FAP was higher than in sporadic patients after the first year of follow-up. AA size (hazard ratio [HR] 1.03, 95% confidence interval [CI] 1.001, 1.056), periampullary extension (HR 2.5, 95% CI 1.5, 4.01), and biliary duct dilation (HR 2.04, 95% CI 1.2, 3.4) increased the risk, while en bloc resection (HR 0.6, 95% CI 0.41, 0.9) decreased the risk of recurrence. CONCLUSION: Recurrence rates are high after EP. Most recurrences in sporadic patients occur within the first year of follow-up, but after the first year of follow-up in patients with FAP. Recurrences are higher with larger adenomas, biliary duct dilation, and periampullary extensions, and may be mitigated by en bloc resection. These factors should be considered in decision-making with the patients.

Chest x-ray scoring as a predictor of COVID-19 disease; correlation with comorbidities and in-hospital mortality.

OBJECTIVES: To devise a novel, simple chest x-ray (CXR) scoring system which would help in prognosticating the disease severity and ability to predict comorbidities and in-hospital mortality. METHODS: We included a total of 343 consecutive hospitalised patients with COVID-19 in this study. The chest x-rays of these patients were scored retrospectively by three radiologists independently. We divided CXR in to six zones (right upper, mid & lower and left, upper mid & lower zones). We scored each zone as- 0, 1 or 2 as follows- if that zone was clear (0) Ground glass opacity (1) or Consolidation (2). A total of score from 0 to 12 could be obtained. RESULTS: A CXR score cut off ≥3 independently predicted mortality. Along with a relatively higher NPV ≥80%, it reinforced the importance of CXR score is a screening tool to triage patients according to risk of mortality. CONCLUSIONS: We propose that Pennine score is a simple tool which can be adapted by various countries, experiencing a large surge in number of patients, to decide which patient would need a tertiary Hospital referral/admission as opposed to patients that can be managed locally or at basic/primary care hospitals.

Effect of I-scan Electronic Chromoendoscopy on Detection of Adenomas During Colonoscopy.

BACKGROUND & AIMS: I-scan is an electronic chromoendoscopy technology that improves resolution of epithelial and mucosal surfaces and vessels. We performed a randomized controlled trial to compare detection of adenomas by i-scan vs standard high-definition white-light (HDWL) colonoscopy. METHODS: From February 1 through December 31, 2017, 740 outpatients (50-75 years old) undergoing screening and surveillance for colorectal neoplasia were randomly assigned to groups that received colonoscopies with i-scan 1 (surface and contrast enhancement) or HDWL. When lesions and polyps were detected, endoscopists could switch between i-scan 1 and HDWL imaging to confirm their finding; polyps were collected and analyzed by histology. The primary outcome was adenoma detection rate (ADR, proportion of subjects with at least 1 adenoma of any size); secondary outcomes included detection of sessile serrated polyps and neoplasias, along with location, size, and morphology of polyps. We performed intent to treat and per-protocol analyses (on 357 patients evaluated by i-scan and 358 evaluated by HDWL colonoscopy) to assess the primary and secondary outcomes. RESULTS: There were no differences in baseline characteristics between the groups. In the intent to treat analysis, the ADR was significantly higher in the i-scan 1 group (47.2%) than in the HDWL colonoscopy group (37.7%) (P = .01). In the per-protocol analysis, the ADR in the i-scan 1 group (47.6%) was also significantly higher than in the HDWL group (37.2%) (P = .005), but this effect was not consistent among all endoscopists. There was no difference between groups in detection of sessile serrated polyps. However, the rate of neoplasia detection was significantly higher in the i-scan 1 group (56.4%) than in the than the HDWL group (46.1%) (P = .005). In secondary analyses, the increase in ADR was associated with improved detection of diminutive flat adenomas in the right colon. CONCLUSION: In a prospective randomized trial, higher proportions of patients with adenomas were identified in a group that underwent colonoscopy with i-scan 1 than in a group evaluated by HDWL colonoscopy. This effect was mainly due to improved detection of diminutive, flat right sided adenomas. I-scan 1 technology may benefit some endoscopists. ClinicalTrials.gov no: NCT02811419.

Experimental adaptation to pathogenic infection ameliorates negative effects of mating on host post-infection survival in Drosophila melanogaster.

Sexual activity (mating) negatively affects immune function in various insect species across both sexes. In Drosophila melanogaster females, mating increases susceptibility to pathogenic challenges and encourages within-host pathogen proliferation. This effect is pathogen and host genotype dependent. We tested if mating-induced increased susceptibility to infections is more, or less, severe in hosts experimentally adapted to pathogenic infection. We selected replicate D. melanogaster populations for increased post-infection survival following infection with a bacterial pathogen, Enterococcus faecalis. We found that females from the selected populations were better at surviving a pathogenic infection compared to the females from the control populations. This was true in the case of both the pathogen used for selection and other novel pathogens (i.e., pathogens the hosts have not encountered in recent history). Additionally, the negative effect of mating on post-infection survival was limited to only the females from control populations. Therefore, we have demonstrated that experimental selection for increased post-infection survival ameliorates negative effects of mating on host susceptibility to infections.

Experimental evolution for improved postinfection survival selects for increased disease resistance in Drosophila melanogaster.

Disease resistance (defined as the host capacity to limit systemic infection intensity) and disease tolerance (defined as the host capacity to limit infection-induced damage) are 2 complementary defense strategies that help the hosts maximize their survival and fitness when infected with pathogens and parasites. In addition to the underlying physiological mechanisms, the existing theory postulates that these 2 strategies differ in terms of the conditions under which each strategy evolves in the host populations, their evolutionary dynamics, and the ecological and epidemiological consequences of their evolution. Here, we explored if one or both of these strategies evolve when host populations are subjected to selection for increased postinfection survival. We experimentally evolved Drosophila melanogaster populations, selecting for the flies that survived an infection with the entomopathogen Enterococcus faecalis. We found that the host populations evolved increased disease resistance in response to selection for increased survival. This was despite the physiological costs associated with increased resistance, the expression of which varied with the phase of infection. We did not find evidence of any change in disease tolerance in the evolved host populations.

Diffuse large B-cell lymphoma presenting as an ileocaecal mass in a post-transplant patient.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. Extranodal involvement, including the gastrointestinal tract, occurs frequently. However, colorectal involvement is extremely rare. We present a case of a man in his 20s with prior renal transplantation on immunosuppression for 10 years who developed symptoms of gas and bloating associated with unintentional weight loss. Colonoscopy revealed a large fungating mass at the ileocaecal valve, and a biopsy of this lesion confirmed stage IV DLBCL. Endoscopy should be considered for early workup of vague gastrointestinal symptoms, even in younger patients, if they have been on long-standing immunosuppression.

Drosophila melanogaster hosts coevolving with Pseudomonas entomophila pathogen show sex-specific patterns of local adaptation.

BACKGROUND: In spatially structured populations, local adaptation improves organisms' fitness in their native environment. Hosts and pathogens can rapidly adapt to their local antagonist. Since males and females can differ in their immunocompetence, the patterns of local adaptation can be different between the sexes. However, there is little information about sex differences in local adaptation in host-pathogen systems. RESULTS: In the current study, we experimentally coevolved four different replicate populations of Drosophila melanogaster (host) and Pseudomonas entomophila (pathogen) along with appropriate controls. We used the four host-pathogen coevolution populations to investigate the occurrence of local adaptation separately in males and females of the coevolving hosts. We also assessed local adaptation in pathogens. We set up a reciprocal infection experiment where we infected each of the four coevolving hosts with their local pathogen or non-local pathogens from the other three replicate populations. We found that overall, male and female hosts had better survivorship when infected with local pathogens, indicating that they were locally adapted. Interestingly, males were more susceptible to non-local pathogens compared to females. In addition, we found no fecundity cost in females infected with either local or non-local pathogens. We found no evidence of local adaptation among the pathogens. CONCLUSION: Our study showed sex-specific adaptation in the coevolving hosts where female hosts had a broader response against allopatric coevolving pathogens with no cost in fecundity. Thus, our results might suggest a novel mechanism that can maintain variation in susceptibility in spatially structured populations.

Ruxolitinib and tuberculosis: A case report with brief review.

JAK 2 inhibitors are widely used for the treatment of primary myelofibrosis. Ruxolitinib is the most commonly used JAK inhibitor in clinical practice. We report two cases of Primary Myelofibrosis who developed tuberculosis on active treatment with ruxolitinib. Our first case was a 48 year male who developed disseminated tuberculosis during fourth month of treatment and second case was a 50 year male developing tubercular lymphadenitis during second month of treatment respectively. These case reports indicate reactivation of underling tubercular infection as a very dreaded complication of this treatment. The prevalence of tuberculosis is much higher in India compared to the west. A thorough pretreatment evaluation should ideally be done using Mantoux test or interferon gamma release assay (IGRA) to rule out latent tuberculosis. Furthermore, the patients should be counselled regarding the possibility of reactivation of infections including tuberculosis. Also, proper follow up is the need of hour in all patients on any kind of immunomodulators.

A Masked Diagnosis: Sigmoid Endometriosis.

Serosal involvement in intestinal endometriosis is relatively common, and patients often present with nonspecific gastrointestinal symptoms; however, presentation with deeper mucosal infiltration and rectal bleeding is rare. We report a case of a 40-year-old woman with a history of breast cancer in remission who presented with periodic rectal bleeding and abdominal pain. Computed tomography scan showed sigmoid lesions concerning for metastatic disease. Colonoscopy showed hypervascular sigmoid lesions which were confirmed to be endometriosis on histopathology. This case highlights endometriosis as a rare differential to be considered in young women with abnormal bowel imaging or catamenial rectal bleeding.

Epiphrenic diverticula: An added source of complexity in achalasia management.

Epiphrenic (pulsion) esophageal diverticula can occur in the setting of underlying esophageal motility disorders such as achalasia and present a unique management challenge to the gastroenterologist. Asymptomatic diverticula do not require treatment, but symptomatic diverticula require therapy targeted to the underlying esophageal motility disorder, or else the diverticula will recur. Generally, laparoscopic or combined laparoscopic/thoracoscopic myotomy, diverticulectomy, and anterior fundoplication are required. However, therapeutic options for epiphrenic diverticula are evolving as peroral endoscopic myotomy (POEM) becomes more commonplace. We review two cases of achalasia complicated by epiphrenic diverticula at our institution. In the first case, type II achalasia was identified and the patient underwent laparoscopic myotomy. In the second case, type III achalasia was present and the patient underwent successful POEM. We discuss the presentation, pathophysiology, and management of epiphrenic diverticula as well as the expanding role for POEM in diverticula.

Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position statement on multigene panel testing for patients with colorectal cancer and/or polyposis.

Multigene panel tests for hereditary cancer syndromes are increasingly utilized in the care of colorectal cancer (CRC) and polyposis patients. However, widespread availability of panels raises a number of questions including which patients should undergo testing, which genes should be included on panels, and the settings in which panels should be ordered and interpreted. To address this knowledge gap, key questions regarding the major issues encountered in clinical evaluation of hereditary CRC and polyposis were designed by the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position Statement Committee and leadership. A literature search was conducted to address these questions. Recommendations were based on the best available evidence and expert opinion. This position statement addresses which genes should be included on a multigene panel for a patient with a suspected hereditary CRC or polyposis syndrome, proposes updated genetic testing criteria, discusses testing approaches for patients with mismatch repair proficient or deficient CRC, and outlines the essential elements for ordering and disclosing multigene panel test results. We acknowledge that critical gaps in access, insurance coverage, resources, and education remain barriers to high-quality, equitable care for individuals and their families at increased risk of hereditary CRC.

Hereditary Polyposis Syndromes.

PURPOSE OF REVIEW: Colorectal cancer (CRC) is the third most common cancer in the USA and inherited cancer syndromes are responsible for approximately 3-5% of all CRCs. Genetic testing costs have plummeted in recent years; however, awareness and referral of high-risk patients for testing is still very low. We review the salient clinical features, genetics, and management of well-defined gastrointestinal (GI) hereditary polyposis syndromes including familial adenomatous polyposis, MUTYH-associated polyposis, and the hamartomatous polyposis syndromes. RECENT FINDINGS: Comprehensive endoscopic surveillance has the potential to prevent the development of GI cancer and to identify early-stage cancer; newer developments like high-definition endoscopes, chromoendoscopy, and the use of cap-assisted endoscopy have shown promise for enhanced lesion detection rates. Several chemoprevention trials have yielded promising results but safety and efficacy data for long-term use is still awaited. Several new polyposis genes have also been identified in the recent years. Multiple societies have recently published updated surveillance guidelines to aid clinicians in the detection and management of patients with hereditary GI polyposis syndromes. Although these syndromes are rare, it is crucial for the clinicians to recognize these in a timely manner, for the appropriate management plans for both the patient and their at risk family members.

Do gender disparities persist in gastroenterology after 10 years of practice?

BACKGROUND: Cross-sectional studies confirm gender disparity in many aspects of the practice of medicine and surgery. Some data suggest the disparities diminish after 10 yr of practice. This study aims to examine gender discrepancies in income, social, and professional status of gastroenterologists after 10 yr of practice. METHODS: Prospective, observational, cohort study of gastroenterologists incepted upon graduation from a U.S. GI fellowship program in 1993 and 1995. A 36-item questionnaire was sent to the cohort at 3, 5, and 10 yr after graduation from GI fellowship training. The following are the results of the final, 10th year survey. RESULTS: A total of 168 men and 25 women (mean age 45.5 yr) responded. Men and women were equally likely to be board certified and married, however, women had fewer children. Men earned a mean annual gross income of $375,000 versus$245,000 for women (P= 0.001). After adjusting for practice setting, work hours, practice-ownership, free endoscopy center practice, and vacation time, female gastroenterologists earned $82,000 (22%) less per year than their male colleagues (95% CI $34,000-130,000, P= 0.001). Women were more frequently in academic practice (38%vs 17%), but were less likely to hold the most advanced academic positions. CONCLUSIONS: After 10 yr of practice, significant economic, professional, and social disparities persist between male and female gastroenterologists in this cohort. Women were more likely to practice in a setting with flexible work hours, a family leave provision, and in a practice with other women. Initiatives to equalize pay and ensure opportunities for professional advancement for women may diminish the significant practice disparities incurred by women in gastroenterology.

Single-domain antibody based thermally stable electrochemical immunosensor.

Conventional monoclonal and polyclonal antibodies are sensitive to changes in environmental factors such as temperature, pH, humidity, etc. This limits the current cost-effective and portable electrochemical immunosensors in harsh environments. Using Ricin Chain-A, a naturally occurring toxin, as a model analyte we report fabrication of a thermally stable electrochemical immunosensor. Single-domain antibodies (sdAb) or nanobodies have been employed as recognition elements for direct detection of Ricin at temperatures great than 4°C. Immunosensor fabricated using the conventional Ricin monoclonal and polyclonal antibodies have also been demonstrated for comparison. In the case of sdAb immunosensor, Ricin was detected in a linear range of 1log(fg/mL)-1log(µg/mL) with a sensitivity of 0.07µA/log(g/mL)/cm(2) using cyclic voltammetry. The fabricated miniaturized sensors have demonstrated higher shelf life and stability at temperatures up to 40°C. Therefore these electrochemical sensors can be integrated as a part of a portable device for point-of-care immunosensing.