Metformin Is Associated With Improved Inflammatory Bowel Disease Outcomes in Patients With Type 2 Diabetes Mellitus: A Propensity-Matched Cohort Study.

Background: Metformin exerts anti-inflammatory properties through a positive effect on oxidative stress, gut barrier integrity, and the gut microbiota. Our aim was to evaluate the influence of metformin on inflammatory bowel disease (IBD) outcomes in patients with type 2 diabetes mellitus (T2DM).

Methods: We conducted a retrospective cohort study using the TriNetX database in patients with IBD and T2DM who initiated metformin vs oral hypoglycemics or insulin (control cohort) between August 31, 2002, and August 31, 2022.

Rates, Predictors, and Outcomes of Ustekinumab Dose Escalation in Inflammatory Bowel Disease.

Objective: Ustekinumab (UST) is effective for the induction and maintenance of remission in inflammatory bowel disease (IBD). However, a significant proportion of patients will require UST dose escalation. We sought to determine the rates, predictors, and outcomes of UST dose escalation in patients with IBD.

Comparative Safety of Biologic Agents in Patients With Inflammatory Bowel Disease With Active or Recent Malignancy: A Multi-Center Cohort Study.

Background & Aims: Safety of biologic agents is a key consideration in patients with inflammatory bowel disease (IBD) and active or recent cancer. We compared the safety of tumor necrosis factor (TNF)-α antagonists vs non-TNF biologics in patients with IBD with active or recent cancer.

Methods: We conducted a multicenter retrospective cohort study of patients with IBD and either active cancer (cohort A) or recent prior cancer (within ≤5 years; cohort B) who were treated with TNFα antagonists or non-TNF biologics after their cancer diagnosis.

Metagenomic and bile acid metabolomic analysis of fecal microbiota transplantation for recurrent Clostridiodes difficile and/or inflammatory bowel diseases.

Background: Fecal microbiota transplantation (FMT) is an effective treatment of recurrent infections (rCDI), but has more limited efficacy in treating either ulcerative colitis (UC) or Crohn's disease (CD), two major forms of inflammatory bowel diseases (IBD). We hypothesize that FMT recipients with rCDI and/or IBD have baseline fecal bile acid (BA) compositions that differ significantly from that of their healthy donors and that FMT will normalize the BA compositions.

Aim: To study the effect of single colonoscopic FMT on microbial composition and function in four recipient groups: 1.

p53-dependent induction of P2X7 on hematopoietic stem and progenitor cells regulates hematopoietic response to genotoxic stress.

Stem and progenitor cells are the main mediators of tissue renewal and repair, both under homeostatic conditions and in response to physiological stress and injury. Hematopoietic system is responsible for the regeneration of blood and immune cells and is maintained by bone marrow-resident hematopoietic stem and progenitor cells (HSPCs). Hematopoietic system is particularly susceptible to injury in response to genotoxic stress, resulting in the risk of bone marrow failure and secondary malignancies in cancer patients undergoing radiotherapy.

Gallbladder Disorders: A Comprehensive Review.

Gallbladder disorders encompass a wide breadth of diseases that vary in severity. We present a comprehensive review of literature for the clinical presentation, pathophysiology, diagnostic evaluation, and management of cholelithiasis-related disease, acute acalculous cholecystitis, functional gallbladder disorder, gallbladder polyps, gallbladder hydrops, porcelain gallbladder, and gallbladder cancer.

MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction.

Ribosomopathies are congenital disorders caused by mutations in the genes encoding ribosomal and other functionally related proteins. They are characterized by anemia, other hematopoietic and developmental abnormalities, and p53 activation. Ribosome assembly requires coordinated expression of many ribosomal protein (RP) genes; however, the regulation of RP gene expression, especially in hematopoietic stem cells (HSCs), remains poorly understood.

Targeting Two Antigens Associated with B-ALL with CD19-CD123 Compound Car T Cell Therapy.

The recent FDA approval of the first CAR immunotherapy marks a watershed moment in the advancement toward a cure for cancer. CD19 CAR treatment for B cell acute lymphocytic leukemia has achieved unprecedented remission rates. However, despite success in treating previously relapsed and refractory patients, CD19 CAR faces similar challenges as traditional chemotherapy, in that malignancy can adapt and overcome treatment.

Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4-specific Chimeric Antigen Receptor (CAR) T Cells and NK Cells.

Acute myeloid leukemia (AML) is an aggressive malignancy lacking targeted therapy due to shared molecular and transcriptional circuits as well as phenotypic markers with normal hematopoietic stem cells (HSCs). Identifying leukemia specific markers expressed on AML or AML subtypes for therapeutic targeting is of exquisite clinical value. Here we show that CD4, a T lymphocytes membrane glycoprotein that interacts with major histocompatibility complex class II antigens and is also expressed in certain AML subsets but not on HSCs is a proper target for genetically engineered chimeric antigen receptor T cells (CAR-T cells).

Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia.

Acute myeloid leukemia (AML) bears heterogeneous cells that can consequently offset killing by single-CAR-based therapy, which results in disease relapse. Leukemic stem cells (LSCs) associated with CD123 expression comprise a rare population that also plays an important role in disease progression and relapse. Here, we report on the robust anti-tumor activity of a compound CAR (cCAR) T-cell possessing discrete scFv domains targeting two different AML antigens, CD123, and CD33, simultaneously.

A role for the histone H2A deubiquitinase MYSM1 in maintenance of CD8 T cells.

Several previous studies outlined the importance of the histone H2A deubiquitinase MYSM1 in the regulation of stem cell quiescence and haematopoiesis. In this study we investigated the role of MYSM1 in T-cell development. Using mouse models that allow conditional Mysm1 ablation at late stages of thymic development, we found that MYSM1 is intricately involved in the maintenance, activation and survival of CD8 T cells.

MYSM1-dependent checkpoints in B cell lineage differentiation and B cell-mediated immune response.

MYSM1 is a chromatin-binding histone deubiquitinase. mutations in humans result in lymphopenia whereas loss of in mice causes severe hematopoietic abnormalities, including an early arrest in B cell development. However, it remains unknown whether MYSM1 is required at later checkpoints in B cell development or for B cell-mediated immune responses.

Mysm1 expression in the bone marrow niche is not essential for hematopoietic maintenance.

Myb-Like SWIRM and MPN domains 1 (MYSM1) is a chromatin-binding protein, essential for hematopoietic stem cell (HSC) maintenance and differentiation in humans and mouse models. HSCs in mammalian bone marrow exist in close interactions with many non-hematopoietic cell types in their microenvironment, collectively known as the bone marrow niche. Although cell-intrinsic activities of MYSM1 within the hematopoietic cells are known to play an important role in hematopoietic homeostasis, Mysm1 expression is also widely observed in non-hematopoietic cells, and MYSM1 is implicated as an important regulator of mesenchymal stem cell differentiation, osteoblast function, and adipogenesis within the bone marrow.

Deubiquitinase MYSM1 Is Essential for Normal Fetal Liver Hematopoiesis and for the Maintenance of Hematopoietic Stem Cells in Adult Bone Marrow.

MYSM1 is a chromatin-interacting deubiquitinase recently shown to be essential for hematopoietic stem cell (HSC) function and normal progression of hematopoiesis in both mice and humans. However, it remains unknown whether the loss of function in Mysm1-deficient HSCs is due to the essential role of MYSM1 in establishing the HSC pool during development or due to a continuous requirement for MYSM1 in adult HSCs. In this study we, for the first time, address these questions first, by performing a detailed analysis of hematopoiesis in the fetal livers of Mysm1-knockout mice, and second, by assessing the effects of an inducible Mysm1 ablation on adult HSC functions.

p53 mediates loss of hematopoietic stem cell function and lymphopenia in Mysm1 deficiency.

MYSM1 is a chromatin-binding transcriptional cofactor that deubiquitinates histone H2A. Studies of Mysm1-deficient mice have shown that it is essential for hematopoietic stem cell (HSC) function and lymphopoiesis. Human carriers of a rare MYSM1-inactivating mutation display similar lymphopoietic deficiencies.