SET domain-containing proteins play a vital role in regulating gene expression during development through modifications in chromatin structure. Here we show that SET domain-containing 5 (Setd5) is divergently transcribed with Gt(ROSA26)Sor, is necessary for mammalian development, and interacts with the PAF1 co-transcriptional complex and other proteins. Setd5-deficient mouse embryos exhibit severe defects in neural tube formation, somitogenesis and cardiac development, have aberrant vasculogenesis in embryos, yolk sacs and placentas, and die between embryonic day 10.5 and 11.5. Setd5-deficient embryonic stem cells have impaired cellular proliferation, increased apoptosis, defective cell cycle progression, a diminished ability to differentiate into cardiomyocytes and greatly perturbed gene expression. SETD5 co-immunoprecipitates with multiple components of the PAF1 and histone deacetylase-containing NCoR complexes and is not solely required for major histone lysine methylation marks. In the absence of Setd5, histone acetylation is increased at transcription start sites and near downstream regions. These findings suggest that SETD5 functions in a manner similar to yeast Set3p and Drosophila UpSET, and that it is essential for regulating histone acetylation during gene transcription.

Implementation of pulsed xenon ultraviolet disinfection is associated with significant decreases in facility-wide and ICU infection rates. These outcomes suggest that enhanced environmental disinfection plays a role in the risk mitigation of hospital-acquired infections.

Summary Using a transgenic mouse model to express MafA, Pdx1, and Neurog3 (3TF) in a pancreatic acinar cell- and doxycycline-dependent manner, we discovered that the outcome of transcription factor-mediated acinar to β-like cellular reprogramming is dependent on both the magnitude of 3TF expression and on reprogramming-induced inflammation. Overly robust 3TF expression causes acinar cell necrosis resulting in marked inflammation and acinar-to-ductal metaplasia. Generation of new β-like cells requires limiting reprogramming-induced inflammation, either by reducing 3TF expression or by eliminating macrophages. The new β-like cells were able to reverse streptozotocin-induced diabetes 6 days after inducing 3TF expression but failed to sustain their function after removal of the reprogramming factors.

BackgroundIn the past decade, a variety of immunotherapy approaches focused predominantly on the adaptive immune system have shown unprecedented responses in patients with advanced-stage malignancies. However, studies in spontaneous regression/complete resistance (SR/CR) mice and humans have shown a novel innate cancer-killing activity mediated by granulocytes, which is completely transferable for prevention or therapy against established malignancies.MethodsThree patients with advanced, relapsed or refractory solid tumors for which no standard therapy was available or was refused were enrolled into this ongoing combined phase I/II open label clinical trial testing the safety, dose tolerance, and possible antineoplastic efficacy of sequential infusions of HLA-mismatched non-irradiated allogeneic white cells (68–91% granulocytes) collected by leukapheresis from young, healthy donors (age 18–35) following mobilization with granulocyte colony stimulating factor (G-CSF) and dexamethasone.ResultsBesides fevers and flushing, no infusional toxicities were observed. All patients remained clinically stable following infusions with mild cytokine release syndrome and no evidence of transfusion-associated graft-versus-host disease, acute tumor lysis syndrome,or transfusion-associated acute lung injury. Pathological examination of all cases post-mortem revealed extensive tumor necrosis up to 80% in patients 1–2, 40–50% in patient 3, and leukocyte infiltration in all cases, which could not be attributed to disease progression.ConclusionsAllogeneic white cell immunotherapy (AWIT) from young, healthy donors is well tolerated with minimal side effects and shows antitumor activity against advanced-stage solid tumors. AWIT represents a novel, safe, and cost-effective immunotherapy that can be administered in an outpatient cancer clinic.