Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981.

Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein. and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis.

Immune cells and their inflammatory mediators modify β cells and cause checkpoint inhibitor-induced diabetes.

Checkpoint inhibitors (CPIs) targeting programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have revolutionized cancer treatment but can trigger autoimmune complications, including CPI-induced diabetes mellitus (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induced diabetes rapidly.

MYCN upregulates the transsulfuration pathway to suppress the ferroptotic vulnerability in -amplified neuroblastoma.

Ferroptosis is an iron-dependent, oxidative form of cell death that is countered mainly by glutathione peroxidase 4 (GPX4) and the production of glutathione (GSH), which is formed from cysteine. The identification of the cancers that may benefit from pharmacological ferroptotic induction is just emerging. We recently demonstrated that inducing ferroptosis genetically or pharmacologically in -amplified neuroblastoma (NB) is a novel and effective way to kill these cells.

Elective Colectomy in a Patient with Active Ulcerative Colitis and Metastatic Melanoma Enabling Successful Treatment with Immune Checkpoint Inhibitors.

Checkpoint inhibitor immunotherapy has significantly advanced treatment of a growing number of advanced malignancies. A consequences of immune system activation that leads to tumor cell destruction by checkpoint inhibitor therapy is the development of immune-related adverse events, some of which can be life threatening. There are limited data on the use of checkpoint inhibitor therapy in patients with preexisting autoimmunity owing to concerns that underlying autoimmune disease may be exacerbated by checkpoint inhibitor treatment.

Type 2 diabetes mellitus and cardiovascular disease: focus on the effect of antihyperglycemic treatments on cardiovascular outcomes.

: Type 2 diabetes mellitus and cardiovascular disease contribute to significant morbidity, mortality, and health-care resource expenditure. The pathophysiological and clinical associations between diabetes and cardiovascular disease have been the subject of multiple studies, most recently culminating in large trials of several new antiglycemic agents being found to confer additional cardiovascular risk reduction. Understanding the potential cardiovascular benefits of antiglycemic medications offers the unique opportunity to reduce the morbidity and mortality presented by both diseases at once.

Hypothyroidism: Cardiovascular Endpoints of Thyroid Hormone Replacement.

Thyroid dysfunction, either thyrotoxicosis or hypothyroidism, represents an important cardiovascular risk factor. Heart disease is the leading cause of death for men and women in the United States. Cardiovascular disease is multifactorial and many efforts have been made to assess precipitants for optimal guideline-based, primary, and secondary prevention.

Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy.

Background: Bullous disorders associated with anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) therapy are increasingly reported and may pose distinct therapeutic challenges. Their frequency and impact on cancer therapy are not well established.

Objective: To evaluate the clinical and histopathologic findings, frequency, and impact on cancer therapy of bullous eruptions due to anti-PD-1/PD-L1 therapy.

Collateral Damage: Insulin-Dependent Diabetes Induced With Checkpoint Inhibitors.

Insulin-dependent diabetes may occur in patients with cancers who are treated with checkpoint inhibitors (CPIs). We reviewed cases occurring over a 6-year period at two academic institutions and identified 27 patients in whom this developed, or an incidence of 0.9%.

Implications of the EMPA-REG Trial for Clinical Care and Research.

EMPA-REG OUTCOME was a multicenter, randomized placebo-controlled trial that examined the effect of empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor in addition to standard of care in patients with type 2 diabetes and established cardiovascular (CV) disease. The primary goal was to assess CV safety, as mandated by the US Food and Drug Administration since 2008 for all new glucose-lowering agents. Secondary goals were to examine the effects of empagliflozin on microvascular outcomes and, in particular, kidney disease.