SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation.

SMARCB1 (also known as SNF5, INI1, and BAF47), a core subunit of the SWI/SNF (BAF) chromatin-remodeling complex, is inactivated in nearly all pediatric rhabdoid tumors. These aggressive cancers are among the most genomically stable, suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here we show that, despite having indistinguishable mutational landscapes, human rhabdoid tumors exhibit distinct enhancer H3K27ac signatures, which identify remnants of differentiation programs.

Functionally distinct patterns of nucleosome remodeling at enhancers in glucocorticoid-treated acute lymphoblastic leukemia.

Background: Precise nucleosome positioning is an increasingly recognized feature of promoters and enhancers, reflecting complex contributions of DNA sequence, nucleosome positioning, histone modification and transcription factor binding to enhancer activity and regulation of gene expression. Changes in nucleosome position and occupancy, histone variants and modifications, and chromatin remodeling are also critical elements of dynamic transcriptional regulation, but poorly understood at enhancers. We investigated glucocorticoid receptor-associated (GR) nucleosome dynamics at enhancers in acute lymphoblastic leukemia.

SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2.

Human cancer genome sequencing has recently revealed that genes that encode subunits of SWI/SNF chromatin remodeling complexes are frequently mutated across a wide variety of cancers, and several subunits of the complex have been shown to have bona fide tumor suppressor activity. However, whether mutations in SWI/SNF subunits result in shared dependencies is unknown. Here we show that EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is essential in all tested cancer cell lines and xenografts harboring mutations of the SWI/SNF subunits ARID1A, PBRM1, and SMARCA4, which are several of the most frequently mutated SWI/SNF subunits in human cancer, but that co-occurrence of a Ras pathway mutation is correlated with abrogation of this dependence.

No improvement noted in overall or cause-specific survival for men presenting with metastatic prostate cancer over a 20-year period.

Background: Prostate cancer mortality in the United States has declined by nearly 40% over the last 25 years. However, to the authors' knowledge, the contribution of prostate-specific antigen (PSA) screening for the early detection of prostate cancer remains unclear and controversial. In the current study, the authors attempted to determine whether improvements in survival over time among patients with metastatic prostate cancer have contributed to the decline in mortality.

ARID1A mutations in cancer: another epigenetic tumor suppressor?

Unlabelled: Although disordered chromatin organization has long been recognized as a feature of cancer, the molecular underpinnings of chromatin structure, epigenetic regulation, and their relationships to transcription are only beginning to be understood. Cancer genome sequencing studies have revealed a novel theme: frequent mutation of epigenetic regulators. Among these, the ARID1A/BAF250A subunit of the SWI/SNF (BRG1-associated factors) chromatin remodeling complex has emerged as recurrently mutated in a broad array of tumor types.

Urolithiasis risk factors in the bariatric population undergoing gastric bypass surgery.

Background: Previous studies have suggested an increased risk of forming symptomatic urolithiasis after Roux-en-Y gastric bypass (RYGB) attributed to the development of hyperoxaluria. The objective of our investigation was to evaluate changes in the urine milieu after RYGB that might explain the increased risk of urolithiasis.

Methods: Patients underwent serum and urine chemistry tests 1 week before and 6 months after RYGB at a university hospital.

Palliative care in urology.

Urological malignancies, especially prostate cancer, are relatively common, but patients may live many years before eventually dying of the disease. Caring for these patients is an important role for urologists, although medical training often does not adequately prepare urologists for the palliative care of patients with advanced malignancies. Palliative care is no longer equated with end-of-life care, but rather integrated throughout illness, even when cure is impossible.

Active surveillance for localized prostate cancer--current practices and recommendations.

Prostate cancer is now the most commonly diagnosed solid tumor in American men, due in part to widespread screening and aggressive diagnostic practices. Prostate cancer autopsy studies show the uniquely high prevalence rates of small, indolent tumors in men dying of other causes. These findings have led to increased concern for the over detection and overtreatment of prostate cancer.

Impaired degranulation but enhanced cytokine production after Fc epsilonRI stimulation of diacylglycerol kinase zeta-deficient mast cells.

Calcium and diacylglycerol are critical second messengers that together effect mast cell degranulation after allergen cross-linking of immunoglobulin (Ig)E-bound FcepsilonRI. Diacylglycerol kinase (DGK)zeta is a negative regulator of diacylglycerol-dependent signaling that acts by converting diacylglycerol to phosphatidic acid. We reported previously that DGKzeta-/- mice have enhanced in vivo T cell function.

Adhesion- and degranulation-promoting adapter protein is required for efficient thymocyte development and selection.

Adhesion- and degranulation-promoting adapter protein (ADAP) is required in TCR-induced activation and proliferation of peripheral T cells. Loss of ADAP also impairs TCR-initiated inside-out activation of the integrin LFA-1 (CD11a/CD18, alphaLbeta2). In this study, we demonstrate that ADAP-deficient CD4/CD8 double-positive (DP) cells have a diminished ability to proliferate, and that these DP thymocytes up-regulate CD69 poorly in vivo.

The SLP-76 family of adapter proteins.

Adapter molecules are multidomain proteins lacking intrinsic catalytic activity, functioning instead by nucleating molecular complexes during signal transduction. The SLP-76 family of adapters includes SH2 domain-containing leukocyte phosphoprotein of 76kDa (SLP-76), B cell linker protein (BLNK), and cytokine-dependent hematopoietic cell linker (Clnk). These proteins are critical for integration of numerous signaling cascades downstream of immunotyrosine-based activation motif (ITAM)-bearing receptors and integrins in diverse hematopoietic cell types.

Differential requirement for adapter proteins Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa and adhesion- and degranulation-promoting adapter protein in FcepsilonRI signaling and mast cell function.

The adapter molecule Src homology 2 (SH2) domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) is essential for FcepsilonRI-mediated signaling, degranulation and IL-6 production in mast cells. To test the structural requirements of SLP-76 in mast cell signaling and function, we have studied the functional responses of murine bone marrow-derived mast cells (BMMCs) expressing mutant forms of SLP-76. We found that the N-terminal tyrosines as well as the central proline-rich region of SLP-76 are required for participation of SLP-76 in FcepsilonRI-mediated signaling and function.

Roles of the proline-rich domain in SLP-76 subcellular localization and T cell function.

The adaptor protein Src homology (SH)2 domain-containing and leukocyte-specific phosphoprotein of 76 kDa (SLP-76) is critical for signal transduction in multiple hematopoietic lineages. It links proximal and distal T cell receptor signaling events through its function as a molecular scaffold in the assembly of multimolecular signaling complexes. Here we studied the functional roles of sub-domains within the SLP-76 proline-rich region, specifically the Gads binding domain and the recently defined P1 domain.

SLP-76 regulates Fcgamma receptor and integrin signaling in neutrophils.

While the contribution of intracellular adaptor proteins to lymphocyte activation has been well studied, the function of these molecules in innate immune effector cells such as neutrophils has not been extensively addressed. Here we demonstrate a critical role for the adaptor molecule SH2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76) in FcgammaR and integrin signaling. Stimulation of these receptors induces tyrosine phosphorylation and cytoplasmic relocalization of SLP-76 in freshly isolated murine neutrophils.

Regulation of hematopoietic cell development and activation by adapter proteins.

Adapter proteins, molecules with modular domains that mediate intermolecular interactions, play critical roles in the regulation of signaling events in all cell types. A major focus of our laboratory has been to examine the role of adapter molecules in hematopoietic cell development and activation. This review will describe the approaches we are taking to identify such proteins and to determine the mechanisms by which they exert their functions.