The Justy mutation identifies Gon4-like as a gene that is essential for B lymphopoiesis

A recessive mutation named Justy was found that abolishes B lymphopoiesis but does not impair other major aspects of hematopoiesis. Transplantation experiments showed that homozygosity for Justy prevented hematopoietic progenitors from generating B cells but did not affect the ability of bone marrow stroma to support B lymphopoiesis. In bone marrow from mutant mice, common lymphoid progenitors and pre-pro–B cells appeared normal, but cells at subsequent stages of B lymphopoiesis were dramatically reduced in number. Under culture conditions that promoted B lymphopoiesis, mutant pre-pro–B cells remained alive and began expressing the B cell marker CD19 but failed to proliferate. In contrast, these cells were able to generate myeloid or T/NK precursors. Genetic and molecular analysis demonstrated that Justy is a point mutation within the Gon4-like (Gon4l) gene, which encodes a protein with homology to transcriptional regulators. This mutation was found to disrupt Gon4l pre-mRNA splicing and dramatically reduce expression of wild-type Gon4l RNA and protein. Consistent with a role for Gon4l in transcriptional regulation, the levels of RNA encoding C/EBPα and PU.1 were abnormally high in mutant B cell progenitors. Our findings indicate that the Gon4l protein is required for B lymphopoiesis and may function to regulate gene expression during this process

The Role of Glucocorticoid Receptor in the Racial/Ethnic Disparity of Aggressive Breast Cancer

Breast cancer is the most common malignancy and the second leading cause of cancer-related death in women worldwide. There is a well-documented variation in breast cancer incidence and mortality across nations and among racial/ethnic groups within these nations. In the United States, the incidence of breast cancer is lower among African American and Hispanic women when compared with white women, yet, as a group African American and Hispanic women have a more aggressive disease at diagnosis and worse survival outcomes. The reasons for racial disparity in breast cancer mortality are largely unknown but likely multifactorial involving environmental and biological factors. A number of epidemiological studies have shown that the cellular alterations resulting from chronic psychosocial stress may increase breast cancer development and progression. One of the primary mediators of stress is glucocorticoid. Glucocorticoid is a steroid hormone with a physiological and pathological role in the body; it acts via its cytoplasmic receptor, the glucocorticoid receptor (GCR). Upon binding to glucocorticoid, GCR is activated and released from a chaperone complex. Activated GCR travels to the nucleus to regulate a myriad of physiological processes such as mammary development and differentiation, inflammation, apoptosis as well as glucose and fatty acid metabolism-processes which have been associated with breast cancer development and progression. The main hypothesis is that alterations in the level or localization of GCR might interfere with the glucocorticoid response, resulting in aberrant downstream cellular responses such as decreased apoptosis and chronic inflammation that might contribute to aggressive breast cancer. And if these characteristics vary by race/ethnicity then this may play a role in the pathogenesis of the racial/ethnic disparity of breast cancer. The overarching theme of this research is to understand the role of GCR in breast cancer and its potential involvement in racial/ethnic disparities. To answer our research question, we used data from the Breast Cancer Care in Chicago (BCCC), a large, multiethnic population of incident breast cancer cases between the ages of 30 and 79 with stored biological samples and linked clinical, genetic ancestry and sociodemographic data

Prognostic Value of SGK1 and Bcl-2 in Invasive Breast Cancer

It is crucial to understand molecular alterations in breast cancer and how they relate to clinicopathologic factors. We have previously shown that the glucocorticoid receptor (GCR) protein expression was reduced in invasive breast carcinoma compared to normal breast tissue. Glucocorticoids, signaling through the GCR, regulate several cellular processes via downstream targets such as serum/glucocorticoid-regulated kinase 1 (SGK1) and B-cell lymphoma 2 (Bcl-2). We measured the expression of SGK1 and Bcl-2, in respective breast cancer tissue arrays, from a multiracial cohort of breast cancer patients. Higher cytoplasmic SGK1 staining was stronger in breast cancer tissue compared to normal tissue, especially in hormone receptor-negative cases. Conversely, the expression of cytoplasmic Bcl-2 was reduced in breast cancer compared to normal tissue, especially in hormone receptor-negative cases. Bcl-2 staining was associated with the self-reported racial/ethnic category, an earlier clinical stage, a lower histological grade, and a higher survival rate. Bcl-2 expression was associated with longer survival in models adjusted for age and race (HR = 0.32, 95% CI: 0.15, 0.65), and Bcl-2 expression remained strongly positively associated with protection from breast cancer death, with additional adjustments for ER/PR status (HR = 0.41, 95% CI: 0.2, 0.85). SGK1 and Bcl-2 may play biological roles in breast cancer development and/or progression

Mice lacking inducible nitric-oxide synthase are more susceptible to herpes simplex virus infection despite enhanced Th1 cell responses

Mice deficient in the inducible nitric-oxide synthase (iNOS), constructed by gene-targeting, were significantly more susceptible to herpes simplex virus (HSV)-1 infection, displayed a delayed clearance of virus from the dorsal root ganglia (DRG) and exhibited an increase in the frequency of virus reactivation in DRG compared with similarly infected heterozygous mice. The infected iNOS-deficient mice developed enhanced Th1-type immune responses and their spleen cells produced higher concentrations of IL-12 than similarly infected heterozygous mice. This finding suggests that iNOS plays an important role in resistance against HSV-1 infection. Furthermore, nitric oxide (NO) may block the development of Th1 cells via inhibition of IL-12 synthesis and thereby play a role in immune regulation.link_to_subscribed_fulltex

Zinc Intake and Risk of Prostate Cancer: Case-Control Study and Meta-Analysis

Zinc is an essential dietary element that has been implicated in the pathogenesis of prostate cancer, a cancer that disproportionately affects men of African descent. Studies assessing the association of zinc intake and prostate cancer have yielded inconsistent results. Furthermore, very little is known about the relationship between zinc intake and prostate cancer among African Americans. We examined the association between self-reported zinc intake and prostate cancer in a hospital-based case-control study of African Americans. We then compared our results with previous studies by performing a meta-analysis to summarize the evidence regarding the association between zinc and prostate cancer. Newly diagnosed African American men with histologically confirmed prostate cancer (n = 127) and controls (n = 81) were recruited from an urban academic urology clinic in Washington, DC. Controls had higher zinc intake, with a mean of 14 mg/day versus 11 mg/day for cases. We observed a non-significant, non-linear increase in prostate cancer when comparing tertiles of zinc intake (OR (12.5mg/day) 1.3, 95% CI: 0.2,6.5). The pooled estimate from 17 studies (including 3 cohorts, 2 nested case-control, 11 case-control studies, and 1 randomized clinical trial, with a total of 111,199 participants and 11,689 cases of prostate cancer) was 1.07 (hi vs lo) 95% CI: 0.98-1.16. Using a dose-response meta-analysis, we observed a non-linear trend in the relationship between zinc intake and prostate cancer (p for nonlinearity = 0.0022). This is the first study to examine the relationship between zinc intake in black men and risk of prostate cancer and systematically evaluate available epidemiologic evidence about the magnitude of the relationship between zinc intake and prostate cancer. Despite of the lower intake of zinc by prostate cancer patients, our meta-analysis indicated that there is no evidence for an association between zinc intake and prostate cancer.National Institutes of Health [5U54CA91431-01]; Egyptian Ministry of Higher Education [GM842]This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

BRCA1 protein expression and subcellular localization in primary breast cancer: Automated digital microscopy analysis of tissue microarrays.

Mutations in BRCA1 are associated with familial as well as sporadic aggressive subtypes of breast cancer, but less is known about whether BRCA1 expression or subcellular localization contributes to progression in population-based settings.We examined BRCA1 expression and subcellular localization in invasive breast cancer tissues from an ethnically diverse sample of 286 patients and 36 normal breast tissue controls. Two different methods were used to label breast cancer tissues for BRCA1: (1) Dual immunofluoresent staining with BRCA1 and cytokeratin 8/18 and (2) immunohistochemical staining using the previously validated MS110 mouse monoclonal antibody. Slides were visualized and quantified using the VECTRA Automated Multispectral Image Analysis System and InForm software.BRCA1 staining was more intense in normal than in invasive breast tissue for both cytoplasmic (p<0.0001) and nuclear (p<0.01) compartments. BRCA1 nuclear to cytoplasmic ratio was higher in breast cancer cells than in normal mammary epithelial cells. Reduced BRCA1 expression was associated with high tumor grade and negative hormone receptors (estrogen receptor, progesterone receptor and Her2). On the other hand, high BRCA1 expression correlated with basal-like tumors (high CK5/6 and EGFR), and high nuclear androgen receptor staining. Lower nuclear to cytoplasmic ratio of BRCA1 correlated significantly with high Ki67 labeling index (p< 0.05) and family history of breast cancer (p = 0.001).Findings of this study indicate that alterations in BRCA1 protein expression and subcellular localization in breast cancer correlate with poor prognostic markers and aggressive tumor features. Further large-scale studies are required to assess the potential relevance of BRCA1 protein expression and localization in routine classification of breast cancer