Mouse Models of Breast Cancer Share Amplification and Deletion Events with Human Breast Cancer

Breast tumor heterogeneity has been well documented through the use of multiplatform –omic studies in human tumors. However, there is no integrative database to capture the heterogeneity within mouse models of breast cancer. This project identifies genomic copy number alterations (CNAs) in 600 tumors across 27 major mouse models of breast cancer through the application of a predictive algorithm to publicly available gene expression data. It was found that despite the presence of strong oncogenic drivers in most mouse models, CNAs are extremely common but heterogeneous both between models and within models. Many mouse CNA events are largely conserved in human tumors and in the mouse we show that they are associated with secondary tumor characteristics such as tumor histology, metastasis, as well as enhanced oncogenic signaling. These data serve as an important resource in guiding investigators when choosing a mouse model to understand the gene copy number changes relevant to human breast cancer.     

Secondary IgA nephropathy presenting as nephrotic syndrome with glomerular crescentic changes and acute renal failure in a patient with autoimmune hepatitis

Patients with end-stage liver disease are prone to hemodynamic and immunologic renal injury, the latter at times manifesting as glomerulonephritis. Elevated serum immunoglobulin A (IgA) levels and mesangial IgG-IgA deposits are common in these patients, but are often clinically silent. We report a patient with autoimmune hepatitis and secondary IgA nephropathy (IgAN) who presented with nephrotic syndrome, acute renal failure (ARF), with 30% of the renal glomeruli having undergone crescentic change, and with IgA2 deposits in the glomerular mesangium. This article discusses secondary IgAN pathogenesis and its therapeutic management.     

Immunosuppression-related fibroproliferative polyps: a substantial subset of acquired pediatric mucocutaneous polyps.

A distinct group of fibroproliferative polyps of the tongue arising in immunosuppressed children and often associated with chromosomal breakpoints at chromosomes 9p34 or 22q11 was recently described. Based on this finding, we reviewed fibroepithelial polyps arising in nonlingual sites in the pediatric population to investigate a possible relationship with immunosuppression. We identified 8 fibroepithelial polyps arising in 6 immunosuppressed patients (4 males and 2 females, median age 17 years) in a wide range of mucocutaneous sites. Histologic features were identical to the common fibroepithelial polyp, or skin tag, with a variably collagenous fibrovascular core covered by unremarkable squamous epithelium. No viral cytopathic changes were identified in any case. Although cytogenetic studies were not performed on any of the biopsy material, 1 patient had a constitutional deletion of chromosome 22q11. We suggest that there may be a relationship between these polyps and the previously described tongue lesions and that immunosuppression may be an important factor in their pathogenesis.     

The influence of a major disaster on suicide risk in the population

The authors investigated the relationship between the September 11, 2001 terrorist attacks and suicide risk in New York City from 1990 to 2006. The average monthly suicide rate over the study period was 0.56 per 100,000 people. The monthly rate after September 2001 was 0.11 per 100,000 people lower as compared to the rate in the period before. However, the rate of change in suicide was not significantly different before and after the disaster, and regression discontinuity analysis indicated no change at this date. There was no net change in the suicide rate in New York City attributable to this disaster, suggesting that factors other than exposure to traumatic events (e.g., cultural norms, availability of lethal methods) may be key drivers of suicide risk in this context.     

N-methylpurine DNA glycosylase and DNA polymerase beta modulate BER inhibitor potentiation of glioma cells to temozolomide

Temozolomide (TMZ) is the preferred chemotherapeutic agent in the treatment of glioma following surgical resection and/or radiation. Resistance to TMZ is attributed to efficient repair and/or tolerance of TMZ-induced DNA lesions. The majority of the TMZ-induced DNA base adducts are repaired by the base excision repair (BER) pathway and therefore modulation of this pathway can enhance drug sensitivity. N-methylpurine DNA glycosylase (MPG) initiates BER by removing TMZ-induced N3-methyladenine and N7-methylguanine base lesions, leaving abasic sites (AP sites) in DNA for further processing by BER. Using the human glioma cell lines LN428 and T98G, we report here that potentiation of TMZ via BER inhibition [methoxyamine (MX), the PARP inhibitors PJ34 and ABT-888 or depletion (knockdown) of PARG] is greatly enhanced by over-expression of the BER initiating enzyme MPG. We also show that methoxyamine-induced potentiation of TMZ in MPG expressing glioma cells is abrogated by elevated-expression of the rate-limiting BER enzyme DNA polymerase β (Polβ), suggesting that cells proficient for BER readily repair AP sites in the presence of MX. Further, depletion of Polβ increases PARP inhibitor-induced potentiation in the MPG over-expressing glioma cells, suggesting that expression of Polβ modulates the cytotoxic effect of combining increased repair initiation and BER inhibition. This study demonstrates that MPG overexpression, together with inhibition of BER, sensitizes glioma cells to the alkylating agent TMZ in a Polβ-dependent manner, suggesting that the expression level of both MPG and Polβ might be used to predict the effectiveness of MX and PARP-mediated potentiation of TMZ in cancer treatment.