Upregulation of IFNɣ-mediated chemokines dominate the immune transcriptome of muscle-invasive urothelial carcinoma

Tumor inflammation is prognostically significant in high-grade muscle-invasive bladder cancer (MIBC). However, the underlying mechanisms remain elusive. To identify inflammation-associated immune gene expression patterns, we performed transcriptomic profiling of 40 MIBC archival tumors using the NanoString nCounter Human v.1.1 PanCancer Panel. Findings were validated using the TCGA MIBC dataset. Unsupervised and supervised clustering identified a distinctive immune-related gene expression profile for inflammation, characterized by significant upregulation of 149 genes, particularly chemokines, a subset of which also had potential prognostic utility. Some of the most enriched biological processes were lymphocyte activation and proliferation, leukocyte adhesion and migration, antigen processing and presentation and cellular response to IFN-γ. Upregulation of numerous IFN-γ-inducible chemokines, class II MHC molecules and immune checkpoint genes was detected as part of the complex immune response to MIBC. Further, B-cell markers linked to tertiary lymphoid structures were upregulated, which in turn is predictive of tumor response to immunotherapy and favorable outcome. Our findings of both an overall activated immune profıle and immunosuppressive microenvironment provide novel insights into the complex immune milieu of MIBC with inflammation and supports its clinical significance for predicting prognosis and immunotherapeutic responsiveness, which warrants further investigation. This may open novel opportunities to identify mechanisms for developing new immunotherapeutic strategies

Illegitimate V(D)J rearrangement in ã-irradiation induced T cell lymphoma in newborn scid mice

grantor: University of TorontoThe production of DNA double strand breaks during V(D)J recombination, makes developing lymphocytes particularly susceptible to neoplasia. Severe combined immunodeficient (scid) mice inefficiently ligate free coding ends generated during V(D)J recombination due to a mutation in the catalytic subunit of DNA-dependent protein kinase (DNA-PK\sb{cs}). Treatment of newborn scid mice with low dose (100 cGy) $\gamma$-irradiation restores V(D)J rearrangement at multiple TcR loci and results in the universal development of T cell lymphoma. In this study, we used a genetic approach to determine that V(D)J rearrangement played an obligate role in radiation-induced lymphoma in scid mice. We also present evidence of abnormal V(D)J rearrangement in irradiated newborn scid (IRNB-SCID) T cell lines. Our results collectively indicate that sequence specific breaks made during V(D)J rearrangement are essential for radiation-induced lymphomagenesis in scid mice, and that mutations accumulated during attempted TcR$\beta$ locus rearrangement may contribute to the invariant outgrowth of thymic lymphoma.M.Sc

The Effect of Age on Prostate Cancer Survival

It is not clear to what extent the age of diagnosis and the attained age impact on cancer mortality rates in men with newly diagnosed prostate cancer. We estimated annual prostate cancer mortality rates and 20-year survival rates according to the age of diagnosis, race, grade and time since diagnosis using data from the Surveillance, Epidemiology and End-Results (SEER) program. We identified 116,796 prostate cancer patients diagnosed between 1992 and 1997 and followed them for 20 years. There were 21,896 deaths from prostate cancer. We calculated actuarial survival rates and annual prostate cancer mortality rates by age of diagnosis and by tumor grade. The risk of a man dying of prostate cancer was 17% for men diagnosed before age 70 and was 21% for those diagnosed after age 70. The mean annual prostate cancer mortality rate calculated over the 20-year period post-diagnosis was 1.5%. The annual rate increased from 0.9% for those diagnosed below age 60 to 2.1% for those diagnosed above age 70. For men with Gleason score ≥ 7 prostate cancer, the annual prostate cancer mortality rate peaked 2–3 years after diagnosis and then declined. For men diagnosed with Gleason score ≤ 6 prostate cancer, the annual prostate cancer mortality rate continued to rise 20 years after diagnosis and peaked after age 85. This suggests that high-grade prostate cancers are aggressive from the outset, but that low-grade prostate cancers may enter a state of dormancy and reactivate as the patient ages

Guys Dont Have Breasts : The Lived Experience of Men Who Have BRCA Gene Mutations and Are at Risk for Male Breast Cancer

Men with BRCA1 or BRCA2 gene mutations are at increased risk of developing breast cancer and may have an indication for breast cancer screening using mammography. Since breast cancer is often viewed as a womans disease, visibilizing and understanding mens experience of having a BRCA mutation and specifically, of screening for breast cancer through mammography, were the objectives of this research study. The theoretical framework of interpretive phenomenology guided the process of data collection, coding, and analysis. Phenomenology is both a philosophy and research method which focuses on understanding the nature of experience from the perspectives of people experiencing a phenomenon, the essence of and commonalities among peoples experiences, and the ways in which people experience the world through their bodies. Data were collected via in-depth interviews with a purposive sample of 15 male participants recruited from the Male Oncology Research and Education (MORE) Program. This article reports findings about participants use of gender-specific language to describe their breasts, awareness of the ways in which their bodies changed overtime, and experiences of undergoing mammograms. This study is the first to describe men with BRCAs perceptions of their breasts and experiences of mammography in a high-risk cancer screening clinic. This study sheds light on an under-researched areabreasts and masculinitiesand could potentially lead to improved clinical understanding of mens embodied experiences of BRCA, as well as suggestions for improving the delivery of male breast cancer screening services

CYP gene polymorphisms and early menarche

Early age at menarche is a risk factor for breast cancer. A previous study reported a significant positive association between the CYP3A4*1B variant allele and early puberty. We investigated whether polymorphisms of the CYP3A4, CYP17, CYP1B1, and CYP1A2 genes predict the age at onset of menarche. Five hundred eighty-three nulliparous women between ages 17 and 35, of various ethnic backgrounds, completed a questionnaire that included information about menstrual history. Samples of DNA were provided and used to genotype these women for polymorphic variants in the four genes. There was no significant difference in mean age at menarche between women who carried two variant CYP17 A2 alleles (12.5 years) and women who carried one or no variant allele (12.5 years) (P = 0.8, adjusted for ethnic group and year of birth). Similar results were found for the CYP1B1*3 variant allele and for the CYP1A2*1F variant allele. Women who carried two variant CYP3A4*1B alleles had an earlier mean age at menarche (12.0 years) than women who carried one or no variant allele (12.6 years) (P = 0.02). However, after adjusting for ethnic group and year of birth, no significant differences in mean age at menarche were found. The polymorphic variants of the CYP3A4, CYP17, CYP1B1, and CYP1A2 genes are unlikely to influence age of menarche