High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune ...microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity. Epithelial CD8+ TILs negatively associated with malignant diversity, reflecting immunological pruning of tumor clones inferred by neoantigen depletion, HLA I loss of heterozygosity, and spatial tracking between T cell and tumor clones. In addition, combinatorial prognostic effects of mutational processes and immune properties were observed, illuminating how specific genomic aberration types associate with immune response and impact survival. We conclude that within-patient spatial immune microenvironment variation shapes intraperitoneal malignant spread, provoking new evolutionary perspectives on HGSC clonal dispersion.
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•Immune infiltrates vary across space within patients at the time of diagnosis•Immune infiltration shapes malignant cell evolutionary trajectories•T cell clones track with tumor clones across spatial sites within patients•Immune infiltrates and mutational processes show prognostic interactions
Integrated multi-region analysis of metastatic sites in patients with high-grade ovarian cancer highlights the connection between immune microenvironment variation and malignant spread, as well as the combinatorial prognostic value of immune and mutational features.
BACKGROUND Across the globe, employment for pay outside the home plays a key role in the lives of women, and increasing the proportion of women involved in high-quality jobs is a critical component ...of reaching several sustainable development goals. While existing research from high-income societies demonstrates that women's employment is not constant over the life course, relatively less is known about women's employment trajectories in lowincome countries. OBJECTIVE We examine employment trajectories among women in rural Nepal, accounting for job type, employment intensity, and earnings. METHODS Using eight years of quarterly employment data from the 2016 Female Labor Force Participation and Child Outcomes Study component of the Chitwan Valley Family Study, we identify typologies of employment trajectories by conducting sequence and cluster analyses. RESULTS First, half of the women in our sample were never employed in the study period. Second, among women who were ever employed, there were considerable transitions into and out of the workforce. Third, women's employment trajectories are largely determined by job type (wage labor, salaried jobs, and self-employment), with little movement across job types. Additionally, self-employed women and those with salaried jobs had higher earnings and higher employment intensity than women with wage labor jobs. CONCLUSIONS We see intense stratification into job types, including no employment at all, and substantial transitions into and out of the workforce among workers. Women experience many employment disruptions over the life course, with little sign of upward employment mobility. CONTRIBUTION This study provides new empirical portraits of women's employment in low-income settings by investigating the multiple dimensions of women's employment from a life course perspective.
We performed phylogenetic analysis of high-grade serous ovarian cancers (68 samples from seven patients), identifying constituent clones and quantifying their relative abundances at multiple ...intraperitoneal sites. Through whole-genome and single-nucleus sequencing, we identified evolutionary features including mutation loss, convergence of the structural genome and temporal activation of mutational processes that patterned clonal progression. We then determined the precise clonal mixtures comprising each tumor sample. The majority of sites were clonally pure or composed of clones from a single phylogenetic clade. However, each patient contained at least one site composed of polyphyletic clones. Five patients exhibited monoclonal and unidirectional seeding from the ovary to intraperitoneal sites, and two patients demonstrated polyclonal spread and reseeding. Our findings indicate that at least two distinct modes of intraperitoneal spread operate in clonal dissemination and highlight the distribution of migratory potential over clonal populations comprising high-grade serous ovarian cancers.
OVARIAN CARCINOMAS CONSIST OF AT LEAST FIVE DISTINCT DISEASES: high-grade serous, low-grade serous, clear cell, endometrioid, and mucinous. Biomarker and molecular characterization may represent a ...more biologically relevant basis for grouping and treating this family of tumors, rather than site of origin. Molecular characteristics have become the new standard for clinical pathology, however development of tailored type-specific therapies is hampered by a failure of basic research to recognize that model systems used to study these diseases must also be stratified. Unrelated model systems do offer value for study of biochemical processes but specific cellular context needs to be applied to assess relevant therapeutic strategies.
We have focused on the identification of clear cell carcinoma cell line models. A panel of 32 "ovarian cancer" cell lines has been classified into histotypes using a combination of mutation profiles, IHC mutation-surrogates, and a validated immunohistochemical model. All cell lines were identity verified using STR analysis.
Many described ovarian clear cell lines have characteristic mutations (including ARID1A and PIK3CA) and an overall molecular/immuno-profile typical of primary tumors. Mutations in TP53 were present in the majority of high-grade serous cell lines. Advanced genomic analysis of bona-fide clear cell carcinoma cell lines also support copy number changes in typical biomarkers such at MET and HNF1B and a lack of any recurrent expressed re-arrangements.
As with primary ovarian tumors, mutation status of cancer genes like ARID1A and TP53 and a general immuno-profile serve well for establishing histotype of ovarian cancer cell We describe specific biomarkers and molecular features to re-classify generic "ovarian carcinoma" cell lines into type specific categories. Our data supports the use of prototype clear cell lines, such as TOV21G and JHOC-5, and questions the use of SKOV3 and A2780 as models of high-grade serous carcinoma.
Ovarian endometrioid carcinomas and endometrial endometrioid carcinomas share many histological and molecular alterations. These similarities are likely due to a common endometrial epithelial ...precursor cell of origin, with most ovarian endometrioid carcinomas arising from endometriosis. To directly compare the mutation profiles of two morphologically similar tumor types, endometrial endometrioid carcinomas (n=307) and ovarian endometrioid carcinomas (n=33), we performed select exon capture sequencing on a panel of genes: ARID1A, PTEN, PIK3CA, KRAS, CTNNB1, PPP2R1A, TP53. We found that PTEN mutations are more frequent in low-grade endometrial endometrioid carcinomas (67%) compared with low-grade ovarian endometrioid carcinomas (17%) (P<0.0001). By contrast, CTNNB1 mutations are significantly different in low-grade ovarian endometrioid carcinomas (53%) compared with low-grade endometrial endometrioid carcinomas (28%) (P<0.0057). This difference in CTNNB1 mutation frequency may be reflective of the distinct microenvironments; the epithelial cells lining an endometriotic cyst within the ovary are exposed to a highly oxidative environment that promotes tumorigenesis. Understanding the distinct mutation patterns found in the PI3K and Wnt pathways of ovarian and endometrial endometrioid carcinomas may provide future opportunities for stratifying patients for targeted therapeutics.
Abstract Objective This study examines how marriage‐cohabitation gaps in household specialization (labor supply and earnings) vary across institutional contexts for same‐sex couples (SSCs) and ...different‐sex couples (DSCs) in Canada. Background Prior research suggests that marriage‐cohabitation gaps are smaller in contexts where cohabitation is more prevalent, but it has overlooked how legal protections (at the contextual level) and gender composition (at the couple level) moderate this association. As a result, little is known about whether differences in household specialization stem from heightened gendered expectations attached to marriage or stronger legal protections for married couples. This study posits that marriage‐cohabitation gaps will be larger in contexts where legal protections for cohabitors are less marriage‐like. Methods Using the 2006 and 2016 Canadian Census and the 2011 National Household Survey, I estimate ordinal and fractional logit models to examine marriage‐cohabitation gaps in specialization among all couples ( N = 2,788,055) and couples with young children ( N = 826,305). Results Among DSCs, marriage‐cohabitation gaps were larger in Québec than in English Canada vis‐à‐vis earnings but not labor supply. Patterns among SSCs were more heterogeneous: gaps in labor supply were larger in English Canada for female couples but larger in Québec for male couples. Gaps in earnings were generally larger in Québec, with few exceptions. However, DSCs consistently specialized more than SSCs. Conclusion While existing research suggests marriage‐cohabitation gaps in household specialization are largely explained by the prevalence of cohabitation, my results indicate that legal protections (at the contextual level) and gender composition (at the couple level) play a more decisive role.
Abstract Evidence-based health care decisions are best informed by comparisons of all relevant interventions used to treat conditions in specific patient populations. Observational studies are being ...performed to help fill evidence gaps. Widespread adoption of evidence from observational studies, however, has been limited because of various factors, including the lack of consensus regarding accepted principles for their evaluation and interpretation. Two task forces were formed to develop questionnaires to assist decision makers in evaluating observational studies, with one Task Force addressing retrospective research and the other Task Force addressing prospective research. The intent was to promote a structured approach to reduce the potential for subjective interpretation of evidence and drive consistency in decision making. Separately developed questionnaires were combined into a single questionnaire consisting of 33 items. These were divided into two domains: relevance and credibility. Relevance addresses the extent to which findings, if accurate, apply to the setting of interest to the decision maker. Credibility addresses the extent to which the study findings accurately answer the study question. The questionnaire provides a guide for assessing the degree of confidence that should be placed from observational studies and promotes awareness of the subtleties involved in evaluating those.
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