Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE).

PURPOSE: Gene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. EXPERIMENTAL DESIGN: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. RESULTS: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. CONCLUSIONS: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications.See related commentary by McMullen et al., p. 5271.Core funding for this project was provided by the National Institutes of Health (R01-CA172404, PI: S.J. Ramus; and R01-CA168758, PIs: J.A. Doherty and M.A.Rossing), the Canadian Institutes for Health Research (Proof-of-Principle I program, PIs: D.G.Huntsman and M.S. Anglesio), the United States Department of Defense Ovarian Cancer Research Program (OC110433, PI: D.D. Bowtell). A. Talhouk is funded through a Michael Smith Foundation for Health Research Scholar Award. M.S. Anglesio is funded through a Michael Smith Foundation for Health Research Scholar Award and the Janet D. Cottrelle Foundation Scholars program managed by the BC Cancer Foundation. J. George was partially supported by the NIH/National Cancer Institute award number P30CA034196. C. Wang was a Career Enhancement Awardee of the Mayo Clinic SPORE in Ovarian Cancer (P50 CA136393). D.G. Huntsman receives support from the Dr. Chew Wei Memorial Professorship in Gynecologic Oncology, and the Canada Research Chairs program (Research Chair in Molecular and Genomic Pathology). M. Widschwendter receives funding from the European Union’s Horizon 2020 European Research Council Programme, H2020 BRCA-ERC under Grant Agreement No. 742432 as well as the charity, The Eve Appeal (https://eveappeal.org.uk/), and support of the National Institute for Health Research (NIHR) and the University College London Hospitals (UCLH) Biomedical Research Centre. G.E. Konecny is supported by the Miriam and Sheldon Adelson Medical Research Foundation. B.Y. Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. H.R. Harris is 20 supported by the NIH/National Cancer Institute award number K22 CA193860. OVCARE (including the VAN study) receives support through the BC Cancer Foundation and The VGH+UBC Hospital Foundation (authors AT, BG, DGH, and MSA). The AOV study is supported by the Canadian Institutes of Health Research (MOP86727). The Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network-Oncology group, was funded by the National Health and Medical Research Council Enabling Grants ID 310670 & ID 628903 and the Cancer Institute NSW Grants ID 12/RIG/1-17 & 15/RIG/1-16. The Australian Ovarian Cancer Study Group was supported by the U.S. Army Medical Research and Materiel Command under DAMD17-01-1-0729, The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Council Tasmania and The Cancer Foundation of Western Australia (Multi-State Applications 191, 211 and 182) and the National Health and Medical Research Council of Australia (NHMRC; ID199600; ID400413 and ID400281). BriTROC-1 was funded by Ovarian Cancer Action (to IAM and JDB, grant number 006) and supported by Cancer Research UK (grant numbers A15973, A15601, A18072, A17197, A19274 and A19694) and the National Institute for Health Research Cambridge and Imperial Biomedical Research Centres. Samples from the Mayo Clinic were collected and provided with support of P50 CA136393 (E.L.G., G.L.K, S.H.K, M.E.S.)

Utilizing Participatory Research to Engage Underserved Populations to Improve Health-Related Outcomes in Delaware

Cooperative Extension is a community outreach program. Despite its large reach, there is a need for the evaluation of changes in health-related outcomes for individuals engaged with Cooperative Extension. A team-based challenge was developed using community-engaged participatory research integrated with Cooperative Extension to encourage healthy eating and physical activity behaviors through Cooperative Extension programming. Thus, the primary purpose of this secondary analysis was to (1) evaluate changes in anthropometric outcomes and (2) evaluate changes in health behavior outcomes. Associations of anthropometric changes and health behavior changes with engagement in the three-month team-based challenge were explored. Anthropometrics were measured using standard procedures, and intake of fruits and vegetables and physical activity were self-reported. Of the 145 participants in the community-engaged participatory research portion of the study, 52.4% (n = 76) had complete anthropometrics before and after the team-based challenge and were included in this study. At 3 months, there was a significant reduction in body mass index (−0.3 kg/m2, p = 0.024) and no significant change in waist circumference (p = 0.781). Fruit and vegetable intake significantly increased (+0.44 servings/day, p = 0.018). Physical activity did not significantly change based on (1) the number of days 30 or more minutes of physical activity was conducted (p = 0.765) and (2) Godin Leisure-Time Exercise Questionnaire scores (p = 0.612). Changes in anthropometrics and health behaviors were not associated with engagement in the team-based challenge. Using community-engaged participatory research with community outreach programs, such as Cooperative Extension, can improve health-related outcomes in underserved populations. However, despite a participatory approach, changes in anthropometrics and health behaviors were not associated with engagement in the developed team-based challenge

A Map of LTP-Related Synaptic Changes in Dorsal Hippocampus Following Unsupervised Learning

Recent work showed that unsupervised learning of a complex environment activates synaptic proteins essential for the stabilization of long-term potentiation (LTP). The present study used automated methods to construct maps of excitatory synapses associated with high concentrations of one of these LTP-related proteins [CaMKII phosphorylated at T286/287, (pCaMKII)]. Labeling patterns across 42 sampling zones covering entire cross sections through rostral hippocampus were assessed for two groups of rats that explored a novel two-room arena for 30 min, with or without a response contingency involving mildly aversive cues. The number of pCaMKII-immunopositive (+) synapses was highly correlated between the two groups for the 21 sampling zones covering the dentate gyrus, CA3c/hilus, and apical dendrites of field CA1, but not for the remainder of the cross section. The distribution of pCaMKII+ synapses in the large uncorrelated segment differed markedly between the groups. Subtracting home-cage values removed high scores (i.e., sampling zones with a high percentage of pCaMKII+ contacts) in the negative contingency group, but not in the free-exploration animals. Three sites in the latter had values that were markedly elevated above other fields. These mapping results suggest that encoding of a form of memory that is dependent upon rostral hippocampus reliably occurs at high levels in discrete anatomical zones, and that this regionally differentiated response is blocked when animals are inhibited from freely exploring the environment by the introduction of a mildly aversive stimulus

A Map of LTP-Related Synaptic Changes in Dorsal Hippocampus Following Unsupervised Learning

Recent work showed that unsupervised learning of a complex environment activates synaptic proteins essential for the stabilization of long-term potentiation (LTP). The present study used automated methods to construct maps of excitatory synapses associated with high concentrations of one of these LTP-related proteins [CaMKII phosphorylated at T286/287, (pCaMKII)]. Labeling patterns across 42 sampling zones covering entire cross sections through rostral hippocampus were assessed for two groups of rats that explored a novel two-room arena for 30 min, with or without a response contingency involving mildly aversive cues. The number of pCaMKII-immunopositive (+) synapses was highly correlated between the two groups for the 21 sampling zones covering the dentate gyrus, CA3c/hilus, and apical dendrites of field CA1, but not for the remainder of the cross section. The distribution of pCaMKII+ synapses in the large uncorrelated segment differed markedly between the groups. Subtracting home-cage values removed high scores (i.e., sampling zones with a high percentage of pCaMKII+ contacts) in the negative contingency group, but not in the free-exploration animals. Three sites in the latter had values that were markedly elevated above other fields. These mapping results suggest that encoding of a form of memory that is dependent upon rostral hippocampus reliably occurs at high levels in discrete anatomical zones, and that this regionally differentiated response is blocked when animals are inhibited from freely exploring the environment by the introduction of a mildly aversive stimulus

Oil impacts on coastal wetlands: Implications for the Mississippi River delta ecosystem after the deepwater horizon oil spill

On 20 April 2010, the Deepwater Horizon explosion, which released a US governmentestimated 4.9 million barrels of crude oil into the Gulf of Mexico, was responsible for the death of 11 oil workers and, possibly, for an environmental disaster unparalleled in US history. For 87 consecutive days, the Macondo well continuously released crude oil into the Gulf of Mexico. Many kilometers of shoreline in the northern Gulf of Mexico were affected, including the fragile and ecologically important wetlands of Louisiana\u27s Mississippi River Delta ecosystem. These wetlands are responsible for a third of the nation\u27s fish production and, ironically, help to protect an energy infrastructure that provides a third of the nations oil and gas supply. Here, we provide a basic overview of the chemistry and biology of oil spills in coastal wetlands and an assessment of the potential and realized effects on the ecological condition of the Mississippi River Delta and its associated flora and fauna. © 2012 by American Institute of Biological Sciences

The Gulf of Mexico: An Overview

The Gulf of Mexico is a place where the environment and the economy both coexist and contend. It is a resilient large marine ecosystem that has changed in response to many drivers and pressures that we are only now beginning to fully understand. Coastlines of the states that border the Gulf comprise about half of the US southern seaboard, and those states are capped by the vast Midwest. The Gulf drains most of North America and is both an economic keystone and an unintended waste receptacle. It is a renowned resource for seafood markets, recreational fishing, and beach destinations and an international maritime highway fueled by vast, but limited, hydrocarbon reserves. Today, more is known about the Gulf than was imagined possible only a few years ago. That gain in knowledge was driven by one of the greatest environmental disasters of this country’s history, the Deepwater Horizon oil spill. The multitude of response actions and subsequent funded research significantly contributed to expanding our knowledge and, perhaps most importantly, to guiding the work needed to restore the damage from that oil spill. Funding for further work should not wait for the next major disaster, which will be too late; progress must be maintained to ensure that the Gulf continues to be resilient

The Gulf of Mexico: An Overview

The Gulf of Mexico is a place where the environment and the economy both coexist and contend. It is a resilient large marine ecosystem that has changed in response to many drivers and pressures that we are only now beginning to fully understand. Coastlines of the states that border the Gulf comprise about half of the US southern seaboard, and those states are capped by the vast Midwest. The Gulf drains most of North America and is both an economic keystone and an unintended waste receptacle. It is a renowned resource for seafood markets, recreational fishing, and beach destinations and an international maritime highway fueled by vast, but limited, hydrocarbon reserves. Today, more is known about the Gulf than was imagined possible only a few years ago. That gain in knowledge was driven by one of the greatest environmental disasters of this country’s history, the Deepwater Horizon oil spill. The multitude of response actions and subsequent funded research significantly contributed to expanding our knowledge and, perhaps most importantly, to guiding the work needed to restore the damage from that oil spill. Funding for further work should not wait for the next major disaster, which will be too late; progress must be maintained to ensure that the Gulf continues to be resilient

Limited Reporting of Histopathologic Details in a Multi-Institutional Academic Cohort of Phyllodes Tumors: Time for Standardization

BackgroundPhyllodes tumors are rare fibroepithelial neoplasms that are classified by tiered histopathologic features. While there are protocols for the reporting of cancer specimens, no standardized reporting protocol exists for phyllodes.MethodsWe performed an 11-institution contemporary review of phyllodes tumors. Granular histopathologic details were recorded, including the features specifically considered for phyllodes grade classification.ResultsOf 550 patients, median tumor size was 3.0 cm, 68.9% (n = 379) of tumors were benign, 19.6% (n = 108) were borderline, and 10.5% (n = 58) were malignant. All cases reported the final tumor size and grade classification. Complete pathologic reporting of all histopathologic features was present in 15.3% (n = 84) of cases, while an additional 35.6% (n = 196) were missing only one or two features in the report. Individual details regarding the degree of stromal cellularity was not reported in 53.5% (n = 294) of cases, degree of stromal atypia in 58.0% (n = 319) of cases, presence of stromal overgrowth in 56.2% (n = 309) of cases, stromal cell mitoses in 37.5% (n = 206) of cases, and tumor border in 54.2% (n = 298) of cases. The final margin status (negative vs. positive) was omitted in only 0.9% of cases, and the final negative margin width was specifically reported in 73.8% of cases. Reporting of details was similar across all sites.ConclusionIn this academic cohort of phyllodes tumors, one or more histopathologic features were frequently omitted from the pathology report. While all features were considered by the pathologist for grading, this limited reporting reflects a lack of reporting consensus. We recommend that standardized reporting in the form of a synoptic-style cancer protocol be implemented for phyllodes tumors, similar to other rare tumors