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BRCA testing services are now offered by various healthcare providers, thus it is important to evaluate whether the implementation of cancer risk management ( CRM) strategies varies by service provider. Using a registry-based sample of 795 female BRCA mutation carriers, we explored the association between uptake of CRM strategies with duration of genetic counseling ( GC) sessions, provider type, and other demographic and clinical variables. All participants completed a baseline questionnaire. Information about uptake of CRM strategies was collected for a subset of 438 participants who completed additional questions. Summary statistics and Pearson chi-squared analysis were used to examine the associations between demographic and clinical variables with service delivery factors and with the uptake of various CRM strategies. Overall uptake of CRM strategies was high across all provider types. However, GC sessions were longer when provided by a genetics professional than by another provider (p < 0.001). Furthermore, higher frequencies of uptake of most CRM strategies were associated with longer GC sessions and when testing was performed by a genetics professional. Identification of factors to optimize delivery of these specialized GC services is important to maximize implementation of CRM strategies in BRCA carriers. [ABSTRACT FROM AUTHOR]

Historically, consumer acceptance of beef was determined by tenderness. Developments in genetics and management over the last couple of decades have improved tenderness to the point that it is secondary to other factors in beef's taste. Flavor, however, is an extraordinarily complex taste attribute dependent on biological sensors in the mouth, sinus cavity, and jaws. The culinary industry has recently focused on innovative ways to give consumers new products satisfying their curiosity about different foods, especially proteins. Competition from plant-based, cell-based, and even other animal-based proteins provides diversity in consumers' ability to select a protein that satisfies their desire to include unique products in their diet. Consequently, the beef industry has focused on flavor for the last 10 to 15 years to determine whether it can provide the guardrails for beef consumption in the future. The U.S. beef industry formed a Flavor Working Group in 2012 composed of the authors listed here to investigate new and innovative ways to manage and measure beef flavor. The results of this working group have resulted in dozens of papers, presentations, abstracts, and symposia. The objective of this manuscript is to summarize the research developed by this working group and by others worldwide that have investigated methodologies that measure beef flavor. This paper will describe the strengths of the research in beef flavor measurement and point out future needs that might be identified as technology advances., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

Beef flavor continues to be one of the largest drivers of beef demand and a differentiation point of beef from other competing proteins. Tenderness has long been identified as the most important palatability trait for consumer satisfaction. However, as technological advancements and industry practices evolve and improve in response to tenderness management, flavor has emerged as a key driver of consumer satisfaction. In response, the beef industry has recently invested in research focused on beef flavor development, measurement, and management to better understand the factors impacting flavor and help beef maintain this advantage. The current review paper is the second of two such papers focused on summarizing the present knowledge and identifying knowledge gaps. While the other review focuses on current practices related to beef flavor measurement, this review will cover research findings related to beef flavor management. Numerous production and product management factors influence beef flavor. Pre-harvest factors including marbling level, animal genetics/cattle type, diet, and animal age, can influence beef flavor. Moreover, numerous post-harvest product management factors, including product type, aging length and conditions, cookery methods, product enhancement, muscle-specific factors, packaging, retail display factors, and antimicrobial interventions, have all been evaluated for their impact on beef flavor characteristics. Results from numerous studies evaluating many of these factors will be outlined within this review in order to present management and production chain factors that can influence beef flavor., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: Currently 11 infectious agents are classified as carcinogenic but the role of infectious agents on outcomes of epithelial ovarian cancer is largely unknown., Objective: To explore the association between infectious agents and ovarian cancer, we investigated the prevalence of viral DNA in primary ovarian cancer tumors and its association with clinical outcomes., Methods: Archived tumors from 98 patients diagnosed with high-grade serous epithelial ovarian cancer were collected between 1/1/1994 and 12/31/2010. After DNA extraction, Luminex technology was utilized to identify polymerase chain reaction-amplified viral DNA for 113 specific viruses. Demographic data and disease characteristics were summarized using descriptive statistics. We used logistic regression and Cox proportional hazards model to assess associations between tumor viral status and disease outcome and between tumor viral presence and overall survival (OS), respectively., Results: Forty-six cases (45.9%) contained at least one virus. Six highly prevalent viruses were associated with clinical outcomes and considered viruses of interest (VOI; Epstein-Barr virus 1, Merkel cell polyomavirus, human herpes virus 6b, and human papillomaviruses 4, 16, and 23). Factors independently associated with OS were presence of VOI (HR 4.11, P = 0.0001) and platinum sensitivity (HR 0.21, P<0.0001). Median OS was significantly decreased when tumors showed VOI versus not having these viruses (22 vs 44 months, P<0.0001). Women <70 year old with VOI in tumors had significantly lower median OS versus age-matched women without VOI (20 vs 57 months, P = 0.0006); however, among women ≥70 years old, there was no difference in OS by tumor virus status., Conclusions: The presence of a VOI was significantly associated with a lower OS. These findings may have implications for clinical management of ovarian cancer but require additional studies., Competing Interests: JL worked at Myriad Genetic Laboratories, Incorporated Company (Inc) and currently works at Regeneron pharmaceuticals, Inc. AG serves as at scientific advisory boards at Merck & CO. TG and MT work at International Agency for Research on Cancer (IARC), World Health Organization (WHO). YX currently works at Aster Insights. The funder provided partial support in the form of salaries for authors (JL, AG, TG, MT and YX), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Robertson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Patients with immunodeficiency-associated antibody disorders are at a higher risk of prolonged/persistent COVID-19 infection, having no viable treatment options., Methods: A retrospective analysis of patients with primary and/or secondary immunodeficiency-associated antibody disorders who received casirivimab and imdevimab (REGEN-COV®) under emergency compassionate use. Objective were to describe safety and response to REGEN-COV, focusing on the subset of patients who had COVID-19 duration ≥21 days before treatment., Results: Quantitative (change in oxygenation status and/or viral load) and/or qualitative (physician-reported clinical status) outcomes data are reported from 64 patients. Improvement in ≥1 outcome was observed in 90.6% of the overall patient group. Thirty-seven of these had COVID-19 duration ≥21 days before treatment; median time from diagnosis to REGEN-COV treatment was 60.5 days. Of the 29 patients with COVID-19 duration ≥21 days before treatment and available outcome data, 96.6% showed improvement in ≥1 outcome. In the 14 patients with post-treatment reverse transcription-polymerase chain reaction (RT-PCR) results available, 11 (78.6%) reported a negative RT-PCR following treatment, with 5 (45.5%) and 8 (72.7%) patients reporting a negative RT-PCR within 5 days and 21 days of treatment, respectively. Ten of 85 patients (11.8%) experienced serious adverse events; only one was an infusion-related reaction, possibly related to REGEN-COV. Two deaths were reported; neither were attributed to REGEN-COV., Conclusions: In this retrospective analysis of immunodeficient patients granted REGEN-COV under emergency compassionate use, REGEN-COV treatment was associated with rapid viral clearance and clinical improvement in patients with longstanding COVID-19. Adverse events were consistent with COVID-19 and its associated complications, and due to patients' concurrent medical conditions., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Animal behavior is indicative of health status and changes in behavior can indicate health issues (i.e., illness, stress, or injury). Currently, human observation (HO) is the only method for detecting behavior changes that may indicate problems in group-housed pigs. While HO is effective, limitations exist. Limitations include HO being time consuming, HO obfuscates natural behaviors, and it is not possible to maintain continuous HO. To address these limitations, a computer vision platform (NU track) was developed to identify (ID) and continuously monitor specific behaviors of group-housed pigs on an individual basis. The objectives of this study were to evaluate the capabilities of the NU track s ystem and evaluate changes in behavior patterns over time of group-housed nursery pigs. The NU track system was installed above four nursery pens to monitor the behavior of 28 newly weaned pigs during a 42-d nursery period. Pigs were stratified by sex, litter, and randomly assigned to one of two pens (14 pigs/pen) for the first 22 d. On day 23, pigs were split into four pens (7 pigs/pen). To evaluate the NU track system's capabilities, 800 video frames containing 11,200 individual observations were randomly selected across the nursery period. Each frame was visually evaluated to verify the NU track system's accuracy for ID and classification of behavior. The NU track system achieved an overall accuracy for ID of 95.6%. This accuracy for ID was 93.5% during the first 22 d and increased ( P < 0.001) to 98.2% for the final 20 d. Of the ID errors, 72.2% were due to mislabeled ID and 27.8% were due to loss of ID. The NU track system classified lying, standing, walking, at the feeder (ATF), and at the waterer (ATW) behaviors accurately at a rate of 98.7%, 89.7%, 88.5%, 95.6%, and 79.9%, respectively. Behavior data indicated that the time budget for lying, standing, and walking in nursery pigs was 77.7% ± 1.6%, 8.5% ± 1.1%, and 2.9% ± 0.4%, respectively. In addition, behavior data indicated that nursery pigs spent 9.9% ± 1.7% and 1.0% ± 0.3% time ATF and ATW, respectively. Results suggest that the NU track system can detect, identify, maintain ID, and classify specific behavior of group-housed nursery pigs for the duration of the 42-d nursery period. Overall, results suggest that, with continued research, the NU track system may provide a viable real-time precision livestock tool with the ability to assist producers in monitoring behaviors and potential changes in the behavior of group-housed pigs., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society of Animal Science.)

Loss of stromal caveolin-1 (Cav-1) is a biomarker of a cancer-associated fibroblast (CAF) phenotype and is related to progression, metastasis, and poor outcomes in several cancers. The objective of this study was to evaluate the clinical significance of Cav-1 expression in invasive epithelial ovarian cancer (OvCa). Epithelial and stromal Cav-1 expression were quantified in serous OvCa and benign ovarian tissue in two, independent cohorts-one quantified expression using immunohistochemistry (IHC) and the other using multiplex immunofluorescence (IF) with digital image analysis designed to target CAF-specific expression. Cav-1 expression was significantly downregulated in OvCa stroma compared to non-neoplastic stroma using both the IHC (p = 0.002) and IF (p = 1.8x10-13) assays. OvCa stroma showed Cav-1 downregulation compared to tumor epithelium with IHC (p = 1.2x10-24). Conversely, Cav-1 expression was higher in OvCa stroma compared to tumor epithelium with IF (p = 0.002). There was moderate correlation between IHC and IF methods for stromal Cav-1 expression (r2 = 0.69, p = 0.006) whereas there was no correlation for epithelial expression (r2 = 0.006, p = 0.98). Irrespective of the staining assay, neither response to therapy or overall survival correlated with the expression level of Cav-1 in the stroma or tumor epithelium. Our findings demonstrate a loss of stromal Cav-1 expression in ovarian serous carcinomas. Studies are needed to replicate these findings and explore therapeutic implications, particularly for immunotherapy response., Competing Interests: Dr. Robert Wenham reports grants and personal fees from Merck, personal fees from Tesaro/GSK, personal fees from Genentech, personal fees from Legend Biotech, personal fees from AbbVie, personal fees from Astrazeneca, grants and personal fees from Ovation Diagnostics, personal fees from Clovis Oncology, personal fees from Regeneron, outside the submitted work. Dr. Johnathan Lancaster employed by Regeneron. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Professional society guidelines recommend risk-reducing salpingo-oophorectomy (RRSO) for women with pathogenic variants (PVs) in ovarian cancer-risk genes. Personalization of that intervention is based on gene-specific phenotypes; however, the age of ovarian cancer diagnosis in women with PVs in moderate penetrance ovarian cancer-risk genes is not well characterized. Women who had hereditary cancer panel testing from September 2013-May 2019 were included (N = 631,950). Clinical/demographic information was compared for women with a PV in BRIP1, RAD51C, or RAD51D versus in BRCA1 or BRCA2., Results: PVs in BRIP1, RAD51C, or RAD51D were identified in 0.5% of all tested women but in 1.6% of women with a history of ovarian cancer (~ 3-fold increase). PVs in BRCA1 or BRCA2 were identified in 2.4% of all tested women but in 6.1% of women with a history of ovarian cancer (~ 2.5-fold increase). The proportion of women with a personal or family history of ovarian cancer was similar among women with a PV in BRIP1, RAD51C, RAD51D, BRCA1, or BRCA2. The median age at ovarian cancer diagnosis was 53 years for BRCA1, 59 years for BRCA2, 65 years for BRIP1, 62 years for RAD51C, and 57 years for RAD51D., Conclusions: These data reinforce the importance of identifying PVs in moderate penetrance ovarian cancer-risk genes. The age at ovarian cancer diagnosis was older for women with PVs in BRIP1, RAD51C, or RAD51D, suggesting that it is safe to delay RRSO until age 45-50 in RAD51D PV carriers and possibly until age 50-55 in BRIP and RAD51C PV carriers.

Pathogenic variants (PVs) in ATM are relatively common, but the scope and magnitude of risk remains uncertain. This study aimed to estimate ATM PV cancer risks independent of family cancer history. This analysis included patients referred for hereditary cancer testing with a multi-gene panel ( N = 627,742). Cancer risks for ATM PV carriers ( N = 4,607) were adjusted for family history using multivariable logistic regression and reported as ORs with 95% confidence intervals (CIs). Subanalyses of the c.7271T>G missense PV were conducted. Moderate-to-high risks for pancreatic (OR, 4.21; 95% CI, 3.24-5.47), prostate (OR, 2.58; 95% CI, 1.93-3.44), gastric (OR, 2.97; 95% CI, 1.66-5.31), and invasive ductal breast (OR, 2.03; 95% CI, 1.89-2.19) cancers were estimated for ATM PV carriers. Notably, c.7271T>G was associated with higher invasive ductal breast cancer risk (OR, 3.76; 95% CI, 2.76-5.12) than other missense and truncating ATM PVs. Low-to-moderate risks were seen for ductal carcinoma in situ (OR, 1.80; 95% CI, 1.61-2.02), male breast cancer (OR, 1.72; 95% CI, 1.08-2.75), ovarian cancer (OR, 1.57; 95% CI, 1.35-1.83), colorectal cancer (OR, 1.49; 95% CI, 1.24-1.79), and melanoma (OR, 1.46; 95% CI, 1.18-1.81). ATM PVs are associated with multiple cancer risks and, while professional society guidelines support that carriers are eligible for increased breast and pancreatic cancer screening, increased screening for prostate and gastric cancer may also be warranted. c.7271T>G is associated with high risk for breast cancer, with a 3- to 4-fold risk increase that supports consideration of strategies for prevention and/or early detection. PREVENTION RELEVANCE: This study estimated risks for multiple cancers associated with ATM pathogenic variants independent of family history. These results indicate that some common variants may be associated with higher breast cancer risks than previously appreciated and increased screening for prostate and gastric cancer may be warranted for carriers of ATM pathogenic variants., (©2021 American Association for Cancer Research.)

Aim: Healthcare utilization and costs were compared following 25-gene panel (panel) or single syndrome (SS) testing for hereditary breast and ovarian cancer. Materials & methods: Retrospective cohort study of patients unaffected by cancer with panel (n = 6359) or SS (n = 4681) testing for hereditary breast and ovarian cancer (01 January 2014 to 31 December 2016). Groups were determined by test type and result (positive, negative, variant of uncertain significance [VUS]). Results: There were no differences in total unadjusted healthcare costs between the panel (US$14,425) and SS (US$14,384) groups (p = 0.942). Among VUS patients in the panel and SS groups, mean all-cause costs were US$14,404 versus US$20,607 (p = 0.361) and mean risk-reduction/early detection-specific costs were US$718 versus US$679 (p = 0.890), respectively. Adjusted medical costs were not significantly different between panel and SS cohorts. Conclusion: Healthcare utilization and costs were comparable between the SS and panel tests overall and for patients with VUS.

Purpose: Screening and prevention decisions for women at increased risk of developing breast cancer depend on genetic and clinical factors to estimate risk and select appropriate interventions. Integration of polygenic risk into clinical breast cancer risk estimators can improve discrimination. However, correlated genetic effects must be incorporated carefully to avoid overestimation of risk., Materials and Methods: A novel Fixed-Stratified method was developed that accounts for confounding when adding a new factor to an established risk model. A combined risk score (CRS) of an 86-single-nucleotide polymorphism polygenic risk score and the Tyrer-Cuzick v7.02 clinical risk estimator was generated with attenuation for confounding by family history. Calibration and discriminatory accuracy of the CRS were evaluated in two independent validation cohorts of women of European ancestry (N = 1,615 and N = 518). Discrimination for remaining lifetime risk was examined by age-adjusted logistic regression. Risk stratification with a 20% risk threshold was compared between CRS and Tyrer-Cuzick in an independent clinical cohort (N = 32,576)., Results: Simulation studies confirmed that the Fixed-Stratified method produced accurate risk estimation across patients with different family history. In both validation studies, CRS and Tyrer-Cuzick were significantly associated with breast cancer. In an analysis with both CRS and Tyrer-Cuzick as predictors of breast cancer, CRS added significant discrimination independent of that captured by Tyrer-Cuzick ( P < 10 -11 in validation 1; P < 10 -7 in validation 2). In an independent cohort, 18% of women shifted breast cancer risk categories from their Tyrer-Cuzick-based risk compared with risk estimates by CRS., Conclusion: Integrating clinical and polygenic factors into a risk model offers more effective risk stratification and supports a personalized genomic approach to breast cancer screening and prevention., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Elisha HughesEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad GeneticsPlacede TshiabaEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad GeneticsSusanne WagnerEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad Genetics Patents, Royalties, Other Intellectual Property: Coauthor of patents held by Myriad Genetics, no royaltiesThaddeus JudkinsEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad Genetics Travel, Accommodations, Expenses: Myriad GeneticsEric RosenthalEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad GeneticsBenjamin RoaEmployment: Myriad Genetics Leadership: Myriad Genetics Stock and Other Ownership Interests: Myriad Genetics Research Funding: Myriad Genetics Patents, Royalties, Other Intellectual Property: Intellectual property held by employer Myriad Genetics Travel, Accommodations, Expenses: Myriad GeneticsShannon GallagherEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad GeneticsStephanie MeekEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad GeneticsKathryn DaltonSpeakers' Bureau: Myriad GeneticsDanna F. GrearConsulting or Advisory Role: Myriad Genetics Speakers' Bureau: Myriad Genetics Travel, Accommodations, Expenses: Myriad GeneticsSusan M. DomchekHonoraria: AstraZeneca, Clovis Oncology, Bristol-Myers Squibb Research Funding: AstraZeneca, Clovis OncologyJudy GarberConsulting or Advisory Role: Novartis, GTx, Helix BioPharma, Konica Minolta, Aleta BioTherapeutics, H3 Biomedicine, Kronos Bio Research Funding: Novartis, Ambry Genetics, InVitae, Myriad Genetics Other Relationship: Susan G. Komen for the Cure, AACR, Diana Helis Henry Medical Foundation, James P. Wilmot Foundation, Adrienne Helis Malvin Medical Research Foundation, Breast Cancer Research Foundation, Facing our Risk of Cancer EmpoweredJohnathan M. LancasterEmployment: Myriad Genetics, Regeneron Leadership: Myriad Genetics, Regeneron Stock and Other Ownership Interests: Myriad Genetics, RegeneronJeffrey N. WeitzelSpeakers' Bureau: AstraZenecaAllison W. KurianResearch Funding: Myriad Genetics Other Relationship: Ambry Genetics, Color Genomics, GeneDx/BioReference, InVitae, GenentechJerry S. LanchburyEmployment: Myriad Genetics Leadership: Myriad Genetics Stock and Other Ownership Interests: Myriad Genetics Patents, Royalties, Other Intellectual Property: I am an inventor on multiple patents filed by Myriad Genetics Travel, Accommodations, Expenses: Myriad GeneticsAlexander GutinEmployment: Myriad Genetics Stock and Other Ownership Interests: Myriad Genetics, Gilead SciencesMark E. RobsonConsulting or Advisory Role: Change HealthCare Research Funding: AstraZeneca, AbbVie, Pfizer, Merck Travel, Accommodations, Expenses: AstraZeneca, Merck Other Relationship: Research to Practice, Clinical Care Options, Physicians' Education Resource, Invitae, Pfizer (OPTIONAL) Uncompensated Relationships: Merck, Pfizer, Daiichi Sankyo, Epic Sciences, https://openpaymentsdata.cms.gov/physician/612669/summary No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Purpose: The role of genetic predisposition in male breast cancer (MBC) patients who test negative for a BRCA mutation is unclear. The aim of this study is to define the association between MBC and family history of breast cancer in patients without mutations in BRCA1 or BRCA2., Methods: We conducted an unmatched case-control study with men who received commercial testing for germline mutations in cancer susceptibility genes, including 3,647 MBC cases who tested negative for deleterious mutations in BRCA1/BRCA2, and 4,269 men with a personal history of colorectal cancer who tested negative for mutations in DNA mismatch repair genes to serve as controls. Associations between family history of breast cancer and MBC were estimated using unconditional multivariable logistic regression with adjustment for age, race/ethnicity and year of testing., Results: Breast cancer in a first- or second-degree relative was associated with a four-fold increased odds of MBC (OR 4.7; 95% CI 4.1, 5.3). Associations with MBC were strongest for family history of breast cancer in 2 or more first-degree relatives (FDR) (OR 7.8; 95% CI 5.2, 11.6), for probands and FDR diagnosed at age < 45 years (OR 6.9; 95% CI 3.9, 12.4), and for family history of MBC (OR 17.9; 95% CI 7.6, 42.1). Findings were confirmed in a sensitivity analysis of MBC cases who tested negative on a 25-gene pan-cancer panel., Conclusions: MBC patients without mutations in BRCA1/2 have significantly higher odds of a family history of breast cancer, suggesting the existence of unidentified MBC susceptibility alleles.

Beef carcass weights in the United States have continued to increase over the past 30 yr. As reported by the United States Department of Agriculture, grid-based carcass weight discounts begin when carcasses exceed 408 kg. Despite weight discounts, beef carcass weights continue to increase. At the same time, an increased prevalence of discoloration and color variability in top round subprimals has been observed throughout the industry which may be influenced by the increases in carcass weights. The objectives of this study were to assess the effects of beef carcass size and its relationship to chill time, color, pH, and tenderness of the beef top round. In the current study, eight industry average weight beef carcasses (AW, 341-397 kg) and eight oversized beef carcasses (OW, exceeding 432 kg) were evaluated. Temperatures and pH measurements were observed on both sides of all carcasses for the initial 48 h postharvest at a consistent superficial and deep anatomical location of the respective top rounds. Carcasses were fabricated into subprimals at 48 h and top rounds were aged at 2 °C for an additional 12 d. The superficial location of both AW and OW carcasses cooled at a faster rate ( P < 0.01) than the deep locations. The deep location of OW carcasses had a lower pH and a more rapid ( P < 0.01) initial pH decline. Quantitative color of steaks from OW carcasses had greater mean L * (lightness; P = 0.01) and initial b * (yellowness; P < 0.01) values. The delayed temperature decline and the accelerated pH decline of the deep location of the top round of OW carcasses occur at different rates than AW carcasses. Delayed rate of cooling leads to irreversible impacts on steak appearance of top round steaks fabricated from OW beef carcasses when compared with AW carcasses., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society of Animal Science.)

The objective of this study was to evaluate the effectiveness of genetic panel marbling indexes [Igenity (IT) and PredicGEN (PG)] to predict marbling and tenderness of crossbred cattle. Steers ( n = 23) were harvested at the University of Idaho Meat Science Laboratory, and blood samples were submitted to Neogen and Zoetis for genetic panel analysis. Forty-eight hours postharvest, one boneless strip loin was collected from each carcass, and six 2.54-cm thick steaks were cut from each strip loin. Steaks were aged for 14 and 21 d and assigned to consumer sensory evaluation or Warner-Bratzler Shear Force (WBSF) analysis. Results were analyzed using the Mixed Model procedure of the Statistical Analysis System (SAS Institute, Inc., Cary, NC). Carcasses were grouped by marbling index score into Low IT (IT indexes 3-6; n = 16; marbling score (MS) = 410), High IT (IT indexes 7-10; n = 7; MS = 496), Low PG (PG index <50; n = 9; MS = 398), or High PG (PG index ≥50; n = 14; MS = 458). Mean MS was observed to be greater in High IT steaks than Low IT ( P < 0.01) and greater in High PG steaks than Low PG ( P = 0.01). There was a trend observed in WBSF between IT marbling groups ( P = 0.06); however, no difference in WBSF was observed between PG marbling groups ( P = 0.83). Consumers did not report differences between IT marbling groups in terms of acceptability ( P = 0.99) or tenderness ( P = 0.24). Additionally, consumers could not detect differences between PG marbling groups in terms of acceptability ( P = 0.75) or tenderness ( P = 0.40). Consumers consistently preferred Choice steaks over Select steaks in terms of acceptability ( P = 0.02) and tenderness ( P = 0.02). In conclusion, though consumers were not able to tell the difference between steaks from each of the genetic panels, using genetic panels to predict marbling, in conjunction with proper nutrition and handling practices, could be a beneficial tool to producers making decisions about retaining ownership at the feedlot., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society of Animal Science.)

Background: Neo-adjuvant chemotherapy (NaCT) facilitates complete surgical resection in locally advanced breast cancer. Due to its association with improved outcome, complete pathologic response (pCR) to neo-adjuvant treatment has been accepted as a surrogate for long-term outcome in clinical trials of human epidermal growth factor receptor 2 (HER2)-positive, triple-negative, or luminal B breast cancer patients. In contrast, NaCT is effective in only ~ 7-10% of estrogen receptor (ER)-positive, HER2-negative disease. Response biomarkers would enable such patients to be selected for NaCT., Methods: Two commercially available breast cancer prognostic signatures [12-gene molecular score (MS) and the 21-gene Recurrence Score (RS)] were compared in their ability to predict pCR to NaCT in ER-positive, HER2-negative breast cancer in six public RNA expression microarray data sets. Scores were approximated according to published algorithms and analyzed by logistic regression., Results: Expression data were available for 764 ER-positive, HER2-negative breast cancer samples, including 59 patients with pCR. The two scores were well correlated. Either score was a significant predictor of pCR (12-gene MS p = 9.4 × 10 -5 ; 21-gene RS p = 0.0041). However, in a model containing both scores, the 12-gene MS remained significant (p = 0.0079), while the 21-gene RS did not (p = 0.79)., Conclusions: In this microarray study, two commercial breast cancer prognostic scores were significant predictors of response to NaCT. In direct comparison, the 12-gene MS outperformed the 21-gene RS as a predictive marker for NaCT. Considering pCR as surrogate for improved survival, these results support the ability of both scores to predict chemotherapy sensitivity.

Triple-negative breast cancer (TNBC) has few therapeutic targets, making nonspecific chemotherapy the main treatment. Therapies enhancing cancer cell sensitivity to cytotoxic agents could significantly improve patient outcomes. A BCL2-associated agonist of cell death (BAD) pathway gene expression signature (BPGES) was derived using principal component analysis (PCA) and evaluated for associations with the TNBC phenotype and clinical outcomes. Immunohistochemistry was used to determine the relative expression levels of phospho-BAD isoforms in tumour samples. Cell survival assays evaluated the effects of BAD pathway inhibition on chemo-sensitivity. BPGES score was associated with TNBC status and overall survival (OS) in breast cancer samples of the Moffitt Total Cancer Care dataset and The Cancer Genome Atlas (TCGA). TNBC tumours were enriched for the expression of phospho-BAD isoforms. Further, the BPGES was associated with TNBC status in breast cancer cell lines of the Cancer Cell Line Encyclopedia (CCLE). Targeted inhibition of kinases known to phosphorylate BAD protein resulted in increased sensitivity to platinum agents in TNBC cell lines compared to non-TNBC cell lines. The BAD pathway is associated with triple-negative status and OS. TNBC tumours were enriched for the expression of phosphorylated BAD protein compared to non-TNBC tumours. These findings suggest that the BAD pathway it is an important determinant of TNBC clinical outcomes.

Purpose: Prognostic molecular assays may aid in treatment decisions for women with estrogen receptor (ER)-positive, HER2-negative breast cancer. The prognostic value of a 12-gene expression assay (EndoPredict) was reevaluated in the combined ABCSG-6/8 cohorts with longer clinical follow-up., Experimental Design: EndoPredict (EP; molecular score, EPclin score) was evaluated in women with ER-positive, HER2-negative node-positive and node-negative breast cancer who received 5 years of endocrine therapy only (median follow-up, 9.6 years; N = 1,702). Distant recurrence-free rate (DRFR; 95% confidence interval) was assessed 10 and 15 years after diagnosis., Results: Overall, 62.6% of patients had low-risk EPclin scores with significantly improved DRFR relative to high-risk patients (HR, 4.77; 95% CI, 3.37-6.67; P < 0.0001). Ten-year DRFR (0-10 years) was improved among patients with low-risk versus high-risk EPclin scores in the full cohort [95.5% (94.1%-97.0%) vs. 80.3% (76.9%-83.9%)] as well as for patients with node-negative disease [95.5% (94.0%-97.1%) vs. 87.0% (82.6%-91.7%)] or with 1 to 3 positive nodes [95.6% (92.2%-99.1%) vs. 80.9% (75.9%-86.1%)]. The molecular and EPclin scores were significant predictors of DRFR after adjusting for clinical variables, regardless of nodal status. Similar results were observed for late recurrence (5-15 years; HR, 4.52; 95% CI, 2.65-7.72; P < 0.0001). The EPclin score significantly added prognostic information to a late metastasis nomogram (CTS5 score; P < 0.001)., Conclusions: This study demonstrates that EPclin can identify patients at low risk for early or late recurrence who may safely forgo adjuvant chemotherapy or extended endocrine therapy, respectively, regardless of nodal status., (©2019 American Association for Cancer Research.)

Purpose: Multiplex gene panel testing (MGPT) allows for the simultaneous analysis of germline cancer susceptibility genes. This study describes the diagnostic yield and patient experiences of MGPT in diverse populations., Patients and Methods: This multicenter, prospective cohort study enrolled participants from three cancer genetics clinics-University of Southern California Norris Comprehensive Cancer Center, Los Angeles County and University of Southern California Medical Center, and Stanford Cancer Institute-who met testing guidelines or had a 2.5% or greater probability of a pathogenic variant (N = 2,000). All patients underwent 25- or 28-gene MGPT and results were compared with differential genetic diagnoses generated by pretest expert clinical assessment. Post-test surveys on distress, uncertainty, and positive experiences were administered at 3 months (69% response rate) and 1 year (57% response rate)., Results: Of 2,000 participants, 81% were female, 41% were Hispanic, 26% were Spanish speaking only, and 30% completed high school or less education. A total of 242 participants (12%) carried one or more pathogenic variant (positive), 689 (34%) carried one or more variant of uncertain significance (VUS), and 1,069 (53%) carried no pathogenic variants or VUS (negative). More than one third of pathogenic variants (34%) were not included in the differential diagnosis. After testing, few patients (4%) had prophylactic surgery, most (92%) never regretted testing, and most (80%) wanted to know all results, even those of uncertain significance. Positive patients were twice as likely as negative/VUS patients (83% v 41%; P < .001) to encourage their relatives to be tested., Conclusion: In a racially/ethnically and socioeconomically diverse cohort, MGPT increased diagnostic yield. More than one third of identified pathogenic variants were not clinically anticipated. Patient regret and prophylactic surgery use were low, and patients appropriately encouraged relatives to be tested for clinically relevant results., Competing Interests: Employees of Myriad Genetic Laboratories served as coinvestigators in this study and provided material support, including germline testing and interpretation, as described in the manuscript. The specific coinvestigators listed as authors participated in the review and final approval of the submitted manuscript., (© 2018 by American Society of Clinical Oncology.)

Background: Patients with ovarian cancer tend to receive the highest quality of care at high-volume cancer centers with gynecological oncologists. However, the care that they receive prior to gynecological oncology consult has not been examined. We investigated the quantity and quality of care given to patients with ovarian cancer before being seen by a gynecological oncologist., Objective: We evaluated the variability, quantity, and quality of diagnostic testing and physician-referral patterns prior to consultation with a gynecological oncologist, in women with suspicious pelvic masses seen on imaging., Study Design: A chart review was performed on patients treated for ovarian cancer at a single institution from 2001 to 2014. We evaluated their workup in 4 categories, drawn from National Comprehensive Care Network guidelines: provider visits, abdominal/pelvic imaging, chest imaging, and tumor markers. Workup was classified as guideline adherent or guideline nonadherent., Results: We identified 335 cases that met our criteria. In the provider visit category, 83.9% of patients received guideline-adherent workup: 77% in the abdominal/pelvic imaging, 98.2% in the chest imaging, and 95.2% in the tumor marker categories. Each patient's workup was assessed as a compilation of the 4 categories, yielding 65.7% patients as having received an adherent workup and 34.3% of workup as nonadherent to guidelines. The timeframe to see a gynecological oncologist for patients with guideline-adherent workup was significantly shorter than for those whose workup was nonadherant (20 vs 86 days, P < .001). A suspicious pelvic mass was identified by obstetrics-gynecology in only 23.9% of patients; 42.7% of patients did not have tumor marker testing before a gynecological oncologist consult. When an obstetrics-gynecology specialist discovered the suspicious pelvic mass, the remaining workup was more likely to be guideline adherent prior to gynecological oncologist referral than when initial imaging was not ordered by an obstetrics-gynecology specialist (P = .18). Survival was not significantly different (P = .103)., Conclusion: With a guideline-adherent workup, including tumor marker testing, gynecological oncologist referral times can be shortened, minimizing cost inefficiencies and delays that can compromise the effectiveness of downstream care for patients with ovarian cancer. Guidelines should be disseminated beyond the obstetrics-gynecology field., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To define the use of complementary and alternative medicine (CAM) in individuals presenting for care at a comprehensive cancer center., Patients and Methods: A total of 17 639 individuals presenting to an NCI-designated Comprehensive Cancer Center (and consortium sites) completed a questionnaire regarding CAM use. Data were analyzed using the univariate χ 2 test to assess CAM use associated with a number of variables, including cancer status, age, gender, marital status, ethnicity, race, employment, and education level., Results: Eighty-seven percent of individuals who completed the CAM survey acknowledged CAM therapy use within the previous 12 months. Of the 5 broad categories of CAM, the most commonly used were biologically based approaches (14 759/17 639 [83.67%]), mind-body interventions (4624/17 485 [26.45%]), manipulative and body-based therapies (3957/17 537 [22.56%]), alternative medical systems (429/15 952 [2.69%]), and energy therapies (270/15 872 [1.7%]). CAM use was more prevalent among women, non-Hispanics, Caucasians, patients 60 to 69 years of age, and those who are married, have a higher level of education, and are employed ( P < .005)., Conclusions: This is the largest report of CAM use in individuals presenting for care at a comprehensive cancer center. Our analysis revealed that a very high percentage of patients utilize CAM. Because many of these CAM interventions are not studied in oncology patients, additional research on safety, efficacy, and mechanisms of action are essential. Furthermore, it is important that oncologists understand CAM modalities and counsel their patients about their use.

Background: With increased demand for hereditary cancer genetic testing, some large national health-care insurance payers (LNHPs) have implemented policies to minimize inappropriate testing by mandating consultation with a geneticist or genetic counselor (GC). We hypothesized such a restriction would reduce access and appropriate testing., Methods: Test cancellation rates (ie, tests ordered that did not result in a reported test result), mutation-positive rates, and turnaround times for comprehensive BRCA1/2 testing for a study LNHP that implemented a GC-mandate policy were determined over the 12 months before and after policy implementation (excluding a 4-month transition period). Cancellation rates were evaluated based on the reason for cancellation, National Comprehensive Cancer Network testing criteria, and self-identified ancestry. A control LNHP was evaluated over the same period for comparison., Results: The study LNHP cancellation rate increased from 13.3% to 42.1% ( P < .001) after policy implementation. This increase was also observed when only individuals who met National Comprehensive Cancer Network criteria for hereditary breast and ovarian cancer testing were considered (9.5% to 37.7%; P < .001). Cancellation rates increased after policy introduction for all ancestries; however, this was more pronounced among individuals of African or Latin American ancestry, for whom cancellation rates rose to 48.9% and 49.6%, respectively, compared with 33.9% for individuals of European ancestry. Over this same time period, control LNHP cancellation rates decreased or stayed the same for all subgroups., Conclusion: These findings demonstrate that a GC-mandate policy implemented by a LNHP substantially decreased access to appropriate genetic testing, disproportionately impacting minority populations without any evidence that inappropriate testing was decreased.

Objective: There are limited data on lesbian, gay, bisexual, and transgender (LGBT) healthcare experiences and interactions with the providers. This study assessed knowledge, attitudes, and practice behaviors of oncology providers regarding LGBT health., Methods: A 32-item web-based survey was emailed to 388 oncology providers at a single institution. The survey assessed: demographics, knowledge, attitudes, and practice behaviors., Results: 108 providers participated in the survey (28% response rate). <50% answered knowledge questions correctly. 94% stated they were comfortable treating this population. 26% actively inquired about a patient's sexual orientation when taking a history. 36% felt the need for mandatory education on LGBT cultural competency at the institution. Results from the open comments section identified multiple misconceptions., Conclusion: This study revealed knowledge gaps about LGBT health risks. Cultural competency training may aid oncology providers to understand the need to inquire about patients' gender identity and sexual orientation., Practice Implications: Health care providers who incorporate the routine collection of gender identity and sexual orientation (SOGI) in their patient history taking may improve patient care by offering tailored education and referrals. While identifying as LGBT does not in itself increase risk for adverse health outcomes, this population tends to have increased risk behaviors., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Experimental and epidemiological data support the potential activity of acetaminophen against ovarian cancer (OVCA). In this study, we sought to confirm the activity of acetaminophen in OVCA cell lines and to investigate the molecular basis of response. A total of 16 OVCA cell lines underwent pretreatment (baseline) genome-wide expression measurements and were then treated with and analyzed for acetaminophen sensitivity. Pearson's correlation analysis was performed to identify genes that were associated with OVCA acetaminophen response. The identified genes were subjected to pathway analysis, and the expression of each represented pathway was summarized using principal component analysis. OVCA acetaminophen response pathways were analyzed in 4 external clinico-genomic datasets from 820 women for associations with overall survival from OVCA. Acetaminophen exhibited antiproliferative activity against all tested OVCA cell lines, with half maximal inhibitory concentration values ranging from 63.2 to 403 µM. Pearson's correlation followed by biological pathway analysis identified 13 pathways to be associated with acetaminophen sensitivity (P<0.01). Associations were observed between patient survival from OVCA and expression of the following pathways: Development/angiotensin signaling via β-arrestin (P=0.04), protein folding and maturation/angiotensin system maturation (P=0.02), signal transduction/c-Jun N-terminal kinase (JNK) pathway (P=0.03) and androstenedione and testosterone biosynthesis and metabolism (P=0.02). We confirmed that acetaminophen was active against OVCA cells in vitro . Furthermore, we identified 4 molecular signaling pathways associated with acetaminophen response that may also affect overall survival in women with OVCA, including the JNK pathway, which has been previously implicated in the mechanism of action of acetaminophen and is predictive of decreased survival in women with OVCA.

Objectives: Ovarian cancer (OVCA) is the leading cause of mortality among women with gynecologic malignancy, in part due to the development of chemoresistance. We sought to identify micro-RNAs (miRNAs) associated with in vitro development of OVCA chemoresistance that may also represent potential targets for therapy., Methods: In this study, four OVCA cell lines (A2780CP, A2780S, IGROV1, and OVCAR5) were serially treated with cisplatin in parallel with measurements of miRNA expression changes., Results: Nine miRNAs were found to be associated with increasing cisplatin resistance (IC50) (p<0.01); however, only 5 of these miRNAs have publically available information. Pathway analysis identified 15 molecular signaling pathways that were represented by genes predicted to be targets of the 5 miRNAs (false discovery rate<0.05), 11 of which are associated with the epithelial-mesenchymal transition (EMT). Further analysis identified 2 of those pathways as being associated with overall survival in 218 patients with OVCA., Conclusions: Collectively, this panel of miRNAs associated with in vitro evolution of OVCA cisplatin resistance and the pathways identified to be associated with EMT and overall patient survival provide a framework for further investigations into EMT as a therapeutic target in patients with OVCA., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Cancer stem cells (CSC) contribute to epithelial ovarian cancer (EOC) progression and therapeutic response. We hypothesized that germline single nucleotide polymorphisms (SNPs) in CSC-related genes may predict an initial therapeutic response for women newly diagnosed with EOC. A nested case-control design was used to study 361 women with advanced-stage serous EOC treated with surgery followed by first-line platinum-based combination therapy at Moffitt Cancer Center or as part of The Cancer Genome Atlas Study. "Cases" included 102 incomplete responders (IRs) and "controls" included 259 complete clinical responders (CRs) to therapy. Using Illumina genotyping arrays and imputation, DNA samples were evaluated for 5,509 SNPs in 24 ovarian CSC-related genes. We also evaluated the overall significance of each CSC gene using the admixture maximum likelihood (AML) test, and correlated genotype with EOC tumor tissue expression. The strongest SNP-level associations with an IR to therapy were identified for correlated (r(2) > 0.80) SNPs within signal transducer and activator of transcription 3 (STAT3) [odds ratio (OR), 2.24; 95% confidence interval (CI), 1.32-3.78; p = 0.0027], after adjustment for age, population stratification, grade and residual disease. At the gene level, STAT3 was significantly associated with an IR to therapy (pAML = 0.006). rs1053004, a STAT3 SNP in a putative miRNA-binding site, was associated with STAT3 expression (p = 0.057). This is the first study to identify germline STAT3 variants as independent predictors of an unfavorable therapeutic response for EOC patients. Findings suggest that STAT3 genotype may identify high-risk women likely to respond more favorably to novel therapeutic combinations that include STAT3 inhibitors., (© 2015 UICC.)

Patients with occult lymph node metastasis in endometrioid-type endometrial cancer (EC) are prone to the development of recurrences and have worse outcomes compared with patients without lymph node metastasis. In the current study, the aim was to identify molecular parameters associated with lymph node metastasis in EC clinically early-stage disease. A univariate analysis of differentially expressed genes, proteins and clinicopathological parameters (including myometrial invasion and tumor grade) was performed, comparing EC patients with and without lymph node metastasis (n=262 patients from The Cancer Genome Atlas). Significant parameters were introduced in a multivariate model and a gene expression pathway analysis. Lymph node metastasis was associated with expression of 268 unique genes (P<0.001), 19 unique proteins (P<0.05), tumor grade and myometrial invasion in univariate analysis. Multivariate analysis demonstrated 10 genes independently associated with lymph node metastasis and 4 independently associated proteins. Myometrial invasion was the only independent clinicopathological parameter associated with lymph node status. The enrichment pathway analysis demonstrated that expression of epidermal growth factor receptor, Bcl2 antagonist of cell death and phosphatase and tensin homolog pathways were significantly involved in lymph node metastasis (P≤0.001). A gene expression signature to predict lymph node status in EC was created for future validation. Few studies have focused on the association between EC's molecular characteristics and nodal metastasis. Defining molecular risk factors for EC lymphatic nodal metastasis may help to individualize treatment and improve patient outcomes.

Objective: We evaluated complementary and alternative medicine (CAM) practices among women presenting to a National Cancer Institute-designated Comprehensive Cancer Center with a gynecologic malignancy., Methods: Women with a gynecologic malignancy who had consented to enrollment in our institutional prospective clinical registry between January 2003 and January 2014 and who had completed a questionnaire assessing sociodemographic characteristics, medical histories, quality of life, and CAM use were considered for analysis., Results: Among the 2508 women identified, responses to questions on CAM use were provided by 534 (21.3%). The majority of CAM question respondents were white (93.5%) and older than 50 years (76%). Overall, 464 women (87% of CAM question respondents) used at least 1 CAM therapy during the previous 12 months. The most commonly used CAM categories were biologically based approaches (83.5%), mind and body interventions (30.6%), and manipulative and body-based therapies (18.8%). The most commonly used individual CAM therapies were vitamins and minerals (78%), herbal supplements (27.9%), spiritual healing and prayer (15.1%), and deep breathing relaxation exercises (13.1%). Complementary and alternative medicine use was greatest in age groups 20 to 30 years and older than 65 years and was more prevalent among those who were widowed (P < 0.005), retired (P = 0.02), and with a higher level of education (P < 0.01). There was no association with cancer type, race, or ethnicity., Conclusions: Complementary and alternative medicine use is common among women being treated for gynecologic malignancy. Given the potential interactions of some CAM modalities with conventional treatment and the possible benefits in controlling symptoms and improving quality of life, providers should discuss CAM with their patients.

Objectives: Cytoreductive surgery is the cornerstone of ovarian cancer (OVCA) treatment. Detractors of initial maximal surgical effort argue that aggressive tumor biology will dictate survival, not the surgical effort. We investigated the role of biology in achieving optimal cytoreduction in serous OVCA using microarray gene expression analysis., Methods: For the initial model, we used a gene expression signature from a microarray expression analysis of 124 women with serous OVCA, defining optimal cytoreduction as removal of all disease greater than 1 cm (with 64 women having optimal and 60 suboptimal cytoreduction). We then applied this model to 2 independent data sets: the Australian Ovarian Cancer Study (AOCS; 190 samples) and The Cancer Genome Atlas (TCGA; 468 samples). We performed a second analysis, defining optimal cytoreduction as removal of all disease to microscopic residual, using data from AOCS to create the gene signature and validating results in TCGA data set., Results: Of the 12,718 genes included in the initial analysis, 58 predicted accuracy of cytoreductive surgery 69% of the time (P = 0.005). The performance of this classifier, measured by the area under the receiver operating characteristic curve, was 73%. When applied to TCGA and AOCS, accuracy was 56% (P = 0.16) and 62% (P = 0.01), respectively, with performance at 57% and 65%, respectively. In the second analysis, 220 genes predicted accuracy of cytoreductive surgery in the AOCS set 74% of the time, with performance of 73%. When these results were validated in TCGA set, accuracy was 57% (P = 0.31) and performance was at 62%., Conclusion: Gene expression data, used as a proxy of tumor biology, do not predict accurately nor consistently the ability to perform optimal cytoreductive surgery. Other factors, including surgical effort, may also explain part of the model. Additional studies integrating more biological and clinical data may improve the prediction model.

The malignant transformation of normal cells is caused in part by aberrant gene expression disrupting the regulation of cell proliferation, apoptosis, senescence and DNA repair. Evidence suggests that the Bcl-2 antagonist of cell death (BAD)-mediated apoptotic pathway influences cancer chemoresistance. In the present study, we explored the role of the BAD-mediated apoptotic pathway in the development and progression of cancer. Using principal component analysis to derive a numeric score representing pathway expression, we evaluated clinico-genomic datasets (n=427) from corresponding normal, pre-invasive and invasive cancers of different types, such as ovarian, endometrial, breast and colon cancers in order to determine the associations between the BAD-mediated apoptotic pathway and cancer development. Immunofluorescence was used to compare the expression levels of phosphorylated BAD [pBAD (serine-112, -136 and -155)] in immortalized normal and invasive ovarian, colon and breast cancer cells. The expression of the BAD-mediated apoptotic pathway phosphatase, PP2C, was evaluated by RT-qPCR in the normal and ovarian cancer tissue samples. The growth-promoting effects of pBAD protein levels in the immortalized normal and cancer cells were assessed using siRNA depletion experiments with MTS assays. The expression of the BAD-mediated apoptotic pathway was associated with the development and/or progression of ovarian (n=106, p<0.001), breast (n=185, p<0.0008; n=61, p=0.04), colon (n=22, p<0.001) and endometrial (n=33, p<0.001) cancers, as well as with ovarian endometriosis (n=20, p<0.001). Higher pBAD protein levels were observed in the cancer cells compared to the immortalized normal cells, whereas PP2C gene expression was lower in the cancer compared to the ovarian tumor tissue samples (n=76, p<0.001). The increased pBAD protein levels after the depletion of PP2C conferred a growth advantage to the immortalized normal and cancer cells. The BAD-mediated apoptotic pathway is thus associated with the development of human cancers likely influenced by the protein levels of pBAD.

Purpose: We evaluated the effects of polyphyllin D (PD), a natural compound with anti-neoplastic activity and a major component of the Chinese herb Paris polyphylla, on ovarian cancer (OVCA) cell line proliferation and platinum sensitivity., Methods: A panel of 20 OVCA cell lines was subjected to PD treatment, MTS proliferation assays, and determination of IC50. Pre-treatment, baseline genome-wide Affymetrix expression analysis was performed on each cell line, and Pearson's correlation was performed to identify genes associated with OVCA PD sensitivity. Twelve cell lines were treated with PD with and without cisplatin, and the effects of PD on cisplatin IC50 were quantified. Genes associated with OVCA PD sensitivity were evaluated for associations with survival in a publically available clinico-genomic dataset of 218 patients with OVCA., Results: Our results showed that PD exhibited anti-proliferative effects against all OVCA cell lines tested, with IC50 values ranging from 0.2 to 1.4 μm. Furthermore, in all cell lines, PD treatment significantly decreased cisplatin IC50 (mean IC50 reduction of 2.1 µm; P < 0.02). Pearson's correlation test identified 25 probe sets, representing 18 unique genes to be associated with PD sensitivity (FDR = 0). We found that one of these genes was associated with overall survival in women with OVCA: CLDN4 (P = 0.014)., Conclusion: Our findings highlight the value of PD as a natural product with anti-cancer properties, which may also enhance the activity of existing therapeutic agents.

Women with germline mutations in the cancer susceptibility genes, BRCA1 or BRCA2, associated with Hereditary Breast & Ovarian Cancer syndrome, have up to an 85% lifetime risk of breast cancer and up to a 46% lifetime risk of ovarian, tubal, and peritoneal cancers. Similarly, women with mutations in the DNA mismatch repair genes, MLH1, MSH2, MSH6, or PMS2, associated with the Lynch/Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome, have up to a 40-60% lifetime risk of both endometrial and colorectal cancers as well as a 9-12% lifetime risk of ovarian cancer. Mutations in other genes including TP53, PTEN, and STK11 are responsible for hereditary syndromes associated with gynecologic, breast, and other cancers. Evaluation of the likelihood of a patient having one of these gynecologic cancer predisposition syndromes enables physicians to provide individualized assessments of cancer risk, as well as the opportunity to provide tailored screening and prevention strategies such as surveillance, chemoprevention, and prophylactic surgery that may reduce the morbidity and mortality associated with these syndromes. Evaluation for the presence of a hereditary cancer syndrome is a process that includes assessment of clinical and tumor characteristics, education and counseling conducted by a provider with expertise in cancer genetics, and may include genetic testing after appropriate consent is obtained. This commentary provides guidance on identification of patients who may benefit from assessment for the presence of a hereditary breast and/or gynecologic cancer syndrome., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Women with metabolic disorders, including obesity and diabetes, have an increased risk of developing endometrial cancer. However, the metabolism of endometrial tumors themselves has been largely understudied. Comparing human endometrial tumors and cells with their nonmalignant counterparts, we found that upregulation of the glucose transporter GLUT6 was more closely associated with the cancer phenotype than other hallmark cancer genes, including hexokinase 2 and pyruvate kinase M2. Importantly, suppression of GLUT6 expression inhibited glycolysis and survival of endometrial cancer cells. Glycolysis and lipogenesis were also highly coupled with the cancer phenotype in patient samples and cells. To test whether targeting endometrial cancer metabolism could be exploited as a therapeutic strategy, we screened a panel of compounds known to target diverse metabolic pathways in endometrial cells. We identified that the glycolytic inhibitor, 3-bromopyruvate, is a powerful antagonist of lipogenesis through pyruvylation of CoA. We also provide evidence that 3-bromopyruvate promotes cell death via a necrotic mechanism that does not involve reactive oxygen species and that 3-bromopyruvate impaired the growth of endometrial cancer xenografts., (©2014 American Association for Cancer Research.)

A third of patients with epithelial ovarian cancer (OVCA) will not respond to standard treatment. The determination of a robust signature that predicts chemoresponse could lead to the identification of molecular markers for response as well as possible clinical implementation in the future to identify patients at risk of failing therapy. This pilot study was designed to identify biologic processes affecting candidate pathways associated with chemoresponse and to create a robust gene signature for follow-up studies. After identifying common pathways associated with chemoresponse in serous OVCA in three independent gene-expression experiments, we assessed the biologic processes associated with them using The Cancer Genome Atlas (TCGA) dataset for serous OVCA. We identified differential copy-number alterations (CNA), mutations, DNA methylation, and miRNA expression between patients that responded to standard treatment and those who did not or recurred prematurely. We correlated these significant parameters with gene expression to create a signature of 422 genes associated with chemoresponse. A consensus clustering of this signature identified two differentiated clusters with unique molecular patterns: cluster 1 was significant for cellular signaling and immune response (mainly cell-mediated); and cluster 2 was significant for pathways involving DNA-damage repair and replication, cell cycle, and apoptosis. Validation through consensus clustering was performed in five independent OVCA gene-expression experiments. Genes were located in the same cluster with consistent agreement in all five studies (κ coefficient ≥ 0.6 in 4). Integrating high-throughput biologic data have created a robust molecular signature that predicts chemoresponse in OVCA., (©2014 American Association for Cancer Research.)

MicroRNA-155 (miR-155) is frequently upregulated in various types of human cancer; however, its role in cancer angiogenesis remains unknown. Here, we demonstrate the role of miR-155 in angiogenesis through targeting von Hippel-Lindau (VHL) tumour suppressor in breast cancer. Ectopic expression of miR-155 induced whereas knockdown of miR-155 inhibited human umbilical vein endothelial cell network formation, proliferation, invasion and migration. Furthermore, mammary fat pad xenotransplantation of ectopically expressed miR-155 resulted in extensive angiogenesis, proliferation, tumour necrosis and recruitment of pro-inflammatory cells such as tumour-associated macrophages. Expression of VHL abrogated these miR-155 effects. Moreover, miR-155 expression inversely correlates with VHL expression level and is associated with late-stage, lymph node metastasis and poor prognosis, as well as triple-negative tumour in breast cancer. These findings indicate that miR-155 has a pivotal role in tumour angiogenesis by downregulation of VHL, and provide a basis for miR-155-expressing tumours to embody an aggressive malignant phenotype, and therefore miR-155 is an important therapeutic target in breast cancer.

Paclitaxel is a mainstay of treatment for many solid tumors, and frequently, clinical outcome is influenced by paclitaxel sensitivity. Despite this, our understanding of the molecular basis of paclitaxel response is incomplete. Recently, it has been shown that microRNAs (miRNAs) influence messenger RNA (mRNA) transcriptional control and can contribute to human carcinogenesis. In the present study, our objective was to identify miRNAs associated with cancer cell line response to paclitaxel and to evaluate these miRNAs as therapeutic targets to increase paclitaxel sensitivity. We measured the expression of 335 unique miRNAs in 40 human cancer cell lines selected from the NCI panel. We then integrated miRNA expression data with publicly available paclitaxel-sensitivity (GI₅₀) data for each of the 40 cell lines to identify miRNAs associated with paclitaxel sensitivity. Ovarian cancer cell lines with differential miRNA expression and paclitaxel sensitivity were transiently transfected with miRNA precursors and inhibitors, and the effects on in vitro cell paclitaxel sensitivity were evaluated. Pearson's correlation identified 2 miRNAs (miR-367 and miR-30a-5p) associated with the NCI40 cell line in vitro paclitaxel response (P<0.0003). Ovarian cancer cells were selected based on the association between paclitaxel sensitivity and miR-367/miR-30a-5p expression. Overexpression of miR-367 in the paclitaxel-sensitive cells [PA1; IC₅₀, 1.69 nM, high miR-367 (2.997), low miR-30a-5p (-0.323)] further increased paclitaxel sensitivity, whereas miR-367 depletion decreased paclitaxel sensitivity. In contrast, overexpression and depletion of miR-30a-5p in the paclitaxel-resistant cells [OVCAR4; IC₅₀, 17.8 nM, low miR-367 (-0.640), high miR-30a-5p (3.270)] decreased and increased paclitaxel sensitivity, respectively. We identified and successfully targeted miRNAs associated with human cancer cell line response to paclitaxel. Our strategy of integrating in vitro miRNA expression and drug sensitivity data may not only aid in the characterization of determinants of drug response but also in the identification of novel therapeutic targets to increase activity of existing therapeutics.

Objective: The objective of the study was to evaluate the biological validity of ovarian cancer (OVCA) screening and early detection efforts and to characterize signaling pathways associated with human cancer metastasis and patient survival., Study Design: Using genome-wide expression profiling and deoxyribonucleic acid sequencing, we compared pelvic and matched extrapelvic implants from 30 patients with advanced-stage OVCA for expression of molecular signaling pathways and p53 gene mutations. Differentially expressed pathways were further evaluated in a series of primary or early-stage vs metastatic or recurrent cancer samples from 389 ovarian, prostate, and oral cancer patients. Metastasis pathways were also evaluated for associations with survival in 9 independent clinicogenomic datasets from 1691 ovarian, breast, colon, brain, and lung cancer and leukemia patients. The inhibitory effects of 1 pathway (transforming growth factor [TGF]-WNT) on in vitro OVCA cell migration were studied., Results: Pelvic and extrapelvic OVCA implants demonstrated similar patterns of signaling pathway expression and identical p53 mutations. However, we identified 3 molecular pathways/cellular processes that were differentially expressed between pelvic and extrapelvic OVCA samples and between primary/early-stage and metastatic/advanced or recurrent ovarian, oral, and prostate cancers. Furthermore, their expression was associated with overall survival from ovarian cancer (P = .006), colon cancer (1 pathway at P = .005), and leukemia (P = .05). Artesunate-induced TGF-WNT pathway inhibition impaired OVCA cell migration., Conclusion: Advanced-stage OVCA has a unifocal origin in the pelvis. Molecular pathways associated with extrapelvic OVCA spread are also associated with metastasis from other human cancers and with overall patient survival. Such pathways represent appealing therapeutic targets for patients with metastatic disease., (Copyright © 2013 Mosby, Inc. All rights reserved.)