The Transcriptional Landscape of Coding and Noncoding RNAs in Recurrent and Nonrecurrent Colon Cancer.

A number of patients with colon cancer with local or local advanced disease suffer from recurrence and there is an urgent need for better prognostic biomarkers in this setting. Here, the transcriptomic landscape of mRNAs, long noncoding RNAs, snRNAs, small nucleolar RNAs (snoRNAs), small Cajal body-specific RNAs, pseudogenes, and circular RNAs, as well as RNAs denoted as miscellaneous RNAs, was profiled by total RNA sequencing. In addition to well-known coding and noncoding RNAs, differential expression analysis also uncovered transcripts that have not been implicated previously in colon cancer, such as RNA5SP149, RNU4-2, and SNORD3A. Moreover, there was a profound global up-regulation of snRNA pseudogenes, snoRNAs, and rRNA pseudogenes in more advanced tumors. A global down-regulation of circular RNAs in tumors relative to normal tissues was observed, although only a few were expressed differentially between tumor stages. Many previously undescribed transcripts, including RNU6-620P, RNU2-20P, VTRNA1-3, and RNA5SP60, indicated strong prognostic biomarker potential in receiver operating characteristics analyses. In summary, this study unveiled numerous differentially expressed RNAs across various classes between recurrent and nonrecurrent colon cancer. Notably, there was a significant global up-regulation of snRNA pseudogenes, snoRNAs, and rRNA pseudogenes in advanced tumors. Many of these newly discovered candidates demonstrate a strong prognostic potential for stage II colon cancer.

Information needs persist after genetic counseling and testing for BRCA1/2 and Lynch Syndrome.

PURPOSE: Research has shown that cancer genetic risk is often not well understood by patients undergoing genetic testing and counseling. We describe the barriers to understanding genetic risk and the needs of high-risk persons and cancer survivors who have undergone genetic testing. METHODS: Using data from an internet survey of adults living in the USA who responded 'yes' to having ever had a genetic test to determine cancer risk (N = 696), we conducted bivariate analyses and multivariable logistic regression models to evaluate associations between demographic, clinical, and communication-related variables by our key outcome of having vs. not having enough information about genetics and cancer to speak with family. Percentages for yes and no responses to queries about unmet informational needs were calculated. Patient satisfaction with counseling and percentage disclosure of genetic risk status to family were also calculated. RESULTS: We found that a lack of resources provided by provider to inform family members and a lack of materials provided along with genetic test results were strongly associated with not having enough information about genetics and cancer (OR 4.54 95% CI 2.40-8.59 and OR 2.19 95% CI 1.16-4.14 respectively). Among participants undergoing genetic counseling, almost half reported needing more information on what genetic risk means for them and their family and how genetic testing results might impact future screening. CONCLUSION: High levels of satisfaction with genetic counseling may not give a full picture of the patient-provider interaction and may miss potential unmet needs of the patient. Accessible resources and ongoing opportunities for updating family history information could reinforce knowledge about genetic risk.

circPVT1 and PVT1/AKT3 show a role in cell proliferation, apoptosis, and tumor subtype-definition in small cell lung cancer.

Small cell lung cancer (SCLC) is treated as a homogeneous disease, although the expression of NEUROD1, ASCL1, POU2F3, and YAP1 identifies distinct molecular subtypes. The MYC oncogene, amplified in SCLC, was recently shown to act as a lineage-specific factor to associate subtypes with histological classes. Indeed, MYC-driven SCLCs show a distinct metabolic profile and drug sensitivity. To disentangle their molecular features, we focused on the co-amplified PVT1, frequently overexpressed and originating circular (circRNA) and chimeric RNAs. We analyzed hsa_circ_0001821 (circPVT1) and PVT1/AKT3 (chimPVT1) as examples of such transcripts, respectively, to unveil their tumorigenic contribution to SCLC. In detail, circPVT1 activated a pro-proliferative and anti-apoptotic program when over-expressed in lung cells, and knockdown of chimPVT1 induced a decrease in cell growth and an increase of apoptosis in SCLC in vitro. Moreover, the investigated PVT1 transcripts underlined a functional connection between MYC and YAP1/POU2F3, suggesting that they contribute to the transcriptional landscape associated with MYC amplification. In conclusion, we have uncovered a functional role of circular and chimeric PVT1 transcripts in SCLC; these entities may prove useful as novel biomarkers in MYC-amplified tumors.

Prevalence of Americans reporting a family history of cancer indicative of increased cancer risk: Estimates from the 2015 National Health Interview Survey.

The collection and evaluation of family health history in a clinical setting presents an opportunity to discuss cancer risk, tailor cancer screening recommendations, and identify people with an increased risk of carrying a pathogenic variant who may benefit from referral to genetic counseling and testing. National recommendations for breast and colorectal cancer screening indicate that men and women who have a first-degree relative affected with these types of cancers may benefit from talking to a healthcare provider about starting screening at an earlier age and other options for cancer prevention. The prevalence of reporting a first-degree relative who had cancer was assessed among adult respondents of the 2015 National Health Interview Survey who had never had cancer themselves (n = 27,999). We found 35.6% of adults reported having at least one first-degree relative with cancer at any site. Significant differences in reporting a family history of cancer were observed by sex, age, race/ethnicity, educational attainment, and census region. Nearly 5% of women under age 50 and 2.5% of adults under age 50 had at least one first-degree relative with breast cancer or colorectal cancer, respectively. We estimated that 5.8% of women had a family history of breast or ovarian cancer that may indicate increased genetic risk. A third of U.S. adults who have never had cancer report a family history of cancer in a first-degree relative. This finding underscores the importance of using family history to inform discussions about cancer risk and screening options between healthcare providers and their patients.

Health-related quality of life outcomes among breast cancer survivors.

BACKGROUND: Data from a nationwide sample of US breast cancer survivors were used to examine associations between patient characteristics (breast cancer clinical features, prognostic factors, and treatments) and health-related quality of life (HRQOL). Associations between postdiagnosis HRQOL and mortality were then evaluated. METHODS: The authors identified female breast cancer survivors (n = 2453) from the Sister Study or Two Sister Study who were at least 1 year from breast cancer diagnosis and who had responded to a survivorship survey in 2012. HRQOL was assessed with the Patient-Reported Outcomes Measurement Information System (PROMIS) Global 10 measures. Multivariable linear regression was used to assess predictors associated with HRQOL. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between HRQOL and all-cause mortality. RESULTS: HRQOL, assessed an average of 4.9 years after the cancer diagnosis (standard deviation of 1.9 years), was negatively associated with a higher cancer stage at diagnosis; a higher comorbidity score at the survey; experience of surgical complications; dissatisfaction with breast surgery; and experience of any recent recurrence, metastasis, or secondary malignancy. Since the completion of the survey, there were 85 deaths (3.5%) during a mean follow-up of 4 years (standard deviation of 0.5 years). In multivariate models, decreases in PROMIS physical T scores and mental T scores were associated with increased mortality (HR for physical T scores, 1.08; 95% CI, 1.05-1.11; HR for mental T scores, 1.03; 95% CI, 1.01-1.06). CONCLUSIONS: Prognostic and cancer treatment-related factors affect HRQOL in breast cancer survivors and may inform targeted survivorship care. PROMIS global health measures may offer additional insights into patients' well-being and mortality risk. LAY SUMMARY: Findings from a study suggest that prognostic and cancer treatment-related factors affect health-related quality of life (HRQOL) in breast cancer survivors and that poor HRQOL may increase the mortality risk. The evaluation of HRQOL is important because it may hold potential as a tool for optimizing survivorship care.

Employment After Breast Cancer Diagnosis and Treatment Among Women in the Sister and the Two Sister Studies.

Purpose Women undergoing diagnosis and treatment for breast cancer may face challenges in employment. We investigated the impact of demographic, clinical, workplace, and psychosocial characteristics on loss of employment after a breast cancer diagnosis and treatment. We further describe changes in work status and work environment for cancer survivors who sustain employment. Methods We analyzed responses from a survey of breast cancer survivors from the Sister Study and the Two Sister Study cohorts who reported being employed at the time of their breast cancer diagnosis and who reported employment status (lost vs. sustained employment) at the time of survey administration. Multivariate logistic regression was used to identify the effects of lymphedema, neuropathy, problems with memory or attention, social support, health insurance, and sick leave on lost employment, adjusting for demographic characteristics, cancer stage, treatment, and general health. Results Of the 1675 respondents who reported being employed at the time of diagnosis, 83.5% reported being 'currently' employed at the time of the survey. Older age, peripheral neuropathy, lack of sick leave, late stage at diagnosis, a recurrence or a new cancer, problems with memory or attention, and poor general health were significantly associated with lost employment. Conclusions The long-term effects of breast cancer treatment and workplace provisions for leave and accommodation may have a substantial effect on women's ability to sustain employment. The findings from this study highlight challenges reported by cancer survivors that may inform clinical and occupational interventions to support survivors' return to work.

Treatment cost and access to care: experiences of young women diagnosed with breast cancer.

PURPOSE: Breast cancer is the leading cause of cancer-related deaths in women younger than 40 years. We aim to evaluate cost as a barrier to care among female breast cancer patients diagnosed between 18 to 39 years. METHODS: In early 2017, we distributed a survey to women diagnosed with breast cancer between the ages of 18 and 39 years, as identified by the central cancer registries of California, Georgia, North Carolina, and Florida. We used multivariable statistics to explore cost-related barriers to receiving breast cancer care for the 830 women that completed the survey. RESULTS: About half of the women (47.4%) reported spending more on breast cancer care than expected, and almost two-thirds (65.3%) had not discussed costs with their care team. A third of the patients (31.8%) indicated forgoing care due to cost. Factors associated with not receiving anticipated care due to cost included age less than35 years at diagnosis, self-insurance, comorbid conditions, and late-stage diagnosis. CONCLUSION: Previous studies using breast cancer registry data have not included detailed insurance information and care received by young women. Young women with breast cancer frequently forgo breast cancer care due to cost. Our results highlight the potential for policies that facilitate optimal care for young breast cancer patients which could include the provision of comprehensive insurance coverage.

Fertility-related experiences after breast cancer diagnosis in the Sister and Two Sister Studies.

BACKGROUND: Commonly used chemotherapies can be toxic to the ovaries. To the authors' knowledge, the majority of studies evaluating receipt of fertility counseling for women in their reproductive years have been performed in specific settings, thereby limiting generalizability. METHODS: A nationwide sample of US women diagnosed with breast cancer before age 45 years completed a survey assessing the prevalence of fertility counseling. Age-adjusted log-binomial regression was used to estimate prevalence ratios (PRs) and 95% CIs for fertility counseling. RESULTS: Among 432 survivors diagnosed between 2004 and 2011, 288 (67%) had not discussed the effects of treatment on fertility with a health care provider before or during treatment. Fertility discussion was associated with younger age (PR, 3.49 [95% CI, 2.66-4.58] for aged <35 years vs ≥40 years) and lower parity (PR, 1.81 [95% CI, 1.29-2.53] for parity 1 vs 2). Approximately 20% of respondents reported that they were interested in future fertility (87 of 432 respondents) at the time of their diagnosis, but not all of these individuals (66 of 87 respondents) received counseling regarding the impact of treatment on their fertility, and few (8 of 87 respondents) used fertility preservation strategies. Among 68 women with a fertility interest who provided reasons for not taking steps to preserve fertility, reasons cited included concern for an adverse impact on cancer treatment (56%), lack of knowledge (26%), decision to not have a child (24%), and cost (18%). CONCLUSIONS: Across multiple treatment settings, the majority of women of reproductive age who are diagnosed with breast cancer did not discuss fertility with a health care provider or use fertility preservation strategies. Discussing the potential impact of cancer treatment on future fertility is an important aspect of patient education.

Evaluating the role of public health in implementation of genomics-related recommendations: a case study of hereditary cancers using the CDC Science Impact Framework.

Public health plays an important role in ensuring access to interventions that can prevent disease, including the implementation of evidence-based genomic recommendations. We used the Centers for Disease Control and Prevention (CDC) Science Impact Framework to trace the impact of public health activities and partnerships on the implementation of the 2009 Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Lynch Syndrome screening recommendation and the 2005 and 2013 United States Preventive Services Task Force (USPSTF) BRCA1 and BRCA2 testing recommendations.The EGAPP and USPSTF recommendations have each been cited by >300 peer-reviewed publications. CDC funds selected states to build capacity to integrate these recommendations into public health programs, through education, policy, surveillance, and partnerships. Most state cancer control plans include genomics-related goals, objectives, or strategies. Since the EGAPP recommendation, major public and private payers now provide coverage for Lynch Syndrome screening for all newly diagnosed colorectal cancers. National guidelines and initiatives, including Healthy People 2020, included similar recommendations and cited the EGAPP and USPSTF recommendations. However, disparities in implementation based on race, ethnicity, and rural residence remain challenges. Public health achievements in promoting the evidence-based use of genomics for the prevention of hereditary cancers can inform future applications of genomics in public health.

Proposed outcomes measures for state public health genomic programs.

PURPOSE: To assess the implementation of evidence-based genomic medicine and its population-level impact on health outcomes and to promote public health genetics interventions, in 2015 the Roundtable on Genomics and Precision Health of the National Academies of Sciences, Engineering, and Medicine formed an action collaborative, the Genomics and Public Health Action Collaborative (GPHAC). This group engaged key stakeholders from public/population health agencies, along with experts in the fields of health disparities, health literacy, implementation science, medical genetics, and patient advocacy. METHODS: In this paper, we present the efforts to identify performance objectives and outcome metrics. Specific attention is placed on measures related to hereditary breast ovarian cancer (HBOC) syndrome and Lynch syndrome (LS), two conditions with existing evidence-based genomic applications that can have immediate impact on morbidity and mortality. RESULTS: Our assessment revealed few existing outcome measures. Therefore, using an implementation research framework, 38 outcome measures were crafted. CONCLUSION: Evidence-based public health requires outcome metrics, yet few exist for genomics. Therefore, we have proposed performance objectives that states might use and provided examples of a few state-level activities already under way, which are designed to collect outcome measures for HBOC and LS.

Trends in utilization and costs of BRCA testing among women aged 18-64 years in the United States, 2003-2014.

PurposeWe examined 12-year trends in BRCA testing rates and costs in the context of clinical guidelines, national policies, and other factors.MethodsWe estimated trends in BRCA testing rates and costs from 2003 to 2014 for women aged 18-64 years using private claims data and publicly reported revenues from the primary BRCA testing provider.ResultsThe percentage of women with zero out-of-pocket payments for BRCA testing increased during 2013-2014, after 7 years of general decline, coinciding with a clarification of Affordable Care Act coverage of BRCA genetic testing. Beginning in 2007, family history accounted for an increasing proportion of women with BRCA tests compared with personal history, coinciding with BRCA testing guidelines for primary care settings and direct-to-consumer advertising campaigns. During 2013-2014, BRCA testing rates based on claims grew at a faster rate than revenues, following 3 years of similar growth, consistent with increased marketplace competition. In 2013, BRCA testing rates based on claims increased 57%, compared with 11% average annual increases over the preceding 3 years, coinciding with celebrity publicity.ConclusionThe observed trends in BRCA testing rates and costs are consistent with possible effects of several factors, including the Affordable Care Act, clinical guidelines and celebrity publicity.

From public health genomics to precision public health: a 20-year journey.

In this paper, we review the evolution of the field of public health genomics in the United States in the past two decades. Public health genomics focuses on effective and responsible translation of genomic science into population health benefits. We discuss the relationship of the field to the core public health functions and essential services, review its evidentiary foundation, and provide examples of current US public health priorities and applications. We cite examples of publications to illustrate how Genetics in Medicine reflected the evolution of the field. We also reflect on how public-health genomics is contributing to the emergence of "precision public health" with near-term opportunities offered by the US Precision Medicine (AllofUs) Initiative.

Factors associated with breast MRI use among women with a family history of breast cancer.

Although annual breast magnetic resonance imaging (MRI) is recommended for women at high risk for breast cancer as an adjunct to screening mammography, breast MRI use remains low. We examined factors associated with breast MRI use in a cohort of women with a family history of breast cancer but no personal cancer history. Study participants came from the Sister Study cohort, a nationwide, prospective study of women with at least 1 sister who had been diagnosed with breast cancer but who themselves had not ever had breast cancer (n = 17 894). Participants were surveyed on breast cancer beliefs, cancer worry, breast MRI use, provider communication, and genetic counseling and testing. Logistic regression was used to assess factors associated with having a breast MRI overall and for those at high risk. Breast MRI was reported by 16.1% and was more common among younger women and those with higher incomes. After adjustment for demographics, ever use of breast MRI was associated with actual and perceived risk. Odds ratios (OR) were 12.29 (95% CI, 8.85-17.06), 2.48 (95% CI, 2.27-2.71), and 2.50 (95% CI, 2.09-2.99) for positive BRCA1/2 test, lifetime breast cancer risk ≥ 20%, and being told by a health care provider of higher risk, respectively. Women who believed they had much higher risk than others or had higher level of worry were twice as likely to have had breast MRI; OR = 2.23 (95% CI, 1.82-2.75) and OR = 1.76 (95% CI, 1.52-2.04). Patterns were similar among women at high risk. Breast cancer risk, provider communication, and personal beliefs were determinants of breast MRI use. To support shared decisions about the use of breast MRI, women could benefit from improved understanding of the chances of getting breast cancer and increased quality of provider communications.

Osteopontin regulates the cross-talk between phosphatidylcholine and cholesterol metabolism in mouse liver.

Osteopontin (OPN) is involved in different liver pathologies in which metabolic dysregulation is a hallmark. Here, we investigated whether OPN could alter liver, and more specifically hepatocyte, lipid metabolism and the mechanism involved. In mice, lack of OPN enhanced cholesterol 7α-hydroxylase (CYP7A1) levels and promoted loss of phosphatidylcholine (PC) content in liver; in vivo treatment with recombinant (r)OPN caused opposite effects. rOPN directly decreased CYP7A1 levels through activation of focal adhesion kinase-AKT signaling in hepatocytes. PC content was also decreased in OPN-deficient (OPN-KO) hepatocytes in which de novo FA and PC synthesis was lower, whereas cholesterol (CHOL) synthesis was higher, than in WT hepatocytes. In vivo inhibition of cholesterogenesis normalized liver PC content in OPN-KO mice, demonstrating that OPN regulates the cross-talk between liver CHOL and PC metabolism. Matched liver and serum samples showed a positive correlation between serum OPN levels and liver PC and CHOL concentration in nonobese patients with nonalcoholic fatty liver. In conclusion, OPN regulates CYP7A1 levels and the metabolic fate of liver acetyl-CoA as a result of CHOL and PC metabolism interplay. The results suggest that CYP7A1 is a main axis and that serum OPN could disrupt liver PC and CHOL metabolism, contributing to nonalcoholic fatty liver disease progression in nonobese patients.

Long-Term Satisfaction and Body Image After Contralateral Prophylactic Mastectomy.

BACKGROUND: Contralateral prophylactic mastectomy (CPM) rates have been increasing in the US, and although high levels of satisfaction with CPM have been reported, few studies have evaluated the long-term effects on body image, comparing CPM with breast-conserving surgery (BCS) and unilateral mastectomy (UM). METHODS: We analyzed responses from a survey of women with both a personal and family history of breast cancer who were enrolled in the Sister Study (n = 1176). Among women who underwent mastectomy, we examined satisfaction with the mastectomy decision, as well as variation in the use of reconstruction and experience of complications. Five survey items, evaluated individually and as a summed total score, were used to compare body image across surgery types (BCS, UM without reconstruction, CPM without reconstruction, UM with reconstruction, and CPM with reconstruction). RESULTS: Participants were, on average, 3.6 years post-diagnosis at the time of survey (standard deviation 1.7). The majority of women (97% of CPM, 89% of UM) were satisfied with their mastectomy decision. Reconstruction was more common after CPM than after UM (70 vs. 47%), as were complications (28 vs. 19%). Body image scores were significantly worse among women who underwent CPM than among women who underwent BCS, with the lowest scores among women who underwent CPM without reconstruction. CONCLUSIONS: In our sample, most women were highly satisfied with their mastectomy decision, including those who elected to undergo CPM. However, body image was lower among those who underwent CPM than among those who underwent BCS. Our findings may inform decisions among women considering various courses of surgical treatment.

CDC Grand Rounds: Family History and Genomics as Tools for Cancer Prevention and Control.

Although many efforts in cancer prevention and control have routinely focused on behavioral risk factors, such as tobacco use, or on the early detection of cancer, such as colorectal cancer screening, advances in genetic testing have created new opportunities for cancer prevention through evaluation of family history and identification of cancer-causing inherited mutations. Through the collection and evaluation of a family cancer history by a trained health care provider, patients and families at increased risk for a hereditary cancer syndrome can be identified, referred for genetic counseling and testing, and make informed decisions about options for cancer risk reduction (1). Although hereditary cancers make up a small proportion of all cancers, the number of affected persons can be large, and the level of risk among affected persons is high. Two hereditary cancer syndromes for which public health professionals have worked to reduce the burden of morbidity and mortality are hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome.

Association between serious psychological distress and health care use and expenditures by cancer history.

BACKGROUND: Serious psychological distress (SPD) is associated with adverse health outcomes such as poor quality of life and shorter survival in cancer survivors, but to the authors' knowledge, the relationship between SPD and health care use and medical expenditures is not clear. METHODS: A total of 4326 cancer survivors and 57,109 noncancer participants were identified from the 2008 through 2010 Medical Expenditure Panel Survey, a nationwide population-based survey, and their psychological distress was assessed with the 6-item Kessler Psychological Distress Scale (SPD defined by a score ≥13). The association between SPD and use and medical expenditures of various types of health care (office-based, outpatient, hospital inpatient, emergency department, dental, and prescriptions) was examined using a 2-part modeling approach that adjusted for demographic, personal, and comorbidity factors. The marginal effects of SPD on health care use and expenditures were calculated for cancer survivors and were compared with those of noncancer participants. RESULTS: The weighted prevalence of SPD in cancer survivors was 8.2% compared with 4.8% in the noncancer participants. SPD was significantly associated with higher use of all care types except dental care in cancer survivors. Cancer survivors with SPD spent $4431 (95% confidence interval, $3419-$5443) more than survivors without SPD on medical services each year, whereas this extra expenditure associated with SPD for participants without cancer was $2685 (95% confidence interval, $2099-$3271). CONCLUSIONS: In a national representative sample of cancer survivors, SPD was found to be associated with higher health care use and medical expenditures. Distress screening and psychosocial care in cancer survivors may help reduce the economic burden of cancer in the United States.

Characteristics associated with genetic counseling referral and BRCA1/2 testing among women in a large integrated health system.

BACKGROUND: Evidence shows underutilization of cancer genetics services. To explore the reasons behind this underutilization, this study evaluated characteristics of women who were referred for genetic counseling and/or had undergone BRCA1/2 testing. METHODS: An ovarian cancer risk perception study stratified 16,720 eligible women from the Henry Ford Health System into average-, elevated-, and high-risk groups based on family history. We randomly selected 3,307 subjects and interviewed 2,524 of them (76.3% response rate). RESULTS: Among the average-, elevated-, and high-risk groups, 2.3, 10.1, and 20.2%, respectively, reported genetic counseling referrals, and 0.8, 3.3, and 9.5%, respectively, reported having undergone BRCA testing. Personal breast cancer history, high risk, and perceived ovarian cancer risk were associated with both referral and testing. Discussion of family history with a doctor predicted counseling referral, whereas belief that family history influenced risk was the strongest BRCA testing predictor. Women perceiving their cancer risk as much higher than other women their age were twice as likely (95% confidence interval: 2.0-9.6) to report genetic counseling referral. CONCLUSION: In a health system with ready access to cancer genetic counseling and BRCA testing, women who were at high risk underutilized these services. There were strong associations between perceived ovarian cancer risk and genetic counseling referral, and between a belief that family history influenced risk and BRCA testing.

SIRT1 controls liver regeneration by regulating bile acid metabolism through farnesoid X receptor and mammalian target of rapamycin signaling.

UNLABELLED: Sirtuin1 (SIRT1) regulates central metabolic functions such as lipogenesis, protein synthesis, gluconeogenesis, and bile acid (BA) homeostasis through deacetylation. Here we describe that SIRT1 tightly controls the regenerative response of the liver. We performed partial hepatectomy (PH) to transgenic mice that overexpress SIRT1 (SIRT). SIRT mice showed increased mortality, impaired hepatocyte proliferation, BA accumulation, and profuse liver injury after surgery. The damaging phenotype in SIRT mice correlated with impaired farnesoid X receptor (FXR) activity due to persistent deacetylation and lower protein expression that led to decreased FXR-target gene expression; small heterodimer partner (SHP), bile salt export pump (BSEP), and increased Cyp7A1. Next, we show that 24-norUrsodeoxycholic acid (NorUDCA) attenuates SIRT protein expression, increases the acetylation of FXR and neighboring histones, restores trimethylation of H3K4 and H3K9, and increases miR34a expression, thus reestablishing BA homeostasis. Consequently, NorUDCA restored liver regeneration in SIRT mice, which showed increased survival and hepatocyte proliferation. Furthermore, a leucine-enriched diet restored mammalian target of rapamycin (mTOR) activation, acetylation of FXR and histones, leading to an overall lower BA production through SHP-inhibition of Cyp7A1 and higher transport (BSEP) and detoxification (Sult2a1) leading to an improved liver regeneration. Finally, we found that human hepatocellular carcinoma (HCC) samples have increased presence of SIRT1, which correlated with the absence of FXR, suggesting its oncogenic potential. CONCLUSION: We define SIRT1 as a key regulator of the regenerative response in the liver through posttranscriptional modifications that regulate the activity of FXR, histones, and mTOR. Moreover, our data suggest that SIRT1 contributes to liver tumorigenesis through dysregulation of BA homeostasis by persistent FXR deacetylation.

Cognitive and affective influences on perceived risk of ovarian cancer.

INTRODUCTION: Studies suggest that both affective and cognitive processes are involved in the perception of vulnerability to cancer and that affect has an early influence in this assessment of risk. We constructed a path model based on a conceptual framework of heuristic reasoning (affect, resemblance, and availability) coupled with cognitive processes involved in developing personal models of cancer causation. METHODS: From an eligible cohort of 16 700 women in a managed care organization, we randomly selected 2524 women at high, elevated, and average risk of ovarian cancer and administered a questionnaire to test our model (response rate 76.3%). Path analysis delineated the relationships between personal and cognitive characteristics (number of relatives with cancer, age, ideas about cancer causation, perceived resemblance to an affected friend or relative, and ovarian cancer knowledge) and emotional constructs (closeness to an affected relative or friend, time spent processing the cancer experience, and cancer worry) on perceived risk of ovarian cancer. RESULTS: Our final model fit the data well (root mean square error of approximation (RMSEA) = 0.028, comparative fit index (CFI) = 0.99, normed fit index (NFI) = 0.98). This final model (1) demonstrated the nature and direction of relationships between cognitive characteristics and perceived risk; (2) showed that time spent processing the cancer experience was associated with cancer worry; and (3) showed that cancer worry moderately influenced perceived risk. DISCUSSION: Our results highlight the important role that family cancer experience has on cancer worry and shows how cancer experience translates into personal risk perceptions. This understanding informs the discordance between medical or objective risk assessment and personal risk assessment. Published in 2014. This article is a U.S. Government work and is in the public domain in the USA.