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Introduction: Clinical trials are being conducted and are being planned to assess the safety and efficacy of multi-cancer early detection (MCED) tests for use in cancer screening. This study aimed to determine the feasibility of primary care patient outreach in recruiting participants to a planned MCED clinical trial, assess patient interest in trial participation, and measure decisional conflict related to participation., Methods: The research team used the electronic medical record of a large, urban health care system to identify primary care patients 50-80 years of age who were potentially eligible for a planned MCED trial. We mailed information about the planned MCED trial to identified patients and then contacted the patients by telephone to obtain consent and administer a baseline survey. Subsequently, we contacted consented patients to complete an interview to review the mailed information and elicit perceptions about trial participation. Finally, a research coordinator administered an endpoint telephone survey to assess patient interest in and decisional conflict related to joining the trial., Results: We randomly identified 1000 eligible patients and were able to make contact with 690 (69%) by telephone. Of the patients contacted, 217 (31%) completed the decision counseling session and 219 (32%) completed the endpoint survey. Among endpoint survey respondents, 177 (81%) expressed interest in joining the MCED trial and 162 (74%) reported low decisional conflict., Conclusions: Most patients were contacted and about a quarter of those contacted expressed interest in and low decisional conflict about joining the planned MCED trial. Research is needed to determine how to optimize patient outreach and engage patients in shared decision-making about MCED trial participation., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Multi-cancer early detection tests (MCEDs) are blood-based tests that detect biomarkers released or induced by cancer cells. If MCED tests are shown to be safe and effective in cancer screening, they are likely to be ordered and managed in primary care. To understand primary care providers' support for and concerns about the implementation and management of MCED testing, the research team developed a cross-sectional survey that was sent to 939 primary care providers (physicians, residents/fellows, and advanced practice providers) in a large academic health system in the greater Philadelphia area. The survey included standard items used to assess provider background characteristics and to measure provider awareness of challenges related to MCED test use (7 items), perceived competence in MCED testing (5 items), and receptivity to MCED test use in the future (4 items). A total of 351 (37.4%) primary care providers completed the survey. Among respondents, the awareness of challenges in MCED testing (mean = 3.95, sd = 0.64), perceived competence (3.67, sd = 0.85), and receptivity to MCED use in practice (mean = 3.62, 0.75) were moderately high. Multiple regression was performed to identify factors associated with receptivity to MCED testing. We found that provider number of years in practice (DATA), awareness of challenges related to MCED testing (DATA), and perceived competence in MCED test use (DATA) were positively and significantly associated with receptivity to MCED test use in practice. An exploratory factor analysis extracted two components: receptivity to MCEDs and awareness of challenges. Surprisingly, these factors had a positive correlation (r = 0.124, p = 0.024). Providers' perceived competence in using MCED tests and providers' experience level were significantly associated with receptivity to MCED testing. While there was strong agreement with potential challenges to implementing MCEDs, PCPs were generally receptive to using MCEDs in cancer screening. Keeping PCPs updated on the evolving knowledge of MCEDs is likely critical to building receptivity to MCED testing.

Multi-cancer early detection (MCED) tests are being developed, but little is known about patient receptivity to their use for cancer screening. The current study assessed patient interest in such testing. Our team conducted a prospective, observational study among primary care patients in a large, urban health system. They were asked to complete a telephone survey that briefly described a new blood test in development to identify multiple types of cancer, but was not currently recommended or covered by insurance. The survey included items to assess respondent background characteristics, perceptions about MCED testing, and interest in having such an MCED test. We also used multivariable analyses to identify factors associated with patient interest in test use. In 2023, we surveyed 159 (32%) of 500 identified patients. Among respondents, 125 (79%) reported a high level of interest in having an MCED test. Interest was not associated with personal background characteristics, but was positively associated with the following expectations: testing would be recommended for cancer screening, be convenient, and be effective in finding early-stage disease (OR = 11.70, 95% CI: 4.02, 34.04, p < 0.001). Research is needed to assess patient interest and actual uptake when detailed information on testing is presented in routine care.

Background: Lung cancer screening uptake for individuals at high risk is generally low across the United States, and reporting of lung cancer screening practices and outcomes is often limited to single hospitals or institutions. We describe a citywide, multicenter analysis of individuals receiving lung cancer screening integrated with geospatial analyses of neighborhood-level lung cancer risk factors., Methods: The Philadelphia Lung Cancer Learning Community consists of lung cancer screening clinicians and researchers at the 3 largest health systems in the city. This multidisciplinary, multi-institutional team identified a Philadelphia Lung Cancer Learning Community study cohort that included 11 222 Philadelphia residents who underwent low-dose computed tomography for lung cancer screening from 2014 to 2021 at a Philadelphia Lung Cancer Learning Community health-care system. Individual-level demographic and clinical data were obtained, and lung cancer screening participants were geocoded to their Philadelphia census tract of residence. Neighborhood characteristics were integrated with lung cancer screening counts to generate bivariate choropleth maps., Results: The combined sample included 37.8% Black adults, 52.4% women, and 56.3% adults who currently smoke. Of 376 residential census tracts in Philadelphia, 358 (95.2%) included 5 or more individuals undergoing lung cancer screening, and the highest counts were geographically clustered around each health system's screening sites. A relatively low percentage of screened adults resided in census tracts with high tobacco retailer density or high smoking prevalence., Conclusions: The sociodemographic characteristics of lung cancer screening participants in Philadelphia varied by health system and neighborhood. These results suggest that a multicenter approach to lung cancer screening can identify vulnerable areas for future tailored approaches to improving lung cancer screening uptake. Future directions should use these findings to develop and test collaborative strategies to increase lung cancer screening at the community and regional levels., (© The Author(s) 2023. Published by Oxford University Press.)

Genomic tests are being developed for use in cancer screening. As most screening is offered in primary care settings, primary care provider and patient perceptions of such tests are likely to affect uptake. We conducted a scoping review to synthesize information on factors likely to affect patient and provider use of biospecimen collection and analysis for cancer screening, methods referred to as liquid biopsy or multi-cancer early detection (MCED) testing when used to detect multiple cancers. We ultimately identified 7 articles for review and analyzed them for major themes. None reported on primary care provider perspectives. Six articles focused on patient perceptions about testing for a single cancer (colorectal), and 1 reported on patient views related to testing for multiple cancers. Factors favoring this type of testing included its non-invasiveness, and the perceived safety, convenience, and effectiveness of testing. There is a dearth of information in the literature on primary care provider perceptions about liquid biopsy and MCED testing. The limited information on patient perceptions suggests that they are receptive to such tests. Research on primary care provider and patient test-related knowledge, attitudes, and behavior is needed to guide future implementation in primary care settings.

Few treatment decision support interventions (DSIs) are available to engage patients diagnosed with late-stage non-small cell lung cancer (NSCLC) in treatment shared decision making (SDM). We designed a novel DSI that includes care plan cards and a companion patient preference clarification tool to assist in shared decision making. The cards answer common patient questions about treatment options (chemotherapy, chemotherapy plus immunotherapy, targeted therapy, immunotherapy, clinical trial participation, and supportive care). The form elicits patient treatment preference. We then conducted interviews with clinicians and patients to obtain feedback on the DSI. We also trained oncology nurse educators to implement the prototype. Finally, we pilot tested the DSI among five patients with NSCLC at the beginning of an office visit scheduled to discuss treatment with an oncologist. Analyses of pilot study baseline and exit survey data showed that DSI use was associated with increased patient awareness of the alternatives' treatment options and benefits/risks. In contrast, patient concern about treatment costs and uncertainty in treatment decision making decreased. All patients expressed a treatment preference. Future randomized controlled trials are needed to assess DSI implementation feasibility and efficacy in clinical care.

Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Although it is a rare subtype, IBC is responsible for roughly 10% of breast cancer deaths. In order to obtain a better understanding of the genomic landscape and intratumor heterogeneity (ITH) in IBC, we conducted whole-exome sequencing of 16 tissue samples (12 tumor and four normal samples) from six hormone-receptor-positive IBC patients, analyzed somatic mutations and copy number aberrations, and inferred subclonal structures to demonstrate ITH. Our results showed that KMT2C was the most frequently mutated gene (42%, 5/12 samples), followed by HECTD1, LAMA3, FLG2, UGT2B4, STK33, BRCA2, ACP4, PIK3CA, and DNAH8 (all nine genes tied at 33% frequency, 4/12 samples). Our data indicated that PTEN and FBXW7 mutations may be considered driver gene mutations for IBC. We identified various subclonal structures and different levels of ITH between IBC patients, and mutations in the genes EIF4G3, IL12RB2, and PDE4B may potentially generate ITH in IBC.

Liquid biopsy-based biomarkers have advantages in monitoring the dynamics of metastatic castration-resistant prostate cancer (mCRPC), a bone-predominant metastatic disease. Previous studies have demonstrated associations between circulating tumor cells (CTCs) and clinical outcomes of mCRPC patients, but little is known about the prognostic value of CTC-clusters. In 227 longitudinally collected blood samples from 64 mCRPC patients, CTCs and CTC-clusters were enumerated using the CellSearch platform. The associations of CTC and CTC-cluster counts with progression-free survival (PFS) and overall survival (OS), individually and jointly, were evaluated by Cox models. CTCs and CTC-clusters were detected in 24 (37.5%) and 8 (12.5%) of 64 baseline samples, and in 119 (52.4%) and 27 (11.9%) of 227 longitudinal samples, respectively. CTC counts were associated with both PFS and OS, but CTC-clusters were only independently associated with an increased risk of death. Among patients with unfavorable CTCs (≥5), the presence of CTC-clusters signified a worse survival (log-rank p = 0.0185). mCRPC patients with both unfavorable CTCs and CTC-clusters had the highest risk for death (adjusted hazard ratio 19.84, p = 0.0072), as compared to those with <5 CTCs. Analyses using longitudinal data yielded similar results. In conclusion, CTC-clusters provided additional prognostic information for further stratifying death risk among patients with unfavorable CTCs.

Objectives: Caring for individuals with intellectual disabilities (ID) or autism spectrum disorder (ASD) can be gratifying as well as stressful. Professional staff employed as caregivers often report compromised mental and physical wellbeing due to the stressful nature of working with clients who exhibit aggressive and destructive behaviors. Prolonged work-related stress results in diminished quality of life for the caregivers. The aim of the present study was to evaluate the comparative effects of three programs-mindfulness program, psychoeducational program, and inservice training-as-usual-on the quality of life of professional caregivers who provide services to adolescent and adult clients with ID and ASD., Methods: Professional caregivers ( N  = 216) were randomized into three experimental conditions, and trained in mindfulness, psychoeducation, and inservice training-as-usual. The effects of the training on the caregivers' quality of life were assessed in terms of perceived stress, compassion satisfaction, compassion fatigue (i.e. burnout, secondary traumatic stress), and symptoms of depression at the end of 32 weeks of implementation., Results: Perceived stress, burnout, and secondary traumatic stress decreased significantly in the mindfulness condition, followed by psychoeducation, but not in the inservice training-as-usual condition. Compassion satisfaction increased significantly in the mindfulness condition, followed by psychoeducation, but not in the inservice training-as-usual condition. Symptoms of depression, which were rated in the borderline clinical range prior to intervention, decreased significantly to within normal levels in the mindfulness condition, decreased minimally in the psychoeducation condition, and showed no change in the training-as usual condition., Conclusions: A 3-day training in mindfulness meditations and associated contemplative practices provides a better basis for enhancing caregivers' quality of life than psychoeducation or inservice training-as-usual., Competing Interests: The authors declare no conflict of interest and they do not work for, consult to, and own shares in or receive funding from any company or organization that would benefit from this article. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study, (© The British Society of Developmental Disabilities 2020.)

Parenting a child with autism spectrum disorder (ASD) or intellectual disabilities (IDs) can be stressful for many parents. Mindfulness-Based Positive Behavior Support (MBPBS) is a customized mindfulness program that enables parents and other caregivers to reduce their perceived psychological stress to normative levels through mindfulness procedures and to support children with ASD or ID to self-manage their challenging behaviors through positive behavior support (PBS). In this study, we evaluated whether MBPBS would have differential effects on the stress levels of mothers of adolescents with ASD ( n = 47) or with ID ( n = 45) and the effects of the program on the aggressive, disruptive, and compliance behaviors of their children. Both groups of mothers participated in the 40-week study (10 weeks control and 30 weeks MBPBS program), rated their own stress levels, and collected daily observational data on the adolescents' behavior. Results showed significant reductions in the level of stress in both groups of mothers, but no differential effects on mothers of children with ASD or with ID. In addition, significant reductions in aggression and disruptive behavior and increases in compliance behaviors were observed in the adolescents in both groups. The results suggest that MBPBS is equally beneficial for mothers of adolescents with ASD or ID. In the present study, although the mothers of children with ID had slightly higher levels of stress at baseline and mothers of children with ASD had lower levels of stress following the MBPBS program, the program can be considered equally effective in reducing the stress levels of both groups of mothers. This suggests that the program may be effective regardless of baseline levels of mothers' stress.

Background: Effective strategies are needed to raise colorectal cancer screening rates among Hispanics., Methods: We surveyed and randomized 400 Hispanic primary care patients either to a Decision Support and Navigation Intervention (DSNI) Group ( n = 197) or a Standard Intervention (SI) Group ( n = 203). Both groups received a colorectal cancer screening kit [bilingual informational booklet, fecal immunochemical stool blood test (SBT), and colonoscopy screening instructions]. The DSNI Group received a telephone contact from a patient navigator. The navigator clarified screening test preference and likelihood of test performance, helped to develop a screening plan, and provided guidance through test performance. An endpoint telephone survey and medical chart review were completed. Multivariable analyses were conducted to assess 12-month screening adherence, change in decision stage, and knowledge and perceptions., Results: Screening adherence was significantly higher in the DSNI Group than the SI Group [OR, 4.8; 95% confidence interval (CI), 3.1-7.6]. The DSNI Group, compared with the SI Group, also displayed higher SBT screening [OR, 4.2; 95% CI, 2.6-6.7), higher colonoscopy screening (OR, 8.8; 95% CI, 4.1-18.7), and greater forward change in screening decision stage (OR, 4.9; 95% CI, 2.6-9.5). At endpoint, study groups did not differ in screening knowledge or perceptions., Conclusions: The DSNI had a greater positive impact on colorectal cancer screening outcomes than the SI., Impact: Health system implementation of DSNI strategies may help to reduce Hispanic colorectal cancer screening disparities in primary care., (©2018 American Association for Cancer Research.)

Accountable care organizations and health systems have the potential to increase patient engagement in medical care, improve population health outcomes, and reduce costs. Characteristics of highly integrated learning health care systems that seek to achieve these goals have been described in the literature. However, there have been few reports on how health systems, especially those that are loosely integrated, can develop the infrastructure needed to support achievement of these goals. In this report, we describe a learning community strategy that involved forming a coordinating team, a steering committee, and patient and stakeholder advisory committees to address cancer screening and disparities in 2 health systems in southeastern Pennsylvania-Jefferson Health and the Lehigh Valley Health Network. This project engaged diverse patients, health care providers, health system leaders, public and private payers, and other stakeholders in identifying and adapting evidence-based methods to increase colorectal and lung cancer screening in primary care. Here, we describe components of a health system learning community. In addition, we describe activities in which different components of the learning community were engaged. Finally, we explore prospects for using this type of approach to catalyze the development of learning health care systems., Competing Interests: The authors have no conflicts of interest to disclose.

Background: Distant metastasis accounts for 90% of deaths from colorectal cancer (CRC). Genomic heterogeneity has been reported in various solid malignancies, but remains largely under-explored in metastatic CRC tumors, especially in primary to metastatic tumor evolution., Patients and Methods: We conducted high-depth whole-exome sequencing in multiple regions of matched primary and metastatic CRC tumors. Using a total of 28 tumor, normal, and lymph node tissues, we analyzed inter- and intra-individual heterogeneity, inferred the tumor subclonal architectures, and depicted the subclonal evolutionary routes from primary to metastatic tumors., Results: CRC has significant inter-individual but relatively limited intra-individual heterogeneity. Genomic landscapes were more similar within primary, metastatic, or lymph node tumors than across these types. Metastatic tumors exhibited less intratumor heterogeneity than primary tumors, indicating that single-region sequencing may be adequate to identify important metastasis mutations to guide treatment. Remarkably, all metastatic tumors inherited multiple genetically distinct subclones from primary tumors, supporting a possible polyclonal seeding mechanism for metastasis. Analysis of one patient with the trio samples of primary, metastatic, and lymph node tumors supported a mechanism of synchronous parallel dissemination from the primary to metastatic tumors that was not mediated through lymph nodes., Conclusions: In CRC, metastatic tumors have different but less heterogeneous genomic landscapes than primary tumors. It is possible that CRC metastasis is, at least partly, mediated through a polyclonal seeding mechanism. These findings demonstrated the rationale and feasibility for identifying and targeting primary tumor-derived metastasis-potent subclones for the prediction, prevention, and treatment of CRC metastasis., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Prospective and longitudinal epidemiological evidence is needed to assess the association between telomere length and risk of hepatocellular carcinoma (HCC). In 323 cancer-free Korean-American HBV patients with 1-year exclusion window (followed for >1 year and did not develop HCC within 1 year), we measured the relative telomere length (RTL) in baseline serum DNAs and conducted extensive prospective and longitudinal analyses to assess RTL-HCC relationship. We found that long baseline RTL conferred an increased HCC risk compared to short RTL [hazard ratio (HR) = 4.93, P = 0.0005). The association remained prominent when the analysis was restricted to patients with a more stringent 5-year exclusion window (HR = 7.51, P = 0.012), indicating that the association was unlikely due to including undetected HCC patients in the cohort, thus minimizing the reverse-causation limitation in most retrospective studies. Adding baseline RTL to demographic variables increased the discrimination accuracy of the time-dependent receiver operating characteristic analysis from 0.769 to 0.868 (P = 1.0 × 10-5). In a nested longitudinal subcohort of 16 matched cases-control pairs, using a mixed effects model, we observed a trend of increased RTL in cases and decreased RTL in controls along 5 years of follow-up, with a significant interaction of case/control status with time (P for interaction=0.002) and confirmed the association between long RTL and HCC risk [odds ratio [OR] = 3.63, P = 0.016]. In summary, serum DNA RTL may be a novel non-invasive prospective marker of HBV-related HCC. Independent studies are necessary to validate and generalize this finding in diverse populations and assess the clinical applicability of RTL in HCC prediction., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Informed and shared decision making are critical aspects of patient-centered care, which has contributed to an emphasis on decision support interventions to promote good medical decision making. However, researchers and healthcare providers have not reached a consensus on what defines a good decision, nor how to evaluate it. This position paper, informed by conference sessions featuring diverse stakeholders held at the 2015 Society of Behavioral Medicine and Society for Medical Decision Making annual meetings, describes key concepts that influence the decision making process itself and that may change what it means to make a good decision: interpersonal factors, structural constraints, affective influences, and values clarification methods. This paper also proposes specific research questions within each of these priority areas, with the goal of moving medical decision making research to a more comprehensive definition of a good medical decision, and enhancing the ability to measure and improve the decision making process., Competing Interests: The authors declare that they have no conflicts of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.

Background: We sought to assess physician interest in molecular prognosic testing for patients with early stage colon cancer, and identify factors associated with the likelihood of test adoption., Methods: We identified physicians who care for patients with early-stage (pN0) colon cancer patients, mailed them a survey, and analyzed survey responses to assess clinician receptivity to the use of a new molecular test (GUCY2C) that identifies patients at risk for recurrence, and clinician readiness to act on abnormal test results., Results: Of 104 eligible potential respondents, 41 completed and returned the survey. Among responding physicians, 56 % were receptive to using the new prognostic test. Multivariable analyses showed that physicians in academic medical centers were significantly more receptive to molecular test use than those in non-academic settings. Forty-one percent of respondents were ready to act on abnormal molecular test results. Physicians who viewed current staging methods as inaccurate and were confident in their capacity to incorporate molecular testing in practice were more likely to say they would act on abnormal test results., Conclusions: Physician receptivity to molecular diagnostic testing for early-stage colon cancer patients is likely to be influenced by practice setting and perceptions related to delivering quality care to patients., Trial Registration: ClinicalTrials.gov Identifier: NCT01972737.

Background & Aims: We evaluated differences in treatment of black vs white patients with colon cancer and assessed their effects on survival, based on cancer stage., Methods: We collected data from the Surveillance, Epidemiology, and End Results-Medicare database and identified 6190 black and 61,951 white patients with colon cancer diagnosed from 1998 through 2009 and followed up through 2011. Three sets of 6190 white patients were matched sequentially, using a minimum distance strategy, to the same set of 6190 black patients based on demographic (age; sex; diagnosis year; and Surveillance, Epidemiology, and End Results registry), tumor presentation (demographic plus comorbidities, tumor stage, grade, and size), and treatment (presentation plus therapies) variables. We conducted sensitivity analyses to explore the effects of socioeconomic status in a subcohort that included 2000 randomly selected black patients. Racial differences in treatment were assessed using a logistic regression model; their effects on racial survival disparity were evaluated using the Kaplan-Meier method and the Cox proportional hazards model., Results: After patients were matched for demographic variables, the absolute 5-year difference in survival between black and white patients was 8.3% (white, 59.2% 5-y survival; blacks, 50.9% 5-y survival) (P < .0001); this value decreased significantly, to 5.0% (P < .0001), after patients were matched for tumor presentation, and decreased to 4.9% (P < .0001) when patients were matched for treatment. Differences in treatment therefore accounted for 0.1% of the 8.3% difference in survival between black and white patients. After patients were matched for tumor presentation, racial disparities were observed in almost all types of treatment; the disparities were most prominent for patients with advanced-stage cancer (stages III or IV, up to an 11.1% difference) vs early stage cancer (stages I or II, up to a 4.3% difference). After patients were matched for treatment, there was a greater reduction in disparity for black vs white patients with advanced-stage compared with early-stage cancer. In sensitivity analyses, the 5-year racial survival disparity was 7.7% after demographic match, which was less than the 8.3% observed in the complete cohort. This reduction likely was owing to the differences between the subcohort and the complete cohort in those variables that were not included in the demographic match. This value was reduced to 6.5% (P = .0001) after socioeconomic status was included in the demographic match. The difference decreased significantly to 2.8% (P = .090) after tumor presentation match, but was not reduced further after treatment match., Conclusions: We observed significant disparities in treatment and survival of black vs white patients with colon cancer. The disparity in survival appears to have been affected more strongly by tumor presentation at diagnosis than treatment. The effects of treatment differences on disparities in survival were greater for patients with advanced-stage vs early-stage cancer., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation represents the most common arrhythmia leading to increased morbidity and mortality, yet, current treatment strategies have proven inadequate. Conventional treatment with antiarrhythmic drugs carries a high risk for proarrhythmias. The soluble epoxide hydrolase enzyme catalyzes the hydrolysis of anti-inflammatory epoxy fatty acids, including epoxyeicosatrienoic acids from arachidonic acid to the corresponding proinflammatory diols. Therefore, the goal of the study is to directly test the hypotheses that inhibition of the soluble epoxide hydrolase enzyme can result in an increase in the levels of epoxyeicosatrienoic acids, leading to the attenuation of atrial structural and electric remodeling and the prevention of atrial fibrillation., Methods and Results: For the first time, we report findings that inhibition of soluble epoxide hydrolase reduces inflammation, oxidative stress, atrial structural, and electric remodeling. Treatment with soluble epoxide hydrolase inhibitor significantly reduces the activation of key inflammatory signaling molecules, including the transcription factor nuclear factor κ-light-chain-enhancer, mitogen-activated protein kinase, and transforming growth factor-β., Conclusions: This study provides insights into the underlying molecular mechanisms leading to atrial fibrillation by inflammation and represents a paradigm shift from conventional antiarrhythmic drugs, which block downstream events to a novel upstream therapeutic target by counteracting the inflammatory processes in atrial fibrillation., (© 2016 American Heart Association, Inc.)

Recent studies have demonstrated a potential link between circulating cell-free mitochondrial DNA (mtDNA) content and cancers. However, there is no study evaluating the association between circulating mtDNA as a non-invasive marker of hepatocellular carcinoma (HCC) risk. We conducted a nested case-control study to determine circulating mtDNA content in serum samples from 116 HBV-related HCC cases and 232 frequency-matched cancer-free HBV controls, and evaluate the retrospective association between mtDNA content and HCC risk using logistic regression and their temporal relationship using a mixed effects model. HCC cases had significantly lower circulating mtDNA content than controls (1.06 versus 2.47, P = 1.7 × 10(-5)). Compared to HBV patients with higher mtDNA content, those with lower mtDNA content had a significantly increased risk of HCC with an odds ratio (OR) of 2.19 (95% confidence interval [CI] 1.28-3.72, P = 0.004). Quartile analyses revealed a significant dose-dependent effect (Ptrend = 0.001) for this association. In a pilot longitudinal sub-cohort of 14 matched cases-control pairs, we observed a trend of dramatically decreased mtDNA content in cases and slightly decreased mtDNA content in controls, with a significant interaction of case-control status with time (Pinteraction = 0.049). Our findings suggest that circulating mtDNA is a potential novel non-invasive biomarker of HCC risk in HBV patients.

Caregivers often manage the aggressive behavior of individuals with intellectual and developmental disabilities that reside in community group homes. Sometimes this results in adverse outcomes for both the caregivers and the care recipients. We provided a 7-day intensive Mindfulness-Based Positive Behavior Support (MBPBS) training to caregivers from community group homes and assessed the outcomes in terms of caregiver variables, individuals' behaviors, and an administrative outcome. When compared to pre-MBPBS training, the MBPBS training resulted in the caregivers using significantly less physical restraints, and staff stress and staff turnover were considerably reduced. The frequency of injury to caregivers and peers caused by the individuals was significantly reduced. A benefit-cost analysis showed substantial financial savings due to staff participation in the MBPBS program. This study provides further proof-of-concept for the effectiveness of MBPBS training for caregivers, and strengthens the call for training staff in mindfulness meditation.

Little is known about the impact of genetic and environmental risk assessment (GERA) feedback on colorectal cancer (CRC) screening. In a recently completed randomized trial, primary care patients received GERA feedback based on a blood test for genetic polymorphisms and serum folate level (GERA Group) versus usual care (Control Group). Subsequently, participants were offered CRC screening. Among participants who received GERA feedback, being at elevated risk was negatively associated with prospective CRC screening adherence. Secondary analyses of data from this study were performed to identify independent predictors of adherence among participants who received GERA feedback. We obtained baseline survey, follow-up survey, and endpoint medical records data on sociodemographic background, knowledge, psychosocial characteristics, risk status, and adherence for 285 GERA Group participants. Univariate and multivariable analyses were performed to identify predictors of CRC screening adherence. Following a 6-month outcomes observation period, we also conducted two focus groups with GERA Group participants to assess their perceptions of GERA risk feedback and screening. Content analyses of focus group data were evaluated to gain insights into participant response to risk feedback. Overall, half of GERA Group participants adhered to screening within 6 months after randomization. Multivariable analyses showed a statistically significant interaction between race and GERA feedback status relative to screening adherence (p = 0.043). Among participants who received average risk feedback, adherence was comparable among whites (49.7 %) and nonwhites (54.1 %); however, among those at elevated risk, adherence was substantially higher among whites (66.7 %) compared to nonwhites (33.3 %). Focus group findings suggest that whites were more likely than nonwhites to view elevated risk feedback as a prompt to screen. In response to receiving elevated risk feedback, nonwhites were more likely than whites to report feeling anxiety about the likelihood of being diagnosed with CRC. Further research is needed to explore race-related CRC screening differences in response to GERA feedback.

Background: Prior randomized, controlled trials (RCTs) indicate that patient navigation can boost colorectal cancer screening rates in primary care. The sparse literature on pragmatic trials of interventions designed to increase colorectal cancer screening adherence motivated this trial on the impact of a patient navigation intervention that included support for performance of the participants' preferred screening test (colonoscopy or stool blood testing)., Materials and Methods: Primary care patients (n = 5,240), 50 to 74 years of age, with no prior diagnosis of bowel cancer and no record of a recent colorectal cancer screening test, were identified at the Group Health Centre in northern Ontario. These patients were randomly assigned to an intervention group (n = 2,629) or a usual care control group (n = 2,611). Intervention group participants were contacted by a trained nurse navigator by telephone to discuss colorectal cancer screening. Interested patients met with the navigator, who helped them identify and arrange for performance of the preferred screening test. Control group participants received usual care. Multivariate analyses were conducted using medical records data to assess intervention impact on screening adherence within 12 months after randomization., Results: Mean patient age was 59 years, and 50% of participants were women. Colorectal cancer screening adherence was higher in the intervention group (35%) than in the control group (20%), a difference that was statistically significant (OR, 2.11; confidence interval, 1.87-2.39)., Conclusion: Preference-based patient navigation increased screening uptake in a pragmatic RCT., Impact: Patient navigation increased colorectal cancer screening rates in a pragmatic RCT in proportions similar to those observed in explanatory RCTs., (©2014 American Association for Cancer Research.)

Background: The study aimed to determine the effect of preference-based tailored navigation on colorectal cancer (CRC) screening adherence and related outcomes among African Americans (AAs)., Methods: We conducted a randomized controlled trial that included 764 AA patients who were age 50 to 75 years, were eligible for CRC screening, and had received care through primary care practices in Philadelphia. Consented patients completed a baseline telephone survey and were randomized to either a Standard Intervention (SI) group (n = 380) or a Tailored Navigation Intervention (TNI) group (n = 384). The SI group received a mailed stool blood test kit plus colonoscopy instructions, and a reminder. The TNI group received tailored navigation (a mailed stool blood test kit or colonoscopy instructions based on preference, plus telephone navigation) and a reminder. A six-month survey and a 12-month medical records review were completed to assess screening adherence, change in overall screening preference, and perceptions about screening. Multivariable analyses were performed to assess intervention impact on outcomes., Results: At six months, adherence in the TNI group was statistically significantly higher than in the SI group (OR = 2.1, 95% CI = 1.5 to 2.9). Positive change in overall screening preference was also statistically significantly greater in the TNI group compared with the SI group (OR = 1.5, 95% CI = 1.0 to 2.3). There were no statistically significant differences in perceptions about screening between the study groups., Conclusions: Tailored navigation in primary care is a promising approach for increasing CRC screening among AAs. Research is needed to determine how to maximize intervention effects and to test intervention impact on race-related disparities in mortality and survival., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Little is known about how colorectal cancer screening test preferences operate together with test access and navigation to influence screening adherence in primary care., Methods: We analyzed data from a randomized trial of 945 primary care patients to assess the independent effects of screening test preference for fecal immunochemical test (FIT) or colonoscopy, mailed access to FIT and colonoscopy, and telephone navigation for FIT and colonoscopy, on screening., Results: Preference was not associated with overall screening, but individuals who preferred FIT were more likely to complete FIT screening (P = 0.005), whereas those who preferred colonoscopy were more likely to perform colonoscopy screening (P = 0.032). Mailed access to FIT and colonoscopy was associated with increased overall screening (OR = 2.6, P = 0.001), due to a 29-fold increase in FIT use. Telephone navigation was also associated with increased overall screening (OR = 2.1, P = 0.005), mainly due to a 3-fold increase in colonoscopy performance. We estimated that providing access and navigation for both screening tests may substantially increase screening compared with a preference-tailored approach, mainly due to increased performance of nonpreferred tests., Conclusions: Preference influences the type of screening tests completed. Test access increases FIT and navigation mainly increases colonoscopy. Screening strategies providing access and navigation to both tests may be more effective than preference-tailored approaches., Impact: Preference tailoring in colorectal cancer screening strategies should be avoided if the objective is to maximize screening rates, although other factors (e.g., costs, necessary follow-up) should also be considered., (©2014 American Association for Cancer Research.)

For an excitable cell to function properly, a precise number of ion channel proteins need to be trafficked to distinct locations on the cell surface membrane, through a network and anchoring activity of cytoskeletal proteins. Not surprisingly, mutations in anchoring proteins have profound effects on membrane excitability. Ca(2+)-activated K(+) channels (KCa2 or SK) have been shown to play critical roles in shaping the cardiac atrial action potential profile. Here, we demonstrate that filamin A, a cytoskeletal protein, augments the trafficking of SK2 channels in cardiac myocytes. The trafficking of SK2 channel is Ca(2+)-dependent. Further, the Ca(2+) dependence relies on another channel-interacting protein, α-actinin2, revealing a tight, yet intriguing, assembly of cytoskeletal proteins that orchestrate membrane expression of SK2 channels in cardiac myocytes. We assert that changes in SK channel trafficking would significantly alter atrial action potential and consequently atrial excitability. Identification of therapeutic targets to manipulate the subcellular localization of SK channels is likely to be clinically efficacious. The findings here may transcend the area of SK2 channel studies and may have implications not only in cardiac myocytes but in other types of excitable cells.

Aims: Small conductance Ca(2+)-activated K(+) channels (K(Ca)2 or SK channels) have been reported in excitable cells, where they aid in integrating changes in intracellular Ca(2+) (Ca(i)²⁺) with membrane potentials. We have recently reported the functional expression of SK channels in human and mouse cardiac myocytes. Additionally, we have found that the channel is highly expressed in atria compared with the ventricular myocytes. We demonstrated that human cardiac myocytes expressed all three members of SK channels (SK1, 2, and 3); moreover, the different members are capable of forming heteromultimers. Here, we directly tested the contribution of SK3 to the overall repolarization of atrial action potentials., Methods and Results: We took advantage of a mouse model with site-specific insertion of a tetracycline-based genetic switch in the 5' untranslated region of the KCNN3 (SK3 channel) gene (SK3(T/T)). The gene-targeted animals overexpress the SK3 channel without interfering with the normal profile of SK3 expression. Whole-cell, patch-clamp techniques show a significant shortening of the action potential duration mainly at 90% repolarization (APD90) in atrial myocytes from the homozygous SK3(T/T) animals. Conversely, treatment with dietary doxycycline results in a significant prolongation of APD90 in atrial myocytes from SK3(T/T) animals. We further demonstrate that the shortening of APDs in SK3 overexpression mice predisposes the animals to inducible atrial arrhythmias., Conclusion: SK3 channel contributes importantly towards atrial action potential repolarization. Our data suggest the important role of the SK3 isoform in atrial myocytes.

Background: Early detection through screening is the best method to reduce death due to breast cancer. It has been shown, having knowledge and generating positive attitudes, influences the decision of women to participate in the screening programs. The aim of this study was to identify the factors associated with breast cancer screening (BCS) and with an intention to have screening among women in Tehran, Iran., Methods: A cross-sectional study was carried out from January to July 2011, among women who had attended to primary health-care centers in West Tehran using multi-stage sampling method. We invited 1,240 women sequentially to complete a self-administered survey questionnaire at the beginning of their visit; and 1,012 (82%) completed the survey. The questionnaire included, items drawn from the Preventive Health Model that assess socio-demographic background and perceptions about BCS. Multiple logistic regression analysis was performed to identify factors associated with screening and intention to do screening in the future., Results: The mean age of subjects was 38.2 years. Women who perceived more screening efficacy (odd ratio [OR] =1.63; confidence interval [CI] 95%: 1.12-2.37) and fewer performance barriers (OR = 0.82; CI 95%: 0.68-0.97) were more likely to perform clinical breast exam in the future. The women who reported higher clinical breast exam self-efficacy (OR = 1.82; CI 95%: 1.39-2.37), mammography self-efficacy (OR = 1.31; CI 95%: 1.04-1.65), screening efficacy (OR = 1.53; CI 95%: 1.18-1.97), and family influence (OR = 1.27; CI 95%: 1.05-1.54), and those who reported fewer screening performance barriers (OR = 0.56; CI 95%: 0.48-0.67) were more likely to decide for carried out mammography in the future. Most respondents indicated that they intended to do clinical breast exam and mammography in the future (75.8% and 72.1% respectively). About 65% of women reported they would do both., Conclusions: We found that women's intention to do BCS was very high and a comprehensive national program is needed to guide their intention. Among different demographic factors, the impact of education level on doing BCS was significant.

Delineating regions is an important first step in understanding the evolution and biogeography of faunas. However, quantitative approaches are often limited at a global scale, particularly in the marine realm. Reef fishes are the most diversified group of marine fishes, and compared to most other phyla, their taxonomy and geographical distributions are relatively well known. Based on 169 checklists spread across all tropical oceans, the present work aims to quantitatively delineate biogeographical entities for reef fishes at a global scale. Four different classifications were used to account for uncertainty related to species identification and the quality of checklists. The four classifications delivered converging results, with biogeographical entities that can be hierarchically delineated into realms, regions and provinces. All classifications indicated that the Indo-Pacific has a weak internal structure, with a high similarity from east to west. In contrast, the Atlantic and the Eastern Tropical Pacific were more strongly structured, which may be related to the higher levels of endemism in these two realms. The "Coral Triangle", an area of the Indo-Pacific which contains the highest species diversity for reef fishes, was not clearly delineated by its species composition. Our results show a global concordance with recent works based upon endemism, environmental factors, expert knowledge, or their combination. Our quantitative delineation of biogeographical entities, however, tests the robustness of the results and yields easily replicated patterns. The similarity between our results and those from other phyla, such as corals, suggests that our approach may be of broad utility in describing and understanding global marine biodiversity patterns.

Background: Anemia refers to low hemoglobin (Hb) level and is a risk factor of cancer patient survival. The National Comprehensive Cancer Network recently suggested that post-diagnosis Hb change, regardless of baseline Hb level, indicates the potential presence of anemia. However, there is no epidemiological study evaluating whether Hb change has direct prognostic values for cancer patients at the population level., Methods: We identified 6675 patients with a diagnosis of primary lung, breast, colorectal, or liver cancer who visited the Kimmel Cancer Center at the Thomas Jefferson University from 1998 to 2011. All patients had at least two Hb measurements within the first six months after diagnosis. We analyzed the main, dose-dependent, and time-dependent effects of Hb changes on patient survival., Results: Compared to patients with a low Hb change (|∆Hb|≤2.6), those having a |∆Hb|>2.6 exhibited a significantly shorter survival (hazard ratio=1.40, 95% confidence interval 1.31-1.50, P=4.5 × 10(-22), Plog rank=1.6 × 10(-39)). This association remained significant across the four cancer types. Bootstrap resampling validated these findings 100% of the time with P<0.01 in all patients and in patients of individual cancers. The association exhibited an apparent U-shape dose-dependent pattern. Time-dependent modeling demonstrated that the effect of Hb change on the survival of the overall patient population persisted for approximately 4.5 years after diagnosis., Conclusion: Post-diagnosis Hb change associates with the survival of multiple cancers and may have clinical values in tailoring anti-anemia treatments. Because Hb level is frequently measured during cancer treatment, Hb changes may be a potentially important variable in building cancer prognosis models.

Rationale: Adenylyl cyclase (AC) represents one of the principal molecules in the β-adrenergic receptor signaling pathway, responsible for the conversion of ATP to the second messenger, cAMP. AC types 5 (ACV) and 6 (ACVI) are the 2 main isoforms in the heart. Although highly homologous in sequence, these 2 proteins play different roles during the development of heart failure. Caveolin-3 is a scaffolding protein, integrating many intracellular signaling molecules in specialized areas called caveolae. In cardiomyocytes, caveolin is located predominantly along invaginations of the cell membrane known as t-tubules., Objective: We take advantage of ACV and ACVI knockout mouse models to test the hypothesis that there is distinct compartmentalization of these isoforms in ventricular myocytes., Methods and Results: We demonstrate that ACV and ACVI isoforms exhibit distinct subcellular localization. The ACVI isoform is localized in the plasma membrane outside the t-tubular region and is responsible for β1-adrenergic receptor signaling-mediated enhancement of the L-type Ca(2+) current (ICa,L) in ventricular myocytes. In contrast, the ACV isoform is localized mainly in the t-tubular region where its influence on ICa,L is restricted by phosphodiesterase. We further demonstrate that the interaction between caveolin-3 with ACV and phosphodiesterase is responsible for the compartmentalization of ACV signaling., Conclusions: Our results provide new insights into the compartmentalization of the 2 AC isoforms in the regulation of ICa,L in ventricular myocytes. Because caveolae are found in most mammalian cells, the mechanism of β- adrenergic receptor and AC compartmentalization may also be important for β-adrenergic receptor signaling in other cell types.

Background: Colorectal cancer screening (CRCS) is the only type of cancer screening where both genders reduce risks by similar proportions with identical procedures. It is an important context for examining gender differences in disease-prevention, as CRCS significantly reduces mortality via early detection and prevention. In efforts to increase screening adherence, there is increasing acknowledgment that obstructive attitudes prevent CRCS uptake. Precise identification of the gender differences in obstructive attitudes is necessary to improve uptake promotion. This study randomly sampled unscreened, screening - eligible individuals in Ontario, employing semi-structured interviews to elicit key differences in attitudinal obstructions towards colorectal cancer screening with the aim of deriving informative differences useful in planning promotions of screening uptake., Methods: N = 81 participants (49 females, 32 males), 50 years and above, with no prior CRCS, were contacted via random-digit telephone dialing, and consented via phone-mail contact. Altogether, N = 4,459 calls were made to yield N = 85 participants (1.9% response rate) of which N = 4 participants did not complete interviews. All subjects were eligible for free-of-charge CRCS in Ontario, and each was classified, via standard interview by CRCS screening decision-stage. Telephone-based, semi-structured interviews (SSIs) were employed to investigate gender differences in CRCS attitudes, using questions focused on 5 attitudinal domains: 1) Screening experience at the time of interview; 2) Barriers to adherence; 3) Predictors of Adherence; 4) Pain-anxiety experiences related to CRCS; 5) Gender-specific experiences re: CRCS, addressing all three modalities accessible through Ontario's program: a) fecal occult blood testing; b) flexible sigmoidoscopy; c) colonoscopy., Results: Interview transcript analyses indicated divergent themes related to CRCS for each gender: 1) bodily intrusion, 2) perforation anxiety, and 3) embarrassment for females and; 1) avoidant procrastination with underlying fatalism, 2) unnecessary health care and 3) uncomfortable vulnerability for males. Respondents adopted similar attitudes towards fecal occult blood testing, flexible sigmoidoscopy and colonoscopy, and were comparable in decision stage across tests. Gender differences were neither closely tied to screening stage nor modality. Women had more consistent physician relationships, were more screening-knowledgeable and better able to articulate views on screening. Men reported less consistent physician relationships, were less knowledgeable and kept decision-making processes vague and emotionally distanced (i.e. at 'arm's length')., Conclusions: Marked differences were observed in obstructive CRCS attitudes per gender. Females articulated reservations about CRCS-associated distress and males suppressed negative views while ambiguously procrastinating about the task of completing screening. Future interventions could seek to reduce CRCS-related stress (females) and address the need to overcome procrastination (males).

Background: This randomized, controlled trial assessed the impact of a tailored navigation intervention versus a standard mailed intervention on colorectal cancer screening adherence and screening decision stage (SDS)., Methods: Primary care patients (n = 945) were surveyed and randomized to a Tailored Navigation Intervention (TNI) Group (n = 312), Standard Intervention (SI) Group (n = 316), or usual care CONTROL GROUP (n = 317). TNI Group participants were sent colonoscopy instructions and/or stool blood tests according to reported test preference, and received a navigation call. The SI Group was sent both colonoscopy instructions and stool blood tests. Multivariable analyses assessed intervention impact on adherence and change in SDS at 6 months., Results: The primary outcome, screening adherence (TNI Group: 38%, SI Group: 33%,, Control Group: 12%), was higher for intervention recipients than controls (P = 0.001 and P = 0.001, respectively), but the two intervention groups did not differ significantly (P = 0.201). Positive SDS change (TNI Group: +45%, SI Group: +37%, and, Control Group: +23%) was significantly greater among intervention recipients than controls (P = 0.001 and P = 0.001, respectively), and the intervention group difference approached significance (P = 0.053). Secondary analyses indicate that tailored navigation boosted preferred test use, and suggest that intervention impact on adherence and SDS was attenuated by limited access to screening options., Conclusions: Both interventions had significant, positive effects on outcomes compared with usual care. TNI versus SI impact had a modest positive impact on adherence and a pronounced effect on SDS., Impact: Mailed screening tests can boost adherence. Research is needed to determine how preference, access, and navigation affect screening outcomes.

Background: In an ongoing clinical trial, the genetic and environmental risk assessment (GERA) blood test offers subjects information about personal colorectal cancer risk through measurement of two novel low-to-moderate risk factors. We sought to examine predictors of uptake of the GERA blood test among participants randomized to the Intervention arm., Methods: Primary care patients aged 50 to 74 years eligible for colorectal cancer screening are randomized to receive a mailed stool blood test kit to complete at home (Control) or to the control condition plus an in-office blood test called GERA that includes assessment of red blood cell folate and DNA-testing for two MTHFR (methylenetetrahydrofolate reductase) single nucleotide polymorphisms (SNPs) (Intervention). For the present study, baseline survey data are examined in participants randomized to the Intervention., Results: The first 351 intervention participants (161 African American/190 white) were identified. Overall, 249 (70.9%) completed GERA testing. Predictors of GERA uptake included race (African American race, odds ratio (OR) 0.51 (0.29 to 0.87)), and being more knowledgeable about GERA and colorectal cancer screening (OR 1.09 (1.01 to 1.18)). Being married (OR 1.81 (1.09 to 3.00)) was also significant in the multivariable model., Conclusions: Participant uptake of GERA testing was high. GERA uptake varied, however, according to socio-demographic background and knowledge.

Angiogenesis plays a key role in the development and treatment response of various tumors. The signaling transductions mediated by the binding of vascular endothelial growth factor (VEGF) to its receptor KDR (kinase insert domain receptor) is the most important pathway in tumor angiogenesis. Single nucleotide polymorphisms (SNPs) in VEGF have been extensively implicated in the etiology and treatment outcome of colorectal cancer (CRC). However, no study has been reported evaluating the role of KDR SNPs in CRC prognosis. We herein assessed the association between four potentially functional KDR SNPs and tumor recurrence in a Chinese population with 408 surgically resected CRC patients. The most significant SNP was for rs10013228 located in the KDR gene promoter. Compared with the homozygous wild-type genotype, the variant-containing genotypes of this SNP were significantly associated with a reduced recurrence risk with a hazard ratio (HR) of 0.53 (95% confidence interval [CI] 0.30-0.95, P = 0.032). Moreover, a borderline significant association was noted for another promoter SNP, rs2071559, with an HR of 0.67 (95% CI 0.42-1.07, P = 0.092). In stratified analysis, the associations of both SNPs were more prominent in patients receiving chemotherapy (HR = 0.47, 95% CI 0.23-0.94, P = 0.033 for rs10013228 and HR = 0.55, 95% CI 0.32-0.95, P = 0.032 for rs2071559). Further analysis revealed a protective effect on patient recurrence by chemotherapy (HR = 0.56, 95% CI 0.32-1.01, P = 0.046), which was more evident in patients with the variant-containing genotypes of each of the two SNPs (HR = 0.09, 95% CI 0.02-0.55, P = 0.009 for rs10013228 and HR = 0.39, 95% CI 0.18-0.86, P = 0.020 for rs2071559). Collectively, our findings suggest SNPs in the KDR gene modulate CRC recurrence, especially in those receiving chemotherapy., (© 2011 Japanese Cancer Association.)

Background: Cumulative data have shown that microRNAs (miRNA) are involved in the etiology and prognosis of colorectal cancer (CRC). Genetic polymorphisms in pre-miRNA genes may influence the biogenesis and functions of their host miRNAs. However, whether these polymorphisms are associated with CRC prognosis remains unknown., Methods: We analyzed the effects of seven single-nucleotide polymorphisms (SNP) in pre-miRNA genes on the prognosis of a Chinese population with 408 CRC patients with surgically-resected adenocarcinoma., Results: Two SNPs were identified to be significantly associated with recurrence-free survival and overall survival of the patients. The most significant SNP was rs6505162 in pre-miR-423. Compared with the homozygous wild-type genotype, the variant-containing genotypes of this SNP were significantly associated with both the overall survival (HR = 2.12, 95% CI = 1.34-3.34, P = 0.001) and the recurrence-free survival (HR = 1.59, 95% CI = 1.08-2.36, P = 0.019). Another SNP, rs4919510 in pre-miR-608, was also associated with altered recurrence-free survival (HR = 0.61, 95% CI = 0.41-0.92, P = 0.017). These effects were evident only in patients receiving chemotherapy but not in those without chemotherapy. In addition, the combined analysis of the two SNPs conferred a 2.84-fold (95% CI = 1.50-5.37, P = 0.001) increased risk of recurrence and/or death. Similarly, this effect was only prominent in those receiving chemotherapy (P < 0.001) but not in those without chemotherapy (P = 0.999)., Conclusions: Our data suggest that genetic polymorphisms in pre-miRNA genes may impact CRC prognosis especially in patients receiving chemotherapy, a finding that warrants further independent validation., Impact: This is one of the first studies showing a prognostic role of pre-miRNA gene SNPs in CRC.

Background: Serum liver enzymes are frequently tested in clinics to aid disease diagnosis. Large observational studies indicated that these enzymes might predict cancer risk and mortality. However, no prospective study has reported on their relationships with the risk of HBV-related hepatocellular carcinoma (HCC)., Methodology/principal Findings: We evaluated the predictive values of four routinely tested liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and gamma-glutamyltransferase [GGT]) in HCC risk in a prospectively enrolled clinical cohort of 588 Korean American HBV patients. For all four enzymes, the baseline level as well as the average and maximum levels during the first 1 or 2 years of follow-up were analyzed using multivariate Cox proportional hazards model. Patients were categorized into a normal or an elevated group based on the clinical cut-off of each enzyme. During a median follow-up of 7.5 years, 52 patients (incidence rate, 8.8%) developed HCC. The incidence rates were higher in the elevated groups for all four enzymes. The most significant finding was for GGT, with the highest incidence rate of 16.4% in the elevated group compared to 4.6% in the normal group (P<0.001). Compared to patients with normal baseline GGT, those with elevated GGT exhibited a significantly increased HCC risk with a hazards ratio (HR) of 2.60 (95% confidence interval [CI], 1.41-4.77, P = 0.002). Further analyses revealed a cumulative effect between baseline GGT and ALP (HR = 3.41, 95% CI 1.54-7.56, P = 0.003)., Conclusions Significance: Serum GGT might predict HCC risk in HBV patients individually or jointly with other enzymes.

Background: The VEGF-independent angiogenic signaling plays an important role in the development of colorectal cancer (CRC). However, its implication in the clinical outcome of CRC has not been reported. This study aimed to investigate the association between genetic variations in several major VEGF-independent signaling pathway genes and the overall survival of CRC patients., Methods: Seven single nucleotide polymorphisms (SNPs) in four important VEGF-independent angiogenic genes (ANGPT1, AMOT, DLL4 and ENG) were genotyped in a Chinese population with 408 CRC patients., Results: One SNP, rs1954727 in ANGPT1, was significantly associated with CRC overall survival. Compared to patients with the homozygous wild-type genotype of rs1954727, those with heterozygous and homozygous variant genotypes exhibited a favorable overall survival with a hazard ratio (HR) of 0.89 (95% confidence interval [CI] 0.55-1.43, P = 0.623), and 0.32 (95% CI 0.15-0.71, P = 0.005), respectively (P trend = 0.008). In stratified analysis, this association remained significant in patients receiving chemotherapy (P trend = 0.012), but not in those without chemotherapy. We further evaluated the effects of chemotherapy on CRC survival that was stratified by rs1954727 genotypes. We found that chemotherapy resulted in a significantly better overall survival in the CRC patients (HR = 0.44, 95% CI 0.26-0.75, P = 0.002), which was especially prominent in those patients with the heterozygous genotype of rs1954727 (HR = 0.45, 95%CI 0.22-0.92, P = 0.028)., Conclusion: Our data suggest that rs1954727 in ANGPT1 gene might be a prognostic biomarker for the overall survival of CRC patients, especially in those receiving chemotherapy, a finding that warrants validation in larger independent populations.

Other than cleavage site mutations, there is little data on specific positions within Gag that impact on HIV protease inhibitor susceptibility. We have recently shown that non-cleavage site mutations in gag, particularly within matrix protein can restore replication capacity and further reduce protease inhibitor drug susceptibility when coexpressed with a drug-resistant (mutant) protease. The matrix protein of this patient-derived virus was studied in order to identify specific changes responsible for this phenotype. Three amino acid changes in matrix (R76K, Y79F, and T81A) had an impact on replication capacity as well as drug susceptibility. Introduction of these three changes into wild-type (WT) matrix resulted in an increase in the replication capacity of the protease mutant virus to a level similar to that achieved by all the changes within the mutant matrix and part of the capsid protein. Pairs of changes to wild-type matrix led to an increased replication capacity of the protease mutant (although less than with all three changes). Having only these three changes to matrix in a wild-type virus (with wild-type protease) resulted in a 5- to 7-fold change in protease inhibitor 50% effective concentration (EC₅₀). Individual changes did not have as great an effect on replication capacity or drug susceptibility, demonstrating an interaction between these positions, also confirmed by sequence covariation analysis. Molecular modeling predicts that each of the three mutations would result in a loss of hydrogen bonds within α-helix-4 of matrix, leading to the hypothesis that more flexibility within this region or altered matrix structure would account for our findings.

Endothelin-1 (ET-1) and activation of protein kinase C (PKC) have been implicated in alterations of myocyte function in cardiac hypertrophy and heart failure. Changes in cellular Ca2+ handling and electrophysiological properties also occur in these states and may contribute to mechanical dysfunction and arrhythmias. While ET-1 or PKC stimulation induces cellular hypertrophy in cultured neonatal rat ventricular myocytes (NRVMs), a system widely used in studies of hypertrophic signaling, there is little data about electrophysiological changes. Here we studied the effects of ET-1 (100 nM) or the PKC activator phorbol 12-myristate 13-acetate (PMA, 1 μM) on ionic currents in NRVMs. The acute effects of PMA or ET-1 (≤30 min) were small or insignificant. However, PMA or ET-1 exposure for 48-72 h increased cell capacitance by 100 or 25%, respectively, indicating cellular hypertrophy. ET-1 also slightly increased Ca2+ current density (T and L type). Na+/Ca2+ exchange current was increased by chronic pretreatment with either PMA or ET-1. In contrast, transient outward and delayed rectifier K+ currents were strongly downregulated by PMA or ET-1 pretreatment. Inward rectifier K+ current tended toward a decrease at larger negative potential, but time-independent outward K+ current was unaltered by either treatment. The enhanced inward and reduced outward currents also result in action potential prolongation after PMA or ET-1 pretreatment. We conclude that chronic PMA or ET-1 exposure in cultured NRVMs causes altered functional expression of cardiac ion currents, which mimic electrophysiological changes seen in whole animal and human hypertrophy and heart failure.

Objective: To obtain data that could be used to optimize the content and design of the targeted, mailed invitations that Ontario's provincewide colorectal cancer (CRC) screening program plans to use to increase screening uptake; to identify other strategies to increase CRC screening uptake; and to describe the effects of this qualitative work on a subsequent quantitative pilot study., Design: Qualitative study using semistructured focus groups., Setting: Four different Ontario communities., Participants: Six focus groups comprising a total of 62 participants., Methods: Six focus groups were conducted in 4 different Ontario communities. For 3 of the communities, participants were recruited from the general population by a private marketing firm, using random-digit dialing, and received a small honorarium for participating. In Sault Ste Marie, participants were convenience samples recruited from a large primary care practice and were not offered compensation. Responses were elicited regarding various strategies for promoting CRC screening. Findings represent all responses observed as well as recommendations to program planners based on focus groups observations., Main Findings: Key themes identified included the importance of receiving a CRC screening invitation from one's family physician; a desire for personalized, brief communications; and a preference for succinct information in mailed materials. Strong support was indicated for direct mailing of the CRC screening kit (fecal occult blood test). Our findings substantially influenced the final design and content of the envelope and letter to be mailed in the subsequent quantitative pilot study., Conclusion: We report strong support from our focus groups for a succinct, personalized invitation for CRC screening from one's own family physician. We have also shown that qualitative evaluation can be used to provide decision makers with pertinent and timely knowledge. Our study is highly relevant to other public health programs, particularly other Canadian jurisdictions planning organized CRC screening programs.

The relationship between obesity and cancer screening varies by screening test, race, and gender. Most studies on cervical cancer screening found a negative association between increasing weight and screening, and this negative association was most consistent in white women. Recent literature on mammography reports no association with weight. However, some studies show a negative association in white, but not black, women. In contrast, obese/overweight men reported higher rates of prostate-specific antigen (PSA) testing. Comparison of prostate cancer screening, mammography, and Pap smears implies a gender difference in the relationship between screening behavior and weight. In colorectal cancer (CRC) screening, the relationship between weight and screening in men is inconsistent, while there is a trend towards lower CRC screening in higher weight women.

Background. The literature on colorectal cancer (CRC) screening is contradictory regarding the impact of weight status on CRC screening. This study was intended to determine if CRC screening rates among 2005 National Health Interview Survey (NHIS) respondent racial/ethnic and gender subgroups were influenced by weight status. Methods. Univariable and multivariable logistic regression analyses were performed to determine if CRC screening use differed significantly among obese, overweight, and normal-weight individuals in race/ethnic and gender subgroups. Results. Multivariable analyses showed that CRC screening rates did not differ significantly for individuals within these subgroups who were obese or overweight as compared to their normal-weight peers. Conclusion. Weight status does not contribute to disparities in CRC screening in race/ethnicity and gender subgroups.

Purpose: Screening for fecal occult blood reduces colorectal cancer mortality by identifying patients with positive results for complete diagnostic evaluation (CDE). CDE rates are suboptimal, however. We sought to determine common reasons for nonperformance of a CDE as recorded by the primary care physician., Methods: We undertook a descriptive analysis of reasons reported by physicians for nonperformance of CDE in a nested sample of patients with positive fecal occult blood test (FOBT) results from a randomized controlled trial designed to evaluate the impact of a physician intervention (CDE reminder-feedback and educational outreach) on recommendation and performance rates in primary care practices. Inspection of administrative data for 1,468 patients with positive results showed that 661 (45%) did not undergo CDE. We reviewed patient follow-up forms, which were completed by physicians for patients who did not have a CDE, to identify reasons for nonperformance., Results: Nonperformance of CDE was due to physician decision for 217 patients (33%). In 123 patients (19%), reasons for nonperformance were compatible with the guidelines, and in 94 patients (14%), they were not. Reasons wholly or partially due to factors other than physician decision were noted in 212 patients (32%); physician action was considered to be appropriate in these patients. For the 232 patients (35%) without a clearly documented reason for CDE nonperformance, the appropriateness of the physicians' action could not be determined., Conclusions: Decision making by primary care physicians had a major effect on nonperformance of CDE after a positive FOBT result. Colorectal cancer screening programs should include guidance for physicians about when a CDE should and should not be performed.

Human immunodeficiency virus type 1 (HIV-1) integrase inhibitors are in clinical trials, and raltegravir and elvitegravir are likely to be the first licensed drugs of this novel class of HIV antivirals. Understanding resistance to these inhibitors is important to maximize their efficacy. It has been shown that natural variation and covariation provide valuable insights into the development of resistance for established HIV inhibitors. Therefore, we have undertaken a study to fully characterize natural polymorphisms and amino acid covariation within an inhibitor-naïve sequence set spanning all defined HIV-1 subtypes. Inter- and intrasubtype variation was greatest in a 50-amino-acid segment of HIV-1 integrase incorporating the catalytic aspartic acid codon 116, suggesting that polymorphisms affect inhibitor binding and pathways to resistance. The critical mutations that determine the resistance pathways to raltegravir and elvitegravir (N155H, Q148K/R/H, and E92Q) were either rare or absent from the 1,165-sequence data set. However, 25 out of 41 mutations associated with integrase inhibitor resistance were present. These mutations were not subtype associated and were more prevalent in the subtypes that had been sampled frequently within the database. A novel modification of the Jaccard index was used to analyze amino acid covariation within HIV-1 integrase. A network of 10 covarying resistance-associated mutations was elucidated, along with a further 15 previously undescribed mutations that covaried with at least two of the resistance positions. The validation of covariation as a predictive tool will be dependent on monitoring the evolution of HIV-1 integrase under drug selection pressure.