Physical Activity Among Utah Cancer Survivors: Analysis From a Population-Based Statewide Survey.

BACKGROUND: Regular physical activity improves cancer survivors' health-related quality of life and physical function. We estimated the proportion of Utah cancer survivors meeting U.S. Department of Health and Human Services guidelines for weekly physical activity (aerobic plus strength exercise) and identify sociodemographic, cancer, and health-related factors associated with meeting guidelines. METHODS: Survivors randomly sampled from Utah Cancer Registry records were surveyed from 2018 to 2022 to ascertain physical activity. We calculated the percent of survivors meeting guidelines and conducted logistic regression to assess predictors of meeting guidelines. Analyses were weighted to account for complex survey sample design and nonresponse and age adjusted. RESULTS: Among Utah cancer survivors, 20.7% (95% CI, 18.5%-23.2%) met guidelines for both aerobic activity and strength exercise. 22.4% reported no aerobic exercise in a typical week, and 59.4% reported no strength exercise. Survivors 75 or older were less likely to meet physical activity guidelines than those under 55 (adjusted odds ratio: 0.40; 95% CI, 0.25-0.65). Survivors with a bachelor's degree or higher were more likely to meet physical activity guidelines than those without a college degree. Individuals with poorer overall health were less likely to report sufficient physical activity. Individuals treated with both chemotherapy and radiation had decreased odds of meeting guidelines compared to no treatment (adjusted odds ratio: 0.54; 95% CI, 0.29-0.99). CONCLUSIONS: Most Utah cancer survivors, and particularly those who received multiple modes of adjuvant treatment, are not participating in sufficient physical activity to improve longevity and quality of life after cancer.

Material financial hardship and insurance-related experiences among Utah's rural and urban cancer survivors.

PURPOSE: Describe material financial hardship (e.g., using savings, credit card debt), insurance, and access to care experienced by Utah cancer survivors; investigate urban-rural differences in financial hardship. METHODS: Cancer survivors were surveyed from 2018 to 2021 about their experiences with financial hardship, access to healthcare, and job lock (insurance preventing employment changes). Weighed percentage responses, univariable and multivariable logistic regression models for these outcomes compared differences in survivors living in rural and urban areas based on Rural-Urban Commuting Area Codes. RESULTS: The N = 1793 participants were predominantly Non-Hispanic White, female, and 65 or older at time of survey. More urban than rural survivors had a college degree (39.8% vs. 31.0%, p = 0.04). Overall, 35% of survivors experienced ≥ 1 financial hardship. In adjusted analyses, no differences were observed between urban and rural survivors for: material financial hardship, the overall amount of hardship reported, insurance status at survey, access to healthcare, or job lock. Hispanic rural survivors were less likely to report financial hardship than Hispanic urban survivors (odds ratio (OR) = 0.24, 95%CI = 0.08-0.73)). Rural survivors who received chemo/immune therapy as their only treatment were more likely to report at least one instance of financial hardship than urban survivors (OR = 2.72, 95%CI = 1.08-6.86). CONCLUSIONS: The relationship between rurality and financial hardship among survivors may be most burdensome for patients whose treatments require travel or specialty medication access. IMPLICATIONS FOR CANCER SURVIVORS: The impact of living rurally on financial difficulties after cancer diagnoses is complex. Features of rurality that may alter financial difficulty after a cancer diagnosis may vary geographically and instead of considering rurality as a stand-alone factor, these features should be investigated independently.

Accuracy of patient race and ethnicity data in a central cancer registry.

PURPOSE: Race and Hispanic ethnicity data can be challenging for central cancer registries to collect. We evaluated the accuracy of the race and Hispanic ethnicity variables collected by the Utah Cancer Registry compared to self-report. METHODS: Participants were 3,162 cancer survivors who completed questionnaires administered in 2015-2022 by the Utah Cancer Registry. Each survey included separate questions collecting race and Hispanic ethnicity, respectively. Registry-collected race and Hispanic ethnicity were compared to self-reported values for the same individuals. We calculated sensitivity and specificity for each race category and Hispanic ethnicity separately. RESULTS: Survey participants included 323 (10.2%) survivors identifying as Hispanic, a lower proportion Hispanic than the 12.1% in the registry Hispanic variable (sensitivity 88.2%, specificity 96.5%). For race, 43 participants (1.4%) self-identified as American Indian or Alaska Native (AIAN), 32 (1.0%) as Asian, 23 (0.7%) as Black or African American, 16 (0.5%) Pacific Islander (PI), and 2994 (94.7%) as White. The registry race variable classified a smaller proportion of survivors as members of each of these race groups except White. Sensitivity for classification of race as AIAN was 9.3%, Asian 40.6%, Black 60.9%, PI 25.0%, and specificity for each of these groups was > 99%. Sensitivity and specificity for White were 98.8% and 47.4%. CONCLUSION: Cancer registry race and Hispanic ethnicity data often did not match the individual's self-identification. Of particular concern is the high proportion of AIAN individuals whose race is misclassified. Continued attention should be directed to the accurate capture of race and ethnicity data by hospitals.

Cancer survivorship experiences in Utah: an evaluation assessing indicators of survivors' quality of life, health behaviors, and access to health services.

PURPOSE: The 2016-2020 Utah Comprehensive Cancer Prevention and Control Plan prioritized strategies to address cancer survivorship experiences. In this paper we present estimates for nine indicators evaluating these priorities, trends over time, and assess disparities in survivorship experiences across demographic subgroups. METHODS: We surveyed a representative sample of Utah cancer survivors diagnosed between 2012 and 2019 with any reportable cancer diagnosis. We calculated weighted percentages and 95% confidence intervals (CI) for each indicator. We assessed change over time using a test for trend across survey years in a logistic regression model and used Rao-Scott F-adjusted chi-square tests to test the association between demographic characteristics and each survivorship indicator. RESULTS: Most of the 1,793 respondents (93.5%) reported their pain was under control, 85.7% rated their overall health as good, very good, or excellent, but 46.5% experienced physical, mental, or emotional limitations. Only 1.7% of survivors aged 75 or older were current smokers, compared to 5.8% of 65-74-year-olds and 7.9% of survivors aged 55-74 (p < 0.006). No regular physical activity was reported by 20.6% and varied by survivor age and education level. The proportion who received a survivorship care plan increased from 34.6% in 2018 to 43.0% in 2021 (p = 0.025). However, survivors under age 55 were significantly less likely to receive a care plan than older survivors. CONCLUSION: This representative survey of cancer survivors fills a gap in understanding of the cancer survivorship experience in Utah. Results can be used to evaluate and plan additional interventions to improve survivorship quality of life.

Cancer survivors' financial hardship and their caregivers' employment: results from a statewide survey.

PURPOSE: Many caregivers take paid and/or unpaid time off work, change from full-time to part-time, or leave the workforce. We hypothesized that cancer survivor-reported material hardship (e.g., loans, bankruptcy), behavioral hardship (e.g., skipping care/medication due to cost), and job lock (i.e., staying at a job for fear of losing insurance) would be associated with caregiver employment changes. METHODS: Adult cancer survivors (N = 627) were surveyed through the Utah Cancer Registry in 2018-2019, and reported whether their caregiver had changed employment because of their cancer (yes, no). Material hardship was measured by 9 items which we categorized by the number of instances reported (0, 1-2, and ≥ 3). Two items represented both behavioral hardship (not seeing doctor/did not take medication because of cost) and survivor/spouse job lock. Odds ratios (OR) were estimated using survey-weighted logistic regression to examine the association of caregiver employment changes with material and behavioral hardship and job lock, adjusting for cancer and sociodemographic factors. RESULTS: There were 183 (29.2%) survivors reporting their caregiver had an employment change. Survivors with ≥ 3 material hardships (OR = 3.13, 95%CI 1.68-5.83), who skipped doctor appointments (OR = 2.88, 95%CI 1.42-5.83), and reported job lock (OR = 2.05, 95%CI 1.24-3.39) and spousal job lock (OR = 2.19, 95%CI 1.17-4.11) had higher odds of caregiver employment changes than those without these hardships. CONCLUSIONS: Caregiver employment changes that occur because of a cancer diagnosis are indicative of financial hardship. IMPLICATIONS FOR CANCER SURVIVORS: Engaging community and hospital support for maintenance of stable caregiver employment and insurance coverage during cancer may lessen survivors' financial hardship.

Adherence to Guideline-Recommended cancer screening among Utah cancer survivors.

BACKGROUND: Adherence to cancer screening is important for cancer survivors because they are at high risk of subsequent cancer diagnoses or recurrence. We assessed adherence to breast, cervical, and colorectal cancer-(CRC)-screening guidelines and evaluated demographic disparities among a population-based sample of survivors. METHODS: A representative sample of Utah survivors diagnosed from 2012-2018 with any reportable invasive cancer was selected from central cancer registry records for a survey about survivorship needs. We estimated the proportion of eligible survivors adhering to U.S. Preventive Services Task Force screening guidelines and calculated risk ratios and 95% confidence intervals. Analyses were age-adjusted and weighted to account for sample design and nonresponse. RESULTS: And 1421 survivors completed the survey (57.2% response rate). Screening adherence was 74.4% for breast, 69.4% for cervical, and 79.7% for CRC. Rural residents were more likely to adhere to breast cancer screening than urban residents (86.1% vs. 72.7%; adjusted RR = 1.19, CI = 1.05, 1.36). Higher educational attainment was associated with increased adherence to cervical and colorectal cancer screening. Younger age was associated with greater adherence to cervical cancer screening (p = 0.006) but lower adherence to CRC screening (p = 0.003). CRC screening adherence was lower among the uninsured and those without a primary care provider (45.6%) compared to those with a regular provider (83.0%; adjusted RR = 0.57, CI = 0.42, 0.79). CONCLUSIONS: Surveys based on samples from central cancer registries can provide population estimates to inform cancer control. Findings demonstrate work is needed to ensure all Utah cancer survivors obtain recommended cancer screenings. Efforts should focus particularly on increasing uptake of breast and cervical cancer screening and reducing demographic disparities in CRC screening. PRECIS: Despite high risk for subsequent cancer diagnosis, Utah cancer survivors are not all obtaining recommended breast, cervical, and colorectal cancer screenings. This presents a significant healthcare gap.

The feasibility of web surveys for obtaining patient-reported outcomes from cancer survivors: a randomized experiment comparing survey modes and brochure enclosures.

BACKGROUND: Central cancer registries are often used to survey population-based samples of cancer survivors. These surveys are typically administered via paper or telephone. In most populations, web surveys obtain much lower response rates than paper surveys. This study assessed the feasibility of web surveys for collecting patient-reported outcomes via a central cancer registry. METHODS: Potential participants were sampled from Utah Cancer Registry records. Sample members were randomly assigned to receive a web or paper survey, and then randomized to either receive or not receive an informative brochure describing the cancer registry. We calculated adjusted risk ratios with 95% confidence intervals to compare response likelihood and the demographic profile of respondents across study arms. RESULTS: The web survey response rate (43.2%) was lower than the paper survey (50.4%), but this difference was not statistically significant (adjusted risk ratio = 0.88, 95% confidence interval = 0.72, 1.07). The brochure also did not significantly influence the proportion responding (adjusted risk ratio = 1.03, 95% confidence interval = 0.85, 1.25). There were few differences in the demographic profiles of respondents across the survey modes. Older age increased likelihood of response to a paper questionnaire but not a web questionnaire. CONCLUSIONS: Web surveys of cancer survivors are feasible without significantly influencing response rates, but providing a paper response option may be advisable particularly when surveying older individuals. Further examination of the varying effects of brochure enclosures across different survey modes is warranted.

Population prevalence of individuals meeting criteria for hereditary breast and ovarian cancer testing.

BACKGROUND: Personal cancer diagnosis and family cancer history factor into which individuals should undergo genetic testing for hereditary breast and ovarian cancer (HBOC) syndrome. Family history is often determined in the research setting through kindreds with disease clusters, or clinically from self-report. The population prevalence of individuals with diagnostic characteristics and/or family cancer history meeting criteria for HBOC testing is unknown. METHODS: Utilizing Surveillance, Epidemiology, and End Results (SEER) cancer registry data and a research resource linking registry records to genealogies, the Utah Population Database, the population-based prevalence of diagnostic and family history characteristics meeting National Comprehensive Cancer Network (NCCN) criteria for HBOC testing was objectively assessed. RESULTS: Among Utah residents with an incident breast cancer diagnosis 2010-2015 and evaluable for family history, 21.6% met criteria for testing based on diagnostic characteristics, but the proportion increased to 62.9% when family history was evaluated. The proportion of cases meeting testing criteria at diagnosis was 94% for ovarian cancer, 23% for prostate cancer, and 51.1% for pancreatic cancer. Among an unaffected Utah population of approximately 1.7 million evaluable for family history, 197,601 or 11.6% met testing criteria based on family history. CONCLUSIONS: This study quantifies the population-based prevalence of HBOC criteria using objectively determined genealogy and cancer incidence data. Sporadic breast cancer likely represents a portion of the high prevalence of family cancer history seen in this study. These results underline the importance of establishing presence of a deleterious mutation in an affected family member, per NCCN guidelines, before testing unaffected relatives.

Predictors of Response Outcomes for Research Recruitment Through a Central Cancer Registry: Evidence From 17 Recruitment Efforts for Population-Based Studies.

When recruiting research participants through central cancer registries, high response fractions help ensure population-based representation. We conducted multivariable mixed-effects logistic regression to identify case and study characteristics associated with making contact with and obtaining cooperation of Utah cancer cases using data from 17 unique recruitment efforts undertaken by the Utah Cancer Registry (2007-2016) on behalf of the following studies: A Population-Based Childhood Cancer Survivors Cohort Study in Utah, Comparative Effectiveness Analysis of Surgery and Radiation for Prostate Cancer (CEASAR Study), Costs and Benefits of Follow-up Care for Adolescent and Young Adult Cancers, Study of Exome Sequencing for Head and Neck Cancer Susceptibility Genes, Genetic Epidemiology of Chronic Lymphocytic Leukemia, Impact of Remote Familial Colorectal Cancer Risk Assessment and Counseling (Family CARE Project), Massively Parallel Sequencing for Familial Colon Cancer Genes, Medullary Thyroid Carcinoma (MTC) Surveillance Study, Osteosarcoma Surveillance Study, Prostate Cancer Outcomes Study, Risk Education and Assessment for Cancer Heredity Project (REACH Project), Study of Shared Genomic Segment Analysis and Tumor Subtyping in High-Risk Breast-Cancer Gene Pedigrees, Study of Shared Genomic Segment Analysis for Localizing Multiple Myeloma Genes. Characteristics associated with lower odds of contact included Hispanic ethnicity (odds ratio (OR) = 0.34, 95% confidence interval (CI): 0.27, 0.41), nonwhite race (OR = 0.46, 95% CI: 0.35, 0.60), and younger age at contact. Years since diagnosis was inversely associated with making contact. Nonwhite race and age ≥60 years had lower odds of cooperation. Study features with lower odds of cooperation included longitudinal design (OR = 0.50, 95% CI: 0.41, 0.61) and study brochures (OR = 0.70, 95% CI: 0.54, 0.90). Increased odds of cooperation were associated with including a questionnaire (OR = 3.19, 95% CI: 1.54, 6.59), postage stamps (OR = 1.60, 95% CI: 1.21, 2.12), and incentives (OR = 1.62, 95% CI: 1.02, 2.57). Among cases not responding after the first contact, odds of eventual response were lower when >10 days elapsed before subsequent contact (OR = 0.71, 95% CI: 0.59, 0.85). Obtaining high response is challenging, but study features identified in this analysis support better results when recruiting through central cancer registries.

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials.

DESNT: A Poor Prognosis Category of Human Prostate Cancer.

BACKGROUND: A critical problem in the clinical management of prostate cancer is that it is highly heterogeneous. Accurate prediction of individual cancer behaviour is therefore not achievable at the time of diagnosis leading to substantial overtreatment. It remains an enigma that, in contrast to breast cancer, unsupervised analyses of global expression profiles have not currently defined robust categories of prostate cancer with distinct clinical outcomes. OBJECTIVE: To devise a novel classification framework for human prostate cancer based on unsupervised mathematical approaches. DESIGN, SETTING, AND PARTICIPANTS: Our analyses are based on the hypothesis that previous attempts to classify prostate cancer have been unsuccessful because individual samples of prostate cancer frequently have heterogeneous compositions. To address this issue, we applied an unsupervised Bayesian procedure called Latent Process Decomposition to four independent prostate cancer transcriptome datasets obtained using samples from prostatectomy patients and containing between 78 and 182 participants. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical failure was assessed using log-rank analysis and Cox regression analysis. RESULTS AND LIMITATIONS: Application of Latent Process Decomposition identified a common process in all four independent datasets examined. Cancers assigned to this process (designated DESNT cancers) are characterized by low expression of a core set of 45 genes, many encoding proteins involved in the cytoskeleton machinery, ion transport, and cell adhesion. For the three datasets with linked prostate-specific antigen failure data following prostatectomy, patients with DESNT cancer exhibited poor outcome relative to other patients (p=2.65×10-5, p=4.28×10-5, and p=2.98×10-8). When these three datasets were combined the independent predictive value of DESNT membership was p=1.61×10-7 compared with p=1.00×10-5 for Gleason sum. A limitation of the study is that only prediction of prostate-specific antigen failure was examined. CONCLUSIONS: Our results demonstrate the existence of a novel poor prognosis category of human prostate cancer and will assist in the targeting of therapy, helping avoid treatment-associated morbidity in men with indolent disease. PATIENT SUMMARY: Prostate cancer, unlike breast cancer, does not have a robust classification framework. We propose that this failure has occurred because prostate cancer samples selected for analysis frequently have heterozygous compositions (individual samples are made up of many different parts that each have different characteristics). Applying a mathematical approach that can overcome this problem we identify a novel poor prognosis category of human prostate cancer called DESNT.

Determination of stable reference genes for RT-qPCR expression data in mechanistic pain studies on pig dorsal root ganglia and spinal cord.

RNA expression levels for genes of interest must be normalised with appropriate reference or "housekeeping" genes that are stably expressed across samples and treatments. This study determined the most stable reference genes from a panel of 6 porcine candidate genes: beta actin (ACTB), beta-2-microglobulin (B2M), eukaryotic elongation factor 1 gamma-like protein (eEF-1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), succinate dehydrogenase complex subunit A (SDHA), Ubiquitin C (UBC) in sacral dorsal root ganglia and spinal cord samples collected from 16 tail docked pigs (2/3rds of tail amputated) 1, 4, 8 and 16weeks after tail injury (4 pigs/time point). Total RNA from pooled samples was measured by SYBRgreen real-time quantitative PCR. Cycle threshold values were analysed using geNorm, BestKeeper and NormFinder PCR analysis software. Average expression stability and pairwise variation values were calculated for each candidate reference gene. GeNorm analysis identified the most stable genes for normalisation of gene expression data to be GAPDH>eEF-1>UBC>B2M>ACTB>SDHA for dorsal root ganglia and ACTB>SDHA>UBC>B2M>GAPDH>eEF-1 for spinal cord samples. Expression stability estimates were verified by BestKeeper and NormFinder analysis. Expression stability varied between genes within and between tissues. Validation of most stably expressed reference genes was performed by normalisation of calcitonin gene related polypeptide beta (CALCB). The results show similar patterns of CALCB expression when the best reference genes selected by all three programs were used. GAPDH, eEF-1 and UBC are suitable reference genes for porcine dorsal root ganglia samples, whereas ACTB, SDHA and UBC are more appropriate for spinal cord samples.

Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data.

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses.

Characterization of short- and long-term mechanical sensitisation following surgical tail amputation in pigs.

Commercial pigs are frequently exposed to tail mutilations in the form of preventive husbandry procedures (tail docking) or as a result of abnormal behaviour (tail biting). Although tissue and nerve injuries are well-described causes of pain hypersensitivity in humans and in rodent animal models, there is no information on the changes in local pain sensitivity induced by tail injuries in pigs. To determine the temporal profile of sensitisation, pigs were exposed to surgical tail resections and mechanical nociceptive thresholds (MNT) were measured in the acute (one week post-operatively) and in the long-term (either eight or sixteen weeks post-surgery) phase of recovery. The influence of the degree of amputation on MNTs was also evaluated by comparing three different tail-resection treatments (intact, 'short tail', 'long tail'). A significant reduction in MNTs one week following surgery suggests the occurrence of acute sensitisation. Long-term hypersensitivity was also observed in tail-resected pigs at either two or four months following surgery. Tail amputation in pigs appears to evoke acute and sustained changes in peripheral mechanical sensitivity, which resemble features of neuropathic pain reported in humans and other species and provides new information on implications for the welfare of animals subjected to this type of injury.

Netrin-1 acts as a non-canonical angiogenic factor produced by human Wharton's jelly mesenchymal stem cells (WJ-MSC).

BACKGROUND: Angiogenesis, the process in which new blood vessels are formed from preexisting ones, is highly dependent on the presence of classical angiogenic factors. Recent evidence suggests that axonal guidance proteins and their receptors can also act as angiogenic regulators. Netrin, a family of laminin-like proteins, specifically Netrin-1 and 4, act via DCC/Neogenin-1 and UNC5 class of receptors to promote or inhibit angiogenesis, depending on the physiological context. METHODS: Mesenchymal stem cells secrete a broad set of classical angiogenic factors. However, little is known about the expression of non-canonical angiogenic factors such as Netrin-1. The aim was to characterize the possible secretion of Netrin ligands by Wharton's jelly-derived mesenchymal stem cells (WJ-MSC). We evaluated if Netrin-1 presence in the conditioned media from these cells was capable of inducing angiogenesis both in vitro and in vivo, using human umbilical vein endothelial cells (HUVEC) and chicken chorioallantoic membrane (CAM), respectively. In addition, we investigated if the RhoA/ROCK pathway is responsible for the integration of Netrin signaling to control vessel formation. RESULTS: The paracrine angiogenic effect of the WJ-MSC-conditioned media is mediated at least in part by Netrin-1 given that pharmacological blockage of Netrin-1 in WJ-MSC resulted in diminished angiogenesis on HUVEC. When HUVEC were stimulated with exogenous Netrin-1 assayed at physiological concentrations (10-200 ng/mL), endothelial vascular migration occurred in a concentration-dependent manner. In line with our determination of Netrin-1 present in WJ-MSC-conditioned media we were able to obtain endothelial tubule formation even in the pg/mL range. Through CAM assays we validated that WJ-MSC-secreted Netrin-1 promotes an increased angiogenesis in vivo. Netrin-1, secreted by WJ-MSC, might mediate its angiogenic effect through specific cell surface receptors on the endothelium, such as UNC5b and/or integrin α6ß1, expressed in HUVEC. However, the angiogenic response of Netrin-1 seems not to be mediated through the RhoA/ROCK pathway. CONCLUSIONS: Thus, here we show that stromal production of Netrin-1 is a critical component of the vascular regulatory machinery. This signaling event may have deep implications in the modulation of several processes related to a number of diseases where angiogenesis plays a key role in vascular homeostasis.

Assessment of listing and categorisation of animal diseases within the framework of the Animal Health Law (Regulation (EU) No 2016/429): enzootic bovine leukosis (EBL).

Enzootic bovine leucosis (EBL) has been assessed according to the criteria of the Animal Health Law (AHL), in particular criteria of Article 7 on disease profile and impacts, Article 5 on the eligibility of EBL to be listed, Article 9 for the categorisation of EBL according to disease prevention and control rules as in Annex IV and Article 8 on the list of animal species related to EBL. The assessment has been performed following a methodology composed of information collection and compilation, expert judgement on each criterion at individual and, if no consensus was reached before, also at collective level. The output is composed of the categorical answer, and for the questions where no consensus was reached, the different supporting views are reported. Details on the methodology used for this assessment are explained in a separate opinion. According to the assessment performed, it is inconclusive whether EBL can be considered eligible to be listed for Union intervention as laid down in Article 5(3) of the AHL because there was no full consensus on the criteria 5 B(i) and 5 B(iii). Consequently, since it is inconclusive whether EBL can be considered eligible to be listed for Union intervention as laid down in Article 5(3) of the AHL, then the assessment on compliance of EBL with the criteria as in Sections 4 and 5 of Annex IV to the AHL, for the application of the disease prevention and control rules referred to in points (d) and (e) of Article 9(1), and which animal species can be considered to be listed for EBL according to Article 8(3) of the AHL is also inconclusive.

Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status.

Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (P < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusion-negative (OR = 0.53, P = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR = 1.30, P = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa.

Economic Evaluation Alongside a Clinical Trial of Telephone Versus In-Person Genetic Counseling for BRCA1/2 Mutations in Geographically Underserved Areas.

PURPOSE: BRCA1/2 counseling and mutation testing is recommended for high-risk women, but geographic barriers exist, and no data on the costs and yields of diverse delivery approaches are available. METHODS: We performed an economic evaluation with a randomized clinical trial comparing telephone versus in-person counseling at 14 locations (nine geographically remote). Costs included fixed overhead, variable staff, and patient time costs; research costs were excluded. Outcomes included average per-person costs for pretest counseling; mutations detected; and overall counseling, testing, and disclosure. Sensitivity analyses were performed to assess the impact of uncertainty. RESULTS: In-person counseling was more costly per person counseled than was telephone counseling ($270 [range, $180 to $400] v $120 [range, $80 to $200], respectively). Counselors averaged 285 miles round-trip to deliver in-person counseling to the participants (three participants per session). There were no differences by arm in mutation detection rates (approximately 10%); therefore, telephone counseling was less costly per positive mutation detected than was in-person counseling ($37,160 [range, $36,080 to$38,920] v $40,330 [range, $38,010 to $43,870]). In-person counseling would only be less costly than telephone counseling if the most favorable assumptions were applied to in personc ounseling and the least favorable assumptions were applied to telephone counseling. CONCLUSION: In geographically underserved areas, telephone counseling is less costly than in-person counseling.

Efficacy of a Telehealth Intervention on Colonoscopy Uptake When Cost Is a Barrier: The Family CARE Cluster Randomized Controlled Trial.

BACKGROUND: We tested the efficacy of a remote tailored intervention Tele-Cancer Risk Assessment and Evaluation (TeleCARE) compared with a mailed educational brochure for improving colonoscopy uptake among at-risk relatives of colorectal cancer patients and examined subgroup differences based on participant reported cost barriers. METHODS: Family members of colorectal cancer patients who were not up-to-date with colonoscopy were randomly assigned as family units to TeleCARE (N = 232) or an educational brochure (N = 249). At the 9-month follow-up, a cost resource letter listing resources for free or reduced-cost colonoscopy was mailed to participants who had reported cost barriers and remained nonadherent. Rates of medically verified colonoscopy at the 15-month follow-up were compared on the basis of group assignment and within group stratification by cost barriers. RESULTS: In intent-to-treat analysis, 42.7% of participants in TeleCARE and 24.1% of participants in the educational brochure group had a medically verified colonoscopy [OR, 2.37; 95% confidence interval (CI) 1.59-3.52]. Cost was identified as a barrier in both groups (TeleCARE = 62.5%; educational brochure = 57.0%). When cost was not a barrier, the TeleCARE group was almost four times as likely as the comparison to have a colonoscopy (OR, 3.66; 95% CI, 1.85-7.24). The intervention was efficacious among those who reported cost barriers; the TeleCARE group was nearly twice as likely to have a colonoscopy (OR, 1.99; 95% CI, 1.12-3.52). CONCLUSIONS: TeleCARE increased colonoscopy regardless of cost barriers. IMPACT: Remote interventions may bolster screening colonoscopy regardless of cost barriers and be more efficacious when cost barriers are absent.