ResearchPad - cancer-risk-factors https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Risk of colorectal cancer in patients with alcoholism: A nationwide, population-based nested case-control study]]> https://www.researchpad.co/article/elastic_article_7832 Colorectal cancer (CRC) is regarded as a multifactorial disease and shares many risk factors with alcoholism. However, the association between alcoholism and CRC remains controversial.ObjectivesIn this study, we aimed to evaluate the association between alcoholism and risk of CRC.MethodsWe performed a large-scale, population-based nested case-control study using the Longitudinal Health Insurance Database 2013, derived from Taiwan’s National Health Insurance Research Database, and collected data from 2000 to 2013. There were 49,095 diagnosed cases of CRC defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification. Each case was matched with three controls by sex, age, index date of CRC, and annual medical visits; a total of 147,285 controls were identified. Multiple risk factors of CRC in alcoholism cases were investigated using unconditional multiple logistic regression analysis.ResultsAmong 49,095 cases of CRC, alcoholism was associated with a significantly higher risk of CRC (adjusted odds ratio (OR), 1.631; 95% CI, 1.565–1.699) in multivariate logistic regression, after adjusting other CRC risk factors, and in stratified analysis with multivariate logistic regression. In addition, there was a time-dependent relationship between alcoholism duration and CRC risk in >1 year, > 2 years, >5 years, and > 11 years groups (adjusted ORs, 1.875, 2.050, 2.662 and 2.670; 95% CI, 1.788–1.967, 1.948–2.158, 2.498–2.835, and 2.511–2.989 respectively).ConclusionAn association between alcoholism and risk of CRC was found in this study. Furthermore, patients with longer alcoholism history showed higher likelihood of developing CRC, which indicates a time-dependent relationship between alcoholism exposure and CRC. Further research on colorectal tumorigenesis is needed. ]]> <![CDATA[Validation of risk factors for recurrence of renal cell carcinoma: Results from a large single-institution series]]> https://www.researchpad.co/article/Ne7ebe4b8-b927-4fd1-a438-3fd04efc5df6

Purpose

To validate prognostic factors and determine the impact of obesity, hypertension, smoking and diabetes mellitus (DM) on risk of recurrence after surgery in patients with localized renal cell carcinoma (RCC).

Materials and methods

We performed a retrospective cohort study among patients that underwent partial or radical nephrectomy at Weill Cornell Medicine for RCC and collected preoperative information on RCC risk factors, as well as pathological data. Cases were reviewed for radiographic evidence of RCC recurrence. A Cox proportional-hazards model was developed to determine the contribution of RCC risk factors to recurrence risk. Disease-free survival and overall survival were analyzed using the Kaplan-Meier method and log-rank test.

Results

We identified 873 patients who underwent surgery for RCC between the years 2000–2015. In total 115 patients (13.2%) experienced a disease recurrence after a median follow up of 4.9 years. In multivariate analysis, increasing pathological T-stage (HR 1.429, 95% CI 1.265–1.614) and Nuclear grade (HR 2.376, 95% CI 1.734–3.255) were independently associated with RCC recurrence. In patients with T1-2 tumors, DM was identified as an additional independent risk factor for RCC recurrence (HR 2.744, 95% CI 1.343–5.605). Patients with DM had a significantly shorter median disease-free survival (1.5 years versus 2.6 years, p = 0.004), as well as median overall survival (4.1 years, versus 5.8 years, p<0.001).

Conclusions

We validated high pathological T-stage and nuclear grade as independent risk factors for RCC recurrence following nephrectomy. DM is associated with an increased risk of recurrence among patients with early stage disease.

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<![CDATA[Integrated structural variation and point mutation signatures in cancer genomes using correlated topic models]]> https://www.researchpad.co/article/5c99020ad5eed0c484b97533

Mutation signatures in cancer genomes reflect endogenous and exogenous mutational processes, offering insights into tumour etiology, features for prognostic and biologic stratification and vulnerabilities to be exploited therapeutically. We present a novel machine learning formalism for improved signature inference, based on multi-modal correlated topic models (MMCTM) which can at once infer signatures from both single nucleotide and structural variation counts derived from cancer genome sequencing data. We exemplify the utility of our approach on two hormone driven, DNA repair deficient cancers: breast and ovary (n = 755 samples total). We show how introducing correlated structure both within and between modes of mutation can increase accuracy of signature discovery, particularly in the context of sparse data. Our study emphasizes the importance of integrating multiple mutation modes for signature discovery and patient stratification, and provides a statistical modeling framework to incorporate additional features of interest for future studies.

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<![CDATA[Tailored NEOadjuvant epirubicin, cyclophosphamide and Nanoparticle Albumin-Bound paclitaxel for breast cancer: The phase II NEONAB trial—Clinical outcomes and molecular determinants of response]]> https://www.researchpad.co/article/5c6f152dd5eed0c48467ae8b

Background

This study evaluated the feasibility of achieving high response rates in stage II or III breast cancer by tailoring neoadjuvant therapy using clinical and histopathological features and the Oncotype DX Breast Recurrence Score. Genomic determinants of response and resistance were also explored.

Patients and outcome measures

Fifty-one patients were enrolled. The primary cohort comprised 40 patients: 15 human epidermal growth factor receptor type 2 (HER2)-amplified; 15 triple-negative (TNBC); and ten hormone receptor (HR)-positive, HER2-non-amplified tumours; with recurrence scores ≥25. Patients were treated with epirubicin and cyclophosphamide, followed by nab-paclitaxel, with the addition of trastuzumab if HER2-amplified. The primary endpoint was pathological complete response (pCR) in the breast. Pre- and post-treatment tumour samples underwent variant burden, gene and gene pathway, mutational signature profile and clonal evolution analyses.

Results

The pCR rates were: overall 55% (n = 22), HER2-amplified 80% (n = 12), triple-negative 46% (n = 7) and HR-positive, HER2-non-amplified 30% (n = 3). Grade 3 or 4 adverse events included febrile neutropenia (8%), neutropenia (18%), sensory neuropathy (5%), deranged transaminases (5%), fatigue (2%), diarrhoea (2%), and pneumothorax (2%). Molecular analyses demonstrated strong similarities between residual disease and matched primary tumour. ATM signalling pathway alterations and the presence of a COSMIC Signature 3 implied the majority of tumours contained some form of homologous repair deficiency. ATM pathway alterations were identified in the subset of TNBC patients who did not achieve pCR; Signature 3 was present in both pCR and non-pCR subgroups. Clonal evolution analyses demonstrated both persistence and emergence of chemoresistant clones.

Conclusions

This treatment regime resulted in a high rate of pCR, demonstrating that tailored neoadjuvant therapy using a genomic recurrence score is feasible and warrants further investigation. Molecular analysis revealed few commonalities between patients. For TNBC future clinical gains will require precision medicine, potentially using DNA sequencing to identify specific targets for individuals with resistant disease.

Trial registration

Clinicaltrials.gov NCT01830244

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<![CDATA[Alcohol and breast cancer risk: Middle-aged women’s logic and recommendations for reducing consumption in Australia]]> https://www.researchpad.co/article/5c6dca15d5eed0c48452a756

Background

We aimed to understand the factors shaping alcohol consumption patterns in middle-aged women (45–64), and to identify participant-driven population- and policy-level strategies that may be used to addresses alcohol consumption and reduce breast cancer risk.

Methods

Semi-structured interviews (n = 35) were conducted with ‘middle-aged’ women conversant in English and living in South Australia with no history of breast cancer diagnosis. Data were deductively coded using a co-developed framework including variables relevant to our study objectives. Women were asked about their current level of awareness of the association between alcohol and breast cancer risk, and their personal recommendations for how to decrease consumption in middle-aged Australian women.

Results

Women discussed their previous efforts to decrease consumption, which we drew on to identify preliminary recommendations for consumption reduction. We identified a low level of awareness of alcohol and breast cancer risk, and confusion related to alcohol as a risk for breast cancer, but not always causing breast cancer. Participants suggested that education and awareness, through various means, may help to reduce consumption.

Conclusions

Participants’ description of strategies used to reduce their own consumption lead us to suggest that campaigns might focus on the more salient and immediate effects of alcohol (e.g. on physical appearance and mental health) rather than longer-term consequences. Critical considerations for messaging include addressing the personal, physical and social pleasures that alcohol provides, and how these may differ across socio-demographics.

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<![CDATA[The dynamic association between Frailty, CD4 and CD4/CD8 ratio in people aging with HIV]]> https://www.researchpad.co/article/5c6f1532d5eed0c48467aeb2

Objective

To investigate the association between current CD4+ T-cell count and CD4/CD8+ ratio with severity of frailty among people aging with HIV.

Methods

Cross-sectional observational study analysing data from all study visits in the ongoing prospective Modena HIV Metabolic Clinic Cohort between 2006 and 2015. Frailty severity was assessed using a frailty index (FI). We visualized the relationships between frailty index score and current CD4 cell count and CD4/CD8 ratio on two different curves adjusted for age, sex, and duration of HIV infection.

Results

Frailty index scores exhibited an inverse relationship with current CD4 count, up to 900 cells/μL. The CD4/CD8 ratio was inversely correlated with frailty index both below and above the cut-off of 900 CD4 cells/μL.

Conclusions

Frailty in PLWH is inversely associated with both immune-activation, depicted by CD4/CD8 ratio and immune-deficit depicted by CD4 count. The first association shows a linear shape while the second shows a hook-shape with a turning point at 900 cells. Above this cut off level CD4 do not represent a significant risk factor for frailty.

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<![CDATA[Belief about the future possibility of national aging security system and its association with mortality]]> https://www.researchpad.co/article/5c6f1530d5eed0c48467aea4

In line with well-known subjective measures of health, such as self-rated health and subjective life expectancy, an individual’s belief about future security provided by the government could also be an important factor affecting his life expectancy. The aim of this study was to use the response of the elderly Korean population in regards to the National Aging Security System (NASS), and assess its association with the risk of mortality even with SRH included in the analysis. Data from the Korean Longitudinal Study of Ageing (KLoSA) from 2006 to 2016 were assessed using longitudinal data analysis and 10,254 research subjects were included at baseline in 2006. To analyze the association between belief about future possibility of NASS and all-cause mortality, Cox proportional hazards model was used. In terms of the future possibility of NASS, people who thought more negatively displayed greater risk of mortality at the end of the follow-up. With the Positive group as reference: Moderate group showed a 18% increase (HR = 1.178, 95% CI: 1.022, 1.357), and Negative groups showed a 19% increase (HR = 1.192, 95% CI: 1.043, 1.362). The results of our study showed that people’s belief regarding future security could be associated with mortality rates. Our finding is important, because it provides additional support to the importance of considering subjective measures of health in epidemiological research. Furthermore, the findings of our research could be useful in terms of future policy making.

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<![CDATA[Trend and projection of mortality rate due to non-communicable diseases in Iran: A modeling study]]> https://www.researchpad.co/article/5c6f1529d5eed0c48467ae6e

Background

Following the epidemiologic and demographic transition, non-communicable disease mortality is the leading cause of death in Iran. Projecting mortality trend can provide valuable tools for policy makers and planners. In this article, we have estimated the trend of non-communicable disease mortality during 2001–2015 and have projected it until 2030 at national and subnational levels in Iran.

Methods

The data employed was gathered from the Iranian death registration system and using the Spatio-temporal model, the trends of 4 major categories of non-communicable diseases (cancers, cardiovascular diseases, asthma and COPD, and diabetes) by 2030 were projected at the national and subnational levels.

Results

The results indicated that age standardized mortality rate for cancers, CVDs, and Asthma and COPD will continue to decrease in both sexes (cancers: from 81.8 in 2015 to 45.2 in 2030, CVDs: 307.3 to 173.0, and Asthma and COPD: from 52.1 to 46.6); however, in terms of diabetes, there is a steady trend in both sexes at national level (from 16.6 to 16.5). Age standardized mortality rates for cancers and CVDs, in males and females, were high in all provinces in 2001. The variation between the provinces is clearer in 2015, and it is expected to significantly decrease in all provinces by 2030.

Conclusion

Generally, the age standardized mortality rate from NCDs will decrease by 2030. Of course, given the experience of the past two decades in Iran, believing that the mortality rate will decrease may not be an easy notion to understand. However hard to believe, this decrease may be the result of better management of risk factors and early detection of patients due to more comprehensive care in all segments of society, as well as improved literacy and awareness across the country.

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<![CDATA[Convergent perturbation of the human domain-resolved interactome by viruses and mutations inducing similar disease phenotypes]]> https://www.researchpad.co/article/5c6dc9afd5eed0c484529ff0

An important goal of systems medicine is to study disease in the context of genetic and environmental perturbations to the human interactome network. For diseases with both genetic and infectious contributors, a key postulate is that similar perturbations of the human interactome by either disease mutations or pathogens can have similar disease consequences. This postulate has so far only been tested for a few viral species at the level of whole proteins. Here, we expand the scope of viral species examined, and test this postulate more rigorously at the higher resolution of protein domains. Focusing on diseases with both genetic and viral contributors, we found significant convergent perturbation of the human domain-resolved interactome by endogenous genetic mutations and exogenous viral proteins inducing similar disease phenotypes. Pan-cancer, pan-oncovirus analysis further revealed that domains of human oncoproteins either physically targeted or structurally mimicked by oncoviruses are enriched for cancer driver rather than passenger mutations, suggesting convergent targeting of cancer driver pathways by diverse oncoviruses. Our study provides a framework for high-resolution, network-based comparison of various disease factors, both genetic and environmental, in terms of their impacts on the human interactome.

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<![CDATA[Preliminary results of identification and quantification of paclitaxel and its metabolites in human meconium from newborns with gestational chemotherapeutic exposure]]> https://www.researchpad.co/article/5c76fe5dd5eed0c484e5b96b

Objective

Cancer diagnosis during pregnancy occurs in 1 out of 1000 pregnancies with common malignancies including breast and hematological cancers. Fetal exposure to currently utilized agents is poorly described. We directly assessed fetal exposure by screening meconium from 23 newborns whose mothers had undergone treatment for cancer during pregnancy.

Study design

Meconium was collected from newborns whose mothers were diagnosed with cancer during pregnancy and underwent chemotherapy in the second or third trimester as part of the Cancer and Pregnancy Registry. We conducted screening of 23 meconium samples for chemotherapeutics and known metabolites of chemotherapeutics by liquid chromatography-high resolution mass spectrometry (LC-HRMS). Putative identification of paclitaxel and/or its metabolites was made in 8 screened samples. In positively screened samples, we quantified paclitaxel, 3’-p-hydroxypaclitaxel, and 6α-hydroxypaclitaxel by stable isotope dilution-LC-HRMS.

Results

Mean (standard deviation) levels of paclitaxel in positively screened samples were 399.9 (248.6) pg/mg in meconium samples from newborn born to mothers that underwent chemotherapy during pregnancy. 3’-p-hydroxypaclitaxel and 6α-hydroxypaclitaxel mean levels were 105.2 (54.6) and 113.4 (48.9) pg/mg meconium, respectively.

Conclusion

Intact paclitaxel, 3’-p-hydroxypaclitaxel, and 6α-hydroxypaclitaxel were detected in meconium, providing unambiguous confirmation of human fetal exposure. Variability in meconium levels between individuals may indicate a potential for reducing fetal exposure based on timing, dosing, and individual characteristics. This preliminary study may provide an approach for examining the effects of cancer diagnosis during pregnancy on other outcomes by providing a measure of direct fetal exposure.

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<![CDATA[Aberrant FAM64A mRNA expression is an independent predictor of poor survival in pancreatic cancer]]> https://www.researchpad.co/article/5c59ff04d5eed0c484135981

FAM64A, a marker of cell proliferation, has been investigated as a potential biomarker in several cancers. In the present study, we examined the value of FAM64A expression in the diagnosis and prognosis of pancreatic cancer through bioinformatics analysis of data obtained from The Cancer Genome Atlas (TCGA) database. The diagnostic value of FAM64A expression in pancreatic cancer tissue was deteremined through receiver operating characteristic (ROC) curve analysis, and based on the obtained cut-off value, patients were divided into two groups (high FAM64A expression and low FAM64A expression). Chi-square and Fisher exact tests were applied to identify associations between FAM64A expression and clinical features. Moreover, the effect of FAM64A expression in the survival of pancreatic cancer patients was observed by Kaplan-Meier and Cox analyses. Gene set enrichment analysis (GSEA) was performed using the TCGA dataset. Our results showed that high FAM64A expression in pancreatic cancer was associated with survival status, overall survival (OS), and recurrence. The area under the ROC curve was 0.736, which indicated modest diagnostic value. Patients with higher FAM64A expression had significantly shorter OS and recurrence-free survival (RFS) times. Multivariate survival analysis demonstrated that high FAM64A expression was an independent risk factor for OS and RFS. GSEA identified mitotic spindles, myc targets, MTORC1 signaling, G2M checkpoint, E2F targets, DNA repair, glycolysis and unfolded protein response as differentially enriched with the high FAM64A expression phenotype. In conclusion, high FAM64A mRNA expression is an independent risk factor for poor prognosis in pancreatic cancer.

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<![CDATA[BAP1 expression is prognostic in breast and uveal melanoma but not colon cancer and is highly positively correlated with RBM15B and USP19]]> https://www.researchpad.co/article/5c61e8c4d5eed0c48496f124

BAP1 is a tumor suppressor gene important to the development and prognosis of many cancers, especially uveal melanoma (UM). Its role in more common cancers such as breast and colon cancer is largely unknown. We collected the transcriptome profiling data sets from the TCGA uveal melanoma (TCGA-UVM), breast cancer (TCGA-BRCA), and colon cancer (TCGA-COAD) projects to analyze the expression of BAP1. We found that patients with UM and breast cancer, but not colon cancer, who died had a lower level of BAP1 gene expression compared to surviving patients. Importantly, in breast cancer patients, the lowest BAP1 expression levels corresponded to the dead young patients (age at diagnosis < 46). Since the number of cases in TCGA-BRCA was much higher than TCGA-UVM, we obtained highly correlated genes with BAP1 in invasive breast carcinomas. Then, we tested if these genes are also highly correlated with BAP1 in UM and colon cancer. We found that BAP1 is highly positively correlated with RBM15B and USP19 expression in invasive breast carcinoma, UM, and colon adenocarcinoma. All three genes are located in close proximity on the 3p21 tumor suppressor region that is commonly altered in many cancers.

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<![CDATA[Lifetime risk and multimorbidity of non-communicable diseases and disease-free life expectancy in the general population: A population-based cohort study]]> https://www.researchpad.co/article/5c61e938d5eed0c48496fa00

Background

Non-communicable diseases (NCDs) are leading causes of premature disability and death worldwide. However, the lifetime risk of developing any NCD is unknown, as are the effects of shared common risk factors on this risk.

Methods and findings

Between July 6, 1989, and January 1, 2012, we followed participants from the prospective Rotterdam Study aged 45 years and older who were free from NCDs at baseline for incident stroke, heart disease, diabetes, chronic respiratory disease, cancer, and neurodegenerative disease. We quantified occurrence/co-occurrence and remaining lifetime risk of any NCD in a competing risk framework. We additionally studied the lifetime risk of any NCD, age at onset, and overall life expectancy for strata of 3 shared risk factors at baseline: smoking, hypertension, and overweight. During 75,354 person-years of follow-up from a total of 9,061 participants (mean age 63.9 years, 60.1% women), 814 participants were diagnosed with stroke, 1,571 with heart disease, 625 with diabetes, 1,004 with chronic respiratory disease, 1,538 with cancer, and 1,065 with neurodegenerative disease. NCDs tended to co-occur substantially, with 1,563 participants (33.7% of those who developed any NCD) diagnosed with multiple diseases during follow-up. The lifetime risk of any NCD from the age of 45 years onwards was 94.0% (95% CI 92.9%–95.1%) for men and 92.8% (95% CI 91.8%–93.8%) for women. These risks remained high (>90.0%) even for those without the 3 risk factors of smoking, hypertension, and overweight. Absence of smoking, hypertension, and overweight was associated with a 9.0-year delay (95% CI 6.3–11.6) in the age at onset of any NCD. Furthermore, the overall life expectancy for participants without these risk factors was 6.0 years (95% CI 5.2–6.8) longer than for those with all 3 risk factors. Participants aged 45 years and older without the 3 risk factors of smoking, hypertension, and overweight at baseline spent 21.6% of their remaining lifetime with 1 or more NCDs, compared to 31.8% of their remaining life for participants with all of these risk factors at baseline. This difference corresponds to a 2-year compression of morbidity of NCDs. Limitations of this study include potential residual confounding, unmeasured changes in risk factor profiles during follow-up, and potentially limited generalisability to different healthcare settings and populations not of European descent.

Conclusions

Our study suggests that in this western European community, 9 out of 10 individuals aged 45 years and older develop an NCD during their remaining lifetime. Among those individuals who develop an NCD, at least a third are subsequently diagnosed with multiple NCDs. Absence of 3 common shared risk factors is associated with compression of morbidity of NCDs. These findings underscore the importance of avoidance of these common shared risk factors to reduce the premature morbidity and mortality attributable to NCDs.

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<![CDATA[Risk factors for Luminal A ductal carcinoma in situ (DCIS) and invasive breast cancer in the Carolina Breast Cancer Study]]> https://www.researchpad.co/article/5c57e67ed5eed0c484ef3431

Purpose

Invasive breast cancers are thought to arise from in situ lesions, but some ductal carcinoma in situ (DCIS) are indolent with low likelihood of progressing to invasive carcinoma. Comparison of risk factor associations between DCIS and invasive disease may elucidate which factors influence early versus late stages of carcinogenesis. Therefore, we determined whether there were differences in risk factor profiles for screen-detected DCIS and invasive breast cancer among Luminal A lesions.

Methods

We conducted a case-control analysis using data from the Carolina Breast Cancer Study (1993–2001). Analyses were restricted to Luminal A tumors and screen-detected tumors among mammography-eligible women, to limit confounding by mode of detection (N = 108 DCIS; N = 203 invasive). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between risk factors and lesion type.

Results

In stratified analyses, we observed qualitative differences in the direction of association for ever smoking, obese BMI, high waist-to-hip-ratio (WHR), and ≥10 years of oral contraceptive use between DCIS and invasive disease. Breastfeeding was inversely associated with invasive disease and was not associated with DCIS. Interaction tests for risk factor associations between Luminal A DCIS and invasive breast cancer were not statistically significant (p>0.05).

Conclusions

Among Luminal A tumors, established breast cancer risk factors may exert stronger effects on progression of early lesions to invasive disease, with lesser effects on risk of DCIS.

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<![CDATA[Lifelong aerobic exercise protects against inflammaging and cancer]]> https://www.researchpad.co/article/5c57e679d5eed0c484ef3350

Biological aging is associated with progressive damage accumulation, loss of organ reserves, and systemic inflammation ('inflammaging'), which predispose for a wide spectrum of chronic diseases, including several types of cancer. In contrast, aerobic exercise training (AET) reduces inflammation, lowers all-cause mortality, and enhances both health and lifespan. In this study, we examined the benefits of early-onset, lifelong AET on predictors of health, inflammation, and cancer incidence in a naturally aging mouse model (C57BL/J6). Lifelong, voluntary wheel-running (O-AET; 26-month-old) prevented age-related declines in aerobic fitness and motor coordination vs. age-matched, sedentary controls (O-SED). AET also provided partial protection against sarcopenia, dynapenia, testicular atrophy, and overall organ pathology, hence augmenting the ‘physiologic reserve’ of lifelong runners. Systemic inflammation, as evidenced by a chronic elevation in 17 of 18 pro- and anti-inflammatory cytokines and chemokines (P < 0.05 O-SED vs. 2-month-old Y-CON), was potently mitigated by lifelong AET (P < 0.05 O-AET vs. O-SED), including master regulators of the cytokine cascade and cancer progression (IL-1β, TNF-α, and IL-6). In addition, circulating SPARC, previously known to be upregulated in metabolic disease, was elevated in old, sedentary mice, but was normalized to young control levels in lifelong runners. Remarkably, malignant tumours were also completely absent in the O-AET group, whereas they were present in the brain (pituitary), liver, spleen, and intestines of sedentary mice. Collectively, our results indicate that early-onset, lifelong running dampens inflammaging, protects against multiple cancer types, and extends healthspan of naturally-aged mice.

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<![CDATA[Iron levels, genes involved in iron metabolism and antioxidative processes and lung cancer incidence]]> https://www.researchpad.co/article/5c466574d5eed0c48451942c

Background

Lung cancer is the most common adult malignancy accounting for the largest proportion of cancer related deaths. Iron (Fe) is an essential trace element and is a component of several major metabolic pathways playing an important role in many physiological processes. In this study we evaluated the association between Fe concentration in serum, iron metabolism parameters and genetic variaton in 7 genes involved in iron metabolism and anti-oxidative processes with the incidence of lung cancer in Poland.

Materials and methods

The study included 200 lung cancer patients and 200 matched healthy control subjects. We analyzed serum iron concentration and iron metabolism parameters (TIBC, UIBC, serum ferritin and transferrin saturation), and genotyped seven variants in seven genes: HFE, TFR1, HAMP, TF, SOD2, CAT and GPX1.

Results

Lung cancer patients compared to their matched controls had significantly higher mean serum iron level (p = 0.01), ferritin level (p = 0.007) and TIBC (p = 0.006). Analysis revealed that higher concentration of iron and ferritin (IVth quartile) compared to the lower concentration (Ist quartile) was associated with over 2-fold increased lung cancer incidence. We also found that higher transferrin saturation (p = 0.01) and lower TIBC (p<0.01) are associated with better survival of lung cancer patients. The analysis of polymorphisms in iron related genes did not reveal a significant difference between lung cancer patients and controls. However, rs10421768 in HAMP showed a borderline statistically significant correlation with lung cancer risk (OR = 2.83, p = 0.05).

Conclusions

The results of this case control study indicate that higher body iron represented by higher Fe and ferritin levels may be associated with lung cancer incidence. Rs10421768 in HAMP may be associated with about 3-times higher lung cancer risk. Higher Fe body content may be associated with better survival of lung cancer patients.

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<![CDATA[BRCA Challenge: BRCA Exchange as a global resource for variants in BRCA1 and BRCA2]]> https://www.researchpad.co/article/5c2d2eb3d5eed0c484d9b2c0

The BRCA Challenge is a long-term data-sharing project initiated within the Global Alliance for Genomics and Health (GA4GH) to aggregate BRCA1 and BRCA2 data to support highly collaborative research activities. Its goal is to generate an informed and current understanding of the impact of genetic variation on cancer risk across the iconic cancer predisposition genes, BRCA1 and BRCA2. Initially, reported variants in BRCA1 and BRCA2 available from public databases were integrated into a single, newly created site, www.brcaexchange.org. The purpose of the BRCA Exchange is to provide the community with a reliable and easily accessible record of variants interpreted for a high-penetrance phenotype. More than 20,000 variants have been aggregated, three times the number found in the next-largest public database at the project’s outset, of which approximately 7,250 have expert classifications. The data set is based on shared information from existing clinical databases—Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database (LOVD)—as well as population databases, all linked to a single point of access. The BRCA Challenge has brought together the existing international Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium expert panel, along with expert clinicians, diagnosticians, researchers, and database providers, all with a common goal of advancing our understanding of BRCA1 and BRCA2 variation. Ongoing work includes direct contact with national centers with access to BRCA1 and BRCA2 diagnostic data to encourage data sharing, development of methods suitable for extraction of genetic variation at the level of individual laboratory reports, and engagement with participant communities to enable a more comprehensive understanding of the clinical significance of genetic variation in BRCA1 and BRCA2.

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<![CDATA[The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study]]> https://www.researchpad.co/article/5c37b789d5eed0c48449037f

Background

Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.

Methods and findings

Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.

Conclusions

This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

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<![CDATA[Penalized negative binomial models for modeling an overdispersed count outcome with a high-dimensional predictor space: Application predicting micronuclei frequency]]> https://www.researchpad.co/article/5c3e4f13d5eed0c484d714a0

Chromosomal aberrations, such as micronuclei (MN), have served as biomarkers of genotoxic exposure and cancer risk. Guidelines for the process of scoring MN have been presented by the HUman MicroNucleus (HUMN) project. However, these guidelines were developed for assay performance but do not address how to statistically analyze the data generated by the assay. This has led to the application of various statistical methods that may render different interpretations and conclusions. By combining MN with data from other high-throughput genomic technologies such as gene expression microarray data, we may elucidate molecular features involved in micronucleation. Traditional methods that can model discrete (synonymously, count) data, such as MN frequency, require that the number of explanatory variables (P) is less than the number of samples (N). Due to this limitation, penalized models have been developed to enable model fitting for such over-parameterized datasets. Because penalized models in the discrete response setting are lacking, particularly when the count outcome is over-dispersed, herein we present our penalized negative binomial regression model that can be fit when P > N. Using simulation studies we demonstrate the performance of our method in comparison to commonly used penalized Poisson models when the outcome is over-dispersed and applied it to MN frequency and gene expression data collected as part of the Norwegian Mother and Child Cohort Study. Our countgmifs R package is available for download from the Comprehensive R Archive Network and can be applied to datasets having a discrete outcome that is either Poisson or negative binomial distributed and a high-dimensional covariate space.

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<![CDATA[Assessing the prognostic factors, survival, and recurrence incidence of triple negative breast cancer patients, a single center study in Iran]]> https://www.researchpad.co/article/5c390bd8d5eed0c48491ea0e

Background

Breast cancer is the second leading cause of death due to cancer in women. Triple negative breast cancer (TNBC) is a subgroup with unique behavior. There is a controversy in organ involvement in metastasis. In this study, we planned to define the prognostic factors, survival, and recurrence incidence of patients.

Materials and method

Among the 583 patients with breast mass referred to hematology and oncology clinic in Shariati hospital, Tehran, Iran from March 2005 to March 2015, fifty four patients entered the survival analysis whom we followed for two years until March 2017. Overall survival (OS) and disease-free survival (DFS) and Cumulative recurrence incidences (RI) were estimated. Univariate and multivariate Cox proportional hazards regression was performed to assess risk factors in predicting OS and DFS.

Results

Median follow up for the patients was 5.00 years. The five-year OS, DFS and RI were 86.13% (95% CI (71.42–93.59), 63.09% (95% CI (47.04–75.49) and 32.15% (95% CI (19.52–47.43) respectively. Among the factors studied OS, DFS and RI differed significantly only between patients with and without nodal involvement (P = 0.004, P = 0.003, and P = 0.02 respectively). On the other hand, based on the univariate modeling, patients with nodal involvement had a higher risk of breast cancer-specific death (HR: 17.99, P = 0.004). Furthermore, patients with nodal involvement had a higher risk of breast cancer-specific death or recurrence (HR = 5.64, P = 0.008). In Multivariate model, just the nodal involvement significantly changed the hazard for OS (HR = 23.91, P = 0.001). As the nodal involvement was the only significant risk factor at the 0.2 level of significance, we can consider the hazard ratio of lymph node positivity in DFS univariate models as adjusted hazard.

Conclusion

The only factor with significant effect on OS, DFS and RI was nodal involvement in the pathology report.

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