Cigarette smoking and prostate cancer aggressiveness among African and European American men.

PURPOSE: Smoking is a modifiable lifestyle factor that has not been established as a prostate cancer risk factor, nor emphasized in prostate cancer prevention. Studies have shown that African American (AA) smokers have a poorer cancer prognosis than European Americans (EAs), while having a lower prevalence of heavy smoking. We examined the relationship between cigarette smoking and prostate cancer aggressiveness and assessed racial differences in smoking habits on the probability of high-aggressive prostate cancer. METHODS: Using data from the North Carolina-Louisiana Prostate Cancer Project (n = 1,279), prostate cancer aggressiveness was defined as high or low based on Gleason scores, serum prostate-specific antigen levels, and tumor stage. Cigarette smoking was categorized as current, former, or never smokers. Multivariable logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Self-reported current (OR = 1.99; 95% CI 1.30-3.06) smoking was associated with high-aggressive prostate cancer relative to never smokers. When stratified by self-reported race, the odds of having high-aggressive cancer increased among AA current (OR = 3.58; 95% CI 2.04-6.28) and former smokers (OR = 2.21; 95% CI 1.38-3.53) compared to AA never smokers, but the odds were diminished among the EA stratum (Pself-reported race x smoking status = 0.003). CONCLUSION: Cigarette smoking is associated with prostate cancer aggressiveness, a relationship modulated by self-reported race. Future research is needed to investigate types of cigarettes smoked and metabolic differences that may be contributing to the racial disparities observed.

Stem Cell Theory of Cancer: Clinical Implications for Cellular Metabolism and Anti-Cancer Metabolomics.

Although Otto Warburg may be right about the role of glycolysis versus OXPHOS in cancer metabolism, it remains unclear whether an altered metabolism is causative or correlative and is the main driver or a mere passenger in the pathogenesis of cancer. Currently, most of our successful treatments are designed to eliminate non-cancer stem cells (non-CSCs) such as differentiated cancer cells. When the treatments also happen to control CSCs or the stem-ness niche, it is often unintended, unexpected, or undetected for lack of a pertinent theory about the origin of cancer that clarifies whether cancer is a metabolic, genetic, or stem cell disease. Perhaps cellular context matters. After all, metabolic activity may be different in different cell types and their respective microenvironments-whether it is in a normal progenitor stem cell vs. progeny differentiated cell and whether it is in a malignant CSC vs. non-CSC. In this perspective, we re-examine different types of cellular metabolism, e.g., glycolytic vs. mitochondrial, of glucose, glutamine, arginine, and fatty acids in CSCs and non-CSCs. We revisit the Warburg effect, an obesity epidemic, the aspartame story, and a ketogenic diet. We propose that a pertinent scientific theory about the origin of cancer and of cancer metabolism influences the direction of cancer research as well as the design of drug versus therapy development in cancer care.

Current Practices in LC-MS Untargeted Metabolomics: A Scoping Review on the Use of Pooled Quality Control Samples.

Untargeted metabolomics is an analytical approach with numerous applications serving as an effective metabolic phenotyping platform to characterize small molecules within a biological system. Data quality can be challenging to evaluate and demonstrate in metabolomics experiments. This has driven the use of pooled quality control (QC) samples for monitoring and, if necessary, correcting for analytical variance introduced during sample preparation and data acquisition stages. Described herein is a scoping literature review detailing the use of pooled QC samples in published untargeted liquid chromatography-mass spectrometry (LC-MS) based metabolomics studies. A literature query was performed, the list of papers was filtered, and suitable articles were randomly sampled. In total, 109 papers were each reviewed by at least five reviewers, answering predefined questions surrounding the use of pooled quality control samples. The results of the review indicate that use of pooled QC samples has been relatively widely adopted by the metabolomics community and that it is used at a similar frequency across biological taxa and sample types in both small- and large-scale studies. However, while many studies generated and analyzed pooled QC samples, relatively few reported the use of pooled QC samples to improve data quality. This demonstrates a clear opportunity for the field to more frequently utilize pooled QC samples for quality reporting, feature filtering, analytical drift correction, and metabolite annotation. Additionally, our survey approach enabled us to assess the ambiguity in the reporting of the methods used to describe the generation and use of pooled QC samples. This analysis indicates that many details of the QC framework are missing or unclear, limiting the reader's ability to determine which QC steps have been taken. Collectively, these results capture the current state of pooled QC sample usage and highlight existing strengths and deficiencies as they are applied in untargeted LC-MS metabolomics.

Increased Utilization of Low-Dose CT for Lung Cancer Screening at an Arkansas Community Oncology Clinic.

BACKGROUND: Low-dose CT (LDCT) is underused in Arkansas for lung cancer screening, a rural state with a high incidence of lung cancer. The objective was to determine whether offering free LDCT increased the number of high-risk individuals screened in a rural catchment area. METHODS: There were 5,402 patients enrolled in screening at Highlands Oncology, a community oncology clinic in Northwest Arkansas, from 2013 to 2020. Screenings were separated into time periods: period 1 (10 months for-fee), period 2 (10 months free with targeted advertisements and primary care outreach), and period 3 (62 months free with only primary care outreach). In all, 5,035 high-risk participants were eligible for analysis based on National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Enrollment rates, incidence densities (IDs), Cox proportional hazard models, and Kaplan-Meier curves were performed to investigate differences between enrollment periods and high-risk groups. RESULTS: Patient volume increased drastically once screenings were offered free of charge (period 1 = 4.6 versus period 2 = 66.0 and period 3 = 69.8 average patients per month). Incidence density per 1,000 person-years increased through each period (IDPeriod 1 = 17.2; IDPeriod 2 = 20.8; IDPeriod 3 = 25.5 cases). Cox models revealed significant differences in lung cancer risk between high-risk groups (P = .012) but not enrollment periods (P = .19). Kaplan-Meier lung cancer-free probabilities differed significantly between high-risk groups (log-rank P = .00068) but not enrollment periods (log-rank P = .18). CONCLUSIONS: This study suggests that eligible patients are more receptive to free LDCT screening, despite most insurances not having a required copay for eligible patients.

Untargeted Metabolomics and Body Mass in Adolescents: A Cross-Sectional and Longitudinal Analysis.

Obesity in children and adolescents has increased globally. Increased body mass index (BMI) during adolescence carries significant long-term adverse health outcomes, including chronic diseases such as cardiovascular disease, stroke, diabetes, and cancer. Little is known about the metabolic consequences of changes in BMI in adolescents outside of typical clinical parameters. Here, we used untargeted metabolomics to assess changing BMI in male adolescents. Untargeted metabolomic profiling was performed on urine samples from 360 adolescents using UPLC-QTOF-MS. The study includes a baseline of 235 subjects in a discovery set and 125 subjects in a validation set. Of them, a follow-up of 81 subjects (1 year later) as a replication set was studied. Linear regression analysis models were used to estimate the associations of metabolic features with BMI z-score in the discovery and validation sets, after adjusting for age, race, and total energy intake (kcal) at false-discovery-rate correction (FDR) ≤ 0.1. We identified 221 and 16 significant metabolic features in the discovery and in the validation set, respectively. The metabolites associated with BMI z-score in validation sets are glycylproline, citrulline, 4-vinylsyringol, 3'-sialyllactose, estrone sulfate, carnosine, formiminoglutamic acid, 4-hydroxyproline, hydroxyprolyl-asparagine, 2-hexenoylcarnitine, L-glutamine, inosine, N-(2-Hydroxyphenyl) acetamide glucuronide, and galactosylhydroxylysine. Of those 16 features, 9 significant metabolic features were associated with a positive change in BMI in the replication set 1 year later. Histidine and arginine metabolism were the most affected metabolic pathways. Our findings suggest that obesity and its metabolic outcomes in the urine metabolome of children are linked to altered amino acids, lipid, and carbohydrate metabolism. These identified metabolites may serve as biomarkers and aid in the investigation of obesity's underlying pathological mechanisms. Whether these features are associated with the development of obesity, or a consequence of changing BMI, requires further study.

Association of DNA methylation signatures with cognitive performance among smokers and ex-smokers.

INTRODUCTION: Alterations in DNA methylation profiles have been associated with cancer, and can be influenced by environmental factors such as smoking. A small but growing literature indicates there are reproducible and robust differences in methylation levels among smokers, never smokers, and ex-smokers. Here, we compared differences in salivary DNA methylation levels among current and ex-smokers (at least 2 years abstinent). METHODS: Smokers (n=26) and ex-smokers (n=30) provided detailed smoking histories, completed the Paced Auditory Serial Addition Test (PASAT), and submitted a saliva sample. Whole-genome DNA methylation from saliva was performed, and ANCOVA models and a receiver operating characteristic (ROC) curve were used for the differences between groups and the performance of significant CpG sites. RESULTS: After controlling for race, age, and gender, smokers had significantly lower methylation levels than ex-smokers in two CpG sites: cg05575921 (AHRR) and cg21566642 (ALPPL2). Based on the ROC analyses, both CpGs had strong classification potentials (cg05575921 AUC=0.97 and cg21566642 AUC=0.93) in differentiating smoking status. Across all subjects, the percent methylation of cg05575921 (AHRR) and cg21566642 (ALPPL2) positively correlated with the length of the last quit attempt (r=0.65 and 0.64, respectively, p<0.001) and PASAT accuracy (r=0.29 and 0.30, respectively, p<0.05). CONCLUSIONS: In spite of the small sample size and preliminary research, our results replicate previously reported differences in AHRR hypomethylation among smokers. Furthermore, we show that the duration of smoking abstinence is associated with a recovery of methylation in ex-smokers, which may be linked to a reduced risk of smoking-associated diseases. The association with cognitive performance suggests that the hypomethylation of AHRR in saliva may reflect systemic exposure to cigarette-related toxicants that negatively affect cognitive performance, and should be validated in larger studies.

Biochemical validation of self-reported electronic nicotine delivery system and tobacco heaviness of use.

Research on tobacco use disorder relies on a combination of self-reported use (e.g., cigarettes per day) and biochemical validation to quantify heaviness of use. However, electronic nicotine delivery system (ENDS) users may be unaware of how much they have vaped per day. The aim of this study was to test the relationship between self-reported heaviness of ENDS/tobacco use and nicotine biomarkers. Young adults (n = 30) who currently use ENDS and other tobacco products completed a detailed tobacco use history, timeline follow-back, and an ENDS topography session. We evaluated the self-reports of own-brand ENDS use and tested correlations to determine which self-report measures of own-brand use, and which self-reported measures of puff topography, had the strongest correlations with urine and/or blood biomarkers of nicotine use. Participants reported using a variety of different ENDS devices and had a range of usage. The sum of the self-reported number of occasions or hours of ENDS use, along with the number of cigarettes and other tobacco products used, over the past 24 hr was significantly correlated with plasma cotinine levels. Puff topography measures correlated with increased nicotine concentrations, although participants underestimated the number of puffs they took during the topography session. This study provides preliminary evidence that summing together the hours of ENDS use, or the number of occasions of ENDS use, in addition to the number of other tobacco products used (i.e., cigarettes) based on self-report may be an accurate method of quantification. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Cognition, Aryl Hydrocarbon Receptor Repressor Methylation, and Abstinence Duration-Associated Multimodal Brain Networks in Smoking and Long-Term Smoking Cessation.

Cigarette smoking and smoking cessation are associated with changes in cognition and DNA methylation; however, the neurobiological correlates of these effects have not been fully elucidated, especially in long-term cessation. Cognitive performance, percent methylation of the aryl hydrocarbon receptor repressor (AHRR) gene, and abstinence duration were used as references to supervise a multimodal fusion analysis of functional, structural, and diffusion magnetic resonance imaging (MRI) data, in order to identify associated brain networks in smokers and ex-smokers. Correlations among these networks and with smoking-related measures were performed. Cognition-, methylation-, and abstinence duration-associated networks discriminated between smokers and ex-smokers and correlated with differences in fractional amplitude of low frequency fluctuations (fALFF) values, gray matter volume (GMV), and fractional anisotropy (FA) values. Long-term smoking cessation was associated with more accurate cognitive performance, as well as lower fALFF and more GMV in the hippocampus complex. The methylation- and abstinence duration-associated networks positively correlated with smoking-related measures of abstinence duration and percent methylation, respectively, suggesting they are complementary measures. This analysis revealed structural and functional co-alterations linked to smoking abstinence and cognitive performance in brain regions including the insula, frontal gyri, and lingual gyri. Furthermore, AHRR methylation, a promising epigenetic biomarker of smoking recency, may provide an important complement to self-reported abstinence duration.

Geospatial Assessment of Pesticide Concentration in Ambient Air and Colorectal Cancer Incidence in Arkansas, 2013-2017.

Exposure to various agricultural pesticides has been linked to colorectal cancer (CRC), mostly among farmworkers and applicators. Given the potential pesticide drift in ambient air, residents near farmland may be exposed to carcinogenic pesticides even if they are not actively engaged in pesticide application. Pesticide air pollution at the county level was estimated using the 2014 National Air Toxics Assessment. CRC incidence data were acquired from the Arkansas Central Cancer Registry for 2013-2017. We ran ordinary least squares (OLS) regression models, finding significant spatial autocorrelation of residuals for most models. Using geographically weighted regression (GWR) we found age-adjusted CRC incidence rates vary in an increasing west-to-east gradient, with the highest rates in the Arkansas Delta region. A similar gradient was observed in the distribution of the population living below the poverty line and the population percentage of Black people. Significant associations between Trifluralin (crude model only), Carbon Tetrachloride, and Ethylene Dibromide with CRC incidence rates in OLS models only explained 5-7% of the variation and exhibited spatial autocorrelation of residuals. GWR models explained 24-32% (adjusted r2 9-16%) of CRC incidence rate variation, suggesting additional factors may contribute to the association between pesticides and CRC.

Metabolomics Signatures and Subsequent Maternal Health among Mothers with a Congenital Heart Defect-Affected Pregnancy.

Congenital heart defects (CHDs) are the most prevalent and serious of all birth defects in the United States. However, little is known about the impact of CHD-affected pregnancies on subsequent maternal health. Thus, there is a need to characterize the metabolic alterations associated with CHD-affected pregnancies. Fifty-six plasma samples were identified from post-partum women who participated in the National Birth Defects Prevention Study between 1997 and 2011 and had (1) unaffected control offspring (n = 18), (2) offspring with tetralogy of Fallot (ToF, n = 22), or (3) hypoplastic left heart syndrome (HLHS, n = 16) in this pilot study. Absolute concentrations of 408 metabolites using the AbsoluteIDQ® p400 HR Kit (Biocrates) were evaluated among case and control mothers. Twenty-six samples were randomly selected from above as technical repeats. Analysis of covariance (ANCOVA) and logistic regression models were used to identify significant metabolites after controlling for the maternal age at delivery and body mass index. The receiver operating characteristic (ROC) curve and area-under-the-curve (AUC) are reported to evaluate the performance of significant metabolites. Overall, there were nine significant metabolites (p < 0.05) identified in HLHS case mothers and 30 significant metabolites in ToF case mothers. Statistically significant metabolites were further evaluated using ROC curve analyses with PC (34:1), two sphingolipids SM (31:1), SM (42:2), and PC-O (40:4) elevated in HLHS cases; while LPC (18:2), two triglycerides: TG (44:1), TG (46:2), and LPC (20:3) decreased in ToF; and cholesterol esters CE (22:6) were elevated among ToF case mothers. The metabolites identified in the study may have profound structural and functional implications involved in cellular signaling and suggest the need for postpartum dietary supplementation among women who gave birth to CHD offspring.

Genome-Wide DNA Methylation Signatures Predict the Early Asymptomatic Doxorubicin-Induced Cardiotoxicity in Breast Cancer.

Chemotherapy with doxorubicin (DOX) may cause unpredictable cardiotoxicity. This study aimed to determine whether the methylation signature of peripheral blood mononuclear cells (PBMCs) prior to and after the first cycle of DOX-based chemotherapy could predict the risk of cardiotoxicity in breast cancer patients. Cardiotoxicity was defined as a decrease in left ventricular ejection fraction (LVEF) by >10%. DNA methylation of PBMCs from 9 patients with abnormal LVEF and 10 patients with normal LVEF were examined using Infinium HumanMethylation450 BeadChip. We have identified 14,883 differentially methylated CpGs at baseline and 18,718 CpGs after the first cycle of chemotherapy, which significantly correlated with LVEF status. Significant differentially methylated regions (DMRs) were found in the promoter and the gene body of SLFN12, IRF6 and RNF39 in patients with abnormal LVEF. The pathway analysis found enrichment for regulation of transcription, mRNA splicing, pathways in cancer and ErbB2/4 signaling. The preliminary results from this study showed that the DNA methylation profile of PBMCs may predict the risk of DOX-induced cardiotoxicity prior to chemotherapy. Further studies with larger cohorts of patients are needed to confirm these findings.

Association between pesticide exposure and colorectal cancer risk and incidence: A systematic review.

BACKGROUND: Studies investigating the association between pesticide exposure and colorectal cancer (CRC) risk have been inconclusive. OBJECTIVES: Investigate the association between pesticide exposure and CRC risk through a systematic literature review. METHODS: CRC has the fourth-highest rate of cancer-caused death in the US after lung cancer, breast cancer in women, and prostate cancer in men. Here we have conducted a systematic literature search on studies examining the association between any pesticide exposure and CRC risk using PubMed, MEDLINE via EBSCO host, and Embase according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. RESULTS: Following the review, 139 articles were included for qualitative evaluation. Study participants were farmers, pesticide applicators, pesticide manufacturers, spouses of pesticide applicators, farm residents, Korean veterans of the Vietnam War, rural communities, and those who consumed food with pesticide residues. The studies' results were split between those with significant positive (39 significant results) and inverse (41 significant results) associations when comparing pesticide exposure and CRC risk. DISCUSSION: From our literature review, we have identified a similar number of significant positive and inverse associations of pesticide exposure with CRC risk and therefore cannot conclude whether pesticide exposure has a positive or inverse association with CRC risk overall. However, certain pesticides such as terbufos, dicamba, trifluralin, S-ethyl dipropylthiocarbamate (EPTC), imazethapyr, chlorpyrifos, carbaryl, pendimethalin, and acetochlor are of great concern not only for their associated elevated risk of CRC, but also for the current legal usage in the United States (US). Aldicarb and dieldrin are of moderate concern for the positive associations with CRC risk, and also for the illegal usage or the detection on imported food products even though they have been banned in the US. Pesticides can linger in the soil, water, and air for weeks to years and, therefore, can lead to exposure to farmers, manufacturing workers, and those living in rural communities near these farms and factories. Approximately 60 million people in the US live in rural areas and all of the CRC mortality hotspots are within the rural communities. The CRC mortality rate is still increasing in the rural regions despite the overall decreasing of incidence and mortality of CRC elsewhere. Therefore, the results from this study on the relationship between pesticide exposure and CRC risk will help us to understand CRC health disparities.

Biomarkers of inflammation, hypercoagulability and endothelial injury predict early asymptomatic doxorubicin-induced cardiotoxicity in breast cancer patients.

Doxorubicin (DOX)-induced cardiotoxicity is a major limitation to its clinical application. Cardiotoxicity of DOX is dose-dependent that begins with the first dose. Oxidative stress and inflammation are involved in DOX-related cardiotoxicity. This study aimed to determine whether multiple markers of inflammation, hypercoagulability and endothelial injury correlate with the risk of early DOX-induced cardiotoxicity in breast cancer patients. Blood samples of 51 breast cancer patients treated with DOX-based chemotherapy were collected before (baseline) and after the first cycle of chemotherapy. The risk of cardiotoxicity was defined as an asymptomatic reduction of cardiac left ventricle ejection fraction (LVEF) >10% at completion of chemotherapy versus baseline. Plasma samples were examined for multiple biomarkers of inflammation, hypercoagulability and endothelial dysfunction, including C-reactive protein (CRP), thrombomodulin (TM), thrombin-antithrombin complex (TAT), myeloperoxidase (MPO), von Willebrand factor (vWF) and P-selectin. Surrogate markers of neutrophil extracellular traps (NETs) nucleosomes and double stranded DNA (dsDNA) were also measured. Patients with abnormal decline of LVEF >10% (n=21) had significantly elevated levels of MPO and TM both at baseline, and after the first dose of DOX-based chemotherapy relative to patients with normal LVEF (n=30) after adjusting for race, age, BMI and type of breast cancer. The first dose of DOX also induced significantly higher circulating levels of TAT complex and nucleosomes in patients at risk of cardiotoxicity in comparison with patients without. The comparison between the means of the biomarkers in after-before DOX-based chemotherapy of the two groups of patients showed significant differences for MPO, TAT complex and CRP. The results from this study suggest that the risk of DOX-induced cardiotoxicity in breast cancer is associated with endothelial dysfunction, inflammation and prothrombotic state before and after the first dose of chemotherapy.

Dissemination and analysis of the quality assurance (QA) and quality control (QC) practices of LC-MS based untargeted metabolomics practitioners.

INTRODUCTION: The metabolomics quality assurance and quality control consortium (mQACC) evolved from the recognized need for a community-wide consensus on improving and systematizing quality assurance (QA) and quality control (QC) practices for untargeted metabolomics. OBJECTIVES: In this work, we sought to identify and share the common and divergent QA and QC practices amongst mQACC members and collaborators who use liquid chromatography-mass spectrometry (LC-MS) in untargeted metabolomics. METHODS: All authors voluntarily participated in this collaborative research project by providing the details of and insights into the QA and QC practices used in their laboratories. This sharing was enabled via a six-page questionnaire composed of over 120 questions and comment fields which was developed as part of this work and has proved the basis for ongoing mQACC outreach. RESULTS: For QA, many laboratories reported documenting maintenance, calibration and tuning (82%); having established data storage and archival processes (71%); depositing data in public repositories (55%); having standard operating procedures (SOPs) in place for all laboratory processes (68%) and training staff on laboratory processes (55%). For QC, universal practices included using system suitability procedures (100%) and using a robust system of identification (Metabolomics Standards Initiative level 1 identification standards) for at least some of the detected compounds. Most laboratories used QC samples (>86%); used internal standards (91%); used a designated analytical acquisition template with randomized experimental samples (91%); and manually reviewed peak integration following data acquisition (86%). A minority of laboratories included technical replicates of experimental samples in their workflows (36%). CONCLUSIONS: Although the 23 contributors were researchers with diverse and international backgrounds from academia, industry and government, they are not necessarily representative of the worldwide pool of practitioners due to the recruitment method for participants and its voluntary nature. However, both questionnaire and the findings presented here have already informed and led other data gathering efforts by mQACC at conferences and other outreach activities and will continue to evolve in order to guide discussions for recommendations of best practices within the community and to establish internationally agreed upon reporting standards. We very much welcome further feedback from readers of this article.

Association of DNA-Methylation Profiles With Immune Responses Elicited in Breast Cancer Patients Immunized With a Carbohydrate-Mimicking Peptide: A Pilot Study.

Immune response to a given antigen, particularly in cancer patients, is complex and is controlled by various genetic and environmental factors. Identifying biomarkers that can predict robust response to immunization is an urgent need in clinical cancer vaccine development. Given the involvement of DNA methylation in the development of lymphocytes, tumorigenicity and tumor progression, we aimed to analyze pre-vaccination DNA methylation profiles of peripheral blood mononuclear cells (PBMCs) from breast cancer subjects vaccinated with a novel peptide-based vaccine referred to as P10s-PADRE. This pilot study was performed to evaluate whether signatures of differentially methylated (DM) loci can be developed as potential predictive biomarkers for prescreening subjects with cancer who will most likely generate an immune response to the vaccine. Genomic DNA was isolated from PBMCs of eight vaccinated subjects, and their DNA methylation profiles were determined using Infinium® MethylationEPIC BeadChip array from Illumina. A linear regression model was applied to identify loci that were differentially methylated with respect to anti-peptide antibody titers and with IFN-γ production. The data were summarized using unsupervised-learning methods: hierarchical clustering and principal-component analysis. Pathways and networks involved were predicted by Ingenuity Pathway Analysis. We observed that the profile of DM loci separated subjects in regards to the levels of immune responses. Canonical pathways and networks related to metabolic and immunological functions were found to be involved. The data suggest that it is feasible to correlate methylation signatures in pre-treatment PBMCs with immune responses post-treatment in cancer patients going through standard-of-care chemotherapy. Larger and prospective studies that focus on DM loci in PBMCs is warranted to develop pre-screening biomarkers before BC vaccination. Clinical Trial Registration: www.ClinicalTrials.gov, Identifier: NCT02229084.

Genome-wide DNA methylation signatures to predict pathologic complete response from combined neoadjuvant chemotherapy with bevacizumab in breast cancer.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00203502.

Transcriptome analysis of Sézary syndrome and lymphocytic-variant hypereosinophilic syndrome T cells reveals common and divergent genes.

Sézary syndrome (SS) is an aggressive cutaneous T cell lymphoma with pruritic skin inflammation and immune dysfunction, driven by neoplastic, clonal memory T cells in both peripheral blood and skin. To gain insight into abnormal gene expression promoting T cell dysfunction, lymphoproliferation and transformation in SS, we first compared functional transcriptomic profiles of both resting and activated CD4+CD45RO+ T cells from SS patients and normal donors to identified differential expressed genes. Next, a meta-analysis was performed to compare our SS data to public microarray data from a novel benign disease control, lymphocytic-variant hypereosinophilic syndrome (L-HES). L-HES is a rare, clonal lymphoproliferation of abnormal memory T cells that produces similar clinical symptoms as SS, including severe pruritus and eosinophilia. Comparison revealed gene sets specific for either SS (370 genes) or L-HES (519 genes), and a subset of 163 genes that were dysregulated in both SS and L-HES T cells compared to normal donor T cells. Genes confirmed by RT-qPCR included elevated expression of PLS3, TWIST1 and TOX only in SS, while IL17RB mRNA was increased only in L-HES. CDCA7 was increased in both diseases. In an L-HES patient who progressed to peripheral T cell lymphoma, the malignant transformation identified increases in the expression of CDCA7, TIGIT, and TOX, which are highly expressed in SS, suggesting that these genes contribute to neoplastic transformation. In summary, we have identified gene expression biomarkers that implicate a common transformative mechanism and others that are unique to differentiate SS from L-HES.

Towards quality assurance and quality control in untargeted metabolomics studies.

We describe here the agreed upon first development steps and priority objectives of a community engagement effort to address current challenges in quality assurance (QA) and quality control (QC) in untargeted metabolomic studies. This has included (1) a QA and QC questionnaire responded to by the metabolomics community in 2015 which recommended education of the metabolomics community, development of appropriate standard reference materials and providing incentives for laboratories to apply QA and QC; (2) a 2-day 'Think Tank on Quality Assurance and Quality Control for Untargeted Metabolomic Studies' held at the National Cancer Institute's Shady Grove Campus and (3) establishment of the Metabolomics Quality Assurance and Quality Control Consortium (mQACC) to drive forward developments in a coordinated manner.

County poverty levels influence genome-wide DNA methylation profiles in African American and European American women.

Our pilot study examined global DNA methylation and telomere length (TL) using DNA from saliva samples provided by 39 participants in the Arkansas Rural Community Health (ARCH) Study. TL was quantified by qPCR, and DNA methylation and DNA methylation age was assessed using the Illumina 850K Epic BeadChip. Ingenuity Pathway Analysis (IPA) was performed to identify biological pathways that were DM between residents of counties with high or low poverty rates and by race [African American descent (AA) versus European American (EA) descent]. Among AA women, hypermethylation was more common in AA residents of counties with low compared to high poverty rates (70% vs. 30%). The top canonical pathways impacted by differential methylation were related to glucocorticoid receptor, p53, and estrogen-dependent breast cancer signaling in AA women. EA women living in low-poverty counties exhibited less hypermethylation of CpGs than those living in high-poverty counties (27% vs. 73%). The top canonical pathways were related to hereditary breast cancer, glucocorticoid receptor, androgen and PI3K/AKT signaling. Several genes involved in telomere maintenance were shown to be DM by county poverty levels. Therefore, the finding of this pilot study suggests county poverty levels may impact DNA methylation patterns in breast cancer-related pathways as well as genes involved in telomere maintenance. Larger studies should confirm our findings.

Metabolomic profiles of current cigarette smokers.

Smoking-related biomarkers for lung cancer and other diseases are needed to enhance early detection strategies and to provide a science base for tobacco product regulation. An untargeted metabolomics approach by ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UHPLC-Q-TOF MS) totaling 957 assays was used in a novel experimental design where 105 current smokers smoked two cigarettes 1 h apart. Blood was collected immediately before and after each cigarette allowing for within-subject replication. Dynamic changes of the metabolomic profiles from smokers' four blood samples were observed and biomarkers affected by cigarette smoking were identified. Thirty-one metabolites were definitively shown to be affected by acute effect of cigarette smoking, uniquely including menthol-glucuronide, the reduction of glutamate, oleamide, and 13 glycerophospholipids. This first time identification of a menthol metabolite in smokers' blood serves as proof-of-principle for using metabolomics to identify new tobacco-exposure biomarkers, and also provides new opportunities in studying menthol-containing tobacco products in humans. Gender and race differences also were observed. Network analysis revealed 12 molecules involved in cancer, notably inhibition of cAMP. These novel tobacco-related biomarkers provide new insights to the effects of smoking which may be important in carcinogenesis but not previously linked with tobacco-related diseases. © 2016 Wiley Periodicals, Inc.