Talking Glossary of Genomics Terminology: A Genomics Education Module for American Indian Communities

This paper describes the development of an audio visual genomics glossary that was designed as an education tool for American Indian communities. This “Talking Glossary of Genomics Terminology” is a multimedia DVD that was modeled on the “Talking Glossary of Genetics,” which was developed by the National Human Genome Research Institute (NHGRI). The NHGRI Glossary was modified and expanded with content designed to increase awareness among American Indians about cancer, genomics, and personalized medicine. Partners on the project include the Inter Tribal Council of Arizona, Inc., Phoenix Indian Medical Center, Arizona Cancer Center at the University of Arizona, the Translational Genomics Research Institute, as well as Arizona State University and University of Arizona graduate students

An Update on the Role of Ploidy in Prostate Carcinoma

One of the characteristic features of prostate carcinoma is its marked variation in biologic behavior. DNA quantitation has been studied in prostate carcinoma using a variety of techniques. Evaluation of tumor ploidy suggests that this may be the best predictor of the biologic behavior of prostate cancer in individual patients. This comprehensive review addresses the current studies, stage by stage, to clarify the clinical significance of these findings

Rv0989c encodes a novel (E)-geranyl diphosphate synthase facilitating decaprenyl diphosphate biosynthesis in Mycobacterium tuberculosis

AbstractMycobacterium tuberculosis (Mtb) has a highly complex cell wall, which is required for both bacterial survival and infection. Cell wall biosynthesis is dependent on decaprenyl diphosphate as a glyco-carrier, which is hence an essential metabolite in this pathogen. Previous biochemical studies indicated (E)-geranyl diphosphate (GPP) is required for the synthesis of decaprenyl diphosphate. Here we demonstrate that Rv0989c encodes the “missing” GPP synthase, representing the first such enzyme to be characterized from bacteria, and which presumably is involved in decaprenyl diphosphate biosynthesis in Mtb. Our investigation also has revealed previously unrecognized substrate plasticity of the farnesyl diphosphate synthases from Mtb, resolving previous discrepancies between biochemical and genetic studies of cell wall biosynthesis

Twenty year predictors of peripheral arterial disease (PAD) compared with coronary heart disease (CHD) in the Scottish Heart Health Extended Cohort (SHHEC)

Background Coronary heart disease (CHD) and peripheral arterial disease (PAD) affect different vascular territories. Supplementing baseline findings with assays from stored serum, we compared their twenty-year predictors. Methods and Results Recruited randomly across Scotland 1984-1995 and followed through 2009 for death and hospital diagnoses, of 15 737 disease-free men and women aged 30-75y, 3098 developed CHD (19.7%), and 499 PAD (3.2%). Hazard ratios (HRs) for 45 variables in the Cox model were adjusted for age and sex, and for factors in the 2007 ASSIGN cardiovascular risk score. Forty four were entered into parsimonious predictive models, tested by c-statistics and NRIs (Net Reclassification Improvements). Many HRs diminished with adjustment and parsimonious modeling, leaving significant survivors. HRs were mostly higher in PAD. New parsimonious models increased the c-statistic and NRI over ASSIGN variables alone, but varied in their components and ranking. CHD and PAD shared seven of the nine factors from ASSIGN: age, sex, family history, socioeconomic status, diabetes mellitus, tobacco smoking, and systolic blood pressure (SBP), (but not total, nor HDL-cholesterol), plus four new ones: NT-pro BNP, cotinine, hsC-Reactive Protein, and cystatin-C. Highest ranked HRs for continuous factors in CHD were: age, total cholesterol, hsTroponin, NT-pro-BNP, cotinine, apolipoprotein A, waist circumference, (…plus ten more); in PAD: age, hsCRP, SBP, expired carbon monoxide, cotinine, socioeconomic status, lipoprotein (a), (…plus five more). Conclusion The mixture of shared with disparate determinants for arterial disease in the heart and the legs implies non-identical pathogenesis–cholesterol dominant in the former–inflammation (hsCRP, diabetes, smoking) in the latter

Protection mechanisms in the resurrection plant Xerophyta viscosa (Baker): both sucrose and raffinose family oligosaccharides (RFOs) accumulate in leaves in response to water deficit

Changes in water-soluble carbohydrates were examined in the leaves of the resurrection plant Xerophyta viscosa under conditions of water deficit. Sucrose and raffinose family oligosaccharides (RFOs), particularly raffinose, increased under these conditions, with the highest concentrations evident at 5% relative water content [RWC; 23.5 mg g−1 dry weight (DW) and 17.7 mg g−1 DW, respectively]. Importantly, these effects were reversible, with concentrations returning to levels comparable with that of the full turgor state 7 d after water deficit conditions were alleviated, providing evidence that both sucrose and RFOs may play a protective role in desiccated leaf tissue of X. viscosa. Further, because the sucrose-to-raffinose mass ratio of 1.3:1 observed in the dehydrated state was very low, compared with published data for other resurrection plants (always >5), it is suggested that, in X. viscosa leaves, RFOs serve the dual purpose of stress protection and carbon storage. XvGolS, a gene encoding a galactinol synthase enzyme responsible for the first catalytic step in RFO biosynthesis, was cloned and functionally expressed. In leaf tissue exposed to water deficit, XvGolS transcript levels were shown to increase at 19% RWC. GolS activity in planta could not be correlated with RFO accumulation, but a negative correlation was observed between RFO accumulation and myo-inositol depletion, during water deficit stress. This correlation was reversed after rehydration, suggesting that during water deficit myo-inositol is channelled into RFO synthesis, but during the rehydration process it is channelled to metabolic pathways related to the repair of desiccation-induced damag

Проблема коррупции в современном обществе

Abstract Background Agricultural workers may be exposed to potential carcinogens including pesticides, sensitizing agents and solar radiation. Previous studies indicate increased risks of hematopoietic cancers and decreased risks at other sites, possibly due to differences in lifestyle or risk behaviours. We present findings from CanCHEC (Canadian Census Health and Environment Cohort), the largest national population-based cohort of agricultural workers. Methods Statistics Canada created the cohort using deterministic and probabilistic linkage of the 1991 Canadian Long Form Census to National Cancer Registry records for 1992–2010. Self-reported occupations were coded using the Standard Occupational Classification (1991) system. Analyses were restricted to employed persons aged 25–74 years at baseline (N = 2,051,315), with follow-up until December 31, 2010. Hazard ratios (HR) and 95% confidence intervals (CI) were modeled using Cox proportional hazards for all workers in agricultural occupations (n = 70,570; 70.8% male), stratified by sex, and adjusted for age at cohort entry, province of residence, and highest level of education. Results A total of 9515 incident cancer cases (7295 in males) occurred in agricultural workers. Among men, increased risks were observed for non-Hodgkin lymphoma (HR = 1.10, 95% CI = 1.00–1.21), prostate (HR = 1.11, 95% CI = 1.06–1.16), melanoma (HR = 1.15, 95% CI = 1.02–1.31), and lip cancer (HR = 2.14, 95% CI = 1.70–2.70). Decreased risks in males were observed for lung, larynx, and liver cancers. Among female agricultural workers there was an increased risk of pancreatic cancer (HR = 1.36, 95% CI = 1.07–1.72). Increased risks of melanoma (HR = 1.79, 95% CI = 1.17–2.73), leukemia (HR = 2.01, 95% CI = 1.24–3.25) and multiple myeloma (HR = 2.25, 95% CI = 1.16–4.37) were observed in a subset of female crop farmers. Conclusions Exposure to pesticides may have contributed to increased risks of hematopoietic cancers, while increased risks of lip cancer and melanoma may be attributed to sun exposure. The array of decreased risks suggests reduced smoking and alcohol consumption in this occupational group compared to the general population

Quantitative Proteomics of Hepatic Drug-Metabolizing Enzymes and Transporters in Patients With Colorectal Cancer Metastasis

The impact of liver cancer metastasis on protein abundance of 22 drug-metabolizing enzymes (DMEs) and 25 transporters was investigated using liquid chromatography-tandem accurate mass spectrometry targeted proteomics. Microsomes were prepared from liver tissue taken from 15 healthy individuals and 18 patients with cancer (2 primary and 16 metastatic). Patient samples included tumors and matching histologically normal tissue. The levels of cytochrome P450 (CYPs 2B6, 2D6, 2E1, 3A4, and 3A5) and uridine 5′-diphospho-glucuronosyltransferases (UGTs 1A1, 1A6, 1A9, 2B15, 2B4, and 2B7) were lower in histologically normal tissue from patients relative to healthy controls (up to 6.6-fold) and decreased further in tumors (up to 21-fold for CYPs and 58-fold for UGTs). BSEP and MRPs were also suppressed in histologically normal (up to 3.1-fold) and tumorous tissue (up to 6.3-fold) relative to healthy individuals. Abundance of OCT3, OAT2, OAT7, and OATPs followed similar trends (up to 2.9-fold lower in histologically normal tissue and up to 16-fold lower in tumors). Abundance of NTCP and OCT1 was also lower (up to 9-fold). Interestingly, monocarboxylate transporter MCT1 was more abundant (3.3-fold) in tumors, the only protein target to show this pattern. These perturbations could be attributed to inflammation. Interindividual variability was substantially higher in patients with cancer. Proteomics-informed physiologically-based pharmacokinetic (PBPK) models of 50 drugs with different attributes and hepatic extraction ratios (Simcyp) showed substantially lower drug clearance with cancer-specific parameters compared with default parameters. In conclusion, this study provides values for decreased abundance of DMEs and transporters in liver cancer, which enables using population-specific abundance for these patients in PBPK modeling

Proteomics of Colorectal Cancer Liver Metastasis: a Quantitative Focus on Drug Elimination and Pharmacodynamics Effects

AIMS: This study aims to quantify drug‐metabolising enzymes, transporters, receptor tyrosine kinases (RTKs) and protein markers (involved in pathways affected in cancer) in pooled healthy, histologically normal and matched cancerous liver microsomes from colorectal cancer liver metastasis (CRLM) patients. METHODS: Microsomal fractionation was performed and pooled microsomes were prepared. Global and accurate mass and retention time liquid chromatography–mass spectrometry proteomics were used to quantify proteins. A QconCAT (KinCAT) for the quantification of RTKs was designed and applied for the first time. Physiologically based pharmacokinetic (PBPK) simulations were performed to assess the contribution of altered abundance of drug‐metabolising enzymes and transporters to changes in pharmacokinetics. RESULTS: Most CYPs and UGTs were downregulated in histologically normal relative to healthy samples, and were further reduced in cancer samples (up to 54‐fold). The transporters, MRP2/3, OAT2/7 and OATP2B1/1B3/1B1 were downregulated in CRLM. Application of abundance data in PBPK models for substrates with different attributes indicated substantially lower (up to 13‐fold) drug clearance when using cancer‐specific instead of default parameters in cancer population. Liver function markers were downregulated, while inflammation proteins were upregulated (by up to 76‐fold) in cancer samples. Various pharmacodynamics markers (e.g. RTKs) were altered in CRLM. Using global proteomics, we examined proteins in pathways relevant to cancer (such as metastasis and desmoplasia), including caveolins and collagen chains, and confirmed general over‐expression of such pathways. CONCLUSION: This study highlights impaired drug metabolism, perturbed drug transport and altered abundance of cancer markers in CRLM, demonstrating the importance of population‐specific abundance data in PBPK models for cancer

Guiding Documents for Engaging with Remote Chronic Disease Management Programs as a Healthcare Provider: A Scoping Review

Introduction: Chronic disease management programs (CDMP) that include education and exercise enhance outcomes and reduce healthcare costs. Remote CDMP have the potential to provide convenient, cost-effective, and accessible options for individuals, but it is unclear how to best implement programs that include education and exercise. This review identified and synthesized resources for implementing remote CDMP programs that incorporate education and exercise. Methods: Peer-reviewed and grey literature were systematically searched from January 1998 to May 2022. Covidence software was used for screening and extraction. The data were synthesized and presented in a narrative and tabular format. Results: Six peer-reviewed manuscripts and six grey literature documents published between 2006-2022 were included. All resources described individual programs targeting various chronic conditions. Provider training, consent, participant screening, and safety considerations were identified. Conclusions: Guidelines for remote CFMP programs are lacking. Additional work is needed to design remote CDMP guidelines incorporating education and exercise.