Complex Deleterious Interactions Associated with Malic Enzyme May Contribute to Reproductive Isolation in the Copepod Tigriopus californicus

Dobzhansky-Muller incompatibilities can result from the interactions of more than a single pair of interacting genes and there are several different models of how such complex interactions can be structured. Previous empirical work has identified complex conspecific epistasis as a form of complex interaction that has contributed to postzygotic reproductive isolation between taxa, but other forms of complexity are also possible. Here, I probe the genetic basis of reproductive isolation in crosses of the intertidal copepod Tigriopus californicus by looking at the impact of markers in genes encoding metabolic enzymes in F2 hybrids. The region of the genome associated with the locus ME2 is shown to have strong, repeatable impacts on the fitness of hybrids in crosses and epistatic interactions with another chromosomal region marked by the GOT2 locus in one set of crosses. In a cross between one of these populations and a third population, these two regions do not appear to interact despite the continuation of a large effect of the ME2 region itself in both crosses. The combined results suggest that the ME2 chromosomal region is involved in incompatibilities with several unique partners. If these deleterious interactions all stem from the same factor in this region, that would suggest a different form of complexity from complex conspecific epistasis, namely, multiple independent deleterious interactions stemming from the same factor. Confirmation of this idea will require more fine-scale mapping of the interactions of the ME2 region of the genome

Therapeutic efficacy of intra-articular delivery of encapsulated human mesenchymal stem cells on early stage osteoarthritis

Mesenchymal stem cells (MSCs) represent a great therapeutic promise in pre-clinical models of osteoarthritis (OA), but many questions remain as to their therapeutic mechanism of action: engraftment versus paracrine action. Encapsulation of human MSCs (hMSCs) in sodium alginate microspheres allowed for the paracrine signaling properties of these cells to be isolated and studied independently of direct cellular engraftment. The objective of the present study was to quantitatively assess the efficacy of encapsulated hMSCs as a disease-modifying therapeutic for OA, using a medial meniscal tear (MMT) rat model. It was hypothesized that encapsulated hMSCs would have a therapeutic effect, through paracrine-mediated action, on early OA development. Lewis rats underwent MMT surgery to induce OA. 1 d post-surgery, rats received intra-articular injections of encapsulated hMSCs or controls (i.e., saline, empty capsules, non-encapsulated hMSCs). Microstructural changes in the knee joint were quantified using equilibrium partitioning of a ionic contrast agent based micro-computed tomography (EPIC-μCT) at 3 weeks post-surgery, an established time point for early OA. Encapsulated hMSCs significantly attenuated MMT-induced increases in articular cartilage swelling and surface roughness and augmented cartilaginous and mineralized osteophyte volumes. Cellular encapsulation allowed to isolate the hMSC paracrine signaling effects and demonstrated that hMSCs could exert a chondroprotective therapeutic role on early stage OA through paracrine signaling alone. In addition to this chondroprotective role, encapsulated hMSCs augmented the compensatory increases in osteophyte formation. The latter should be taken into strong consideration as many clinical trials using MSCs for OA are currently ongoing

Current opportunities to catalyze research in nutrition and cancer prevention – an interdisciplinary perspective

Cancer Research UK and Ludwig Cancer Research convened an inaugural international Cancer Prevention and Nutrition Conference in London on December 3–4, 2018. Much of the discussion focused on the need for systematic, interdisciplinary approaches to better understand the relationships of nutrition, exercise, obesity and metabolic dysfunction with cancer development. Scientists at the meeting underscored the importance of studying the temporal natural history of exposures that may cumulatively impact cancer risk later in life. A robust dialogue identified obesity as a major risk for cancer, and the food environment, especially high energy and low nutrient processed foods, as strong and prevalent risk factors for obesity. Further engagement highlighted challenges in the post-diagnostic setting, where similar opportunities to understand the complex interplay of nutrition, physical activity, and weight will inform better health outcomes. Going forward, holistic research approaches, encompassing insights from multiple disciplines and perspectives, will catalyze progress urgently needed to prevent cancer and improve public health

B Vitamins, Methionine and Alcohol Intake and Risk of Colon Cancer in Relation to BRAF Mutation and CpG Island Methylator Phenotype (CIMP)

One-carbon metabolism appears to play an important role in DNA methylation reaction. Evidence suggests that a low intake of B vitamins or high alcohol consumption increases colorectal cancer risk. How one-carbon nutrients affect the CpG island methylator phenotype (CIMP) or BRAF mutation status in colon cancer remains uncertain.Utilizing incident colon cancers in a large prospective cohort of women (the Nurses' Health Study), we determined BRAF status (N = 386) and CIMP status (N = 375) by 8 CIMP-specific markers [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and 8 other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT-1, MINT-31, p14, and WRN). We examined the relationship between intake of one-carbon nutrients and alcohol and colon cancer risk, by BRAF mutation or CIMP status.Higher folate intake was associated with a trend towards low risk of CIMP-low/0 tumors [total folate intake ≥400 µg/day vs. <200 µg/day; the multivariate relative risk = 0.73; 95% CI = 0.53-1.02], whereas total folate intake had no influence on CIMP-high tumor risks (P(heterogeneity) = 0.73). Neither vitamin B(6), methionine or alcohol intake appeared to differentially influence risks for CIMP-high and CIMP-low/0 tumors. Using the 16-marker CIMP panel did not substantially alter our results. B vitamins, methionine or alcohol intake did not affect colon cancer risk differentially by BRAF status.This molecular pathological epidemiology study suggests that low level intake of folate may be associated with an increased risk of CIMP-low/0 colon tumors, but not that of CIMP-high tumors. However, the difference between CIMP-high and CIMP-low/0 cancer risks was not statistically significant, and additional studies are necessary to confirm these observations

A comprehensive evaluation of food fortification with folic acid for the primary prevention of neural tube defects

BACKGROUND: Periconceptional use of vitamin supplements containing folic acid reduces the risk of a neural tube defect (NTD). In November 1998, food fortification with folic acid was mandated in Canada, as a public health strategy to increase the folic acid intake of all women of childbearing age. We undertook a comprehensive population based study in Newfoundland to assess the benefits and possible adverse effects of this intervention. METHODS: This study was carried out in women aged 19–44 years and in seniors from November 1997 to March 1998, and from November 2000 to March 2001. The evaluation was comprised of four components: I) Determination of rates of NTDs; II) Dietary assessment; III) Blood analysis; IV) Assessment of knowledge and use of folic acid supplements. RESULTS: The annual rates of NTDs in Newfoundland varied greatly between 1976 and 1997, with a mean rate of 3.40 per 1,000 births. There was no significant change in the average rates between 1991–93 and 1994–97 (relative risk [RR] 1.01, 95% confidence interval [CI] 0.76–1.34). The rates of NTDs fell by 78% (95% CI 65%–86%) after the implementation of folic acid fortification, from an average of 4.36 per 1,000 births during 1991–1997 to 0.96 per 1,000 births during 1998–2001 (RR 0.22, 95% CI 0.14–0.35). The average dietary intake of folic acid due to fortification was 70 μg/day in women aged 19–44 years and 74 μg/day in seniors. There were significant increases in serum and RBC folate levels for women and seniors after mandatory fortification. Among seniors, there were no significant changes in indices typical of vitamin B(12 )deficiencies, and no evidence of improved folate status masking haematological manifestations of vitamin B(12 )deficiency. The proportion of women aged 19–44 years taking a vitamin supplement containing folic acid increased from 17% to 28%. CONCLUSIONS: Based on these findings, mandatory food fortification in Canada should continue at the current levels. Public education regarding folic acid supplement use by women of childbearing age should also continue

Quantitative global studies of reactomes and metabolomes using a vectorial representation of reactions and chemical compounds

<p>Abstract</p> <p>Background</p> <p>Global studies of the protein repertories of organisms are providing important information on the characteristics of the protein space. Many of these studies entail classification of the protein repertory on the basis of structure and/or sequence similarities. The situation is different for metabolism. Because there is no good way of measuring similarities between chemical reactions, there is a barrier to the development of global classifications of "metabolic space" and subsequent studies comparable to those done for protein sequences and structures.</p> <p>Results</p> <p>In this work, we propose a vectorial representation of chemical reactions, which allows them to be compared and classified. In this representation, chemical compounds, reactions and pathways may be represented in the same vectorial space. We show that the representation of chemical compounds reflects their physicochemical properties and can be used for predictive purposes. We use the vectorial representations of reactions to perform a global classification of the reactome of the model organism <it>E. coli</it>.</p> <p>Conclusions</p> <p>We show that this unsupervised clustering results in groups of enzymes more coherent in biological terms than equivalent groupings obtained from the EC hierarchy. This hierarchical clustering produces an optimal set of 21 groups which we analyzed for their biological meaning.</p

Blood Donation and Colorectal Cancer Incidence and Mortality in Men

Background: Although blood donations may reduce body iron stores, to date, prospective data on frequent blood donation and colorectal cancer risk are limited. Methodology/Principal Findings: We tested whether frequent blood donation is associated with a lower risk of colorectal cancer in the Health Professionals Follow-up Study. We prospectively followed 35,121men who provide the information on lifetime number of blood donations in 1992 through 2008. Serum ferritin levels were measured in a random sample of 305 men. Cox proportional hazard regression models were used to calculate the multivariable relative risks (RRs, 95%CIs) after adjusting for age and other established colorectal cancer risk factors. We documented 684 incident colorectal cancer cases and 224 deaths from colorectal cancer. The mean serum ferritin levels varied from 178 µg/L for men who did not donate blood to 98 µg/L for men who had at least 30 donations. Age-adjusted results for both incidence and mortality were essentially the same as the multivariable-adjusted results. Comparing with non-donors, the multivariable RRs (95%CIs) for colorectal cancer incidence were 0.92 (0.77, 1.11) for 1–5 donation, 0.85 (0.64, 1.11) for 6–9 donations, 0.96 (0.73, 1.26) for 10–19 donations, 0.91 (0.63, 1.32) for 20–29 donations, and 0.97 (0.68, 1.38) for at least 30 donations (Ptrend = 0.92). The multivariable RRs for colorectal cancer mortality were 0.99 (0.72, 1.36) for 1–5 donation, 0.93 (0.57, 1.51) for 6–9 donations, 0.85 (0.50, 1.42) for 10–19 donations, and 1.14 (0.72, 1.83) for at least 20 donations (Ptrend = 0.82). The results did not vary by cancer sub-sites, intake levels of total iron, heme iron, or family history of colorectal cancer. Conclusions/Significance: Frequent blood donations were not associated with colorectal cancer incidence and mortality in men. Our results do not support an important role of body iron stores in colorectal carcinogenesis

Preoperative bevacizumab combined with letrozole and chemotherapy in locally advanced ER- and/or PgR-positive breast cancer: clinical and biological activity

The antiangiogenic agent bevacizumab showed synergistic effects when combined with chemotherapy in advanced breast cancer. We presently investigated the activity of bevacizumab in combination with chemotherapy, including capecitabine and vinorelbine, and endocrine therapy, including letrozole (+triptorelin in premenopausal women), as primary therapy for patients with ER and/or PgR ⩾10% T2–T4a-c, N0–N2, M0 breast cancer. Biological end point included the proliferative activity (Ki67), whereas clinical end points were clinical response rate, pathological complete response (pCR) and tolerability. Circulating endothelial cells (CECs) and their progenitors, as surrogate markers of antiangiogenic activity, were measured at baseline and at surgery.Thirty-six women are evaluable. A clinical response rate of 86% (95% CI, 70–95) and no pCR were observed; Ki67 was significantly decreased by 71% (interquartile range, −82%, −62%). Toxicity was manageable: two grade 3 hypertension, four grade 3 deep venous thrombosis and no grade >2 proteinuria were observed. Treatment significantly decreased the percentage of viable CECs and prevented the chemotherapy-induced mobilisation of circulating progenitors. Basal circulating progenitors were positively associated with clinical response. In conclusion, bevacizumab is feasible and active in association with primary chemoendocrine therapy for ER-positive tumours in terms of proliferation inhibition, clinical response and antiangiogenic activity

Association between television viewing and the risk of metabolic syndrome in a community-based population

<p>Abstract</p> <p>Background</p> <p>As a result of metabolic syndrome becoming an important issue during recent decades, many studies have explored the risk factors contributing to its development. However, less attention has been paid to the risk associated with sedentary behavior, especially television viewing. This study examined the association between television viewing time and the risk of having metabolic syndrome in a population of Taiwanese subjects.</p> <p>Methods</p> <p>This community-based cross-sectional study included 2,353 subjects (1,144 men and 1,209 women) aged 40 and over from October, 2004 to September, 2005. Information about the time spent watching TV was obtained using a self-administered questionnaire. The definition of metabolic syndrome was according to the Third Report of the National Cholesterol Education Program's Adult Treatment Panel modified for Asians.</p> <p>Results</p> <p>Compared to subjects who viewed TV < 14 hr/week, those who viewed TV > 20 hr/week had a 1.50-fold (95% confidence intervals (CI): 1.10, 2.03) risk for men and a 1.93-fold (95% CI: 1.37, 2.71) risk for women of having metabolic syndrome, after adjusting for physical activity and other covariates. Stratifying by the three categories of total activity levels, TV viewing time > 20 hr/week was found to still hold a significant risk for having metabolic syndrome in the lowest of the three categories of total activity level for men and in all three categories of total activity level for women.</p> <p>Conclusion</p> <p>The findings suggest that TV viewing is an independent risk factor associated with metabolic syndrome in Taiwanese people.</p