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A Prospective Study of Leukocyte Telomere Length and Risk of Type 2 Diabetes in Postmenopausal Women
Telomere length (TL) has been implicated in the pathogenesis of age-related disorders. However, there are no prospective studies directly investigating the role of TL and relevant genes in diabetes development. In the multiethnic Women’s Health Initiative, we identified 1,675 incident diabetes case participants in 6 years of follow-up and 2,382 control participants matched by age, ethnicity, clinical center, time of blood draw, and follow-up duration. Leukocyte TL at baseline was measured using quantitative PCR, and Mendelian randomization analysis was conducted to test whether TL is causally associated with diabetes risk. After adjustment for matching and known diabetes risk factors, odds ratios per 1-kilobase increment were 1.00 (95% CI 0.90–1.11) in whites, 0.95 (0.85–1.06) in blacks, 0.96 (0.79–1.17) in Hispanics, and 0.88 (0.70–1.10) in Asians. Of the 80 single nucleotide polymorphisms (SNPs) in nine genes involved in telomere regulation, 14 SNPs were predictive of TL, but none were significantly associated with diabetes risk. Using ethnicity-specific SNPs as randomization instruments, we observed no statistically significant association between TL and diabetes risk (P = 0.52). Although leukocyte TL was weakly associated with diabetes risk, this association was not independent of known risk factors. These prospective findings indicate limited clinical utility of TL in diabetes risk stratification among postmenopausal women
Obesity and risk of pancreatic cancer among postmenopausal women: the Women's Health Initiative (United States)
A total of 138 503 women in the Women's Health Initiative in the United States were followed (for an average of 7.7 years) through 12 September 2005 to examine obesity, especially central obesity in relation to pancreatic cancer (n=251). Women in the highest quintile of waist-to-hip ratio had 70% (95% confidence interval 10–160%) excess risk of pancreatic cancer compared with women in the lowest quintile
Synthetic Nanoparticles for Vaccines and Immunotherapy
The immune system plays a critical role in our health. No other component of human physiology plays a decisive role in as diverse an array of maladies, from deadly diseases with which we are all familiar to equally terrible esoteric conditions: HIV, malaria, pneumococcal and influenza infections; cancer; atherosclerosis; autoimmune diseases such
as lupus, diabetes, and multiple sclerosis. The importance of understanding the function of the immune system and learning how to modulate immunity to protect against or treat disease thus cannot be overstated. Fortunately, we are entering an exciting era where the
science of immunology is defining pathways for the rational manipulation of the immune system at the cellular and molecular level, and this understanding is leading to dramatic advances in the clinic that are transforming the future of medicine.1,2 These initial advances are being made primarily through biologic drugs– recombinant proteins (especially antibodies) or patient-derived cell therapies– but exciting data from preclinical studies suggest that a marriage of approaches based in biotechnology with the materials science and chemistry of nanomaterials, especially nanoparticles, could enable more effective and safer immune engineering strategies. This review will examine these nanoparticle-based strategies to immune modulation in detail, and discuss the promise and outstanding challenges facing the field of immune engineering from a chemical biology/materials engineering perspectiveNational Institutes of Health (U.S.) (Grants AI111860, CA174795, CA172164, AI091693, and AI095109)United States. Department of Defense (W911NF-13-D-0001 and Awards W911NF-07-D-0004
Efficacy of aerobic exercise and a prudent diet for improving selected lipids and lipoproteins in adults: a meta-analysis of randomized controlled trials
Background
Studies addressing the effects of aerobic exercise and a prudent diet on lipid and lipoprotein concentrations in adults have reached conflicting conclusions. The purpose of this study was to determine the effects of aerobic exercise combined with a prudent diet on lipid and lipoprotein concentrations in adults. Methods
Studies were located by searching nine electronic databases, cross-referencing, and expert review. Two independent reviewers selected studies that met the following criteria: (1) randomized controlled trials, (2) aerobic exercise combined with diet recommendations (saturated/trans fat intake less than 10% of total calories and cholesterol less than 300 mg/day and/or fiber intake ≥25 g/day in women and ≥35 grams per day in men), (3) intervention ≥4 weeks, (4) humans ≥18 years of age, (5) published studies, including dissertations and Master\u27s theses, (6) studies published in any language, (7) studies published between January 1, 1955 and May 1, 2009, (8) assessment of one or more of the following lipid and lipoprotein concentrations: total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), ratio of TC to HDL-C, non-HDL-C, low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). Two reviewers independently extracted all data. Random-effects models that account for heterogeneity and 95% confidence intervals were used to pool findings. Results
Of the 1,401 citations reviewed, six studies representing 16 groups (8 intervention, 8 control) and up to 559 men and women (282 intervention, 277 control) met the criteria for analysis. Statistically significant intervention minus control reductions were found for TC (-15.5 mg/dl, 95% CI, -20.3 to -10.7), TC:HDL-C (-0.4 mg/dl, 95% CI, -0.7 to -0.2), LDL-C (-9.2 mg/dl, 95% CI, -12.7 to -5.8) and TG (-10.6 mg/dl, 95% CI, -17.2 to -4.0) but not HDL-C (-0.5 mg/dl, 95% CI, -4.0 to 3.1). Changes were equivalent to reductions of 7.5%, 6.6%, 7.2% and 18.2% respectively, for TC, TC:HDL-C, LDL-C and TG. Because of missing variance statistics, non-HDL-C was excluded. Conclusions
Aerobic exercise combined with a prudent diet is highly efficacious for improving TC, TC:HDL-C, LDL-C and TG, but not HDL-C concentrations, in adults. However, additional studies are needed, including effectiveness studies using intention-to-treat analysis
Histological modifications of the rat prostate following transection of somatic and autonomic nerves
Potential Reporting Bias in Neuroimaging Studies of Sex Differences
Numerous functional magnetic resonance imaging (fMRI) studies have reported sex differences. To empirically evaluate for evidence of excessive significance bias in this literature, we searched for published fMRI studies of human brain to evaluate sex differences, regardless of the topic investigated, in Medline and Scopus over 10 years. We analyzed the prevalence of conclusions in favor of sex differences and the correlation between study sample sizes and number of significant foci identified. In the absence of bias, larger studies (better powered) should identify a larger number of significant foci. Across 179 papers, median sample size was n = 32 (interquartile range 23-47.5). A median of 5 foci related to sex differences were reported (interquartile range, 2-9.5). Few articles (n = 2) had titles focused on no differences or on similarities (n = 3) between sexes. Overall, 158 papers (88%) reached "positive" conclusions in their abstract and presented some foci related to sex differences. There was no statistically significant relationship between sample size and the number of foci (-0.048% increase for every 10 participants, p = 0.63). The extremely high prevalence of "positive" results and the lack of the expected relationship between sample size and the number of discovered foci reflect probable reporting bias and excess significance bias in this literature
Nonchromatographic Affinity Precipitation Method for the Purification of Bivalently Active Pharmaceutical Antibodies from Biological Fluids
This
Article describes an affinity-based precipitation method for
the rapid and nonchromatographic purification of bivalently active
monoclonal antibodies by combining the selectivity of affinity chromatography
with the simplicity of salt-induced precipitation. This procedure
involves (i) precipitation of proteins heavier than immunoglobulins
with ammonium sulfate; (ii) formation and selective precipitation
of cyclic antibody complexes created by binding to trivalent haptens
specific for the antibody; and (iii) membrane filtration of the solubilized
antibody pellet to remove the trivalent hapten from the purified antibody.
We applied this technique to the purification of two pharmaceutical
antibodies, trastuzumab and rituximab, by synthesizing trivalent haptens
specific for each antibody. Using this method, we were able to purify
both antibodies from typical contaminants including CHO cell conditioned
media, ascites fluid, DNA, and other antibodies with yields >85%
and
with >95% purity. The purified antibodies displayed native binding
levels to cell lines expressing the target proteins demonstrating
that the affinity-based precipitation method did not adversely affect
the antibodies. The selectivity of the affinity-based precipitation
method for bivalently active antibodies was established by purifying
trastuzumab from a solution containing both active and chemically
denatured trastuzumab. Prior to purification, the solutions displayed
20–76% reduction in binding activity, and after purification,
native binding activity was restored, indicating that the purified
product contained only bivalently active antibody. Taken together,
the affinity-based precipitation method provides a rapid and straightforward
process for the purification of antibodies with the potential to improve
product quality while decreasing the purification costs at both the
lab and the industrial scale
Enhancement of Antibody Selectivity via Bicyclic Complex Formation
This study describes a strategy where antibody selectivity
for
high antigen-density surfaces is enhanced by forming a thermodynamically
stable bicyclic complex. The bicyclic complex was formed via multivalent
interactions of the antibody with a synthetic trivalent mimotope at
a 3:2 molar ratio. Complex formation was analyzed using dynamic light
scattering and analytical ultracentrifugation, showing a hydrodynamic
radius of ∼22 nm and a calculated molecular weight of 397 kDa,
depicting a trimeric complex formation. The complex has high thermodynamic
stability and results in a 10-fold higher binding affinity for the
trivalent mimotope (<i>K</i><sub>d</sub> = 0.14 μM)
compared to the monovalent mimotope (<i>K</i><sub>d</sub> = 1.4 μM). As bicyclic complexes, the antibodies showed ∼18%
binding of the monomeric form to low antigen-density surfaces. At
high antigen-density, antibody binding was equal whether delivered
as a complex or a monomer. These results establish bicyclic complex
selectivity for high antigen-density surfaces and suggest a potential
method to enhance therapeutic antibody selectivity for diseased cells
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