IL10 and IL10 receptor gene variation and outcomes after unrelated and related hematopoietic cell transplantation.

BACKGROUND: Results of a previous study with human leukocyte antigen (HLA)-identical siblings showed individual and synergistic associations of single nucleotide polymorphisms in the promoter region of the recipient's IL10 gene and the donor's IL10 receptor beta (IL-10RB) gene with development of grades III-IV acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. METHODS: In this study of 936 patients who had unrelated donors, genotypes of single nucleotide polymorphisms in the IL10 gene and the IL-10RB gene were evaluated as correlates with outcomes after transplantation. RESULTS: We found no statistically significant associations of polymorphisms at positions -3575, -2763, -1082, and -592 of the IL10 gene or codon 238 of the IL10RB gene with severe acute GVHD, extensive chronic GVHD or nonrelapse mortality after hematopoietic cell transplantation. Among HLA-matched unrelated pairs, the patient's IL10/-592 genotype and donor's IL10RB/c238 genotype showed trends suggesting individual and combined associations with grades III-IV acute GVHD similar to those observed among patients with HLA-identical sibling donors. CONCLUSIONS: Although genetic variation in IL10 pathway affects risk of acute GVHD and non-relapse mortality in HLA-identical sibling transplants, the current results indicate that genetic variation in the IL10 pathway does not significant affect these outcomes in unrelated donor transplants suggesting that the strength of the alloimmune response in the latter exceeds the anti-inflammatory activity of IL10

f(R) theories

Over the past decade, f(R) theories have been extensively studied as one of the simplest modifications to General Relativity. In this article we review various applications of f(R) theories to cosmology and gravity - such as inflation, dark energy, local gravity constraints, cosmological perturbations, and spherically symmetric solutions in weak and strong gravitational backgrounds. We present a number of ways to distinguish those theories from General Relativity observationally and experimentally. We also discuss the extension to other modified gravity theories such as Brans-Dicke theory and Gauss-Bonnet gravity, and address models that can satisfy both cosmological and local gravity constraints.Comment: 156 pages, 14 figures, Invited review article in Living Reviews in Relativity, Published version, Comments are welcom

Novel Prognostic and Therapeutic Targets for Oral Squamous Cell Carcinoma

In oral squamous cell carcinoma (OSCC), metastasis to lymph nodes is associated with a 50% reduction in 5-year survival. To identify a metastatic gene set based on DNA copy number abnormalities (CNAs) of differentially expressed genes, we compared DNA and RNA of OSCC cells laser-microdissected from non-metastatic primary tumors (n = 17) with those from lymph node metastases (n = 20), using Affymetrix 250K Nsp single-nucleotide polymorphism (SNP) arrays and U133 Plus 2.0 arrays, respectively. With a false discovery rate (FDR)<5%, 1988 transcripts were found to be differentially expressed between primary and metastatic OSCC. Of these, 114 were found to have a significant correlation between DNA copy number and gene expression (FDR<0.01). Among these 114 correlated transcripts, the corresponding genomic regions of each of 95 transcripts had CNAs differences between primary and metastatic OSCC (FDR<0.01). Using an independent dataset of 133 patients, multivariable analysis showed that the OSCC-specific and overall mortality hazards ratio (HR) for patients carrying the 95-transcript signature were 4.75 (95% CI: 2.03-11.11) and 3.45 (95% CI: 1.84-6.50), respectively. To determine the degree by which these genes impact cell survival, we compared the growth of five OSCC cell lines before and after knockdown of over-amplified transcripts via a high-throughput siRNA-mediated screen. The expression-knockdown of 18 of the 26 genes tested showed a growth suppression ≥ 30% in at least one cell line (P<0.01). In particular, cell lines derived from late-stage OSCC were more sensitive to the knockdown of G3BP1 than cell lines derived from early-stage OSCC, and the growth suppression was likely caused by increase in apoptosis. Further investigation is warranted to examine the biological role of these genes in OSCC progression and their therapeutic potentials

Stain-Free Quantification of Chromosomes in Live Cells Using Regularized Tomographic Phase Microscopy

Refractive index imaging is a label-free technique that enables long-term monitoring of the internal structures and molecular composition in living cells with minimal perturbation. Existing tomographic methods for the refractive index imaging lack 3-D resolution and result in artifacts that prevent accurate refractive index quantification. To overcome these limitations without compromising the capability to observe a sample in its most native condition, we have developed a regularized tomographic phase microscope (RTPM) enabling accurate refractive index imaging of organelles inside intact cells. With the enhanced accuracy, we quantify the mass of chromosomes in intact living cells, and differentiate two human colon cancer lines, HT-29 and T84 cells, solely based on the non-aqueous (dry) mass of chromosomes. In addition, we demonstrate chromosomal imaging using a dual-wavelength RTPM, which shows its potential to determine the molecular composition of cellular organelles in live cells.National Institute of Biomedical Imaging and Bioengineering (U.S.) (9P41EB015871-26A1

Asthma susceptible genes in Chinese population: A meta-analysis

<p>Abstract</p> <p>Background</p> <p>Published data regarding the associations between genetic variants and asthma risk in Chinese population were inconclusive. The aim of this study was to investigate asthma susceptible genes in Chinese population.</p> <p>Methods</p> <p>The authors conducted 18 meta-analyzes for 18 polymorphisms in 13 genes from eighty-two publications.</p> <p>Results</p> <p>Seven polymorphisms were found being associated with risk of asthma, namely: <it>A Disintegrin and Metalloprotease 33 </it>(<it>ADAM33</it>) T1-C/T (odds ratio [OR] = 6.07, 95% confidence interval [CI]: 2.69-13.73), <it>Angiotensin-Converting Enzyme </it>(<it>ACE</it>) D/I (OR = 3.85, 95%CI: 2.49-5.94), <it>High-affinity IgE receptor β chain </it>(<it>FcεRIβ</it>) -6843G/A (OR = 1.49, 95%CI: 1.01-2.22), <it>Interleukin 13</it>(<it>IL-13</it>) -1923C/T (OR = 2.99, 95%CI: 2.12-4.24), <it>IL-13 </it>-2044A/G (OR = 1.49, 95%CI: 1.07-2.08), <it>Regulated upon Activation, Normal T cell Expressed and Secreted </it>(<it>RANTES</it>) -28C/G (OR = 1.64, 95%CI: 1.09-2.46), <it>Tumor Necrosis Factor-α </it>(<it>TNF-α</it>) -308G/A(OR = 1.42, 95%CI: 1.09, 1.85). After subgroup analysis by age, the <it>ACE </it>D/I, <it>β2-Adrenergic Receptor </it>(<it>β2-AR</it>) -79G/C, <it>TNF-α </it>-308G/A, <it>Interleukin 4 receptor</it>(<it>IL-4R</it>) -1902G/A and <it>IL-13 </it>-1923C/T polymorphisms were found significantly associated with asthma risk in Chinese children. In addition, the <it>ACE </it>D/I, <it>FcεRIβ </it>-6843G/A, <it>TNF-α </it>-308G/A, <it>IL-13 </it>-1923C/T and <it>IL-13 </it>-2044A/G polymorphisms were associated with asthma risk in Chinese adults.</p> <p>Conclusion</p> <p><it>ADAM33, FcεRIβ, RANTES, TNF-α, ACE, β2-AR, IL-4R </it>and <it>IL-13 </it>genes could be proposed as asthma susceptible genes in Chinese population. Given the limited number of studies, more data are required to validate these associations.</p

The modular systems biology approach to investigate the control of apoptosis in Alzheimer's disease neurodegeneration

Apoptosis is a programmed cell death that plays a critical role during the development of the nervous system and in many chronic neurodegenerative diseases, including Alzheimer's disease (AD). This pathology, characterized by a progressive degeneration of cholinergic function resulting in a remarkable cognitive decline, is the most common form of dementia with high social and economic impact. Current therapies of AD are only symptomatic, therefore the need to elucidate the mechanisms underlying the onset and progression of the disease is surely needed in order to develop effective pharmacological therapies. Because of its pivotal role in neuronal cell death, apoptosis has been considered one of the most appealing therapeutic targets, however, due to the complexity of the molecular mechanisms involving the various triggering events and the many signaling cascades leading to cell death, a comprehensive understanding of this process is still lacking. Modular systems biology is a very effective strategy in organizing information about complex biological processes and deriving modular and mathematical models that greatly simplify the identification of key steps of a given process. This review aims at describing the main steps underlying the strategy of modular systems biology and briefly summarizes how this approach has been successfully applied for cell cycle studies. Moreover, after giving an overview of the many molecular mechanisms underlying apoptosis in AD, we present both a modular and a molecular model of neuronal apoptosis that suggest new insights on neuroprotection for this disease