A gene based approach to test genetic association based on an optimally weighted combination of multiple traits.

There is increasing evidence showing that pleiotropy is a widespread phenomenon in complex diseases for which multiple correlated traits are often measured. Joint analysis of multiple traits could increase statistical power by aggregating multiple weak effects. Existing methods for multiple trait association tests usually study each of the multiple traits separately and then combine the univariate test statistics or combine p-values of the univariate tests for identifying disease associated genetic variants. However, ignoring correlation between phenotypes may cause power loss. Additionally, the genetic variants in one gene (including common and rare variants) are often viewed as a whole that affects the underlying disease since the basic functional unit of inheritance is a gene rather than a genetic variant. Thus, results from gene level association tests can be more readily integrated with downstream functional and pathogenic investigation, whereas many existing methods for multiple trait association tests only focus on testing a single common variant rather than a gene. In this article, we propose a statistical method by Testing an Optimally Weighted Combination of Multiple traits (TOW-CM) to test the association between multiple traits and multiple variants in a genomic region (a gene or pathway). We investigate the performance of the proposed method through extensive simulation studies. Our simulation studies show that the proposed method has correct type I error rates and is either the most powerful test or comparable with the most powerful tests. Additionally, we illustrate the usefulness of TOW-CM based on a COPDGene study

Fighting the global cancer burden: a promising molecular based cancer therapy

Glioblastoma, which occurs in adults primarily between ages of 40 to 70 years and accounts for 15% of all brain tumors, is a devastating diagnosis with a median survival rate of less than a year. Invasiveness of glioblastoma cells significantly reduces the effectiveness of current treatments, highlighting the importance of understanding the characteristics of the invasive population. In glioblastoma cells, influxes of Ca²⁺ activate Ca²⁺-dependent signaling pathways, which promote cell invasion. Calpain 2 is a calcium dependent protease. Previous studies have shown a 90% reduction of glioblastoma cells invasiveness by knocking down calpain 2, demonstrating calpain 2 expression is required for glioblastoma cell invasion. Understanding the mechanism through which calpain 2 promotes cell invasion may lead to an effective treatment for glioblastoma. In collaboration with Dr. Issac Donkor, we are screening novel synthetic calpain 2 inhibitors for the ability to inhibit glioblastoma cell invasion in culture. Four synthetic calpain 2 inhibitors were examined. Initial screening identified one calpain 2 inhibitor (LJ351) that blocked cell invasion at concentrations of 50-100 μM. Our morphology assay showed that LJ351 does not have an effect on cell morphology. We are currently in the process of testing these inhibitors in the zebrafish xenograft model, which is a rapid and inexpensive method for measuring glioblastoma invasion in a dynamic brain microenvironment. Use of the xCELLigence system combined with the zebrafish xenograft model provides an efficient approach for identifying calpain 2 inhibitors with the potential to inhibit tumor cell invasion in glioblastoma. Identifying molecular based treatment can reduce the global burden for cancer. At the same time, the socioeconomic differential in cancer survival should also be considered and addressed

Loss to Follow-Up from HIV Screening to ART Initiation in Rural China.

BackgroundPatients who are newly screened HIV positive by EIA are lost to follow-up due to complicated HIV testing procedures. Because this is the first step in care, it affects the entire continuum of care. This is a particular concern in rural China.Objective(s)To assess the routine HIV testing completeness and treatment initiation rates at 18 county-level general hospitals in rural Guangxi.MethodsWe reviewed original hospital HIV screening records. Investigators also engaged with hospital leaders and key personnel involved in HIV prevention activities to characterize in detail the routine care practices in place at each county.Results699 newly screened HIV-positive patients between January 1 and June 30, 2013 across the 18 hospitals were included in the study. The proportion of confirmatory testing across the 18 hospitals ranged from 14% to 87% (mean of 43%), and the proportion of newly diagnosed individuals successfully initiated antiretroviral treatment across the hospitals ranged from 3% to 67% (mean of 23%). The average interval within hospitals for individuals to receive the Western Blot (WB) and CD4 test results from HIV positive screening (i.e. achieving testing completion) ranged from 14-116 days (mean of 41.7 days) across the hospitals. The shortest interval from receiving a positive EIA screening test result to receiving WB and CD4 testing and counseling was 0 day and the longest was 260 days.ConclusionThe proportion of patients newly screened HIV positive that completed the necessary testing procedures for HIV confirmation and received ART was very low. Interventions are urgently needed to remove barriers so that HIV patients can have timely access to HIV/AIDS treatment and care in rural China

Spred2 controls the severity of Concanavalin A-induced liver damage by limiting interferon-gamma production by CD4(+) and CD8(+) T cells

Introduction: Mitogen-activated protein kinases (MAPKs) are involved in T cell-mediated liver damage. However, the inhibitory mechanism(s) that controls T cell-mediated liver damage remains unknown. Objectives: We investigated whether Spred2 (Sprouty-related, EVH1 domain-containing protein 2) that negatively regulates ERK-MAPK pathway has a biological impact on T cell-mediated liver damage by using a murine model. Methods: We induced hepatotoxicity in genetically engineered mice by intravenously injecting Concanavalin A (Con A) and analyzed the mechanisms using serum chemistry, histology, ELISA, qRT-PCR, Western blotting and flow cytometry. Results: Spred2-deficient mice (Spred2(-/-)) developed more sever liver damage than wild-type (WT) mice with increased interferon-gamma (IFNy) production. Hepatic ERK phosphorylation was enhanced in Spred2(-/-) mice, and pretreatment of Spred2(-/-) mice with the MAPK/ERK inhibitor U0126 markedly inhibited the liver damage and reduced IFN gamma production. Neutralization of IFNy abolished the damage with decreased hepatic Stat1 activation in Spred2(-/-) mice. IFN gamma was mainly produced from CD4(+) and CD8(+) T cells, and their depletion decreased liver damage and IFN gamma production. Transplantation of CD4(+) and/or CD8(+) T cells from Spred2(-/-) mice into RAG1(-/-) mice deficient in both T and B cells caused more severe liver damage than those from WT mice. Hepatic expression of T cell attractants, CXCL9 and CXCL10, was augmented in Spred2(-/-) mice as compared to WT mice. Conversely, liver damage, IFN gamma production and the recruitment of CD4(+) and CD8(+) T cells in livers after Con A challenge were lower in Spred2 transgenic mice, and Spred2-overexpressing CD4(+) and CD8(+) T cells produced lower levels of IFN gamma than WT cells upon stimulation with Con A in vitro. Conclusion: We demonstrated, for the first time, that Spred2 functions as an endogenous regulator of T cell IFNy production and Spred2-mediated inhibition of ERK-MAPK pathway may be an effective remedy for T cell-dependent liver damage

A New Hip Fracture Risk Index Derived from FEA-Computed Proximal Femur Fracture Loads and Energies-to-Failure

Hip fracture risk assessment is an important but challenging task. Quantitative CT-based patient specific finite element analysis (FEA) computes the force (fracture load) to break the proximal femur in a particular loading condition. It provides different structural information about the proximal femur that can influence a subject overall fracture risk. To obtain a more robust measure of fracture risk, we used principal component analysis (PCA) to develop a global FEA computed fracture risk index that incorporates the FEA-computed yield and ultimate failure loads and energies to failure in four loading conditions (single-limb stance and impact from a fall onto the posterior, posterolateral, and lateral aspects of the greater trochanter) of 110 hip fracture subjects and 235 age and sex matched control subjects from the AGES-Reykjavik study. We found that the first PC (PC1) of the FE parameters was the only significant predictor of hip fracture. Using a logistic regression model, we determined if prediction performance for hip fracture using PC1 differed from that using FE parameters combined by stratified random resampling with respect to hip fracture status. The results showed that the average of the area under the receive operating characteristic curve (AUC) using PC1 was always higher than that using all FE parameters combined in the male subjects. The AUC of PC1 and AUC of the FE parameters combined were not significantly different than that in the female subjects or in all subjectsComment: 27 pages, 4 figure

Preparation of Pullulan Polysaccharide/Thermoplastic Polyurethane Coaxial Electrospinning Film with Oregano Essential Oil as Core Material and Its Preservative Effect on the Quality of Lateolabrax japonicus Fillets

The use of plant essential oils as an antibacterial agent for food packaging has become a new trend. In order to obtain biodegradable films for the preservation of aquatic products, coaxial electrospinning films were prepared by electrospinning using the antimicrobial preservative oregano essential oil (OEO) or its main components as core material, pullulan (Pul) as film-forming substrate, and thermoplastic polyurethane (TPU) as shell material and were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy. Also, its thermal stability, physicochemical properties was determined as well as the release performance of the antimicrobial preservative from the coaxial electrospinning films and its efficacy in preserving the quality of refrigerated Lateolabrax japonicus fillets. The results showed that OEO was effectively encapsulated in the electrospinning fibers, improving the micromorphology, water vapor barrier properties and wettability and significantly reducing the tensile strength (TS), and swelling degree (SD) of the film (P < 0.05), but not changing the thermal stability of the film significantly. The fibers inside the film had a coaxial core-shell structure, and the release behavior of the preservative was a complex coupling of disintegration and dissolution, resulting in controlled OEO release for up to 60 h. In addition, the film effectively inhibited the growth of microorganisms, and thus had excellent preservative effect on fresh L. japonicus fillets. It effectively delayed the deterioration of the smell, texture and apparent quality of the fillets, and extended the shelf life from 8 to 12 d. This study can provide a theoretical basis and technical support for the development of biodegradable antibacterial packaging materials based on biological antibacterial agents

Spred-2 deficiency exacerbates acetaminophen-induced hepatotoxicity in mice

MAPKs are involved in acetaminophen (APAP)-hepatotoxicity, but the regulatory mechanism remains unknown. Here, we explored the role of Spred-2 that negatively regulates Ras/ERK pathway in APAP-hepatotoxicity. Spred-2 knockout (KO) mice demonstrated exacerbated liver injury, an event that was associated with increased numbers of CD4(+) T, CD8(+) T and NK cells in the liver compared to the control. Levels of CXCL9/CXCL10 that attract and activate these cells were increased in Spred-2 KO-liver. Kupffer cells isolated from Spred-2 KO mice after APAP challenge expressed higher levels of CXCL9/CXCL10 than those from the control. Upon stimulation with APAP or IFN gamma, naive Kupffer cells from Spred-2 KO mice expressed higher levels of CXCL9/CXCL10. NK cell-depletion attenuated APAP-hepatotoxicity with lowered hepatic IFN gamma and decreased numbers of not only NK cells but also CD4(+) T and CD8(+) T cells in the liver. These results suggest that Spred-2 negatively regulates APAP-hepatotoxicity under the control of Kupffer cells and NK cells

Effects of high CD4 cell counts on death and attrition among HIV patients receiving antiretroviral treatment: an observational cohort study

Current WHO guidelines recommend initiating ART regardless of CD4+ cell count. In response, we conducted an observational cohort study to assess the effects of pre-ART CD4+ cell count levels on death, attrition, and death or attrition in HIV treated patients. This large HIV treatment cohort study (n = 49,155) from 2010 to 2015 was conducted in Guangxi, China. We used a Cox regression model to analyze associations between pre-ART CD4+ cell counts and death, attrition, and death or attrition. The average mortality and ART attrition rates among all treated patients were 2.63 deaths and 5.32 attritions per 100 person-years, respectively. Compared to HIV patients with 500 CD4+ cells/mm 3 at ART initiation had a significantly lower mortality rate (Adjusted hazard ratio: 0.56, 95% CI: 0.40-0.79), but significantly higher ART attrition rate (AHR: 1.17, 95% CI: 1.03-1.33). Results from this study suggest that HIV patients with high CD4+ cell counts at the time of ART initiation may be at greater risk of treatment attrition. To further reduce ART attrition, it is imperative that patient education and healthcare provider training on ART adherence be enhanced and account for CD4 levels at ART initiation