The Expression of TMPRSS4 and Erk1 Correlates with Metastasis and Poor Prognosis in Chinese Patients with Gastric Cancer

Purpose

The present study investigated the clinical significance of transmembrane protease, serine 4(TMPRSS4) and extracellular signal-regulated kinases 1 (Erk1) in the development, progression and metastasis of gastric cancer.

Methods

Immunohistochemistry was employed to analyze TMPRSS4 and Erk1 expression in 436 gastric cancer cases and 92 non-cancerous human gastric tissues.

Results

Protein levels of TMPRSS4 and Erk1 were up-regulated in gastric cancer lesions compared with adjacent noncancerous tissues. High expression of TMPRSS4 correlated with age, size, Lauren’s classification, depth of invasion, lymph node and distant metastases, regional lymph node stage and TNM stage, and also with expression of Erk1. In stages I, II and III, the 5-year survival rate of patients with high TMPRSS4 expression was significantly lower than in patients with low expression. Further multivariate analysis suggests that up-regulation of TMPRSS4 and Erk1 were independent prognostic indicators for the disease, along with depth of invasion, lymph node and distant metastasis and TNM stage.

Conclusions

Expression of TMPRSS4 in gastric cancer is significantly associated with lymph node and distant metastasis, high Erk1 expression, and poor prognosis. TMPRSS4 and Erk1 proteins could be useful markers to predict tumor progression and prognosis of gastric cancer.     

Multi-Dimensional Prioritization of Dental Caries Candidate Genes and Its Enriched Dense Network Modules

A number of genetic studies have suggested numerous susceptibility genes for dental caries over the past decade with few definite conclusions. The rapid accumulation of relevant information, along with the complex architecture of the disease, provides a challenging but also unique opportunity to review and integrate the heterogeneous data for follow-up validation and exploration. In this study, we collected and curated candidate genes from four major categories: association studies, linkage scans, gene expression analyses, and literature mining. Candidate genes were prioritized according to the magnitude of evidence related to dental caries. We then searched for dense modules enriched with the prioritized candidate genes through their protein-protein interactions (PPIs). We identified 23 modules comprising of 53 genes. Functional analyses of these 53 genes revealed three major clusters: cytokine network relevant genes, matrix metalloproteinases (MMPs) family, and transforming growth factor-beta (TGF-β) family, all of which have been previously implicated to play important roles in tooth development and carious lesions. Through our extensive data collection and an integrative application of gene prioritization and PPI network analyses, we built a dental caries-specific sub-network for the first time. Our study provided insights into the molecular mechanisms underlying dental caries. The framework we proposed in this work can be applied to other complex diseases.     

The Post-Resuscitative Urinalysis Associate the Survival of Patients with Non-Traumatic Out-of-Hospital Cardiac Arrest

Objective

To analyze whether urine output and urinalysis results are predictive of survival and neurologic outcomes in patients with non-traumatic out-of-hospital cardiac arrest (OHCA).

Methods

Information was obtained from 1,340 patients with non-traumatic OHCA who had achieved a sustained return of spontaneous circulation (ROSC). Factors that were associated with survival in the post-resuscitative period were evaluated. The association between urine output and fluid challenge in the early resuscitative period was analyzed and compared between the survivors and the non-survivors. The results of the initial urinalysis, including the presence of proteinuria and other findings, were used to evaluate the severity of vascular protein leakage and survival. The association between proteinuria and the neurologic outcomes of the survivors was also analyzed. The clinical features of capillary leakage were examined during the post-resuscitative period.

Results

Of the 1,340 patients, 312 survived. A greater urine output was associated with a higher chance of survival. The initial urine output increased in proportion to the amount of fluid that was administered during early resuscitation in the emergency department for the survivors but not for the non-survivors (p<0.05). In the initial urinalysis, proteinuria was strongly associated with survival, and severe proteinuria indicated significantly poorer neurologic outcomes (p<0.05 for both comparisons). Proteinuria was associated with a risk of developing signs of capillary leakage, including body mass index gain and pitting edema (both p<0.001).

Conclusion

The severity of proteinuria during the early post-resuscitative period was predictive of survival.     

Trauma History and Depression Predict Incomplete Adherence to Antiretroviral Therapies in a Low Income Country

Background

As antiretroviral therapy (ART) for HIV becomes increasingly available in low and middle income countries (LMICs), understanding reasons for lack of adherence is critical to stemming the tide of infections and improving health. Understanding the effect of psychosocial experiences and mental health symptomatology on ART adherence can help maximize the benefit of expanded ART programs by indicating types of services, which could be offered in combination with HIV care.

Methodology

The Coping with HIV/AIDS in Tanzania (CHAT) study is a longitudinal cohort study in the Kilimanjaro Region that included randomly selected HIV-infected (HIV+) participants from two local hospital-based HIV clinics and four free-standing voluntary HIV counselling and testing sites. Baseline data were collected in 2008 and 2009; this paper used data from 36 month follow-up interviews (N = 468). Regression analyses were used to predict factors associated with incomplete self-reported adherence to ART.

Results

Incomplete ART adherence was significantly more likely to be reported amongst participants who experienced a greater number of childhood traumatic events: sexual abuse prior to puberty and the death in childhood of an immediate family member not from suicide or homicide were significantly more likely in the non-adherent group and other negative childhood events trended toward being more likely. Those with incomplete adherence had higher depressive symptom severity and post-traumatic stress disorder (PTSD). In multivariable analyses, childhood trauma, depression, and financial sacrifice remained associated with incomplete adherence.

Discussion

This is the first study to examine the effect of childhood trauma, depression and PTSD on HIV medication adherence in a low income country facing a significant burden of HIV. Allocating spending on HIV/AIDS toward integrating mental health services with HIV care is essential to the creation of systems that enhance medication adherence and maximize the potential of expanded antiretroviral access to improve health and reduce new infections.     

Analysis of Variations in the Glutamate Receptor,N-Methyl D-Aspartate 2A (GRIN2A) Gene Reveals Their Relative Importance as Genetic Susceptibility Factors for Heroin Addiction

The glutamate receptor, N-methyl D-aspartate 2A (GRIN2A) gene that encodes the 2A subunit of the N-methyl D-aspartate (NMDA) receptor was recently shown to be involved in the development of opiate addiction. Genetic polymorphisms in GRIN2A have a plausible role in modulating the risk of heroin addiction. An association of GRIN2A single-nucleotide polymorphisms (SNPs) with heroin addiction was found earlier in African Americans. To identify markers that contribute to the genetic susceptibility to heroin addiction, we examined the potential association between heroin addiction and forty polymorphisms of the GRIN2A gene using the MassARRAY system and GeneScan in this study. The frequency of the (GT)26 repeats (rs3219790) in the heroin addiction group was significantly higher than that in the control group (χ² = 5.360, P = 0.021). The allele frequencies of three polymorphisms (rs1102972, rs1650420, and rs3104703 in intron 3) were strongly associated with heroin addiction (P<0.001, 0.0002, and <0.001, after Bonferroni correction). Three additional SNPs from the same intron (rs1071502, rs6497730, and rs1070487) had nominally significant P values for association (P<0.05), but did not pass the threshold value. Haplotype analysis revealed that the G-C-T-C-C-T-A (block 6) and T-T (block 10) haplotypes of the GRIN2A gene displayed a protective effect (P = <0.001 and 0.003). These findings point to a role for GRIN2A polymorphisms in heroin addiction among the Han Chinese from Shaanxi province, and may be informative for future genetic or neurobiological studies on heroin addiction.     

Down-Regulation of OsSPX1 Causes High Sensitivity to Cold and Oxidative Stresses in Rice Seedlings

Rice SPX domain gene, OsSPX1, plays an important role in the phosphate (Pi) signaling network. Our previous work showed that constitutive overexpression of OsSPX1 in tobacco and Arabidopsis plants improved cold tolerance while also decreasing total leaf Pi. In the present study, we generated rice antisense and sense transgenic lines of OsSPX1 and found that down-regulation of OsSPX1 caused high sensitivity to cold and oxidative stresses in rice seedlings. Compared to wild-type and OsSPX1-sense transgenic lines, more hydrogen peroxide accumulated in seedling leaves of OsSPX1-antisense transgenic lines for controls, cold and methyl viologen (MV) treatments. Glutathione as a ROS scavenger could protect the antisense transgenic lines from cold and MV stress. Rice whole genome GeneChip analysis showed that some oxidative-stress marker genes (e.g. glutathione S-transferase and P450s) and Pi-signaling pathway related genes (e.g. OsPHO2) were significantly down-regulated by the antisense of OsSPX1. The microarray results were validated by real-time RT-PCR. Our study indicated that OsSPX1 may be involved in cross-talks between oxidative stress, cold stress and phosphate homeostasis in rice seedling leaves.     

Single,Double and Quadruple Alanine Substitutions at Oligomeric Interfaces Identify Hydrophobicity as the Key Determinant of Human Neutrophil Alpha Defensin HNP1 Function

HNP1 is a human alpha defensin that forms dimers and multimers governed by hydrophobic residues, including Tyr¹⁶, Ile²⁰, Leu²⁵, and Phe²⁸. Previously, alanine scanning mutagenesis identified each of these residues and other hydrophobic residues as important for function. Here we report further structural and functional studies of residues shown to interact with one another across oligomeric interfaces: I20A-HNP1 and L25A-HNP1, plus the double alanine mutants I20A/L25A-HNP1 and Y16A/F28A-HNP1, and the quadruple alanine mutant Y16A/I20A/L25A/F28A-HNP1. We tested binding to HIV-1 gp120 and HNP1 by surface plasmon resonance, binding to HIV-1 gp41 and HNP1 by fluorescence polarization, inhibition of anthrax lethal factor, and antibacterial activity using the virtual colony count assay. Similar to the previously described single mutant W26A-HNP1, the quadruple mutant displayed the least activity in all functional assays, followed by the double mutant Y16A/F28A-HNP1. The effects of the L25A and I20A single mutations were milder than the double mutant I20A/L25A-HNP1. Crystallographic studies confirmed the correct folding and disulfide pairing, and depicted an array of dimeric and tetrameric structures. These results indicate that side chain hydrophobicity is the critical factor that determines activity at these positions.     

To Control False Positives in Gene-Gene Interaction Analysis: Two Novel Conditional Entropy-Based Approaches

Genome-wide analysis of gene-gene interactions has been recognized as a powerful avenue to identify the missing genetic components that can not be detected by using current single-point association analysis. Recently, several model-free methods (e.g. the commonly used information based metrics and several logistic regression-based metrics) were developed for detecting non-linear dependence between genetic loci, but they are potentially at the risk of inflated false positive error, in particular when the main effects at one or both loci are salient. In this study, we proposed two conditional entropy-based metrics to challenge this limitation. Extensive simulations demonstrated that the two proposed metrics, provided the disease is rare, could maintain consistently correct false positive rate. In the scenarios for a common disease, our proposed metrics achieved better or comparable control of false positive error, compared to four previously proposed model-free metrics. In terms of power, our methods outperformed several competing metrics in a range of common disease models. Furthermore, in real data analyses, both metrics succeeded in detecting interactions and were competitive with the originally reported results or the logistic regression approaches. In conclusion, the proposed conditional entropy-based metrics are promising as alternatives to current model-based approaches for detecting genuine epistatic effects.     

Reconstructive Treatment of Ruptured Intracranial Spontaneous Vertebral Artery Dissection Aneurysms: Long-Term Results and Predictors of Unfavorable Outcomes

Introduction

Few studies focused on predictors of unfavorable outcomes (modified Rankin Scale, 2–6) after reconstructive treatment of the ruptured intracranial spontaneous vertebral artery dissection aneurysms (ris-VADAs), which was evaluated based on 57 reconstructed lesions in this study.

Methods

Results of 57 consecutive patients (M:F = 29∶28; median age, 48 years; range, 27 to 69 years) harboring 57 ris-VADAs, which were treated with coils combined with single stent(n = 32), double overlapping stents (n = 16), and triple overlapping stents (n = 9) between October 2000 to March 2011, were retrospectively reviewed and analyzed.

Results

The available (n = 54) mean durations of angiographic and clinical follow-ups were 27 months (range, 12 to 78) and 62 months (range, 12 to 132), respectively. The involvement of PICA (p = 0.004), size of lesions (p = 0.000), quantity of stent (p = 0.001), and coil type (p = 0.002) affected the immediate obliteration grade, which was only risk factor for angiographic recurrences (p = 0.031). Although the post-treatment outcomes did not differ between single stent and multiple stents (p = 0.434), 5 angiographic recurrences, 1 rebleeding and 1 suspected rebleeding, all occurred in partial obliteration after single-stent-assisted coiling. Progressive thrombosis and in-stent obliteration were not detected on follow-up angiograms. Older age (odds ratio [OR] = 1.090; 95% confidence interval [CI], 1.004–1.184; p = 0.040) and unfavorable Hunt-Hess scale (OR = 4.289; 95%CI, 1.232–14.933; p = 0.022) were independent predictors of unfavorable outcomes in the reconstructed ris-VADAs.

Conclusions

Immediate obliteration grade was only risk factor for angiographic recurrence after reconstructive treatment. Unfavorable Hunt-Hess grade and older age were independent predictors of unfavorable outcomes in ris-VADAs.