Mutations other than 103N in human immunodeficiency virus type 1 reverse transcriptase (RT) emerge from K103R polymorphism under non-nucleoside RT inhibitor pressure

AbstractK103N mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) confers high-level resistance against non-nucleoside RT inhibitors (NNRTIs) and it easily occurs partly because it arises by a single nucleotide substitution from wild-type K103. There are polymorphisms at codon 103 of HIV-1 RT. We found K103R polymorphic mutation in 3.3% of treatment-naive HIV-1-infected patients. R103N does not seem to occur as easily as K103N because R103N requires two nucleotide substitutions. To induce NNRTI resistance-associated mutations, HIV-1K103R was propagated in the presence of increasing concentrations of efavirez (EFV) or nevirapine (NVP). V179D emerged in all three EFV cultures and in two of four NVP cultures. R103G emerged by a single nucleotide substitution in one of three EFV cultures. R103N did not emerge in any of 7 NNRTI cultures. Analysis of recombinant HIV-1s showed that HIV-1K103R/V179D was significantly resistant and HIV-1K103G was moderately resistant against EFV and NVP

A Pilot Study: The Beneficial Effects of Combined Statin-exercise Therapy on Cognitive Function in Patients with Coronary Artery Disease and Mild Cognitive Decline.

Objective Hypercholesterolemia, a risk factor in cognitive impairment, can be treated with statins. However, cognitive decline associated with "statins" (HMG-CoA reductase inhibitors) is a clinical concern. This pilot study investigated the effects of combining statins and regular exercise on cognitive function in coronary artery disease (CAD) patients with prior mild cognitive decline. Methods We recruited 43 consecutive CAD patients with mild cognitive decline. These patients were treated with a statin and weekly in-hospital aerobic exercise for 5 months. We measured serum lipids, exercise capacity, and cognitive function using the mini mental state examination (MMSE). Results Low-density lipoprotein cholesterol levels were significantly decreased, and maximum exercise capacity (workload) was significantly increased in patients with CAD and mild cognitive decline after treatment compared with before. Combined statin-exercise therapy significantly increased the median (range) MMSE score from 24 (22-25) to 25 (23-27) across the cohort (p<0.01). Changes in body mass index (BMI) were significantly and negatively correlated with changes in the MMSE. After treatment, MMSE scores in the subgroup of patients that showed a decrease in BMI were significantly improved, but not in the BMI-increased subgroup. Furthermore, the patients already on a statin at the beginning of the trial displayed a more significant improvement in MMSE score than statin-naïve patients, implying that exercise might be the beneficial aspect of this intervention as regards cognition. In a multivariate logistic regression analysis adjusted for age >65 years, sex, and presence of diabetes mellitus, a decrease in BMI during statin-exercise therapy was significantly correlated with an increase in the MMSE score (odds ratio: 4.57, 95% confidence interval: 1.05-20.0; p<0.05). Conclusion Statin-exercise therapy may help improve cognitive dysfunction in patients with CAD and pre-existing mild cognitive decline

Network Features and Pathway Analyses of a Signal Transduction Cascade

The scale-free and small-world network models reflect the functional units of networks. However, when we investigated the network properties of a signaling pathway using these models, no significant differences were found between the original undirected graphs and the graphs in which inactive proteins were eliminated from the gene expression data. We analyzed signaling networks by focusing on those pathways that best reflected cellular function. Therefore, our analysis of pathways started from the ligands and progressed to transcription factors and cytoskeletal proteins. We employed the Python module to assess the target network. This involved comparing the original and restricted signaling cascades as a directed graph using microarray gene expression profiles of late onset Alzheimer's disease. The most commonly used method of shortest-path analysis neglects to consider the influences of alternative pathways that can affect the activation of transcription factors or cytoskeletal proteins. We therefore introduced included k-shortest paths and k-cycles in our network analysis using the Python modules, which allowed us to attain a reasonable computational time and identify k-shortest paths. This technique reflected results found in vivo and identified pathways not found when shortest path or degree analysis was applied. Our module enabled us to comprehensively analyse the characteristics of biomolecular networks and also enabled analysis of the effects of diseases considering the feedback loop and feedforward loop control structures as an alternative path

Plasma Leptin Level, the Adipocyte-Specific Product of the Obese Gene, Is Associated with Tumor Progression and Is a Marker of the Nutritional Status of Patients with Gastric Cancer

Leptin, a product of the obese gene, is synthesized and released into the circulation in response to increased energy storage in adipose tissue. Leptin plays an important role in the regulation of body weight and energy balance. However, leptin levels in patients with malignant tumor have not been fully examined. The purpose of the present study is to clarify the clinical implications of leptin levels in the circulation in patients with gastric cancer. The subjects were 103 patients with gastric cancer at various stages. Levels of leptin in the plasma were determined with a commercially available human leptin-selective quantitative enzyme immunoassay kit. There were clear decreasing trends in leptin levels along with tumor progression in both males and females, and statistically significant differences were observed in males between stages II and IV, and in females between stages I and IV. Plasma leptin levels of females were consistently higher than those of males when we compared them with patients in the same stages. Moreover, statistically significant decreases in leptin levels were observed postoperatively. However, there were no statistically significant relationships between leptin levels and clinicopathological findings. There was a positive correlation between levels of plasma leptin and values of the body mass index. These findings may indicate that plasma leptin levels do not involve factors relevant to specific tumor growth but involve some tumor-related nutritional status due to tumor progression. We conclude that leptin levels are reflected during tumor-bearing status, and these are also useful markers for both indicating tumor progression and discovering the nutritional status of patients with gastric cancer

Paediatric HIV and elimination of mother-to-child transmission of HIV in the ASEAN region: a call to action

Recent achievements in scaling up paediatric antiretroviral therapy (ART) have changed the life of children living with HIV, who now stay healthy and live longer lives. However, as it becomes more of a chronic infection, a range of new problems have begun to arise. These include the disclosure of HIV serostatus to children, adherence to ART, long-term toxicities of antiretroviral drugs and their sexual and reproductive health, which are posing significant challenges to the existing health systems caring for children with HIV with limited resources, experiences and capacities. While intensified efforts and actions to improve care and treatment for these children are needed, it is crucial to accelerate the prevention of mother-to-child transmission (PMTCT) of HIV, which is the main cause of paediatric HIV in the ASEAN region so as to eliminate the fundamental cause of the problem. This report argues that given over 70% of women have access to at least one antenatal care visit in the region and acceptance of HIV testing after receiving counselling on PMTCT could be as high as 90%, there is an opportunity to strengthen PMTCT services and eventually eliminate new paediatric HIV infections in the ASEAN countries

Novel Conserved-region T-cell Mosaic Vaccine With High Global HIV-1 Coverage Is Recognized by Protective Responses in Untreated Infection

An effective human immunodeficiency virus type 1 (HIV-1) vaccine is the best solution for halting the acquired immune deficiency syndrome epidemic. Here, we describe the design and preclinical immunogenicity of T-cell vaccine expressing novel immunogens tHIVconsvX, vectored by DNA, simian (chimpanzee) adenovirus, and poxvirus modified vaccinia virus Ankara (MVA), a combination highly immunogenic in humans. The tHIVconsvX immunogens combine the three leading strategies for elicitation of effective CD8+ T cells: use of regions of HIV-1 proteins functionally conserved across all M group viruses (to make HIV-1 escape costly on viral fitness), inclusion of bivalent complementary mosaic immunogens (to maximize global epitope matching and breadth of responses, and block common escape paths), and inclusion of epitopes known to be associated with low viral load in infected untreated people (to induce field-proven protective responses). tHIVconsvX was highly immunogenic in two strains of mice. Furthermore, the magnitude and breadth of CD8+ T-cell responses to tHIVconsvX-derived peptides in treatment-naive HIV-1+ patients significantly correlated with high CD4+ T-cell count and low viral load. Overall, the tHIVconsvX design, combining the mosaic and conserved-region approaches, provides an indisputably better coverage of global HIV-1 variants than previous T-cell vaccines. These immunogens delivered in a highly immunogenic framework of adenovirus prime and MVA boost are ready for clinical development

Visceral Fat Accumulation is Associated with Oxidative Stress and Increased Matrix Metalloproteinase-9 Expression in Atherogenic Factor-overlapped Model Rats

Visceral fat accumulation in lifestyle-related diseases increases the risk of atherosclerosis. Matrix metalloproteinases (MMPs) play an important role in the progression of atherosclerosis. We examined atherogenic factor-overlapped model rats to clarify the relationships among visceral fat, oxidative stress, and MMPs. We used four groups of male, 11-month-old, spontaneously hypertensive hyperlipidemic rats (SHHRs) or Sprague-Dawley (SD) rats. Animals were fed either a diet of high fat and 30% sucrose solution (HFDS) or a normal diet (ND) ad libitum for 6 months. The visceral fat weight increased by approximately three fold in SHHR-HFDS compared to SHHR-ND. The oxidative stress marker in plasma and MMP-9 mRNA expression in white blood cells increased in SHHR-HFDS compared to the other groups. A correlation was determined between oxidative stress and visceral fat or MMP-9 mRNA in all rats. Lipid deposition and immunostaining of CD68 and MMP-9 were observed mainly in the intima of aorta in SHHR-HFDS, while tissue inhibitor of metalloproteinase-1 mRNA expression decreased in both SHHR groups. The findings suggested that increased oxidative stress due to the visceral fat accumulation induced MMP-9 expression and macrophage accumulation in the intima of aorta in lifestyle-related disease model rats

Cytokeratin-Positive Cells in Lymph Nodes in Which Metastases Are Undetectable by Conventional Histological Staining in Advanced Gastric Cancer

Detection of occult metastases in lymph nodes by immunostaining is becoming of increasing interest as a way to improve the accuracy of predicting the prognosis for patients with gastric cancer. Immunohistochemical detection of cytokeratin (CK) is recognized as the most sensitive method for identification of cancerous epithelial cells. In this study, lymph nodes were stained for CK in an effort to detect micrometastases and the clinical implications of the results were examined. We immunostained sections from a total of 1,198 lymph nodes from 25 totally gastrectomized patients with T3 or T4 gastric cancer who had been diagnosed as having no nodal involvement by conventional hematoxylin-eosin (HE) staining. Eighty (6.7%) of 1,198 lymph nodes from 15 (60%) of the 25 patients were immunostained with a CK-specific monoclonal antibody. CK-positive cells were more frequent in patients with macroscopic types of 3,4 and 5 gastric cancer. Patients with nodes that were both HE-negative and CK-negative had the best postoperative survival, followed by patients with HE-negative and CK-positive nodes and, finally, by patiof micrometastases in lymph nodes is a reliable indicator of the prognosis of patients with advanced gastric cancer

FGF2 Has Distinct Molecular Functions from GDNF in the Mouse Germline Niche

Both glial cell line-derived neurotrophic factor (GDNF) and fibroblast growth factor 2 (FGF2) are bona fide self-renewal factors for spermatogonial stem cells, whereas retinoic acid (RA) induces spermatogonial differentiation. In this study, we investigated the functional differences between FGF2 and GDNF in the germline niche by providing these factors using a drug delivery system in vivo. Although both factors expanded the GFRA1+ subset of undifferentiated spermatogonia, the FGF2-expanded subset expressed RARG, which is indispensable for proper differentiation, 1.9-fold more frequently than the GDNF-expanded subset, demonstrating that FGF2 expands a differentiation-prone subset in the testis. Moreover, FGF2 acted on the germline niche to suppress RA metabolism and GDNF production, suggesting that FGF2 modifies germline niche functions to be more appropriate for spermatogonial differentiation. These results suggest that FGF2 contributes to induction of differentiation rather than maintenance of undifferentiated spermatogonia, indicating reconsideration of the role of FGF2 in the germline niche