Background The association between hepatitis C virus (HCV) infection and coronary artery disease (CAD) is controversial. We conducted this study to determine and quantify this association. Methods We used an established, national, observational cohort of all HCV-infected veterans receiving care at all Veterans Affairs facilities, the Electronically Retrieved Cohort of HCV Infected Veterans, to identify HCV-infected subjects and HCV-uninfected control subjects. We used the Cox proportional-hazards model to determine the risk of CAD among HCV-infected subjects and control subjects. Results We identified 82,083 HCV-infected and 89,582 HCV-uninfected subjects. HCV-infected subjects were less likely to have hypertension, hyperlipidemia, and diabetes but were more likely to abuse alcohol and drugs and to have renal failure and anemia. HCV-infected subjects had lower mean (± standard deviation) total plasma cholesterol (175 ± 40.8 mg/dL vs. 198 ± 41.0 mg/dL), low-density lipoprotein cholesterol (102 ± 36.8 mg/dL vs. 119 ± 38.2 mg/dL), and triglyceride (144 ± 119 mg/dL vs. 179 ± 151 mg/dL) levels, compared with HCV-uninfected subjects. In multivariable analysis, HCV infection was associated with a higher risk of CAD (hazard ratio, 1.25; 95% confidence interval, 1.20–1.30; P < .001 for all comparisons). Traditional risk factors (age, hypertension, chronic obstructive pulmonary disease, diabetes, and hyperlipidemia) were associated with a higher risk of CAD in both groups, whereas minority race and female sex were associated with a lower risk of CAD. Conclusions HCV-infected persons are younger and have lower lipid levels and a lower prevalence of hypertension. Despite a favorable risk profile, HCV infection is associated with a higher risk of CAD after adjustment for traditional risk factors.
Tumor hypoxia greatly suppresses the therapeutic efficacy of photodynamic therapy (PDT), mainly because the generation of toxic reactive oxygen species (ROS) in PDT is highly oxygen-dependent. In contrast to ROS, the generation of oxygen-irrelevant free radicals is oxygen-independent. A new therapeutic strategy based on the light-induced generation of free radicals for cancer therapy is reported. Initiator-loaded gold nanocages (AuNCs) as the free-radical generator were synthesized. Under near-infrared light (NIR) irradiation, the plasmonic heating effect of AuNCs can induce the decomposition of the initiator to generate alkyl radicals (R ), which can elevate oxidative-stress (OS) and cause DNA damages in cancer cells, and finally lead to apoptotic cell death under different oxygen tensions. As a proof of concept, this research opens up a new field to use various free radicals for cancer therapy.
Two major bottlenecks in elucidating the structure and function of membrane proteins are the difficulty of producing large quantities of functional receptors, and stabilizing them for a sufficient period of time. Selecting the right surfactant is thus crucial. Here we report using peptide surfactants in commercial Escherichia coli cell-free systems to rapidly produce milligram quantities of soluble G protein-coupled receptors (GPCRs). These include the human formyl peptide receptor, human trace amine-associated receptor, and two olfactory receptors. The GPCRs expressed in the presence of the peptide surfactants were soluble and had α-helical secondary structures, suggesting that they were properly folded. Microscale thermophoresis measurements showed that one olfactory receptor expressed using peptide surfactants bound its known ligand heptanal (molecular weight 114.18). These short and simple peptide surfactants may be able to facilitate the rapid production of GPCRs, or even other membrane proteins, for structure and function studies.in vitro translation | label-free M embrane proteins play vital roles in all living systems. Approximately 30% of genes in almost all sequenced genomes code for membrane proteins (1-3). However, our detailed understanding of membrane protein structure and function lags far behind that of soluble proteins. Indeed, as of April 2011, there are over 72,000 structures in the Protein Data Bank. Of these, only 280 are unique membrane proteins, and only six are unique G protein-coupled receptors (GPCRs). This surprising disparity is due to bottlenecks at nearly every stage of experimentation, from large-scale membrane protein production to X-ray crystal diffraction.Recent advances have overcome several bottlenecks in studying membrane proteins. Commercial development of nanoliter drop-setting robots and a wide variety of kits have made crystal screening less laborious. The development of worldwide accessible synchrotron facilities, and microfocus beamlines capable of collecting data from crystals <10-60 μm, have overcome the bottlenecks in data collection. Likewise, rapid advancements in computing power and an increase in open access software development have made the determination of structures a much less daunting task. However, inexpensive large-scale production of soluble and nonaggregated membrane proteins still remains a formidable challenge. Likewise, systematic surfactant screens still remain one of the most time-consuming and expensive experimental tasks. To overcome these bottlenecks, the discovery or invention of simple and broadly useful surfactants is crucial.Several cell-based membrane protein production systems have been developed, but they are costly and require months to generate sufficient quantities of protein. Commercial cell-free systems are alternative methods of producing membrane proteins. However, to produce nonaggregated membrane proteins, optimal selection of surfactants is critical: The newly produced membrane proteins must not only fold correctly, they must al...
The effect of hepatitis C virus (HCV) and its treatment on survival is not well defined. We undertook this study to determine the effect of HCV and its treatment on survival in a national cohort of HCV-infected veterans and uninfected controls. We used a national sample of HCV-infected persons and HCV-uninfected controls from the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) to compare survival between the two groups. We also compared the effect of treatment and treatment duration on survival in the HCV-infected group. We used matched Cox proportional hazards model to determine the predictors of mortality. Kaplan-Meier survival plots were generated to determine and compare survival among HCV-infected and HCV-uninfected persons, and among treated and untreated HCV-infected persons. We identified 34,480 matched pairs of HCV-infected subjects and controls. HCV infection was independently associated with a higher risk of mortality (hazards ratio, 1.37; 95% confidence interval, 1.31-1.47). Subjects treated for 48 weeks or longer had the lowest mortality among HCV-infected subjects (hazards ratio, 0.41; 95% confidence interval, 0.27-0.64), whereas those who received less than 48 week of treatment had intermediate mortality ( I t is estimated that more than 170 million persons are infected with the hepatitis C virus (HCV) worldwide. 1 HCV infection is a leading cause of liver cirrhosis, end-stage liver disease, hepatocellular carcinoma, and liver transplantation. 2,3 Treatment for HCV is associated with a reduced risk of liver disease progression and a lower incidence of hepatocellular carcinoma, even when the treatment does not achieve viral eradication. [4][5][6] The impact of HCV infection on survival in the general population is controversial. Some studies have shown a significant increase in mortality in HCV-infected persons, 7,8 whereas others have shown relatively low mortality rate and liver disease progression in otherwise healthy persons. 9,10 In subsets of patients who have undergone liver transplantation, who have human immunodeficiency virus coinfection, or those on hemodialysis, HCV is associated with significantly shortened survival. [11][12][13][14][15][16] Treatment for chronic HCV has been found to be cost-effective 17 and is associated with sustained viral clearance in approximately 54% to 63% of patients overall. [18][19][20][21] However, the effect of HCV infection itself and its treatment on longterm survival is not well known. We used a large national electronically retrieved cohort of HCV infected veterans (ERCHIVES) to compare survival between HCV-infected and HCV-uninfected subjects and to determine the effect of HCV treatment on survival within the HCVinfected subjects. Our study does not attempt to define or determine the appropriateness of treatment initiation,
Mesoporous silica nanoparticles (MSNs) have proved to be an effective carrier for controlled drug release and can be functionalized easily for use as stimuli-responsive vehicles. Here, a novel intelligent drug-delivery system (DDS), camptothecin (CPT)-loaded and doxorubicin (DOX)-conjugated MSN (CPT@MSN-hyd-DOX), is reported via a facile one-pot preparation for use in synergistic chemotherapy of glioblastoma. DOX was conjugated to MSNs via acid-labile hydrazone bonds, and CPT was loaded in the pores of the MSNs. At pH 6.5 (analogous to the pH in tumor tissues), a fast DOX release was observed that was attributed to the hydrolysis of the hydrazone bonds. In addition, a further burst release of DOX was found at pH 5.0 (analogous to the pH in lyso/endosomes of tumor cells), leading to a strong synergistic effect. In all, CPT and DOX could be delivered simultaneously into tumor cells, and this intelligent DDS has great potential for tumor-trigged drug release for use in the synergistic chemotherapy of tumors.
The patS gene encodes a small peptide that is required for normal heterocyst pattern formation in the cyanobacterium Anabaena sp. strain PCC 7120. PatS is proposed to control the heterocyst pattern by lateral inhibition. patS minigenes were constructed and expressed by different developmentally regulated promoters to gain further insight into PatS signaling. patS minigenes patS4 to patS8 encode PatS C-terminal 4 (GSGR) to 8 (CDERGSGR) oligopeptides. When expressed by P petE , P patS , or P rbcL promoters, patS5 to patS8 inhibited heterocyst formation but patS4 did not. In contrast to the full-length patS gene, P hepA -patS5 failed to restore a wild-type pattern in a patS null mutant, indicating that PatS-5 cannot function in cell-to-cell signaling if it is expressed in proheterocysts. To establish the location of the PatS receptor, PatS-5 was confined within the cytoplasm as a gfp-patS5 fusion. The green fluorescent protein GFP-PatS-5 fusion protein inhibited heterocyst formation. Similarly, full-length PatS with a C-terminal hexahistidine tag inhibited heterocyst formation. These data indicate that the PatS receptor is located in the cytoplasm, which is consistent with recently published data indicating that HetR is a PatS target. We speculated that overexpression of other Anabaena strain PCC 7120 RGSGR-encoding genes might show heterocyst inhibition activity. In addition to patS and hetN, open reading frame (ORF) all3290 and an unannotated ORF, orf77, encode an RGSGR motif. Overexpression of all3290 and orf77 under the control of the petE promoter inhibited heterocyst formation, indicating that the RGSGR motif can inhibit heterocyst development in a variety of contexts.
Chordoid meningioma is a rare subtype of meningioma, and is often found supratentorially. There is an absence of association with Castleman's syndrome. Aggressive factors and the extent of resection are helpful in predicting recurrence. It might be more pertinent to downgrade CM to grade I, unless it shows aggressive factors.
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