The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-α-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA-dependent RNA polymerase (RdRp) has been targeted for antiviral development. Direct acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs) in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens. 相似文献
Objective: Depression afflicts 14% of individuals with type 1 diabetes (T1D). Depression is a robust risk factor for dementia but it is unknown if this holds true for individuals with T1D, who recently started living to an age conferring dementia risk. We examined if depression is a dementia risk factor among elderly individuals with T1D.
Methods: 3,742 individuals with T1D age ≥50 were followed for dementia from 1/1/96-9/30/2015. Depression, dementia, and comorbidities were abstracted from electronic medical records. Cox proportional hazard models estimated the association between depression and dementia adjusting for demographics, glycosylated hemoglobin, severe dysglycemic epidsodes, stroke, heart disease, nephropathy, and end stage renal disease. The cumulative incidence of dementia by depression was estimated conditional on survival dementia-free to age 55.
Results: Five percent (N = 182) were diagnosed with dementia and 20% had baseline depression. Depression was associated with a 72% increase in dementia (fully adjusted HR = 1.72; 95% CI:1.12-2.65). The 25-year cumulative incidence of dementia was more than double for those with versus without depression (27% vs. 12%).
Conclusions: For people with T1D, depression significantly increases dementia risk. Given the pervasiveness of depression in T1D, this has major implications for successful aging in this population recently living to old age. 相似文献
Sirt5 is known to functionally regulate mitochondrial proteins by altering posttranslational modifications, including lysine desuccinylation. While roles for Sirt5 as either a tumor promoter or suppressor, or in chemoresistance, have been implicated in other cancers, the function of Sirt5 in cutaneous melanoma has not been well examined. Therefore, to determine whether Sirt5 is necessary for BrafV600E‐mediated melanoma formation and/or disease progression, we crossed a genetically engineered murine melanoma model (TyrCreERT2/+; BrafLSL‐V600E/+; Ptenflox/flox) to Sirt5?/? knockout animals. In addition, we tested for synergism with a selective BRAF (V600E) inhibitor in Sirt5?/? mouse melanoma cells. Taken together, this report demonstrates that, in these models, Sirt5 is dispensable for BrafV600E‐mediated cutaneous melanoma formation and growth in vivo, and does not improve sensitivity to a selective BRAF inhibitor. 相似文献
The purpose of this analysis is to describe the differences in cardiac magnetic resonance characteristics between benign and malignant tumors, which would be helpful for surgical planning.
Methods
This was a prospective cohort study of 130 patients who underwent cardiac magnetic resonance imaging for evaluation of a suspected cardiac mass. After excluding thrombi and tumors without definitive diagnosis, 66 tumors were evaluated for morphologic features and tissue composition.
Results
Of the 66 patients, 39 (59.0%) had malignant tumors and 27 (41.0%) had benign tumors. Patients with malignant tumors were younger when compared with those with benign tumors (age 51 years [42.8-60.0] vs 65 years [60.0-71.0] median). Malignant tumors more often demonstrated tumor invasion (69% vs 0% P < .001) and were more often associated with pericardial effusion (41% vs 7.4% P = .004). Presence of first-pass perfusion (100% vs 33% P < .001) and late gadolinium enhancement (100% vs 59.2%, P < .001) were significantly higher in malignant tumors. In logistic regression modeling, tumor invasion (P < .001) and first-pass perfusion (P < .001) were independently associated with malignancy. Furthermore, using classification and regression tree analysis, we developed a decision tree algorithm to help differentiate benign from malignant tumors (diagnostic accuracy ~90%). The algorithm-weighted cost of misclassifying a malignant tumor as benign was twice that of classifying a benign tumor as malignant.
Conclusions
Our study demonstrates that cardiac magnetic resonance imaging is a useful noninvasive method for differentiating malignant from benign cardiac tumors. Tumor size, invasion, and first-pass perfusion were useful imaging characteristics in differentiating benign from malignant tumors. 相似文献