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BackgroundThis randomized, open-label, multicenter, phase II clinical trial was conducted to assess the anti-tumor efficacy and safety of replication-deficient adenovirus mutant thymidine kinase (ADV-TK) in combination with ganciclovir administration in patients with recurrent high-grade glioma (HGG).Patients and Methods53 patients with recurrent HGG were randomly allocated to receive intra-arterial cerebral infusion of ADV-TK or conventional treatments. The primary end point was 6-month progression-free survival (PFS-6). Secondary end points included progression-free survival (PFS), overall survival (OS), safety, and clinical benefit. This trial is registered with Clinicaltrials.gov, NCT00870181.ResultsIn ADV-TK group, PFS-6 was 54.5%, the median PFS was 29.6 weeks, the median OS was 45.4 weeks, and better survivals were achieved when compared with control group. The one-year PFS and OS were 22.7% and 44.6% in ADV-TK group respectively, and clinical benefit was 68.2%. There are 2 patients alive for more than 4 years without progression in ADV-TK group. In the subgroup of glioblastoma received ADV-TK, PFS-6 was 71.4%, median PFS was 34.9 weeks, median OS was 45.7 weeks respectively, much better than those in control group. The one-year PFS and OS were 35.7% and 50.0% in ADV-TK group respectively. ADV-TK/ganciclovir gene therapy was well tolerated, and no treatment-related severe adverse events were noted.ConclusionOur study demonstrated a notable improvement of PFS-6, PFS and OS in ADV-TK treated group, and the efficacy and safety appear to be comparable to other reported treatments used for recurrent HGG. ADV-TK gene therapy is therefore a valuable therapeutic option for recurrent HGG.

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Hypertension is the leading risk factor for cardiovascular disorders. This study aimed to explore roles of microRNA (miR)-122-5p in hypertension. Angiotensin II (Ang II; 1.5 mg/kg/day) with an osmotic minipump was used to induce hypertensive rats pretreated by rAAV-miR-122-5p or rAAV-GFP, respectively. Notably, Ang II infusion caused marked increases in myocardial fibrosis, inflammation, oncosis, and oxidant injury in rats, which were aggravated by rAAV-miR-122-5p. RAAV-miR-122-5p exacerbated Ang II-mediated cardiac dysfunction and structural injury in hypertensive rats, with downregulated levels of apelin, elabela, ACE2, and GDF15, as well as upregulated expression of porimin and CTGF. In cultured rat cardiac fibroblasts, Ang II contributed to augmentation of cellular oncosis, migration, inflammation, and oxidative stress, with reduction of apelin, elabela, ACE2, and GDF15 levels, which were rescued by miR-122 inhibitor. In summary, miR-122-5p exacerbates myocardial fibrosis and dysfunction in hypertensive rats by modulating the elabela/apelin-ACE2-GDF15 signaling. MiR-122-5p has potential therapeutic significance for hypertension and hypertensive cardiac injury.

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Background Stress hyperglycemia is strongly associated with poor clinical outcomes in patients with acute coronary syndrome (ACS). Recently, the stress hyperglycemia ratio (SHR) has been proposed to represent relative hyperglycemia. Studies regarding the relationship between SHR and mortality in coronary artery disease (CAD) are limited. This study aimed to clarify the association between SHR and in-hospital mortality in patients with CAD. Methods A total of 19,929 patients with CAD who were hospitalized in Beijing Hospital were enrolled in this study. Patients with an estimated glomerular filtration rate < 30 ml/min, cancer, or missing blood glucose/HbA1c data were excluded; therefore, 8,196 patients were included in the final analysis. The patients were divided into three groups based on tertiles of SHR: T1 group (SHR < 0.725, n = 2,732), T2 group (0.725 ≤ SHR < 0.832, n = 2,730), and T3 group (SHR ≥ 0.832, n = 2,734). The primary endpoint was in-hospital mortality. Results The overall in-hospital mortality rate was 0.91% (n = 74). After adjusting for covariates, SHR was significantly associated with in-hospital mortality in patients with CAD [odds ratio (OR) = 17.038; 95% confidence interval (CI) = 9.668–30.027; P < 0.001], and the T3 group had a higher risk of in-hospital mortality (OR = 4.901; 95% CI = 2.583–9.297; P < 0.001) compared with T1 group. In the subgroup analysis, the T3 group had an increased risk of mortality among patients with pre-diabetes mellitus (pre-DM) (OR = 9.670; 95% CI = 1.886–49.571; P = 0.007) and diabetes mellitus (DM) (OR = 5.023; 95% CI = 2.371–10.640; P < 0.001) after adjustments for covariates. The relationship between SHR and in-hospital mortality among patients with ACS and chronic coronary syndrome was consistent with the main finding. SHR and in-hospital mortality exhibited a dose-response relationship, and the risk of in-hospital mortality increased when the SHR index was above 1.20. Moreover, the area under the curve of SHR for predicting in-hospital mortality in patients with CAD was 0.741. Conclusion SHR is significantly associated with in-hospital mortality in patients with CAD. SHR may be an effective predictor of in-hospital mortality in patients with CAD, especially for those with pre-DM and DM.

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Salivary virome is important for oral ecosystem, but there are few reports on people living with HIV. We performed metagenomic sequencing to compare composition and functional genes of salivary virobiota between one HIV-negative and four HIV-positive groups in which participants were all men who have sex with men (MSM) with different immunosuppression statuses (five samples per group) to find the evidence that salivary virobiota plays a role in the pathogenesis of oral disease. Acute-stage subjects achieved a positive result of HIV RNA, but HIV antibody negative or indeterminate, whereas individuals with mild, moderate, and severe immunosuppression exhibited CD4+ T-lymphocyte counts of at least 500, 200–499, and less than 200 cells/μL or opportunistic infection, respectively. The results showed the composition of salivary virus genera in subjects with mild immunosuppression was the most similar to that in healthy people, followed by that in the acute stage; under severe immunosuppression, virus genera were suppressed and more similar to that under moderate immunosuppression. Furthermore, abnormally high abundance of Lymphocryptovirus was particularly obvious in MSM with HIV infection. Analysis of KEGG Pathway revealed that Caulobacter cell cycle, which affects cell duplication, became shorter in HIV-positive subjects. It is worth noting that in acute-stage participants, protein digestion and absorption related to the anti-HIV-1 activity of secretory leukocyte protease inhibitor was increased. Moreover, in the severely immunosuppressed subjects, glutathione metabolism, which is associated with the activation of lymphocytes, was enhanced. Nevertheless, the ecological dysbiosis in HIV-positive salivary virobiota possibly depended on the changes in blood viral load, and salivary dysfunction of MSM infected with HIV may be related to CD4 counts. Ribonucleoside diphosphate reductase subunit M1 in purine metabolism was negatively correlated, though weakly, to CD4 counts, which may be related to the promotion of HIV-1 DNA synthesis in peripheral blood lymphocytes. 7-Cyano-7-deazaguanine synthase in folate biosynthesis was weakly positively correlated with HIV viral load, suggesting that this compound was produced excessively to correct oral dysfunction for maintaining normal cell development. Despite the limited number of samples, the present study provided insight into the potential role of salivary virome in the oral function of HIV infected MSM.