Mitochondrial diseases and mtDNA editing.

Mitochondrial diseases are a heterogeneous group of inherited disorders characterized by mitochondrial dysfunction, and these diseases are often severe or even fatal. Mitochondrial diseases are often caused by mitochondrial DNA mutations. Currently, there is no curative treatment for patients with pathogenic mitochondrial DNA mutations. With the rapid development of traditional gene editing technologies, such as zinc finger nucleases and transcription activator-like effector nucleases methods, there has been a search for a mitochondrial gene editing technology that can edit mutated mitochondrial DNA; however, there are still some problems hindering the application of these methods. The discovery of the DddA-derived cytosine base editor has provided hope for mitochondrial gene editing. In this paper, we will review the progress in the research on several mitochondrial gene editing technologies with the hope that this review will be useful for further research on mitochondrial gene editing technologies to optimize the treatment of mitochondrial diseases in the future.

White blood cell count combined with LDL cholesterol as a valuable biomarker for coronary artery disease.

OBJECTIVE: Inflammation and dyslipidemia are important pathophysiological bases for the occurrence and development of coronary artery disease (CAD); however, combination of these two entities is rarely used to diagnose CAD and its severity. Our aim was to determine whether the combination of white blood cell count (WBCC) and LDL cholesterol (LDL-C) can serve as a biomarker for CAD. METHODS: We enrolled 518 registered patients and measured serum WBCC and LDL-C on admission. The clinical data were collected, and the Gensini score was used to assess the severity of coronary atherosclerosis. RESULTS: WBCC and LDL-C levels in the CAD group were higher than in the control group ( P  < 0.01). Spearman correlation analysis showed that WBCC combined with LDL-C was positively correlated with the Gensini score ( r  = 0.708, P  < 0.01) and the number of coronary artery lesions ( r  = 0.721, P  < 0.01). Receiver operating characteristic curve analysis revealed that WBCC combined with LDL-C had a higher predictive value for CAD, severe CAD, and three-vessel CAD [area under the curve (AUC) values were 0.909, 0.867, and 0.811, respectively] than WBCC (AUC values were 0.814, 0.753, 0.716, respectively) and LDL-C (AUC values were 0.779, 0.806, 0.715, respectively) alone (all P  < 0.05). CONCLUSION: WBCC combined with LDL-C is correlated with the degree of coronary artery lesion. It had high sensitivity and specificity in the diagnosis of CAD, severe CAD, and three-vessel CAD.

Determination of rivaroxaban in rat plasma by ultra-high-performance liquid chromatography-Q-Orbitrap high-resolution mass spectrometry and its application to a pharmacokinetic study.

Therapeutic drug monitoring is critical to decrease the incidence rate of bleeding and thrombosis for personalized treatment with rivaroxaban, especially for drug interaction treatment, patients with renal dysfunction, elderly patients, patients with cardiovascular problems, and so on. In addition, an accurate analytical method is necessary for therapeutic drug monitoring. This study developed a ultra-HPLC-tandem Orbitrap high-resolution MS (UHPLC-Q-Orbitrap HRMS) method to accurately identify and quantify rivaroxaban in rat plasma. The isotope internal standard method was applied for accurate quantification. Rivaroxaban-d4 was selected as the isotope internal standard substance. The m/z 436.07263 ([M + H]+ ) was selected as the precursor ion and m/z 144.95085 and m/z 231.11259 were selected as the main product ions for rivaroxaban. The lower limit of quantification of rivaroxaban in plasma was 0.01 mg/L. The intra- and inter-day precisions were ≤3.65% and ≤8.16%, while the recoveries ranged from 87.4% to 95.2%. This analysis method was simple, low cost, and easy to operate. The developed and validated method was subsequently applied to successfully investigate the pharmacokinetic parameters of rivaroxaban in rats after its oral administration. These results could be helpful to promote further research regarding the mechanisms of rivaroxaban and drug interaction, which can avoid false positives due to high-precision identification of the proposed method.

Effects of alprostadil combined with tanshinone IIa injection on microcirculation disorder, outcomes, and cardiac function in AMI patients after PCI.

BACKGROUND: Alprostadil can effectively dilate blood vessels, improve cardiac microcirculation, and reduce cardiac load. Tanshinone IIa injection can protect against atherosclerosis and reduce myocardial oxygen consumption. However, the effects of alprostadil combined with tanshinone IIa injection on microcirculation disorder, outcomes, and cardiac function in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI) are still not fully clear. METHODS: A total of 300 AMI patients who underwent PCI in our hospital from January 2013 to June 2018 were randomly selected and divided into group A, B, C by using the random number table method, with 100 patients in each group. The group A was treated with alprostadil, the group B was treated with tanshinone IIa injection, and the group C was treated with alprostadil combined with tanshinone IIa injection. 7 days after treatment, the cardiac functions of all patients were observed by ultrasonic Doppler, as were the microcirculations by myocardial contrast echocardiography (MCE). The major adverse cardiac events (MACEs) in both groups were observed in the 12-month follow-up. RESULTS: After treatment, the left ventricular end-diastolic diameter (LVEDD), end-diastolic left ventricular posterior wall thickness (LVPWD), left ventricular ejection fraction (LVEF), left ventricular end-systolic diameter (LVESD), interventricular septum thickness (IVST), and ratio of maximal early to late diastolic filling velocities (E/A) in the group C were superior to those in the group A and B, the differences were statistically significant (PP<0.05). After treatment, MCE showed that the Aß value of the group aC was higher than that of the group A and B, the difference was statistically significant (P<0.05). The thrombolysis in myocardial infarction myocardial perfusion grade classification showed that the patients with grades 2‒3 were more abundant in the group C than the group A and B, the difference was statistically significant (PP<0.05). The incidences of MACEs, such as malignant arrhythmia, recurrent heart failure (HF), recurrent myocardial infarction, and death, in the group C were significantly lower than those in the group A and B (PP<0.05). CONCLUSIONS: For AMI patients after PCI, alprostadil combined with tanshinone IIa injection can effectively improve microcirculation and ventricular remodeling, improve cardiac function and reduce the occurrence of MACEs. This combination can be widely used in clinical practice.

Downregulation of SIRT6 is associated with poor prognosis in patients with non-small cell lung cancer.

Objective To explore the prognostic significance of nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase sirtuin-6 (SIRT6), encoded by the sirtuin 6 ( SIRT6) gene, in a population of Chinese Han patients with non-small cell lung cancer (NSCLC). Methods Cancer tissues and normal lung tissues (>5 cm adjacent to cancer tissue) were collected from Chinese Han patients with NSCLC. Expression levels of SIRT6 and histone H3-acetyl K56 ( H3K56), in cancer and normal lung tissues from patients with NSCLC, were detected by reverse-transcription polymerase chain reaction, Western blot and immunohistochemistry. Correlations between SIRT6 expression and various clinicopathologic features were investigated. Results Out of 86 patients included in the study, mRNA and protein SIRT6 levels were down-regulated in NSCLC tissue versus normal lung tissue, and SIRT6 levels were inversely correlated with H3K56 levels. Positive rates of SIRT6 were significantly correlated with degree of cell differentiation, TNM stage, lymph node metastasis, overall survival and metastasis-free survival. Conclusion Downregulation of SIRT6 expression may promote NSCLC malignancy in the Chinese Han population. SIRT6 may be a potential therapeutic target in Chinese Han patients with NSCLC.

The role of angiogenesis inhibitors in the treatment of elderly patients with advanced non-small-cell lung cancer: A meta-analysis of eleven randomized controlled trials.

PURPOSE: Data on the role of angiogenesis inhibitors (AIs) in the treatment of elderly patients with advanced non-small-cell lung cancer (NSCLC) remains limited. We aimed to assess the overall efficacy of AIs-containing regimens in the treatment of advanced NSCLC in this setting. MATERIALS AND METHODS: Databases from PubMed, Web of Science, and abstracts presented at American Society of Clinical Oncology (ASCO) meeting up to October 31, 2014 were searched to identify relevant studies. Eligible studies included prospective randomized controlled trials (RCTs) evaluating therapies with or without AIs in elderly patients with advanced NSCLC. The endpoints were overall survival (OS) and progression-free survival (PFS). Statistical analyses were conducted by using random effects models and 95% confidence intervals (CIs) were calculated. RESULTS: A total of 3,709 elderly patients with advanced NSCLC from 11 RCTs were identified for analysis. The pooled results demonstrated that there was a clinical benefit in PFS for AIs-containing regimens (hazard ratio (HR) 0.88, 95%CI: 0.78-1.00, P = 0.053) when compared to non-AIs-containing regimens, but not for OS (HR 0.99, 95%CI: 0.90-1.10, P = 0.89). On subgroup analysis, similar results were found based on treatment line. No publication bias was detected by Begg's and Egger's tests for OS. CONCLUSIONS: In elderly patients with advanced NSCLC, AIs-containing therapies offer a clinical benefit in PFS but for OS. With present available data from RCTs, we are still unable to clearly set the role of specific AIs in the treatment of advanced NSCLC in this setting.

Serum YKL-40 is increased in patients with slow coronary flow.

OBJECTIVES: There is accumulating evidence that inflammation plays a major role in the development of the slow coronary flow (SCF) phenomenon. YKL-40 has been suggested to be a potential biomarker of inflammation. In this study, we aimed to study YKL-40 as it relates to SCF. MATERIALS AND METHODS: Patients who underwent coronary angiography before and had angiographically normal coronary arteries of varying coronary flow rates without any atherosclerotic lesion were enrolled in this study. Patients who had thrombolysis in myocardial infarction frame counts (TFC) above the normal cutoffs were considered to have SCF and those within normal limits were considered to have normal coronary flow (NCF). The YKL-40 levels and biochemical profiles of all patients were studied and analyzed. RESULTS: There were 41 patients in the SCF group and 209 patients in the NCF group. Compared with the NCF patients, SCF patients had higher serum high-sensitivity C-reactive protein (hs-CRP) (P=0.0003) and YKL-40 (P=0.0007) levels. A positive correlation was detected between the YKL-40 levels and hs-CRP (r=0.7021, P<0.001), and the mean TFC (r=0.4038, P=0.0088) in SCF patients. CONCLUSION: Our study showed that YKL-40 levels are higher and correlated positively with TFC and hs-CRP in SCF patients. This finding suggests that YKL-40 may be a useful marker and predictor for SCF.