Citations

AbstractBackgroundProfiling of mitochondrial DNA is surely to provide valuable investigative clues for forensic cases involving highly degraded specimens or complex maternal lineage kinship determination. But traditionally used hypervariable region sequencing of mitochondrial DNA is less frequently suggested by the forensic community for insufficient informativeness. Genome‐wide sequencing of mitochondrial DNA can provide considerable amount of variant information but can be high cost at the same time.MethodsEfficiency of the 60 mitochondrial DNA polymorphic sites dispersing across the control region and coding region of mitochondrial DNA genome was evaluated with 106 Mongolians recruited from the Xinjiang Uyghur Autonomous Region, China, and allele‐specific PCR technique was employed for mitochondrial DNA typing.ResultsAltogether 58 haplotypes were observed and the haplotypic diversity, discrimination power and random match probability were calculated to be 0.981, 0.972, and 0.028, respectively. Mitochondrial DNA haplogroup affiliation exhibited an exceeding percentage (12.26%) of west Eurasian lineage (H haplogroup) in the studied Mongolian group, which needed to be further verified with more samples. Furthermore, the genetic relationships between the Xinjiang Mongolian group and the comparison populations were also investigated and the genetic affinity was discovered between the Xinjiang Mongolian group and the Xinjiang Kazak group in this study.ConclusionIt was indicated that the panel was potentially enough to be used as a supplementary tool for forensic applications. And the matrilineal genetic structure analyses based on mitochondrial DNA variants in the Xinjiang Mongolian group could be helpful for subsequent anthropological studies.

Abstract The metabolic signatures of cancer cells are often associated with elevated glycolysis which promotes alteration in cellular bioenergetics. 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a critical control point in the glycolytic pathway has emerged as a potential anti-cancer target associated with many aspects of neoplastic progression. Pharmacological (PFK158 treatment) and genetic inhibition of PFKFB3 activity, decreases glucose uptake, ATP production, and lactate dehydrogenase activity and inhibits cell proliferation in vitro by arresting the cells in the G0/G1 phase induced cell death in malignant pleural mesothelioma (MPM). It induces an early response of increased macropinocytosis and drastic endosomal vacuolization to overcome the nutrient stress both in sarcomatoid (H28) and epithelioid (EMMeso) MPM cells. Inhibition of PFKFB3 leads to the activation of the endocytic Rac1-Rab5-Rab7 pathway resulting in a unique form of cell death called “methuosis”. Transmission Electron Microscopy analysis showed that pharmacological and genetic inhibition of PFKFB3 activity leads to the formation of nascent macropinocytotic vesicles, which rapidly coalesced to form large vacuoles with compromised lysosomal function. Confocal microscopy revealed F-actin and α-tubulin disassembly leading to the disruption of cell structure integrity. In parallel, PFKFB3 expression inversely modulates endoplasmic reticulum (ER) stress in MPM. Pharmacological and genetic inhibition of PFKFB3 led to an escalation in ER activity and aggravated ER stress mostly by upregulating BiP and GADD153 expression levels. However, EHT1864, a Rac1 inhibitor, could not rescue MPM cells from ER stress, suggesting that the activation of macropinocytosis and ER stress are a result of two independent PFKFB3 modulated adaptive responses. Both immunofluorescence microscopy and co-immunoprecipitation analyses revealed that the two crucial biomolecules of each pathway, Rac1 and Calnexin, interact with each other only at the later stages of PFKFB3 inhibition. Finally, PFK158, in a combination of with CBPt, demonstrated a significant reduction in tumor weight in mesothelin overexpressed EMMeso xenograft model. Since most cancer cells exhibit an increased glycolytic rate, these results provide evidence for PFK158, in combination with standard chemotherapy, may have a potential in the treatment of MPM. Citation Format: Sayantani Sarkar Bhattacharya, Ling Jin, Debarshi Roy, Deokbeom Jung, Prabhu Thirusangu, Yinan Xiao, Julie Staub, Julian Molina, Viji Shridhar. PFKFB3 inhibition reprograms malignant pleural mesothelioma to glycolytic stress-induced macropinocytosis and ER stress as independent binary adaptive responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2658.

Objective The hypertrophic cardiomyopathy (HCM) risk-sudden cardiac death (SCD) calculator endorsed by the 2014 European Society of Cardiology has not been independently validated in the Asians. We aimed to investigate whether the HCM Risk-SCD calculator effectively predicts SCD in Korean HCM population. Methods An observational, longitudinal cohort study was performed in 730 patients with HCM from 2007 to 2017. The primary endpoint was a composite of SCD and appropriate implantable cardioverter-defibrillator (ICD) therapy. Results During a follow-up period of 4288 person-years, 16 (2.2%) patients reached the primary endpoint. This validation study revealed a calibration slope of 0.892 and C-statistics of 0.718. The primary endpoint occurred in 1.1% (7/615), 4.6% (3/65) and 12.0% (6/50) of low-risk, intermediate-risk and high-risk groups, respectively. Although most patients (85.2%) without the primary endpoint were classified into the low-risk group, 7 of 11 SCD (63.6%) occurred in the low-risk group. In univariable and multivariable analysis, sex (woman) was significantly associated with the primary endpoint and emerged as independent predictor. The addition of sex to the HCM Risk-SCD calculator significantly improved the predictive value of the primary endpoint (net reclassification improvement 0.557, p=0.015). Conclusions In the Korean HCM population, the HCM Risk-SCD calculator had a high negative predictive value and accuracy for predicting SCD or appropriate ICD therapy, but misclassified a few patients experiencing the primary endpoint as low-risk or intermediate-risk groups.

Background and Purpose— Hypertrophic cardiomyopathy patients with atrial fibrillation are at increased risk of stroke, and anticoagulation is strongly recommended. However, limited data are available regarding the safety and effectiveness of non–vitamin K antagonist oral anticoagulants (NOACs) for primary prevention of stroke. Methods— Using the Korean Health Insurance Review and Assessment Service database, we identified 2397 patients with hypertrophic cardiomyopathy and nonvalvular atrial fibrillation on oral anticoagulation from 2013 to 2016 without history of ischemic stroke, intracranial hemorrhage (ICH), or gastrointestinal bleeding (992 on warfarin and 1405 on NOACs). Inverse probability of treatment weighting with propensity scores was used to balance covariates between treatment groups. Risk for ischemic stroke, ICH, gastrointestinal bleeding, death, and their composite outcome associated with NOAC use was assessed with warfarin use as the reference. Results— During a mean follow-up of 1.6 years, the incidence rates of ischemic stroke, ICH, gastrointestinal bleeding, death, and composite outcome were all significantly lower in the NOAC than in the warfarin group (stroke, 2.8 versus 5.0; ICH, 0.5 versus 1.3; gastrointestinal bleeding, 2.3 versus 3.0; death, 3.0 versus 5.1; composite, 7.5 versus 12.5 events per 100 person-years). NOACs were associated with significantly lower risks of ischemic stroke (hazard ratio [HR], 0.47; 95% CI, 0.32–0.68), ICH (HR, 0.31; 95% CI, 0.14–0.69), gastrointestinal bleeding (HR, 0.62; 95% CI, 0.40–0.96), death (HR, 0.45; 95% CI, 0.31–0.65), and the composite outcome (HR, 0.48; 95% CI, 0.38–0.61) than warfarin. The same trend was observed regardless of the NOAC dose and across various high-risk subgroups. In analysis of individual NOACs, all NOACs were associated with lower risks of ischemic stroke and composite outcome. Conclusions— NOACs showed superior effectiveness and safety versus warfarin in the primary prevention of stroke versus warfarin in real-world Asian hypertrophic cardiomyopathy with atrial fibrillation.

Is tau load associated with long-term outcomes of TBI? By using PET to assess tau deposits in patients with chronic TBI, Takahata et al. reveal elevated tau load compared to age-matched controls, and show that the abundance of tau in white matter is associated with late-onset neuropsychiatric symptoms.

Abstract Aims Native T1 times from T1 mapping cardiac magnetic resonance (CMR) are associated with myocardial fibrosis in aortic stenosis (AS). We investigated whether changing patterns in native T1 predict clinical outcomes after aortic valve replacement (AVR) in severe AS patients. Methods and results Forty-three patients with severe AS (65.9 ± 8.1 years; 24 men) who underwent T1 mapping CMR at baseline and 1 year after AVR were prospectively enrolled. Upper limit of native T1 from healthy volunteers was used to define normal myocardium and diffuse fibrosis (native T1 < 1208.4 and ≥1208.4 ms, respectively). Participants were categorized into Group 1 (pre- and post-AVR normal myocardium; n = 11), Group 2 (pre-AVR diffuse fibrosis and post-AVR normal myocardium; n = 18), and Group 3 (post-AVR diffuse fibrosis; n = 14). Native T1 significantly decreased 1 year after AVR (pre-AVR, 1233.8 ± 49.7 ms; post-AVR, 1189.1 ± 58.4 ms; P < 0.001), which was associated with left ventricular (LV) mass regression (△native T1 vs. △LV mass index, r = 0.454, P = 0.010) and systolic function improvement (△native T1 vs. △LV ejection fraction, r = −0.379, P = 0.012). Group 2 showed greater functional improvements, whereas these benefits were blunted in Group 3. Group 3 had significantly worse outcomes than Group 1 [hazard ratio (HR), 9.479, 95% confidence interval (CI) 1.176–76.409; P = 0.035] and Group 2 (HR 3.551, 95% CI 1.178–10.704; P = 0.024). Conclusion AVR-induced changes in native T1 values are associated with LV systolic functional changes as well as prognosis in severe AS. Post-AVR T1 mapping CMR can be used as an imaging biomarker.