Transcription and replication of mitochondrial DNA (mtDNA) are regulated by nuclear DNA-encoded proteins that are targeted into mitochondria. A decrease in mtDNA copy number results in mitochondrial dysfunction, which may lead to insulin resistance and metabolic syndromes. We analyzed mitochondrial proteins that physically bind to human mitochondrial D-loop DNA using a shot-gun proteomics approach following protein enrichment by D-loop DNA-linked affinity chromatography. A total of 152 D-loop DNA binding proteins were identified by peptide sequencing using ultra high pressure capillary reverse-phase liquid chromatography/tandem mass spectrometry. Bioinformatic analysis showed that 68 were mitochondrial proteins, 96 were DNA/RNA/protein binding proteins and 114 proteins might form a complex via protein-protein interactions. Histone family members of H1, H2A, H2B, H3, and H4, were detected in abundance among them. In particular, histones H2A and H2B were present in the mitochondrial membrane as integral membrane proteins and not bound directly to mtDNA inside the organelle. Histones H1.2, H3 and H4 were associated with the outer mitochondrial membrane. Silencing of H2AX expression inhibited mitochondrial protein transport. Our data suggests that many mitochondrial proteins may reside in multiple subcellular compartments like H2AX and exert multiple functions.

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ObjectivesTo assess the association between hand grip strength (HGS) and health-related quality of life (HRQoL) among Korean cancer survivors.DesignPopulation-based cross-sectional study.SettingA nationally representative population survey data (face-to-face interviews and health examinations were performed in mobile examination centres).ParticipantsA total of 1037 cancer survivors (person with cancer of any type who is still living) with available data on HGS and HRQoL in the sixth and seventh Korea National Health and Nutrition Examination Surveys (2014–2017).Primary outcome measuresPrevalence of impaired HRQoL by HGS.ResultsAmong 1037 cancer survivors (60.7% women, mean age=62.2 years), 19.2% of them had weak HGS according to gender-specific cut-off values (lowest quintile<29.7 kg in men and <19.7 kg in women). In the study population, the most common cancer site was the stomach, followed by the thyroid, breast, colorectal and cervix. Individuals with weak HGS showed statistically significantly increased impairment in all five dimensions of the EuroQoL-5 dimension (EQ-5D) compared with those in patients with normal HGS. In a multinomial logistic regression analysis, impaired HRQoL (some or extreme problem in EQ-5D) was significantly reduced in each dimension of the EQ-5D, except for anxiety/depression, when HGS was increased. The OR for impaired HRQoL ranged from 0.86 to 0.97 per 1 kg increase in HGS in four dimensions (mobility, self-care, usual activity and pain/discomfort).ConclusionsWeak HGS was associated with impaired HRQoL in cancer survivors. Future longitudinal studies are needed to confirm the causality between HGS and HRQoL in cancer survivors.

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ObjectivesPD-1/PD-L1 and CTLA-4 have been investigated and are thought to play an important role in tumor evasion. This study aimed to investigate expression patterns of immune-related molecules, and their clinical impacts in malignant salivary gland tumors.Patients and methodsWe performed immunohistochemical staining for PD-L1, PD-L2, CTLA-4, PD-1, and CD8+ tumor-infiltrating lymphocytes in 70 malignant salivary gland tumors. Protein expression was assessed by H-score by multiplying the staining intensity by the percentage of cells with positive staining.ResultsThe tumors comprised mucoepidermoid carcinomas (38.6%), adenoid cystic carcinomas (21.4%), salivary duct carcinomas (15.7%), and others. In malignant salivary gland tumors, PD-L2 expression was high, while expression of PD-L1 was relatively low in terms of the percentage of positively stained cells and the staining intensity. In univariate analysis, PD-L2 expression (H-score <1 vs ≥1), PD-1 (H-score <1 vs ≥1), and CD8+ tumor-infiltrating lymphocytes (H-score <1 vs ≥1) were significant prognostic factors. In multivariate analysis, low PD-L2 expression (H-score <1) was independently associated with shorter relapse-free survival (hazard ratio =6.514; 95% confidence interval, 1.2–36.2; P=0.032).ConclusionIn summary, PD-L2 is potentially an important biomarker in malignant salivary gland tumors, especially in regard to relapse.

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Background:This prospective, phase II trial evaluated the efficacy and safety of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours (GISTs) after failure of at least imatinib and sunitinib.Methods:Patients received oral dovitinib, 500 mg once daily, for 5 consecutive days, followed by a 2-day rest, every 28 days. The primary endpoint was disease control rate (DCR; objective response+stable disease (SD)) at 24 weeks, assessed by computed tomography (CT) scan according to RECIST v1.0. Metabolic response was evaluated by positron emission tomography (PET)–CT scans performed at baseline and after 4 weeks of treatment.Results:Between September 2011 and April 2012, 30 patients were enroled. DCR at 24 weeks by RECIST v1.0 was 13% and one patient (3%) had a partial response. Based on the European Organization for Research and Treatment of Cancer PET response criteria, four patients (13%) had a metabolic partial response after 4 weeks of treatment. At a median follow-up of 8.3 months (range, 6.3–12.2 months), median progression-free survival (PFS) was 3.6 months (95% confidence interval (CI), 3.5–3.7 months) and median overall survival was 9.7 months (95% CI, 6.0–13.4 months). Metabolic progressive disease at Week 4 was significantly associated with shorter PFS (P=0.03). Grade 3/4 adverse events included asthenia (20%), neutropenia (13%), thrombocytopenia (10%), and hypertriglyceridaemia (10%). Most toxicities were manageable by dose modification.Conclusion:Dovitinib showed modest antitumour activity with manageable toxicities in heavily pretreated patients with advanced GISTs.

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