Transcript availability dictates the balance between strand-asynchronous and strand-coupled mitochondrial DNA replication.

Mammalian mitochondria operate multiple mechanisms of DNA replication. In many cells and tissues a strand-asynchronous mechanism predominates over coupled leading and lagging-strand DNA synthesis. However, little is known of the factors that control or influence the different mechanisms of replication, and the idea that strand-asynchronous replication entails transient incorporation of transcripts (aka bootlaces) is controversial. A firm prediction of the bootlace model is that it depends on mitochondrial transcripts. Here, we show that elevated expression of Twinkle DNA helicase in human mitochondria induces bidirectional, coupled leading and lagging-strand DNA synthesis, at the expense of strand-asynchronous replication; and this switch is accompanied by decreases in the steady-state level of some mitochondrial transcripts. However, in the so-called minor arc of mitochondrial DNA where transcript levels remain high, the strand-asynchronous replication mechanism is instated. Hence, replication switches to a strand-coupled mechanism only where transcripts are scarce, thereby establishing a direct correlation between transcript availability and the mechanism of replication. Thus, these findings support a critical role of mitochondrial transcripts in the strand-asynchronous mechanism of mitochondrial DNA replication; and, as a corollary, mitochondrial RNA availability and RNA/DNA hybrid formation offer means of regulating the mechanisms of DNA replication in the organelle

MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria

MPV17 is a mitochondrial inner membrane protein whose dysfunction causes mitochondrial DNA abnormalities and disease by an unknown mechanism. Perturbations of deoxynucleoside triphosphate (dNTP) pools are a recognized cause of mitochondrial genomic instability; therefore, we determined DNA copy number and dNTP levels in mitochondria of two models of MPV17 deficiency. In Mpv17 ablated mice, liver mitochondria showed substantial decreases in the levels of dGTP and dTTP and severe mitochondrial DNA depletion, whereas the dNTP pool was not significantly altered in kidney and brain mitochondria that had near normal levels of DNA. The shortage of mitochondrial dNTPs in Mpv17-/- liver slows the DNA replication in the organelle, as evidenced by the elevated level of replication intermediates. Quiescent fibroblasts of MPV17-mutant patients recapitulate key features of the primary affected tissue of the Mpv17-/- mice, displaying virtual absence of the protein, decreased dNTP levels and mitochondrial DNA depletion. Notably, the mitochondrial DNA loss in the patients’ quiescent fibroblasts was prevented and rescued by deoxynucleoside supplementation. Thus, our study establishes dNTP insufficiency in the mitochondria as the cause of mitochondrial DNA depletion in MPV17 deficiency, and identifies deoxynucleoside supplementation as a potential therapeutic strategy for MPV17-related disease. Moreover, changes in the expression of factors involved in mitochondrial deoxynucleotide homeostasis indicate a remodeling of nucleotide metabolism in MPV17 disease models, which suggests mitochondria lacking functional MPV17 have a restricted purine mitochondrial salvage pathway

Long extensive transverse myelitis associated with aquaporin-4 antibody and breast cancer: Favorable response to cancer treatment

Context: Long extensive transverse myelitis (LETM) seldom develops in patients with breast cancer who are aquaporin-4 antibody (Aqp-4 Ab)-positive. Whether this association is coincidental is not well understood

Histological Follow-Up In Patients With Atypical Glandular Cells On Pap Smears

Context: Atypical glandular cells (AGCs) result in the Papanicolaou (Pap) smear may be associated with significant genital and nongenital neoplastic processes. Aims: To evaluate the underlying histopathology in women who had AGCs on Pap smears. Settings and Design: Retrospective cross-sectional study. Patients and Methods: Clinicopathological data of patients who had AGC on Pap smears and underwent histological workup between January 2004 and December 2014 were retrieved from the computerized database of a tertiary care center. Patients with a prior history of cervical intraepithelial neoplasia or gynecological cancer were excluded. Statistical Analysis Used: Chi-square test or Fisher's exact tests were used as appropriate. Results: Cytological examination of the uterine cervix was carried out in 117,560 patients. We identified 107 patients (0.09%) with AGC and 80 of those with histological follow-up were included in the study. The median age at diagnosis was 47 years (range, 18–79), and 32 women (40%) were postmenopausal, while 56 (70%) had gynecological symptoms. Significant preinvasive or invasive lesions on pathological examination were detected in 27 (33.8%) patients, including 12 endometrial adenocarcinomas (15%), 8 cervical carcinomas (10%), 3 cervical intraepithelial neoplasia II/III (3.75%), 2 ovarian adenocarcinomas (2.5%), and 2 metastatic tumors (2.5%). Univariate analysis showed that postmenopausal status (P 50 years old (P < 0.001), having symptoms at the time of admission (P = 0.041), and AGC “favor neoplasia” smear results (P = 0.041) were the clinical factors associated with significant pathological outcome. Conclusions: Patients with AGC on Pap smears should be evaluated vigilantly with histological workup, especially if they are postmenopausal or symptomatic

Review of Current Status of Radiotherapy Facilities and Assessment of Required Time for Radiotherapy Delivery Workflow in Turkey: On Behalf of Turkish Society for Radiation Oncology

The aim this study is to evaluate current status and workload of radiotherapy (RT) centers in Turkey, by assessing time and staff required during core treatment procedures in patients with different tumor sites. A survey sent via e-mail to all hospitals that are actively treating patients with RT, that aimed expose the details on type of the techniques being used and the time spent for treatment planning and delivery for the different techniques according to different tumor sites. The results were evaluated by several variables, the type of the center (university hospitals or state-run hospitals) and the number of patients treated per year per center (<1000 patients/year treated vs. 000 patients/year treated). The survey was sent to 48 centers and the return rate was 71% (34 centers). Average daily treatment course performed by one physician was 192 per year (range: 41 - 650). Median number of patients treated by a specialist per year was 210 (range: 79 - 650) in the university hospitals and 101 (range: 41 - 167) in the state-run hospitals. Median time spent for treating a patient with 3-dimensional conformal RT (3DCRT) was 4 h, and it was 5 h 45 min for intensity-modulated AT (IMRT). The time spent for all cancer types treated with 3DCRT and IMRT was higher in state-run hospitals compared to university hospitals. With increasing use of newer AT techniques, the time spent for treating patients increases. Besides adequate equipment, sufficient and well-trained staff is required to achieve these newer AT technique benefits for the patients

Daily workflow and workload of radiation oncology specialists in Turkey

WOS: 000379361000004OBJECTIVES This study aimed to research the effort required by patient evaluation, radiotherapy planning and treatment processes in the daily applications of radiation oncology in terms of time, and to use this effort as the primary source for human power and infrastructure planning required in radiotherapy. METHODS The surveys carried out by Turkish Radiation Oncology Association Proficiency Board, Curriculum Preparation and Evaluation Commission on Education Institutions, Surveys delivered to the officers of the center via electronic mail, were answered and evaluated in accordance with the data of 2012. RESULTS 26 University and 8 Ministry of Health Hospitals participated in the study. The total number of specialists employed in the participant centers, were 227. For per specialist, 383 hours in a year were spent for the patients at follow-up, 334 hours were spent for the patients that were in treatment, and 950 hours were spent for planning and treatment set-ups. It was determined that the time spent for per patient in intensity modulated radiotherapy technique, was 2-3 times more when compared to the location of tumor, which is a conformal technique. It was observed that this duration was much longer in special radiotherapy applications such as brachytherapy, total body irradiation and radiosurgery. CONCLUSION Technological advancements in radiotherapy, require more effort and working time for new job descriptions and in daily practice

Liver transplantation for acute liver failure due to toxic agent ingestion in children

WOS: 000271811200015PubMed ID: 19210266ALF is characterized by sudden onset, impaired liver function, jaundice and encephalopathy, without previous liver disease. We analyzed the patients who underwent LT due to toxic agent induced ALF to raise community awareness about preventing the toxic agent induced ALF. Five children (three boys, two girls) underwent LT due to toxic agent ingestion. Toxic agents were mushroom poisoning (n = 2), Datura stramonium (n = 1), yellow phosphorous (n = 1) and INH (n = 1). On admission, one patient had stage IV, two had stage III and two had stage II hepatic encephalopathy but worsened during the follow-up. One patient had renal failure, and three patients required mechanical ventilation. Three patients underwent LRLT and others from a DD. Post-operative complications were managed by supportive managements successfully, and overall all the patients are alive (100% survival) without any organ sequelae. Although outcome of these patients are excellent, ALF may be prevented in these cases by educating the public about consuming mushrooms and toxic effects of wild plants, prohibiting fireworks and serial liver enzyme measurements after initiating INH

A View from Young Oncologists on Clinical Trials in Turkey: Obstacles and Solution Proposals

There is a new improvement in oncology nearly in every day as a result of preclinical or clinical. As the number of publication per capita, Turkey is far behind the other developed European countries. For example, the number of publications in oncology field is 2.134.964 in the world, it is 15.576 in our country. The most important obstacles for clinical trials in Turkey may be listed as financial problems, difficulties of working conditions, time limitation due to work intensity, inadequate experienced/trained man-power, absence of assistance team at all steps of a scientific trial, difficulties faced during project planning and ethics committee submissions, and lack of motivation. In this article, we, as young oncologists, aimed to discuss the place of Turkey in areas of scientific and clinical trials in the world; underlying causes for inadequate number, type and quality of national studies and possible solution proposals in our country