Incidence and impact of Dihydropyrimidine dehydrogenase gene mutation on neoadjuvant chemotherapy in head and neck cancers

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Publication date: Available online 22 May 2017
Source:Oral Oncology
Author(s): Anuradha Chougule, Vijay M. Patil, Vanita Noronha, Amit Joshi, Siddharth Turkkar, Arun Chandrasekharan, Nikhil Pande, Priyanka Bagayatkar, Kumar Prabhash

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Osteoporosis associated vertebral fractures—Health economic implications

by Julian Joestl, Nikolaus Lang, Adam Bukaty, Thomas M. Tiefenboeck, Patrick Platzer

Introduction

Osteoporosis-associated vertebral fractures represent an increasing clinical and public health problem, one with important socioeconomic effects within western countries.The purpose of this study was to analyse demographic, medical, gender and socioeconomic aspects of osteoporotic vertebral fractures of the thoracic or lumbar spine over a period of at least 10-years.

Material and methods

Included for analysis were 694 patients who had suffered a vertebral fracture due to primary or secondary osteoporosis, and who were treated at our Level-I trauma center between 2000 and 2013. Collected data included demographic, medical and socioeconomic aspects.

Results

Clinical results revealed that 669 patients (96%) were treated conservatively. The remaining 25 patients (4%) underwent surgical therapy: 4 were treated with vertebroplasty, 15 with kyphoplasty and 6 patients with posterior stabilization. The mean age was 75.6 years (range: 50–98), with the vast majority of patients being female (n = 515). A statistically significant demographic difference (i.e., increase) in fractures was observed between the age groups 60–69 and 70–79 (p = 0.041). Concerning socioeconomic aspects, statistical analysis showed that the number of sick leaves and the need for professional domestic help was higher in female patients. Concerning treatment costs, statistical analysis did not reveal any significant differences between female and male patients.

Conclusion

Significant gender differences–to the detriment of the female population–could be demonstrated within this study. A regrettably low rate of adequate treatment after diagnosis of osteoporosis and its associated fractures–specifically relating to primary and secondary prevention–could also be identified. To prospectively avoid complications and consequential cost increases, more awareness of the necessity for prevention, early diagnosis and adequate treatment of osteoporosis and its related fractures should be considered.

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Associations between quality of life, physical activity, worry, depression and insomnia: A cross-sectional designed study in healthy pregnant women

by Danielle Mourady, Sami Richa, Rita Karam, Tatiana Papazian, Fabienne Hajj Moussa, Nada El Osta, Assaad Kesrouani, Joseph Azouri, Hicham Jabbour, Aline Hajj, Lydia Rabbaa Khabbaz

Health-related quality of life (QOL) is reported to be reduced during pregnancy. Associations between QOL, physical activity (PA), insomnia, depression and worry are insufficiently investigated among pregnant women. The aim of this study was to evaluate QOL and PA patterns among healthy pregnant women, and to examine how QOL might correlate to PA, sleep, worry and depression. This is an observational cross-sectional study, conducted among a convenient sample of 141 healthy pregnant women using five questionnaires: WHOQOL-brief (WHO quality of life questionnaire, brief version, ISI (Insomnia Severity Index), PSWQ (Penn State Worry Questionnaire), ZSRDS (Zung Self-Rating Depression Scale), and Pregnancy Physical Activity Questionnaire (PPAQ). Pre-gestational BMI was inversely correlated to overall health while education was positively correlated to psychological health, social relationships and environment domains. Smoking before and during pregnancy significantly impacted the general health and psychological health. Total and light PA were positively correlated to psychological health and social relationships. Sports/exercise showed positive correlations with several QOL domains. Insomnia and depression were significantly associated with a decrease in all domains of QOL, while worries were associated with a decrease in physical, psychological and environmental domains. There were significant negative correlations between ZSRDS scores and total activity. PA, worries, depression and insomnia affected QOL during pregnancy. Furthermore, pregnant women presenting depression had a reduced total PA. Sleep and mental health as well as encouraging PA during pregnancy are necessary to improve the quality of life of pregnant women.

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Benzoapyrene activates interleukin-6 induction and suppresses nitric oxide-induced apoptosis in rat vascular smooth muscle cells

by Huei-Ping Tzeng, Kuo-Cheng Lan, Ting-Hua Yang, Min-Ni Chung, Shing Hwa Liu

Benzo[a]pyrene, a ubiquitous environmental pollutant, has been suggested to be capable of initiating and/or accelerating atherosclerosis. Accumulation of vascular smooth muscle cells (VSMCs) in vessel intima is a hallmark of atherosclerosis. Nitric oxide (NO) can suppress VSMCs proliferation and induce VSMCs apoptosis. NO plays a compensatory role in the vascular lesions to reduce proliferation and/or accelerate apoptosis of VSMCs. The aim of this study was to investigate whether benzo[a]pyrene can affect VSMCs growth and apoptosis induced by NO. Benzo[a]pyrene (1–30 μmol/L) did not affect the cell number and cell cycle distribution in VSMCs under serum deprivation condition. Sodium nitroprusside (SNP), a NO donor, decreased cell viability and induced apoptosis in VSMCs. Benzo[a]pyrene significantly suppressed SNP-induced cell viability reduction and apoptosis. VSMCs cultured in conditioned medium from cells treated with benzo[a]pyrene could also prevent SNP-induced apoptosis. Benzo[a]pyrene was capable of inducing the activation of nuclear factor (NF)-κB and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in VSMCs. Both NF-κB inhibitor and p38 MAPK inhibitor significantly reversed the anti-apoptotic effect of benzo[a]pyrene on SNP-treated VSMCs. Incubation of VSMCs with benzo[a]pyrene significantly and dose-dependently increased interleukin (IL)-6 production. A neutralizing antibody to IL-6 effectively reversed the anti-apoptotic effect of benzo[a]pyrene on SNP-treated VSMCs. Taken together, these results demonstrate for the first time that benzo[a]pyrene activates IL-6 induction and protects VSMCs from NO-induced apoptosis. These findings propose a new mechanism for the atherogenic effect of benzo[a]pyrene.

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Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline

by Eleni Giannoulatou, Geoffrey J. Maher, Zhihao Ding, Ad J. M. Gillis, Lambert C. J. Dorssers, Alexander Hoischen, Ewa Rajpert-De Meyts, WGS500 Consortium , Gilean McVean, Andrew O. M. Wilkie, Leendert H. J. Looijenga, Anne Goriely

Adult male germline stem cells (spermatogonia) proliferate by mitosis and, after puberty, generate spermatocytes that undertake meiosis to produce haploid spermatozoa. Germ cells are under evolutionary constraint to curtail mutations and maintain genome integrity. Despite constant turnover, spermatogonia very rarely form tumors, so-called spermatocytic tumors (SpT). In line with the previous identification of FGFR3 and HRAS selfish mutations in a subset of cases, candidate gene screening of 29 SpTs identified an oncogenic NRAS mutation in two cases. To gain insights in the etiology of SpT and into properties of the male germline, we performed whole-genome sequencing of five tumors (4/5 with matched normal tissue). The acquired single nucleotide variant load was extremely low (~0.2 per Mb), with an average of 6 (2–9) non-synonymous variants per tumor, none of which is likely to be oncogenic. The observed mutational signature of SpTs is strikingly similar to that of germline de novo mutations, mostly involving C>T transitions with a significant enrichment in the ACG trinucleotide context. The tumors exhibited extensive aneuploidy (50–99 autosomes/tumor) involving whole-chromosomes, with recurrent gains of chr9 and chr20 and loss of chr7, suggesting that aneuploidy itself represents the initiating oncogenic event. We propose that SpT etiology recapitulates the unique properties of male germ cells; because of evolutionary constraints to maintain low point mutation rate, rare tumorigenic driver events are caused by a combination of gene imbalance mediated via whole-chromosome aneuploidy. Finally, we propose a general framework of male germ cell tumor pathology that accounts for their mutational landscape, timing and cellular origin.

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Psychosine enhances the shedding of membrane microvesicles: Implications in demyelination in Krabbe’s diseas e

by Ludovic D’Auria, Cory Reiter, Emma Ward, Ana Lis Moyano, Michael S. Marshall, Duc Nguyen, Giuseppe Scesa, Zane Hauck, Richard van Breemen, Maria I. Givogri, Ernesto R. Bongarzone

In prior studies, our laboratory showed that psychosine accumulates and disrupts lipid rafts in brain membranes of Krabbe’s disease. A model of lipid raft disruption helped explaining psychosine’s effects on several signaling pathways important for oligodendrocyte survival and differentiation but provided more limited insight in how this sphingolipid caused demyelination. Here, we have studied how this cationic inverted coned lipid affects the fluidity, stability and structure of myelin and plasma membranes. Using a combination of cutting-edge imaging techniques in non-myelinating (red blood cell), and myelinating (oligodendrocyte) cell models, we show that psychosine is sufficient to disrupt sphingomyelin-enriched domains, increases the rigidity of localized areas in the plasma membrane, and promotes the shedding of membranous microvesicles. The same physicochemical and structural changes were measured in myelin membranes purified from the mutant mouse Twitcher, a model for Krabbe’s disease. Areas of higher rigidity were measured in Twitcher myelin and correlated with higher levels of psychosine and of myelin microvesiculation. These results expand our previous analyses and support, for the first time a pathogenic mechanism where psychosine’s toxicity in Krabbe disease involves deregulation of cell signaling not only by disruption of membrane rafts, but also by direct local destabilization and fragmentation of the membrane through microvesiculation. This model of membrane disruption may be fundamental to introduce focal weak points in the myelin sheath, and consequent diffuse demyelination in this leukodystrophy, with possible commonality to other demyelinating disorders.

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Plasmid-free CRISPR/Cas9 genome editing in Plasmodium falciparum confirms mutations conferring resistance to the dihydroisoquinolone clinical candidate SJ733

by Emily D. Crawford, Jenai Quan, Jeremy A. Horst, Daniel Ebert, Wesley Wu, Joseph L. DeRisi

Genetic manipulation of the deadly malaria parasite Plasmodium falciparum remains challenging, but the rise of CRISPR/Cas9-based genome editing tools is increasing the feasibility of altering this parasite’s genome in order to study its biology. Of particular interest is the investigation of drug targets and drug resistance mechanisms, which have major implications for fighting malaria. We present a new method for introducing drug resistance mutations in P. falciparum without the use of plasmids or the need for cloning homologous recombination templates. We demonstrate this method by introducing edits into the sodium efflux channel PfATP4 by transfection of a purified CRISPR/Cas9-guide RNA ribonucleoprotein complex and a 200-nucleotide single-stranded oligodeoxynucleotide (ssODN) repair template. Analysis of whole genome sequencing data with the variant-finding program MinorityReport confirmed that only the intended edits were made, and growth inhibition assays confirmed that these mutations confer resistance to the antimalarial SJ733. The method described here is ideally suited for the introduction of mutations that confer a fitness advantage under selection conditions, and the novel finding that an ssODN can function as a repair template in P. falciparum could greatly simplify future editing attempts regardless of the nuclease used or the delivery method.

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