Focused screening identifies different sensitivities of human TET oxygenases to the oncometabolite 2-hydroxyglutarate

Ten-eleven translocation enzymes (TETs) are Fe(II)/2-oxoglutarate (2OG) oxygenases that catalyze the sequential oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine in eukaryotic DNA. Despite their roles in epigenetic regulation, there is a lack of reported TET inhibitors. The extent to which 2OG oxygenase inhibitors, including clinically used inhibitors and oncometabolites, modulate DNA modifications via TETs has been unclear. Here, we report studies on human TET1–3 inhibition by a set of 2OG oxygenase-focused inhibitors, employing both enzyme-based and cellular assays. Most inhibitors manifested similar potencies for TET1–3 and caused increases in cellular 5hmC levels. (R)-2-Hydroxyglutarate, an oncometabolite elevated in isocitrate dehydrogenase mutant cancer cells, showed different degrees of inhibition, with TET1 being less potently inhibited than TET3 and TET2, potentially reflecting the proposed role of TET2 mutations in tumorigenesis. The results highlight the tractability of TETs as drug targets and provide starting points for selective inhibitor design

Determining the origin of synchronous multifocal bladder cancer by exome sequencing

BACKGROUND: Synchronous multifocal tumours are commonly observed in urothelial carcinomas of the bladder. The origin of these physically independent tumours has been proposed to occur by either intraluminal migration (clonal) or spontaneous transformation of multiple cells by carcinogens (field effect). It is unclear which model is correct, with several studies supporting both hypotheses. A potential cause of this uncertainty may be the small number of genetic mutations previously used to quantify the relationship between these tumours. METHODS: To better understand the genetic lineage of these tumours we conducted exome sequencing of synchronous multifocal pTa urothelial bladder cancers at a high depth, using multiple samples from three patients. RESULTS: Phylogenetic analysis of high confidence single nucleotide variants (SNV) demonstrated that the sequenced multifocal bladder cancers arose from a clonal origin in all three patients (bootstrap value 100 %). Interestingly, in two patients the most common type of tumour-associated SNVs were cytosine mutations of TpC* dinucleotides (Fisher’s exact test p < 10(−41)), likely caused by APOBEC-mediated deamination. Incorporating these results into our clonal model, we found that TpC* type mutations occurred 2-5× more often among SNVs on the ancestral branches than in the more recent private branches (p < 10(−4)) suggesting that TpC* mutations largely occurred early in the development of the tumour. CONCLUSIONS: These results demonstrate that synchronous multifocal bladder cancers frequently arise from a clonal origin. Our data also suggests that APOBEC-mediated mutations occur early in the development of the tumour and may be a driver of tumourigenesis in non-muscle invasive urothelial bladder cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1859-8) contains supplementary material, which is available to authorized users

NÜKLEER TIPTA KULLANILAN BAZI HAFİF DEFORME RADYOAKTİF ÇEKİRDEKLERİN KOLLEKTİF BAND YAPISININ İNCELENMESİ

Bu çalışmada, nükleer tıpta kullanılan, kütle numarası 40 < A < 100 aralığındaki bazı hafif deforme radyoaktif çekirdeklerin seviye yoğunluk parametreleri, her radyoaktif çekirdeğin farklı bandları için, enerji spektrumlarından yararlanılarak hesaplanmıştır. İncelenen radyoaktif çekirdeklerin uyarılma enerjisine bağlı olarak enerji seviye yoğunluk parametrelerinin hesaplanmasında hafif deforme çekirdeklerin enerji seviyelerinin eş-aralıklı ve nükleonların kollektif hareketlerini dikkate alan bir model kullanılmıştır. Elde edilen sonuçlar, s dalgalı nötron rezonans verileri için diğer çalışmalardan elde edilen diğer değerler ile karşılaştırılmıştır.In this study, the nuclear energy level density parameters of some light deformed radioactive nucleus used in nuclear medicine have been determined by using energy spectrum of the interest radioactive nucleus for different band. The investigated radionuclides have been considered in the region of mass number 40 < A < 100. In calculation of nuclear energy level density parameters dependent upon excitation energy of radioactive nuclei studied, a model was considered which relies on the fact that energy levels of deformed light nuclei are equidistant and which relies on collective motions of their nucleons. The present calculated results have been compared with the compiled values from the literatures for s-wave neutron resonance data

L'Écho : grand quotidien d'information du Centre Ouest

25 septembre 19261926/09/25 (A55).Appartient à l’ensemble documentaire : PoitouCh

Additional file 2: Figure S1. of Determining the origin of synchronous multifocal bladder cancer by exome sequencing

Neighbour-joining tree of indels in the 4 samples and the human reference genome based on 2130–2555 indels. Bootstrap support for each internal node is indicated. (PDF 301 kb

Consensus statement: Long-term results of ABI in children with complex inner ear malformations and decision making between CI and ABI

7th IEEE Asia-Pacific Conference on Applied Electromagnetics, APACE 2016 -- 11 December 2016 through 13 December 2016 -- 127632‘Second Consensus Meeting on Management of Complex Inner Ear Malformations: Long Term Results of ABI in Children and Decision Making Between CI and ABI’ took place on 5–6 April 2013 in Kyrenia, Northern Cyprus with the participation of 20 centers from 11 countries. These centers presented their auditory brainstem implantation (ABI) experience in children and infants and also provided the selection criteria and cochlear implant (CI) results in patients with an abnormal cochlea and nerve. In addition, Cochlear and Med El companies provided presentations regarding solutions to problems during revision surgery and future projections of device technology. According to the results from different centers, it was evident that an ABI is capable of providing hearing sensation in prelingually deafened children with complex inner ear malformations and diseases. It is possible to obtain a pure tone average with an ABI between 30 and 60 dB HL in most of these patients. It has been observed that the majority of children obtain Categories of Auditory Performance (CAP) scores around 5, but occasionally certain ABI users obtained scores of up to CAP 8-II, NEAP-Nottingham Early Assessment Package. The Ear Foundation 2009). CAP scores tend to increase with earlier implantation, i.e. under 2 years of age. However, after 3 years of use, it usually reaches a plateau. Children with additional disorders cannot reach CAP scores of children without disorders. However, they obtain an improvement of cognitive functions but duration of ABI use and increasing chronological age also play a role in this improvement

Immunogenicity and protection efficacy of a COVID-19 DNA vaccine encoding spike protein with D614G mutation and optimization of large-scale DNA vaccine production

Abstract Severe acute respiratory syndrome coronavirus 2 had devastating consequences for human health. Despite the introduction of several vaccines, COVID-19 continues to pose a serious health risk due to emerging variants of concern. DNA vaccines gained importance during the pandemic due to their advantages such as induction of both arms of immune response, rapid development, stability, and safety profiles. Here, we report the immunogenicity and protective efficacy of a DNA vaccine encoding spike protein with D614G mutation (named pcoSpikeD614G) and define a large-scale production process. According to the in vitro studies, pcoSpikeD614G expressed abundant spike protein in HEK293T cells. After the administration of pcoSpikeD614G to BALB/c mice through intramuscular (IM) route and intradermal route using an electroporation device (ID + EP), it induced high level of anti-S1 IgG and neutralizing antibodies (P < 0.0001), strong Th1-biased immune response as shown by IgG2a polarization (P < 0.01), increase in IFN-γ levels (P < 0.01), and increment in the ratio of IFN-γ secreting CD4+ (3.78–10.19%) and CD8+ (5.24–12.51%) T cells. Challenging K18-hACE2 transgenic mice showed that pcoSpikeD614G administered through IM and ID + EP routes conferred 90–100% protection and there was no sign of pneumonia. Subsequently, pcoSpikeD614G was evaluated as a promising DNA vaccine candidate and scale-up studies were performed. Accordingly, a large-scale production process was described, including a 36 h fermentation process of E. coli DH5α cells containing pcoSpikeD614G resulting in a wet cell weight of 242 g/L and a three-step chromatography for purification of the pcoSpikeD614G DNA vaccine

TÜRKIYE’DE YOĞUN BAKIM ÜNITELERINDE VENTILATÖR ILIŞKILI PNÖMONIYI ÖNLEMEK IÇIN ALINAN GÜNCEL ÖNLEMLER: TÜRK TORAKS DERNEĞI SOLUNUM YETMEZLIĞI VE YOĞUN BAKIM ÇALIŞMA GRUBU NOKTA PREVALANS ÇALIŞMASI

Objectives: The inadequate quality and nature of sleep is a commonly reported problem among hospitalized patients. The purpose of this study is to examine the effects of progressive muscle relaxation training program on sleep quality, sleep state, pain and life quality of patients who underwent pulmonary resection