Oligodendroglioma cells lack glutamine synthetase and are auxotrophic for glutamine, but do not depend on glutamine anaplerosis for growth

In cells derived from several types of cancer, a transcriptional program drives high consumption of glutamine (Gln), which is used for anaplerosis, leading to a metabolic addiction for the amino acid. Low or absent expression of Glutamine Synthetase (GS), the only enzyme that catalyzes de novo Gln synthesis, has been considered a marker of Gln-addicted cancers. In this study, two human cell lines derived from brain tumors with oligodendroglioma features, HOG and Hs683, have been shown to be GS-negative. Viability of both lines depends from extracellular Gln with EC of 0.175 ± 0.056 mM (Hs683) and 0.086 ± 0.043 mM (HOG), thus suggesting that small amounts of extracellular Gln are sufficient for OD cell growth. Gln starvation does not significantly affect the cell content of anaplerotic substrates, which, consistently, are not able to rescue cell growth, but causes hindrance of the Wnt/β-catenin pathway and protein synthesis attenuation, which is mitigated by transient GS expression. Gln transport inhibitors cause partial depletion of intracellular Gln and cell growth inhibition, but do not lower cell viability. Therefore, GS-negative human oligodendroglioma cells are Gln-auxotrophic but do not use the amino acid for anaplerosis and, hence, are not Gln addicted, exhibiting only limited Gln requirements for survival and growth

Epidemiological surveillance of human enteric viruses by monitoring of different environmental matrices.

In the aim of studying possible relations between viruses detected in clinical specimens and the ones found in different environmental matrices, in the period May 2004 to April 2005, the collection of faecal samples from gastroenteritis cases and the monthly monitoring of raw and treated wastewater, river water, seawater and mussels were carried out. The viruses considered for environmental monitoring were adenovirus, rotavirus, enterovirus, norovirus, hepatitis A virus (HAV) and Torque teno virus (TTV): they were searched for with PCR and RT-PCR and confirmed by gene sequencing. Faecal coliforms and somatic coliphages' counts were also determined. The surveillance of case detected 45 positive faecal samples out of 255 (17.6%) while 35 of 56 environmental samples (62.5%) resulted positive for at least one of the considered viruses. The detection of the same viral strain in the faeces of gastroenteritis cases and in water was possible for adenovirus and rotavirus, which were also predominant in environmental matrices; thus they could be considered as a reference for risk assessment

Nocturnal Heart Rate Variability Might Help in Predicting Severe Obstructive Sleep-Disordered Breathing

Obstructive sleep apnea (OSA) can have long-term cardiovascular and metabolic effects. The identification of OSA-related impairments would provide diagnostic and prognostic value. Heart rate variability (HRV) as a measure of cardiac autonomic regulation is a promising candidate marker of OSA and OSA-related conditions. We took advantage of the Physionet Apnea-ECG database for two purposes. First, we performed time- and frequency-domain analysis of nocturnal HRV on each recording of this database to evaluate the cardiac autonomic regulation in patients with nighttime sleep breathing disorders. Second, we conducted a logistic regression analysis (backward stepwise) to identify the HRV indices able to predict the apnea-hypopnea index (AHI) categories (i.e., "Severe OSA", AHI ≥ 30; "Moderate-Mild OSA", 5 ≥ AHI < 30; and "Normal", AHI < 5). Compared to the "Normal", the "Severe OSA" group showed lower high-frequency power in normalized units (HFnu) and higher low-frequency power in normalized units (LFnu). The standard deviation of normal R-R intervals (SDNN) and the root mean square of successive R-R interval differences (RMSSD) were independently associated with sleep-disordered breathing. Our findings suggest altered cardiac autonomic regulation with a reduced parasympathetic component in OSA patients and suggest a role of nighttime HRV in the characterization and identification of sleep breathing disorders

Biomarkers of nucleic acid oxidation, polymorphism in, and expression of, hOGG1 gene in styrene-exposed workers.

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Novel sample-substrates for the determination of new psychoactive substances in oral fluid by desorption electrospray ionization-high resolution mass spectrometry

A reliable screening and non invasive method based on the use of microextraction by packed sorbent coupled with desorption electrospray ionization-high resolution mass spectrometry was developed and validated for the detection of new psychoactive substances in oral fluid. The role of different sample substrates in enhancing signal intensity and stability was evaluated by testing the performances of two polylactide-based materials, i.e. non-functionalized and functionalized with carbon nanoparticles, and a silica-based material compared to commercially available polytetrafluorethylene supports. The best results were achieved by using the nonfunctionalized polylactide substrates to efficiently ionize compounds in positive ionization mode, whereas the silica coating proved to be the best choice for operating in negative ionization mode. LLOQs in the low μg/L, a good precision with CV% always lower than 16% and RR% in the 83(±4)-120(±2)% range, proved the suitability of the developed method for the determination of the analytes in oral fluid. Finally, the method was applied for screening oral fluid samples for the presence of psychoactive substances during private parties, revealing mephedrone in only one sample out of 40 submitted to analysis

Metabolism of the EGFR tyrosin kinase inhibitor gefitinib by cytochrome P450 1A1 enzyme in EGFR-wild type non small cell lung cancer cell lines

<p>Abstract</p> <p>Background</p> <p>Gefitinib is a tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) especially effective in tumors with activating EGFR gene mutations while EGFR wild-type non small cell lung cancer (NSCLC) patients at present do not benefit from this treatment.</p> <p>The primary site of gefitinib metabolism is the liver, nevertheless tumor cell metabolism can significantly affect treatment effectiveness.</p> <p>Results</p> <p>In this study, we investigated the intracellular metabolism of gefitinib in a panel of EGFR wild-type gefitinib-sensitive and -resistant NSCLC cell lines, assessing the role of cytochrome P450 1A1 (CYP1A1) inhibition on gefitinib efficacy. Our results indicate that there is a significant difference in drug metabolism between gefitinib-sensitive and -resistant cell lines. Unexpectedly, only sensitive cells metabolized gefitinib, producing metabolites which were detected both inside and outside the cells. As a consequence of gefitinib metabolism, the intracellular level of gefitinib was markedly reduced after 12-24 h of treatment. Consistent with this observation, RT-PCR analysis and EROD assay showed that mRNA and activity of CYP1A1 were present at significant levels and were induced by gefitinib only in sensitive cells. Gefitinib metabolism was elevated in crowded cells, stimulated by exposure to cigarette smoke extract and prevented by hypoxic condition. It is worth noting that the metabolism of gefitinib in the sensitive cells is a consequence and not the cause of drug responsiveness, indeed treatment with a CYP1A1 inhibitor increased the efficacy of the drug because it prevented the fall in intracellular gefitinib level and significantly enhanced the inhibition of EGFR autophosphorylation, MAPK and PI3K/AKT/mTOR signalling pathways and cell proliferation.</p> <p>Conclusion</p> <p>Our findings suggest that gefitinib metabolism in lung cancer cells, elicited by CYP1A1 activity, might represent an early assessment of gefitinib responsiveness in NSCLC cells lacking activating mutations. On the other hand, in metabolizing cells, the inhibition of CYP1A1 might lead to increased local exposure to the active drug and thus increase gefitinib potency.</p

Sex-associated and gender-associated differences in the diagnosis and management of axial spondyloarthritis: addressing the unmet needs of female patients

Emerging evidence suggests that axial spondyloarthritis (axSpA) should not be seen as a predominantly male disease, as the non-radiographic form occurs with roughly equal frequency in women and men. However, men and women experience this disease differently. The purpose of this review is to highlight sex-associated and gender-associated differences in the patient's journey through the diagnosis and management of axSpA, in order to increase the awareness about the unmet needs of female axSpA patients. Female patients experience a longer diagnostic delay compared with men, possibly due to the different pattern of clinical presentations across genders. Therefore, it is crucial to sensitise physicians to pay attention and identify the red flags of axSpA in women and promote early referral to a rheumatologist. Women with a diagnosis of axSpA experience greater limitations in physical function, although they have less structural spinal damage compared with men. Women tend to have less adherence and a lower response to treatment, so more gender-oriented data are needed about drugs used for axSpA, especially biological disease-modifying antirheumatic drugs. Lifestyle factors have a strong impact on the disease course. Interventions regarding physical activity, smoking cessation and diet should be communicated to the patients, with particular attention to the gender-related cultural background. Patients of childbearing age living with axSpA should be engaged in a discussion about reproductive health, in terms of preservation of fertility, management of pregnancy and delivery and use of biologic drugs during pregnancy and breastfeeding

A organização de simulações das Nações Unidas por estudantes do ensino secundário. De desafios metodológicos a experiências emancipatórias

The Model United Nations (MUN) is increasingly known for its importance in human rights education. It consists of activities that students in high school and college can learn about the manner in which the United Nations operate their programmes, councils, courts and specialized agencies through diplomacy’s simulations, among others, in addition to variations that include the representation of other international organizations or nationals. This paper reports the experience of a teaching project inspired by MUN, developed at the Instituto Federal do Rio Grande do Sul. We present the insertion of IFMUNdi in high school integrated with the vocational teaching, its history of creation, its theoretical-methodological strategies and developments, without losing sight of its educational character. Among the results, the potential of these MUNs in the articulation between theory and practice, in the development of reading, writing and oratory skills, and, above all, in education for democracy, is discussed.O Modelo das Nações Unidas (MUN) é reconhecido por seu caráter interdisciplinar e dinâmico, fazendo uso de estratégias que tornam o ambiente escolar propício à educação emancipadora. Consiste em atividades extracurriculares que promovem simulações de reuniões, cúpulas e assembleias da Organização das Nações Unidas (ONU) e, em alguns casos, de diferentes organismos internacionais e/ou nacionais. Nesses exercícios, estudantes do ensino secundário ou superior representam Estados-membros da ONU, parlamentares, jornalistas, entre outros atores, em debates voltados para a formulação de agendas políticas em torno de problemáticas globais ou regionais. Este artigo recorre à experiência de um projeto inspirado no MUN para apresentar aspectos metodológicos do processo de construção de simulações em uma instituição pública de educação profissional e tecnológica brasileira. Para tanto, contextualiza o projeto no âmbito do ensino secundário, seu histórico de criação, dinâmica, estratégias e desdobramentos, sem perder de vista seu caráter educativo. Nos resultados, discute o potencial do MUN para a articulação entre teoria e prática, o desenvolvimento de habilidades de leitura, de escrita e de oratória, e, sobretudo, para o fomento de práticas de educação para a democracia

The prevalence of risk for hearing impairment in newborns with congenital syphilis in a newborn hearing screening program (NHS)

ObjectiveTo study the prevalence of risk for hearing impairment in neonates with congenital syphilis in a newborn hearing screening program.Study designThe study design is retrospective, documentary, and is cross-sectional. The sample consisted of newborns who were born between January 2019 and December 2021 and who underwent neonatal hearing screening in a public maternity hospital. Demographic data and the presence and specification of risk indicators for hearing impairment (RIHL) were collected. In retest cases, the results and the final score were also collected. For data analysis, the Kruskal–Wallis and Conover-Iman post-hoc tests were used, comparing the groups that passed and failed the hearing screening that had RIHL, using a significance level of p of &lt;0.5.ResultsAmong the RIHL observed in the sample, prematurity was more frequent in newborns who passed the screening (55.26%) than in those who failed the test (45.67%). Congenital syphilis was the ninth most frequent RIHL (8.04%) among the newborns who passed the test and the 15th factor (3.03%), with the highest occurrence in those who failed the hearing screening. When comparing the two groups (pass and fail), we found significant differences (p &lt; 0.05) between them.ConclusionCongenital syphilis was the ninth risk indicator for the most common hearing impairment and, in isolation, did not present a risk for failure in neonatal hearing screening. Notably, congenital syphilis can cause late hearing loss during child development. Thus, there is an indication of audiological monitoring of these neonates