Effect of short range order on electronic and magnetic properties of disordered Co based alloys

We here study electronic structure and magnetic properties of disordered CoPd and CoPt alloys using Augmented Space Recursion technique coupled with the tight-binding linearized muffin tin orbital (TB-LMTO) method. Effect of short range ordering present in disordered phase of alloys on electronic and magnetic properties has been discussed. We present results for magnetic moments, Curie temperatures and electronic band energies with varying degrees of short range order for different concentrations of Co and try to understand and compare the magnetic properties and ordering phenomena in these systems.Comment: 15 pages,17 postscript figures,uses own style file

Deregulation of cancer-stem-cell-associated miRNAs in tissues and sera of colorectal cancer patients

Colorectal cancer (CRC) is a deadly tumour in Western countries characterized by high cellular/molecular heterogeneity. Cancer stem cells (CSC) act in cancer recurrence, drug-resistance and in metastatic epithelial-to-mesenchymal transition. microRNAs (miRNAs) contribute to cancer is increasing, and miRNA roles in CSC phenotype and fate and their utility as CRC biomarkers have also been reported. Here, we investigated miR-21, miR-221, miR-18a, miR-210, miR-31, miR-34a, miR-10b and miR-16 expression in experimental ALDH+ and CD44+/CD326+ colorectal CSCs obtained from the human CRC cell lines HCT-116, HT-29 and T-84. Then, we moved our analysis in cancer tissue (CT), healthy tissue (HT) and serum (S) of adult CRC patients (n=12), determining relationships with clinical parameters (age, sex, metastasis, biochemical serum markers). Specific miRNA patterns were evident in vitro (normal, monolayers and CSCs) and in patients' samples stratified by TNM stage (LOW vs HIGH) or metastasis (Met vs no-Met). miR-21, miR-210, miR-34a upregulation ad miR-16 dowregulation associated with the CSCs phenotype. miR-31b robustly overexpressed in monolayers and CSCs, and in CT ad S of HIGH grade and Met patients, suggesting a role as marker of CRC progression and metastasis. miR-18a upregulated in all cancer models and associated to CSC phenotype, and to metastasis and age in patients. miR-10b downregulated in CT and S of LOW/HIGH grade and no-Met patients. Our results identify miRNAs useful as colorectal CSC biomarker and that miR-21, miR-210, miR-10b and miR-31b are promising markers of CRC. A specific role of miR-18a as metastatic CRC serum biomarker in adult patients was also highlighted

Translational toxicology in setting occupational exposure limits for dusts and hazard classification – a critical evaluation of a recent approach to translate dust overload findings from rats to humans

Background We analyze the scientific basis and methodology used by the German MAK Commission in their recommendations for exposure limits and carcinogen classification of “granular biopersistent particles without known specific toxicity” (GBS). These recommendations are under review at the European Union level. We examine the scientific assumptions in an attempt to reproduce the results. MAK’s human equivalent concentrations (HECs) are based on a particle mass and on a volumetric model in which results from rat inhalation studies are translated to derive occupational exposure limits (OELs) and a carcinogen classification. Methods We followed the methods as proposed by the MAK Commission and Pauluhn 2011. We also examined key assumptions in the metrics, such as surface area of the human lung, deposition fractions of inhaled dusts, human clearance rates; and risk of lung cancer among workers, presumed to have some potential for lung overload, the physiological condition in rats associated with an increase in lung cancer risk. Results The MAK recommendations on exposure limits for GBS have numerous incorrect assumptions that adversely affect the final results. The procedures to derive the respirable occupational exposure limit (OEL) could not be reproduced, a finding raising considerable scientific uncertainty about the reliability of the recommendations. Moreover, the scientific basis of using the rat model is confounded by the fact that rats and humans show different cellular responses to inhaled particles as demonstrated by bronchoalveolar lavage (BAL) studies in both species. Conclusion Classifying all GBS as carcinogenic to humans based on rat inhalation studies in which lung overload leads to chronic inflammation and cancer is inappropriate. Studies of workers, who have been exposed to relevant levels of dust, have not indicated an increase in lung cancer risk. Using the methods proposed by the MAK, we were unable to reproduce the OEL for GBS recommended by the Commission, but identified substantial errors in the models. Considerable shortcomings in the use of lung surface area, clearance rates, deposition fractions; as well as using the mass and volumetric metrics as opposed to the particle surface area metric limit the scientific reliability of the proposed GBS OEL and carcinogen classification.International Carbon Black Associatio

Estudo clínico-eletrencefalográfico longitudinal em pacientes epilépticos tratados com Ro 5-4023

Estudaram-se as modificações do quadro clínico e do quadro eletrencefalográfico em 22 pacientes com manifestações epilépticas diárias (5 com ausências típicas, 3 com crises psicomotoras, 5 com ausências mioclônicas, 1 com mioclonias de ação e 8 com síndrome de Lennox), tratados com 7-nitro-5-(2clorofenil)-3H-1,4 benzodiazepina 2 (1H)-one ou Ro 5-4023. Vinte pacientes tinham sido submetidos a terapêuticas anticonvulsivantes usuais sem resultados apreciáveis. Com o uso de Ro 5-4023 as crises foram controladas desde o primeiro dia em 14 pacientes. Em mais 6 doentes houve redução rápida e significativa da intensidade e da freqüência das crises. Destes, um não mais apresentou manifestações a partir da segunda semana de tratamento. Recidivas parciais ocorreram em 8 pacientes. Destaca-se o amplo campo de ação da droga, que age nas epilepsias generalizadas (ausências típicas e ausências mioclônicas), em epilepsias parciais, particularmente crises psicomotoras da infância com ponta-ondas lentas, nas encefalopatias epilépticas graves da infância, de tipo Lennox, e também em síndrome epiléptico degenerativo. Os efeitos colaterais, presentes em 11 pacientes, foram passageiros em 9. Precipitação de crises generalizadas tônico-clônicas ocorreu em dois pacientes; contudo há indícios que esse fenômeno é mais freqüente com outros derivados benzodiazepínicos. As modificações do EEG incluiram desaparecimento ou diminuição das descargas bilaterais e difusas, espontâneas e/ou desencadeadas pela estimulação luminosa intermitente, aparecimento de ritmos rápidos e difusos, persistência ou aparecimento de anormalidades focais lentas ou de tipo irritativo

Espasmos em flexão: estudo clínico longitudinal de pacientes tratados com Nitrazepam (mogadon)

O tratamento foi satisfatório em 11 dos 12 pacientes com espasmos em flexão. Em dois pacientes as crises foram controladas desde o primeiro dia. Em 9 houve redução rápida e significativa da intensidade e da freqüência dos surtos de espasmos em flexão desde o primeiro dia. Iniciado o tratamento, verificamos que: (1) os espasmos conservaram seu aspecto maciço, embora a amplitude e a violência da contração geralmente estivessem diminuidas; (2) ao lado das crises maciças ocorreram crises parciais; (3) o caráter maciço da mioclonia desapareceu, atenuando-se a tendência à repetição em série das crises. O intervalo entre o início dos espasmos em flexão e o início do tratamento com Nitrazepam, bem como o insucesso de tratamentos anteriores com anticonvulsivantes usuais e mesmo com ACTH, não foram fatores desfavoráveis quanto aos resultados, pelo menos iniciais, da terapêutica com Nitrazepam. A médio e longo prazo, foram registradas recidivas parciais das crises em 7 pacientes. As recidivas estiveram nitidamente relacionadas com redução da dose do Nitrazepam ou com episódios infecciosos agudos. Em três: pacientes o controle das crises, após recidiva parcial, foi mais difícil. Em 6 pacientes com espasmos em flexão, os processos respiratórios agudos recidivantes foram mais freqüentes depois de iniciado o tratamento com Nitrazepam. Durante esse tratamento, crises tônicas generalizadas surgiram, pela primeira vez, em 7 pacientes. De acordo com a época de seu aparecimento puderam ser subdivididas em: (1) crises precoces, surgidas entre duas semanas e um mês de tratamento que desapareceram espontâneamente em três meses; (2) crises tardias, surgidas após 5 a 13 meses de tratamento. Ao contrário das tardias, as crises precoces não tiveram relação com redução da dosagem da droga ou com a intercorrência de episódios infecciosos. A ocorrência de outras manifestações críticas e de alterações do comportamento simultâneamente à incidência das crises tônicas tardias, sugere clinicamente a instalação de síndrome de Lennox, embora incompleta

EZH2 endorses cell plasticity to non-small cell lung cancer cells facilitating mesenchymal to epithelial transition and tumour colonization

CGL was funded by the Consejería de Salud y Familias, Junta de Andalucía (RH-0139-2020) and SG-P is funded by Instituto de Salud Carlos III (CP19/00029, PI15/00336, PI19/01533). JAM is supported by RTI2018.101309B-C22 funded by MCIN/AEI/10.13039/501100011033/FEDER “Una manera de hacer Europa” and by the Chair “Doctors Galera-Requena in cancer stem cell research”. PCS is funded by Ministerio de Ciencia e Innovación (grant PID2020-119032RB-I00) and FEDER/Junta de Andalucía-Consejería de Transformación Económica, Industria, Conocimiento y Universidades (grants P20_00335 and B‐CTS‐40‐UGR20). The Landeira lab is supported by the Spanish ministry of science and innovation (PID2019-108108-100, EUR2021-122005), the Andalusian regional government (PC-0246-2017, PIER-0211-2019, PY20_00681) and the University of Granada (A-BIO-6-UGR20) grants.Reversible transition between the epithelial and mesenchymal states are key aspects of carcinoma cell dissemination and the metastatic disease, and thus, characterizing the molecular basis of the epithelial to mesenchymal transition (EMT) is crucial to find druggable targets and more effective therapeutic approaches in cancer. Emerging studies suggest that epigenetic regulators might endorse cancer cells with the cell plasticity required to conduct dynamic changes in cell state during EMT. However, epigenetic mechanisms involved remain mostly unknown. Polycomb Repressive Complexes (PRCs) proteins are well-established epigenetic regulators of development and stem cell differentiation, but their role in different cancer systems is inconsistent and sometimes paradoxical. In this study, we have analysed the role of the PRC2 protein EZH2 in lung carcinoma cells. We found that besides its described role in CDKN2A-dependent cell proliferation, EZH2 upholds the epithelial state of cancer cells by repressing the transcription of hundreds of mesenchymal genes. Chemical inhibition or genetic removal of EZH2 promotes the residence of cancer cells in the mesenchymal state during reversible epithelial–mesenchymal transition. In fitting, analysis of human patient samples and tumour xenograft models indicate that EZH2 is required to efficiently repress mesenchymal genes and facilitate tumour colonization in vivo. Overall, this study discloses a novel role of PRC2 as a master regulator of EMT in carcinoma cells. This finding has important implications for the design of therapies based on EZH2 inhibitors in human cancer patients.Junta de Andalucía (RH-0139-2020)Instituto de Salud Carlos III (CP19/00029, PI15/00336, PI19/01533)MCIN/AEI/10.13039/501100011033/FEDER “Una manera de hacer Europa” RTI2018.101309B-C22Chair “Doctors Galera-Requena in cancer stem cell research”Ministerio de Ciencia e Innovación (grant PID2020-119032RB-I00)FEDER/Junta de Andalucía-Consejería de Transformación Económica, Industria, Conocimiento y Universidades (grants P20_00335 and B‐CTS‐40‐UGR20)Spanish ministry of science and innovation (PID2019-108108-100, EUR2021-122005)Andalusian regional government (PC-0246-2017, PIER-0211-2019, PY20_00681)University of Granada (A-BIO-6-UGR20

Secondary late-onset Lennox-Gastaut syndrome: a critical view

From a group of 66 patients with the Lennox-Gastaut syndrome, 12 whose manifestations had started after the 6th year of life were selected for study. These patients were observed clinically and electroencephalographically for an average period of 2.5 years. We concluded that the late-onset syndrome can: occur after a long interval between diffuse encephalopathy and the first clinical manifestations, with or without previous alterations in psychomotor development; be associated from the onset with serious mental retardation; exhibit simple, complex and mixed seizures similar to those observed in the early form. These patients can also: suffer complex and mixed epileptic seizures previously unreported; paroxismal interictal EEG abnormalities that overlap those of the early form; and spike-slow wave complexes in the EEG that can be actived by hyperpnea. Our results demonstrate that the incidence of LGS after 6 years of age does not necessarily imply a lower frequency of organic antecedents, or beter neu-ropsychomotor development up to the onset of the syndrome or the presence of a higher rate of nonspecific seizures (generalized or partial seizures, and mainly those with elaborate symptomatolgy). The critical and encephalographic expression of the syndrome, which is secondary and starts after the 6th year of age, may depend at least in part on the age when diffuse encephalopathy started

Holoprosencephaly

Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and the 28th day of gestation and affecting both the forebrain and the face. It is estimated to occur in 1/16,000 live births and 1/250 conceptuses. Three ranges of increasing severity are described: lobar, semi-lobar and alobar HPE. Another milder subtype of HPE called middle interhemispheric variant (MIHF) or syntelencephaly is also reported. In most of the cases, facial anomalies are observed in HPE, like cyclopia, proboscis, median or bilateral cleft lip/palate in severe forms, ocular hypotelorism or solitary median maxillary central incisor in minor forms. These latter midline defects can occur without the cerebral malformations and then are called microforms. Children with HPE have many medical problems: developmental delay and feeding difficulties, epilepsy, instability of temperature, heart rate and respiration. Endocrine disorders like diabetes insipidus, adrenal hypoplasia, hypogonadism, thyroid hypoplasia and growth hormone deficiency are frequent. To date, seven genes have been positively implicated in HPE: Sonic hedgehog (SHH), ZIC2, SIX3, TGIF, PTCH, GLI2 and TDGF1. A molecular diagnosis can be performed by gene sequencing and allele quantification for the four main genes SHH, ZIC2, SIX3 and TGIF. Major rearrangements of the subtelomeres can also be identified by multiplex ligation-dependent probe amplification (MLPA). Nevertheless, in about 70% of cases, the molecular basis of the disease remains unknown, suggesting the existence of several other candidate genes or environmental factors. Consequently, a "multiple-hit hypothesis" of genetic and/or environmental factors (like maternal diabetes) has been proposed to account for the extreme clinical variability. In a practical approach, prenatal diagnosis is based on ultrasound and magnetic resonance imaging (MRI) rather than on molecular diagnosis. Treatment is symptomatic and supportive, and requires a multidisciplinary management. Child outcome depends on the HPE severity and the medical and neurological complications associated. Severely affected children have a very poor prognosis. Mildly affected children may exhibit few symptoms and may live a normal life

The electroencephalogram during spontaneous night sleep in epileptic patients

The sleep sistem results of the activity of two components: a descending component originated in the limbic structures, and an ascending system involving the bulbopontine structures which receives projections from the spinal cord components. Although the neocortex is not necessary for sleep mechanisms, it plays a very important role in sleep. Therefore, during the sleep state there is no significant quantitative difference in brain activity, but qualitative changes are recorded in EEG of epileptics patients during all night sleep