Myelin pathology: Involvement of molecular chaperones and the promise of chaperonotherapy

The process of axon myelination involves various proteins including molecular chaperones. Myelin alteration is a common feature in neurological diseases due to structural and functional abnormalities of one or more myelin proteins. Genetic proteinopathies may occur either in the presence of a normal chaperoning system, which is unable to assist the defective myelin protein in its folding and migration, or due to mutations in chaperone genes, leading to functional defects in assisting myelin maturation/migration. The latter are a subgroup of genetic chaperonopathies causing demyelination. In this brief review, we describe some paradigmatic examples pertaining to the chaperonins Hsp60 (HSPD1, or HSP60, or Cpn60) and CCT (chaperonin-containing TCP-1). Our aim is to make scientists and physicians aware of the possibility and advantages of classifying patients depending on the presence or absence of a chaperonopathy. In turn, this subclassification will allow the development of novel therapeutic strategies (chaperonotherapy) by using molecular chaperones as agents or targets for treatment

Prognostic significance of serine-phosphorylated STAT3 expression in pT1-T2 oral tongue carcinoma

Objectives. Phosphorylated (activated) STAT3 (pSTAT3) is a regulator of numerous genes that play an essential part in the onset, development and progression of cancer; it is involved in cell proliferation and preventing apoptosis, and in invasion, angiogenesis, and the evasion of immune surveillance. This study aimed mainly to investigate the potential prognostic role of pSTAT3 expression in oral tongue squamous cell carcinoma (SCC). Methods. Phospho-ser727 STAT3 immunolabeling was correlated with prognostic parameters in 34 consecutive cases of pT1\u2013T2 tongue SCCs undergoing primary surgery. Computer-based image analysis was used for the immunohistochemical reactions analysis. Results. Statistical analysis showed a difference in disease-free survival (DFS) when patients were stratified by pN status (P=0.031). Most tumors had variable degrees (mean\ub1SD, 80.7%\ub123.8%) of intense nuclear immunoreaction to pSTAT3. Our findings rule out any significant association of serine-phosphorylated nuclear STAT3 expression with tumor stage, grade, lymph node metastasis, recurrence rate, or DFS. Conclusion. In spite of these results, it is worth further investigating the role of pSTAT3 (serine-and tyrosine-pSTAT3) in oral tongue SCC in larger series because preclinical models are increasingly showing that several anticancer strategies would benefit from STAT3 phosphorylation inhibition

A Visual Inspection System for Rail Detection and Tracking in Real Time Railway Maintenance

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Inflammatory markers as prognostic factors of survival in patients affected by hepatocellular carcinoma undergoing transarterial chemoembolization

Transarterial chemoembolization (TACE) is a good choice for hepatocellular carcinoma (HCC) treatment when surgery and liver transplantation are not feasible. Few studies reported the value of prognostic factors influencing survival after chemoembolization. In this study, we evaluated whether preoperative inflammatory factors such as neutrophil to lymphocyte ratio and platelet to lymphocyte ratio affected our patient survival when affected by hepatocellular carcinoma. Methods. We retrospectively evaluated a total of 72 patients with hepatocellular carcinoma that underwent TACE. We enrolled patients with different etiopathogeneses of hepatitis and histologically proven HCC not suitable for surgery. The overall study population was dichotomized in two groups according to the median NLR value and was analyzed also according to other prognostic factors. Results. The global median overall survival (OS) was 28 months. The OS in patients with high NLR was statistically significantly shorter than that in patients with low NLR. The following pretreatment variables were significantly associated with the OS in univariate analyses: age, Child-Pugh score, BCLC stage, INR, and NLR. Pretreated high NLR was an independently unfavorable factor for OS. Conclusion. NLR could be considered a good prognostic factor of survival useful to stratify patients that could benefit from TACE treatment

Formação continuada de professores : há possibilidades para o lúdico nas atividades educacionais?

A partir da caracterização histórica e cultural do brinquedo, é possível compreender a importância dos materiais lúdicos na formação da subjetividade infantil, bem como no desenvolvimento físico e psíquico das crianças, ficando clara a sua aplicabilidade nos processos de ensino e aprendizagem nas escolas no país. Este trabalho tem por objetivo viabilizar a aplicação de oficinas de construção de brinquedos e jogos no ensino de Física, junto aos educadores das séries da Educação Infantil de escolas públicas brasileiras. Estas oficinas foram desenvolvidas pelo Centro de Educação Continuada em Educação Matemática Científica e Ambiental (CECEMCA), integrante da Rede Nacional de Formação Continuada, desenvolvido pelo Ministério da Educação Brasileiro (MEC) em parceria com as universidades públicas

C and N abundances of MS and SGB stars in NGC 1851

We present the first chemical analysis of stars on the double subgiant branch (SGB) of the globular cluster NGC 1851. We obtained 48 Magellan IMACS spectra of subgiants and fainter stars covering the spectral region between 3650-6750\AA, to derive C and N abundances from the spectral features at 4300\AA (G-band) and at ~ 3883\AA (CN). We added to our sample ~ 45 unvevolved stars previously observed with FORS2 at the VLT. These two datasets were homogeneously reduced and analyzed. We derived abundances of C and N for a total of 64 stars and found considerable star-to-star variations in both [C/H] and [N/H] at all luminosities extending to the red giant branch (RGB) base (V~18.9). These abundances appear to be strongly anticorrelated, as would be expected from the CN-cycle enrichment, but we did not detect any bimodality in the C or N content. We used HST and ground-based photometry to select two groups of faint- and bright-SGB stars from the visual and Str\"omgren color-magnitude diagrams. Significant variations in the carbon and nitrogen abundances are present among stars of each group, which indicates that each SGB hosts multiple subgenerations of stars. Bright- and faint-SGB stars differ in the total C+N content, where the fainter SGB have about 2.5 times the C+N content of the brighter ones. Coupling our results with literature photometric data and abundance determinations from high-resolution studies, we identify the fainter SGB with the red-RGB population, which also should be richer on average in Ba and other s-process elements, as well as in Na and N, when compared to brighter SGB and the blue-RGB population.Comment: 17 pages, 3 tables, 16 figures; typos corrected, added checks on temperature scale; A&A accepted (in press

Functional single nucleotide polymorphisms in dopaminergic receptors D2 predict clinical response to Cariprazine

Cariprazine (CAR) is an antipsychotic drug for the treatment of schizophrenia (SCZ) and bipolar disorder (BD), and it acts as a partial agonist on the dopamine receptors (DR), D2, and D3. Although many single nucleotide polymorphisms (SNPs) in genes coding for these receptors are known to influence response to antipsychotics, to date, no study on CAR pharmacogenetics exists. In this pilot study, we investigated the relationship between SNPs in DRD2 (rs1800497 and rs6277) and DRD3 (rs6280), and response to CAR treatment, evaluated by the psychometric Brief Psychiatric Rating Scale (BPRS), in a cohort of Caucasian patients. We found a significant association between DRD2 rs1800497 and rs6277 and response to CAR treatment. When genotypes were combined into an arbitrary score, the receiver operating characteristic curve analysis showed that using a cut-off value of -2.5 the response to CAR treatment could be predicted with a positive likelihood ratio of 8.0. Our study report, for the first time, a correlation between SNPs in DRD2 and response to CAR treatment. After confirmation in a larger cohort of patients, our results could open the way for the identification of new tools for the provision of response to CAR treatment

Alzheimer’s disease and molecular chaperones: Current knowledge and the future of chaperonotherapy

Background: Alzheimer’s disease (AD) is a dementia, a neurodegenerative condition, and a protein-misfolding disease or proteinopathy, characterized by protein deposits, extracellular plaques and intracellular neurofibrillary tangles, which contain the AD’s typical pathological proteins, abnormal [1]-amyloid and hyperphosphorylated tau, respectively, and are located predominantly in the cortex of the frontal, parietal, and temporal brain lobes. What is the role of molecular chaperones in AD? Data indicate that molecular chaperones, also known as Hsp, are involved in AD, probably displaying protective roles and/or acting as pathogenic factors as it occurs in chaperonopathies in which case AD would be suitable to chaperonotherapy. Hsp60, Hsp70, and Hsp90 can be augmented and overexpressed or diminished and downregulated in various situations in AD affected tissues and cells, indicating they are active during disease development and progression. Question: What is the role of molecular chaperones in AD? Data indicate that molecular chaperones, also known as Hsp, are involved in AD, probably displaying protective roles and/or acting as pathogenic factors as it occurs in chaperonopathies in which case AD would be suitable to chaperonotherapy. Objective: Investigate the role of Hsp in AD, focusing on Hsp60, Hsp70, and Hsp90. Method: Critical examination of published data. Results: Hsp60, Hsp70, and Hsp90 can be augmented and overexpressed or diminished and downregulated in various situations in AD affected tissues and cells, indicating they are active during disease development and progression. Conclusion and Perspectives: Notwithstanding that the roles and mechanisms of action of chaperones in AD are still incompletely understood, there is already enough evidence to encourage the development of therapeutic strategies targeting them, either to block their activity in case they promote disease progression or to boost their performance when they are protective. The latter is an example of positive chaperonotherapy, which also includes chaperone replacement via gene or protein administration. On the contrary, if a chaperone is found to help the disease, it has to be blocked or eliminated, which constitute modalities of negative chaperonotherapy