Acute leukemias in Piauí: comparison with features observed in other regions of Brazil

Differences in age and sex distribution as well as FAB (French-American-British classification) types have been reported for acute leukemias in several countries. We studied the demographics and response to treatment of patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) between 1989 and 2000 in Teresina, Piauí, and compared these results with reports from Brazil and other countries. Complete data concerning 345 patients (230 ALL, 115 AML) were reviewed. AML occurred predominantly in adults (77%), with a median age of 34 years, similar to that found in the southeast of Brazil but lower than the median age in the United States and Europe (52 years). FAB distribution was similar in children and adults and FAB-M2 was the most common type, as also found in Japan. The high frequency of FAB-M3 described in most Brazilian studies and for Hispanics in the United States was not observed. Overall survival for adults was 40%, similar to other studies in Brazil. A high mortality rate was observed during induction. No clinical or hematological parameter influenced survival in the Cox model. ALL presented the characteristic peak of incidence between 2-8 years. Most of the cases were CD10+ pre-B ALL. In 25%, abnormal expression of myeloid antigens was observed. Only 10% of the patients were older than 30 years. Overall survival was better for children. Age and leukocyte count were independent prognostic factors. These data demonstrate that, although there are regional peculiarities, the application of standardized treatments and good supportive care make it possible to achieve results observed in other countries for the same chemotherapy protocols.33133

Screening for hotspot mutations in PI3K, JAK2, FLT3 and NPM1 in patients with myelodysplastic syndromes

INTRODUCTION: Myelodysplastic syndromes encompass a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, refractory cytopenia and a tendency to progress toward acute myeloid leukemia. The accumulation of genetic alterations is closely associated with the progression of myelodysplastic syndromes toward acute myeloid leukemia. OBJECTIVE: To investigate the presence of mutations in the points most frequent for mutations (hotspot mutations) in phosphatidylinositol-3-kinase (PI3K), Janus kinase 2 (JAK2), FMS-like tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1), which are involved in leukemia and other cancers, in a population of Brazilian MDS patients. METHODS: Fifty-one myelodysplastic syndromes patients were included in the study. According to French-American-British classification, the patients were distributed as follows: 31 with refractory anemia, 8 with refractory anemia with ringed sideroblasts, 7 with refractory anemia with excess blasts, 3 with refractory anemia with excess blasts in transformation and 2 with chronic myelomonocytic leukemia. Bone marrow samples were obtained and screened for the presence of hotspot mutations using analysis based on amplification with the polymerase chain reaction, sequencing, fragment size polymorphisms or restriction enzyme digestion. All patients were screened for mutations at the time of diagnosis, and 5 patients were also screened at the time of disease progression. RESULTS: In the genes studied, no mutations were detected in the patients at the time of diagnosis. One patient with chronic myelomonocytic leukemia was heterozygous for a Janus kinase 2 mutation after disease progression. CONCLUSIONS: These results show that hotspot mutations in the PI3K, JAK2, FLT3 and NPM1 genes are not common in MDS patients; nevertheless, JAK2 mutations may be present in myelodysplasia during disease progression

Platinum-group elements, S, Se and Cu in highly depleted abyssal peridotites from the Mid-Atlantic Ocean Ridge (ODP Hole 1274A): Influence of hydrothermal and magmatic processes

Highly depleted harzburgites and dunites were recovered from ODP Hole 1274A, near the intersection between the Mid-Atlantic Ocean Ridge and the 15°20′N Fracture Zone. In addition to high degrees of partial melting, these peridotites underwent multiple episodes of melt-rock reaction and intense serpentinization and seawater alteration close to the seafloor. Low concentrations of Se, Cu and platinum-group elements (PGE) in harzburgites drilled at around 35-85 m below seafloor are consistent with the consumption of mantle sulfides after high degrees (>15-20 %) of partial melting and redistribution of chalcophile and siderophile elements into PGE-rich residual microphases. Higher concentrations of Cu, Se, Ru, Rh and Pd in harzburgites from the uppermost and lowest cores testify to late reaction with a sulfide melt. Dunites were formed by percolation of silica- and sulfur-undersaturated melts into low-Se harzburgites. Platinum-group and chalcophile elements were not mobilized during dunite formation and mostly preserve the signature of precursor harzburgites, except for higher Ru and lower Pt contents caused by precipitation and removal of platinum-group minerals. During serpentinization at low temperature (<250 °C) and reducing conditions, mantle sulfides experienced desulfurization to S-poor sulfides (mainly heazlewoodite) and awaruite. Contrary to Se and Cu, sulfur does not record the magmatic evolution of peridotites but was mostly added in hydrothermal sulfides and sulfate from seawater. Platinum-group elements were unaffected by post-magmatic low-temperature processes, except Pt and Pd that may have been slightly remobilized during oxidative seawater alteration

Substrate specificity of microbial transglutaminase as revealed by three-dimensional docking simulation and mutagenesis

Transglutaminases (TGases) are used in fields such as food and pharmaceuticals. Unlike other TGases, microbial transglutaminase (MTG) activity is Ca2+-independent, broadening its application. Here, a three-dimensional docking model of MTG binding to a peptide substrate, CBZ-Gln-Gly, was simulated. The data reveal CBZ-Gln-Gly to be stretched along the MTG active site cleft with hydrophobic and/or aromatic residues interacting directly with the substrate. Moreover, an oxyanion binding site for TGase activity may be constructed from the amide groups of Cys64 and/or Val65. Alanine mutagenesis verified the simulated binding region and indicated that large molecules can be widely recognized on the MTG cleft

Fractal Characteristics of May-Grünwald-Giemsa Stained Chromatin Are Independent Prognostic Factors for Survival in Multiple Myeloma

The use of computerized image analysis for the study of nuclear texture features has provided important prognostic information for several neoplasias. Recently fractal characteristics of the chromatin structure in routinely stained smears have shown to be independent prognostic factors in acute leukemia. In the present study we investigated the influence of the fractal dimension (FD) of chromatin on survival of patients with multiple myeloma.We analyzed 67 newly diagnosed patients from our Institution treated in the Brazilian Multiple Myeloma Study Group. Diagnostic work-up consisted of peripheral blood counts, bone marrow cytology, bone radiograms, serum biochemistry and cytogenetics. The International Staging System (ISS) was used. In every patient, at least 40 digital nuclear images from diagnostic May-Grünwald-Giemsa stained bone marrow smears were acquired and transformed into pseudo-3D images. FD was determined by the Minkowski-Bouligand method extended to three dimensions. Goodness-of-fit of FD was estimated by the R(2) values in the log-log plots. The influence of diagnostic features on overall survival was analyzed in Cox regressions. Patients that underwent autologous bone marrow transplantation were censored at the day of transplantation.Median age was 56 years. According to ISS, 14% of the patients were stage I, 39% were stage II and 47% were stage III. Additional features of a bad prognosis were observed in 46% of the cases. When stratifying for ISS, both FD and its goodness-of-fit were significant prognostic factors in univariate analyses. Patients with higher FD values or lower goodness-of-fit showed a worse outcome. In the multivariate Cox-regression, FD, R(2), and ISS stage entered the final model, which showed to be stable in a bootstrap resampling study.Fractal characteristics of the chromatin texture in routine cytological preparations revealed relevant prognostic information in patients with multiple myeloma

A demonstration of an affinity between pyrite and organic matter in a hydrothermal setting

One of the key-principles of the iron-sulphur world theory is to bring organic molecules close enough to interact with each other, using the surface of pyrite as a substrate in a hydrothermal setting. The present paper explores the relationship of pyrite and organic matter in a hydrothermal setting from the geological record; in hydrothermal calcite veins from Carboniferous limestones in central Ireland. Here, the organic matter is accumulated as coatings around, and through, pyrite grains. Most of the pyrite grains are euhedral-subhedral crystals, ranging in size from ca 0.1-0.5 mm in diameter, and they are scattered throughout the matrix of the vein calcite. The organic matter was deposited from a hydrothermal fluid at a temperature of at least 200°C, and gives a Raman signature of disordered carbon. This study points to an example from a hydrothermal setting in the geological record, demonstrating that pyrite can have a high potential for the concentration and accumulation of organic materials

Rochechouart 2017-Drilling Campaign: First Results

No abstract available

Molecular characteristics and chromatin texture features in acute promyelocytic leukemia

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Background: Acute promyelocytic leukemia is a cytogenetically well defined entity. Nevertheless, some features observed at diagnosis are related to a worse outcome of the patients. Methods: In a prospective study, we analyzed peripheral (PB) leukocyte count, immunophenotype, methylation status of CDKN2B, CDKN2A and TP73; FLT3 and NPM1 mutations besides nuclear chromatin texture characteristics of the leukemic cells. We also examined the relation of these features with patient's outcome. Results: Among 19 cases, 4 had a microgranular morphology, 7 presented PB leukocytes >10x10(9)/l, 2 had FLT3-ITD and 3 had FLT3-TKD (all three presenting a methylated CDKN2B). NPM1 mutation was not observed. PB leukocyte count showed an inverse relation with standard deviation of gray levels, contrast, cluster prominence, and chromatin fractal dimension (FD). Cases with FLT3-ITD presented a microgranular morphology, PB leukocytosis and expression of HLA-DR, CD34 and CD11b. Concerning nuclear chromatin texture variables, these cases had a lower entropy, contrast, cluster prominence and FD, but higher local homogeneity, and R(2)45, in keeping with more homogeneously distributed chromatin. In the univariate Cox analysis, a higher leukocyte count, FLT3-ITD mutation, microgranular morphology, methylation of CDKN2B, besides a higher local homogeneity of nuclear chromatin, a lower chromatin entropy and FD were associated to a worse outcome. All these features lost significance when the cases were stratified for FLT3-ITD mutation. Methylation status of CDNK2A and TP73 showed no relation to patient's survival. Conclusion: in APL, patients with FLT3-ITD mutation show different clinical characteristics and have blasts with a more homogeneous chromatin texture. Texture analysis demonstrated that FLTD-ITD was accompanied not only by different cytoplasmic features, but also by a change in chromatin structure in routine cytologic preparations. Yet we were not able to detect chromatin changes by nuclear texture analysis of patients with the FTLD-TKD or methylation of specific genes.7Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [2007/54686-0]CNPq [302277/2009-9, 307270/2010-6, 402022/2010-6

Fractal dimension of chromatin is an independent prognostic factor for survival in melanoma

<p>Abstract</p> <p>Background</p> <p>Prognostic factors in malignant melanoma are currently based on clinical data and morphologic examination. Other prognostic features, however, which are not yet used in daily practice, might add important information and thus improve prognosis, treatment, and survival. Therefore a search for new markers is desirable. Previous studies have demonstrated that fractal characteristics of nuclear chromatin are of prognostic importance in neoplasias. We have therefore investigated whether the fractal dimension of nuclear chromatin measured in routine histological preparations of malignant melanomas could be a prognostic factor for survival.</p> <p>Methods</p> <p>We examined 71 primary superficial spreading cutaneous melanoma specimens (thickness ≥ 1 mm) from patients with a minimum follow up of 5 years. Nuclear area, form factor and fractal dimension of chromatin texture were obtained from digitalized images of hematoxylin-eosin stained tissue micro array sections. Clark's level, tumor thickness and mitotic rate were also determined.</p> <p>Results</p> <p>The median follow-up was 104 months. Tumor thickness, Clark's level, mitotic rate, nuclear area and fractal dimension were significant risk factors in univariate Cox regressions. In the multivariate Cox regression, stratified for the presence or absence of metastases at diagnosis, only the Clark level and fractal dimension of the nuclear chromatin were included as independent prognostic factors in the final regression model.</p> <p>Conclusion</p> <p>In general, a more aggressive behaviour is usually found in genetically unstable neoplasias with a higher number of genetic or epigenetic changes, which on the other hand, provoke a more complex chromatin rearrangement. The increased nuclear fractal dimension found in the more aggressive melanomas is the mathematical equivalent of a higher complexity of the chromatin architecture. So, there is strong evidence that the fractal dimension of the nuclear chromatin texture is a new and promising variable in prognostic models of malignant melanomas.</p

Silly Questions and Arguments for the Implicit, Cinematic Narrator

My chapter aims to advance the debate on a problem often raised by philosophers who are skeptical of implied narrators in movies. This is the concern that positing such elusive narrators gives rise to absurd imaginings (Gaut 2004: 242; Carroll 2006: 179-180). Friends of the implied cinematic narrator reply that the questions critics raise about the workings of the implied cinematic narrator are "silly ones" to ask. I examine how the "absurd imaginings" problem arises for all the central arguments for the elusive cinematic narrator and discuss why the questions critics pose about this narrator are legitimate ones to ask