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La enfermedad de Paget es una neoplasia intraepitelial tipo adenocarcinoma que involucra las glándulas apocrinas de los anexos cutáneos, su mayor incidencia es en piel de la mama. Se presenta el caso de una mujer de 61 años con una lesión cutánea liquenoide de dos años de evolución. Tratada con múltiples tratamientos dermatológicos sin éxito. La biopsia escisional con resultado histopatológico positivo a células pagetoides clásicas de una enfermedad de Paget confirmado por inmunohistoquímica.

Molecular profile of breast cancer in Latin-American women was studied in five countries: Argentina, Brazil, Chile, Mexico, and Uruguay. Data about socioeconomic characteristics, risk factors, prognostic factors, and molecular subtypes were described, and the 60-month overall cumulative survival probabilities (OS) were estimated. From 2011 to 2013, 1,300 eligible Latin-American women 18 years or older, with a diagnosis of breast cancer in clinical stage II or III, and performance status ≦̸1 were invited to participate in a prospective cohort study. Face-to-face interviews were conducted, and clinical and outcome data, including death, were extracted from medical records. Unadjusted associations were evaluated by Chi-squared and Fisher’s exact tests and the OS by Kaplan–Meier method. Log-rank test was used to determine differences between cumulative probability curves. Multivariable adjustment was carried out by entering potential confounders in the Cox regression model. The OS at 60 months was 83.9%. Multivariable-adjusted death hazard differences were found for women living in Argentina (2.27), Chile (1.95), and Uruguay (2.42) compared with Mexican women, for older (≥60 years) (1.84) compared with younger (≤40 years) women, for basal-like subtype (5.8), luminal B (2.43), and HER2-enriched (2.52) compared with luminal A subtype, and for tumor clinical stages IIB (1.91), IIIA (3.54), and IIIB (3.94) compared with stage IIA women. OS was associated with country of residence, PAM50 intrinsic subtype, age, and tumor stage at diagnosis. While the latter is known to be influenced by access to care, including cancer screening, timely diagnosis and treatment, including access to more effective treatment protocols, it may also influence epigenetic changes that, potentially, impact molecular subtypes. Data derived from heretofore understudied populations with unique geographic ancestry and sociocultural experiences are critical to furthering our understanding of this complexity.

PurposesMost molecular-based published studies on breast cancer do not adequately represent the unique and diverse genetic admixture of the Latin American population. Searching for similarities and differences in molecular pathways associated with these tumors and evaluating its impact on prognosis may help to select better therapeutic approaches.Patients and MethodsWe collected clinical, pathological, and transcriptomic data of a multi-country Latin American cohort of 1,071 stage II-III breast cancer patients of the Molecular Profile of Breast Cancer Study (MPBCS) cohort. The 5-year prognostic ability of intrinsic (transcriptomic-based) PAM50 and immunohistochemical classifications, both at the cancer-specific (OSC) and disease-free survival (DFS) stages, was compared. Pathway analyses (GSEA, GSVA and MetaCore) were performed to explore differences among intrinsic subtypes.ResultsPAM50 classification of the MPBCS cohort defined 42·6% of tumors as LumA, 21·3% as LumB, 13·3% as HER2E and 16·6% as Basal. Both OSC and DFS for LumA tumors were significantly better than for other subtypes, while Basal tumors had the worst prognosis. While the prognostic power of traditional subtypes calculated with hormone receptors (HR), HER2 and Ki67 determinations showed an acceptable performance, PAM50-derived risk of recurrence best discriminated low, intermediate and high-risk groups. Transcriptomic pathway analysis showed high proliferation (i.e. cell cycle control and DNA damage repair) associated with LumB, HER2E and Basal tumors, and a strong dependency on the estrogen pathway for LumA. Terms related to both innate and adaptive immune responses were seen predominantly upregulated in Basal tumors, and, to a lesser extent, in HER2E, with respect to LumA and B tumors.ConclusionsThis is the first study that assesses molecular features at the transcriptomic level in a multicountry Latin American breast cancer patient cohort. Hormone-related and proliferation pathways that predominate in PAM50 and other breast cancer molecular classifications are also the main tumor-driving mechanisms in this cohort and have prognostic power. The immune-related features seen in the most aggressive subtypes may pave the way for therapeutic approaches not yet disseminated in Latin America.Clinical Trial RegistrationClinicalTrials.gov (Identifier: NCT02326857).

Sequencing of cancer genomes has identified recurrent somatic mutations in histones, termed oncohistones, which are frequently poorly understood. Previously we showed that fission yeast expressing only the H3.3G34R mutant identified in aggressive pediatric glioma had reduced H3K36 trimethylation and acetylation, increased genomic instability and replicative stress, and defective homology-dependent DNA damage repair. Here we show that surprisingly distinct phenotypes result from G34V (also in glioma) and G34W (giant cell tumors of bone) mutations, differentially affecting H3K36 modifications, subtelomeric silencing, genomic stability; sensitivity to irradiation, alkylating agents, and hydroxyurea; and influencing DNA repair. In cancer, only 1 of 30 alleles encoding H3 is mutated. Whilst co-expression of wild-type H3 rescues most G34 mutant phenotypes, G34R causes dominant hydroxyurea sensitivity, homologous recombination defects, and dominant subtelomeric silencing. Together, these studies demonstrate the complexity associated with different substitutions at even a single residue in H3 and highlight the utility of genetically tractable systems for their analysis.

Interest in the structure, function, and evolutionary relations of circulating and intracellular globins dates back more than 60 years to the first determination of the three-dimensional structure of these proteins. Non-erythrocytic globins have been implicated in circulatory control through reactions that couple nitric oxide (NO) signaling with cellular oxygen availability and redox status. Small artery endothelial cells (ECs) express free α-globin, which causes vasoconstriction by degrading NO. This reaction converts reduced (Fe2+) α-globin to the oxidized (Fe3+) form, which is unstable, cytotoxic, and unable to degrade NO. Therefore, (Fe3+) α-globin must be stabilized and recycled to (Fe2+) α-globin to reinitiate the catalytic cycle. The molecular chaperone α-hemoglobin-stabilizing protein (AHSP) binds (Fe3+) α-globin to inhibit its degradation and facilitate its reduction. The mechanisms that reduce (Fe3+) α-globin in ECs are unknown, although endothelial nitric oxide synthase (eNOS) and cytochrome b5 reductase (CyB5R3) with cytochrome b5 type A (CyB5a) can reduce (Fe3+) α-globin in solution. Here, we examine the expression and cellular localization of eNOS, CyB5a, and CyB5R3 in mouse arterial ECs and show that α-globin can be reduced by either of two independent redox systems, CyB5R3/CyB5a and eNOS. Together, our findings provide new insights into the regulation of blood vessel contractility.

The angular discordance of the Eocene that puts B sands of the Misoa Formation in contact with the La Rosa Formation affects, structure up, the thickness of the B6 member truncating it until eroding it in a northwesterly direction, with the presence of facies changes and local faults. With the objective of contributing to the recovery of gas reserves, a geological review was initiated to locate drainage points; the present investigation had the purpose of identifying the favorable stratigraphic and structural framework to locate in the upper part of the structure, monobore wells to drain the remaining reserves of gas from reservoir B6 LL 370, from the Tia Juana Lago field. It was established that plot A-226 is the most prospective for the establishment of drainage points for the drilling of monobore wells due to the best geological and reservoir conditions. Two locations are proposed (LL-Z-AB-AC-306-A4 and LL-AC-6-C5A1) to complete monobore with 5-1/2” pipe for a production potential of 2,8 MMPCND.

Recurrent somatic mutations of H3F3A in aggressive pediatric high-grade gliomas generate K27M or G34R/V mutant histone H3.3. H3.3-G34R/V mutants are common in tumors with mutations in p53 and ATRX, an H3.3-specific chromatin remodeler. To gain insight into the role of H3-G34R, we generated fission yeast that express only the mutant histone H3. H3-G34R specifically reduces H3K36 tri-methylation and H3K36 acetylation, and mutants show partial transcriptional overlap with set2 deletions. H3-G34R mutants exhibit genomic instability and increased replication stress, including slowed replication fork restart, although DNA replication checkpoints are functional. H3-G34R mutants are defective for DNA damage repair by homologous recombination (HR), and have altered HR protein dynamics in both damaged and untreated cells. These data suggest H3-G34R slows resolution of HR-mediated repair and that unresolved replication intermediates impair chromosome segregation. This analysis of H3-G34R mutant fission yeast provides mechanistic insight into how G34R mutation may promote genomic instability in glioma.

Foi estudado o desempenho de vacas canchim submetidas à estação de monta outubro-janeiro (estação A), em comparação ao daquelas que participaram da estação abril- -julho (estação B), durante o período outubro de 1970 a janeiro de 1975. As porcentagens de nascimentos e de sobrevivência dos bezerros observadas até à desmama e a taxa de desmama foram, respectivamente, 67.73. 80,31 e 54,40% para a estação de monta A e 71.17, 88,21 e 62,77% para a estação de monta B. Testes de quiquadrado indicaram que a estação de monta teve efeitos significativos (P < 0,05) na porcentagem de sobrevivência e na taxa de desmama. Foram utilizadas análises de variância compreendendo efeitos de: ano da estação de monta, estação de monta, interação ano-estação de monta e touro acasalado ou pai do bezerro. Nenhum dos efeitos incluídos no modelo estatístico influenciou significativamente a porcentagem de nascimentos e a taxa de desmama. A porcentagem de sobrevivência foi influenciada significativamente pela estação de monta (P

Durante quatro anos registrou-se o desempenho reprodutivo de cinqüenta matrizes da raça Guzerá, à campo e sujeitas a uma estação de monta de três meses, tendo como testemunha outro grupo de vacas semelhantes, nas mesmas condições, porém, submetidas a um período de cobertura de cinco meses de duração. A porcentagem maior era 3,1% de vacas fecundadas do lote testemunha, não justificou a admissão de que o período de cobertura limitado a três meses de duração tivesse alterado significativamente o número de vacas fecundadas.

Foi estudado o desempenho de vacas canchim submetidas à estação de monta outubro-janeiro (estação A), em comparação ao daquelas que participaram da estação abril- -julho (estação B), durante o período outubro de 1970 a janeiro de 1975. As porcentagens de nascimentos e de sobrevivência dos bezerros observadas até à desmama e a taxa de desmama foram, respectivamente, 67.73. 80,31 e 54,40% para a estação de monta A e 71.17, 88,21 e 62,77% para a estação de monta B. Testes de quiquadrado indicaram que a estação de monta teve efeitos significativos (P < 0,05) na porcentagem de sobrevivência e na taxa de desmama. Foram utilizadas análises de variância compreendendo efeitos de: ano da estação de monta, estação de monta, interação ano-estação de monta e touro acasalado ou pai do bezerro. Nenhum dos efeitos incluídos no modelo estatístico influenciou significativamente a porcentagem de nascimentos e a taxa de desmama. A porcentagem de sobrevivência foi influenciada significativamente pela estação de monta (P

Durante quatro anos registrou-se o desempenho reprodutivo de cinqüenta matrizes da raça Guzerá, à campo e sujeitas a uma estação de monta de três meses, tendo como testemunha outro grupo de vacas semelhantes, nas mesmas condições, porém, submetidas a um período de cobertura de cinco meses de duração. A porcentagem maior era 3,1% de vacas fecundadas do lote testemunha, não justificou a admissão de que o período de cobertura limitado a três meses de duração tivesse alterado significativamente o número de vacas fecundadas.

Foi estudado o desempenho de vacas canchim submetidas à estação de monta outubro-janeiro (estação A), em comparação ao daquelas que participaram da estação abril- -julho (estação B), durante o período outubro de 1970 a janeiro de 1975. As porcentagens de nascimentos e de sobrevivência dos bezerros observadas até à desmama e a taxa de desmama foram, respectivamente, 67.73. 80,31 e 54,40% para a estação de monta A e 71.17, 88,21 e 62,77% para a estação de monta B. Testes de quiquadrado indicaram que a estação de monta teve efeitos significativos (P < 0,05) na porcentagem de sobrevivência e na taxa de desmama. Foram utilizadas análises de variância compreendendo efeitos de: ano da estação de monta, estação de monta, interação ano-estação de monta e touro acasalado ou pai do bezerro. Nenhum dos efeitos incluídos no modelo estatístico influenciou significativamente a porcentagem de nascimentos e a taxa de desmama. A porcentagem de sobrevivência foi influenciada significativamente pela estação de monta (P

Se estudiaron 6 menús de almuerzo ofrecidos por una Universidad en Caracas que incluían sopa, plato principal, pan, jugo y postre. Los resultados mostraron que cada uno de estos menús estaba integrado por unos 15 a 20 alimentos diferentes y que en promedio, de acuerdo al análisis químico de un homogenato de su parte comestible, satisfacía un 37% de los requerimientos calóricos, 57% de los requerimientos proteicos y entre la mitad y un tercio de los requerimientos de hierro de los estudiantes usuarios del comedor. Estos menús, además aportaban una cantidad importante de fibra dietaria y tenían una distribución de las calorías totales como carbohidratos, grasa y proteínas (promedio de los seis menús estudiados) de 63%, 16% y 21%. Esto indica que su principal componente energético fueron los carbohidratos y que de acuerdo con los hábitos alimenticios de la población venezolana, el aporte calórico de las grasas fue bajo. El análisis de los ácidos grasos presentes en dos de los seis menús, mostró una proporción entre los saturados, monoinsaturados y polinsaturados de aproximadamente 2:1:1. Sin embargo, a pesar de esta predominancia de los ácidos grasos saturados, el bajo contenido graso de los menús estudiados, hizo que en promedio, el aporte de los ácidos grasos saturados a las calorías totales aportadas, no fuera mayor al 10%. Adicionalmente, se estableció que los menús estudiados aportaban más sodio que potasio y se estimó que en promedio, en una sola comida, aportaban casi la totalidad de la sal que se recomienda consumir diariamente. En líneas generales, los resultados obtenidos señalan que los almuerzos servidos en el comedor universitario, aportan una proporción importante de los requerimientos nutricionales diarios de los usuarios y satisfacen los lineamientos para una alimentación saludable. Sin embargo, podrían mejorar usando grasos más insaturadas y reduciendo la sal agregada. Asimismo, estos resultados ilustran las ventajas de la comida tradicional venezolana ya que el menú que incluyó su plato nacional, el Pabellón Criollo, fue el que tuvo el menor contenido graso y de sodio de todos los menús estudiadosMacronutrients, fiber, fatty acids and minerals in meals served in a university dinning room. We studied the nutrional quality of six lunch menus offered in a university’s dinning room locate in Caracas City. Each of these menus included soup, main dish, salad, bread and dessert. The results showed that each lunch offered 15 to 20 different kinds of foods. Comparing the results of the chemical analysis of the edible part of these lunch menus with the requirements of the students users of the university dinning room, indicated that on the average, they offered 37% and 57% of the energy and protein requirements, 30% to 50% of the iron requirements and a substantial amount of dietary fiber. Their fat concentration, according to the dietary habits of the venezuelan population, was low and ranged from 15% to 25% of the total calories. The analysis of the fatty acids present in two of the six studied menus, showed that the proportion of saturated: monoinsaturated: polyinsaturated was approximatel y 2:1:1. Despite the predominance of the saturated, the proportion of the total calories present in these lunch menus, provided by these meals offered more sodium than potassium and the calculated amount of sodium chloride they provided, was close to the total amount recommended to be consumed in a day. In general, the results of this study, showed that the lunch offered by this university dinning room can fulfill an important proportion of the sudent’nutritional requierements, providing at the same time a meal adjusted to modern nutritional guidelines for good health. The results also emphasize the advantages of the traditional Venezuelan food, since the Venezuelan national plate, has the least amount of fat and salt of all the menus here analyzed

We show that the Ge concentration in Si1−xGex alloys grown under strong out-of-equilibrium conditions determines the character of the population of threading dislocations (TDs). Above a critical value x ∼ 0.25 vertical TDs dominate over the common slanted ones. This is demonstrated by exploiting a statistically relevant analysis of TD orientation in micrometer-sized Si1−xGex crystals, deposited on deeply patterned Si(001) substrates. Experiments involving an abrupt change of composition in the middle of the crystals clarify the role of misfit-strain versus chemical composition in favoring the vertical orientation of TDs. A scheme invoking vacancy-mediated climb mechanism is proposed to rationalize the observed behavior.

To gain a better understanding of the sequence patterns that characterize positioned nucleosomes, we first performed an analysis of the periodicities of the 256 tetranucleotides in a yeast genome-wide library of nucleosomal DNA sequences that was prepared by in vitro reconstitution. The approach entailed the identification and analysis of 24 unique tetranucleotides that were defined by 8 consensus sequences. These consensus sequences were shown to be responsible for most if not all of the tetranucleotide and dinucleotide periodicities displayed by the entire library, demonstrating that the periodicities of dinucleotides that characterize the yeast genome are, in actuality, due primarily to the 8 consensus sequences. A novel combination of experimental and bioinformatic approaches was then used to show that these tetranucleotides are important for preferred formation of nucleosomes at specific sites along DNA in vitro. These results were then compared to tetranucleotide patterns in genome-wide in vivo libraries from yeast and C. elegans in order to assess the contributions of DNA sequence in the control of nucleosome residency in the cell. These comparisons revealed striking similarities in the tetranucleotide occurrence profiles that are likely to be involved in nucleosome positioning in both in vitro and in vivo libraries, suggesting that DNA sequence is an important factor in the control of nucleosome placement in vivo. However, the strengths of the tetranucleotide periodicities were 3-4 fold higher in the in vitro as compared to the in vivo libraries, which implies that DNA sequence plays less of a role in dictating nucleosome positions in vivo. The results of this study have important implications for models of sequence-dependent positioning since they suggest that a defined subset of tetranucleotides is involved in preferred nucleosome occupancy and that these tetranucleotides are the major source of the dinucleotide periodicities that are characteristic of positioned nucleosomes.

Stem cells/progenitors are central to the development of cell therapy approaches for vascular ischemic diseases. The crucial step in rescuing tissues from ischemia is improvement of vascularization that can be achieved by promoting neovascularization. Endothelial progenitor cells (EPCs) are the best candidates for developing such an approach due to their ability to self-renew, circulate and differentiate into mature endothelial cells (ECs). Studies showed that intravenously administered progenitors isolated from bone marrow, peripheral or cord blood home to ischemic sites. However, the successful clinical application of such transplantation therapy is limited by low quantities of EPCs that can be generated from patients. Hence, the ability to amplify the numbers of autologous EPCs by long term in vitro expansion while preserving their angiogenic potential is critically important for developing EPC based therapies. Therefore, the objective of this study was to evaluate the capacity of cord blood (CB)-derived AC133+ cells to differentiate, in vitro, towards functional, mature endothelial cells (ECs) after long term in vitro expansion.We systematically characterized the properties of CB AC133+ cells over the 30 days of in vitro expansion. During 30 days of culturing, CB AC133+ cells exhibited significant growth potential that was manifested as 148-fold increase in cell numbers. Flow cytometry and immunocytochemistry demonstrated that CB AC133+ cells' expression of endothelial progenitor markers was not affected by long term in vitro culturing. After culturing under EC differentiation conditions, cells exhibited high expression of mature ECs markers, such as CD31, VEGFR-2 and von Willebrand factor, as well as the morphological changes indicative of differentiation towards mature ECs. In addition, throughout the 30 day culture cells preserved their functional capacity that was demonstrated by high uptake of DiI fluorescently conjugated-acetylated-low density lipoprotein (DiI-Ac-LDL), in vitro and in vivo migration towards chemotactic stimuli and in vitro tube formation.These studies demonstrate that primary CB AC133+ culture contained mainly EPCs and that long term in vitro conditions facilitated the maintenance of these cells in the state of commitment towards endothelial lineage.

El capítulo nosológico del cáncer mamario, cuyo estudio abarca una considerable extensión por la profundidad de conocimientos a que hemos llegado, está lejos de poder considerarse agotado, especialmente en su sector más importante: la terapéutica. Los resultados poco satisfactorios que arrojan las estadísticas globales, ocasionan discusiones que aún están en la orden del día. El cáncer de la mama, considerando como tal todos los tumores malignos del órgano, sean epiteliales o conjuntivos, constituye todavía un serio problema clínico y terapéutico. Debido a su situación topográfica de fácil abordaje se cifraron las más grandes esperanzas desde la éra quirúrgica listeriana y la operación de HALSTED pretendió resolver el problema.

The mechanisms underlying susceptibility to and defense against Pseudomonas syringae (Pph) of the common bean (Phaseolus vulgaris) have not yet been clarified. To investigate these, 15-day-old plants of the variety Riñón were infected with Pph and the transcriptomic changes at 2 h and 9 h post-infection were analysed. RNA-seq analysis showed an up-regulation of genes involved in defense/signaling at 2 h, most of them being down-regulated at 9 h, suggesting that Pph inhibits the transcriptomic reprogramming of the plant. This trend was also observed in the modulation of 101 cell wall-related genes. Cell wall composition changes at early stages of Pph infection were associated with homogalacturonan methylation and the formation of egg boxes. Among the cell wall genes modulated, a pectin methylesterase inhibitor 3 (PvPMEI3) gene, closely related to AtPMEI3 , was detected. PvPMEI3 protein was located in the apoplast and its pectin methylesterase inhibitory activity was demonstrated. PvPMEI3 seems to be a good candidate to play a key role in Pph infection, which was supported by analysis of an Arabidopsis pmei3 mutant, which showed susceptibility to Pph, in contrast to resistant Arabidopsis Col-0 plants. These results indicate a key role of the degree of pectin methylesterification in host resistance to Pph during the first steps of the attack. [ABSTRACT FROM AUTHOR]