An atypical GABARAP binding module drives the pro-autophagic potential of the AML-associated NPM1c variant.

The nucleolar scaffold protein NPM1 is a multifunctional regulator of cellular homeostasis, genome integrity, and stress response. NPM1 mutations, known as NPM1c variants promoting its aberrant cytoplasmic localization, are the most frequent genetic alterations in acute myeloid leukemia (AML). A hallmark of AML cells is their dependency on elevated autophagic flux. Here, we show that NPM1 and NPM1c induce the autophagy-lysosome pathway by activating the master transcription factor TFEB, thereby coordinating the expression of lysosomal proteins and autophagy regulators. Importantly, both NPM1 and NPM1c bind to autophagy modifiers of the GABARAP subfamily through an atypical binding module preserved within its N terminus. The propensity of NPM1c to induce autophagy depends on this module, likely indicating that NPM1c exerts its pro-autophagic activity by direct engagement with GABARAPL1. Our data report a non-canonical binding mode of GABARAP family members that drives the pro-autophagic potential of NPM1c, potentially enabling therapeutic options.

Fluid mixing by an electromagnetically driven floating rotor.

We analyze the mixing properties of a floating stirrer driven electromagnetically in a thin layer of electrolyte, consisting of two free-floating magnets with opposite polarities connected by a rigid coupling. The magnetic rotor is set in circular motion using Lorentz forces created due to the interaction of the magnetic field of the rotor with dc currents actuated in logic sequence. We identify a coherent structure similar to a tripolar vortex whose central vortex rotates in the same direction of the rotor promoting chaotic mixing of the fluid in the laminar regime (Re=45). Dyed water visualization and particle image velocimetry were performed to characterize experimentally the mixing and flow dynamics at the surface of the electrolyte layer. A quasitwo-dimensional numerical simulation based on the immersed boundary method, which incorporates the fluid-solid interaction and reproduces the experimental observations satisfactorily, was carried out. Optimal mixing conditions are determined through the exponential growth of the material interfaces, which are established mainly by varying the distance separating the magnets of the rotor.

Identification of potential selective autophagy receptors from protein-content profiling of autophagosomes.

Selective autophagy receptors (SARs) are central to cellular homeostatic and organellar recycling pathways. Over the last two decades, more than 30 SARs have been discovered and validated using a variety of experimental approaches ranging from cell biology to biochemistry, including high-throughput imaging and screening methods. Yet, the extent of selective autophagy pathways operating under various cellular contexts, for example, under basal and starvation conditions, remains unresolved. Currently, our knowledge of all known SARs and their associated cargo components is fragmentary and limited by experimental data with varying degrees of resolution. Here, we use classical predictive and modeling approaches to integrate high-quality autophagosome content profiling data with disparate datasets. We identify a global set of potential SARs and their associated cargo components active under basal autophagy, starvation-induced, and proteasome-inhibition conditions. We provide a detailed account of cellular components, biochemical pathways, and molecular processes that are degraded via autophagy. Our analysis yields a catalog of new potential SARs that satisfy the characteristics of bonafide, well-characterized SARs. We categorize them by the subcellular compartments they emerge from and classify them based on their likely mode of action. Our structural modeling validates a large subset of predicted interactions with the human ATG8 family of proteins and shows characteristic, conserved LC3-interacting region (LIR)-LIR docking site (LDS) and ubiquitin-interacting motif (UIM)-UIM docking site (UDS) binding modes. Our analysis also revealed the most abundant cargo molecules targeted by these new SARs. Our findings expand the repertoire of SARs and provide unprecedented details into the global autophagic state of HeLa cells. Taken together, our findings provide motivation for the design of new experiments, testing the role of these novel factors in selective autophagy.

NS1 from Two Zika Virus Strains Differently Interact with a Membrane: Insights to Understand Their Differential Virulence.

Zika virus (ZIKV) from Uganda (UG) expresses a phenotype related to fetal loss, whereas the variant from Brazil (BR) induces microcephaly in neonates. The differential virulence has a direct relation to biomolecular mechanisms that make one strain more aggressive than the other. The nonstructural protein 1 (NS1) is a key viral toxin to comprehend these viral discrepancies because of its versatility in many processes of the virus life cycle. Here, we aim to examine through coarse-grained models and molecular dynamics simulations the protein-membrane interactions for both NS1ZIKV-UG and NS1ZIKV-BR dimers. A first evaluation allowed us to establish that the NS1 proteins, in the membrane presence, explore new conformational spaces when compared to systems simulated without a lipid bilayer. These events derive from both differential coupling patterns and discrepant binding affinities to the membrane. The N-terminal domain, intertwined loop, and greasy finger proposed previously as binding membrane regions were also computationally confirmed by us. The anchoring sites have aromatic and ionizable residues that manage the assembly of NS1 toward the membrane, especially for the Ugandan variant. Furthermore, in the presence of the membrane, the difference in the dynamic cross-correlation of residues between the two strains is particularly pronounced in the putative epitope regions. This suggests that the protein-membrane interaction induces changes in the distal part related to putative epitopes. Taken together, these results open up new strategies for the treatment of flaviviruses that would specifically target these dynamic differences.

Self-association features of NS1 proteins from different flaviviruses.

Flaviviruses comprise a large group of arboviral species that are distributed in several countries of the tropics, neotropics, and some temperate zones. Since they can produce neurological pathologies or vascular damage, there has been intense research seeking better diagnosis and treatments for their infections in the last decades. The flavivirus NS1 protein is a relevant clinical target because it is involved in viral replication, immune evasion, and virulence. Being a key factor in endothelial and tissue-specific modulation, NS1 has been largely studied to understand the molecular mechanisms exploited by the virus to reprogram host cells. A central part of the viral maturation processes is the NS1 oligomerization because many stages rely on these protein-protein assemblies. In the present study, the self-associations of NS1 proteins from Zika, Dengue, and West Nile viruses are examined through constant-pH coarse-grained biophysical simulations. Free energies of interactions were estimated for different oligomeric states and pH conditions. Our results show that these proteins can form both dimers and tetramers under conditions near physiological pH even without the presence of lipids. Moreover, pH plays an important role mainly controlling the regimes where van der Waals interactions govern their association. Finally, despite the similarity at the sequence level, we found that each flavivirus has a well-characteristic protein-protein interaction profile. These specific features can provide new hints for the development of binders both for better diagnostic tools and the formulation of new therapeutic drugs.

How the Strain Origin of Zika Virus NS1 Protein Impacts Its Dynamics and Implications to Their Differential Virulence.

Viruses can impact and affect human populations in a severe way. The appropriate differentiation among several species or strains of viruses is one of the biggest challenges for virology and infectiology studies. The detection of measurables-quantified discrepancies allows for more accurate clinical diagnoses and treatments for viral diseases. In the present study, we have used a computational approach to explore the dynamical properties of the nonstructural protein 1 from two strains of Zika virus. Our results show that despite a high sequence similarity, the two viral proteins from different origins can exhibit significant dissimilar structural dynamics, which complement their reported differential virulence. The present study opens up new ways in the understanding of the infectivity for these biological entities.

Neutrophil-lymphocyte index as prognostic factor for overall survival and disease-free survival in breast cancer patients / Índice neutrófilo-linfocito como factor pronóstico de sobrevida global y periodo libre de enfermedad en pacientes con cáncer de mama

BACKGROUND: Since 2006 breast cancer has been the leading cause of death by cancer in Mexican women. Recently several studies have shown the relationship of neutrophil-lymphocyte index (NLI) and breast cancer as a predictor of overall survival (OS) and disease-free survival (DFS). METHODS: The study included 2711 patients of the Institute of Breast Diseases (FUCAM) treated since April 2006 to March 2011. The NLI and its relation with OS and DFS were evaluated. A receiver operating characteristic curve was used to obtain the cut-off point of greater sensitivity and specificity for the NLI. A multivariate analysis was used to analyze the clinical parameters of prognostic factor. RESULTS: 342 patients were included for the analysis. The follow-up time average of 80.1 months and the mean of NLI was 2.1. In this model, sensitivity was 66.7% (95% CI: 46-64) p = 0.04. The Kaplan-Meier analysis was applied to evaluate OS and the DFS of all patients according to the NLI, comparing two groups: ≤2.1 and ≥ 2.1. No differences were reported between these groups. In triple negative patients (n=32), patients with NLI>2.1 had a shorter DFS in comparison to patients with NLI<2.1 (20 vs 55.6% in 5 years, p = 0.04). The univariate Cox risk model revealed that a NLI>2.1 pretreatment, lymph node stage and Ki-67 were correlated independently with the DFS. CONCLUSIONS: Our study suggests that there is a relationship between the NLI and the breast cancer DFS; especially in triple negative subtypes

ANTECEDENTES: El cáncer de mama tiene un enorme impacto en la salud de las mujeres. En México, desde el año 2006, el cáncer de mama ha sido la principal causa de muerte por cáncer en las mujeres mexicanas, y que representa 14% de las muertes relacionadas con el cáncer. Existen diversos factores que representan un papel importante en el desarrollo, progresión y persistencia del cáncer; entre ellos se reconoce a la respuesta inflamatoria. Múltiples estudios han demostrado la relación del índice linfocito neutrófilo (INL) y el cáncer de mama como predictor de sobrevida global y período libre de enfermedad. MATERIAL Y MÉTODOS: El diseño de estudio fue retrospectivo, transversal. Se revisaron 2.711 expedientes de pacientes con cáncer de mama tratados en el Instituto de Enfermedades de la Mama, FUCAM, en el período de abril de 2006 a marzo de 2011; se evaluó el INL previo a recibir tratamiento, y se obtuvo la relación con el período libre de enfermedad y la sobrevida global. Análisis estadístico: para obtener el punto de corte de mayor sensibilidad y especificidad para el INL se utilizó una curva de característica operativa del receptor (COR). Para variables dicotómicas se utilizó la prueba de Chi-cuadrado, mientras que para sobrevida y periodo libre de enfermedad se utilizaron las curvas de Kaplan-Meier. Un análisis multivariable se realizó para analizar el factor pronóstico de los parámetros clínicos. RESULTADOS: De la muestra inicial de 2.711, 342 cumplieron criterios de inclusión y fueron analizados. La media de edad al momento del diagnóstico fue de 51,38 años, un seguimiento promedio de 80,1 meses y la media del INL fue de 2,1. Se evaluó la sensibilidad/especificidad de la prueba para el INL, mediante la curva COR, la sobrevida libre de enfermedad y la sobrevida global. En este modelo, la sensibilidad fue del 66,7%. Al evaluar la sobrevida global y el periodo libre de enfermedad de todas las pacientes con cáncer de mama, de acuerdo al INL, comparando en 2 grupos, por INL, grupo 1, menor a 2,1 y grupo 2, ≥2,1 no se encontraron diferencias estadísticamente significativas. Se realizó otro análisis a una submuestra de pacientes con subtipo triple negativos (n=32), las que obtuvieron un INL>2,1 mostraron una menor supervivencia libre de enfermedad en comparación con los pacientes con IN<2,1 (a 5 años, 20 frente al 55,6%; p = 0,04). Al realizarse el modelo de riesgo univariante de Cox se identificó que un INL>2,1 pretratamiento, el estadio nodular y Ki-67 fueron variables que correlacionaron de manera independiente con el periodo libre de enfermedad. CONCLUSIONES: No se encontraron diferencias estadísticamente significativas en periodo libre de enfermedad, ni en sobrevida global, en pacientes con cáncer de mama agrupados acorde a INL. En la submuestra de pacientes con subtipo triple negativo (n=32), el grupo con mayor INL (> 2,1), mostró una menor supervivencia libre de enfermedad en comparación con el que tuvo menor INL (<2,1). Las variables que mostraron correlación con el periodo libre de enfermedad en este subgrupo (triple negativo), fueron un INL>2,1 pretratamiento, el estadio nodular y Ki-67

Identification of Electrostatic Epitopes in Flavivirus by Computer Simulations: The PROCEEDpKa Method.

Viruses are enthusiastically studied due to the great impact that these organisms can have on human health. Computational approaches can contribute offering tools that can shed light on important molecular mechanisms that help to design new diagnostic procedures. Several cellular processes between the immune-host system and the pathogenic organism are dependent on specific intermolecular interactions. In this study, we evaluated theoretical approaches to understand some properties of the antigen-antibody interactions considering the titratable properties of all ionizable residues of the nonstructural viral protein 1 (NS1) of the West Nile virus (WNV) and the Zika virus (ZIKV). Constant-pH Monte Carlo simulations were performed to estimate electrostatic properties such as the pKa shifts (ΔpKa). We proposed an alternative criterion for the discrimination of antigenic residues based on ΔpKas. Our outcomes were analyzed by an evaluation of the sensitivity and specificity through a receiver operating characteristic (ROC). As a starting point, we used the known crystallographic structure for the complex of NS1WNV(176-352) and the specific antibody 22NS1 (PDB ID 4OII ) to differentiate the residues belonging to that interface. With an optimal threshold for the absolute value of the pKa shifts, we found that is possible to predict antigenic epitopes reproducing the interfaces as defined by the X-ray structure. After this validation, we evaluated theoretical predictions based on protein-protein (PP) complexation simulations. From them, we observe amino acids with an antigenic potential and defined the optimum threshold that was applied for two strains of ZIKV (i.e., Uganda and Brazil). Several ionizable residues with antigenic capacity were identified. This is favorably related to some studies that show the high immunogenicity of secreted NS1. This approach opens up an important discussion about what are termed here "electrostatic epitopes" and how they work as an important reference in the paratope-epitope interaction for viral systems.

miR­145­5p is associated with pathological complete response to neoadjuvant chemotherapy and impairs cell proliferation by targeting TGFßR2 in breast cancer.

Cancer patients who better benefit from neoadjuvant chemotherapy (NeoCh) are those who achieve a successful pathological complete response (pCR) represented by the absence of residual disease. Unfortunately, no highly sensitive and specific tumor biomarkers for predicting the clinical response to NeoCh have yet been defined. The aim of the present study was to ascertain whether miR­145­5p could discriminate between pCR and no­pCR in triple­negative breast cancer patients that received a cisplatin/doxorubicin­based neoadjuvant treatment. miR­145­5p expression was determined in breast tumors by quantitative RT­PCR. Our data showed that miR­145­5p had a significant low expression (P<0.005) in patients that achieved pCR in comparison to the non­responder group. Kaplan Meier analysis indicated that low levels of miR­145­5p were associated with increased disease­free survival. In addition, receiver operating characteristic (ROC) curve analysis suggested that miR­145­5p is a good predictor of pCR (P<0.003, AUC=0.7899, 95% CI, 0.6382­0.9416). Quantitative RT­PCR expression analysis also revealed that miR­145­5p was downregulated in four breast cancer cell lines relative to normal cells. To study the functions of miR­145­5p, its expression was restored in triple­negative MDA­MB­231 cells and its effects in cell proliferation were evaluated by MTT assays and in apoptosis using Annexin V experiments. Data revealed that ectopic expression of miR­145­5p resulted in a significant inhibition of cell proliferation and also induced apoptosis. Moreover, miR­145­5p led to sensitization of breast cancer cells to cisplatin therapy. In addition, western blot assays indicated that miR­145­5p downregulated the TGFßR2 protein. In conclusion, miR­145­5p could be a potential biomarker of clinical response to NeoCh in triple­negative breast cancer. Functionally miR­145­5p may regulate cell proliferation, at least in part, by targeting TGFßR2.

Loss of function of miR-342-3p results in MCT1 over-expression and contributes to oncogenic metabolic reprogramming in triple negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive neoplasia lacking the expression of hormonal receptors and human epidermal growth factor receptor-2. Accumulating evidence has highlighted the importance of miRNAs dysregulation in the establishment of cancer programs, but the functional role of many miRNAs remains unclear. The description of miRNAs roles might provide novel strategies for treatment. In the present work, an integrated analysis of miRNA transcriptional landscape was performed (N = 132), identifying the significant down-modulation of miR-342-3p in TNBC, probably because of the aberrant activity of estrogen receptor, which serves as a transcription factor of the miRNA, as demonstrated by a siRNA-knockdown approach. The enhanced expression of miR-342-3p significantly decreased cell proliferation, viability and migration rates of diverse TN cells in vitro. Bioinformatic and functional analyses revealed that miR-342-3p directly targets the monocarboxylate transporter 1 (MCT1), which promotes lactate and glucose fluxes alteration, thus disrupting the metabolic homeostasis of tumor cells. Optical metabolic imaging assay defined a higher optical redox ratio in glycolytic cells overexpressing miR-342-3p. Furthermore, we found that hypoxic conditions and glucose starvation attenuate miR-342-3p expression, suggesting a crosstalk program between these metabolic factors. Consistently, miR-342-3p down-modulation is associated with an increased MCT1 expression level and glycolytic score in human triple negative tumors. Overall, we described for the first time the regulatory activity of miR-342-3p on relevant metabolic carcinogenic pathways in TN breast cancers.

Complete sequence of the ATP6 and ND3 mitochondrial genes in breast cancer tissue of postmenopausal women with different body mass indexes.

Due to the fact that mitochondrial defects and oxidative stress have been related with obesity and breast cancer is more aggressive in women with obesity, we investigated if postmenopausal Mexican-Mestizo women with breast cancer presented somatic mutations in the sequence of the ATP6 and/or ND3 genes. Twenty one postmenopausal Mexican-Mestizo women with breast cancer who underwent mastectomy or breast conserving surgery were studied. Height and weight were used to calculate body mass index. DNA from tumor tissue samples and blood leukocytes was amplified by polymerase chain reaction and sequenced the ATP6 and ND3 mitochondrial genes. Ages ranged from 46 to 82. According to World Health Organization criteria among the 21 women, 7 had a normal BMI, 7 were overweight and 7 had obesity. In regard to the molecular study, after sequencing the coding region of ATP6 and ND3 genes of the DNA obtained from both leukocytes and tumor tissue, we did not find somatic mutations. All of the changes that we found in both genes were polymorphisms: in ATP6, we identified in ten patients 3 non-synonymous nucleotide changes and in ND3 we observed that six patients presented polymorphisms, three of them were synonymous and two non-synonymous. To our knowledge, this constitutes the first report where the complete sequence of the ATP6 and ND3 genes has been analyzed in postmenopausal Mexican-Mestizo women with breast cancer and diverse BMI. Our results differ with those reported in Caucasian and Asian populations, possibly due to ethnic differences.

Insights into the ZIKV NS1 Virology from Different Strains through a Fine Analysis of Physicochemical Properties.

The flavivirus genus has several organisms responsible for generating various diseases in humans. Recently, especially in tropical regions, Zika virus (ZIKV) has raised great health concerns due to the high number of cases affecting the area during the last years that has been accompanied by a rise in the cases of the Guillain-Barré syndrome and fetal and neonatal microcephaly. Diagnosis is still difficult since the clinical symptoms between ZIKV and other flaviviruses (e.g., dengue and yellow fever) are highly similar. The understanding of their common physicochemical properties that are pH-dependent and biomolecular interaction features and their differences sheds light on the relation strain-virulence and might suggest alternative strategies toward differential serological diagnostics and therapeutic intervention. Due to their immunogenicity, the primary focus of this study was on the ZIKV nonstructural proteins 1 (NS1). By means of computational studies and semiquantitative theoretical analyses, we calculated the main physicochemical properties of this protein from different strains that are directly responsible for the biomolecular interactions and, therefore, can be related to the differential infectivity of the strains. We also mapped the electrostatic differences at both the sequence and structural levels for the strains from Uganda to Brazil, which could suggest possible molecular mechanisms for the increase of the virulence of ZIKV in Brazil. Exploring the interfaces used by NS1 to self-associate in some different oligomeric states and interact with membranes and the antibody, we could map the strategy used by the ZIKV during its evolutionary process. This indicates possible molecular mechanisms that can be correlated with the different immunological responses. By comparing with the known antibody structure available for the West Nile virus, we demonstrated that this antibody would have difficulties to neutralize the NS1 from the Brazilian strain. The present study also opens up perspectives to computationally design high-specificity antibodies.

Severe Phenotype of Keratitis-Ichthyosis-Deafness Syndrome With Presumed Ocular Surface Squamous Neoplasia.

PURPOSE: The aim of this study was to describe a case of severe keratitis-ichthyosis-deafness (KID) syndrome with ocular surface squamous neoplasia. METHODS: The affected patient underwent complete ocular and systemic examinations. The molecular studies included polymerase chain reaction amplification and automated DNA sequencing of the complete gap junction beta-2 (GJB2) gene coding sequence. RESULTS: A 30-year-old man presented with generalized erythro-hyperkeratosis and deafness and complaints of decreased visual acuity, tearing, and photophobia. Ophthalmic examination showed corneal erosion, vascularization, and a gray gelatinous lesion partially covering the right cornea, suggestive of squamous neoplasia. The clinical features were characteristic of KID syndrome. This diagnosis was confirmed with a DNA analysis showing the pathogenic variant p.D50N in the GJB2 gene. Presumed squamous neoplasia was treated with topical interferon α2b. CONCLUSIONS: KID syndrome is a very rare disease that has been reported with an incremental incidence of squamous cell carcinoma of the mucous membranes and skin (12%-15%). Here, we presented a case of severe systemic KID syndrome with ocular surface squamous neoplasia.

Malachite Green and Crystal Violet Decolorization by Ganoderma lucidum and Pleurotus ostreatus Supernatant and by rGlLCC1 and rPOXA 1B Concentrates: Molecular Docking Analysis.

Laccases catalyze the oxidation of various aromatic organic compounds concomitantly with molecular oxygen reduction to water. Triphenylmethane dyes are synthetic compounds widely used in diverse industries. Their removal from effluents is difficult, due to their high degree of structural complexity; hence, their high concentration in effluents cause a negative impact on the environment. In the present work, molecular docking was used to evaluate interactions between rGlLCC1 or rPOXA 1B enzymes with Crystal Violet (CV) or Malachite Green (MG) dyes. In addition, removal tests of the two dyes were performed. Van der Waals interactions were obtained for only the CV dye for both GlLCC1 and POXA 1B enzymes. Nevertheless, in the GlLCC1 model, two π-π interactions were observed. For the MG dye only, Van der Waals interactions were obtained. Moreover, amino acid composition interacting in each model with each dye was similar. It is important to highlight that by molecular docking, none of the estimated ligand configurations generated hydrogen bonds. Thus, explaining the difficulty to degrade CV and MG. Regarding CV, maximum decolorization percentage was 23.6 ± 1.0% using Ganoderma lucidum supernatant and 5.0 ± 0.5% with Pleurotus ostreatus supernatant. When using recombinant laccase enzyme concentrates, decolorization percentages were 9.9 ± 0.1 and 7.5 ± 1.0% for rGlLCC1 and rPOXA 1B, respectively. On the other hand, for the MG dye, maximum decolorization percentages were 52.1 ± 5.1 and 2.3 ± 0.2% using G. lucidum and P. ostreatus concentrates, respectively. Whereas with recombinant laccase enzymatic concentrates, values of 9.4 ± 0.8% were obtained, with rGlLCC1, and 2.1 ± 0.1% when using rPOXA 1B. These findings represent an important step in bioremediation processes improvement and efficiency of industry-generated products, using environmentally friendly alternatives.

Correction to: Malachite Green and Crystal Violet Decolorization by Ganoderma lucidum and Pleurotus ostreatus Supernatant and by rGlLCC1 and rPOXA 1B Concentrates: Molecular Docking Analysis.

The original version of this article unfortunately contained a mistake. The replacement image of Fig. 4 provided by the first corresponding author, Aura M. Pedroza-Rodríguez, is incorrect and that the originally submitted Fig. 4 should have been retained. The original article has been corrected.

Sociodemographic and psychological factors associated with self-care and quality of life in Mexican adults with type 2 Diabetes Mellitus / Fatores sociodemográficos e psicológicos associados ao autocuidado e à qualidade de vida em adultos mexicanos com diabetes mellitus tipo 2 / Factores sociodemográficos y psicológicos asociados al autocuidado y la calidad de vida en adultos mexicanos con Diabetes Mellitus tipo 2

Abstract The purpose of the present study was to identify sociodemographic and psychological variables related to self-care and quality of life in Mexican adults with type 2 Diabetes Mellitus. A cross-sectional design was used in a sample of 60 people (93% women) aged between 36 and 66 years ( M = 54.3, SD = 4.71) attached to the public health system in San Luis Potosí, Mexico. Self-care, self-efficacy, knowledge about diabetes, anxiety, depression and quality of life were measured using the EECAC, EAG, DKQ-24, AMAS, BDI-II and SF-36 scales. For data processing, a linear regression analysis was used to evaluate the impact of the measured variables on self-care and quality of life. In general, the model explained 33.9% of the variance of self-care through the variables depression (β = -.27) and self-efficacy (β = .74). The 56% variance in quality of life related to physical health was explained by the variables depression (ß = -34) and self-care ( β = .34). In their mental health component, 43.4% of variance in quality of life was explained through anxiety (β = -.26) and depression ( β = -.40). Finally, the positive perception of self-efficacy and health status free from anxiety and depression were determinant factors for self-care and health-related quality of life.

Resumo O propósito deste trabalho foi identificar as variáveis sociodemográficas e psicológicas relacionadas com o autocuidado e a qualidade de vida em adultos mexicanos com diabetes mellitus tipo 2. Utilizou-se um desenho transversal numa amostra de 60 pessoas (93 % mulheres) entre 36 e 66 anos (M = 54.3, DP = 4.71), vinculadas ao sistema de saúde pública em San Luis Potosí, México. Foram medidas as variáveis de autocuidado, autoeficácia, conhecimento em diabetes, ansiedade, depressão e qualidade de vida com a aplicação das escalas EECAC, EAG, DKQ-24, AMAS, BDI-II e SF-36. Na análise de resultados, utilizou-se a análise de regressão linear para avaliar o impacto das variáveis medidas sobre o autocuidado e a qualidade de vida. Em geral, o modelo explicou 33.9 % da variação do autocuidado por meio das variáveis depressão (β = -.27) e autoeficácia (β = .74). 56 % de variação em qualidade de vida relacionada com a saúde física foram explicadas a partir das variáveis depressão (β = -.34) e autocuidado (β = .34). Em seu componente de saúde mental, 43.4 % da variação em qualidade de vida foram explicadas por meio da ansiedade (β = -.26) e da depressão (β = -.40). Finalmente, a percepção positiva de autoeficácia e o estado de saúde livre de ansiedade e depressão foram fatores determinantes para o autocuidado e a qualidade de vida relacionada com a saúde.

Resumen El propósito del presente trabajo fue identificar las variables sociodemográficas y psicológicas relacionadas con el autocuidado y la calidad de vida en adultos mexicanos con diabetes mellitus tipo 2. Se utilizó un diseño transversal en una muestra de 60 personas (93 % mujeres) entre 36 y 66 años de edad (M = 54.3, DE = 4.71) adscritas al sistema de salud pública en San Luis Potosí, México. Se midieron las variables de autocuidado, autoeficacia, conocimientos en diabetes, ansiedad, depresión y calidad de vida con la aplicación de las escalas EECAC, EAG, DKQ-24, AMAS, BDI-II y SF-36. En el análisis de resultados se utilizó un análisis de regresión lineal para evaluar el impacto de las variables medidas sobre el autocuidado y la calidad de vida. En general, el modelo explicó 33.9 % de la variación del autocuidado a través de las variables depresión (β = -.27) y autoeficacia (β = .74). El 56 % de variación en calidad de vida relacionada con la salud física se explicó a partir de las variables se explicó a través de la ansiedad (β = -.26) y la depresión (β = -.40). Finalmente, la percepción positiva de autoeficacia y el estado de salud libre de ansiedad y depresión resultaron ser factores determinantes para el autocuidado y la calidad de vida relacionada con la salud.

Recurrent and functional regulatory mutations in breast cancer.

Genomic analysis of tumours has led to the identification of hundreds of cancer genes on the basis of the presence of mutations in protein-coding regions. By contrast, much less is known about cancer-causing mutations in non-coding regions. Here we perform deep sequencing in 360 primary breast cancers and develop computational methods to identify significantly mutated promoters. Clear signals are found in the promoters of three genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbours a mutational hotspot in its promoter leading to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that affect protein binding to their promoters and alter expression levels. Our study shows that promoter regions harbour recurrent mutations in cancer with functional consequences and that the mutations occur at similar frequencies as in coding regions. Power analyses indicate that more such regions remain to be discovered through deep sequencing of adequately sized cohorts of patients.

A microRNA signature associated with pathological complete response to novel neoadjuvant therapy regimen in triple-negative breast cancer.

Neoadjuvant chemotherapy aims to improve the outcome of breast cancer patients, but only few would benefit from this treatment. Pathological complete response has been proposed as a surrogate marker for the prediction of long-term clinical benefits; however, 50%-85% patients have an unfavorable pathological complete response to chemotherapy. MicroRNAs are known biomarkers of breast cancer progression; nevertheless, their potential to identify patients with pathological complete response remains poorly understood. Here, we investigated whether a microRNA profile could be associated with pathological complete response in triple-negative breast cancer patients receiving 5-fluorouracil, adriamycin, cyclophosphamide-cisplatin/paclitaxel as a novel neoadjuvant chemotherapy. In the discovery cohort, the expression of 754 microRNAs was examined in tumors from 10 triple-negative breast cancer patients who achieved pathological complete response and 8 without pathological complete response using TaqMan Low-Density Arrays. Unsupervised hierarchical cluster analysis identified 11 microRNAs with significant differences between responder and no-responder patients (fold change ≥ 1.5; p < 0.05). The differential expression of miR-30a, miR-9-3p, miR-770, and miR-143-5p was validated in an independent group of 17 patients with or without pathological complete response. Moreover, Kaplan-Meier analysis showed that expression of these four microRNAs was associated with an increased disease-free survival. Gene ontology classification of predicted microRNA targets indicated that numerous genes are involved in pathways related to chemoresistance, such as vascular endothelial growth factor, focal adhesion kinase, WNT, ERbB, phosphoinositide 3-kinase, and AKT signaling. In summary, we identified a novel microRNA expression signature associated with pathological complete response in breast cancer. We propose that the four validated microRNAs could be used as molecular biomarkers of clinical response in triple-negative breast cancer patients with pathological complete response to neoadjuvant therapy.

Effects of Conjugated Linoleic Acid and Metformin on Insulin Sensitivity in Obese Children: Randomized Clinical Trial.

Context: Insulin resistance precedes metabolic syndrome abnormalities and may promote cardiovascular disease and type 2 diabetes in children with obesity. Results of lifestyle modification programs have been discouraging, and the use of adjuvant strategies has been necessary. Objective: This study aimed to evaluate the effects of metformin and conjugated linoleic acid (CLA) on insulin sensitivity, measured via euglycemic-hyperinsulinemic clamp technique and insulin pathway expression molecules in muscle biopsies of children with obesity. Design: A randomized, double-blinded, placebo-controlled clinical trial was conducted. Setting: Children with obesity were randomly assigned to receive metformin, CLA, or placebo. Results: Intervention had a positive effect in all groups. For insulin sensitivity Rd value (mg/kg/min), there was a statistically significant difference between the CLA vs placebo (6.53 ± 2.54 vs 5.05 ± 1.46, P = 0.035). Insulinemia and homeostatic model assessment of insulin resistance significantly improved in the CLA group (P = 0.045). After analysis of covariance was performed and the influence of body mass index, age, Tanner stage, prescribed diet, and fitness achievement was controlled, a clinically relevant effect size on insulin sensitivity remained evident in the CLA group (37%) and exceeded lifestyle program benefits. Moreover, upregulated expression of the insulin receptor substrate 2 was evident in muscle biopsies of the CLA group. Conclusions: Improvement of insulin sensitivity, measured via euglycemic-hyperinsulinemic clamp and IRS2 upregulation, favored patients treated with CLA.