Association of ESR1 Germline Variants with TP53 Somatic Variants in Breast Tumors in a Genome-wide Study.

In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors. A genome-wide association study was conducted in 2,850 women of European ancestry with breast cancer using TP53 and PIK3CA mutation status (positive or negative) as well as specific functional categories [e.g., TP53 gain-of-function (GOF) and loss-of-function, PIK3CA activating] as phenotypes. Germline variants showing evidence of association were selected for validation analyses and tested in multiple independent datasets. Discovery association analyses found five variants associated with TP53 mutation status with P values <1 × 10-6 and 33 variants with P values <1 × 10-5. Forty-four variants were associated with PIK3CA mutation status with P values <1 × 10-5. In validation analyses, only variants at the ESR1 locus were associated with TP53 mutation status after multiple comparisons corrections. Combined analyses in European and Malaysian populations found ESR1 locus variants rs9383938 and rs9479090 associated with the presence of TP53 mutations overall (P values 2 × 10-11 and 4.6 × 10-10, respectively). rs9383938 also showed association with TP53 GOF mutations (P value 6.1 × 10-7). rs9479090 showed suggestive evidence (P value 0.02) for association with TP53 mutation status in African ancestry populations. No other variants were significantly associated with TP53 or PIK3CA mutation status. Larger studies are needed to confirm these findings and determine if additional variants contribute to ancestry-specific differences in mutation frequency. SIGNIFICANCE: Emerging data show ancestry-specific differences in TP53 and PIK3CA mutation frequency in breast tumors suggesting that germline variants may influence somatic mutational processes. This study identified variants near ESR1 associated with TP53 mutation status and identified additional loci with suggestive association which may provide biological insight into observed differences.

Diorganotin (IV) amino acid complexes as potential anticancer agents. Synthesis, structural characterization, and in vitro assays.

Nine new organotin (IV) derivatives from L-amino acids (l-lysine, L-ornithine, L-glutamic acid, and L-aspartic acid) were synthesized by one-pot ultrasound-assisted methodology. All compounds were characterized by ATR-FTIR (Attenuated Total Reflectance-Fourier Transform Infrared), LRMS (Low-Resolution Mass Spectrometry), and solution NMR (1H, 13C, 119Sn Nuclear Magnetic Resonance) spectroscopies. Complexes Bu2Sn(Lys) (1), Ph2Sn(Lys) (2), Bu2Sn(Orn) (3), and Ph2Sn (Glu-OMe) (6a) were crystallized, and the structures were established by single-crystal X-ray diffraction analysis. Diffraction results evidenced that complexes 1 to 3 were five-coordinated mononuclear species while the phenyl substituted derivative Ph2Sn (Glu-OMe) (6a) forms a polymeric network via Sn-O-Sn bridging whereby the tin atom is six-coordinated. In turn, 119Sn NMR results revealed that all tin complexes exist as mononuclear penta-coordinated species in solution. The tin derivatives were screened for ADME (Adsorption, Distribution, Metabolism, and Excretion) properties via the freely available tools SWISS ADME, and the results were analyzed hereafter. The antiproliferative activity of the complexes was tested against three human cancer cell lines: colorectal adenocarcinoma HT-29, breast adenocarcinoma MDA-MB-231, and chondrosarcoma SW-1353 using a non-tumoral cell line of human osteoblast as control, demonstrating selective inhibitory activities against cancer cells. Hence, these compounds could be a promising alternative to classical chemotherapy agents.

Association of ESR1 germline variants with TP53 somatic variants in breast tumors in a genome-wide study.

Background: In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. HER2 positive and triple negative breast cancers (TNBC) have a higher frequency of TP53 somatic mutations than other subtypes. PIK3CA mutations are more frequently observed in hormone receptor positive tumors. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors. Methods: A genome-wide association study was conducted using breast cancer mutation status of TP53 and PIK3CA and functional mutation categories including TP53 gain of function (GOF) and loss of function mutations and PIK3CA activating/hotspot mutations. The discovery analysis consisted of 2850 European ancestry women from three datasets. Germline variants showing evidence of association with somatic mutations were selected for validation analyses based on predicted function, allele frequency, and proximity to known cancer genes or risk loci. Candidate variants were assessed for association with mutation status in a multi-ancestry validation study, a Malaysian study, and a study of African American/Black women with TNBC. Results: The discovery Germline x Mutation (GxM) association study found five variants associated with one or more TP53 phenotypes with P values <1×10-6, 33 variants associated with one or more TP53 phenotypes with P values <1×10-5, and 44 variants associated with one or more PIK3CA phenotypes with P values <1×10-5. In the multi-ancestry and Malaysian validation studies, germline ESR1 locus variant, rs9383938, was associated with the presence of TP53 mutations overall (P values 6.8×10-5 and 9.8×10-8, respectively) and TP53 GOF mutations (P value 8.4×10-6). Multiple variants showed suggestive evidence of association with PIK3CA mutation status in the validation studies, but none were significant after correction for multiple comparisons. Conclusions: We found evidence that germline variants were associated with TP53 and PIK3CA mutation status in breast cancers. Variants near the estrogen receptor alpha gene, ESR1, were significantly associated with overall TP53 mutations and GOF mutations. Larger multi-ancestry studies are needed to confirm these findings and determine if these variants contribute to ancestry-specific differences in mutation frequency.

Halogen Bonding in Brominated BODIPY Crystals: a Crystallographic and Computational Study.

The study of halogen bonds (XBs) has been a subject of great interest in recent years due to its clear application in catalysis, liquid crystals, and crystal engineering. In this study, we analyzed the intermolecular interactions, in particular halogen bonds in BODIPYs with an increasing number of bromine atoms. The computational study included analyses through three different methods: the first approach of close contacts provided by mercury, then the expanded approach of the electron density partition of the molecules in the crystals provided by the analysis of Hirshfeld surfaces, and finally, the approach of the Quantum Theory of Atoms in Molecules (QT-AIM) to characterize the non-covalent interactions through finding electron density critical points between atoms and between neighboring molecules. The use of different computational methods allowed to gain insight into the interactions directing the crystal packing as the number of bromine atoms increased in the BODIPY moiety. Monocoordinated and bifurcated halogen bonds involving halide/halide were found. The penta-brominated BODIPY showed four-center cyclic nodes where each node is linked via XBs. This kind of motif can be useful in supramolecular chemistry and self-assembly.

COVID-19 y complicaciones cardiovasculares / COVID-19 and cardiovascular complications

RESUMEN Objetivo: Analizar el COVID - 19 y complicaciones cardiovasculares. Método: revisión sistemática. Análisis de los resultados: Una gran proporción de pacientes tiene enfermedad cardiovascular subyacente y factores de riesgo cardíaco. Los factores asociados con la mortalidad incluyen el sexo masculino, la edad avanzada y la presencia de comorbilidades como las enfermedades cardiovasculares. La lesión cardíaca aguda determinada por niveles elevados de troponina de alta sensibilidad se observa comúnmente en casos graves y está fuertemente asociada con la mortalidad, al igual que el síndrome de dificultad respiratoria aguda. Conclusión: La infección por el SARS-CoV-2 presenta una baja mortalidad en la mayoría de los casos, pero un porcentaje significativo de los infectados sufren una enfermedad pulmonar con diferentes grados de afección sistémica que sí conlleva mayor mortalidad. Estos pacientes presentan grados variables de afección miocárdica, tanto directa por el virus como por la situación sistémica grave, que incrementan el riesgo de muerte.

Objective: To analyze COVID-19 and cardiovascular complications. Methods: Systematic review. Analysis of results: A large proportion of patients have underlying cardiovascular disease and cardiac risk factors. Factors associated with mortality include male sex, advanced age and the presence of comorbidities such as cardiovascular disease. Acute cardiac injury as determined by elevated high-sensitivity troponin levels is commonly seen in severe cases and is strongly associated with mortality, as is acute respiratory distress syndrome. Conclusion: SARS-CoV-2 infection has a low mortality in most cases, but a significant percentage of those infected have pulmonary disease with varying degrees of systemic involvement that does lead to increased mortality. These patients have varying degrees of myocardial involvement, both direct from the virus and from the severe systemic situation, which increase the risk of death.

Dibromo-BODIPY as an Organic Photocatalyst for Radical-Ionic Sequences.

A new dibrominated 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) is reported as a new metal-free photocatalyst. This BODIPY showed similar optoelectronic, electrochemical, and performance properties to those of Ru(bpy)3Cl2, one of the most common photocatalysts in a known radical-ionic transformation, such as the formation of 1,4-dicarbonyl compounds. Moreover, additional sequences in which the generated oxonium ion is trapped by an internal nucleophile were developed using this BODIPY photocatalyst. These new sequences allowed the straightforward preparation of γ-alkoxylactones, monoprotected 1,4-ketoaldehydes, and dihydrofurans. This new catalyst, the methodology, and the forged functional groups could be important tools in organic synthesis.

Impacto de una intervención sanitaria en los cuidados oculares en pacientes de la unidad de cuidados intensivos pediátricos

RESUMEN Introducción: El cuidado de los ojos forma parte de los cuidados para los pacientes en las unidades de cuidados intensivos (UCI). Objetivo: analizar el impacto de una intervención sanitaria en el cumplimiento del organigrama de cuidados oculares y la incidencia de lesiones oculares en pacientes de la UCI pediátricos antes y después de una capacitación del personal sanitario. Materiales y Métodos: El estudio fue realizado en las UCI pediátricas, del Hospital general Pediátrico Niños de Acosta Ñu. Se diseño un estudio cuasi experimental de antes y después. En la cohorte pre intervención (octubre-diciembre 2017) y en la cohorte post intervención (julio-diciembre 2018), se determinó la incidencia de lesiones oculares y el porcentaje de cumplimiento del organigrama, se realizó la capacitación del personal entre ambas cohortes, finalmente fueron comparados los resultados obtenidos. Se incluyeron niños de 0 a 18 años internados en las UCI pediátricos. Los datos fueron analizados en el sistema SPSSv21. Resultados: Durante el periodo de estudio ingresaron 70 pacientes en la cohorte pre - intervención y 120 después de la misma. Fueron del sexo masculino 51(58,6%) y 63 (52,5%), presentaron apertura ocular anormal 18 (25,7%) y 19 (15,8%), lesión corneal 6(8,6%) y 3 (3,3%), las lesiones oculares observadas fueron erosión de la córnea en el 8,5% (6/70) y 3,3% (3/120), el cumplimiento del organigrama se dio en 54 (77,1 %) y en 120 (100%) respectivamente en las cohortes pre y post intervención. Conclusión: La capacitación del personal sanitario en cuidados oculares disminuyó la frecuencia de lesiones corneales.

ABSTRACT Introduction: Eye care is part of patient care in intensive care units (ICU). Objective: to analyze the impact of a health intervention on compliance with eye care measures and the incidence of ocular injuries in pediatric ICU patients before and after training for healthcare personnel. Materials and Methods: The study was carried out in the pediatric ICUs of the Acosta Ñu Pediatric General Hospital. A quasi-experimental before and after study was designed. In the pre-intervention cohort (October-December 2017) and in the post-intervention cohort (July-December 2018), the incidence of eye injuries and the percentage of compliance with the eye care measures were determined, staff training was carried out between both cohorts, finally the results obtained were compared. Children aged 0 to 18 years admitted to pediatric ICUs were included. The data were analyzed in the SPSSv21 system. Results: During the study period, 70 patients were admitted to the pre-intervention cohort and 120 in the post-intervention cohort. 51 (58.6%) and 63 (52.5%) were male, respectively, 18 (25.7%) and 19 (15.8%) presented abnormal eye opening, 6 (8.6%) and 3 (3.3%) had corneal injuries, the most common ocular lesions observed were corneal erosion in 8.5% (6/70) and 3.3% (3/120), compliance with eye care measures occurred in 54 (77, 1%) and 120 (100%) respectively in the pre and post intervention cohorts. Conclusion: The training of healthcare personnel in eye care decreased the frequency of corneal injuries.

Catheter-Associated Urinary Tract Infections: Implementing a Protocol to Decrease Incidence in Oncology Populations
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BACKGROUND: The impact of catheter-associated urinary tract infections (CAUTIs) on immunocompromised patients with cancer requires preventive intervention from bedside nurses.
. OBJECTIVES: This protocol aims to prevent CAUTIs in the inpatient oncology population by implementing an evidence-based, nurse-driven protocol for discontinuing indwelling urinary catheters (IUCs).
. METHODS: Following a literature review of 34 articles, a nurse-driven CAUTI prevention protocol was developed and implemented on two 26-bed oncology units. Unit staff were educated on the protocol and use of the audit tool.
. FINDINGS: Although CAUTI rates remained unchanged, infections per 1,000 IUC days decreased, and adherence among oncology nurses rose 66%-90% within the first two months. The protocol encouraged preventive intervention from RNs to protect patients with cancer from CAUTIs.

[Lung diseases among HIV infected patients admitted to the "Instituto Nacional del Torax" in Santiago, Chile]. / Enfermedades pulmonares en pacientes infectados con VIH hospitalizados en el Instituto Nacional del Tórax.

BACKGROUND: Pulmonary diseases are common among HIV infected patients. The prevalence of the different diseases varies greatly. AIM: To identify the different pulmonary diseases that affect a Chilean population of HIV infected patients and to identify factors associated with in hospital mortality. MATERIAL AND METHODS: Retrospective review of the clinical records of all HIV infected patients with lung diseases discharged from our institution during a period of 3.5 years. Collection of demographic and biomedical data. RESULTS: One hundred seventy one patients (aged 35.7 years, 86% men) had 236 episodes of lung diseases. Only 13.5% of the patients were receiving antiretroviral therapy and 18% were on pneumocystis prophylaxis. Infectious diseases accounted for 87% of the discharges, neoplasm for 5.1%. Pneumocystis jirovecii infection was responsible for 37.7% of the episodes, community acquired pneumonia was seen in 24.1% and mycobacterial diseases in 14.4%. Two or more conditions were present in 13.6%. Death during hospital stay occurred in 19.5%. Multivariate analysis identified pneumothorax as the only significant independent predictor of in-hospital mortality in patients with pneumocystis pneumonia, while nosocomial pneumonia was the only predictor of death among patients with non-pneumocystis pulmonary diseases. CONCLUSIONS: Infectious diseases were the main cause of hospitalization among Chilean HIV infected patients. Mortality among these patients remains high. Appropriate antiretroviral therapy and prophylaxis may alter pulmonary disease prevalence in the future. Every effort should be made to avoid the development of pneumothorax and nosocomial pneumonia.

Association between 10 microsatellite markers and nonsyndromic cleft lip palate in the Chilean population.

OBJECTIVES: The objective of this case-control study was to evaluate the possible association between nonsyndromic cleft lip/palate (NSCLP) and 10 genetic markers in four chromosomal regions in the admixed Spanish-Amerindian Chilean population. SETTING: Study participants included 56 patients with NSCLP identified and interviewed for positive family history during the course of clinical examinations at different rehabilitation centers in the cities of Santiago and Talca, Chile. A control group of 59 normal individuals without known familial antecedents of clefting was obtained from blood bank donors of the University Hospital, University of Chile. Cases and controls belonged to low- to low-middle socioeconomic strata. RESULTS: Ten markers from chromosome 4p, 4q, 6p, 17q, and 19q were assessed (MSX1, D4S175, D4S192, F13A1, EDN1, D6S89, D6S105, D6S109, D17S579, BCL3). Four of them showed significant deviations from Hardy-Weinberg expectations in controls, according to the exact test (D4S192, BCL3, F13A1, and D6S89). The case-control comparison by means of the CLUMP program showed significant differences only in BCL3, and D6S109 almost reached statistical significance. CONCLUSIONS: Most of the genetic regions with positive results in Caucasian populations may not be involved in NSCLP in Chile, regardless of the positive evidence for the candidate region on chromosome 19. Similar findings have been reported recently in the Chinese population.

La donación de ovocitos / Donation of ovules

Se analizan las indicaciones de la donación de óvulos tanto en los casos de fallo ovárico como en aquellos otros en los que la mujer mantiene su función ovárica pero presenta problemas. Se analizan también los requisitos para ser receptora y para ser donante, los aspectos legales sobre este tema y el procedimiento seguido para la donación (AU)

[Evaluation of the association between microsatellite markers located on 6p22-25 and no syndromic cleft lip palate using the case-parents trio design in Chilean population ]. / Evaluación de la asociación entre marcadores de microsatélite en 6p22-25 y fisura labiopalatina no sindrómica utilizando el diseño de tríos caso-progenitores en la población chilena.

BACKGROUND: Genetic studies indicate that nonsyndromic cleft lip/palate (NSCLP) has the characteristics of a complex genetic trait. Reports from different authors have suggested several candidate genes mapping in different chromosome regions. Association studies have suggested that a clefting locus is located on chromosome 6p. On these grounds we have investigated the possible association between five microsatellite markers located on 6p22-25 and NSCLP. AIM: To test the hypothesis on the possible association of a clefting locus with microsatellite markers located in 6p22-25. PATIENTS AND METHODS: The sample consisted of 54 unrelated case-parent trios that comprise 54 NSCLP probands and 108 parents. Five microsatellite markers spanning the region 6p22-25 were analyzed for each individual by means of polymerase chain reaction with fluorescent labeled microsatellite markers. Electrophoresis of the PCR products was performed on a laser-fluorescent DNA sequencer. Nonparametric ETDT and MCETDT programs, were used to analyze the genotype data. RESULTS: The family based association study showed that for the genotype wise analysis, only D6S259 presented a significant p-value (0.03). Nevertheless no individual allele of this marker showed an evident preferential transmission from heterozygous parents to affected offspring. CONCLUSIONS: The results of the present study do not show a clear evidence that a candidate gene for NSCLP may be located within or near the analyzed chromosome region in our sample. Nevertheless, it must be emphasized that the genotype wise analysis shows a significant p-value for D6S259 marker.

[Oocyte donation]. / La donación de ovocitos.

The author analyzes when conditions warrant the donation of ovules in such cases as when ovaries fail to produce ovules and other cases in which a woman maintains her ovarian functions but has problems. The author also analyzes the requirements for one to be a receptor and a donor of ovules, the legal aspects related to this topic, and the procedure to be followed for donation of ovules.

Compromiso neurologico en la lepra / Neurophaties in leprosy patients

La lepra, enfermedad producida por Mycobacteríum leprae, es una de las causas más frecuentes y más antiguas de afección neural periférica. Posee un espectro clínico en piel y en nervio que va desde las formas paucibacilares (tuberculoide) hasta las formas multibacilares (lepromatosa) pasando por una forma intermedia (dimorfa). El diagnóstico se realiza por la historia y la presentación clínica del paciente, sumado a las baciloscopias y hallazgos de biopsias de piel. La biopsia de nervio periférico es un método diagnóstico de alta morbilidad que se utiliza sólo en casos muy seleccionados. La detección precoz del compromiso neurológico en la enfermedad de Hansen sumado a una adecuada terapia farmacológica e interdisciplinaria para el manejo de sus discapacidades hace la diferencia en el pronóstico y calidad de vida de los pacientes afectados

[Association between cleft lip/palate phenotype and non syndrome microsatellite markers located in 6p, 17q and 19q]. / Asociación entre el fenotipo fisura labiopalatina no sindrómica y marcadores de microsatélites ubicados en 6p, 17q y 19q.

BACKGROUND: In the search of the major genes responsible for the genetic etiology of Nonsyndromic Cleft Lip and Palate (NSCLP), an association study between this malformation and four molecular markers, F13A1 and EDN1 (6p), D17S579 (17q) and BCL3 (19q), was done. AIM: To determine, in a Chilean population, the presence of NSCLP susceptibility regions, as proposed for Caucasian populations in the 6p, 17q and 19q chromosomal regions. MATERIAL AND METHODS: A sample of unrelated NSCLP patients, that belonged to Simplex (Sx) and Multiplex (Mx) families, was analyzed. Blood donors were used as a control group (Co). The DNA of the four markers was amplified by means of PCR, their products analyzed by PAGE denaturants and visualized by silver staining. Statistical analysis was performed using chi 2 log ratio. RESULTS: Allele frequency distribution of D17S579 was significantly different in all patients with NSCLP and their subgroups, when compared to control subjects. Significant differences in EDN1 frequency were observed between the total groups of NSCLP patients and those pertaining to the Mx subgroup, when compared to controls. Differences in F13A1 distribution were only observed between NSCLP-Mx patients and controls. There was a slight difference in BCL3 distribution, between the total sample of NSCLP patients and controls. CONCLUSIONS: Our results support the hypothesis of the existence of cleft susceptibility regions in 6p and 17q. The small significance of BCL3, suggests that ethnicity can influence the interactions between involved genes.

Complex segregation analysis of nonsyndromic cleft lip/palate in a Chilean population

A populaçäo urbana Chilena contemporânea deriva da mistura de ameríndios nativos com espanhóis, apresentando uma incidência média de fissura labial näo sindrômica associada ou näo a fissura palativa (NSCLP) de 1,8 por 1000 nascimentos vivos. A análise de segregaçäo complexa usando o programa de computador POINTER foi feita em 249 pedigrees estendidos, distribuídos em 202 famílias simplex e 47 famílias multiplex obtidas de probands de NSCLP afetados (157 homens e 92 mulheres). Esses pedigrees deram origem a 326 indivíduos afetados e mais de 1454 parentes. Oito modelos hipotéticos foram examinados e comparados pelo teste X²log2 razäo de máxima verossimilhança. Os modelos que postulam que NSCLP näo era transmitida nestas famílias foram rejeitados, assim como os modelos que postulam apenas um componente multifatorial (P<0,0001). O modelo que postula näo haver componente poligênico para a transmissäo do efeito mais importante foi rejeitado (P<0,0001). Entre os modelos do locus mais importante apenas o modelo recessivo de transmissäo foi rejeitado, enquanto que as heranças codominante e dominante sem um componente multifatorial näo puderam ser excluídas. O modelo näo restrito sugere que a freqüência do alelo de suscetibilidade a NSCLP no locus mais importante é 0,0037 e sua penetrância é de 92 por cento.