Efficacy and delivery strategies of the dual Rac/Cdc42 inhibitor MBQ-167 in HER2 overexpressing breast cancer.

Trastuzumab and trastuzumab-based treatments are the standard of care for breast cancer patients who overexpress the human epidermal growth factor receptor 2 (HER2). However, patients often develop resistance to trastuzumab via signaling from alternative growth factor receptors that converge to activate guanine nucleotide exchange factors (GEFs) that in turn activate the Rho GTPases Rac and Cdc42. Since Rac and Cdc42 have been implicated in high tumor grade and therapy resistance, inhibiting the activity of Rac and Cdc42 is a rational strategy to overcome HER2-targeted therapy resistance. Therefore, our group developed MBQ-167, a dual Rac/Cdc42 inhibitor with IC50s of 103 nM and 78 nM for Rac and Cdc42, respectively, which is highly effective in reducing cell and tumor growth and metastasis in breast cancer cell and mouse models. Herein, we created a trastuzumab resistant variant of the SKBR3 HER2 positive breast cancer cell line and show that Rac activation is a central mechanism in trastuzumab resistance. Next, we tested the potential of targeting MBQ-167 to HER2 overexpressing trastuzumab-resistant cell lines in vitro, and show that MBQ-167, but not trastuzumab, reduces cell viability and induces apoptosis. When MBQ-167 was targeted to mammary fatpad tumors established from HER2 overexpressing cells via immunoliposomes functionalized with trastuzumab, MBQ-167 and MBQ-167-loaded liposomes show equal efficacy in reducing the viability of trastuzumab-resistant cells, inhibiting tumor growth in mouse xenografts, and reducing metastasis to lungs and liver. This study demonstrates the efficacy of MBQ-167 as an alternative therapeutic in HER2 overexpressing cancers, delivered either in free form or in liposomes.

Estado inicial de la virtualización del proceso de formación en una Universidad

El desarrollo de las Tecnologías de la Información y las Comunicaciones (TIC) genera nuevas demandas sociales a la educación. En los últimos años, la utilización de elementos tecnológicos en los contextos educativos ha conllevado a la realización de profundas transformaciones en las instituciones y en la forma de organizar y trabajar el proceso docente educativo. El objetivo de este artículo fue analizar el estado inicial de la virtualización del proceso de formación en la Universidad de Ciencias de la Cultura Física y Deporte Manuel Fajardo. Para lograr este propósito se aplicó un conjunto de instrumentos (encuestas a estudiantes y profesores, entrevistas a directivos y guía de observación a los cursos implementados en la plataforma virtual Moodle). Se asumió un enfoque mixto que posibilitó buscar información sobre la virtualización del proceso de formación de la Universidad de Ciencias de la Cultura Física y el Deporte (UCCFD) Manuel Fajardo desde las miradas de los distintos actores del proceso, lo que permitió lograr una mayor fidelidad de los resultados obtenidos en los instrumentos aplicados. Los resultados de las encuestas a estudiantes y profesores fueron divididos en positivos y negativos (Carencias y Fortalezas), para destacar la necesidad de elaborar un modelo de virtualización del proceso de formación de la UCCFD "Manuel Fajardo".

O desenvolvimento das Tecnologias de Informação e Comunicação (TIC) gera novas demandas sociais para a educação. Nos últimos anos, o uso de elementos tecnológicos em contextos educacionais levou a profundas transformações nas instituições e na forma de organizar e trabalhar o processo de ensino e educação. O objetivo deste artigo foi analisar o estado inicial da virtualização do processo de treinamento na Universidade Manuel Fajardo de Cultura Física e Ciências do Esporte. Para atingir esse objetivo, foi aplicado um conjunto de instrumentos (pesquisas com alunos e professores, entrevistas com diretores e um guia de observação dos cursos implementados na plataforma virtual Moodle). Foi adotada uma abordagem mista, que possibilitou a busca de informações sobre a virtualização do processo de treinamento na Universidade de Ciências da Cultura Física e do Esporte Manuel Fajardo (UCCFD) a partir dos pontos de vista dos diferentes atores do processo, o que permitiu obter maior precisão nos resultados obtidos nos instrumentos aplicados. Os resultados das pesquisas com alunos e professores foram divididos em positivos e negativos (deficiências e pontos fortes), a fim de destacar a necessidade de desenvolver um modelo de virtualização para o processo de formação na UCCFD "Manuel Fajardo".

The development of Information and Communication Technologies (ICT) generates new social demands on education. In recent years, the use of technological elements in educational contexts has led to profound transformations in institutions and in the way of organizing and working the educational teaching process. The objective of this article was to analyze the initial state of the virtualization of the training process at the Manuel Fajardo University of Physical Culture and Sports Sciences. To achieve this purpose, a set of instruments was applied (surveys to students and teachers, interviews with managers and an observation guide to the courses implemented on the Moodle virtual platform). A mixed approach was assumed that made it possible to search for information on the virtualization of the training process of the "Manuel Fajardo" University of Physical Culture and Sports Sciences (UCCFD in Spanish) from the perspectives of the different actors in the process, which allowed achieving greater fidelity of the results obtained in the applied instruments. The results of the surveys to students and teachers were divided into positive and negative (Shortcomings and Strengths), to highlight the need to develop a virtualization model of the training process of the UCCFD "Manuel Fajardo".

How the COVID-19 pandemic affects the moral reasoning of pediatric residents and the general population.

BACKGROUND: Kohlberg's theory of moral development asserts that people progress through different stages of moral reasoning as their cognitive abilities and social interactions mature. Individuals at the lowest stage of moral reasoning (preconventional stage) judge moral issues based on self-interest, those with a medium stage (conventional stage) judge them based on compliance with rules and norms, and those at the highest stage (postconventional stage) judge moral issues based on universal principles and shared ideals. Upon attaining adulthood, it can be considered that there is stability in the stage of individuals' moral development; however, the effect of a global population crisis such as the one experienced in March 2020, when the World Health Organization (WHO) declared the COVID-19 pandemic, is unknown. The purpose of this study was to evaluate the changes in the moral reasoning of pediatric residents before and after one year of the COVID-19 pandemic and compare them with a general population group. METHODS: This is a naturalistic quasi-experimental study conducted with two groups, one comprised 47 pediatric residents of a tertiary hospital converted into a COVID hospital during the pandemic and another group comprised 47 beneficiaries of a family clinic who were not health workers. The defining issues test (DIT) was applied to the 94 participants during March 2020, before the pandemic initiated in Mexico, and later during March 2021. To assess intragroup changes, the McNemar-Bowker and Wilcoxon tests were used. RESULTS: Pediatric residents showed higher baseline stages of moral reasoning: 53% in the postconventional group compared to the general population group (7%). In the preconventional group, 23% were residents and 64% belonged to the general population. In the second measurement, one year after the start of the pandemic, the group of residents had a significant decrease of 13 points in the P index, unlike the general population group in which a decrease of 3 points was observed. This decrease however, did not equalize baseline stages. Pediatric residents remained 10 points higher than the general population group. Moral reasoning stages were associated with age and educational stage. CONCLUSIONS: After a year of the COVID-19 pandemic, we found a decrease in the stage of moral reasoning development in pediatric residents of a hospital converted for the care of patients with COVID-19, while it remained stable in the general population group. Physicians showed higher stages of moral reasoning at baseline than the general population.

Cell cycle, apoptosis, cell differentiation, and lipid metabolism gene expression in endometriotic tissue and exposure to parabens and benzophenones.

AIM: To describe the expression profile in endometriotic tissue of genes involved in four signaling pathways related to the development and progression of endometriosis (cell cycle, apoptosis, cell differentiation and lipid metabolism) and to explore its relationship with the women exposure to chemicals with hormonal activity released from cosmetics and personal care products (PCPs). METHODS: This cross-sectional study, encompassed within the EndEA study, comprised a subsample of 33 women with endometriosis. Expression levels of 13 genes (BMI1, CCNB1, CDK1, BAX, BCL2L1, FOXO3, SPP1, HOXA10, PDGFRA, SOX2, APOE, PLCG1 and PLCG2) in endometriotic tissue and urinary concentrations of 4 paraben (PB) and 3 benzophenone (BP) congeners were quantified. Bivariate linear and logistic regression analyses were performed to explore the associations between exposure and gene expression levels. RESULTS: A total of 8 out 13 genes (61.5 %) were expressed in >75 % of the samples. Exposure to congeners of PBs and/or BPs was associated with the overexpression of CDK1 gene (whose protein drives cells through G2 phase and mitosis), HOXA10 and PDGFRA genes (whose proteins favor pluripotent cell differentiation to endometrial cells), and APOE (whose protein regulates the transport and metabolism of cholesterol, triglycerides and phospholipids in multiple tissues) and PLCG2 genes (whose protein creates 1D-myo-inositol 1,4,5-trisphosphate and diacylglycerol, two important second messengers). CONCLUSIONS: Our findings suggest that women exposure to cosmetic and PCP-released chemicals might be associated with the promotion of cell cycle and cell differentiation as well as with lipid metabolism disruption in endometriotic tissue, three crucial signaling pathways in the development and progression of endometriosis. However, further studies should be accomplished to confirm these preliminary data.

Asociación de la infección por SARS-CoV-2 y la administración de las vacunas contra la COVID-19 con alteraciones en el ciclo menstrual. Revisión de la literatura / Association of SARS-CoV-2 infection and administration of COVID-19 vaccines with alterations in the menstrual cycle. Literature review

Son diversos los factores que pueden afectar al ciclo menstrual de la mujer, entre ellos enfermedades o fármacos, como la enfermedad COVID-19 y las vacunas. El objetivo de esta revisión es explorar los estudios publicados hasta la fecha que han estudiado la presencia de alteraciones que puedan relacionarse con la COVID-19 o la vacunación contra el virus SARS-CoV-2.Se ha realizado una revisión en la base de datos PubMed, seleccionando 10 artículos en los que se ha estudiado el ciclo menstrual de mujeres adultas en edad fértil, tres de ellos en los que las participantes han sido diagnosticadas de COVID-19 y siete en los que las participantes han sido vacunadas contra el virus SARS-CoV-2.Respecto a las alteraciones relacionadas con la COVID-19, entre un 16 y un 47,2% de las participantes presentaron una prolongación de su ciclo, siendo más frecuente en aquellas que informaron de más síntomas de COVID-19, observando una normalización tras uno a dos ciclos.Respecto a las alteraciones descritas tras la vacunación contra el SARS-CoV-2, el 45-78% de las participantes refirieron alteraciones del ciclo menstrual, con resultados dispares respecto a los diferentes parámetros analizados, excepto en que las alteraciones se resolvían en unos dos meses.Tanto la enfermedad COVID-19 como la vacunación parecen estar relacionadas con la presentación de alteraciones en la menstruación, siendo estas limitadas en el tiempo y no graves. Sin embargo, los estudios son escasos hasta la fecha, por lo que es importante seguir desarrollando estudios que aporten evidencia científica.(AU)

A number of factors can affect a woman's menstrual cycle, including diseases or drugs, such as COVID-19 disease and vaccinations. The aim of this review is to explore the studies published to date that have studied the presence of alterations that may be related to COVID-19 or vaccination against the SARS-CoV-2 virus.We conducted a review in the PubMed database, selecting 10 articles in which the menstrual cycle of adult women of childbearing age was studied, 3 of them in which the participants had been diagnosed with COVID-19 and 7 in which the participants had been vaccinated against the SARS-CoV-2 virus.Regarding COVID-19-related disturbances, 16%-47.2% of the participants presented a prolongation of their cycle, which was more frequent in those who reported more COVID-19 symptoms, and which normalised after 1-2 cycles.Regarding the alterations described after SARS-CoV-2 vaccination, 45%-78% of participants reported menstrual cycle alterations, with disparate results for the different parameters analysed, except that the alterations resolved in about 2 months.Both COVID-19 disease and vaccination appear to be associated with the occurrence of menstrual disturbances, which are limited in time and not severe. However, studies are scarce to date, and it is important to continue to develop studies that provide scientific evidence.(AU)

[Association of SARS-CoV-2 infection and administration of COVID-19 vaccines with alterations in the menstrual cycle. Literature review]. / Asociación de la infección por SARS-CoV-2 y la administración de las vacunas contra la COVID-19 con alteraciones en el ciclo menstrual. Revisión de la literatura.

A number of factors can affect a woman's menstrual cycle, including diseases or drugs, such as COVID-19 disease and vaccinations. The aim of this review is to explore the studies published to date that have studied the presence of alterations that may be related to COVID-19 or vaccination against the SARS-CoV-2 virus.We conducted a review in the PubMed database, selecting 10 articles in which the menstrual cycle of adult women of childbearing age was studied, 3 of them in which the participants had been diagnosed with COVID-19 and 7 in which the participants had been vaccinated against the SARS-CoV-2 virus.Regarding COVID-19-related disturbances, 16%-47.2% of the participants presented a prolongation of their cycle, which was more frequent in those who reported more COVID-19 symptoms, and which normalised after 1-2 cycles.Regarding the alterations described after SARS-CoV-2 vaccination, 45%-78% of participants reported menstrual cycle alterations, with disparate results for the different parameters analysed, except that the alterations resolved in about 2 months.Both COVID-19 disease and vaccination appear to be associated with the occurrence of menstrual disturbances, which are limited in time and not severe. However, studies are scarce to date, and it is important to continue to develop studies that provide scientific evidence.

Efficacy of Rac and Cdc42 Inhibitor MBQ-167 in Triple-negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer, with a high predisposition for locally invasive and metastatic cancer. With the objective to reduce cancer metastasis, we developed small molecule inhibitors to target the drivers of metastasis, the Rho GTPases Rac and Cdc42. Of these, MBQ-167 inhibits both Rac and Cdc42 with IC50s of 103 and 78 nmol/L, respectively; and consequently, inhibits p21-activated kinase (PAK) signaling, metastatic cancer cell proliferation, migration, and mammosphere growth; induces cell-cycle arrest and apoptosis; and decreases HER2-type mammary fatpad tumor growth and metastasis (Humphries-Bickley and colleagues, 2017). Herein, we used nuclear magnetic resonance to show that MBQ-167 directly interacts with Rac1 to displace specific amino acids, and consequently inhibits Rac.GTP loading and viability in TNBC cell lines. Phosphokinome arrays in the MDA-MB-231 human TNBC cells show that phosphorylation status of kinases independent of the Rac/Cdc42/PAK pathway are not significantly changed following 200 nmol/L MBQ-167 treatment. Western blotting shows that initial increases in phospho-c-Jun and phospho-CREB in response to MBQ-167 are not sustained with prolonged exposure, as also confirmed by a decrease in their transcriptional targets. MBQ-167 inhibits tumor growth, and spontaneous and experimental metastasis in immunocompromised (human TNBC) and immunocompetent (mouse TNBC) models. Moreover, per oral administration of MBQ-167 at 100 mg/kg body weight is not toxic to immunocompetent BALB/c mice and has a half-life of 4.6 hours in plasma. These results highlight the specificity, potency, and bioavailability of MBQ-167, and support its clinical potential as a TNBC therapeutic.

Targeting Lipocalin-2 in Inflammatory Breast Cancer Cells with Small Interference RNA and Small Molecule Inhibitors.

Inflammatory Breast Cancer (IBC) is an aggressive form of invasive breast cancer, highly metastatic, representing 2-4% of all breast cancer cases in the United States. Despite its rare nature, IBC is responsible for 7-10% of all breast cancer deaths, with a 5-year survival rate of 40%. Thus, targeted and effective therapies against IBC are needed. Here, we proposed Lipocalin-2 (LCN2)-a secreted glycoprotein aberrantly abundant in different cancers-as a plausible target for IBC. In immunoblotting, we observed higher LCN2 protein levels in IBC cells than non-IBC cells, where the LCN2 levels were almost undetectable. We assessed the biological effects of targeting LCN2 in IBC cells with small interference RNAs (siRNAs) and small molecule inhibitors. siRNA-mediated LCN2 silencing in IBC cells significantly reduced cell proliferation, viability, migration, and invasion. Furthermore, LCN2 silencing promoted apoptosis and arrested the cell cycle progression in the G0/G1 to S phase transition. We used in silico analysis with a library of 25,000 compounds to identify potential LCN2 inhibitors, and four out of sixteen selected compounds significantly decreased cell proliferation, cell viability, and the AKT phosphorylation levels in SUM149 cells. Moreover, ectopically expressing LCN2 MCF7 cells, treated with two potential LCN2 inhibitors (ZINC00784494 and ZINC00640089) showed a significant decrease in cell proliferation. Our findings suggest LCN2 as a promising target for IBC treatment using siRNA and small molecule inhibitors.

Efficacy of Virtual Reality in Neurorehabilitation of Spinal Cord Injury Patients: A Systematic Review / Eficacia de la Realidad Virtual en la Neurorrehabilitación de Pacientes con Lesión de Médula Espinal: una Revisión Sistemática

ABSTRACT This systematic review (SR) analyzed the effectiveness of interventions using virtual reality (VR) technology as a neurorehabilitation therapy in people with spinal cord injury (SCI). The SR was developed under the guidelines of the PRISMA statement and the recommendations of the Cochrane Collaboration, along with the PEDro and National Institute of Health scales to assess the risk of bias and methodological quality. The Cochrane, IEEE, BVS/LILACS, MEDLINE/PubMed, and Web of Science databases were browsed to identify studies that, between 2010 and 2020, evaluated the efficacy of these therapies. Out of 353 retrieved studies, 11 were finally selected after the application of the defined inclusion and exclusion criteria. These articles presented good methodological quality as they were mostly controlled clinical trials that analyzed mixed therapies with conventional therapies. Interventions based on non-immersive or immersive VR technology that achieved functional motor, balance, and psycho-emotional health improvement with positive effects on motivation, self-confidence, commitment, and active participation were identified in a total sample of 155 SCI patients. It was concluded that such VR technology is an effective tool of neurorehabilitation complementary to conventional therapies, which promotes functional improvement in SCI patients both in the clinic and at home.

RESUMEN Esta revisión sistemática (RS) analizó la eficacia de las intervenciones que utilizan la tecnología de realidad virtual (RV) como terapia de neurorrehabilitación en personas con lesión de médula espinal (LME). La RS fue desarrollada bajo los lineamientos de la declaración PRISMA y las recomendaciones de la Colaboración Cochrane, junto con las escalas de PEDro y del National Institute of Health para evaluar el riego de sesgo y la calidad metodológica. Se revisaron las bases de Cochrane, IEEE, BVS/LILACS, MEDLINE/PubMed y Web of Science para identificar estudios que, entre 2010 y 2020, evaluaron la eficacia de dichas terapias. De 353 estudios recuperados, 11 fueron finalmente seleccionados tras la aplicación de los criterios de inclusión y exclusión definidos. Dichos artículos presentaron una buena calidad metodológica, al ser mayormente ensayos clínicos controlados que analizaron terapias mixtas con terapias convencionales. Se identificaron intervenciones basadas en tecnología de RV no inmersiva o inmersiva que lograron una mejora funcional motora, de equilibrio y de salud psico-emocional con efectos positivos de motivación, seguridad, compromiso y activa participación en una muestra total de 155 pacientes con LME. Se concluyó que dicha tecnología de RV es una herramienta eficaz de neurorrehabilitación complementaria a las terapias convencionales, al promover una mejora funcional en pacientes con LME tanto en la clínica como en casa.

Effects of substrate temperature on patterns produced by dried droplets of proteins.

Rapid diagnosis provides better clinical management of patients, helps control possible outbreaks, and increases survival. The study of deposits produced by the evaporation of droplets is a useful tool in the diagnosis of some health problems. With the aim to improve diagnostic time in clinical practice where we use the evaporation of droplets, we explored the effects of substrate temperature on pattern formation of dried droplets in globular protein solutions. Three deposit groups were observed: "functional" patterns (from 25 to 37 ∘C), "transition" patterns (from 44 to 50 ∘C), and "eye" patterns (from 58 to 63 ∘C). The dried droplets of the first two groups show a ring structure ("coffee-ring") that confines a great diversity of aggregates such as needle-like structures, tiny blade-shape crystals, highly symmetrical crystallization patterns, and amorphous salt aggregates. In contrast, the "eye" patterns are deposits with a large inner aggregate surrounded by a coffee ring, and they can appear from the evaporation of droplets in protein binary mixtures and blood serum. Interestingly, the unfolding proteins correlates with the formation of "eye" patterns. We measured stain diameter, "coffee-ring" thickness, radial density profile, and entropy computed by GLCM-statistics to quantify the structural differences among deposit groups. We found that "functional" patterns are structurally indistinguishable among them, but they are clearly different from elements of the other deposit groups. An exponential decay function describes pattern formation time as a function of substrate temperature, which is independent from protein concentration. Patterns formation at 32 ∘C takes place up to 63% less time and preserves the structural characteristics of dried droplets in proteins formed at room temperature. Therefore, we argue that droplet evaporation at this substrate temperature could be an excellent candidate to make a more efficient diagnosis based on droplet evaporation of biofluids.

Role of Chiral Two-Body Currents in

A direct measurement of the decay width of the excited 0_{1}^{+} state of ^{6}Li using the relative self-absorption technique is reported. Our value of Γ_{γ,0_{1}^{+}→1_{1}^{+}}=8.17(14)_{stat.}(11)_{syst.} eV provides sufficiently low experimental uncertainties to test modern theories of nuclear forces. The corresponding transition rate is compared to the results of ab initio calculations based on chiral effective field theory that take into account contributions to the magnetic dipole operator beyond leading order. This enables a precision test of the impact of two-body currents that enter at next-to-leading order.

Strain wave pathway to semiconductor-to-metal transition revealed by time-resolved X-ray powder diffraction.

One of the main challenges in ultrafast material science is to trigger phase transitions with short pulses of light. Here we show how strain waves, launched by electronic and structural precursor phenomena, determine a coherent macroscopic transformation pathway for the semiconducting-to-metal transition in bistable Ti3O5 nanocrystals. Employing femtosecond powder X-ray diffraction, we measure the lattice deformation in the phase transition as a function of time. We monitor the early intra-cell distortion around the light absorbing metal dimer and the long range deformations governed by acoustic waves propagating from the laser-exposed Ti3O5 surface. We developed a simplified elastic model demonstrating that picosecond switching in nanocrystals happens concomitantly with the propagating acoustic wavefront, several decades faster than thermal processes governed by heat diffusion.

Evaluation of ponatinib in vitro effect in three canine mast cell tumor cell lines expressing FGFR-1, PDGFR-α, and VEGFR-2.

Ponatinib is a broad-spectrum tyrosine kinase inhibitor that targets numerous receptor tyrosine kinases (RTKs), including but not limited to fibroblast growth factor receptor (FGFR)-1, platelet derived growth factor receptor (PDGFR)-α, and vascular endothelial growth factor receptor (VEGFR)-2. This study evaluated the expression of FGFR-1, PDGFR-α, and VEGFR-2 in three canine mast cell tumor (MCT) cell lines (CM-MC1, VI-MC1, CoMS) and the effects of ponatinib on these MCT cell lines. Quantitative RT-PCR confirmed the expression of FGFR-1, PDGFR-α, and VEGFR-2 in the three MCT cell lines. Ponatinib exhibited dose- and time-dependent cytotoxicity in MCT cell lines via MTT assay. The IC50 for 24, 48, and 72 h across the three cell lines ranged from 38.47 nM to 103.3 nM, which is clinically comparable to dose ranges established for humans. Significantly increased apoptosis in each cell line was seen between 12 and 18 h after treatment with IC50 of ponatinib via Annexin-V and Caspase-3/7 assays. These data suggest that ponatinib could be a possible therapeutic agent for canine MCTs. Further studies are needed to investigate the prognostic value of FGFR-1, PDGFR-α, and VEGFR-2 in canine MCTs.

Cosmetic and personal care product use, urinary levels of parabens and benzophenones, and risk of endometriosis: results from the EndEA study.

AIM: To explore the relationship of urinary concentrations of different congeners of benzophenones and parabens with the utilization of cosmetics and personal care products (PCPs) and their impact on the risk of endometriosis, and to evaluate the influence of oxidative stress on associations found. METHODS: This case-control study comprised a subsample of 124 women (35 cases; 89 controls). Endometriosis was confirmed (cases) or ruled out (controls) by laparoscopy, with visual inspection of the pelvis and biopsy of suspected lesions (histological diagnosis). Urinary concentrations of benzophenone-1 (BP-1), benzophenone-3 (BP-3), 4-hydroxibenzophenone (4-OH-BP), methyl- (MeP), ethyl- (EtP), propyl- (PrP), and butyl-paraben (BuP), and biomarkers of oxidative stress [lipid peroxidation (TBARS) and total antioxidant power (TAP)] were quantified. Information was gathered on the frequency of use of cosmetics and PCPs. Associations between the frequency of cosmetics/PCP use, urinary concentrations of benzophenones and parabens, oxidative stress, and endometriosis risk were explored in logistic and linear multivariable regression analyses. RESULTS: The frequency of utilization of certain cosmetics and PCPs was significantly associated with urinary concentrations of benzophenones and parabens. After adjustment for potential confounders, the risk of endometriosis was increased in women in the second versus first terciles of MeP (OR = 5.63; p-value<0.001), BP-1 (OR = 5.12; p-value = 0.011), BP-3 (OR = 4.98; p-value = 0.008), and Æ©BPs (OR = 3.34; p-value = 0.032). A close-to-significant relationship was observed between TBARS concentrations and increased endometriosis risk (OR = 1.60, p-value = 0.070) and an inverse association between TAP concentrations and this risk (OR = 0.15; p-value = 0.048). Oxidative stress results did not modify associations observed between benzophenone/paraben exposure and endometriosis risk. CONCLUSIONS: Our findings indicate that the frequency of cosmetics and PCP utilization is a strong predictor of exposure to certain benzophenone and paraben congeners. These compounds may increase the risk of endometriosis in an oxidative stress-independent manner. Further studies are warranted to corroborate these findings.

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2. The MD involves temperature replica exchange enhanced sampling, making use of massively parallel supercomputing to quickly sample the configurational space of protein drug targets. Using the Summit supercomputer at the Oak Ridge National Laboratory, more than 1 ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to 10 configurations of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison to experiment demonstrates remarkably high hit rates for the top scoring tranches of compounds identified by our ensemble approach. We also demonstrate that, using Autodock-GPU on Summit, it is possible to perform exhaustive docking of one billion compounds in under 24 h. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and artificial intelligence (AI) methods to cluster MD trajectories and rescore docking poses.

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in-silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. We also describe preliminary results obtained for 23 systems involving eight protein targets of the proteome of SARS CoV-2. THe MD performed is temperature replica-exchange enhanced sampling, making use of the massively parallel supercomputing on the SUMMIT supercomputer at Oak Ridge National Laboratory, with which more than 1ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to ten configurations of each of the 23 SARS CoV-2 systems using AutoDock Vina. We also demonstrate that using Autodock-GPU on SUMMIT, it is possible to perform exhaustive docking of one billion compounds in under 24 hours. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and AI methods to cluster MD trajectories and rescore docking poses.

Cuidados generales en el manejo del traumatismo craneoencefálico grave: consenso latinoamericano / General care in the management of severe traumatic brain injury: Latin American consensus

El traumatismo craneoencefálico grave (TCEg) continúa siendo prevalente en la población adulta joven. Lejos de descender, su incidencia se mantiene elevada. Uno de los pilares en los que se asienta su tratamiento es evitar, detectar y corregir complicaciones secundarias de origen sistémico que agravan la lesión primaria. Gran parte de este objetivo se logra manteniendo un microambiente fisiológico adecuado que permita la recuperación del tejido cerebral lesionado. Las medidas de cuidados generales son acciones inespecíficas destinadas a cumplir dicho objetivo. Las guías disponibles de manejo del TCEg no han incluido la mayoría de los tópicos motivo de este consenso. Para ello, hemos reunido un grupo de profesionales miembros del Consorcio latinoamericano de Injuria Cerebral (LABIC), involucrados en los diferentes aspectos del manejo agudo del TCEg (neurocirujanos, intensivistas, anestesiólogos, neurólogos, enfermeros, fisioterapeutas). Se efectuó una búsqueda bibliográfica en las bases de datos LILACS, PubMed, Embasse, Scopus, Cochrane Controlled Register of Trials y Web of Science de los tópicos seleccionados. Para establecer recomendaciones o sugerencias con su respectiva fortaleza o debilidad, fue aplicada la metodología Grading of Recommendations, Assessment, Development and Evaluation (GRADE). Adicionalmente, ciertas recomendaciones (incluidas en material complementario) no fueron valoradas por GRADE, por ser las mismas un conjunto de acciones terapéuticas de cumplimento efectivo, en las que no fue posible aplicar dicha metodología. Fueron establecidas 32 recomendaciones; 16 fuertes y 16 débiles, con su respectivo nivel de evidencia. El presente consenso intenta homogeneizar y establecer medidas de cuidados generales básicas en esta población de individuos

Severe traumatic brain injury (sTBI) remains prevalent in the young adult population. Indeed, far from descending, the incidence of sTBI remains high. One of the key bases of treatment is to avoid, detect and correct secondary injuries of systemic origin, which aggravate the primary lesion. Much of this can be achieved by maintaining an adequate physiological microenvironment allowing recovery of the damaged brain tissue. General care measures are nonspecific actions designed to meet that objective. The available guidelines on the management of sTBI have not included the topics contemplated in this consensus. In this regard, a group of members of the Latin American Brain Injury Consortium (LABIC), involved in the different aspects of the acute management of sTBI (neurosurgeons, intensivists, anesthesiologists, neurologists, nurses and physiotherapists) were gathered. An exhaustive literature search was made of selected topics in the LILACS, PubMed, Embase, Scopus, Cochrane Controlled Register of Trials and Web of Science databases. To establish recommendations or suggestions with their respective strength or weakness, the GRADE methodology (Grading of Recommendations, Assessment, Development and Evaluation) was applied. Additionally, certain recommendations (included in complementary material) were not assessed by GRADE, because they constitute a set of therapeutic actions of effective compliance, in which it was not possible to apply the said methodology. Thirty-two recommendations were established, 16 strong and 16 weak, with their respective levels of evidence. This consensus attempts to standardize and establish basic general care measures in this particular patient population