Globospiramine from Voacanga globosa Exerts Robust Cytotoxic and Antiproliferative Activities on Cancer Cells by Inducing Caspase-Dependent Apoptosis in A549 Cells and Inhibiting MAPK14 (p38α): In Vitro and Computational Investigations.

Bisindole alkaloids are a source of inspiration for the design and discovery of new-generation anticancer agents. In this study, we investigated the cytotoxic and antiproliferative activities of three spirobisindole alkaloids from the traditional anticancer Philippine medicinal plant Voacanga globosa, along with their mechanisms of action. Thus, the alkaloids globospiramine (1), deoxyvobtusine (2), and vobtusine lactone (3) showed in vitro cytotoxicity and antiproliferative activities against the tested cell lines (L929, KB3.1, A431, MCF-7, A549, PC-3, and SKOV-3) using MTT and CellTiter-Blue assays. Globospiramine (1) was also screened against a panel of breast cancer cell lines using the sulforhodamine B (SRB) assay and showed moderate cytotoxicity. It also promoted the activation of apoptotic effector caspases 3 and 7 using Caspase-Glo 3/7 and CellEvent-3/7 apoptosis assays. Increased expressions of cleaved caspase 3 and PARP in A549 cells treated with 1 were also observed. Apoptotic activity was also confirmed when globospiramine (1) failed to promote the rapid loss of membrane integrity according to the HeLa cell membrane permeability assay. Network pharmacology analysis, molecular docking, and molecular dynamics simulations identified MAPK14 (p38α), a pharmacological target leading to cancer cell apoptosis, as a putative target. Low toxicity risks and favorable drug-likeness were also predicted for 1. Overall, our study demonstrated the anticancer potentials and apoptotic mechanisms of globospiramine (1), validating the traditional medicinal use of Voacanga globosa.

Research Note: Bovine lactoferrin in chickens: an investigation into its viability as an antibiotic alternative.

Finding effective antibiotic alternatives is crucial to managing the re-emerging health risk of Clostridium perfringens (CP) type A/G-induced avian necrotic enteritis (NE), a disease that has regained prominence in the wake of governmental restrictions on antibiotic use in poultry. Known for its antimicrobial and immunomodulatory effects, the use of bovine lactoferrin (bLF) in chickens is yet to be fully explored. In this study, we hypothesized that bLF can accumulate in the small intestines of healthy chickens through gavage and intramuscular supplementation and serves as a potential antibiotic alternative. Immunohistochemistry located bLF in various layers of the small intestines and ELISA testing confirmed its accumulation. Surprisingly, sham-treated chickens also showed the presence of bLF, prompting a western blotting analysis that dismissed the notion of cross-reactivity between bLF and the avian protein ovotransferrin. Although the significance of the route of administration remains inconclusive, this study supports the hypothesis that bLF is a promising and safe antibiotic alternative with demonstrated resistance to the degradative environment of the chicken intestines. Further studies are needed to determine its beneficial pharmacological effects in CP-infected chickens.

Psychological wellbeing in teachers. Study in teachers of early childhood and primary education.

Recently, there has been a growing interest in emotional wellbeing, even from the early stages of education. In order to work wellbeing among the students it is essential to analyze the wellbeing of the teachers who are teaching and working with the children. This study examines psychological wellbeing in early childhood (0-6 years) and primary school teachers (6-12 years). The study comprised 236 early childhood and primary school teachers - 76 men (32.2%) and 160 women (67.8%) - with ages ranging from 25 to 61 years (average 37.69 years - s.d.=2.47). The study examined psychological wellbeing (happiness, eudemonic wellbeing, self-esteem, and life satisfaction) and several sociodemographic variables (gender, age, years in the job, type of contract, and educational stage). Participants answered an ad-hoc sociodemographic questionnaire and subjective happiness, eudemonic wellbeing, self-esteem, and life satisfaction standard questionnaires. Early childhood schoolteachers yielded higher wellbeing-related scores. All the wellbeing-related variables were found to be correlated with one another, except for happiness and self-esteem. Teachers working in different educational stages were found to yield significantly different wellbeing-related scores. For the first time, network analysis revealed differences in the associations of the variables under study among Early Childhood Education and Primary Education teachers. Thus, while happiness and satisfaction with life were found to be correlated in both groups, stronger correlations between self-esteem and eudaimonic wellbeing were found in early childhood education teachers, while in primary education teachers the correlation was with satisfaction with life, which indicates that early childhood teachers present greater spiritual and existential understanding, leading to eudaimonic wellbeing. These differences between educational stages are considered greatly significant. It was concluded that more research is needed, ideally with broader and longitudinal studies, to understand and describe the relationship between personal and even structural variables and wellbeing.

Molecular dynamics simulations suggest the potential toxicity of fluorinated graphene to HP35 protein via unfolding the α-helix structure.

Fluorinated graphene, a two-dimensional nanomaterial composed of three atomic layers, a central carbon layer sandwiched between two layers of fluorine atoms, has attracted considerable attention across various fields, particularly for its potential use in biomedical applications. Nonetheless, scant effort has been devoted to assessing the potential toxicological implications of this nanomaterial. In this study, we scrutinize the potential impact of fluorinated graphene on a protein model, HP35 by utilizing extensive molecular dynamics (MD) simulation methods. Our MD results elucidate that upon adsorption to the nanomaterial, HP35 undergoes a denaturation process initiated by the unraveling of the second helix of the protein and the loss of the proteins hydrophobic core. In detail, substantial alterations in various structural features of HP35 ensue, including alterations in hydrogen bonding, Q value, and RMSD. Subsequent analyses underscore that hydrophobic and van der Waals interactions (predominant), alongside electrostatic energy (subordinate), exert influence over the adsorption of HP35 on the fluorinated graphene surface. Mechanistic scrutiny attests that the unrestrained lateral mobility of HP35 on the fluorinated graphene nanomaterial primarily causes the exposure of HP35's hydrophobic core, resulting in the eventual structural denaturation of HP35. A trend in the features of 2D nanostructures is proposed that may facilitate the denaturation process. Our findings not only substantiate the potential toxicity of fluorinated graphene but also unveil the underlying molecular mechanism, which thereby holds significance for the prospective utilization of such nanomaterials in the field of biomedicine.

Oligodendrocytes in amyotrophic lateral sclerosis and frontotemporal dementia: the new players on stage.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal adult-onset neurodegenerative disorders that share clinical, neuropathological and genetic features, which forms part of a multi-system disease spectrum. The pathological process leading to ALS and FTD is the result of the combination of multiple mechanisms that operate within specific populations of neurons and glial cells. The implication of oligodendrocytes has been the subject of a number of studies conducted on patients and related animal models. In this review we summarize our current knowledge on the alterations specific to myelin and the oligodendrocyte lineage occurring in ALS and FTD. We also consider different ways by which specific oligodendroglial alterations influence neurodegeneration and highlight the important role of oligodendrocytes in these two intrinsically associated neurodegenerative diseases.

Digital imaging, virtual and augmented reality.

The sensorial perception of what is captured is what we know as "image" and consists of a static component and a dynamic process. This continuous process of images capture is essential in surgery. The image is crucial for the surgeon, who requires it for the diagnosis, for the therapeutic process and for postoperative follow-up. In minimally invasive surgery the sequence of images is essential and promotes the appearance of digital video. Digital video is the representation of moving images in the form of encoded digital data, unlike classic analog video, with continuous analog signals. Beyond what we can consider the "real image" (what we see as part of the existing reality) other realities appear in these decades; the Virtual Reality and Augmented Reality. With these realities we refer in the medical ambitus to the creation or superposition, respectively, of a three-dimensional virtual environment to support healthcare and teaching or research processes. Today, these technologies have already begun to be integrated into various surgical specialties, with predictive surgical planning and intraoperative navigation us their main applications. When using these digital environments, it is difficult to completely separate virtual reality from augmented reality, often being Mixed Reality. The current developments offer an environment that mixes the best aspects of both, unifying the simulation and requiring a single helmet or glasses to enjoy the sensorial experience. In this fusion of realities it will be possible to simultaneously create a virtual world from scratch to which we can add virtual elements from our real environment.

Peptide-based allosteric inhibitor targets TNFR1 conformationally active region and disables receptor-ligand signaling complex.

Tumor necrosis factor (TNF) receptor 1 (TNFR1) plays a pivotal role in mediating TNF induced downstream signaling and regulating inflammatory response. Recent studies have suggested that TNFR1 activation involves conformational rearrangements of preligand assembled receptor dimers and targeting receptor conformational dynamics is a viable strategy to modulate TNFR1 signaling. Here, we used a combination of biophysical, biochemical, and cellular assays, as well as molecular dynamics simulation to show that an anti-inflammatory peptide (FKCRRWQWRMKK), which we termed FKC, inhibits TNFR1 activation allosterically by altering the conformational states of the receptor dimer without blocking receptor-ligand interaction or disrupting receptor dimerization. We also demonstrated the efficacy of FKC by showing that the peptide inhibits TNFR1 signaling in HEK293 cells and attenuates inflammation in mice with intraperitoneal TNF injection. Mechanistically, we found that FKC binds to TNFR1 cysteine-rich domains (CRD2/3) and perturbs the conformational dynamics required for receptor activation. Importantly, FKC increases the frequency in the opening of both CRD2/3 and CRD4 in the receptor dimer, as well as induces a conformational opening in the cytosolic regions of the receptor. This results in an inhibitory conformational state that impedes the recruitment of downstream signaling molecules. Together, these data provide evidence on the feasibility of targeting TNFR1 conformationally active region and open new avenues for receptor-specific inhibition of TNFR1 signaling.

Characterization of Gelatin-Polycaprolactone Membranes by Electrospinning.

New advances in materials science and medicine have enabled the development of new and increasingly sophisticated biomaterials. One of the most widely used biopolymers is polycaprolactone (PCL) because it has properties suitable for biomedical applications, tissue engineering scaffolds, or drug delivery systems. However, PCL scaffolds do not have adequate bioactivity, and therefore, alternatives have been studied, such as mixing PCL with bioactive polymers such as gelatin, to promote cell growth. Thus, this work will deal with the fabrication of nanofiber membranes by means of the electrospinning technique using PCL-based solutions (12 wt.% and 20 wt.%) and PCL with gelatin (12 wt.% and 8 wt.%, respectively). Formic acid and acetic acid, as well as mixtures of both in different proportions, have been used to prepare the preliminary solutions, thus supporting the electrospinning process by controlling the viscosity of the solutions and, therefore, the size and uniformity of the fibers. The physical properties of the solutions and the morphological, mechanical, and thermal properties of the membranes were evaluated. Results demonstrate that it is possible to achieve the determined properties of the samples with an appropriate selection of polymer concentrations as well as solvents.

Clinical presentation and outcomes in patients with antiphospholipid syndrome-associated adrenal hemorrhage. A multicenter cohort study and systematic literature review.

BACKGROUND: Adrenal hemorrhage (AH) can occur in patients with antiphospholipid Syndrome (APS). We aimed to characterize the clinical manifestations, treatments, and outcomes of patients presenting with APS-associated AH (APS-AH) through a retrospective cohort and a systematic literature review (SLR). METHODS: We performed a mixed-source approach combining a multicenter cohort with an SLR of patients with incident APS-AH. We included patients from Mayo Clinic and published cases with persistent positivity for antiphospholipid antibodies and presenting with AH, demonstrated by imaging or biopsy. We extracted demographics, clinical characteristics, laboratory findings, treatment strategies, and outcomes (primary adrenal insufficiency and mortality). We used Kaplan-Meier and Cox models for survival analysis. RESULTS: We included 256 patients in total, 61 (24%) from Mayo Clinic and 195 (76%) from the SLR. The mean age was 46.8 (SD 15.2) years, and 45% were female. 69% of patients had bilateral adrenal involvement and 64% presented adrenal insufficiency. The most common symptoms at presentation were abdominal pain in 79%, and nausea and vomiting 46%. Hyponatremia (77%) was the most common electrolyte abnormality. Factors associated with primary adrenal insufficiency were bilateral adrenal involvement at initial imaging (OR 3.73, CI; 95%, 1.47-9.46) and anticardiolipin IgG positivity (OR 3.80, CI; 95%, 1.30-11.09). The survival rate at five years was 82%. History of stroke was associated with 3.6-fold increase in mortality (HR 3.62, 95% CI; 1.33-9.85). CONCLUSION: AH is a severe manifestation of APS with increased mortality. Most patients developed permanent primary adrenal insufficiency, particularly those positive for anticardiolipin IgG and bilateral adrenal involvement.

Villin headpiece unfolding upon binding to boridene mediated by the "anchoring-perturbation" mechanism.

We employ molecular dynamics (MD) simulations to investigate the influence of boridene on the behavior of a protein model, HP35, with the aim of assessing the potential biotoxicity of boridene. Our MD results reveal that HP35 can undergo unfolding via an "anchoring-perturbation" mechanism upon adsorption onto the boridene surface. Specifically, the third helix of HP35 becomes tightly anchored to the boridene surface through strong electrostatic interactions between the abundant molybdenum atoms on the boridene surface and the oxygen atoms on the HP35 backbone. Meanwhile, the first helix, experiencing continuous perturbation from the surrounding water solution over an extended period, suffers from potential breakage of hydrogen bonds, ultimately resulting in its unfolding. Our findings not only propose, for the first time to our knowledge, the "anchoring-perturbation" mechanism as a guiding principle for protein unfolding but also reveal the potential toxicity of boridene on protein structures.

Performance and explainability of feature selection-boosted tree-based classifiers for COVID-19 detection.

In this paper, we evaluate the performance and analyze the explainability of machine learning models boosted by feature selection in predicting COVID-19-positive cases from self-reported information. In essence, this work describes a methodology to identify COVID-19 infections that considers the large amount of information collected by the University of Maryland Global COVID-19 Trends and Impact Survey (UMD-CTIS). More precisely, this methodology performs a feature selection stage based on the recursive feature elimination (RFE) method to reduce the number of input variables without compromising detection accuracy. A tree-based supervised machine learning model is then optimized with the selected features to detect COVID-19-active cases. In contrast to previous approaches that use a limited set of selected symptoms, the proposed approach builds the detection engine considering a broad range of features including self-reported symptoms, local community information, vaccination acceptance, and isolation measures, among others. To implement the methodology, three different supervised classifiers were used: random forests (RF), light gradient boosting (LGB), and extreme gradient boosting (XGB). Based on data collected from the UMD-CTIS, we evaluated the detection performance of the methodology for four countries (Brazil, Canada, Japan, and South Africa) and two periods (2020 and 2021). The proposed approach was assessed in terms of various quality metrics: F1-score, sensitivity, specificity, precision, receiver operating characteristic (ROC), and area under the ROC curve (AUC). This work also shows the normalized daily incidence curves obtained by the proposed approach for the four countries. Finally, we perform an explainability analysis using Shapley values and feature importance to determine the relevance of each feature and the corresponding contribution for each country and each country/year.

Rendimiento en los Juegos Panamericanos de Santiago 2023: Predicción mediante método de suavización exponencial simple

El objetivo del presente trabajo es analizar el desempeño deportivo de la delegación chilena en los Juegos Panamericanos celebrados entre los años 1951 y 2023, haciendo uso de datos retrospectivos y proyectivos a través de series temporales de tiempo. Para esto se empleó un diseño cuantitativo, no experimental y longitudinal de tendencias y un método de suavización exponencial simple, que utiliza promedios históricos y que permite realizar una predicción o comportamiento futuro basado en una media ponderada de los valores actuales y de los pasados. A partir de los resultados obtenidos, fue posible concluir que, en las últimas décadas, la ubicación de Chile en el ranking de los Juegos Panamericanos se ha estabilizado en torno a un onceavo lugar, posición pronosticada para Santiago 2023. Manteniéndose condiciones similares, el desempeño deportivo general y específico no tendría un quiebre exponencial de la tendencia y los resultados no resultan favorables, específicamente en lo que respecta a la obtención de medallas de oro y la posición general de la delegación.

The objective of this paper is to analyze the sports performance of the Chilean delegation in the Pan American Games held between 1951 and 2023, using retrospective and projective data through time series. For this purpose, a quantitative, non-experimental and longitudinal design of trends and a simple exponential smoothing method was used, which uses historical averages and allows a prediction or future behavior based on a weighted average of current and past values. From the results obtained, it was possible to conclude that, in recent decades, Chile's position in the Pan American Games ranking has stabilized around eleventh place, a position predicted for Santiago 2023. Maintaining similar conditions, the general and specific sporting performance would not have an exponential break in the trend and the results are not favorable, specifically in terms of obtaining gold medals and the overall position of the delegation.

O objetivo deste artigo é analisar o desempenho esportivo da delegação chilena nos Jogos Pan-Americanos realizados entre 1951 e 2023, usando dados retrospectivos e projetivos por meio de séries temporais. Para isso, foi utilizado um desenho quantitativo, não experimental e longitudinal de tendências e um método de suavização exponencial simples, que utiliza médias históricas e permite uma previsão do comportamento futuro com base em uma média ponderada dos valores atuais e passados. Com base nos resultados obtidos, foi possível concluir que, nas últimas décadas, a posição do Chile no ranking dos Jogos Pan-Americanos se estabilizou em torno do 11º lugar, posição prevista para Santiago 2023. Mantendo-se condições semelhantes, o desempenho esportivo geral e específico não teria uma quebra exponencial na tendência e os resultados não são favoráveis, especificamente em termos de conquista de medalhas de ouro e posição geral da delegação.

Influencia de la sensibilidad, la calidad y la empatía en la satisfacción de proveedores de servicios de Internet

Este trabajo proporciona elementos para el desarrollo de un modelo conceptual del efecto que presentan la sensibilidad y la empatía sobre la percepción de calidad y la satisfacción, al momento de contratar a proveedores de servicios de internet en el sur del Estado de Quintana Roo, México. El objetivo del estudio es comprender cómo afecta la sensibilidad, la empatía y la calidad sobre la satisfacción de los clientes de los proveedores de servicios de Internet. Se utilizó la técnica de muestreo no probabilístico "bola de nieve" para integrar una muestra de 384 usuarios que proporcionaron información mediante la técnica de encuesta. Se desarrolló un modelo probado empíricamente utilizando el modelo de ecuaciones estructurales para analizar el impacto de las variables en la satisfacción. Los resultados muestran que la calidad del proveedor de internet se encuentra altamente influenciada por la empatía del personal y por la sensibilidad, todos estos factores inciden de manera directa y positiva en la satisfacción del cliente, siendo más importante el valor percibido de la empatía que puede afectar en la opinión del usuario, lo que es relevante porque ayuda a comprender por qué los clientes se quedan con un proveedor de servicios en particular. CLASIFICACIÓN JEL M31, L86

This research provides elements for the development of a conceptual model of the effect that sensitivity and empathy have on the perception of quality and satisfaction, when hiring internet service providers in the south of the State of Quintana Roo, Mexico. The objective of the study is to understand how sensitivity empathy and quality affect the satisfaction of customers of Internet service providers. The non-probabilistic "snowball" sampling technique was used to integrate a sample of 384 users who provided information through the survey technique. An empirically tested model was developed using the structural equation model to analyze the impact of variables on satisfaction. The results show that the quality of the Internet provider is highly influenced by the empathy of the staff and by the sensitivity all these factors directly and positively affect customer satisfaction, being more important the perceived value of empathy that can affect the opinion of the user which is relevant because it helps to understand why customers stay with a particular service provider. JEL CLASSIFICATION M3I, L86

Este artigo fornece elementos para o desenvolvimento de um modelo conceitual do efeito da sensibilidade e da empatia na percepção da qualidade e da satisfação ao contratar provedores de serviços de Internet no sul do estado de Quintana Roo, México. O objetivo do estudo é entender como a sensibilidade, a empatia e a qualidade afetam a satisfação do cliente com os provedores de serviços de Internet. A técnica de amostragem não probabilística "bola de neve" foi usada para integrar uma amostra de 384 usuários que forneceram informações por meio da técnica de pesquisa. Um modelo testado empiricamente foi desenvolvido usando modelagem de equação estrutural para analisar o impacto das variáveis na satisfação. Os resultados mostram que a qualidade do provedor de Internet é altamente influenciada pela empatia e pela capacidade de resposta da equipe, todas com impacto direto e positivo na satisfação do cliente, sendo que o valor percebido da empatia é mais importante e pode afetar a opinião do usuário, o que é relevante porque ajuda a entender por que os clientes permanecem com um determinado provedor de serviços. CLASSIFICAÇÃO JEL M31, L86

Multimorbidity in systemic lupus erythematosus in a population-based cohort: the lupus Midwest network.

OBJECTIVES: To assess the prevalence and incidence of multimorbidity and the association with the SLICC/ACR damage index (SDI) among patients with systemic lupus erythematosus (SLE). METHODS: Using prevalent and incident population-based cohorts of patients with SLE and their matched comparators, we assessed 57 chronic conditions. Chronic conditions were categorized as SDI-related or SDI-unrelated. Multimorbidity was defined as the presence of 2+ chronic conditions. Multimorbidity at prevalence and incidence/index was compared between cohorts using logistic regression. Cox models were used to examine development of multimorbidity after SLE incidence. RESULTS: The prevalent cohort included 449 patients with established SLE on January 1, 2015. They were three times more likely to have multimorbidity compared with non-SLE comparators (OR 2.98, 95% CI 2.18-4.11). The incident cohort included 270 patients with new-onset SLE. At SLE incidence, patients with SLE were more likely to have multimorbidity than comparators (OR 2.27, 95% CI 1.59-3.27). After incidence, the risk of developing multimorbidity was 2-fold higher among patients with SLE than comparators (hazard ratio (HR) 2.11, 95% CI 1.59-2.80). Development of multimorbidity was higher in patients with SLE based on SDI-related (HR 2.91, 95% CI 2.17-3.88) and SDI-unrelated conditions (HR 1.73, 95% CI, 1.32-2.26). CONCLUSION: Patients with SLE have a higher burden of multimorbidity, even before the onset of the disease. The risk disparity continues after SLE classification and is also seen in a prevalent SLE cohort. Multimorbidity is driven both by SDI-related and unrelated conditions.

Polarizing white light interferometry for phase measurements using two simultaneous interferograms.

Our research introduces a design for a polarization phase-shifting white light interferometric system (PPS-WLIS) that operates in a transmissive mode for measuring the slope phase of transparent objects. It comprises a cyclic path interferometer (lateral shear interferometer) coupled with a multiplexing Michelson interferometer. The system uses polarization to produce two parallel interferograms with polarization modulated with relative shifts simultaneously. To determine the optical phase, we used a two-step algorithm for phase demodulation that does not necessitate precise phase shifts, making the system more straightforward to operate. As a result, we could observe variations in the object associated with optical phase changes. Furthermore, our method simplifies the phase-shift interferometry process by requiring only one capture, making it an effective way to examine objects at dynamic events. As an illustration, we demonstrated the temperature measurement generated by a section of a candle flame.

Case studies of clinical decision-making through prescriptive models based on machine learning.

BACKGROUND: The development of computational methodologies to support clinical decision-making is of vital importance to reduce morbidity and mortality rates. Specifically, prescriptive analytic is a promising area to support decision-making in the monitoring, treatment and prevention of diseases. These aspects remain a challenge for medical professionals and health authorities. MATERIALS AND METHODS: In this study, we propose a methodology for the development of prescriptive models to support decision-making in clinical settings. The prescriptive model requires a predictive model to build the prescriptions. The predictive model is developed using fuzzy cognitive maps and the particle swarm optimization algorithm, while the prescriptive model is developed with an extension of fuzzy cognitive maps that combines them with genetic algorithms. We evaluated the proposed approach in three case studies related to monitoring (warfarin dose estimation), treatment (severe dengue) and prevention (geohelminthiasis) of diseases. RESULTS: The performance of the developed prescriptive models demonstrated the ability to estimate warfarin doses in coagulated patients, prescribe treatment for severe dengue and generate actions aimed at the prevention of geohelminthiasis. Additionally, the predictive models can predict coagulation indices, severe dengue mortality and soil-transmitted helminth infections. CONCLUSIONS: The developed models performed well to prescribe actions aimed to monitor, treat and prevent diseases. This type of strategy allows supporting decision-making in clinical settings. However, validations in health institutions are required for their implementation.

BMP signaling inhibition overcomes chemoresistance of prostate cancer.

Chemoresistance is a major therapeutic challenge to prostate cancer and its underlying molecular mechanism is poorly understood. Previously, it has been suggested that bone morphogenetic protein (BMP) signaling is down-regulated during the prostate cancer progression from the early androgen-sensitive stage to the metastatic castration-resistant stage. However, no literature reports are available for BMP signaling in more advanced-chemoresistant prostate cancer. In this study, we found the expression levels of the BMP type I receptor members, Activin-like kinase-2 (ALK2) and Activin-like kinase-3 (ALK3), were significantly higher in the chemoresistant prostate cancer cells than those in the chemosensitive prostate cancer cells. In addition, the phospho-Smad1/5/9 proteins, the pivotal intracellular effectors of the BMP signaling, were notably elevated in the chemoresistant prostate cancer cells over the chemosensitive prostate cancer cells, indicating that BMP signaling is highly activated in the chemoresistant prostate cancer cells. We also found that BMP signaling inhibition with either DMH1 or the knockdown of ALK2/ALK3 sensitized chemoresistant prostate cancer cells to the chemotherapy drug docetaxel in a dose-dependent manner. Our further study indicates that DMH1 suppressed the migration and invasion of chemoresistant prostate cancer cells in vitro, and attenuated chemoresistant prostate tumor growth in the mouse xenograft model in vivo. In addition, we showed that DMH1 disrupted the sphere formation in DU145-TxR and PC3-TxR cells, and suppressed the expression of marker genes of the cancer stem cells (CSCs). In conclusion, our study demonstrates that BMP signaling is associated with prostate cancer chemoresistance and BMP signaling inhibition effectively overcomes the cancer chemoresistance potentially through the disruption of CSCs' stemness.

Recipient With Influenza A Infection: Contraindication to Transplant? A Case Report.

Active infections in recipients are considered an absolute contraindication to liver transplantation due to the risk of severe disease caused by the required immunosuppression. Even though viral infections, such as Influenza A, have been treated in liver transplant patients both in the immediate and late postoperative period with favorable outcomes, no cases of prediagnosed Influenza A have been described in which the decision to proceed with the indication had to be made. In certain viral infections, like Influenza A, the paucisymptomatic state and the availability of appropriate treatment could open the door to performing liver transplants with positive results.

Heart Failure with Reduced Ejection Fraction and COVID-19, when the Sick Get Sicker: Unmasking Racial and Ethnic Inequities During a Pandemic.

Minoritized racial and ethnic groups have the highest incidence, prevalence, and hospitalization rate for heart failure. Despite improvement in medical therapies and overall survival, the morbidity and mortality of these groups remain elevated. The reasons for this disparity are multifactorial, including social determinant of health (SDOH) such as access to care, bias, and structural racism. These same factors contributed to higher rates of COVID-19 infection among minoritized racial and ethnic groups. In this review, we aim to explore the lessons learned from the COVID-19 pandemic and its interconnection between heart failure and SDOH. The pandemic presents a window of opportunity for achieving greater equity in the health care of all vulnerable populations.

Clinical features, risk factors, and outcomes of diffuse alveolar hemorrhage in antiphospholipid syndrome: A mixed-method approach combining a multicenter cohort with a systematic literature review.

BACKGROUND: Antiphospholipid syndrome (APS) is a systemic autoimmune disease clinically associated with thrombotic and obstetric events. Additional manifestations have been associated with APS, like diffuse alveolar hemorrhage (DAH). We aimed to summarize all the evidence available to describe the presenting clinical features, their prognostic factors, and short- and long-term outcomes. METHODS: We performed a mixed-method approach combining a multicenter cohort with a systematic literature review (SLR) of patients with incident APS-associated DAH. We described their clinical features, treatments, prognostic factors, and outcomes (relapse, mortality, and requirement of mechanical ventilation [MV]). Kaplan-Meier methods were used to estimate relapse and mortality rates, and Cox and logistic regression models were used to assess the factors associated as appropriate. RESULTS: We included 219 patients with incident APS-associated DAH (61 from Mayo Clinic and 158 from SLR). The median age was 39.5 years, 51% were female, 29% had systemic lupus erythematosus, and 34% presented with catastrophic APS (CAPS). 74% of patients had a history of thrombotic events, and 26% of women had a history of pregnancy morbidity; half of the patients had a history of thrombocytopenia, and a third had valvulopathy. Before DAH, 55% of the patients were anticoagulated. At DAH onset, 65% of patients presented hemoptysis. The relapse rate was 47% at six months and 52% at one year. Triple positivity (HR 4.22, 95% CI 1.14-15.59) was associated with relapse at six months. The estimated mortality at one and five years was 30.3% and 45.8%. Factors associated with mortality were severe thrombocytopenia (< 50 K/µL) (HR 3.10, 95% CI 1.39-6.92), valve vegetations (HR 3.22, 95% CI 1.14-9.07), CAPS (HR 3.80, 95% CI 1.84-7.87), and requirement of MV (HR 2.22, 95% CI 1.03-4.80). Forty-two percent of patients required MV on the incident DAH episode. Patients presenting with severe thrombocytopenia (OR 6.42, 95% CI 1.77-23.30) or CAPS (OR 4.30, 95% CI 1.65-11.16) were more likely to require MV. CONCLUSION: APS-associated DAH is associated with high morbidity and mortality, particularly when presenting with triple positivity, thrombocytopenia, valvular involvement, and CAPS.