Pure estrogen receptor antagonists potentiate capecitabine activity in ESR1-mutant breast cancer.

The ESR1 ligand binding domain activating mutations are the most prevalent genetic mechanism of acquired endocrine resistance in metastatic hormone receptor-positive breast cancer. These mutations confer endocrine resistance that remains estrogen receptor (ER) dependent. We hypothesized that in the presence of the ER mutations, continued ER blockade with endocrine therapies that target mutant ER is essential for tumor suppression even with chemotherapy treatment. Here, we conducted comprehensive pre-clinical in vitro and in vivo experiments testing the efficacy of adding fulvestrant to fluorouracil (5FU) and the 5FU pro-drug, capecitabine, in models of wild-type (WT) and mutant ER. Our findings revealed that while this combination had an additive effect in the presence of WT-ER, in the presence of the Y537S ER mutation there was synergy. Notably, these effects were not seen with the combination of 5FU and selective estrogen receptor modulators, such as tamoxifen, or in the absence of intact P53. Likewise, in a patient-derived xenograft (PDX) harboring a Y537S ER mutation the addition of fulvestrant to capecitabine potentiated tumor suppression. Moreover, multiplex immunofluorescence revealed that this effect was due to decreased cell proliferation in all cells expressing ER and was not dependent on the degree of ER expression. Taken together, these results support the clinical investigation of the combination of ER antagonists with capecitabine in patients with metastatic hormone receptor-positive breast cancer who have experienced progression on endocrine therapy and targeted therapies, particularly in the presence of an ESR1 activating mutation.

Accuracy of early pregnancy diagnosis and determining pregnancy loss using different biomarkers and machine learning applications in dairy cattle.

This study aimed to compare the accuracy of IFN-τ stimulated gene abundance (ISGs) in peripheral blood mononuclear cells (PBMCs), CL blood perfusion by Doppler ultrasound (Doppler-US), plasma concentration of P4 on Day 21 and pregnancy-associated glycoproteins (PAGs) test on Day 25 after timed-artificial insemination (TAI) for early pregnancy diagnosis in dairy cows and heifers. Holstein cows (n = 140) and heifers (n = 32) were subjected to a hormonal synchronization protocol and TAI on Day 0. On Day 21 post-TAI, blood samples were collected for PBMC isolation and plasma concentration of P4. The CL blood perfusion was evaluated by Doppler-US. Plasma samples collected on Day 25 were assayed for PAGs. The abundance of ISGs (ISG15 and RSAD2) in PBMCs was determined by RT-qPCR. Pregnancy was confirmed on Days 32 and 60 post-TAI by B-mode ultrasonography. Statistical analyses were performed by ANOVA using the MIXED procedure and GLIMMIX in SAS software. The pregnancy biomarkers were used to categorize the females as having undergone late luteolysis (LL); early embryonic mortality (EEM); late embryonic mortality (LEM); or late pregnancy loss (LPL). The abundance of ISGs, CL blood perfusion by Doppler-US, and concentrations of P4 on Day 21, and PAGs test on Day 25 were significant (P < 0.05) predictors of early pregnancy in dairy cows and heifers. Dairy cows had a greater (P = 0.01) occurrence of LL than heifers, but there was no difference (P > 0.1) for EEM, LEM, and LPL in heifers compared to cows. Cows with postpartum reproductive issues had a greater (P = 0.008) rate of LEM and a lesser (P = 0.01) rate of LPL compared to cows without reproductive issues. In summary, the CL blood perfusion by Doppler-US had the highest accuracy and the least number of false negatives, suggesting it is the best predictor of pregnancy on Day 21 post-TAI. The PAGs test was the most reliable indicator of pregnancy status on Day 25 post-TAI in dairy heifers and cows. The application of machine learning, specifically the MARS algorithm, shows promise in enhancing the accuracy of predicting early pregnancies in cows.

Combined PIK3CA and SOX2 Gene Amplification Predicts Laryngeal Cancer Risk beyond Histopathological Grading.

The PIK3CA and SOX2 genes map at 3q26, a chromosomal region frequently amplified in head and neck cancers, which is associated with poor prognosis. This study explores the clinical significance of PIK3CA and SOX2 gene amplification in early tumorigenesis. Gene copy number was analyzed by real-time PCR in 62 laryngeal precancerous lesions and correlated with histopathological grading and laryngeal cancer risk. Amplification of the SOX2 and PIK3CA genes was frequently detected in 19 (31%) and 32 (52%) laryngeal dysplasias, respectively, and co-amplification in 18 (29%) cases. The PIK3CA and SOX2 amplifications were predominant in high-grade dysplasias and significantly associated with laryngeal cancer risk beyond histological criteria. Multivariable Cox analysis further revealed PIK3CA gene amplification as an independent predictor of laryngeal cancer development. Interestingly, combined PIK3CA and SOX2 amplification allowed us to distinguish three cancer risk subgroups, and PIK3CA and SOX2 co-amplification was found the strongest predictor by ROC analysis. Our data demonstrate the clinical relevance of PIK3CA and SOX2 amplification in early laryngeal tumorigenesis. Remarkably, PIK3CA amplification was found to be an independent cancer predictor. Furthermore, combined PIK3CA and SOX2 amplification is emerging as a valuable and easy-to-implement tool for cancer risk assessment in patients with laryngeal precancerous lesions beyond current WHO histological grading.

Selective CDK7 Inhibition Suppresses Cell Cycle Progression and MYC Signaling While Enhancing Apoptosis in Therapy-resistant Estrogen Receptor-positive Breast Cancer.

PURPOSE: Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER)-positive (ER+) breast cancer. Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine-resistant ER+ breast cancer models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ breast cancer. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ breast cancer remain elusive. Herein, we sought to unravel these mechanisms. EXPERIMENTAL DESIGN: We conducted multi-omic analyses in ER+ breast cancer models in vitro and in vivo, including models with different genetic backgrounds. We also performed genome-wide CRISPR/Cas9 knockout screens to identify potential therapeutic vulnerabilities in CDK4/6i-resistant models. RESULTS: We found that the on-target antitumor effects of CDK7 inhibition in ER+ breast cancer are in part p53 dependent, and involve cell cycle inhibition and suppression of c-Myc. Moreover, CDK7 inhibition exhibited cytotoxic effects, distinctive from the cytostatic nature of ET and CDK4/6i. CDK7 inhibition resulted in suppression of ER phosphorylation at S118; however, long-term CDK7 inhibition resulted in increased ER signaling, supporting the combination of ET with a CDK7i. Finally, genome-wide CRISPR/Cas9 knockout screens identified CDK7 and MYC signaling as putative vulnerabilities in CDK4/6i resistance, and CDK7 inhibition effectively inhibited CDK4/6i-resistant models. CONCLUSIONS: Taken together, these findings support the clinical investigation of selective CDK7 inhibition combined with ET to overcome treatment resistance in ER+ breast cancer. In addition, our study highlights the potential of increased c-Myc activity and intact p53 as predictors of sensitivity to CDK7i-based treatments.

Tumor mutational burden predictability in head and neck squamous cell carcinoma patients treated with immunotherapy: systematic review and meta-analysis.

BACKGROUND: Tumor mutational burden (TMB) has been demonstrated to predict the response to immune checkpoint inhibitors (ICIs) in various cancers. However, the role of TMB in head and neck squamous cell carcinoma (HNSCC) has not yet been specifically addressed. Since HNSCC patients exhibit a rather limited response to ICIs, there is an unmet need to develop predictive biomarkers to improve patient selection criteria and the clinical benefit of ICI treatment. METHODS: We conducted a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. HNSCC cohort studies were selected when TMB prior to ICI treatment was evaluated, TMB cutoff value was available, and the prognostic value of TMB was evaluated by time-to-event survival analysis. A total of 11 out of 1960 articles were analyzed, including 1200 HNSCC patients. RESULTS: The results showed that those patients harboring high TMB exhibited a significantly superior overall response rate (OR = 2.62; 95% CI 1.74-3.94; p < 0.0001) and a survival advantage (HR = 0.53; 95% CI 0.39-0.71; p < 0.0001) after ICI treatment. CONCLUSION: This is the first meta-analysis to demonstrate a higher response and clinical benefit from ICI therapy in HNSCC patients with high TMB.

Visual manifestations in giant cell arteritis: identification of risk factors from the ARTESER Registry.

OBJECTIVE: To determine the prevalence and predictive factors of visual manifestations in a large registry of patients with GCA. METHODS: ARTESER is a large Spanish multicentre registry supported by the Spanish Society of Rheumatology. It includes patients with GCA from across the entire country diagnosed between June 2013 and March 2019. The variables collected at diagnosis were demographics, clinical manifestations (including all visual manifestations), laboratory, temporal artery biopsy, and imaging findings (ultrasound, FDG-PET/CT, MRI angiography, CT angiography). Patients with and without visual involvement were compared in a bivariate analysis. Multivariate logistic regression was performed to determine potential predictive factors of visual manifestations. RESULTS: The study population comprised 1636 GCA patients, of whom 599 (36.6%) presented visual manifestations. Anterior ischemic optic neuropathy was the most frequent (n = 274 of 599; 45.7%) ocular complication. The independent predictors that increased the risk (OR; 95% confidence interval) of visual involvement were older age (1.027; 1.009-1.045) and jaw claudication (1.724; 1.325-2.243). The variables associated with a reduced risk were polymyalgia rheumatica (0.541; 0.414-0.708), fever (0.373; 0.264-0.527), longer symptom duration (0.946; 0.909-0.985), and higher erythrocyte sedimentation rate (ESR) (0.992; 0.988-0.997), common features of patients with large vessel-GCA. CONCLUSION: One-third of GCA patients present visual manifestations at diagnosis. Older age and jaw claudication are independent predictors of visual manifestations, whereas polymyalgia rheumatica, fever, longer symptom duration, and high ESR reduce the risk of visual involvement.

Usefulness of a low-cost simulation model for teaching internal manual aortic compression. A survey-based mannequin evaluation.

OBJECTIVE: To evaluate the users' opinion on internal manual aortic compression (IMAC) training, using a low-cost simulation model. METHODS: An educational strategy was designed to teach IMAC, which included: (1) guided reading of educational material and viewing an explanatory video of IMAC; (2) an introductory lecture with the anatomical considerations, documentation of the cessation of femoral arterial flow during IMAC, and real clinical cases in which this procedure was used; and (3) simulated practice of IMAC with a new low-cost manikin. The educational strategy was applied during three postpartum hemorrhage workshops in three Latin American countries and the opinions of the participants were measured with a survey. RESULTS: Almost all of the participants in the IMAC workshop, including the simulation with the low-cost mannikin, highlighted the usefulness of the strategy (scores of 4/5 and 5/5 on the Likert scale) and would recommend it to colleagues. CONCLUSION: We present a low-cost simulation model for IMAC as the basis of an educational strategy perceived as very useful by most participants. The execution of this strategy in other populations and its impact on postpartum hemorrhage management should be evaluated in further studies.

Conocimiento y manejo de cuidados respiratorios especializados en pacientes con enfermedades neuromusculares en unidades de cuidado intensivo: aproximación por encuesta a profesionales de la salud

Introducción: En las enfermedades neuromusculares la disminución de la capacidad vital se relaciona con dismunición de la capacidad tusígena y luego ventilatoria, la combinación de ambas genera complicaciones graves por falla ventilatoria. En los pacientes que son intubados, limita la extubación, sino se realizan cuidados respiratorios especializados. El conocimiento y aplicación de los profesionales que atienden a estos pacientes en cuidados intensivos resulta esencial. Objetivos: Reportar el conocimiento y aplicación especializada de cuidados respiratorios en enfermedades neuromusculares en las Unidades de Cuidados Intensivos. Materiales y métodos: Estudio cualitativo, descriptivo de corte transversal, no probabilístico, a criterio. La población accesible fueron profesionales de la Salud de las Unidades de Cuidados Intensivos, y el análisis de las respuestas de una encuesta estructurada, enviada a distintos profesionales a nivel mundial. Resultados: Se incluyeron los cuestionarios de 41 profesionales, el 34% de los profesionales reportaron la utilización regular de Asistente Mecánico de la Tos; 22% refirieron la utilización regular de apilamiento de aire; 31% reportaron la utilización regular de Asistencia Ventilatoria No Invasiva, 56.1% de los profesionales afirmaron conocer la diferencia entre Ventilación No Invasiva y Soporte Ventilatorio No Invasivo, 34% de los profesionales refirieron tener formación especializada en el área. Conclusión: Pese a existir una alta proporción de profesionales con conocimiento especializado, un grupo importante no los aplica rutinariamente. La justificación es principalmente por la dificultad de adquisición y financiación de los equipos necesarios.

Introduction: In neuromuscular diseases, the decrease in vital capacity relates to decreased coughing and then ventilatory capacity, the combination of both generating serious complications due to ventilatory failure. In intubated patients, the extubation process is difficult unless specialized respiratory care is provided. The knowledge and treatment application of the professionals who care for these patients in intensive care is of outmost importance. Objectives: Report the knowledge and specialized application of respiratory care in neuromuscular diseases in Intensive Care Units. Materials and methods: Qualitative, descriptive, cross-sectional, non-probabilistic study, at criteria. The accessible population were Health professionals from the Intensive Care Units, and the analysis of the responses of a structured survey, sent to different professionals worldwide. Results: The questionnaires of 41 professionals were included, 34% of the professionals reported the regular use of the Mechanical Cough Assistant; 22% reported the regular use of air stacking; 31% reported the regular use of Non-Invasive Ventilatory Assistance. 56.1% of the professionals stated that they knew the difference between Non-Invasive Ventilation and Non-Invasive Ventilatory Support, 34% of the professionals reported having specialized training in the area. Conclusion: Despite the existence of a high proportion of professionals with specialized knowledge, an important group does not routinely apply them. The justification is mainly due to the difficulty of acquiring and financing the necessary equipment.

Conocimiento y manejo de cuidados respiratorios especializados en pacientes con enfermedades neuromusculares en unidades de cuidado intensivo: aproximación por encuesta a profesionales de la salud / Knowledge and management in specialized respiratory care of patients with neuromuscular diseases in intensive care units: survey to health professionals

Introducción: En las enfermedades neuromusculares la disminución de la capacidad vital se relaciona con disminución de la capacidad tusígena y luego ventilatoria, la combinación de ambas genera complicaciones graves por falla ventilatoria. En los pacientes que son intubados, limita la extubación, sino se realizan cuidados respiratorios especializados. El conocimiento y aplicación de los profesionales que atienden a estos pacientes en cuidados intensivos resulta esencial. Objetivos: Reportar el conocimiento y aplicación especializada de cuidados respiratorios en enfermedades neuromusculares en las Unidades de Cuidados Intensivos. Materiales y métodos: Estudio cualitativo, descriptivo de corte transversal, no probabilístico, a criterio. La población accesible fueron profesionales de la Salud de las Unidades de Cuidados Intensivos, y el análisis de las respuestas de una encuesta estructurada, enviada a distintos profesionales a nivel mundial. Resultados: Se incluyeron los cuestionarios de 41 profesionales, el 34% de los profesionales reportaron la utilización regular de Asistente Mecánico de la Tos; 22% refirieron la utilización regular de apilamiento de aire; 31% reportaron la utilización regular de Asistencia Ventilatoria No Invasiva, 56.1% de los profesionales afirmaron conocer la diferencia entre Ventilación No Invasiva y Soporte Ventilatorio No Invasivo, 34% de los profesionales refirieron tener formación especializada en el área. Conclusión: Pese a existir una alta proporción de profesionales con conocimiento especializado, un grupo importante no los aplica rutinariamente. La justificación es principalmente por la dificultad de adquisición y financiación de los equipos necesarios.

Introduction: In neuromuscular diseases, the decrease in vital capacity relates to decreased coughing and then ventilatory capacity, the combination of both generating serious complications due to ventilatory failure. In intubated patients, the extubation process is difficult unless specialized respiratory care is provided. The knowledge and treatment application of the professionals who care for these patients in intensive care is of outmost importance. Objectives: Report the knowledge and specialized application of respiratory care in neuromuscular diseases in Intensive Care Units. Materials and methods: Qualitative, descriptive, cross-sectional, non-probabilistic study, at criteria. The accessible population were Health professionals from the Intensive Care Units, and the analysis of the responses of a structured survey, sent to different professionals worldwide. Results: The questionnaires of 41 professionals were included, 34% of the professionals reported the regular use of the Mechanical Cough Assistant; 22% reported the regular use of air stacking; 31% reported the regular use of Non-Invasive Ventilatory Assistance. 56.1% of the professionals stated that they knew the difference between Non-Invasive Ventilation and Non-Invasive Ventilatory Support, 34% of the professionals reported having specialized training in the area. Conclusion: Despite the existence of a high proportion of professionals with specialized knowledge, an important group does not routinely apply them. The justification is mainly due to the difficulty of acquiring and financing the necessary equipment.

Endocrine Therapy Synergizes with SMAC Mimetics to Potentiate Antigen Presentation and Tumor Regression in Hormone Receptor-Positive Breast Cancer.

Immunotherapies have yet to demonstrate significant efficacy in the treatment of hormone receptor-positive (HR+) breast cancer. Given that endocrine therapy (ET) is the primary approach for treating HR+ breast cancer, we investigated the effects of ET on the tumor immune microenvironment (TME) in HR+ breast cancer. Spatial proteomics of primary HR+ breast cancer samples obtained at baseline and after ET from patients enrolled in a neoadjuvant clinical trial (NCT02764541) indicated that ET upregulated ß2-microglobulin and influenced the TME in a manner that promotes enhanced immunogenicity. To gain a deeper understanding of the underlying mechanisms, the intrinsic effects of ET on cancer cells were explored, which revealed that ET plays a crucial role in facilitating the chromatin binding of RelA, a key component of the NF-κB complex. Consequently, heightened NF-κB signaling enhanced the response to interferon-gamma, leading to the upregulation of ß2-microglobulin and other antigen presentation-related genes. Further, modulation of NF-κB signaling using a SMAC mimetic in conjunction with ET augmented T-cell migration and enhanced MHC-I-specific T-cell-mediated cytotoxicity. Remarkably, the combination of ET and SMAC mimetics, which also blocks prosurvival effects of NF-κB signaling through the degradation of inhibitors of apoptosis proteins, elicited tumor regression through cell autonomous mechanisms, providing additional support for their combined use in HR+ breast cancer. SIGNIFICANCE: Adding SMAC mimetics to endocrine therapy enhances tumor regression in a cell autonomous manner while increasing tumor immunogenicity, indicating that this combination could be an effective treatment for HR+ patients with breast cancer.

Driving role of head and neck cancer cell secretome on the invasion of stromal fibroblasts: Mechanistic insights by phosphoproteomics.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are major players in tumor-stroma communication, and participate in several cancer hallmarks to drive tumor progression and metastatic dissemination. This study investigates the driving effects of tumor-secreted factors on CAF biology, with the ultimate goal of identifying effective therapeutic targets/strategies for head and neck squamous cell carcinomas (HNSCC). METHODS: Functionally, conditioned media (CM) from different HNSCC-derived cell lines and normal keratinocytes (Kc) were tested on the growth and invasion of populations of primary CAFs and normal fibroblasts (NFs) using 3D invasion assays in collagen matrices. The changes in MMPs expression were evaluated by RT-qPCR and kinase enrichment was analyzed using mass spectrometry phosphoproteomics. RESULTS: Our results consistently demonstrate that HNSCC-secreted factors (but not Kc CM) specifically and robustly promoted pro-invasive properties in both CAFs and NFs, thereby reflecting the plasticity of fibroblast subtypes. Concomitantly, HNSCC-secreted factors massively increased metalloproteinases levels in CAFs and NFs. By contrast, HNSCC CM and Kc CM exhibited comparable growth-promoting effects on stromal fibroblasts. Mechanistically, phosphoproteomic analysis predominantly revealed phosphorylation changes in fibroblasts upon treatment with HNSCC CM, and various promising kinases were identified: MKK7, MKK4, ASK1, RAF1, BRAF, ARAF, COT, PDK1, RSK2 and AKT1. Interestingly, pharmacologic inhibition of RAF1/BRAF using sorafenib emerged as the most effective drug to block tumor-promoted fibroblast invasion without affecting fibroblast viability CONCLUSIONS: Our findings demonstrate that HNSCC-secreted factors specifically fine tune the invasive potential of stromal fibroblasts, thereby generating tumor-driven pro-invasive niches, which in turn to ultimately facilitate cancer cell dissemination. Furthermore, the RAF/BRAF inhibitor sorafenib was identified as a promising candidate to effectively target the onset of pro-invasive clusters of stromal fibroblasts in the HNSCC microenvironment.

Targeting oncogenic functions of miR-301a in head and neck squamous cell carcinoma by PI3K/PTEN and MEK/ERK pathways.

Treatment of head and neck squamous cell carcinomas (HNSCC), the sixth most frequent cancer worldwide, remains challenging. miRNA dysregulation is closely linked to tumorigenesis and tumor progression, thus emerging as suitable targets for cancer treatment. Transcriptomic analysis of TCGA HNSCC dataset revealed that miR-301a expression levels significantly increased in primary tumors, as compared to patient-matched normal tissue. This prompted us to investigate its pathobiological role and potential as new therapeutic target using different preclinical HNSCC models. miR-301a overexpression in HNSCC-derived cell lines led to enhanced proliferation and invasion, whereas miR-301 inhibition reduced these effects. In vivo validation was performed using an orthotopic mouse model. Results concordantly showed that the mitotic counts, the percentage of infiltration depth and Ki67 proliferative index were significantly augmented in the subgroup of mice harboring miR-301a-overexpressing tumors. Further mechanistic characterization revealed PI3K/PTEN/AKT and MEK/ERK pathways as central signaling nodes responsible for mediating the oncogenic activity of miR-301a observed in HNSCC cells. Notably, pharmacological disruption of PI3K and ERK signals with BYL-719 and PD98059, respectively, was effective to completely revert/abolish miR-301a-promoted tumor cell growth and invasion. Altogether, these findings demonstrate that miR-301a dysregulation plays an oncogenic role in HNSCC, thus emerging as a candidate therapeutic target for this disease. Importantly, available PI3K and ERK inhibitors emerge as promising anti-tumor agents to effectively target miR-301a-mediated signal circuit hampering growth-promoting and pro-invasive functions.

Pathobiological functions and clinical implications of annexin dysregulation in human cancers.

Annexins are an extensive superfamily of structurally related calcium- and phospholipid-binding proteins, largely conserved and widely distributed among species. Twelve human annexins have been identified, referred to as Annexin A1-13 (A12 remains as of yet unassigned), whose genes are spread throughout the genome on eight different chromosomes. According to their distinct tissue distribution and subcellular localization, annexins have been functionally implicated in a variety of biological processes relevant to both physiological and pathological conditions. Dysregulation of annexin expression patterns and functions has been revealed as a common feature in multiple cancers, thereby emerging as potential biomarkers and molecular targets for clinical application. Nevertheless, translation of this knowledge to the clinic requires in-depth functional and mechanistic characterization of dysregulated annexins for each individual cancer type, since each protein exhibits varying expression levels and phenotypic specificity depending on the tumor types. This review specifically and thoroughly examines the current knowledge on annexin dysfunctions in carcinogenesis. Hence, available data on expression levels, mechanism of action and pathophysiological effects of Annexin A1-13 among different cancers will be dissected, also further discussing future perspectives for potential applications as biomarkers for early diagnosis, prognosis and molecular-targeted therapies. Special attention is devoted to head and neck cancers (HNC), a complex and heterogeneous group of aggressive malignancies, often lately diagnosed, with high mortality, and scarce therapeutic options.

A Distinct Chromatin State Drives Therapeutic Resistance in Invasive Lobular Breast Cancer.

Most invasive lobular breast cancers (ILC) are of the luminal A subtype and are strongly hormone receptor-positive. Yet, ILC is relatively resistant to tamoxifen and associated with inferior long-term outcomes compared with invasive ductal cancers (IDC). In this study, we sought to gain mechanistic insights into these clinical findings that are not explained by the genetic landscape of ILC and to identify strategies to improve patient outcomes. A comprehensive analysis of the epigenome of ILC in preclinical models and clinical samples showed that, compared with IDC, ILC harbored a distinct chromatin state linked to gained recruitment of FOXA1, a lineage-defining pioneer transcription factor. This resulted in an ILC-unique FOXA1-estrogen receptor (ER) axis that promoted the transcription of genes associated with tumor progression and poor outcomes. The ILC-unique FOXA1-ER axis led to retained ER chromatin binding after tamoxifen treatment, which facilitated tamoxifen resistance while remaining strongly dependent on ER signaling. Mechanistically, gained FOXA1 binding was associated with the autoinduction of FOXA1 in ILC through an ILC-unique FOXA1 binding site. Targeted silencing of this regulatory site resulted in the disruption of the feed-forward loop and growth inhibition in ILC. In summary, ILC is characterized by a unique chromatin state and FOXA1-ER axis that is associated with tumor progression, offering a novel mechanism of tamoxifen resistance. These results underscore the importance of conducting clinical trials dedicated to patients with ILC in order to optimize treatments in this breast cancer subtype. SIGNIFICANCE: A unique FOXA1-ER axis in invasive lobular breast cancer promotes disease progression and tamoxifen resistance, highlighting a potential therapeutic avenue for clinical investigations dedicated to this disease. See related commentary by Blawski and Toska, p. 3668.

Curso e-learning "desafíos de la pandemia COVID-19 en pediatría": caracterización y relación con los resultados de aprendizaje y grado de satisfacción / E-learning course "challenges of the COVID-19 pandemic in pediatrics": characterization and association with learning results and grade of satisfaction

Frente a la pandemia del CoVID-19, resulta fundamental establecer estrategias manteniendo distanciamiento social, que permitan educar a profesionales de la salud sobre aspectos relacionados con SARS-CoV-2. La Sociedad Chilena de Neumología Pediátrica creó un E-learnig de contingencia de acceso libre. OBJETIVO: Describir las características del curso online "Desafíos de la pandemia CoVID-19 en Pediatría", y evaluar el grado de satisfacción de quienes lo cursaron. Estudio transversal. Todos los inscritos en el curso, entre mayo 2020 y julio 2020. Se grabaron 12 clases dictadas por especialistas con representación académica de Chile. Se realizó una prueba final y una encuesta de satisfacción, con puntaje de 1 a 7. Se realizó análisis descriptivo e inferencial, evaluando asociación entre clasificación final del curso, profesión y zona geográfica de los participantes con test de Kruskal Wallis, significancia estadística p<0,05. Aprobado por comité ética. Participaron 2541 alumnos, 73% mujeres. Mediana de edad 32,7 años. 90,7% de Chile, de estos 63,2% de regiones. De procedencia extranjera destacó Bolivia (2,9%) y Ecuador (2,5%). De los que realizaron la prueba, el 98,6% aprobó. Existió diferencia entre notas según profesión, Médicos-Kinesiólogos(p=0.025) y Médicos-Enfermeros(p=0.002); y según procedencia, Región Metropolitana (RM)-Otras regiones (p=0.041), RM-Internacional(p<0,001) y Otras regiones-Internacional(p<0,001). La evaluación de contenidos ponderó 6,6 y la accesibilidad 6,8. El 98% contestó que el curso cumplió sus expectativas. Concluimos que se inscribió un gran número de alumnos de Chile y Latinoamérica. Más del 98% aprobó la prueba final y refirió un alto nivel de satisfacción. Sugerimos emplear estrategias similares en situaciones de catástrofes sanitarias.

In the face of the CoVID-19 pandemic, it is essential to establish strategies, maintaining social distancing, that allow educating health professionals on aspects related to SARS-CoV-2. The Chilean Society of Pediatric Pulmonology created a free access contingency E-learning. OBJECTIVE: To describe the characteristics of the online course "Challenges of the CoVID-19 pandemic in Pediatrics", and to evaluate the grade of satisfaction of those who attended it.Transversal study. All those enrolled in the course, between May 2020 and July 2020. 12 classes taught by specialists with academic representation from Chile were recorded. A final test and a satisfaction survey were carried out, with a score from 1 to 7. A descriptive and inferential analysis was implemented, evaluating the association between the final classification of the course, profession and geographical area of the participants with the Kruskal Wallis test, statistical significance p< 0.05. Approved by ethics committee. 2541 students participated, 73% women. Median age 32.7 years. 90.7% from Chile, of these 63.2% from regions. Of foreign origin, Bolivia (2.9%) and Ecuador (2.5%) stand out. Of those who took the test, 98.6% were successful. There was a difference between grades according to profession, Physicians-Kinesiologists(p=0.025) and Physicians-Nurses(p=0.002); and according to origin, Metropolitan Region (RM)-Other regions (p=0.041), RM-International (p<0.001) and Other regions-International (p<0.001). The content evaluation pondered 6.6 and accessibility 6.8. 98% responded that the course met their expectations. CONCLUSION: A large number of students from Chile and Latin America were enrolled. More than 98% passed the final test and reported a high level of satisfaction. We suggest using similar strategies in situations of health catastrophes.

Abordaje respiratorio del paciente con enfermedad neuromuscular en la unidad de cuidado intensivo pediátrica / Respiratory approach to the patient with neuromuscular disease in the pediatric intensive care unit

En algunas ocasiones, los pacientes con enfermedades neuromusculares infantojuveniles, pueden requerir internación en unidades de cuidados intensivos pediátricos. La principal causa de ingreso hospitalario es la insuficiencia respiratoria aguda, desencadenada por atelectasias y neumonías que, en la mayoría de los casos, tienen su inicio en infecciones del tracto respiratorio superior. Independientemente de su forma de presentación, las enfermedades neuromusculares en periodo infantojuvenil, pueden comprometer en grados distintos a los 3 grupos musculares vinculados a la ventilación pulmonar y protección glótica. Es posible dar asistencia a los músculos inspiratorios y espiratorios con soporte ventilatorio no invasivo y asistencia mecánica de la tos respectivamente. Esta estrategia combinada permite el manejo no invasivo de este tipo de pacientes, logrando extubar o decanular a aquellos considerados potencialmente no destetables con las estrategias clásicas utilizadas en unidades de cuidados intensivos en pediatría. El objetivo de esta revisión es sugerir recomendaciones en cuidados respiratorios no invasivos para pacientes con enfermedades neuromusculares ingresados en unidades de paciente crítico pediátrico. Se presentan 2 casos clínicos ilustrativos, en los cuales estas estrategias fueron utilizadas en forma exitosa.

On some occasions, patients with childhood and adolescent neuromuscular diseases may require hospitalization in pediatric intensive care units. The main cause of hospital admission is acute respiratory failure triggered by atelectasis and pneumonia, which, in most cases, start with upper respiratory tract infections. Regardless of their form of presentation, neuromuscular diseases in children and adolescents can damage the 3 muscle groups linked to pulmonary ventilation and glottic protection to different degrees. Inspiratory and expiratory muscles can be assisted with noninvasive ventilatory support and mechanical cough assist, respectively. This combined strategy allows the non-invasive management of this type of patients, managing to extubate or decannulate those considered potentially unweanable with the classic strategies used in pediatric intensive care units. The aim of this review is present noninvasive respiratory care recommendations for patients with neuromuscular diseases admitted to pediatric intensive critical care unit and illustrated with clinical reports of two patients treated with these strategies successfully.

Recomendaciones para el manejo respiratorio de los pacientes con atrofia muscular espinal / Recommendations for respiratory management of patients with spinal muscular atrophia / Recomendações para a manipulação respiratória de pacientes com atrofia muscular espinhal

Resumen: La atrofia muscular espinal (AME) es una enfermedad del asta anterior de la médula espinal, genéticamente determinada y causada por síntesis insuficiente de la proteína de supervivencia de la motoneurona. La debilidad muscular lleva a una disminución progresiva de la capacidad vital y de flujos medibles durante la tos. La intensidad y precocidad de la expresión motora se vincula con los grados de afectación de los grupos musculares respiratorios, determinando la meseta en la capacidad vital y progresión a la insuficiencia ventilatoria, como también el compromiso de los músculos inervados bulbares. Las formas clínicas más severas de AME, en especial aquellas con presentaciones más tempranas y respiración paradojal, tienen capacidades vitales y flujos pico tosidos menores. La evaluación secuencial de estos parámetros es esencial para el pronóstico funcional y vital de estos pacientes. La subclasificación de AME tipo 1 y 2 se relaciona con momentos deseables para la realización de cuidados respiratorios no invasivos en la infancia temprana y en la edad escolar, que mejoran la sobrevida y calidad de vida. Este documento sintetiza dichas recomendaciones con especial referencia a intervenciones guiadas por etapas que incluyan apilamiento de aire (air stacking), protocolos de tos asistida y soporte ventilatorio no invasivo con alta intensidad de presiones de soporte, incluso en aquellos pacientes con pérdida de la autonomía respiratoria, minimizando el riesgo de traqueotomía. La no consideración de estas recomendaciones en la valoración regular de los pacientes resta la oferta de tratamientos oportunos.

Summary: Spinal Muscular Atrophy (SMA) is a disease of the anterior horn of the spinal cord, genetically determined, and caused by deficiency of survival motor neuron (SMN) protein. Muscle weakness leads to a progressive decrease in vital capacity and to diminished cough flows. Respiratory morbidity and mortality are a function of respiratory and bulbar-innervated muscle impairment. It can be measured by the sequential evaluation of vital capacity to determine the life time maximum (plateau) and its subsequent rate of decline, progressing to ventilatory failure. Bulbar-innervated muscle impairment can also be monitored and measured by spirometry. The more severe clinical forms of SMA, especially those with earlier onsets and paradoxical breathing, have lower vital capacities and cough peak flows. The sequential assessment of these parameters is key for the vital and functional prognosis of these patients. SMA sub-classification types 1 and 2 of SMA involve appropriate times for non-invasive respiratory interventions in early childhood and school age and improve afterlife and quality of life. This document summarizes these recommendations, as a function of SMA type, with special reference to interventions that include air stacking, manually and mechanically assisted coughing protocols and noninvasive ventilatory support techniques, even for patients who have no ventilator-free breathing ability to minimize or eliminate the need to resort to tracheotomy. Failure to properly evaluate these patients regularly reduces their survival and chances to avoid invasive airway tubes.

Resumo: A Atrofia Muscular Espinhal (SMA) é uma doença do corno anterior da medula espinhal, geneticamente determinada e causada pela síntese insuficiente da proteína de sobrevivência dos neurônios motores. A fraqueza muscular leva a uma diminuição progressiva da capacidade vital e fluxos mensuráveis durante a tosse. A intensidade e a precocidade da expressão motora estão relacionadas aos graus de envolvimento dos grupos musculares respiratórios, determinando o platô da capacidade vital e a progressão para insuficiência ventilatória, bem como o envolvimento dos músculos inervados do bulbar. As formas clínicas mais graves de SMA, especialmente aquelas com apresentações anteriores e respiração paradoxal, têm capacidades vitais mais baixas e fluxos de tosse mais baixos. A avaliação sequencial desses parâmetros é essencial para o prognóstico funcional e vital desses pacientes. A subclassificação de SMA tipo 1 e 2 está relacionada aos momentos desejáveis para cuidados respiratórios não invasivos na primeira infância e idade escolar, que melhoram a sobrevida e a qualidade de vida. Este documento resume essas recomendações com referência especial às intervenções guiadas por etapas que incluem empilhamento de ar, protocolos de tosse assistida e suporte ventilatório não invasivo com suporte pressórico de alta intensidade, mesmo em pacientes com perda de autonomia respiratória, minimizando o risco de traqueostomia. A não consideração dessas recomendações na avaliação regular dos pacientes reduz a oferta de tratamentos oportunos.

Proposed Decannulation Criteria for COVID-19 Patients.

ABSTRACT: A 66-yr-old man had been intubated for 21 days for severe COVID-19 infection. He then underwent tracheotomy, retained the tube for 2 mos, and then was discharged home on 10 liters of O2/min breathing via a tracheostomy collar. We were consulted for tracheostomy tube decannulation. Mechanical insufflation-exsufflation was used via the tracheostomy tube to clear secretions, increase vital capacity, and normalize O2 saturation. He practiced nasal and mouthpiece noninvasive ventilatory support once a capped fenestrated cuffless tracheostomy tube was placed, although he did not need noninvasive ventilatory support after decannulation. He was decannulated despite O2 dependence. Although he required antibiotics for almost 3 mos before decannulation and after it, he had no further episodes of lung infection for at least the next 4 mos from the point of decannulation.

Evaluación de la función respiratoria en pacientes con patologías neuromusculares / Evaluation of Respiratory Function in Patients with Neuromuscular Diseases

Introducción: La Enfermedades Neuromusculares se caracterizan por la pérdida progresiva de la fuerza muscular, la morbi-mortalidad aumenta con la exageración de la debilidad muscular determinando mayor riesgo de complicaciones respiratorias. Es de suma importancia evaluar e interpretar adecuadamente la función pulmonar y ventilatoria para poder realizar intervenciones que pueda prevenir dichas complicaciones. Objetivos: El objetivo del estudio fue reportar el estado funcional respiratorio de un grupo de pacientes con ENM en control ambulatorio y relacionar estos hallazgos con umbrales clínicamente relevantes de complicaciones respiratorias, reforzando intervenciones basadas en opiniones de expertos. Materiales y métodos: Se realizó un estudio Descriptivo-Observacional de corte transversal, donde fueron evaluados en forma ambulatoria, de marzo del 2017 a agosto del 2018, 30 niños y adolescentes con enfermedades neuromusculares. Resultados: El 46% del total de pacientes presenta capacidad tusígena no funcional con alto riesgo de complicaciones. No obstante, sólo el 10% del total de pacientes fueron aptos para realizar adecuadamente estudios de espirometría. Durante las pruebas espirométricas, sólo el 50% de los pacientes logró mantener 6 segundos la espiración. Conclusión: Si bien la espirometría es la principal prueba de función pulmonar y una alta proporción de pacientes presentó alteraciones en su morfología, su realización en estados avanzados de enfermedad fue poco factible. Para detectar umbrales de complicaciones respiratorias graves, la medición del flujo generado durante la tos resultó mejor. Conclusión: Si bien la espirometría es la principal prueba de función pulmonar y una alta proporción de pacientes presentó alteraciones en su morfología, su realización en estados avanzados de enfermedad fue poco factible. Para detectar umbrales de complicaciones respiratorias graves, la medición del flujo generado durante la tos resultó mejor.

Introduction: Neuromuscular Diseases are characterized by the progressive loss of muscle mass, morbidity and mortality increases with the progress of muscle weakness due to the increased risk of respiratory complications, so it is very important to properly evaluate and interpret the measurements of lung functions and ventilation to be able to carry out a specific treatment that can reduce respiratory complications. Objectives: The purpose of this work is to present the results of the measurements of flows, volumes, respiratory capacities and spirometric patterns in outpatients with neuromuscular diseases and to verify their usefulness to detect vital risks. Materials and methods: A cross-sectional Descriptive-Observational study was carried out, where 30 children and adolescents with neuromuscular diseases were evaluated on an outpatient basis, from March 2017 to August 2018. Results: 46% of all patients presented a non-functional cough with a high risk of complications and only 10% of all patients were eligible for spirometry studies. During the spirometric tests, 50% of the patients managed to maintain expiration for 6 seconds. In 70% of the patients, abnormalities in the Flow-Volume curve could be detected. Conclusion: Although spirometry is the main pulmonary function test, its usefulness and efficacy in neuromuscular diseases depends on the findings of specific alterations in the morphology of the flow-volume curve, which in many cases are not possible to distinguish.