Combined therapy targeting AR and EZH2 curbs castration-resistant prostate cancer enhancing anti-tumor T-cell response.

Aim: Castration-resistant prostate cancer (CRPC) eventually becomes resistant to androgen receptor pathway inhibitors like enzalutamide. Immunotherapy also fails in CRPC. We propose a new approach to simultaneously revert enzalutamide resistance and rewire anti-tumor immunity. Methods: We investigated in vitro and in subcutaneous and spontaneous mouse models the effects of combining enzalutamide and GSK-126, a drug inhibiting the epigenetic modulator EZH2. Results: Enzalutamide and GSK-126 synergized to reduce CRPC growth, also restraining tumor neuroendocrine differentiation. The anti-tumor activity was lost in immunodeficient mice. Indeed, the combination treatment awoke cytotoxic activity and IFN-γ production of tumor-specific CD8+ T lymphocytes. Conclusion: These results promote the combination of enzalutamide and GSK-126 in CRPC, also offering new avenues for immunotherapy in prostate cancer.

Prostate cancer depends on hormones called androgens for its growth. Therefore, hormonal therapies are commonly used. However, the tumor often does not respond to these treatments and new therapeutic approaches are needed. Here, using cell and mouse models, we have tested a new combination between hormone therapy and a drug that restrains an enzyme regulating gene expression. Our results have shown that this combination therapy not only reduces the growth of the tumor but also stops it from becoming more aggressive. This is really important because aggressive prostate cancer is much harder to treat. We have also found that this approach helps the immune system recognizing and attacking cancer cells. More research is needed to identify the mechanism of action of this treatment. However, our findings suggest that this approach could pave the way for new therapeutic strategies, including using immunotherapy, typically unsuccessful in treating prostate cancer.

Intracellular osteopontin promotes the release of TNF by mast cells to restrain neuroendocrine prostate cancer.

Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer that emerges as tumors become resistant to hormone therapies or, rarely, arises de novo in treatment-naïve patients. The urgent need for effective therapies against NEPC is hampered by the limited knowledge of the biology governing this lethal disease. Based on our prior observations in the TRAMP spontaneous prostate cancer model, in which the genetic depletion of either mast cells (MCs) or the matricellular protein osteopontin (OPN) increases NEPC frequency, we tested the hypothesis that MCs can restrain NEPC through OPN production, using in vitro co-cultures between murine or human tumor cell lines and MCs, and in vivo experiments. We unveiled a role for the intracellular isoform of OPN (iOPN), so far neglected compared to the secreted isoform. Mechanistically, we unraveled that iOPN promotes TNF production in MCs via the TLR2/TLR4-MyD88 axis, specifically triggered by the encounter with NEPC cells. We found that MC-derived TNFin turn, hampered the growth of NEPC. We then identified the protein syndecan-1 (SDC1) as the NEPC-specific TLR2/TLR4 ligand that triggered this pathway. Interrogating published single-cell RNA-sequencing data we validated this mechanism in a different mouse model. Translational relevance of the results was provdied by in silco analyses of available human NEPC datasets, and by immunofluorescence on patient-derived adenocarcinoma and NEPC lesions. Overall, our results show that MCs actively inhibit NEPC, paving the way for innovative MC-based therapies for this fatal tumor. We also highlight SDC1 as a potential biomarker for incipient NEPC.

¿Limitar la presión de distensión protege contra la lesión pulmonar adquirida por la ventilación mecánica (VALI)? / Does limiting the distension pressure protect against lung injury acquired by mechanical ventilation (VALI)? / A limitação da pressão de distensão protege contra lesão pulmonar adquirida por ventilação mecânica (VALI)?

Resumen: El incremento en la presión de las vías respiratorias causa lesión de la membrana alveolar proponiendo el barotrauma como causa de lesión pulmonar adquirida por el ventilador (VALI), esta afección se presenta de forma frecuente, lo que conduce a entender mejor el papel desempeñado por los ajustes del ventilador mecánico, la fisiopatología pulmonar subyacente y su interacción. En la última década se ha dado relevancia al término presión de distensión (PD), que surge del cálculo del delta de presión (∆P = Vt/CRS). La PD representa los cambios dinámicos de la presión que se genera en la vía aérea en cada ciclo ventilatorio. Aunque se instalen medidas de protección pulmonar de manera inicial, existen diversas condiciones que modifican las propiedades elásticas, tales como reanimación hídrica y el balance positivo de líquidos, procesos infecciosos agregados, etc. Sin embargo, aun cuando se cumplan estas medidas de protección puede haber distensión pulmonar excesiva, por lo que la monitorización de la PD puede ser una herramienta útil para determinar de manera sistemática los cambios en la rigidez pulmonar, estableciendo intervenciones. En ausencia de ensayos que usen PD como objetivo al establecer el ventilador, se sugiere que se utilice como complemento y no como un sustituto de parámetros de protección pulmonar.

Abstract: The increase in airway pressure causes injury in the alveolar membrane by proposing barotrauma as the cause of ventilator-acquired Lung Injury (VALI), this condition occurs frequently, which leads to a better understanding of the roles played by the mechanical ventilator settings, underlying lung pathophysiology and their interaction. In the last decade, the term pressure of distension (PD) has emerged, arising from the calculation of the pressure delta (ΔP = Vt/CRS). The PD represents the dynamic changes of the pressure that is generated in the airway in each ventilatory cycle. Although pulmonary protection measures are initially installed, there are several conditions that modify elastic properties, such as fluid resuscitation and positive fluid balance, aggregated infectious processes, etc. However, even if these protective measures are met, excessive pulmonary distention may occur, so PD monitoring may be a useful tool for systematically determining changes in pulmonary stiffness by establishing interventions. In the absence of assays using PD as a target when establishing the ventilator, it is suggested that it be used as a complement and not as a substitute for pulmonary protection parameters.

Resumo: O aumento da pressão das vias aéreas causa lesão da membrana alveolar, propondo o barotrauma como causa de Lesão Pulmonar Adquirida pelo Ventilador (VALI), esta condição ocorre com frequência, o que leva a uma melhor compreensão dos papéis desempenhados pelos ajustes do ventilador mecânico, a fisiopatologia pulmonar subjacente e sua interação. Na última década, o termo pressão de distensão (PD) tem recebido relevância decorrente do cálculo do delta de pressão (ΔP = Vt/CRS). A DP representa as mudanças dinâmicas da pressão gerada na via aérea em cada ciclo ventilatório. Embora as medidas de proteção pulmonar sejam instaladas inicialmente, existem várias condições que modificam as propriedades elásticas, tais como ressuscitação hídrica e balanço hídrico positivo, processos infecciosos agregados, etc. No entanto, mesmo que essas medidas de proteção sejam atendidas, pode haver distensão pulmonar excessiva, de modo que a monitorização da DP possa ser uma ferramenta útil para determinar sistematicamente as mudanças na rigidez pulmonar, estabelecendo intervenções. Na ausência de ensaios que utilizem a PD como objetivo no estabelecimento do ventilador, sugere-se que seja utilizado como complemento e não como substituto dos parâmetros de proteção pulmonar.

Streptococcus pneumoniae serotypes isolated from the middle ear of Mexican children diagnosed with acute otitis media / Serotipificación de Streptococcus pneumoniae aislados de líquido de oído medio en niños mexicanos con diagnóstico de otitis media aguda

OBJECTIVE: The aim of this study was to identify the etiology and the serotypes of S. pneumoniae (Sp) in Mexican children with acute otitis media (AOM). MATERIALS AND METHODS: The study includessamples frompatientsdiagnosed with AOM at the Federico Gomez Children's Hospital of Mexico (2002-2003),with positive culture for Sp bacteriologically confirmed in middle ear fluid obtained by tympanocentesis. All Sp were serotyped. A total of 138 samples from 135 children with AOM were included. RESULTS: Sp was isolated in 72 samples from 70 children. Sixty (85.7 percent) were previously healthy and 10 (14.3 percent) were immunocompromised. The most common serotypes were 6B and 19F (16.67 percent), and 6 A, 14 and 23F (15.27 percent). CONCLUSION: The distribution of serotypes among the children with AOM in the study is similar to that reported in developing cities, and 63.9 percent of the isolated serotypes are found to be included in the 7-Valent Pneumococcal Conjugate Vaccine (PCV), 68.1 percent in the 10-Valent PCV and 83.3 percent in 13-Valent PCV.

OBJETIVO: Conocer la etiología y serotipos de S. pneumoniae (Sp) en niños mexicanos, con otitis media aguda (OMA). MATERIAL Y MÉTODOS: Se incluyeron las muestras de pacientes con OMA del Hospital Infantil de México Federico Gómez (2002-2003), con cultivo positivo para Sp, (bacteriológicamente confirmados en el líquido del oído medio obtenido por timpanocentesis). Todos los Sp. fueron serotipificados. Se incluyeron 138 muestras de 135 niños con OMA. RESULTADOS: Sp. se aisló en 72 muestras de 70 niños: 60 (85.7 por ciento) eran previamente sanos y 10 (14.3 por ciento) eran inmunocomprometidos. Los serotipos más frecuentes fueron 6B y 19F (16.67 por ciento), y 6 A, 14 y 23F (15.27 por ciento). CONCLUSIONES: La distribución de los serotipos en niños con otitis media aguda fue similar a la reportada en ciudades en desarrollo y se observó que 63.9 por ciento de los serotipos aislados están incluidos en la vacuna conjugada 7-valente, 68.1 por ciento en la 10-valente y 83.3 por ciento en la 13-valente.

Invasive pneumococcal disease in a third level pediatric hospital in Mexico City: epidemiology and mortality risk factors / Enfermedad neumocócica invasora en un hospital pediátrico de tercer nivel en la Ciudad de México: características epidemiológicas y factores de riesgo asociados con mortalidad

Objective. To assess the epidemiologic characteristics of invasive pneumococcal diseases (IPD) among a population in a pediatric hospital in Mexico City and analyze mortality-related risk factors, serotype distribution and antibiotic susceptibility related to S.pneumoniae. Material and Methods. We performed a retrospective review of IPD cases at a third level pediatric hospital between 1997-2004. Results. A total of 156 patients were included. The mortality rate was 27.5 percent and was associated with six pneumococcal serotypes: 14, 6B, 23F, 6A, 19F and 19A. There was no relationship between mortality and antimicrobial susceptibility pattern. A total of 28.2 percent of isolates were resistant to penicillin and 24.6 percent were resistant to cefotaxime. A statistically significant relationship was observed between mortality and previous underlying disease (CI 95 percent; 2.5-18.3; p< 0.05) using a multivariate logistic regression model. Conclusions. Our outcomes show that IPD mortality in our population is closely related to underlying disease and to six serotypes, five of which are included in the 7-valent pneumococcal conjugate vaccine.

Objetivo. Conocer la epidemiología de la enfermedad neumocócica invasora (ENI) en un hospital pediátrico y analizar los factores de riesgo relacionados con la mortalidad, la distribución de serotipos y el patrón de susceptibilidad de S. pneumoniae. Material y métodos. Revisión retrospectiva de los casos de ENI en un hospital pediátrico de tercer nivel, entre 1997 y 2004. Resultados. En 156 pacientes la mortalidad fue de 27.5 por ciento. Los serotipos de neumococo más frecuentemente relacionados con la mortalidad fueron: 14, 6B, 23F, 6A, 19F y 19A; no hubo relación de mortalidad con la resistencia a antibióticos. El 28.2 por ciento mostró resistencia a penicilina y 24.6 por ciento a cefotaxima. A través del modelo multivariado, se encontró una relación estadísticamente significativa entre la mortalidad y enfermedad previa (IC 95 por ciento; 2.5-18.3; p<0.05). Conclusiones. La mortalidad asociada a la ENI tuvo relación significativa con antecedente de una enfermedad previa y con seis serotipos, cinco incluidos en la vacuna neumocócica conjugada 7-valente.