Cancer-associated fibroblasts expressing fibroblast activation protein and podoplanin in non-small cell lung cancer predict poor clinical outcome.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are a dominant cell type in the stroma of non-small cell lung cancer (NSCLC). Fibroblast heterogeneity reflects subpopulations of CAFs, which can influence prognosis and treatment efficacy. We describe the subtypes of CAFs in NSCLC. METHODS: Primary human NSCLC resections were assessed by flow cytometry and multiplex immunofluorescence for markers of fibroblast activation which allowed identification of CAF subsets. Survival data were analysed for our NSCLC cohort consisting of 163 patients to understand prognostic significance of CAF subsets. RESULTS: We identified five CAF populations, termed CAF S1-S5. CAF-S5 represents a previously undescribed population, and express FAP and PDPN but lack the myofibroblast marker αSMA, whereas CAF-S1 populations express all three. CAF-S5 are spatially further from tumour regions then CAF-S1 and scRNA data demonstrate an inflammatory phenotype. The presence of CAF-S1 or CAF-S5 is correlated to worse survival outcome in NSCLC, despite curative resection, highlighting the prognostic importance of CAF subtypes in NSCLC. TCGA data suggest the predominance of CAF-S5 has a poor prognosis across several cancer types. CONCLUSION: This study describes the fibroblast heterogeneity in NSCLC and the prognostic importance of the novel CAF-S5 subset where its presence correlates to worse survival outcome.

Location of CD39+ T cell subpopulations within tumors predict differential outcomes in non-small cell lung cancer.

PURPOSE: An improved mechanistic understanding of immunosuppressive pathways in non-small cell lung cancer (NSCLC) is important to develop novel diagnostic and therapeutic approaches. Here, we investigate the prognostic significance of the ectonucleotidases CD39 and CD73 in NSCLC. EXPERIMENTAL DESIGN: The expression and localization of CD39, CD73 and CD103 was digitally quantified in a cohort of 162 early treatment naïve NSCLC patients using multiplex-immunofluorescence and related to patient outcome. Expression among different cell-populations was assessed via flow cytometry. Targeted RNA-Seq was performed on CD4+ and CD8+ T cells from digested NSCLC tumor tissue and single-cell RNA-Seq data was analyzed to investigate the functional significance of CD39+ T cell populations. RESULTS: We demonstrate that flow cytometry of early untreated NSCLC patients shows an upregulation of CD39 expression in the tumor tissue among natural killer (NK) cells, fibroblasts and T cells. CD73 expression is mainly found among fibroblasts and Epcam+cells in the tumor tissue. Multiplex Immunofluorescence in a cohort of 162 early untreated NSCLC patients demonstrates that CD39 expression is mainly localized in the tumor stroma while CD73 expression is equally distributed between tumor nest and stroma, and high expression of CD39 and CD73 in the tumor stroma is associated with poor recurrence-free survival (RFS) at 5 years. Additionally, we find that CD8+T cells located in the tumor nest express CD103 and the density of CD39+CD103+CD8+ T cells in the tumor nest predicts improved RFS at 5 years. Targeted RNA-Seq shows that the tumor microenvironment of NSCLC upregulates regulatory pathways in CD4+ T cells and exhaustion in CD8+ T cells, and analysis of a single cell RNA sequencing dataset shows that CD39+CD4+ cells are enriched in Treg signature gene-sets, and CD39+CD103+ cytotoxic T lymphocyte show gene signatures indicative of an exhausted cytotoxic phenotype with upregulated expression of CXCL13. CONCLUSIONS: Knowledge of patterns of distribution and location are required to understand the prognostic impact of CD39+ T cell populations in NSCLC. This study provides an improved understanding of spatial and functional characteristics of CD39+ T cells and their significance to patient outcome.

Cancer-associated fibroblasts drive CXCL13 production in activated T cells via TGF-beta.

Introduction: Tumour-reactive T cells producing the B-cell attractant chemokine CXCL13, in solid tumours, promote development of tertiary lymphoid structures (TLS) and are associated with improved prognosis and responsiveness to checkpoint immunotherapy. Cancer associated fibroblasts are the dominant stromal cell type in non-small cell lung cancer (NSCLC) where they co-localise with T cells and can influence T cell activation and exhaustion. We questioned whether CAF directly promote CXCL13-production during T cell activation. Methods: We characterised surface markers, cytokine production and transcription factor expression in CXCL13-producing T cells in NSCLC tumours and paired non-cancerous lung samples using flow cytometry. We then assessed the influence of human NSCLC-derived primary CAF lines on T cells from healthy donors and NSCLC patients during activation in vitro measuring CXCL13 production and expression of cell-surface markers and transcription factors by flow cytometry. Results: CAFs significantly increased the production of CXCL13 by both CD4+ and CD8+ T cells. CAF-induced CXCL13-producing cells lacked expression of CXCR5 and BCL6 and displayed a T peripheral helper cell phenotype. Furthermore, we demonstrate CXCL13 production by T cells is induced by TGF-ß and limited by IL-2. CAF provide TGF-ß during T cell activation and reduce availability of IL-2 both directly (by reducing the capacity for IL-2 production) and indirectly, by expanding a population of activated Treg. Inhibition of TGF-ß signalling prevented both CAF-driven upregulation of CXCL13 and Treg expansion. Discussion: Promoting CXCL13 production represents a newly described immune-regulatory function of CAF with the potential to shape the immune infiltrate of the tumour microenvironment both by altering the effector-function of tumour infiltrating T-cells and their capacity to attract B cells and promote TLS formation.

Mother-to-infant microbiota transmission and infant microbiota development across multiple body sites.

Early-life microbiota seeding and subsequent development is crucial to future health. Cesarean-section (CS) birth, as opposed to vaginal delivery, affects early mother-to-infant transmission of microbes. Here, we assess mother-to-infant microbiota seeding and early-life microbiota development across six maternal and four infant niches over the first 30 days of life in 120 mother-infant pairs. Across all infants, we estimate that on average 58.5% of the infant microbiota composition can be attributed to any of the maternal source communities. All maternal source communities seed multiple infant niches. We identify shared and niche-specific host/environmental factors shaping the infant microbiota. In CS-born infants, we report reduced seeding of infant fecal microbiota by maternal fecal microbes, whereas colonization with breastmilk microbiota is increased when compared with vaginally born infants. Therefore, our data suggest auxiliary routes of mother-to-infant microbial seeding, which may compensate for one another, ensuring that essential microbes/microbial functions are transferred irrespective of disrupted transmission routes.

Bacterial and fungal communities in tracheal aspirates of intubated COVID-19 patients: a pilot study.

Co-infections with bacterial or fungal pathogens could be associated with severity and outcome of disease in COVID-19 patients. We, therefore, used a 16S and ITS-based sequencing approach to assess the biomass and composition of the bacterial and fungal communities in endotracheal aspirates of intubated COVID-19 patients. Our method combines information on bacterial and fungal biomass with community profiling, anticipating the likelihood of a co-infection is higher with (1) a high bacterial and/or fungal biomass combined with (2) predominance of potentially pathogenic microorganisms. We tested our methods on 42 samples from 30 patients. We observed a clear association between microbial outgrowth (high biomass) and predominance of individual microbial species. Outgrowth of pathogens was in line with the selective pressure of antibiotics received by the patient. We conclude that our approach may help to monitor the presence and predominance of pathogens and therefore the likelihood of co-infections in ventilated patients, which ultimately, may help to guide treatment.

Cancer Associated Fibroblasts - An Impediment to Effective Anti-Cancer T Cell Immunity.

The presence of functionally efficient cytotoxic T lymphocytes (CTL) in the Tumour nest is crucial in mediating a successful immune response to cancer. The detection and elimination of cancer cells by CTL can be impaired by cancer-mediated immune evasion. In recent years, it has become increasingly clear that not only neoplastic cells themselves, but also cells of the tumour microenvironment (TME) exert immunosuppressive functions and thereby play an integral part in the immune escape of cancer. The most abundant stromal cells of the TME, cancer associated fibroblasts (CAFs), promote tumour progression via multiple pathways and play a role in dampening the immune response to cancer. Recent research indicates that T cells react to CAF signalling and establish bidirectional crosstalk that plays a significant role in the tumour immune response. This review discusses the various mechanisms by which the CAF/T cell crosstalk may impede anti-cancer immunity.

T cells drive negative feedback mechanisms in cancer associated fibroblasts, promoting expression of co-inhibitory ligands, CD73 and IL-27 in non-small cell lung cancer.

The success of immune checkpoint therapy shows tumor-reactive T cells can eliminate cancer cells but are restrained by immunosuppression within the tumor micro-environment (TME). Cancer associated fibroblasts (CAFs) are the dominant stromal cell in the TME and co-localize with T cells in non-small cell lung cancer. We demonstrate the bidirectional nature of CAF/T cell interactions; T cells promote expression of co-inhibitory ligands, MHC molecules and CD73 on CAFs, increasing their production of IL-6 and eliciting production of IL-27. In turn CAFs upregulate co-inhibitory receptors on T cells including the ectonucleotidase CD39 promoting development of an exhausted but highly cytotoxic phenotype. Our results highlight the bidirectional interaction between T cells and CAFs in promoting components of the immunosuppressive CD39, CD73 adenosine pathway and demonstrate IL-27 production can be induced in CAF by activated T cells.

Diseño curricular para la licenciatura de Fisioterapia y Kinesiología de la UMSA / Curriculum design for the degree of Fisioterapía and Kinesiology of the UMSA

Se planteó la necesidad de diseñar un nuevo curriculum para la carrera de fisioterapia de la UMSA que responda a la nueva demanda social, partiendo de un diagnóstico situacional previo, de un nuevo perfil diferenciado y la identificación de los problemas dominantes de salud que abordarìa ese profecional, se prosedio a la construcción de un nuevo curriculum siguiendo lineas metodológicas y científicas en el marco de las corrientes contemporáneas. Ofertar la oportunidad de elevar el nivel científico y técnico de los profecionales de esta carrera, complementando hasta el grado de Licenciatura la formación de los Técnicos Superiores a través de un nuevo diseño curricular, fueron los objetivos generales de este trabajo, manteniendo la salida intermedia de Técnico Superior y generando un programa complementario para ya los profesionalizados como técnicos. Partiendo del análisis de documentos y la elavoración de una matriz F. O. D. A. se alcanzó un diagnóstico seguido de la construcción metodológica del currículum, cumpliendo los pasos que corresponden a un enfoque sistémico. Despues de revisados los diferentes enfoques del diseño curricular se definió por un enfoque humanista y dialéctico, con un modelo centrado en los objetivos y en el estudiante. La consistencia de la propuesta permitió que se aprobara su aplicación apartir de la gestión 1999 en su plan de nivelación para los profesionales Técnico Superiores y desde la gestión 2000 en el plan regular. El programa, por necesidades de demanda, tuvo que abrir tres sedes en el interior del pais (Oruro, Cochabamba y Santa Cruz) Al ingresar al segundo año de su aplicación. La evaluación inicial factible, ha demostrado cumplimiento del cronograma y un alto grado de satisfacción de los beneficiarios relacionado con el cumplimiento del cronograma, los contenidos inpartidos, modelo educativo y nivel docente. Al elevar el grado académico con un nuevo perfil profesional se formará un fisioterapeuta capaz de atender los problemas de salud con mayor calidad, calidez y mayor nivel científico técnico

El sistema de valuacion y calificación en la carrera de medicina de la Universidad Mayor de San Andrés / Ehe evaluation and claification system in the medicine career of the San Andres University

La eavaluación es un mecanismo regulador del proceso enseñanza-aprendizaje que implica un control del proceso de los estudiantes en su formación. Conforma unsistema complejo con caracteristicas propias: funciones, principios, formas, métodos, procedimientos y técnicas. en la Carrera de Medicina nuestros sistemas de evaluación y calificación, no garantizan una evaluación justa, precisa y real, que mida con exacatitud el nivel de conocimientos, habikidades y destresas adqiridad por los estudiantes a lo largo de la carrera, debido a la no aplicación de las caracteristicas delsistema. Para corregir esta debilidad es necesario organizar talleres de reingenieria del sistema de evaluación en el seno de nuestra Facultad.

Diseño curricular para licenciatura en fisioterapia y kinesiología en la Universidad Mayor de San Andrés / Curricular design in pre graduate level in fisioteraphy and kinesiology at the san andres university

Se presenta el nuevo proyecto del diseño curricular para Fisioterapia y Kinesiología, producto del curso de Especialidad en Psicopedagogía, Planificación, EValuación Gestión y Educación Superior (PPEGESS) y actualmente en trámite de aprobación para su implementación.

Sindrome de hombro doloroso / Painful shoulder syndrome

Se revisaron 40 historias clínicas de pacientes remitidos al servicio de Medicina Física y Rehabilitación de Clinica Modelo y CENEFRI por Sindrome de Hombro Doloroso, se infiltro con lidocaína al 2 porciento más acetato de metilprednisolona a quienes presentaban puntos dolorosos, implementándose n programa en base a ultrasonido, calor superficial por compresa eléctrica, cinesisterapia y mecanoterapia, los de dolor difuso en vez de U.S. y calor superficial, recibieron Diatermia, algunos pacientes fueron medados con A.I.N.E. Este Cuadro predominó en el hombro derecho, más frecuentemente en mujeres y entre la tercera y sexta década de vida. La causa más frecuente fue la traumática, seguida de inflamatoria y degenerativa, pocos casos de causa vascular y post quirúrgica de mama y torax. Los resltados satisfactorios se obtuvieron en el 77 porciento, mejorias parciales 5.7 porciento y fracasos 5.7 porciento, abandonaron el tratamiento 11.4 porciento de los pacientes. El 47,5 porciento recibieron A.I.N.E. más terapia física, solo terapia física 40 porciento y resuletos con solo infiltración 12.5 porciento. El número medio de seciones fue 16. Se concluye que el uso de estos medios físicos dan resultados satisfactorio, siendo alternativos el U.S. en lesiones localizadas y D.T. en difusa. La infiltración en lesiones de partes blandas localizadas es efectiva. Se trata de un síndrome muy frecuente constituido por dolor, ebilidad muscular y limitaciones de la movilidad articular con repercusión enla función del miembro torácico de etiología diversa. Tabién se emplean los sinónimos de Sindrome de Arco Doloroso, Periartritis Escápulo- Humoreal, Capsulitis adhesiva, hombro bloqueado, hombro rigido. En sumanejo se han venido emoleando diversos procedimientos, en forma única o conbinada, estos uncluyen los antiinflamatorios no esteroides, medios físicos como ultrasonido, diatermia, termoterapia superficial, cinesiterapia, mecanoterapia, emplean otros medios comola terapia laser y corrientes analgesicas. Los resultados son variables. Se hace necesario en nuestro medio, valorar programas de tratamiento en medicina física y rehabilitación.