Modulation of the tumour promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma

Background and aims: Esophageal adenocarcinoma (EAC) is chemoresistant in the majority of cases. The tumor-promoting biology of cancer associated fibroblasts (CAF) make them a target for novel therapies. Phosphodiesterase type 5 inhibitors (PDE5i) have been shown to regulate the activated fibroblast phenotype in benign disease. We investigated the potential for CAF modulation in EAC using PDE5i to enhance the efficacy of chemotherapy. Methods: EAC fibroblasts were treated with PDE5i and phenotypic effects examined using immunoblotting, immunohistochemistry, gel contraction, transwell invasion, organotypics, single cell RNAseq and shotgun proteomics. The combination of PDE5i with standard-of-care chemotherapy (Epirubicin, 5-Fluorouracil and Cisplatin) was tested for safety and efficacy in validated near-patient model systems (3D tumor growth assays (3D-TGAs) and patient derived xenograft (PDX) mouse models). Results: PDE5i treatment reduced alpha-SMA expression in CAFs by 50% (p<0.05), associated with a significant reduction in the ability of CAFs to contract collagen-1 gels and induce cancer cell invasion, (p<0.05). RNAseq and proteomic analysis of CAF and EAC cell lines revealed PDE5i specific regulation of pathways related to fibroblast activation and tumor promotion. 3D-TGA assays confirmed the importance of stromal cells to chemoresistance in EAC, which could be attenuated by PDE5i. Chemotherapy+PDE5i in PDX-bearing mice was safe and significantly reduced PDX tumor volume (p<0.05). Conclusion: PDE5 is a candidate for clinical trials to alter the fibroblast phenotype in esophageal cancer. We demonstrate the specificity of PDE5i for fibroblasts to prevent transdifferentiation and revert the CAF phenotype. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient in vitro and in vivo PDX-based model systems

Genomic Analysis of Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma.

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (20-37%), as is the overall survival benefit at five years (9%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1-2 (n = 27) and non-responders classified as TRG4-5 (n =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, p = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, p < 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC

Mapping local patterns of childhood overweight and wasting in low- and middle-income countries between 2000 and 2017

A double burden of malnutrition occurs when individuals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4% (62.3 (55.1–70.8) million) to 6.4% (58.3 (47.6–70.7) million), but is predicted to remain above the World Health Organization’s Global Nutrition Target of <5% in over half of LMICs by 2025. Prevalence of overweight increased from 5.2% (30 (22.8–38.5) million) in 2000 to 6.0% (55.5 (44.8–67.9) million) children aged under 5 years in 2017. Areas most affected by double burden of malnutrition were located in Indonesia, Thailand, southeastern China, Botswana, Cameroon and central Nigeria. Our estimates provide a new perspective to researchers, policy makers and public health agencies in their efforts to address this global childhood syndemic

Network Mining Indicated the Triglycerides as the Most Related Clinical Relevance to Age-related Transcriptional Changes in the Aorta

Background: Aging is believed to be one of the main causes of cardiovascular diseases. The incidence of cardiovascular dysfunctions has increased substantially over the past few years. However, our understanding of molecular mechanisms of age-related vascular disorders remains somehow unclear, and an effective treatment has not been developed. A biological network is a collection of interactions between molecular regulators and their targets in cells governing gene expression level that is usually built by employing omics data, facilitating the inference of molecular basis of complex diseases. Materials and Methods: GSE50833 series containing aorta samples of 6-month-old mice (n = 6) and 20-month-old mice (n = 6) obtained from Janvier labs (Saint Berthevin, France) were downloaded from Gene Expression Omnibus database and the verified Agilent probe IDs were subjected to build a weighted gene coexpression network by a bioinformatics tool known as Weighted Gene Coexpression Network Analysis. We then conducted a network-driven integrative analysis to find significant modules and underlying pathways. Results: The unique genes extracted from normalized gene expression values were parsed into six modules. Among the incorporated clinical traits, the most significant module was associated with triglycerides enriched in biological terms, including proteolysis, blood circulation, and circulatory system process. Moreover, Enpp5, Fez1, Kif1a, F3, H2-Q7, and Pa × 8 were taken as putative hallmark molecules by further screening. Conclusion: the main goal of this analysis was the prioritization of genes that likely play a role in the pathogenesis of vascular diseases. We attempted to provide a system understanding of the potential connections among these genes

Quick and Easy Measurements of the Inherent Optical Property of Water by Laser

To compare properties of different waters we measured the reflectance of the second harmonic of Nd: YAG laser light through different water samples in the laboratory. To generate realistic images of natural waters one must consider in some details the interaction of light with the water body. The diagrams have been utilized to represent effective parameters in the water's reflectivity such as: the angle of incidence or the bottom conditions, height of the laser from water surface, wavelength of the laser light, radiant intensities, depth of water and also the impurities of water. The reflectance of the bottom from a mirror at the bottom of an aquarium with different depths of water will depend on the bottom slope relative to the direction of incidence of the laser light and the coating to prevent damaging the mirror against the laser light so it is necessary to change the mirror after several experiments.El presente trabajo muestra las mediciones hechas en diferentes líquidos para comparar sus propiedades, tomando como referencia la reflectancia de la segunda armónica de un laser Nd. YAG, esto a través de diferentes muestras de líquidos en el laboratorio. Para poder generar imágenes realistas se debe de considerar algunos detalles de interacción de la luz con el cuerpo líquido. Los diagramas fueron utilizados para representar parámetros efectivos de la reflexión del liquido como puede ser el ángulo de incidencia y las condiciones de fondo, la altura del laser respecto a la superficie del liquido, la longitud de onda de la luz laser, la intensidades de radiación la profundidad del líquido y las impurezas que pudieran existir. La reflexión de la profundidad utilizando un espejo a diferentes profundidades depende de la inclinación relativa a la dirección de incidencia del laser y de la protección del espejo para que no se dañe, por lo que es necesario cambiar el espejo después de varios experimentos

Soy product consumption and association with health characteristics and dietary quality indices in Isfahan, Iran

BACKGROUND: To determine the average intake of soy products and its association with socio-demographic, general and health characteristics, and dietary quality indices among the population of Isfahan, Iran. METHODS: In this descriptive cross-sectional study conducted on 491 subjects in 2013-2014, grocery stores, nuts stores, chain stores, and supermarkets from different areas of Isfahan Municipality were visited. Shop owners were asked to report the amounts of soy products sales (soy nut, processed soy protein, soy milk and soy yogurt). Furthermore, a food frequency questionnaire was completed from 496 customers by an experienced nutritionist. Mean sales and intake of soy products and dietary intakes including dietary quality indices and mean adequacy ratio (MAR) as well as anthropometric and socio-demographic variables were assessed. RESULTS: Soy protein and soy yogurt are the highest [673 &plusmn; 81 (g/month)] and lowest [420 &plusmn; 148 (g/month)] purchased soy products, respectively. While soy nut [63 &plusmn; 10 (g/month)] was consumed to the lowest amount, soy protein [236 &plusmn; 39 (g/month)] was the most consumed soy product. Subjects with higher consumption of soy products were older and had higher intake of protein, vitamin C, zinc and iron, and lower intake of whole grains, legumes, and vegetables as well as greater values of MAR and dietary diversity score as well as nutrient adequacy ratio for vitamin C. CONCLUSION: Soy protein is the most purchased and consumed soy product among people living in Isfahan. More intakes of whole grains and vegetables among those with higher consumption of soy foods could define greater quantities of zinc, iron and vitamin C in the diet. Soy consumption had a reverse correlation with body mass index.&nbsp;</div

Modulation of the tumour promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma

These are whole-slide digital pathology images of esophageal adenocarcinoma (EAC) patient-derived xenograft models. EAC biopsy specimens were cultured in vitro before implanting into immuno-deficient mice. Mice were then divided into the following treatment groups and treated with combinations of chemotherapy and PDE5 inhibitors as follows: 1. Untreated 2. Epirubicin + Cisplatin + Capecitabine (ECX) 3. ECX + Vardenafil 4. ECX + Tadalafil All whole slide images are in Olympus .vsi format and can be opened using the BioFormats library in QuPath. We have also included classifiers and scripts for performing the digital pathology analysis in QuPath, and information to link each mouse with treatment groups and corresponding whole slide images.</span

Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts

The chemotherapy resistance of esophageal adenocarcinomas (EACs) is underpinned by cancer cell extrinsic mechanisms of the tumor microenvironment (TME). We demonstrate that, by targeting the tumor-promoting functions of the predominant TME cell type, cancer-associated fibroblasts (CAFs) with phosphodiesterase type 5 inhibitors (PDE5i), we can enhance the efficacy of standard-of-care chemotherapy. In ex vivo conditions, PDE5i prevent the transdifferentiation of normal fibroblasts to CAF and abolish the tumor-promoting function of established EAC CAFs. Using shotgun proteomics and single-cell RNA-seq, we reveal PDE5i-specific regulation of pathways related to fibroblast activation and tumor promotion. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient and in vivo PDX-based model systems. These findings demonstrate that CAFs drive chemotherapy resistance in EACs and can be targeted by repurposing PDE5i, a safe and well-tolerated class of drug administered to millions of patients world-wide to treat erectile dysfunction.</p