A Transgenic Model Reveals the Role of Klotho in Pancreatic Cancer Development and Paves the Way for New Klotho-Based Therapy

Klotho; Càncer de pàncrees; Supressor del tumorKlotho; Cáncer de páncreas; Supresor de tumorKlotho; Pancreatic cancer; Tumor suppressorKlotho is an anti-aging transmembrane protein, which can be shed and can function as a hormone. Accumulating data indicate that klotho is a tumor suppressor in a wide array of malignancies, and designate the subdomain KL1 as the active region of the protein towards this activity. We aimed to study the role of klotho as a tumor suppressor in pancreatic ductal adenocarcinoma (PDAC). Bioinformatics analyses of The Cancer Genome Atlas (TCGA) datasets revealed a correlation between the survival of PDAC patients, levels of klotho expression, and DNA methylation, and demonstrated a unique hypermethylation pattern of klotho in pancreatic tumors. The in vivo effects of klotho and KL1 were examined using three mouse models. Employing a novel genetic model, combining pancreatic klotho knockdown with a mutation in Kras, the lack of klotho contributed to PDAC generation and decreased mousece survival. In a xenograft model, administration of viral particles carrying sKL, a spliced klotho isoform containing the KL1 domain, inhibited pancreatic tumors. Lastly, treatment with soluble sKL prolonged survival of Pdx1-Cre; KrasG12D/+;Trp53R172H/+ (KPC) mice, a model known to recapitulate human PDAC. In conclusion, this study provides evidence that klotho is a tumor suppressor in PDAC. Furthermore, these data suggest that the levels of klotho expression and DNA methylation could have prognostic value in PDAC patients, and that administration of exogenous sKL may serve as a novel therapeutic strategy to treat PDAC.This project was funded by the The Sami and Tova Sagol Foundation for the Study of Aging, the Margaret Stultz foundation for Pancreatic Cancer Research, the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Ministerio de Ciencia e Innovación ‘Proyectos I+D+I 2019, to M.C., (grant number PID2019-104034RB-I00) and by the TASMC excellence fund. to I.W

Patterns of psychiatric hospitalizations of Arab and Jewish adults with chronic psychotic disorders, before and after national mental health reforms, Israel, 1991–2016

Abstract Background Members of the Arab minority in Israel are at increased risk of developing mental illness, although less likely to seek care and have accessible treatment. This study compares trends in psychiatric hospitalizations between Arabs and Jews with chronic psychotic disorders, before and after introduction of the Community Rehabilitation of Persons with Mental Disability Law in 2000, and governmental recognition of the need to allocate resources for patients with co-occurring substance use disorder and mental illness in 2010. Methods The National Psychiatric Case Registry provided data on 18,684 adults with schizophrenia/schizoaffective disorder, hospitalized in 1991–2016 (at least once in 2010–2015). Repeated-measures ANOVA was used to measure the effect (and interactions) of population-group (Arabs and Jews), time-period (Period1: 1991–2000, Period2: 2001–2009, Period3: 2010–2016) and sex, on average length of stay (LOS), annual number of hospitalizations and hospitalization days. Results The proportion of Arab patients hospitalized with a diagnosis of chronic psychotic disorder (14.4%) was significantly lower than their proportion in the general population (21%), and their average age at first hospitalization (28.4 years) was older than that of Jewish inpatients (27.0 years). The average number of hospitalization days and LOS of Jewish patients were double that of Arab patients in Period1. Following implementation of the Rehabilitation Law, hospitalization days increased among Arab patients and decreased slightly among Jewish patients, such that by Period3 the average number of hospitalization days was similar among Jewish (41) and Arab (37) patients. The increase in hospitalization days among Arab patients was limited to men with no change noted among women. The number of hospitalization days among Arab women was about half that of Jewish women (p < 0.0001). Conclusions The findings reveal a narrowing of disparities in psychiatric hospitalizations between Arab and Jewish patients in Israel over time. However, among Arab women the number of hospitalization days remains considerably lower than that of Jewish women, raising concerns that Arab women may be receiving insufficient care. Further study is needed to fully understand the underpinnings of these disparities, although increasing the number of Arabic-language mental health services and providing psycho-education, will help further close the gap

A Transgenic Model Reveals the Role of Klotho in Pancreatic Cancer Development and Paves the Way for New Klotho-Based Therapy

Klotho is an anti-aging transmembrane protein, which can be shed and can function as a hormone. Accumulating data indicate that klotho is a tumor suppressor in a wide array of malignancies, and designate the subdomain KL1 as the active region of the protein towards this activity. We aimed to study the role of klotho as a tumor suppressor in pancreatic ductal adenocarcinoma (PDAC). Bioinformatics analyses of The Cancer Genome Atlas (TCGA) datasets revealed a correlation between the survival of PDAC patients, levels of klotho expression, and DNA methylation, and demonstrated a unique hypermethylation pattern of klotho in pancreatic tumors. The in vivo effects of klotho and KL1 were examined using three mouse models. Employing a novel genetic model, combining pancreatic klotho knockdown with a mutation in Kras, the lack of klotho contributed to PDAC generation and decreased mousece survival. In a xenograft model, administration of viral particles carrying sKL, a spliced klotho isoform containing the KL1 domain, inhibited pancreatic tumors. Lastly, treatment with soluble sKL prolonged survival of Pdx1-Cre; KrasG12D/+;Trp53R172H/+ (KPC) mice, a model known to recapitulate human PDAC. In conclusion, this study provides evidence that klotho is a tumor suppressor in PDAC. Furthermore, these data suggest that the levels of klotho expression and DNA methylation could have prognostic value in PDAC patients, and that administration of exogenous sKL may serve as a novel therapeutic strategy to treat PDAC

Common model of stress, anxiety, and depressive symptoms in pregnant women from seven high-income Western countries at the COVID-19 pandemic onset.

Increases in stress, anxiety, and depression among women pregnant during the COVID-19 pandemic have been reported internationally. Yet rigorous comparison of the prevalence of maternal mental health problems across countries is lacking. Moreover, whether stress is a common predictor of maternal mental health during the pandemic across countries is unknown. 8148 pregnant women from Germany, Israel, Italy, Poland, Spain, Switzerland, and the United States were enrolled in the International COVID-19 Pregnancy Experiences (I-COPE) Study between April 17 and May 31, 2020. Sociodemographic characteristics, pandemic-related stress, pregnancy-specific stress, anxiety, and depression were assessed with well-validated instruments. The magnitude of stress and mood disturbances was compared across countries. A path model predicting clinically significant levels of anxiety and depression from maternal characteristics and stress was tested for all study participants and then examined separately in each country with >200 participants. Countries differed significantly in magnitude of pandemic-related pregnancy stress and pandemic-unrelated pregnancy-specific stress, and in prevalence of clinically significant anxiety and depression levels. A well-fitting common path model for the entire sample indicated that mood and anxiety disturbances were strongly predicted by pandemic-related and pregnancy-specific stress after accounting for maternal characteristics. The model was replicated in individual countries. Although pregnant women in high-income Western countries experienced different levels of stress resulting from the COVID-19 pandemic, stress is a strong, common predictor of anxiety and depressive symptoms in these individuals. The common model can be used to inform research and clinical interventions to protect against adverse consequences of prenatal maternal stress, anxiety, and depression for mothers and infants