Urinary bladder lesions induced by persistent chronic low-dose ionizing radiation

The incidence of urinary bladder cancer in the Ukraine increased from 26.2 to 43.3 per 100 000 population between 1986 and 2001 after the Chernobyl accident. The present study was conducted to evaluate the development of radiation-dependent lesions in the urinary bladders of people living in cesium 137 (¹³⁷Cs) radio-contaminated areas of the Ukraine. Bladder urothelial biopsies from 159 male and 5 female patients were subjected to histological examination and immunohistochemical study of p38 mitogen-acti-vated protein kinase (MAPK), as well as the p50 and p65 subunits of nuclear factor kappa B (NF- k B). A pattern of chronic proliferative atypical cystitis accompanied with large areas of sclerosis of connective tissue in the lamina propria was commonly observed in all cases. Interestingly, these lesions were associated with a dramatic increase in the incidences of dysplasia/carcinoma in situ , and, moreover, small urothelial carcinomas were incidentally detected. We defined the overall condition as "Chernobyl cystitis.'Greatly elevated levels of p38, p65 and p50 expression in the urothelium were evident and the patients showed increased ¹³⁷Cs in urine. The data support conclusions from our previous studies of a critical role for increased oxidative stress in generation of urinary bladder urothelial lesions in individuals chronically exposed to low-dose ¹³⁷Cs radiation. Alterations in the p38 MARK cascade and accumulation of NF- k B subunits could be crucial early molecular events in the pathogenesis of Chernobyl cystitis. (Cancer Sci 2003; 94: 328–333)     

Systemic PPARγ Antagonism Reduces Metastatic Tumor Progression in Adipocyte-Rich Bone in Excess Weight Male Rodents

Primary tumors are widely associated with an excess in body fat. The role of adipose tissue on tumor cell homing to bone is yet poorly defined. In this study, we aimed to assess whether bone colonization by tumor cells is favored by an adipocyte-rich bone marrow. We delineated the accompanying alterations of the bone microenvironment and established a treatment approach that interferes with high fat diet (HFD)-induced bone metastasis formation. We were able to show that adipocytes affect skeletal tumor growth in a metastatic model of breast cancer in male rats and melanoma in male mice as well as in human breast cancer bone biopsies. Indeed, HFD-induced bone marrow adiposity was accompanied by accelerated tumor progression and increased osteolytic lesions. In human bone metastases, bone marrow adiposity correlated with tumor cell proliferation. By antagonization of the adipocyte differentiation and storage pathway linked to the peroxisome proliferator-activated receptor gamma (PPARγ) with bisphenol-A-diglycidylether (BADGE), we were able to decelerate tumor progression and subsequent osteolytic damage in the bones of two distinct metastatic animal models exposed to HFD. Overall these data show that adipose tissue is a critical factor in bone metastases and cancer-induced bone loss. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Die Blutfermente und die periodische T?tigkeit des Verdauungsapparates

Zusammenfassung 1. In den meisten unserer F?lle unterlag bei gesunden Menschen im nüchternen Zustand die Menge der Blutfermente (Amylase, Lipase, Katalase und Protease) im Laufe eines Tages gewissen Schwankungen. 2. Au?erhalb der Verdauung, bei Vorhandensein einer periodischen T?tigkeit des Verdauugsapparates, weisen die Schwankungen der Lipase und der Amylase in der Mehrzahl der F?lle einen periodischen Charakter auf, indem sie im allgemeinen der periodischen T?tigkeit des Verdauungstraktus entsprechen. 3. Die Katalase zeigt solche periodische Schwankungen in einer bedeutenden Anzahl der F?lle. 4. Was die Protease betrifft, so konnten wir vorl?ufig zu keinen bestimmten Schlüssen kommen. Mitgeteilt auf dem I. Allukrainischen Therapeutenkongre?. Charkow, Januar 1926.     

Involvement of ubiquitination and sumoylation in bladder lesions induced by persistent long-term low dose ionizing radiation in humans

PURPOSE: We determined whether ubiquitination and sumoylation processes are up-regulated in bladder urothelium by chronic, long-term, persistent low doses of ionizing radiation in male patients with benign prostate hyperplasia and females with chronic cystitis living more than 19 years in 137Cs contaminated areas after the Chernobyl accident in Ukraine. MATERIALS AND METHODS: Bladder urothelial biopsies from 45 patients were subjected to histopathological and immunohistochemical study of Ub, SUMO1, SUMO E2 conjugating enzyme Ubc9, and the cell cycle inhibitors p53 and p27(Kip1). RESULTS: Of 25 group 1 patients from radio contaminated areas chronic proliferative atypical cystitis (Chernobyl cystitis), featuring multiple foci of dysplasia, and carcinoma in situ were observed in 23 (92%) and 19 (76%), respectively, in addition to 1 small pTa grade 1 urothelial carcinoma. Chronic cystitis with areas of dysplasia and urothelial hyperplasia were detected in 2 (10%) and 3 (15%), respectively of the 20 patients in control group 2 from clean (without radio contamination) areas of Ukraine. Greatly increased levels of Ub, SUMO1, Ubc9 and p53 as well as decreased levels of p27(Kip1) were evident in patients in group 1 compared to those in group 2 (all p <0.001). CONCLUSIONS: These findings support the hypothesis that up-regulated ubiquitination and sumoylation processes might be an adaptive response to unscheduled proteolysis of aberrant p53 and p27(Kip1) cell cycle regulators occurring with long-term low dose rate ionizing radiation exposure with a possible contribution to urothelial carcinogenesis.