BackgroundPreventive health care programs can save lives and contribute to a better quality of life by diagnosing serious medical conditions early. The Preventive Health Care Facility Location (PHCFL) problem is to identify optimal locations for preventive health care facilities so as to maximize participation. When identifying locations for preventive health care facilities, we need to consider the characteristics of the preventive health care services. First, people should have more flexibility to select service locations. Second, each preventive health care facility needs to have a minimum number of clients in order to retain accreditation.ResultsThis paper presents a new methodology for solving the PHCFL problem. In order to capture the characteristics of preventive health care services, we define a new accessibility measurement that combines the two-step floating catchment area method, distance factor, and the Huff-based competitive model. We assume that the accessibility of preventive health care services is a major determinant for participation in the service. Based on the new accessibility measurement, the PHCFL problem is formalized as a bi-objective model based on efficiency and coverage. The bi-objective model is solved using the Interchange algorithm. In order to accelerate the solving process, we implement the Interchange algorithm by building two new data structures, which captures the spatial structure of the PHCFL problem. In addition, in order to measure the spatial barrier between clients and preventive health care facilities accurately and dynamically, this paper estimates travelling distance and travelling time by calling the Google Maps Application Programming Interface (API).ConclusionsExperiments based on a real application for the Alberta breast cancer screening program show that our work can increase the accessibility of breast cancer screening services in the province.

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| INTRODUC TI ONRenal cell carcinoma (RCC) is a common cancer that accounts for 2%-3% of all cancerous diseases in adults. 1 There are approximately 65 000 cases of RCC each year, and RCC is the eighth most common cause of cancer mortality. 2 RCC affects quality of life and life expectancy and has important health and economic implications related to metabolic syndromes, increased cardiovascular risk and end-stage kidney disease. 3 In addition, clear cell renal cell carcinoma (ccRCC) is the most universal subtype of RCC, accounting for approximately 75% of RCC. Furthermore, the morbidity and mortality rates of RCC are rising globally. 4 Besides traditional surgery, RCC is resistant to the other forms of therapies chemotherapy and radiotherapy. The 5-year survival rate of RCC is approximately 55%, while the 5-year survival rate of metastatic RCC is approximately 10%. 5 Patients with metastatic RCC are faced with a depressing prognosis and limited therapeutic options. The median survival time in a recent cohort study was only 1.5 years, and the survival rate was less than 10% in patients who survived 5 years. 6 Thus, it is vital to study the molecular basis of RCC to design novel therapeutic drugs to improve survival rates.Abstract Objective: We aimed to investigate the roles of the lncRNA MALAT1 in renal cell carcinoma (RCC) progression. Methods: qRT-PCR was used for the assessment of BIRC5, miRNA-203 and MALAT1 expression. Furthermore, the targeted relationships between miR-203 and BIRC5, as well as MALAT1 and miR-203, were predicted by the miRanda/starBase database and verified by dual-luciferase reporter gene assay. The effects of MALAT1, miRNA-203 and BIRC5 on cell proliferation, cell cycle, cell apoptosis, cell invasion and cell migration were studied by using CCK-8, flow cytometry, transwell and wound healing assays, respectively. In addition, the effects of MALAT1 on RCC tumorigenesis were evaluated in vivo by nude mouse tumorigenesis. Results: The expression levels of BIRC5 and MALAT1 were higher in RCC tissues and cell lines than in adjacent normal tissues and a normal renal cortex proximal tubule epithelial cell line. In contrast, the expression of miRNA-203 in RCC tissues and cell lines was higher than that in adjacent normal tissues and a normal renal cortex proximal tubule epithelial cell line. BIRC5 and MALAT1 promoted cell proliferation yet decreased the percentage of RCC cells at G0/G1 phase. Conclusions:Our study demonstrated that MALAT1 functions as a miR-203 decoy to increase BIRC5 expression in RCC.

Clear cell renal cell carcinoma (ccRCC) is regarded as the most aggressive subtype of RCC, with high rates of metastasis and recurrence. An extensive body of studies had proved long noncoding RNAs (lncRNAs) play pivotal parts in the development and evolution of diverse malignant tumors. However, the potential of LINC01094 in ccRCC tumorigenesis is still unexplored. In the present research, with the aid of the TCGA database, we found that LINC01094 was highly expressed in ccRCC tissues. Upregulation of LINC01094 was also confirmed in ccRCC cell lines, and functional experiments delineated that LINC01094 knockdown led to inhibition on ccRCC cell growth and metastasis. Moreover, LINC01094 was activated by FOXM1 at the transcriptional level. Further assay demonstrated that LINC01094 worked as a sponge of microRNA 224-5p (miR-224-5p) and CHSY1 was a miR-224-5p-targeted mRNA. Further, we verified that LINC01094 acted as a competing endogenous RNA in ccRCC to regulate CHSY1 expression via competitively bind to miR-224-5p. Lastly, our results expounded that LINC01094 exerted its tumor-promoting performance in ccRCC development through miR-224-5p/CHSY1 regulatory axis, which shed light on the molecular mechanism underlying LINC01094 in ccRCC and opened a new prospective for the treatment of ccRCC.

Melatonin is a well-known anti-inflammatory and antioxidant molecule, which plays a crucial role in various physiological functions. In this study, mice received a single dose of 15 Gy radiation delivered to the lungs and daily intraperitoneal administration of melatonin. After 7 days, mice were processed to harvest either bronchoalveolar lavage fluid for cytokine assays or lungs for flow cytometry and histopathological studies. Herein, we showed that melatonin markedly alleviated the oxidative stress and injury, especially suppressing the infiltration of macrophages (CD11b+CD11c−) and neutrophils (CD11b+Ly6G+) to the irradiated lungs. Moreover, in the irradiated RAW 264.7 cells, melatonin blocked the NLRP3 inflammasome activation accompanied with the inhibition of the IL-1β release and caspase-1 activity. However, melatonin restored the downregulated miR-30e levels. Quantitative PCR analysis of miR-30e and NLRP3 indicated the negative correlation between them. Notably, immunofluorescence staining showed that overexpression of miR-30e dramatically diminished the increased NLRP3 expression. Luciferase reporter assay confirmed that NLRP3 was a target gene of miR-30e. Western blotting revealed that transfection with miR-30e mimics markedly reduced the expressions of NLRP3 and cleaved caspase-1, whereas this phenomenon was reversed by the miR-30e inhibitor. Consistent with this, the beneficial effect of melatonin under irradiated exposure was blunted in cells transfected with anti-miR-30e. Collectively, our results demonstrate that the NLRP3 inflammasome contributed to the pathogenesis of radiation-induced lung injury. Meanwhile, melatonin exerted its protective effect through negatively regulating the NLRP3 inflammasome in macrophages. The melatonin-mediated miR-30e/NLRP3 signaling may provide novel therapeutic targets for radiation-induced injury.

Chronic intermittent hypoxia (CIH), as the foremost pathophysiological change of obstructive sleep apnea (OSA), contributes to continued deterioration in renal function. Nucleotide-binding domain like receptor protein 3 (NLRP3) inflammasome is a multiprotein complex that triggers innate immune responses to infection and cell stress through activation of caspase-1 and maturation of inflammatory pro-interleukin-1β cytokine. Emerging evidence indicates that inhibition of the NLRP3 inflammasome ameliorates renal injury. Nevertheless, it is uncertain whether NLRP3 inflammasome participates in CIH-induced renal injury. The molecular mechanisms modulating NLRP3 inflammasome activation remain to be elucidated. Compared with wild-type mice, NLRP3 knockout mice dramatically protected them from kidney injury, as indicated by the restoration of creatinine levels, lessened histopathological alterations, and the suppression of macrophages infiltration stained with F4/80. NLRP3 deficiency notably reversed CIH-induced oxidative stress (malondialdehyde and superoxide dismutase), concomitantly with the abrogated apoptosis-related proteins and proinflammatory signaling pathway. Consistently, NLRP3-deficient tubular cells remarkably inhibited reactive oxygen species generation and NLRP3 inflammasome activation. Furthermore, our study revealed that microRNA-155 (miR-155) was augmented in the renal tissue and HK-2 cells exposed to CIH. In addition, we investigated the role of miR-155 in the regulation of NLRP3 inflammasome. Inhibition of miR-155 suppressed the CIH-induced NLRP3 inflammasome activation in renal tubular cells, whereas overexpression of miR-155 promoted oxidation and enhanced NLRP3 pathway. Collectively, we demonstrated that miR-155 might be a positive-regulator of NLRP3 pathway by inhibiting the targeted FOXO3a gene. These results established a link between the miR-155/FOXO3a pathway and the NLRP3 inflammasome, suggesting pharmacological blockage of NLRP3 as a potential therapeutic strategy for OSA-associated chronic kidney disease.

Obstructive sleep apnea (OSA) associated chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH) triggered tissue damage. Receptor for advanced glycation end product (RAGE) and its ligand high mobility group box 1 (HMGB1) are expressed on renal cells and mediate inflammatory responses in OSA-related diseases. To determine their roles in CIH-induced renal injury, soluble RAGE (sRAGE), the RAGE neutralizing antibody, was intravenously administered in a CIH model. We also evaluated the effect of sRAGE on inflammation and apoptosis. Rats were divided into four groups: (1) normal air (NA), (2) CIH, (3) CIH+sRAGE, and (4) NA+sRAGE. Our results showed that CIH accelerated renal histological injury and upregulated RAGE-HMGB1 levels involving inflammatory (NF-κB, TNF-α, and IL-6), apoptotic (Bcl-2/Bax), and mitogen-activated protein kinases (phosphorylation of P38, ERK, and JNK) signal transduction pathways, which were abolished by sRAGE but p-ERK. Furthermore, sRAGE ameliorated renal dysfunction by attenuating tubular endothelial apoptosis determined by immunofluorescence staining of CD31 and TUNEL. These findings suggested that RAGE-HMGB1 activated chronic inflammatory transduction cascades that contributed to the pathogenesis of the CIH-induced renal injury. Inhibition of RAGE ligand interaction by sRAGE provided a therapeutic potential for CIH-induced renal injury, inflammation, and apoptosis through P38 and JNK pathways.