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Predictors of mental re-hospitalization within older adults with significant mental disease.
BACKGROUND After accounting for known risk factors for CKD progression in children, clinical outcomes among children with CKD still vary substantially. Biomarkers of tubular injury (such as KIM-1), repair (such as YKL-40), or inflammation (such as MCP-1, suPAR, TNF receptor-1 [TNFR-1], and TNFR-2) may identify children with CKD at risk for GFR decline. METHODS We investigated whether plasma KIM-1, YKL-40, MCP-1, suPAR, TNFR-1, and TNFR-2 are associated with GFR decline in children with CKD and in subgroups defined by glomerular versus nonglomerular cause of CKD. We studied participants of the prospective CKiD Cohort Study which enrolled children with an eGFR of 30-90 ml/min per 1.73 m2 and then assessed eGFR annually. Biomarkers were measured in plasma collected 5 months after study enrollment. The primary endpoint was CKD progression, defined as a composite of a 50% decline in eGFR or incident ESKD. RESULTS Of the 651 children evaluated (median age 11 years; median baseline eGFR of 53 ml/min per 1.73 m2), 195 (30%) had a glomerular cause of CKD. Over a median follow-up of 5.7 years, 223 children (34%) experienced CKD progression to the composite endpoint. After multivariable adjustment, children with a plasma KIM-1, TNFR-1, or TNFR-2 concentration in the highest quartile were at significantly higher risk of CKD progression compared with children with a concentration for the respective biomarker in the lowest quartile (a 4-fold higher risk for KIM-1 and TNFR-1 and a 2-fold higher risk for TNFR-2). Plasma MCP-1, suPAR, and YKL-40 were not independently associated with progression. When stratified by glomerular versus nonglomerular etiology of CKD, effect estimates did not differ significantly. CONCLUSIONS Higher plasma KIM-1, TNFR-1, and TNFR-2 are independently associated with CKD progression in children. Copyright © 2020 by the American Society of Nephrology.Glioblastoma multiforme (GBM) continues to have a dismal prognosis. Even though detailed information on the genetic aberrations in cell signaling and cell cycle checkpoint control is available, no effective targeted treatment has been developed. Despite the advanced molecular defects, glioblastoma cells may have remnants of normal growth inhibitory pathways, such as the bone morphogenetic protein (BMP) signaling pathway. We have evaluated the growth inhibitory effect of BMP4 across a broad spectrum of patient samples, using a panel of 40 human glioblastoma initiating cell (GIC) cultures. A wide range of responsiveness was observed. BMP4 sensitivity was positively correlated with a proneural mRNA expression profile, high SOX2 activity, and BMP4-dependent up-regulation of genes associated with inhibition of the MAPK pathway, as demonstrated by gene set enrichment analysis (GSEA). BMP4 response in sensitive cells was mediated by the canonical BMP receptor pathway involving SMAD1/5/9 phosphorylation and SMAD4 expression. SOX2 was consistently down-regulated in BMP4-treated cells. Forced expression of SOX2 attenuated the BMP4 sensitivity including a reduced up-regulation of MAPK inhibitory genes, implying a functional relationship between SOX2 down-regulation and sensitivity. Scutellarin inhibitor The results show an extensive heterogeneity in BMP4 responsiveness among GICs, and identify a BMP4 sensitive subgroup, in which SOX2 is a mediator of the response. Implications Development of agonists targeting the BMP signaling pathway in glioblastoma remains an attractive avenue towards a better treatment - our study may help find biomarkers that predict the outcome of such treatment and help stratification of patients. Copyright ©2020, American Association for Cancer Research.Advances in curative treatment to remove the primary tumor have increased survival of localized cancers for most solid tumor types, yet cancers that have spread are typically incurable and account for >90% of cancer-related deaths. Metastatic disease remains incurable because, somehow, tumors evolve resistance to all known compounds, including therapies. In all of these incurable patients, de novo lethal cancer evolves capacities for both metastasis and resistance. Therefore, cancers in different patients appear to follow the same eco-evolutionary path that independently manifests in affected patients. This convergent outcome that always includes the ability to metastasize and exhibit resistance demands an explanation beyond the slow and steady accrual of stochastic mutations. The common denominator may be that cancer starts as a speciation event when a unicellular protist breaks away from its multicellular host and initiates a cancer clade within the patient. As the cancer cells speciate and diversify further, some evolve the capacity to evolve evolvability. Evolvability becomes a heritable trait that influences the available variation of other phenotypes that can then be acted upon by natural selection. Evolving evolvability may be an adaptation for cancer cells. By generating and maintaining considerable heritable variation, the cancer clade can with high certainty serendipitously produce cells resistant to therapy and cells capable of metastasizing. Understanding that cancer cells can swiftly evolve responses to novel and varied stressors create opportunities for adaptive therapy, double-bind therapies, and extinction therapies; all involving strategic decision making that steers and anticipates the convergent co-evolutionary responses of the cancers. Copyright ©2020, American Association for Cancer Research.Cancer related venous thromboembolisms (VTE) are associated with metastasis and reduced survival in patients with urothelial cancer of the bladder (UCB). Although previous reports suggest the contribution of tissue factor and podoplanin, the mechanistic linkage between VTE and bladder cancer cell derived molecules is unknown. Therefore, we compared distinct procoagulant pathways in four different cell lines. In vitro findings were further confirmed by microfluidic experiments mimicking the pathophysiology of tumor blood vessels and in tissue samples of bladder cancer patients by transcriptome analysis and immunohistology. In vitro and microfluidic experiments identified bladder cancer derived vascular endothelial growth factor A (VEGF-A) as highly procoagulant because it promoted the release of von Willebrand factor (VWF) from endothelial cells and thus platelet aggregation. In tissue sections from bladder cancer patients, we found that VWF mediated blood vessel occlusions were associated with a poor outcome.
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