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- ArticleGheinani AH, Kiss B, Moltzahn F, Keller I, Bruggmann R, Rehrauer H, Fournier CA, Burkhard FC, Monastyrskaya K.JCI Insight. 2017 01 26;2(2):e89560.Bladder outlet obstruction (BOO) induces significant organ remodeling, leading to lower urinary tract symptoms accompanied by urodynamic changes in bladder function. Here, we report mRNA and miRNA transcriptome sequencing of bladder samples from human patients with different urodynamically defined states of BOO. Patients' miRNA and mRNA expression profiles correlated with urodynamic findings. Validation of RNA sequencing results in an independent patient cohort identified combinations of 3 mRNAs (NRXN3, BMP7, UPK1A) and 3 miRNAs (miR-103a-3p, miR-10a-5p, miR-199a-3p) sufficient to discriminate between bladder functional states. All BOO patients shared cytokine and immune response pathways, TGF-β and NO signaling pathways, and hypertrophic PI3K/AKT signaling pathways. AP-1 and NFkB were dominant transcription factors, and TNF-α was the top upstream regulator. Integrated miRNA-mRNA expression analysis identified pathways and molecules targeted by differentially expressed miRNAs. Molecular changes in BOO suggest an increasing involvement of miRNAs in the control of bladder function from the overactive to underactive/acontractile states.
- ArticleJanke H, Pastore F, Schumacher D, Herold T, Hopfner KP, Schneider S, Berdel WE, Büchner T, Woermann BJ, Subklewe M, Bohlander SK, Hiddemann W, Spiekermann K, Polzer H.PLoS One. 2014;9(3):e89560.About 30% of patients with acute myeloid leukemia (AML) harbour mutations of the receptor tyrosine kinase FLT3, mostly internal tandem duplications (ITD) and point mutations of the second tyrosine kinase domain (TKD). It was the aim of this study to comprehensively analyze clinical and functional properties of various FLT3 mutants. In 672 normal karyotype AML patients FLT3-ITD, but not FLT3-TKD mutations were associated with a worse relapse free and overall survival in multivariate analysis. In paired diagnosis-relapse samples FLT3-ITD showed higher stability (70%) compared to FLT3-TKD (30%). In vitro, FLT3-ITD induced a strong activating phenotype in Ba/F3 cells. In contrast, FLT3-TKD mutations and other point mutations--including two novel mutations--showed a weaker but clear gain-of-function phenotype with gradual increase in proliferation and protection from apoptosis. The pro-proliferative capacity of the investigated FLT3 mutants was associated with cell surface expression and tyrosine 591 phosphorylation of the FLT3 receptor. Western blot experiments revealed STAT5 activation only in FLT3-ITD positive cell lines, in contrast to FLT3-non-ITD mutants, which displayed an enhanced signal of AKT and MAPK activation. Gene expression analysis revealed distinct difference between FLT3-ITD and FLT3-TKD for STAT5 target gene expression as well as deregulation of SOCS2, ENPP2, PRUNE2 and ART3. FLT3-ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. Although poor prognosis in AML is only associated with FLT3-ITD, all activating FLT3 mutations can contribute to leukemogenesis and are thus potential targets for therapeutic interventions.
- BookJim deMaine.Summary: Is it possible to have a good death, free from unnecessary pain and trauma? What if our final days were designed to bring about reconciliation and release? In this wise and large-hearted book, Dr. Jim deMaine offers advice pointing the way toward a grace-filled transition out of life. Facing Death is both a memoir-in-vignettes and a handbook full of practical advice from Dr. deMaine's forty years in busy hospitals and ICUs. Using stories from his own life and practice, the veteran physician walks readers through ethical questions around "heroic" interventions: Do we fully understand what we're asking when we tell doctors to "do everything" to prolong life, even in cases when a patient has no chance of regaining consciousness? If we write advance directives outlining the kinds of care we would, or would not want, how can we ensure that they will be followed? As a pulmonary and critical care specialist, Dr. deMaine developed deep experience navigating such quandaries with patients and their families. In Facing Death he also treads into territory many physicians avoid, such as the role of spirituality; conflicts between doctors and families; cultural traditions that can aid or impede the goal of a peaceful transition, and ways to leave a moral legacy for our descendants.