Transcriptome data further indicate that elevated expression levels of enzymes modulating VEGF-A availability were significantly connected to a decreased survival in bladder cancer patients.  https://www.selleckchem.com/products/CP-673451.html  In comparison to previously postulated molecular players, we identified tumor cell derived VEGF-A and endothelial VWF as procoagulant mediators in bladder cancer. Therapeutic strategies that prevent the VEGF-A mediated release of VWF may reduce tumor-associated hypercoagulation and metastasis in bladder cancer patients. Implications We identified the VEGF-A mediated release of VWF from endothelial cells to be associated with bladder cancer progression. Copyright ©2020, American Association for Cancer Research.OBJECTIVES To investigate (1) the prevalence of REM sleep behavior disorder (RBD) as mode of disease onset in a cohort of patients with multiple system atrophy (MSA) and (2) disease progression and prognosis in patients with MSA with RBD predating (pre-RBD) and following (post-RBD) disease onset. METHODS We retrospectively identified all patients with a clinical diagnosis of MSA evaluated at least once a year during the disease course. Type of onset was defined by the first reported motor or autonomic symptom/sign related to MSA. The occurrence of symptoms/signs and milestone of disease progression, and their latency from disease onset, were collected. Survival data were calculated. RBD was confirmed by video-polysomnography. RESULTS Of a total of 158 patients, pre-RBD represented the mode of disease onset in 27% of patients, preceding disease onset according to the international criteria with a median of 3 (2-5) years. Comparing pre-RBD and post-RBD patients, the first group showed an increased prevalence of autonomic onset of disease, a reduced prevalence of parkinsonism, an earlier onset of stridor, pyramidal signs, symptomatic orthostatic hypotension, urinary dysfunction, severe dysphagia, and wheelchair dependency. The risk of death was higher in patients with pre-RBD. CONCLUSIONS In our MSA cohort, RBD represented the most frequent mode of disease presentation. A more rapid progression of disease was observed in the pre-RBD group. These findings suggested a careful assessment of sleep disorders to early recognize RBD and a closer follow-up of autonomic dysfunction and stridor in patients with pre-RBD. © 2020 American Academy of Neurology.OBJECTIVE To characterize subclinical abnormalities in asymptomatic heterozygote NPC1 mutation carriers as markers of neurodegeneration. METHODS Motor function, cognition, mood, sleep, and smell function were assessed in 20 first-degree heterozygous relatives of patients with Niemann-Pick disease type C (NPC) (13 male, age 52.7 ± 9.9 years). Video-oculography and abdominal ultrasound with volumetry were performed to assess oculomotor function and size of liver and spleen. NPC biomarkers in blood were analyzed. 18F-fluorodesoxyglucose PET was performed (n = 16) to detect patterns of brain hypometabolism. RESULTS NPC heterozygotes recapitulated characteristic features of symptomatic NPC disease and demonstrated the oculomotor abnormalities typical of NPC. Hepatosplenomegaly (71%) and increased cholestantriol (33%) and plasma chitotriosidase (17%) levels were present. The patients also showed signs seen in other neurodegenerative diseases, including hyposmia (20%) or pathologic screening for REM sleep behavior disorder (24%). Cognitive function was frequently impaired, especially affecting visuoconstructive function, verbal fluency, and executive function. PET imaging revealed significantly decreased glucose metabolic rates in 50% of participants, affecting cerebellar, anterior cingulate, parieto-occipital, and temporal regions, including 1 with bilateral abnormalities. CONCLUSION NPC heterozygosity, which has a carrier frequency of 1200 in the general population, is associated with abnormal brain metabolism and functional consequences. Clinically silent heterozygous gene variations in NPC1 may be a risk factor for late-onset neurodegeneration, similar to the concept of heterozygous GBA mutations underlying Parkinson disease. © 2020 American Academy of Neurology.OBJECTIVE We aimed to investigate changes in atrial fibrillation (AF)-related symptoms and quality of life (QoL) over time, and their impact on prognosis. METHODS We prospectively followed 3836 patients with known AF for a mean of 3.7 years. Information on AF-related symptoms and QoL was obtained yearly. The primary end point was a composite of stroke or systemic embolism. Main secondary end points included stroke subtypes, all-cause mortality, cardiovascular death, hospitalisation for congestive heart failure (CHF), myocardial infarction and major bleeding. We assessed associations using multivariable, time-updated Cox proportional hazards models. RESULTS Mean age was 72 years, 72% were male. Patients with AF-related symptoms (66%) were younger (70 vs 74 years, p less then 0.0001), more often had paroxysmal AF (56% vs 37%, p less then 0.0001) and had lower QoL (71 vs 72 points, p=0.009). The incidence of the primary end point was 1.05 and 1.02 per 100 person-years in patients with and without symptoms, respectively. The multivariable adjusted HR (aHR) (95% CIs) for the primary end point was 1.11 (0.77 to 1.59; p=0.56) for AF-related symptoms. AF-related symptoms were not associated with any of the secondary end points. QoL was not significantly related to the primary end point (aHR per 5-point increase 0.98 (0.94 to 1.03; p=0.37)), but was significantly related to CHF hospitalisations (0.92 (0.90 to 0.94; p less then 0.0001)), cardiovascular death (0.90 (0.86 to 0.95; p less then 0.0001)) and all-cause mortality (0.88 (0.86 to 0.90; p less then 0.0001)). CONCLUSIONS AF-related symptoms were not associated with adverse outcomes and should therefore not be the basis for prognostic treatment decisions. QoL was strongly associated with CHF, cardiovascular death and all-cause mortality. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.Bacillus anthracis is a spore-forming bacterium that causes devastating infections and has been used as a bioterror agent. This pathogen can survive hostile environments through the signaling activity of two-component systems, which couple environmental sensing with transcriptional activation to initiate a coordinated response to stress. In this work, we describe the identification of a two-component system, EdsRS, which mediates the B. anthracis response to the antimicrobial compound targocil. Targocil is a cell envelope-targeting compound that is toxic to B. anthracis at high concentrations. Exposure to targocil causes damage to the cellular barrier and activates EdsRS to induce expression of a previously uncharacterized cardiolipin synthase, which we have named ClsT. Both EdsRS and ClsT are required for protection against targocil-dependent damage. Induction of clsT by EdsRS during targocil treatment results in an increase in cardiolipin levels, which protects B. anthracis from envelope damage. Together, these results reveal that a two-component system signaling response to an envelope-targeting antimicrobial induces production of a phospholipid associated with stabilization of the membrane.