Prognostic value of prostate circulating cells detection in prostate cancer patients: a prospective study

In clinically organ-confined prostate cancer patients, bloodstream tumour cell dissemination generally occurs, and may be enhanced by surgical prostate manipulation. To evaluate cancer-cell seeding impact upon patient recurrence-free survival, 155 patients were prospectively enrolled then followed. Here, 57 patients presented blood prostate cell shedding preoperatively and intraoperatively (group I). Of the 98 preoperatively negative patients, 53 (54%) remained negative (group II) and 45 (46%) became intraoperatively positive (group III). Median biological and clinical recurrence-free time was far shorter in group I (36.2 months, P<0.0001) than in group II (69.6 months) but did not significantly differ in group II and III (69.6 months vs 65.0). Such 5-year follow-up data show that preoperative circulating prostate cells are an independent prognosis factor of recurrence. Moreover, tumour handling induces cancer-cell seeding but surgical blood dissemination does not accelerate cancer evolution

Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p &lt; 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM &gt; 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM &gt; 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration: ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015

Elucidation of the ATP7B N-Domain Mg2+-ATP Coordination Site and Its Allosteric Regulation

The diagnostic of orphan genetic disease is often a puzzling task as less attention is paid to the elucidation of the pathophysiology of these rare disorders at the molecular level. We present here a multidisciplinary approach using molecular modeling tools and surface plasmonic resonance to study the function of the ATP7B protein, which is impaired in the Wilson disease. Experimentally validated in silico models allow the elucidation in the Nucleotide binding domain (N-domain) of the Mg2+-ATP coordination site and answer to the controversial role of the Mg2+ ion in the nucleotide binding process. The analysis of protein motions revealed a substantial effect on a long flexible loop branched to the N-domain protein core. We demonstrated the capacity of the loop to disrupt the interaction between Mg2+-ATP complex and the N-domain and propose a role for this loop in the allosteric regulation of the nucleotide binding process

In silico platform for xenobiotics ADME-T pharmacological properties modeling and prediction. Part I: Beyond the reduction of animal model use.

Contains fulltext : 80294.pdf (publisher's version ) (Closed access)There is an urgent need for efficient in silico ADME-T prediction tools for the selection of potent therapeutic drugs as well as the elimination of toxic compounds. This is particularly important in view of the high costs and ethical issues inherent to the use of animal models for drugs filtering. To achieve this mission, not only does the accuracy of in silico tools need to be improved, but also new experts in the field with skills in theoretical chemistry, clinical and fundamental biology have to be trained. Similarly, clinical biologists committed to the obligation of means and legally responsible for the results they generate could establish a legal framework that defines legal responsibilities when performing in silico predictions

Ablation of Serotonin 5-HT 2B

International audienceBackground-Identification of factors regulating myocardial structure and function is important to understand the pathogenesis of heart disease. Since little is known about the molecular mechanism of cardiac functions triggered by serotonin, the link between downstream signaling circuitry of its receptors and the heart physiology is of widespread interest. None of the serotonin receptor (5-HT 1A , 5-HT 1B , or 5-HT 2C) disruptions in mice have resulted in cardiovascular defects. In this study, we examined 5-HT 2B receptor mutant mice to assess the putative role of serotonin in heart structure and function. Methods and Results-We have generated Gq-coupled 5-HT 2B receptor null mice by homologous recombination. Surviving 5-HT 2B receptor mutant mice exhibit cardiomyopathy with a loss of ventricular mass due to a reduction in number and size of cardiomyocytes. This phenotype is intrinsic to cardiac myocytes. 5-HT 2B receptor mutant ventricles exhibit dilation and abnormal organization of contractile elements, including Zstripe enlargement and N-cadherin down regulation. Echocardiography and electrocardiography both confirm the presence of left ventricular dilatation and decreased systolic function in the adult 5-HT 2B receptor mutant mice. Conclusions-Mutation of 5-HT 2B receptor leads to a cardiomyopathy without hypertrophy and a disruption of intercalated discs. 5-HT 2B receptor is required for cytoskeleton assembly to membrane structures by regulating the N-cadherin expression. These results constitute, for the first time, strong genetic evidence that serotonin, via 5-HT 2B receptor, regulates cardiac structure and function

Imbalanced Angiogenesis in Peripartum Cardiomyopathy - Diagnostic Value of Placenta Growth Factor

BACKGROUND: Concentrations of the anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1) are altered in peripartum cardiomyopathy (PPCM). In this study we investigated changes in the angiogenesis balance in PPCM.Methods and Results:Plasma concentrations of sFlt-1 and the pro-angiogenic placenta growth factor (PlGF) were determined in patients with PPCM during the post-partum phase (n=83), in healthy women at delivery (n=30), and in patients with acute heart failure (AHF; n=65). Women with cardiac failure prepartum or associated with any form of hypertension, including pre-eclampsia, were excluded. Compared with non-pregnant women, in women with AHF and PPCM, median PlGF concentrations were greater (19 [IQR 16-22] and 98 [IQR 78-126] ng/mL, respectively; P0.94. Median plasma concentrations of the anti-angiogenic factor relaxin-2 were lower in PPCM and AHF (0.3 [IQR 0.3-1.7] and 0.3 [IQR 0.3-1] ng/mL, respectively) compared with normal deliveries (1,807 [IQR 1,101-4,050] ng/mL; P<0.001). CONCLUSIONS: Plasma of PPCM patients shows imbalanced angiogenesis. High PlGF and/or low sFlt-1/PlGF may be used to diagnose PPCM

Community-wide assessment of GPCR structure modelling and ligand docking: GPCR Dock 2008

With the recent breakthroughs in G protein-coupled receptor structure, one can now compare experimentally determined structures with the most recent modeling and docking methods. A community-wide blind prediction experiment (GPCR Dock 2008) was conducted in coordination with the publication of the human adenosine A2A receptor bound to the ligand ZM241385 crystal structure (Science 322, 1211 (2008)). Twenty-nine participating groups submitted 206 models that were evaluated for the accuracy of the ligand binding mode and the overall receptor model. Several new insights emerged including the critical importance of disulfide bonds in the extracellular loops, helix residue registry, and domain knowledge