Gamma-hydroxybutyrate (GHB) for prevention and treatment of alcohol withdrawal

This is the protocol for a review and there is no abstract. The objectives are as follows: To evaluate the efficacy and safety of GHB in prevention and treatment of the AWS, more specifically • to compare the efficacy of GHB with placebo or other drugs; • to identify the most effective GHB dosage and schedules; • to estimate the incidence of side effects; • to carry out a risk-benefit analysis

Role of Gas6 and TAM Receptors in the Identification of Cardiopulmonary Involvement in Systemic Sclerosis and Scleroderma Spectrum Disorders

Background: Few biomarkers are available for early identification of pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) in systemic sclerosis (SS) and scleroderma spectrum disorders (SSD). Aims: To evaluate Gas6, sAxl, and sMer as biomarkers for cardiopulmonary complications of SS and SSD. Methods: In a cross-sectional observational study, we recruited 125 consecutive patients, affected by SS and SSD and referred to a tertiary-level pulmonary hypertension outpatient clinic. All patients underwent a comprehensive evaluation for identification of PAH and ILD. Gas6, sMer, and sAxl concentrations were measured with ELISA protocols, and concentrations were compared according to PAH or ILD. Results: Nineteen subjects had pulmonary hypertension (PH) (14 PAH), and 39 had ILD (6 severe). Plasma sMer was increased in PAH (18.6 ng/ml IQR [11.7-20.3]) with respect to the absence (12.4 [8.0-15.8]) or other form of pulmonary hypertension (9.6 [7.4-12.5]; K-W variance p < 0.04). Conversely, Gas6 and sAxl levels were slightly increased in mild ILD (25.8 ng/ml [19.5-32.1] and 24.6 [20.1-32.5]) and reduced in severe ILD (16.6 [15.0-22.1] and 15.5 [14.9-22.4]) in comparison to no evidence of ILD (23.4 [18.8-28.1] and 21.6 [18.1-28.4]; K-W, p 64 0.05). Plasma sMer 65 19 ng/ml has 50% sensitivity and 92% specificity in PAH identification (area under the ROC curve (AUC) 0.697, p < 0.03). Values of Gas6 64 24.5 ng/ml and of sAxl 64 15.5 ng/ml have 100% and 67% sensitivity and 47% and 86% specificity, respectively, in identifying severe ILD (Gas6 AUC 0.787, p < 0.001; sAxl AUC 0.705, p < 0.05). Conclusions: The assay of Gas6 sAxl and sMer may be useful to help in the identification of PAH and ILD in SS and SSD patients. The Gas6/TAM system seems to be relevant in cardiopulmonary complications of SS and SSD and merits further investigations

Recurrent growth factor starvation promotes drug resistance in human leukaemic cells

Multi-drug resistance can be induced by various environmental stresses including an exposure to chemical drugs and X-ray irradiation. In addition, hypo-nutritive conditions are known to promote multi-drug resistance in solid tumours. To understand the importance of nutritive conditions in the development of drug resistance in non-solid tumours and to know whether a transient malnutrition could induce a permanent reduction in drug sensitivity, leukaemic cells were transiently cultured under growth factor-starved conditions. Granulocyte-macrophage colony-stimulating factor-dependent human leukaemic MO7e cells were cultured in the absence of granulocyte-macrophage colon-stimulating factor for 2 weeks, during which the majority of the cells died, and the minor viable cells were expanded in the presence of granulocyte-macrophage colon-stimulating factor for following 1 week. This procedure was repeated three times, and the surviving cells were cloned by limiting dilution. These clones underwent G1 arrest in the absence of granulocyte-macrophage colon-stimulating factor, while parental cells underwent apoptosis. Interestingly, activities of the downstream targets of granulocyte-macrophage colon-stimulating factor receptor were regulated in a granulocyte-macrophage colon-stimulating factor-independent manner, indicating that the ligand-independent activation of granulocyte-macrophage colon-stimulating factor receptor had not taken place. Moreover, the 4–7-fold increases in IC50 for etoposide and the 2–6-fold increase in IC90 for doxorubicin was observed. Furthermore, Bcl-2 protein expression was significantly up-regulated in the clones while no significant changes in Bax, Bcl-xL, P-glycoprotein and Hsp70 protein expression and no consistent changes in p53 expression were detected. We propose that recurrent growth factor starvation, which may occur in vivo when stromal function is damaged after intensive chemotherapy or bone marrow occupation by malignant cells, causes selection of drug resistant leukaemia cells that will expand when the growth factor supply recovers

Change over time of COVID-19 hospital presentation in Northern Italy

none40After the first autochthonous case described on February 19, also in Italy the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARSCoV-2) infection rapidly circulated, mainly in the Northern regions of the country. The earliest reports on Coronavirus disease-19 (COVID-19) have described worldwide a high prevalence of severe respiratory illness [1]. A suggestive feature of COVID-19 has been a rapid progression of the respiratory impairment, leading to acute respiratory distress syndrome (ARDS) and often requiring ventilation support [2]. To date, whether clinical features at hospital presentation and outcome of COVID-19 have changed over the outbreak course is unknown. We explored this issue in a multicenter cohort of patients hospitalized for COVID-19 in Northern Italy.mixedPatti G.; Mennuni M.; Della Corte F.; Spinoni E.; Sainaghi P. P.; COVID-UPO Clinical Team; Azzolina D; Hayden E; Rognon A; Grisafi L; Colombo C; Lio V; Pirisi M; Vaschetto R; Aimaretti G; Krengli M; Avanzi GC; Balbo PE; Capponi A; Castello LM; Bellan M; Malerba M; Garavelli PL; Zeppegno P; Savoia P; Chichino G; Olivieri C; Re R; Maconi A; Comi C; Roveta A; Bertolotti M; Carriero A; Betti M; Mussa M; Borrè S; Cantaluppi V; Cantello R; Bobbio F; GavellI F.Patti, G.; Mennuni, M.; Della Corte, F.; Spinoni, E.; Sainaghi, P. P.; COVID-UPO Clinical, Team; Azzolina, D; Hayden, E; Rognon, A; Grisafi, L; Colombo, C; Lio, V; Pirisi, M; Vaschetto, R; Aimaretti, G; Krengli, M; Avanzi, Gc; Balbo, Pe; Capponi, A; Castello, Lm; Bellan, M; Malerba, M; Garavelli, Pl; Zeppegno, P; Savoia, P; Chichino, G; Olivieri, C; Re, R; Maconi, A; Comi, C; Roveta, A; Bertolotti, M; Carriero, A; Betti, M; Mussa, M; Borrè, S; Cantaluppi, V; Cantello, R; Bobbio, F; Gavelli, F

Prolonged Exposure to a Mer Ligand in Leukemia: Gas6 Favors Expression of a Partial Mer Glycoform and Reveals a Novel Role for Mer in the Nucleus

Mer tyrosine kinase is ectopically expressed in acute lymphoblastic leukemia and associated with enhanced chemoresistance and disease progression. While such effects are generally ascribed to increased engagement of oncogenic pathways downstream of Mer stimulation by its ligand, Gas6, Mer has not been characterized beyond the scope of its signaling activity. The present study explores Mer behavior following prolonged exposure to Gas6, a context similar to the Gas6-enriched microenvironment of the bone marrow, where a steady supply of ligand facilitates continuous engagement of Mer and likely sustains the presence of leukemic cells. Long-term Gas6 exposure induced production of a partially N-glycosylated form of Mer from newly synthesized stores of protein. Preferential expression of the partial Mer glycoform was associated with diminished levels of Mer on the cell surface and altered Mer localization within the nuclear-soluble and chromatin-bound fractions. The presence of Mer in the nucleus is a novel finding for this receptor, and the glycoform-specific preferences observed in each nuclear compartment suggest that glycosylation may influence Mer function within particular subcellular locales. Previous studies have established Mer as an attractive cancer biologic target, and understanding the complexity of its activity has important implications for potential strategies of Mer inhibition in leukemia therapy. Our results identify several novel features of Mer that expand the breadth of its functions and impact the development of therapeutic modalities designed to target Mer

Identification of proteins involved in neural progenitor cell targeting of gliomas

<p>Abstract</p> <p>Background</p> <p>Glioblastoma are highly aggressive tumors with an average survival time of 12 months with currently available treatment. We have previously shown that specific embryonic neural progenitor cells (NPC) have the potential to target glioma growth in the CNS of rats. The neural progenitor cell treatment can cure approximately 40% of the animals with malignant gliomas with no trace of a tumor burden 6 months after finishing the experiment. Furthermore, the NPCs have been shown to respond to signals from the tumor environment resulting in specific migration towards the tumor. Based on these results we wanted to investigate what factors could influence the growth and progression of gliomas in our rodent model.</p> <p>Methods</p> <p>Using microarrays we screened for candidate genes involved in the functional mechanism of tumor inhibition by comparing glioma cell lines to neural progenitor cells with or without anti-tumor activity. The expression of candidate genes was confirmed at RNA level by quantitative RT-PCR and at the protein level by Western blots and immunocytochemistry. Moreover, we have developed <it>in vitro </it>assays to mimic the antitumor effect seen <it>in vivo</it>.</p> <p>Results</p> <p>We identified several targets involved in glioma growth and migration, specifically CXCL1, CD81, TPT1, Gas6 and AXL proteins. We further showed that follistatin secretion from the NPC has the potential to decrease tumor proliferation. <it>In vitro </it>co-cultures of NPC and tumor cells resulted in the inhibition of tumor growth. The addition of antibodies against proteins selected by gene and protein expression analysis either increased or decreased the proliferation rate of the glioma cell lines <it>in vitro</it>.</p> <p>Conclusion</p> <p>These results suggest that these identified factors might be useful starting points for performing future experiments directed towards a potential therapy against malignant gliomas.</p

Are correlations real or imagined?

Actuaries Benjamin Avanzi, Greg Taylor and Bernard Wong challenge preconceptions regarding the high level of dependence between general insurance claims from different classes. Using real life data, they show how more detailed analyses can often reveal systemic effects, such as weather events or seasonality, which can account for much of the observed correlation, leaving much lower levels of residual correlation