A Human Monoclonal Antibody with Neutralizing Activity against Highly Divergent Influenza Subtypes

The interest in broad-range anti-influenza A monoclonal antibodies (mAbs) has recently been strengthened by theidentification of anti-hemagglutinin (HA) mAbs endowed with heterosubtypic neutralizing activity to be used in the designof ‘‘universal’’ prophylactic or therapeutic tools. However, the majority of the single mAbs described to date do not bindand neutralize viral isolates belonging to highly divergent subtypes clustering into the two different HA-based influenzaphylogenetic groups: the group 1 including, among others, subtypes H1, H2, H5 and H9 and the group 2 including, amongothers, H3 subtype. Here, we describe a human mAb, named PN-SIA28, capable of binding and neutralizing all testedisolates belonging to phylogenetic group 1, including H1N1, H2N2, H5N1 and H9N2 subtypes and several isolates belongingto group 2, including H3N2 isolates from the first period of the 1968 pandemic. Therefore, PN-SIA28 is capable ofneutralizing isolates belonging to subtypes responsible of all the reported pandemics, as well as other subtypes withpandemic potential. The region recognized by PN-SIA28 has been identified on the stem region of HA and includes residueshighly conserved among the different influenza subtypes. A deep characterization of PN-SIA28 features may represent auseful help in the improvement of available anti-influenza therapeutic strategies and can provide new tools for thedevelopment of universal vaccinal strategies

The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia

Cytarabine (ara-C) is the most effective agent for the treatment of acute myeloid leukaemia (AML). Aberrant expression of enzymes involved in the transport/metabolism of ara-C could explain drug resistance. We determined mRNA expression of these factors using quantitative-real-time-PCR in leukemic blasts from children diagnosed with de novo AML. Expression of the inactivating enzyme pyrimidine nucleotidase-I (PN-I) was 1.8-fold lower in FAB-M5 as compared to FAB-M1/2 (P=0.007). In vitro sensitivity to deoxynucleoside analogues was determined using the MTT-assay. Human equilibrative nucleoside transporter-1 (hENT1) mRNA expression and ara-C sensitivity were significantly correlated (rp=−0.46; P=0.001), with three-fold lower hENT1 mRNA levels in resistant patients (P=0.003). hENT1 mRNA expression also seemed to correlate inversely with the LC50 values of cladribine (rp=−0.30; P=0.04), decitabine (rp=−0.29; P=0.04) and gemcitabine (rp=−0.33; P=0.02). Deoxycytidine kinase (dCK) and cytidine deaminase (CDA) mRNA expression seemed to correlate with in vitro sensitivity to gemcitabine (rp=−0.31; P=0.03) and decitabine (rp=0.33; P=0.03), respectively. The dCK/PN-I ratio correlated inversely with LC50 values for gemcitabine (rp=−0.45, P=0.001) and the dCK/CDA ratio seemed to correlate with LC50 values for decitabine (rp=−0.29; 0.04). In conclusion, decreased expression of hENT1, which transports ara-C across the cell membrane, appears to be a major factor in ara-C resistance in childhood AML

Strong vacuum squeezing from bichromatically driven Kerrlike cavities: from optomechanics to superconducting circuits

Squeezed light, displaying less fluctuation than vacuum in some observable, is key in the flourishing field of quantum technologies. Optical or microwave cavities containing a Kerr nonlinearity are known to potentially yield large levels of squeezing, which have been recently observed in optomechanics and nonlinear superconducting circuit platforms. Such Kerr-cavity squeezing however suffers from two fundamental drawbacks. First, optimal squeezing requires working close to turning points of a bistable cycle, which are highly unstable against noise thus rendering optimal squeezing inaccessible. Second, the light field has a macroscopic coherent component corresponding to the pump, making it less versatile than the so-called squeezed vacuum, characterised by a null mean field. Here we prove analytically and numerically that the bichromatic pumping of optomechanical and superconducting circuit cavities removes both limitations. This finding should boost the development of a new generation of robust vacuum squeezers in the microwave and optical domains with current technology

A Randomized Controlled Phase IIb Trial of Antigen-Antibody Immunogenic Complex Therapeutic Vaccine in Chronic Hepatitis B Patients

BACKGROUND: The safety of the immune complexes composed of yeast-derived hepatitis B surface antigen (HBsAg) and antibodies (abbreviated as YIC) among healthy adults and chronic hepatitis B patients has been proved in phase I and phase IIa trial. A larger number of patients for study of dosage and efficacy are therefore needed. METHODS AND PRINCIPAL FINDINGS: Two hundred forty two HBeAg-positive chronic hepatitis B patients were immunized with six injections of either 30 microg YIC, 60 microg of YIC or alum adjuvant as placebo at four-week intervals under code. HBV markers and HBV DNA were monitored during immunization and 24 weeks after the completion of immunization. The primary endpoint was defined as loss of HBeAg, or presence of anti-HBe antibody or suppression of HBV DNA, while the secondary endpoint was both HBeAg seroconversion and suppression of HBV DNA. Statistical significance was not reached in primary endpoints four weeks after the end of treatment among three groups, however, at the end of follow-up, HBeAg sero-conversion rate was 21.8% (17/78) and 9% (7/78) in the 60 microg YIC and placebo groups respectively (p = 0.03), with 95% confidence intervals at 1.5% to 24.1%. Using generalized estimating equations (GEEs) model, a significant difference of group effects was found between 60 microg YIC and the placebo groups in terms of the primary endpoint. Eleven serious adverse events occurred, which were 5.1%, 3.6%, and 5.0% in the placebo, 30 microg YIC and 60 microg YIC groups respectively (p>0.05). CONCLUSIONS: Though statistical differences in the preset primary and secondary endpoints among the three groups were not reached, a late and promising HBeAg seroconversion effect was shown in the 60 microg YIC immunized regimen. By increasing the number of patients and injections, the therapeutic efficacy of YIC in chronic hepatitis B patients will be further evaluated. TRIAL REGISTRATION: ChiCTR.org ChiCTR-TRC-00000022

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Repair of Parastomal Hernias with Biologic Grafts: A Systematic Review

Contains fulltext : 98303.pdf (publisher's version ) (Open Access)BACKGROUND: Biologic grafts are increasingly used instead of synthetic mesh for parastomal hernia repair due to concerns of synthetic mesh-related complications. This systematic review was designed to evaluate the use of these collagen-based scaffolds for the repair of parastomal hernias. METHODS: Studies were retrieved after searching the electronic databases MEDLINE, EMBASE and Cochrane CENTRAL. The search terms 'paracolostomy', 'paraileostomy', 'parastomal', 'colostomy', 'ileostomy', 'hernia', 'defect', 'closure', 'repair' and 'reconstruction' were used. Selection of studies and assessment of methodological quality were performed with a modified MINORS index. All reports on repair of parastomal hernias using a collagen-based biologic scaffold to reinforce or bridge the defect were included. Outcomes were recurrence rate, mortality and morbidity. RESULTS: Four retrospective studies with a combined enrolment of 57 patients were included. Recurrence occurred in 15.7% (95% confidence interval [CI] 7.8-25.9) of patients and wound-related complications in 26.2% (95% CI 14.7-39.5). No mortality or graft infections were reported. CONCLUSIONS: The use of reinforcing or bridging biologic grafts during parastomal hernia repair results in acceptable rates of recurrence and complications. However, given the similar rates of recurrence and complications achieved using synthetic mesh in this scenario, the evidence does not support use of biologic grafts

Colour terms affect detection of colour and colour-associated objects suppressed from visual awareness

The idea that language can affect how we see the world continues to create controversy. A potentially important study in this field has shown that when an object is suppressed from visual awareness using continuous flash suppression (a form of binocular rivalry), detection of the object is differently affected by a preceding word prime depending on whether the prime matches or does not match the object. This may suggest that language can affect early stages of vision. We replicated this paradigm and further investigated whether colour terms likewise influence the detection of colours or colour-associated object images suppressed from visual awareness by continuous flash suppression. This method presents rapidly changing visual noise to one eye while the target stimulus is presented to the other. It has been shown to delay conscious perception of a target for up to several minutes. In Experiment 1 we presented greyscale photos of objects. They were either preceded by a congruent object label, an incongruent label, or white noise. Detection sensitivity (d’) and hit rates were significantly poorer for suppressed objects preceded by an incongruent label compared to a congruent label or noise. In Experiment 2, targets were coloured discs preceded by a colour term. Detection sensitivity was significantly worse for suppressed colour patches preceded by an incongruent colour term as compared to a congruent term or white noise. In Experiment 3 targets were suppressed greyscale object images preceded by an auditory presentation of a colour term. On congruent trials the colour term matched the object’s stereotypical colour and on incongruent trials the colour term mismatched. Detection sensitivity was significantly poorer on incongruent trials than congruent trials. Overall, these findings suggest that colour terms affect awareness of coloured stimuli and colour- associated objects, and provide new evidence for language-perception interaction in the brain

Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases

Background:This multi-centre phase II clinical trial is the first prospective evaluation of radioembolisation of patients with colorectal liver metastases (mCRC) who failed previous oxaliplatin-and irinotecan-based systemic chemotherapy regimens.Methods:Eligible patients had adequate hepatic, haemopoietic and renal function, and an absence of major hepatic vascular anomalies and hepato-pulmonary shunting. Gastroduodenal and right gastric arteries were embolised before hepatic arterial administration of yttrium-90 resin microspheres (median activity, 1.7 GBq; range, 0.9-2.2).Results:Of 50 eligible patients, 38 (76%) had received 654 lines of chemotherapy. Most presented with synchronous disease (72%), <4 hepatic metastases (58%), 25-50% replacement of total liver volume (60%) and bilateral spread (70%). Early and intermediate (<48 h) WHO G1-2 adverse events (mostly fever and pain) were observed in 16 and 22% of patients respectively. Two died due to renal failure at 40 days or liver failure at 60 days respectively. By intention-to-treat analysis using Response Evaluation Criteria in Solid Tumours, 1 patient (2%) had a complete response, 11 (22%) partial response, 12 (24%) stable disease, 22 (44%) progressive disease; 4 (8%) were non-evaluable. Median overall survival was 12.6 months (95% CI, 7.0-18.3); 2-year survival was 19.6%.Conclusion: Radioembolisation produced meaningful response and disease stabilisation in patients with advanced, unresectable and chemorefractory mCRC. \ua9 2010 Cancer Research UK All rights reserved