A comparative analysis of biosimilar vs. originator filgrastim in combination with plerixafor for stem cell mobilization in lymphoma and multiple myeloma: a propensity-score weighted multicenter approach

The combination of biosimilar filgrastim and plerixafor appears to be at least equally and might be more effective as compared to originator filgrastim and plerixafor for stem cell mobilization in patients at high risk of mobilization failure. This data strongly support standard inclusion of biosimilar filgrastim in mobilizing protocols even in the challenging setting of patients who mobilize poorly, as significant cost saving seems to be accompanied by strong efficacy

Gene expression profile predicts response to the combination of tosedostat and low-dose cytarabine in elderly AML

Tosedostat is an orally administered metalloenzyme inhibitor with antiproliferative and antiangiogenic activity against hematological and solid human cancers. Clinical activity has been demonstrated in relapsed acutemyeloid leukemia (AML). Thirty-three elderly patients with AML (median age, 75 years) received 120mgtosedostat orally once daily combinedwith subcutaneous low-dose cytarabine (20 mg twice per day for 10 days, up to 8 cycles), until disease progression. Inductionmortality was 12%. According to an intention-to-treat analysis, the complete remission (CR) rate was 48.5%, and thus the primary end point of the study was reached (expected CR, 25%). The partial remission rate was 6.1%,with an overall response rate of 54.5%. Furthermore, 4 of 33 patients had stable disease (median: 286 days). Themedian progression-free survival and overall survival (OS)were 203 days and 222 days, respectively. Responding patients had a longer median OS than nonresponding patients (P=.001). Amicroarray analysis performed in 29 of 33 patients identified 188 genes associated with clinical response (CR vs no CR). Three of them (CD93, GORASP1, CXCL16) were validated by quantitative polymerase chain reaction, which correctly classified 83% of the patients. Specifically, CR achievement was efficiently predicted by the gene expression patterns, with an overall accuracy exceeding 90%. Finally, a negative predictive value of 100% was validated in an independent series, thus representing the first molecular predictor for clinical response to a specific combination drug treatment for AML

Post-weaning A1/A2 β-casein milk intake modulates depressive-like behavior, brain μ-opioid receptors, and the metabolome of rats

The postnatal period is critical for brain and behavioral development and is sensitive to environmental stimuli, such as nutrition. Prevention of weaning from maternal milk was previously shown to cause depressive-like behavior in rats. Additionally, loss of dietary casein was found to act as a developmental trigger for a population of brain opioid receptors. Here, we explore the effect of exposure to milk containing A1 and A2 β-casein beyond weaning. A1 but not A2 β-casein milk significantly increased stress-induced immobility in rats, concomitant with an increased abundance of Clostridium histolyticum bacterial group in the caecum and colon of A1 β-casein fed animals, brain region-specific alterations of μ-opioid and oxytocin receptors, and modifications in urinary biochemical profiles. Moreover, urinary gut microbial metabolites strongly correlated with altered brain metabolites. These findings suggest that consumption of milk containing A1 β-casein beyond weaning age may affect mood via a possible gut-brain axis mechanism

Steps towards the hyperfine splitting measurement of the muonic hydrogen ground state: pulsed muon beam and detection system characterization

The high precision measurement of the hyperfine splitting of the muonic-hydrogen atom ground state with pulsed and intense muon beam requires careful technological choices both in the construction of a gas target and of the detectors. In June 2014, the pressurized gas target of the FAMU experiment was exposed to the low energy pulsed muon beam at the RIKEN RAL muon facility. The objectives of the test were the characterization of the target, the hodoscope and the X-ray detectors. The apparatus consisted of a beam hodoscope and X-rays detectors made with high purity Germanium and Lanthanum Bromide crystals. In this paper the experimental setup is described and the results of the detector characterization are presented.Comment: 22 pages, 14 figures, published and open access on JINS

Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: outcome of the patients alive after a 6-year follow-up

Background Imatinib mesylate is the first line treatment for chronic myeloid leukemia. In patients with advanced phase of the disease, the advent of imatinib significantly increased survival. However, few long-term data, based on large, prospective and controlled trials are available on the outcome of these patients. Design and Methods We conducted a phase II trial of imatinib 600 mg daily in patients with chronic myeloid leukemia in blast crisis. The return to chronic phase was defined as <15% blasts and <30% blasts plus promyelocytes in blood or bone marrow and <20% peripheral basophils. A complete hematologic response required the normalization of platelet and white cell differential counts and absence of extramedullary involvement. Cytogenetic response was assessed by the standard banding technique and rated as usual. Results Ninety-two patients were enrolled (20 with lymphoid blast crisis and 72 with myeloid blast crisis). Forty-six patients (50%) returned to chronic phase, and 24 patients (26%) achieved also a complete hematologic response. Sixteen patients (17%) had a cytogenetic response (9 complete, 1 partial, and 6 minor or minimal). The complete cytogenetic response was subsequently lost by all but two patients between 2 and 12 months after first having achieved it: the median duration of complete cytogenetic response was 7 months. All responses were sustained for a minimum of 4 weeks. The median survival of all the patients was 7 months. After a median observation time of 66 months, seven (8%) patients are alive. Three of these patients are on imatinib treatment (1 in complete hematologic remission, 1 in partial cytogenetic response and 1 in complete cytogenetic remission). Three patients are in complete remission after allogeneic stem cell transplantation. One patient is alive in blast crisis, on therapy with a second-generation tyrosine kinase inhibitor. Conclusions Imatinib was effective and safe in the short-term treatment of chronic myeloid leukemia in blast crisis, but longer-term outcome was not significantly influenced (ClinicalTrials.gov identifier: [NCT00514969][1]). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00514969&atom=%2Fhaematol%2F93%2F12%2F1792.ato

Characterization of the VEGA ASIC coupled to large area position-sensitive Silicon Drift Detectors

Low-noise, position-sensitive Silicon Drift Detectors (SDDs) are particularly useful for experiments in which a good energy resolution combined with a large sensitive area is required, as in the case of X-ray astronomy space missions and medical applications. This paper presents the experimental characterization of VEGA, a custom Application Specific Integrated Circuit (ASIC) used as the front-end electronics for XDXL-2, a large-area (30.5 cm^2) SDD prototype. The ASICs were integrated on a specifically developed PCB hosting also the detector. Results on the ASIC noise performances, both stand-alone and bonded to the large area SDD, are presented and discussed.Comment: 15 pages, 11 figures. Accepted for publication in Journal of Instrumentation (JINST

FAMU: study of the energy dependent transfer rate \u39b \u3bcp \u2192 \u3bcO

The main goal of the FAMU experiment is the measurement of the hyperfine splitting (hfs) in the 1S state of muonic hydrogen \u394Ehfs (\u3bc - p)1S. The physical process behind this experiment is the following: \u3bcp are formed in a mixture of hydrogen and a higher-Z gas. When absorbing a photon at resonance-energy \u394Ehfs 48 0.182 eV, in subsequent collisions with the surrounding H 2 molecules, the \u3bcp is quickly de-excited and accelerated by ~ 2/3 of the excitation energy. The observable is the time distribution of the K-lines X-rays emitted from the \u3bcZ formed by muon transfer (\u3bcp) + Z \u2192 (\u3bcZ)* + p, a reaction whose rate depends on the \u3bcp kinetic energy. The maximal response, to the tuned laser wavelength, of the time distribution of X-ray from K-lines of the (\u3bcZ)* cascade indicate the resonance. During the preparatory phase of the FAMU experiment, several measurements have been performed both to validate the methodology and to prepare the best configuration of target and detectors for the spectroscopic measurement. We present here the crucial study of the energy dependence of the transfer rate from muonic hydrogen to oxygen (\u39b \u3bcp \u2192 \u3bc0 ), precisely measured for the first time

First FAMU observation of muon transfer from \u3bcp atoms to higher-Z elements

Abstract: The FAMU experiment aims to accurately measure the hyperfine splitting of the ground state of the muonic hydrogen atom. A measurement of the transfer rate of muons from hydrogen to heavier gases is necessary for this purpose. In June 2014, within a preliminary experiment, a pressurized gas-target was exposed to the pulsed low-energy muon beam at the RIKEN RAL muon facility (Rutherford Appleton Laboratory, U.K.). The main goal of the test was the characterization of both the noise induced by the pulsed beam and the X-ray detectors. The apparatus, to some extent rudimental, has served admirably to this task. Technical results have been published that prove the validity of the choices made and pave the way for the next steps. This paper presents the results of physical relevance of measurements of the muon transfer rate to carbon dioxide, oxygen, and argon from non-thermalized excited \u3bcp atoms. The analysis methodology and the approach to the systematics errors are useful for the subsequent study of the transfer rate as function of the kinetic energy of the \u3bcp currently under way

First administration to man of Org 25435, an intravenous anaesthetic: A Phase 1 Clinical Trial

BACKGROUND: Org 25435 is a new water-soluble alpha-amino acid ester intravenous anaesthetic which proved satisfactory in animal studies. This study aimed to assess the safety, tolerability and efficacy of Org 25435 and to obtain preliminary pharmacodynamic and pharmacokinetic data. METHODS: In the Short Infusion study 8 healthy male volunteers received a 1 minute infusion of 0.25, 0.5, 1.0, or 2.0 mg/kg (n = 2 per group); a further 10 received 3.0 mg/kg (n = 5) or 4.0 mg/kg (n = 5). Following preliminary pharmacokinetic modelling 7 subjects received a titrated 30 minute Target Controlled Infusion (TCI), total dose 5.8-20 mg/kg. RESULTS: Within the Short Infusion study, all subjects were successfully anaesthetised at 3 and 4 mg/kg. Within the TCI study 5 subjects were anaesthetised and 2 showed signs of sedation. Org 25435 caused hypotension and tachycardia at doses over 2 mg/kg. Recovery from anaesthesia after a 30 min administration of Org 25435 was slow (13.7 min). Pharmacokinetic modelling suggests that the context sensitive half-time of Org 25435 is slightly shorter than that of propofol in infusions up to 20 minutes but progressively longer thereafter. CONCLUSIONS: Org 25435 is an effective intravenous anaesthetic in man at doses of 3 and 4 mg/kg given over 1 minute. Longer infusions can maintain anaesthesia but recovery is slow. Hypotension and tachycardia during anaesthesia and slow recovery of consciousness after cessation of drug administration suggest this compound has no advantages over currently available intravenous anaesthetics