Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia.

In this study, we randomly compared high doses of the tyrosine kinase inhibitor imatinib combined with reduced-intensity chemotherapy (arm A) to standard imatinib/hyperCVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) therapy (arm B) in 268 adults (median age, 47 years) with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The primary objective was the major molecular response (MMolR) rate after cycle 2, patients being then eligible for allogeneic stem cell transplantation (SCT) if they had a donor, or autologous SCT if in MMolR and no donor. With fewer induction deaths, the complete remission (CR) rate was higher in arm A than in arm B (98% vs 91%; P = .006), whereas the MMolR rate was similar in both arms (66% vs 64%). With a median follow-up of 4.8 years, 5-year event-free survival and overall survival (OS) rates were estimated at 37.1% and 45.6%, respectively, without difference between the arms. Allogeneic transplantation was associated with a significant benefit in relapse-free survival (hazard ratio [HR], 0.69; P = .036) and OS (HR, 0.64; P = .02), with initial white blood cell count being the only factor significantly interacting with this SCT effect. In patients achieving MMolR, outcome was similar after autologous and allogeneic transplantation. This study validates an induction regimen combining reduced-intensity chemotherapy and imatinib in Ph+ ALL adult patients and suggests that SCT in first CR is still a good option for Ph+ ALL adult patients. This trial was registered at www.clinicaltrials.gov as #NCT00327678.

Fiscal sustainability and fiscal shocks in a dollarized and oil-exporting country: Ecuador

This paper investigates the fiscal sustainability of an emerging, dollarized, oil-exporting country: Ecuador. A cointegrated VAR approach is adopted in testing, first, if the intertemporal budget constraint is satisfied in Ecuador and, second, in identifying the permanent and transitory shocks that affect a fiscal policy characterized by inertia and a heavy dependence on oil revenues. Following confirmation that the debt-GDP ratio does not place the Ecuadorian budget under any pressure, we reformulate the model and identify two forces that push the fiscal system out of equilibrium, namely, economic activity and oil revenues implemented in the government budget. We argue that Ecuador needs to recover control of its monetary policy and to promote the diversification of its economy in order that non-oil tax revenues can replace oil revenues as a pushing force. Finally, we calculate quarterly elasticities of tax revenues with respect to Ecuador’s GDP and that of eight Eurozone countries. We illustrate graphically how the Eurozone countries with low positive or high negative elasticities’ levels suffer debt problems after the crisis. This finding emphasizes the pressing need for Ecuador to strengthen the connection between its tax revenues and output, and also suggests that the convergence of these elasticities in the Eurozone might contribute to the success of an eventually future fiscal union.

Effects of business-to-business customer orientation, satisfaction and retention on firm profitability

The objective of this master’s thesis was to examine the effect of customer orientation on customer satisfaction and how customer satisfaction and customer retention contribute to firm profitability. Beside customer orientation, also other antecedents of customer satisfaction, i.e. service quality, flexibility, trust and commitment, were investigated as control variables. Literature review revealed several research gaps concerning research of the key concepts. These research calls were also answered. The empirical study focused on one case company, a telecommunication expert. The data for the empirical part was collected with web-based questionnaire from case company’s business customers in January-February 2008. Sample (N=95) produced 59 answers, thus the response rate of the survey was 62,1%. The data was analyzed by using statistical analysis program, SPSS. As a conclusion, the results indicate that customer orientation do not affect customer satisfaction directly, but through service quality, flexibility and trust. Moreover, customer satisfaction has positive impacts on commitment and intentions to stay as a customer in the future, but not on profitability. In the present study, only past purchase behavior, measured with customer database measure, is positively related to firm profitability.

Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver.

Diurnal oscillations of gene expression are a hallmark of rhythmic physiology across most living organisms. Such oscillations are controlled by the interplay between the circadian clock and feeding rhythms. Although rhythmic mRNA accumulation has been extensively studied, comparatively less is known about their transcription and translation. Here, we quantified simultaneously temporal transcription, accumulation, and translation of mouse liver mRNAs under physiological light-dark conditions and ad libitum or night-restricted feeding in WT and brain and muscle Arnt-like 1 (Bmal1)-deficient animals. We found that rhythmic transcription predominantly drives rhythmic mRNA accumulation and translation for a majority of genes. Comparison of wild-type and Bmal1 KO mice shows that circadian clock and feeding rhythms have broad impact on rhythmic gene expression, Bmal1 deletion affecting surprisingly both transcriptional and posttranscriptional levels. Translation efficiency is differentially regulated during the diurnal cycle for genes with 5'-Terminal Oligo Pyrimidine tract (5'-TOP) sequences and for genes involved in mitochondrial activity, many harboring a Translation Initiator of Short 5'-UTR (TISU) motif. The increased translation efficiency of 5'-TOP and TISU genes is mainly driven by feeding rhythms but Bmal1 deletion also affects amplitude and phase of translation, including TISU genes. Together this study emphasizes the complex interconnections between circadian and feeding rhythms at several steps ultimately determining rhythmic gene expression and translation.

How differential management strategies affect Ips typographus L. dispersal

Bark beetle outbreaks have a devastating effect on economically important forests worldwide, thus requiring extensive application of management control strategies. The presence of unmanaged protected areas in close proximity to managed forests can instigate concerns that bark beetle infestations may spread from unmanaged into managed stands. We studied the impact of differential management of forest stands on the dispersal dynamics of the European spruce bark beetle, Ips typographus, making use of inferential population genetics on mitochondrial and nuclear genomes. Bayesian inferences of migration rates and a most parsimonious dispersal tree show that outgoing gene flow was consistently higher from managed to unmanaged areas. Reason for that is likely the thorough removal of potential breeding material in managed forests and thus the dispersal of the base stock beetles from these areas to unmanaged areas where breeding material is available. Our study suggests that the potential threat posed by unmanaged to managed forests in regard to I. typographus infestation needs to be carefully re-considered.

Randomised, multicentre, phase III, open-label study of alectinib vs crizotinib in treatment-naïve anaplastic lymphoma kinase (ALK)-positive advanced NSCLC (ALEX study).

Background: In ∼5% of advanced NSCLC tumours, ALK tyrosine kinase is constitutively activated after translocation of ALK. ALK+ NSCLC was shown to be highly sensitive to the first approved ALK inhibitor, crizotinib. However, all pts eventually relapse on crizotinib mainly due to secondary ALK mutations/amplification or CNS metastases. Alectinib is a highly selective, potent, oral next-generation ALK inhibitor. Clinical phase II alectinib data in 46 crizotinib-naïve pts with ALK+ NSCLC reported an objective response rate (ORR) of 93.5% and a 1-year progression-free rate of 83% (95% CI: 68-92) (Inoue et al. J Thorac Oncol 2013). CNS activity was seen: of 14 pts with baseline brain metastasis, 11 had prior CNS radiation, 9 of these experienced CNS and systemic PFS of >12 months; of the 3 pts without prior CNS radiation, 2 were >15 months progression free. Trial design: Randomised, multicentre, phase III, open-label study in pts with treatment-naïve ALK+ advanced, recurrent, or metastatic NSCLC. All pts must provide pretreatment tumour tissue to confirm ALK rearrangement (by IHC). Pts (∼286 from ∼180 centres, ∼30 countries worldwide) will be randomised to alectinib (600mg oral bid, with food) or crizotinib (250mg oral bid, with/without food) until disease progression (PD), unacceptable toxicity, withdrawal of consent, or death. Stratification factors are: ECOG PS (0/1 vs 2), race (Asian vs non-Asian), baseline CNS metastases (yes vs no). Primary endpoint: PFS by investigators (RECIST v1.1). Secondary endpoints: PFS by Independent Review Committee (IRC); ORR; duration of response; OS; safety; pharmacokinetics; quality of life. Additionally, time to CNS progression will be evaluated (MRI) for the first time in a prospective randomised NSCLC trial as a secondary endpoint. Pts with isolated asymptomatic CNS progression will be allowed to continue treatment beyond documented progression until systemic PD and/or symptomatic CNS progression, according to investigator opinion. Time to CNS progression will be retrospectively assessed by the IRC using two separate criteria, RECIST and RANO. Further details: ClinicalTrials.gov (NCT02075840). Disclosure: T.S.K. Mok: Advisory boards: AZ, Roche, Eli Lilly, Merck Serono, Eisai, BMS, AVEO, Pfizer, Taiho, Boehringer Ingelheim, Novartis, GSK Biologicals, Clovis Oncology, Amgen, Janssen, BioMarin; board of directors: IASLC; corporate sponsored research: AZ; M. Perol: Advisory boards: Roche; S.I. Ou: Consulting: Pfizer, Chugai, Genentech Speaker Bureau: Pfizer, Genentech, Boehringer Ingelheim; I. Bara: Employee: F. Hoffmann-La Roche Ltd; V. Henschel: Employee and stock: F. Hoffmann-La Roche Ltd.; D.R. Camidge: Honoraria: Roche/Genentech. All other authors have declared no conflicts of interest.

Overspeed HIIT in Lower-Body Positive Pressure Treadmill Improves Running Performance.

PURPOSE: Optimal high-intensity interval training (HIIT) regimens for running performance are unknown, although most protocols result in some benefit to key performance factors (running economy (RE), anaerobic threshold (AT), or maximal oxygen uptake (V˙O2max)). Lower-body positive pressure (LBPP) treadmills offer the unique possibility to partially unload runners and reach supramaximal speeds. We studied the use of LBPP to test an overspeed HIIT protocol in trained runners. METHODS: Eleven trained runners (35 ± 8 yr, V˙O2max, 55.7 ± 6.4 mL·kg·min) were randomized to an LBPP (n = 6) or a regular treadmill (CON, n = 5), eight sessions over 4 wk of HIIT program. Four to five intervals were run at 100% of velocity at V˙O2max (vV˙O2max) during 60% of time to exhaustion at vV˙O2max (Tlim) with a 1:1 work:recovery ratio. Performance outcomes were 2-mile track time trial, V˙O2max, vV˙O2max, vAT, Tlim, and RE. LBPP sessions were carried out at 90% body weight. RESULTS: Group-time effects were present for vV˙O2max (CON, 17.5 vs. 18.3, P = 0.03; LBPP, 19.7 vs. 22.3 km·h; P < 0.001) and Tlim (CON, 307.0 vs. 404.4 s, P = 0.28; LBPP, 444.5 vs. 855.5, P < 0.001). Simple main effects for time were present for field performance (CON, -18; LBPP, -25 s; P = 0.002), V˙O2max (CON, 57.6 vs. 59.6; LBPP, 54.1 vs. 55.1 mL·kg·min; P = 0.04) and submaximal HR (157.7 vs. 154.3 and 151.4 vs. 148.5 bpm; P = 0.002). RE was unchanged. CONCLUSIONS: A 4-wk HIIT protocol at 100% vV˙O2max improves field performance, vV˙O2max, V˙O2max and submaximal HR in trained runners. Improvements are similar if intervals are run on a regular treadmill or at higher speeds on a LPBB treadmill with 10% body weight reduction. LBPP could provide an alternative for taxing HIIT sessions.

Sponge Mass Mortalities in a Warming Mediterranean Sea: Are Cyanobacteria-Harboring Species Worse Off?

Mass mortality events are increasing dramatically in all coastal marine environments. Determining the underlying causes of mass mortality events has proven difficult in the past because of the lack of prior quantitative data on populations and environmental variables. Four-year surveys of two shallow-water sponge species, Ircinia fasciculata and Sarcotragus spinosulum, were carried out in the western Mediterranean Sea. These surveys provided evidence of two severe sponge die-offs (total mortality ranging from 80 to 95% of specimens) occurring in the summers of 2008 and 2009. These events primarily affected I. fasciculata, which hosts both phototrophic and heterotrophic microsymbionts, while they did not affect S. spinosulum, which harbors only heterotrophic bacteria. We observed a significant positive correlation between the percentage of injured I. fasciculata specimens and exposure time to elevated temperature conditions in all populations, suggesting a key role of temperature in triggering mortality events. A comparative ultrastructural study of injured and healthy I. fasciculata specimens showed that cyanobacteria disappeared from injured specimens, which suggests that cyanobacterial decay could be involved in I. fasciculata mortality. A laboratory experiment confirmed that the cyanobacteria harbored by I. fasciculata displayed a significant reduction in photosynthetic efficiency in the highest temperature treatment. The sponge disease reported here led to a severe decrease in the abundance of the surveyed populations. It represents one of the most dramatic mass mortality events to date in the Mediterranean Sea

Accuracy of cognitive MRI-targeted biopsy in hitting prostate cancer-positive regions of interest.

PURPOSE: Prostate cancer (PCa) diagnosis relies on clinical suspicion leading to systematic transrectal ultrasound-guided biopsy (TRUSGB). Multiparametric magnetic resonance imaging (mpMRI) allows for targeted biopsy of suspicious areas of the prostate instead of random 12-core biopsy. This method has been shown to be more accurate in detecting significant PCa. However, the precise spatial accuracy of cognitive targeting is unknown. METHODS: Consecutive patients undergoing mpMRI-targeted TRUSGB with cognitive registration (MRTB-COG) followed by robot-assisted radical prostatectomy were included in the present analysis. The regions of interest (ROIs) involved by the index lesion reported on mpMRI were subsequently targeted by two experienced urologists using the cognitive approach. The 27 ROIs were used as spatial reference. Mapping on radical prostatectomy specimen was used as reference to determine true-positive mpMRI findings. Per core correlation analysis was performed. RESULTS: Forty patients were included. Overall, 40 index lesions involving 137 ROIs (mean ROIs per index lesion 3.43) were identified on MRI. After correlating these findings with final pathology, 117 ROIs (85 %) were considered as true-positive lesions. A total of 102 biopsy cores directed toward such true-positive ROIs were available for final analysis. Cognitive targeted biopsy hit the target in 82 % of the cases (84/102). The only identified risk factor for missing the target was an anterior situated ROI (p = 0.01). CONCLUSION: In experienced hands, cognitive MRTB-COG allows for an accuracy of 82 % in hitting the correct target, given that it is a true-positive lesion. Anterior tumors are less likely to be successfully targeted.

Development of the Positive Emotions Program for Schizophrenia (PEPS): an intervention to improve pleasure and motivation in schizophrenia

Objectives: The efficacy of drug-based treatments and psychological interventions on the primary negative symptoms of schizophrenia remains limited. Recent literature has distinguished negative symptoms associated with a diminished capacity to experience, from those associated with a limited capacity for expression. The positive emotions program for schizophrenia (PEPS) is a new method that specifically aims to reduce the syndrome of a diminished capacity to experience. Methods: The intervention's vital ingredients were identified through a literature review of emotion in schizophrenia and positive psychology. The program has been beta-tested on various groups of health-care professionals. Results: A detailed description of the final version of PEPS is presented here. The French version of the program is freely downloadable. Conclusion: PEPS is a specific, short, easy to use, group-based intervention to improve pleasure, and motivation in schizophrenia. It was built considering a recovery-oriented approach to schizophrenia.

Workgroup climates and employees' counterproductive work behaviors: A social-cognitive perspective

This research examines employees' anticipation of social and self-sanctions as a self-regulatory mechanism linking workgroup climates and counterproductive work behaviors (CWBs) and personality as a limit to these effects. A cross-level study with 158 employees from 26 workgroups demonstrated that in groups with a high compliance climate-a climate emphasizing the importance of complying with organizational rules-employees anticipate more social and self-sanctions, leading those low in conscientiousness and low in agreeableness to engage less frequently in CWBs. In contrast, a high relational climate-a climate emphasizing the importance of positive social relations over self-interest-indirectly unbridles the CWBs of these employees by alleviating the social and self-sanctions they anticipate for CWBs. Climates did not have indirect effects for employees high in agreeableness and high in conscientiousness. These findings elucidate why workgroup climates do not affect the CWBs of all members in the same way.