Low low-density lipoprotein (LDL), cholesterol and triglycerides plasma levels are associated with reduced risk of arterial occlusive events in chronic myeloid leukemia patients treated with ponatinib in the real-life. A Campus CML study

36noopenopenCaocci G.; Mulas O.; Capodanno I.; Abruzzese E.; Iurlo A.; Luciano L.; Albano F.; Annunziata M.; Tiribelli M.; Bonifacio M.; Galimberti S.; Castagnetti F.; Sgherza N.; Stagno F.; Gozzini A.; Orlandi E.M.; Luzi D.; Binotto G.; Pregno P.; Fozza C.; Efficace F.; Simula M.P.; Trawinska M.M.; Cattaneo D.; De Gregorio F.; Attolico I.; Stella R.; Scaffidi L.; Barate C.; Gugliotta G.; Scalzulli E.; Elena C.; Pirillo F.; Foa R.; Breccia M.; Nasa G.L.Caocci, G.; Mulas, O.; Capodanno, I.; Abruzzese, E.; Iurlo, A.; Luciano, L.; Albano, F.; Annunziata, M.; Tiribelli, M.; Bonifacio, M.; Galimberti, S.; Castagnetti, F.; Sgherza, N.; Stagno, F.; Gozzini, A.; Orlandi, E. M.; Luzi, D.; Binotto, G.; Pregno, P.; Fozza, C.; Efficace, F.; Simula, M. P.; Trawinska, M. M.; Cattaneo, D.; De Gregorio, F.; Attolico, I.; Stella, R.; Scaffidi, L.; Barate, C.; Gugliotta, G.; Scalzulli, E.; Elena, C.; Pirillo, F.; Foa, R.; Breccia, M.; Nasa, G. L

Clinical implications of discordant early molecular responses in CML patients treated with imatinib

A reduction in BCR-ABL1/ABL1IS transcript levels to <10% after 3 months or <1% after 6 months of tyrosine kinase inhibitor therapy are associated with superior clinical outcomes in chronic myeloid leukemia (CML) patients. In this study, we investigated the reliability of multiple BCR-ABL1 thresholds in predicting treatment outcomes for 184 subjects diagnosed with CML and treated with standard-dose imatinib mesylate (IM). With a median follow-up of 61 months, patients with concordant BCR-ABL1/ABL1IS transcripts below the defined thresholds (10% at 3 months and 1% at 6 months) displayed significantly superior rates of event-free survival (86.1% vs. 26.6%) and deep molecular response (≥ MR4; 71.5% vs. 16.1%) compared to individuals with BCR-ABL1/ABL1IS levels above these defined thresholds. We then analyzed the outcomes of subjects displaying discordant molecular transcripts at 3-and 6-month time points. Among these patients, those with BCR-ABL1/ABL1IS values >10% at 3 months but <1% at 6 months fared significantly better than individuals with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (event-free survival 68.2% vs. 32.7%; p < 0.001). Likewise, subjects with BCR-ABL1/ABL1IS at 3 months >10% but <1% at 6 months showed a higher cumulative incidence of MR4 compared to patients with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (75% vs. 18.2%; p < 0.001). Finally, lower BCR-ABL1/GUSIS transcripts at diagnosis were associated with BCR-ABL1/ABL1IS values <1% at 6 months (p < 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month BCR-ABL1/ABL1IS level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points

Evidence for a reducing Archean ambient mantle and its effects on the carbon cycle

Chemical reduction-oxidation mechanisms within mantle rocks link to the terrestrial carbon cycle by influencing the depth at which magmas can form, their composition, and ultimately the chemistry of gases released into the atmosphere. The oxidation state of the uppermost mantle has been widely accepted to be unchanged over the past 3800 m.y., based on the abundance of redox-sensitive elements in greenstone belt–associated samples of different ages. However, the redox signal in those rocks may have been obscured by their complex origins and emplacement on continental margins. In contrast, the source and processes occurring during decompression melting at spreading ridges are relatively well constrained. We retrieve primary redox conditions from metamorphosed mid-oceanic ridge basalts (MORBs) and picrites of various ages (ca. 3000–550 Ma), using V/Sc as a broad redox proxy. Average V/Sc values for Proterozoic suites (7.0 ± 1.4, 2s, n = 6) are similar to those of modern MORB (6.8 ± 1.6), whereas Archean suites have lower V/Sc (5.2 ± 0.4, n = 5). The lower Archean V/Sc is interpreted to reflect both deeper melt extraction from the uppermost mantle, which becomes more reduced with depth, and an intrinsically lower redox state. The pressure-corrected oxygen fugacity (expressed relative to the fayalite-magnetite-quartz buffer, DFMQ, at 1 GPa) of Archean sample suites (DFMQ –1.19 ± 0.33, 2s) is significantly lower than that of post-Archean sample suites, including MORB (DFMQ –0.26 ± 0.44). Our results imply that the reducing Archean atmosphere was in equilibrium with Earth’s mantle, and further suggest that magmatic gases crossed the threshold that allowed a build-up in atmospheric O2 levels ca. 3000 Ma, accompanied by the first “whiffs” of oxygen in sediments of that age

BCR-ABL1 doubling-times and halving-times may predict CML response to tyrosine kinase inhibitors

In Chronic Myeloid Leukemia (CML), successful treatment requires accurate molecular monitoring to evaluate disease response and provide timely interventions for patients failing to achieve the desired outcomes. We wanted to determine whether measuring BCR-ABL1 mRNA doubling-times (DTs) could distinguish inconsequential rises in the oncogene’s expression from resistance to tyrosine kinase inhibitors (TKIs). Thus, we retrospectively examined BCR-ABL1 evolution in 305 chronic-phase CML patients receiving imatinib mesylate (IM) as a first line treatment. Patients were subdivided in two groups: those with a confirmed rise in BCR-ABL1 transcripts without MR3.0 loss and those failing IM. We found that the DTs of the former patients were significantly longer than those of patients developing IM resistance (57.80 vs. 41.45 days, p = 0.0114). Interestingly, the DT values of individuals failing second-generation (2G) TKIs after developing IM resistance were considerably shorter than those observed at the time of IM failure (27.20 vs. 41.45 days; p = 0.0035). We next wanted to establish if decreases in BCR-ABL1 transcripts would identify subjects likely to obtain deep molecular responses. We therefore analyzed the BCR-ABL1 halving-times (HTs) of a different cohort comprising 174 individuals receiving IM in first line and observed that, regardless of the time point selected for our analyses (6, 12, or 18 months), HTs were significantly shorter in subjects achieving superior molecular responses (p = 0.002 at 6 months; p < 0.001 at 12 months; p = 0.0099 at 18 months). Moreover, 50 patients receiving 2G TKIs as first line therapy and obtaining an MR3.0 (after 6 months; p = 0.003) or an MR4.0 (after 12 months; p = 0.019) displayed significantly shorter HTs than individuals lacking these molecular responses. Our findings suggest that BCR-ABL1 DTs and HTs are reliable tools to, respectively, identify subjects in MR3.0 that are failing their assigned TKI or to recognize patients likely to achieve deep molecular responses that should be considered for treatment discontinuation

Glycerol as an Energy Source for Ruminants: a Meta-Analysis of in Vitro Experiments

Glycerol or glycerin is generally recognized as a safe compound to be used in animal feed, especially for ruminants. A number of in vitro studies related to glycerol supplementation in ruminant ration have been published but to date the results have not been summarized. The objective of this study was, therefore, to evaluate in vitro digestibility, ruminal fermentation characteristics, total gas and methane production through the meta-analysis approach. Meta-analysis was applied to 13 experiments and 42 treatments dealing with glycerol supplementation in ruminants. Data were analyzed by general linear model procedure in which the glycerol levels and the different studies were treated as fixed effects. Results revealed that glycerol supplementation did not affect the in vitro digestibility and total VFA production, but significantly decreased molar proportion of acetate and iso-valerate (P<0.05). In contrast, molar proportion of propionate, butyrate, and valerate significantly increased, and thus the ratio of acetate to propionate declined linearly (P<0.05). Methane production decreased linearly and accompanied with an increase of total gas production with increasing levels of glycerol supplementation (P<0.05). It is concluded that the use of glycerol as an energy substitution in animal feed has no detrimental effects in the rumen and environmentally friendly

Effects and outcome of a policy of intermittent imatinib treatment in elderly patients with chronic myeloid leukemia.

none25We report a study of an alternative treatment schedule of imatinib (IM) in chronic myeloid leukemia (CML). Seventy-six Philadelphia-positive (Ph+), BCR-ABL-positive patients aged 65 years or older who had been treated with IM for more than 2 years and who were in stable complete cytogenetic response (CCgR) and major molecular response (MMR) were enrolled in a single-arm study to test the effects of a policy of intermittent IM (INTERIM) therapy for 1 month on and 1 month off. With a minimum follow-up of 4 years, 13 patients (17%) lost CCgR and MMR and 14 (18%) lost MMR only. All these patients resumed continuous IM and all but one (lost to follow-up) regained CCgR and MMR. No patients progressed to accelerated or blastic phase or developed clonal chromosomal abnormalities in Ph+ cells or BCR-ABL mutations. In elderly Ph+ CML patients carefully selected for a stable CCgR (lasting >2 years), the policy of INTERIM treatment affected the markers of residual disease, but not the clinical outcomes (overall and progression-free survival). This trial was registered at www.clinicaltrials.gov as NCT 00858806.noneRusso D; Martinelli G; Malagola M; Skert C; Soverini S; Iacobucci I; De Vivo A; Testoni N; Castagnetti F; Gugliotta G; Turri D; Bergamaschi M; Pregno P; Pungolino E; Stagno F; Breccia M; Martino B; Intermesoli T; Fava C; Abruzzese E; Tiribelli M; Bigazzi C; Cesana BM; Rosti G; Baccarani M.Russo D; Martinelli G; Malagola M; Skert C; Soverini S; Iacobucci I; De Vivo A; Testoni N; Castagnetti F; Gugliotta G; Turri D; Bergamaschi M; Pregno P; Pungolino E; Stagno F; Breccia M; Martino B; Intermesoli T; Fava C; Abruzzese E; Tiribelli M; Bigazzi C; Cesana BM; Rosti G; Baccarani M

Report on session QG3 of the 15th Marcel Grossmann Meeting

We summarize the talks presented at the QG3 session (loop quantum gravity: cosmology and black holes) of the 15th Marcel Grossmann Meeting held in Rome, Italy on July 1-7 2018.Comment: 5 pages, no figures, to appear in the conference proceeding

Reforms in the Holy Infirmary, 1680

The Holy Infirmary, at least in theory, bore witness to the very raison d'etre of the Order of St John ­ the care of the infirm. If the knights came to be known as the Hospitallers, it is because the care of the sick became their historical mission through the centuries, a mission they never abandoned.peer-reviewe

Marketing higher education in Africa : challenges and opportunities

This chapter examines the global marketing environment of today’s higher education institutions (HEIs). (Semi) Autonomous HEIs and business schools are increasingly behaving like for-profit organisations as they seek new opportunities and resources to prioritise revenue creation. Therefore, they are diversifying the portfolio of their student populations by recruiting domestic and international students. In this light, this contribution deliberates on contemporary integrated marketing communications that are intended to support HEIs to promote their quality, student-centred education as well as their high-impact and meaningful research in global markets. Moreover, it reports on how HEIs’ marketing endeavours will be able to forge fruitful and collaborative relationships with industry stakeholders; foster student mobility and engagement in exchange programmes, as they can create partnership agreements with other institutions, among other strategic avenues. These issues imply that tomorrow’s educational institutions will have to keep investing in adequate resources, competences and capabilities to leverage themselves amid intensifying competition in challenging socio-economic environments.peer-reviewe