Molecular complexity of diffuse large B-cell lymphoma: Can it be a roadmap for precision medicine?

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma; it features extreme molecular heterogeneity regardless of the classical cell-of-origin (COO) classification. Despite this, the standard therapeutic approach is still immunochemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone—R-CHOP), which allows a 60% overall survival (OS) rate, but up to 40% of patients experience relapse or refractory (R/R) disease. With the purpose of searching for new clinical parameters and biomarkers helping to make a better DLBCL patient characterization and stratification, in the last years a series of large discovery genomic and transcriptomic studies has been conducted, generating a wealth of information that needs to be put in order. We reviewed these researches, trying ultimately to understand if there are bases offering a roadmap toward personalized and precision medicine also for DLBCL

Undamped electrostatic plasma waves

Electrostatic waves in a collision-free unmagnetized plasma of electrons with fixed ions are investigated for electron equilibrium velocity distribution functions that deviate slightly from Maxwellian. Of interest are undamped waves that are the small amplitude limit of nonlinear excitations, such as electron acoustic waves (EAWs). A deviation consisting of a small plateau, a region with zero velocity derivative over a width that is a very small fraction of the electron thermal speed, is shown to give rise to new undamped modes, which here are named {\it corner modes}. The presence of the plateau turns off Landau damping and allows oscillations with phase speeds within the plateau. These undamped waves are obtained in a wide region of the $(k,\omega_{_R})$ plane ($\omega_{_R}$ being the real part of the wave frequency and $k$ the wavenumber), away from the well-known `thumb curve' for Langmuir waves and EAWs based on the Maxwellian. Results of nonlinear Vlasov-Poisson simulations that corroborate the existence of these modes are described. It is also shown that deviations caused by fattening the tail of the distribution shift roots off of the thumb curve toward lower $k$-values and chopping the tail shifts them toward higher $k$-values. In addition, a rule of thumb is obtained for assessing how the existence of a plateau shifts roots off of the thumb curve. Suggestions are made for interpreting experimental observations of electrostatic waves, such as recent ones in nonneutral plasmas.Comment: 11 pages, 10 figure

Fotemustine plus etoposide, cytarabine and melphalan (FEAM) as a new conditioning regimen for lymphoma patients undergoing auto-SCT: A multicenter feasibility study

BEAM is a widely used conditioning regimen for relapsed/refractory lymphoma patients undergoing auto-SCT. We conducted a multicenter study with an alternative regimen (fotemustine plus etoposide, cytarabine and melphalan (FEAM)) in which BCNU was substituted by the chloroethylnitrosourea fotemustine (FTM). Eighty-four patients with relapsed/refractory Hodgkin's (n20) and non-Hodgkin's lymphoma (n64) were conditioned with a FEAM regimen (FTM 150 mg/m 2 on days -7, -6, etoposide 200 mg/m 2 and cytarabine 400 mg/m 2 on days -5, -4, -3, -2 and melphalan 140 mg/m 2 on day -1). Patients were evaluated for toxicity and engraftment parameters. Median times to neutrophil (500 × 10 9 /l) and plt (20 000 × 10 9 /l) engraftment were 11 and 13 days, respectively. Grade 3 mucositis occurred in 19 patients (23%), while G3 nausea/vomiting and G3 diarrhea were observed in 13 (15%) and 6 (7%) patients, respectively. No severe hepatic, renal or pulmonary toxicity was detected. Seven patients (7%) experienced G4 mucositis, while no other G4 toxicities or unexpected adverse events of any grade were recorded. Transplant-related mortality was 2.4%. We conclude that a FEAM regimen is feasible and safe. Although toxicity and engraftment times compared favorably with BEAM, longer follow-up is needed to evaluate fully its efficacy and long-term safety. © 2010 Macmillan Publishers Limited All rights reserved

AT7519, a Novel Small Molecule Multi-Cyclin Dependent Kinase Inhibitor, Induces Apoptosis in Multiple Myeloma VIA GSK3 beta

Dysregulated cell cycling is a universal hallmark of cancer and is often mediated by abnormal activation of cyclin-dependent kinases (CDKs) and their cyclin partners. Overexpression of individual complexes are reported in multiple myeloma (MM), making them attractive therapeutic targets. In this study, we investigate the preclinical activity of a novel small-molecule multi-CDK inhibitor, AT7519, in MM. We show the anti-MM activity of AT7519 displaying potent cytotoxicity and apoptosis; associated with in vivo tumor growth inhibition and prolonged survival. At the molecular level, AT7519 inhibited RNA polymerase II (RNA pol II) phosphorylation, a CDK9, 7 substrate, associated with decreased RNA synthesis confirmed by [(3)H] Uridine incorporation. In addition, AT7519 inhibited glycogen synthase kinase 3beta (GSK-3beta) phosphorylation; conversely pretreatment with a selective GSK-3 inhibitor and shRNA GSK-3beta knockdown restored MM survival, suggesting the involvement of GSK-3beta in AT7519-induced apoptosis. GSK-3beta activation was independent of RNA pol II dephosphorylation confirmed by alpha-amanitin, a specific RNA pol II inihibitor, showing potent inhibition of RNA pol II phosphorylation without corresponding effects on GSK-3beta phosphorylation. These results offer new insights into the crucial, yet controversial role of GSK-3beta in MM and show significant anti-MM activity of AT7519, providing the rationale for its clinical evaluation in MM

Upper Bounds on the Neutrino-Nucleon Inelastic Cross Section

Extraterrestrial neutrinos can initiate deeply developing air showers, and those that traverse the atmosphere unscathed may produce cascades in the ice or water. Up to now, no such events have been observed. This can be translated into upper limits on the diffuse neutrino flux. On the other hand, the observation of cosmic rays with primary energies > 10^{10} GeV suggests that there is a guaranteed flux of cosmogenic neutrinos, arising from the decay of charged pions (and their muon daughters) produced in proton interactions with the cosmic microwave background. In this work, armed with these cosmogenic neutrinos and the increased exposure of neutrino telescopes we bring up-to-date model-independent upper bounds on the neutrino-nucleon inelastic cross section. Uncertainties in the cosmogenic neutrino flux are discussed and taken into account in our analysis. The prospects for improving these bounds with the Pierre Auger Observatory are also estimated. The unprecedented statistics to be collected by this experiment in 6 yr of operation will probe the neutrino-nucleon inelastic cross section at the level of Standard Model predictions.Comment: To be published in JCA

A new intra-specific and high-resolution genetic map of eggplant based on a ril population, and location of QTLS related to plant anthocyanin pigmentation and seed vigour

Eggplant is the second most important solanaceous berry-producing crop after tomato. Despite mapping studies based on bi-parental progenies and GWAS approaches having been performed, an eggplant intraspecific high-resolution map is still lacking. We developed a RIL population from the intraspecific cross ‘305E40’, (androgenetic introgressed line carrying the locus Rfo-Sa1 conferring Fusarium resistance) x ‘67/3’ (breeding line whose genome sequence was recently released). One hundred and sixty-three RILs were genotyped by a genotype-by-sequencing (GBS) approach, which allowed us to identify 10,361 polymorphic sites. Overall, 267 Gb of sequencing data were generated and ~773 M Illumina paired end (PE) reads were mapped against the reference sequence. A new linkage map was developed, including 7249 SNPs assigned to the 12 chromosomes and spanning 2169.23 cM, with iaci@liberoan average distance of 0.4 cM between adjacent markers. This was used to elucidate the genetic bases of seven traits related to anthocyanin content in different organs recorded in three locations as well as seed vigor. Overall, from 7 to 17 QTLs (at least one major QTL) were identified for each trait. These results demonstrate that our newly developed map supplies valuable information for QTL fine mapping, candidate gene identification, and the development of molecular markers for marker assisted selection (MAS) of favorable alleles

Percutaneous Venous Angioplasty in Patients With Multiple Sclerosis And Chronic Cerebrospinal Venous Insufficiency: A Randomized Wait List Control Study

Objectives: Venous percutaneous transluminal angioplasty (vPTA) in patients with multiple sclerosis (MS) and chronic cerebrospinal venous insufficiency (CCSVI) have shown contradictory results. Aim of the study is to evaluate the efficacy of the procedure in a randomized wait list control study. Materials: 66 adults with neurologist-confirmed diagnosis of MS and sonographic diagnosis of CCSVI were allocated in to vPTA-yes group (n=31) or vPTA-not group (n=35, control group). Venous PTA was performed immediately 15 days after randomization in PTA-yes group and 6 months later in the control group. Methods: Evoked potentials (EPs), clinical-functional measures (CFM) and upper limb kinematic measures (ULKM) were measured at baseline (T0) and six months after in both groups, just before the venous angioplasty in vPTA-not group (T1). Results: Comparing vPTA-yes and vPTA-not group, the CFM derived composite functional outcome showed 11(37%) versus 7(20%) improved, 1(3%) versus 3(8%) stable, 0 versus 7(20%) worsened and 19(61%) versus 18(51%) mixed patients (\u3c72=8.71, df=3, p=0.03). Unadjusted and adjusted (for baseline confounding variables) OR at 95% confident interval (95%CI) were respectively 1.93(1.3-2.8) P-value 0.0007 and 1.85(1.2-1.7) P-value 0.002. EPs and ULKM derived composite functional outcome showed no significant difference between the two groups. Conclusions: Venous angioplasty can positively impact a few CFM especially for the quality of life, but achieving disability improvement is unlikel

The Particle Physics Reach of High-Energy Neutrino Astronomy

We discuss the prospects for high-energy neutrino astronomy to study particle physics in the energy regime comparable to and beyond that obtainable at the current and planned colliders. We describe the various signatures of high-energy cosmic neutrinos expected in both neutrino telescopes and air shower experiments and discuss these measurements within the context of theoretical models with a quantum gravity or string scale near a TeV, supersymmetry and scenarios with interactions induced by electroweak instantons. We attempt to access the particle physics reach of these experiments.Comment: Mini-review article for New Journal of Physics, "Focus on Neutrinos" issue. 27 pages, 11 figure