Methotrexate Increases Skeletal Muscle GLUT4 Expression and Improves Metabolic Control in Experimental Diabetes

Long-term administration of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) mimics the effects of endurance exercise by activating AMP kinase and by increasing skeletal muscle expression of GLUT4 glucose transporter. AICAR is an intermediate in the purine de novo synthesis, and its tissue concentrations can be increased, in vivo, by low doses of methotrexate (MTX) through the inhibition of the enzyme AICAR transformylase. We report here the first evidence that, in experimental type 2 diabetes, chronic treatment with low doses of MTX increases skeletal muscle GLUT4 expression and improves metabolic control. MTX (0.5 mg/kg body weight) or vehicle was administered intraperitoneally, once a week for 4 weeks, to genetically diabetic female C57BL/KsJ-m+/+Leptdb mice (db+/db+) and their normoglycemic littermates (db+/+m). In the db+/db+ mice, MTX treatment was associated with a ∼2-fold increase in skeletal muscle GLUT4 protein concentration and a >4-fold increase in GLUT4 mRNA expression (P<0.01, all), as compared to vehicle-treated mice; no significant differences were noted in controls. MTX treatment was also associated with a significant reduction of glucose and insulin serum concentrations in diabetic mice (P<0.001), and glucose levels only (P<0.05) in controls. These data indicate a different route to increase skeletal muscle GLUT4 expression, through the potential inhibition of the enzyme AICAR transformylase

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

Key Points INTERIM treatment affects cytogenetic and molecular response, but not the outcome. No patients treated with INTERIM progressed to accelerated or blast phase.</jats:p

Digital PCR improves the quantitation of DMR and the selection of CML candidates to TKIs discontinuation

Treatment-free remission (TFR) by tyrosine kinase inhibitors (TKI) discontinuation in patients with deep molecular response (DMR) is a paramount goal in the current chronic myeloid leukemia (CML) therapeutic strategy. The best DMR level by real-time quantitative PCR (RT-qPCR) for TKI discontinuation is still a matter of debate. To compare the accuracy of digital PCR (dPCR) and RT-qPCR for BCR-ABL1 transcript levels detection, 142 CML patients were monitored for a median time of 24\ua0months. Digital PCR detected BCR-ABL1 transcripts in the RT-qPCR undetectable cases. The dPCR analysis of the samples, grouped by the MR classes, revealed a significant difference between MR4.0 and MR4.5 (P\ua0=\ua00.0104) or MR5.0 (P\ua0=\ua00.0032). The clinical and hematological characteristics of the patients grouped according to DMR classes (MR4.0 vs MR4.5-5.0 ) were superimposable. Conversely, patients with dPCR values <0.468 BCR-ABL1 copies/\ub5L (as we previously described) showed a longer DMR duration (P\ua0=\ua00.0220) and mainly belonged to MR4.5-5.0 (P\ua0=\ua00.0442) classes compared to patients with higher dPCR values. Among the 142 patients, 111 (78%) discontinued the TKI treatment; among the 111 patients, 24 (22%) lost the MR3.0 or MR4.0 . RT-qPCR was not able to discriminate patients with higher risk of MR loss after discontinuation (P\ua0=\ua00.8100). On the contrary, according to dPCR, 12/25 (48%) patients with BCR-ABL1 values 650.468 and 12/86 (14%) patients with BCR-ABL1 values <0.468 lost DMR in this cohort, respectively (P\ua0=\ua00.0003). Treatment-free remission of patients who discontinued TKI with a dPCR <0.468 was significantly higher compared to patients with dPCR\ua0 65\ua00.468 (TFR at 2\ua0years 83% vs 52% P\ua0=\ua00.0017, respectively). In conclusion, dPCR resulted in an improved recognition of stable DMR and of candidates to TKI discontinuation

Managing chronic myeloid leukemia for treatment-free remission: a proposal from the GIMEMA CML WP

Several papers authored by international experts have proposed recommendations on the management of BCR-ABL1+ chronic myeloid leukemia (CML). Following these recommendations, survival of CML patients has become very close to normal. The next, ambitious, step is to bring as many patients as possible into a condition of treatment-free remission (TFR). The Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA; Italian Group for Hematologic Diseases of the Adult) CML Working Party (WP) has developed a project aimed at selecting the treatment policies that may increase the probability of TFR, taking into account 4 variables: the need for TFR, the tyrosine kinase inhibitors (TKIs), the characteristics of leukemia, and the patient. A Delphi-like method was used to reach a consensus among the representatives of 50 centers of the CML WP. A consensus was reached on the assessment of disease risk (EUTOS Long Term Survival [ELTS] score), on the definition of the most appropriate age boundaries for the choice of first-line treatment, on the choice of the TKI for first-line treatment, and on the definition of the responses that do not require a change of the TKI (BCR-ABL1 6410% at 3 months, 641% at 6 months, 640.1% at 12 months, 640.01% at 24 months), and of the responses that require a change of the TKI, when the goal is TFR (BCR-ABL1 &gt;10% at 3 and 6 months, &gt;1% at 12 months, and &gt;0.1% at 24 months). These suggestions may help optimize the treatment strategy for TFR

Osservazioni

di Calogero Piro. Convertire la realtà che ci circonda in immagini, è stata fin dai primordi dell’essere umano un’atavica necessità. Ancora oggi nella nostra cultura visiva è tutto basato sull’utilizzo dell’immagine per conoscere la realtà che ci circonda. Con la scoperta della fotografia, la riflessione intorno alla natura si fa sempre più interessante. Il ruolo della macchina fotografica in questo progetto per raccontare l’ambiente, la struttura, gli oggetti, i segni, i colori e le atmosfere che caratterizzano il centro del CNR di capo Granitola ha trovato prepotentemente in questi giovani allievi della cattedra di fotografia dell’Accademia di Belle Arti di Palermo, diretta dal Professore Sandro Scalia, momenti di grande professionalità, realizzando un grande reportage con tutti gli aspetti essenziali della struttura e delle articolazioni primarie del linguaggio fotografico. Questa esperienza extradidattica difficile ed impegnativa non soltanto per la necessità del confronto col “nuovo” in termini organizzativi, ma anche per la necessità di descrivere attraverso la fotografia il tema della Biodiversità, è stato affrontato brillantemente. Mettendo in primo piano, siti naturali, siti storici come: Mozia e Selinunte, i laboratori del centro di ricerche, la Flora e la Fauna, sono riusciti a raggiungere con acuta osservazione ottimi risultati visibili in questo catalogo, e con la tangibile riprova di cosa possa e debba essere una educazione estetica assolutamente “libera” da condizionamenti, viatico ineludibile perché l’espressione artistica, sotto qualunque forma, sia artefice dei grandi processi di vera maturazione culturale, si avverte in questi giovani artisti la purezza e la consapevolezza dei propri messaggi ancora privi, e speriamo sempre, di qualunque tipo di inquinamento tendenzioso

I diabetologi italiani e le vaccinazioni anti-influenzale e anti-difterite-tetano-pertosse nei soggetti con diabete mellito: la survey di AMD

Diabetes mellitus is associated with an increased incidence of some infections and a greater severity and/or frequency of complications related to these diseases. Influenza is characterized by an increased severity of clinical course and risk of complications, especially in diabetic patients who are more susceptible to influenza infection. For these reasons, the Italian Vaccine Prevention Plan 2017-19 provides an active and free offer of influenza vaccine for the diabetic subjects. In addition, among the vaccinations recommended by the Italian Prevention Plan in adults, including the diabetes ones, there is the diphtheria-tetanus-pertussis vaccine and the decennial booster. To investigate what is the perception of Italian diabetologists on the role and importance of the influenza and the diphtheria-tetanus-pertussis vaccines, AMD has promoted an online survey. Participants claimed to be aware of the importance of carrying out and recommending influenza vaccination, while awareness of the usefulness of performing and suggesting the decennial booster for diphtheria-tetanus-pertussis was lower. Diabetologists attribute to patients\u2019 resistance and lack of interest in such vaccinations the main motivation for which they are not used to recommend them, even if they acknowledge that they have little knowledge about the decennial booster of diphtheria-tetanus-pertussis vaccine. The survey shows that the percentage of patients with diabetes who seek advice on these vaccinations is inadequate and the diabetologists\u2019 knowledge of the National Vaccination Prevention recommendations and the need to actively promote vaccinations is inappropriate. This survey has allowed to highlight the opinion, of a significant percentage of Italian diabetologists, on some key aspects of the vaccination therapy indicated in diabetic patient, allowing to gather important information to open a debate, to know strengths and weaknesses on this topic and implement training activities

Meso- to nano-scale evidence of fluid-assisted co-seismic slip along the normal Mt. Morrone Fault, Italy: Implications for earthquake hydrogeochemical precursors

Fluids play an important role in seismic faulting both at hypocentral depths during earthquake nucleation and at shallower crustal levels during rupture propagation. Pre- to co-seismic anomalies of crustal fluid circulation have been identified by hydrogeochemical and seismological monitoring and interpreted as potential precursors of strong earthquakes. To shed light on the role of fluids in seismic and precursory mechanisms, the active carbonate-hosted principal slip zone (7-8 cm thick) of the exhumed (exhumation < 3 km) normal Mt. Morrone Fault (central Apennines) has been investigated with a multi-disciplinary approach from the macro- to the nano-scale. The distal slip zone consists of white cementitious calcite-rich bands and red cataclastic bands composed of dolomite and calcite clasts embedded in a clay-rich matrix. The proximal slip zone consists of subparallel ultracataclastic layers separated by sharp slip surfaces. The ultracataclastic layers mutually inject/overprint, bearing evidence of granular fluidization, dolomite thermal decomposition, and clay amorphization. Fluid inclusions and the distribution of both trace and major elements reveal the inflow of both shallow and deep external fluids into the slip zone. Presumably, the deep fluids originated from a magmatic-like source and ascended along the fault during pre-seismic dilation and seismic ruptures, interacting with shallow phyllosilicate-rich flysch deposits and the fluids hosted within them. In this context, vanadium-rich fluidized microlayers along the exhumed Mt. Morrone Fault are reminiscent of vanadium-rich potential hydrogeochemical precursors arose in the shallow aquifers of the study area since a few months before the 2016 M-w 6.0 Amatrice earthquake. (C) 2021 Elsevier B.V. All rights reserved