What links BRAF to the heart function? New insights from the cardiotoxicity of BRAF inhibitors in cancer treatment

none11noThe RAS-related signalling cascade has a fundamental role in cell. It activates differentiation and survival. It is particularly important one of its molecules, B-RAF. B-RAF has been a central point for research, especially in melanoma. Indeed, it lacked effective therapeutic weapons since the early years of its study. Molecules targeting B-RAF have been developed. Nowadays, two classes of molecules are approved by FDA. Multi-target molecules, such as Sorafenib and Regorafenib, and selective molecules, such as Vemurafenib and Dabrafenib. Many other molecules are still under investigation. Most of them are studied in phase 1 trials. Clinical studies correlate B-RAF inhibitors and QT prolongation. Though this cardiovascular side effect is not common using these drugs, it must be noticed early and recognize its signals. Indeed, Oncologists and Cardiologists should work in cooperation to prevent lethal events, such as fatal arrhythmias or sudden cardiac death. These events could originate from an uncontrolled QT prolongation.openBronte E.; Bronte G.; Novo G.; Bronte F.; Bavetta M.G.; Re G.L.; Brancatelli G.; Bazan V.; Natoli C.; Novo S.; Russo A.Bronte, E.; Bronte, G.; Novo, G.; Bronte, F.; Bavetta, M. G.; Re, G. L.; Brancatelli, G.; Bazan, V.; Natoli, C.; Novo, S.; Russo, A

Beyond evidence-based data: Scientific rationale and tumor behavior to drive sequential and personalized therapeutic strategies for the treatment of metastatic renal cell carcinoma

none8noThe recent advances in identification of the molecular mechanisms related to tumorigenesis and angiogenesis, along with the understanding of molecular alterations involved in renal cell carcinoma (RCC) pathogenesis, has allowed the development of several new drugs which have revolutionized the treatment of metastatic renal cell carcinoma (mRCC). This process has resulted in clinically significant improvements in median overall survival and an increasing number of patients undergoes two or even three lines of therapy. Therefore, it is necessary a long-term perspective of the treatment: Planning a sequential and personalized therapeutic strategy to improve clinical outcome, the potential to achieve long-term response, and to preserve quality of life (QOL), minimizing treatment-related toxicity and transforming mRCC into a chronically treatable condition. Because of the challenges still encountered to draw an optimal therapeutic sequence, the main focus of this article will be to propose the optimal sequencing of existing, approved, oral targeted agents for the treatment of mRCC using evidencebased data along with the knowledge available on the tumor behavior and mechanisms of resistance to anti-angiogenic treatment to provide complementary information and to help the clinicians to maximize the effectiveness of targeted agents in the treatment of mRCC.openIncorvaia L.; Bronte G.; Bazan V.; Badalamenti G.; Rizzo S.; Pantuso G.; Natoli C.; Russo A.Incorvaia, L.; Bronte, G.; Bazan, V.; Badalamenti, G.; Rizzo, S.; Pantuso, G.; Natoli, C.; Russo, A

Effect of Processing Methods on Proximate Composition and Functional Properties of Improved Chickpea (Cicer arietinum L.) Varieties Grown in Ethiopia

Chickpea (Cicer arietinum L.) is an important and cheap source of legume protein which can be used as a substitute for animal protein that is limited in supply and expensive. However, the presence of certain antinutritional factors has become a hindrance to the availability of the protein during human consumption. This study was, initiated with the objective of determining the effect of different processing methods on Proximate composition and functional properties of selected improved Chickpea Varieties (Natoli of Desi and Arerti of Kabuli) grown in Ethiopia. The experiment was carried out in a CRD with chickpea variety as the first factor of two levels (Natoli and Arerti) and processing method as a second factor of the five levels (dry roasting, dehulling, soaking, germinating and boiling). The result indicated that the ash, crude protein, crude fiber, crude fat, total carbohydrates and energy of the unprocessed chickpeas were 3.77%, 18.71%, 5.81%, 6.97%, 55.90%, and 361.13 kcal/100g, respectively. After processing the values of these same parameter ranged from 3.21 to 3.67%, 12.51 to 22.62%, 2.43 to 5.32%, 6.94 to 8.48%, 53.34 to 68.52%, and 360.20 to 392.86 kcal/100g, respectively. Bulk density, water absorption capacity, oil absorption capacity, solubility and swelling power were 0.46glcm3, 1.55 g/g, 2.02g/g, 28.49% and 16.08%, respectively while after processing the values remained between 0.40 to 0.58 g/cm3, 1.25 to 2.73 g/g, 1.91 to 2.30 g/g, 18.05 to 28.62% and 10.04 to 15.66%, respectively. The results clearly indicated that, among processing methods, dehulling and germination significantly increase the nutritional content while boiling method is best for high water and oil absorption capacity. The present study recommends that dehuling is the best method to increase protein, fat, and energy values and the lower bulk density value in the formulation of complementary foods for children below of two years. Keywords: Improved Chickpea varieties, proximate composition, Functional propertie

Careful breakthrough cancer pain treatment through rapid-onset transmucosal fentanyl improves the quality of life in cancer patients: Results from the best multicenter study

open18noObjectives: To explore the effect of breakthrough cancer pain (BTcP) treatment on quality of sleep and other aspects of the health-related quality of life (HRQoL) in patients with cancer pain. Methods: In an observational, multicenter, cohort study, cancer patients from palliative care units, oncology departments, and pain clinics and affected by BTcP were included. Enrolled patients were assessed at the four visits: T0 (baseline), T7, T14, and T28. Stable chronic background pain (numeric rating scale, NRS ≤ 4) during the whole study period was mandatory. BTcP was treated through transmucosal fentanyl. Three questionnaires were used to measure the HRQoL: EORTC QLQ-C15-PAL, Pittsburgh Sleep Quality Index (PSQI), and the Edmonton Symptom Assessment System (ESAS). RESULTS: In 154 patients, the HRQoL showed a significant improvement for all physical and emotional characteristics in the EORTC QLQ-C15-PAL, except for nausea and vomiting (linear p-value = 0.1) and dyspnea (Linear p-value = 0.05). The ESAS and PSQI questionnaires confirmed these positive results (p < 0.0001 and p = 0.002, respectively). Conclusions: This prospective investigation by an Italian expert group, has confirmed that careful management of BTcP induces a paramount improvement on the HRQoL. Because in cancer patients there is a high prevalence of BTcP and this severe acute pain has deleterious consequences, this information can have an important clinical significance.noneCuomo A.; Cascella M.; Forte C.A.; Bimonte S.; Esposito G.; De Santis S.; Cavanna L.; Fusco F.; Dauri M.; Natoli S.; Maltoni M.; Morabito A.; Mediati R.D.; Lorusso V.; Barni S.; Porzio G.; Mercadante S.; Crispo A.Cuomo A.; Cascella M.; Forte C.A.; Bimonte S.; Esposito G.; De Santis S.; Cavanna L.; Fusco F.; Dauri M.; Natoli S.; Maltoni M.; Morabito A.; Mediati R.D.; Lorusso V.; Barni S.; Porzio G.; Mercadante S.; Crispo A

Physicochemical Properties and Effect of Processing Methods on Mineral Composition and Antinutritional Factors of Improved Chickpea (Cicer arietinum L.) Varieties Grown in Ethiopia

Chickpea (Cicer arietinum L.) is an important pulse crop grown and consumed all over the world because it is a good source of carbohydrates and protein. However, presence of antinutritional components restricts its use by interfering with digestion of macronutrients during consumption. Therefore, the objective of this study was to evaluate physicochemical properties and effect of processing methods on antinutritional factors and mineral composition of improved chickpea varieties (Natoli of Desi and Arerti of Kabuli) grown in Ethiopia. The experiment was factorial with complete randomized design. The result indicated that physicochemical properties such as seed mass, seed density, hydration capacity, swelling capacity, unhydrated seeds, and cooking time of Arerti and Natoli chickpeas had 260.69 and 280.65 g/1000 seeds, 3.48 and 3.61g/ml, 1.07 and 1.03 g/g, 2.12 and 1.94ml/g, 1.64 and 14.75%, and 21.00 and 246.33 min, respectively. After processing, Zn, Fe, and Ca contents of improved chickpea varieties had 4.48 to 5.85mg/kg, 8.52 to 10.17mg/kg, and 536.56 to 1035mg/kg, respectively. The antinutritional factors, tannin and phytic acid, in the raw chickpeas were reduced to 25 to 82.25% and 5.89 to 57.35%, respectively. The results of the current study showed that Arerti of Kabuli variety showed low antinutritional factors and better physicochemical properties, specifically low cooking time, than Natoli of Desi variety. All processing methods were effective in reduction of antinutritional factors; however, boiling was found to be the best for reduction of antinutritional factors

Drivers of non-zero physician global scores during periods of inactive disease in juvenile idiopathic arthritis

open16Objective To investigate the frequency in which the physician provides a global assessment of disease activity (PhGA) >0 and an active joint count (AJC)=0 in children with juvenile idiopathic arthritis (JIA) and search for determinants of divergence between the two measures. Methods Data were extracted from a multinational cross-sectional dataset of 9966 patients who had JIA by International League of Associations for Rheumatology criteria, were recruited between 2011 and 2016, and had both PhGA and AJC recorded by the caring paediatric rheumatologist at the study visit. Determinants of discordance between PhGA>0 and AJC=0 were searched for by multivariable logistic regression and dominance analyses. Results The PhGA was scored >0 in 1647 (32.3%) of 5103 patients who had an AJC of 0. Independent associations with discordant assessment were identified for tender or restricted joint count >0, history of enthesitis, presence of active uveitis or systemic features, enthesitis-related or systemic arthritis, increased acute phase reactants, pain visual analogue scale (VAS)>0, and impaired physical or psychosocial well-being. In dominance analysis, tender joint count accounted for 35.43% of PhGA variance, followed by pain VAS>0 (17.72%), restricted joint count >0 (16.14%) and physical health score >0 (11.42%). Conclusion We found that many paediatric rheumatologists did not mark a score of 0 for patients who they found not to have active joints. The presence of pain in joints not meeting the definition of active joint used in JIA was the main determinant of this phenomenon.openAlongi A.; Giancane G.; Naddei R.; Natoli V.; Ridella F.; Burrone M.; Rosina S.; Chedeville G.; Alexeeva E.; Horneff G.; Foeldvari I.; Filocamo G.; Constantin T.; Ruperto N.; Ravelli A.; Consolaro A.Alongi, A.; Giancane, G.; Naddei, R.; Natoli, V.; Ridella, F.; Burrone, M.; Rosina, S.; Chedeville, G.; Alexeeva, E.; Horneff, G.; Foeldvari, I.; Filocamo, G.; Constantin, T.; Ruperto, N.; Ravelli, A.; Consolaro, A

Prognostic significance of K-Ras mutation rate in metastatic colorectal cancer patients

none24noIntroduction: Activating mutations of K-Ras gene have a well-established role as predictors of resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC) patients. Their prognostic value is controversial, and no data regarding the prognostic value of mutation rate, defined as the percentage of mutated alleles/ tumor sample, are available. We aimed to evaluate the prognostic value of K-Ras mutation rate in a homogenous cohort of mCRC patients receiving first-line doublet plus bevacizumab. Patients and Methods: This retrospective study enrolled 397 K-Ras mutant mCRC patients from 6 Italian centers, and 263 patients were fully evaluable for our analysis. K-Ras mutation rate was assessed by pyrosequencing. Patients with less than 60% of cancer cells in tumor tissue were excluded. No patients received anti-EGFR containing anticancer therapy, at any time. Median mutation rate was 40% and was adopted as cut-off. The primary and secondary endpoints were PFS and OS respectively. Results: At univariate analysis, K-Ras mutation rate higher than 40% was significantly associated with lower PFS (7.3 vs 9.1 months; P < 0.0001) and OS (21 vs 31 months; P = 0.004). A multivariate model adjusted for age at diagnosis, site of origin of tumor tissue (primary vs metastases), referral center, number of metastatic sites, and first-line chemotherapy backbone, showed that K-Ras mutation rate remained a significant predictor of PFS and OS in the whole population. Discussion: Our data demonstrate an association between K-Ras mutation rate and prognosis in mCRC patients treated with bevacizumab-containing first-line therapy. These data deserve to be verified in an independent validation set.openVincenzi B.; Cremolini C.; Sartore-Bianchi A.; Russo A.; Mannavola F.; Perrone G.; Pantano F.; Loupakis F.; Rossini D.; Ongaro E.; Bonazzina E.; Dell'Aquila E.; Imperatori M.; Zoccoli A.; Bronte G.; Maglio G.D.; Fontanini G.; Natoli C.; Falcone A.; Santini D.; Onetti-Muda A.; Siena S.; Tonini G.; Aprile G.Vincenzi, B.; Cremolini, C.; Sartore-Bianchi, A.; Russo, A.; Mannavola, F.; Perrone, G.; Pantano, F.; Loupakis, F.; Rossini, D.; Ongaro, E.; Bonazzina, E.; Dell'Aquila, E.; Imperatori, M.; Zoccoli, A.; Bronte, G.; Maglio, G. D.; Fontanini, G.; Natoli, C.; Falcone, A.; Santini, D.; Onetti-Muda, A.; Siena, S.; Tonini, G.; Aprile, G

Role of the exchange and correlation potential into calculating the x-ray absorption spectra of half-metallic alloys: the case of Mn and Cu K-edge XANES in Cu2_2MnM (M = Al, Sn, In) Heusler alloys

This work reports a theoretical study of the x-ray absorption near-edge structure spectra at both the Cu and the Mn K-edge in several Cu$_2$MnM (M= Al, Sn and In) Heusler alloys. Our results show that {\it ab-initio} single-channel multiple-scattering calculations are able of reproducing the experimental spectra. Moreover, an extensive discussion is presented concerning the role of the final state potential needed to reproduce the experimental data of these half-metallic alloys. In particular, the effects of the cluster-size and of the exchange and correlation potential needed in reproducing all the experimental XANES features are discussed.Comment: 15 pages, 5 figure