Monitoring Chronic Myeloid Leukemia: How Molecular Tools May Drive Therapeutic Approaches

More than 15 years ago, imatinib entered into the clinical practice as a "magic bullet"; from that point on, the prognosis of patients affected by chronic myeloid leukemia (CML) became comparable to that of aged-matched healthy subjects. The aims of treatment with tyrosine kinase inhibitors (TKIs) are for complete hematological response after 3 months of treatment, complete cytogenetic response after 6 months, and a reduction of the molecular disease of at least 3 logs after 12 months. Patients who do not reach their goal can switch to another TKI. Thus, the molecular monitoring of response is the main consideration of management of CML patients. Moreover, cases in deep and persistent molecular response can tempt the physician to interrupt treatment, and this "dream" is possible due to the quantitative PCR. After great international effort, today the BCR-ABL1 expression obtained in each laboratory is standardized and expressed as "international scale." This aim has been reached after the establishment of the EUTOS program (in Europe) and the LabNet network (in Italy), the platforms where biologists meet clinicians. In the field of quantitative PCR, the digital PCR is now a new and promising, sensitive and accurate tool. Some authors reported that digital PCR is able to better classify patients in precise "molecular classes," which could lead to a better identification of those cases that will benefit from the interruption of therapy. In addition, digital PCR can be used to identify a point mutation in the ABL1 domain, mutations that are often responsible for the TKI resistance. In the field of resistance, a prominent role is played by the NGS that enables identification of any mutation in ABL1 domain, even at sub-clonal levels. This manuscript reviews how the molecular tools can lead the management of CML patients, focusing on the more recent technical advances

Self-physical and emotional perception in rhythmic gymnastics for drop out

In rhythmic gymnastics, very young athletes undertake a competitive activity and support workloads of four or five hours, almost unthinkable for such small girls, yet to achieve maximum results it is necessary to start at a young age and work hard. The purpose of the study is to study, in different groups of athletes (3-7 years, 8-12 years, 13-18 years) of rhythmic gymnastics, how they face emotionally and physically the physical and emotional workloads and especially if you find physical and mental well-being. The method of the study is qualitative/quantitative and the administration of 10 questions: 5 to identify the physical self-perception and 5 for the emotional one, is done anonymously. The data shows that the self-perception for physical performance is average (positive or negative and put the percentage) and the self-perception for motivation performance is average (positive or negative) and put the percentage. This data is significant for the perceptive state of the athletes to whom it is necessary to refer in order to realistically face the problem. Given the data and their significance, the study must be deepened with a more significant and detailed sample of data

Effect of Dewaxed Coffee on Gastroesophageal Symptoms in Patients with {GERD}: A Randomized Pilot Study

Gastroesophageal Reflux Disease (GERD) is multifactorial pathogenesis characterized by the abnormal reflux of stomach contents into the esophagus. Symptoms are worse after the ingestion of certain foods, such as coffee. Hence, a randomized pilot study conducted on 40 Italian subjects was assessed to verify the effect of standard (SC) and dewaxed coffee (DC) consumption on gastroesophageal reflux symptoms and quality of life in patients with gastrointestinal diseases. The assessment of patient diaries highlighted a significant percentage reduction of symptoms frequency when consuming DC and a significant increase in both heartburn-free and regurgitation-free days. Consequentially, patients had a significant increase of antacid-free days during the DC assumption. Moreover, the polyphenolic profile of coffee pods was ascertained through UHPLC-Q-Orbitrap HRMS analysis. Chlorogenic acids (CGAs) were the most abundant investigated compounds with a concentration level ranging between 7.316 (DC) and 6.721 mg/g (SC). Apart from CGAs, caffeine was quantified at a concentration level of 5.691 mg/g and 11.091 for DC and SC, respectively. While still preliminary, data obtained from the present pilot study provide promising evidence for the efficacy of DC consumption in patients with GERD. Therefore, this treatment might represent a feasible way to make coffee more digestible and better tolerated

The Blackholic energy and the canonical Gamma-Ray Burst IV: the "long", "genuine short" and "fake - disguised short" GRBs

(Shortened) [...] After recalling the basic features of the "fireshell model", we emphasize the following novel results: 1) the interpretation of the X-ray flares in GRB afterglows as due to the interaction of the optically thin fireshell with isolated clouds in the CircumBurst Medium (CBM); 2) an interpretation as "fake - disguised" short GRBs of the GRBs belonging to the class identified by Norris & Bonnell [...] consistent with an origin from the final coalescence of a binary system in the halo of their host galaxies with particularly low CBM density [...]; 3) the first attempt to study a genuine short GRB with the analysis of GRB 050509B, that reveals indeed still an open question; 4) the interpretation of the GRB-SN association in the case of GRB 060218 via the "induced gravitational collapse" process; 5) a first attempt to understand the nature of the "Amati relation", a phenomenological correlation between the isotropic-equivalent radiated energy of the prompt emission E_{iso} with the cosmological rest-frame \nu F_{\nu} spectrum peak energy E_{p,i}. In addition, recent progress on the thermalization of the electron-positron plasma close to their formation phase, as well as the structure of the electrodynamics of Kerr-Newman Black Holes are presented. An outlook for possible explanation of high-energy phenomena in GRBs to be expected from the AGILE and the Fermi satellites are discussed. As an example of high energy process, the work by Enrico Fermi dealing with ultrarelativistic collisions is examined. It is clear that all the GRB physics points to the existence of overcritical electrodynamical fields. In this sense we present some progresses on a unified approach to heavy nuclei and neutron stars cores, which leads to the existence of overcritical fields under the neutron star crust.Comment: 68 pages, 50 figures, in the Proceedings of the XIII Brazilian School on Cosmology and Gravitation, M. Novello, S.E. Perez-Bergliaffa, editor

Thromboembolic events and haematological diseases: a case of stroke as clinical onset of a paroxysmal nocturnal haemoglobinuria

Some haematological diseases are associated to an increased risk of thromboembolic events. We report a case of paroxysmal nocturnal haemoglobinuria (PNH) in which a cerebrovascular event represented the first clinical manifestation of disease. PNH is associated to thromboembolic events, generally of venous districts often involving unusual locations such as mesenteric vessels, sagittal veins, inferior vena cava and renal veins. To our knowledge arterial thrombotic episodes are rare and the involvement of arterial cerebral vessels is exceptional. Then, our case points out the importance of investigating about haematological disorders in all patients presenting with a stroke, in which the common predisposing conditions are excluded

Depressed Myocardial Energetic Efficiency Increases Risk of Incident Heart Failure: The Strong Heart Study

An estimation of myocardial mechano-energetic efficiency (MEE) per unit of left ventricular (LV) mass (MEEi) can significantly predict composite cardiovascular (CV) events in treated hypertensive patients with normal ejection fraction (EF), after adjustment for LV hypertrophy (LVH). We have tested whether MEEi predicts incident heart failure (HF), after adjustment for LVH, in the population-based cohort of a "Strong Heart Study" (SHS) with normal EF. We included 1,912 SHS participants (age 59 ± 8 years; 64% women) with preserved EF (≥50%) and without prevalent CV disease. MEE was estimated as the ratio of stroke work to the "double product" of heart rate times systolic blood pressure. MEEi was calculated as MEE/LV mass, and analyzed in quartiles. During a follow-up study of 9.2 ± 2.3 years, 126 participants developed HF (7%). HF was preceded by acute myocardial infarction (AMI) in 94 participants. A Kaplan-Meier plot, in quartiles of MEEi, demonstrated significant differences, substantially due to the deviation of the lowest quartile (p < 0.0001). Using AMI as a competing risk event, sequential models of Cox regression for incident HF (including significant confounders), demonstrated that low MEEi predicted incident HF not due to AMI (p = 0.026), after adjustment for significant effect of age, LVH, prolonged LV relaxation, diabetes, and smoking habits with negligible effects for sex, hypertension, antihypertensive therapy, obesity, and hyperlipemia. Low LV mechano-energetic efficiency per unit of LVM, is a predictor of incident, non-AMI related, HF in subjects with initially normal EF

A Novel Combination of High-Load Omega-3 Lysine Complex (AvailOm®) and Anthocyanins Exerts Beneficial Cardiovascular Effects

Omega-3 fatty acids have been shown to exert several beneficial effects in the prevention of cardiovascular and cerebrovascular diseases. The objective of the present study was to analyze the effects of a novel high-load omega-3 lysine complex, AvailOm®, its related constituents and a novel mixture of AvailOm® with specific vasoactive anthocyanins on vascular function in mice resistance artery. Pressure myograph was used to perform vascular reactivity studies. Nitric oxide and oxidative stress were assessed by difluorofluorescein diacetate and dihydroethidium, respectively. Increasing doses of AvailOm® exerted a dose-response vasorelaxation via AMPK-eNOS-mediated signaling. Omega-3 Ethyl Ester was identified as the main bioactive derivative of AvailOm®, being capable of inducing vasorelaxant action to the same extent of entire product. The combination of AvailOm® with a mix of potent vasoactive anthocyanins (C3-glu + DP3-glu + Mal3-glu + Mal3-gal + PEO3-gal), strongly protected mesenteric arteries from vascular dysfunction and oxidative stress evoked by oxidized-LDL. These data demonstrate for the first time the direct effects of AvailOm® on resistance arteries. The evidence that the combination of specific vasoactive anthocyanins and AvailOm® further enhanced the vasculoprotective properties of these compounds, may offer new promising perspectives for preventing the onset of cardiovascular and cerebrovascular events

Imatinib mesylate therapy in chronic myeloid leukemia patients in stable complete cytogenetic response after interferon-alpha results in any high complete molecular response.

To determine the impact on minimal residual disease by switching to imatinib chronic phase chronic myeloid leukaemia (CP-CML) patients responsive to interferon-alpha (IFNα), in stable complete cytogenetic response (CCR) but with persistent PCR positivity. Twenty-six Philadelphia positive (Ph+) CML patients in stable CCR after IFNα but persistently positive at PCR analysis during this treatment, were given imatinib mesylate at standard dose. At enrolment into the study, median IFN treatment and CCR duration were 88 months (range 15–202) and 73 months (range 10–148), respectively. Imatinib treatment resulted in a progressive and consistent decline of the residual disease as measured by quantitative PCR (RQ-PCR) in all but one of the 26 patients; at the end of follow-up, after a median of 32 months (range 21–49) of treatment, a major molecular response (BCR/ABL levels <0.1) was reached in 20 patients (77%), and BCR/ABL transcripts were undetectable in 13 (50%). The achievement of molecular response was significantly correlated with post-IFN baseline transcript level (mean 1.194 for patients achieving complete molecular response versus 18.97 for those who did not; p < 0.001), but not with other clinical/biological disease characteristics. These results indicate that patients induced into CCR by IFN treatment represent a subset with very favourable prognosis, which can significantly improve molecular response with imatinib and further support investigative treatment schedules combining these two drugs