Management of imatinib-resistant CML patients

Imatinib has had marked impact on outcomes in chronic myelogenous leukemia (CML) patients for all stages of the disease and is endorsed by international treatment guidelines as the first line option. Although imatinib is highly effective and well tolerated, the development of resistance represents a clinical challenge. Since the most frequently identified mechanism of acquired imatinib resistance is bcr-abl kinase domain point mutations, periodic hematologic, cytogenetic, and molecular monitoring is critical throughout imatinib therapy. Once cytogenetic remission is achieved, residual disease can be monitored by bcr-abl transcript levels as assayed by reverse transcription polymerase chain reaction (RT-PCR). Detection of bcr-abl mutants prior to and during imatinib therapy can aid in risk stratification as well as in determining therapeutic strategies. Thus, mutation screening is indicated in patients lacking or losing hematologic response. Moreover, search for mutations should also be performed when a 3-log reduction of bcr-abl transcripts is not achieved or there is a reproducible increase of transcript levels. In patients harboring mutations which confer imatinib resistance, novel second line tyrosine kinase inhibitors have demonstrated encouraging efficacy with low toxicity. Only the T315I bcr-abl mutant has proved totally resistant to all clinically available bcr-abl inhibitors. Strategies to further increase the rates of complete molecular remissions represent the next frontier in the targeted therapy of CML patients

Learning environment, attitudes and anxiety across the transition from primary to secondary school mathematics

Past research has revealed that, relative to primary-school students, high-school students have less-positive attitudes to mathematics and perceive their classroom environments and teacher–student relationships less favourably. This study involved the transition experience of 541 students in 47 classes in 15 primary (year 7) and secondary (year 8) government and Catholic schools in metropolitan and regional South Australia. Scales were adapted from three established instruments, namely, the What Is Happening In this Class?, Test of Mathematics Related Attitudes and Revised Mathematics Anxiety Ratings Scale, to identify changes across the transition from primary to secondary school in terms of the classroom learning environment and students’ attitude/anxiety towards mathematics. Relative to year 7 students, year 8 students reported less Involvement, less positive Attitude to Mathematical Inquiry, less Enjoyment of Mathematics and greater Mathematics Anxiety. Differences between students in Years 7 and 8 were very similar for male and female students, although the magnitude of sex differences in attitudes was slightly different in Years 7 and 8

The effect of the dual Src/Abl kinase inhibitor AZD0530 on Philadelphia positive leukaemia cell lines

Background Imatinib mesylate, a selective inhibitor of Abl tyrosine kinase, is efficacious in treating chronic myeloid leukaemia (CML) and Ph+ acute lymphoblastic leukaemia (ALL). However, most advanced-phase CML and Ph+ ALL patients relapse on Imatinib therapy. Several mechanisms of refractoriness have been reported, including the activation of the Src-family kinases (SFK). Here, we investigated the biological effect of the new specific dual Src/Abl kinase inhibitor AZD0530 on Ph+ leukaemic cells. Methods Cell lines used included BV173 (CML in myeloid blast crisis), SEM t(4;11), Ba/F3 (IL-3 dependent murine pro B), p185Bcr-Abl infected Ba/F3 cells, p185Bcr-Abl mutant infected Ba/F3 cells, SupB15 (Ph+ ALL) and Imatinib resistant SupB15 (RTSupB15) (Ph+ ALL) cells. Cells were exposed to AZD0530 and Imatinib. Cell proliferation, apoptosis, survival and signalling pathways were assessed by dye exclusion, flow cytometry and Western blotting respectively. Results AZD0530 specifically inhibited the growth of, and induced apoptosis in CML and Ph+ ALL cells in a dose dependent manner, but showed only marginal effects on Ph- ALL cells. Resistance to Imatinib due to the mutation Y253F in p185Bcr-Abl was overcome by AZD0530. Combination of AZD0530 and Imatinib showed an additive inhibitory effect on the proliferation of CML BV173 cells but not on Ph+ ALL SupB15 cells. An ongoing transphosphorylation was demonstrated between SFKs and Bcr-Abl. AZD0530 significantly down-regulated the activation of survival signalling pathways in Ph+ cells, resistant or sensitive to Imatinib, with the exception of the RTSupB15. Conclusion Our results indicate that AZD0530 targets both Src and Bcr-Abl kinase activity and reduces the leukaemic maintenance by Bcr-Abl

New dosing schedules of dasatinib for CML and adverse event management

Resistance to imatinib in patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has emerged as a significant clinical issue. Dasatinib is a tyrosine kinase inhibitor that has 325-fold greater in vitro activity against native BCR-ABL (breakpoint cluster region-Abelson leukemia virus) compared with imatinib and can overcome primary (intrinsic) and secondary (acquired) imatinib resistance. Here, we review the clinical profile of dasatinib in imatinib-resistant and -intolerant patients and share clinical approaches for managing adverse events (AEs) to ensure maximum patient benefit. References were obtained through literature searches on PubMed as well as from the Proceedings of Annual Meetings of the American Society of Clinical Oncology, the American Society of Hematology, and European Hematology Association. Phase II and III studies of dasatinib in patients with imatinib-resistant or -intolerant CML in any phase or Ph+ ALL were selected for discussion. Dasatinib is currently indicated for the treatment of patients with imatinib-resistant or -intolerant CML or Ph+ ALL. AEs associated with dasatinib are typically mild to moderate, and are usually resolved with temporary treatment interruption and/or dose adjustments. A Phase III dose optimization study showed that in patients with chronic phase (CP) CML, 100 mg once-daily dasatinib improves the safety profile, particularly pleural effusion and thrombocytopenia, while maintaining efficacy compared with the previously recommended dose of 70 mg twice-daily. Dasatinib has a manageable safety profile. For patients with CP CML, a new recommended starting dose of 100 mg once daily has recently been approved. The recommended dose for patients with advanced CML or Ph+ ALL remains 70 mg twice daily

Micronuclei formation in liver fibrosis samples from patients infected by hepatitis C virus

Genetic research on fibrosis outset and its progression in chronic hepatitis (CH) by hepatitis C virus (HCV) are limited. The lack of cytogenetic data led us to investigate the presence of micronuclei (MNi), as a sign of genomic damage. Hepatocytes of hepatic parenchyma from 62 cases diagnosed with CH associated with HCV and displaying different degrees of fibrosis (F1-F4) were analyzed. These data were compared to 15 cases without fibrosis (F0). Twelve healthy liver parenchyma samples were included as control. All samples were obtained from paraffin-embedded archival material. Micronucleated hepatocytes (MN-Heps) were analyzed through Feulgen/Fast-green staining. Results showed that the rates of MN-Heps in the F4 group were statistically significant (p < 0.05) and higher than those in the control group. Like results were also obtained on comparing F4 with F0, F1, F2 and F3 cases. Conversely, differences were not significant (p > 0.05) on comparing F0, F1, F2, F3, one against the other, as well as individual versus control. Although chromosomal losses in CH were detected, it was shown that liver parenchyma with fibrosis in the initial stages (F1-F3) cannot be considered cytogenetically abnormal

Echocardiography in patients with hypertrophic cardiomyopathy: usefulness of old and new techniques in the diagnosis and pathophysiological assessment

Hypertrophic cardiomyopathy (HCM) is one of the most common inherited cardiomyopathy. The identification of patients with HCM is sometimes still a challenge. Moreover, the pathophysiology of the disease is complex because of left ventricular hyper-contractile state, diastolic dysfunction, ischemia and obstruction which can be coexistent in the same patient. In this review, we discuss the current and emerging echocardiographic methodology that can help physicians in the correct diagnostic and pathophysiological assessment of patients with HCM

A lack of association between elevated serum levels of S100B protein and autoimmunity in autistic children

<p>Abstract</p> <p>Background</p> <p>S100B is a calcium-binding protein that is produced primarily by astrocytes. Increased serum S100B protein levels reflect neurological damage. Autoimmunity may have a role in the pathogenesis of autism in some patients. Autoantibodies may cross the blood-brain barrier and combine with brain tissue antigens, forming immune complexes and resulting in neurological damage. We are the first to investigate the relationship between serum levels of S100B protein, a marker of neuronal damage, and antiribosomal P protein antibodies in autistic children.</p> <p>Methods</p> <p>Serum S100B protein and antiribosomal P antibodies were measured in 64 autistic children in comparison to 46 matched healthy children.</p> <p>Results</p> <p>Autistic children had significantly higher serum S100B protein levels than healthy controls (<it>P </it>< 0.001). Children with severe autism had significantly higher serum S100B protein than patients with mild to moderate autism (<it>P </it>= 0.01). Increased serum levels of antiribosomal P antibodies were found in 40.6% of autistic children. There were no significant correlations between serum levels of S100B protein and antiribosomal P antibodies (<it>P </it>= 0.29).</p> <p>Conclusions</p> <p>S100B protein levels were elevated in autistic children and significantly correlated to autistic severity. This may indicate the presence of an underlying neuropathological condition in autistic patients. Antiribosomal P antibodies may not be a possible contributing factor to the elevated serum levels of S100B protein in some autistic children. However, further research is warranted to investigate the possible link between serum S100B protein levels and other autoantibodies, which are possible indicators of autoimmunity to central nervous system in autism.</p

A review of elliptical and disc galaxy structure, and modern scaling laws

A century ago, in 1911 and 1913, Plummer and then Reynolds introduced their models to describe the radial distribution of stars in `nebulae'. This article reviews the progress since then, providing both an historical perspective and a contemporary review of the stellar structure of bulges, discs and elliptical galaxies. The quantification of galaxy nuclei, such as central mass deficits and excess nuclear light, plus the structure of dark matter halos and cD galaxy envelopes, are discussed. Issues pertaining to spiral galaxies including dust, bulge-to-disc ratios, bulgeless galaxies, bars and the identification of pseudobulges are also reviewed. An array of modern scaling relations involving sizes, luminosities, surface brightnesses and stellar concentrations are presented, many of which are shown to be curved. These 'redshift zero' relations not only quantify the behavior and nature of galaxies in the Universe today, but are the modern benchmark for evolutionary studies of galaxies, whether based on observations, N-body-simulations or semi-analytical modelling. For example, it is shown that some of the recently discovered compact elliptical galaxies at 1.5 < z < 2.5 may be the bulges of modern disc galaxies.Comment: Condensed version (due to Contract) of an invited review article to appear in "Planets, Stars and Stellar Systems"(www.springer.com/astronomy/book/978-90-481-8818-5). 500+ references incl. many somewhat forgotten, pioneer papers. Original submission to Springer: 07-June-201

Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at √s = 7 TeV with the ATLAS detector

This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of √s = 7 TeV;{\rm Te}{\rm V}$and correspond to an integrated luminosity of$4.6\;{\rm f}{{{\rm b}}^{-1}}$. The measurement is performed by reconstructing the boosted W or Z bosons in single jets. The reconstructed jet mass is used to identify the W and Z bosons, and a jet substructure method based on energy cluster information in the jet centre-of-mass frame is used to suppress the large multi-jet background. The cross-section for events with a hadronically decaying W or Z boson, with transverse momentum${{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}$and pseudorapidity$|\eta |\lt 1.9$, is measured to be${{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT