Screening for hotspot mutations in PI3K, JAK2, FLT3 and NPM1 in patients with myelodysplastic syndromes

INTRODUCTION: Myelodysplastic syndromes encompass a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, refractory cytopenia and a tendency to progress toward acute myeloid leukemia. The accumulation of genetic alterations is closely associated with the progression of myelodysplastic syndromes toward acute myeloid leukemia. OBJECTIVE: To investigate the presence of mutations in the points most frequent for mutations (hotspot mutations) in phosphatidylinositol-3-kinase (PI3K), Janus kinase 2 (JAK2), FMS-like tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1), which are involved in leukemia and other cancers, in a population of Brazilian MDS patients. METHODS: Fifty-one myelodysplastic syndromes patients were included in the study. According to French-American-British classification, the patients were distributed as follows: 31 with refractory anemia, 8 with refractory anemia with ringed sideroblasts, 7 with refractory anemia with excess blasts, 3 with refractory anemia with excess blasts in transformation and 2 with chronic myelomonocytic leukemia. Bone marrow samples were obtained and screened for the presence of hotspot mutations using analysis based on amplification with the polymerase chain reaction, sequencing, fragment size polymorphisms or restriction enzyme digestion. All patients were screened for mutations at the time of diagnosis, and 5 patients were also screened at the time of disease progression. RESULTS: In the genes studied, no mutations were detected in the patients at the time of diagnosis. One patient with chronic myelomonocytic leukemia was heterozygous for a Janus kinase 2 mutation after disease progression. CONCLUSIONS: These results show that hotspot mutations in the PI3K, JAK2, FLT3 and NPM1 genes are not common in MDS patients; nevertheless, JAK2 mutations may be present in myelodysplasia during disease progression

A Schur complement approach to preconditioning sparse linear least-squares problems with some dense rows

The effectiveness of sparse matrix techniques for directly solving large-scale linear least-squares problems is severely limited if the system matrix A has one or more nearly dense rows. In this paper, we partition the rows of A into sparse rows and dense rows (A s and A d ) and apply the Schur complement approach. A potential difficulty is that the reduced normal matrix AsTA s is often rank-deficient, even if A is of full rank. To overcome this, we propose explicitly removing null columns of A s and then employing a regularization parameter and using the resulting Cholesky factors as a preconditioner for an iterative solver applied to the symmetric indefinite reduced augmented system. We consider complete factorizations as well as incomplete Cholesky factorizations of the shifted reduced normal matrix. Numerical experiments are performed on a range of large least-squares problems arising from practical applications. These demonstrate the effectiveness of the proposed approach when combined with either a sparse parallel direct solver or a robust incomplete Cholesky factorization algorithm

Application of the Jacobi Davidson method for spectral low-rank preconditioning in computational electromagnetics problems

[EN] We consider the numerical solution of linear systems arising from computational electromagnetics applications. For large scale problems the solution is usually obtained iteratively with a Krylov subspace method. It is well known that for ill conditioned problems the convergence of these methods can be very slow or even it may be impossible to obtain a satisfactory solution. To improve the convergence a preconditioner can be used, but in some cases additional strategies are needed. In this work we study the application of spectral lowrank updates (SLRU) to a previously computed sparse approximate inverse preconditioner.The updates are based on the computation of a small subset of the eigenpairs closest to the origin. Thus, the performance of the SLRU technique depends on the method available to compute the eigenpairs of interest. The SLRU method was first used using the IRA s method implemented in ARPACK. In this work we investigate the use of a Jacobi Davidson method, in particular its JDQR variant. The results of the numerical experiments show that the application of the JDQR method to obtain the spectral low-rank updates can be quite competitive compared with the IRA s method.Mas Marí, J.; Cerdán Soriano, JM.; Malla Martínez, N.; Marín Mateos-Aparicio, J. (2015). Application of the Jacobi Davidson method for spectral low-rank preconditioning in computational electromagnetics problems. Journal of the Spanish Society of Applied Mathematics. 67:39-50. doi:10.1007/s40324-014-0025-6S395067Bergamaschi, L., Pini, G., Sartoretto, F.: Computational experience with sequential, and parallel, preconditioned Jacobi–Davidson for large sparse symmetric matrices. J. Comput. Phys. 188(1), 318–331 (2003)Carpentieri, B.: Sparse preconditioners for dense linear systems from electromagnetics applications. PhD thesis, Institut National Polytechnique de Toulouse, CERFACS (2002)Carpentieri, B., Duff, I.S., Giraud, L.: Sparse pattern selection strategies for robust Frobenius-norm minimization preconditioners in electromagnetism. Numer. Linear Algebr. Appl. 7(7–8), 667–685 (2000)Carpentieri, B., Duff, I.S., Giraud, L.: A class of spectral two-level preconditioners. SIAM J. Sci. Comput. 25(2), 749–765 (2003)Carpentieri, B., Duff, I.S., Giraud, L., Magolu monga Made, M.: Sparse symmetric preconditioners for dense linear systems in electromagnetism. Numer. Linear Algebr. Appl. 11(8–9), 753–771 (2004)Carpentieri, B., Duff, I.S., Giraud, L., Sylvand, G.: Combining fast multipole techniques and an approximate inverse preconditioner for large electromagnetism calculations. SIAM J. Sci. Comput. 27(3), 774–792 (2005)Darve, E.: The fast multipole method I: error analysis and asymptotic complexity. SIAM J. Numer. Anal. 38(1), 98–128 (2000)Fokkema, D.R., Sleijpen, G.L., Van der Vorst, H.A.: Jacobi–Davidson style QR and QZ algorithms for the reduction of matrix pencils. SIAM J. Sci. Comput. 20(1), 94–125 (1998)Greengard, L., Rokhlin, V.: A fast algorithm for particle simulations. J. Comput. Phys. 73(3), 325–348 (1987)Grote, M., Huckle, T.: Parallel preconditioning with sparse approximate inverses. SIAM J. Sci. Comput. 18(3), 838–853 (1997)Harrington, R.: Origin and development of the method of moments for field computation. IEEE Antenna Propag. Mag. (1990)Kunz, K.S., Luebbers, R.J.: The finite difference time domain method for electromagnetics. SIAM J. Sci. Comput. 18(3), 838–853 (1997)Maxwell, J.C.: A dynamical theory of the electromagnetic field. Roy. S. Trans. CLV, (1864). Reprinted in Tricker, R. A. R. The Contributions of Faraday and Maxwell to Electrial Science, Pergamon Press (1966)Marín, J., Malla M.: Some experiments preconditioning via spectral low rank updates for electromagnetism applications. In: Proceedings of the international conference on preconditioning techniques for large sparse matrix problems in scientific and industrial applications (Preconditioning 2007), Toulouse (2007)Meijerink, J.A., van der Vorst, H.A.: An iterative solution method for linear systems of which the coefficient matrix is a symmetric M-matrix. Math. Comput. 31, 148–162 (1977)Sorensen, D.C., Lehoucq, R.B., Yang, C.: ARPACK users’ guide: solution of large-scale eigenvalue problems with implicitly restarted Arnoldi methods. SIAM, Philadelphia (1998)Rao, S.M., Wilton, D.R., Glisson, A.W.: Electromagnetic scattering by surfaces of arbitrary shape. IEEE Trans. Antenna Propag. 30, 409–418 (1982)Saad, Y.: Iterative methods for sparse linear systems. PWS Publishing Company, Boston (1996)Silvester, P.P., Ferrari, R.L.: Finite elements for electrical engineers. Cambridge University Press, Cambridge (1990)Sleijpen, S.L., van der Vorst, H.A.: A Jacobi–Davidson iteration method for linear eigenvalue problems. SIAM J. Matrix Anal. Appl. 17, 401–425 (1996)van der Vorst, H.A.: Bi-CGSTAB: a fast and smoothly converging variant of Bi-CG for the solution of non-symmetric linear systems. SIAM J. Sci. Stat. Comput. 12(6), 631–644 (1992

The interplay of microscopic and mesoscopic structure in complex networks

Not all nodes in a network are created equal. Differences and similarities exist at both individual node and group levels. Disentangling single node from group properties is crucial for network modeling and structural inference. Based on unbiased generative probabilistic exponential random graph models and employing distributive message passing techniques, we present an efficient algorithm that allows one to separate the contributions of individual nodes and groups of nodes to the network structure. This leads to improved detection accuracy of latent class structure in real world data sets compared to models that focus on group structure alone. Furthermore, the inclusion of hitherto neglected group specific effects in models used to assess the statistical significance of small subgraph (motif) distributions in networks may be sufficient to explain most of the observed statistics. We show the predictive power of such generative models in forecasting putative gene-disease associations in the Online Mendelian Inheritance in Man (OMIM) database. The approach is suitable for both directed and undirected uni-partite as well as for bipartite networks

Depression, Suicidal Tendencies, Hopelessness, and Stress among Patients with Learning Disabilities

Self-harm and suicide are most commonly observed in adolescents specially females in Asian countries and in western. The psychosocial predictors, along with hopelessness and non-suicidal injury (NSSI), have not been studied properly before. Therefore, there is a need to address these issues. The objective of the study was to ascertain the psychosocial and clinical features predicting suicide and NSSI in adolescents with major depression. Increased number of suicidality and impaired family function at entry is autonomously connected with a suicidal attempt. NSSI are connected at base line and apply additive effect on likelihood, one keeping on through treatment period. Poor family functions, as well as family problems and social problems, were the causative agents for adolescent’s high suicidality and NSSI. A history of NSSI treatment is a clinical marker for suicidality. The previous suicidal attempts should be evaluated in depressed juvenile patients as indicators of future suicidal intent and behavior. Both suicidal and NSSI adolescents during the therapy and after treatment endure to be depressed when they are engaged in study. Major causes of suicide among our study participants were lost friend(s), drug abuse, living alone, disturbed parental marriage, sexual abuse, and other domestic problems

Dead on arrival in a low-income country: results from a multicenter study in Pakistan

BACKGROUND: This study assessed the characteristics of dead on arrival (DOA) patients in Pakistan. METHODS: Data about the DOA patients were extracted from Pakistan National Emergency Department Surveillance study (Pak-NEDS). This study recruited all ED patients presenting to seven tertiary care hospitals during a four-month period between November 2010 and March 2011. This study included patients who were declared dead-on-arrival by the ED physician. RESULTS: A total of 1,557 DOA patients (7 per 1,000 visits) were included in the Pak-NEDS. Men accounted for two-thirds (64%) of DOA patients. Those aged 20-49 years accounted for about 46% of DOA patients. Nine percent (n = 72) of patients were brought by ambulance, and most patients presented at a public hospital (80%). About 11% of DOA patients had an injury. Factors significantly associated (p \u3c 0.05) with ambulance use were men (adjusted odds ratio [aOR] = 2.72), brought to a private hospital (OR = 2.74), and being injured (aOR = 1.89). Cardiopulmonary resuscitation (CPR) was performed on 6% (n = 42) of patients who received treatment. Those brought to a private hospital were more likely to receive CPR (aOR = 2.81). CONCLUSION: This study noted a higher burden of DOA patients in Pakistan compared to other resourceful settings (about 1 to 2 per 1,000 visits). A large proportion of patients belonging to productive age groups, and the low prevalence of ambulance and CPR use, indicate a need for improving the prehospital care and basic life support training in pakistan

Managing bone mineral density with oral bisphosphonate therapy in women with breast cancer receiving adjuvant aromatase inhibition

The use of adjuvant aromatase inhibitors is associated with an increased risk of osteoporosis and fractures. The oral bisphosphonate, risedronate - dosed as the US Food and Drug Administration approved for the treatment or prevention of postmenopausal osteoporosis - appears to mitigate bone loss associated with 2 years of adjuvant anastrozole in women with early-stage breast cancer

Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases

PURPOSE: Bone metastases secondary to solid tumors increase the risk of skeletal-related events (SREs), including the occurrence of pathological fracture (PF), radiation to bone (RB), surgery to bone (SB), and spinal cord compression (SCC). The aim of this study was to evaluate the impact of SREs on patients' pain, analgesic use, and pain interference with daily functioning. METHODS: Data were combined from patients with solid tumors and bone metastases who received denosumab or zoledronic acid across three identically designed phase 3 trials (N = 5543). Pain severity (worst pain) and pain interference were assessed using the Brief Pain Inventory at baseline and each monthly visit. Analgesic use was quantified using the Analgesic Quantification Algorithm. RESULTS: The proportion of patients with moderate/severe pain and strong opioid use generally increased in the 6 months preceding an SRE and remained elevated, while they remained relatively consistent over time in patients without an SRE. Regression analysis indicated that all SRE types were significantly associated with an increased risk of progression to moderate/severe pain and strong opioid use. PF, RB, and SCC were associated with significantly greater risk of pain interference overall. Results were similar for pain interference with emotional well-being. All SRE types were associated with significantly greater risk of pain interference with physical function. CONCLUSIONS: SREs are associated with increased pain and analgesic use in patients with bone metastases. Treatments that prevent SREs may decrease pain and the need for opioid analgesics and reduce the impact of pain on daily functioning

Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases

PURPOSE: Bone metastases secondary to solid tumors increase the risk of skeletal-related events (SREs), including the occurrence of pathological fracture (PF), radiation to bone (RB), surgery to bone (SB), and spinal cord compression (SCC). The aim of this study was to evaluate the impact of SREs on patients' pain, analgesic use, and pain interference with daily functioning. METHODS: Data were combined from patients with solid tumors and bone metastases who received denosumab or zoledronic acid across three identically designed phase 3 trials (N = 5543). Pain severity (worst pain) and pain interference were assessed using the Brief Pain Inventory at baseline and each monthly visit. Analgesic use was quantified using the Analgesic Quantification Algorithm. RESULTS: The proportion of patients with moderate/severe pain and strong opioid use generally increased in the 6 months preceding an SRE and remained elevated, while they remained relatively consistent over time in patients without an SRE. Regression analysis indicated that all SRE types were significantly associated with an increased risk of progression to moderate/severe pain and strong opioid use. PF, RB, and SCC were associated with significantly greater risk of pain interference overall. Results were similar for pain interference with emotional well-being. All SRE types were associated with significantly greater risk of pain interference with physical function. CONCLUSIONS: SREs are associated with increased pain and analgesic use in patients with bone metastases. Treatments that prevent SREs may decrease pain and the need for opioid analgesics and reduce the impact of pain on daily functioning