Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study results

Glasdegib is a Hedgehog pathway inhibitor. This ongoing, open-label, phase 2 study (NCT01546038) evaluated glasdegib plus cytarabine/daunorubicin in patients with untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). Patients received glasdegib 100 mg orally, once daily in continuous 28-day cycles from day -3, with intravenous cytarabine 100 mg/

Genomic patterns of malignant peripheral nerve sheath tumor (MPNST) evolution correlate with clinical outcome and are detectable in cell-free DNA

UNLABELLED: Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis. SIGNIFICANCE: MPNST is the most common cause of death and morbidity for individuals with NF1, a relatively common tumor predisposition syndrome. Our results suggest that somatic copy-number and methylation profiling of tumor or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups. This article is highlighted in the In This Issue feature, p. 517

Robotics-Inspired Methods for the Simulation of Conformational Changes in Proteins

Cette thèse présente une approche de modélisation inspirée par la robotique pour l'étude des changements conformationnels des protéines. Cette approche est basée sur une représentation mécanistique des protéines permettant l'application de méthodes efficaces provenant du domaine de la robotique. Elle fournit également une méthode appropriée pour le traitement gros-grains des protéines sans perte de détail au niveau atomique. L'approche présentée dans cette thèse est appliquée à deux types de problèmes de simulation moléculaire. Dans le premier, cette approche est utilisée pour améliorer l'échantillonnage de l'espace conformationnel des protéines. Plus précisément, cette approche de modélisation est utilisée pour implémenter des classes de mouvements pour l'échantillonnage, aussi bien connues que nouvelles, ainsi qu'une stratégie d'échantillonnage mixte, dans le contexte de la méthode de Monte Carlo. Les résultats des simulations effectuées sur des protéines ayant des topologies différentes montrent que cette stratégie améliore l'échantillonnage, sans toutefois nécessiter de ressources de calcul supplémentaires. Dans le deuxième type de problèmes abordés ici, l'approche de modélisation mécanistique est utilisée pour implémenter une méthode inspirée par la robotique et appliquée à la simulation de mouvements de grande amplitude dans les protéines. Cette méthode est basée sur la combinaison de l'algorithme RRT (Rapidly-exploring Random Tree) avec l'analyse en modes normaux, qui permet une exploration efficace des espaces de dimension élevée tels les espaces conformationnels des protéines. Les résultats de simulations effectuées sur un ensemble de protéines montrent l'efficacité de la méthode proposée pour l'étude des transitions conformationnellesProteins are biological macromolecules that play essential roles in living organisms. Un- derstanding the relationship between protein structure, dynamics and function is indis- pensable for advances in fields such as biology, pharmacology and biotechnology. Study- ing this relationship requires a combination of experimental and computational methods, whose development is the object of very active interdisciplinary research. In such a context, this thesis presents a robotics-inspired modeling approach for studying confor- mational changes in proteins. This approach is based on a mechanistic representation of proteins that enables the application of efficient methods originating from the field of robotics. It also provides an accurate method for coarse-grained treatment of proteins without loosing full-atom details.The presented approach is applied in this thesis to two different molecular simulation problems. First, the approach is used to enhance sampling of the conformational space of proteins using the Monte Carlo method. The modeling approach is used to implement new and known Monte Carlo trial move classes as well as a mixed sampling strategy. Results of simulations performed on proteins with different topologies show that this strategy enhances sampling without demanding higher computational resources. In the second problem tackled in this thesis, the mechanistic modeling approach is used to implement a robotics-inspired method for simulating large amplitude motions in proteins. This method is based on the combination of the Rapidly-exploring Random Tree (RRT) algorithm with Normal Mode Analysis (NMA), which allows efficient exploration of the high dimensional conformational spaces of proteins. Results of simulations performed on ten different proteins of different sizes and topologies show the effectiveness of the proposed method for studying conformational transitionsTOULOUSE-INSA-Bib. electronique (315559905) / SudocSudocFranceF

The effect of four commercially available steel decontamination processes on the performance of external coatings

External coatings used for corrosion protection often have to perform under severely corrosive environments. One major concern regarding coating performance is the negative effect of soluble salts on the steel substrate at the time of coating application, particularly for marine maintenance coating applications. These salts impact the ability of the applied coating systems to protect the steel in several ways including osmotic coating blistering, promotion of under-film metallic corrosion and coating disbondment. This paper focuses on removal of soluble salts contamination by commercially available decontamination processes in relation to external coating systems. We directly compare the effectiveness of four cleaning methods with the performance of ten coating systems. The methodology of surface contamination and preparation of test panels is discussed. After cleaning, sample evaluation for chloride ion contamination levels was carried out using Field method (commercial chloride ion test kit for surfaces) and Ion Chromatography method. Additionally, Scanning Electron Microscopy Energy Dispersive X-ray Spectroscopy (SEM/EDX) and elemental surface mapping analysis were carried out. Laboratory testing of coating systems included Adhesion, Porosity, Electrochemical Impedance Spectroscopy (EIS) analysis and cyclic UV/Salt Fog exposure. The performance of the ten coatings on all the substrates was good, but there were differences in gloss retention and on the degree of checking of the different coatings. The only significant difference in performance of the coatings compared to the method used for cleaning the substrate was higher undercreep observed for most of the coatings applied to the ultra-high pressure water jetted system. This shows the importance of substrate preparation due to the sensitivity of the coatings to even low levels of salt. Two coatings did not show increased undercreep and these may be more applicable for offshore maintenance applications where dry abrasive blasting is sometimes not used. The chemical treatment cleaning method used prior to coating application did not show any significant positive or negative effect on the performance of the applied coatings. The fact that the only differences in performance for the coatings applied to the differently prepared substrates was seen for undercreep suggests that the difference may be exacerbated for immersion situations. A follow up study to this one will examine the performance of internal coatings using immersion tests, and it will be interesting to see if these show increased effect on coating performance

Composition of Constraint, Hypothesis and Error Models to improve interaction in Human-Machine Interfaces

We use Weighted Finite-State Transducers (WFSTs) to represent the different sources of information available: the initial hypotheses, the possible errors, the constraints imposed by the task (interaction language) and the user input. The fusion of these models to find the most probable output string can be performed efficiently by using carefully selected transducer operations. The proposed system initially suggests an output based on the set of hypotheses, possible errors and Constraint Models. Then, if human intervention is needed, a multimodal approach, where the user input is combined with the aforementioned models, is applied to produce, with a minimum user effort, the desired output. This approach offers the practical advantages of a de-coupled model (e.g. input-system + parameterized rules + post-processor), keeping at the same time the error-recovery power of an integrated approach, where all the steps of the process are performed in the same formal machine (as in a typical HMM in speech recognition) to avoid that an error at a given step remains unrecoverable in the subsequent steps. After a presentation of the theoretical basis of the proposed multi-source information system, its application to two real world problems, as an example of the possibilities of this architecture, is addressed. The experimental results obtained demonstrate that a significant user effort can be saved when using the proposed procedure. A simple demonstration, to better understand and evaluate the proposed system, is available on the web https://demos.iti.upv.es/hi/. (C) 2015 Elsevier B.V. All rights reserved.Navarro Cerdan, JR.; Llobet Azpitarte, R.; Arlandis, J.; Perez-Cortes, J. (2016). Composition of Constraint, Hypothesis and Error Models to improve interaction in Human-Machine Interfaces. Information Fusion. 29:1-13. doi:10.1016/j.inffus.2015.09.001S1132

Child-OIDP index in Brazil: Cross-cultural adaptation and validation

Background: Oral health-related quality of life (OHRQoL) measures are being increasingly used to introduce dimensions excluded by normative measures. Consequently, there is a need for an index which evaluates children's OHRQoL validated for Brazilian population, useful for oral health needs assessments and for the evaluation of oral health programs, services and technologies. The aim of this study was to do a cross-cultural adaptation of the Child Oral Impacts on Daily Performances (Child-OIDP) index, and assess its reliability and validity for application among Brazilian children between the ages of eleven and fourteen. Methods: For cross-cultural adaptation, a translation/back-translation method integrated with expert panel reviews was applied. A total of 342 students from four public schools took part of the study. Results: Overall, 80.7% of the sample reported at least one oral impact in the last three months. Cronbach's alpha was 0.63, the weighted kappa 0.76, and the intraclass correlation coefficient (ICC) 0.79. The index had a significant association with self-reported health measurements (self-rated oral health, satisfaction with oral health, perceived dental treatment needs, self-rated general health; all p < 0.01). Conclusion: It was concluded that the Child-OIDP index is a measure of oral health-related quality of life that can be applied to Brazilian children

Pulmonary Hypertension Is a Frequent Event in Patients with Chronic Myeloid Leukemia Treated with Tyrosine Kinase Inhibitors

Poster presented at American Society of Clinical Oncology in Chicago Illinois. Background: Tyrosine kinase inhibitors (TKI) are the current standard therapy for patients with chronic myeloid leukemia (CML). Fluid retention and pleural effusions have been reported in patients treated with TKIs, particularly with dasatinib. Although TKIs have been shown to reverse pulmonary hypertension (PH) in animal models, there have been some reports of development of reversible PH with dasatinib. Methods: We conducted a retrospective analysis on 401 patients diagnosed with CML in chronic phase (CP) who were treated with TKIs (imatinib, dasatinib, or nilotinib) as initial therapy for CML and had a transthoracic echocardiogram (TTE) done at some point during the course of therapy. PH was diagnosed if the patient had an estimated right ventricular systolic pressure (RVSP) of 35 mm Hg or greater. Secondary causes of PH (systolic or diastolic dysfunction on TTE, chronic obstructive pulmonary diseases [COPD], obstructive sleep apnea [OSA] and pulmonary embolism) were investigated during chart review. Results: Twenty (23%) out of 87 patients had evidence of PH by TTE; median age 57 years, with 46% being males. Six pts (30%) received nilotinib 400mg twice daily, 4 (20%) patients had imatinib (400mg; n=1, 600mg; n=1 and 800mg daily; n=2), and 10 (50%) patients received dasatinib (dose varied 40-140mg daily). Five (25%) patients had coronary artery disease, 9 (45%) had systemic hypertension, 2 (10%) had COPD and 3 (15%) had OSA. Thirteen pts had serial TTE to compare the progression of PH including 6 (7%) who had a TTE prior to starting TKI. Among these 13 pts with serial TTE, 7 had rising RVSP with one patient having mild global hypokinesia, another with diastolic dysfunction and another with OSA. Four of those 7 patients had normal RVSP on their TTE prior to starting therapy. Six other pts had improvement in the RVSP on serial TTE, 4 of them with systemic hypertension. Two of those 6 patients had elevated RVSP on their TTE prior to starting therapy; one pt had no change. Eleven patients had pleural effusions (7 dasatinib, 3 imatinib, 1 nilotinib) associated with PH. Conclusions: TKI therapy is occasionally associated with development of PH, but RVSP may improve spontaneously in some patients. A prospective study is needed to further investigate the relationship between TKIs and the development of PH

Simple models of the chemical field around swimming plankton

Background. Cervical cancer is the fourth most common cancer in women, and we recently reported human leukocyte antigen (HLA) alleles showing strong associations with cervical neoplasia risk and protection. HLA ligands are recognized by killer immunoglobulin-like receptors (KIRs) expressed on a range of immune cell subsets, governing their proinflammatory activity. We hypothesized that the inheritance of particular HLA-KIR combinations would increase cervical neoplasia risk. Methods. Here, we used HLA and KIR dosages imputed from single-nucleotide polymorphism genotype data from 2143 cervical neoplasia cases and 13 858 healthy controls of European decent. Results. The following 4 novel HLA alleles were identified in association with cervical neoplasia, owing to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles: HLA-DRB3*9901 (odds ratio [OR], 1.24; P = 2.49 × 10−9), HLA-DRB5*0101 (OR, 1.29; P = 2.26 × 10−8), HLA-DRB5*9901 (OR, 0.77; P = 1.90 × 10−9), and HLA-DRB3*0301 (OR, 0.63; P = 4.06 × 10−5). We also found that homozygosity of HLA-C1 group alleles is a protective factor for human papillomavirus type 16 (HPV16)-related cervical neoplasia (C1/C1; OR, 0.79; P = .005). This protective association was restricted to carriers of either KIR2DL2 (OR, 0.67; P = .00045) or KIR2DS2 (OR, 0.69; P = .0006). Conclusions. Our findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism