Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma.

Purpose: Pazopanib, a multireceptor tyrosine kinase inhibitor targeting primarily VEGFRs1–3, is approved for advanced soft tissue sarcoma (STS) and renal cell cancer. Downstream of VEGFR, trametinib is an FDA-approved MEK inhibitor used for melanoma. We hypothesized that vertical pathway inhibition using trametinib would synergize with pazopanib in advanced STS. Experimental Design: In an open-label, multicenter, investigator-initiated National Comprehensive Cancer Network (NCCN)-sponsored trial, patients with metastatic or advanced STS received pazopanib 800 mg and 2 mg of trametinib continuously for 28-day cycles. The primary endpoint was 4-month progression-free survival (PFS). Secondary endpoints were overall survival, response rate, and disease control rate. Results: Twenty-five patients were enrolled. The median age was 49 years (range, 22–77 years) and 52% were male. Median PFS was 2.27 months [95% confidence interval (CI), 1.9–3.9], and the 4-month PFS rate was 21.1% (95% CI, 9.7–45.9), which was not an improvement over the hypothesized null 4-month PFS rate of 28.3% (P ¼ 0.79). Median overall survival was 9.0 months (95% CI, 5.7–17.7). A partial response occurred in 2 (8%) of the evaluable patients (95% CI, 1.0–26.0), one with PIK3CA E542K-mutant embryonal rhabdomyosarcoma and another with spindle cell sarcoma. The disease control rate was 14/25 (56%; 95% CI, 34.9–75.6). The most common adverse events were diarrhea (84%), nausea (64%), and fatigue (56%). Conclusions: The combination of pazopanib and trametinib was tolerable without indication of added activity of the combination in STS. Further study may be warranted in RAS/RAF aberrant sarcomas. ©2017 AACR

A phase-field model for fracture of unidirectional fiber-reinforced polymer matrix composites

This study presents a crack phase-field approach for anisotropic continua to model, in particular, fracture of fiber-reinforced matrix composites. Starting with the variational formulation of the multi-field problem of fracture in terms of the deformation and the crack phase fields, the governing equations feature the evolution of the anisotropic crack phase-field and the balance of linear momentum, presented for finite and small strains. A recently proposed energy-based anisotropic failure criterion is incorporated into the model with a constitutive threshold function regulating the crack initiation in regard to the matrix and the fibers in a superposed framework. Representative numerical examples are shown for the crack initiation and propagation in unidirectional fiber-reinforced polymer composites under Mode-I, Mode-II and mixed-mode bending. Model parameters are obtained by fitting to sets of experimental data. The associated finite element results are able to capture anisotropic crack initiation and growth in unidirectional fiber-reinforced composite laminates

Spectral characterizations and antibacterial effect of 2-(5-R-1H-benzimidazol-2-YL)-4-methyl/bromo-phenols and some metal complexes

2-(5-H/Cl/Me/NO2-1H-benzimidazol-2-yl)-4-Me/Br-phenols (HL1–HL5) were synthesized. HL1 complexes with Cu(NO3)2, AgNO3, Zn(ClO4)2 and; HL4, HL5 complexes with Zn(ClO4)2 were prepared. The structures of the compounds were confirmed on the basis of elemental analysis, molar conductivity, magnetic moment, FT-IR, 1H- and 13C-NMR. Antibacterial activity of the ligands and the complexes were evaluated using the disk diffusion method in dimethyl sulfoxide (DMSO) as well as the minimal inhibitory concentration (MIC) dilution method, against nine bacteria, and the results were compared with penicillin–G and oxytetracycline. While HL1 ligand has considerable antibacterial activity on B. cereus only; it’s Ag(I) complex show antibacterial effect toward almost all the bacteria. It is highly interesting that HL5 and [Zn(HL5)(L5)]ClO4 exhibit considerable high antibacterial activity toward K. pneumoniae, B. cereus, S. epidermidis and B. subtilis. KEY WORDS: Benzimidazole, Phenol, Metal complexes, Antibacterial activity  Bull. Chem. Soc. Ethiop. 2010, 24(3), 391-400

Vancomycin-resistant enterococci colonization in patients with hematological malignancies: screening and its cost-effectiveness

Background and objective: We evaluated the rates of vancomycin-resistant enterococci (VRE) colonization and VRE related bacteremia in patients with hematological malignancies in terms of routine screening culture and its cost-effectiveness.Materials and Methods: All patients of the hematology department who were older than 14 years of age and who developed at least one febrile neutropenia episode during chemotherapy for hematological cancers between November 2010 and November 2012 were evaluated retrospectively.Results: We retrospectively analyzed 282 febrile episodes in 126 neutropenic patients during a two-year study period. The study included 65 cases in the first study-year and 78 cases in the second study-year. The numbers of colonization days and colonized patient were 748 days of colonization in 29 patients (44%) in the first study-year and 547 colonization days in 21 patients (26%) in the second study-year, respectively. Routine screening culture for VRE cost $4516,4 (427 cultures) in the first study-year,$5082,7 (504 cultures) in the second study-year depending on the number of patients and their length of stay.Conclusion: In line with our study results, routine screening of hematological patients for VRE colonization is not costeffective. Routine surveillance culture for VRE should be considered with respect to the conditions of health care setting.Keywords: Hematological patients, febrile neutropenia, vancomycin-resistant enterococci, vancomycin-sensitive enterococci, bacteremia, colonization

Adipose tissue-specific ablation of PGC-1β impairs thermogenesis in brown fat

Adrenergic control; Lipid metabolism; MiceControl adrenèrgic; Metabolisme dels lípids; RatolinsControl adrenérgico; Metabolismo de los lípidos; RatonesImpaired thermogenesis observed in mice with whole-body ablation of peroxisome proliferator-activated receptor-γ coactivator-1β (PGC-1β; officially known as PPARGC1B) may result from impaired brown fat (brown adipose tissue; BAT) function, but other mechanism(s) could be involved. Here, using adipose-specific PGC-1β knockout mice (PGC-1β-AT-KO mice) we aimed to learn whether specific PGC-1β ablation in adipocytes is sufficient to drive cold sensitivity. Indeed, we found that warm-adapted (30°C) mutant mice were relatively sensitive to acute cold exposure (6°C). When these mice were subjected to cold exposure for 7 days (7-day-CE), adrenergic stimulation of their metabolism was impaired, despite similar levels of thermogenic uncoupling protein 1 in BAT in PGC-1β-AT-KO and wild-type mice. Gene expression in BAT of mutant mice suggested a compensatory increase in lipid metabolism to counteract the thermogenic defect. Interestingly, a reduced number of contacts between mitochondria and lipid droplets associated with low levels of L-form of optic atrophy 1 was found in BAT of PGC-1β-AT-KO mice. These genotypic differences were observed in warm-adapted mutant mice, but they were partially masked by 7-day-CE. Collectively, our results suggest a role for PGC-1β in controlling BAT lipid metabolism and thermogenesis.The research was supported by the Czech Science Foundation (Grantová Agentura České Republiky; 18-04483S) and by a grant from the Ministerio de Economía y Competitividad, co-funded by the European Regional Development Fund (ERDF) (RTI2018-099250-B-100 to J.A.V.)

Translational Research from an Informatics Perspective

Clinical and translational research (CTR) is an essential part of a sustainable global health system. Informatics is now recognized as an important en-abler of CTR and informaticians are increasingly called upon to help CTR efforts. The US National Institutes of Health mandated biomedical informatics activity as part of its new national CTR grant initiative, the Clinical and Translational Science Award (CTSA). Traditionally, translational re-search was defined as the translation of laboratory discoveries to patient care (bench to bedside). We argue, however, that there are many other kinds of translational research. Indeed, translational re-search requires the translation of knowledge dis-covered in one domain to another domain and is therefore an information-based activity. In this panel, we will expand upon this view of translational research and present three different examples of translation to illustrate the point: 1) bench to bedside, 2) Earth to space and 3) academia to community. We will conclude with a discussion of our local translational research efforts that draw on each of the three examples

A metabolomic strategy defines the regulation of lipid content and global metabolism by Δ9 desaturases in Caenorhabditis elegans.

BACKGROUND: Caenorhabditis elegans provides a genetically tractable model organism to investigate the network of genes involved in fat metabolism and how regulation is perturbed to produce the complex phenotype of obesity. C. elegans possess the full range of desaturases, including the Δ9 desaturases expressed by fat-5, fat-6 and fat-7. They regulate the biosynthesis of monounsaturated fatty acids, used for the synthesis of lipids including phospholipids, triglycerides and cholesteryl esters. RESULTS: Liquid chromatography mass spectrometry (LC-MS), gas chromatography mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) spectroscopy were used to define the metabolome of all the possible knock-outs for the Δ9 desaturases, including for the first time intact lipids. Despite the genes having similar enzymatic roles, excellent discrimination was achievable for all single and viable double mutants highlighting the distinctive roles of fat-6 and fat-7, both expressing steroyl-CoA desaturases. The metabolomic changes extend to aqueous metabolites demonstrating the influence Δ9 desaturases have on regulating global metabolism and highlighting how comprehensive metabolomics is more discriminatory than classically used dyes for fat staining. CONCLUSIONS: The propagation of metabolic changes across the network of metabolism demonstrates that modification of the Δ9 desaturases places C.elegans into a catabolic state compared with wildtype controls.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

An Exploratory Analysis of the Neural Correlates of Human-Robot Interactions With Functional Near Infrared Spectroscopy

Functional near infrared spectroscopy (fNIRS) has been gaining increasing interest as a practical mobile functional brain imaging technology for understanding the neural correlates of social cognition and emotional processing in the human prefrontal cortex (PFC). Considering the cognitive complexity of human-robot interactions, the aim of this study was to explore the neural correlates of emotional processing of congruent and incongruent pairs of human and robot audio-visual stimuli in the human PFC with fNIRS methodology. Hemodynamic responses from the PFC region of 29 subjects were recorded with fNIRS during an experimental paradigm which consisted of auditory and visual presentation of human and robot stimuli. Distinct neural responses to human and robot stimuli were detected at the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) regions. Presentation of robot voice elicited significantly less hemodynamic response than presentation of human voice in a left OFC channel. Meanwhile, processing of human faces elicited significantly higher hemodynamic activity when compared to processing of robot faces in two left DLPFC channels and a left OFC channel. Significant correlation between the hemodynamic and behavioral responses for the face-voice mismatch effect was found in the left OFC. Our results highlight the potential of fNIRS for unraveling the neural processing of human and robot audio-visual stimuli, which might enable optimization of social robot designs and contribute to elucidation of the neural processing of human and robot stimuli in the PFC in naturalistic conditions

Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy.

Preclinical models suggest that histone deacetylase (HDAC) and mammalian target of rapamycin (mTOR) inhibitors have synergistic anticancer activity. We designed a phase I study to determine the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of combined mTOR inhibitor sirolimus (1 mg-5 mg PO daily) and HDAC inhibitor vorinostat (100 mg-400 mg PO daily) in patients with advanced cancer. Seventy patients were enrolled and 46 (66%) were evaluable for DLT assessment since they completed cycle 1 without dose modification unless they had DLT. DLTs comprised grade 4 thrombocytopenia (n = 6) and grade 3 mucositis (n = 1). Sirolimus 4 mg and vorinostat 300 mg was declared RP2D because MTD with sirolimus 5 mg caused significant thrombocytopenia. The grade 3 and 4 drug-related toxic effects (including DLTs) were thrombocytopenia (31%), neutropenia (8%), anemia (7%), fatigue (3%), mucositis (1%), diarrhea (1%), and hyperglycemia (1%). Of the 70 patients, 35 (50%) required dose interruption or modification and 61 were evaluable for response. Partial responses were observed in refractory Hodgkin lymphoma (-78%) and perivascular epithelioid tumor (-54%), and stable disease in hepatocellular carcinoma and fibromyxoid sarcoma. In conclusion, the combination of sirolimus and vorinostat was feasible, with thrombocytopenia as the main DLT. Preliminary anticancer activity was observed in patients with refractory Hodgkin lymphoma, perivascular epithelioid tumor, and hepatocellular carcinoma