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Target-to treat

Pei Y Liu, Nicholas Sokolowski, Su T Guo, Faraz Siddiqi, Bernard Atmadibrata, Thomas J Telfer, Yuting Sun, Lihong Zhang, Denise Yu, Joshua Mccarroll, Bing Liu, Rui H Yang, Xiang Y Guo, Andrew E Tee, Ken Itoh, Jenny Wang, Maria Kavallaris, Michelle Haber, Murray D Norris, Belamy B Cheung, Jennifer A Byrne, David S Ziegler, Glenn M Marshall, Marcel E Dinger, Rachel Codd, Xu D Zhang, Tao Liu
BET bromodomain inhibitors are very promising novel anticancer agents, however, single therapy does not cause tumor regression in mice, suggesting the need for combination therapy. After screening a library of 2697 small molecule compounds, we found that two classes of compounds, the quinone-containing compounds such as nanaomycin and anti-microtubule drugs such as vincristine, exerted the best synergistic anticancer effects with the BET bromodomain inhibitor JQ1 in neuroblastoma cells. Mechanistically, the quinone-containing compound nanaomycin induced neuroblastoma cell death but also activated the Nrf2-antioxidant signaling pathway, and the BET bromodomain proteins BRD3 and BRD4 formed a protein complex with Nrf2...
October 13, 2016: Oncotarget
James P Strassner, John E Harris
Vitiligo is an autoimmune disease of the skin that leads to life-altering depigmentation and remains difficult to treat. However, clinical observations and translational studies over 30-40 years have led to the development of an insightful working model of disease pathogenesis: Genetic risk spanning both immune and melanocyte functions is pushed over a threshold by known and suspected environmental factors to initiate autoimmune T cell-mediated killing of melanocytes. While under cellular stress, melanocytes appear to signal innate immunity to activate T cells...
October 17, 2016: Current Opinion in Immunology
Xianxiu Wan, Jian-Jun Wen, Sue-Jie Koo, Lisa Yi Liang, Nisha Jain Garg
Chronic chagasic cardiomyopathy (CCM) is presented by increased oxidative/inflammatory stress and decreased mitochondrial bioenergetics. SIRT1 senses the redox changes and integrates mitochondrial metabolism and inflammation; and SIRT1 deficiency may be a major determinant in CCM. To test this, C57BL/6 mice were infected with Trypanosoma cruzi (Tc), treated with SIRT1 agonists (resveratrol or SRT1720), and monitored during chronic phase (~150 days post-infection). Resveratrol treatment was partially beneficial in controlling the pathologic processes in Chagas disease...
October 2016: PLoS Pathogens
Qie He, Junfeng Zhu, David Dingli, Jasmine Foo, Kevin Zox Leder
Over the past decade, several targeted therapies (e.g. imatinib, dasatinib, nilotinib) have been developed to treat Chronic Myeloid Leukemia (CML). Despite an initial response to therapy, drug resistance remains a problem for some CML patients. Recent studies have shown that resistance mutations that preexist treatment can be detected in a substantial number of patients, and that this may be associated with eventual treatment failure. One proposed method to extend treatment efficacy is to use a combination of multiple targeted therapies...
October 2016: PLoS Computational Biology
Gerard Adams, Matthew Foote, Simon Brown, Bryan Burmeister
Radiotherapy after lymph node dissection is recommended in high-risk melanoma cases. The aim of this study is to assess whether intensity-modulated radiotherapy (IMRT) offers advantages over three-dimensional conformal radiotherapy (3DCRT) in the groin nodal basin. Fifteen consecutively treated patients (5 3DCRT and 10 IMRT) were selected. Optimized theoretical plans using the other modality were created - enabling direct comparisons of 3DCRT and IMRT. Target volume and organs at risk constraints were assessed as achieved or as having minor (≤5%) or major (>5%) deviations...
October 19, 2016: Melanoma Research
Grzegorz Fila, Anna Kawiak, Mariusz Grinholc
Pseudomonas aeruginosa is among the most common pathogens responsible for both acute and chronic infections of high incidence and severity. Additionally, P. aeruginosa resistance to conventional antimicrobials has increased rapidly over the past decade. Therefore, it is crucial to explore new therapeutic options, particularly options that specifically target the pathogenic mechanisms of this microbe. The ability of a pathogenic bacterium to cause disease is dependent upon the production of agents termed 'virulence factors', and approaches to mitigate these agents have gained increasing attention as new antibacterial strategies...
October 20, 2016: Virulence
Lu Cao, Mingui Fu, Santosh Kumar, Anil Kumar
Methamphetamine (METH), a commonly used controlled substance, is known to exacerbate neuropathological dysfunction in HIV-infected individuals. The neuropathological manifestation results from cell death or dysfunction in the central nervous system (CNS) wherein autophagy is expected to have an important role. Autophagy is generally considered protective during deprivation/stress. However, excessive autophagy can be destructive, leading to autophagic cell death. This study was designed to investigate if METH and HIV-1 gp120 interact to induce autophagy in SVGA astrocytes, and whether autophagy is epiphenomenal or it has a role in METH- and gp120-induced cytotoxicity...
October 20, 2016: Cell Death & Disease
Kipp Weiskopf, Peter J Schnorr, Wendy W Pang, Mark P Chao, Akanksha Chhabra, Jun Seita, Mingye Feng, Irving L Weissman
The hematopoietic stem cell (HSC) is a multipotent stem cell that resides in the bone marrow and has the ability to form all of the cells of the blood and immune system. Since its first purification in 1988, additional studies have refined the phenotype and functionality of HSCs and characterized all of their downstream progeny. The hematopoietic lineage is divided into two main branches: the myeloid and lymphoid arms. The myeloid arm is characterized by the common myeloid progenitor and all of its resulting cell types...
October 2016: Microbiology Spectrum
Jennie Engstrand, Grzegorz Toporek, Piotr Harbut, Eduard Jonas, Henrik Nilsson, Jacob Freedman
OBJECTIVE: The purpose of the present study is to evaluate the accuracy and safety of antenna placement performed with the use of a CT-guided stereotactic navigation system for percutaneous ablation of liver tumors and to assess the safety of high-frequency jet ventilation for target motion control. MATERIALS AND METHODS: Twenty consecutive patients with malignant liver lesions for which surgical resection was contraindicated or that were not readily visible on ultrasound or not accessible by ultrasound guidance were included in the study...
October 20, 2016: AJR. American Journal of Roentgenology
Erik Richter, Manuela Harms, Katharina Ventz, Rolf Nölker, Martin J Fraunholz, Jörg Mostertz, Falko Hochgräfe
Internalization of Staphylococcus aureus by non-professional phagocytic cells is a major suspected cause of persistent and difficult-to-treat infections, including pneumonia. In this study, we established an infection model with 16HBE14o- human bronchial epithelial cells and demonstrated internalization, escape from phagosomal clearance and intracellular replication of S. aureus HG001 within the first four hours post-infection. We used quantitative phosphoproteomics to identify characteristic signaling networks in the host at different infection stages...
October 20, 2016: Journal of Proteome Research
Xiangbin Song, Zifa Li, Fei Liu, Zhenyong Wang, Lin Wang
Previous study has demonstrated that puerarin (PU) exerts nephroprotective effect against Pb-induced cytotoxicity in primary rat proximal tubular (rPT) cells. Autophagy can protect cells from various cytotoxic stimuli, but its role in the process of PU against Pb-induced nephrotoxicity is still unknown. This study aims to investigate whether PU can alleviate Pb-induced renal damage by recovering autophagy. Data showed that Pb inhibited the autophagic flux, as evidenced by the accumulation of LC3-II and p62 as well as the confocal microscopy analysis of GFP-LC3 puncta and punctate spots of monodansylcadaverine staining, whereas coadministration of PU could restore Pb-induced autophagy inhibition...
October 20, 2016: Journal of Biochemical and Molecular Toxicology
Jennifer E Adair, Timothy Waters, Kevin G Haworth, Sara P Kubek, Grant D Trobridge, Jonah D Hocum, Shelly Heimfeld, Hans-Peter Kiem
Haematopoietic stem cell (HSC) gene therapy has demonstrated potential to treat many diseases. However, current state of the art requires sophisticated ex vivo gene transfer in a dedicated Good Manufacturing Practices facility, limiting availability. An automated process would improve the availability and standardized manufacture of HSC gene therapy. Here, we develop a novel program for semi-automated cell isolation and culture equipment to permit complete benchtop generation of gene-modified CD34(+) blood cell products for transplantation...
October 20, 2016: Nature Communications
Merete L Hetland, Niels Steen Krogh, Kim Hørslev-Petersen, Berit Schiøttz-Christensen, Inge Juul Sørensen, Jensen Dorte Vendelbo
OBJECTIVES: Electronic platforms have been developed to help the clinician monitor disease activity in rheumatoid arthritis (RA) to support at treat-to-target strategy. We present an initiative to interactively improve disease control in patients with rheumatoid arthritis. METHODS: In patients who presented with one or more swollen joints AND moderate/high disease activity (i.e. either CDAI≥10.1 and/or DAS-28CRP>3.2, which is automatically calculated in the DANBIO registry), a red alert was shown, which activated a pop-up: "This patient has at least one swollen joint AND either CDAI≥ 10...
September 2016: Clinical and Experimental Rheumatology
Laura C Coates
As in rheumatoid arthritis, treating to target in psoriatic arthritis (PsA) has been shown to improve outcomes over standard therapy. As a result of this, the European League Against Rheumatism (EULAR) updated recommendations for the management of PsA now recommend a treat-to-target approach for all patients with PsA. However, translating the results of this research remains challenging in clinical practice. Prolonged consultation time associated with implementing this into practice can be minimised using a simple to calculate but inclusive target for treatment and assessing this within information technology (IT) systems...
September 2016: Clinical and Experimental Rheumatology
Johannes W G Jacobs
The history, issues and result of the development of the computer decision software tool used for the two tight control and treat-to-target CAMERA (Computer Assisted Management in Early Rheumatoid Arthritis) studies are described. The software tool is simple and can be used with various protocolled strategies and visit intervals both in clinical trials and daily practice, because it does not dictate strategy steps and is independent of visit intervals. The tool gives information on whether enough improvement since the last visit is present and whether there is remission or not...
September 2016: Clinical and Experimental Rheumatology
Yinghe Huo, Renske D Veldhuizen, Desiree M van der Heijde, Nick J Besselink, Johannes W G Jacobs, Jacob M van Laar, Max A Viergever, Koen L Vincken, Floris P Lafeber, Maria J H de Hair
OBJECTIVES: To compare as proof of concept the sensitivity to change of automated quantification of radiographic wrist and hand joint space width (JSW) with scoring JSW according to the Sharp/van der Heijde scoring method (SHS) in two strategy groups of a treat-to-target and tight-control early rheumatoid arthritis (RA) study. METHODS: Digital radiographs were assessed for JSW changes of 134 patients of the 236 patients participating in the second Computer Assisted Management in Early Rheumatoid Arthritis trial, of whom both baseline and year 2 radiographs were available (year 1 radiographs n=125)...
September 2016: Clinical and Experimental Rheumatology
Feng Zhang, Bo Yang, Kailiang Zhang, Mei-Ling Hou, Xue-Chun Lu, Yu-Xin Li
Amifostine (AMF), 2-(3-Aminopropyl) aminoethyl phosphorothioate is a broad-spectrum cytoprotective agent used to treat nuclear radiation and chemical weapon injuries. Recently, amifostine has been shown to have a profound biological influence on tumor cells. In order to examine the effects and mechanisms underlying the effects of amifostine on human acute megakaryocytic leukemia, we evaluated the efficacy of amifostine against Dami cells and observed a cell cycle arrest in G2 /M phase. Amifostine treatment also induced cell apoptosis of Dami cells which corresponds to formal studies...
October 19, 2016: Chemical Biology & Drug Design
Simon Sawyer, Jan Coles, Angela Williams, Brett Williams
CONTEXT: Intimate partner violence (IPV) is a significant cause of morbidity and mortality in women worldwide. Numerous health organisations have called for increased education for health care practitioners who encounter IPV patients and the first clinical guidelines for health services responding to IPV were recently published. This renewed focus has created a need to examine the current evidence for IPV education so that it may inform the next generation of educational interventions...
November 2016: Medical Education
Isabelle Biseul, Romain Icick, Perrine Seguin, Frank Bellivier, Jan Scott
OBJECTIVES: We investigated the feasibility and acceptability of an integrated group therapy (called HABIT) for comorbid bipolar disorder (BD) and alcohol and substance use disorders (ASUD) (BD-ASUD), a disabling clinical presentation for which no specific treatment has been validated. The 14-session HABIT programme employs psychoeducation-oriented cognitive-behaviour therapy (CBT) followed by mindfulness-based relapse prevention (MBRP) therapy. METHOD: Potential group participants were recruited from adult clients with a DSM-IV diagnosis of BD and an ASUD who were referred by their treating clinician...
October 20, 2016: Clinical Psychology & Psychotherapy
Guy Bar-Klein, Rebecca Klee, Claudia Brandt, Marion Bankstahl, Pablo Bascuñana, Kathrin Töllner, Hotjensa Dalipaj, Jens P Bankstahl, Alon Friedman, Wolfgang Löscher
OBJECTIVE: Acquired epilepsy is a devastating long-term risk of various brain insults, including trauma, stroke, infections, and status epilepticus (SE). There is no preventive treatment for patients at risk. Due to the complex alterations involved in epileptogenesis, it is likely that multi-targeted approaches are required for epilepsy prevention. We report novel preclinical findings with isoflurane, which exerts various non-anesthetic effects that may be relevant for anti-epileptogenesis...
October 19, 2016: Annals of Neurology
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