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Animesh Pardanani
: Disease overview:Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extra-cutaneous organs. DIAGNOSIS: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. Risk stratification: The 2008 World Health Organization (WHO) classification of SM has been shown to be prognostically relevant...
November 2016: American Journal of Hematology
Felix M Wensveen, Erik Slinger, Martijn Ha van Attekum, Robert Brink, Eric Eldering
Upon antigen encounter, the responsive B cell pool undergoes stringent selection which eliminates cells with low B cell receptor (BCR) affinity. Already before formation of the germinal center, activated B cells of low-affinity are negatively selected in a process that is molecularly not well understood. In this study, we investigated the mechanism behind pre-GC affinity-mediated B cell selection. We applied affinity mutants of HEL antigen and found that rapidly after activation B cells become highly dependent on the cytokine BAFF...
October 20, 2016: Scientific Reports
Emily C Lumley, Acadia R Osborn, Jessica E Scott, Amanda G Scholl, Vicki Mercado, Young T McMahan, Zachary G Coffman, Jay L Brewster
The endoplasmic reticulum (ER) has the ability to signal organelle dysfunction via a complex signaling network known as the unfolded protein response (UPR). In this work, hamster fibroblast cells exhibiting moderate levels of ER stress were compared to those exhibiting severe ER stress. Inhibition of N-linked glycosylation was accomplished via a temperature-sensitive mutation in the Dad1 subunit of the oligosaccharyltransferase (OST) complex or by direct inhibition with tunicamycin (Tm). Temperature shift (TS) treatment generated weak activation of ER stress signaling when compared to doses of Tm that are typically used in ER stress studies (500-1000 nM)...
October 20, 2016: Cell Stress & Chaperones
Taku Hatta, Shingo Nobuta, Toshitake Aizawa, Koichi Sasajima, Soichi Nakajima, Masahito Honda, Gosuke Oki, Yoshiaki Yamanaka, Eiji Itoi
The aim of our study is to evaluate the clinical and radiologic outcomes in patients with terrible triad injury, who underwent surgical treatment with or without the medial collateral ligament (MCL) repair. Fourteen patients who underwent surgery with a minimum of 12-month follow-up (mean, 17 months) were reviewed. Based on the systematic treatment protocol, radial head fracture, lateral collateral ligament, and coracoid fracture were treated. Subsequently, torn MCL was repaired in 7 patients, whereas in the remaining 7 patients, the MCL was not treated...
September 19, 2016: Orthopedic Reviews
Zhenlong Liu, Xiaoqing Hu, Zhentao Man, Jiying Zhang, Yanfang Jiang, Yingfang Ao
Though many surgical animal models have been used to induce osteoarthritis (OA) of the knee joint, they always open the capsule of the joint. Any surgical procedures that incises the capsule may cause inflammation, pain, and possibly altered gait. One common disadvantage of these surgically induced animal models is that they may affect the initial structures and synovial fluid in joint. These animal models may not be suitable for research into synovial fluid changes during early OA. This study aimed to create an animal model of early OA by resecting the medial collateral ligament (MCL) outside of the capsule...
October 19, 2016: Scientific Reports
Arianna Bottoni, Lara Rizzotto, Tzung-Huei Lai, Chaomei Liu, Lisa L Smith, Rose Mantel, Sean Reiff, Dalia El-Gamal, Karilyn Larkin, Amy J Johnson, Rosa Lapalombella, Amy Lehman, William Plunkett, John C Byrd, James S Blachly, Jennifer A Woyach, Deepa Sampath
BTK is a critical mediator of survival in B cell neoplasms. While BTK inhibitors have transformed therapy in CLL, high genetic risk patients are at risk for relapse and have a poor prognosis. Identification of novel therapeutic strategies for this group of patients is an urgent unmet clinical need, and therapies that target BTK via alternative mechanisms may fill this niche. Herein, we identify a set of miRNAs that target BTK in primary CLL cells and show that the HDAC repressor complex is recruited to these miRNA promoters to silence their expression...
October 17, 2016: Blood
Young Yong Kim, Gu Hyun Kang, Won Hee Kim, Hyun Young Choi, Yong Soo Jang, Young Jae Lee, Jae Guk Kim, Hyeongtae Kim, Gyoung Yong Kim
OBJECTIVE: This study aimed to compare intubation performance between blind intubation through supraglottic airway devices and direct laryngoscopy by novices under manikin simulation. We hypothesized that the intubation time by novices using supraglottic airway devices was superior to that with the Macintosh laryngoscope (MCL). METHODS: A prospective, randomized crossover study was conducted with 95 participants, to evaluate i-gel, air-Q, LMA Fastrach, and MCL devices...
June 2016: Clin Exp Emerg Med
Nurbek Mambetsariev, Wai W Lin, Alicia M Wallis, Laura L Stunz, Gail A Bishop
The adaptor protein TNF receptor-associated factor 3 (TRAF3) is a critical regulator of B lymphocyte survival. B cell-specific TRAF3 deficiency results in enhanced viability and is associated with development of lymphoma and multiple myeloma. We show that TRAF3 deficiency led to induction of two proteins important for glucose metabolism, Glut1 and Hexokinase 2 (HXK2). This was associated with increased glucose uptake. In the absence of TRAF3, anaerobic glycolysis and oxidative phosphorylation were increased in B cells without changes in mitochondrial mass or reactive oxygen species...
October 18, 2016: Scientific Reports
Matthew D Seftel, John Kuruvilla, Tom Kouroukis, Versha Banerji, Graeme Fraser, Michael Crump, Rajat Kumar, Haji I Chalchal, Muhammad Salim, Rob C Laister, Susan Crocker, Spencer B Gibson, Marcia Toguchi, John F Lyons, Hao Xu, Jean Powers, Joana Sederias, Lesley Seymour, Annette E Hay
AT7519M is a small molecule inhibitor of cyclin-dependent kinases 1, 2, 4, 5, and 9 with in vitro activity against lymphoid malignancies. In two concurrent Phase II trials, we evaluated AT7519M in relapsed or refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) using the recommended Phase II dosing of 27 mg/m(2) twice weekly for 2 of every 3 weeks. Primary objective was objective response rate (ORR). Nineteen patients were accrued (7 CLL, 12 MCL). Four CLL patients achieved stable disease (SD)...
October 17, 2016: Leukemia & Lymphoma
Emanuel Hupf, Ralf Kather, Matthias Vogt, Enno Lork, Stefan Mebs, Jens Beckmann
The previously reported bis(6-diphenylphosphinoacenaphth-5-yl)mercury (1) was used as ligand for the preparation of the copper(I) complexes, 1·CuCl and [1·Cu(NCMe)]BF4, which were characterized by multinuclear NMR spectroscopy and X-ray crystallography. DFT calculations employing topological analysis of the electron and electron pair densities within the AIM and ELI-D space-partitioning schemes revealed significant metallophilic Hg···Cu interactions. Evaluation of noncovalent bonding aspects according to the noncovalent interaction (NCI) index was applied not only for the Cu complexes 1·CuCl and [1·Cu(NCMe)]BF4 but also for the previously reported Ag and Au complexes, namely, [1·MCl] (M = Ag, Au) and [1·M(NCMe)n](+) (M = Ag, n = 2; M = Au, n = 0), and facilitated the assignment of attractive dispersive Hg···M interactions with the Hg···Cu contacts being comparable to the Hg···Ag but weaker than the Hg···Au interactions...
October 17, 2016: Inorganic Chemistry
Jianheng Wu, Linfan Li, Guangyuan Jiang, Hui Zhan, Nannan Wang
Aberrant expression of oncogenes and/or tumor suppressors play fundamental roles in the pathogenesis of glioma. B-cell CLL/lymphoma 3 (BCL3) was previously found to be a putative proto-oncogene in human cancers and the decoy receptor DcR1 is induced in a p50/Bcl3-dependent manner and attenuates the efficacy of temozolomide in glioblastoma cells. However, its expression status, clinical significance and biological functions in glioma remain largely unknown. In the present study, the levels of BCL3 were overexpressed in glioma compared to normal brain tissues...
October 12, 2016: International Journal of Oncology
Geetha C Rajappa, Leena Harshad Parate, C A Tejesh, P T Prathima
BACKGROUND: Mask ventilation (MV) is an essential basic life support skill. We used chin lift maneuver for MV and named as modified chin lift technique (MCL). EC technique is most common technique used for MV. AIMS: The aim of this study is to compare the efficacy of both techniques for MV in term of expired tidal volume (TV). Secondarily, we also assessed the effect of experience on the performance of these both techniques. SETTINGS AND DESIGN: The study area was operation theater of our hospital...
September 2016: Anesthesia, Essays and Researches
Lijia Chen, Steven Fletcher
The myeloid cell leukemia -1 (MCL-1) protein is one of the key anti-apoptotic protein members of the B-cell lymphoma-2 (BCL-2) protein family. Over-expression of MCL-1 has been closely related to tumor progression as well as resistance to not only traditional chemotherapies but also targeted therapeutics including BCL-2 inhibitors such as ABT-263. Therefore, extensive research and development in the last fifteen years in both academic and industrial settings to address this unmet medical need. Areas covered: This review covers research and patent literature of the past 10 years in the field of discovery and development of small-molecule inhibitors of the MCL-1 anti-apoptotic protein...
October 17, 2016: Expert Opinion on Therapeutic Patents
Caron Jacobson, Nadja Kopp, Jacob V Layer, Robert A Redd, Sebastian Tschuri, Sarah Haebe, Diederik van Bodegom, Liat Bird, Amanda L Christie, Alexandra Christodoulou, Amy Saur, Trevor Tivey, Stefanie Zapf, Deepak Bararia, Ursula Zimber-Strobl, Scott J Rodig, Oliver Weigert, David M Weinstock
The BTK inhibitor ibrutinib induces responses in 70% of patients with relapsed and refractory mantle cell lymphoma. Intrinsic resistance can occur through activation of the non-classical NFκB pathway and acquired resistance may involve the BTK C481S mutation. Outcomes after ibrutinib failure are dismal, indicating an unmet medical need. We reasoned that newer HSP90 inhibitors could overcome ibrutinib resistance by targeting multiple oncogenic pathways in MCL. HSP90 inhibition induced the complete degradation of both BTK and IKKα in MCL lines and CD40-dependent B cells, with downstream loss of MAP kinase and non-classical NFκB signaling...
October 14, 2016: Blood
Rong Chu, Sarah E Alford, Katherine Hart, Anisha Kothari, Samuel G Mackintosh, Matthew R Kovak, Timothy C Chambers
Microtubule targeting agents (MTAs) characteristically promote phosphorylation and degradation of Mcl-1, and this represents a critical pro-apoptotic signal in mitotic death. While several phosphorylation sites and kinases have been implicated in mitotic arrest-induced Mcl-1 phosphorylation, a comprehensive biochemical analysis has been lacking. Contrary to previous reports suggesting that T92 phosphorylation by Cdk1 regulates Mcl-1 degradation, a T92A Mcl-1 mutant expressed in HeLa cells was phosphorylated and degraded with the same kinetics as wild-type Mcl-1 following vinblastine treatment...
October 12, 2016: Oncotarget
Matthieu Hanf, David Chiron, Sophie de Visme, Cyrille Touzeau, Hervé Maisonneuve, Henry Jardel, Catherine Pellat-Deceunynck, Martine Amiot, Steven le Gouill
BACKGROUND: Mantle Cell Lymphoma (MCL) is often associated with progression, temporary response to therapy and a high relapse rate over time resulting in a poor long-term prognosis. Because MCL is classified as an incurable disease, therapeutic resistance is of great interest. However, knowledge about the biological mechanisms underlying resistance associated with MCL therapies and about associated predictors remains poor. The REFRACT-LYMA Cohort, a multicenter prospective cohort of patients with MCL, is set up to address this limitation...
October 14, 2016: BMC Cancer
Yvonne Voges, Martin Michaelis, Florian Rothweiler, Torsten Schaller, Constanze Schneider, Katharina Politt, Marco Mernberger, Andrea Nist, Thorsten Stiewe, Mark N Wass, Franz Rödel, Jindrich Cinatl
Resistance formation after initial therapy response (acquired resistance) is common in high-risk neuroblastoma patients. YM155 is a drug candidate that was introduced as a survivin suppressant. This mechanism was later challenged, and DNA damage induction and Mcl-1 depletion were suggested instead. Here we investigated the efficacy and mechanism of action of YM155 in neuroblastoma cells with acquired drug resistance. The efficacy of YM155 was determined in neuroblastoma cell lines and their sublines with acquired resistance to clinically relevant drugs...
October 13, 2016: Cell Death & Disease
Tao Zhang, Suoyuan Li, Jingjie Li, Fei Yin, Yingqi Hua, Zhouying Wang, Binhui Lin, Hongsheng Wang, Dongqing Zou, Zifei Zhou, Jing Xu, Chengqing Yi, Zhengdong Cai
Signal transducer and activator of transcription 3 (STAT3) has important roles in cancer aggressiveness and has been confirmed as an attractive target for cancer therapy. In this study, we used a dual-luciferase assay to identify that pectolinarigenin inhibited STAT3 activity. Further studies showed pectolinarigenin inhibited constitutive and interleukin-6-induced STAT3 signaling, diminished the accumulation of STAT3 in the nucleus and blocked STAT3 DNA-binding activity in osteosarcoma cells. Mechanism investigations indicated that pectolinarigenin disturbed the STAT3/DNA methyltransferase 1/HDAC1 histone deacetylase 1 complex formation in the promoter region of SHP-1, which reversely mediates STAT3 signaling, leading to the upregulation of SHP-1 expression in osteosarcoma...
October 13, 2016: Cell Death & Disease
Adebayo Ogunniyi, Mabel Rodriguez, Sean Devlin, Nelly Adel, Heather Landau, David J Chung, Nikoletta Lendvai, Alexander Lesokhin, Guenther Koehne, Sham Mailankody, Neha Korde, Lilian Reich, Ola Landgren, Sergio Giralt, Hani Hassoun
Plerixafor (P), an agent that selectively and reversibly binds to the chemokine receptor CXCR4, has been approved in combination with G-CSF (P + G-CSF) for stem cell (SC) mobilization in patients with multiple myeloma (MM). The goal of this study was to determine the SC collection success rate of P + G-CSF using a clinically relevant outcome defined as the ability to collect at least 5 × 10(6) CD34(+) cells/kg to allow safely two transplants, and identify risk factors impacting SC mobilization...
October 13, 2016: Leukemia & Lymphoma
J-G Cao, L Wang, H-W Zhao, J Liu
OBJECTIVE: The objective of the study is to evaluate the clinic effectiveness of semitendinosus and gracilis transfer for the treatment of medial collateral ligament (MCL) injury of total knee arthroplasty (TKA). PATIENTS AND METHODS: From March 2009 to May 2014, a series of 11 patients with MCL injuries of primary TKA were treated by semitendinosus and gracilis transfer. Another 18 patients (21 knees) were recruited as control group. The two groups of patients were comparable for gender, age, body mass index, varus knee deformity, KSS score, joint activity degree and type of prosthesis comparison without significant difference (p > 0...
September 2016: European Review for Medical and Pharmacological Sciences
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