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https://www.readbyqxmd.com/read/28198370/smac-mimetics-synergize-with-immune-checkpoint-inhibitors-to-promote-tumour-immunity-against-glioblastoma
#1
Shawn T Beug, Caroline E Beauregard, Cristin Healy, Tarun Sanda, Martine St-Jean, Janelle Chabot, Danielle E Walker, Aditya Mohan, Nathalie Earl, Xueqing Lun, Donna L Senger, Stephen M Robbins, Peter Staeheli, Peter A Forsyth, Tommy Alain, Eric C LaCasse, Robert G Korneluk
Small-molecule inhibitor of apoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumours to TNF-α-induced killing while simultaneously blocking TNF-α growth-promoting activities. SMCs also regulate several immunomodulatory properties within immune cells. We report that SMCs synergize with innate immune stimulants and immune checkpoint inhibitor biologics to produce durable cures in mouse models of glioblastoma in which single agent therapy is ineffective. The complementation of activities between these classes of therapeutics is dependent on cytotoxic T-cell activity and is associated with a reduction in immunosuppressive T-cells...
February 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28195242/the-alternative-complement-pathway-is-dysregulated-in-patients-with-chronic-heart-failure
#2
Negar Shahini, Annika E Michelsen, Per H Nilsson, Karin Ekholt, Lars Gullestad, Kaspar Broch, Christen P Dahl, Pål Aukrust, Thor Ueland, Tom Eirik Mollnes, Arne Yndestad, Mieke C Louwe
The complement system, an important arm of the innate immune system, is activated in heart failure (HF). We hypothesized that HF patients are characterized by an imbalance of alternative amplification loop components; including properdin and complement factor D and the alternative pathway inhibitor factor H. These components and the activation product, terminal complement complex (TCC), were measured in plasma from 188 HF patients and 67 age- and sex- matched healthy controls by enzyme immunoassay. Our main findings were: (i) Compared to controls, patients with HF had significantly increased levels of factor D and TCC, and decreased levels of properdin, particularly patients with advanced clinical disorder (i...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28195072/complement-activation-contributes-to-ventilator-induced-lung-injury-in-rats
#3
B Petersen, T Busch, J Gaertner, J J Haitsma, S Krabbendam, M Ebsen, B Lachmann, U X Kaisers
The complement system contributes to ventilator induced lung injury (VILI). We hypothesized that pretreatment with the C1 esterase inhibitor (C1INH) Berinert® constrains complement activation consecutively inducing improvements in arterial oxygenation and histological pulmonary damage. At baseline, male Sprague-Dawley rats underwent mechanical ventilation in a conventional mode (PIP 13 cm H2O, PEEP 3 cm H2O). In the Control group, the ventilator setting was maintained (Control, n = 15). The other animals randomly received intravenous pretreatment with either 100 units/kg of the C1-INH Berinert® (VILI-C1INH group, n = 15) or 1 ml saline solution (VILI-C group, n = 15)...
December 2016: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
https://www.readbyqxmd.com/read/28192254/effect-of-dietary-phosphorus-deficiency-on-the-growth-immune-function-and-structural-integrity-of-head-kidney-spleen-and-skin-in-young-grass-carp-ctenopharyngodon-idella
#4
Kang Chen, Wei-Dan Jiang, Pei Wu, Yang Liu, Sheng-Yao Kuang, Ling Tang, Wu-Neng Tang, Yong-An Zhang, Xiao-Qiu Zhou, Lin Feng
This study evaluates the effects of dietary phosphorus on the growth, immune function and structural integrity (head kidney, spleen and skin) of young grass carp (Ctenopharyngodon idella) that were fed graded levels of available phosphorus (0.95-8.75 g/kg diet). Results indicated that phosphorus deficiency decreased the growth performance of young grass carp. In addition, the results first demonstrated that compared with the optimal phosphorus level, phosphorus deficiency depressed the lysozyme (LZ) and acid phosphatase (ACP) activities and the complement 3 (C3), C4 and immunoglobulin M (IgM) contents, and down-regulated the mRNA levels of antimicrobial peptides, anti-inflammatory cytokines, inhibitor of κBα (IκBα) and target of rapamycin (TOR), whereas it up-regulated pro-inflammatory cytokines, nuclear factor kappa B (NF-κB) p65 and NF-κB p52 mRNA levels to decrease fish head kidney and spleen immune functions...
February 9, 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28186697/complement-activated-vitronectin-enhances-the-invasion-of-non-phagocytic-cells-by-bacterial-pathogens-burkholderia-and-klebsiella
#5
Yi Han Tan, Akshamal Gamage, Yunn-Hwen Gan
Burkholderia pseudomallei is a serum-resistant Gram-negative bacterium capable of causing disseminated infections with metastatic complications. However, their interaction with non-phagocytic cells is poorly understood. We observed that exposure of B. pseudomallei and the closely related yet avirulent B. thailandensis to human plasma increased epithelial cell invasion by >20 fold. Enhanced invasion was primarily driven by a plasma factor which required a functional complement cascade, but surprisingly, was downstream of C3 mediated opsonisation...
February 10, 2017: Cellular Microbiology
https://www.readbyqxmd.com/read/28178280/knockdown-of-hspa9-induces-tp53-dependent-apoptosis-in-human-hematopoietic-progenitor-cells
#6
Tuoen Liu, Kilannin Krysiak, Cara Lunn Shirai, Sanghyun Kim, Jin Shao, Matthew Ndonwi, Matthew J Walter
Myelodysplastic syndromes (MDS) are the most common adult myeloid blood cancers in the US. Patients have increased apoptosis in their bone marrow cells leading to low peripheral blood counts. The full complement of gene mutations that contribute to increased apoptosis in MDS remains unknown. Up to 25% of MDS patients harbor and acquired interstitial deletion on the long arm of chromosome 5 [del(5q)], creating haploinsufficiency for a large set of genes including HSPA9. Knockdown of HSPA9 in primary human CD34+ hematopoietic progenitor cells significantly inhibits growth and increases apoptosis...
2017: PloS One
https://www.readbyqxmd.com/read/28176849/a-versatile-assay-to-determine-bacterial-and-host-factors-contributing-to-opsonophagocytotic-killing-in-hirudin-anticoagulated-whole-blood
#7
Erika van der Maten, Marien I de Jonge, Ronald de Groot, Michiel van der Flier, Jeroen D Langereis
Most bacteria entering the bloodstream will be eliminated through complement activation on the bacterial surface and opsonophagocytosis. However, when these protective innate immune systems do not work optimally, or when bacteria are equipped with immune evasion mechanisms that prevent killing, this can lead to serious infections such as bacteremia and meningitis, which is associated with high morbidity and mortality. In order to study the complement evasion mechanisms of bacteria and the capacity of human blood to opsonize and kill bacteria, we developed a versatile whole blood killing assay wherein both phagocyte function and complement activity can easily be monitored and modulated...
February 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28176475/life-threatening-pregnancy-associated-atypical-haemolytic-uraemic-syndrome-and-its-response-to-eculizumab
#8
REVIEW
Ryan Gately, Aye San, Jagadeesh Kurtkoti, Alan Parnham
Pregnancy-associated atypical haemolytic uraemic syndrome (P-aHUS) is a rare, potentially lethal condition that can complicate pregnancy in up to 1 in 25 000 cases. Without prompt diagnosis and initiation of appropriate treatment, this condition can lead to disastrous consequences for both mother and child. Given the broad spectrum of conditions that can present similarly in the peripartum period, it is often difficult to establish the correct diagnosis in a timely manner. Recently, the terminal complement cascade inhibitor eculizumab has been used with considerable success in non-pregnancy HUS; however, its use in P-aHUS is limited to isolated case reports...
February 2017: Nephrology
https://www.readbyqxmd.com/read/28174205/the-vdac2-bak-axis-regulates-peroxisomal-membrane-permeability
#9
Ken-Ichiro Hosoi, Non Miyata, Satoru Mukai, Satomi Furuki, Kanji Okumoto, Emily H Cheng, Yukio Fujiki
Peroxisomal biogenesis disorders (PBDs) are fatal genetic diseases consisting of 14 complementation groups (CGs). We previously isolated a peroxisome-deficient Chinese hamster ovary cell mutant, ZP114, which belongs to none of these CGs. Using a functional screening strategy, VDAC2 was identified as rescuing the peroxisomal deficiency of ZP114 where VDAC2 expression was not detected. Interestingly, knockdown of BAK or overexpression of the BAK inhibitors BCL-XL and MCL-1 restored peroxisomal biogenesis in ZP114 cells...
February 7, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28173805/serum-proteomic-profiles-in-ckcs-with-mitral-valve-disease
#10
Chiara Locatelli, Cristian Piras, Giulia Riscazzi, Isabella Alloggio, Ilaria Spalla, Alessio Soggiu, Viviana Greco, Luigi Bonizzi, Paola Roncada, Paola G Brambilla
BACKGROUND: Myxomatous mitral valve disease (MVD) is the most common acquired heart disease in dogs, and the Cavalier King Charles Spaniel (CKCS) is the most studied breed because of the high prevalence, early onset and hereditary component evidenced in the breed. MVD has different severity levels, and there are many practical limitations in identifying its asymptomatic stages. Proteomic techniques are valuable for studying the proteins and peptides involved in cardiovascular diseases, including the period prior to the clinical onset of the disease...
February 7, 2017: BMC Veterinary Research
https://www.readbyqxmd.com/read/28173629/enhanced-dependency-of-kras-mutant-colorectal-cancer-cells-on-rad51-dependent-homologous-recombination-repair-identified-from-genetic-interactions-in-saccharomyces-cerevisiae
#11
Murugan Kalimutho, Amanda L Bain, Bipasha Mukherjee, Purba Nag, Devathri M Nanayakkara, Sarah K Harten, Janelle L Harris, Goutham Narayanan Subramanian, Debottam Sinha, Senji Shirasawa, Sriganesh Srihari, Sandeep Burma, Kum Kum Khanna
Activating KRAS mutations drive colorectal cancer tumorigenesis and influence response to anti-EGFR targeted therapy. Despite recent advances in understanding Ras signaling biology and the revolution in therapies for melanoma using BRAF inhibitors, no targeted agents have been effective in KRAS mutant cancers, mainly due to activation of compensatory pathways. Here, by leveraging the largest synthetic lethal genetic interactome in yeast, we identify that KRAS-mutated colorectal cancer cells have augmented homologous recombination repair (HRR) signaling...
February 7, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28170236/protonation-and-sulfido-versus-oxo-ligation-changes-at-the-molybdenum-cofactor-in-xanthine-dehydrogenase-xdh-variants-studied-by-x-ray-absorption-spectroscopy
#12
Stefan Reschke, Stefan Mebs, Kajsa G V Sigfridsson-Clauss, Ramona Kositzki, Silke Leimkühler, Michael Haumann
Enzymes of the xanthine oxidase family are among the best characterized mononuclear molybdenum enzymes. Open questions about their mechanism of transfer of an oxygen atom to the substrate remain. The enzymes share a molybdenum cofactor (Moco) with the metal ion binding a molybdopterin (MPT) molecule via its dithiolene function and terminal sulfur and oxygen groups. For xanthine dehydrogenase (XDH) from the bacterium Rhodobacter capsulatus, we used X-ray absorption spectroscopy to determine the Mo site structure, its changes in a pH range of 5-10, and the influence of amino acids (Glu730 and Gln179) close to Moco in wild-type (WT), Q179A, and E730A variants, complemented by enzyme kinetics and quantum chemical studies...
February 7, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28163174/arterial-blood-pressure-induces-transient-c4b-binding-protein-in-human-saphenous-vein-grafts
#13
Koba Kupreishvili, Christof Meischl, Alexander B A Vonk, Wim Stooker, Leon Eijsman, Anna M Blom, Paul H A Quax, Victor W M van Hinsbergh, Hans W M Niessen, Paul A J Krijnen
BACKGROUND: Complement is an important mediator in arterial blood pressure-induced vein graft failure. Previously we noted activation of cell protective mechanisms in human saphenous veins too. Here we have analyzed whether C4b-binding protein (C4bp), an endogenous complement inhibitor, is present in the vein wall. MATERIALS AND METHODS: Human saphenous vein segments obtained from patients undergoing coronary artery bypass grafting (n=55) were perfused in vitro at arterial blood pressure with either autologous blood for 1, 2, 4 or 6 hours or with autologous blood supplemented with reactive oxygen species scavenger N-acetylcysteine...
February 2, 2017: Annals of Vascular Surgery
https://www.readbyqxmd.com/read/28162031/successful-treatment-of-refractory-systemic-lupus-erythematosus-using-proteasome-inhibitor-bortezomib-followed-by-belimumab-description-of-two-cases
#14
C Sjöwall, M Hjorth, P Eriksson
Although the putative therapeutic options for patients with systemic lupus erythematosus (SLE) are steadily increasing, refractory disease is indeed a major challenge to many clinicians and patients. The proteasome inhibitor bortezomib - approved for the treatment of multiple myeloma since the beginning of this century - was recently reported successful in twelve cases of refractory SLE by German colleagues. Herein, we describe two Swedish SLE cases with refractory renal and pulmonary manifestations that were rescued by bortezomib as induction of remission followed by monthly doses of belimumab...
January 1, 2017: Lupus
https://www.readbyqxmd.com/read/28159709/role-of-the-plasma-cascade-systems-in-ischemia-reperfusion-injury-of-bone
#15
Shengye Zhang, Carlos Wotzkow, Anjan K Bongoni, Jane Shaw-Boden, Mark Siegrist, Adriano Taddeo, Fabian Blank, Willy Hofstetter, Robert Rieben
Ischemia/reperfusion (I/R) injury has been extensively studied in organs such as heart, brain, liver, kidney, and lung. As a vascularized organ, bone is known to be susceptible to I/R injury too, but the respective mechanisms are not well understood to date. We therefore hypothesized that, similar to other organs, plasma cascade-induced inflammation also plays a role in bone I/R injury. Reperfusion injury in rat tibia was induced by unilateral clamping of the femoral artery and additional use of a tourniquet, while keeping the femoral vein patent to prevent venous congestion...
January 31, 2017: Bone
https://www.readbyqxmd.com/read/28157311/structure-based-library-design-and-fragment-screening-for-the-identification-of-reversible-complement-factor-d-protease-inhibitors
#16
Anna Vulpetti, Stefan Randl, Simon Rüdisser, Nils Ostermann, Paulus Erbel, Aengus MacSweeney, Thomas Zoller, Bahaa Salem, Bernd Gerhartz, Frederic Cumin, Ulrich Hommel, Claudio Dalvit, Edwige Lorthiois, Jürgen Maibaum
Chronic dysregulation of alternative complement pathway activation has been associated with diverse clinical disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinurea. Factor D is a trypsin-like serine protease with a narrow specificity for arginine in the P1 position, which catalyses the first enzymatic reaction of the amplification loop of the alternative pathway. In this paper, we describe two hit finding approaches leading to the discovery of new chemical matter for this pivotal protease of the complement system: in silico active site mapping for hot spots identification to guide rational structure-based design and NMR screening of focussed and diverse fragment libraries...
February 3, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28154563/host-immune-evasion-by-lyme-and-relapsing-fever-borreliae-findings-to-lead-future-studies-for-borrelia-miyamotoi
#17
REVIEW
Brandee L Stone, Catherine A Brissette
The emerging pathogen, Borrelia miyamotoi, is a relapsing fever spirochete vectored by the same species of Ixodes ticks that carry the causative agents of Lyme disease in the US, Europe, and Asia. Symptoms caused by infection with B. miyamotoi are similar to a relapsing fever infection. However, B. miyamotoi has adapted to different vectors and reservoirs, which could result in unique physiology, including immune evasion mechanisms. Lyme Borrelia utilize a combination of Ixodes-produced inhibitors and native proteins [i...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28153734/high-throughput-screening-for-survivin-and-borealin-interaction-inhibitors-in-hepatocellular-carcinoma
#18
Liyun Yue, Lu Li, Dan Li, Zhuo Yang, Shuai Han, Ming Chen, Shujue Lan, Xiaojun Xu, Lijian Hui
Survivin, a key member of the chromatin passenger complex (CPC), is often highly expressed in human cancers, making it a promising target for cancer treatment. Out of the numerous reported Survivin inhibitors, YM155 is only one entering clinical trial, but was recently failed in the Phase II trial. It is important to develop Survivin inhibitors with new strategies. We recently reported that both Survivin and its binding protein Borealin in the CPC complex are essential for the development of hepatocellular carcinoma, suggesting that disrupting the interaction between Survivin and Borealin would be a promising strategy...
January 31, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28150310/plasma-treated-with-amotosalen-and-ultraviolet-a-light-retains-activity-for-hemostasis-after-5-days-post-thaw-storage-at-1-to-6-o-c
#19
Anna Erickson, Katie Waldhaus, Tovo David, Norman Huang, Salvador Rico, Laurence Corash, Nina Mufti, Richard J Benjamin
BACKGROUND: Plasma thawed and stored at 1 to 6(°) C for up to 5 days (thawed plasma [TP]) provides rapid availability in emergencies and reduces plasma waste, but it carries risks of coagulation factor loss or activation, bacterial outgrowth, and viral contamination. We characterized changes in amotosalen/ultraviolet A (UVA) light pathogen-reduced, fresh-frozen plasma (FFP) and plasma frozen within 24 hours (PF24) with post-thaw storage. STUDY DESIGN AND METHODS: Amotosalen/UVA light-treated FFP and PF24 were thawed after approximately 3 to more than 12 months of frozen storage and held at 1 to 6(°) C for 5 days...
February 1, 2017: Transfusion
https://www.readbyqxmd.com/read/28148731/prelp-enhances-host-innate-immunity-against-the-respiratory-tract-pathogen-moraxella-catarrhalis
#20
Guanghui Liu, David Ermert, Martin E Johansson, Birendra Singh, Yu-Ching Su, Magnus Paulsson, Kristian Riesbeck, Anna M Blom
Respiratory tract infections are one of the leading causes of mortality worldwide urging better understanding of interactions between pathogens causing these infections and the host. Here we report that an extracellular matrix component proline/arginine-rich end leucine-rich repeat protein (PRELP) is a novel antibacterial component of innate immunity. We detected the presence of PRELP in human bronchoalveolar lavage fluid and showed that PRELP can be found in alveolar fluid, resident macrophages/monocytes, myofibroblasts, and the adventitia of blood vessels in lung tissue...
February 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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