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https://www.readbyqxmd.com/read/29341863/distinct-gene-signatures-predict-insulin-resistance-in-young-mice-with-high-fat-diet-induced-obesity
#1
Katherine Chen, Alice Jih, Olivia Osborn, Sarah T Kavaler, Wenxian Fu, Roman Sasik, Rintaro Saito, Jane J Kim
Highly inbred C57BL/6 mice show wide variation in their degree of insulin resistance in response to diet-induced obesity even though they are almost genetically identical. Here we employed transcriptional profiling by RNA sequencing (RNA-Seq) of visceral adipose tissue (VAT) and liver in young mice to determine how gene expression patterns correlate with the later development of high-fat diet (HFD)-induced insulin resistance in adulthood. To accomplish this goal, we partially removed and banked tissues from pubertal mice...
January 8, 2018: Physiological Genomics
https://www.readbyqxmd.com/read/29338843/current-status-of-animal-models-of-posttraumatic-stress-disorder-behavioral-and-biological-phenotypes-and-future-challenges-in-improving-translation
#2
REVIEW
Jessica Deslauriers, Mate Toth, Andre Der-Avakian, Victoria B Risbrough
Increasing predictability of animal models of posttraumatic stress disorder (PTSD) has required active collaboration between clinical and preclinical scientists. Modeling PTSD is challenging, as it is a heterogeneous disorder with ≥20 symptoms. Clinical research increasingly utilizes objective biological measures (e.g., imaging, peripheral biomarkers) or nonverbal behaviors and/or physiological responses to complement verbally reported symptoms. This shift toward more-objectively measurable phenotypes enables refinement of current animal models of PTSD, and it supports the incorporation of homologous measures across species...
November 20, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/29337311/dinaciclib-induces-immunogenic-cell-death-and-enhances-anti-pd-1-mediated-tumor-suppression
#3
Dewan Md Sakib Hossain, Sarah Javaid, Mingmei Cai, Chunsheng Zhang, Anandi Sawant, Marlene Hinton, Manjiri Sathe, Jeff Grein, Wendy Blumenschein, Elaine M Pinheiro, Alissa Chackerian
Blockade of the checkpoint inhibitor programmed death 1 (PD1) has demonstrated remarkable success in the clinic for the treatment of cancer; however, a majority of tumors are resistant to anti-PD1 monotherapy. Numerous ongoing clinical combination therapy studies will likely reveal additional therapeutics that complement anti-PD1 blockade. Recent studies found that immunogenic cell death (ICD) improves T cell responses against different tumors, thus indicating that ICD may further augment antitumor immunity elicited by anti-PD1...
January 16, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29335241/the-mfhr1-fusion-protein-is-a-novel-synthetic-multitarget-complement-inhibitor-with-therapeutic-potential
#4
Stefan Michelfelder, Friedericke Fischer, Astrid Wäldin, Kim V Hörle, Martin Pohl, Juliana Parsons, Ralf Reski, Eva L Decker, Peter F Zipfel, Christine Skerka, Karsten Häffner
The complement system is essential for host defense, but uncontrolled complement system activation leads to severe, mostly renal pathologies, such as atypical hemolytic uremic syndrome or C3 glomerulopathy. Here, we investigated a novel combinational approach to modulate complement activation by targeting C3 and the terminal pathway simultaneously. The synthetic fusion protein MFHR1 links the regulatory domains of complement factor H (FH) with the C5 convertase/C5b-9 inhibitory fragment of the FH-related protein 1...
January 15, 2018: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/29331477/atypical-presentation-of-pregnancy-related-hemolytic-uremic-syndrome
#5
Salim Baghli, Catherine Abendroth, Umar Farooq, Jennifer A Schaub
The cause of acute kidney injury during pregnancy and in the postpartum period can be particularly challenging to diagnose, especially when it is necessary to differentiate among preeclampsia; eclampsia; hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome; and thrombotic microangiopathies (TMAs). All these disease entities can present with kidney failure, microangiopathic hemolytic anemia, and thrombocytopenia. We present a teaching case of atypical hemolytic uremic syndrome in the postpartum period in a young woman who was found to have mutations of uncertain clinical significance in the complement cascade, including in C3, CFH, and CFI...
January 10, 2018: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
https://www.readbyqxmd.com/read/29329521/treating-c3-glomerulopathy-with-eculizumab
#6
Thomas Welte, Frederic Arnold, Julia Kappes, Maximilian Seidl, Karsten Häffner, Carsten Bergmann, Gerd Walz, Elke Neumann-Haefelin
BACKGROUND: C3 glomerulopathy (C3G) is a rare, but severe glomerular disease with grim prognosis. The complex pathogenesis is just unfolding, and involves acquired as well as inherited dysregulation of the alternative pathway of the complement cascade. Currently, there is no established therapy. Treatment with the C5 complement inhibitor eculizumab may be a therapeutic option. However, due to rarity of the disease, parameters predicting treatment response remain largely unknown. METHODS: Seven patients with C3G (five with C3 glomerulonephritis and two with dense deposit disease) were treated with eculizumab...
January 12, 2018: BMC Nephrology
https://www.readbyqxmd.com/read/29324883/masp-1-of-the-complement-system-enhances-clot-formation-in-a-microvascular-whole-blood-flow-model
#7
Lorenz Jenny, József Dobó, Péter Gál, Gábor Pál, Wilbur A Lam, Verena Schroeder
The complement and coagulation systems closely interact with each other. These interactions are believed to contribute to the proinflammatory and prothrombotic environment involved in the development of thrombotic complications in many diseases. Complement MASP-1 (mannan-binding lectin-associated serine protease-1) activates coagulation factors and promotes clot formation. However, this was mainly shown in purified or plasma-based static systems. Here we describe the role of MASP-1 and complement activation in fibrin clot formation in a microvascular, whole blood flow model...
2018: PloS One
https://www.readbyqxmd.com/read/29323279/structural-basis-of-trpv5-channel-inhibition-by-econazole-revealed-by-cryo-em
#8
Taylor E T Hughes, David T Lodowski, Kevin W Huynh, Aysenur Yazici, John Del Rosario, Abhijeet Kapoor, Sandip Basak, Amrita Samanta, Xu Han, Sudha Chakrapani, Z Hong Zhou, Marta Filizola, Tibor Rohacs, Seungil Han, Vera Y Moiseenkova-Bell
The transient receptor potential vanilloid 5 (TRPV5) channel is a member of the transient receptor potential (TRP) channel family, which is highly selective for Ca2+, that is present primarily at the apical membrane of distal tubule epithelial cells in the kidney and plays a key role in Ca2+ reabsorption. Here we present the structure of the full-length rabbit TRPV5 channel as determined using cryo-EM in complex with its inhibitor econazole. This structure reveals that econazole resides in a hydrophobic pocket analogous to that occupied by phosphatidylinositides and vanilloids in TRPV1, thus suggesting conserved mechanisms for ligand recognition and lipid binding among TRPV channels...
January 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29317551/characteristics-of-real-world-metastatic-non-small-cell-lung-cancer-patients-treated-with-nivolumab-and-pembrolizumab-during-the-year-following-approval
#9
Sean Khozin, Amy P Abernethy, Nathan C Nussbaum, Jizu Zhi, Melissa D Curtis, Melisa Tucker, Shannon E Lee, David E Light, Anala Gossai, Rachael A Sorg, Aracelis Z Torres, Payal Patel, Gideon Michael Blumenthal, Richard Pazdur
BACKGROUND: Evidence from cancer clinical trials can be difficult to generalize to real-world patient populations, but can be complemented by real-world evidence to optimize personalization of care. Further, real-world usage patterns of programmed cell death protein 1 (PD-1) inhibitors following approval can inform future studies of subpopulations underrepresented in clinical trials. MATERIALS AND METHODS: We performed a multicenter analysis using electronic health record data collected during routine care of patients treated in community cancer care clinics in the Flatiron Health network...
January 9, 2018: Oncologist
https://www.readbyqxmd.com/read/29315141/the-treatment-of-antibody-mediated-rejection-in-kidney-transplantation-an-updated-systematic-review-and-meta-analysis
#10
Susan S Wan, Tracey D Ying, Kate Wyburn, Darren M Roberts, Melanie Wyld, Steven J Chadban
BACKGROUND: Current treatments for antibody-mediated rejection (AMR) in kidney transplantation are based on low-quality data from a small number of controlled trials. Novel agents targeting B-cells, plasma-cells and the complement system have featured in recent studies of AMR. METHODS: We conducted a systematic review and meta-analysis of controlled trials in kidney transplant recipients using Medline, EMBASE and CENTRAL from inception to February 2017. RESULTS: Of 14,380 citations we identified 21 studies, including 10 randomized controlled trials, involving 751 participants...
January 8, 2018: Transplantation
https://www.readbyqxmd.com/read/29314145/toward-complement-inhibition-2-0-next-generation-anti-complement-agents-for-paroxysmal-nocturnal-hemoglobinuria
#11
Antonio M Risitano, Serena Marotta
Therapeutic complement inhibition by eculizumab has revolutionized the treatment of paroxysmal nocturnal hemoglobinuria (PNH) with a major impact on its natural history. Nevertheless, emerging unmet clinical needs may benefit from the development of novel complement inhibitors. Novel strategies of complement inhibition exploit different agents targeting C5, as well as compound intercepting the complement cascade at the level of its key component C3, or even upstream at the level of components involved in complement alternative pathway initiation...
January 4, 2018: American Journal of Hematology
https://www.readbyqxmd.com/read/29312858/de-novo-glomerular-diseases-after-renal-transplantation-how-is-it-different-from-recurrent-glomerular-diseases
#12
REVIEW
Fedaey Abbas, Mohsen El Kossi, Jon Kim Jin, Ajay Sharma, Ahmed Halawa
The glomerular diseases after renal transplantation can occur de novo, i.e., with no relation to the native kidney disease, or more frequently occur as a recurrence of the original disease in the native kidney. There may not be any difference in clinical features and histological pattern between de novo glomerular disease and recurrence of original glomerular disease. However, structural alterations in transplanted kidney add to dilemma in diagnosis. These changes in architecture of histopathology can happen due to: (1) exposure to the immunosuppression specifically the calcineurin inhibitors (CNI); (2) in vascular and tubulointerstitial alterations as a result of antibody mediated or cell-mediated immunological onslaught; (3) post-transplant viral infections; (4) ischemia-reperfusion injury; and (5) hyperfiltration injury...
December 24, 2017: World Journal of Transplantation
https://www.readbyqxmd.com/read/29311237/evaluation-of-cpxra-as-a-therapeutic-target-for-uropathogenic-escherichia-coli-infections
#13
Lana Dbeibo, Julia J van Rensburg, Sara N Smith, Kate R Fortney, Dharanesh Gangaiah, Hongyu Gao, Juan Marzoa, Yunlong Liu, Harry L T Mobley, Stanley M Spinola
CpxRA is an envelope stress response system found in all species of Enterobacteriaceae; CpxA has kinase activity for CpxR and phosphatase activity for phospho-CpxR, a transcription factor. CpxR also accepts phosphate groups and acetyl phosphate, a glucose metabolite. Activation of CpxR increases transcription of genes encoding for membrane repair and downregulates virulence determinants. We hypothesized that activation of CpxR could serve as an antimicrobial/antivirulence strategy and discovered compounds that activate CpxR in Escherichia coli by inhibiting CpxA phosphatase activity...
January 8, 2018: Infection and Immunity
https://www.readbyqxmd.com/read/29300009/structure-of-the-complement-c5a-receptor-bound-to-the-extra-helical-antagonist-ndt9513727
#14
Nathan Robertson, Mathieu Rappas, Andrew S Doré, Jason Brown, Giovanni Bottegoni, Markus Koglin, Julie Cansfield, Ali Jazayeri, Robert M Cooke, Fiona H Marshall
The complement system is a crucial component of the host response to infection and tissue damage. Activation of the complement cascade generates anaphylatoxins including C5a and C3a. C5a exerts a pro-inflammatory effect via the G-protein-coupled receptor C5a anaphylatoxin chemotactic receptor 1 (C5aR1, also known as CD88) that is expressed on cells of myeloid origin. Inhibitors of the complement system have long been of interest as potential drugs for the treatment of diseases such as sepsis, rheumatoid arthritis, Crohn's disease and ischaemia-reperfusion injuries...
January 3, 2018: Nature
https://www.readbyqxmd.com/read/29299869/combination-therapy-with-low-dose-ivig-and-a-c1-esterase-inhibitor-ameliorates-brain-damage-and-functional-deficits-in-experimental-ischemic-stroke
#15
Xinzhi Chen, Thiruma V Arumugam, Yi-Lin Cheng, Jong-Hwan Lee, Srinivasulu Chigurupati, Mark P Mattson, Milan Basta
Acute ischemic stroke causes a high rate of deaths and permanent neurological deficits in survivors. Current interventional treatment, in the form of enzymatic thrombolysis, benefits only a small percentage of patients. Brain ischemia triggers mobilization of innate immunity, specifically the complement system and Toll-like receptors (TLRs), ultimately leading to an exaggerated inflammatory response. Here we demonstrate that intravenous immunoglobulin (IVIG), a scavenger of potentially harmful complement fragments, and C1-esterase inhibitor (C1-INH), an inhibitor of complement activation, exert a beneficial effect on the outcome of experimental brain ischemia (I) and reperfusion (R) injury induced by transient occlusion of middle cerebral artery in mice...
January 3, 2018: Neuromolecular Medicine
https://www.readbyqxmd.com/read/29299575/new-organometallic-imines-of-rhenium-i-as-potential-ligands-of-gsk-3%C3%AE-synthesis-characterization-and-biological-studies
#16
Michelle Muñoz-Osses, Fernando Godoy, Angélica Fierro, Alejandra Gómez, Nils Metzler-Nolte
Substituted amino-piperazine derivatives were synthesized and used as precursors for the preparation of a series of new organometallic Re(i) imine complexes with the general formula [(η5-C5H4CH[double bond, length as m-dash]N-(CH2)5-Pz-R)Re(CO)3] (Pz-R: -alkyl or aryl piperazine). The piperazine-based ligands were designed to be potential inhibitors of GSK-3β kinase. All the ligands and complexes were fully characterized and evaluated against the HT-29 and PT-45 cancer cell lines, in which GSK-3β plays a crucial role...
January 4, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/29296844/potential-impact-of-complement-regulator-deficiencies-on-hemolytic-reactions-due-to-minor-abo-mismatched-transfusions
#17
Priyanka Pandey, Waseem Q Anani, Jerome L Gottschall, Gregory A Denomme
Minor ABO-mismatched transfusions are a common occurrence, although infrequent transfusion reactions occur. We sought to investigate the regulation of complement C3 activation induced by anti-A. In vitro complement C3 activation was observed with 10 of 30 group O samples and correlated with immunoglobulin M (IgM) anti-A titers. We developed an in vitro paroxysmal nocturnal hemoglobinuria (PNH) model of hemolysis in which group A1 red blood cells (RBCs) were chemically treated with 2-aminoethylisothiouronium (AET) to alter regulators of complement C3 activation...
October 24, 2017: Blood Advances
https://www.readbyqxmd.com/read/29296765/use-of-the-complement-inhibitor-coversin-to-treat-hsct-associated-tma
#18
Timothy H J Goodship, Fernando Pinto, Wynn H Weston-Davies, Juliana Silva, Jun-Ichi Nishimura, Miles A Nunn, Ian Mackie, Samuel J Machin, Liina Palm, Jeremy W Pryce, Robert Chiesa, Persis Amrolia, Paul Veys
Finding an inherited complement abnormality in HSCT-associated TMA provides a rationale for the use of a complement inhibitor.Alternative complement inhibitors such as Coversin should be considered in patients who are resistant to eculizumab.
July 11, 2017: Blood Advances
https://www.readbyqxmd.com/read/29296560/medicinal-leech-therapy-an-overall-perspective
#19
REVIEW
Ali K Sig, Mustafa Guney, Aylin Uskudar Guclu, Erkan Ozmen
Complementary medicine methods have a long history, but modern medicine has just recently focused on their possible modes of action. Medicinal leech therapy (MLT) or hirudotherapy, an old technique, has been studied by many researchers for possible effects on various diseases such as inflammatory diseases, osteoarthritis, and after different surgeries. Hirudo medicinalis has widest therapeutic usage among the leeches, but worldwide, many different species were tested and studied. Leeches secrete more than 20 identified bioactive substances such as antistasin, eglins, guamerin, hirudin, saratin, bdellins, complement, and carboxypeptidase inhibitors...
December 2017: Integrative Medicine Research
https://www.readbyqxmd.com/read/29288280/is-eculizumab-efficacious-in-shigatoxin-associated-hemolytic-uremic-syndrome-a-narrative-review-of-current-evidence
#20
REVIEW
Werner Keenswijk, Ann Raes, Johan Vande Walle
Severe complications due to Shigatoxin-associated hemolytic uremic syndrome (STEC-HUS) currently present a serious challenge since no specific treatment for this condition is available. Eculizumab, a terminal complement inhibitor, has been used especially in STEC-HUS patients with severe neurological involvement, but the efficacy remains undetermined. In order to determine its efficacy, we searched the databases Pubmed, Web of Science, Embase, and LiLACS for reports describing outcomes of eculizumab administration in STEC-HUS...
December 29, 2017: European Journal of Pediatrics
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