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https://www.readbyqxmd.com/read/28447417/diagnostic-approach-to-microangiopathic-hemolytic-disorders
#1
REVIEW
K Kottke-Marchant
Thrombotic micro-angiopathies (TMA) are a group of related disorders that are characterized by thrombosis of the microvasculature and associated organ dysfunction, and encompass congenital, acquired, and infectious etiologies. A hall mark of TMAs is the fragmentation of erythrocytes by the microvascular thrombi, resulting in a hemolytic anemia. There are several distinct pathophysiologies leading to microangiopathic hemolysis, ranging from decreased degradation of von Willebrand factor as seen in thrombotic thrombocytopenic purpura (TTP) to endothelial damage facilitated by Escherichia coli shiga toxin or complement dysregulation, seen in shiga toxin-related hemolytic-uremic syndrome (Stx-HUS) and complement-mediated TMA (also called atypical hemolytic-uremic syndrome), respectively...
May 2017: International Journal of Laboratory Hematology
https://www.readbyqxmd.com/read/28446616/early-immune-responses-are-independent-of-rgc-dysfunction-in-glaucoma-with-complement-component-c3-being-protective
#2
Jeffrey M Harder, Catherine E Braine, Pete A Williams, Xianjun Zhu, Katharine H MacNicoll, Gregory L Sousa, Rebecca A Buchanan, Richard S Smith, Richard T Libby, Gareth R Howell, Simon W M John
Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wld(s) allele, which protects from axon dysfunction. We demonstrate that DBA/2J.Wld(s) mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma...
April 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28446504/feasibility-of-ultra-high-throughput-functional-screening-of-melanoma-biopsies-for-discovery-of-novel-cancer-drug-combinations
#3
Adam A Friedman, Yun Xia, Lorenzo Trippa, Long P Le, Vivien Igras, Dennie T Frederick, Jennifer A Wargo, Kenneth K Tanabe, Donald P Lawrence, Donna S Neuberg, Keith T Flaherty, David Fisher
Purpose: Successful development of targeted therapy combinations for cancer patients depends on first discovering such combinations in predictive preclinical models. Stable cell lines and mouse xenograft models can have genetic and phenotypic drift and may take too long to generate to be useful as a personalized medicine tool. <p>Experimental Design: To overcome these limitations, we have used a platform of ultra-high-throughput functional screening of primary biopsies preserving both cancer and stroma cell populations from melanoma patients to nominate such novel combinations from a library of  thousands of drug combinations in a patient-specific manner within days of biopsy...
April 26, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28445475/grhl3-binding-and-enhancers-rearrange-as-epidermal-keratinocytes-transition-between-functional-states
#4
Rachel Herndon Klein, Ziguang Lin, Amelia Soto Hopkin, William Gordon, Lam C Tsoi, Yun Liang, Johann E Gudjonsson, Bogi Andersen
Transcription factor binding, chromatin modifications and large scale chromatin re-organization underlie progressive, irreversible cell lineage commitments and differentiation. We know little, however, about chromatin changes as cells enter transient, reversible states such as migration. Here we demonstrate that when human progenitor keratinocytes either differentiate or migrate they form complements of typical enhancers and super-enhancers that are unique for each state. Unique super-enhancers for each cellular state link to gene expression that confers functions associated with the respective cell state...
April 26, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28444979/false-negative-single-antigen-bead-assay-is-it-always-an-effect-of-prozone
#5
Dharmendra Jain, Jui Choudhuri, Rajni Chauhan, Pranav Dorwal, Deepak Sharma, Aseem K Tiwari, Vimarsh Raina
BACKGROUND: Bead based flow cytometry and Luminex play a major role in identification of alloantibodies in renal transplant work-up. Strong sensitization events may lead to prozone phenomenon that can affect single antigen bead (SAB) assay and result in false negativity. However, this can also be due to high titer of other blocking antibodies. While methods like, heat inactivation, C1 inhibitor, Ethylene diamine tetra-acetic-acid and Dithio threitol treatment can remove interfering antibodies of complement and IgM, these methods are not optimal if false negativity is due to prozone effect, which is high titer of antibodies alone...
April 26, 2017: Journal of Clinical Laboratory Analysis
https://www.readbyqxmd.com/read/28444847/complement-dependence-of-murine-costimulatory-blockade-resistant-cellular-cardiac-allograft-rejection
#6
Nicholas Chun, Robert L Fairchild, Yansui Li, Jinhua Liu, Ming Zhang, William M Baldwin, Peter S Heeger
Building upon studies showing that ischemia/reperfusion-(IR)-injury is complement-dependent, we tested links among complement activation, transplant associated ischemia-reperfusion injury, and murine cardiac allograft rejection. We transplanted BALB/c hearts subjected to 8h cold ischemic storage (CIS) into CTLA4Ig-treated WT or c3(-/-) B6 recipients. Whereas allografts subjected to 8h CIS rejected in WT recipients with a median survival time (MST) of 37d, identically treated hearts survived >60d in c3(-/-) mice (p<0...
April 26, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28439485/treatment-of-atypical-hemolytic-uremic-syndrome-in-the-era-of-eculizumab
#7
Rawaa Ebrahem, Salam Kadhem, Quoc Truong
Hemolytic-uremic syndrome (HUS) is the triad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury (AKI); the main cause of multi-organ failure is related to thrombotic microangiopathy (TMA). Atypical HUS (aHUS) is a disease of uncontrolled complement activation associated with a high mortality rate and most cases progress to end-stage renal disease. About 50% of patients with this syndrome carry mutations in genes that encode complement proteins. Also, aHUS constitutes an over-activation of the complement pathway which is either inherited, acquired, or both...
March 23, 2017: Curēus
https://www.readbyqxmd.com/read/28438765/longitudinal-characterization-of-renal-proximal-tubular-markers-in-normotensive-and-preeclamptic-pregnancies
#8
Elisabeth Codsi, Vesna D Garovic, Maria L Gonzalez-Suarez, Natasa Milic, Kristi S Borowski, Carl H Rose, Norman P Davies, Kianoush Kashani, John C Lieske, Wendy M White
Glomerular damage is common in preeclampsia (PE), but the extent and etiology of tubular injury are not well understood. The aim of this study was to evaluate tubular injury in patients with PE and to assess whether it predates clinical disease. We performed a prospective cohort study of 315 pregnant women who provided urine samples at the end of the second trimester and at delivery. This analysis included women who developed PE (n=15), gestational hypertension (GH) (n=14), and normotensive controls (NC) (n=44)...
April 24, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/28438066/angiogenesis-inhibitors-in-tackling-recurrent-glioblastoma
#9
Thomas Hundsberger, David A Reardon, Patrick Y Wen
Despite aggressive multimodality treatment of glioblastoma, outcome remains poor and patients mostly die of local recurrences. Besides reoperation and occasionally reirradiation, systemic treatment of recurrent glioblastoma consists of alkylating chemotherapy (lomustine, temozolomide), bevacizumab and combinations thereof. Unfortunately, antiangiogenic agents failed to improve survival either as a monotherapy or in combination treatments. This review provides current insights into tumor-derived escape mechanisms and other areas of treatment failure of antiangiogenic agents in glioblastoma...
April 24, 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/28438039/anti-complementary-constituents-of-anchusa-italica
#10
Yu-Zhen Hou, Kui-Kui Chen, Xi-Ling Deng, Ze-Long Fu, Dao-Feng Chen, Qi Wang
Activity-guided fractionation for complement inhibitors led to the isolation of 24 known compounds from Anchusa italica. Chemical types include eight megastigmane compounds, five triterpenoid compounds, five lignan compounds, three flavonoid compounds, two alkaloid compounds and one phenthyl alcohol compound. Among which, a lignan (medioresinol), an alkaloid (5-hydroxypyrrolidin-2-one) and a flavonoid (5-hydroxyl-3', 4', 6, 7-tetramethoxy flavone) exhibited better anticomplementary effects with CH50 values ranging from 0...
April 24, 2017: Natural Product Research
https://www.readbyqxmd.com/read/28437395/global-survey-of-the-immunomodulatory-potential-of-common-drugs
#11
Gregory I Vladimer, Berend Snijder, Nikolaus Krall, Johannes W Bigenzahn, Kilian V M Huber, Charles-Hugues Lardeau, Kumar Sanjiv, Anna Ringler, Ulrika Warpman Berglund, Monika Sabler, Oscar Lopez de la Fuente, Paul Knöbl, Stefan Kubicek, Thomas Helleday, Ulrich Jäger, Giulio Superti-Furga
Small-molecule drugs may complement antibody-based therapies in an immune-oncology setting, yet systematic methods for the identification and characterization of the immunomodulatory properties of these entities are lacking. We surveyed the immumomodulatory potential of 1,402 small chemical molecules, as defined by their ability to alter the cell-cell interactions among peripheral mononuclear leukocytes ex vivo, using automated microscopy and population-wide single-cell image analysis. Unexpectedly, ∼10% of the agents tested affected these cell-cell interactions differentially...
April 24, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28435009/selective-small-molecule-inhibitors-as-chemical-tools-to-define-the-roles-of-matrix-metalloproteinases-in-disease
#12
REVIEW
Jayda E Meisel, Mayland Chang
The focus of this article is to highlight novel inhibitors and current examples where the use of selective small-molecule inhibitors has been critical in defining the roles of matrix metalloproteinases (MMPs) in disease. Selective small-molecule inhibitors are surgical chemical tools that can inhibit the targeted enzyme; they are the method of choice to ascertain the roles of MMPs and complement studies with knockout animals. This strategy can identify targets for therapeutic development as exemplified by the use of selective small-molecule MMP inhibitors in diabetic wound healing, spinal cord injury, stroke, traumatic brain injury, cancer metastasis, and viral infection...
April 20, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28434814/novel-protein-biomarkers-associated-with-coronary-artery-disease-in-statin-treated-patients-with-familial-hypercholesterolemia
#13
Sven Bos, Michael Phillips, Gerald F Watts, Adrie J M Verhoeven, Eric J G Sijbrands, Natalie C Ward
BACKGROUND: Familial hypercholesterolemia (FH) is the most common and serious monogenic disorder of lipid metabolism. The incidence of coronary artery disease (CAD) varies among both treated and untreated FH patients. OBJECTIVE: The aim of the study was to utilize proteomics to identify novel protein biomarkers that differentiate genetically confirmed heterozygous patients with FH at high CAD risk from those at low CAD risk. METHODS: Sixty genetically confirmed FH patients were recruited and stratified into (1) asymptomatic FH with low atherosclerotic burden (FH, n = 20); (2) asymptomatic FH with high atherosclerotic burden (FH + Ca, n = 20); and (3) FH with previously confirmed symptomatic CAD (FH + CAD, n = 20)...
April 4, 2017: Journal of Clinical Lipidology
https://www.readbyqxmd.com/read/28433622/diminished-capacity-of-opsonization-and-immune-complex-solubilization-and-detection-of-anti-c1q-antibodies-in-sera-from-patients-with-hereditary-angioedema
#14
Daisuke Honda, Isao Ohsawa, Nobuyuki Sato, Hiroyuki Inoshita, Satoshi Mano, Yasuhiko Tomino, Yusuke Suzuki
BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant disease caused by deficiency of C1 esterase inhibitor. Symptoms of HAE include edema, which can potentially cause suffocation. Some patients with HAE exhibit immunological abnormalities, which could prevent an accurate diagnosis. Low levels of complement components are characteristic of HAE and in other settings are thought to reduce elimination of apoptotic cells and immune complex (IC). Thus, we aimed to experimentally clarify the mechanism of immunological abnormalities using sera from HAE patients...
April 19, 2017: Allergology International: Official Journal of the Japanese Society of Allergology
https://www.readbyqxmd.com/read/28432221/biological-considerations-of-plasma-derived-and-recombinant-factor-viii-immunogenicity
#15
Jesse Lai, Christine Hough, Julie Tarrant, David Lillicrap
In hemophilia A, the most severe complication of factor VIII (FVIII) replacement therapy involves the formation of FVIII neutralizing antibodies, also known as inhibitors, in 25-30% of patients. This adverse event is associated with a significant increase in morbidity and economic burden, thus highlighting the need to identify methods to limit FVIII immunogenicity. Inhibitor development is regulated by a complex balance of genetic factors, such as FVIII genotype, and environmental variables, such as coexistent inflammation...
April 21, 2017: Blood
https://www.readbyqxmd.com/read/28428059/the-decreased-growth-performance-and-impaired-immune-function-and-structural-integrity-by-dietary-iron-deficiency-or-excess-are-associated-with-tor-nf-%C3%AE%C2%BAb-p38mapk-nrf2-and-mlck-signaling-in-head-kidney-spleen-and-skin-of-grass-carp-ctenopharyngodon-idella
#16
Yan-Lin Guo, Wei-Dan Jiang, Pei Wu, Yang Liu, Xiao-Qiu Zhou, Sheng-Yao Kuang, Ling Tang, Wu-Neng Tang, Yong-An Zhang, Lin Feng
This study was conducted to investigate the effects of dietary iron on the growth, and immune function and structural integrity in head kidney, spleen and skin as well as the underlying signaling of young grass carp (Ctenopharyngodon idella). Total 630 grass carp (242.32 ± 0.58 g) were fed diets containing graded levels of iron at 12.15 (basal diet), 35.38, 63.47, 86.43, 111.09, 136.37 mg/kg (diets 2-6 were added with ferrous fumarate) and 73.50 mg/kg (diet 7 was added with ferrous sulfate) diet for 60 days...
April 18, 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28426283/identification-of-the-proteome-complement-of-humantlk1-reveals-it-binds-and-phosphorylates-nek1-regulating-its-activity
#17
Vibha Singh, Zachary M Connelly, Xinggui Shen, Arrigo De Benedetti
The Tousled Like kinases (TLKs) are involved in numerous cellular functions, including the DNA Damage Response (DDR), but only a handful of substrates have been identified thus far. Through a novel proteomic screen, we have now identified 165 human proteins interacting with TLK1, and we have focused this work on NEK1 because of its known role in the DDR, upstream of ATR and Chk1. TLK1 and NEK1 were found to interact by coIP, and their binding is strengthened following exposure of cells to H2O2. Following incubation with doxorubicin, TLK1 and NEK1 relocalize with nuclear repair foci along with γH2AX...
April 20, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28424577/investigation-of-endocytic-pathways-for-the-internalization-of-exosome-associated-oligomeric-alpha-synuclein
#18
Marion Delenclos, Teodora Trendafilova, Divya Mahesh, Ann M Baine, Simon Moussaud, Irene K Yan, Tushar Patel, Pamela J McLean
Misfolding and aggregation of alpha-synuclein (αsyn) resulting in cytotoxicity is a hallmark of Parkinson's disease (PD) and related synucleinopathies. The recent body of evidence indicates that αsyn can be released from neuronal cells by nonconventional exocytosis involving extracellular vesicles (EVs) such as exosomes. The transfer of αsyn between cells has been proposed to be an important mechanism of disease propagation in PD. To date, exosome trafficking mechanisms, including release and cell-cell transmission, have not been fully described...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28416734/the-angiotensin-receptor-blocker-losartan-inhibits-mammary-tumor-development-and-progression-to-invasive-carcinoma
#19
Rhiannon Coulson, Seng H Liew, Angela A Connelly, Nicholas S Yee, Siddhartha Deb, Beena Kumar, Ana C Vargas, Sandra A O'Toole, Adam C Parslow, Ashleigh Poh, Tracy Putoczki, Riley J Morrow, Mariah Alorro, Kyren A Lazarus, Evie F W Yeap, Kelly L Walton, Craig A Harrison, Natalie J Hannan, Amee J George, Colin D Clyne, Matthias Ernst, Andrew M Allen, Ashwini L Chand
Drugs that target the Renin-Angiotensin System (RAS) have recently come into focus for their potential utility as cancer treatments. The use of Angiotensin Receptor Blockers (ARBs) and Angiotensin-Converting Enzyme (ACE) Inhibitors (ACEIs) to manage hypertension in cancer patients is correlated with improved survival outcomes for renal, prostate, breast and small cell lung cancer. Previous studies demonstrate that the Angiotensin Receptor Type I (AT1R) is linked to breast cancer pathogenesis, with unbiased analysis of gene-expression studies identifying significant up-regulation of AGTR1, the gene encoding AT1R in ER+ve/HER2-ve tumors correlating with poor prognosis...
March 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414448/substrate-profiling-and-high-resolution-co-complex-crystal-structure-of-a-secreted-c11-protease-conserved-across-commensal-bacteria
#20
Emily J Roncase, Clara Moon, Sandip Chatterjee, Gonzalo E González-Páez, Charles S Craik, Anthony J O'Donoghue, Dennis W Wolan
Cysteine proteases are among the most abundant hydrolytic enzymes produced by bacteria, and this diverse family of proteins have significant biological roles in bacterial viability and environmental interactions. Members of the clostripain-like (C11) family of cysteine proteases from commensal gut bacterial strains have recently been shown to mediate immune responses by inducing neutrophil phagocytosis and activating bacterial pathogenic toxins. Development of substrates, inhibitors, and probes that target C11 proteases from enteric bacteria will help to establish the role of these proteins at the interface of the host and microbiome in health and disease...
April 27, 2017: ACS Chemical Biology
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