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https://www.readbyqxmd.com/read/28319049/resisting-fatal-attraction-a-glioma-oncometabolite-prevents-cd8-t-cell-recruitment
#1
Liliana E Lucca, David A Hafler
Immunotherapy has emerged as a potent approach for treating aggressive cancers, such as non-small-cell lung tumors and metastatic melanoma. Clinical trials are now in progress for patients with malignant gliomas; however, a better understanding of how these tumors escape immune surveillance is required to enhance antitumor immune responses. With gliomas, the recruitment of CD8+ T cells to the tumor is impaired, in part preventing containment or elimination of the tumor. In this issue of the JCI, Kohanbash and colleagues present an elegant dissection of how gliomas exploit an enzymatic activity acquired through a common mutation to abrogate the migration of CD8+ T cells to the tumor...
March 20, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28315675/low-intensity-training-and-the-c5a-complement-antagonist-nox-d21-rescue-the-mdx-phenotype-through-modulation-of-inflammation
#2
Janek Hyzewicz, Jun Tanihata, Mutsuki Kuraoka, Yuko Nitahara-Kasahara, Teiva Beylier, Urs T Ruegg, Axel Vater, Shin'ichi Takeda
Inflammatory events occurring in dystrophic muscles contribute to the progression of Duchenne muscular dystrophy (DMD). Low-intensity training (LIT) attenuates the phenotype of mdx mice, an animal model for DMD. Therefore, we postulated that LIT could have anti-inflammatory properties. We assessed levels of inflammatory cytokines and infiltrated immune cells in gastrocnemius muscle of mdx mice after LIT. We detected high levels of complement component C5a, chemokine ligand (CCL) 2, CD68(+) monocytes/macrophages, and proinflammatory M1 macrophages in muscles of mdx mice...
March 15, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28302171/clinical-characteristics-and-real-life-diagnostic-approaches-in-all-danish-children-with-hereditary-angioedema
#3
Anne Aabom, Klaus E Andersen, Christina Fagerberg, Niels Fisker, Marianne A Jakobsen, Anette Bygum
BACKGROUND: With a potentially early onset, hereditary angioedema (HAE) requires special knowledge also in infancy and early childhood. In children from families with HAE, the diagnosis should be confirmed or refuted early, which can be difficult. Studies of childhood HAE and the diagnostic approaches are limited. Our aim was to investigate the entire Danish cohort of children with HAE and non-HAE children of HAE patients for diagnostic approaches and clinical characteristics. RESULTS: We included 41 children: 22 with HAE and 19 non-HAE...
March 16, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28301387/antibody-mediated-rejection-in-heart-transplantation-new-developments-and-old-uncertainties
#4
Valentina Manfredini, Ornella Leone, Valentina Agostini, Luciano Potena
PURPOSE OF REVIEW: Antibody-mediated rejection (AMR) currently represents one of the main problems for clinical management of heart transplant because of its diagnostic complexity and poor evidences supporting treatments. RECENT FINDINGS: Disorder-based diagnosis is a cornerstone in defining AMR. The limitations of the current classification have been partially overcome by novel studies improving the description of the immune-pathological graft abnormalities, and by new molecular approaches allowing a better understanding of the mechanisms behind AMR and of its relationship with cellular rejection and chronic vasculopathy...
March 15, 2017: Current Opinion in Organ Transplantation
https://www.readbyqxmd.com/read/28299833/unsupervised-pharmacophore-modeling-combined-with-qsar-analyses-revealed-novel-low-micromolar-sirt2-inhibitors
#5
Mohammad A Khanfar, Mutasem O Taha
Situin 2 (SIRT2) enzyme is a histone deacetylase that has important role in neuronal development. SIRT2 is clinically validated target for neurodegenerative diseases and some cancers. In this study, exhaustive unsupervised pharmacophore modeling was combined with quantitative structure-activity relationship (QSAR) analysis to explore the structural requirements for potent SIRT2 inhibitors using 146 known SIRT2 ligands. A computational workflow that combines genetic function algorithm with k-nearest neighbor or multiple linear regression was implemented to build self-consistent and predictive QSAR models based on combinations of pharmacophores and physicochemical descriptors...
March 15, 2017: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/28298523/identification-of-c3b-binding-small-molecule-complement-inhibitors-using-cheminformatics
#6
Brandon L Garcia, D Andrew Skaff, Arindam Chatterjee, Anders Hanning, John K Walker, Gerald J Wyckoff, Brian V Geisbrecht
The complement system is an elegantly regulated biochemical cascade formed by the collective molecular recognition properties and proteolytic activities of more than two dozen membrane-bound or serum proteins. Complement plays diverse roles in human physiology, such as acting as a sentry against invading microorganisms, priming of the adaptive immune response, and removal of immune complexes. However, dysregulation of complement can serve as a trigger for a wide range of human diseases, which include autoimmune, inflammatory, and degenerative conditions...
March 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28296924/changes-in-surface-glycosylation-and-glycocalyx-shedding-in-trichobilharzia-regenti-schistosomatidae-during-the-transformation-of-cercaria-to-schistosomulum
#7
Jana Řimnáčová, Libor Mikeš, Libuše Turjanicová, Jana Bulantová, Petr Horák
The invasive larvae (cercariae) of schistosomes penetrate the skin of their definitive hosts. During the invasion, they undergo dramatic ultrastructural and physiological transitions. These changes result in the development of the subsequent stage, schistosomulum, which migrates through host tissues in close contact with host's immune system. One of the striking changes in the transforming cercariae is the shedding of their thick tegumental glycocalyx, which represents an immunoattractive structure; therefore its removal helps cercariae to avoid immune attack...
2017: PloS One
https://www.readbyqxmd.com/read/28296762/effect-on-mother-and-child-of-eculizumab-given-before-caesarean-section-in-a-patient-with-severe-antiphospholipid-syndrome-a-case-report
#8
Alice Gustavsen, Lillemor Skattum, Grethe Bergseth, Bjorg Lorentzen, Yngvar Floisand, Vidar Bosnes, Tom Eirik Mollnes, Andreas Barratt-Due
RATIONALE: Antiphospholipid syndrome (APS) in pregnancy may trigger the life-threatening catastrophic antiphospholipid syndrome (CAPS). Complement activation is implicated in the pathogenesis, and inhibition of complement factor C5 is suggested as an additional treatment option. PATIENT CONCERNS, DIAGNOSIS AND INTERVENTIONS: We present a pregnant patient treated with the C5-inhibitor eculizumab due to high risk of developing devastating APS-related complications...
March 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28294107/antifungal-mechanisms-of-zno-and-ag-nanoparticles-to-sclerotinia-homoeocarpa
#9
Junli Li, Hyunkyu Sang, Huiyuan Guo, James T Popko, Lili He, Jason C White, Om Parkash Dhankher, Geunhwa Jung, Baoshan Xing
Fungicides have extensively been used to effectively combat fungal diseases on a range of plant species, but resistance to multiple active ingredients has developed in pathogens such as Sclerotinia homoeocarpa, the causal agent of dollar spot on cool-season turfgrasses. Recently, ZnO and Ag nanoparticles (NPs) have received increased attention due to their antimicrobial activities. In this study, the NPs' toxicity and mechanisms of action were investigated as alternative antifungal agents against S. homoeocarpa isolates that varied in their resistance to demethylation inhibitor (DMI) fungicides...
April 18, 2017: Nanotechnology
https://www.readbyqxmd.com/read/28290199/unbinding-kinetics-of-a-p38-map-kinase-type-ii-inhibitor-from-metadynamics-simulations
#10
Rodrigo Casasnovas, Vittorio Limongelli, Pratyush Tiwary, Paolo Carloni, Michele Parrinello
Understanding the structural and energetic requisites of ligand binding towards its molecular target is of paramount relevance in drug design. In the recent years atomistic free energy calculations have proven to be a valid tool to complement experiments in characterizing the thermodynamic and kinetic properties of protein/ligand interaction. Here, we investigate, through a recently developed metadynamics-based protocol, the unbinding mechanism of an inhibitor of the pharmacologically relevant target p38 MAP kinase...
March 14, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28288993/a-combined-pd-1-c5a-blockade-synergistically-protects-against-lung-cancer-growth-and-metastasis
#11
Daniel Ajona, Sergio Ortiz-Espinosa, Haritz Moreno, Teresa Lozano, Maria J Pajares, Jackeline Agorreta, Cristina Bértolo, Juan J Lasarte, Silvestre Vicent, Axel Vater, Fernando Lecanda, Luis M Montuenga, Ruben Pio
Disruption of the programmed cell death protein 1 (PD-1) pathway with immune checkpoint inhibitors represents a major breakthrough in the treatment of non-small cell lung cancer. We hypothesized that a combined inhibition of C5a/C5aR1 and PD-1 signaling may have an antitumor synergistic effect. RMP1-14 antibody was used to block PD-1 and an L-aptamer to inhibit signaling of complement C5a with its receptors. Using syngeneic models of lung cancer we demonstrate that the combination of C5a and PD-1 blockade markedly reduces tumor growth and metastasis, and leads to prolonged survival...
March 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28287636/transplant-associated-thrombotic-microangiopathy-opening-pandora-s-box
#12
REVIEW
E Gavriilaki, I Sakellari, A Anagnostopoulos, R A Brodsky
Transplant-associated thrombotic microangiopathy (TA-TMA) is an early complication of hematopoietic cell transplantation (HCT). A high mortality rate is documented in patients who are refractory to calcineurin inhibitor cessation. Estimates of TA-TMA prevalence vary significantly and are higher in allogeneic compared with autologous HCT. Furthermore, our understanding of the pathophysiology that is strongly related to diagnosis and treatment options is limited. Recent evidence has linked TA-TMA with atypical hemolytic uremic syndrome, a disease of excessive activation of the alternative pathway of complement, opening the Pandora's box in treatment options...
March 13, 2017: Bone Marrow Transplantation
https://www.readbyqxmd.com/read/28286522/assessment-of-105-patients-with-angiotensin-converting-enzyme-inhibitor-induced-angioedema
#13
Eva Rye Rasmussen, Christian von Buchwald, Mia Wadelius, Sumangali Chandra Prasad, Shailajah Kamaleswaran, Kawa Khaled Ajgeiy, Georg Authried, Kristine Appel U Pallesen, Anette Bygum
Objective. To asses a cohort of 105 consecutive patients with angiotensin converting enzyme-inhibitor induced angioedema with regard to demographics, risk factors, family history of angioedema, hospitalization, airway management, outcome, and use of diagnostic codes used for the condition. Study Design. Cohort study. Methods. This was a retrospective cohort study of 105 patients with angiotensin converting enzyme-inhibitor induced angioedema in the period 1995-2014. Results. The cohort consisted of 67 females and 38 males (F : M ratio 1...
2017: International Journal of Otolaryngology
https://www.readbyqxmd.com/read/28278621/anti-complementary-constituents-of-viola-kunawarensis
#14
Hui Wang, Wen-Li Cong, Ze-Long Fu, Dao-Feng Chen, Qi Wang
Activity-guided fractionation for complement inhibitors led to the isolation of 22 known compounds from Viola kunawarensis. Chemical types include six sterol compounds, three coumarin compounds, five megastigmane compounds, two triterpenoid compounds, two phenylpropanoid compounds, one chlorophyll, one amide, and two lipid compounds. Among which, two sterols (stigmasta-4-ene-3β,6β-diol and saringosterone), one amide (aurantiamide acetate) and a norsesquiterpenoid (solalyratin B) exhibited better anti-complementary effects with CH50 values ranging from 0...
March 3, 2017: Natural Product Research
https://www.readbyqxmd.com/read/28278252/complement-inhibition-by-sarcoptes-scabiei-protects-streptococcus-pyogenes-an-in-vitro-study-to-unravel-the-molecular-mechanisms-behind-the-poorly-understood-predilection-of-s-pyogenes-to-infect-mite-induced-skin-lesions
#15
Pearl M Swe, Lindsay D Christian, Hieng C Lu, Kadaba S Sriprakash, Katja Fischer
BACKGROUND: On a global scale scabies is one of the most common dermatological conditions, imposing a considerable economic burden on individuals, communities and health systems. There is substantial epidemiological evidence that in tropical regions scabies is often causing pyoderma and subsequently serious illness due to invasion by opportunistic bacteria. The health burden due to complicated scabies causing cellulitis, bacteraemia and sepsis, heart and kidney diseases in resource-poor communities is extreme...
March 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28277903/a-human-monoclonal-antibody-that-specifically-binds-and-inhibits-the-staphylococcal-complement-inhibitor-protein-scin
#16
Hedzer Hoekstra, Francisco Romero Pastrana, Hendrik P J Bonarius, Kok P M van Kessel, Goffe S Elsinga, Neeltje Kooi, Herman Groen, Jan Maarten van Dijl, Girbe Buist
Staphylococcus aureus is a serious public health burden causing a wide variety of infections. Earlier detection of such infections could result in faster and more directed therapies that also prevent resistance development. Human monoclonal antibodies (humAbs) are promising tools for diagnosis and therapy owing to their relatively straightforward synthesis, long history of safe clinical use and high target specificity. Here we show that the humAb 6D4, which was obtained from a random screen of B-cells producing antibodies that bind to whole cells of S...
February 16, 2017: Virulence
https://www.readbyqxmd.com/read/28276660/complement-alternative-pathway-deficiency-in-recipients-protects-kidney-allograft-from-ischemia-reperfusion-injury-and-alloreactive-t-cell-response
#17
Federica Casiraghi, Nadia Azzollini, Marta Todeschini, Sonia Fiori, Regiane Aparecida Cavinato, Paola Cassis, Samantha Solini, Francesca Pezzuto, Marilena Mister, Joshua M Thurman, Ariela Benigni, Giuseppe Remuzzi, Marina Noris
Despite the introduction of novel and more targeted immunosuppressive drugs, the long-term survival of kidney transplants has not improved satisfactorily. Early antigen-independent intra-graft inflammation plays a critical role in the initiation of the alloimmune response and impacts long-term graft function. Complement activation is a key player both in ischemia/reperfusion injury (IRI) as well as in adaptive anti-graft immune response after kidney transplantation. Since the alternative pathway (AP) amplifies complement activation regardless of the initiation pathways and renal IR injured cells undergo uncontrolled complement activation, we wondered whether selective blockade of AP could be a strategy for prolonging kidney graft survival...
March 9, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28275964/reversal-of-threatening-blindness-after-initiation-of-eculizumab-in-purtscher-like-retinopathy-secondary-to-atypical-hemolytic-uremic-syndrome
#18
J E Ramos de Carvalho, R O Schlingemann, M Oranje, F J Bemelman, M J van Schooneveld
Purtscher-like retinopathy, a rare manifestation of systemic thrombotic microangiopathy, is a potentially visually debilitating condition with no effective proven treatment. Distinct pathogenic pathways have been proposed as etiological factors. We revisit the etiology of Purtscher-like retinopathy based on the rapid response and profound visual improvement after initiation of systemic intravenous eculizumab, an inhibitor of the complement cascade, in a patient with Purtscher-like retinopathy secondary to familial atypical hemolytic uremic syndrome (aHUS) due to a mutation in complement factor H...
March 8, 2017: International Ophthalmology
https://www.readbyqxmd.com/read/28275852/ga-della-pathway-is-involved-in-regulation-of-nitrogen-deficiency-induced-anthocyanin-accumulation
#19
Yongqiang Zhang, Zhongjuan Liu, Jianping Liu, Sheng Lin, Jianfeng Wang, Wenxiong Lin, Weifeng Xu
DELLA proteins positively regulate nitrogen deficiency-induced anthocyanin accumulation through directly interaction with PAP1 to enhance its transcriptional activity on anthocyanin biosynthetic gene expressions. Plants can survive a limiting nitrogen supply by undergoing adaptive responses, including induction of anthocyanin production. However, the detailed mechanism is still unclear. In this study, we found that this process was impaired and enhanced, respectively, by exogenous GA3 (an active form of GAs) and paclobutrazol (PAC, a specific GA biosynthesis inhibitor) in Arabidopsis seedlings...
March 8, 2017: Plant Cell Reports
https://www.readbyqxmd.com/read/28275134/the-complement-anaphylatoxins-c5a-and-c3a-suppress-ifn-%C3%AE-production-in-response-to-listeria-monocytogenes-by-inhibition-of-the-cyclic-dinucleotide-activated-cytosolic-surveillance-pathway
#20
Stacey L Mueller-Ortiz, Daniel G Calame, Nancy Shenoi, Yi-Dong Li, Rick A Wetsel
Listeria monocytogenes is an intracellular Gram-positive bacterium that induces expression of type I IFNs (IFN-α/IFN-β) during infection. These cytokines are detrimental to the host during infection by priming leukocytes to undergo L. monocytogenes-mediated apoptosis. Our previous studies showed that C5aR1(-/-) and C3aR(-/-) mice are highly susceptible to L. monocytogenes infection as a result of increased IFN-β-mediated apoptosis of major leukocyte cell populations, including CD4(+) and CD8(+) T cells. However, the mechanisms by which C3a and C5a modulate IFN-β expression during L...
March 8, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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