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https://www.readbyqxmd.com/read/29769450/heat-shock-protein-peptide-complex-96-vaccination-for-newly-diagnosed-glioblastoma-a-phase-i-single-arm-trial
#1
Nan Ji, Yang Zhang, Yunpeng Liu, Jian Xie, Yi Wang, Shuyu Hao, Zhixian Gao
BACKGROUND: Heat shock protein peptide complex-96 (HSPPC-96) triggers adaptive and innate antitumor immune responses. The safety and efficacy of HSPPC-96 vaccination was examined in patients with newly diagnosed glioblastoma multiforme (GBM). METHODS: In this open-label, single-arm, phase I study, adult patients were vaccinated with HSPPC-96 in combination with the standard treatment for newly diagnosed GBM after surgical resection. Primary endpoints were frequency of adverse events and progression-free survival (PFS) at 6 months...
May 17, 2018: JCI Insight
https://www.readbyqxmd.com/read/29769449/fatty-acid-receptor-modulator-pbi-4050-inhibits-kidney-fibrosis-and-improves-glycemic-control
#2
Yan Li, Sungjin Chung, Zhilian Li, Jessica M Overstreet, Lyne Gagnon, Brigitte Grouix, Martin Leduc, Pierre Laurin, Ming-Zhi Zhang, Raymond C Harris
Extensive kidney fibrosis occurs in several types of chronic kidney diseases. PBI-4050, a potentially novel first-in-class orally active low-molecular weight compound, has antifibrotic and antiinflammatory properties. We examined whether PBI-4050 affected the progression of diabetic nephropathy (DN) in a mouse model of accelerated type 2 diabetes and in a model of selective tubulointerstitial fibrosis. eNOS-/- db/db mice were treated with PBI-4050 from 8-20 weeks of age (early treatment) or from 16-24 weeks of age (late treatment)...
May 17, 2018: JCI Insight
https://www.readbyqxmd.com/read/29769448/tlr-adjuvanted-nanoparticle-vaccines-differentially-influence-the-quality-and-longevity-of-responses-to-malaria-antigen-pfs25
#3
Elizabeth A Thompson, Sebastian Ols, Kazutoyo Miura, Kelly Rausch, David L Narum, Mats Spångberg, Michal Juraska, Ulrike Wille-Reece, Amy Weiner, Randall F Howard, Carole A Long, Patrick E Duffy, Lloyd Johnston, Conlin P O'Neil, Karin Loré
Transmission-blocking vaccines (TBVs) are considered an integral element of malaria eradication efforts. Despite promising evaluations of Plasmodium falciparum Pfs25-based TBVs in mice, clinical trials have failed to induce robust and long-lived Ab titers, in part due to the poorly immunogenic nature of Pfs25. Using nonhuman primates, we demonstrate that multiple aspects of Pfs25 immunity were enhanced by antigen encapsulation in poly(lactic-co-glycolic acid)-based [(PLGA)-based] synthetic vaccine particles (SVP[Pfs25]) and potent TLR-based adjuvants...
May 17, 2018: JCI Insight
https://www.readbyqxmd.com/read/29769447/aquaporin-1-regulates-platelet-procoagulant-membrane-dynamics-and-in-vivo-thrombosis
#4
Ejaife O Agbani, Christopher M Williams, Yong Li, Marion Tj van den Bosch, Samantha F Moore, Adele Mauroux, Lorna Hodgson, Alan S Verkman, Ingeborg Hers, Alastair W Poole
In response to collagen stimulation, platelets use a coordinated system of fluid entry to undergo membrane ballooning, procoagulant spreading, and microvesiculation. We hypothesized that water entry was mediated by the water channel aquaporin-1 (AQP1) and aimed to determine its role in the platelet procoagulant response and thrombosis. We established that human and mouse platelets express AQP1 and localize to internal tubular membrane structures. However, deletion of AQP1 had minimal effects on collagen-induced platelet granule secretion, aggregation, or membrane ballooning...
May 17, 2018: JCI Insight
https://www.readbyqxmd.com/read/29769446/ubiquitination-and-deubiquitination-emerge-as-players-in-idiopathic-pulmonary-fibrosis-pathogenesis-and-treatment
#5
REVIEW
Shuang Li, Jing Zhao, Dong Shang, Daniel J Kass, Yutong Zhao
Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease that is associated with aberrant activation of TGF-β, myofibroblast differentiation, and abnormal extracellular matrix (ECM) production. Proper regulation of protein stability is important for maintenance of intracellular protein homeostasis and signaling. Ubiquitin E3 ligases mediate protein ubiquitination, and deubiquitinating enzymes (DUBs) reverse the process. The role of ubiquitin E3 ligases and DUBs in the pathogenesis of IPF is relatively unexplored...
May 17, 2018: JCI Insight
https://www.readbyqxmd.com/read/29769445/vegf-vegfr2-blockade-does-not-cause-retinal-atrophy-in-amd-relevant-models
#6
Da Long, Yogita Kanan, Jikui Shen, Sean F Hackett, Yuanyuan Liu, Zibran Hafiz, Mahmood Khan, Lili Lu, Peter A Campochiaro
Intraocular injections of VEGF-neutralizing proteins provide tremendous benefits in patients with choroidal neovascularization (NV) due to age-related macular degeneration (AMD), but during treatment some patients develop retinal atrophy. Suggesting that VEGF is a survival factor for retinal neurons, a clinical trial group attributed retinal atrophy to VEGF suppression and cautioned against frequent anti-VEGF injections. This recommendation may contribute to poor outcomes in clinical practice from insufficient treatment...
May 17, 2018: JCI Insight
https://www.readbyqxmd.com/read/29769444/glioblastoma-targeted-cd4-car-t-cells-mediate-superior-antitumor-activity
#7
Dongrui Wang, Brenda Aguilar, Renate Starr, Darya Alizadeh, Alfonso Brito, Aniee Sarkissian, Julie R Ostberg, Stephen J Forman, Christine E Brown
Chimeric antigen receptor-modified (CAR-modified) T cells have shown promising therapeutic effects for hematological malignancies, yet limited and inconsistent efficacy against solid tumors. The refinement of CAR therapy requires an understanding of the optimal characteristics of the cellular products, including the appropriate composition of CD4+ and CD8+ subsets. Here, we investigated the differential antitumor effect of CD4+ and CD8+ CAR T cells targeting glioblastoma-associated (GBM-associated) antigen IL-13 receptor α2 (IL13Rα2)...
May 17, 2018: JCI Insight
https://www.readbyqxmd.com/read/29769443/acetylation-contributes-to-hypertrophy-caused-maturational-delay-of-cardiac-energy-metabolism
#8
Arata Fukushima, Liyan Zhang, Alda Huqi, Victoria H Lam, Sonia Rawat, Tariq Altamimi, Cory S Wagg, Khushmol K Dhaliwal, Lisa K Hornberger, Paul F Kantor, Ivan M Rebeyka, Gary D Lopaschuk
A dramatic increase in cardiac fatty acid oxidation occurs following birth. However, cardiac hypertrophy secondary to congenital heart diseases (CHDs) delays this process, thereby decreasing cardiac energetic capacity and function. Cardiac lysine acetylation is involved in modulating fatty acid oxidation. We thus investigated what effect cardiac hypertrophy has on protein acetylation during maturation. Eighty-four right ventricular biopsies were collected from CHD patients and stratified according to age and the absence (n = 44) or presence of hypertrophy (n = 40)...
May 17, 2018: JCI Insight
https://www.readbyqxmd.com/read/29769442/distinct-biomarker-signatures-in-hiv-acute-infection-associate-with-viral-dynamics-and-reservoir-size
#9
Jeffrey E Teigler, Louise Leyre, Nicolas Chomont, Bonnie Slike, Ningbo Jian, Michael A Eller, Nittaya Phanuphak, Eugène Kroon, Suteeraporn Pinyakorn, Leigh Anne Eller, Merlin L Robb, Jintanat Ananworanich, Nelson L Michael, Hendrik Streeck, Shelly J Krebs
Estimating the size of the viral reservoir is critical for HIV cure strategies. Biomarkers in peripheral circulation may give insights into the establishment of the viral reservoir in compartments not easily accessible. We therefore measured systemic levels of 84 soluble biomarkers belonging to a broad array of immune pathways in acute HIV infection in both antiretroviral therapy-naive (ART-naive) individuals as well as individuals who began ART upon early detection of HIV infection. These biomarkers were measured longitudinally during acute and chronic infection and their relationship to viral reservoir establishment and persistence was assessed...
May 17, 2018: JCI Insight
https://www.readbyqxmd.com/read/29769441/unique-features-and-clinical-importance-of-acute-alloreactive-immune-responses
#10
Charlotte F Inman, Suzy A Eldershaw, Joanne E Croudace, Nathaniel J Davies, Archana Sharma-Oates, Tanuja Rai, Hayden Pearce, Mirjana Sirovica, Y L Tracey Chan, Kriti Verma, Jianmin Zuo, Sandeep Nagra, Francesca Kinsella, Jane Nunnick, Rasoul Amel-Kashipaz, Charles Craddock, Ram Malladi, Paul Moss
Allogeneic stem cell transplantation (allo-SCT) can cure some patients with hematopoietic malignancy, but this relies on the development of a donor T cell alloreactive immune response. T cell activity in the first 2 weeks after allo-SCT is crucial in determining outcome, despite the clinical effects of the early alloreactive immune response often not appearing until later. However, the effect of the allogeneic environment on T cells is difficult to study at this time point due to the effects of profound lymphopenia...
May 17, 2018: JCI Insight
https://www.readbyqxmd.com/read/29769440/elevated-hepatic-expression-of-h19-long-noncoding-rna-contributes-to-diabetic-hyperglycemia
#11
Na Zhang, Tingting Geng, Zhangsheng Wang, Ruling Zhang, Tiefeng Cao, Joao Paulo Camporez, Shi-Ying Cai, Ya Liu, Luisa Dandolo, Gerald I Shulman, Gordon G Carmichael, Hugh S Taylor, Yingqun Huang
Excessive hepatic glucose production (HGP) contributes significantly to the hyperglycemia of type 2 diabetes; however, the molecular mechanism underlying this dysregulation remains poorly understood. Here, we show that fasting temporally increases the expression of H19 long noncoding RNA (lncRNA) in nondiabetic mouse liver, whereas its level is chronically elevated in diet-induced diabetic mice, consistent with the previously reported chronic hepatic H19 increase in diabetic patients. Importantly, liver-specific H19 overexpression promotes HGP, hyperglycemia, and insulin resistance, while H19 depletion enhances insulin-dependent suppression of HGP...
May 17, 2018: JCI Insight
https://www.readbyqxmd.com/read/29769439/csf1r-dependent-myeloid-cells-are-required-for-nk%C3%A2-mediated-control-of-metastasis
#12
Michal Beffinger, Paulino Tallón de Lara, Sònia Tugues, Marijne Vermeer, Yannick Montagnolo, Isabel Ohs, Virginia Cecconi, Giulia Lucchiari, Aron Gagliardi, Nikola Misljencevic, James Sutton, Roman Spörri, Burkhard Becher, Anurag Gupta, Maries van den Broek
Myeloid leukocytes are essentially involved in both tumor progression and control. We show that neo-adjuvant treatment of mice with an inhibitor of CSF1 receptor (CSF1R), a drug that is used to deplete tumor-associated macrophages, unexpectedly promoted metastasis. CSF1R blockade indirectly diminished the number of NK cells due to a paucity of myeloid cells that provide the survival factor IL-15 to NK cells. Reduction of the number of NK cells resulted in increased seeding of metastatic tumor cells to the lungs but did not impact on progression of established metastases...
May 17, 2018: JCI Insight
https://www.readbyqxmd.com/read/29769438/cytometry-tof-identifies-alveolar-macrophage-subtypes-in-acute-respiratory-distress-syndrome
#13
Eric D Morrell, Alice Wiedeman, S Alice Long, Sina A Gharib, T Eoin West, Shawn J Skerrett, Mark M Wurfel, Carmen Mikacenic
Studies in human peripheral blood monocyte-derived macrophages in vitro have shown clear evidence that multiple macrophage polarization states exist. The extent to which different alveolar macrophage (AM) polarization states exist in homeostasis or in the setting of severe injury such as acute respiratory distress syndrome (ARDS) is largely unknown. We applied single-cell cytometry TOF (CyTOF) to simultaneously measure 36 cell-surface markers on CD45+ cells present in bronchoalveolar lavage from healthy volunteers, as well as mechanically ventilated subjects with and without ARDS...
May 17, 2018: JCI Insight
https://www.readbyqxmd.com/read/29769437/exosome-delivered-micrornas-promote-ifn-%C3%AE-secretion-by-human-plasmacytoid-dcs-via-tlr7
#14
Valentina Salvi, Veronica Gianello, Sara Busatto, Paolo Bergese, Laura Andreoli, Ugo D'Oro, Alessandra Zingoni, Angela Tincani, Silvano Sozzani, Daniela Bosisio
The excessive production of type I IFNs is a hallmark and a main pathogenic mechanism of many autoimmune diseases, including systemic lupus erythematosus (SLE). In these pathologies, the sustained secretion of type I IFNs is dependent on the improper activation of plasmacytoid DCs (pDCs) by self-nucleic acids. However, the nature and origin of pDC-activating self-nucleic acids is still incompletely characterized. Here, we report that exosomes isolated from the plasma of SLE patients can activate the secretion of IFN-α by human blood pDCs in vitro...
May 17, 2018: JCI Insight
https://www.readbyqxmd.com/read/29720578/targeting-inflammatory-monocytes-in-sepsis-associated-encephalopathy-and-long-term-cognitive-impairment
#15
Graciela Andonegui, Erin L Zelinski, Courtney L Schubert, Derrice Knight, Laura A Craig, Brent W Winston, Simon C Spanswick, Björn Petri, Craig N Jenne, Janice C Sutherland, Rita Nguyen, Natalie Jayawardena, Margaret M Kelly, Christopher J Doig, Robert J Sutherland, Paul Kubes
Sepsis-associated encephalopathy manifesting as delirium is a common problem in critical care medicine. In this study, patients that had delirium due to sepsis had significant cognitive impairments at 12-18 months after hospital discharge when compared with controls and Cambridge Neuropsychological Automated Test Battery-standardized scores in spatial recognition memory, pattern recognition memory, and delayed-matching-to-sample tests but not other cognitive functions. A mouse model of S. pneumoniae pneumonia-induced sepsis, which modeled numerous aspects of the human sepsis-associated multiorgan dysfunction, including encephalopathy, also revealed similar deficits in spatial memory but not new task learning...
May 3, 2018: JCI Insight
https://www.readbyqxmd.com/read/29720577/universal-monitoring-of-minimal-residual-disease-in-acute-myeloid-leukemia
#16
Elaine Coustan-Smith, Guangchun Song, Sheila Shurtleff, Allen Eng-Juh Yeoh, Wee Joo Chng, Siew Peng Chen, Jeffrey E Rubnitz, Ching-Hon Pui, James R Downing, Dario Campana
BACKGROUND: Optimal management of acute myeloid leukemia (AML) requires monitoring of treatment response, but minimal residual disease (MRD) may escape detection. We sought to identify distinctive features of AML cells for universal MRD monitoring. METHODS: We compared genome-wide gene expression of AML cells from 157 patients with that of normal myeloblasts. Markers encoded by aberrantly expressed genes, including some previously associated with leukemia stem cells, were studied by flow cytometry in 240 patients with AML and in nonleukemic myeloblasts from 63 bone marrow samples...
May 3, 2018: JCI Insight
https://www.readbyqxmd.com/read/29720576/efficient-exon-skipping-of-sgcg-mutations-mediated-by-phosphorodiamidate-morpholino-oligomers
#17
Eugene J Wyatt, Alexis R Demonbreun, Ellis Y Kim, Megan J Puckelwartz, Andy H Vo, Lisa M Dellefave-Castillo, Quan Q Gao, Mariz Vainzof, Rita C M Pavanello, Mayana Zatz, Elizabeth M McNally
Exon skipping uses chemically modified antisense oligonucleotides to modulate RNA splicing. Therapeutically, exon skipping can bypass mutations and restore reading frame disruption by generating internally truncated, functional proteins to rescue the loss of native gene expression. Limb-girdle muscular dystrophy type 2C is caused by autosomal recessive mutations in the SGCG gene, which encodes the dystrophin-associated protein γ-sarcoglycan. The most common SGCG mutations disrupt the transcript reading frame abrogating γ-sarcoglycan protein expression...
May 3, 2018: JCI Insight
https://www.readbyqxmd.com/read/29720575/prediction-of-acute-gvhd-and-relapse-by-metabolic-biomarkers-after-allogeneic-hematopoietic-stem-cell-transplantation
#18
Xiaojin Wu, Yiyu Xie, Chang Wang, Yue Han, Xiebing Bao, Shoubao Ma, Ahmet Yilmaz, Bingyu Yang, Yuhan Ji, Jinge Xu, Hong Liu, Suning Chen, Jianying Zhang, Jianhua Yu, Depei Wu
BACKGROUND: There are very few studies investigating metabolic biomarkers to predict acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Metabolic models can provide a framework for analyzing the information-rich omics data sets in this setting. METHODS: Four hundred and fifty-six samples from one hundred and fourteen consecutive patients who underwent HSCT from January 2012 to May 2014 were collected for this study...
May 3, 2018: JCI Insight
https://www.readbyqxmd.com/read/29720574/neutrophils-are-essential-for-induction-of-vaccine-like-effects-by-antiviral-monoclonal-antibody-immunotherapies
#19
Mar Naranjo-Gomez, Jennifer Lambour, Marc Piechaczyk, Mireia Pelegrin
Using a mouse retroviral model, we have shown that mAb-based immunotherapy can induce life-long endogenous protective immunity (vaccine-like effects). This observation has potentially important consequences for treating life-threatening human viral infections. Here, we investigated the role of neutrophils in this effect. Neutrophils are innate immunity effector cells with well-established microbe-killing activities that are rapidly mobilized upon infection. They are also emerging as orchestrators of innate and adaptive immunities...
May 3, 2018: JCI Insight
https://www.readbyqxmd.com/read/29720573/parabiosis-and-single-cell-rna-sequencing-reveal-a-limited-contribution-of-monocytes-to-myofibroblasts-in-kidney-fibrosis
#20
Rafael Kramann, Flavia Machado, Haojia Wu, Tetsuro Kusaba, Konrad Hoeft, Rebekka K Schneider, Benjamin D Humphreys
Fibrosis is the common final pathway of virtually all chronic injury to the kidney. While it is well accepted that myofibroblasts are the scar-producing cells in the kidney, their cellular origin is still hotly debated. The relative contribution of proximal tubular epithelium and circulating cells, including mesenchymal stem cells, macrophages, and fibrocytes, to the myofibroblast pool remains highly controversial. Using inducible genetic fate tracing of proximal tubular epithelium, we confirm that the proximal tubule does not contribute to the myofibroblast pool...
May 3, 2018: JCI Insight
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