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https://www.readbyqxmd.com/read/28628637/survival-bacterial-clearance-and-thrombocytopenia-are-improved-in-polymicrobial-sepsis-by-targeting-nuclear-transport-shuttles
#1
Ruth Ann Veach, Yan Liu, Jozef Zienkiewicz, Lukasz S Wylezinski, Kelli L Boyd, James L Wynn, Jacek Hawiger
The rising tide of sepsis, a leading cause of death in the US and globally, is not adequately controlled by current antimicrobial therapies and supportive measures, thereby requiring new adjunctive treatments. Severe microvascular injury and multiple organ failure in sepsis are attributed to a "genomic storm" resulting from changes in microbial and host genomes encoding virulence factors and endogenous inflammatory mediators, respectively. This storm is mediated by stress-responsive transcription factors that are ferried to the nucleus by nuclear transport shuttles importins/karyopherins...
2017: PloS One
https://www.readbyqxmd.com/read/28621306/targeted-two-photon-chemical-apoptotic-ablation-of-defined-cell-types-in-vivo
#2
Robert A Hill, Eyiyemisi C Damisah, Fuyi Chen, Alex C Kwan, Jaime Grutzendler
A major bottleneck limiting understanding of mechanisms and consequences of cell death in complex organisms is the inability to induce and visualize this process with spatial and temporal precision in living animals. Here we report a technique termed two-photon chemical apoptotic targeted ablation (2Phatal) that uses focal illumination with a femtosecond-pulsed laser to bleach a nucleic acid-binding dye causing dose-dependent apoptosis of individual cells without collateral damage. Using 2Phatal, we achieve precise ablation of distinct populations of neurons, glia and pericytes in the mouse brain and in zebrafish...
June 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28617431/nicotine-protects-rat-hypoglossal-motoneurons-from-excitotoxic-death-via-downregulation-of-connexin-36
#3
Silvia Corsini, Maria Tortora, Rossana Rauti, Andrea Nistri
Motoneuron disease including amyotrophic lateral sclerosis may be due, at an early stage, to deficit in the extracellular clearance of the excitatory transmitter glutamate. A model of glutamate-mediated excitotoxic cell death based on pharmacological inhibition of its uptake was used to investigate how activation of neuronal nicotinic receptors by nicotine may protect motoneurons. Hypoglossal motoneurons (HMs) in neonatal rat brainstem slices were exposed to the glutamate uptake blocker DL-threo-β-benzyloxyaspartate (TBOA) that evoked large Ca(2+) transients time locked among nearby HMs, whose number fell by about 30% 4 h later...
June 15, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28614691/a-trial-of-itraconazole-or-amphotericin-b-for-hiv-associated-talaromycosis
#4
Thuy Le, Nguyen Van Kinh, Ngo T K Cuc, Nguyen L N Tung, Nguyen T Lam, Pham T T Thuy, Do D Cuong, Pham T H Phuc, Vu H Vinh, Doan T H Hanh, Vu Van Tam, Nguyen T Thanh, Tran P Thuy, Nguyen T Hang, Hoang B Long, Ho T Nhan, Heiman F L Wertheim, Laura Merson, Cecilia Shikuma, Jeremy N Day, Nguyen V V Chau, Jeremy Farrar, Guy Thwaites, Marcel Wolbers
BACKGROUND: Talaromyces marneffei infection is a major cause of human immunodeficiency virus (HIV)-related death in South and Southeast Asia. Guidelines recommend initial treatment with amphotericin B deoxycholate, but this drug has substantial side effects, a high cost, and limited availability. Itraconazole is available in oral form, is associated with fewer unacceptable side effects than amphotericin, and is widely used in place of amphotericin; however, clinical trials comparing these two treatments are lacking...
June 15, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28611673/reversing-egfr-mediated-immunoescape-by-targeted-monoclonal-antibody-therapy
#5
REVIEW
Fernando Concha-Benavente, Robert L Ferris
Uncontrolled growth is a signature of carcinogenesis, in part mediated by overexpression or overstimulation of growth factor receptors. The epidermal growth factor receptor (EGFR) mediates activation of multiple oncogenic signaling pathways and escape from recognition by the host immune system. We discuss how EGFR signaling downregulates tumor antigen presentation, upregulates suppressive checkpoint receptor ligand programmed death ligand (PD-L1), induces secretion of inhibitory molecules such as transforming growth factor beta (TGFβ) and reprograms the metabolic pathways in cancer cells to upregulate aerobic glycolysis and lactate secretion that ultimately lead to impaired cellular immunity mediated by natural killer (NK) cell and cytotoxic T lymphocytes (CTL)...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28605468/attenuation-of-insulin-action-by-an-allosteric-insulin-receptor-antibody-in-healthy-volunteers
#6
Kirk W Johnson, Ann Neale, Allan Gordon, Julie Roessig, Padma Bezwada, Sabine Vukelich, Ira Goldfine, Paul Rubin
Background: X358 (X358) is a fully human monoclonal antibody to the insulin receptor (InsR) that acts as a negative allosteric modulator of insulin signaling. It is being developed as a novel treatment for hyperinsulinemic hypoglycemia. This report describes pharmacokinetic (PK), and pharmacodynamic (PD) data from a first-in-human clinical trial. Methods: A double-blind, placebo-controlled, single ascending dose study was performed with 29 healthy adult males randomized to intravenous infusion of placebo or X358 at 0...
June 9, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28604474/impact-of-cyp2c19-genotype-and-liver-function-on-voriconazole-pharmacokinetics-in-renal-transplant-recipients
#7
Zi-Wei Li, Feng-Hua Peng, Miao Yan, Wu Liang, Xiao-Lei Liu, Yan-Qin Wu, Xiao-Bin Lin, Sheng-Lan Tan, Feng Wang, Ping Xu, Ping-Fei Fang, Yi-Ping Liu, Da-Xiong Xiang, Bui-Kui Zhang
BACKGROUND: Invasive fungal infection (IFI) is one of the leading causes of early death after renal transplantation. Voriconazole (VRC) is the first-line drug of IFI. Because of the large inter- and intra-individual variability in VRC plasma concentrations and the narrow therapeutic window for treating patients with IFIs, it is crucial to study the factors which could influence pharmacokinetic variability. We performed a population pharmacokinetics (PPK) study of VRC for personalized medicine...
June 8, 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/28604170/efficacy-of-mycobacterium-vaccae-immunotherapy-for-patients-with-tuberculosis-a-systematic-review-and-meta-analysis
#8
Chen-Yi Huang, Wen-Yeh Hsieh
Tuberculosis (TB) is a significant cause of illness and death worldwide. Immunotherapy has been investigated in the treatment of TB. The purpose of this study was to perform a meta-analysis investigating the effectiveness of the M. vaccae vaccine. Medline, Cochrane, EMBASE, and Google Scholar were searched until November 5, 2015 using the keywords: tuberculosis, pulmonary TB, therapeutic vaccines, immunotherapy, M. vaccae, sputum smear. Randomized controlled trials (RCTs) or 2-arm prospective studies were included...
June 12, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28600283/inhibition-of-pcsk9-does-not-improve-lipopolysaccharide-induced-mortality-in-mice
#9
Jean-Mathieu Berger, Angel Loza Valdes, Jesper Gromada, Norma Anderson, Jay D Horton
PCSK9 is a secreted protein that targets LDL receptors (LDLR) for degradation in liver. Blocking the interaction of PCSK9 with the LDLR potently reduces plasma LDL-cholesterol levels and cardiovascular events. Recently, it has been suggested that inhibition of PCSK9 might also improve outcomes in mice and humans with sepsis, possibly by increasing LDL receptor (LDLR)-mediated clearance of endotoxins. Sepsis is a complication of a severe microbial infection that has shared pathways with lipid metabolism. Here, we tested whether anti-PCSK9 antibodies prevent death from lipopolysaccharide (LPS)-induced endotoxemia...
June 9, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28600101/non-cardiac-factors-for-prediction-of-response-to-cardiac-resynchronization-therapy-the-value-of-baseline-and-of-serial-changes-in-red-cell-distribution-width
#10
Erberto Carluccio, Paolo Biagioli, Gianfranco Alunni, Adriano Murrone, Gianluca Zingarini, Stefano Coiro, Antonella D'Antonio, Anna Mengoni, Maria Francesca Cerasa, Giuseppe Ambrosio
BACKGROUND: Increased red blood cell distribution width (RDW) has been associated with poor outcome after cardiac resynchronization therapy (CRT). However, whether baseline RDW, and its serial changes after CRT implant, have incremental prognostic value is unknown. METHODS AND RESULTS: In 148 consecutive patients (age, 68±9years; 122 men) undergoing CRT, RDW was assessed before and 3months after implant. Patients were categorized according to baseline RDW (≤14...
June 2, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/28591008/plasma-resuscitation-improved-survival-in-a-cecal-ligation-and-puncture-rat-model-of-sepsis
#11
Ronald Chang, John B Holcomb, Par I Johansson, Shibani Pati, Martin A Schreiber, Charles E Wade
BACKGROUND: The paradigm shift from crystalloid to plasma resuscitation of traumatic hemorrhagic shock has improved patient outcomes due in part to plasma-mediated reversal of catecholamine and inflammation-induced endothelial injury, decreasing vascular permeability and attenuating organ injury. Since sepsis induces a similar endothelial injury as seen in hemorrhage, we hypothesized that plasma resuscitation would increase 48-hour survival in a rat sepsis model. METHODS: Adult male Sprague-Dawley rats (375-425 g) were subjected to 35% cecal ligation and puncture (CLP) (t = 0 h)...
June 6, 2017: Shock
https://www.readbyqxmd.com/read/28589286/extracorporeal-cytokine-elimination-as-rescue-therapy-in-refractory-septic-shock-a-prospective-single-center-study
#12
Sigrun Friesecke, Stephanie-Susanne Stecher, Stefan Gross, Stephan B Felix, Axel Nierhaus
Sepsis is the most common cause of death in medical intensive care units (ICU). If sepsis progresses to refractory septic shock, mortality may reach 90-100% despite optimum current therapy. Extracorporeal cytokine adsorption in addition to regular therapy was studied prospectively in refractory septic shock patients on a medical ICU. Refractory shock was defined as increasing vasopressor dose required to maintain mean arterial blood pressure above 65 mmHg or increasing lactate levels despite protocol-guided shock therapy for 6 h...
June 6, 2017: Journal of Artificial Organs: the Official Journal of the Japanese Society for Artificial Organs
https://www.readbyqxmd.com/read/28589151/advanced-role-of-neutrophils-in-common-respiratory-diseases
#13
REVIEW
Jinping Liu, Zhiqiang Pang, Guoqiang Wang, Xuewa Guan, Keyong Fang, Ziyan Wang, Fang Wang
Respiratory diseases, always being a threat towards the health of people all over the world, are most tightly associated with immune system. Neutrophils serve as an important component of immune defense barrier linking innate and adaptive immunity. They participate in the clearance of exogenous pathogens and endogenous cell debris and play an essential role in the pathogenesis of many respiratory diseases. However, the pathological mechanism of neutrophils remains complex and obscure. The traditional roles of neutrophils in severe asthma, chronic obstructive pulmonary diseases (COPD), pneumonia, lung cancer, pulmonary fibrosis, bronchitis, and bronchiolitis had already been reviewed...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28589085/immune-system-friend-or-foe-of-oncolytic-virotherapy
#14
REVIEW
Anna C Filley, Mahua Dey
Oncolytic viruses (OVs) are an emerging class of targeted anticancer therapies designed to selectively infect, replicate in, and lyse malignant cells without causing harm to normal, healthy tissues. In addition to direct oncolytic activity, OVs have shown dual promise as immunotherapeutic agents. The presence of viral infection and subsequently generated immunogenic tumor cell death trigger innate and adaptive immune responses that mediate further tumor destruction. However, antiviral immune responses can intrinsically limit OV infection, spread, and overall therapeutic efficacy...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28588151/in-vivo-imaging-of-the-programmed-death-ligand-1-by-18-f-positron-emission-tomography
#15
Dinko E Gonzalez Trotter, Xiangjun Meng, Paul McQuade, Daniel Rubins, Michael Klimas, Zhizhen Zhang, Brett M Connolly, Patricia J Miller, Stacey S O'Malley, Shu-An Lin, Krista L Getty, Laurence Fayadat-Dilman, Linda Liang, Elisabet Wahlberg, Olof Widmark, Caroline Ekblad, Fredrik Y Frejd, Eric D Hostetler, Jeffrey L Evelhoch
Introduction: PD-L1 (Programmed Death Ligand 1) is an immune regulatory ligand that binds to the T-cell immune check point PD-1 (Programmed Death 1). Tumor expression of PD-L1 is correlated with immune suppression and poor prognosis. It is also correlated with therapeutic efficacy of PD-1 and PD-L1 inhibitors. In vivo imaging may enable real-time follow-up of changing PD-L1 expression and heterogeneity evaluation of PD-L1 expression across tumors in the same subject. We have radiolabeled the PD-L1 binding Affibody® molecule NOTA-ZPD-L1_1 with (18)F and evaluated its in vitro and in vivo binding affinity, targeting and specificity...
June 6, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28584007/t-cell-derived-il-10-impairs-host-resistance-to-mycobacterium-tuberculosis-infection
#16
Lúcia Moreira-Teixeira, Paul S Redford, Evangelos Stavropoulos, Nico Ghilardi, Craig L Maynard, Casey T Weaver, Ana Paula Freitas do Rosário, Xuemei Wu, Jean Langhorne, Anne O'Garra
Tuberculosis (TB), caused by Mycobacterium tuberculosis infection, is a leading cause of mortality and morbidity, causing ∼1.5 million deaths annually. CD4(+) T cells and several cytokines, such as the Th1 cytokine IFN-γ, are critical in the control of this infection. Conversely, the immunosuppressive cytokine IL-10 has been shown to dampen Th1 cell responses to M. tuberculosis infection impairing bacterial clearance. However, the critical cellular source of IL-10 during M. tuberculosis infection is still unknown...
June 5, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28580145/lysosome-oriented-dual-stage-ph-responsive-polymeric-micelles-for-%C3%AE-lapachone-delivery
#17
Yinjian Zhou, Ying Dong, Gang Huang, Yiguang Wang, Xiaonan Huang, Fayun Zhang, David A Boothman, Jinming Gao, Wei Liang
β-Lapachone (β-lap), a novel anticancer agent, is bioactivated by NADP(H):quinone oxidoreductase 1 (NQO1), an enzyme over-expressed in numerous tumors, including lung, pancreas, breast, and prostate cancers. Fast renal clearance and methemaglobinemia / hemolytic side-effects from the clinical formulation (β-lap-hydroxyl propyl-β-cyclodextrin complex) hindered its clinical translation. Here, we investigated a dual model pH responsive polymers for β-lap delivery. Three pH-sensitive linkages, including acylhydrazone, ketal and imine bonds for β-lap prodrug syntheses result in an aryl imine linkage the most optimal linkage...
December 14, 2016: Journal of Materials Chemistry. B, Materials for Biology and Medicine
https://www.readbyqxmd.com/read/28579300/correcting-a-fundamental-flaw-in-the-paradigm-for-antimicrobial-susceptibility-testing
#18
Selvi C Ersoy, Douglas M Heithoff, Lucien Barnes, Geneva K Tripp, John K House, Jamey D Marth, Jeffrey W Smith, Michael J Mahan
The emergence and prevalence of antibiotic-resistant bacteria are an increasing cause of death worldwide, resulting in a global 'call to action' to avoid receding into an era lacking effective antibiotics. Despite the urgency, the healthcare industry still relies on a single in vitro bioassay to determine antibiotic efficacy. This assay fails to incorporate environmental factors normally present during host-pathogen interactions in vivo that significantly impact antibiotic efficacy. Here we report that standard antimicrobial susceptibility testing (AST) failed to detect antibiotics that are in fact effective in vivo; and frequently identified antibiotics that were instead ineffective as further confirmed in mouse models of infection and sepsis...
May 29, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28578081/expectant-management-of-gallbladder-stones-after-endoscopic-removal-of-common-bile-duct-stones
#19
Anne Mattila, Johanna Mrena, Ilmo Kellokumpu
BACKGROUND: Wait-and-see policy after endoscopic sphincterotomy (ES) for common bile duct (CBD) stones in patients with concomitant gallbladder stones may lead to recurrent biliary complications. The aim of this study was to assess the short and long-term results of wait-and-see policy in patients with intact gallbladder after endoscopic clearance of CBD stones. MATERIALS AND METHODS: From January 1999 to December 2014 a total of 181 consecutive patients with intact gallbladder underwent ES for CBD stones...
May 31, 2017: International Journal of Surgery
https://www.readbyqxmd.com/read/28573468/time-dependent-pharmacokinetics-of-pembrolizumab-in-patients-with-solid-tumor-and-its-correlation-with-best-overall-response
#20
Hongshan Li, Jingyu Yu, Chao Liu, Jiang Liu, Sriram Subramaniam, Hong Zhao, Gideon M Blumenthal, David C Turner, Claire Li, Malidi Ahamadi, Rik de Greef, Manash Chatterjee, Anna G Kondic, Julie A Stone, Brian P Booth, Patricia Keegan, Atiqur Rahman, Yaning Wang
Pembrolizumab is a monoclonal antibody that targets the programmed death-1 receptor to induce immune-mediated clearance (CL) of tumor cells. Originally approved by the US Food and Drug Administration in 2014 for treating patients with unresectable or metastatic melanoma, pembrolizumab is now also used to treat patients with non-small-cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, and urothelial cancer. This paper describes the recently identified feature of pembrolizumab pharmacokinetics, the time-dependent or time-varying CL...
June 1, 2017: Journal of Pharmacokinetics and Pharmacodynamics
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