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https://www.readbyqxmd.com/read/28636208/a-phase-i-trial-of-prn1008-a-novel-reversible-covalent-inhibitor-of-bruton-s-tyrosine-kinase-in-healthy-volunteers
#1
Patrick F Smith, Janakan Krishnarajah, Philip A Nunn, Ron J Hill, Dane Karr, D Tam, Mohammad Masjedizadeh, Jens O Funk, Steve G Gourlay
AIM: To evaluate the safety, tolerability, and PK/PD of PRN1008, a novel BTK inhibitor, in healthy volunteers, and thus determine the dose range for future clinical studies. METHODS: This was a two-part randomized, placebo controlled study in healthy volunteers using a liquid formulation. Part I was a single ascending dose design with dose levels of 50 to 1200 mg (n=6 active, 2 placebo per cohort); Part II was a multiple ascending dose design, with dose regimens ranging from 300 mg to 900 mg daily, either qd or bd for 10 days...
June 21, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28636184/pharmacokinetics-pharmacodynamics-of-bococizumab-a-monoclonal-antibody-to-pcsk9-after-single-subcutaneous-injection-at-3-sites-nct-02043301
#2
Ellen Q Wang, Anna Plotka, Joanne Salageanu, Catherine Sattler, Carla Yunis
AIM: To characterize the single-dose pharmacokinetics (PK) and pharmacodynamics (PD) of bococizumab, a monoclonal antibody inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), administered subcutaneously (s.c.) to the abdomen, thigh, or upper arm (NCT02043301). METHODS: Seventy-five adults with low-density lipoprotein cholesterol (LDL-C) ≥130 mg/dL and not on background lipid-lowering therapy were randomized (1:1:1) to a single 150-mg s.c. dose of bococizumab administered to the abdomen, thigh, or upper arm...
June 21, 2017: Cardiovascular Therapeutics
https://www.readbyqxmd.com/read/28636179/discontinuation-and-non-publication-of-neurodegenerative-disease-trials-a-cross-sectional-analysis
#3
J D Stefaniak, T C H Lam, N E Sim, R Al-Shahi Salman, D P Breen
BACKGROUND AND PURPOSE: Trial discontinuation and non-publication represent major sources of research waste in clinical medicine. No previous studies have investigated non-dissemination bias in clinical trials of neurodegenerative diseases. METHODS: ClinicalTrials.gov was searched for all randomized, interventional, phase II-IV trials that were registered between 1 January 2000 and 31 December 2009 and included adults with Alzheimer's disease, motor neurone disease, multiple sclerosis or Parkinson's disease...
June 21, 2017: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
https://www.readbyqxmd.com/read/28636141/binocular-facilitation-of-cone-specific-visual-evoked-potentials-in-colour-deficiency
#4
Jeff Rabin, Andrew Kryder, Dan Lam
BACKGROUND: Neural compensatory mechanisms have been proposed, which preserve the binocular visual field in glaucoma, as well as cognition in Alzheimer's disease and motor function in Parkinson's disease. It is conceivable that comparable mechanisms operate to preserve function in congenital and/or dystrophic disease. In hereditary colour vision deficiency (CVD), we observed significant facilitation in the amplitude of the binocular cone-specific visual evoked potential (VEP) compared to the monocular amplitude for the cone type corresponding to the CVD...
June 21, 2017: Clinical & Experimental Optometry: Journal of the Australian Optometrical Association
https://www.readbyqxmd.com/read/28635653/virtual-screening-against-phosphoglycerate-kinase-1-in-quest-of-novel-apoptosis-inhibitors
#5
Jie Xia, Bo Feng, Qianhang Shao, Yuhe Yuan, Xiang Simon Wang, Naihong Chen, Song Wu
Inhibition of apoptosis is a potential therapy to treat human diseases such as neurodegenerative disorders (e.g., Parkinson's disease), stroke, and sepsis. Due to the lack of druggable targets, it remains a major challenge to discover apoptosis inhibitors. The recent repositioning of a marketed drug (i.e., terazosin) as an anti-apoptotic agent uncovered a novel target (i.e., human phosphoglycerate kinase 1 (hPgk1)). In this study, we developed a virtual screening (VS) pipeline based on the X-ray structure of Pgk1/terazosin complex and applied it to a screening campaign for potential anti-apoptotic agents...
June 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28635644/pd-1-pd-l1-blockade-therapy-for-tumors-with-downregulated-mhc-class-i-expression
#6
REVIEW
Michal Šmahel
The therapy of different advanced-stage malignancies with monoclonal antibodies blocking programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) signaling has had an impressive long-lasting effect in a portion of patients, but in most cases, this therapy was not successful, or a secondary resistance developed. To enhance its efficacy in treated patients, predictive biomarkers are searched for and various combination treatments are intensively investigated. As the downregulation of major histocompatibility complex (MHC) class I molecules is one of the most frequent mechanisms of tumor escape from the host's immunity, it should be considered in PD-1/PD-L1 checkpoint inhibition...
June 21, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28635639/immune-checkpoints-as-a-target-for-colorectal-cancer-treatment
#7
REVIEW
Alessandro Passardi, Matteo Canale, Martina Valgiusti, Paola Ulivi
Anti-tumor immunity is a new line of research for the treatment of patients with solid tumors. In this field, negative regulators of the immune system called immune checkpoints play a key role in limiting antitumor immunologic responses. For this reason, immune checkpoint-inhibiting agents, such as those directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 receptor (PD1) and its ligand PD-L1, have been developed as antitumor drugs, producing interesting results in preclinical and clinical studies...
June 21, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28635509/induced-pluripotent-stem-cell-derived-dopaminergic-neurons-from-adult-common-marmoset-fibroblasts
#8
Scott C Vermilyea, Scott Guthrie, Michael Meyer, Kim Smuga-Otto, Katarina Braun, Sara Howden, James A Thomson, Su-Chun Zhang, Marina Emborg, Dr Thaddeus G Golos
The common marmoset monkey (Callithrix jacchus; Cj) is an advantageous nonhuman primate species for modeling age-related disorders, including Parkinson's disease, due to their shorter lifespan compared to macaques. Cj-derived induced pluripotent stem cells (Cj-iPSCs) from somatic cells are needed for in vitro disease modeling and testing regenerative medicine approaches. Here we report the development of a novel Cj-iPSC line derived from adult marmoset fibroblasts. The Cj-iPSCs showed potent pluripotency properties including development of mesodermal lineages in tumors after injection to immunocompromised mice, as well as ectoderm and endoderm lineages after in vitro differentiation regimens, demonstrating differentiated derivatives of all three embryonic layers...
June 21, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/28634612/pd-0-catalyzed-intramolecular-arylative-dearomatization-of-%C3%AE-naphthols
#9
Ren-Qi Xu, Ping Yang, Shu-Li You
An efficient Pd(0)-catalyzed intramolecular arylative dearomatization of β-naphthols is described. Using Q-Phos as a ligand, the arylative dearomatization reaction proceeded smoothly affording excellent yields and chemoselectivity even when the catalyst loading was reduced to 0.1 mol%. This method offers an efficient access to a series of structurally diverse spirocarbocycles. Preliminary investigation indicates that an enantioselective reaction is feasible in the presence of a chiral phosphoramidite ligand...
June 21, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28634551/mechanisms-and-consequences-of-dopamine-depletion-induced-attenuation-of-the-spinophilin-neurofilament-medium-interaction
#10
Andrew C Hiday, Michael C Edler, Asma B Salek, Cameron W Morris, Morrent Thang, Tyler J Rentz, Kristie L Rose, Lisa M Jones, Anthony J Baucum
Signaling changes that occur in the striatum following the loss of dopamine neurons in the Parkinson disease (PD) are poorly understood. While increases in the activity of kinases and decreases in the activity of phosphatases have been observed, the specific consequences of these changes are less well understood. Phosphatases, such as protein phosphatase 1 (PP1), are highly promiscuous and obtain substrate selectivity via targeting proteins. Spinophilin is the major PP1-targeting protein enriched in the postsynaptic density of striatal dendritic spines...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/28634464/anti-inflammatory-and-neuroprotective-effects-of-co-ultrapealut-in-a-mouse-model-of-vascular-dementia
#11
Rosalba Siracusa, Daniela Impellizzeri, Marika Cordaro, Rosalia Crupi, Emanuela Esposito, Stefania Petrosino, Salvatore Cuzzocrea
Vascular dementia (VaD), the second most common cause of cognitive impairment in the population, is a disease that results from reduction in regional cerebral blood flow and involves oxidative stress and inflammation. Co-ultramicronized PEALut (co-ultra PEALut) is a new compound with beneficial effects, which include anti-inflammatory and antioxidant properties. Recently, co-ultraPEALut has been shown to exhibit neuroprotective effects in models of Parkinson's disease, cerebral ischemia and Alzheimer's disease...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28634347/decreased-circulating-zinc-levels-in-parkinson-s-disease-a-meta-analysis-study
#12
Ke Du, Ming-Yan Liu, Xin Zhong, Min-Jie Wei
There is no consensus on the involvement of zinc (Zn) dysfunctions in Parkinson's Disease (PD). We performed a meta-analysis to evaluate whether circulating Zn levels in the serum, plasma, and cerebrospinal fluid (CSF) are altered in PD. Twenty-three published studies were selected by searching the databases of PubMed and China National Knowledge Infrastructure (CNKI). A total of 803 PD patients and 796 controls, 342 PD patients and 392 controls, and 135 PD patients and 93 controls were included to study Zn levels in the serum, plasma, and CSF, respectively...
June 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28634283/phase-ib-study-of-utomilumab-pf-05082566-a-4-1bb-cd137-agonist-in-combination-with-pembrolizumab-mk-3475-in-patients-with-advanced-solid-tumors
#13
Anthony W Tolcher, Mario Sznol, Siwen Hu-Lieskovan, Kyriakos P Papadopoulos, Amita Patnaik, Drew Rasco, Donna Di Gravio, Bo Huang, Dhiraj Gambhire, Ying Chen, Aron Thall, Nuzhat Pathan, Emmett V Schmidt, Laura Q M Chow
Purpose:  This phase Ib study (NCT02179918) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination with the humanized, PD-1-blocking IgG4 mAb pembrolizumab in patients with advanced solid tumors. <p>Experimental Design:  Utomilumab (0.45-5.0 mg/kg) and pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab dose escalation was conducted using the time-to-event-continual reassessment method...
June 20, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28634215/vaccination-with-high-affinity-epitopes-impairs-antitumor-efficacy-by-increasing-pd-1expression-on-cd8-t-cells
#14
Christopher D Zahm, Viswa Colluru, Douglas G McNeel
Antitumor vaccines encoding self-antigens generally have low immunogenicity in clinical trials. Several approaches are aimed at improving vaccine immunogenicity, including efforts to alter encoded epitopes. Immunization with epitopes altered for increased affinity for the major histocompatibility complex (MHC) or T-cell receptor (TCR) elicits greater numbers of CD8 T cells but inferior antitumor responses. Our previous results suggested that programmed death 1 (PD-1) and its ligand (PD-L1) increased on antigen-specific CD8 T cells and tumor cells, respectively, after high-affinity vaccination...
June 20, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28634084/drug-delivery-to-melanoma-brain-metastases-can-current-challenges-lead-to-new-opportunities
#15
Gautham Gampa, Shruthi Vaidhyanathan, Jann N Sarkaria, William F Elmquist
Melanoma has a high propensity to metastasize to the brain, and patients with melanoma brain metastases (MBM) have an extremely poor prognosis. The recent approval of several molecularly-targeted agents (e.g., BRAF, MEK inhibitors) and biologics (anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies) has brought new hope to patients suffering from this formerly untreatable and lethal disease. Importantly, there have been recent reports of success in some clinical studies examining the efficacy of both targeted agents and immunotherapies that show similar response rates in both brain metastases and extracranial disease...
June 17, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28633628/olfactory-testing-in-consecutive-patients-referred-with-suspected-dementia
#16
Ib Thrane Christensen, Elna-Marie Larsson, Ida E Holm, Ole B F Nielsen, Stig Andersen
BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia and early and accurate diagnosis is important. Olfactory dysfunction is an early sign of AD. The contribution by test of olfactory function has been surveyed in AD vs a line of conditions but remains to be settled in the workup of unselected patients referred with suspected dementia. METHODS: We performed a two-step investigation: first, a comparative study of healthy controls and probable AD patients to test the applicability of the chosen scents (cuisine study); second, a study of consecutive patients referred to our geriatric outpatient clinic for suspected dementia with the investigating personnel blinded to the results of the Olfactory Test (blinded study)...
June 20, 2017: BMC Geriatrics
https://www.readbyqxmd.com/read/28633555/glutamine-administration-in-early-or-late-septic-phase-downregulates-lymphocyte-pd-1-pd-l1-expression-and-the-inflammatory-response-in-mice-with-polymicrobial-sepsis
#17
Ya-Mei Hu, Yuan-Chin Hsiung, Man-Hui Pai, Sung-Ling Yeh
BACKGROUND: Sepsis is a severe inflammatory response to infection. Excessive compensation to inflammation leads to dysregulated immune response that ultimately results in organ damage and lethality of sepsis. This study administered glutamine (GLN) in the early or late phase of sepsis to investigate its effects on regulating leukocyte programmed cell death 1 (PD-1) and its ligand (programmed cell death ligand 1 [PD-L1]) expression, macrophage function, inflammation, and acute kidney injury in sepsis...
March 1, 2017: JPEN. Journal of Parenteral and Enteral Nutrition
https://www.readbyqxmd.com/read/28633409/the-effect-of-pd-l1-testing-on-the-cost-effectiveness-and-economic-impact-of-immune-checkpoint-inhibitors-for-the-second-line-treatment-of-nsclc
#18
P N Aguiar, L Perry, J Penny-Dimr, H Babiker, H Tadokoro, R A de Mello, G L Lopes
Background: Immune checkpoint inhibitors improve outcomes compared to chemotherapy in lung cancer. Tumor PD-L1 receptor expression is being studied as a predictive biomarker. The objective of this study was to assess the cost-effectiveness and economic impact of second-line treatment with nivolumab, pembrolizumab, and atezolizumab with and without the use of PD-L1 testing for patient selection. Design: We developed a decision-analytic model to determine the cost-effectiveness of PD-L1 assessment and second-line immunotherapy versus docetaxel...
June 15, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28632757/molecular-mechanism-of-drp1-assembly-studied-in-vitro-by-cryo-electron-microscopy
#19
Kaustuv Basu, Driss Lajoie, Tristan Aumentado-Armstrong, Jin Chen, Roman I Koning, Blaise Bossy, Mihnea Bostina, Attila Sik, Ella Bossy-Wetzel, Isabelle Rouiller
Mitochondria are dynamic organelles that continually adapt their morphology by fusion and fission events. An imbalance between fusion and fission has been linked to major neurodegenerative diseases, including Huntington's, Alzheimer's, and Parkinson's diseases. A member of the Dynamin superfamily, dynamin-related protein 1 (DRP1), a dynamin-related GTPase, is required for mitochondrial membrane fission. Self-assembly of DRP1 into oligomers in a GTP-dependent manner likely drives the division process. We show here that DRP1 self-assembles in two ways: i) in the presence of the non-hydrolysable GTP analog GMP-PNP into spiral-like structures of ~36 nm diameter; and ii) in the presence of GTP into rings composed of 13-18 monomers...
2017: PloS One
https://www.readbyqxmd.com/read/28632753/mait-cells-launch-a-rapid-robust-and-distinct-hyperinflammatory-response-to-bacterial-superantigens-and-quickly-acquire-an-anergic-phenotype-that-impedes-their-cognate-antimicrobial-function-defining-a-novel-mechanism-of-superantigen-induced-immunopathology
#20
Christopher R Shaler, Joshua Choi, Patrick T Rudak, Arash Memarnejadian, Peter A Szabo, Mauro E Tun-Abraham, Jamie Rossjohn, Alexandra J Corbett, James McCluskey, John K McCormick, Olivier Lantz, Roberto Hernandez-Alejandro, S M Mansour Haeryfar
Superantigens (SAgs) are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a "cytokine storm" with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS). Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm's initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host's ability to combat and clear infections...
June 2017: PLoS Biology
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