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https://www.readbyqxmd.com/read/29346838/first-in-human-study-to-assess-safety-pharmacokinetics-and-pharmacodynamics-of-bms-962212-a-direct-reversible-small-molecule-factor-xia-inhibitor-in-non-japanese-and-japanese-healthy-subjects
#1
Vidya Perera, Joseph M Luettgen, Zhaoqing Wang, Charles E Frost, Cynthia Yones, Cesare Russo, John Lee, Yue Zhao, Frank P LaCreta, Xuewen Ma, Robert M Knabb, Dietmar Seiffert, Mary DeSouza, Pierre Mugnier, Brenda Cirincione, Takayo Ueno, Robert J A Frost
AIMS: To assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-962212, a first-in-class Factor XIa inhibitor, in Japanese and non-Japanese healthy subjects. METHODS: This was a randomized, placebo-controlled, double-blind, sequential, ascending dose study of 2 hour (Part A) and 5 day (Part B) intravenous (IV) infusions of BMS-962212. Part A used 4 doses (1.5, 4, 10, and 25 mg h-1 ) assigned to BMS-962212 or placebo in a 3:1 ratio per dose. Part B used 4 doses (1, 3, 9, and 20 mg h-1 ) enrolling Japanese (n = 4 active, n = 1 placebo) and non-Japanese subjects (n = 4 active, n = 1 placebo) per dose...
January 18, 2018: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29336888/lxr-apoe-activation-restricts-innate-immune-suppression-in-cancer
#2
Masoud F Tavazoie, Ilana Pollack, Raissa Tanqueco, Benjamin N Ostendorf, Bernardo S Reis, Foster C Gonsalves, Isabel Kurth, Celia Andreu-Agullo, Mark L Derbyshire, Jessica Posada, Shugaku Takeda, Kimia N Tafreshian, Eric Rowinsky, Michael Szarek, Roger J Waltzman, Elizabeth A Mcmillan, Connie Zhao, Monica Mita, Alain Mita, Bartosz Chmielowski, Michael A Postow, Antoni Ribas, Daniel Mucida, Sohail F Tavazoie
Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed the treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSCs)-an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial...
January 9, 2018: Cell
https://www.readbyqxmd.com/read/29335386/safety-and-feasibility-of-a-novel-second-generation-robotic-assisted-system-for-percutaneous-coronary-intervention-first-in-human-report
#3
Christopher C Smitson, Lawrence Ang, Ali Pourdjabbar, Ryan Reeves, Mitul Patel, Ehtisham Mahmud
OBJECTIVES: The goal of this study is to evaluate the safety and efficacy of the second-generation robotic-assisted system CorPath GRX (Corindus) for percutaneous coronary intervention (PCI). BACKGROUND: The first-generation CorPath 200 robotic-assisted system for PCI is effective, but is limited by the lack of an active robotic guide-catheter control. The CorPath GRX device enables robotic guide-catheter manipulation, in addition to guidewire and balloon/stent delivery...
January 15, 2018: Journal of Invasive Cardiology
https://www.readbyqxmd.com/read/29330000/histotripsy-treatment-of-benign-prostatic-enlargement-using-the-vortx-rx-system-initial-human-safety-and-efficacy-outcomes
#4
T G Schuster, J T Wei, K Hendlin, R Jahnke, W W Roberts
OBJECTIVES: To assess clinical safety (primary) and efficacy (secondary) of histotripsy for treatment of symptomatic benign prostatic enlargement (BPE) in a first-in human study. METHODS: Twenty-five male subjects with moderate to severe lower urinary tract symptoms (LUTS), prostate size between 30 and 80 grams and no evidence of prostate cancer were enrolled at two sites in a prospective, single-arm study. Treatment consisted of acoustic energy delivery through the perineum with integrated real-time TRUS monitoring using the Vortx RX system...
January 9, 2018: Urology
https://www.readbyqxmd.com/read/29329556/cancer-immunotherapy-beyond-immune-checkpoint-inhibitors
#5
REVIEW
Julian A Marin-Acevedo, Aixa E Soyano, Bhagirathbhai Dholaria, Keith L Knutson, Yanyan Lou
Malignant cells have the capacity to rapidly grow exponentially and spread in part by suppressing, evading, and exploiting the host immune system. Immunotherapy is a form of oncologic treatment directed towards enhancing the host immune system against cancer. In recent years, manipulation of immune checkpoints or pathways has emerged as an important and effective form of immunotherapy. Agents that target cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) are the most widely studied and recognized...
January 12, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29327570/the-detour-procedure-no-more-need-for-conventional-bypass-surgery
#6
Dainis Krievins, Janis Savlovskis, Natalija Ezite, Andrew Hill, Kaspars Kisis, Marcis Gedins, Edgars Zellans, Andrew Holden
BACKGROUND: Long segment occlusive disease in the superficial femoral artery remains a treatment challenge despite advances in open surgical and endovascular approaches. We report initial clinical results of an entirely new procedure to perform femoropopliteal bypass using the DETOUR System to create a stentgraft bypass which originates in the SFA, travels through the femoral vein, and ends in the popliteal artery, bypassing the diseased segment. METHODS: Review the initial results of the first five patients at a single site enrolled in IRB-approved, prospective clinical study using the DETOUR System...
January 9, 2018: Journal of Cardiovascular Surgery
https://www.readbyqxmd.com/read/29311291/balloon-fracture-of-a-surgical-mitral-bioprosthesis-during-valve-in-valve-transcatheter-mitral-valve-replacement-first-in-human-report
#7
Tsuyoshi Kaneko, Bryan Piccirillo, Harsh Golwala, Agnieszka Trzcinka, Charles Nyman, Douglas Shook, Marc Pelletier, Natalia Berry, Piotr Sobieszczyk, Pinak Shah
No abstract text is available yet for this article.
January 2018: Circulation. Cardiovascular Interventions
https://www.readbyqxmd.com/read/29308669/an-open-label-study-of-a-novel-immunosuppression-intervention-for-the-treatment-of-amyotrophic-lateral-sclerosis
#8
Christina N Fournier, David Schoenfeld, James D Berry, Merit E Cudkowicz, James Chan, Colin Quinn, Robert H Brown, Johnny S Salameh, Malu G Tansey, David R Beers, Stanley H Appel, Jonathan D Glass
Neuroinflammation is increasingly tied to disease progression in amyotrophic lateral sclerosis (ALS). Participants in the first-in-human trial of intra-spinal allogeneic stem cell therapy for ALS received immunosuppression, and one participant saw dramatic improvement across multiple outcome measures. The primary objective of this study (NCT01884571) was to assess the rate of clinical response to the same immunosuppressive regimen using basiliximab, tacrolimus, mycophenolate, and prednisone in people with ALS...
January 8, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/29296912/hemophilia-gene-therapy-comes-of-age
#9
REVIEW
Lindsey A George
Concurrent with the development of recombinant factor replacement products, the characterization of the F9 and F8 genes over 3 decades ago allowed for the development of recombinant factor products and made the hemophilias a target disease for gene transfer. The progress of hemophilia gene therapy has been announced in 3 American Society of Hematology scientific plenary sessions, including the first "cure" in a large animal model of hemophilia B in 1998, first in human sustained vector-derived factor IX activity in 2011, and our clinical trial results reporting sustained vector-derived factor IX activity well into the mild or normal range in 2016...
December 12, 2017: Blood Advances
https://www.readbyqxmd.com/read/29285748/an-industry-perspective-on-the-2017-ema-guideline-on-first-in-human-and-early-clinical-trials
#10
Joseph DeGeorge, Sarah Robertson, Lynne Butler, Mazin Derzi, S Aubrey Stoch, Dolores Diaz, James Hartke, Peggy Guzzie-Peck, Elisabeth Mortimer-Cassen, Matthew Bogdanffy, Yvonne Will, Nigel Greene
The European Medicines Agency (EMA) in 2017 issued a revised guideline on nonclinical and clinical aspects of first-in-human (FIH) and early clinical trials (CTs). External input was solicited during a draft comment phase, and although some industry suggestions were adopted, others were not. We agree that subject safety is of utmost priority, and believe that minimizing risk must be balanced with efficient and informative study designs to bring new medicines to patients.
December 29, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29259721/characterization-of-polydactyly-derived-chondrocyte-sheets-versus-adult-chondrocyte-sheets-for-articular-cartilage-repair
#11
Miki Maehara, Masato Sato, Eriko Toyoda, Takumi Takahashi, Eri Okada, Tomomi Kotoku, Masahiko Watanabe
Background: We previously conducted a first-in-human clinical study of articular cartilage repair using autologous chondrocyte sheets and confirmed the regeneration of hyaline-like cartilage in all eight patients. However, regenerative medicine with autologous chondrocyte sheets requires the harvesting of tissue from healthy regions, and the quality of this tissue varies between individuals. To overcome such limitations, allogeneic transplantation is a promising treatment method, particularly for articular cartilage repair...
2017: Inflammation and Regeneration
https://www.readbyqxmd.com/read/29247021/first-in-class-erk1-2-inhibitor-ulixertinib-bvd-523-in-patients-with-mapk-mutant-advanced-solid-tumors-results-of-a-phase-i-dose-escalation-and-expansion-study
#12
Ryan J Sullivan, Jeffrey R Infante, Filip Janku, Deborah Jean Lee Wong, Jeffrey A Sosman, Vicki Keedy, Manish R Patel, Geoffrey I Shapiro, James W Mier, Anthony W Tolcher, Andrea Wang-Gillam, Mario Sznol, Keith Flaherty, Elizabeth Buchbinder, Richard D Carvajal, Anna M Varghese, Mario E Lacouture, Antoni Ribas, Sapna P Patel, Gary A DeCrescenzo, Caroline M Emery, Anna L Groover, Saurabh Saha, Mary Varterasian, Dean J Welsch, David M Hyman, Bob T Li
Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood...
December 15, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29246915/first-in-human-implantations-of-the-navigate-bioprosthesis-in-a-severely-dilated-tricuspid-annulus-and-in-a-failed-tricuspid-annuloplasty-ring
#13
Jose L Navia, Samir Kapadia, Haytham Elgharably, Serge C Harb, Amar Krishnaswamy, Shinya Unai, Stephanie Mick, Leonardo Rodriguez, Donald Hammer, A Marc Gillinov, Lars G Svensson
No abstract text is available yet for this article.
December 2017: Circulation. Cardiovascular Interventions
https://www.readbyqxmd.com/read/29244745/immunotherapeutic-potential-of-oncolytic-h-1-parvovirus-hints-of-glioblastoma-microenvironment-conversion-towards-immunogenicity
#14
Assia L Angelova, Milena Barf, Karsten Geletneky, Andreas Unterberg, Jean Rommelaere
Glioblastoma, one of the most aggressive primary brain tumors, is characterized by highly immunosuppressive microenvironment. This contributes to glioblastoma resistance to standard treatment modalities and allows tumor growth and recurrence. Several immune-targeted approaches have been recently developed and are currently under preclinical and clinical investigation. Oncolytic viruses, including the autonomous protoparvovirus H-1 (H-1PV), show great promise as novel immunotherapeutic tools. In a first phase I/IIa clinical trial (ParvOryx01), H-1PV was safe and well tolerated when locally or systemically administered to recurrent glioblastoma patients...
December 15, 2017: Viruses
https://www.readbyqxmd.com/read/29243353/first-in-human-evaluation-of-the-vascular-biocompatibility-and-biomechanical-performance-of-a-novel-ultra-high-molecular-weight-amorphous-plla-bioresorbable-scaffold-in-the-absence-of-anti-proliferative-drugs-two-year-imaging-results-in-humans
#15
Miguel Moncada, Juan A Delgado, Antonio Colombo, Pawel Gasior, Kamal Ramzipoor, Alex Estrada, Chang Lee, Danny Dokko, Juan F Granada
OBJECTIVES: In this first-in-human study, we prospectively studied the vascular compatibility and mechanical performance of a novel bare ultra-high molecular weight amorphous PLLA bioresorbable scaffold (BRS, FORTITUDE®, Amaranth Medical, Mountain View, California) up to two years after implantation using multimodality imaging techniques. BACKGROUND: The vascular biocompatibility of polymers used in BRS has not been fully characterized in the absence of anti-proliferative drugs...
December 15, 2017: Catheterization and Cardiovascular Interventions
https://www.readbyqxmd.com/read/29234903/biodistribution-and-radiation-dosimetry-of-64cu-copper-dichloride-first-in-human-study-in-healthy-volunteers
#16
M A Avila-Rodriguez, C Rios, J Carrasco-Hernandez, J C Manrique-Arias, R Martinez-Hernandez, F O García-Pérez, A R Jalilian, E Martinez-Rodriguez, M E Romero-Piña, A Diaz-Ruiz
BACKGROUND: In recent years, Copper-64 (T1/2 = 12.7 h) in the chemical form of copper dichloride ([64Cu]CuCl2) has been identified as a potential agent for PET imaging and radionuclide therapy targeting the human copper transporter 1, which is overexpressed in a variety of cancer cells. Limited human biodistribution and radiation dosimetry data is available for this tracer. The aim of this research was to determine the biodistribution and estimate the radiation dosimetry of [64Cu]CuCl2, using whole-body (WB) PET scans in healthy volunteers...
December 12, 2017: EJNMMI Research
https://www.readbyqxmd.com/read/29233904/autologous-dendritic-cells-pulsed-with-allogeneic-tumor-cell-lysate-in-mesothelioma-from-mouse-to-human
#17
Joachim G Aerts, Pauline L de Goeje, Robin Cornelissen, Margaretha E H Kaijen-Lambers, Koen Bezemer, Cor van der Leest, Niken M Mahaweni, Andre Kunert, Ferry A L M Eskens, Cynthia Waasdorp, Eric Braakman, Bronno van der Holt, Arnold G Vulto, Rudi W Hendriks, Joost P J J Hegmans, Henk C Hoogsteden
PURPOSE: Mesothelioma has been regarded as a non-immunogenic tumor, which is also shown by the low response rates to treatments targeting the PD-1/PD-L1 axis.  Previously, we demonstrated that autologous tumor lysate-pulsed dendritic cell (DC) immunotherapy increased T-cell response towards malignant mesothelioma. However, the use of autologous tumor material hampers implementation in large clinical trials, which might be overcome by using allogeneic tumor cell lines as tumor antigen source...
December 12, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29227146/time-dependent-recovery-of-human-synovial-membrane-mesenchymal-stem-cell-function-after-high-dose-steroid-therapy-case-report-and-laboratory-study
#18
Yukihiko Yasui, David A Hart, Norihiko Sugita, Ryota Chijimatsu, Kota Koizumi, Wataru Ando, Yu Moriguchi, Kazunori Shimomura, Akira Myoui, Hideki Yoshikawa, Norimasa Nakamura
BACKGROUND: The use of mesenchymal stem cells from various tissue sources to repair injured tissues has been explored over the past decade in large preclinical models and is now moving into the clinic. PURPOSE: To report the case of a patient who exhibited compromised mesenchymal stem cell (MSC) function shortly after use of high-dose steroid to treat Bell's palsy, who recovered 7 weeks after therapy. STUDY DESIGN: Case report and controlled laboratory study...
December 1, 2017: American Journal of Sports Medicine
https://www.readbyqxmd.com/read/29226626/randomized-clinical-study-of-safety-pharmacokinetics-and-pharmacodynamics-of-ripk1-inhibitor-gsk2982772-in-healthy-volunteers
#19
Kathleen Weisel, Nicola E Scott, Debra J Tompson, Bartholomew J Votta, Sujith Madhavan, Kat Povey, Allen Wolstenholme, Monica Simeoni, Todd Rudo, Lauren Richards-Peterson, Tarjinder Sahota, J Gene Wang, John Lich, Joshua Finger, Adeline Verticelli, Michael Reilly, Peter J Gough, Philip A Harris, John Bertin, Mei-Lun Wang
GSK2982772 is a highly selective inhibitor of receptor-interacting protein kinase 1 (RIPK1) being developed to treat chronic inflammatory diseases. This first-in-human study evaluated safety, tolerability, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of GSK2982772 administered orally to healthy male volunteers. This was a Phase I, randomized, placebo-controlled, double-blind study. In Part A, subjects received single ascending doses of GSK2982772 (0.1-120 mg) or placebo in a crossover design during each of 4 treatment periods...
December 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29222308/hemophilia-gene-therapy-comes-of-age
#20
REVIEW
Lindsey A George
Concurrent with the development of recombinant factor replacement products, the characterization of the F9 and F8 genes over 3 decades ago allowed for the development of recombinant factor products and made the hemophilias a target disease for gene transfer. The progress of hemophilia gene therapy has been announced in 3 American Society of Hematology scientific plenary sessions, including the first "cure" in a large animal model of hemophilia B in 1998, first in human sustained vector-derived factor IX activity in 2011, and our clinical trial results reporting sustained vector-derived factor IX activity well into the mild or normal range in 2016...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
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