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https://www.readbyqxmd.com/read/28350814/compensatory-changes-in-cyp-expression-in-three-different-toxicology-mouse-models-car-null-cyp3a-null-and-cyp2b9-10-13-null-mice
#1
Ramiya Kumar, Linda C Mota, Elizabeth J Litoff, John P Rooney, W Tyler Boswell, Elliott Courter, Charles M Henderson, Juan P Hernandez, J Christopher Corton, David D Moore, William S Baldwin
Targeted mutant models are common in mechanistic toxicology experiments investigating the absorption, metabolism, distribution, or elimination (ADME) of chemicals from individuals. Key models include those for xenosensing transcription factors and cytochrome P450s (CYP). Here we investigated changes in transcript levels, protein expression, and steroid hydroxylation of several xenobiotic detoxifying CYPs in constitutive androstane receptor (CAR)-null and two CYP-null mouse models that have subfamily members regulated by CAR; the Cyp3a-null and a newly described Cyp2b9/10/13-null mouse model...
2017: PloS One
https://www.readbyqxmd.com/read/28346697/car-t-cell-therapy-for-pancreatic-cancer
#2
REVIEW
Carl J DeSelm, Zachary E Tano, Anna M Varghese, Prasad S Adusumilli
Chimeric antigen receptor (CAR) T-cell therapy utilizes genetic engineering to redirect a patient's own T cells to target cancer cells. The remarkable results in hematological malignancies prompted investigating this approach in solid tumors such as pancreatic cancer. The complex tumor microenvironment, stromal hindrance in limiting immune response, and expression of checkpoint blockade on T cells pose hurdles. Herein, we summarize the opportunities, challenges, and state of knowledge in targeting pancreatic cancer with CAR T-cell therapy...
March 27, 2017: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28346400/t-lymphocyte-homing-an-underappreciated-yet-critical-hurdle-for-successful-cancer-immunotherapy
#3
Robert Sackstein, Tobias Schatton, Steven R Barthel
Advances in cancer immunotherapy have offered new hope for patients with metastatic disease. This unfolding success story has been exemplified by a growing arsenal of novel immunotherapeutics, including blocking antibodies targeting immune checkpoint pathways, cancer vaccines, and adoptive cell therapy (ACT). Nonetheless, clinical benefit remains highly variable and patient-specific, in part, because all immunotherapeutic regimens vitally hinge on the capacity of endogenous and/or adoptively transferred T-effector (Teff) cells, including chimeric antigen receptor (CAR) T cells, to home efficiently into tumor target tissue...
March 27, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28346010/non-healing-perianal-ulcers-in-a-healthy-elderly-male
#4
Alia Cloutier-Bosworth, Karen Naert, Carly Kirshen
BACKGROUND: Perforating dermatoses are a rare group of dermatologic conditions characterized by transepidermal elimination of dermal material that can be primary or acquired secondary to systemic disease. OBJECTIVE: We present an atypical case of perforating dermatosis resembling elastosis perforans serpiginosa (EPS) presenting with perianal ulcers in an elderly male with no systemic disease or medications and outline his successful treatment course. CONCLUSIONS: Perianal ulcers in an otherwise healthy individual is an unusual presentation for perforating disorders but should be considered in cases not responding to traditional treatment options...
March 1, 2017: Journal of Cutaneous Medicine and Surgery
https://www.readbyqxmd.com/read/28345929/utility-of-cyp3a4-and-pxr-car-cyp3a4-3a7-transgenic-mouse-models-to-assess-the-magnitude-of-cyp3a4-mediated-drug-drug-interactions
#5
Justin Q Ly, Kirsten Messick, Ann Qin, Ryan H Takahashi, Edna F Choo
Species differences in the expression, activity, regulation and substrate specificity of metabolizing enzymes preclude the use of animal models to predict clinical drug-drug interactions (DDI). The objective of this work is to determine if the transgenic (Tg) Cyp3a-/-Tg-3A4Hep/Int and Nr1i2/Nr1i3-/--Cyp3a-/-Tg-PXR-CAR-3A4/3A7Hep/Int (PXR-CAR-CYP3A4/3A7) mouse models could be used to predict in vivo DDI of 10 drugs; alprazolam, bosutinib, crizotinib, dasatinib, gefitinib, ibrutinib, regorafenib, sorafenib, triazolam, and vandetinib (as victims), with varying magnitudes of reported CYP3A4 clinical DDI...
March 27, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28345195/diagnosing-neonatal-transphyseal-fractures-of-the-distal-humerus
#6
Matthew Kay, Carly Simpkins, Peter Shipman, Colin Whitewood
A traumatic birth can cause significant upper limb injury; the presenting features are non-specific and the differential diagnosis long. Transphyseal fractures of the distal humerus are a rare but clinically important birth injury. This injury has typical radiographic findings, which due to the un-ossified nature of the distal humeral epiphysis can easily be misinterpreted. This article presents the radiographic appearance correlated with arthrography, ultrasound and MRI obtained from four cases of neonatal transphyseal fracture of the distal humerus...
March 27, 2017: Journal of Medical Imaging and Radiation Oncology
https://www.readbyqxmd.com/read/28345023/enhancement-of-psma-directed-car-adoptive-immunotherapy-by-pd-1-pd-l1-blockade
#7
Inna Serganova, Ekaterina Moroz, Ivan Cohen, Maxim Moroz, Mayuresh Mane, Juan Zurita, Larissa Shenker, Vladimir Ponomarev, Ronald Blasberg
Chimeric antigen receptor (CAR) T cell therapy in hematologic malignancies has shown remarkable responses, but the same level of success has not been observed in solid tumors. A new prostate cancer model (Myc-CaP:PSMA(+)) and a second-generation anti-hPSMA human CAR T cells expressing a Click Beetle Red luciferase reporter) were used to study hPSMA targeting and assess CAR T cell trafficking and persistence by bioluminescence imaging (BLI). We investigated the antitumor efficacy of human CAR T cells targeting human prostate-specific membrane antigen (hPSMA), in the presence and absence of the target antigen; first alone and then combined with a monoclonal antibody targeting the human programmed death receptor 1 (anti-hPD1 mAb)...
March 17, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28345004/homology-directed-recombination-for-enhanced-engineering-of-chimeric-antigen-receptor-t-cells
#8
Malika Hale, Baeckseung Lee, Yuchi Honaker, Wai-Hang Leung, Alexandra E Grier, Holly M Jacobs, Karen Sommer, Jaya Sahni, Shaun W Jackson, Andrew M Scharenberg, Alexander Astrakhan, David J Rawlings
Gene editing by homology-directed recombination (HDR) can be used to couple delivery of a therapeutic gene cassette with targeted genomic modifications to generate engineered human T cells with clinically useful profiles. Here, we explore the functionality of therapeutic cassettes delivered by these means and test the flexibility of this approach to clinically relevant alleles. Because CCR5-negative T cells are resistant to HIV-1 infection, CCR5-negative anti-CD19 chimeric antigen receptor (CAR) T cells could be used to treat patients with HIV-associated B cell malignancies...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28344995/global-manufacturing-of-car-t-cell-therapy
#9
REVIEW
Bruce L Levine, James Miskin, Keith Wonnacott, Christopher Keir
Immunotherapy using chimeric antigen receptor-modified T cells has demonstrated high response rates in patients with B cell malignancies, and chimeric antigen receptor T cell therapy is now being investigated in several hematologic and solid tumor types. Chimeric antigen receptor T cells are generated by removing T cells from a patient's blood and engineering the cells to express the chimeric antigen receptor, which reprograms the T cells to target tumor cells. As chimeric antigen receptor T cell therapy moves into later-phase clinical trials and becomes an option for more patients, compliance of the chimeric antigen receptor T cell manufacturing process with global regulatory requirements becomes a topic for extensive discussion...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28344886/car-t-cell-intrinsic-pd-1-checkpoint-blockade-a-two-in-one-approach-for-solid-tumor-immunotherapy
#10
Nan Chen, Aurore Morello, Zachary Tano, Prasad S Adusumilli
PD-L1/2 expression in solid tumors inhibits chimeric antigen receptor (CAR) T-cell efficacy. A PD-1 dominant negative receptor expressed in CAR T cells provides cell-intrinsic checkpoint blockade and augments antitumor efficacy. A combinatorial immunotherapeutic strategy of combining CAR T cells with checkpoint blockade is a promising treatment approach for solid tumors.
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28344808/safety-tumor-trafficking-and-immunogenicity-of-chimeric-antigen-receptor-car-t-cells-specific-for-tag-72-in-colorectal-cancer
#11
Kristen M Hege, Emily K Bergsland, George A Fisher, John J Nemunaitis, Robert S Warren, James G McArthur, Andy A Lin, Jeffrey Schlom, Carl H June, Stephen A Sherwin
BACKGROUND: T cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s. METHODS: Patients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells)...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28344526/delayed-repair-of-ulnar-artery-at-the-distal-forearm
#12
Jorge G Boretto, Ezequiel Zaidenberg, Gerardo L Gallucci, Verónica Alfie, Pablo De Carli
Background:The purpose of this study was to evaluate the rate of patency after delayed repair of the ulnar artery following primary ligation. Methods: Adult patients with primary ligation of the injured ulnar artery at the forearm who had a delayed repair of the artery were included. Postoperative arterial patency was determined by either physical examination or color Doppler ultrasonographic imaging. Postoperative complications and Disabilities of the Arm, Shoulder and Hand score were recorded. Results: Eight consecutive patients during a 3-year period were included...
March 2017: Hand: Official Journal of the American Association for Hand Surgery
https://www.readbyqxmd.com/read/28343903/-spinal-cord-injuries-resulting-from-diving-accidents-in-the-canary-islands
#13
Enrique Bárbara-Bataller, José Luis Méndez-Suárez, Carolina Alemán-Sánchez, Jesús Sánchez-Enríquez, Manuel Sosa-Henríquez
OBJECTIVE: Diving accidents is one of the leading causes of spinal cord injury after falls and car accidents. The objective of this study was to determine the epidemiological and clinical characteristics of these patients in our setting to better prevent these injuries. MATERIAL AND METHODS: We performed a retrospective, descriptive study of patients who have suffered from a traumatic spinal cord injury after a diving accident in the Canary Islands, Spain from 2000 to 2014...
March 23, 2017: Neurocirugía
https://www.readbyqxmd.com/read/28343356/development-of-a-novel-strategy-to-target-cd39-antithrombotic-activity-to-the-endothelial-platelet-microenvironment-in-kidney-ischemia-reperfusion-injury
#14
Maithili Sashindranath, Karen M Dwyer, Shala Dezfouli, Carly Selan, Sandra Crikis, Bo Lu, Yuping Yuan, Michael J Hickey, Karlheinz Peter, Simon C Robson, Peter J Cowan, Harshal H Nandurkar
Kidney ischemia-reperfusion injury (IRI) is common during transplantation. IRI is characterised by inflammation and thrombosis and associated with acute and chronic graft dysfunction. P-selectin and its ligand PSGL-1 are cell adhesion molecules that control leukocyte-endothelial and leukocyte-platelet interactions under inflammatory conditions. CD39 is the dominant vascular nucleotidase that facilitates adenosine generation via extracellular ATP/ADP-phosphohydrolysis. Adenosine signalling is protective in renal IRI, but CD39 catalytic activity is lost with exposure to oxidant stress...
March 25, 2017: Purinergic Signalling
https://www.readbyqxmd.com/read/28343124/effects-of-acute-alcohol-consumption-on-measures-of-simulated-driving-a-systematic-review-and-meta-analysis
#15
Christopher Irwin, Elizaveta Iudakhina, Ben Desbrow, Danielle McCartney
Driving simulators are used in a wide range of research settings to help develop an understanding of driver behavior in complex environments. Acute alcohol impairment is an important research topic for traffic safety and a large number of studies have indicated levels of simulated driving impairment imposed by alcohol across a range of performance outcome variables. The aim of the present study was to examine the impact of acute alcohol consumption on simulated driving performance by conducting a systematic review and meta-analysis of the available evidence...
March 23, 2017: Accident; Analysis and Prevention
https://www.readbyqxmd.com/read/28343101/the-influence-of-odd-even-car-trial-on-fine-and-coarse-particles-in-delhi
#16
Prashant Kumar, Sunil Gulia, Roy M Harrison, Mukesh Khare
The odd-even car trial scheme, which reduced car traffic between 08.00 and 20.00 h daily, was applied from 1 to 15 January 2016 (winter scheme, WS) and 15-30 April 2016 (summer scheme, SS). The daily average PM2.5 and PM10 exceeded national standards, with highest concentrations (313 μg m(-3) and 639 μg m(-3), respectively) during winter and lowest (53 μg m(-3) and 130 μg m(-3)) during the monsoon (June-August). PM concentrations during the trials can be interpreted either as reduced or increased, depending on the periods used for comparison purposes...
March 23, 2017: Environmental Pollution
https://www.readbyqxmd.com/read/28342824/development-of-car-t-cells-designed-to-improve-antitumor-efficacy-and-safety
#17
REVIEW
Janneke E Jaspers, Renier J Brentjens
Chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy against hematologic malignancies. Antitumor activity of CAR T cells, however, needs to be improved to increase therapeutic efficacy in both hematologic and solid cancers. Limitations to overcome are 'on-target, off-tumor' toxicity, antigen escape, short CAR T cell persistence, little expansion, trafficking to the tumor and inhibition of T cell activity by an inhibitory tumor microenvironment. Here we will discuss how optimizing the design of CAR T cells through genetic engineering addresses these limitations and improves the antitumor efficacy of CAR T cell therapy in pre-clinical models...
March 22, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28341563/avoidance-of-on-target-off-tumor-activation-using-a-co-stimulation-only-chimeric-antigen-receptor
#18
Jonathan Fisher, Pierre Abramowski, Nisansala Dilrukshi Wisidagamage Don, Barry Flutter, Anna Capsomidis, Gordon Weng-Kit Cheung, Kenth Gustafsson, John Anderson
Chimeric antigen receptors (CARs) combine T cell activation with antibody-mediated tumor antigen specificity, bypassing the need for T cell receptor (TCR) ligation. A limitation of CAR technology is on-target off-tumor toxicity caused by target antigen expression on normal cells. Using GD2 as a model cancer antigen, we hypothesized that this could be minimized by using T cells expressing Vγ9Vδ2 TCR, which recognizes transformed cells in a major histocompatibility complex (MHC)-unrestricted manner, in combination with a co-stimulatory CAR that would function independently of the TCR...
March 21, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28339039/the-effects-of-air-pollutants-on-the-mortality-rate-of-lung-cancer-and-leukemia
#19
Mansooreh Dehghani, Laila Keshtgar, Mohammad Reza Javaheri, Zahra Derakhshan, Gea Oliveri Conti, Pietro Zuccarello, Margherita Ferrante
World Health Organization classifies air pollution as the first cause of human cancer. The present study investigated impact of air pollutants on the mortality rates of lung cancer and leukemia in Shiraz, one of the largests cities of Iran. This cross‑sectional (longitudinal) study was carried out in Shiraz. Data on six main pollutants, CO, SO2, O3, NO2, PM10 and PM2.5, were collected from Fars Environmental Protection Agency for 3,001 days starting from 1 January, 2005. Also, measures of climatic factors (temperature, humidity, and air pressure) were obtained from Shiraz Meteorological Organization...
March 24, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28338214/light-therapies-for-acne-abridged-cochrane-systematic-review-including-grade-assessments
#20
REVIEW
J Barbaric, R Abbott, P Posadzki, M Car, L H Gunn, A M Layton, A Majeed, J Car
We undertook a Cochrane review of randomized controlled trials (RCTs) evaluating the effects of light-based interventions for acne vulgaris. We searched the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, ISI Web of Science, and grey literature sources (September 2015). We used the Grading of Recommendations Assessment, Development and Evaluation Working Group approach to assess the quality of evidence (QE). We included 71 RCTs (4211 participants, median sample size 31). Results from a single study (n = 266, low QE) showed little or no difference in effectiveness on participants' assessment of improvement between 20% aminolevulinic acid (ALA) photodynamic therapy (PDT), activated by blue light, versus vehicle plus blue light, whereas another study (n = 180) of a comparison of ALA-PDT (red light) concentrations showed 20% ALA-PDT was no more effective than 15%, but better than 10% and 5% ALA-PDT...
March 24, 2017: British Journal of Dermatology
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