120 results match your criteria physiologically humanized

Descriptive and Functional Genomics in Acute Myeloid Leukemia (AML): Paving the Road for a Cure.

Cancers (Basel) 2021 Feb 11;13(4). Epub 2021 Feb 11.

Université de Paris, APHP, Hôpital Saint-Louis, 75010 Paris, France.

Over the past decades, genetic advances have allowed a more precise molecular characterization of AML with the identification of novel oncogenes and tumor suppressors as part of a comprehensive AML molecular landscape. Recent advances in genetic sequencing tools also enabled a better understanding of AML leukemogenesis from the preleukemic state to posttherapy relapse. These advances resulted in direct clinical implications with the definition of molecular prognosis classifications, the development of treatment recommendations based on minimal residual disease (MRD) measurement and the discovery of novel targeted therapies, ultimately improving AML patients' overall survival. Read More

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February 2021

Use of Porous Polystyrene Scaffolds to Bioengineer Human Epithelial Tissues In Vitro.

Methods Mol Biol 2021 ;2273:279-296

Department of Biosciences, Durham University, Durham, UK.

In vitro epithelial models are valuable tools for both academic and industrial laboratories to investigate tissue physiology and disease. Epithelial tissues comprise the surface epithelium, basement membrane, and underlying supporting stromal cells. There are various types of epithelial tissue and they have a diverse and intricate architecture in vivo, which cannot be successfully recapitulated using two-dimensional (2D) cell culture. Read More

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Real-world case series and summary of current literature of infants and toddlers with severe hemophilia A with inhibitor on prophylaxis with emicizumab.

Pediatr Blood Cancer 2021 May 8;68(5):e28942. Epub 2021 Feb 8.

UT Southwestern, Dallas, Texas, USA.

Emicizumab is a recombinant, humanized, and a bispecific monoclonal antibody that bridges activated factor (F) IX and FX in place of FVIII to restore hemostasis in persons with hemophilia A (PHA). Data on the efficacy and safety of emicizumab in young children is limited. Immunologic naivety, physiologically decreased production of vitamin K dependent proteins, specifically FIX, and enhanced clearance of emicizumab in infants may support decreased emicizumab effectiveness. Read More

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In Vitro and In Vivo Tumor Models for the Evaluation of Anticancer Nanoparticles.

Adv Exp Med Biol 2021 ;1295:271-299

CNC - Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Faculty of Medicine (Polo 1), Rua Larga, Coimbra, Portugal.

Multiple studies about tumor biology have revealed the determinant role of the tumor microenvironment in cancer progression, resulting from the dynamic interactions between tumor cells and surrounding stromal cells within the extracellular matrix. This malignant microenvironment highly impacts the efficacy of anticancer nanoparticles by displaying drug resistance mechanisms, as well as intrinsic physical and biochemical barriers, which hamper their intratumoral accumulation and biological activity.Currently, two-dimensional cell cultures are used as the initial screening method in vitro for testing cytotoxic nanocarriers. Read More

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February 2021

Prediction of Transporter-Mediated Drug-Drug Interactions and Phenotyping of Hepatobiliary Transporters Involved in the Clearance of E7766, a Novel Macrocycle-Bridged Dinucleotide.

Drug Metab Dispos 2021 Mar 18;49(3):265-275. Epub 2020 Dec 18.

Drug Metabolism and Pharmacokinetics (R.J., V.D., W.G.L., A.H.) and Genetics Guided Dementia Discovery, Eisai Inc, Cambridge, Massachusetts (L.B., D.-S.K.)

E7766 represents a novel class of macrocycle-bridged dinucleotides and is under clinical development for immuno-oncology. In this report, we identified mechanism of systemic clearance E7766 and investigated the hepatobiliary transporters involved in the disposition of E7766 and potential drug interactions of E7766 as a victim of organic anion-transporting polypeptide (OATP) inhibitors. In bile-duct cannulated rats and dogs, E7766 was mainly excreted unchanged in bile (>80%) and to a lesser extent in urine (<20%). Read More

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Different Hepatic Concentrations of Bromobenzene, 1,2-Dibromobenzene, and 1,4-Dibromobenzene in Humanized-Liver Mice Predicted Using Simplified Physiologically Based Pharmacokinetic Models as Putative Markers of Toxicological Potential.

Chem Res Toxicol 2020 Dec 6;33(12):3048-3053. Epub 2020 Dec 6.

Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.

Bromobenzene is an industrial solvent that elicits toxicity predominantly in the liver. In this study, the hepatic concentrations of bromobenzene and its related compounds 1,2-dibromobenzene and 1,4-dibromobenzene in humanized-liver mice were predicted after single oral administrations by simplified physiologically based pharmacokinetic (PBPK) models that had been set up on experimental plasma concentrations after single oral doses of 100 mg/kg to rats and 100-250 mg/kg to control mice and humanized-liver mice. The output values by simplified PBPK models were consistent with measured blood substrate concentrations in rats, control mice, and humanized-liver mice with suitable input parameter values derived from in silico prediction and the literature or estimated by fitting the measured plasma substrate concentrations. Read More

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December 2020

Metabolic Profiles of Tetrabromobisphenol A in Humans Extrapolated from Humanized-Liver Mouse Data Using a Simplified Physiologically Based Pharmacokinetic Model.

Chem Res Toxicol 2021 Feb 16;34(2):522-528. Epub 2020 Nov 16.

Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.

Tetrabromobisphenol A, a brominated flame retardant, is increasingly prevalent worldwide and presents a potential health risk. Adjusted animal biomonitoring equivalents of tetrabromobisphenol A after orally administered doses in humanized-liver mice were scaled up to humans using known species allometric scaling factors to set up simplified physiologically based pharmacokinetic (PBPK) models. Absorbed tetrabromobisphenol A was slightly, moderately, and extensively metabolized to its glucuronide in rats, control mice, and humanized-liver mice tested, respectively. Read More

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February 2021

Thermoneutrality-Induced Macrophage Accumulation in Brown Adipose Tissue Does Not Impair the Tissue's Competence for Cold-Induced Thermogenic Recruitment.

Front Endocrinol (Lausanne) 2020 30;11:568682. Epub 2020 Oct 30.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

Brown adipose tissue from mice living under conditions approaching human thermal and nutritional conditions (prolonged exposure to thermoneutral temperature and to an energy-rich (high-fat, high-sugar) diet) - referred to as "physiologically humanized" mice, displays morphological and molecular characteristics significantly different from those observed in young, chow-fed mice maintained at room temperature - referred to as "standard" mice. Here, we further examined brown fat from physiologically humanized and standard mice, as well as from mice exposed to thermoneutrality for a long time but not to an energy-rich diet - referred to here as "long-term thermoneutral" mice. Global transcriptome analysis of brown fat revealed that genes that were the most upregulated in brown fat of thermoneutral mice (both physiologically humanized and long-term thermoneutral) were those related to inflammatory processes, including genes expressed selectively in macrophages. Read More

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October 2020

Human and mouse bones physiologically integrate in a humanized mouse model while maintaining species-specific ultrastructure.

Sci Adv 2020 Oct 28;6(44). Epub 2020 Oct 28.

Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Potsdam, Germany.

Humanized mouse models are increasingly studied to recapitulate human-like bone physiology. While human and mouse bone architectures differ in multiple scales, the extent to which chimeric human-mouse bone physiologically interacts and structurally integrates remains unknown. Here, we identify that humanized bone is formed by a mosaic of human and mouse collagen, structurally integrated within the same bone organ, as shown by immunohistochemistry. Read More

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October 2020

Functional humanization of immunoglobulin heavy constant gamma 1 Fc domain human transgenic mice.

MAbs 2020 Jan-Dec;12(1):1829334

The Jackson Laboratory , Bar Harbor, ME, USA.

A major asset of many monoclonal antibody (mAb)-based biologics is their persistence in circulation. The MHC class I family Fc receptor, FCGRT, is primarily responsible for this extended pharmacokinetic behavior. Engagement of FCGRT with the crystallizable fragment (Fc) domain protects IgG from catabolic elimination, thereby extending the persistence and bioavailability of IgG and related Fc-based biologics. Read More

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October 2020

Utilization of an in vitro biofabricated 3D skin as a pathological model of cutaneous candidiasis.

New Microbiol 2020 Oct 4;43(4):171-179. Epub 2020 Sep 4.

Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand.

Candida albicans is an opportunistic fungal infectious agent that can cause cutaneous candidiasis in humans. Biofilms formation of C. albicans is thought to be the major cause of antifungal drug resistance. Read More

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October 2020

Functional recreation of age-related CD8 T cells in young mice identifies drivers of aging- and human-specific tissue pathology.

Mech Ageing Dev 2020 10 8;191:111351. Epub 2020 Sep 8.

Dept. Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, United States; Brain Mapping Foundation, Society for Brain Mapping & Therapeutics, 860 Via De la Paz, Pacific Palisades, CA 90272, United States; T-Neuro Pharma, 1451 Innovation Parkway SE, Albuquerque, NM 87123, United States. Electronic address:

Mitigating effects of aging on human health remains elusive because aging impacts multiple systems simultaneously, and because experimental animals exhibit critical aging differences relative to humans. Separation of aging into discrete processes may identify targetable drivers of pathology, particularly when applied to human-specific features. Gradual homeostatic expansion of CD8 T cells dominantly alters their function in aging humans but not in mice. Read More

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October 2020

Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice.

Nat Metab 2019 08 19;1(8):830-843. Epub 2019 Aug 19.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 °C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. Read More

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Location First: Targeting Acute Myeloid Leukemia Within Its Niche.

J Clin Med 2020 May 18;9(5). Epub 2020 May 18.

Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, 20900 Monza, Italy.

Despite extensive research and development of new treatments, acute myeloid leukemia (AML)-backbone therapy has remained essentially unchanged over the last decades and is frequently associated with poor outcomes. Eradicating the leukemic stem cells (LSCs) is the ultimate challenge in the treatment of AML. Emerging evidence suggests that AML remodels the bone marrow (BM) niche into a leukemia-permissive microenvironment while suppressing normal hematopoiesis. Read More

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Human brown adipose tissue: Classical brown rather than brite/beige?

Exp Physiol 2020 08 30;105(8):1191-1200. Epub 2020 May 30.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

New Findings: What is the topic of this review? It has been suggested that human brown adipose tissue (BAT) is more similar to the brite/beige adipose tissue of mice than to classical BAT of mice. The basis of this is discussed in relationship to the physiological conditions of standard experimental mice. What advances does it highlight? We highlight that, provided mouse adipose tissues are examined under physiological conditions closer to those prevalent for most humans, the gene expression profile of mouse classical BAT is more similar to that of human BAT than is the profile of mouse brite/beige adipose tissue. Read More

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Fat-On-A-Chip Models for Research and Discovery in Obesity and Its Metabolic Comorbidities.

Tissue Eng Part B Rev 2020 12 3;26(6):586-595. Epub 2020 Dec 3.

LaCell LLC, New Orleans, Louisiana, USA.

The obesity epidemic and its associated comorbidities present a looming challenge to health care delivery throughout the world. Obesity is characterized as a sterile inflammatory process within adipose tissues leading to dysregulated secretion of bioactive adipokines such as adiponectin and leptin, as well as systemic metabolic dysfunction. The majority of current obesity research has focused primarily on preclinical animal models and two-dimensional cell culture models . Read More

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December 2020

Novel Engraftment and T Cell Differentiation of Human Hematopoietic Cells in SCID Pigs.

Front Immunol 2020 6;11:100. Epub 2020 Feb 6.

Department of Animal Science, Iowa State University, Ames, IA, United States.

Pigs with severe combined immunodeficiency (SCID) are an emerging biomedical animal model. Swine are anatomically and physiologically more similar to humans than mice, making them an invaluable tool for preclinical regenerative medicine and cancer research. One essential step in further developing this model is the immunological humanization of SCID pigs. Read More

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Art of Making Artificial Liver: Depicting Human Liver Biology and Diseases in Mice.

Semin Liver Dis 2020 05 19;40(2):189-212. Epub 2020 Feb 19.

Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California.

Advancement in both bioengineering and cell biology of the liver led to the establishment of the first-generation humanized liver chimeric mouse (HLCM) model in 2001. The HLCM system was initially developed to satisfy the necessity for a convenient and physiologically representative small animal model for studies of hepatitis B virus and hepatitis C virus infection. Over the last two decades, the HLCM system has substantially evolved in quality, production capacity, and utility, thereby growing its versatility beyond the study of viral hepatitis. Read More

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Effects of Interleukin-1β Inhibition on Blood Pressure, Incident Hypertension, and Residual Inflammatory Risk: A Secondary Analysis of CANTOS.

Hypertension 2020 02 30;75(2):477-482. Epub 2019 Dec 30.

Center for Cardiovascular Disease Prevention (J.M., R.J.G., P.M.R.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

While hypertension and inflammation are physiologically inter-related, the effect of therapies that specifically target inflammation on blood pressure is uncertain. The recent CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) afforded the opportunity to test whether IL (interleukin)-1β inhibition would reduce blood pressure, prevent incident hypertension, and modify relationships between hypertension and cardiovascular events. CANTOS randomized 10 061 patients with prior myocardial infarction and hsCRP (high sensitivity C-reactive protein) ≥2 mg/L to canakinumab 50 mg, 150 mg, 300 mg, or placebo. Read More

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February 2020

Fluorescently-labeled fremanezumab is distributed to sensory and autonomic ganglia and the dura but not to the brain of rats with uncompromised blood brain barrier.

Cephalalgia 2020 03 19;40(3):229-240. Epub 2019 Dec 19.

Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston MA, USA.

Background: The presence of calcitonin gene-related peptide and its receptors in multiple brain areas and peripheral tissues previously implicated in migraine initiation and its many associated symptoms raises the possibility that humanized monoclonal anti-calcitonin gene-related peptide antibodies (CGRP-mAbs) can prevent migraine by modulating neuronal behavior inside and outside the brain. Critical to our ability to conduct a fair discussion over the mechanisms of action of CGRP-mAbs in migraine prevention is data generation that determines which of the many possible peripheral and central sites are accessible to these antibodies - a question raised frequently due to their large size.

Material And Methods: Rats with uncompromised and compromised blood-brain barrier (BBB) were injected with Alexa Fluor 594-conjugated fremanezumab (Frema594), sacrificed 4 h or 7 d later, and relevant tissues were examined for the presence of Frema594. Read More

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A human-like bile acid pool induced by deletion of hepatic modulates effects of FXR activation in mice.

J Lipid Res 2020 03 10;61(3):291-305. Epub 2019 Sep 10.

Departments of Laboratory Medicine University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Bile acids (BAs) facilitate intestinal absorption of lipid-soluble nutrients and modulate various metabolic pathways through the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5. These receptors are targets for therapy in cholestatic and metabolic diseases. However, dissimilarities in BA metabolism between humans and mice complicate translation of preclinical data. Read More

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Human plasma and liver concentrations of styrene estimated by combining a simple physiologically based pharmacokinetic model with rodent data.

J Toxicol Sci 2019 ;44(8):543-548

Showa Pharmaceutical University.

Long-term exposure to certain volatile organic compounds is a significant public health concern. A variety of food containers and drinking cups prepared from polystyrene or polystyrene-related plastics could contain styrene monomer. In the current study, the concentrations of styrene in plasma and liver were surveyed and determined after oral doses of 25 mg/kg to rats and 200 mg/kg to control and humanized-liver mice. Read More

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December 2019

and Models to Study Mosquito-Borne Flavivirus Neuropathogenesis, Prevention, and Treatment.

Front Cell Infect Microbiol 2019 9;9:223. Epub 2019 Jul 9.

Center for Alternatives to Animal Testing, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States.

Mosquito-borne flaviviruses can cause disease in the nervous system, resulting in a significant burden of morbidity and mortality. Disease models are necessary to understand neuropathogenesis and identify potential therapeutics and vaccines. Non-human primates have been used extensively but present major challenges. Read More

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February 2020

[Zr]A2cDb Immuno-PET of Prostate Cancer in a Human Prostate Stem Cell Antigen Knock-in (hPSCA KI) Syngeneic Model.

Mol Imaging Biol 2020 04;22(2):367-376

Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA.

Purpose: A great challenge in the diagnosis and treatment of prostate cancer is distinguishing between indolent or local disease and aggressive or metastatic disease. Antibody-based positron emission tomography (immuno-PET) as a cancer-specific imaging modality could improve diagnosis of primary disease, aid the detection of metastases to regional lymph nodes as well as to distant sites (e.g. Read More

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Defining the Contribution of CYP1A1 and CYP1A2 to Drug Metabolism Using Humanized CYP1A1/1A2 and Cyp1a1/Cyp1a2 Knockout Mice.

Drug Metab Dispos 2019 08 30;47(8):907-918. Epub 2019 May 30.

Systems Medicine, School of Medicine, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital, Dundee, United Kingdom (Y.K., C.J.H., C.R.W.) and Taconic Biosciences Inc., Rensselaer, New York (N.S., A.R.)

Cytochrome P450s CYP1A1 and CYP1A2 can metabolize a broad range of foreign compounds and drugs. However, these enzymes have significantly overlapping substrate specificities. To establish their relative contribution to drug metabolism in vivo, we used a combination of mice humanized for CYP1A1 and CYP1A2 together with mice nulled at the Cyp1a1 and Cyp1a2 gene loci. Read More

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Steady-State Human Pharmacokinetics of Monobutyl Phthalate Predicted by Physiologically Based Pharmacokinetic Modeling Using Single-Dose Data from Humanized-Liver Mice Orally Administered with Dibutyl Phthalate.

Chem Res Toxicol 2019 02 5;32(2):333-340. Epub 2019 Feb 5.

Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Machida , Tokyo 194-8543 , Japan.

Dibutyl phthalate (DBP) was widely used as a plasticizer but it has been recently replaced with other kinds of phthalates such as di(2-ethylhexyl)phthalate and diisononyl phthalate because of its toxicity. To evaluate the human risk of DBP, forward and reverse dosimetry was conducted using in silico simplified physiologically based pharmacokinetic (PBPK) modeling based on in vivo experimental pharmacokinetic data in humanized-liver mice (HL-mice) obtained after an oral dose of 100 mg/kg. Absorbed DBP was converted to monobutyl phthalate (MBP) and its glucuronide extensively in vivo. Read More

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February 2019

Development and Evaluation of a Physiologically Based Pharmacokinetic Model for Predicting the Effects of Anti-FcRn Therapy on the Disposition of Endogenous IgG in Humans.

J Pharm Sci 2019 Jan 22;108(1):714-724. Epub 2018 Nov 22.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York 14214. Electronic address:

This work scaled up a previously developed physiologically based pharmacokinetic model to predict the effects of anti-FcRn agents on the disposition of endogenous IgG in human subjects. Simulations were performed with the scaled model to predict the effects of single- and multiple-dose administration of anti-FcRn monoclonal antibodies (1-256 mg/kg) and high-dose intravenous immune globulin (0.4-2 g/kg). Read More

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January 2019

Expansion and Adoptive Transfer of Human Vδ2 T Cells to Assess Antitumor Effects In Vivo.

Methods Mol Biol 2019 ;1884:57-72

Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

Recent clinical trials have yielded promising results suggesting that γδ T cell62-based immunotherapies can be effective against hematological malignancies. Human T cells expressing Vγ9Vδ2 receptors are particularly attractive candidates for this application, since they can be readily expanded in vitro in large quantities for adoptive transfer and do not require HLA-matching of donors and recipients. While it is well established that Vγ9Vδ2 T cells are potently cytolytic against many human cancers and it has been shown that they can control transplanted human tumors in xenogeneic model systems, little is known about the parameters that determine the antitumor efficacy of adoptively transferred Vγ9Vδ2 T cells in physiologically relevant scenarios. Read More

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Protein Abundance of Clinically Relevant Drug Transporters in the Human Liver and Intestine: A Comparative Analysis in Paired Tissue Specimens.

Clin Pharmacol Ther 2019 05 11;105(5):1204-1212. Epub 2019 Jan 11.

Department of Clinical Pharmacology, University Medicine of Greifswald, Greifswald, Germany.

Bioavailability of orally administered drugs is partly determined by function of drug transporters in the liver and intestine. Therefore, we explored adenosine triphosphate-binding cassette (ABC) and solute carriers family transporters expression (quantitative polymerase chain reaction) and protein abundance (liquid chromatography tandem mass spectrometry (LC-MS/MS)) in human liver and duodenum, jejunum, ileum, and colon in paired tissue specimens from nine organ donors. The transporter proteins were detected in the liver (permeability-glycoprotein (P-gp), multidrug resistance protein (MRP)2, MRP3, breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP)1B1, OATP1B3, OATP2B1, organic cation transporter (OCT)1, OCT3, organic anion transporter 2, Na+-taurocholate cotransporting polypeptide, monocarboxylate transporter (MCT)1, and multidrug and toxin extrusion 1) and the intestine (P-gp, multidrug-resistance protein (MRP)2, MRP3, MRP4, BCRP, OATP2B1, OCT1, apical sodium-bile acid transporter (only ileum), MCT1, and peptide transporter (PEPT1)). Read More

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