Tumor-Derived Exosomes in Immunosuppression and Immunotherapy.

J Immunol Res. 2020;2020:6272498

Authors: Olejarz W, Dominiak A, Żołnierzak A, Kubiak-Tomaszewska G, Lorenc T

Abstract
Tumor-derived exosomes (TEX) are involved in cancer development, metastasis, and disease progression. They can modulate angiogenesis to elevate the malignant degree of tumor cells. TEX carry immunosuppressive factors affecting the antitumor activities of immune cells. Tumor cells as well as immune cells secrete immunologically active exosomes which affect intercellular communication, antigen presentation, activation of immune cells, and immune surveillance. Cell proliferation and immune response suppression create a favorable microenvironment for tumor. TEX can inhibit immune cell proliferation, induce apoptosis of activated CD8+ Teffs, suppress NK cell activity, interfere with monocyte differentiation, and promote Treg as well as MDSC expansion. Exosomes of microenvironment cells may also contribute to the development of drug resistance in cancer therapy. An important role of TEX in modulating the sensitivity of tumor cells to immunotherapy is a promising area of research to make the cancer therapy more successful.

PMID: 32537468 [PubMed - in process]

Individualized Medication Management in Ontario Long-Term Care Clinical Impact on Management of Depression, Pain, and Dementia.

J Am Med Dir Assoc. 2020 Jun;21(6):823-829.e5

Authors: Dorfman R, London Z, Metias M, Kabakchiev B, Mukerjee G, Moser A

Abstract
OBJECTIVES: Assess the potential benefits of identifying drug-gene interactions in nursing home (NH) residents on multiple medications. Reduce the use of high-risk medications for residents with reduced drug metabolism.
DESIGN: Open-label, nonrandomized, mixed methods study.
SETTING: Four NHs in Ontario.
MEASUREMENTS: Potential drug therapy problems (DTPs) for study cohort were identified during a medication review by a pharmacist using pharmacogenetic (PGx) clinical decision support to identify medication change opportunities. The number of DTPs identified during a standard medication review was compared with the number of DTPs identified with a PGx clinical decision support. Analysis of medication dispensing data at enrollment compared with dispensing in a 60-day window following medication review were compared for the PGx-tested study cohort with controls.
RESULTS: Prescription patterns of 90 study participants were compared with 895 controls for the same time period. Study participants were on 7 to 47 drugs, of which drugs with PGx indications ranged from 1 to 17 medications. The average medication load was 4.6 medications with PGx indications per person, whereas the controls were on 3.5 PGx drugs. Furthermore, 94% of cases and 84% of controls were on 2 or more drugs with PGx indication during the study period. Pharmacogenetic analysis identified 114 distinct DTPs in the 90 study participants, of which 29 were classified as serious. In this study, over 35% of residents were treated with antidepressants; of these, 64% have altered CYP2C19 or CYP2D6 metabolism and could benefit from drug dose adjustment or from a switch to alternative antidepressants. Twenty percent of residents were treated with hydromorphone, of which 30% have reduced response to opioids because of variations in the OPRM1 gene.
CONCLUSIONS AND IMPLICATIONS: This study demonstrated the clinical potential of PGx-based medication optimization for NH residents, impacting the management of depression, chronic pain, heart disease, and gastrointestinal symptoms.

PMID: 32536434 [PubMed - in process]

Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model.

J Clin Invest. 2019 03 18;129(4):1756-1771

Authors: Zhou Y, Carmona S, Muhammad AKMG, Bell S, Landeros J, Vazquez M, Ho R, Franco A, Lu B, Dorn GW, Wang S, Lutz CM, Baloh RH

Abstract
Mitofusin-2 (MFN2) is a mitochondrial outer-membrane protein that plays a pivotal role in mitochondrial dynamics in most tissues, yet mutations in MFN2, which cause Charcot-Marie-Tooth disease type 2A (CMT2A), primarily affect the nervous system. We generated a transgenic mouse model of CMT2A that developed severe early onset vision loss and neurological deficits, axonal degeneration without cell body loss, and cytoplasmic and axonal accumulations of fragmented mitochondria. While mitochondrial aggregates were labeled for mitophagy, mutant MFN2 did not inhibit Parkin-mediated degradation, but instead had a dominant negative effect on mitochondrial fusion only when MFN1 was at low levels, as occurs in neurons. Finally, using a transgenic approach, we found that augmenting the level of MFN1 in the nervous system in vivo rescued all phenotypes in mutant MFN2R94Q-expressing mice. These data demonstrate that the MFN1/MFN2 ratio is a key determinant of tissue specificity in CMT2A and indicate that augmentation of MFN1 in the nervous system is a viable therapeutic strategy for the disease.

PMID: 30882371 [PubMed - indexed for MEDLINE]

Sirt6 alleviated liver fibrosis by deacetylating conserved lysine 54 on Smad2 in hepatic stellate cells.

Hepatology. 2020 Jun 14;:

Authors: Zhang J, Li Y, Liu Q, Huang Y, Li R, Wu T, Zhang Z, Zhou J, Huang H, Tang Q, Huang C, Zhao Y, Zhang G, Jiang W, Mo L, Zhang J, Xie W, He J

Abstract
Activation of hepatic stellate cells (HSCs) is a central driver of fibrosis. This study aimed to elucidate the role of the deacetylase Sirt6 in HSC activation and liver fibrosis. Gain- and loss-of-function models were used to study the function of Sirt6 in HSC activation. Mass spectrometry was used to determine the specific acetylation site. The lecithin retinol acyltransferase (Lrat)-driven CreERT2 mouse line was created to generate HSC-specific conditional Sirt6-knockout mice (Sirt6△HSC ). We found that Sirt6 is most abundantly expressed in HSCs as compared with other liver cell types. The expression of Sirt6 was decreased in activated HSCs and in fibrotic livers of mice and humans. Sirt6 knockdown and Sirt6 overexpression increased and decreased fibrogenic gene expression, respectively, in HSCs. Mechanistically, Sirt6 inhibited the phosphorylation and nuclear localization of Smad2. Further study demonstrated that Sirt6 could directly interact with Smad2, deacetylate Smad2, and decrease the transcription of TGF-β/Smad2 signaling. Mass spectrometry revealed that Sirt6 deacetylated conserved lysine 54 on Smad2. Mutation of lysine 54 to alanine in Smad2 abolished the regulatory effect of Sirt6. In vivo, specific ablation of Sirt6 in HSCs exacerbated hepatocyte injury and cholestasis-induced liver fibrosis in mice. With targeted delivery of the Sirt6 agonist MDL-800, its concentration was 9.28-fold higher in HSCs as compared with other liver cells and alleviated hepatic fibrosis. CONCLUSIONS: Sirt6 plays a key role in HSC activation and liver fibrosis by deacetylating the pro-fibrogenic transcription factor Smad2. Sirt6 may be a potential therapeutic target for liver fibrosis.

PMID: 32535965 [PubMed - as supplied by publisher]

Developing drugs for tissue agnostic indications: a paradigm shift in leveraging cancer biology for precision medicine.

Clin Pharmacol Ther. 2020 Jun 14;:

Authors: Seligson ND, Knepper TC, Ragg S, Walko CM

Abstract
Targeted therapies have reshaped the landscape of the development of cancer therapeutics. Recent biomarker driven, tissue agnostic clinical trials represent a significant paradigm shift in precision cancer medicine. Despite their growth in pre-clinical and clinical studies, to date only a few biomarker driven, tissue agnostic indications have seen approval by the FDA. These approvals include pembrolizumab in microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as well as both larotrectinib and entrectinib in NTRK fusion positive tumors. Complex cancer biology, clinical trial design, and identification of resistance mechanisms represent some of the challenges that future tissue agnostic therapies have to overcome. In this review, we present a brief history of the development of tissue agnostic therapies, comparing the similarities in the approval of pembrolizumab, larotrectinib, and entrectinib for tissue agnostic indications. We also explore the future of tissue agnostic cancer therapeutics while identifying important challenges for the future of drug targeting tissue agnostic indications will face.

PMID: 32535906 [PubMed - as supplied by publisher]

Role of wzxE in Salmonella Typhimurium lipopolysaccharide biosynthesis and interleukin-8 secretion regulation in human intestinal epithelial cells.

Microbiol Res. 2020 May 15;238:126502

Authors: Wang KC, Huang CH, Chang PR, Huang MT, Fang SB

Abstract
In Salmonella Typhimurium (S. Typhimurium), lipopolysaccharide (LPS) anchored on the bacterial outer membrane is a major immune stimulus that can broadly activate immune cells and induce innate immune responses. wzxE is involved in bacterial LPS biosynthesis but has rarely been reported in Salmonella; wzxE encodes a flipase that can flip the precursor of LPS across the membrane into the periplasm space. Our preliminary data showed that the wzxE transposon mutant of S. Typhimurium could not significantly adhere to and invade into HEp-2 cells, but the mechanism remains unknown. In this study, we infected human LS174T, Caco-2, HeLa, and THP-1 cells with the wild-type S. Typhimurium strain SL1344, its wzxE mutant, and its complemented strain. wzxE depletion significantly attenuated bacterial adhesion and internalization in the four cell types. In addition, the postinfectious production of interleukin-8 (IL-8) was significantly decreased in the Caco-2 cells infected with the wzxE mutant. Bacterial LPS stained with polymyxin B probe also exhibited a reduced signal in the wzxE mutant. The silver staining of purified LPS demonstrated a significant reduction of the O-antigen (OAg) chain in the wzxE mutant. To confirm the role of OAg in the wzxE mutant during infection, we treated the HT-29 cells with the S. Typhimurium strain SL1344, its wzxE mutant, and their purified LPS, which revealed significantly decreased IL-8 secretion in the HT-29 cells treated with purified LPS from the wzxE mutant and with the wzxE mutant. In conclusion, wzxE mediates LPS biosynthesis and plays a major role in bacterial pathogenesis by regulating OAg flipping.

PMID: 32535400 [PubMed - as supplied by publisher]

Pharmacogenomic Biomarkers in Allergy and Immunology Practice.

J Allergy Clin Immunol. 2020 Jun 10;:

Authors: Khan DA, Phillips E

PMID: 32533972 [PubMed - as supplied by publisher]

Clinical implementation of pharmacogenetics and model-informed precision dosing to improve patient care.

Br J Clin Pharmacol. 2020 Jun 11;:

Authors: Mizuno T, Dong M, Taylor ZL, Ramsey LB, Vinks AA

Abstract
Providing maximal therapeutic efficacy without toxicity is a universal goal of rational drug therapy. However, substantial between patient variability in drug response often impedes such successful treatments and brings the necessity of tailoring drug dose to individual needs for more precise therapy. In many cases plenty of patient's characteristics such as body size, genetic makeup and environmental factors needs to be taken into consideration to find optimal dose in clinical practice. Pharmacokinetics and pharmacodynamics (PK/PD) model-informed approach offers integration of various patient information to provide an expectation of drug response and derive practical dose estimates to support clinicians' dosing decisions. Such an approach was pioneered in the late 1970s, but its broad clinical acceptance and implementation have been hampered by the lack of widespread computer technology including user-friendly software tools. This has significantly changed in recent years. With the advent of the electronic health records (EHR) and the ubiquity of user-friendly software tools, we now experience a convergence of clinical information, pharmacogenetics, systems pharmacology and pharmacometrics, and technology. Advanced pharmacometrics research is now more appliable and implementable to improve health care. This article presents examples of successful development and implementation of pharmacogenetics-guided and PK/PD model-informed decision support to facilitate precision dosing including a development of EHR-embedded decision support tool. Through the integration of clinical decision support tools into the EHR, clinical pharmacometrics support can be brought directly to the clinical team and at the bedside.

PMID: 32529759 [PubMed - as supplied by publisher]

New DPYD variants causing DPD deficiency in patients treated with fluoropyrimidine.

Cancer Chemother Pharmacol. 2020 Jun 11;:

Authors: García-González X, Kaczmarczyk B, Abarca-Zabalía J, Thomas F, García-Alfonso P, Robles L, Pachón V, Vaz Á, Salvador-Martín S, Sanjurjo-Sáez M, López-Fernández LA

Abstract
PURPOSE: Several clinical guidelines recommend genetic screening of DPYD, including coverage of the variants c.1905 + 1G>A(DPYD*2A), c.1679T>G(DPYD*13), c.2846A>T, and c.1129-5923C>G, before initiating treatment with fluoropyrimidines. However, this screening is often inadequate at predicting the occurrence of severe fluoropyrimidine-induced toxicity in patients.
METHODS: Using a complementary approach combining whole DPYD exome sequencing and in silico and structural analysis, as well as phenotyping of DPD by measuring uracilemia (U), dihydrouracilemia (UH2), and the UH2/U ratio in plasma, we were able to characterize and interpret DPYD variants in 28 patients with severe fluoropyrimidine-induced toxicity after negative screening.
RESULTS: Twenty-five out of 28 patients (90%) had at least 1 variant in the DPYD coding sequence, and 42% of the variants (6/14) were classified as potentially deleterious by at least 2 of the following algorithms: SIFT, Poly-Phen-2, and DPYD varifier. We identified two very rare deleterious mutations, namely, c.2087G>A (p.R696H) and c.2324T>G (p.L775W). We were able to demonstrate partial DPD deficiency, as measured by the UH2/U ratio in a patient carrying the variant p.L775W for the first time.
CONCLUSION: Whole exon sequencing of DPYD in patients with suspicion of partial DPD deficiency can help to identify rare or new variants that lead to enzyme inactivation. Combining different techniques can yield abundant information without increasing workload and cost burden, thus making it a useful approach for implementation in patient care.

PMID: 32529295 [PubMed - as supplied by publisher]

Adverse Drug Reactions in the Emergency Department: Is There a Role for Pharmacogenomic Profiles at Risk?-Results from the ADRED Study.

J Clin Med. 2020 Jun 09;9(6):

Authors: Just KS, Dormann H, Schurig M, Böhme M, Fracowiak J, Steffens M, Scholl C, Seufferlein T, Gräff I, Schwab M, Stingl JC

Abstract
Individual differences in required drug dosages exist based on the pharmacogenomic (PGx) profiles. This study aimed to assess associations between PGx profiles and adverse drug reactions (ADR) that lead to admissions to the emergency department (ED). ADR cases of the prospective multi-center observational trial in EDs (ADRED study) were analyzed (n = 776) together with the relevant PGx phenotypes of the enzymes CYP2D6, CYP2C19, CYP2C9, and VKORC1. Overall, the allele frequency distribution in this cohort did not differ from the population frequencies. We compared the frequencies of phenotypes in the subgroups with the drugs suspected of certain ADR, in the remaining cases. The frequency distribution of CYP2C19 differed for the ADR bleeding cases suspected of clopidogrel (p = 0.020). In a logistic regression analysis, higher CYP2C19 activity (OR (95% CI): 4.97 (1.73-14.27)), together with age (1.05 (1.02-1.08)), showed an impact on the clopidogrel-suspecting ADRs, when adjusting for the clinical parameters. There was a trend for an association of phenprocoumon-risk profiles (low VKORC1 or CYP2C9 activity) with phenprocoumon-suspecting ADRs (p = 0.052). The PGx impact on serious ADRs might be highest in drugs that cannot be easily monitored or those that do not provoke mild ADR symptoms very quickly. Therefore, patients that require the intake of those drugs with PGx variability such as clopidogrel, might benefit from PGx testing.

PMID: 32527038 [PubMed]

Toward High-Throughput Fungal Electroculturomics and New Omics Methodologies in 21st-Century Microbiology and Ecology.

OMICS. 2020 Jun 11;:

Authors: Stathoulias A, Milioni A, Kritikou S, Karmakolia A, Goudoudaki S, Siamoglou S, Chassomeris C, Basilakis S, Karamperis K, Velegraki A, Anastassopoulou C, Manoussopoulos Y, Patrinos GP, Kambouris ME

Abstract
Modern microbiology and drug development are in a watershed moment with the advent of electroceuticals. In addition to genomics, electrical impulses in an organism are believed to contribute to tissue and cellular plasticity. Hence, electroceuticals or bioelectronics offers the promise to identify innovative approaches to treat human diseases. However, applications toward electromicrobiology are still limited and rare, despite the high potential to innovate the fields of both microbiology and therapeutics. For example, electric modalities for manipulating microbial growth are highly sustainable; can be combined with biopharmaceuticals, probiotics, and pharmacobiotics; and, thus, are well poised for use in medicine, public health, and ecology and diverse industries. We report here the introduction of a new research framework and technology platform for electroculturomics, by coupling standard solid-state mycological cultures with conductive treatment using a conformité Européene (CE-)-certified medical ionophoresis device. We share our experience with a diverse range of fungi that have been treated with the electroculturomics approach reported herein. We suggest that this line of inquiry can be extended to electrotranscriptomics and electrometabolomics by deploying electroculturomics in tandem with multi-omics approaches in the future. This article makes a specific contribution to fungal microbiology, and a broader contribution to advance the theory and practice of the field of electroculturomics emerging in 21st-century microbiology and ecology research.

PMID: 32525758 [PubMed - as supplied by publisher]

Perspective on CYP2C19 genotyping test among patients with acute coronary syndrome - a qualitative study.

Future Cardiol. 2020 Jun 11;:

Authors: Png WY, Wong XY, Kwan YH, Lin YY, Tan DS

Abstract
Aim: Identify factors patients consider regarding CYP2C19 genotyping test to guide choice of antiplatelet therapy. Patients & methods: Patient's perception and attitude toward use of CYP2C19 genotyping test was gathered according to an interview guide. Thematic analysis was conducted. Results: A total of 14 patients were interviewed. The main factors found to influence uptake of CYP2C19 genotyping test are, convenience of genotyping test (n = 4), physician's recommendation (n = 11), prior explanation of genetic testing by medical personnel (n = 5) and inclination toward clopidogrel, with three sub-factors; less frequent dosing (n = 3), lower cost (n = 7) and lower risk of bleeding (n = 9). Conclusion: This study provided the information needed to develop a discrete choice experiment to empirically quantify patients' preference and willingness to pay for genetic testing and to simulate uptake.

PMID: 32524842 [PubMed - as supplied by publisher]

Measuring preferences for CYP2C19 genotyping in patients with acute coronary syndrome - a discrete choice experiment.

Future Cardiol. 2020 Jun 11;:

Authors: Wee JW, Png WY, Wong XY, Kwan YH, Lin YY, Tan DS, Wee HL

Abstract
Aim: To evaluate the relative importance of CYP2C19 genotype-guided treatment attributes to patients. Patients & methods: A discrete choice experiment questionnaire was administered to 63 patients with acute coronary syndrome. Attributes examined in the discrete choice experiment questionnaire were: cost of genetic testing (S$50, S$100, S$200); cost of antiplatelet medication (S$100, S$500, S$1000); heart attack or stroke risk (5 in 100, 15 in 100, 25 in 100); bleeding risk (5 in 100, 15 in 100, 25 in 100); doctor's recommendation (yes, neutral). Mixed logit model was used for analysis. Results & conclusion: All attributes were important in patients' decision-making. Most displayed strong preference for doctor's recommendation and reduced heart attack or stroke risk. Genotyping was chosen by 63.5% of the patients.

PMID: 32524837 [PubMed - as supplied by publisher]

Understanding pharmacogenomic testing and its role in medicine prescribing.

Nurs Stand. 2020 Jun 11;:

Authors: Youssef E, Buck J, Wright DJ

Abstract
When making prescribing decisions, it is important for healthcare professionals to remember that individual patients may respond differently to medicines. For example, some patients may experience a therapeutic benefit while others may experience an adverse drug reaction. The aim of personalised medicine is to tailor treatment based not only on a patient's clinical factors, but also on their genetic profile. Pharmacogenomics is a branch of personalised medicine that is concerned with how differences in people's genomes affect their response to medicines. Pharmacogenomic testing, which recently has become less expensive and increasingly available, can inform nurses' prescribing decisions and improve patient outcomes. This article discusses personalised medicine and pharmacogenomics, including how pharmacogenomic testing can optimise medicine prescribing, and explains the role of nurses in the process.

PMID: 32524796 [PubMed - as supplied by publisher]

Methylation-directed glycosylation of chromatin factors represses retrotransposon promoters.

Proc Natl Acad Sci U S A. 2020 Jun 10;:

Authors: Boulard M, Rucli S, Edwards JR, Bestor TH

Abstract
The mechanisms by which methylated mammalian promoters are transcriptionally silenced even in the presence of all of the factors required for their expression have long been a major unresolved issue in the field of epigenetics. Repression requires the assembly of a methylation-dependent silencing complex that contains the TRIM28 protein (also known as KAP1 and TIF1β), a scaffolding protein without intrinsic repressive or DNA-binding properties. The identity of the key effector within this complex that represses transcription is unknown. We developed a methylation-sensitized interaction screen which revealed that TRIM28 was complexed with O-linked β-N-acetylglucosamine transferase (OGT) only in cells that had normal genomic methylation patterns. OGT is the only glycosyltransferase that modifies cytoplasmic and nuclear protein by transfer of N-acetylglucosamine (O-GlcNAc) to serine and threonine hydroxyls. Whole-genome analysis showed that O-glycosylated proteins and TRIM28 were specifically bound to promoters of active retrotransposons and to imprinting control regions, the two major regulatory sequences controlled by DNA methylation. Furthermore, genome-wide loss of DNA methylation caused a loss of O-GlcNAc from multiple transcriptional repressor proteins associated with TRIM28. A newly developed Cas9-based editing method for targeted removal of O-GlcNAc was directed against retrotransposon promoters. Local chromatin de-GlcNAcylation specifically reactivated the expression of the targeted retrotransposon family without loss of DNA methylation. These data revealed that O-linked glycosylation of chromatin factors is essential for the transcriptional repression of methylated retrotransposons.

PMID: 32522876 [PubMed - as supplied by publisher]

Maternal Immune Activation Induces Neuroinflammation and Cortical Synaptic Deficits in the Adolescent Rat Offspring.

Int J Mol Sci. 2020 Jun 08;21(11):

Authors: Cieślik M, Gąssowska-Dobrowolska M, Jęśko H, Czapski GA, Wilkaniec A, Zawadzka A, Dominiak A, Polowy R, Filipkowski RK, Boguszewski PM, Gewartowska M, Frontczak-Baniewicz M, Sun GY, Beversdorf DQ, Adamczyk A

Abstract
Maternal immune activation (MIA), induced by infection during pregnancy, is an important risk factor for neuro-developmental disorders, such as autism. Abnormal maternal cytokine signaling may affect fetal brain development and contribute to neurobiological and behavioral changes in the offspring. Here, we examined the effect of lipopolysaccharide-induced MIA on neuro-inflammatory changes, as well as synaptic morphology and key synaptic protein level in cerebral cortex of adolescent male rat offspring. Adolescent MIA offspring showed elevated blood cytokine levels, microglial activation, increased pro-inflammatory cytokines expression and increased oxidative stress in the cerebral cortex. Moreover, pathological changes in synaptic ultrastructure of MIA offspring was detected, along with presynaptic protein deficits and down-regulation of postsynaptic scaffolding proteins. Consequently, ability to unveil MIA-induced long-term alterations in synapses structure and protein level may have consequences on postnatal behavioral changes, associated with, and predisposed to, the development of neuropsychiatric disorders.

PMID: 32521803 [PubMed - in process]

Genome-wide identification and characterization of long non-coding RNAs involved in acquired resistance to gefitinib in non-small-cell lung cancer.

Comput Biol Chem. 2020 May 19;87:107288

Authors: Shi J, Huang Y, Wen C, He S, Wu L, Zhou H

Abstract
Acquired resistance is a major obstacle to the therapeutic efficacy of gefitinib in non-small-cell lung cancer (NSCLC). Current knowledge about the role of long non-coding RNAs (lncRNAs) in this phenomenon is insufficient. In this study, we searched RNA sequencing data for lncRNAs associated with acquired resistance to gefitinib in NSCLC, and constructed a functional lncRNA-mRNA co-expression network and protein-protein interaction (PPI) network to analyze their putative target genes and biological functions. The expression levels of 14 outstanding dysregulated lncRNAs and mRNA were verified using real-time PCR. Changes in the expression levels of 39 lncRNAs and 121 mRNAs showed common patterns in our two pairs of gefitinib-sensitive and gefitinib-resistant NSCLC cell lines. The co-expression network included 1235 connections among these common differentially expressed lncRNAs and mRNAs. The significantly enriched signaling pathways based on dysregulated mRNAs were mainly involved in the Hippo signaling pathway; proteoglycans in cancer; and valine, leucine, and isoleucine biosynthesis. The results show that LncRNAs play an important part in acquired gefitinib resistance in NSCLC by regulating mRNA expression and function, and may represent potential new molecular biomarkers and therapeutic targets for gefitinib-resistant NSCLC.

PMID: 32521497 [PubMed - as supplied by publisher]

New approach methodologies (NAMs) for human-relevant biokinetics predictions: Meeting the paradigm shift in toxicology towards an animal-free chemical risk assessment.

ALTEX. 2020 Jun 08;:

Authors: Punt A, Bouwmeester H, Blaauboer BJ, Coecke S, Hakkert B, Hendriks DFG, Jennings P, Kramer NI, Neuhoff S, Masereeuw R, Paini A, Peijnenburg AACM, Rooseboom M, Shuler ML, Sorrell I, Spee B, Strikwold M, Van der Meer AD, Van der Zande M, Vinken M, Yang H, Bos PMJ, Heringa MB

Abstract
For almost fifteen years, the availability and regulatory acceptance of new approach methodologies (NAMs) to assess the absorption, distribution, metabolism and excretion (ADME/biokinetics) in chemical risk evaluations are a bottleneck. To enhance the field, a team of 24 experts from science, industry, and regulatory bodies, including new generation toxicologists, met at the Lorentz Centre in Leiden, The Netherlands. A range of possibilities for the use of NAMs for biokinetics in risk evaluations were formulated (for example to define species differences and human variation or to perform quantitative in vitro-in vivo extrapolations). To increase the regulatory use and acceptance of NAMs for biokinetics for these ADME considerations within risk evaluations, the development of test guidelines (protocols) and of overarching guidance documents is considered as a critical step. To this end, a need for an expert group on biokinetics within the Organisation of Economic Cooperation and Development (OECD) was formulated to supervise this process. The workshop discussions revealed that method development is still required, particularly to adequately capture transporter mediated processes as well as to obtain cell models that reflect the physiology and kinetic characteristics of relevant organs. Developments in the field of stem-cells, organoids and organ-on-a-chip provide promising tools to meet these research needs in the future.

PMID: 32521035 [PubMed - as supplied by publisher]

Measuring Intracellular Concentrations of Calcineurin Inhibitors: Expert Consensus from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) Expert Panel.

Ther Drug Monit. 2020 Jun 08;:

Authors: Lemaitre F, Vethe NT, D'Avolio A, Tron C, Robertsen I, De Winter B, Denicolo A, Koch BCP, Venkataramanan R, Van Gelder T, Brunet M, Bergan S, Hesselink DA, Wallemacq P

Abstract
BACKGROUND: Therapeutic drug monitoring (TDM) of the two calcineurin inhibitors (CNIs), tacrolimus (TAC) and cyclosporine A (CsA), has resulted in improvements in the management of patients who have undergone solid organ transplantation. As a result of TDM, acute rejection rates and treatment-related toxicities have been reduced. Irrespective, acute rejection and toxicity still occur in patients who have undergone transplantation showing blood CNI concentrations within the therapeutic range. Moreover, the acute rejection rate is no longer decreasing. Hence, smarter TDM approaches are necessary. As CNIs exert their action inside T-lymphocytes, intracellular CNIs may be a promising candidate for improving therapeutic outcomes. Intracellular CNI concentration may be more directly related to drug effect and has been favorably compared with the standard, whole-blood TDM for TAC in liver transplant recipients. However, measuring intracellular CNIs concentrations is not without pitfalls at both the pre-analytical and analytical stages, and standardization appears essential in this area. To date, there are no guidelines for the TDM of intracellular CNI concentrations.
METHODS: Under the auspices of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology and its Immunosuppressive Drug committees, a group of leading investigators in this field have shared experiences and have presented pre-analytical and analytical recommendations for measuring intracellular CNI concentrations.

PMID: 32520841 [PubMed - as supplied by publisher]

Pharmacogenetic considerations when prescribing cholinesterase inhibitors for the treatment of Alzheimer's disease.

Expert Opin Drug Metab Toxicol. 2020 Jun 10;:

Authors: Cacabelos R

Abstract
INTRODUCTION: Cholinergic dysfunction, demonstrated in the late 1970s and early 1980s, led to the introduction of acetylcholinesterase inhibitors (AChEIs) in 1993 (Tacrine) to enhance cholinergic neurotransmission as the first line of treatment against Alzheimer's disease (AD). The new generation of AChEIs, represented by Donepezil (1996), Galantamine (2001) and Rivastigmine (2002), is the only treatment for AD to date, together with Memantine (2003). AChEIs are not devoid of side-effects and their cost-effectiveness is limited. An option to optimize the correct use of AChEIs is the implementation of pharmacogenetics (PGx) in the clinical practice.
AREAS COVERED: (i) The cholinergic system in AD, (ii) principles of AD PGx, (iii) PGx of Donepezil, Galantamine, Rivastigmine, Huperzine and other treatments, and (iv) practical recommendations.
EXPERT OPINION: The most relevant genes influencing AChEI efficacy and safety are APOE and CYPs. APOE-4 carriers are the worst responders to AChEIs. With the exception of Rivastigmine (UGT2B7, BCHE-K), the other AChEIs are primarily metabolized via CYP2D6, CYP3A4, and UGT enzymes, with involvement of ABC transporters and cholinergic genes (CHAT, ACHE, BCHE, SLC5A7, SLC18A3, CHRNA7) in most ethnic groups. Defective variants may affect the clinical response to AChEIs. PGx geno-phenotyping is highly recommended prior to treatment.

PMID: 32520597 [PubMed - as supplied by publisher]