Structural and functional characterization of G protein-coupled receptors with deep mutational scanning.

Elife. 2020 Oct 21;9:

Authors: Jones EM, Lubock NB, Venkatakrishnan AJ, Wang J, Tseng AM, Paggi JM, Latorraca NR, Cancilla D, Satyadi M, Davis JE, Babu MM, Dror RO, Kosuri S

Abstract
In humans, the >800 G protein-coupled receptors (GPCRs) are responsible for transducing diverse chemical stimuli to alter cell state, and are the largest class of drug targets. Their myriad structural conformations and various modes of signaling make it challenging to understand their structure and function. Here we developed a platform to characterize large libraries of GPCR variants in human cell lines with a barcoded transcriptional reporter of G-protein signal transduction. We tested 7,800 of 7,828 possible single amino acid substitutions to the beta-2 adrenergic receptor (β2AR) at four concentrations of the agonist isoproterenol. We identified residues specifically important for β2AR signaling, mutations in the human population that are potentially loss of function, and residues that modulate basal activity. Using unsupervised learning, we resolve residues critical for signaling, including all major structural motifs and molecular interfaces. We also find a previously uncharacterized structural latch spanning the first two extracellular loops that is highly conserved across Class A GPCRs and is conformationally rigid in both the inactive and active states of the receptor. More broadly, by linking deep mutational scanning with engineered transcriptional reporters, we establish a generalizable method for exploring pharmacogenomics, structure and function across broad classes of drug receptors.

PMID: 33084570 [PubMed - as supplied by publisher]

Global distribution of CYP2C19 risk phenotypes affecting safety and effectiveness of medications.

Pharmacogenomics J. 2020 Oct 20;:

Authors: Biswas M

Abstract
Genetic variability of CYP2C19 may affect safety or efficacy of many clinically important medications as outlined in the clinical pharmacogenetics implementation consortium (CPIC) dosing guidelines. To determine the predictive prevalence of high-risk phenotypes due to CYP2C19 genetic variants collectively in the world population and to establish a correlation how the identified high-risk phenotypes may affect safety or effectiveness of drugs, this study was conducted. Frequency of CYP2C19*2, *3 and *17 alleles were obtained from 1000 Genomes project Phase III in line with Fort Lauderdale principles. Phenotypes were assigned using international standardized consensus terms based on the carrier of characteristics alleles. Association of predicted high-risk phenotypes with the safety or effectiveness of medications was gained from CPIC dosing guidelines. Ultrarapid and poor metabolizers were considered as being as high-risk phenotypes for at least ten clinically important medications. Meta-analysis of the prevalence of high-risk phenotypes showed that it was statistically significant (p<0.0001) in different ethnic groups with pooled prevalence of 27.4% (95% CI 18-37%). The present study suggests that African (37.2; 95% CI 34-41%) and European (35.4; 95% CI 31-40%) population are being at particularly higher risk of either sub therapeutic drug responses or toxicities due to combined effects of CYP2C19*2, *3 and *17 variants. Large scale clinical studies are warranted to assess clinical outcomes of these medications considering CYP2C19 pharmacogenomics effects.

PMID: 33082528 [PubMed - as supplied by publisher]

[Practical aspects of using donepezil in the treatment of dementia].

Zh Nevrol Psikhiatr Im S S Korsakova. 2020;120(9):137-143

Authors: Chebotareva AD, Levin OS

Abstract
Donepezil is the most commonly used drug of the group of cholinesterase inhibitors. It is recommended for tretament of Alzheimer's disease. Donepezil is also used to treat dementia in Lewy body disease, Parkinson's disease with dementia, and vascular dementia. In Russia, donepezil is not used as often, which is facilitated by the concern of doctors about the possibility of serious side-effects. Clinical studies demonstrate the safety and good tolerability of donepezil. Our study included 62 patients with dementia due to various neurodegenerative diseases (Alzheimer's disease, Lewy body disease, Parkinson's disease with dementia). Thirty-seven patients (59.7%) started to receive donepezil. Side-effects, including bradycardia, hypertension, aggressive behavior, increased tremor, were observed in 7 patients (18.9%). There was no correlation between the development of side-effects and polymorphisms of the CYP2D6 and MDR1 genes.

PMID: 33081459 [PubMed - in process]

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pharmacogenomics

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pharmacogenomics

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pharmacogenomics

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pharmacogenomics

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Association between polymorphisms in the vitamin D receptor and susceptibility to multiple sclerosis.

Pharmacogenet Genomics. 2020 Oct 08;:

Authors: Cancela Díez B, Pérez-Ramírez C, Maldonado-Montoro MDM, Carrasco-Campos MI, Sánchez Martín A, Pineda Lancheros LE, Martínez-Martínez F, Calleja-Hernández MÁ, Ramírez-Tortosa MC, Jiménez-Morales A

Abstract
Multiple sclerosis (MS) is a neurodegenerative chronic inflammatory. Mutations in the vitamin D receptor (VDR) gene can substantially affect serum vitamin D levels or alter its functionality, and can consequently increase susceptibility to developing MS. The objective of this study was to evaluate the association between polymorphisms in the VDR gene and risk of MS in a (Spanish) Caucasian population. We conducted a retrospective case-control study comprising 209 patients with relapsing-remitting multiple sclerosis (RRMS) and 836 controls of Caucasian origin from southern Spain. The ApaI (rs7975232), BsmI (rs1544410), Cdx2 (rs11568820), FokI (rs2228570), and TaqI (rs731236) gene polymorphisms were determined by allelic discrimination real-time PCR using TaqMan probes. The recessive logical regression model, adjusted for age and sex, revealed that the TT genotype for VDR FokI (rs2228570) polymorphism was associated with higher risk of MS (P = 0.0150; OR = 1.82; 95% CI = 1.12-2.94; TT vs. CT + CC). No association between the other polymorphisms and development of MS was found in any of the models analyzed. The haplotype analysis, adjusted for age, smoking, and sex, did not find any statistically significant association between the haplotypes analyzed and risk of MS. The VDR FokI (rs2228570) polymorphism was significantly associated with developing MS. We found no influence of the ApaI (rs7975232), BsmI (rs1544410), Cdx2 (rs11568820), FokI (rs2228570), and TaqI (rs731236) gene polymorphisms on the risk of developing MS in our patients.

PMID: 33044390 [PubMed - as supplied by publisher]

Tri-allelic haplotypes determine and differentiate functionally normal allele CYP2D6*2 and impaired allele CYP2D6*41.

Clin Pharmacol Ther. 2020 Oct 12;:

Authors: Zanger UM, Momoi K, Hofmann U, Schwab M, Klein K

Abstract
CYP2D6 metabolizes 20-25% of all clinically used drugs and its complex genetic polymorphism is a major determinant of drug safety and efficacy. We investigated the basis for the functional difference between the two common alleles *2 (g.2851C>T+g.4181G>T, normal function) and *41 (additional intronic g.2989G>A, reduced function). A recently reported far-distant enhancer polymorphism rs5758550A/G linked to *2 has been suggested to play a decisive role. Genotyping of two Caucasian cohorts confirmed strong linkage of rs5758550G to *2, whereas no influence was found on metabolic ratio of sparteine or hepatic expression. Genomic plasmid constructs carrying individual variants or combinations thereof were expressed in COS1 and Huh7 cells. Both g.2851C>T(R296C) and g.2989G>A reduced enzyme activity and protein levels similarly by ~50-65% compared to reference (*1), whereas the double variant had only ~20% activity. While the unexpected loss of function caused by g.2851C>T was compensated by g.4181G>T (mimicking the EM-phenotype of *2), the additional loss of function due to intronic g.2989G>A in the triple variant was not compensated (mimicking the IM-phenotype of *41). We also confirmed increased erroneous splicing in carriers of g.2989G>A but not of g.2851C>T as likely explanation for the impaired function of *41. In conclusion, our data demonstrate g.2989G>A as causal variant of impaired allele CYP2D6*41 while triple-haplotypes have to be considered to explain the functional difference between *2 and *41. These data are important for genotyping strategies and clinical implementation of CYP2D6 pharmacogenetics.

PMID: 33043448 [PubMed - as supplied by publisher]

Pharmacogenetics in Psychiatry: An Update on Clinical Usability.

Front Pharmacol. 2020;11:575540

Authors: van Schaik RHN, Müller DJ, Serretti A, Ingelman-Sundberg M

Abstract
Using pharmacogenetics in guiding drug therapy experiences a steady increase in uptake, although still leads to discussions as to its clinical use. Psychiatry constitutes a field where pharmacogenomic testing might help in guiding drug therapy. To address current challenges, this minireview provides an update regarding genotyping (SNP analysis/arrays/NGS), structural variant detection (star-alleles/CNVs/hybrid alleles), genotype-to-phenotype translations, cost-effectiveness, and actionability of results (FDA/CPIC/PharmGKB) regarding clinical importance of pre-emptive pharmacogenomic testing for prescription of antidepressants and antipsychotics.

PMID: 33041820 [PubMed]

A model-based cost-effectiveness analysis of pharmacogenomic panel testing in cardiovascular disease management: preemptive, reactive, or none?

Genet Med. 2020 Oct 12;:

Authors: Zhu Y, Moriarty JP, Swanson KM, Takahashi PY, Bielinski SJ, Weinshilboum R, Wang L, Borah BJ

Abstract
PURPOSE: Pharmacogenomics (PGx) studies how inherited genetic variations in individuals affect drug absorption, distribution, and metabolism. PGx panel testing can potentially help improve efficiency and accuracy in individualizing therapy. This study compared the cost-effectiveness between preemptive PGx panel testing, reactive PGx panel testing and usual care (no testing) in cardiovascular disease management.
METHODS: We developed a decision analytic model from the US payer's perspective for a hypothetical cohort of 10,000 patients ≥45 years old, using a short-term decision tree and long-term Markov model. The testing panel included the following gene-drug pairs: CYP2C19-clopidogrel, CYP2C9/VKORC1-warfarin, and SLCO1B1-statins with 30 test-return days. Costs were reported in 2019 US dollars and effectiveness was measured in quality-adjusted life years (QALYs). The primary outcome was incremental cost-effectiveness ratio (ICER = ΔCost/ΔQALY), assuming 3% discount rate for costs and QALYs. Scenario and probabilistic sensitivity analyses were performed to assess the impact of demographics, risk level, and follow-up timeframe.
RESULTS: Preemptive testing was found to be cost-effective compared with usual care (ICER $86,227/QALY) at the willingness-to-pay threshold of $100,000/QALY while reactive testing was not (ICER $148,726/QALY). Sensitivity analyses suggested that our cost-effectiveness results were sensitive to longer follow-up, and the age group 45-64 years.
CONCLUSION: Compared with usual care, preemptive PGx panel testing was cost-effective in cardiovascular disease management.

PMID: 33041335 [PubMed - as supplied by publisher]

The effect of genetic variations for interleukin-10 (IL-10) on the efficacy of immunosuppressive therapy in patients after kidney transplantation.

Int Immunopharmacol. 2020 Oct 08;89(Pt A):107059

Authors: Bogacz A, Polaszewska A, Bartkowiak-Wieczorek J, Tejchman K, Dziewanowski K, Ostrowski M, Czerny B, Grześkowiak E, Sieńko M, Machaliński B, Sieńko J, Kotowski M

Abstract
Kidney transplantation is the target method of treating chronic kidney disorders. It improves the comfort of patient life by eliminating the need for repeated dialysis. The aim of the study was to examine the correlation between tacrolimus (TAC) dose and genetic variation for interleukin-10 (IL-10) and its effect on the therapeutic outcome. In addition, the correlations between the IL-10 polymorphism andthe clinical and the biochemical parameters of TAC patients were also analyzed. The study included 209 subjects after kidney transplantation, who received TAC every 12 and 24 h. Drug concentrations in blood, selected morphological and biochemical parameters, and the genetic variation of IL-10 (-1082A > G) which may affect immunosuppressant dosage and risk of acute graft rejection were analyzed. Genetic analyses were performed using real-time PCR. No significant correlations between the clinical and the biochemical parameters and IL-10-1082A > G polymorphism for patients receiving TAC after kidney transplantation were found. The analysis of the correlation between TAC dose and IL-10 genetic variation for the -1082A > G polymorphism revealed that patients with the AA genotype required lower immunosuppressive drug doses (AA: 3.54 ± 2.38 mg/day vs AG: 6.18 ± 5.10 mg/day, GG: 4.44 ± 3.01 mg/day). Furthermore, frequencies of the genotypes for the IL-10 -1082A > G polymorphism were characterized by a significantly higher frequency of the AA genotype among TAC 24 as compared to TAC 12 patients. The results of the study indicated that the IL-10 -1082A > G polymorphism may in fact influence the TAC dose. The biochemical parameters of the renal profile in relation to the IL-10 genetic variations were not indicative of higher risk of acute rejection after transplantation.

PMID: 33039969 [PubMed - as supplied by publisher]

A phase I dose-escalation study of oxaliplatin delivered via a laparoscopic approach using pressurised intraperitoneal aerosol chemotherapy for advanced peritoneal metastases of gastrointestinal tract cancers.

Eur J Cancer. 2020 Oct 08;140:37-44

Authors: Dumont F, Passot C, Raoul JL, Kepenekian V, Lelièvre B, Boisdron-Celle M, Hiret S, Senellart H, Pein F, Blanc-Lapierre A, Raimbourg J, Thibaudeau E, Glehen O, BIG-RENAPE Networks

Abstract
OBJECTIVE: The objectives were to define the maximum tolerated dose (MTD), safety profile and pharmacokinetics (PKs) of intraperitoneal oxaliplatin delivered by pressurised intraperitoneal aerosol chemotherapy (PIPAC) in patients with advanced peritoneal carcinomatosis from gastrointestinal tract cancers.
METHODS: PIPAC was applied every 4-6 weeks, for 5 cycles, in a phase I dose-escalation study using a 3 + 3 design. The first dose level was 90 mg/m2 with planned increases of 50 mg/m2 per level. Platinum concentration was measured in plasma, tissues and intraperitoneal fluid samples. The trial was registered at ClinicalTrials.gov (NCT03294252).
RESULTS: Ten patients with 33 PIPAC sessions were included. No dose limiting toxicity (DLT) occurred at 90 mg/m2 and two at 140 mg/m2. The MTD was therefore set at 90 mg/m2. Overall treatment included a median number of three PIPAC sessions (range: 1-5) and secondary complete cytoreductive surgery for two patients. Overall safety showed 67 grade I-II and 11 grade III-IV toxicities, usually haematologic, digestive (nausea/vomiting, abdominal pain), and fatigue. Oxaliplatin concentrations were three- to four-fold higher in tissue in contact with aerosol than in muscle without contact. At 140 mg/m2, the plasma oxaliplatin concentration was high with Cmax and area under the curve (AUC)0-48h of 1035 μg/l and 9028 μg h/L, respectively.
CONCLUSIONS: The MTD of oxaliplatin during PIPAC is 90 mg/m2. PK data demonstrate a high tumour concentration and a significant systemic absorption.

PMID: 33039812 [PubMed - as supplied by publisher]

COVID-19 and first trimester spontaneous abortion: a case-control study of 225 pregnant patients.

Am J Obstet Gynecol. 2020 Oct 08;:

Authors: Cosma S, Carosso AR, Cusato J, Borella F, Carosso M, Bovetti M, Filippini C, D'Avolio A, Ghisetti V, DI Perri G, Benedetto C

Abstract
BACKGROUND: The disease caused by the "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2) was named Coronavirus Disease 19 (COVID-19) and classified as a global public health emergency. The evidence related to the impact of COVID-19 on pregnancy are limited to the second and the third trimester of pregnancy, while data on the first trimester are scant. Many viral infections can be harmful to the fetus during the first trimester of pregnancy, and whether SARS-CoV-2 is one of them is still unknown.
OBJECTIVE(S): With this study we evaluated SARS-CoV-2 infection as a risk factor for early pregnancy loss in first trimester of pregnancy. Furthermore, COVID-19 course in the first trimester was assessed.
STUDY DESIGN: Between February 22 and May 21, 2020, we conducted a case-control study at S. Anna Hospital, Turin, among first trimester pregnant women, paired for last menstruation. The cumulative incidence of COVID-19 was compared between women with spontaneous abortion (case group, n=100) and those with ongoing pregnancy (control group, n=125). Current or past infection was determined by detection of SARS-CoV-2 from nasopharingeal swab and SARS-CoV-2 IgG/IgM antibodies in blood sample. Patient demographics, COVID-19-related symptoms, and the main risk factors for abortion were collected.
RESULTS: Twenty-three of the 225 women (23/225, 10.2%) tested positive for COVID-19 infection. There was no difference in the cumulative incidence of COVID-19 between the cases (11/100, 11%) and the controls (12/125, 9.6%) (p=0.73). Logistic regression analysis confirmed that COVID-19 was not an independent predictor of early pregnancy loss (Odd Ratio 1.28, confidence interval 0.53-3.08). COVID-19 related symptoms in the first trimester were fever, anosmia, ageusia, cough, arthralgia and diarrhea; no pneumonia or Hospital admission due to COVID-19-related symptoms were recorded. No difference in the incidence of symptoms was noted between the two groups.
CONCLUSION(S): SARS-CoV-2 infection during the first trimester of pregnancy does not appear to predispose to early pregnancy loss; its cumulative incidence did not differ between women with spontaneous abortion and women with ongoing pregnancy. COVID-19 appears to have a favorable maternal course at the beginning of pregnancy, consistent with what has been observed during the second and the third trimester.

PMID: 33039396 [PubMed - as supplied by publisher]

Mitochondrial architecture in cardiac myocytes depends on cell shape and matrix rigidity.

J Mol Cell Cardiol. 2020 Oct 07;:

Authors: Lyra-Leite DM, Petersen AP, Ariyasinghe NR, Cho N, McCain ML

Abstract
Contraction of cardiac myocytes depends on energy generated by the mitochondria. During cardiac development and disease, the structure and function of the mitochondrial network in cardiac myocytes is known to remodel in concert with many other factors, including changes in nutrient availability, hemodynamic load, extracellular matrix (ECM) rigidity, cell shape, and maturation of other intracellular structures. However, the independent role of each of these factors on mitochondrial network architecture is poorly understood. In this study, we tested the hypothesis that cell aspect ratio (AR) and ECM rigidity regulate the architecture of the mitochondrial network in cardiac myocytes. To do this, we spin-coated glass coverslips with a soft, moderate, or stiff polymer. Next, we microcontact printed cell-sized rectangles of fibronectin with AR matching cardiac myocytes at various developmental or disease states onto the polymer surface. We then cultured neonatal rat ventricular myocytes on the patterned surfaces and used confocal microscopy and image processing techniques to quantify sarcomeric α-actinin volume, nucleus volume, and mitochondrial volume, surface area, and size distribution. On some substrates, α-actinin volume increased with cell AR but was not affected by ECM rigidity. Nucleus volume was mostly uniform across all conditions. In contrast, mitochondrial volume increased with cell AR on all substrates. Furthermore, mitochondrial surface area to volume ratio decreased as AR increased on all substrates. Large mitochondria were also more prevalent in cardiac myocytes with higher AR. For select AR, mitochondria were also smaller as ECM rigidity increased. Collectively, these results suggest that mitochondrial architecture in cardiac myocytes is strongly influenced by cell shape and moderately influenced by ECM rigidity. These data have important implications for understanding the factors that impact metabolic performance during heart development and disease.

PMID: 33038389 [PubMed - as supplied by publisher]

Do myeloproliferative neoplasms and multiple myeloma share the same genetic susceptibility loci?

Int J Cancer. 2020 Oct 10;:

Authors: Macauda A, Giaccherini M, Sainz J, Gemignani F, Sgherza N, Sánchez-Maldonado JM, Gora-Tybor J, Martinez-Lopez J, Carreño-Tarragona G, Jerez A, Spadano R, Gołos A, Jurado M, Hernández-Mohedo F, Mazur G, Tavano F, Butrym A, Várkonyi J, Canzian F, Campa D

Abstract
Myeloproliferative neoplasms (MPNs) are a group of diseases that cause myeloid hematopoietic cells to over-proliferate. Epidemiological and familial studies suggest that genetic factors contribute to the risk of developing MPN, but the genetic susceptibility of MPN is still not well known. Indeed, only few loci are known to have a clear role in the predisposition to this disease. Some studies reported a diagnosis of MPNs and multiple myeloma (MM) in the same patients, but the biological causes are still unclear. We tested the hypothesis that the two diseases share at least partly the same genetic risk loci. In the context of a European multi-center study with 460 cases and 880 controls, we analyzed the effect of the known MM risk loci, individually and in a polygenic risk score (PRS). The most significant result was obtained among patients with chronic myeloid leukemia (CML) for PS0RS1C1-rs2285803, which showed to be associated with an increased risk (OR = 3.28, 95% C.I. 1.79-6.02, P = 0.00012, P = 0.00276 when taking into account multiple testing). Additionally, the PRS showed an association with MPN risk when comparing the last with the first quartile of the PRS (OR = 2.39, 95% C.I. 1.64-3.48, P = 5.98x10-6 ). In conclusion, our results suggest a potential common genetic background between MPN and MM, which needs to be further investigated. This article is protected by copyright. All rights reserved.

PMID: 33038278 [PubMed - as supplied by publisher]

SMAD3 Hypomethylation as a Biomarker for Early Prediction of Colorectal Cancer.

Int J Mol Sci. 2020 Oct 07;21(19):

Authors: Ansar M, Wang CJ, Wang YH, Shen TH, Hung CS, Chang SC, Lin RK

Abstract
The incidence and mortality rates of colorectal cancer (CRC) have been high in recent years. Prevention and early detection are crucial for decreasing the death rate. Therefore, this study aims to characterize the alteration patterns of mothers against decapentaplegic homolog 3 (SMAD3) in patients with CRC and its applications in early detection by using a genome-wide methylation array to identify an aberrant hypomethylation site in the intron position of the SMAD3 gene. Quantitative methylation-specific polymerase chain reaction showed that hypomethylated SMAD3 occurred in 91.4% (501/548) of Taiwanese CRC tissues and 66.6% of benign tubular adenoma polyps. In addition, SMAD3 hypomethylation was observed in 94.7% of patients with CRC from The Cancer Genome Atlas dataset. A decrease in circulating cell-free methylation SMAD3 was detected in 70% of CRC patients but in only 20% of healthy individuals. SMAD3 mRNA expression was low in 42.9% of Taiwanese CRC tumor tissues but high in 29.4% of tumors compared with paired adjacent normal tissues. Hypomethylated SMAD3 was found in cancers of the digestive system, such as liver cancer, gastric cancer, and colorectal cancer, but not in breast cancer, endometrial cancer, and lung cancer. In conclusion, SMAD3 hypomethylation is a potential diagnostic marker for CRC in Western and Asian populations.

PMID: 33036415 [PubMed - as supplied by publisher]

Effect of DPYD, MTHFR, ABCB1, XRCC1, ERCC1 and GSTP1 on chemotherapy related toxicity in colorectal carcinoma.

Surg Oncol. 2020 Sep 19;35:388-398

Authors: Puerta-García E, Urbano-Pérez D, Carrasco-Campos MI, Pérez-Ramírez C, Segura-Pérez A, Calleja-Hernández, Cañadas-Garre M

Abstract
ABCB1, DPYD, MHTFR, XRCC1, ERCC1, GSTP1 and UGT1A1 genetic variants affect proteins related to CRC chemotherapy toxicity. A retrospective cohort study was conducted in 194 CRC patients. In first line treatment, DPYD rs17376848 AG genotype was associated with hematological toxicity (OR = 4.85; p = 0.03); GSTP1 G-allele (OR = 3.01; p = 0.005) and MTHFR rs1801133 T allele (OR = 2.51; p = 0.03) with respiratory toxicity; GSTP1 G-allele with cardiovascular toxicity (OR = 4.05; p = 0.01); ERCC1 rs11615 GG genotype with neurological toxicity (OR = 3.98; p = 0.01) and with asthenia (OR = 2.91; p = 0.08); XRCC1 rs1799782 T allele (OR = 0.31; p = 0.03) and GSTP1 G-allele (OR = 1.81; p = 0.01) with cutaneous toxicity. In second line treatment, XRCC1 rs1799782 T-allele was associated with asthenia (OR = 0.17; p = 0.03) and XRCC1 rs25487 T-allele with gastrointestinal toxicity (OR = 3.03; p = 0.005). After stratifying by treatment, in the 5-Fluorouracil group, the DPYD rs17376848 AG genotype was associated with hematological toxicity (OR = 2.76; p = 0.003), ABCB1 rs1045642 T-allele with the need of treatment adjustment due to toxicity (OR = 3.06; p = 0.01), and rs1045642 CC genotype with gastrointestinal toxicity (OR = 5.80; p = 0.03). In the capecitabine group, the MTHFR rs1801131 CC genotype was associated with asthenia (OR = 3.48; p = 0.009). In the oxaliplatin group, rs1045642 TT genotype was associated with the need to adjust treatment (OR = 0.32; p = 0.02), ERCC1 rs11615 GG genotype with asthenia (OR = 3.01; p = 0.01) and rs1615 GSTP1 GG genotype with respiratory toxicity (OR = 5.07; p = 0.009). ABCB1 rs1045642 T-allele reduces the need for treatment modification with both 5FU and oxaliplatin. Although several biomarkers predicted different toxic effects, they cannot be considered as risk factors for severe toxicity.

PMID: 33035787 [PubMed - as supplied by publisher]

The need of a multicomponent guiding approach to personalize clopidogrel treatment.

Pharmacogenomics J. 2020 Oct 09;:

Authors: Valeria C, Carmine S, Valentina M, Teresa I, Maria C, Martina T, Giancarlo A, Giovanna N, Graziamaria C, Amelia F

Abstract
Patients bearing polymorphisms termed CYP2C19 loss of function (LoF) alleles and ABCB1-C3435T may do not properly respond to standard dosage of clopidogrel and have an increased risk of thrombosis. Moreover, co-administration of proton pump inhibitors (PPIs) and clopidogrel may attenuate the antiplatelet effect. The role of pharmacogenetics and PPIs/clopidogrel drug-drug interaction has been extensively investigated in patients with acute coronary syndrome after stent implantation (ACS/PCI), while data in patients undergoing vascular surgery are scarce. Here we have performed a systematic review to evaluate the available literature in such a clinical setting and have discussed the controversies about the use of CYP2C19 pharmacogenetics and platelet function testing to personalize clopidogrel treatment. In addition, we have made a comparison of the literature data with our findings concerning patients eligible for vascular surgery and treated with clopidogrel, in whom we used a combined management based on the CYP2C19 and ABCB1 pharmacogenetic testing with monitoring of therapeutic adherence and PPIs-clopidogrel interaction. Both our data and those produced during both observational studies and randomized clinical trials confirm the validity of pharmacogenetics to personalize clopidogrel treatment and stress the importance to make a drug monitoring considering all the known variables, potentially responsible for treatment failure. However, the American Heart Association and the European Cardiovascular Society recommend against the routine use of clopidogrel pharmacogenetic testing. An update of the international guidelines on antiplatelet therapy, incorporating the evidence related to CYP2C19 pharmacogenetics and PPIs-clopidogrel drug-drug interactions is warranted both in ACS/PCI patients and subjects undergoing vascular surgery.

PMID: 33033370 [PubMed - as supplied by publisher]

Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection.

Science. 2020 Oct 09;370(6513):

Authors: Habibi MS, Thwaites RS, Chang M, Jozwik A, Paras A, Kirsebom F, Varese A, Owen A, Cuthbertson L, James P, Tunstall T, Nickle D, Hansel TT, Moffatt MF, Johansson C, Chiu C, Openshaw PJM

Abstract
The variable outcome of viral exposure is only partially explained by known factors. We administered respiratory syncytial virus (RSV) to 58 volunteers, of whom 57% became infected. Mucosal neutrophil activation before exposure was highly predictive of symptomatic RSV disease. This was associated with a rapid, presymptomatic decline in mucosal interleukin-17A (IL-17A) and other mediators. Conversely, those who resisted infection showed presymptomatic activation of IL-17- and tumor necrosis factor-related pathways. Vulnerability to infection was not associated with baseline microbiome but was reproduced in mice by preinfection chemokine-driven airway recruitment of neutrophils, which caused enhanced disease mediated by pulmonary CD8+ T cell infiltration. Thus, mucosal neutrophilic inflammation at the time of RSV exposure enhances susceptibility, revealing dynamic, time-dependent local immune responses before symptom onset and explaining the as-yet unpredictable outcomes of pathogen exposure.

PMID: 33033192 [PubMed - in process]