Endoxifen levels and metabolic phenotype-associated factors in Mexican Mestizo patients under tamoxifen treatment.

Pharmacogenomics. 2020 Aug 18;:

Authors: Jorge-Aarón RM, Rodrigo RC, Esther MR

Abstract
Aim: To evaluate plasma endoxifen levels and metabolic phenotype-associated factors in Mexican Mestizo patients under tamoxifen treatment. Patients & methods: A total of 138 breast cancer patients under tamoxifen treatment were cross-sectionally evaluated and side effects (SE) were recorded. CYP2D6 genetic phenotypes (GP) and metabolic phenotypes (MP) were assessed (metabolic poor [mPM], intermediate [mIM], normal [mNM], and ultrarapid [mUM] metabolizer). Associations were tested in uni-multivariate models for endoxifen >5.9 ng/ml and for mNM + mUM MP. Results: The main SE was hot flashes (62%). Distribution of the CYP2D6 MP was 4.3% mPM; 14.5% mIM; 75.4% mNM; and 5.8% mUM. Endoxifen >5.9 ng/ml was partially associated with SE (p = 0.06); the mNM + mUM MP was associated with treatment time (p = 0.03). Conclusion: The endoxifen-associated factors in Mexican Mestizo patients remain inconclusive, although treatment time was associated with MP.

PMID: 32808577 [PubMed - as supplied by publisher]

Low-molecular mimetics of nerve growth factor and brain-derived neurotrophic factor: Design and pharmacological properties.

Med Res Rev. 2020 Aug 18;:

Authors: Gudasheva TA, Povarnina PY, Tarasiuk AV, Seredenin SB

Abstract
To overcome the limitations of the clinical use of neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), scientists have been trying to create their low-molecular-weight mimetics having improved pharmacokinetic properties and lacking side effects of full-sized proteins since the 90s of the last century. The efforts of various research groups have led to the production of peptide and nonpeptide mimetics, being agonists or modulators of the corresponding Trk or p75 receptors that reproduced the therapeutic effects of full-sized proteins. This review discusses different strategies and approaches to the design of such compounds. The relationship between the structure of the mimetics obtained and their action mechanisms and pharmacological properties are analyzed. Special attention is paid to the dipeptide mimetics of individual NGF and BDNF loops having different patterns of activation of Trk receptors signal transduction pathways, phosphoinositide 3-kinase/protein kinase B and mitogen-activated protein kinase/extracellular signal-regulated kinase, which allowed to evaluate the contribution of each pathway to different pharmacological effects. In conclusion, data on therapeutically promising compounds being at different stages of preclinical and clinical studies are summarized.

PMID: 32808322 [PubMed - as supplied by publisher]

Clinical, genomics and networking analyses of a high-altitude native American Ecuadorian patient with congenital insensitivity to pain with anhidrosis: a case report.

BMC Med Genomics. 2020 Aug 17;13(1):113

Authors: López-Cortés A, Zambrano AK, Guevara-Ramírez P, Echeverría BA, Guerrero S, Cabascango E, Pérez-Villa A, Armendáriz-Castillo I, García-Cárdenas JM, Yumiceba V, Pérez-M G, Leone PE, Paz-Y-Miño C

Abstract
BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder characterized by insensitivity to pain, inability to sweat and intellectual disability. CIPA is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) that encodes the high-affinity receptor of nerve growth factor (NGF).
CASE PRESENTATION: Here, we present clinical and molecular findings in a 9-year-old girl with CIPA. The high-altitude indigenous Ecuadorian patient presented several health problems such as anhidrosis, bone fractures, self-mutilation, osteochondroma, intellectual disability and Riga-Fede disease. After the mutational analysis of NTRK1, the patient showed a clearly autosomal recessive inheritance pattern with the pathogenic mutation rs763758904 (Arg602*) and the second missense mutation rs80356677 (Asp674Tyr). Additionally, the genomic analysis showed 69 pathogenic and/or likely pathogenic variants in 46 genes possibly related to phenotypic heterogeneity, including the rs324420 variant in the FAAH gene. The gene ontology enrichment analysis showed 28 mutated genes involved in several biological processes. As a novel contribution, the protein-protein interaction network analysis showed that NTRK1, SPTBN2 and GRM6 interact with several proteins of the pain matrix involved in the response to stimulus and nervous system development.
CONCLUSIONS: This is the first study that associates clinical, genomics and networking analyses in a Native American patient with consanguinity background in order to better understand CIPA pathogenesis.

PMID: 32807182 [PubMed - in process]

Pharmacotherapies and personalized medicine for alcohol use disorder: a review.

Pharmacogenomics. 2020 Aug 18;:

Authors: Lohoff FW

Abstract
Alcohol use disorder (AUD) is highly prevalent and among the leading causes of morbidity and mortality in the United States. Pharmacotherapies for AUD are limited, thus making identification of patient subgroups that are most likely to respond favorably crucial. In this article, pharmacogenetic research on US FDA-approved and commonly prescribed off-label medications for the treatment of AUD is comprehensively reviewed. While the field has advanced in understanding pharmacotherapies for AUD and potential genetic moderators of treatment responses, the pharmacogenetic data to guide the prescribing clinician are limited and should be interpreted with caution. Precision medicine for AUD with more beneficial treatment responses and minimal side effects remains a high priority for further research.

PMID: 32807012 [PubMed - as supplied by publisher]

Computational Identification and Characterization of New microRNAs in Human Platelets Stored in a Blood Bank.

Biomolecules. 2020 Aug 12;10(8):

Authors: Maués JHDS, Moreira-Nunes CFA, Burbano RMR

Abstract
Platelet concentrate (PC) transfusions are widely used to save the lives of patients who experience acute blood loss. MicroRNAs (miRNAs) comprise a class of molecules with a biological role which is relevant to the understanding of storage lesions in blood banks. We used a new approach to identify miRNAs in normal human platelet sRNA-Seq data from the GSE61856 repository. We identified a comprehensive miRNA expression profile, where we detected 20 of these transcripts potentially expressed in PCs stored for seven days, which had their expression levels analyzed with simulations of computational biology. Our results identified a new collection of miRNAs (miR-486-5p, miR-92a-3p, miR-103a-3p, miR-151a-3p, miR-181a-5p, and miR-221-3p) that showed a sensitivity expression pattern due to biological platelet changes during storage, confirmed by additional quantitative real-time polymerase chain reaction (qPCR) validation on 100 PC units from 500 healthy donors. We also identified that these miRNAs could transfer regulatory information on platelets, such as members of the let-7 family, by regulating the YOD1 gene, which is a deubiquitinating enzyme highly expressed in platelet hyperactivity. Our results also showed that the target genes of these miRNAs play important roles in signaling pathways, cell cycle, stress response, platelet activation and cancer. In summary, the miRNAs described in this study, have a promising application in transfusion medicine as potential biomarkers to also measure the quality and viability of the PC during storage in blood banks.

PMID: 32806499 [PubMed - in process]

Dabrafenib treatment in a patient with BRAF V600E ganglioglioma: circulating exosome-derived cancer RNA supports treatment choice and clinical monitoring.

Neuro Oncol. 2019 12 17;21(12):1610-1611

Authors: Pasqualetti F, Restante G, Gonnelli A, Rofi E, Molinari A, Crucitta S, Paiar F, Rudà R, Danesi R, Soffietti R, Del Re M

PMID: 31504796 [PubMed - indexed for MEDLINE]

16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/08/18

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Optimising Seniors' Metabolism of Medications and Avoiding Adverse Drug Events Using Data on How Metabolism by Their P450 Enzymes Varies with Ancestry and Drug-Drug and Drug-Drug-Gene Interactions.

J Pers Med. 2020 Aug 11;10(3):

Authors: Thomas RE

Abstract
Many individuals ≥65 have multiple illnesses and polypharmacy. Primary care physicians prescribe >70% of their medications and renew specialists' prescriptions. Seventy-five percent of all medications are metabolised by P450 cytochrome enzymes. This article provides unique detailed tables how to avoid adverse drug events and optimise prescribing based on two key databases. DrugBank is a detailed database of 13,000 medications and both the P450 and other complex pathways that metabolise them. The Flockhart Tables are detailed lists of the P450 enzymes and also include all the medications which inhibit or induce metabolism by P450 cytochrome enzymes, which can result in undertreatment, overtreatment, or potentially toxic levels. Humans have used medications for a few decades and these enzymes have not been subject to evolutionary pressure. Thus, there is enormous variation in enzymatic functioning and by ancestry. Differences for ancestry groups in genetic metabolism based on a worldwide meta-analysis are discussed and this article provides advice how to prescribe for individuals of different ancestry. Prescribing advice from two key organisations, the Dutch Pharmacogenetics Working Group and the Clinical Pharmacogenetics Implementation Consortium is summarised. Currently, detailed pharmacogenomic advice is only available in some specialist clinics in major hospitals. However, this article provides detailed pharmacogenomic advice for primary care and other physicians and also physicians working in rural and remote areas worldwide. Physicians could quickly search the tables for the medications they intend to prescribe.

PMID: 32796505 [PubMed - as supplied by publisher]

Structural Insights into the Specificity of Ligand Binding and Coactivator Assembly by Estrogen-Related Receptor β.

J Mol Biol. 2020 Aug 11;:

Authors: Yao B, Zhang S, Wei Y, Tian S, Lu Z, Jin L, He Y, Xie W, Li Y

Abstract
Estrogen-related receptor β (ERRβ) is a nuclear receptor critical for many biological processes. Despite the biological and pharmaceutical importance of ERRβ, deciphering the structure of ERRβ have been hampered by the difficulties in obtaining a pure and stable protein for structural studies. In fact, the ERRβ ligand binding domain (LBD) remains the last unsolved ERR structure and also one of only a few unknown nuclear receptor structures. Here, we report the identification of a critical single residue mutation resulted in robust solubility and stability of an active ERRβ LBD, thereby providing a protein tool enabling the first probe into the biochemical and structural studies of this important receptor. The crystal structure reveals key structural features that have enabled the integration of the molecular determinants of signals transduced across the ligand binding and coregulator recruitment by all three ERR subtypes, which also provides a framework for the rational design of selective and potent ligands for the treatment of various ERR-mediated diseases.

PMID: 32795533 [PubMed - as supplied by publisher]

Exome Sequencing Reveals Signal Transduction Genes Involved in Impulse Control Disorders in Parkinson's Disease.

Front Neurol. 2020;11:641

Authors: Prud'hon S, Bekadar S, Rastetter A, Guégan J, Cormier-Dequaire F, Lacomblez L, Mangone G, You H, Daniau M, Marie Y, Bertrand H, Lesage S, Tezenas Du Montcel S, Anheim M, Brice A, Danjou F, Corvol JC

Abstract
Introduction: Impulse control disorders (ICDs) frequently complicate dopamine agonist (DA) therapy in Parkinson's disease (PD). There is growing evidence of a high heritability for ICDs in the general population and in PD. Variants on genes belonging to the reward pathway have been shown to account for part of this heritability. We aimed to identify new pathways associated with ICDs in PD. Methods: Thirty-six Parkinsonian patients on DA therapy with (n = 18) and without ICDs (n = 18) matched on age at PD's onset, and gender was selected to represent the most extreme phenotypes of their category. Exome sequencing was performed, and variants with a strong functional impact in brain-expressed genes were selected. Allele frequencies and their distribution in genes and pathways were analyzed with single variant and SKAT-O tests. The 10 most associated variants, genes, and pathways were retained for replication in the Parkinson's progression markers initiative (PPMI) cohort. Results: None of markers tested passed the significance threshold adjusted for multiple comparisons. However, the "Adenylate cyclase activating" pathway, one of the top associated pathways in the discovery data set (p = 1.6 × 10-3) was replicated in the PPMI cohort and was significantly associated with ICDs in a post hoc pooled analysis (combined p-value 3.3 × 10-5). Two of the 10 most associated variants belonged to genes implicated in cAMP and ERK signaling (rs34193571 in RasGRF2, p = 5 × 10-4; rs1877652 in PDE2A, p = 8 × 10-4) although non-significant after Bonferroni correction. Conclusion: Our results suggest that genes implicated in the signaling pathways linked to G protein-coupled receptors participate to genetic susceptibility to ICDs in PD.

PMID: 32793093 [PubMed]

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/08/14

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/08/14

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Risk factors of severe hospitalized respiratory syncytial virus infection in tertiary care center in Thailand.

Influenza Other Respir Viruses. 2020 Aug 12;:

Authors: Aikphaibul P, Theerawit T, Sophonphan J, Wacharachaisurapol N, Jitrungruengnij N, Puthanakit T

Abstract
AIM: To determine factors associated with severe hospitalized Respiratory syncytial virus (RSV)-associated LRTI and to describe management in tertiary care center.
METHODS: Retrospective medical record review was conducted among children under 5 years old hospitalized with RSV-associated LRTI at King Chulalongkorn Memorial Hospital. Severe RSV-associated LRTI was defined as death, mechanical ventilator, or positive pressure ventilation use, prolonged hospitalization >7 days. Factors associated with severe RSV were analyzed using univariate and multivariate logistic regression.
RESULTS: From January 2011 to December 2016, 427 children were hospitalized. Median age was 10 months (IQR 4.2-23.0). One hundred seventy-four (41%) patients had severe RSV (11 deaths, 56 mechanical ventilators, 19 positive pressure ventilation, and 88 prolonged hospitalization). Factors associated with severe RSV were chronic lung disease (aOR 15.16 [4.26-53.91]), cirrhosis/biliary atresia (aOR 15.01 [3.21-70.32]), congenital heart disease (aOR 5.11 [1.97-13.23]), chemotherapy (aOR 4.7 [1.34-16.56]), and pre-term (aOR 2.03 [1.13-3.67]). Oxygen therapy was mainly low flow oxygen delivery. 88% of cases received bronchodilator. Parenteral antibiotics were prescribed in 37.9% of cases.
CONCLUSIONS: Children with co-morbidities have higher risk of severe RSV-associated LRTI. More than two-third of patients received bronchodilator, of which was not recommended by American Academy of Pediatrics. The specific treatment and prevention for RSV are urgently needed.

PMID: 32783380 [PubMed - as supplied by publisher]

Pharmacogenomics Instruction Depth, Extent, and Perception in US Medical Curricula.

J Med Educ Curric Dev. 2020 Jan-Dec;7:2382120520930772

Authors: Basyouni D, Shatnawi A

Abstract
Introduction: This descriptive study aimed to evaluate the depth, extent, and perception of pharmacogenomics instruction in schools and colleges of medicine in the United States. Changes in medical pharmacogenomics instruction over the past decade were also assessed by comparing our results with those of a previous study.
Methods: An electronic survey was emailed to all accredited allopathic and osteopathic medical schools across the US using Qualtrics online survey software. Multiple email reminders were sent to increase the response rate.
Results: Of 151 targeted eligible medical schools across the United States, 22 responded to the survey. One invalid response was excluded, resulting in a response rate of 13.9%. Of responding schools, 85.7% cover pharmacogenomics in their curriculum, mainly in the second year, however, none teach pharmacogenomics as a stand-alone course. The depth and the extent of pharmacogenomics coverage varied among responding programs. Although 66.7% of respondents believe that neither physicians nor other health care professionals possess appropriate knowledge in pharmacogenomics, only 23.8% plan to increase pharmacogenomics instruction in their curricula in the near future.
Conclusions: Most medical schools surveyed include some pharmacogenomics instruction in their curricula, although the depth and the extent of the instruction varies. Most respondents believe that physicians and other health care professionals today do not possess an appropriate level of knowledge in pharmacogenomics; however, few institutions report short-term plans to increase pharmacogenomics instruction. Pharmacogenomics plays a significant role in personalized medicine; greater efforts by medical school decision-makers are needed to improve the level of pharmacogenomics instruction in medical curricula.

PMID: 32782929 [PubMed]

Are anti-PD1 and anti-PD-L1 alike? The non-small-cell lung cancer paradigm.

Oncol Rev. 2020 Jul 06;14(2):490

Authors: Banna GL, Cantale O, Bersanelli M, Del Re M, Friedlaender A, Cortellini A, Addeo A

Abstract
Anti-PD1 and anti-PD-L1 agents may have intrinsic and clinically relevant differences in the treatment of non-small cell lung cancer (NSCLC) patients. By reviewing currently available indirect evidence on these agents for NSCLC treatment, highlighting possible inter- and intra-class dissimilarities, anti-PD1 agents showed a higher response rate and a better outcome when combined with chemotherapy for the first-line treatment of patients with squamous and PD-L1 low advanced NSCLC, as compared to anti-PD-L1 agents. Conversely, anti-PD-L1 agents were responsible for less severe adverse events (AEs), particularly, immunerelated AEs. These differences could be explained by their different specific properties. Considering possible differences between anti-PD1 and anti-PD-L1 agents could be clinically relevant for treatment tailoring and inspiring new investigational approaches.

PMID: 32782728 [PubMed]

Biomarker phenotyping drives clinical management in axillary sentinel node: A retrospective study on women with primary breast cancer in 2002.

Oncol Lett. 2020 Sep;20(3):2469-2476

Authors: Diotaiuti S, De Summa S, Altieri R, Dantona C, Tommasi S, Di Gennaro M, Rubini G, Pastena MI, Argentiero A, Zito FA, Silvestris N, Paradiso AV

Abstract
The current study examined if cancer biomarker phenotyping could predict the clinical/pathological status of axillary nodes in women with primary breast cancer. Primary breast cancers from 2002 were analyzed for tumor size, estrogen receptor (ER), progesterone receptor (PgR), Ki-67MIB expression and Her2/neu amplification. Relationships between the clinical and pathological status of the axilla and the biological subtypes classification were analyzed using univariate, multivariate and regression tree analysis. A total of 65% of women with axillary nodes clinically involved had complete axillary node dissection (ALND) while 705 women with clinically negative axillary underwent sentinel lymph node biopsy (SLNB), 18.5% of the latter had at least one pathologically SLNB involved node. Multivariate analysis revealed that the Luminal A subtype was significantly associated (OR 0.62; P<10-9) with clinical negative axilla while HER2pos/not Luminal was associated with clinical positivity (OR 1.71; P<0.01). No significant association between biological subtypes and SLNB status was demonstrated. Regression tree analysis revealed that subgroups with significantly different probability of SLNB status were separated according to tumor size and PgR values. In conclusion, the current study demonstrated that biomarker breast cancer phenotyping is significantly associated with clinical status of axillary nodes but not with pathological involvement of nodes at SLNB. Regression tree analysis could represent a valid attempt to individualize some patients subgroups candidate to different surgical axilla approaches.

PMID: 32782565 [PubMed]

Challenges and Opportunities for Clinical Pharmacogenetic Research Studies in Resource-Limited Settings: Conclusions From the Council for International Organizations of Medical Sciences-Ibero-American Network of Pharmacogenetics and Pharmacogenomics Meeting.

Clin Ther. 2020 Aug 08;:

Authors: Peñas-LLedó E, Terán E, Sosa-Macías M, Galaviz-Hernández C, Gil JP, Nair S, Diwakar S, Hernández I, Lara-Riegos J, Ramírez-Roa R, Verde I, Tarazona-Santos E, Molina-Guarneros J, Moya G, Rägo L, LLerena A

Abstract
PURPOSE: The symposium Health and Medicines in Indigenous Populations of America was organized by the Council for International Organizations of Medical Sciences (CIOMS) Working Group on Clinical Research in Resource-Limited Settings (RLSs) and the Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF). It was aimed to share and evaluate investigators' experiences on challenges and opportunities on clinical research and pharmacogenetics.
METHODS: A total of 33 members from 22 countries participated in 2 sessions: RIBEF studies on population pharmacogenetics about the relationship between ancestry with relevant drug-related genetic polymorphisms and the relationship between genotype and phenotype in Native Americans (session 1) and case examples of clinical studies in RLSs from Asia (cancer), America (diabetes and women health), and Africa (malaria) in which the participants were asked to answer in free text their experiences on challenges and opportunities to solve the problems (session 2). Later, a discourse analysis grouping common themes by affinity was conducted.
FINDINGS: The main result of session 1 was that the pharmacogenetics-related ancestry of the population should be considered when designing clinical studies in RLSs. In session 2, 21 challenges and 20 opportunities were identified. The social aspects represent the largest proportion of the challenges (43%) and opportunities (55%), and some of them seem to be common.
IMPLICATIONS: The main discussion points were gathered in the Declaration of Mérida/T'Hó and announced on the Parliament of Extremadura during the CIOMS-RIBEF meeting in 4 of the major Latin American autochthonous languages (Náhualth, Mayan, Miskito, and Kichwa). The declaration highlighted the following: (1) the relevance of population pharmacogenetics, (2) the sociocultural contexts (interaction with traditional medicine), and (3) the education needs of research teams for clinical research in vulnerable and autochthonous populations.

PMID: 32782137 [PubMed - as supplied by publisher]

Genome-wide sequence analyses of ethnic populations across Russia.

Genomics. 2020 01;112(1):442-458

Authors: Zhernakova DV, Brukhin V, Malov S, Oleksyk TK, Koepfli KP, Zhuk A, Dobrynin P, Kliver S, Cherkasov N, Tamazian G, Rotkevich M, Krasheninnikova K, Evsyukov I, Sidorov S, Gorbunova A, Chernyaeva E, Shevchenko A, Kolchanova S, Komissarov A, Simonov S, Antonik A, Logachev A, Polev DE, Pavlova OA, Glotov AS, Ulantsev V, Noskova E, Davydova TK, Sivtseva TM, Limborska S, Balanovsky O, Osakovsky V, Novozhilov A, Puzyrev V, O'Brien SJ

Abstract
The Russian Federation is the largest and one of the most ethnically diverse countries in the world, however no centralized reference database of genetic variation exists to date. Such data are crucial for medical genetics and essential for studying population history. The Genome Russia Project aims at filling this gap by performing whole genome sequencing and analysis of peoples of the Russian Federation. Here we report the characterization of genome-wide variation of 264 healthy adults, including 60 newly sequenced samples. People of Russia carry known and novel genetic variants of adaptive, clinical and functional consequence that in many cases show allele frequency divergence from neighboring populations. Population genetics analyses revealed six phylogeographic partitions among indigenous ethnicities corresponding to their geographic locales. This study presents a characterization of population-specific genomic variation in Russia with results important for medical genetics and for understanding the dynamic population history of the world's largest country.

PMID: 30902755 [PubMed - indexed for MEDLINE]

Ligand stabilization and effect on unfolding by polymorphism in human flavin-containing monooxygenase 3.

Int J Biol Macromol. 2020 Aug 08;:

Authors: Catucci G, Aramini D, Sadeghi SJ, Gilardi G

Abstract
Pharmacogenomics is a powerful tool to prevent adverse reactions caused by different response of individuals to drug administration. Single nucleotide polymorphisms (SNPs) represent up to 90% of genetic variations among individuals. Drug metabolizing enzymes are highly polymorphic therefore the kinetic parameters of their catalytic reactions can be significantly influenced. This work reports on the unfolding process of a phase I drug metabolizing enzyme, human flavin-containing monooxygenase 3 (hFMO3) and its single nucleotide polymorphic variants (SNPs) V257M, E158K and E308G. Differential scanning calorimetry (DSC) indicates that the thermal denaturation of the enzyme is irreversible. The melting temperature (Tm) for the (Wild Type) WT and its polymorphic variants is found to be in a range from 46 °C to 50 °C. Also the activation energies of unfolding (Ea) show no significant differences among all proteins investigated (290-328 KJ/mol), except for the E308G variant that showed a significantly higher Ea of 412 KJ/mol. The presence of the bound NADP+ cofactor is found to stabilize all the variants by shifting the main Tm by 4-5 °C for all the proteins, exception made for E308G where no changes are observed. Isothermal titration calorimetry (ITC) was used to characterize the interaction of the protein with NADP+ in terms of dissociation constant (Kd), enthalpy (ΔH) and entropy (ΔS). Kd values of 1.6 and 0.7 μM, ΔH of -13.9 Kcal/mol and -16.8 Kcal/mol, ΔS of -20.5 cal/mol/deg, and -28.5 cal/mol/deg were found for V257M and E158K respectively. E308G was found to be unable to bind the NADP+ cofactor, a result that is in line with the Tm results. Circular dichroism also confirmed an overall lower stability of E308G, while NADP+ was found to give a strong positive shift of the Tm stabilizing the structure of E158K (46.2 to 50.6 °C). Previous data highlighted significant differences in terms of activity among the SNPs of hFMO3. In this work a minor impact of the SNPs was found on the stability of the enzyme in the ligand free form, except for E308G, whereas the binding of NADP+ reveals major differences among WT and polymorphic variants that are all measurable in terms of heat capacity, enthalpy and secondary structure content. These data provide the first direct evidence of ligand stabilization effects on hFMO3 that can explain the differences observed in catalytic efficiencies and serve as the starting point for the development of inhibitors of this enzyme.

PMID: 32781122 [PubMed - as supplied by publisher]

Pharmacogenetics for severe adverse drug reactions induced by molecular-targeted therapy.

Cancer Sci. 2020 Aug 11;:

Authors: Udagawa C, Zembutsu H

Abstract
Molecular-targeted drugs specifically interfere with molecules that are frequently overexpressed or mutated in cancer cells. As such, these drugs are generally considered to precisely attack cancer cells, thereby inducing fewer adverse drug reactions (ADRs). However, molecular-targeted drugs can still cause characteristic ADRs that, although rarely severe, can be life-threatening. Therefore, it is becoming increasingly important to be able to predict which patients are at risk of developing ADRs after treatment with molecular-targeted therapy. The emerging field of pharmacogenetics aims to better distinguish the genetic variants associated with drug toxicity and efficacy to improve the selection of therapeutic strategies for each genetic profile. Here, we provide an overview of the current reports on the relation between genetic variants and molecular-targeted drug-induced severe ADRs in oncology.

PMID: 32780457 [PubMed - as supplied by publisher]