Nat Genet. 2021 Feb 15. doi: 10.1038/s41588-021-00785-3. Online ahead of print.

ABSTRACT

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

PMID:33589841 | DOI:10.1038/s41588-021-00785-3

Acta Pharmacol Sin. 2021 Feb 15. doi: 10.1038/s41401-020-00604-1. Online ahead of print.

ABSTRACT

PARP inhibitors are a group of inhibitors targeting poly(ADP-ribose) polymerases (PARP1 or PARP2) involved in DNA repair and transcriptional regulation, which may induce synthetic lethality in BRCAness tumors. Systematic analyzes of genomic sequencing in prostate cancer show that ~10%-19% of patients with primary prostate cancer have inactivated DNA repair genes, with a notably higher proportion of 23%-27% in patients with metastatic castration-resistant prostate cancer (mCRPC). These characteristic genomic alterations confer possible vulnerability to PARP inhibitors in patients with mCRPC who benefit only modestly from other therapies. However, only a small proportion of patients with mCRPC shows sensitivity to PARP inhibitors, and these sensitive patients cannot be fully identified by existing response prediction biomarkers. In this review, we provide an overview of the potential response prediction biomarkers and synergistic combinations studied in the preclinical and clinical stages, which may expand the population of patients with prostate cancer who may benefit from PARP inhibitors.

PMID:33589795 | DOI:10.1038/s41401-020-00604-1

Pharmacogenomics J. 2021 Feb 15. doi: 10.1038/s41397-021-00206-y. Online ahead of print.

ABSTRACT

Temozolomide (TMZ), an alkylating agent with a broad-spectrum antitumor activity, ability to cross blood-brain barrier (BBB), shown to be effective against malignant glioma. This study aims to investigate the effect of 1236C>T (rs1128503) single-nucleotide gene polymorphisms of ABCB1 (MDR1) in north-Indian patients diagnosed with glioma undergoing TMZ-based chemoradiotherapy. Genotyping was performed in 100 patients diagnosed with malignant glioma (50 anaplastic astrocytoma (AA) patients and 50 glioblastoma multiforme (GBM) patients) and 150 age and sex-matched controls by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) method, followed by sanger sequencing. TMZ plasma levels were analyzed by reverse phase HPLC method. Glioma patient's survival time was analyzed by Kaplan-Meier's curve. Results of MDR1 gene 1236C>T polymorphism showed significant allelic and genotypic frequency association between glioma patients and controls. The plasma TMZ levels between metabolizers group in Grade III and Grade IV were found to be statistically significant (p < 0.05). The mutant genotype (TT) has less survival benefit compared with other genotypes (CT/CC) and the survival difference between AA and GBM was found to be statistically significant (p < 0.05). Though CT and TT polymorphisms have significant association with lower TMZ levels in both Grade III (AA) and IV (GBM) tumors, the survival difference seems to be mainly among patients with Grade III tumors. Our findings suggest that the MDR1 gene polymorphism plays a role in plasma TMZ levels and in survival time of glioma patients and, hence, TMZ therapy in malignant glioma can be predicted by genotyping MDR1 (1236C>T) gene polymorphism.

PMID:33589792 | DOI:10.1038/s41397-021-00206-y

Pharmacogenomics J. 2021 Feb 15:1-8. doi: 10.1038/s41397-021-00211-1. Online ahead of print.

ABSTRACT

This study examined rates of genetic testing in two cohorts of publicly insured individuals who have newly prescribed medication with FDA pharmacogenomic labeling guidance. Genetic testing was rare (4.4% and 10.5% in Medicaid and Medicare cohorts, respectively) despite the fact that all participants selected were taking medications that contained pharmacogenomic labeling information. When testing was conducted it was typically done before the initial use of a target medication. Factors that emerged as predictors of the likelihood of undergoing genetic testing included White ethnicity (vs. Black), female gender, and age. Cost analyses indicated higher expenditures in groups receiving genetic testing vs. matched comparators with no genetic testing, as well as disparities between proactively and reactively tested groups (albeit in opposite directions across cohorts). Results are discussed in terms of the possible reasons for the low base rate of testing, mechanisms of increased cost, and barriers to dissemination and implementation of these tests.

PMID:33589791 | PMC:PMC7883752 | DOI:10.1038/s41397-021-00211-1

Pharmacogenomics J. 2021 Feb 15. doi: 10.1038/s41397-021-00212-0. Online ahead of print.

ABSTRACT

The opioid epidemic has had a devastating impact on our country, with wide-ranging effects on healthcare, corrections, employment, and social systems. Programs have been put in place for monitoring prescriptions, initiating and expanding medications for opioid use disorder, and harm reduction (i.e., naloxone distribution, needle exchanges). However, opportunities for personalization of opioid therapy based on addiction risk have been limited. The goal of the present study was to develop an objective risk assessment algorithm based on genetic markers that are correlated with opioid use disorder (OUD). A total of 180 single-nucleotide polymorphisms (SNPs) were tested in patients with and without OUD. SNPs selected for testing were associated with opioid metabolism and drug reward pathways based on previous studies. Of the 394 patients recruited, 200 had OUD and 194 served as controls without OUD but with prior opioid exposure. Logistic regression analyses stratified by sex identified ten unique SNPs in females and nine unique SNPs in males that were significantly associated with OUD. A Genetics Opioid Risk Score (GenORs) was calculated by counting the number of OUD risk-associated SNPs/genotypes for each patient. To evaluate the discrimination of the GenORs, a receiver operating characteristic (ROC) curve for each sex was generated and determined to be sensitive and specific. This represents the first published example of a sex-based genetic risk score with potential to predict OUD, and the first OUD algorithm to include opioid-associated pharmacokinetic genes.

PMID:33589790 | DOI:10.1038/s41397-021-00212-0

Eur J Cancer. 2021 Feb 12:S0959-8049(21)00013-7. doi: 10.1016/j.ejca.2021.01.003. Online ahead of print.

NO ABSTRACT

PMID:33589368 | DOI:10.1016/j.ejca.2021.01.003

Eur J Med Chem. 2021 Feb 6;215:113169. doi: 10.1016/j.ejmech.2021.113169. Online ahead of print.

ABSTRACT

The study focuses on the prudent design and synthesis of anilide type class I HDAC inhibitors employing a functionalized pyrrolo[2,3-d]pyrimidine skeleton as the surface recognition part. Utilization of the bicyclic aromatic ring to fabricate the target compounds was envisioned to confer rigidity to the chemical architecture of MS-275 and chidamide. In-vitro enzymatic and cellular assays led to the identification of compound 7 as a potent inhibitor of HDAC1 and 2 isoform that exerted substantial cell growth inhibitory effects against human breast MDA-MB-231, cervical HeLa, breast MDA-MB-468, colorectal DLD1, and colorectal HCT116 cell lines with an IC50 values of 0.05-0.47 μM, better than MS-275 and chidamide. In addition, the anilide 7 was also endowed with a superior antiproliferative profile than MS275 and chidamide towards the human cutaneous T cell lymphoma (HH and HuT78), leukemia (HL60 and KG-1), and HDACi sensitive/resistant gastric cell lines (YCC11 and YCC3/7). Exhaustive exploration of the construct 7 confirmed it to be a microtubule-targeting agent that could trigger the cell-cycle arrest in mitosis. In pursuit of extracting the benefits of evidenced microtubule-destabilizing activity of the anilide 7, it was further evaluated against non-small-cell lung cancer cell lines as well as the multiple-drug resistant uterine cancer cell line (MES-SA/Dx5) and overwhelmingly positive results in context of inhibitory effects were attained. Furthermore, molecular modelling studies were performed and some key interactions of the anilide 7 with the amino acid residues of the active site of HDAC1 isoform and tubulin were figured out.

PMID:33588178 | DOI:10.1016/j.ejmech.2021.113169

Contemp Clin Trials. 2021 Feb 12;103:106318. doi: 10.1016/j.cct.2021.106318. Online ahead of print.

ABSTRACT

The INdividual response to VITamin D (INVITe) trial was a randomized, placebo-controlled, parallel group trial of vitamin D3 supplementation (2000 IU daily) designed to determine clinical and genetic characteristics that modify the response to vitamin D supplementation. To enhance internal and external validity and reduce cost, the INVITe trial was nested within the Multi-Ethnic Study of Atherosclerosis (MESA), an ongoing prospective observational cohort study. The INVITe trial enrolled a community-based population of 666 racially and ethnically diverse participants from January 2017 to April 2019. This represents 30% of 2210 MESA participants approached for screening, and 96% of those found to be eligible. Barriers to enrollment included delayed initiation of the trial relative to scheduled MESA study visits, a lower number of available MESA participants than expected, and a high prevalence (18%) of high-dose vitamin D supplementation (>1000 IU daily, an exclusion criterion). The final study visit was attended by 611 participants (92%), and median adherence was 98%. Our experience suggests that integration of a randomized trial into an existing observational cohort study may leverage strengths of the source population and enhance enrollment, retention, and adherence, although with limited enrollment capacity. The INVITe trial will use rigorously-collected data to advance understanding of individual determinants of vitamin D response.

PMID:33588078 | DOI:10.1016/j.cct.2021.106318

Pharmacogenomics. 2021 Feb 15. doi: 10.2217/pgs-2020-0134. Online ahead of print.

ABSTRACT

Background: Pharmacogenetics study was added into 2 bioequivalence trials of aripiprazole. The correlation between CYP2D6 polymorphisms and aripiprazole pharmacokinetics (PK) was analyzed. Materials & methods: A total of 140 subjects were included. A total of 26 CYP2D6 gene alleles were detected. The plasma concentration of aripiprazole was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). SPSS Statistics 21 was used to analyze the correlation between CYP2D6 polymorphisms and aripiprazole PK parameters. Results: All of the four PK parameters were significantly influenced by CYP2D6 rs1058164 and rs28371699. t1/2 and area under the concentration-time curve (AUC0-∞) exhibited significant difference between CYP2D6 extensive metabolizers and intermediate metabolizers. Conclusion: Aripiprazole PK was greatly influenced by CYP2D6. Attention should be paid to the possible dose adjustment for CYP2D6 intermediate metabolizer population when the drug is used in Chinese patients.

PMID:33586456 | DOI:10.2217/pgs-2020-0134

Probl Endokrinol (Mosk). 2021 Jan 26;67(1):13-19. doi: 10.14341/probl12730.

ABSTRACT

The National Medical Research Center for Endocrinology (NMRCE) received the right to implement the development program of the World-class Research Centre "The National Center for personalized medicine of endocrine diseases" (NMCPMED). The objective of the NMCPMED will be not only the creation of a system of personalized treatment, but also the training of new specialists for medicine. Fundamental researches, carried out on the basis of the already existing institutes and laboratories of the NMRCE will be expanded by creating new laboratories of the NCPMED created de novo in accordance with the approved project. This article introduces the reader to the most important laboratories that would be created in NCPMED. These are laboratories of general, molecular and population genetics, bioinformatics, pharmacogenomics, microbiota, genome editing, mathematical and digital technologies, non-invasive technologies for the diagnosis of endocrinopathies, cellular technologies, artificial intelligence and a fundamentally new laboratory of metabolic visualization and radioteranostics. The authors hope that readers of one of the main journals for endocrinologists in our country will actively participate in the implementation of NMRCE, as both young and experienced talented researchers will have a chance to be a part of the Centre. To realize the ambitious implementation plans for the achievements of the Centre, it is necessary to radically change the worldview of the doctors in our country, to train them in a new way, and to expand the structure of the Center's team by increasing the number of specialists in medical genetics, transcriptomics, biostatistics and bioinformatics, working at the intersection of experimental and clinical endocrinology, and ensuring the transit of innovative technologies into clinical practice. New laboratories of the World-Class Research Center, will become the place of routine work of a new generation of doctors, who possess not only the basics of clinical work, but also the skills of fundamental researches that will allow them to significantly improve the methods of diagnosis and treatment.

PMID:33586388 | DOI:10.14341/probl12730

J Am Pharm Assoc (2003). 2021 Feb 11:S1544-3191(21)00023-6. doi: 10.1016/j.japh.2021.01.021. Online ahead of print.

ABSTRACT

OBJECTIVES: To demonstrate the successful use of pharmacogenomic testing to specifically tailor antifungal treatment to the phenotype of a patient with human immunodeficiency virus (HIV) and disseminated histoplasmosis who had clinical progression while on itraconazole and subsequently had insufficient therapeutic drug levels of voriconazole.

CASE SUMMARY: We present the case of a patient with HIV and disseminated histoplasmosis with a persistently elevated serum Histoplasma capsulatum antigen and subtherapeutic levels of voriconazole. Pharmacogenomic testing revealed he was a CYP2C19 rapid metabolizer, thus explaining his persistent, subtherapeutic levels of voriconazole and prompting a change in therapy.

PRACTICE IMPLICATIONS: Our case illustrates the importance of pharmacogenomic testing as a tool to evaluate subtherapeutic itraconazole or voriconazole levels, especially in patients with failed clinical or Histoplasmosis Ag response despite reporting full adherence to prescribed therapy.

PMID:33583749 | DOI:10.1016/j.japh.2021.01.021

Use of Clopidogrel and Proton Pump Inhibitors Alone or in Combinations in Persons with Diabetes in Denmark; Potential for CYP2C19 Genotype-Guided Drug Therapy.

Metabolites. 2021 Feb 10;11(2):

Authors: Westergaard N, Tarnow L, Vermehren C

Abstract
BACKGROUND: Clopidogrel and proton pump inhibitors (PPIs) are among the most used drugs in Denmark for which there exists pharmacogenomics (PGx)-based dosing guidelines and FDA annotations. In this study, we further scrutinized the use of clopidogrel and PPIs when prescriptions were redeemed from Danish Pharmacies alone or in combination in the Danish population and among persons with diabetes in Denmark. The focus deals with the potential of applying PGx-guided antiplatelet therapy taking both drug-drug interactions (DDI) and drug-gene interactions (DGI) into account.
METHODS: The Danish Register of Medicinal Product Statistics was the source to retrieve consumption data.
RESULTS: The consumption of PPIs and clopidogrel in terms of prevalence (users/1000 inhabitants) increased over a five-year period by 6.3% to 103.1 (PPIs) and by 41.7% to 22.1 (clopidogrel), respectively. The prevalence of the use of clopidogrel and PPIs in persons with diabetes are 3.8 and 2.1-2.8 times higher compared to the general population. When redeemed in combination, the prevalence increased to 4.7. The most used combination was clopidogrel and pantoprazole.
CONCLUSIONS: The use of clopidogrel and PPIs either alone or in combination is quite widespread, in particular among the elderly and persons with diabetes. This further supports the emerging need of accessing and accounting for not only DDI but also for applying PGx-guided drug therapy in clinical decision making for antiplatelet therapy with clopidogrel having a particular focus on persons with diabetes and the elderly.

PMID: 33578832 [PubMed - as supplied by publisher]

Low-Molecular Weight BDNF Mimetic, Dimeric Dipeptide GSB-106, Reverses Depressive Symptoms in Mouse Chronic Social Defeat Stress.

Biomolecules. 2021 Feb 10;11(2):

Authors: Gudasheva TA, Tallerova AV, Mezhlumyan AG, Antipova TA, Logvinov IO, Firsova YN, Povarnina PY, Seredenin SB

Abstract
A mimetic of the BDNF loop 4, bis (N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide, named GSB-106, was designed and synthesized in our scientific group. The compound activated TrkB, MAPK/ERK, PI3K/AKT, and PLCγ in in vitro experiments. In vivo experiments with rodents revealed its antidepressant-like activity in the forced swim and the tail suspension tests at the dose range of 0.1-5.0 mg/kg (i.p., p.o.). However, GSB-106 was not studied in depression models modulating major depression in humans. In the present study, the GSB-106 antidepressant-like activity was revealed in mice at the depression model induced by 28-day social defeat stress with 21-days oral administration (0.1 mg/kg) after stress. At the same time, GSB-106 restored reduced locomotor activity and completely eliminated the anhedonia manifestations. The compound also restored reduced levels of synaptophysin and CREB in the hippocampus. In addition, the Trk receptor antagonist K252A, and the PLC inhibitor U73122, were found to completely block the antidepressant-like activity of GSB-106 in the forced swimming test in mice. Thus, the present results demonstrate the dipeptide BDNF mimetic GSB-106 reversed depressive-like behavior and restored hippocampal neuroplasticity in a rodent depression model. These effects of GSB-106 are probably regulated by TrkB signaling.

PMID: 33578683 [PubMed - as supplied by publisher]

J Reprod Immunol. 2021 Feb 2;144:103285. doi: 10.1016/j.jri.2021.103285. Online ahead of print.

ABSTRACT

We report herein the longest-lasting study of SARS-CoV-2 antibody profile in pregnancy, from first trimester-infection to delivery. Seventeen out of 164 pregnant women tested positive for COVID-19. Throughout pregnancy, the neutralizing antibody titer remained stable, whilst a significant decline in the non-neutralizing antibodies was observed after 16 weeks of gestation. All the newborns of women who developed IgG antibodies showed the presence of the same antibodies in arterial cord blood. Knowledge on the longevity and type of SARS-CoV-2 antibody response may help to guide vaccination strategies in pregnancy.

PMID:33582489 | DOI:10.1016/j.jri.2021.103285

A novel immunochemotherapy based on targeting of cyclooxygenase and induction of immunogenic cell death.

Biomaterials. 2021 Feb 04;270:120708

Authors: Huang H, Huang Y, Chen Y, Luo Z, Zhang Z, Sun R, Wan Z, Sun J, Lu B, Zhang L, Hu J, Li S

Abstract
Cyclooxygenase (COX) plays a crucial role in the "inflammogenesis of cancer", which leads to tumor progression, metastasis, and immunotherapy resistance. Therefore, reducing "inflammogenesis" by COX inhibition may be a key perspective for cancer therapy. However, the role of tumor-derived COX in the actions of COX inhibitors remains incompletely understood. In this study, applying "old drug new tricks" to repurpose 5-aminosalicylic acid (5-ASA), a COX inhibitor, we examined the effect of 5-ASA, alone or in combination with doxorubicin (DOX), in several cancer cell lines with different levels of COX expression. To facilitate the evaluation of the combination effect on tumors in vivo, a new micellar carrier based on PEG-b-PNHS polymer-conjugated 5-ASA (PASA) was developed to enhance codelivery of 5-ASA and DOX. Folate was also introduced to the polymer (folate-PEG-NH2-conjugated PASA (FASA)) to further improve delivery to tumors via targeting both tumor cells and tumor macrophages. An unprecedented high DOX loading capacity of 42.28% was achieved through various mechanisms of carrier/drug interactions. FASA was highly effective in targeting to and in inhibiting the growth of both 4T1.2 and CT26 tumors in BALB/c mice. However, FASA was more effective in CT26 tumor that has a high level of COX expression. Codelivery of DOX via PASA and FASA led to a further improvement in antitumor activity. Mechanistic studies suggest that inhibition of COX in vivo led to a more active tumor immune microenvironment. Interestingly, treatment with FASA led to upregulation of PD-1 on T cells, likely due to repressing the inhibitory effect of prostaglandin E2 (PGE2) on PD-1 expression on T cells. Combination of FASA/DOX with anti-PD-1 antibody led to a drastic improvement in the overall antitumor activity including regression of some established tumors at a suboptimal dose of FASA/DOX. Our data suggest that FASA/DOX may represent a new and effective immunochemotherapy for various types of cancers, particularly those cancers with high levels of COX expression.

PMID: 33578254 [PubMed - as supplied by publisher]

Early detection of neutralizing antibodies against SARS-CoV-2 in COVID-19 patients in Thailand.

PLoS One. 2021;16(2):e0246864

Authors: Putcharoen O, Wacharapluesadee S, Chia WN, Paitoonpong L, Tan CW, Suwanpimolkul G, Jantarabenjakul W, Ruchisrisarod C, Wanthong P, Sophonphan J, Chariyavilaskul P, Wang LF, Hemachudha T

Abstract
BACKGROUND: The presence of neutralizing antibodies (NAbs) is an indicator of protective immunity for most viral infections. A newly developed surrogate viral neutralization assay (sVNT) offers the ability to detect total receptor binding domain-targeting NAbs in an isotype-independent manner, increasing the test sensitivity. Thus, specimens with low IgM/ IgG antibody levels showed strong neutralization activity in sVNT.
METHODS: This study aimed to measure the %inhibition of NAbs measured by sVNT in PCR-confirmed COVID-19 patients. The sensitivity of sVNT for the diagnosis of SARS-CoV-2 infection and its kinetics were determined.
RESULTS: Ninety-seven patients with PCR-confirmed SARS-CoV-2 infection were included in this study. Majority of the patients were 21-40 years old (67%) and 63% had mild symptoms. The sensitivity of sVNT for the diagnosis of SARS-CoV-2 infection was 99% (95% confidence interval (CI) 94.4-100%) and the specificity was 100% (95% CI 98.3-100%). The negative predictive value of sVNT from the samples collected before and after 7 days of symptom onset was 99.5% (95% CI 97.4-100%) and 100% (95% CI 93.8-100%), respectively. The level of inhibition at days 8-14 were significantly higher than days 0-7 (p<0.001). The median %inhibition values by severity of COVID-19 symptoms were 79.9% (interquartile range (IQR) 49.7-91.8%); 89.0% (IQR 71.2-92.4%); and 86.6% (IQR 69.5-92.8%), for mild, moderate and severe/critical symptoms respectively. The median level of sVNT %inhibition of severe was significantly higher than the mild group (p = 0.05).
CONCLUSION: The sVNT is a practical and robust serological test for SARS-CoV-2 infection and does not require specialized biosafety containment. It can be used clinically to aid diagnosis in both early and late infection especially in cases when the real-time RT-PCR results in weakly negative or weakly positive, and to determine the protective immune response from SARS-CoV-2 infection in patients.

PMID: 33577615 [PubMed - as supplied by publisher]

Pharmacogenomics of COVID-19 therapies.

NPJ Genom Med. 2020 Aug 18;5(1):35

Authors: Takahashi T, Luzum JA, Nicol MR, Jacobson PA

Abstract
A new global pandemic of coronavirus disease 2019 (COVID-19) has resulted in high mortality and morbidity. Currently numerous drugs are under expedited investigations without well-established safety or efficacy data. Pharmacogenomics may allow individualization of these drugs thereby improving efficacy and safety. In this review, we summarized the pharmacogenomic literature available for COVID-19 drug therapies including hydroxychloroquine, chloroquine, azithromycin, remdesivir, favipiravir, ribavirin, lopinavir/ritonavir, darunavir/cobicistat, interferon beta-1b, tocilizumab, ruxolitinib, baricitinib, and corticosteroids. We searched PubMed, reviewed the Pharmacogenomics Knowledgebase (PharmGKB®) website, Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, the U.S. Food and Drug Administration (FDA) pharmacogenomics information in the product labeling, and the FDA pharmacogenomics association table. We found several drug-gene variant pairs that may alter the pharmacokinetics of hydroxychloroquine/chloroquine (CYP2C8, CYP2D6, SLCO1A2, and SLCO1B1); azithromycin (ABCB1); ribavirin (SLC29A1, SLC28A2, and SLC28A3); and lopinavir/ritonavir (SLCO1B1, ABCC2, CYP3A). We also identified other variants, that are associated with adverse effects, most notable in hydroxychloroquine/chloroquine (G6PD; hemolysis), ribavirin (ITPA; hemolysis), and interferon β -1b (IRF6; liver toxicity). We also describe the complexity of the risk for QT prolongation in this setting because of additive effects of combining more than one QT-prolonging drug (i.e., hydroxychloroquine/chloroquine and azithromycin), increased concentrations of the drugs due to genetic variants, along with the risk of also combining therapy with potent inhibitors. In conclusion, although direct evidence in COVID-19 patients is lacking, we identified potential actionable genetic markers in COVID-19 therapies. Clinical studies in COVID-19 patients are deemed warranted to assess potential roles of these markers.

PMID: 33574271 [PubMed]

Molecules and Mechanisms to Overcome Oxidative Stress Inducing Cardiovascular Disease in Cancer Patients.

Life (Basel). 2021 Jan 30;11(2):

Authors: Sabbatino F, Conti V, Liguori L, Polcaro G, Corbi G, Manzo V, Tortora V, Carlomagno C, Vecchione C, Filippelli A, Pepe S

Abstract
Reactive oxygen species (ROS) are molecules involved in signal transduction pathways with both beneficial and detrimental effects on human cells. ROS are generated by many cellular processes including mitochondrial respiration, metabolism and enzymatic activities. In physiological conditions, ROS levels are well-balanced by antioxidative detoxification systems. In contrast, in pathological conditions such as cardiovascular, neurological and cancer diseases, ROS production exceeds the antioxidative detoxification capacity of cells, leading to cellular damages and death. In this review, we will first describe the biology and mechanisms of ROS mediated oxidative stress in cardiovascular disease. Second, we will review the role of oxidative stress mediated by oncological treatments in inducing cardiovascular disease. Lastly, we will discuss the strategies that potentially counteract the oxidative stress in order to fight the onset and progression of cardiovascular disease, including that induced by oncological treatments.

PMID: 33573162 [PubMed]

PPAR-Mediated Toxicology and Applied Pharmacology.

Cells. 2020 02 03;9(2):

Authors: Xi Y, Zhang Y, Zhu S, Luo Y, Xu P, Huang Z

Abstract
Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor family, attract wide attention as promising therapeutic targets for the treatment of multiple diseases, and their target selective ligands were also intensively developed for pharmacological agents such as the approved drugs fibrates and thiazolidinediones (TZDs). Despite their potent pharmacological activities, PPARs are reported to be involved in agent- and pollutant-induced multiple organ toxicity or protective effects against toxicity. A better understanding of the protective and the detrimental role of PPARs will help to preserve efficacy of the PPAR modulators but diminish adverse effects. The present review summarizes and critiques current findings related to PPAR-mediated types of toxicity and protective effects against toxicity for a systematic understanding of PPARs in toxicology and applied pharmacology.

PMID: 32028670 [PubMed - indexed for MEDLINE]

Genetic Interactions and Tissue Specificity Modulate the Association of Mutations with Drug Response.

Mol Cancer Ther. 2020 03;19(3):927-936

Authors: Cramer D, Mazur J, Espinosa O, Schlesner M, Hübschmann D, Eils R, Staub E

Abstract
In oncology, biomarkers are widely used to predict subgroups of patients that respond to a given drug. Although clinical decisions often rely on single gene biomarkers, machine learning approaches tend to generate complex multi-gene biomarkers that are hard to interpret. Models predicting drug response based on multiple altered genes often assume that the effects of single alterations are independent. We asked whether the association of cancer driver mutations with drug response is modulated by other driver mutations or the tissue of origin. We developed an analytic framework based on linear regression to study interactions in pharmacogenomic data from two large cancer cell line panels. Starting from a model with only covariates, we included additional variables only if they significantly improved simpler models. This allows to systematically assess interactions in small, easily interpretable models. Our results show that including mutation-mutation interactions in drug response prediction models tends to improve model performance and robustness. For example, we found that TP53 mutations decrease sensitivity to BRAF inhibitors in BRAF-mutated cell lines and patient tumors, suggesting a therapeutic benefit of combining inhibition of oncogenic BRAF with reactivation of the tumor suppressor TP53. Moreover, we identified tissue-specific mutation-drug associations and synthetic lethal triplets where the simultaneous mutation of two genes sensitizes cells to a drug. In summary, our interaction-based approach contributes to a holistic view on the determining factors of drug response.

PMID: 31826931 [PubMed - indexed for MEDLINE]