Bioinformatics. 2021 May 11:btab320. doi: 10.1093/bioinformatics/btab320. Online ahead of print.

ABSTRACT

MOTIVATION: Ordinal classification problems arise in a variety of real-world applications, in which samples need to be classified into categories with a natural ordering. An example of classifying high-dimensional ordinal data is to use gene expressions to predict the ordinal drug response, which has been increasingly studied in pharmacogenetics. Classical ordinal classification methods are typically not able to tackle high-dimensional data and standard high-dimensional classification methods discard the ordering information among the classes. Existing work of high-dimensional ordinal classification approaches usually assume a linear ordinality among the classes. We argue that manually-labeled ordinal classes may not be linearly arranged in the data space, especially in high-dimensional complex problems.

RESULTS: We propose a new approach that can project high-dimensional data into a lower discriminating subspace, where the innate ordinal structure of the classes is uncovered. The proposed method weights the features based on their rank correlations with the class labels and incorporates the weights into the framework of linear discriminant analysis. We apply the method to predict the response to two types of drugs for patients with Multiple Myeloma, respectively. A comparative analysis with both ordinal and nominal existing methods demonstrates that the proposed method can achieve a competitive predictive performance while honoring the intrinsic ordinal structure of the classes. We provide interpretations on the genes that are selected by the proposed approach to understand their drug-specific response mechanisms.

AVAILABILITY AND IMPLEMENTATION: The data underlying this article are available in the Gene Expression Omnibus Database at https://www.ncbi.nlm.nih.gov/geo/ and can be accessed with accession number GSE9782 and GSE68871. The source code for FWOC can be accessed at https://github.com/pisuduo/Feature-Weighted-Ordinal-Classification-FWOC.

PMID:33974007 | DOI:10.1093/bioinformatics/btab320

Per Med. 2021 May 11. doi: 10.2217/pme-2020-0120. Online ahead of print.

ABSTRACT

This article summarizes the background, content and outcomes of a special meeting that was convened among oncologists and scientists to discuss the role of pharmacogenetic (PGx) testing in pediatric clinical oncology practice. This meeting provided an opportunity for what the lead author (AM Issa) refers to as the 'voice of the clinician' dynamic to be amplified in order to better understand how personalized or precision medicine applications such as PGx testing are adopted and incorporated into clinical settings and what we can learn from the experiences of current and ongoing implementation PGx approaches to further the implementation of precision medicine applications in real-world environments. Group dynamics and clinical experience with PGx testing and return of results shaped the discussion.

PMID:33973801 | DOI:10.2217/pme-2020-0120

Pharmacogenomics. 2021 May 11. doi: 10.2217/pgs-2020-0187. Online ahead of print.

ABSTRACT

Pharmacogenetic testing is available to healthcare professionals to guide drug selection and prevent adverse events. However, its implementation in the clinical practice of psychiatry/neurology still has barriers, mainly due to a lack of evidence. We conducted a literature search on Cochrane Library, Embase and Pubmed, from their inception to 18 June 2020. We included 16 published systematic reviews. The most studied drug categories were anticonvulsants and selective serotonin reuptake inhibitors associated with human leukocyte antigen and cytochrome P450 genes (HLA-A, HLA-B, CYP2C9, CYP2D6, CYP2C19), classified as critically low quality/low quality. There is a need for more robust studies with adequate design to assess the potential benefits of adopting pharmacogenetics in health systems and services.

PMID:33973477 | DOI:10.2217/pgs-2020-0187

Lakartidningen. 2021 May 11;118:20176.

ABSTRACT

Serious adverse drug reactions, drug intolerance, and lack of effect are major problems in healthcare. Pharmacogenomics is the part of precision medicine that aims to develop predictive risk markers in this respect and establish such testing in clinical practice. The nation-wide project Genomic Medicine Sweden (GMS) is undertaking large-scale sequencing to predict risk of drug toxicity and lack of efficacy in malignant diseases. The aim is to facilitate an improved, individualized treatment with increased patient safety. In addition to accurate genotyping, other technical or infrastructure-related aspects need to be considered for a successful implementation in healthcare, for example electronic accessibility and visibility of pharmacogenomic data of long-standing relevance for an individual's ongoing and future drug treatment.

PMID:33973222

J Immunother Cancer. 2021 May;9(5):e002372. doi: 10.1136/jitc-2021-002372.

ABSTRACT

BACKGROUND: Emerging evidence has highlighted the importance of extracellular vesicle (EV)-based biomarkers of resistance to immunotherapy with checkpoint inhibitors in metastatic melanoma. Considering the tumor-promoting implications of urokinase-type plasminogen activator receptor (uPAR) signaling, this study aimed to assess uPAR expression in the plasma-derived EVs of patients with metastatic melanoma to determine its potential correlation with clinical outcomes.

METHODS: Blood samples from 71 patients with metastatic melanoma were collected before initiating immunotherapy. Tumor-derived and immune cell-derived EVs were isolated and analyzed to assess the relative percentage of uPAR+ EVs. The associations between uPAR and clinical outcomes, sex, BRAF status, baseline lactate dehydrogenase levels and number of metastatic sites were assessed.

RESULTS: Responders had a significantly lower percentage of tumor-derived, dendritic cell (DC)-derived and CD8+ T cell-derived uPAR +EVs at baseline than non-responders. The Kaplan-Meier survival curves for the uPAR+EV quartiles indicated that higher levels of melanoma-derived uPAR+ EVs were strongly correlated with poorer progression-free survival (p<0.0001) and overall survival (p<0.0001). We also found a statistically significant correlation between lower levels of uPAR+ EVs from both CD8+ T cells and DCs and better survival.

CONCLUSIONS: Our results indicate that higher levels of tumor-derived, DC-derived and CD8+ T cell-derived uPAR+ EVs in non-responders may represent a new biomarker of innate resistance to immunotherapy with checkpoint inhibitors. Moreover, uPAR+ EVs represent a new potential target for future therapeutic approaches.

PMID:33972390 | DOI:10.1136/jitc-2021-002372

Int J Biol Macromol. 2021 May 7:S0141-8130(21)01015-1. doi: 10.1016/j.ijbiomac.2021.05.046. Online ahead of print.

ABSTRACT

Human serum albumin (HSA) is widely used for the treatment of diverse clinical conditions to restore plasma volume, manage burns and treat hypoproteinemia.Although the HSA preparations should ideally preserve its functionality, the structural integrity and antioxidant properties of HSA may be compromised as a result of the manufacturing process. The present study examined seven commercially available HSA preparations for clinical use to investigate their post-translational modifications (PTMs) and antioxidant activity, including DPPH radical-scavenging, peroxyl radical antioxidant and metal binding activities, by means of mass spectrometry and Ellman's assay. The results confirmed that most of the PTMs of HSA and especially the oxidation of the free thiol residue varied between the different commercial albumins and the percentage of these PTMs were higher than those of physiological HSA. Moreover, HSA-DA isoform was increased at the end of the stability time and new oxidative modifications occurred in these samples. In conclusion, the bioprocesses for production of commercial albumins are responsible of their wide heterogeneity, being the ethanol fractionation and their storage conditions the more critical phases. Nonetheless, the Kedrion albumin shows a high content of free thiol and a lower concentration of PTMs than other commercial albumins.

PMID:33971232 | DOI:10.1016/j.ijbiomac.2021.05.046

CNS Neurosci Ther. 2021 May 10. doi: 10.1111/cns.13654. Online ahead of print.

ABSTRACT

AIMS: Glioma is a highly invasive brain tumor, which makes prognosis challenging and renders patients resistant to various treatments. Induction of cell death is promising in cancer therapy. Ferroptosis, a recently discovered regulated cell death, can be induced for killing glioma cells. However, the prognostic prediction of ferroptosis-related genes (FRGs) in glioma remains elusive.

METHODS: The mRNA expression profiles and gene variation and corresponding clinical data of glioma patients and NON-TUMOR control were downloaded from public databases. Risk score based on a FRGs signature was constructed in REMBRANDT cohort and validated in other datasets including CGGA-693, CGGA-325, and TCGA.

RESULTS: Our results demonstrated that the majority of FRGs was differentially expressed among GBM, LGG, and NON-TUMOR groups (96.6%). Furthermore, the glioma patients with low-risk score exhibited a more satisfactory clinical outcome. The better prognosis was also validated in the glioma patients with low-risk score no matter to which grade they were affiliated. Functional analysis revealed that the high-risk score group was positively correlated with the enrichment scores for immune checkpoint blockade-related positive signatures, indicating the critical role of glioma immunotherapy via risk score.

CONCLUSION: A novel FRGs-related risk score can predict prognosis and immunotherapy in glioma patients.

PMID:33969928 | DOI:10.1111/cns.13654

Front Genet. 2021 Apr 21;12:667231. doi: 10.3389/fgene.2021.667231. eCollection 2021.

ABSTRACT

The transmembrane serine protease 2 (TMPRSS2) is the major host protease that enables entry of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) into host cells by spike (S) protein priming. Single nucleotide polymorphisms (SNPs) in the gene TMPRSS2 have been associated with susceptibility to and severity of H1N1 or H1N9 influenza A virus infections. Functional variants may influence SARS-CoV-2 infection risk and severity of Coronavirus disease 2019 (COVID-19) as well. Therefore, we analyzed the role of SNPs in the gene TMPRSS2 in a German case-control study. We performed genotyping of the SNPs rs2070788, rs383510, and rs12329760 in the gene TMPRSS2 in 239 SARS-CoV-2-positive and 253 SARS-CoV-2-negative patients. We analyzed the association of the SNPs with susceptibility to SARS-CoV-2 infection and severity of COVID-19. SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding their demographics. The CC genotype of TMPRSS2 rs383510 was associated with a 1.73-fold increased SARS-CoV-2 infection risk, but was not correlated to severity of COVID-19. Neither TMPRSS2 rs2070788 nor rs12329760 polymorphisms were related to SARS-CoV-2 infection risk or severity of COVID-19. In a multivariable analysis (MVA), the rs383510 CC genotype remained an independent predictor for a 2-fold increased SARS-CoV-2 infection risk. In summary, our report appears to be the first showing that the intron variant rs383510 in the gene TMPRSS2 is associated with an increased risk to SARS-CoV-2 infection in a German cohort.

PMID:33968142 | PMC:PMC8097083 | DOI:10.3389/fgene.2021.667231

Front Pharmacol. 2021 Apr 22;12:653525. doi: 10.3389/fphar.2021.653525. eCollection 2021.

ABSTRACT

Background: Tacrolimus (TAC) and mycophenolic acid (MPA) are the main immunosuppressive drugs used in pediatric kidney transplantation. Single nucleotide polymorphisms (SNPs) in metabolizing enzymes and transporters might influence plasma levels of these drugs. Herein, we sought to determine the influence of SNPs on CYP3A5, MRP2 and UGT1A9 genes in Chilean pediatric kidney recipients using TAC and MPA. Patients and Methods: A prospective study was performed on 104 pediatric kidney recipients that used TAC and MPA for immunosuppression. The median age at the time of transplantation was 8.1 years [Q1-Q3 4.5-11.6 years] and the main clinical diagnosis was a structural anomaly. In a subgroup of patients, a complete steroid withdrawal was made at day 7. The CYP3A5 polymorphism (ancestral allele *1; variant allele *3) was determined in the entire cohort, while MRP2 -24G > A, UGT1A9 -275T > A, and UGT1A9 -2152C > T polymorphisms were determined in 53 patients. Genotypes were associated with trough drug concentrations (C0), dose requirements normalized by weight (TAC-D mg/kg) or body surface (MPA-D mg/m2), trough levels normalized by dose requirements (C0/D), and area under the curve in 12 h normalized by dose requirements (AUC0-12h/D). Results: The frequencies of the variant alleles CYP3A5*3, MRP2-24A, UGT1A9-275A, and UGT1A9-2152T were 76.9, 22.1, 6.6, and 2.9%, respectively. AUC0-12h/TAC-D were 1.6-fold higher in CYP3A5*3/*3 patients than in CYP3A5*1 carriers (CYP3A5*1/*3 and CYP3A5*1/*1). When analyzing patients with steroid withdrawal, CYP3A5*3/*3 patients had 1.7-fold higher AUC0-12h/TAC-D than the other genotypes. Patients carrying the CYP3A5*3/*3 genotype had higher TAC-C0, lower TAC-D and higher TAC-C0/D, consistently in a 6-months follow-up. Creatinine clearance was stable during the follow-up, regardless of the genotype. No significant differences between MRP2 and UGT1A9 genotypes were observed in MPA-C0, MPA-D or MPA-C0/D. However, patients carrying the UGT1A9-275A allele had lower AUC0-12h/MPA-D than those carrying the UGT1A9-275T ancestral allele. Conclusions: These results support that CYP3A5 and UGT1A9 genotyping in pediatric recipients might be useful and advisable to guide TAC and MPA dosing and monitoring in children that undergo kidney transplantation.

PMID:33967795 | PMC:PMC8100460 | DOI:10.3389/fphar.2021.653525

Front Pharmacol. 2021 Apr 22;12:650750. doi: 10.3389/fphar.2021.650750. eCollection 2021.

ABSTRACT

Genetic differences in cytochrome P450 (CYP)-mediated metabolism have been known for several decades. The clinically most important polymorphic CYP enzyme is CYP2D6, which plays a key role in the metabolism of many antidepressants and antipsychotics, along with a range of non-psychiatric medications. Dose individualization based on CYP2D6 genotype to improve the effect and safety of drug treatment has been an ambition for a long time. Clinical use of CYP2D6 genotyping is steadily increasing; however, for pre-emptive genotyping to be successful in predicting individual dose requirements, high precision of genotype-to-phenotype translations are required. Recently, guidelines for assigning CYP2D6 enzyme activity scores of CYP2D6 variant alleles, and subsequent diplotype-to-phenotype translations, were published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group. Consensus on assigning activity scores of CYP2D6 variant alleles and translating diplotype scores into CYP2D6 poor, intermediate, normal, or ultrarapid metabolizer groups were obtained by consulting 37 international experts. While assigning enzyme activities of non-functional (score 0) and fully functional (score 1) alleles are straightforward, reduced function variant alleles are more complex. In this article, we present data showing that the assigned activity scores of reduced function variant alleles in current guidelines are not of sufficient precision; especially not for CYP2D6*41, where the guideline activity score is 0.5 compared to 0.05-0.15 in pharmacogenetic studies. Due to these discrepancies, CYP2D6 genotypes with similar guidelinediplotype scores exhibit substantial differences in CYP2D6 metabolizer phenotypes. Thus, it is important that the guidelines are updated to be valid in predicting individual dose requirements of psychiatric drugs and others metabolized by CYP2D6.

PMID:33967790 | PMC:PMC8100508 | DOI:10.3389/fphar.2021.650750

Front Pharmacol. 2021 Mar 19;12:634686. doi: 10.3389/fphar.2021.634686. eCollection 2021.

ABSTRACT

Purpose: Serum creatinine (SCr) is used as a marker of kidney function to guide dosing of renally eliminated drugs. Serum Cystatin C (S-CysC) has been suggested as a more reliable kidney marker than SCr in adults and children. Purpose of this study was to investigate S-CysC as alternative renal marker to SCr for estimating vancomycin clearance in neonates undergoing intensive care. Methods: Vancomycin pharmacokinetics (PK), SCr and S-CysC data were collected in patients undergoing vancomycin treatment in the neonatal intensive care unit of Robert Debré Hospital - Paris. A population PK analysis was performed utilizing routine therapeutic drug monitoring samples. S-CysC and SCr were compared as covariates on vancomycin clearance using stepwise covariate modeling (forward inclusion [p < 0.05] and backward elimination [p < 0.01]). Model performance was evaluated by graphical and statistical criteria. Results: A total of 108 vancomycin concentrations from 66 patients (postmenstrual age [PMA] of 26-46 weeks) were modeled with an allometric one-compartment model. The median (range) values for SCr and S-CysC were 41 (12-153) µmol/l and 1.43 (0.95-2.83) mg/l, respectively. Following stepwise covariate model building, SCr was retained as single marker of kidney function (after accounting for weight and PMA) in the final model. Compared to the final model based on SCr, the alternative model based on S-CysC showed very similar performance (e.g. BIC of 578.3 vs. 576.4) but included one additional covariate: impact of mechanical ventilation on vancomycin clearance, in addition to the effects of size and maturation. Conclusion: ill neonates. However, if using S-CysC for this purpose mechanical ventilation needs to be taken into account.

PMID:33967770 | PMC:PMC8104087 | DOI:10.3389/fphar.2021.634686

Front Pharmacol. 2021 Apr 22;12:605764. doi: 10.3389/fphar.2021.605764. eCollection 2021.

ABSTRACT

Statins can cause muscle symptoms resulting in poor adherence to therapy and increased cardiovascular risk. We hypothesize that combinations of potentially functional SNPs (pfSNPs), rather than individual SNPs, better predict myalgia in patients on atorvastatin. This study assesses the value of potentially functional single nucleotide polymorphisms (pfSNPs) and employs six machine learning algorithms to identify the combination of SNPs that best predict myalgia. Methods: Whole genome sequencing of 183 Chinese, Malay and Indian patients from Singapore was conducted to identify genetic variants associated with atorvastatin induced myalgia. To adjust for confounding factors, demographic and clinical characteristics were also examined for their association with myalgia. The top factor, sex, was then used as a covariate in the whole genome association analyses. Variants that were highly associated with myalgia from this and previous studies were extracted, assessed for potential functionality (pfSNPs) and incorporated into six machine learning models. Predictive performance of a combination of different models and inputs were compared using the average cross validation area under ROC curve (AUC). The minimum combination of SNPs to achieve maximum sensitivity and specificity as determined by AUC, that predict atorvastatin-induced myalgia in most, if not all the six machine learning models was determined. Results: Through whole genome association analyses using sex as a covariate, a larger proportion of pfSNPs compared to non-pf SNPs were found to be highly associated with myalgia. Although none of the individual SNPs achieved genome wide significance in univariate analyses, machine learning models identified a combination of 15 SNPs that predict myalgia with good predictive performance (AUC >0.9). SNPs within genes identified in this study significantly outperformed SNPs within genes previously reported to be associated with myalgia. pfSNPs were found to be more robust in predicting myalgia, outperforming non-pf SNPs in the majority of machine learning models tested. Conclusion: Combinations of pfSNPs that were consistently identified by different machine learning models to have high predictive performance have good potential to be clinically useful for predicting atorvastatin-induced myalgia once validated against an independent cohort of patients.

PMID:33967749 | PMC:PMC8100589 | DOI:10.3389/fphar.2021.605764

Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2021 Apr 28;46(4):404-413. doi: 10.11817/j.issn.1672-7347.2021.200256.

ABSTRACT

The human leukocyte antigen (HLA) molecules encoded within the human major histocompatibility complex are a group of highly conserved cell surface proteins, which are related to antigen recognition. HLA genes display a high degree of genetic polymorphism, which is the basis of individual differences in immunity. Specific HLA genotypes have been highly associated with typical adverse drug reactions. HLA-A*31:01 and HLA-B*15:02 are associated with carbamazepine-induced severe cutaneous adverse reactions, HLA-B*57:01 is related to abacavir-induced drug-induced hypersensitivity syndrome and flucloxacillin/pazopanib-induced drug-induced liver injury, while HLA-B*35:01 is a potential biomarker for predicting polygonum multiflorum-induced liver injury. It is not clear how small drug molecules to interact with HLA molecules and T cell receptors (TCR). There are four mechanistic hypotheses, including the hapten/prohapten theory, the pharmacological interaction concept, the altered peptide repertoire model, and the altered TCR repertoire model.

PMID:33967088 | DOI:10.11817/j.issn.1672-7347.2021.200256

Clin Colorectal Cancer. 2021 Apr 6:S1533-0028(21)00027-X. doi: 10.1016/j.clcc.2021.03.002. Online ahead of print.

NO ABSTRACT

PMID:33965356 | DOI:10.1016/j.clcc.2021.03.002

Drug Saf. 2021 May 8. doi: 10.1007/s40264-021-01068-w. Online ahead of print.

NO ABSTRACT

PMID:33964001 | DOI:10.1007/s40264-021-01068-w

Mycoses. 2021 May 8. doi: 10.1111/myc.13300. Online ahead of print.

ABSTRACT

BACKGROUND: Isavuconazole is a triazole antifungal drug, approved for the treatment of invasive aspergillosis and mucormycosis. Isavuconazole is metabolized by CYP3A4 and CYP3A5 and it has been shown that the CYP3A inducer rifampin reduces isavuconazole exposure. By extrapolation, the concomitant use of isavuconazole with moderate and strong CYP450-inducers is contra-indicated, although it is known that some CYP450-inducers are less potent in comparison with rifampin.

OBJECTIVES: We aim to document exposure to isavuconazole in patients concomitantly treated with a CYP450 inducer that is less potent compared to rifampin. Moreover, although it is well known that CYP3A enzymes are important for the metabolism of isavuconazole, this induction-effect has never been studied in combination with the patient's CYP3A genotype.

PATIENTS: We report three patients treated with both isavuconazole and a CYP3A inducer that is less potent compared to rifampin (rifabutin or phenobarbital), in whom we determined isavuconazole concentrations.

RESULTS: These cases suggest that the CYP3A4/5 genotype is an important determinant for isavuconazole exposure and that it might also influence the CYP450-induction interaction.

CONCLUSIONS: CYP3A-inducers that are less potent compared to rifampin, may be combined with isavuconazole in patients with loss of CYP3A5 activity (CYP3A5*3/*3). Therapeutic drug monitoring is recommended during this combination. However, low isavuconazole exposure was observed in the extensive metabolizer with CYP3A4*1/*1 and CYP3A5*1/*3 alleles.

PMID:33963620 | DOI:10.1111/myc.13300

Br J Clin Pharmacol. 2021 May 7. doi: 10.1111/bcp.14888. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Enalapril is a prodrug and needs to be activated by carboxylesterase 1 (CES1). A previous in vitro study demonstrated the CES1 genetic variant, G143E (rs71647871), significantly impaired enalapril activation. Two previous clinical studies examined the impact of G143E on single-dose enalapril PK (10 mg); however, the results were inconclusive. A prospective, multi-dose, pharmacokinetics, and pharmacodynamics (PK/PD) study was conducted to determine the impact of the CES1 G143E variant on enalapril steady-state PK and PD in healthy volunteers.

METHODS: Study participants were stratified to G143E non-carriers (n=15) and G143E carriers (n=6). All the carriers were G143E heterozygotes. Study subjects received enalapril 10 mg daily for seven consecutive days prior to a 72h PK/PD study. Plasma concentrations of enalapril and its active metabolite enalaprilat were quantified by an established LC-MS/MS method.

RESULTS: The CES1 G143E carriers had 30.9% lower enalaprilat Cmax (P = 0.03) compared to the non-carriers (38.01 vs. 55.01 ng/mL). The carrier group had 27.5% lower AUC0-∞ (P = 0.02) of plasma enalaprilat compared to the non-carriers (374.29 vs. 515.91 ng*hr/mL). The carriers also had a 32.3% lower enalaprilat-to-enalapril AUC0-∞ ratio (P = 0.003) relative to the non-carriers. The average maximum reduction of systolic blood pressure in the non-carrier group was approximately 12.4% at the end of the study compared to the baseline (P = 0.001). No statistically significant blood pressure reduction was observed in the G143E carriers.

CONCLUSIONS: The CES1 loss-of-function G143E variant significantly impaired enalapril activation and its systolic blood pressure-lowering effect in healthy volunteers.

PMID:33963573 | DOI:10.1111/bcp.14888

Nat Commun. 2021 May 7;12(1):2557. doi: 10.1038/s41467-021-22821-w.

ABSTRACT

The genetic modules that contribute to human evolution are poorly understood. Here we investigate positive selection in the Epidermal Differentiation Complex locus for skin barrier adaptation in diverse HapMap human populations (CEU, JPT/CHB, and YRI). Using Composite of Multiple Signals and iSAFE, we identify selective sweeps for LCE1A-SMCP and involucrin (IVL) haplotypes associated with human migration out-of-Africa, reaching near fixation in European populations. CEU-IVL is associated with increased IVL expression and a known epidermis-specific enhancer. CRISPR/Cas9 deletion of the orthologous mouse enhancer in vivo reveals a functional requirement for the enhancer to regulate Ivl expression in cis. Reporter assays confirm increased regulatory and additive enhancer effects of CEU-specific polymorphisms identified at predicted IRF1 and NFIC binding sites in the IVL enhancer (rs4845327) and its promoter (rs1854779). Together, our results identify a selective sweep for a cis regulatory module for CEU-IVL, highlighting human skin barrier evolution for increased IVL expression out-of-Africa.

PMID:33963188 | DOI:10.1038/s41467-021-22821-w

Cell Death Dis. 2021 May 7;12(5):454. doi: 10.1038/s41419-021-03728-2.

ABSTRACT

Radioresistance continues to be the leading cause of recurrence and metastasis in nasopharyngeal cancer. Long noncoding RNAs are emerging as regulators of DNA damage and radioresistance. LINC-PINT was originally identified as a tumor suppressor in various cancers. In this study, LINC-PINT was significantly downregulated in nasopharyngeal cancer tissues than in rhinitis tissues, and low LINC-PINT expressions showed poorer prognosis in patients who received radiotherapy. We further identified a functional role of LINC-PINT in inhibiting the malignant phenotypes and sensitizing cancer cells to irradiation in vitro and in vivo. Mechanistically, LINC-PINT was responsive to DNA damage, inhibiting DNA damage repair through ATM/ATR-Chk1/Chk2 signaling pathways. Moreover, LINC-PINT increased radiosensitivity by interacting with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and negatively regulated the expression and recruitment of DNA-PKcs. Therefore, these findings collectively support the possibility that LINC-PINT serves as an attractive target to overcome radioresistance in NPC.

PMID:33963177 | DOI:10.1038/s41419-021-03728-2

Drug Metab Rev. 2021 May 7:1-2. doi: 10.1080/03602532.2021.1909614. Online ahead of print.

ABSTRACT

AbstratThe coronavirus disease (COVID-19) pandemic further revealed the barriers to accelerated discovery and development of transformative medicines for life threatening diseases. To effectively and efficiently respond to unmet medical needs, efforts should be directed towards revolutionizing the predictive capability of non-clinical surrogates that inform drug discovery and development programs. I developed this mini special issue amidst the COVID-19 pandemic to evaluate recent advancements and opportunities for four main subthemes that support drug discovery and development including prediction of metabolic pathways, translational pharmacokinetic and pharmacodynamic studies, pharmacogenomics, and trends in bioanalysis. Scientific papers in these areas were covered by investigators from the International Society for the Study of Xenobiotics New Investigator Group and other investigators. Advancement in the predictive capability of in silico, in vitro, and in vivo models used to determine the absorption, distribution, metabolism, excretion, and toxicity profile of investigational drugs can help offset the cost of unexpected safety and/or efficacy issues during clinical studies. Likewise, extensive application of pharmacogenomics in drug development and clinical care can help direct therapeutic benefits to the appropriate patient population with the overall goal of accelerating drug development and mitigating failed drug cost. Finally, I hope that the scientific contributions in this mini special issue will stimulate practical advancements across all aspects of basic science research that support drug discovery and development to help unlock the door to the next generation of drug discovery and development that features reduced failure rates and accelerated development.

PMID:33962522 | DOI:10.1080/03602532.2021.1909614