Hepatol Commun. 2022 Jan 3. doi: 10.1002/hep4.1880. Online ahead of print.

ABSTRACT

The oxysterol receptor liver X receptor (LXR) is a nuclear receptor best known for its function in the regulation of lipid and cholesterol metabolism. LXRs, both the α and β isoforms, have been suggested as potential therapeutic targets for several cancer types. However, there was a lack of report on whether and how LXRα plays a role in the development of hepatocellular carcinoma (HCC). In the current study, we found that systemic activation of LXRα in the VP-LXRα knock-in (LXRαKI) mice or hepatocyte-specific activation of LXRα in the VP-LXRα transgenic mice sensitized mice to liver tumorigenesis induced by the combined treatment of diethylnitrosamine (DEN) and 3,3',5,5'-tetrachloro-1,4-bis (pyridyloxy) benzene (TCPOBOP). Mechanistically, the LXRα-responsive up-regulation of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway and the complement system, and down-regulation of bile acid metabolism, may have contributed to increased tumorigenesis. Accumulations of secondary bile acids and oxysterols were found in both the serum and liver tissue of LXRα activated mice. We also observed an induction of monocytic myeloid-derived suppressor cells accompanied by down-regulation of dendritic cells and cytotoxic T cells in DEN/TCPOBOP-induced liver tumors, indicating that chronic activation of LXRα may have led to the activation of innate immune suppression. The HCC sensitizing effect of LXRα activation was also observed in the c-MYC driven HCC model. Conclusion: Our results indicated that chronic activation of LXRα promotes HCC, at least in part, by promoting innate immune suppressor as a result of accumulation of oxysterols, as well as up-regulation of the IL-6/Janus kinase/STAT3 signaling and complement pathways.

PMID:34981658 | DOI:10.1002/hep4.1880

Reprod Biol Endocrinol. 2022 Jan 3;20(1):2. doi: 10.1186/s12958-021-00871-5.

ABSTRACT

BACKGROUND: Women with uterine adenomyosis seeking assisted reproduction have been associated with compromised endometrial receptivity to embryo implantation. To understand the mechanisms involved in this process, we aimed to compare endometrial transcriptome profiles during the window of implantation (WOI) between women with and without adenomyosis.

METHODS: We obtained endometrial biopsies LH-timed to the WOI from women with sonographic features of adenomyosis (n=10) and controls (n=10). Isolated RNA samples were subjected to RNA sequencing (RNA-seq) by the Illumina NovaSeq 6000 platform and endometrial receptivity classification with a molecular tool for menstrual cycle phase dating (beREADY®, CCHT). The program language R and Bioconductor packages were applied to analyse RNA-seq data in the setting of the result of accurate endometrial dating. To suggest robust candidate pathways, the identified differentially expressed genes (DEGs) associated with the adenomyosis group in the receptive phase were further integrated with 151, 173 and 42 extracted genes from published studies that were related to endometrial receptivity in healthy uterus, endometriosis and adenomyosis, respectively. Enrichment analyses were performed using Cytoscape ClueGO and CluePedia apps.

RESULTS: Out of 20 endometrial samples, 2 were dated to the early receptive phase, 13 to the receptive phase and 5 to the late receptive phase. Comparison of the transcriptomics data from all 20 samples provided 909 DEGs (p<0.05; nonsignificant after adjusted p value) in the adenomyosis group but only 4 enriched pathways (Bonferroni p value < 0.05). The analysis of 13 samples only dated to the receptive phase provided suggestive 382 DEGs (p<0.05; nonsignificant after adjusted p value) in the adenomyosis group, leading to 33 enriched pathways (Bonferroni p value < 0.05). These included pathways were already associated with endometrial biology, such as "Expression of interferon (IFN)-induced genes" and "Response to IFN-alpha". Data integration revealed pathways indicating a unique effect of adenomyosis on endometrial molecular organization (e.g., "Expression of IFN-induced genes") and its interference with endometrial receptivity establishment (e.g., "Extracellular matrix organization" and "Tumour necrosis factor production").

CONCLUSIONS: Accurate endometrial dating and RNA-seq analysis resulted in the identification of altered response to IFN signalling as the most promising candidate of impaired uterine receptivity in adenomyosis.

PMID:34980152 | DOI:10.1186/s12958-021-00871-5

BMC Med Genomics. 2022 Jan 3;15(1):3. doi: 10.1186/s12920-021-01153-0.

ABSTRACT

BACKGROUND: Few studies have annotated the whole mitochondrial DNA (mtDNA) genome associated with drug responses in Asian populations. This study aimed to characterize mtDNA genetic profiles, especially the distribution and frequency of well-known genetic biomarkers associated with diseases and drug-induced toxicity in a Korean population.

METHOD: Whole mitochondrial genome was sequenced for 118 Korean subjects by using a next-generation sequencing approach. The bioinformatic pipeline was constructed for variant calling, haplogroup classification and annotation of mitochondrial mutation.

RESULTS: A total of 681 variants was identified among all subjects. The MT-TRNP gene and displacement loop showed the highest numbers of variants (113 and 74 variants, respectively). The m.16189T > C allele, which is known to reduce the mtDNA copy number in human cells was detected in 25.4% of subjects. The variants (m.2706A > G, m.3010A > G, and m.1095T > C), which are associated with drug-induced toxicity, were observed with the frequency of 99.15%, 30.51%, and 0.08%, respectively. The m.2150T > A, a genotype associated with highly disruptive effects on mitochondrial ribosomes, was identified in five subjects. The D and M groups were the most dominant groups with the frequency of 34.74% and 16.1%, respectively.

CONCLUSIONS: Our finding was consistent with Korean Genome Project and well reflected the unique profile of mitochondrial haplogroup distribution. It was the first study to annotate the whole mitochondrial genome with drug-induced toxicity to predict the ADRs event in clinical implementation for Korean subjects. This approach could be extended for further study for validation of the potential ethnic-specific mitochondrial genetic biomarkers in the Korean population.

PMID:34980117 | DOI:10.1186/s12920-021-01153-0

BMC Cancer. 2022 Jan 3;22(1):16. doi: 10.1186/s12885-021-09072-0.

ABSTRACT

BACKGROUND: Cancer-related fatigue (CRF) is one of the most common and distressing complaints reported by cancer patients during chemotherapy considerably impacting all aspects of a patient's life (physical, psychosocial, professional, and socioeconomic). The aim of this study was to assess the severity of cancer-related fatigue in a group of breast cancer patients undergoing chemotherapy and explore the association between fatigue scores and sociodemographic, clinical, biological, psychiatric, and genetic factors.

METHODS: A cross-sectional pilot study carried out at the oncology outpatient unit of Hôtel-Dieu de France University Hospital recruited 67 breast cancer patients undergoing chemotherapy between November 2017 and June 2019 to evaluate fatigue using the EORTC QLQ-C30 scale (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire). Genotyping for seven gene polymorphisms (COMT, DRD2, OPRM1, CLOCK, PER2, CRY2, ABCB1) was performed using the Lightcycler® (Roche).

RESULTS: The prevalence of fatigue was 46.3%. Multivariable analysis taking the fatigue score as the dependent variable showed that a higher number of cycles and a lower hemoglobin level were significantly associated with higher odds of exhibiting fatigue. Moreover, having at least one C allele for DRD2 SNP (vs. TT) was significantly associated with a 4.09 higher odds of expressing fatigue compared to TT patients. Finally, patients with at least one C allele for CLOCK SNP tended to display higher fatigue levels than TT patients.

CONCLUSIONS: Our study showed that anemic breast cancer patients with a high number of chemotherapy cycles and those carrying at least one C allele for DRD2 and CLOCK SNPs are at greater risk of exhibiting fatigue. Since no previous research has reported such genetic results, future studies are necessary to confirm our findings.

PMID:34979978 | DOI:10.1186/s12885-021-09072-0

Clin Ther. 2021 Dec 30:S0149-2918(21)00463-X. doi: 10.1016/j.clinthera.2021.11.008. Online ahead of print.

ABSTRACT

PURPOSE: Polmacoxib, a new coxib dually inhibiting cyclooxygenase-2 and carbonic anhydrase I/II, was recently approved for osteoarthritis treatment in South Korea. This study explored the population pharmacokinetic and pharmacodynamic characteristics of polmacoxib.

METHODS: Nonlinear mixed-effects modeling was performed using pooled pharmacokinetic data from a Phase I study in healthy individuals and pharmacokinetic properties and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) data from a Phase IIb study in patients with osteoarthritis. Pharmacodynamic models for WOMAC were sequentially fit using individual pharmacokinetic parameter estimates.

FINDINGS: Polmacoxib concentrations in whole blood were adequately described by the 2-compartment model, with mixed zero- and first-order absorption kinetics. Iron concentration was the significant covariate associated with clearance of polmacoxib. The relationship between the whole blood concentration of polmacoxib and WOMAC was best described by a 2-effect compartment model that consisted of central and peripheral compartments with the rate constant of 0.408 min-1 for distribution to the central effect compartment. A decrease in WOMAC was linked to the central effect site compartment concentration through an ordinary maximum effect model with an effect site concentration needed to achieve 50% of the maximum effect of 508 ng/mL.

IMPLICATIONS: The current model accurately characterized the pharmacokinetic and pharmacodynamic properties of polmacoxib and could provide a basis for individualized drug therapy. (Clin Ther. 2021;XX:XXX-XXX) © 2021 Elsevier HS Journals, Inc.

PMID:34974943 | DOI:10.1016/j.clinthera.2021.11.008

J Allergy Clin Immunol. 2021 Dec 28:S0091-6749(21)02734-2. doi: 10.1016/j.jaci.2021.11.025. Online ahead of print.

ABSTRACT

BACKGROUND: Inhaled corticosteroid (ICS) response among patients with asthma is influenced by genetics, but biologically actionable insights based on associations have not been found. Various glucocorticoid response omics datasets are available to interrogate their biological effects.

OBJECTIVE: We sought to identify functionally relevant ICS response genetic associations by integrating complementary multiomics datasets.

METHODS: Variants with p-values<10-4 from a previous ICS response genome-wide association study were re-ranked based on integrative scores determined from: i) glucocorticoid receptor (GR)- and ii) RNA polymerase II (RNAP II)-binding regions inferred from ChIP-Seq data for three airway cell types, iii) glucocorticoid response element (GRE) motifs, iv) differentially expressed genes in response to glucocorticoid exposure according to 20 transcriptomic datasets, and v) expression quantitative trait loci (eQTLs) from GTEx. Candidate variants were tested for association with ICS response and asthma in six independent studies.

RESULTS: Four variants had significant (q-value<0.05) multiomics integrative scores. These variants were in a locus consisting of 52 variants in high LD (r2≥0.8) near GR-binding sites by the gene BIRC3. Variants were also BIRC3 eQTLs in lung, and two were within/near putative GRE motifs. BIRC3 had increased RNAP II occupancy and gene expression with glucocorticoid exposure in two ChIP-Seq and 13 transcriptomic datasets. Some BIRC3 variants in the 52-variant locus were associated (p-value<0.05) with ICS response in three independent studies and others with asthma in one study.

CONCLUSION: BIRC3 should be prioritized for further functional studies of ICS response.

CLINICAL IMPLICATION: Genetic variation near BIRC3 may influence ICS response in people with asthma.

PMID:34971648 | DOI:10.1016/j.jaci.2021.11.025

Mil Med. 2021 Dec 30;187(Supplement_1):9-17. doi: 10.1093/milmed/usab481.

ABSTRACT

INTRODUCTION: Clinical utilization of pharmacogenomics (PGx) testing is highly institutionally dependent, and little information is known about provider practices of PGx testing in the Military Health System (MHS). In this study, we aimed to characterize Clinical Pharmacogenetics Implementation Consortium (CPIC) actionable prescription (Rx) patterns and their temporal relationship with PGx testing in the MHS.

METHODS: Using data from the Military Health System Management Analysis and Reporting Tool (M2) database, this retrospective cohort study included all patients receiving at least one PGx test and at least one CPIC actionable Rx from January 2015 to August 2020 (845 patients, 1,471 PGx, 7,725 index CPIC actionable Rxs). Rx patterns and temporal relationships with PGx testing were characterized via descriptive statistics. Binomial regression was used to determine which patient and provider characteristics were associated with a patient receiving a PGx test within 30 days of an index Rx.

RESULTS: Patients had a median of 9 index CPIC actionable Rx's (range 1-26). Pain medications were most commonly prescribed (N = 794, 94% patients with at least 1 Rx). However, pain medication had the lowest Rx-PGx match rate (40%) compared to an average of 62% Rx-PGx match rate for all CPIC drugs. Antidepressants were also commonly prescribed (N = 668, 79.1% patients with at least 1 Rx), and antidepressants had the highest Rx-PGx match rate of 86.7%. A minority of providers (20%, N = 249) ordered the majority of PGx tests (86.1%, N = 1,266) and only 8.3% of PGx tests (N = 398) matched to a CPIC actionable drug within 30 days of the test (defined by Rxs ordered within 30 days before or after the PGx test). However, approximately 39.8% of patients (N = 317) had at least one drug match to a PGx test within 30 days. The largest predictor of whether a patient received a PGx test within 30 days of any index Rx was whether or not a specific psychiatry provider ordered the PGx test (odds ratio; OR 3.7, 95% CI 2.13-6.54, P < 0.001). Neither the CPIC level of evidence nor FDA PGx actionable or informative labels had a significant effect on PGx test timing.

CONCLUSIONS: PGx testing was generally limited to high Rx-drug users and was found to be an under-utilized resource. PGx testing did not typically follow CPIC guidelines. Implementing PGx testing protocols, simplifying PGx test-ordering by incorporating at minimum CYP2D6, CYP2C19, and CYP2C9 into PGx-testing panels, and unifying providers' PGx knowledgebase in the MHS are feasible and would improve the clinical utilization of PGx tests in the MHS.

PMID:34967405 | DOI:10.1093/milmed/usab481

Mil Med. 2021 Dec 30;187(Supplement_1):1-8. doi: 10.1093/milmed/usab098.

ABSTRACT

Pharmacogenomics (PGx) plays a fundamental role in personalized medicine, providing an evidence-based treatment approach centered on the relationship between genomic variations and their effect on drug metabolism. Cytochrome P450 (CYP450) enzymes are responsible for the metabolism of most clinically prescribed drugs and a major source of variability in drug pharmacokinetics and pharmacodynamics. To assess the prevalence of PGx testing within the Military Health System (MHS), testing of specific CYP450 enzymes was evaluated. Data were retrospectively obtained from the Military Health System Management Analysis and Reporting Tool (M2) database. Patient demographics were identified for each test, along with TRICARE status, military treatment facility, clinic, and National Provider Identifier. A total of 929 patients received 1,833 PGx tests, predominantly composed of active duty/guard service members (N = 460; 49.5%), with highest testing rates in the army (51.5%). An even distribution in testing was observed among gender, with the highest rates in Caucasians (41.7%). Of the CYP enzymes assessed, CYP2C19 and CYP2D6 accounted for 87.8% of all PGx CYP testing. The majority of patients were tested in psychiatry clinics (N = 496; 53.4%) and primary care clinics (N = 233; 25.1%), accounting for 56.4% and 24.8% of all tests, respectively. Testing was found to be provider driven, suggesting a lack of a standardized approach to PGx and its application in patient care within the MHS. We initially recommend targeted education and revising testing labels to be more uniform and informative. Long-term recommendations include establishing pharmacy-driven protocols and point-of-care PGx testing to optimize patient outcomes.

PMID:34967404 | DOI:10.1093/milmed/usab098

Mil Med. 2021 Dec 30;187(Supplement_1):18-24. doi: 10.1093/milmed/usab333.

ABSTRACT

Pharmacogenomics is a pillar of personalized medicine that has the potential to deliver optimized treatment in many medical settings. Military medicine in the deployed setting is unique and therefore warrants separate assessment pertaining to its potential capabilities and impact. Pharmacogenomics for United States Active Duty Service Members medical care in the deployed setting has not, to our knowledge, been previously reviewed. We present potential applications of pharmacogenomics to forward medical care through two comprehensive references for deployed medical care, the Tactical Combat Casualty Care Guidelines (TCCC) and Emergency War Surgery (EWS) fifth edition. All drugs within the deployment manuals, TCCC guidelines and EWS book, were identified and the list was cross-referenced to the Clinical Pharmacogenetics Implementation Consortium guidelines and genes-drugs interactions list as well as the Food and Drug Administration Table of Pharmacogenomics Biomarkers in Drug Labeling. Ten pharmacologic categories were identified, consisting of 15 drugs, along with the classes, aminogylcosides, beta-blockers, and volatile anesthetics. Drugs and pharmacogenomics liabilities were tabulated. Eight specific drugs or classes are expounded upon given the belief of the authors of their potential for impacting future treatment on the battlefield in the setting of prolonged field care. This review outlines several genes with liabilities in the prolonged field care setting and areas that may produce improved care with further study.

PMID:34967401 | DOI:10.1093/milmed/usab333

Mil Med. 2021 Dec 30;187(Supplement_1):25-31. doi: 10.1093/milmed/usab243.

ABSTRACT

INTRODUCTION: Providing patient-specific clinical care is an expanding focus for medical professionals and researchers, more commonly referred to as personalized or precision medicine. The goal of using a patient-centric approach is to provide safer care while also increasing the probability of therapeutic success through careful consideration of the influence of certain extrinsic and intrinsic human factors in developing the patient care plan. Of increasing influence on patient care is the phenotype and genotype information gathered from employing various next-generation sequencing methods. Guided by and partnered with our civilian colleagues, clinical components within the DoD are embracing and advancing genomic medicine in many facets-from the bench to the bedside-and in many therapeutic areas, from Psychiatry to Oncology. In this PubMed-based review, we describe published clinical research and interventions within the DoD using genome-informed data and emphasize precision medicine efforts in earlier stages of development with the potential to revolutionize the approach to therapeutics.

MATERIALS AND METHODS: The new PubMed database was searched for articles published between 2015 and 2020 with the following key search terms: precision medicine, genomic, pharmacogenetic, pharmacogenomic, US military, and Department of Defense.

RESULTS: Eighty-one articles were retrieved in our initial search. After screening the abstracts for studies that only involved direct testing of (or clinical interaction with) active duty, Reserve, National Guard, or civilian personnel working within the DoD and excluding any epidemiological or microbial isolation studies, seven were included in this review.

CONCLUSION: There are several programs and studies within the DoD, which investigate or use gene-based biomarkers or gene variants to deliver more precise clinical assessment and treatment. These genome-based precision medicine efforts aim to optimize the clinical care of DoD beneficiaries, particularly service members in the operational environment.

PMID:34967400 | DOI:10.1093/milmed/usab243

Pediatr Pulmonol. 2021 Dec 29. doi: 10.1002/ppul.25809. Online ahead of print.

ABSTRACT

Patients with cystic fibrosis (CF) are exposed to many drugs in their lifetime and many of these drugs have Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines that are available to guide dosing. Contemporary CF treatments are targeted to specific mutations in the CF transmembrane conductance regulator (CFTR) gene, and thus, require patients to have genetic testing prior to initiation of modulator therapy. However, aside from CFTR genetic testing, pharmacogenomic testing is not standard of care for CF patients. The aim of this study was to determine the number of non-CFTR modulator medications with CPIC guidelines that are prescribed to patient with CF. We identified all patients with a diagnosis of CF and queried our hospital electronic medical records (EMR) for all orders, including inpatient and prescriptions, for all drugs or drug classes that have CPIC actionable guidelines for drug-gene pairs that can be used to guide therapy. We identified 576 patients with a diagnosis of CF that were treated at our institution during this 16-year period between June 2005 - May 2021. Of these patients, 504 patients (87.5%) received at least one drug that could have been dosed according to CPIC guidelines if pharmacogenomic results would have been available. Patients with CF have a high utilization of drugs with CPIC guidelines, therefore preemptive pharmacogenomic testing should be considered in CF patients at the time of CFTR genetic testing. This article is protected by copyright. All rights reserved.

PMID:34967155 | DOI:10.1002/ppul.25809

Genes Immun. 2021 Dec 29. doi: 10.1038/s41435-021-00159-z. Online ahead of print.

ABSTRACT

Two non-inbred mouse lines, phenotypically selected for maximal (AIRmin) and minimal (AIRmax) acute inflammatory response, show differential susceptibility/resistance to the development of several chemically-induced tumor types. An intercross pedigree of these mice was generated and treated with the chemical carcinogen dimethylhydrazine, which induces lung and intestinal tumors. Genome wide high-density genotyping with the Restriction Site-Associated DNA genotyping (2B-RAD) technique was used to map genetic loci modulating individual genetic susceptibility to both lung and intestinal cancer. Our results evidence new common quantitative trait loci (QTL) for those phenotypes and provide an improved understanding of the relationship between genomic variation and individual genetic predisposition to tumorigenesis in different organs.

PMID:34966170 | DOI:10.1038/s41435-021-00159-z

Mol Cancer Ther. 2021 Dec 29:molcanther.0561.2021. doi: 10.1158/1535-7163.MCT-21-0561. Online ahead of print.

ABSTRACT

Targeting the PD-1/PD-L1 pathway with immunotherapy has revolutionized the treatment of many cancers. Somatic tumor mutational burden (TMB) and T-cell-inflamed gene expression profile (GEP) are clinically validated pan-tumor genomic biomarkers that can predict responsiveness to anti-PD-1/PD-L1 monotherapy in many tumor types. We analyzed the association between these biomarkers and efficacy of PD-1 inhibitor in 11 commonly used preclinical syngeneic tumor mouse models using murinized rat anti-mouse PD-1 DX400 antibody muDX400, a surrogate for pembrolizumab. Response to muDX400 treatment was broadly classified into three categories: highly responsive, partially responsive, and intrinsically resistant to therapy. Molecular and cellular profiling validated differences in immune cell infiltration and activation in the tumor microenvironment of muDX400-responsive tumors. Baseline and on-treatment genomic analysis showed an association between TMB, murine T-cell-inflamed-gene expression profile (murine-GEP), and response to muDX400 treatment. We extended our analysis to investigate a canonical set of cancer and immune biology-related gene signatures, including signatures of angiogenesis, myeloid-derived suppressor cell, and stromal/epithelial-mesenchymal transition/transforming growth factor-β biology previously shown to be inversely associated with clinical efficacy of immune checkpoint blockade. Finally, we evaluated the association between murine-GEP and preclinical efficacy with standard-of-care chemotherapy or anti-angiogenic agents that previously demonstrated promising clinical activity, in combination with muDX400. Our profiling studies begin to elucidate the underlying biological mechanisms of response and resistance to PD-1/PD-L1 blockade represented by these models, thereby providing insight into which models are most appropriate for the evaluation of orthogonal combination strategies.

PMID:34965960 | DOI:10.1158/1535-7163.MCT-21-0561

Clin Cancer Res. 2021 Dec 29:clincanres.3329.2021. doi: 10.1158/1078-0432.CCR-21-3329. Online ahead of print.

ABSTRACT

PURPOSE: To explore relationships between biological gene expression signatures and pembrolizumab response.

EXPERIMENTAL DESIGN: RNA sequencing data on baseline tumor tissue from 1188 patients across seven tumor types treated with pembrolizumab monotherapy in nine clinical trials were used. A total of eleven prespecified gene expression signatures (18-gene T-cell-inflamed gene expression profile [TcellinfGEP], angiogenesis, hypoxia, glycolysis, proliferation, MYC, RAS, granulocytic myeloid-derived suppressor cell, monocytic myeloid-derived suppressor cell [mMDSC], stroma/EMT/TGF-β, WNT) were evaluated for their relationship to objective response rate (per Response Evaluation Criteria in Solid Tumors, version 1.1). Logistic regression analysis of response for consensus signatures was adjusted for tumor type, Eastern Cooperative Oncology Group performance status, and TcellinfGEP, an approach equivalent to evaluating the association between response and the residuals of consensus signatures after detrending them for their relationship with the TcellinfGEP (previously identified as a determinant of pembrolizumab response) and tumor type. Testing of the 10 prespecified non-TcellinfGEP consensus signatures for negative association (except proliferation [hypothesized positive association]) with response was adjusted for multiplicity RESULTS: Covariance patterns of the 11 signatures (including TcellinfGEP) identified in Merck-Moffitt and The Cancer Genome Atlas datasets showed highly concordant coexpression patterns in the RNA sequencing data from pembrolizumab trials. TcellinfGEP was positively associated with response; signatures for angiogenesis, mMDSC, and stroma/EMT/TGF-β were negatively associated with response to pembrolizumab monotherapy.

CONCLUSIONS: These findings suggest that features beyond interferon-γ-related T-cell inflammation may be relevant to anti-programmed death 1 monotherapy response and may define other axes of tumor biology as candidates for pembrolizumab combinations.

PMID:34965943 | DOI:10.1158/1078-0432.CCR-21-3329

Eur J Neurol. 2021 Dec 29. doi: 10.1111/ene.15236. Online ahead of print.

ABSTRACT

BACKGROUND: Erenumab (ERE) is the first anti-calcitonin gene related peptide (CGRP) receptor monoclonal antibody approved for migraine prevention. A proportion of patients does not adequately respond to ERE.

METHODS: Prospective, multicenter study involving 110 migraine patients starting ERE 70 mg monthly. Baseline socio-demographics and migraine characteristics including mean monthly migraine days (MMDs), migraine-related burden (MIDAS and HIT-6 scales) and use of abortive medications during 3 months before and after ERE start were collected. Real-time PCR was used to determine polymorphic variants of calcitonin receptor-like receptor and receptor activity-modifying protein-1 genes. Logistic regression models were used to identify independent predictors for 50% (50-RESP) and 75% (75-RESP) responder patients.

RESULTS: At month 3, MMDs decreased from 17.2 to 9.2 (p<0.0001), 59/110 (53.6%) patients were 50-RESP, and 30/110 (27.3%) were 75-RESP. Age at migraine onset [OR (95%CI):1.062(1.008-1.120), p=0.024], number of failed preventive medications [0.753(0.600-0.946) p=0.015], and MIDAS score [1.011(1.002-1.020) p=0.017] were associated with 75-RESP. Among the genetic variants investigated, RAMP1 rs7590387 was found associated to a lower probability of being 75-RESP [per G allele OR (95%CI): 0.53(0.29-0.99), p=0.048], but this association did not survive adjustment for confounding clinical variables [per G allele, 0.55 (0.28-1.10), p=0.09].

CONCLUSIONS: In this real word study treatment with ERE significant reduced MMDs. Number of failed preventive medications, migraine burden, and age at migraine onset predicted response to ERE. Larger studies are required to confirm a possible role of RAMP1 rs7590387 as genetic predictor of ERE efficacy.

PMID:34965002 | DOI:10.1111/ene.15236

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2022 Jan 10;39(1):108-111. doi: 10.3760/cma.j.cn511374-20201012-00712.

ABSTRACT

Genetic background can lead to differences in drug effects among different populations when they use the same drug. To delineate the pharmacogenomics and population genetic differences may help to clarify the role of polymorphisms of drug metabolism-related genes in drug effect heterogeneity among different populations. This article has summarized the latest progress on the polymorphisms of drug metabolism-related genes among different populations in China.

PMID:34964980 | DOI:10.3760/cma.j.cn511374-20201012-00712

World J Gastroenterol. 2021 Dec 7;27(45):7859-7861. doi: 10.3748/wjg.v27.i45.7859.

ABSTRACT

Fasudil has the potential to prevent liver fibrosis by activating natural killer cells and inhibiting the proliferation of hepatic stellate cells. Fasudil may be a promising clinical therapeutic drug for the prevention and treatment of liver fibrosis.

PMID:34963748 | PMC:PMC8661378 | DOI:10.3748/wjg.v27.i45.7859

Comput Methods Programs Biomed. 2021 Dec 17;214:106589. doi: 10.1016/j.cmpb.2021.106589. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: A novel research field in bioinformatics is pharmacogenomics and the corresponding applications of artificial intelligence tools. Pharmacogenomics is the study of the relationship between genotype and responses to medical measures such as drug use. One of the most effective drugs is warfarin anticoagulant, but determining its initial treatment dose is challenging. Mistakes in the determination of the initial treatment dose can result directly in patient death.

METHODS: Some of the most successful techniques for estimating the initial treatment dose are kernel-based methods. However, all the available studies use pre-defined and constant kernels that might not necessarily address the problem's intended requirements. The present study seeks to define and present a new computational kernel extracted from a data set. This process aims to utilize all the data-related statistical features to generate a dose determination tool proportional to the data set with minimum error rate. The kernel-based version of the least square support vector regression estimator was defined. Through this method, a more appropriate approach was proposed for predicting the adjusted dose of warfarin.

RESULTS AND CONCLUSION: This paper benefits from the International Warfarin Pharmacogenomics Consortium (IWPC) Database. The results obtained in this study demonstrate that the support vector regression with the proposed new kernel can successfully estimate the ideal dosage of warfarin for approximately 68% of patients.

PMID:34963093 | DOI:10.1016/j.cmpb.2021.106589

Chin J Nat Med. 2021 Dec;19(12):921-929. doi: 10.1016/S1875-5364(21)60113-9.

ABSTRACT

This work was aimed to establish a quality control method for evaluating the effects on glucose and lipids of the fruiting body of Isaria cicadae Miquel from strain Ic-17-7 (Ic-17-7fb) using a rat model of type 2 diabetes (T2DM). Random amplified polymorphic DNA, sequence-characterized amplified region, and high-performance liquid chromatography (HPLC) were used for the quality control of Ic-17-7fb. The pharmacological effects on streptozocin (STZ)-induced high fat diet (HFD)-fed Albino Wistar rats were evaluated. The rats underwent the following treatments: control, metformin, Ic-17-7fb (0.166 and 0.5 g·kg-1) or without treatment. The fasting blood glucose (FBG), blood glucose, total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL-c), and low-density lipoprotein (LDL-c) were measured. Ic-17-7fb amplified a single specific band by S11-2-F3 and S11-2-R3 primers. An HPLC-based quality and quantity method was established for industrial application. The contents of adenosine and N6-(2-hydroxyethyl) adenosine (HEA) of the cultivated Ic-17-7fb were analyzed. All of the validation lots of cultured Ic-17-7fb passed the quantity control of the training set (0.90 mg·g-1 of adenosine and 0.89 mg·g-1 of HEA). After two weeks of administration, the average FBG was 4.89 ± 0.42 (control), 26.10 ± 5.77 (model), 23.63 ± 6.15 (metformin), 17.96 ± 9.36 (Ic-17-7fb for 0.166 g·kg-1), and 19.69 ± 8.71 mmol·L-1 (Ic-17-7fb for 0.5 g·kg-1). The FBG of Ic-17-7fb (0.166 g·kg-1) treatment significantly reduced by 31.19%, compared with the model after two weeks of administration (P < 0.01). Metformin, Ic-17-7fb (0.166 g·kg -1), and Ic-17-7fb (0.5 g·kg-1) reduced TC, TG, HDL-c, and LDL-c compared with the T2DM model treatment at the 6th week of treatment (P < 0.05). This study established the first quality standard for Ic-17-7fb, which can be effectively applied in the treatment of T2DM. The reliable quality control method and pharmacological effect will broaden its application space.

PMID:34961590 | DOI:10.1016/S1875-5364(21)60113-9

Pharmaceuticals (Basel). 2021 Dec 17;14(12):1324. doi: 10.3390/ph14121324.

ABSTRACT

High-throughput screening of drug response in cultured cell lines is essential for studying therapeutic mechanisms and identifying molecular variants associated with sensitivity to drugs. Assessment of drug response is typically performed by constructing a dose-response curve of viability and summarizing it to a representative, such as IC50. However, this is limited by its dependency on the assay duration and lack of reflections regarding actual cellular response phenotypes. To address these limitations, we consider how each response-phenotype contributes to the overall growth behavior and propose an alternative method of drug response screening that takes into account the cellular response phenotype. In conventional drug response screening methods, the ranking of sensitivity depends on either the metric used to construct the dose-response curve or the representative factor used to summarize the curve. This ambiguity in conventional assessment methods is due to the fact that assessment methods are not consistent with the underlying principles of population dynamics. Instead, the suggested phenotype metrics provide all phenotypic rates of change that shape overall growth behavior at a given dose and better response classification, including the phenotypic mechanism of overall growth inhibition. This alternative high-throughput drug-response screening would improve preclinical pharmacogenomic analysis and the understanding of a therapeutic mechanism of action.

PMID:34959724 | DOI:10.3390/ph14121324