Transl Oncol. 2022 Sep 11;25:101532. doi: 10.1016/j.tranon.2022.101532. Online ahead of print.

ABSTRACT

Multiple myeloma (MM) is an aggressive cancer characterised by malignancy of the plasma cells and a rising global incidence. The gold standard for optimum response is aggressive chemotherapy followed by autologous stem cell transplantation (ASCT). However, majority of the patients are above 60 years and this presents the clinician with complications such as ineligibility for ASCT, frailty, drug-induced toxicity and differential/partial response to treatment. The latter is partly driven by heterogenous genotypes of the disease in different subpopulations. In this review, we discuss emerging single cell technologies and applications in MM, population pharmacogenetics of MM, resistance to chemotherapy, genetic determinants of drug-induced toxicity, molecular signal transduction, as well as the role(s) played by epigenetics and noncoding RNAs including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) that influence the risk and severity of the disease. Taken together, our discussions further our understanding of genetic variability in 'myelomagenesis' and drug-induced toxicity, augment our understanding of the myeloma microenvironment at the molecular and cellular level and provide a basis for developing precision medicine strategies to combat this malignancy.

PMID:36103755 | DOI:10.1016/j.tranon.2022.101532

Pharmacogenomics. 2022 Sep 14. doi: 10.2217/pgs-2022-0070. Online ahead of print.

ABSTRACT

Cognitive dysfunction is a core feature of psychosis-spectrum illnesses, and the characterization of related genetic mechanisms may provide insights regarding the disease pathophysiology. Substantial efforts have been made to determine the genetic component of cognitive symptoms, without clear success. Illness-related moderators and environmental factors such as medications hinder the detection of genomic association with cognition. Polypharmacy is common in psychotic disorders, and the cumulative effects of medication regimens can confound gene-cognition associations. A review of the relative contributions of important pharmacological and genetic relationships identifies that the effects of medications on cognition in psychotic disorders may be at least, if not more, impactful than individual genes, thus underscoring the importance of accounting for medication exposure in gene-cognition association studies.

PMID:36102182 | DOI:10.2217/pgs-2022-0070

Pharmacogenomics. 2022 Sep 14. doi: 10.2217/pgs-2022-0087. Online ahead of print.

ABSTRACT

Tweetable abstract Clinical phenoconversion needs to be incorporated when interpreting and applying CYP2D6 results in clinical care. This article describes how this can be performed either manually or by utilizing online tools and resources. #Phenoconversion #Pharmacogenomics.

PMID:36102178 | DOI:10.2217/pgs-2022-0087

Clin Toxicol (Phila). 2022 Sep 14:1-7. doi: 10.1080/15563650.2022.2117053. Online ahead of print.

ABSTRACT

BACKGROUND: Several studies have suggested genetic variants associated with acetaminophen induced liver injury (DILI) following overdose. Genetic variation associated with acetaminophen-induced alanine aminotransferase elevation during therapeutic dosing has not been examined.

METHODS: We performed genetic analyses on patients that ingested therapeutic doses of 4 grams of acetaminophen for up to 16 days. We examined 20 genes previously implicated in the metabolism of acetaminophen or the development of immune-mediated DILI using the Illumina Multi-Ethnic Global Array 2. Autosomes were aligned and imputed using TOPMed. A candidate gene region analysis was performed by testing each gene individually using linkage disequilibrium (LD) pruned variants with the adaptive sum of powered scores (aSPU) test from the aSPU R package. The highest measured ALT during therapy, the maximum ALT, was used as the outcome.

RESULTS: 192 subjects taking therapeutic APAP were included in the genetic analysis. 136 (70.8%) were female, 133 (69.2%) were Caucasian race, and the median age was 34 years (IQR: 26, 46). Age > 50 years was the only clinical factor associated with maximum ALT increase. Variants in SULT1E1, the gene responsible for Sulfotransferase Family 1E Member 1 enzyme production, were associated with maximum ALT. No single variant drove this association, but rather the association was due to the additive effects of numerous variants within the gene. No other genes were associated with maximum ALT increase in this cohort.

CONCLUSION: Acetaminophen induced ALT elevation at therapeutic doses was not associated with variation in most genes associated with acetaminophen metabolism or immune-induced DILI in this cohort. The role of SULT1E1 polymorphism in acetaminophen-induced elevated ALT needs further examination.

PMID:36102175 | DOI:10.1080/15563650.2022.2117053

J Clin Endocrinol Metab. 2022 Sep 14:dgac527. doi: 10.1210/clinem/dgac527. Online ahead of print.

ABSTRACT

OBJECTIVE: A hypothesis-free genetic association analysis has not been reported for patients with primary hyperparathyroidism (PHPT). We aimed to investigate genetic associations with PHPT using both genome-wide association study (GWAS) and candidate gene approaches.

METHODS: A cross-sectional study was done among patients of European Caucasian ethnicity recruited in Tayside (Scotland, UK). Electronic medical records were used to identify PHPT cases and controls, and linked to genetic biobank data. Genetic associations were performed by logistic regression models and Odds Ratios (ORs). The combined effect of the genotypes was researched by genetic risk score (GRS) analysis.

RESULTS: We identified 15,622 individuals for the GWAS that yielded 34 top single-nucleotide polymorphisms, and LPAR3-rs147672681 reached genome-wide statistical significance (P=1.2e-08). Using a more restricted PHPT definition 8,722 individuals with data on the GWAS-identified loci were found. Age-sex adjusted ORs for the effect alleles of SOX9-rs11656269, SLITRK5-rs185436526, and BCDIN3D-AS1-rs2045094 showed significant increased risks (P<1.5e-03). GRS analysis of 5482 individuals showed an OR of 2.51 (P=1.6e-04), 3.78 (P=4.0e-08) and 7.71 (P=5.3e-17) for the second, third and fourth quartiles respectively compared to the first, and there was a significant linear trend across quartiles (P<1.0e-04). Results were similar when stratifying by gender.

CONCLUSIONS: Using genetic loci discovered in a GWAS of PHPT carried out in a Scottish population, this study suggests new evidence for the involvement of genetic variants at SOX9, SLITRK5, LPAR3 and BCDIN3D-AS1. It also suggests that both male and female carriers of greater numbers of PHPT-risk alleles have a significant increased risk of PHPT.

PMID:36102151 | DOI:10.1210/clinem/dgac527

Radiat Environ Biophys. 2022 Sep 13. doi: 10.1007/s00411-022-00991-5. Online ahead of print.

ABSTRACT

Exosomes are spherical membrane nanovesicles secreted from cells, and they play an important role in tumor immune response, metastasis, angiogenesis, and survival. Studies investigating exosomes isolated from cells exposed to photon radiation commonly used in conventional radiotherapy demonstrate the influence of this type of radiation on exosome characteristics and secretion. There is currently no research investigating the effects of densely ionizing particles such as protons and alpha radiation on exosomes. Thus we have evaluated the cellular response of human prostate cancer cells exposed to 0, 2, and 6 Gy of alpha radiation emitted from the Am-241 source. Irradiated PC3 and DU145 cell lines, characterized by differences in radiosensitivity, were studied using apoptosis, LDH, and IL-6 assays. Additionally, the corresponding concentration and size of isolated exosomes were measured using NTA. We found that exposure to ionizing radiation resulted in gross changes in viability and cell damage. There were increased amounts of apoptotic or necrotic cells as a function of radiation dose. We demonstrated that irradiated PC3 cells secrete higher quantities of exosomes compared to DU145 cells. Additionally, we also found no statistical difference in exosome size for control and irradiated cells.

PMID:36098819 | DOI:10.1007/s00411-022-00991-5

BMC Med Genomics. 2022 Sep 12;15(Suppl 3):193. doi: 10.1186/s12920-022-01308-7.

ABSTRACT

BACKGROUND: Personalized medicine is an emerging field, aiming to improve the safety and efficacy of pharmacotherapy. The field's implementation in clinical care is steadily increasing. Pharmacogenomics are one example of personalized approaches in the clinic and direct-to-consumer (DTC) pharmacogenomic tests have become publicly available. We aimed to assess public opinion on pharmacogenomic research and testing to foster integration within Belgian health care.

METHODS: A cross-sectional survey was created and disseminated online, focusing on the citizen perspective. Participants' willingness to engage in pharmacogenomic research was the primary outcome. In addition, their awareness, understanding, expectations and overall acceptance towards pharmacogenomic testing was investigated.

RESULTS: A total of 156 participants (54.5% aged between 18 and 30 years, 45.5% > 30 years; 73.1% females) completed the survey. Half ever experienced side effects (46.2%) and treatment failure (52.6%). Up to 45.5% (n = 71) were willing to participate in pharmacogenomics research, and the majority (78.8%) were convinced that pharmacogenomic tests could help doctors to prescribe them the right medications. Additionally, 76.3% (n = 118) supported a partial reimbursement of pharmacogenomics tests. A minority (5.1%, n = 8) of participants showed interest in DTC tests, and 15.4% (n = 24) expressed privacy concerns regarding pharmacogenomics testing. Participants preferred their healthcare professionals' to perform the test and access their data, but refused commercial providers.

CONCLUSION: Overall, participants showed a positive attitude towards precision medicine and pharmacogenomics research. Our findings may help guiding future pharmacogenomic implementation initiatives to optimize drug use by using pharmacogenomic information integrated within health care.

PMID:36096833 | DOI:10.1186/s12920-022-01308-7

Drug Discov Today. 2022 Sep 9:103349. doi: 10.1016/j.drudis.2022.103349. Online ahead of print.

ABSTRACT

Sulfotransferases (SULTs) are Phase II drug-metabolizing enzymes (DMEs) catalyzing the sulfation of a variety of endogenous compounds, natural products, and drugs. Various drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDS) can inhibit SULTs, affecting drug-drug interactions. Several polymorphisms have been identified for SULTs that might be crucial for interindividual variability in drug response and toxicity or for increased disease risk. Here, we review current knowledge on non-synonymous single nucleotide polymorphisms (nsSNPs) of human SULTs, focusing on the coded SULT allozymes and molecular mechanisms explaining their variable activity, which is essential for personalized medicine. We discuss the structural and dynamic bases of key amino acid (AA) variants implicated in the impacts on drug metabolism in the case of SULT1A1, as revealed by molecular modeling approaches. Teaser: Sulfotransferases (SULTs) are drug-metabolizing enzymes catalyzing the sulfation of many endogenous compounds and drugs. We review current knowledge on polymorphisms of SULTs, focusing on coded SULT allozymes that might be crucial for interindividual variability in drug response and toxicity.

PMID:36096358 | DOI:10.1016/j.drudis.2022.103349

Proc Natl Acad Sci U S A. 2022 Sep 20;119(38):e2205454119. doi: 10.1073/pnas.2205454119. Epub 2022 Sep 12.

ABSTRACT

Trastuzumab is the first-line therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but often patients develop acquired resistance. Although other agents are in clinical use to treat trastuzumab-resistant (TR) breast cancer; still, the patients develop recurrent metastatic disease. One of the primary mechanisms of acquired resistance is the shedding/loss of the HER2 extracellular domain, where trastuzumab binds. We envisioned any new agent acting downstream of the HER2 should overcome trastuzumab resistance. The mixed lineage kinase 3 (MLK3) activation by trastuzumab is necessary for promoting cell death in HER2+ breast cancer. We designed nanoparticles loaded with MLK3 agonist ceramide (PPP-CNP) and tested their efficacy in sensitizing TR cell lines, patient-derived organoids, and patient-derived xenograft (PDX). The PPP-CNP activated MLK3, its downstream JNK kinase activity, and down-regulated AKT pathway signaling in TR cell lines and PDX. The activation of MLK3 and down-regulation of AKT signaling by PPP-CNP induced cell death and inhibited cellular proliferation in TR cells and PDX. The apoptosis in TR cells was dependent on increased CD70 protein expression and caspase-9 and caspase-3 activities by PPP-CNP. The PPP-CNP treatment alike increased the expression of CD70, CD27, cleaved caspase-9, and caspase-3 with a concurrent tumor burden reduction of TR PDX. Moreover, the expressions of CD70 and ceramide levels were lower in TR than sensitive HER2+ human breast tumors. Our in vitro and preclinical animal models suggest that activating the MLK3-CD70 axis by the PPP-CNP could sensitize/overcome trastuzumab resistance in HER2+ breast cancer.

PMID:36095190 | DOI:10.1073/pnas.2205454119

Curr Med Res Opin. 2022 Sep 12:1-21. doi: 10.1080/03007995.2022.2124072. Online ahead of print.

ABSTRACT

The large-scale implementation of genomic medicine in Africa has not been achieved. This overview describes how routine molecular genetics and advanced protein engineering/structural biotechnology could accelerate its implementation. First, by using data mining and analysis approaches, we analysed relevant information obtained from public genomic databases on pharmacogenomics biomarkers, and reviewed published studies to discuss the ideas. The results showed that only 68 very important pharmacogenes currently exist, while 867 drug label annotations, 201 curated functional pathways, and 746 annotated drugs have been catalogued on the largest pharmacogenomics database (PharmGKB). Only about 5009 variants of the reported ∼25000 have been clinically annotated. Predominantly, the genetic variants were derived from forty-three (43) genes that contribute to 2318 clinically relevant variations in 57 diseases. Majority (∼60%) of the clinically relevant genetic variations in the pharmacogenes are missense variants (1390). The enrichment analysis showed that 15 pharmacogenes are connected biologically and are involved in the metabolism of cardiovascular and cancer drugs. The labelled drugs are based on measurable or identifiable genetic information and phenotypic data derived mainly from non-Africans. The review of studies showed that cardiovascular diseases are the most frequent non-communicable diseases responsible for approximately 13% of all deaths in Africa. Also, warfarin pharmacogenomics is the most studied drug on the continent, while CYP2D6, CYP2C9, DPD and TPMT are the most investigated pharmacogenes with allele activities indicated in African and considered to be intermediate metaboliser for DPD and TPMT (8.4% and 11%). In summary, we highlighted a framework for implementing genomic medicine starting from the available resources on ground. However, there is urgent need for researchers and clinicians to harness innovations and skills in the areas of molecular genetics, molecular biology, biotechnology, bioinformatics and pharmacogenomics to achieve quality health services. The existing genomic initiatives in Africa like the Human Heredity and Health in Africa (H3Africa) consortium (https://h3africa.org/) must drive these areas with passion for expansive genetic discovery to drug allelic annotations, translational studies, and clinical trials of novel drug designs. We conclude that personalized medicine for Africans is possible by fine-tuning the strategies and holistically harnessing the modern approaches and techniques.

PMID:36094413 | DOI:10.1080/03007995.2022.2124072

Clin Pharmacol Ther. 2022 Sep 12. doi: 10.1002/cpt.2746. Online ahead of print.

ABSTRACT

Major depressive disorder (MDD) is a common disorder in pregnancy. Although sertraline is the most frequently prescribed antidepressant for pregnant people in the United States, limited information about its pharmacokinetics in pregnancy is available. Our objectives were to characterize plasma sertraline concentration to dose (C/D) ratios across pregnancy and postpartum and investigate the effect of pharmacogenetic variability on sertraline elimination. We performed a prospective observational cohort study in people with a singleton pregnancy ≤18 weeks gestation and a lifetime diagnosis of MDD at the 3 NICHD-funded Obstetrical-Fetal Pharmacology Research Center sites. Subjects (N=47) were receiving maintenance sertraline therapy and chose to continue it during pregnancy. Blood samples were obtained 24-hours post-dose every four weeks across pregnancy and twice postpartum for measurement of plasma concentrations of sertraline and desmethylsertraline. Overall mean sertraline C/D ratios were decreased at study onset and remained consistently low until after delivery. During the last 4 weeks of pregnancy the mean sertraline C/D ratio (95% CI), 0.25 (0.19, 0.3) ng/mL/dose (mg/day), was smaller than the mean ratio at ≥ 8 weeks after delivery, 0.32 (0.27, 0.37) ng/mL/dose (mg/day), a 22% difference. Mean sertraline/desmethylsertraline ratios were highest after birth, which confirmed increased sertraline elimination during pregnancy. Sertraline C/D ratios in participants with functional CYP2C19 activity did not change significantly during pregnancy, while ratios in participants with poor or intermediate CYP2C19 activity decreased by 51%. Exploratory pharmacogenomic analysis indicated that pregnant people with poor or intermediate CYP2C19 activity are at risk for subtherapeutic sertraline concentrations during pregnancy.

PMID:36094046 | DOI:10.1002/cpt.2746

Pharmacogenomics. 2022 Sep 12:0. doi: 10.2217/pgs-2022-0048. Online ahead of print.

ABSTRACT

Aims: To study the readiness of Russian physicians with experience and younger physicians undergoing clinical residency and postgraduate education to apply pharmacogenetic testing in their clinical practice. Materials & methods: The sociological study involved physicians (n = 378) living in different regions of the Russian Federation, as well as residents and graduate students (n = 185) of the Russian Medical Academy of Continuing Professional Medical Education. The survey consisted of 35 questions, and 23 were created on the online platform of professional surveys, Testograf.ru. Results: Every second respondent was willing to use pharmacogenetic testing in clinical practice to predict the efficacy and safety of medications in patients with cardiovascular disease (p = 0.06). Factors impeding the clinical implementation of pharmacogenetic testing in Russia were identified: physicians' ignorance of pharmacogenetics (p = 0.015), a lack of pharmacogenetic testing in clinical guidelines and treatment standards (p = 0.175) and a lack of economic justification for using pharmacogenetic testing (p = 0.320). Conclusion: Russian physicians have a positive attitude toward pharmacogenetic testing. However, the level of test implementation remains low.

PMID:36093937 | DOI:10.2217/pgs-2022-0048

Front Genet. 2022 Aug 25;13:948616. doi: 10.3389/fgene.2022.948616. eCollection 2022.

ABSTRACT

Pharmacogenetic (PGx) testing has not been well adopted in current clinical practice. The phenotypic distribution of clinically relevant pharmacogenes remains to be fully characterized in large population cohorts. In addition, no study has explored actionable PGx alleles in the East Asian population at a large scale. This study comprehensively analyzed 14 actionable pharmacogene diplotypes and phenotypes in 172,854 Taiwanese Han individuals by using their genotype data. Furthermore, we analyzed data from electronic medical records to investigate the effect of the actionable phenotypes on the individuals. The PGx phenotype frequencies were comparable between our cohort and the East Asian population. Overall, 99.9% of the individuals harbored at least one actionable PGx phenotype, and 29% of them have been prescribed a drug to which they may exhibit an atypical response. Our findings can facilitate the clinical application of PGx testing and the optimization of treatment and dosage individually.

PMID:36092904 | PMC:PMC9452738 | DOI:10.3389/fgene.2022.948616

Transl Androl Urol. 2022 Aug;11(8):1083-1095. doi: 10.21037/tau-22-113.

ABSTRACT

BACKGROUND: In recent years, a large number of clinical and epidemiological studies have revealed the anti-cancer activity of propranolol in solid tumors, though the underline mechanism is yet to be clarified.

METHODS: The proliferation of bladder cancer cells treated with propranolol was detected by MTS assays. In vivo tumor xenograft experiments were used to observe the effect of propranolol on bladder cancer growth in mice. The expression levels of Na+/H+ exchanger (NHE1) was measured by western blot. The frequency of CD8+ T cells and CD4+ T cells were detected via flow cytometry.

RESULTS: In this study, propranolol inhibited the expression of NHE1 and sequentially led to a decrease of intracellular pH to 5.88 in MB49 cells and 6.85 in 5637 cells, thereafter, inhibited cell viability and induced apoptosis. Furthermore, propranolol inhibited the growth of bladder cancer in mice xenograft model. Flow cytometry found that the frequency of CD8+ T cells (34.58±2.11 vs. 32.34±0.6, P=0.35) and CD4+ T cells (57.80±2.45 vs. 51.44±0.79, P=0.06) in the spleen did not change compared with the control group, while the expression of IFN-γ, GZMB and T-bet secreted by CD8+ T cells increased respectively (IFN-γ 7.3±0.17 vs. 3.37±0.58, P=0.0017; GZMB 16.66±2.13 vs. 4.53±0.62, P=0.0034; T-bet 3.62±0.35 vs. 1.74±0.26, P=0.0027). Meantime, the expression of FoxP3 on CD4+ T cells decreased both in spleen and tumor tissue (1.53±0.11 vs. 0.91±0.1, P=0.004; 4.52±0.48 vs. 1.76±0.40, P=0.003).

CONCLUSIONS: These results suggested that propranolol exerted anti-proliferation and pro-apoptosis effects in bladder cancer cell by inhibiting Na+/H+ exchange and activated systemic anti-tumor immune response in vivo.

PMID:36092839 | PMC:PMC9459546 | DOI:10.21037/tau-22-113

PeerJ Comput Sci. 2022 Aug 18;8:e1050. doi: 10.7717/peerj-cs.1050. eCollection 2022.

ABSTRACT

CONTEXT: The computerization of both fetal heart rate (FHR) and intelligent classification modeling of the cardiotocograph (CTG) is one of the approaches that are utilized in assisting obstetricians in conducting initial interpretation based on (CTG) analysis. CTG tracing interpretation is crucial for the monitoring of the fetal status during weeks into the pregnancy and childbirth. Most contemporary studies rely on computer-assisted fetal heart rate (FHR) feature extraction and CTG categorization to determine the best precise diagnosis for tracking fetal health during pregnancy. Furthermore, through the utilization of a computer-assisted fetal monitoring system, the FHR patterns can be precisely detected and categorized.

OBJECTIVE: The goal of this project is to create a reliable feature extraction algorithm for the FHR as well as a systematic and viable classifier for the CTG through the utilization of the MATLAB platform, all the while adhering to the recognized Royal College of Obstetricians and Gynecologists (RCOG) recommendations.

METHOD: The compiled CTG data from spiky artifacts were cleaned by a specifically created application and compensated for missing data using the guidelines provided by RCOG and the MATLAB toolbox after the implemented data has been processed and the FHR fundamental features have been extracted, for example, the baseline, acceleration, deceleration, and baseline variability. This is followed by the classification phase based on the MATLAB environment. Next, using the guideline provided by the RCOG, the signals patterns of CTG were classified into three categories specifically as normal, abnormal (suspicious), or pathological. Furthermore, to ensure the effectiveness of the created computerized procedure and confirm the robustness of the method, the visual interpretation performed by five obstetricians is compared with the results utilizing the computerized version for the 150 CTG signals.

RESULTS: The attained CTG signal categorization results revealed that there is variability, particularly a trivial dissimilarity of approximately (+/-4 and 6) beats per minute (b.p.m.). It was demonstrated that obstetricians' observations coincide with algorithms based on deceleration type and number, except for acceleration values that differ by up to (+/-4).

DISCUSSION: The results obtained based on CTG interpretation showed that the utilization of the computerized approach employed in infirmaries and home care services for pregnant women is indeed suitable.

CONCLUSIONS: The classification based on CTG that was used for the interpretation of the FHR attribute as discussed in this study is based on the RCOG guidelines. The system is evaluated and validated by experts based on their expert opinions and was compared with the CTG feature extraction and classification algorithms developed using MATLAB.

PMID:36092005 | PMC:PMC9454876 | DOI:10.7717/peerj-cs.1050

Her Russ Acad Sci. 2022;92(4):456-463. doi: 10.1134/S1019331622040141. Epub 2022 Sep 6.

ABSTRACT

The COVID-19 pandemic has served as a catalyst for a whole layer of scientific research, including in Russia, where, since 2020, international multicenter studies have been conducted on the impact of the coronavirus infection on the course of oncological diseases, as well as on the development and application of new clinical methods in oncology. In the years 2020-2022, new methods of nuclear medicine based on the targeted effect of ionizing radiation of radiopharmaceuticals began to be actively developed, in particular, new domestic radiopharmaceuticals (RPs) for diagnostics and therapy and methods of intra-arterial radioembolization developed by RPs with 90Y and 188Re of primary and metastatic tumors of various localization. New methods of radiation therapy have been introduced into clinical practice, including remote radiation therapy with "fast" neutrons, which makes it possible to overcome the resistance of a tumor to radiation and drug treatment. In addition, the search for and introduction into clinical practice of new approaches in the field of gene therapy and the use of oncolytic viruses continues. Platforms for complex pharmacogenomic analysis based on global knowledge and deep machine learning are being used in Russia, allowing for the precise selection of the most effective therapy. New multidisciplinary technologies are being developed.

PMID:36091860 | PMC:PMC9447986 | DOI:10.1134/S1019331622040141

Front Pharmacol. 2022 Aug 25;13:952250. doi: 10.3389/fphar.2022.952250. eCollection 2022.

ABSTRACT

Chronic myeloid leukemia (CML) is caused by constitutively active fusion protein BCR-ABL1, and targeting ABL1 is a promising therapy option. Imatinib, dasatinib, and nilotinib have all been shown to work effectively in clinical trials. ABL1 mutations, particularly the T315I gate-keeper mutation, cause resistance in patients. As a result, broad-spectrum ABL1 medicines are desperately needed. In order to screen potential drugs targeting CML, mebendazole (MBZ) was subjected to the in vitro test against CML cell lines (K562 and FEPS) and computational assays. The antiproliferative effect of MBZ and the combination with tyrosine kinase inhibitors (TKIs) was tested using end-point viability assays, cell cycle distribution analysis, cell membrane, and mitochondrial dyes. By interrupting the cell cycle and causing cell death, MBZ and its combination with imatinib and dasatinib have a significant antiproliferative effect. We identified MBZ as a promising "new use" drug targeting wild-type and mutant ABL1 using molecular docking. Meanwhile, we determined which residues in the allosteric site are important in ABL1 drug development. These findings may not only serve as a model for repositioning current authorized medications but may also provide ABL1-targeted anti-CML treatments a fresh lease of life.

PMID:36091760 | PMC:PMC9452629 | DOI:10.3389/fphar.2022.952250

Front Neurosci. 2022 Aug 24;16:1000783. doi: 10.3389/fnins.2022.1000783. eCollection 2022.

NO ABSTRACT

PMID:36090269 | PMC:PMC9450854 | DOI:10.3389/fnins.2022.1000783

Front Neurosci. 2022 Aug 25;16:994458. doi: 10.3389/fnins.2022.994458. eCollection 2022.

ABSTRACT

BACKGROUND PURPOSE: A substantial number of patients with acute ischemic stroke (AIS) experience multiple acute lesions (MAL). We here aimed to scrutinize MAL in a large radiologically deep-phenotyped cohort.

MATERIALS AND METHODS: Analyses relied upon imaging and clinical data from the international MRI-GENIE study. Imaging data comprised both Fluid-attenuated inversion recovery (FLAIR) for white matter hyperintensity (WMH) burden estimation and diffusion-weighted imaging (DWI) sequences for the assessment of acute stroke lesions. The initial step featured the systematic evaluation of occurrences of MAL within one and several vascular supply territories. Associations between MAL and important imaging and clinical characteristics were subsequently determined. The interaction effect between single and multiple lesion status and lesion volume was estimated by means of Bayesian hierarchical regression modeling for both stroke severity and functional outcome.

RESULTS: We analyzed 2,466 patients (age = 63.4 ± 14.8, 39% women), 49.7% of which presented with a single lesion. Another 37.4% experienced MAL in a single vascular territory, while 12.9% featured lesions in multiple vascular territories. Within most territories, MAL occurred as frequently as single lesions (ratio ∼1:1). Only the brainstem region comprised fewer patients with MAL (ratio 1:4). Patients with MAL presented with a significantly higher lesion volume and acute NIHSS (7.7 vs. 1.7 ml and 4 vs. 3, p FDR < 0.001). In contrast, patients with a single lesion were characterized by a significantly higher WMH burden (6.1 vs. 5.3 ml, p FDR = 0.048). Functional outcome did not differ significantly between patients with single versus multiple lesions. Bayesian analyses suggested that the association between lesion volume and stroke severity between single and multiple lesions was the same in case of anterior circulation stroke. In case of posterior circulation stroke, lesion volume was linked to a higher NIHSS only among those with MAL.

CONCLUSION: Multiple lesions, especially those within one vascular territory, occurred more frequently than previously reported. Overall, multiple lesions were distinctly linked to a higher acute stroke severity, a higher total DWI lesion volume and a lower WMH lesion volume. In posterior circulation stroke, lesion volume was linked to a higher stroke severity in multiple lesions only.

PMID:36090258 | PMC:PMC9453031 | DOI:10.3389/fnins.2022.994458

Lancet Gastroenterol Hepatol. 2022 Sep 8:S2468-1253(22)00274-6. doi: 10.1016/S2468-1253(22)00274-6. Online ahead of print.

ABSTRACT

BACKGROUND: COVID-19 vaccine-induced antibody responses are reduced in patients with inflammatory bowel disease (IBD) taking anti-TNF or tofacitinib after two vaccine doses. We sought to assess whether immunosuppressive treatments were associated with reduced antibody and T-cell responses in patients with IBD after a third vaccine dose.

METHODS: VIP was a multicentre, prospective, case-control study done in nine centres in the UK. We recruited immunosuppressed patients with IBD and non-immunosuppressed healthy individuals. All participants were aged 18 years or older. The healthy control group had no diagnosis of IBD and no current treatment with systemic immunosuppressive therapy for any other indication. The immunosuppressed patients with IBD had an established diagnosis of Crohn's disease, ulcerative colitis, or unclassified IBD using standard definitions of IBD, and were receiving established treatment with one of six immunosuppressive regimens for at least 12 weeks at the time of first dose of SARS-CoV-2 vaccination. All participants had to have received three doses of an approved COVID-19 vaccine. SARS-CoV-2 spike antibody binding and T-cell responses were measured in all participant groups. The primary outcome was anti-SARS-CoV-2 spike (S1 receptor binding domain [RBD]) antibody concentration 28-49 days after the third vaccine dose, adjusted by age, homologous versus heterologous vaccine schedule, and previous SARS-CoV-2 infection. The primary outcome was assessed in all participants with available data.

FINDINGS: Between Oct 18, 2021, and March 29, 2022, 352 participants were included in the study (thiopurine n=65, infliximab n=46, thiopurine plus infliximab combination therapy n=49, ustekinumab n=44, vedolizumab n=50, tofacitinib n=26, and healthy controls n=72). Geometric mean anti-SARS-CoV-2 S1 RBD antibody concentrations increased in all groups following a third vaccine dose, but were significantly lower in patients treated with infliximab (2736·8 U/mL [geometric SD 4·3]; p<0·0001), infliximab plus thiopurine (1818·3 U/mL [6·7]; p<0·0001), and tofacitinib (8071·5 U/mL [3·1]; p=0·0018) compared with the healthy control group (16 774·2 U/mL [2·6]). There were no significant differences in anti-SARS-CoV-2 S1 RBD antibody concentrations between the healthy control group and patients treated with thiopurine (12 019·7 U/mL [2·2]; p=0·099), ustekinumab (11 089·3 U/mL [2·8]; p=0·060), or vedolizumab (13 564·9 U/mL [2·4]; p=0·27). In multivariable modelling, lower anti-SARS-CoV-2 S1 RBD antibody concentrations were independently associated with infliximab (geometric mean ratio 0·15 [95% CI 0·11-0·21]; p<0·0001), tofacitinib (0·52 [CI 0·31-0·87]; p=0·012), and thiopurine (0·69 [0·51-0·95]; p=0·021), but not with ustekinumab (0·64 [0·39-1·06]; p=0·083), or vedolizumab (0·84 [0·54-1·30]; p=0·43). Previous SARS-CoV-2 infection (1·58 [1·22-2·05]; p=0·0006) was independently associated with higher anti-SARS-CoV-2 S1 RBD antibody concentrations and older age (0·88 [0·80-0·97]; p=0·0073) was independently associated with lower anti-SARS-CoV-2 S1 RBD antibody concentrations. Antigen-specific T-cell responses were similar in all groups, except for recipients of tofacitinib without evidence of previous infection, where T-cell responses were significantly reduced relative to healthy controls (p=0·021).

INTERPRETATION: A third dose of COVID-19 vaccine induced a boost in antibody binding in immunosuppressed patients with IBD, but these responses were reduced in patients taking infliximab, infliximab plus thiopurine, and tofacitinib. Tofacitinib was also associated with reduced T-cell responses. These findings support continued prioritisation of immunosuppressed groups for further vaccine booster dosing, particularly patients on anti-TNF and JAK inhibitors.

FUNDING: Pfizer.

PMID:36088954 | DOI:10.1016/S2468-1253(22)00274-6