J Pers Med. 2022 Sep 15;12(9):1515. doi: 10.3390/jpm12091515.

ABSTRACT

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a tangle-shaped accumulation of beta-amyloid peptide fragments and Tau protein in brain neurons. The pathophysiological mechanism involves the presence of Aβ-amyloid peptide, Tau protein, oxidative stress, and an exacerbated neuro-inflammatory response. This review aims to offer an updated compendium of the most recent and promising advances in AD treatment through the administration of phytochemicals. The literature survey was carried out by electronic search in the following specialized databases PubMed/Medline, Embase, TRIP database, Google Scholar, Wiley, and Web of Science regarding published works that included molecular mechanisms and signaling pathways targeted by phytochemicals in various experimental models of Alzheimer's disease in vitro and in vivo. The results of the studies showed that the use of phytochemicals against AD has gained relevance due to their antioxidant, anti-neuroinflammatory, anti-amyloid, and anti-hyperphosphorylation properties of Tau protein. Some bioactive compounds from plants have been shown to have the ability to prevent and stop the progression of Alzheimer's.

PMID:36143299 | DOI:10.3390/jpm12091515

J Pers Med. 2022 Sep 11;12(9):1488. doi: 10.3390/jpm12091488.

ABSTRACT

Genetic polymorphisms affect lipid profiles and are associated with disease complications. Genetic variants in the vitamin D receptor (VDR) gene are associated with type 2 diabetes mellitus (T2DM). In this study, we investigated the effects of VDR genotypes on the lipid profile and disease complications of T2DM patients in a Jordanian population. Ninety T2DM patients were genotyped for four major functional VDR genetic variants, rs2228570 C > T (FokI), rs7975232 A > C (ApaI), rs731236 T > C (TaqI), and rs1544410 C > T (BsmI), using the polymerase chain reaction-restriction fragment length polymorphism method. Lipid profiles and diabetes complications were analyzed and correlated with VDR genotypes. We found that the VDR rs7975232 and rs1544410 alleles were significantly (p = 0.008-0.04) associated with high-density lipoprotein (HDL) levels and retinopathy among patients. Carriers of the rs7975232 A/A genotype exhibited higher levels (49.68 ± 15.86 mg/dL) of HDL than patients with the A/C (44.73 ± 13.38 mg/dL) and C/C (37.93 ± 9.22 mg/dL) genotypes. Moreover, carriers of the rs1544410 T/T genotype had higher levels of HDL (54.31 ± 16.45 mg/dL) than patients with the C/T (43.57 ± 13.24 mg/dL) and C/C (43.98 ± 13.17 mg/dL) genotypes. T2DM patients who carry the rs7975232 C/C genotype were at higher risk (odds ratio [OR] = 7.88) of developing retinopathy compared with carriers of the rs7975232 C/A and A/A genotypes. In addition, T2DM patients with the rs1544410 C/C genotype had a higher risk (OR = 4.21) of developing retinopathy than patients with the rs1544410 C/T and T/T genotypes. Therefore, we concluded that the VDR rs7975232 and rs1544410 alleles were associated with HDL levels and retinopathy and can be considered as potential genetic biomarkers for the lipid profile and retinopathy complication among T2DM patients in a Jordanian population of Arabic origin. Further studies with larger sample sizes are needed to confirm our findings.

PMID:36143273 | DOI:10.3390/jpm12091488

J Pers Med. 2022 Sep 4;12(9):1452. doi: 10.3390/jpm12091452.

ABSTRACT

BACKGROUND: Psoriasis can present different phenotypes and could affect diverse body areas. In contrast to the high effectiveness of biological drugs in the treatment of trunk and extremities plaque psoriasis, in palmoplantar phenotypes and in plaque scalp psoriasis, these same drugs usually have reduced efficacy. Anti-TNF drugs could induce the appearance of palmoplantar pustulosis (PPP) in patients with other inflammatory diseases. The objective of this study is to identify if there are DNA Copy Number Variations (CNVs) associated with these different clinical phenotypes, which could justify the differences found in clinical practice. Moreover, we intend to elucidate if anti-TNF-induced PPP has a similar genetic background to idiopathic PPP.

METHODS: Skin samples were collected from 39 patients with different patterns of psoriasis and six patients with anti-TNF-induced PPP. The CNVs were obtained from methylation array data (Illumina Infinium Human Methylation) using the conumee R package.

RESULTS: No significant CNVs were found between the different phenotypes and the locations of psoriasis compared. Nevertheless, we found two significant bins harboring five different genes associated with anti-TNF-induced PPP in patients with a different background other than psoriasis.

CONCLUSIONS: Our results may help to predict which patients could develop anti-TNF-induced PPP.

PMID:36143237 | DOI:10.3390/jpm12091452

J Pers Med. 2022 Aug 29;12(9):1402. doi: 10.3390/jpm12091402.

ABSTRACT

Pharmacogenetics-a branch of precision medicine-holds the promise of becoming a novel tool to reduce the social and healthcare burdens of cardiovascular disease (CVD) and coronary artery disease (CAD) in diabetes. The improvement in cardiovascular risk stratification resulting from adding genetic characteristics to clinical data has moved from the modest results obtained with genetic risk scores based on few genetic variants, to the progressively better performances of polygenic risk scores based on hundreds to millions of variants (CAD-PGRS). Similarly, over the past few years, the number of studies investigating the use of CAD-PGRS to identify different responses to cardio-preventive treatment has progressively increased, yielding striking results for lipid-lowering drugs such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and statins. The use of CAD-PGRS to stratify patients based on their likely response to diabetes-specific interventions has been less successful, but promising results have been obtained with regard to specific genetic variants modulating the effects of interventions such as intensive glycemic control and fenofibrate. The finding of diabetes-specific CAD-loci, such as GLUL, has also led to the identification of promising new targets that might hopefully result in the development of specific therapies to reduce CVD burden in patients with diabetes. As reported in consensus statements from international diabetes societies, some of these pharmacogenetic approaches are expected to be introduced in clinical practice over the next decade. For this to happen, in addition to continuing to improve and validate these tools, it will be necessary to educate physicians and patients about the opportunities and limits of pharmacogenetics, as summarized in this review.

PMID:36143187 | DOI:10.3390/jpm12091402

J Pers Med. 2022 Aug 29;12(9):1398. doi: 10.3390/jpm12091398.

ABSTRACT

Ensuring that patients have an adequate understanding of pharmacogenomic (PGx) test results is a critical component of implementing precision medicine into clinical care. However, no PGx-specific validated literacy assessment has yet been developed. To address this need, we developed and validated the Minnesota Assessment of Pharmacogenomic Literacy (MAPLTM). Foundational work included a scoping review of patient and general public attitudes and experiences with pharmacogenomic testing, three focus groups, readability assessments, and review by experts and members of the general public. This resulted in a 15-item assessment designed to assess knowledge in four domains: underlying concepts, limitations, benefits, and privacy. For validation, 646 participants completed the MAPL as a part of a larger survey about pharmacogenomic research and statewide PGx implementation. Two items were deemed to be "too easy" and dropped. The remaining 13 items were retained in the final MAPL with good internal reliability (Cronbach's alpha = 0.75). Confirmatory factor analysis validated the four-domain construct of MAPL and suggested good model performance and high internal validity. The estimated coefficient loadings across 13 questions on the corresponding domains are all positive and statistically significant (p < 0.05). The MAPL covers multiple knowledge domains of specific relevance to PGx and is a useful tool for clinical and research settings where quantitative assessment of PGx literacy is of value.

PMID:36143184 | DOI:10.3390/jpm12091398

J Pers Med. 2022 Aug 28;12(9):1399. doi: 10.3390/jpm12091399.

ABSTRACT

Thiopurine methyltransferase (TPMT) is the rate-limiting enzyme in Azathioprine (AZA) metabolization. Although studies have discussed the association between the TPMT polymorphisms and myelosuppression, the data about the relationship between TPMT genotypes and hepatoxicity in Asian patients remain limited. This study investigated the correlation between TPMT polymorphisms and AZA-related hepatotoxicity. This study enrolled the patients who had prior exposure to AZA from the Taichung Veterans General Hospital (TCVGH)-Taiwan Precision Medicine Initiative (TPMI) cohort. Genetic variants were determined using a single nucleotide polymorphism (SNP) array. Participants were accordingly categorized into normal metabolizer (NM) and non-normal metabolizer (non-NM) groups. From the TCVGH-TPMI cohort, we included 50 TPMT non-NM patients, including 1 poor metabolizer (PM), 49 intermediate metabolizers (IMs), and 1000 NM patients. The non-NM genotype was associated with hepatotoxicity compared with the NM genotype (hazard ratio (HR): 3.85, 95% confidence interval (CI): 1.83-8.10). In the non-NM group, the 3-year cumulative incidence of hepatotoxicity was higher than that in the NM group at 8.5% in the first year and 18.6% in the second and third years (p < 0.001). A TPMT non-NM genotype was associated with the occurrence of hepatotoxicity following AZA therapy. Preemptive testing helps individualize AZA therapy by minimizing the risk of hepatotoxicity.

PMID:36143183 | DOI:10.3390/jpm12091399

J Pers Med. 2022 Aug 27;12(9):1394. doi: 10.3390/jpm12091394.

ABSTRACT

Polygenic models have emerged as promising prediction tools for the prediction of complex traits. Currently, the majority of polygenic models are developed in the context of predicting disease risk, but polygenic models may also prove useful in predicting drug outcomes. This study sought to understand how polygenic models incorporating pharmacogenetic variants are being used in the prediction of drug outcomes. A systematic review was conducted with the aim of gaining insights into the methods used to construct polygenic models, as well as their performance in drug outcome prediction. The search uncovered 89 papers that incorporated pharmacogenetic variants in the development of polygenic models. It was found that the most common polygenic models were constructed for drug dosing predictions in anticoagulant therapies (n = 27). While nearly all studies found a significant association with their polygenic model and the investigated drug outcome (93.3%), less than half (47.2%) compared the performance of the polygenic model against clinical predictors, and even fewer (40.4%) sought to validate model predictions in an independent cohort. Additionally, the heterogeneity of reported performance measures makes the comparison of models across studies challenging. These findings highlight key considerations for future work in developing polygenic models in pharmacogenomic research.

PMID:36143179 | DOI:10.3390/jpm12091394

J Pers Med. 2022 Aug 26;12(9):1387. doi: 10.3390/jpm12091387.

ABSTRACT

Human papilloma virus (HPV) infection could be considered a social disease, both for its high incidence, especially in younger subjects, and for the risk of neoplastic evolution linked to viral infection. Therefore, the National Health System, in collaboration with the state, must help women to understand the oncological risk of HPV and suitable methods of prevention. We conducted an Italian monocentric survey on HPV risk information as part of cervical cancer screening. An anonymous questionnaire was administered to 200 women with high-risk positive HPV and low-grade cervical lesions during second-level cervical cancer screening at the Gynecology and Obstetrics Unit of the "San Paolo" Hospital. From this survey, the need to improve communication for patients has emerged, as currently it is not exhaustive. In response to this need, organizational changes have been implemented to centralize the moment of counseling in the second levels of screening and to improve the training of health workers in level I as well as family doctors. In addition, psychological support was also proposed to patients who requested it, as was the dissemination of material such as that produced by GISCI (Italian Cervico-Carcinoma Screening Group) and updated in May 2018, which provides 100 answers to questions on HPV in order to achieve effective and comprehensive communication. This investigation requires further development, and the expansion of this investigation to the multicenter level is already underway. Therefore, this survey will represent a cornerstone for further discussion on the topic considering the necessity of appropriate communication in the oncological context.

PMID:36143172 | DOI:10.3390/jpm12091387

Int J Mol Sci. 2022 Sep 19;23(18):10960. doi: 10.3390/ijms231810960.

ABSTRACT

In the presence of established atherosclerosis, estrogens are potentially harmful. MMP-2 and MMP-9, their inhibitors (TIMP-2 and TIMP-1), RANK, RANKL, OPG, MCP-1, lysyl oxidase (LOX), PDGF-β, and ADAMTS-4 play critical roles in plaque instability/rupture. We aimed to investigate (i) the effect of estradiol on the expression of the abovementioned molecules in endothelial cells, (ii) which type(s) of estrogen receptors mediate these effects, and (iii) the role of p21 in the estrogen-mediated regulation of the aforementioned factors. Human aortic endothelial cells (HAECs) were cultured with estradiol in the presence or absence of TNF-α. The expression of the aforementioned molecules was assessed by qRT-PCR and ELISA. Zymography was also performed. The experiments were repeated in either ERα- or ERβ-transfected HAECs and after silencing p21. HAECs expressed only the GPR-30 estrogen receptor. Estradiol, at low concentrations, decreased MMP-2 activity by 15-fold, increased LOX expression by 2-fold via GPR-30, and reduced MCP-1 expression by 3.5-fold via ERβ. The overexpression of ERα increased MCP-1 mRNA expression by 2.5-fold. In a low-grade inflammation state, lower concentrations of estradiol induced the mRNA expression of MCP-1 (3.4-fold) and MMP-9 (7.5-fold) and increased the activity of MMP-2 (1.7-fold) via GPR-30. Moreover, p21 silencing resulted in equivocal effects on the expression of the abovementioned molecules. Estradiol induced different effects regarding atherogenic plaque instability through different ERs. The balance of the expression of the various ER subtypes may play an important role in the paradoxical characterization of estrogens as both beneficial and harmful.

PMID:36142876 | DOI:10.3390/ijms231810960

Genes (Basel). 2022 Sep 2;13(9):1575. doi: 10.3390/genes13091575.

ABSTRACT

Since the beginning of pharmacology, several variations in responses to drugs have been recorded [...].

PMID:36140743 | DOI:10.3390/genes13091575

Antibiotics (Basel). 2022 Sep 17;11(9):1263. doi: 10.3390/antibiotics11091263.

ABSTRACT

Antimicrobial resistance represents a serious threat for global health, causing an unacceptable burden in terms of morbidity, mortality and healthcare costs. In particular, in 2017, carbapenem-resistant organisms were listed by the WHO among the group of pathogens for which novel treatment strategies are urgently needed. Fortunately, several drugs and combinations have been introduced in recent years to treat multi-drug-resistant (MDR) bacteria. However, a correct use of these molecules is needed to preserve their efficacy. In the present paper, we will provide an overview on the epidemiology and mechanisms of resistance of the most common MDR Gram-negative bacteria, proposing a treatment algorithm for the management of infections due to carbapenem-resistant bacteria based on the most recent clinical evidence.

PMID:36140042 | DOI:10.3390/antibiotics11091263

Cancers (Basel). 2022 Sep 8;14(18):4365. doi: 10.3390/cancers14184365.

ABSTRACT

Radiotherapy (RT) for breast cancer significantly impacts patient survival and causes adverse events. Double-strand breaks are the most harmful type of DNA damage associated with RT, which is repaired through homologous recombination (HRR). As genetic variability of DNA repair genes could affect response to RT, we aimed to evaluate the association of polymorphisms in HRR genes with tumor characteristics and the occurrence of RT adverse events in early HER2-positive breast cancer. Our study included 101 breast cancer patients treated with adjuvant RT and trastuzumab. All patients were genotyped for eight single nucleotide polymorphisms in NBN, RAD51 and XRCC3 using competitive allele-specific PCR. Carriers of XRCC3 rs1799794 GG genotype were less likely to have higher tumor differentiation grade (OR = 0.05, 95% CI = 0.01-0.44, p = 0.007). Carriers of RAD51 rs1801321 TT genotype were more likely to have higher NYHA class in univariable (OR = 10.0; 95% CI = 1.63-61.33; p = 0.013) and multivariable (OR = 9.27; 95% CI = 1.28-67.02; p = 0.027) analysis. Carriers of RAD51 rs12593359 GG genotype were less likely to have higher NYHA class in univariable (OR = 0.09; 95% CI = 0.01-0.79; p = 0.030) and multivariable (OR = 0.07; 95% CI = 0.01-0.81; p = 0.034) analysis. Carriers of XRCC3 rs1799794 GG genotypes experienced more skin adverse events based on LENT-SOMA scale in univariable (OR = 5.83; 95% CI = 1.22-28.00; p = 0.028) and multivariable (OR = 10.90; 95% CI = 1.61-73.72; p = 0.014) analysis. In conclusion, XRCC3 and RAD51 polymorphisms might contribute to RT adverse events in early HER2-positive breast cancer patients.

PMID:36139526 | DOI:10.3390/cancers14184365

Biomolecules. 2022 Sep 16;12(9):1307. doi: 10.3390/biom12091307.

ABSTRACT

Human diseases are generally influenced by SNPs (single nucleotide polymorphisms). The mutations in amino acid residues generated by deleterious SNPs contribute to the structural and functional diversity of the encoded protein. Tumor necrosis factor-α (TNF-α), Glucocorticoid receptor gene (NR3C1), and Cytochrome P450 3A5 (CYP3A5) play a key role in glucocorticoid resistance susceptibility in humans. Possible causative mutations could be used as therapeutic targets and diagnostic markers for glucocorticoid resistance. This study evaluated the missense SNPs of TNF-α, NR3C1, and CYP3A5 to predict their impact on amino acid changes, protein interaction, and functional stability. The protein sequence of dbSNP was obtained and used online in silico method to screen deleterious mutants for the in silico analysis. In the coding regions of TNF-α, NR3C1, and CYP3A5, 14 deleterious mutations were discovered. The protein functional and stability changes in the amino acid between native and mutant energy were identified by analyzing the changes in the hydrogen bonding of these mutants from native, which were all measured using Swiss PDB and PyMOL. F446S and R439K had the highest root-mean-square deviation (RMSD) values among the 14 deleterious mutants. Additionally, the conserved region of amino acid protein interaction was analyzed. This study could aid in the discovery of new detrimental mutations in TNF-α, NR3C1, and CYP3A5, as well as the development of long-term therapy for corticosteroid resistance in several inflammatory diseases. However, more research into the deleterious mutations of the TNF-α, NR3C1, and CYP3A5 genes is needed to determine their role in corticosteroid resistance.

PMID:36139147 | DOI:10.3390/biom12091307

Biomolecules. 2022 Sep 2;12(9):1226. doi: 10.3390/biom12091226.

ABSTRACT

Immune dysfunction and pro-oncogenic inflammation play critical roles in malignant progression and non-response to immunotherapy for hepatocellular carcinoma (HCC). In particular, PD-1/PD-L1 blockade therapy could induce durable tumor remissions and improve the prognosis of patients to a certain extent. However, PD-L1, as a promising biomarker, has limited knowledge about its relevance to tumor microenvironment (TME) characterization and endogenous inflammatory immune responses. In this study, we systematically investigated and characterized the important intercommunication of PD-L1 with immunosuppressive TME and inflammatory response activity in HCC and predicted promising therapeutic drugs to improve the current therapeutic strategy for specific patients. We identified aberrant expression patterns of PD-L1 in HCC and completely different clinical and molecular characteristics among the PD-L1 subgroups. PD-L1 positively associated with immunosuppressive macrophages and macrophage-derived cytokines, which may contribute to the polarization of macrophages. Moreover, inflammatory response activity exhibited significant differences between high and low PD-L1 expression groups and had robust positive correlativity of the infiltration level of tumor-associated macrophages. Notably, given the immunosuppressive and inflammatory microenvironment in HCC, we screened four candidate drugs, including dasatinib, vemurafenib, topotecan and AZD6482, and corroborated in two pharmacogenomics databases, which might have potential therapeutic implications in specific HCC patients. Our results enhanced the understanding of linkage in PD-L1 expression patterns with macrophages and inflammation, which may provide new insight into the pathogenic mechanisms and potential therapeutic strategy for HCC.

PMID:36139065 | DOI:10.3390/biom12091226

Biomolecules. 2022 Aug 31;12(9):1206. doi: 10.3390/biom12091206.

ABSTRACT

Cisplatin (cis-diamminedichloroplatinum (II), DDP) is an antineoplastic agent widely used in the treatment of solid tumors because of its extensive cytotoxic activity. However, the main limiting side effect of DDP use is nephrotoxicity, a rapid deterioration in kidney function due to toxic chemicals. Several studies have shown that epigenetic processes are involved in DDP-induced nephrotoxicity. Noncoding RNAs (ncRNAs), a class of epigenetic processes, are molecules that regulate gene expression under physiological and pathological conditions. MicroRNAs (miRNAs) are the most characterized class of ncRNAs and are engaged in many cellular processes. In this review, we describe how different miRNAs regulate some pathways leading to cell death by apoptosis, specifically the intrinsic apoptosis pathway. Accordingly, many classes of natural products have been tested for their ability to prevent DDP-induced apoptosis. The study of epigenetic regulation for underlying cell death is still being studied, which will allow new strategies for the diagnosis and therapy of this unwanted disease, which is presented as a side effect of antineoplastic treatment.

PMID:36139046 | DOI:10.3390/biom12091206

Brain Sci. 2022 Sep 3;12(9):1189. doi: 10.3390/brainsci12091189.

ABSTRACT

Genetic influences on acute responses to psychoactive drugs may contribute to individual variability in addiction risk. ABCB1 is a human gene that encodes P-glycoprotein, an ATP-dependent efflux pump that may influence the pharmacokinetics of delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis. Using data from 48 young adults (aged 19-25 years) reporting 1-4 days of cannabis use per week who completed a placebo-controlled human laboratory experiment, we tested the hypothesis that the rs2235048 polymorphism of ABCB1 would influence acute responses to smoked cannabis. C-allele carriers reported on average greater frequency of weekly cannabis use compared to the TT genotype carriers (TC/CC mean ± SEM = 2.74 ± 0.14, TT = 1.85 ± 0.24, p = 0.004). After smoking a single cannabis cigarette to their desired high, C-allele carriers had higher area-under-the-curve (AUC) of both THC metabolites (11-OH-THC TC/CC = 7.18 ± 9.64, TT = 3.28 ± 3.40, p = 0.05; THC-COOH TC/CC = 95.21 ± 116.12, TT = 45.92 ± 42.38, p = 0.043), and these results were impact by self-reported ethnicity. There were no significant differences in self-reported subjective drug effects except for a greater AUC of visual analogue scale rating of drug liking (TC/CC = 35,398.33 ± 37,233.72, TT = 15,895.56 ± 13,200.68, p = 0.017). Our preliminary findings suggest that further work in a larger sample should investigate whether human ABCB1 influences cannabis-related phenotypes and plays a role in the risk of developing a cannabis use disorder.

PMID:36138925 | DOI:10.3390/brainsci12091189

J Chemother. 2022 Sep 22:1-10. doi: 10.1080/1120009X.2022.2125736. Online ahead of print.

ABSTRACT

Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer death. 5-Fluorouracil (5-FU) is an essential component of systemic chemotherapy for CRC. Our objective was to determine the genotypic frequency of polymorphisms affecting dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthetase (TYMS) genes and to correlate the genetic profile with the toxicity due to 5-FU, also considering nongenetic factors. This is a prospective study that involved 66 patients. We extracted DNA by salting out methods. We carried out the genotyping of the different polymorphisms by simple PCR for the TYMS 5'UTR and by PCR-RFLP for DPYD: 1905 + 1 G > A, 85 T > C, 496 A > G, 1679 T > G, c.483 + 18G > A and the TYMS: 5'UTR VNTR, 5'UTR G > C and 3'UTR. The study of the association of DPYD and TYMS polymorphisms with the various signs of toxicity under 5-FU revealed that the polymorphisms 496 A > G were significantly associated with hepatotoxicity: OR = 3.85 (p = 0.04). In addition, 85 T > C was significantly associated with mucositis and neurotoxicity: OR = 4.35 (p = 0.03), OR = 3.79 (p = 0.02). For TYMS, the only significant association we observed for 5'UTR with vomiting: OR = 3.34 (p = 0.04). The incidence of adverse reactions related to 5-FU appears to be influenced in patients with CRC by the identified DPYD and TYMS gene polymorphisms in the Tunisian population.

PMID:36137946 | DOI:10.1080/1120009X.2022.2125736

Chem Res Toxicol. 2022 Sep 22. doi: 10.1021/acs.chemrestox.2c00231. Online ahead of print.

ABSTRACT

β-Lactamase inhibitors such as clavulanic acid and tazobactam were developed to overcome β-lactam antibiotic resistance. Hypersensitivity reactions to these drugs have not been studied in detail, and the antigenic determinants that activate T-cells have not been defined. The objectives of this study were to (i) characterize clavulanate- and tazobactam-responsive T-cells from hypersensitive patients, (ii) explore clavulanate and tazobactam T-cell crossreactivity, and (iii) define the antigenic determinants that contribute to T-cell reactivity. Antigen specificity, pathways of T-cell activation, and crossreactivity with clavulanate- and tazobactam-specific T-cell clones were assessed by proliferation and cytokine release assays. Antigenic determinants were analyzed by mass spectrometry-based proteomics methods. Clavulanate- and tazobactam-responsive CD4+ T-cell clones were stimulated to proliferate and secrete IFN-γ in an MHC class II-restricted and dose-dependent manner. T-cell activation with clavulanate- and tazobactam was dependent on antigen presenting cells because their fixation prevented the T-cell response. Strong crossreactivity was observed between clavulanate- and tazobactam-T-cells; however, neither drug activated β-lactam antibiotic-responsive T-cells. Mass spectrometric analysis revealed that both compounds form multiple antigenic determinants with lysine residues on proteins, including an overlapping aldehyde and hydrated aldehyde adduct with mass additions of 70 and 88 Da, respectively. Collectively, these data show that although clavulanate and tazobactam are structurally distinct, the antigenic determinants formed by both drugs overlap, which explains the observed T-cell cross-reactivity.

PMID:36137197 | DOI:10.1021/acs.chemrestox.2c00231

OMICS. 2022 Sep 22. doi: 10.1089/omi.2022.0121. Online ahead of print.

NO ABSTRACT

PMID:36137061 | DOI:10.1089/omi.2022.0121

JCI Insight. 2022 Sep 22:e162695. doi: 10.1172/jci.insight.162695. Online ahead of print.

ABSTRACT

Primary immune regulatory disorders (PIRD) are a group of disorders characterized by immune dysregulation, presenting with a wide range of clinical disease including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 result in a PIRD with a broad clinical spectrum. Studies in patients have documented a decreased frequency of FOXP3+ regulatory T (Treg) cells and an increased frequency of Th17 cells in some patients with active disease. However, the mechanisms of disease pathogenesis in STAT3 GOF syndrome remain largely unknown, and treatment is challenging. We developed a knock-in mouse model harboring a de novo pathogenic human STAT3 variant (p.G421R) and found these mice developed T cell dysregulation, lymphoproliferation and CD4+ Th1 cell skewing. Surprisingly, Treg cell numbers, phenotype, and function remained largely intact, however mice had a selective deficiency in the generation of iTreg cells. In parallel, we performed single-cell RNA-sequencing on T cells from STAT3 GOF patients. We demonstrate only minor changes in the Treg cell transcriptional signature and an expanded, effector CD8+ T cell population. Together, these findings suggest Treg cells are not the primary driver of disease and highlight the importance of preclinical models in the study of disease mechanisms in rare PIRD.

PMID:36136607 | DOI:10.1172/jci.insight.162695