Spectrochim Acta A Mol Biomol Spectrosc. 2023 Jun 28;302:123087. doi: 10.1016/j.saa.2023.123087. Online ahead of print.

ABSTRACT

Due to the background interference from biological samples, detecting viruses using surface-enhanced Raman scattering (SERS) in clinical samples is challenging. This study is based on SERS by reducing sodium borohydride and aggregating silver nanoparticles to develop suitable virus detection "hot spot." The monkeypox virus and human papillomavirus fingerprints were quickly obtained, tested, and identified in serum and artificial vaginal discharge, respectively, by combining the principal component analysis method. Therefore, these viruses were successfully identified in the biological background. In addition, the lowest detection limit was 100 copies/mL showing good reproducibility and signal-to-noise ratio. The concentration-dependent curve of the monkeypox virus had a good linear relationship. This method helps solve the SERS signal interference problem in complex biological samples, with low detection limits and high selectivity in virus characterization and quantitative analysis. Therefore, this method has a reasonable prospect of clinical application.

PMID:37406546 | DOI:10.1016/j.saa.2023.123087

Microbiome. 2023 Jul 6;11(1):138. doi: 10.1186/s40168-023-01578-y.

ABSTRACT

BACKGROUND: Following solid organ transplantation, tacrolimus (TAC) is an essential drug in the immunosuppressive strategy. Its use constitutes a challenge due to its narrow therapeutic index and its high inter- and intra-pharmacokinetic (PK) variability. As the contribution of the gut microbiota to drug metabolism is now emerging, it might be explored as one of the factors explaining TAC PK variability. Herein, we explored the consequences of TAC administration on the gut microbiota composition. Reciprocally, we studied the contribution of the gut microbiota to TAC PK, using a combination of in vivo and in vitro models.

RESULTS: TAC oral administration in mice resulted in compositional alterations of the gut microbiota, namely lower evenness and disturbance in the relative abundance of specific bacterial taxa. Compared to controls, mice with a lower intestinal microbial load due to antibiotics administration exhibit a 33% reduction in TAC whole blood exposure and a lower inter-individual variability. This reduction in TAC levels was strongly correlated with higher expression of the efflux transporter ABCB1 (also known as the p-glycoprotein (P-gp) or the multidrug resistance protein 1 (MDR1)) in the small intestine. Conventionalization of germ-free mice confirmed the ability of the gut microbiota to downregulate ABCB1 expression in a site-specific fashion. The functional inhibition of ABCB1 in vivo by zosuquidar formally established the implication of this efflux transporter in the modulation of TAC PK by the gut microbiota. Furthermore, we showed that polar bacterial metabolites could recapitulate the transcriptional regulation of ABCB1 by the gut microbiota, without affecting its functionality. Finally, whole transcriptome analyses pinpointed, among others, the Constitutive Androstane Receptor (CAR) as a transcription factor likely to mediate the impact of the gut microbiota on ABCB1 transcriptional regulation.

CONCLUSIONS: We highlight for the first time how the modulation of ABCB1 expression by bacterial metabolites results in changes in TAC PK, affecting not only blood levels but also the inter-individual variability. More broadly, considering the high number of drugs with unexplained PK variability transported by ABCB1, our work is of clinical importance and paves the way for incorporating the gut microbiota in prediction algorithms for dosage of such drugs. Video Abstract.

PMID:37408070 | DOI:10.1186/s40168-023-01578-y

Expert Opin Drug Deliv. 2023 Jul 5. doi: 10.1080/17425247.2023.2233900. Online ahead of print.

ABSTRACT

INTRODUCTION: The trillions of microorganisms that comprise the gut microbiome form dynamic bidirectional interactions with orally administered drugs and host health. These relationships can alter all aspects of drug pharmacokinetics and pharmacodynamics (PK/PD); thus, there is a desire to control these interactions to maximize therapeutic efficacy. Attempts to modulate drug-gut microbiome interactions have spurred advancements within the field of 'pharmacomicrobiomics' and are poised to become the next frontier of oral drug delivery.

AREAS COVERED: This review details the bidirectional interactions that exist between oral drugs and the gut microbiome, with clinically relevant case examples outlining a clear motive for controlling pharmacomicrobiomic interactions. Specific focus is attributed to novel and advanced strategies that have demonstrated success in mediating drug-gut microbiome interactions.

EXPERT OPINION: Co-administration of gut-active supplements (e.g. pro-, pre-biotics), innovative drug delivery vehicles, and strategic polypharmacy serve as the most promising and clinically viable approaches for controlling pharmacomicrobiomic interactions. Targeting the gut microbiome through these strategies presents new opportunities for improving therapeutic efficacy by precisely mediating PK/PD, while mitigating metabolic disturbances caused by drug-induced gut dysbiosis. However, successfully translating preclinical potential into clinical outcomes relies on overcoming key challenges related to interindividual variability in microbiome composition and study design parameters.

PMID:37405390 | DOI:10.1080/17425247.2023.2233900

Front Mol Biosci. 2023 Jun 19;10:1201912. doi: 10.3389/fmolb.2023.1201912. eCollection 2023.

ABSTRACT

Psoriasis is a common inflammatory disease that affects mainly the skin. However, the moderate to severe forms have been associated with several comorbidities, such as psoriatic arthritis, Crohn's disease, metabolic syndrome and cardiovascular disease. Keratinocytes and T helper cells are the dominant cell types involved in psoriasis development via a complex crosstalk between epithelial cells, peripheral immune cells and immune cells residing in the skin. Immunometabolism has emerged as a potent mechanism elucidating the aetiopathogenesis of psoriasis, offering novel specific targets to diagnose and treat psoriasis early. The present article discusses the metabolic reprogramming of activated T cells, tissue-resident memory T cells and keratinocytes in psoriatic skin, presenting associated metabolic biomarkers and therapeutic targets. In psoriatic phenotype, keratinocytes and activated T cells are glycolysis dependent and are characterized by disruptions in the TCA cycle, the amino acid metabolism and the fatty acid metabolism. Upregulation of the mammalian target of rapamycin (mTOR) results in hyperproliferation and cytokine secretion by immune cells and keratinocytes. Metabolic reprogramming through the inhibition of affected metabolic pathways and the dietary restoration of metabolic imbalances may thus present a potent therapeutic opportunity to achieve long-term management of psoriasis and improved quality of life with minimum adverse effects.

PMID:37405259 | PMC:PMC10317015 | DOI:10.3389/fmolb.2023.1201912

Health Sci Rep. 2023 Jul 2;6(7):e1377. doi: 10.1002/hsr2.1377. eCollection 2023 Jul.

ABSTRACT

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 novel coronavirus, is a highly communicable disease that gave rise to the ongoing pandemic. Despite prompt action across many laboratories in many countries, effective management of this disease is still out of reach. The focus of this review is to describe various vaccination approaches and nanomedicine-based delivery systems against COVID-19.

METHODS: The articles included in this study were searched and added from different electronic databases, including PubMed, Scopus, Cochrane, Embase, and preprint databases.

RESULTS: Mass immunization with vaccines is currently at the forefront of COVID-19 infection control. Such vaccines are live attenuated vaccines, inactivated vaccines, nucleic acid-based vaccines, protein subunit vaccines, viral-vector vaccines, and virus-like particle platforms. However, many promising avenues are currently being explored in laboratory and clinical settings, including treatment options, prevention, diagnosis, and management of the disease. Soft nanoparticles like lipid nanoparticles (solid lipid nanoparticles (SLNPs), liposomes, nanostructured lipid carriers, nanoemulsions, and protein nanoparticles play an essential role in nanomedicine. Because of their unique and excellent properties, nanomedicines have potential applications in treating COVID-19 disease.

CONCLUSIONS: This review work provides an overview of the therapeutic aspects of COVID-19, including vaccination and the role of nanomedicines in the diagnosis, treatment, and prevention of COVID-19.

PMID:37404449 | PMC:PMC10315735 | DOI:10.1002/hsr2.1377

J Manag Care Spec Pharm. 2023 Jul;29(7):721-731. doi: 10.18553/jmcp.2023.29.7.721.

ABSTRACT

BACKGROUND: Asthma is the most common inflammatory lung disease in the United States. Since 2015, biologic therapies have provided targeted treatment for patients with severe asthma. OBJECTIVE: To evaluate the trends for in-hospital outcomes of asthma before (2012-2014) and after (2016-2018) the introduction of biologic therapies for asthma. METHODS: We conducted a nationwide cross-sectional analysis of patients aged 2 years or older who were hospitalized for asthma between 2012 and 2018 using data from the Nationwide Readmissions Database. Outcomes included rates of asthma hospital admission and asthma-related 30-day readmission, hospital length of stay, hospital costs, and inpatient mortality. Generalized linear models assessed trends in rates of asthma admission and readmission, length of stay, costs, and mortality quarterly during 2012-2014 and 2016-2018. RESULTS: Among 691,537 asthma-related admissions, quarterly asthma admission rates significantly decreased (-0.90%, 95% CI = -1.46% to - 0.34%; P = 0.002) during 2016-2018, mainly among adults, but not during 2012-2014. Quarterly assessed readmission rates decreased by 2.40% (-2.85% to -1.96%; P < 0.0001) during 2012-2014 and by 2.12% (-2.74% to - 1.50%; P < 0.0001) during 2016-2018. Mean length of stay for asthma admissions decreased quarterly by 0.44% (-0.49% to - 0.38%; P < 0.0001) during 2012-2014 and by 0.27% (-0.34% to - 0.20%; P < 0.0001) during 2016-2018. Quarterly hospital costs for admissions were unchanged during 2012-2014 but increased by 0.28% (0.21% to 0.35%; P < 0.0001) during 2016-2018. There were no significant trends in inpatient mortality during 2012-2014 and 2016-2018. CONCLUSIONS: After the introduction of new biologics for severe asthma in 2015, asthma-related hospital admissions decreased significantly, whereas hospital costs increased. Asthma-related 30-day readmission rates and length of stay for asthma admissions continuously decreased, whereas inpatient mortality rates remained stable. DISCLOSURES: This work was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number R01HL136945. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The data that support the findings of this study are available from the Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of the Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project.

PMID:37404074 | DOI:10.18553/jmcp.2023.29.7.721

BMC Genomics. 2023 Jul 4;24(1):373. doi: 10.1186/s12864-023-09472-5.

ABSTRACT

BACKGROUND: Protein kinase CK2 activity is implicated in the pathogenesis of various hematological malignancies like Acute Myeloid Leukemia (AML) that remains challenging concerning treatment. This kinase has emerged as an attractive molecular target in therapeutic. Antitumoral peptide CIGB-300 blocks CK2 phospho-acceptor sites on their substrates but it also binds to CK2α catalytic subunit. Previous proteomic and phosphoproteomic experiments showed molecular and cellular processes with relevance for the peptide action in diverse AML backgrounds but earlier transcriptional level events might also support the CIGB-300 anti-leukemic effect. Here we used a Clariom S HT assay for gene expression profiling to study the molecular events supporting the anti-leukemic effect of CIGB-300 peptide on HL-60 and OCI-AML3 cell lines.

RESULTS: We found 183 and 802 genes appeared significantly modulated in HL-60 cells at 30 min and 3 h of incubation with CIGB-300 for p < 0.01 and FC > = │1.5│, respectively; while 221 and 332 genes appeared modulated in OCI-AML3 cells. Importantly, functional enrichment analysis evidenced that genes and transcription factors related to apoptosis, cell cycle, leukocyte differentiation, signaling by cytokines/interleukins, and NF-kB, TNF signaling pathways were significantly represented in AML cells transcriptomic profiles. The influence of CIGB-300 on these biological processes and pathways is dependent on the cellular background, in the first place, and treatment duration. Of note, the impact of the peptide on NF-kB signaling was corroborated by the quantification of selected NF-kB target genes, as well as the measurement of p50 binding activity and soluble TNF-α induction. Quantification of CSF1/M-CSF and CDKN1A/P21 by qPCR supports peptide effects on differentiation and cell cycle.

CONCLUSIONS: We explored for the first time the temporal dynamics of the gene expression profile regulated by CIGB-300 which, along with the antiproliferative mechanism, can stimulate immune responses by increasing immunomodulatory cytokines. We provided fresh molecular clues concerning the antiproliferative effect of CIGB-300 in two relevant AML backgrounds.

PMID:37400761 | DOI:10.1186/s12864-023-09472-5

Zhonghua Gan Zang Bing Za Zhi. 2023 Jun 20;31(6):653-658. doi: 10.3760/cma.j.cn501113-20230418-00172.

ABSTRACT

Drug-induced liver injury (DILI) risk prediction, diagnosis establishment, clinical management, and all other aspects are facing great challenges. Although the current understanding of its pathogenesis is still incomplete, research over the past 20 years has shown that genetic susceptibility may play an important role in the occurrence and development of DILI. In recent years, pharmacogenomics studies have further revealed the association between human leukocyte antigen (HLA) genes, some non-HLA genes, and hepatotoxicity from certain drugs. However, due to the lack of well-designed, prospective, large-sample cohort validation and low positive predictive values, there may still be some way to go before the current results can be truly translated into clinical practice for precise prediction and prevention of DILI risk.

PMID:37400394 | DOI:10.3760/cma.j.cn501113-20230418-00172

bioRxiv. 2023 Jun 15:2023.06.14.544860. doi: 10.1101/2023.06.14.544860. Preprint.

ABSTRACT

BACKGROUND: Statins lower circulating low-density lipoprotein cholesterol (LDLC) levels and reduce cardiovascular disease risk. Though highly efficacious in general, there is considerable inter-individual variation in statin efficacy that remains largely unexplained.

METHODS: To identify novel genes that may modulate statin-induced LDLC lowering, we used RNA-sequencing data from 426 control- and 2 μM simvastatin-treated lymphoblastoid cell lines (LCLs) derived from European and African American ancestry participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial ( ClinicalTrials.gov Identifier: NCT00451828 ). We correlated statin-induced changes in LCL gene expression with plasma LDLC statin response in the corresponding CAP participants. For the most correlated gene identified ( ZNF335 ), we followed up in vivo by comparing plasma cholesterol levels, lipoprotein profiles, and lipid statin response between wild-type mice and carriers of a hypomorphic (partial loss of function) missense mutation in Zfp335 (the mouse homolog of ZNF335 ).

RESULTS: The statin-induced expression changes of 147 human LCL genes were significantly correlated to the plasma LDLC statin responses of the corresponding CAP participants in vivo (FDR=5%). The two genes with the strongest correlations were zinc finger protein 335 ( ZNF335 aka NIF-1 , rho=0.237, FDR-adj p=0.0085) and CCR4-NOT transcription complex subunit 3 ( CNOT3 , rho=0.233, FDR-adj p=0.0085). Chow-fed mice carrying a hypomorphic missense (R1092W; aka bloto) mutation in Zfp335 had significantly lower non-HDL cholesterol levels than wild type C57BL/6J mice in a sex combined model (p=0.04). Furthermore, male (but not female) mice carrying the Zfp335 R1092W allele had significantly lower total and HDL cholesterol levels than wild-type mice. In a separate experiment, wild-type mice fed a control diet for 4 weeks and a matched simvastatin diet for an additional 4 weeks had significant statin-induced reductions in non-HDLC (-43±18% and -23±19% for males and females, respectively). Wild-type male (but not female) mice experienced significant reductions in plasma LDL particle concentrations, while male mice carrying Zfp335 R1092W allele(s) exhibited a significantly blunted LDL statin response.

CONCLUSIONS: Our in vitro and in vivo studies identified ZNF335 as a novel modulator of plasma cholesterol levels and statin response, suggesting that variation in ZNF335 activity could contribute to inter-individual differences in statin clinical efficacy.

PMID:37397985 | PMC:PMC10312755 | DOI:10.1101/2023.06.14.544860

JACC CardioOncol. 2023 Mar 28;5(3):360-373. doi: 10.1016/j.jaccao.2022.10.017. eCollection 2023 Jun.

ABSTRACT

BACKGROUND: Anthracycline chemotherapies cause heart failure in a subset of cancer patients. We previously reported that the anthracycline doxorubicin (DOX) induces cardiotoxicity through the activation of cyclin-dependent kinase 2 (CDK2).

OBJECTIVES: The aim of this study was to determine whether retinoblastoma-like 2 (RBL2/p130), an emerging CDK2 inhibitor, regulates anthracycline sensitivity in the heart.

METHODS: Rbl2-/- mice and Rbl2+/+ littermates received DOX (5 mg/kg/wk for 4 weeks intraperitoneally, 20 mg/kg cumulative). Heart function was monitored with echocardiography. The association of RBL2 genetic variants with anthracycline cardiomyopathy was evaluated in the SJLIFE (St. Jude Lifetime Cohort Study) and CPNDS (Canadian Pharmacogenomics Network for Drug Safety) studies.

RESULTS: The loss of endogenous Rbl2 increased basal CDK2 activity in the mouse heart. Mice lacking Rbl2 were more sensitive to DOX-induced cardiotoxicity, as evidenced by rapid deterioration of heart function and loss of heart mass. The disruption of Rbl2 exacerbated DOX-induced mitochondrial damage and cardiomyocyte apoptosis. Mechanistically, Rbl2 deficiency enhanced CDK2-dependent activation of forkhead box O1 (FOXO1), leading to up-regulation of the proapoptotic protein Bim. The inhibition of CDK2 desensitized Rbl2-depleted cardiomyocytes to DOX. In wild-type cardiomyocytes, DOX exposure induced Rbl2 expression in a FOXO1-dependent manner. Importantly, the rs17800727 G allele of the human RBL2 gene was associated with reduced anthracycline cardiotoxicity in childhood cancer survivors.

CONCLUSIONS: Rbl2 is an endogenous CDK2 inhibitor in the heart and represses FOXO1-mediated proapoptotic gene expression. The loss of Rbl2 increases sensitivity to DOX-induced cardiotoxicity. Our findings suggest that RBL2 could be used as a biomarker to predict the risk of cardiotoxicity before the initiation of anthracycline-based chemotherapy.

PMID:37397090 | PMC:PMC10308060 | DOI:10.1016/j.jaccao.2022.10.017

Genes Dis. 2022 May 26;10(3):771-785. doi: 10.1016/j.gendis.2022.05.011. eCollection 2023 May.

ABSTRACT

Vascular remodeling and angiogenesis are two key processes in the maintenance of vascular homeostasis and involved in a wide array of vascular pathologies. Following these processes, extracellular matrix (ECM) provides the mechanical foundation for vascular walls. Lysyl oxidase (LOX), the key matrix-modifying enzyme, has been demonstrated to significantly affect structural abnormality and dysfunction in the blood vessels. The role of LOX in vascular remodeling and angiogenesis has always been the subject in the current medical research. Therefore, we presently make a summarization of the biosynthesis of LOX and the mechanisms involved in vascular remodeling and angiogenesis, as well as the role of LOX in diseases associated with vascular abnormalities and the therapeutic potential via targeting LOX. In particular, we give a proposal that LOX likely reshapes matrisome-associated genes expressions in the regulation of vascular remodeling and angiogenesis, which serves as a mechanistic insight into the critical role of LOX in these two aspects. Additionally, LOX has also dual effects on the vascular dysfunction, namely, inhibition of LOX for improving hypertension, restenosis and malignant tumor while activation of LOX for curing arterial aneurysm and dissection. LOX-targeted therapy may provide a promising therapeutic strategy for the treatment of various vascular pathologies associated with vascular remodeling and angiogenesis.

PMID:37396555 | PMC:PMC10308135 | DOI:10.1016/j.gendis.2022.05.011

Front Genet. 2023 Jun 15;14:1217049. doi: 10.3389/fgene.2023.1217049. eCollection 2023.

ABSTRACT

Pharmacogenomics (PGx) aims at tailoring drug therapy by considering patient genetic makeup. While drug dosage guidelines have been extensively based on single gene mutations (single nucleotide polymorphisms) over the last decade, polygenic risk scores (PRS) have emerged in the past years as a promising tool to account for the complex interplay and polygenic nature of patients' genetic predisposition affecting drug response. Even though PRS research has demonstrated convincing evidence in disease risk prediction, the clinical utility and its implementation in daily care has yet to be demonstrated, and pharmacogenomics is no exception; usual endpoints include drug efficacy or toxicity. Here, we review the general pipeline in PRS calculation, and we discuss some of the remaining barriers and challenges that must be undertaken to bring PRS research in PGx closer to patient care. Besides the need in following reporting guidelines and larger PGx patient cohorts, PRS integration will require close collaboration between bioinformatician, treating physicians and genetic consultants to ensure a transparent, generalizable, and trustful implementation of PRS results in real-world medical decisions.

PMID:37396043 | PMC:PMC10311496 | DOI:10.3389/fgene.2023.1217049

Pharmacol Ther. 2023 Jun 29:108487. doi: 10.1016/j.pharmthera.2023.108487. Online ahead of print.

ABSTRACT

Protoporphyrin IX (PPIX) is an intermediate in the heme biosynthesis pathway. Abnormal accumulation of PPIX due to certain pathological conditions such as erythropoietic protoporphyria and X-linked protoporphyria causes painful phototoxic reactions of the skin, which can significantly impact daily life. Endothelial cells in the skin have been proposed as the primary target for PPIX-induced phototoxicity through light-triggered generation of reactive oxygen species. Current approaches for the management of PPIX-induced phototoxicity include opaque clothing, sunscreens, phototherapy, blood therapy, antioxidants, bone marrow transplantation, and drugs that increase skin pigmentation. In this review, we discuss the present understanding of PPIX-induced phototoxicity including PPIX production and disposition, conditions that lead to PPIX accumulation, symptoms and individual differences, mechanisms, and therapeutics.

PMID:37392940 | DOI:10.1016/j.pharmthera.2023.108487

Curr Pharm Teach Learn. 2023 Jun 28:S1877-1297(23)00154-5. doi: 10.1016/j.cptl.2023.06.017. Online ahead of print.

ABSTRACT

INTRODUCTION: No current guidance exists to inform the content area credit hours for doctor of pharmacy (PharmD) programs in the United States (US).

METHODS: Public websites were accessed for all Accreditation Council for Pharmacy Education (ACPE) accredited PharmD programs in the US to record the credit hours devoted to drug therapy, clinical skills, experiential learning, scholarship, social and administrative sciences, physiology/pathophysiology, pharmacogenomics, medicinal chemistry, pharmacology, pharmaceutics, and pharmacokinetics/pharmacodynamics in the didactic curricula. Due to the high prevalence of programs that integrate drug therapy, pharmacology, and medicinal chemistry into a single course, we subdivided programs based upon whether drug therapy courses were "integrated" or "non-integrated." A regression analyses was conducted to explore the relationship between each content area and North American Pharmacist Licensure Examination (NAPLEX) pass rates and residency match rates.

RESULTS: Data were available for 140 accredited PharmD programs. Drug therapy had the highest credit hours in programs with both integrated and non-integrated drug therapy courses. Programs with integrated drug therapy courses had significantly more credit hours in experiential and scholarship and fewer credit hours in stand-alone courses for pathophysiology, medicinal chemistry, and pharmacology. Credit hours in content areas did not predict NAPLEX pass rate nor residency match success rate.

CONCLUSIONS: This is the first comprehensive description of all ACPE accredited pharmacy schools with credit hours broken down by content areas. While content areas did not directly predict success criteria, these results may still be useful to describe curricular norms or inform the design of future pharmacy curricula.

PMID:37391352 | DOI:10.1016/j.cptl.2023.06.017

Kidney Int. 2023 Jun 28:S0085-2538(23)00475-1. doi: 10.1016/j.kint.2023.06.021. Online ahead of print.

ABSTRACT

For three decades, tacrolimus (Tac) dose adjustment in clinical practice has been calculated empirically according to the manufacturer's labeling based on a patient's body weight. Here, we developed and validated a Population pharmacokinetic (PPK) model including pharmacogenetics (cluster CYP3A4/CYP3A5), age, and hematocrit. Our study aimed to assess the clinical applicability of this PPK model in the achievement of Tac Co (therapeutic trough Tac concentration) compared to the manufacturer's labelling dosage. A prospective two-arm, randomized, clinical trial was conducted to determine Tac starting and subsequent dose adjustments in 90 kidney transplant recipients. Patients were randomized to a control group with Tac adjustment according to the manufacturer's labeling or the PPK group adjusted to reach target Co (6-10 ng/ml) after the first steady state (primary endpoint) using a Bayesian prediction model (NONMEM). A significantly higher percentage of patients from the PPK group (54.8%) compared with the control group (20.8%) achieved the therapeutic target fulfilling 30% of the established superiority margin defined. Patients receiving PPK showed significantly less intra-patient variability compared to the control group, reached the Tac Co target sooner (5 days vs 10 days), and required significantly fewer Tac dose modifications compared to the control group within 90 days following kidney transplant. No statistically significant differences occurred in clinical outcomes. Thus, PPK-based Tac dosing offers significant superiority for starting Tac prescription over classical labeling-based dosing according to the body weight, which may optimize Tac-based therapy in the first days following transplantation.

PMID:37391040 | DOI:10.1016/j.kint.2023.06.021

Longhua Chin Med. 2022;5:35. doi: 10.21037/lcm-21-72. Epub 2022 Dec 30.

ABSTRACT

BACKGROUND AND OBJECTIVE: Cancer is a major public health problem in the world, and it dramatically affects the life expectancy of patients and their quality of life. Natural products from botanicals could be beneficial in the prevention or treatment of a variety of cancers. Saffron (the extract of Crocus sativus) includes its major constituent, crocin, have been used as a folk medicine for a long time, and they have shown obvious cancer chemoprevention potential. The objectives of this review are to present the progress of research on the effects of saffron and crocin in cancer management and the underlying mechanisms of action.

METHODS: We searched publications in the English language, published between January 1, 1980 and September 30, 2022, of saffron and crocin on cancer through several search engines, i.e., PubMed, SciFinder and Web of Science.

KEY CONTENT AND FINDINGS: In this article, we first summarize the phytochemical studies of this botanical. Then, we present the anticancer effects of saffron and crocin on different human cancer cells. Saffron and crocin showed obvious antiproliferative effects on human cancer cell lines, including colorectal cancer, breast cancer, lung cancer, prostate cancer, cervical cancer, leukemia, glioblastoma and rhabdomyosarcoma. Finally, the anticancer-related mechanisms of action are summarized, including cell cycle arrest at G0/G1 or G2/M phases, induction of caspase-dependent apoptosis, signaling pathway-linked tumor metabolism regulation, and adaptive immunity regulated inflammation of host immune responses.

CONCLUSIONS: Previous studies related to saffron and crocin in cancer management have been reviewed and reported results have been analyzed. Clinical data suggest that saffron and crocin have beneficial effects to improve quality of life in cancer patients. Thus, saffron and crocin can be considered promising candidates for future clinical cancer studies.

PMID:37389090 | PMC:PMC10309162 | DOI:10.21037/lcm-21-72

Front Genet. 2023 Jun 14;14:1085864. doi: 10.3389/fgene.2023.1085864. eCollection 2023.

ABSTRACT

Advances in genomic research have significantly enhanced modern drug development. However, equitable benefit sharing of the results of scientific advancement has not always been achieved. This paper shows how molecular biology has modified medicines development while also leaving open significant challenges for benefit sharing. Presented here is a conceptual modeling describing the processes in genetic-related medicines development and how these are related to specific ethical considerations. The focus is on three important areas: 1) population genetics and the need for discrimination prevention; 2) pharmacogenomics and the need for inclusive governance; and 3) global health to be achieved in open science frameworks. Benefit sharing is taken as the ethical value that underlies all these aspects. The implementation of benefit sharing requires a value shift in which the outcomes of health science are not viewed simply as trade commodities but also as a "global public good". This approach should lead to genetic science to contribute to promoting the fundamental human right to health to all members of the global community.

PMID:37388927 | PMC:PMC10300349 | DOI:10.3389/fgene.2023.1085864

Asia Pac Allergy. 2023 Jun;13(2):72-76. doi: 10.5415/apallergy.0000000000000101. Epub 2023 Jun 6.

ABSTRACT

Drug-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are non-immunoglobulin E-mediated severe cutaneous adverse reactions with a high risk of morbidity, mortality, and physical and mental health impact. These are associated with certain high-risk drugs, human leukocyte antigen (HLA)-specific genotypes and ethnicities. HLA class I-restricted oligoclonal CD8 cytotoxic T-cell responses occur at the tissue level in SJS/TEN. Cytotoxic T cells are the T effector cells that result in keratinocyte apoptosis (cell death) mediated by T effector molecules granzyme B, perforin, granulysin, gamma interferon, tumor necrosis factor-alpha, and lipocalin-2. The clinical hallmarks of SJS/TEN include fever, ≥2 mucosal involvements (ocular, oral, and genital), and positive Nikolsky sign with epidermal detachment. Systematic reviews on immunomodulatory treatments remain limited by the paucity of randomized controlled trials, heterogeneity of studies, and non-standardization of outcome measures. Preventive HLA genotype screening before the prescription of carbamazepine and allopurinol may further reduce the incidence of SJS/TEN. The role of immunomodulatory treatments in SJS/TEN is at present not supported by robust evidence from systematic reviews given the lack of randomized controlled trials. The evidence for improved survival with off-label use of corticosteroids plus intravenous immunoglobulins, ciclosporin plus intravenous immunoglobulins, and ciclosporin alone has not been demonstrated by network meta-analyses and meta-regression. In the real-world clinical setting, systemic corticosteroids (in SJS and overlap SJS/TEN), ciclosporin, and etanercept (in TEN) appear to be the off-label treatments currently most widely used.

PMID:37388817 | PMC:PMC10287110 | DOI:10.5415/apallergy.0000000000000101

Br J Haematol. 2023 Jun 30. doi: 10.1111/bjh.18940. Online ahead of print.

ABSTRACT

Since the publication in 2017 of the revised 4th Edition of the World Health Organization (WHO) classification of haematolymphoid tumours, here referred to as WHO-HAEM4, significant clinicopathological, immunophenotypic and molecular advances have been made in the field of lymphomas, contributing to refining the diagnostic criteria of several diseases, upgrading entities previously defined as provisional and identifying new entities. This process has resulted in two recent classification proposals of lymphoid neoplasms: the International Consensus Classification (ICC) and the 5th edition of the WHO classification (WHO-HAEM5). In this paper, we review and compare the two classifications in terms of diagnostic criteria and entity definition, focusing on T-cell lymphomas and histiocytic/dendritic cell tumours. Moreover, we update the genetic data of the various pathological entities. The main goal is to provide a tool to facilitate the work of the pathologists, haematologists and researchers involved in the diagnosis and treatment of these haematological malignancies.

PMID:37387351 | DOI:10.1111/bjh.18940

Biomed Pharmacother. 2023 Jun 27;165:115058. doi: 10.1016/j.biopha.2023.115058. Online ahead of print.

ABSTRACT

Rivaroxaban is a direct inhibitor of factor Xa, a member of direct oral anticoagulant group of drugs (DOACs). Despite being a widely extended alternative to vitamin K antagonists (i.e., acenocoumarol, warfarin) the interindividual variability of DOACs is significant, and may be related to adverse drug reaction occurrence or drug inefficacy, namely hemorrhagic or thromboembolic events. Since there is not a consistent analytic practice to monitor the anticoagulant activity of DOACs, previously reported polymorphisms in genes coding for proteins responsible for the activation, transport, or metabolism of DOACs were studied. The study population comprised 60 healthy volunteers, who completed two randomized, crossover bioequivalence clinical trials between two different rivaroxaban formulations. The effect of food, sex, biogeographical origin and 55 variants (8 phenotypes and 47 single nucleotide polymorphisms) in drug metabolizing enzyme genes (such as CYP2D6, CYP2C9, NAT2) and transporters (namely, ABCB1, ABCG2) on rivaroxaban pharmacokinetics was tested. Individuals dosed under fasting conditions presented lower tmax (2.21 h vs 2.88 h, β = 1.19, R2 =0.342, p = 0.012) compared to fed volunteers. NAT2 slow acetylators presented higher AUC∞ corrected by dose/weight (AUC∞/DW; 8243.90 vs 7698.20 and 7161.25 h*ng*mg /ml*kg, β = 0.154, R2 =0.250, p = 0.044), higher Cmax/DW (1070.99 vs 834.81 and 803.36 ng*mg /ml*kg, β = 0.245, R2 =0.320, p = 0.002), and lower tmax (2.63 vs 3.19 and 4.15 h, β = -0.346, R2 =0.282, p = 0.047) than NAT2 rapid and intermediate acetylators. No other association was statistically significant. Thus, slow NAT2 appear to have altered rivaroxaban pharmacokinetics, increasing AUC∞ and Cmax. Nonetheless, further research should be conducted to verify NAT2 involvement on rivaroxaban pharmacokinetics and to determine its clinical significance.

PMID:37385211 | DOI:10.1016/j.biopha.2023.115058