Daru. 2024 Oct 19. doi: 10.1007/s40199-024-00538-7. Online ahead of print.

ABSTRACT

BACKGROUND: Cancer treatment has improved over the past decades, but many cancer patients still experience adverse drug reactions (ADRs). Pharmacogenomics (PGx), known as personalized treatment, is a pillar of precision medicine that aims to optimize the efficacy and safety of medications by studying the germline variations. Germline variations in the DPYD lead to significant ADRs. The present cross-sectional study aims to evaluate the allele frequency of the DPYD gene variations in the Iranian population to provide insights into personalized treatment decisions in the Iranian population.

METHODS: The allele frequency of 51 pharmacogenetic variations in the clinically relevant DPYD was assessed in a representative sample set of 1142 unrelated Iranian individuals and subpopulations of different ethnic groups who were genotyped using the Infinium Global Screening Array-24 BeadChip.

RESULTS: The genotyping assay revealed eight pharmacogenetic variants including DPYD rs1801265 (c.85T > C; DPYD*9A), rs2297595 (c.496A > G), rs1801158 (c.1601G > A; DPYD*4), rs1801159 (c.1627A > G; DPYD*5), rs1801160 (c.2194G > A; DPYD*6), rs17376848 (c.1896T > C), rs56038477 (c.1236G > A; HapB3), and rs75017182 (c.1129-5923C > G; HapB3) with minor allele frequency (MAF) ≥ 1%.

CONCLUSION: The results of the study reveal significant genetic variations among Iranian population that could significantly influence clinical decision-making. These variants, with their potential to explain the substantial variability in drug response phenotypes among different populations, shed light on a crucial aspect of pharmacogenomics. These findings not only provide valuable insights but also inspire the design and implementation of future pharmacogenomic clinical trials, motivating further research in this crucial area.

PMID:39424756 | DOI:10.1007/s40199-024-00538-7

Neuroreport. 2024 Oct 1. doi: 10.1097/WNR.0000000000002103. Online ahead of print.

ABSTRACT

The objective of this study is to explore whether sodium valproate (VPA) alleviates epileptic seizures via suppressing lysyl oxidase (Lox)-mediated ferroptosis. Epileptic seizure mouse model was prepared via intrahippocampal injection of kainic acid (250 ng/μl). After treatment with kainic acid, VPA was injected intraperitoneally by the dose of 250 mg/kg twice daily for 4 days. Ferroptosis-associated indices including lipid peroxides (LPO) level and Ptgs2 mRNA in hippocampal tissue samples were detected. Additionally, effects of VPA on Lox mRNA and enzymatic activity were assessed by quantitative real-time PCR and a commercial kit, respectively. Neuronal survival was assessed by Nissl staining. In kainic acid-induced epileptic seizure mouse model, VPA significantly suppressed LPO level and Ptgs2 mRNA and the suppression of ferroptosis was positively correlated with its anti-seizure effect. Lox mRNA and enzymatic activity were also found to decrease in hippocampus of epileptic seizure mice after VPA treatment. Furthermore, overexpression of Lox via adeno-associated virus infection remarkably abrogated the inhibitory effect of VPA on ferroptosis and neuronal impairment together with its anti-seizure effect. VPA suppresses Lox-mediated ferroptosis process, which can provide the explanation for its anti-seizure property.

PMID:39423328 | DOI:10.1097/WNR.0000000000002103

Diabetologia. 2024 Oct 18. doi: 10.1007/s00125-024-06287-1. Online ahead of print.

ABSTRACT

AIMS/HYPOTHESIS: Metformin is an important first-line treatment for type 2 diabetes and acts by increasing the body's ability to dispose of glucose. Metformin's efficacy can be affected by genetic variants in the transporters that regulate its uptake into cells. The SLC22A3 gene (also known as EMT; EMTH; OCT3) codes for organic cation transporter 3 (OCT3), which is a broad-specificity cation transporter that also transports metformin. Most SLC22A3 variants reduce the rate of metformin transport but the rs8187715 variant (p.Thr44Met) is reported to increase uptake of metformin in vitro. However, the impact of this on in vivo metformin transport and efficacy is unknown. Very few carriers of this variant have been reported globally, but, notably, all were of Pacific Island descent. Therefore, this study aims to understand the prevalence of this variant in Polynesian peoples (Māori and Pacific peoples) and to understand its impact on metformin transport and efficacy in vivo.

METHODS: rs8187715 was genotyped in 310 individuals with Māori and Pacific ancestry recruited in Aotearoa New Zealand. To study this variant in a physiological context, an orthologous knockin mouse model with C57BL/6J background was used. Pharmacokinetic analysis compared uptake rate of metformin into tissues. Plasma growth/differentiation factor 15 (GDF-15) was also measured as a marker of metformin efficacy. Glucose and insulin tolerance was assessed after acute or sustained metformin treatment in knockin and wild-type control mice to examine the impact of the variant on metformin's glycaemic control.

RESULTS: The minor allele frequency of this variant in the Māori and Pacific participants was 15.4%. There was no association of the variant with common metabolic parameters including diabetes status, BMI, blood pressure, lipids, or blood glucose and HbA1c. However, in the orthologous knockin mouse model, the rate of metformin uptake into the blood and tissues was increased. Acute metformin dosing increased insulin sensitivity in variant knockin mice but this effect was lost after longer-term metformin treatment. Metformin's effects on GDF-15 levels were also lost in variant knockin mice with longer-term metformin treatment.

CONCLUSIONS/INTERPRETATION: These data provide evidence that the SLC22A3 rs8187715 variant accelerates metformin uptake rate in vivo. While this acutely improves insulin sensitivity, there was no increased effect of metformin with longer-term dosing. Thus, our finding of a high prevalence of this variant specifically in Māori and Pacific peoples identifies it as a potential population-specific pharmacogenetic marker with potential to guide metformin therapy in these peoples.

PMID:39422716 | DOI:10.1007/s00125-024-06287-1

Front Psychiatry. 2024 Oct 3;15:1436875. doi: 10.3389/fpsyt.2024.1436875. eCollection 2024.

ABSTRACT

INTRODUCTION: Genetic counseling and testing in psychiatry warrant attention, but research results on attitude, knowledge, personal experience and interest are limited. There are only a few studies that have compared the opinions of the general population and experts regarding genetic counseling and genetic testing in mental illness.

METHODS: This study aimed to investigate these gaps through a cross-sectional survey conducted in Austria, involving a sample of the web-active population, representative according to gender, age and geographical location (n=1,000, 24.5% of them had a psychiatric diagnosis), and experts (n=145, 83.4% of them psychiatrists). Two questionnaires were developed. Pearson chi-square statistics were used to compare responses, and regression analyses were employed to measure the strength of psycho-sociodemographic influences on answers.

RESULTS: The findings revealed that public considered genetic counseling to be more important than experts did (68.8% versus 54.2%; Pearson chi-square 12.183; df=1; p<0.001). The general population believed that genetic testing is useful for diagnosing mental disorders, which contrasted with experts' opinions (67.9% versus 17.2%; Pearson chi-square 137.236; df=1; p<0.001). Both groups agreed on the potential benefits of pharmacogenetic testing (79% versus 80%). A small number of individuals from the public had sought genetic counseling (8%), and only a minority of experts had specific training and experience in this field (28%).

DISCUSSION: This is the first survey study on the topic conducted in Austria, with limited international studies available. Austrian experts place less value on genetic counseling compared to their counterparts in other countries. Despite recognized importance placed on genetic counseling and testing, utilization rates remain low. The value of pharmacogenetics is predicted to increase in the future. Consequently, it is crucial for medical training programs to emphasize the significance of genetic counseling and enhance the understanding of genetic aspects related to mental illnesses to enable experts to provide adequate psychoeducation and personalized care to the extent possible to patients and their families.

PMID:39421071 | PMC:PMC11484073 | DOI:10.3389/fpsyt.2024.1436875

medRxiv [Preprint]. 2024 Oct 10:2023.10.13.23296963. doi: 10.1101/2023.10.13.23296963.

ABSTRACT

BACKGROUND: Temozolomide (TMZ) treatment has demonstrated, but variable, impact on glioma prognosis. This study examines associations of survival with DNA repair gene germline polymorphisms among glioma patients who did and did not have TMZ treatment. Identifying genetic markers which sensitize tumor cells to TMZ could personalize therapy and improve outcomes.

METHODS: We evaluated TMZ-related survival associations of pathogenic germline SNPs and genetically predicted transcript levels within 34 DNA repair genes among 1504 glioma patients from the UCSF Adult Glioma Study and Mayo Clinic whose diagnoses spanned pre- and post-TMZ eras within the major known glioma prognostic molecular subtypes.

RESULTS: Among those who received TMZ, 5 SNPs were associated with overall survival, but not in those who did not receive TMZ. Only rs2308321-G, in MGMT, was associated with decreased survival (HR=1.21, p=0.019) for all glioma subtypes. Rs73191162-T (near UNG), rs13076508-C (near PARP3), rs7840433-A (near NEIL2), and rs3130618-A (near MSH5) were only associated with survival and TMZ treatment for certain subtypes, suggesting subtype-specific germline chemo-sensitization.Genetically predicted elevated compared to normal brain expression of PNKP was associated with dramatically worse survival for TMZ-treated patients with IDH-mutant and 1p/19q non-codeleted gliomas (p=0.015). Similarly, NEIL2 and TDG expressions were associated with altered TMZ-related survival only among certain subtypes.

CONCLUSIONS: Functional germline alterations within DNA repair genes were associated with TMZ sensitivity, measured by overall survival, among adults with glioma, these variants should be evaluated in prospective analyses and functional studies.

PMID:39417102 | PMC:PMC11482862 | DOI:10.1101/2023.10.13.23296963

Med Clin (Barc). 2024 Oct 16:S0025-7753(24)00553-0. doi: 10.1016/j.medcli.2024.07.021. Online ahead of print.

ABSTRACT

INTRODUCTION: Hyponatraemia has negative effects on cognitive function and gait stability and is a risk factor for osteoporosis, falls, fractures and hospital mortality. Acute hyponatraemia can lead to neurological dysfunction due to cerebral oedema. Its rapid correction can also be fatal, leading to osmotic demyelination syndrome. For some antiepileptics, thiazides, benzodiazepines or antidepressants this reaction is widely described. Knowing which drugs are most likely to cause hyponatraemia will allow early detection and prevention of its complications, as well as individualising the prescription of these drugs according to the patient's characteristics.

OBJECTIVE: The main objectives are to identify potential new safety signals related to hyponatraemia and to analyse the cases of hyponatraemia reported to the Spanish Pharmacovigilance System for Medicines for Human Use (SEFV-H).

METHOD: A disproportionality and a descriptive analysis of individual case safety reports (ICSR) was performed in the SEFV-H database (FEDRA).

RESULTS: Six hundred and fifty-nine cases of suspected drug-induced hyponatraemia were found (0.6% of the total database). Over the 5 years period studied, there was a 57% increase in the number of hyponatraemia reports in Spain. Most of the reported cases were serious (93%). Patients were most often women (63.7%) and elderly (71.9%). The time to onset ranged from 1 to 7030 days (median, 79 days) and approximately 70% of the total occurred within the first year of treatment. Five hundred and forty-six patients (82.9%) showed complete recovery after the withdrawal of the suspected medicine. Diuretics (reported in 57.7% of the cases), antidepressants (in 25%), drugs acting on renin angiotensin system (in 24%) and antiepileptics (in 20.2%) were the most frequent involved drugs. Disproportionate reporting has been found for almost all the substances most frequently reported, higher for amiloride and oxcarbazepine. Regarding new safety signals, the Reporting Odds Ratio (ROR) (95% CI) was found to be statistically significant for valsartan [7.7 (5.1-11.5)], olmesartan [7.3 (4.7-11.1)], amlodipine [3.4 (2.1-5.4)], pregabalin [2.5 (1.4-4.5)], irbesartan [18.6 (9.6-35.9)], paliperidone [2.7 (1.3-5.7)], ritonavir [2.4 (1.1-5.5)], atosiban [29.7 (8.6-102.2)], melphalan [9.7 (3.5-26.8)] and clozapine [4.4 (1.6-11.8)]. These active ingredients do not include this reaction on their SPC and comply with the EMA criteria for a safety signals.

CONCLUSION: There are increasing reports of drug-induced hyponatraemia. It can be serious and seems to most often affect women over 65 years of age who take more than 1 medication. The time to onset varies and can be very long, so patient monitoring should be continuous throughout treatment. Hydrochlorothiazide is the drug with the highest number of reported cases in our setting. In terms of disproportionate reporting, diuretics leads the list, followed by antiepileptics as oxcarbazepine and eslicarbazepine. Safety signals were found for several drugs, more plausibly for pregabalin and paliperidone, thus a possible association between these drugs and hyponatraemia/SIAD is identified. This signal must be further studied. Meanwhile healthcare professionals should pay attention to this possibility. The reporting of suspected ADRs is essential to understand the risks associated with medicines once they are on the market.

PMID:39419657 | DOI:10.1016/j.medcli.2024.07.021

Am J Cancer Res. 2024 Sep 15;14(9):4286-4305. doi: 10.62347/VIQM5219. eCollection 2024.

ABSTRACT

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer. The crosstalk between tumor tissue and adjacent adipose tissue has been appreciated recently. This study examines the predictive usefulness of brown adipocyte-related genes (BARGs) in ccRCC.

METHODS: The transcriptome and clinical data of ccRCC patients were obtained from TCGA-KIRC and USA-ccRCC cohorts (848 tumor samples; 72 normal samples). Lasso-Cox methods were used to construct the risk prognostic signature model. We used Kaplan-Meier survival analysis to evaluate the prognostic significance of the risk model with ROC curves ascertaining prediction accuracy. The differences in immune cell infiltrates and signature risk scores between different risk categories were analyzed. Finally, biological experiments were performed to explore the functions of candidate genes.

RESULTS: TCGA-KIRC patients were classified into two clusters that differed significantly regarding overall survival (OS) and tumor microenvironment. After screening BARGs candidates, a signature consisting of PPP1R1A, DPYSL3, and PTPRM was created to calculate risk score. Patients were assigned to the high or low-risk group, and the high-risk group had a significantly worse prognosis. Consistent trend was validated in external USA-ccRCC cohort. Meanwhile, the signature risk score affected immune cell infiltrates within the ccRCC microenvironment, positively correlated with the infiltration of CD4+ T cells, CD8+ T cells, CD56dim, CD56bright NK cells, MDSCs, and macrophage cells, while negatively correlated with neutrophil, iDCs, mast cells, and eosinophil. Finally, knockdown of PPP1R1A and DPYSL3 in renal cancer cells showed impairment in tumor proliferation ability of ccRCC in vitro and in vivo. Conversely, knockdown of PTPRM exhibited a promotive effect.

CONCLUSION: We developed a predictive BARGs-related risk signature for early diagnosis and classifying ccRCC patients, which offers potential targets for individualized treatment of ccRCC.

PMID:39417181 | PMC:PMC11477832 | DOI:10.62347/VIQM5219

J Clin Pharmacol. 2024 Oct 17. doi: 10.1002/jcph.6153. Online ahead of print.

ABSTRACT

Tenofovir disoproxil fumarate (TDF) requires dosage adjustments from the standard 300 mg once daily to every 48-96 h for moderate-to-severe renal impairment to avoid excessive exposure. However, this extended interval can lead to variable drug exposure and inconvenience. This study aimed to utilize the population pharmacokinetic (PPK) models to optimize TDF dosing regimens for HIV-infected patients with renal impairment. A systematic literature search was conducted across PubMed, Cochrane Library, and Scopus databases to identify relevant PPK studies of TDF in HIV-infected patients. From the included studies, the PPK models and associated parameters were extracted. Monte Carlo simulations (n = 2000) were performed to generate concentration-time profiles and derive PK parameters compared against reference ranges. For moderate renal impairment, the TDF 150 mg once-daily regimen achieved cumulative exposure comparable to the approved 300 mg every-other-day regimen. In severe renal impairment, TDF 75-100 mg administered once daily provided similar cumulative exposure as 300 mg every 72-96 h regimen while maintaining daily exposure comparable to the standard dose in patients with normal renal function. The approved extended dosing intervals of 72-96 h exhibited high drug exposure variability, initially resulting in supratherapeutic levels followed by suboptimal levels preceding the subsequent dose administration. In conclusion, administering smaller once-daily doses of TDF maintains consistent daily drug exposure comparable to the standard dose in patients with normal renal function while reducing variability in drug exposure, potentially mitigating the risk of nephrotoxicity. However, additional clinical studies are required to confirm these findings.

PMID:39415758 | DOI:10.1002/jcph.6153

BMC Infect Dis. 2024 Oct 16;24(1):1168. doi: 10.1186/s12879-024-10073-0.

ABSTRACT

BACKGROUND: Although several genetic biomarkers have been reported in the tocilizumab (TCZ) response in rheumatoid arthritis, no studies have addressed the pharmacogenomics effect of TCZ in COVID-19.

METHODS: In this prospective longitudinal study, 95 individuals with severe COVID-19 were selected between 2020-2022. The recovery process was measured at 24 h, 48 h, and 10 days before and after taking TCZ. All participants were genotyped using RFLP-PCR. Different genotypes of FCGR2A rs1801274 and IL-6R rs2228145 were compared in terms of the recovery process.

RESULTS: 43.2% of patients were male and 56.8% were female with an average age of 58.20(± 16.214) years. The GA genotype for FCGR2A rs1801274 increased the risk of death (OR = 2.83, P = 0.038) and ventilation (OR = 2.71, P = 0.047) in TCZ-treated individuals. However, there was no risk of death and ventilation with IL-6R rs2228145 (P > 0.05). Additionally, docking analysis showed that not only IL6R but also FCGR2A can be a ligand for TCZ.

CONCLUSION: This study provides valuable insights into the impact of genetic variations on the response rate of TCZ in COVID-19 patients. The GA genotype for FCGR2A rs1801274 was associated with poor treatment outcomes.

PMID:39415081 | DOI:10.1186/s12879-024-10073-0

Pharmacol Rev. 2024 Oct 16;76(6):1089-1101. doi: 10.1124/pharmrev.124.001433.

ABSTRACT

Karolinska Institutet is a medical university encompassing 21 departments distributed across three departmental or campus groups. Pharmacological research has a long and successful tradition at the institute with a multitude of seminal findings in the areas of neuronal control of vasodilatation, cardiovascular pharmacology, neuropsychopharmacology, receptor pharmacology, and pharmacogenomics that resulted in, among many other recognitions, two Nobel prizes in Physiology and Medicine, one in 1970 to Ulf von Euler for his discovery of the processes involved in storage, release, and inactivation of neurotransmitters and the other in 1982 to Sune Bergström and Bengt Samuelsson for their work on prostaglandins and the discovery of leukotrienes. Pharmacology at Karolinska Institutet has over the last decade been ranked globally among the top 10 according to the QS World University Ranking. With the Department of Physiology and Pharmacology now celebrating its 75-year anniversary, we wanted to take this as an opportunity to showcase recent research achievements and how they paved the way for current activities at the department. We emphasize examples from preclinical and clinical research where the dpartment's integrative environment and robust infrastructure have successfully facilitated the translation of findings into clinical applications and patient benefits. The close collaboration between preclinical scientists and clinical researchers across various disciplines, along with a strong network of partnerships within the department and beyond, positions us to continue leading world-class pharmacological research at the Department of Physiology and Pharmacology for decades to come. SIGNIFICANCE STATEMENT: Pharmacological research at Karolinska Institutet has a long and successful history. Given the 75-year anniversary of the Department of Physiology and Pharmacology, this perspective provides an overview of recent departmental achievements and future trajectories. For these developments, interdisciplinary and intersectoral collaborations and a clear focus on result translation are key elements to continue its legacy of world-leading pharmacological research.

PMID:39414365 | DOI:10.1124/pharmrev.124.001433

J Natl Compr Canc Netw. 2024 Oct;22(8):e247073. doi: 10.6004/jnccn.2024.7073.

NO ABSTRACT

PMID:39413814 | DOI:10.6004/jnccn.2024.7073

CPT Pharmacometrics Syst Pharmacol. 2024 Oct 16. doi: 10.1002/psp4.13240. Online ahead of print.

ABSTRACT

The use of synthetic data in pharmacology research has gained significant attention due to its potential to address privacy concerns and promote open science. In this study, we implemented and compared three synthetic data generation methods, CT-GAN, TVAE, and a simplified implementation of Avatar, for a previously published pharmacogenetic dataset of 253 patients with one measurement per patient (non-longitudinal). The aim of this study was to evaluate the performance of these methods in terms of data utility and privacy trade off. Our results showed that CT-GAN and Avatar used with k = 10 (number of patients used to create the local model of generation) had the best overall performance in terms of data utility and privacy preservation. However, the TVAE method showed a relatively lower level of performance in these aspects. In terms of Hazard ratio estimation, Avatar with k = 10 produced HR estimates closest to the original data, whereas CT-GAN slightly underestimated the HR and TVAE showed the most significant deviation from the original HR. We also investigated the effect of applying the algorithms multiple times to improve results stability in terms of HR estimation. Our findings suggested that this approach could be beneficial, especially in the case of small datasets, to achieve more reliable and robust results. In conclusion, our study provides valuable insights into the performance of CT-GAN, TVAE, and Avatar methods for synthetic data generation in pharmacogenetic research. The application to other type of data and analyses (data driven) used in pharmacology should be further investigated.

PMID:39412034 | DOI:10.1002/psp4.13240

J Pediatr Pharmacol Ther. 2024 Oct;29(5):554-557. doi: 10.5863/1551-6776-29.5.554. Epub 2024 Oct 14.

NO ABSTRACT

PMID:39411408 | PMC:PMC11472404 | DOI:10.5863/1551-6776-29.5.554

Diagnostics (Basel). 2024 Oct 2;14(19):2202. doi: 10.3390/diagnostics14192202.

ABSTRACT

BACKGROUND/OBJECTIVES: Our previous retrospective single-center cohort study found, at 3-year follow-up, a trend toward low tacrolimus trough levels and an increased risk of de novo donor-specific anti-HLA antibodies (DSAs) and of antibody-mediated rejection (ABMR) in CYP3A5-expressing patients. Determining CYP3A5-expression status immediately after renal transplant would allow early genotype-based dosage adjustment of tacrolimus and might prevent the occurrence of de novo DSAs and ABMR, improving transplant outcome.

METHODS: 160 renal allograft recipients who underwent renal transplant at the University Hospital Essen between May 2019 and May 2022 were genotyped for the CYP3A5 rs776746 polymorphism within the first two weeks after transplant, and genotype-based dose adjustment of tacrolimus was performed for the follow-up of 2 years.

RESULTS: CYP3A5 expression was detected in 33 (21%) of the 160 patients. Tacrolimus trough levels were similar in CYP3A5 expressers and nonexpressers over the entire 2-year follow-up period. However, we observed a trend toward slightly higher tacrolimus trough levels in CYP3A5 expressers, who, as expected, required tacrolimus dosages twice as high as did nonexpressers during follow-up. Calcineurin inhibitor (CNI) nephrotoxicity-free survival rates were comparable between CYP3A5 expressers and nonexpressers (p = 0.49). Rejection-free survival rates (p = 0.89), de novo anti-HLA antibody-free survival rates (p = 0.57) and de novo DSA-free survival rates (p = 0.61) did not differ between the two groups.

CONCLUSIONS: Early detection of CYP3A5-expression status and resultant genotype-based adjustment of tacrolimus dosage after renal transplant protected patients from transplant rejection and de novo DSA formation and was not associated with increased incidence of CNI toxicity among CYP3A5 expressers.

PMID:39410605 | DOI:10.3390/diagnostics14192202

Cancers (Basel). 2024 Sep 29;16(19):3339. doi: 10.3390/cancers16193339.

ABSTRACT

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment for relapsed/refractory B-cell lymphomas. Despite its success, this therapy is accompanied by a significant frequency of adverse events, including cytokine release syndrome (CRS), immune-effector-cell-associated neurotoxicity syndrome (ICANS), or cytopenias, reaching even up to 80% of patients following CAR-T cell therapy. CRS results from the uncontrolled overproduction of proinflammatory cytokines, which leads to symptoms such as fever, headache, hypoxia, or neurological complications. CAR-T cell detection is possible by the use of flow cytometry (FC) or quantitative polymerase chain reaction (qPCR) assays, the two primary techniques used for CAR-T evaluation in peripheral blood, bone marrow (BM), and cerebrospinal fluid (CSF). State-of-the-art imaging technologies play a crucial role in monitoring the distribution and persistence of CAR-T cells in clinical trials. Still, they can also be extended with the use of FC and digital PCR (dPCR). Monitoring the changes in cell populations during disease progression and treatment gives an important insight into how the response to CAR-T cell therapy develops on a cellular level. It can help improve the therapeutic design and optimize CAR-T cell therapy to make it more precise and personalized, which is crucial to overcoming the problem of tumor relapse.

PMID:39409959 | DOI:10.3390/cancers16193339

Int J Mol Sci. 2024 Oct 1;25(19):10577. doi: 10.3390/ijms251910577.

ABSTRACT

Cancer cell mitochondria are functionally different from those in normal cells and could be targeted to develop novel anticancer agents. The aryl-ureido fatty acid CTU (16({[4-chloro-3-(trifluoromethyl)phenyl]-carbamoyl}amino)hexadecanoic acid) is the prototype of a new class of targeted agents that enhance the production of reactive oxygen species (ROS) that disrupt the outer mitochondrial membrane (OMM) and kill cancer cells. However, the mechanism by which CTU disrupts the inner mitochondrial membrane (IMM) and activates apoptosis is not clear. Here, we show that CTU-mediated ROS selectively dysregulated the OMA1/OPA1 fusion regulatory system located in the IMM. The essential role of ROS was confirmed in experiments with the lipid peroxyl scavenger α-tocopherol, which prevented the dysregulation of OMA1/OPA1 and CTU-mediated MDA-MB-231 cell killing. The disruption of OMA1/OPA1 and IMM fusion by CTU-mediated ROS accounted for the release of cytochrome c from the mitochondria and the activation of apoptosis. Taken together, these findings demonstrate that CTU depolarises the mitochondrial membrane, activates ROS production, and disrupts both the IMM and OMM, which releases cytochrome c and activates apoptosis. Mitochondrial-targeting agents like CTU offer a novel approach to the development of new therapeutics with anticancer activity.

PMID:39408906 | DOI:10.3390/ijms251910577

Int J Mol Sci. 2024 Sep 26;25(19):10352. doi: 10.3390/ijms251910352.

ABSTRACT

Pharmacogenomic analysis based on drug transcriptome characteristics is widely used to identify mechanisms of action. The purpose of this study was to elucidate the molecular mechanism of protective effect against adriamycin (ADM)-induced mpc5 cell injury of Chinese cordyceps aqueous extracts (WCCs) by a systematic transcriptomic analysis. The phytochemicals of WCCs were analyzed via the "phenol-sulfuric acid method", high-performance liquid chromatography (HPLC), and HPLC-mass spectrometry (MS). We analyzed the drug-reaction transcriptome profiles of mpc5 cell after treating them with WCCs. RNA-seq analysis revealed that WCCs alleviated ADM-induced mpc5 cell injury via restoring the expression of certain genes to normal level mainly in the one-carbon pool by the folate pathway, followed by the relaxin, apelin, PI3K-Akt, and nucleotide-binding, oligomerization domain (NOD)-like receptor signaling pathway, enhancing DNA synthesis and repair, cell proliferation, fibrosis reduction, and immune regulation. Otherwise, WCCs also modulated the proliferation and survival of the mpc5 cell by regulating metabolic pathways, and partially restores the expression of genes related to human disease pathways. These findings provide an innovative understanding of the molecular mechanism of the protective effect of WCCs on ADM-induced mpc5 cell injury at the molecular transcription level, and Mthfd2, Dhfr, Atf4, Creb5, Apln, and Serpine1, etc., may be potential novel targets for treating nephrotic syndrome.

PMID:39408685 | DOI:10.3390/ijms251910352

J Clin Med. 2024 Oct 8;13(19):5995. doi: 10.3390/jcm13195995.

ABSTRACT

Background/Objectives: Integrating the cytotoxic drug busulfan into a high-dose chemotherapy regimen prior to autologous hematopoietic stem cell rescue in patients with high-risk neuroblastoma has improved the survival of children battling this deadly disease. Busulfan-induced toxicities can, however, be severe. Here, we describe the diagnosis and successful treatment of acute pulmonary injury by total-body-weight-adjusted busulfan therapy in two children with high-risk neuroblastoma. Case series: Patient 1 developed life-threatening biphasic acute respiratory failure on days +60 and +100 after busulfan therapy, requiring intubation and invasive mechanical ventilation. Despite intensive anti-inflammatory and immunomodulatory therapy, including systemic corticosteroids, topical inhalation regimens, azithromycin, nintedanib and extracorporal photopheresis, patient 1 required extended intensive care measures and non-invasive respiratory support for a total of 20 months. High-resolution computed tomography showed diffuse intra-alveolar and interstitial patterns. Patient 2 developed partial respiratory failure with insufficient oxygen saturation and dyspnea on day +52 after busulfan therapy. Symptoms were resolved after 6 months of systemic corticosteroids, topical inhalation regimens and azithromycin. High-resolution computed tomography showed atypical pneumonic changes with ground-glass opacities. While both patients fully recovered without evidence of pulmonary fibrosis, cancer therapy had to be paused and then modified until full recovery from busulfan-induced lung injury. Conclusions: Busulfan-induced lung injury requires prompt diagnosis and intervention. Symptoms and signs are nonspecific and difficult to differentiate from other causes. Therapeutic busulfan drug level monitoring and the identification of patients at risk for drug overdosing through promoter polymorphisms in the glutathione S-transferase alpha 1 gene encoding the main enzyme in busulfan metabolism are expected to reduce the risk of busulfan-induced toxicities.

PMID:39408056 | DOI:10.3390/jcm13195995

BMC Psychiatry. 2024 Oct 15;24(1):690. doi: 10.1186/s12888-024-06162-8.

ABSTRACT

BACKGROUND: There is no doubt that genetic factors have the potential to predict the therapeutic outcomes of antidepressants in patients with major depressive disorder (MDD). This study investigated the association between genetic variants involved in serotonin signaling and brain-derived neurotrophic factor (BDNF) with the response to escitalopram treatment in patients with MDD. We focused on examining the influence of 5-HTTLPR (ins/del), HTR2A rs9316233, BDNF rs962369, CYP2C19 and CYP2D6 on the clinical response to escitalopram.

METHODS: The patients were recruited from outpatient psychiatric clinics in Košice between 2020 and 2022. Patients received escitalopram for 12 weeks at a fixed dose of 10 mg daily. Clinical assessment was done at baseline and after 4, 8, and 12 weeks using the 21-item Hamilton Depression Rating Scale (HAMD-21).

RESULTS: At the end of week 12, 57 (65%) patients were defined as responders to escitalopram treatment, while 31 (35%) patients were non-responders. Genotyping revealed that carriers of the short allele (S) of 5-HTTLPR exhibit a significantly lower therapeutic response to escitalopram measured by HAMD-21 than the long allele (L) carriers (p = 0.01). Adjusting for CYP2C19 and CYP2D6 metabolizer genotypes did not modify the observed relationship between 5-HTTLPR and treatment response. No significant associations were found for HTR2A rs9316233 or BDNF rs962369 variants and the treatment response.

CONCLUSIONS: These findings underscore the utility of 5-HTTLPR genotyping in guiding escitalopram therapy for MDD patients. Further research with larger cohorts is warranted to validate these results and elucidate additional genetic determinants of antidepressant efficacy.

PMID:39407134 | DOI:10.1186/s12888-024-06162-8

Inflammopharmacology. 2024 Oct 16. doi: 10.1007/s10787-024-01578-w. Online ahead of print.

ABSTRACT

As of the 7th of July 2024, 775,754,322 confirmed cases of COVID-19, including 7,053,902 deaths worldwide, had been reported to the WHO (World Health Organization). Nevertheless, untill the 15th of July 2024, a total of 13,578,710,228 vaccine doses had been administered, with almost no country spared from COVID-19 attacks. The pathophysiology of this virus is complicated, and several symptoms require a deep understanding of the actual mechanisms. It is unclear why some patients develop severe symptoms while others do not, although literature suggests a role for vitamin D. Vitamin D plays a crucial role in the infection or in ameliorating the severity of symptoms. The mechanism of action of vitamin D and vitamin D deficiency (VDD) is well understood. VDD is associated with increased hospitalization of severely ill patients and increased levels of COVID-19-caused mortality. Recent studies suggest that vitamin D levels and genetic variations in the vitamin D receptor (VDR) gene significantly impact the severity and outcomes of COVID-19, especially in the infections caused by Delta and Omicron variants. Furthermore, VDD causes immune system dysregulation upon infection with SARS-CoV-2, indicating that vitamin D sufficiency is crucial in fighting against COVID-19 infection. The therapeutic effect of vitamin D raises interest in its potential role as a prophylactic and treatment adjunct. We evaluate the immunomodulatory effects of vitamin D and its ability to enhance the efficacy of new antiviral drugs like molnupiravir and paxlovid against SARS-CoV-2. This review discusses the role of vitamin D sufficiency and VDD in COVID-19 initiation and progression, emphasizing the molecular mechanisms by which vitamin D exerts its actions as a proactive step for the next pandemic. However, there is still no clear evidence of vitamin D's impact on prevention and treatment, leading to contradictory findings. Therefore, large-scale randomized trials are required to reach a definitive conclusion. A bibliometric analysis of publications related to vitamin D, immunity, and COVID-19 revealed a significant increase in research activity in this area, particularly in 2020-2024, underscoring the growing recognition of vitamin D's potential role in the context of the pandemic.

PMID:39406981 | DOI:10.1007/s10787-024-01578-w