Endocr Connect. 2025 Feb 1:EC-24-0082. doi: 10.1530/EC-24-0082. Online ahead of print.

ABSTRACT

INTRODUCTION: We previously observed that continuous subcutaneous gonadotropin infusion (CSGI) in infants with congenital hypogonadotropic hypogonadism (CHH) can mimic minipuberty.

OBJECTIVE: to describe the early adolescence outcome of boys treated during the first year of life.

METHODS: In this retrospective cohort study, we describe 11 CHH boys aged 12 years [11.5-14.6] treated at the age of 4.5 months [2.0-11] with CSGI. To caompare we report testicular function of 12 untreated CHH boys aged 12 years [12-15.9].

RESULTS: In response to CSGI, serum testosterone and inhibinB levels increased from 0.03 ng/mL [0-0.07] to 2.25 ng/mL [1.12-3.86] and from 73 [11-173] to 401 [185-727] pg/mL, respectively. Testicular volume increased from 0.50 mL [0.5-1] to 1.50 mL [0.7-3]. Between end of CSGI and early adolescence, testicular volume in the treated group decreased from 1.5 mL [0.7-3] to 1.05 ml [0.7-2.36] (p=0.024) and differed from that in untreated boys (0.3 mL [0.13-1.3]). Hormone levels were higher in the treated group : serum AMH and inhibin B levels in treated patients decreased from 1028 pmol/l [550-1750] and 356 [185-727] pg/mL at neonatal period to 331 pmol/l [85-479] and 68 pg/ml [19-239] respectively at early adolescence and differed from those in untreated patients (57.5 [30-169] and 8 pg/ml [<5-37] (p<0.001)).

CONCLUSION: We report the first long-term follow-up of CHH boys treated with CSGI in infancy. Our results shown that the CSGI treatment resulted in higher inhibin B, AMH levels and testicular volume at early adolescence age. Follow-up should be continued until the end of puberty to assess spermatogenesis.

PMID:40042209 | DOI:10.1530/EC-24-0082

Mol Pain. 2025 Mar 4:17448069251327805. doi: 10.1177/17448069251327805. Online ahead of print.

ABSTRACT

μ-opioid receptor (MOP) plays a critical role in mediating opioid analgesic effects. Genetic variations, particularly those in the MOP gene (Oprm1), significantly influence individual variations in opioid efficacy and side effects across species, highlighting the need for pharmacogenomic research in human and veterinary contexts. This study aimed to identify single-nucleotide variations (SNVs) within Oprm1 in 100 cats of various breeds. Oprm1 spans over 170 kb and consists of five exons that combine to yield three splice variants in the cat Ensembl database. Among these variants, Oprm1-202 is an ortholog of the MOR-1 transcript, which is the most abundant in humans and mice. Oprm1-202 shares 92% and 87% coding sequences (CDS) and 96% and 94% amino acid sequence identity with human and mouse MOR-1, respectively. Phylogenetic trees were constructed from the CDS and amino acid sequences of nine species, including humans, cats, and mice. Both the CDS and amino acid sequences of MOP in cats showed phylogenetic development closer to that of primates than of rodents. Four SNVs were identified in the CDS of Oprm1. One SNV was located in exon 1 and the other three in exon 2 of Oprm1, all of which were synonymous substitutions. Although synonymous mutations generally have a limited functional impact, they may influence splicing and receptor expression. Further research is required to assess the effects of these SNVs on opioid efficacy, receptor expression, and analgesic responses across breeds, considering the potential breed-specific genetic factors in cat species.

PMID:40040278 | DOI:10.1177/17448069251327805

Nat Commun. 2025 Mar 4;16(1):2152. doi: 10.1038/s41467-025-57361-0.

ABSTRACT

Numerous patients with rheumatoid arthritis (RA) manifest severe syndromes, including elevated synovial fluid volumes (SF) with abundant immune cells, which can be controlled by TNF/JAK inhibitors. Here, we apply single-cell RNA sequencing (scRNA-seq) and subsequent validations in SF from RA patients. These analyses of synovial tissue show reduced density of SF-derived pathogenic cells (e.g., SPP1+ macrophages and CXCL13+CD4+ T cells), altered gene expression (e.g., SPP1 and STAT1), molecular pathway changes (e.g., JAK/STAT), and cell-cell communications in drug-specific manners in samples from patients pre-/post-treated with adalimumab/tofacitinib. Particularly, SPP1+ macrophages exhibit pronounced communication with CXCL13+CD4+ T cells, which are abolished after treatment and correlate with treatment efficacy. These pathogenic cell types alone or in combination can augment inflammation of fibroblast-like synoviocytes in vitro, while conditional Spp1 knocking-out reduces RA-related cytokine expression in collagen-induced arthritis mice models. Our study shows the functional role of SF-derived pathogenic cells in progression and drug-specific treatment outcomes in RA.

PMID:40038288 | DOI:10.1038/s41467-025-57361-0

Mol Pharmacol. 2025 Feb 7;107(3):100021. doi: 10.1016/j.molpha.2025.100021. Online ahead of print.

ABSTRACT

Ritonavir (RTV) is an important drug for anti-human immunodeficiency virus treatment and is mainly metabolized by cytochrome P450 (CYP) 3A4. Clinically, the most common side effect of RTV treatment is hepatoxicity. We previously showed that the long noncoding RNA hepatocyte nuclear factor 4 alpha (HNF4A) antisense 1 (HNF4A-AS1) negatively regulated CYP3A4 expression and participated in RTV-induced hepatotoxicity in vitro, but the mechanism has not been well understood. In this study, similar results were observed in the mouse, where liver-specific knockdown of Hnf4aos (homolog of human HNF4A-AS1) led to increased serum aspartate (∼1.8-fold) and alanine transaminase (∼2.4-fold) levels and enlarged and degenerated hepatocytes 24 hours after RTV administration. Meanwhile, endoplasmic reticulum stress markers GRP78, PDI, and XBP-1 increased about 2.4-fold, 2.1-fold, and 2.7-fold, respectively. The aggravated liver injury correlated with Hnf4aos knockdown, attributable to heightened Cyp3a11 (homolog of human CYP3A4) expression (mRNA and protein levels were 1.8-fold and 2.5-fold, respectively). Importantly, in vitro studies revealed the underlying mechanism that HNF4A-AS1 mediated the interaction between heterogeneous nuclear ribonucleoprotein C and HNF4A, whereas heterogeneous nuclear ribonucleoprotein C promoted HNF4A degradation through the ubiquitination pathway, thereby decreasing CYP3A4 expression and alleviating RTV-induced liver injury. Overall, our findings unveil a novel mechanism by which HNF4A-AS1 regulates CYP3A4 expression to influence RTV-induced liver injury. SIGNIFICANCE STATEMENT: HNF4A-AS1 negatively regulates the expression of CYP3A4, whose overexpression is highly correlated with ritonavir (RTV)-induced liver injury. In this study, the role of Hnf4aos (homolog of human HNF4A-AS1) in RTV-induced hepatotoxicity was confirmed in mice. We found that HNF4A-AS1 and HNRNPC form a complex and facilitate the ubiquitination and degradation of HNF4A protein, thereby decreasing CYP3A4 expression and alleviating RTV hepatotoxicity.

PMID:40037142 | DOI:10.1016/j.molpha.2025.100021

J Infect Dis. 2025 Feb 26:jiaf098. doi: 10.1093/infdis/jiaf098. Online ahead of print.

ABSTRACT

Dolutegravir treatment can lead to neuropsychiatric adverse events (NPAE). This study assessed the association between NPAE and polymorphisms in dolutegravir-related pharmacogenes, determined by next-generation sequencing panel testing. Using a case-control design, 36 patients having previously discontinued dolutegravir due to NPAE were compared to 98 patients tolerating dolutegravir. In the latter group, psychometric scores were compared according to genotype, targeting polymorphisms associated with drug intolerance. NR1I2 c.-22-7659C>T was independently associated with a reduced risk of NPAE-related dolutegravir discontinuation (odds ratio of 0.36 [95% confidence interval, .15-.88] for T-variant allele carriage) and was linked to decreased anxiety scores in control-group participants.

PMID:40036182 | DOI:10.1093/infdis/jiaf098

Am J Respir Crit Care Med. 2025 Mar 4. doi: 10.1164/rccm.202409-1698OC. Online ahead of print.

ABSTRACT

OBJECTIVES: To evaluate the effect of genetic variant status on sotatercept efficacy and effect of sotatercept treatment on biomarkers in pulmonary arterial hypertension Methods: PULSAR (NCT03496207) was a phase 2, randomized, controlled study of sotatercept vs placebo added to background therapy for pulmonary arterial hypertension. Participants had DNA sequencing done at baseline to detect genetic variants in disease-associated genes (ACVRL1, BMPR2, CAV1, EIF2AK4, ENG, KCNA3, KCNK3, and SMAD9). Safety (adverse events) and efficacy (pulmonary vascular resistance, 6-minute walk distance) were assessed by variant status and treatment at 24 weeks. Serum levels of BMPR2 mRNA and N-terminal pro-hormone B-type natriuretic peptide were assessed at baseline and 24 weeks by treatment and variant status. Analysis of covariance was used to compare the change from baseline by treatment and variant status.

RESULTS: Of 76 participants included, 25 had pathogenic variants detected (23 BMPR2; 2 other) and 51 had no variants or variants of uncertain significance. BMPR2 mutation carriers were younger and more frequently on triple therapy but had less severe clinical characteristics at baseline. Changes at 24 weeks in pulmonary vascular resistance and 6-minute walk distance did not differ by variant status. BMPR2 gene expression varied less than twofold from baseline over time, irrespective of treatment or variant status. The adverse events profile was generally consistent with that seen in the parent PULSAR study.

CONCLUSIONS: These results suggest consistent safety and clinical efficacy of sotatercept for treatment of pulmonary arterial hypertension, irrespective of BMPR2 variant status. Clinical trial registration available at www.

CLINICALTRIALS: gov, ID: NCT03496207.

PMID:40035659 | DOI:10.1164/rccm.202409-1698OC

Int Rev Psychiatry. 2025 Feb;37(1):52-58. doi: 10.1080/09540261.2024.2432369. Epub 2024 Dec 2.

ABSTRACT

Substance Use Disorders (SUD) lead to a collection of health challenges such as overdoses and clinical diseases. Populations that are vulnerable and lack straightforward treatment access are vulnerable to significant economic and social effects linked to SUD. The ongoing advances in technology, especially Artificial Intelligence (AI), promise new ways to reduce the effects of SUD, refine treatment standards, and minimize the risk of relapse through tailored treatment plans. Recent innovations in functional neuroimaging techniques, such as fMRI, have led to the ability to detect brain patterns associated with drug use, and biomarkers in blood testing provide crucial diagnostic support. In addition, digital platforms applied for behavioral assessment supported by AI and natural language processing improve the early recognition of substance consumption trends, allowing for targeted interventions reliant on real-time data. Using pharmacogenetics and resources like mobile apps and wearable devices makes the development of care programs that continuously track substance use, mental health, and physical changes possible. At the core of ethical issues related to the application of AI for SUD are the rights of patients to have their privacy protected to ensure that all people justly have access to these technologies. The advancement of AI models provides significant possibilities to support clinical judgment and enhance patient outcomes.

PMID:40035372 | DOI:10.1080/09540261.2024.2432369

iScience. 2025 Feb 1;28(3):111943. doi: 10.1016/j.isci.2025.111943. eCollection 2025 Mar 21.

ABSTRACT

Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer with limited treatment options. Patients often respond well to initial chemo-immunotherapy but relapse quickly, necessitating new strategies to enhance immune responsiveness. Recent research explores combining DNA-damaging therapies with immunotherapy to activate the STING pathway and improve the antitumor immune response. The addition of DNA Damage Repair (DDR) inhibitors, such as DNA-PKcs inhibitors, after chemotherapy has shown promise in activating innate immune sensors and enhancing CD8+ T cell and NK cell pathways in SCLC models. This approach could potentially reshape the tumor microenvironment and sustain an antitumor immune response, offering a maintenance strategy for SCLC treatment.

PMID:40034862 | PMC:PMC11875153 | DOI:10.1016/j.isci.2025.111943

Clin Pharmacol Ther. 2025 Mar 3. doi: 10.1002/cpt.3617. Online ahead of print.

ABSTRACT

Tailoring pharmacogenomic (PGx) implementation to diverse populations is vital to promoting health equity. We assessed prescriptions for medications with potentially actionable PGx information to identify patient characteristics associated with differential PGx medication exposure. We analyzed the nationally-representative MEPS dataset of adults who reported receiving prescriptions between 2014 and 2021. PGx medications include those the FDA and CPIC designate as having drug-gene associations supported by scientific evidence. With the primary outcome being PGx prescriptions, we performed Poisson regression adjusted for all other relevant covariates. In our final population (N = 119,722, 72% White/20% Black/4% Asian/8% Hispanic), 61% were prescribed a PGx medication, 56% were female, and 97% held health insurance coverage. Adults with private health insurance (65%) or public Medicaid/Medicare coverage (32%) were more likely to have PGx prescriptions than the uninsured (3%). Individuals with cardiovascular conditions [adjusted IRR (aIRR) = 1.45, 95% CI 1.41, 1.48], high cholesterol [aIRR = 1.37, 95% CI 1.35, 1.40], high blood pressure [aIRR = 1.14, 95% CI 1.12, 1.16], and cancer [aIRR = 1.02, 95% CI 1.00, 1.04] were more likely to receive PGx prescriptions. Self-reported Blacks were less likely than Whites to receive PGx medications [aIRR = 0.92, 95% CI 0.90, 0.94], and among those with health conditions, the likelihood of PGx medication exposure for underrepresented groups (Blacks, Hispanics, and Asians) was lower than for Whites. Our study using a comprehensive list of PGx medications in a nationally representative dataset indicates that certain populations are differentially exposed to genomically informed medications. This may suggest that if implementing a pharmacogenomics program based on reactive testing initiated by a prescription, a small underrepresentation of the Black population could be expected because of an underlying prescription disparity. Secondly, if implementing a pharmacogenomics program based on targeted preemptive testing, using clinical indication/comorbidity may be a reasonable way to enrich the population for prescriptions that would benefit from genotype tailoring.

PMID:40033674 | DOI:10.1002/cpt.3617

Clin Pharmacol Ther. 2025 Mar 3. doi: 10.1002/cpt.3623. Online ahead of print.

ABSTRACT

A clinical trial was carried out to investigate the pharmacogenetics of single-dose pravastatin and pitavastatin pharmacokinetics in 173 and 164 healthy participants. Additionally, 96 participants were included from previous pharmacogenetic studies with pravastatin. In a genome-wide meta-analysis of pravastatin including all 269 participants, SLCO1B1 c.521T>C (rs4149056) was associated with increased AUC0-∞ (P = 9.8 × 10-12). Similarly, SLCO1B1 c.521T>C was genome-wide significantly associated with increased AUC0-∞ of pitavastatin (P = 9.7 × 10-15). Candidate gene analyses suggested that participants with increased function SLCO1B1 variants had decreased pravastatin exposure. Furthermore, decreased function CYP2C9 variants may increase pitavastatin and pitavastatin lactone exposure. Compared to participants with normal function SLCO1B1 genotype, the AUC0-∞ of pravastatin was 140% (90% confidence interval: 86-210%; P = 4.7 × 10-8) and 37% (20-56%; P = 1.1 × 10-4) greater in participants with poor and decreased function SLCO1B1 genotype, respectively, while participants with highly increased function SLCO1B1 genotype had a 60% (39-75%; P = 6.0 × 10-4) lower AUC0-∞. The AUC0-∞ of pitavastatin was 153% (100-222%; P = 1.6 × 10-9) and 35% (8-69%; P = 0.027) greater in participants with poor and decreased function SLCO1B1 genotype, respectively, than in those with normal function SLCO1B1 genotype. Participants with intermediate metabolizer CYP2C9 genotype had 18% (3-34%; P = 0.046) greater AUC0-∞ of pitavastatin than those with normal metabolizer CYP2C9 genotype. This study demonstrates the important role of SLCO1B1 in pravastatin and pitavastatin pharmacokinetics and suggests that CYP2C9 variants also affect the pharmacokinetics of pitavastatin.

PMID:40029062 | DOI:10.1002/cpt.3623

Heliyon. 2025 Feb 8;11(4):e42572. doi: 10.1016/j.heliyon.2025.e42572. eCollection 2025 Feb 28.

ABSTRACT

BACKGROUND: Volvariella volvacea is a highly nutritious edible mushroom grown mainly in Southeast Asian countries. However, the low yield of V. volvacea has discouraged farmers from engaging in its production.

OBJECTIVE: The study was conducted to observe the improvement of V. volvacea yield depending on various physiochemical parameters of V. volvacea growth.

METHODS: The parameters tested in this study include the weight of the substrate, i.e., 2 kg (W1) and 6 kg (W2); the surface area of the substrate: A1 (1218 cm2), A2 (1530 cm2) and A3 (2000 cm2); and four different substrate formulations (F1, F2, F3 and F4).

RESULTS: Substrate weight and surface area were found to be important, but not critical, factors in determining fruiting bodies formation, total fungal mass, and BE rate. However, the formulation media showed a significant contribution that could help in the induction of fruiting bodies. According to the results, the culture medium with a mixture of EFB substrate and black soil showed the highest BE percentage of 17.75 % (at optimised substrate weights = 2 kg).

CONCLUSION: The results of this study can be used as a reference for further studies to improve the cultivation of V. volvacea, especially when EFB fibres are used as the main substrate. Future studies to identify genes involved in the formation of fruiting bodies are strongly recommended.

PMID:40028610 | PMC:PMC11869036 | DOI:10.1016/j.heliyon.2025.e42572

Cardiovasc Ther. 2025 Feb 21;2025:5711316. doi: 10.1155/cdr/5711316. eCollection 2025.

ABSTRACT

Background: Cardiovascular diseases (CVDs) encompass a group of diseases that affect the heart and/or blood vessels, making them the leading cause of global mortality. In our study, we performed proteome-wide Mendelian randomization (MR) and colocalization analyses to identify novel therapeutic protein targets for CVDs and evaluate the potential drug-related protein side effects. Methods: We conducted a comprehensive proteome-wide MR study to assess the causal relationship between plasma proteins and the risk of CVDs. Summary-level data for 4907 circulating protein levels were extracted from a large-scale protein quantitative trait loci (pQTL) study involving 35,559 individuals. Additionally, genome-wide association study (GWAS) data for CVDs were extracted from the UK Biobank and the Finnish database. Colocalization analysis was utilized to identify causal variants shared between plasma proteins and CVDs. Finally, we conducted a comprehensive phenome-wide association study (PheWAS) using the R10 version of the Finnish database. This study was aimed at examining the potential drug-related protein side effects in the treatment of CVDs. A total of 2408 phenotypes were included in the analysis, categorized into 44 groups. Results: The research findings indicate the following associations: (1) In coronary artery disease (CAD), the plasma proteins A4GNT, COL6A3, KLC1, CALB2, KPNA2, MSMP, and ADH1B showed a positive causal relationship (p-fdr < 0.05). LAYN and GCKR exhibited a negative causal relationship (p-fdr < 0.05). (2) In chronic heart failure (CHF), PLG demonstrated a positive causal relationship (p-fdr < 0.05), while AZGP1 displayed a negative causal relationship (p-fdr < 0.05). (3) In ischemic stroke (IS), ALDH2 exhibited a positive causal relationship (p-fdr < 0.05), while PELO showed a negative causal relationship (p-fdr < 0.05). (4) In Type 2 diabetes (T2DM), the plasma proteins MCL1, SVEP1, PIP4K2A, RFK, HEXIM2, ALDH2, RAB1A, APOE, ANGPTL4, JAG1, FGFR1, and MLN demonstrated a positive causal relationship (p-fdr < 0.05). PTPN9, SNUPN, VAT1, COMT, CCL27, BMP7, and MSMP displayed a negative causal relationship (p-fdr < 0.05). Colocalization analysis conclusively identified that AZGP1, ALDH2, APOE, JAG1, MCL1, PTPN9, PIP4K2A, SNUPN, and RAB1A share a single causal variant with CVDs (PPH3 + PPH4 > 0.8). Further phenotype-wide association studies have shown some potential side effects of these nine targets (p-fdr < 0.05). Conclusions: This study identifies plasma proteins with significant causal associations with CVDs, providing a more comprehensive understanding of potential therapeutic targets. These findings contribute to our knowledge of the underlying mechanisms and offer insights into potential avenues for treatment.

PMID:40026415 | PMC:PMC11870767 | DOI:10.1155/cdr/5711316

Iran J Med Sci. 2025 Feb 1;50(2):98-111. doi: 10.30476/ijms.2024.101852.3450. eCollection 2025 Feb.

ABSTRACT

BACKGROUND: Next-Generation Sequencing (NGS) methods specifically Whole-Exome Sequencing (WES) have demonstrated promising findings with a high accuracy of 91%-99% in Pharmacogenomics (PGx). A PGx-based panel can be utilized to minimize adverse drug reactions (ADRs) and maximize the treatment efficacy. Remarkably, Cancer Pain Management (CPM) is a cutting-edge concept in modern medicine. Thus, this study aimed to investigate the WES results by a PGx-based panel containing genes involved in Pain, Anti-inflammatory, and Immunomodulating agents (PAIma) signaling pathways.

METHODS: A total of 200 unrelated Iranians (100 western and 100 northern) were included. 100 WES results were analyzed through the PAIma panel. After DNA extraction, 100 samples were genotyped by Multiplex-Amplification-Refractory Mutation System (ARMS) PCR. A primary in silico investigation performed on 128 candidate genes through Protein-Protein Interactions (PPIs) and Gene-miRNA Interactions (GMIs) via the STRING database, and miRTargetLink2, respectively. Additionally, Enrichment Analysis (EA) was applied to find the unknown interplays among these three major pathways by Enrichr.

RESULTS: 55,590 annotations through 21 curated pathways were filtered, 900 variants were found, and 128 genes were refined. Finally, 54 candidate variants (48 non-synonymous single nucleotide variants (nsSNVs), 2 stop-gained, 1 frameshift, and 3 splicing) remained.

CONCLUSION: Conclusively, six potentially actionable variants including rs1695 (GSTP1), rs628031 (SLC22A1), rs17863778 (UGT1A7), rs16947 (CYP2D6), rs2257401 (CYP3A7), and rs2515641 (CYP2E1) had the most deviations among Iranians, compared with the reference genome, which should be genotyped for drug prescribing. Remarkably, PPIs, GMIs, and EA revealed potential risks of carcinogenesis and cancer phenotypes resulting from PAIma pathways genes.

PMID:40026294 | PMC:PMC11870856 | DOI:10.30476/ijms.2024.101852.3450

Wiad Lek. 2024;78(1):90-99. doi: 10.36740/WLek/200331.

ABSTRACT

OBJECTIVE: Aim: The aims of this study are to detect the genetic polymorphisms of FSHR rs6166 (C> T) and rs6165 (C> T) gene particularly that associated with the response to FSH treatment and their effects on the pathogenesis of infertility in Iraqi women.

PATIENTS AND METHODS: Materials and Methods: 210 Iraqi women, aged 20 to 34, who had just been diagnosed with infertility were included in this prospective case control research, whereas the control group consisted of 50 clinically healthy women who were free of any disorders. Following the guidelines for inclusion and exclusion in the study, each of the participating women saw a gynecologist to confirm. The time frame for this From November 2021 to June 2022, the investigation was carried out.

RESULTS: Results: The findings of this study in infertile women, clearly indicates that multiple genotypes of FSHR gene particularly (rs6166) (C>T) and (rs6165) (C>T), that include the homozygous wild genotype (CC), homozygous mutant (TT) and heterozygous (CT) genotype. The T allele was significantly increased (P<0.05) in poor responder infertile women for both rs6166 and rs6165 in FSHR which associated significantly with poor response to FSH in Iraqi infertile women.

CONCLUSION: Conclusions: Polymorphisms in FSHR gene may be associated with decrease in response to FSH treatment and it was associated with pathogenesis of infertility in Iraqi women/ Kerbala province.

PMID:40023860 | DOI:10.36740/WLek/200331

Wiad Lek. 2024;78(1):71-81. doi: 10.36740/WLek/199949.

ABSTRACT

OBJECTIVE: Aim: To examine prevalence of genotypic distribution, particularly assessing how genetic polymorphisms in Insulin Receptor gene influence effectiveness of insulin therapy in a sample of Iraqi population.

PATIENTS AND METHODS: Materials and Methods: Effect of Single Nucleotide Polymorphisms rs2229429 G>A have been investigated in 99 T1DM individuals, with a mean age of 12.3 years. These patients were managed with exogenous insulin through a basal-bolus monotherapy regimen. Genotyping was performed using an allele-specific polymerase chain reaction technique, and the data were statistically analyzed.

RESULTS: Results: The prevalence of the minor allele frequency is 12% in a sample of Iraqi population. Homozygous mutant carriers of rs2229429 G>A were 10.479 times at higher risk for developing poor glycemic control (HbA1c >86 mmol/mol) compared to wild genotype in type 1 diabetes mellitus, p=0.008. Ultimately poor responders to exogenous insulin, demonstrating significantly higher plasma insulin receptors levels p<0.001.

CONCLUSION: Conclusions: The investigated Single Nucleotide Polymorphisms is significantly associated with hyperglycemia in type 1 diabetes mellitus and contributes to the development of double diabetes.

PMID:40023858 | DOI:10.36740/WLek/199949

J Pharmacol Exp Ther. 2025 Feb;392(2):100057. doi: 10.1016/j.jpet.2024.100057. Epub 2024 Dec 9.

ABSTRACT

Cisplatin causes permanent hearing loss or cisplatin-induced ototoxicity in over 50% of treated patients with cancer, leading to significant social and functional limitations. Interindividual variability in developing hearing loss suggests the role of genetic predispositions to cisplatin-induced hearing loss. We investigated genetic associations between cisplatin-induced ototoxicity and toll-like receptor 4 (TLR4), an immune receptor known to mediate inflammatory responses to cisplatin. Using a case-control candidate gene approach, we identified 20 single nucleotide polymorphisms at the TLR4 locus with significant protection against ototoxicity in a cohort of 213 adult patients, followed by an independent pediatric patient cohort (n = 357). Combined cohort analysis demonstrated a significant association between cisplatin-induced ototoxicity protection and a single variant in the TLR4 promoter, rs10759932. We showed that rs10759932 downregulated TLR4 expression that is normally induced by cisplatin. This work provides pharmacogenetic and functional evidence to implicate TLR4 with cisplatin-induced hearing loss in patients. SIGNIFICANCE STATEMENT: Adult and pediatric patients carrying toll-like receptor 4 (TLR4) genetic variants were protected against developing cisplatin-induced hearing loss following cisplatin treatment. Important variants in the TLR4 promoter disrupted a drug-gene interaction between cisplatin and TLR4, mirroring the protective effect conferred by genetic inhibition of TLR4. These variants have the potential to improve the prediction of cisplatin toxicity, allowing for more precise chemotherapy treatment.

PMID:40023593 | DOI:10.1016/j.jpet.2024.100057

J Exp Clin Cancer Res. 2025 Feb 28;44(1):77. doi: 10.1186/s13046-025-03308-8.

ABSTRACT

BACKGROUND: Chromosomal instability (CIN) is involved in about 70% of colorectal cancers (CRCs) and is associated with poor prognosis and drug resistance. From a clinical perspective, a better knowledge of these tumour's biology will help to guide therapeutic strategies more effectively.

METHODS: We used high-density chromosomal microarray analysis to evaluate CIN level of patient-derived organoids (PDOs) and their original mCRC tissues. We integrated the RNA-seq and mass spectrometry-based proteomics data from PDOs in a functional interaction network to identify the significantly dysregulated processes in CIN. This was followed by a proteome-wGII Pearson correlation analysis and an in silico validation of main findings using functional genomic databases and patient-tissues datasets to prioritize the high-confidence CIN features.

RESULTS: By applying the weighted Genome Instability Index (wGII) to identify CIN, we classified PDOs and demonstrated a good correlation with tissues. Multi-omics analysis showed that our organoids recapitulated genomic, transcriptomic and proteomic CIN features of independent tissues cohorts. Thanks to proteotranscriptomics, we uncovered significant associations between mitochondrial metabolism and epithelial-mesenchymal transition in CIN CRC PDOs. Correlating PDOs wGII with protein abundance, we identified a subset of proteins significantly correlated with CIN. Co-localisation analysis in PDOs strengthened the putative role of IPO7 and YAP, and, through in silico analysis, we found that some of the targets give significant dependencies in cell lines with CIN compatible status.

CONCLUSIONS: We first demonstrated that PDO models are a faithful reflection of CIN tissues at the genetic and phenotypic level. Our new findings prioritize a subset of genes and molecular processes putatively required to cope with the burden on cellular fitness imposed by CIN and associated with disease aggressiveness.

PMID:40022181 | DOI:10.1186/s13046-025-03308-8

Eur J Clin Pharmacol. 2025 Feb 28. doi: 10.1007/s00228-025-03816-8. Online ahead of print.

ABSTRACT

PURPOSE: Although already a lot of research has been done on pharmacogenetic tests to inform the choice and/or dosing of medicines, the implementation and clinical uptake remain limited. This study assessed the implementation of pharmacogenetic (PGx) testing on a national scale by analyzing access to and volumes of reimbursed PGx.

METHODS: The use of pharmacogenetic tests was examined via a cross-sectional online survey among the Belgian laboratories, collecting data on PGx targets, testing volumes and technologies used. The focus was on reimbursed tests. Additional data were sourced from the national reimbursement database to describe uptake of testing per medication.

RESULTS: The uptake of PGx testing in Belgium varied by medication, with significant implementation for fluoropyrimidines, abacavir, and thiopurines. DPYD gene testing was the most frequently performed PGx test, due to endorsed (inter)national guidelines. Reimbursement rules shape access to PGx, with the majority of PGx tests performed in dedicated centers for human genetics (CHG). Access to HLA laboratories for HLA targets was not optimal and some laboratories without a CHG also included constitutional PGx targets in somatic oncology panels.

CONCLUSION: This nationwide study demonstrates that in a country where the prescribers have access to a relatively extensive list of reimbursable PGx tests, the implementation of PGx testing is shaped by the presence of endorsed evidence-based clinical practice guidelines, as well as organizational and logistical factors.

PMID:40019504 | DOI:10.1007/s00228-025-03816-8

Pharmacogenomics. 2025 Feb 28:1-12. doi: 10.1080/14622416.2025.2470613. Online ahead of print.

ABSTRACT

Posttransplantation diabetes mellitus (PTDM) is a form of diabetes developed after solid organ or stem cell transplantation. This condition shares physiopathological traits with type 2 diabetes, including insulin resistance and β-cells dysfunction and its prevalence varies significantly based on the diagnostic criteria used. Immunosuppressive drugs directly contribute to PTDM risk through intricate impacts on glucose regulation, insulin secretion, and inflammation. In addition, modifiable and non-modifiable environmental risk factors are associated with the onset of this condition. This review aims to provide a comprehensive overview of the multifactorial nature of PTDM in order to highlight candidate genes and variants for pharmacogenetic research. An extensive literature search was conducted to identify studies on pharmacological and genetic factors influencing PTDM development. This review stresses the importance of understanding these interactions for improving PTDM management and underscores the need for further research to refine preventive approaches, ultimately enhancing patient outcomes post-transplantation.

PMID:40017426 | DOI:10.1080/14622416.2025.2470613

Pediatr Emerg Care. 2025 Feb 28. doi: 10.1097/PEC.0000000000003360. Online ahead of print.

ABSTRACT

OBJECTIVES: This study aims to evaluate patient characteristics associated with bronchodilator (BD) use at various stages of bronchiolitis illness and evaluate corresponding patient outcomes in the emergency department (ED).

METHODS: This retrospective, cross-sectional study involves secondary data analysis from a sample of 932 children ages 3 to 24 months who received a diagnosis of bronchiolitis during an ED visit (1057 cases). Predictor variables included demographics, past medical history, family history, physical findings, medication use, and disposition. Outcomes included BD use for bronchiolitis symptoms in the pre-ED and ED settings, and associated care outcomes in the ED. Predictors of BD use in the ED with statistical significance were incorporated in a predictive multivariable logistic regression model with a training-validation split of 70% to 30%.

RESULTS: Children with prior BD use were significantly more likely than children without such history to receive BD treatment during their current bronchiolitis illness before the ED [odds ratio (OR): 23.7, 95% CI: 14.4-39], in the ED (OR: 2.6, 95% CI: 1.76-3.77), and as a prescription upon discharge from the ED (OR: 3.7, 95% CI: 2.49-5.58). In multivariable regression analyses, older age, parental asthma history, and wheezes and retractions on ED physical examination were significantly associated with BD use in the ED (P<0.05). The area under the curve for the validation model with these variables was 0.826 (95% CI: 0.794-0.858).

CONCLUSIONS: Prior BD use was associated with subsequent use during the current illness, during ED care, and subsequent prescription, forming a cyclical pattern. A perceived bronchospastic phenotype of bronchiolitis may influence clinical practice in ED settings.

PMID:40016874 | DOI:10.1097/PEC.0000000000003360