Nevin Manimala

Arch Toxicol. 2023 Sep 4. doi: 10.1007/s00204-023-03572-7. Online ahead of print.

ABSTRACT

Omics techniques have been increasingly recognized as promising tools for Next Generation Risk Assessment. Targeted metabolomics offer the advantage of providing readily interpretable mechanistic information about perturbed biological pathways. In this study, a high-throughput LC-MS/MS-based broad targeted metabolomics system was applied to study nitrofurantoin metabolic dynamics over time and concentration and to provide a mechanistic-anchored approach for point of departure (PoD) derivation. Upon nitrofurantoin exposure at five concentrations (7.5 µM, 15 µM, 20 µM, 30 µM and 120 µM) and four time points (3, 6, 24 and 48 h), the intracellular metabolome of HepG2 cells was evaluated. In total, 256 uniquely identified metabolites were measured, annotated, and allocated in 13 different metabolite classes. Principal component analysis (PCA) and univariate statistical analysis showed clear metabolome-based time and concentration effects. Mechanistic information evidenced the differential activation of cellular pathways indicative of early adaptive and hepatotoxic response. At low concentrations, effects were seen mainly in the energy and lipid metabolism, in the mid concentration range, the activation of the antioxidant cellular response was evidenced by increased levels of glutathione (GSH) and metabolites from the de novo GSH synthesis pathway. At the highest concentrations, the depletion of GSH, together with alternations reflective of mitochondrial impairments, were indicative of a hepatotoxic response. Finally, a metabolomics-based PoD was derived by multivariate PCA using the whole set of measured metabolites. This approach allows using the entire dataset and derive PoD that can be mechanistically anchored to established key events. Our results show the suitability of high throughput targeted metabolomics to investigate mechanisms of hepatoxicity and derive point of departures that can be linked to existing adverse outcome pathways and contribute to the development of new ones.

PMID:37665362 | DOI:10.1007/s00204-023-03572-7

Integr Environ Assess Manag. 2023 Sep 4. doi: 10.1002/ieam.4836. Online ahead of print.

ABSTRACT

Quantifying the effects of environmental stressors on natural resources is problematic due to complex interactions among environmental factors that influence endpoints of interest. This complexity, coupled with data limitations, propagates uncertainty that can make it difficult to causally associate specific environmental stressors with injury endpoints. The Natural Resource Damage Assessment and Restoration (NRDAR) regulations under the Comprehensive Environmental Response, Compensation, and Liability Act and Oil Pollution Act aims to restore natural resources injured by oil spills and hazardous substance releases into the environment; exploration of alternative statistical methods to evaluate effects could be beneficial to addressing NRDAR legal claims. Bayesian networks (BNs) are statistical tools that can be used estimate the influence and interrelatedness of abiotic and biotic environmental variables on environmental endpoints of interest. We investigated the application of a BN for injury assessment using a hypothetical case study by simulating data of acid mine drainage (AMD) affecting a fictional stream-dwelling bird species. We compared the BN-generated probability estimates for injury to a more traditional approach using toxicity thresholds for water and sediment chemistry. BNs offered several distinct advantages compared to traditional approaches, including formalizing the use of expert knowledge, probabilistic estimates of injury using intermediate direct and indirect effects, and the incorporation of a more nuanced and ecologically relevant representation of effects. Given the potential that BNs have for natural resource injury assessment, more research and field-based application is needed to determine their efficacy in NRDAR. We expect the resulting methods will be of interest to many U.S. Federal, State, and Tribal programs devoted to the evaluation, mitigation, remediation, and/or restoration of natural resources injured by releases or spills of contaminants.

PMID:37664978 | DOI:10.1002/ieam.4836

Pediatr Blood Cancer. 2023 Sep 4:e30658. doi: 10.1002/pbc.30658. Online ahead of print.

ABSTRACT

BACKGROUND: Topotecan, an antitumor drug with systemic exposure (SE)-dependent activity against many pediatric tumors has wide interpatient pharmacokinetic variability, making it challenging to attain the desired topotecan SE. The study objectives were to update our topotecan population pharmacokinetic model, to evaluate the feasibility of determining individual topotecan clearance using a single blood sample, and to apply this approach to topotecan data from a neuroblastoma trial to explore exposure-response relationships.

PROCEDURE: Our previous population pharmacokinetic and covariate model was updated using data from 13 clinical pediatric studies. A simulation-based Bayesian analysis was performed to determine if a single blood sample could be sufficient to estimate individual topotecan clearance. Following the Bayesian approach, single pharmacokinetic samples collected from a Children’s Oncology Group Phase III clinical trial (ANBL0532; NCT0056767) were analyzed to estimate individual topotecan SE. Associations between topotecan SE and toxicity or early response were then evaluated.

RESULTS: The updated population model included the impact of patient body surface area (BSA), age, and renal function on topotecan clearance. The Bayesian analysis with the updated model and single plasma samples showed that individual topotecan clearance values were estimated with good precision (mean absolute prediction error ≤16.2%) and low bias (mean prediction error ≤7.2%). Using the same approach, topotecan SE was derived in patients from ANBL0532. The exposure-response analysis showed an increased early response after concomitant cyclophosphamide and topotecan up to a topotecan SE of 45 h ng/mL.

CONCLUSIONS: A simple single-sample approach during topotecan therapy could guide dosing for patients, resulting in more patients reaching target attainment.

PMID:37664968 | DOI:10.1002/pbc.30658

Front Biosci (Landmark Ed). 2023 Aug 23;28(8):175. doi: 10.31083/j.fbl2808175.

ABSTRACT

BACKGROUND: The cause of ulcerative colitis (UC) is not yet fully understood. Previous research has pointed towards a potential role for mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in promoting the onset and progression of inflammatory bowel disease (IBD) by altering the microbiota of the gut. However, the relationship between toll-like receptor 4 (TLR4) and gut microbiota in IBD is not well understood. To shed light on this, the interaction between TLR4 and gut microbiota was studied using a mouse model of IBD.

METHODS: To examine the function of TLR4 signaling in intestinal injury repair, researchers developed Dextran Sulfate Sodium Salt (DSS)-induced colitis and injury models in both wild-type (WT) mice and TLR4 knockout (TLR4-KO) mice. To assess changes in the gut microbiota, 16S rRNA sequencing was conducted on fecal samples from both the TLR4-KO and WT enteritis mouse models.

RESULTS: The data obtained depicted a protective function of TLR4 against DSS-induced colitis. The gut microbiota composition was found to vary considerably between the WT and TLR4-KO mice groups as indicated by β-diversity analysis and operational taxonomic units (OTUs) cluster. Statistical analysis of microbial multivariate variables depicted an elevated abundance of Escherichia coli/Shigella, Gammaproteobacteria, Tenerlcutes, Deferribacteres, Enterobacteria, Rikenellaceae, and Proteobacteria in the gut microbiota of TLR4-KO mice, whereas there was a considerable reduction in Bacteroidetes at five different levels of the phylogenetic hierarchy including phylum, class, order, family, and genus in comparison with the WT control.

CONCLUSIONS: TLR4 may protect intestinal epithelial cells from damage in response to DSS-induced injury by controlling the microbiota in the gut.

PMID:37664927 | DOI:10.31083/j.fbl2808175

Front Biosci (Landmark Ed). 2023 Aug 31;28(8):189. doi: 10.31083/j.fbl2808189.

ABSTRACT

BACKGROUND: Bladder urothelial carcinoma (BLCA) is a malignancy with a high incidence worldwide. One-third of patients may experience aggressive progression later on, and 70% of patients who have undergone surgical intervention will still suffer from metastasis.

MATERIALS AND METHODS: RNA sequencing profiles of BLCA samples were obtained from The Cancer Genome Atlas (TCGA) database. Differential expression and univariate Cox regression analyses were performed to identify prognosis-related differentially expressed immune genes (DEIGs). Subsequently, a proportional hazards model of DEIGs was then constructed by univariate regression analysis. Differential expression and correlation analyses, CIBERSORT, Single Sample Gene Set Enrichment Analysis (ssGSEA), GSVA were conducted on transcription factors (TFs), immune cells/pathways and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The regulation network was then constructed. Eventually, ATAC-seq, ChIP-seq, scRNA-seq, and multiple online databases were employed for further validation.

RESULTS: A proportional hazards model of 31 DEIGs was constructed and risk score was calculated and proven to be a independent prognostic factor. Then 5 immune genes were characterized to be significantly correlated with bone metastasis, stage and TF expression simultaneously. 4 TFs were identified to be significantly correlated with prognosis and RBP7 expression. 5 immune cells/pathways were revealed to be significantly correlated with RBP7 expression. Only 1 KEGG pathway was identified to be significant in Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) analyses. The regulatory relationship was then constructed, in which the correlation between EBF1 and RBP7 (R = 0.677, p < 0.001), Th2 cells and RBP7 (R = 0.23, p < 0.001), the oocyte meiosis pathway and RBP7 (R = 0.14, p = 0.042) were the most statistically significant. The results were further confirmed by Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq), Chromatin Immunoprecipitation sequencing (ChIP-seq), single-cell RNA sequencing (scRNA-seq), and multiple online databases validation.

CONCLUSIONS: This study revealed that the EBF1-RBP7 regulatory relationship had potential importance in the bone metastasis in BLCA through Th2 cells and the oocyte meiosis pathway.

PMID:37664915 | DOI:10.31083/j.fbl2808189

Physiother Res Int. 2023 Sep 4:e2048. doi: 10.1002/pri.2048. Online ahead of print.

ABSTRACT

BACKGROUND AND AIM: Nocturnal enuresis (NE) is prevalent in children and adolescents and affects their social life later. Therefore, the objective of this study was to ascertain laser acupuncture (LA) therapy’s effect on NE in adolescent females.

METHODS: Sixty adolescent females diagnosed with chronic monosymptomatic nocturnal enuresis (MNE) were randomly divided into two equal groups: The intervention group (received LA and desmopressin) and the control group (received desmopressin only) (n = 30 each). Treatment was delivered and LA was used three times a week for 12 successive weeks. Abdominal ultrasonography and voiding calendar were used to assess bladder capacity and maximum voiding volume (MVV), respectively. The frequency of bed wetness was assessed throughout the trial period in a diary.

RESULTS: Statistically significant differences were reported in the intervention group. Bladder capacity significantly increased in the intervention group (LA and desmopressin) than in the control group.

CONCLUSIONS: The results of this study suggest the beneficial influences of LA on MNE, despite the very poor quality of the literature’s available evidence.

PMID:37664896 | DOI:10.1002/pri.2048

J Ment Health. 2023 Sep 4:1-29. doi: 10.1080/09638237.2023.2245902. Online ahead of print.

ABSTRACT

BACKGROUND: Substance use amongst young people poses developmental and clinical challenges, necessitating early detection and treatment. Considering the widespread use of technology in young people, delivering interventions digitally may help to reduce and monitor their substance use.

AIMS: We conducted a systematic review and two meta-analyses to assess the effectiveness of digital interventions for reducing substance use (alcohol, smoking, and other substances) among young people aged 10 to 24 years old.

METHOD: Embase, Global Health, Medline, PsychINFO, Web of Science and reference lists of relevant papers were searched in November 2020. Studies were included if they quantitatively evaluated the effectiveness of digital health technologies for treating substance use. A narrative synthesis and meta-analysis were conducted.

RESULTS: Forty-two studies were included in the systematic review and 18 in the meta-analyses. Digital interventions showed small, but statistically significant reductions in weekly alcohol consumption compared to controls (SMD= -0.12, 95% CI= -0.17 to -0.06, I²=0%), but no overall effect was seen on 30-day smoking abstinence (OR = 1.12, 95% CI = 0.70 to 1.80, I²=81%). The effectiveness of digital interventions for reducing substance use is generally weak, however, promising results such as reducing alcohol use were seen. Large-scale studies should investigate the viability of digital interventions, collect user feedback, and determine cost-effectiveness.

PRISMA/PROSPERO: This systematic review was conducted following Cochrane methodology PRISMA guidelines. The review was registered with PROSPERO in November 2020 (CRD42020218442).

PMID:37664884 | DOI:10.1080/09638237.2023.2245902

Front Endocrinol (Lausanne). 2023 Aug 17;14:1198779. doi: 10.3389/fendo.2023.1198779. eCollection 2023.

ABSTRACT

OBJECTIVE: To evaluate the effects of different ovarian stimulation protocols on in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes in infertile women with adenomyosis.

METHODS: We carried out a retrospective cohort study among infertile women with adenomyosis receiving IVF/ICSI treatment, including 257 fresh embryo transfer (ET) cycles and 305 frozen embryo transfer (FET) cycles. In fresh ET cycles, ultra-long, long, short, and antagonist protocols were adopted. In FET cycles, patients received long-acting GnRH agonist (GnRHa) pretreatment or not. The primary outcome was clinical pregnancy rate (CPR), and the secondary outcomes included implantation rate (IR), miscarriage rate (MR), and live birth rate (LBR).

RESULTS: In fresh ET cycles, compared with ultra-long and long protocols, IR (49.7%, 52.1% versus 28.2%, P=0.001) and CPR (64.3%, 57.4% versus 35.6%, P=0.004) significantly decreased in the short protocol. Similarly, compared with ultra-long and long protocols, a decreased inclination of IR (49.7%, 52.1% versus 33.3%) and CPR (57.4%, 64.3% versus 38.2%) existed in the antagonist protocol, although no statistical significance was detected because of strict P adjustment of Bonferroni method (P_adj=0.008). Compared with long protocol, LBR in short protocol decreased obviously (48.2% versus 20.3%, P<0.001). In FET cycles, no matter which origin of embryos, there were no statistical differences in IR, CPR, and LBR. For women ≥35 years receiving fresh ET, CPR was higher in ultra-long and long protocols (52.1%, 50.0% versus 20.0%, 27.5%, P=0.031) compared to antagonist and short protocols. For women ≥35 years receiving FET, compared with ultra-long and antagonist protocols, cycles with embryos originating from long and short protocols had higher proportions of long-acting GnRHa pretreatment (30.4%,30.00 versus 63.9%, 51.4%, P=0.009). IR (61.1%, 48.6% versus 32.6%, 25.0%, P=0.020) and CPR (58.3%, 48.6% versus 30.4%, 25.0%, P=0.024) in long and short protocols were higher than rates of ultra-long and antagonist protocols, but no statistical differences were supported because of strict Bonferroni method (P_adj=0.008).

CONCLUSION: In infertile women with adenomyosis, if a fresh embryo was planned for transfer, an ultra-long or long protocol might be beneficial. If antagonist and short protocols were used, whole embryos frozen followed by FET was recommended. In FET cycles, embryos derived from different protocols had no impact on pregnancy outcomes.

PMID:37664864 | PMC:PMC10472936 | DOI:10.3389/fendo.2023.1198779

Front Endocrinol (Lausanne). 2023 Aug 18;14:1230445. doi: 10.3389/fendo.2023.1230445. eCollection 2023.

ABSTRACT

BACKGROUND: Obesity represents a major and preventable global health challenge as a complex disease and a modifiable risk factor for developing other non-communicable diseases. In recent years, obesity prevalence has risen more rapidly in low- and middle-income countries (LMICs) compared to high-income countries (HICs). Obesity traits are shown to be modulated by an interplay of genetic and environmental factors such as unhealthy diet and physical inactivity in studies from HICs focused on populations of European descent; however, genetic heterogeneity and environmental differences prevent the generalisation of study results to LMICs. Primary research investigating gene-environment interactions (GxE) on obesity in LMICs is limited but expanding. Synthesis of current research would provide an overview of the interactions between genetic variants and environmental factors that underlie the obesity epidemic and identify knowledge gaps for future studies.

METHODS: Three databases were searched systematically using a combination of keywords such as “genes”, “obesity”, “LMIC”, “diet”, and “physical activity” to find all relevant observational studies published before November 2022.

RESULTS: Eighteen of the 1,373 articles met the inclusion criteria, of which one was a genome-wide association study (GWAS), thirteen used a candidate gene approach, and five were assigned as genetic risk score studies. Statistically significant findings were reported for 12 individual SNPs; however, most studies were small-scale and without replication.

CONCLUSION: Although the results suggest significant GxE interactions on obesity in LMICs, updated robust statistical techniques with more precise and standardised exposure and outcome measurements are necessary for translatable results. Future research should focus on improved quality replication efforts, emphasising large-scale and long-term longitudinal study designs using multi-ethnic GWAS.

PMID:37664850 | PMC:PMC10474324 | DOI:10.3389/fendo.2023.1230445

Front Endocrinol (Lausanne). 2023 Aug 17;14:1158581. doi: 10.3389/fendo.2023.1158581. eCollection 2023.

ABSTRACT

BACKGROUND: The management guidelines of radioactive Iodine (RAI) therapy for distinct types of differentiated thyroid carcinoma (DTC) were the same in clinical practice. However, in distinct types DTC, differences in RAI avidity and response existed and the effect of RAI therapy could not be equated.

METHODS: DTC patients’ data in SEER database were extracted to perform retrospective analysis. The differences between case group and control group were compared by chi-square tests. We used Kaplan-Meier statistics and Cox regression analyses to investigate cancer-specific survival (CSS). Propensity score-matched was performed to make 1:1 case-control matching.

RESULTS: 105195 patients who receiving total thyroidectomy were identified in SEER database. Compared to papillary thyroid carcinoma (PTC) (52.3%), follicular thyroid carcinoma (FTC) (63.8%) and oncocytic carcinoma of thyroid (OCA) (64.4%) had higher rates of RAI therapy. In the multivariable Cox regression model, RAI therapy was independent prognosis factor in PTC but not in OCA and FTC. In subgroup analysis, RAI therapy could improve prognosis in PTC when gross extrathyroidal extension or lymph node metastases or early survival when distant metastases (DM) were presented. However, OCA and FTC patients with DM rather than regional lesions only could benefit from RAI therapy. High-risk patients receiving RAI therapy showed a better prognosis in PTC but not in OCA and FTC.

CONCLUSION: RAI therapy was an effective treatment for DTC and should be considered individually in PTC, OCA and FTC patients. Our results provided further guideline for treatment selection in DTC.

PMID:37664843 | PMC:PMC10471126 | DOI:10.3389/fendo.2023.1158581