Functional genetic variants of the disulfidptosis-related INF2 gene predict survival of hepatitis B virus-related hepatocellular carcinoma.

Disulfidptosis is a novel form of programmed cell death involved in migration and invasion of cancer cells, but few studies investigated the roles of genetic variants in disulfidptosis-related genes in survival of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We used Cox proportional hazards regression analyses, Kaplan-Meier curves and receiver operating characteristic curves to assess effects of genetic variants in 14 disulfidptosis-related genes on overall survival of 866 HBV-HCC patients. The Bayesian false discovery probability was used for multiple testing corrections. We also investigated biological mechanisms of the significant variants through expression quantitative trait loci analyses using the data from publicly available databases, luciferase reporter assays and differential expression analyses. As a result, we identified two independently functional single nucleotide polymorphisms (SNPs) (INF2 rs4072285 G > A and INF2 rs4444271 A > T) that predicted overall survival of HBV-HCC patients, with adjusted hazard ratios of 1.60 (95% CI = 1.22-2.11, P = 0.001) and 1.50 (95% CI = 1.80-1.90, P < 0.001), respectively, after multiple testing correction. Luciferase reporter assays indicated that both INF2 rs4072285 A and INF2 rs4444271 T alleles increased INF2 mRNA expression levels (P < 0.001) that were also higher in HCC tumor tissues than in adjacent normal tissues (P < 0.001); such elevated INF2 expression levels were associated with a poorer survival of HBV-HCC patients (P < 0.001) in the TCGA database. In summary, this study supported that INF2 rs4072285 and INF2 rs4444271 may be novel biomarkers for survival of HBV-HCC patients.

Development and evaluation of a polygenic risk score for lung cancer in never-smoking women: A large-scale prospective Chinese cohort study.

The proportion of lung cancer in never smokers is rising, especially among Asian women, but there is no effective early detection tool. Here, we developed a polygenic risk score (PRS), which may help to identify the population with higher risk of lung cancer in never-smoking women. We first performed a large GWAS meta-analysis (8595 cases and 8275 controls) to systematically identify the susceptibility loci for lung cancer in never-smoking Asian women and then generated a PRS using GWAS datasets. Furthermore, we evaluated the utility and effectiveness of PRS in an independent Chinese prospective cohort comprising 55 266 individuals. The GWAS meta-analysis identified eight known loci and a novel locus (5q11.2) at the genome-wide statistical significance level of P < 5 × 10-8 . Based on the summary statistics of GWAS, we derived a polygenic risk score including 21 variants (PRS-21) for lung cancer in never-smoking women. Furthermore, PRS-21 had a hazard ratio (HR) per SD of 1.29 (95% CI = 1.18-1.41) in the prospective cohort. Compared with participants who had a low genetic risk, those with an intermediate (HR = 1.32, 95% CI: 1.00-1.72) and high (HR = 2.09, 95% CI: 1.56-2.80) genetic risk had a significantly higher risk of incident lung cancer. The addition of PRS-21 to the conventional risk model yielded a modest significant improvement in AUC (0.697 to 0.711) and net reclassification improvement (24.2%). The GWAS-derived PRS-21 significantly improves the risk stratification and prediction accuracy for incident lung cancer in never-smoking Asian women, demonstrating the potential for identification of high-risk individuals and early screening.

Integrative analyses of N6-methyladenosine-associated single-nucleotide polymorphisms (m6A-SNPs) identify tumor suppressor gene AK9 in lung cancer.

N6 -methyladenosine (m6 A) modification has been identified as one of the most important epigenetic regulation mechanisms in the development of human cancers. However, the association between m6 A-associated single-nucleotide polymorphisms (m6 A-SNPs) and lung cancer risk remains largely unknown. Here, we identified m6 A-SNPs and examined the association of these m6 A-SNPs with lung cancer risk in 13,793 lung cancer cases and 14,027 controls. In silico functional annotation was used to identify causal m6 A-SNPs and target genes. Furthermore, methylated RNA immunoprecipitation and quantitative real-time polymerase chain reaction (MeRIP-qPCR) assay was performed to assess the m6 A modification level of different genotypes of the causal SNP. In vitro assays were performed to validate the potential role of the target gene in lung cancer. A total of 8794 m6 A-SNPs were detected, among which 397 SNPs in nine susceptibility loci were associated with lung cancer risk, including six novel loci. Bioinformatics analyses indicated that rs1321328 in 6q21 was located around the m6 A modification site of AK9 and significantly reduced AK9 expression (ß = -0.15, p = 2.78 × 10-8 ). Moreover, AK9 was significantly downregulated in lung cancer tissues than that in adjacent normal tissues of samples from the Cancer Genome Atlas and Nanjing Lung Cancer Cohort. MeRIP-qPCR assay suggested that C allele of rs1321328 could significantly decrease the m6 A modification level of AK9 compared with G allele. In vitro assays verified the tumor-suppressing role of AK9 in lung cancer. These findings shed light on the pathogenic mechanism of lung cancer susceptibility loci linked with m6 A modification.

Associations between modifiable risk factors and hepatocellular carcinoma: a trans-ancestry Mendelian randomization study.

BACKGROUND: Potentially modifiable risk factors for hepatocellular carcinoma (HCC) have been investigated in observational epidemiology studies in East Asian and European populations, whereas the causal associations of most of these risk factors remain unclear. METHODS: We collected genome-wide association summary statistics of 22 modifiable risk factors in East Asians and 33 risk factors in Europeans. Genetic summary statistics of HCC were sourced from the Biobank Japan study (1,866 cases and 195,745 controls) for East Asians, and the deCODE genetics study (406 cases and 49,302 controls) and the UK Biobank (168 cases and 372 016 controls) for Europeans. Two-sample Mendelian randomization (MR) analyses were performed independently for East Asian and European populations. RESULTS: In East Asians, genetically predicted alcohol frequency, ever drinkers, aspartate aminotransferase (AST), hypothyroidism, chronic hepatitis B, and chronic hepatitis C, metabolic dysfunction-associated steatotic liver disease (MASLD), and autoimmune hepatitis were significantly associated with an increased HCC risk (P < 0.05/22). Among European population, alanine transaminase, AST, MASLD, percent liver fat, and liver iron content were significantly associated with a higher risk of HCC (P < 0.05/33). The replication dataset and meta-analysis further confirmed these results. CONCLUSIONS: Although East Asian and European populations have different factors for HCC, their common modifiable risk factors AST and MASLD for HCC, offer valuable insights for targeted intervention strategies to mitigate society burden of HCC.

Genetic variants in m5C modification genes are associated with survival of patients with HBV-related hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a high mortality rate. The 5-methylcytosine (m5C), a type of RNA modification, plays crucial regulatory roles in HCC carcinogenesis, metastasis, and prognosis. However, a few studies have investigated the effect of genetic variants in m5C modification genes on survival of patients with hepatitis B virus (HBV)-related HCC. In the present study, we evaluated associations between 144 SNPs in 15 m5C modification genes and overall survival (OS) in 866 patients with the HBV-related HCC. Expression quantitative trait loci (eQTL) analysis and differential expression analysis were conducted to investigate biological mechanisms. As a result, we identified that two SNPs (NSUN7 rs2437325 A > G and TRDMT1 rs34434809 G > C) were significantly associated with HBV-related HCC OS with adjusted allelic hazards ratios of 1.25 (95% confidence interval = 1.05-1.48 and P = 0.011) and 1.19 (1.02-1.38 and P = 0.027), respectively, with a trend of combined risk genotypes (Ptrend < 0.001). Moreover, the results of eQTL analyses showed that both NSUN7 rs2437325 G and TRDMT1 rs34434809 C alleles were associated with a reduced mRNA expression level in 208 normal liver tissues (P = 0.007 and P < 0.001, respectively). Taken together, genetic variants in the m5C modification genes may be potential prognostic biomarkers of HBV-related HCC after hepatectomy, likely through mediating the mRNA expression of corresponding genes.

The assessment and detection rate of intrinsic capacity deficits among older adults: a systematic review and meta-analysis.

BACKGROUND: Assessing and monitoring intrinsic capacity (IC) is an effective strategy to promote healthy ageing by intervening early in high-risk populations. This review systematically analyzed the global detection rates of IC deficits and explored variations across diverse populations and data collection methods. METHODS: This study was preregistered with PROSPERO, CRD42023477315. In this systematic review and meta-analysis, we systematically searched ten databases from January 2015 to October 2023, for peer-reviewed, observational studies or baseline survey of trials that assessed IC deficits among older adults aged 50 and above globally following the condition, context and population approach. The main outcome was intrinsic capacity deficits which could be assessed by any tools. Meta-analyses were performed by a random-effect model to pool the detection rates across studies and subgroup analyses were conducted by populations and data collection methods. RESULTS: Fifty-six studies conducted in 13 countries were included in the review and 44 studies with detection rates of IC were included in the meta-analysis. The pooled detection rate of IC deficits was 72.0% (65.2%-78.8%) and deficits were most detected in sensory (49.3%), followed by locomotion (40.0%), cognition (33.1%), psychology (21.9%), and vitality (20.1%). Variations in detection rates of IC deficits were observed across studies, with higher rates observed in low- and middle-income countries (74.0%) and hyper-aged societies (85.0%). Study population and measurement tools also explained the high heterogeneity across studies. CONCLUSION: IC deficits are common among older adults, while heterogeneity exists across populations and by measurement. Early monitoring with standardized tools and early intervention on specific subdomains of IC deficits are greatly needed for effective strategies to promote healthy ageing.

Anastrozole for the prevention of breast cancer in high-risk postmenopausal women: cost-effectiveness analysis in the UK and the USA.

PURPOSE: The effectiveness of anastrozole for breast cancer prevention has been demonstrated. The objective of this study was to evaluate the cost-effectiveness of anastrozole for the prevention of breast cancer in women with a high risk of breast cancer and to determine whether anastrozole for the primary prevention of breast cancer can improve the quality of life of women and save health-care resources. METHODS: A decision-analytic model was used to assess the costs and effects of anastrozole prevention versus no prevention among women with a high risk of breast cancer. The key parameters of probability were derived from the IBIS-II trial, and the cost and health outcome data were derived from published literature. Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated for the two strategies,One-way and probabilistic sensitivity analyses were performed. RESULTS: In the base case, the incremental cost per QALY of anastrozole prevention was £125,705.38/QALY in the first 5 years compared with no prevention in the UK, above the threshold of WTP (£3,000/QALY),and in the 12-year period, the ICER was £8,313.45/QALY, less than WTP. For the US third-party payer, ICER was $134,232.13/QALY in the first 5 years and $8,843.30/QALY in the 12 years, both less than the WTP threshold ($150,000/QALY). CONCLUSION: In the UK and US, anastrozole may be a cost-effective strategy for the prevention of breast cancer in high-risk postmenopausal women. Moreover, the longer the cycle of the model, the higher the acceptability. The results of this study may provide a scientific reference for decision-making for clinicians, patients, and national medical and health care government departments.

One-pot synthesis and hydrogen peroxide electrochemical sensing of 3D TiO2/MnO2 nanorods assembled microspheres.

Nanorods assembled 3D microspheres of TiO2/MnO2 were prepared via a simple one-pot hydrothermal approach. The resultant composite material exhibited remarkable electrocatalytic activity for hydrogen peroxide (H2O2) in comparison to each single component. The electrochemical sensor constructed with TiO2/MnO2 exhibited a linear relationship within the range 0.0001-5.6 mmol·L-1 for H2O2. The limit of detection (LOD) and sensitivity for H2O2 were 0.03 µmol·L-1 (S/N = 3) and 316.6 µA (mmol·L-1)-1 cm-2. Moreover, this sensor can be employed to detect trace amount of H2O2 in serum and urine samples successfully, supporting an insight and strategy for a more sensitive electrochemical sensor.

Circulating C-reactive protein increases lung cancer risk: Results from a prospective cohort of UK Biobank.

Chronic inflammation has been associated with the development of lung cancer. In this study, we examined the association between C-reactive protein (CRP) and lung cancer in a prospective cohort study and used Mendelian randomization (MR) to clarify the causality. We included 420 977 participants from the UK Biobank (UKB) in the analyses; 1892 thereof were diagnosed with lung cancer during the follow-up. Hazards ratios (HRs) of CRP concentrations were estimated by Cox proportional hazard models and two approaches of MR analysis were performed. Besides, we added CRP concentrations to epidemiological model of lung cancer to evaluate its prediagnostic role through time-dependent receiver operating characteristic curve analysis. Elevated CRP levels were associated with a 22% increased lung cancer risk per 1 SD increase (HR = 1.22, 95% confidence interval [CI] = 1.18-1.26). Positive associations were observed in small cell lung cancer (HR = 1.21, 95% CI = 1.10-1.33), lung adenocarcinoma (HR = 1.17, 95% CI = 1.11-1.23) and lung squamous cell carcinoma (HR = 1.22, 95% CI = 1.14-1.31). No genetical association of circulating CRP levels and lung cancer risk was observed in MR analysis. When added to a risk model of lung cancer, CRP improved the performance of model as long as 8 years among current smokers (basic model: C-statistic = 0.78 [95% CI = 0.75-0.80]; CRP model: C-statistic = 0.79 [95% CI = 0.76-0.81]; Pnonadjusted  = .003, Padjusted  = .014). Our results did not support the causal association of circulating CRP with lung cancer risk. However, circulating CRP could be a prediagnostic marker of lung cancer as long as 8 years in advance for current smokers.

Functional characterization and clinical significance of super-enhancers in lung adenocarcinoma.

Super-enhancers (SEs) are important transcriptional regulators in tumorigenesis; however, the functional characterization and clinical significance of SEs in lung adenocarcinoma (LUAD) remain unclear. By using H3K27ac ChIP-seq data of two LUAD cell lines and eight lung tissues, we detected 1045 cancer-specific and 5032 normal-specific SEs. Compared to normal-specific SEs, cancer-specific SEs have different regulatory mechanisms where associated target genes were enriched in critical tumor-related pathways and tended to be regulated by transcription factors of Fos Proto-Oncogene, AP-1 Transcription Factor Subunit and Jun Proto-Oncogene, AP-1 Transcription Factor Subunit families. By using expression data of 513 LUAD and 57 adjacent samples from The Cancer Genome Atlas and 80 tumor-normal paired LUAD samples from the Nanjing Lung Cancer Cohort study, we performed differential expression analysis of target genes for SEs and defined 243 crucial SEs. Unsupervised clustering of crucial SEs revealed two subtypes with different levels of genomic aberrations (i.e., mutation and copy number alteration) and clinical outcomes (progression-free interval: p = 0.030; disease-free interval: p = 0.047). In addition, patients with adverse clinical outcomes were more sensitive to three small molecule inhibitors (bortezomib, doxorubicin, and etoposide), and their targets (PSMB5 and TOP2A) also have elevated expression levels among these patients. Taken together, our findings provided a comprehensive characterization of SEs in LUAD and emphasized their clinical significance in LUAD therapy.

Risk factors of unilateral breast cancer-related lymphedema: an updated systematic review and meta-analysis of 84 cohort studies.

PURPOSE: To review and update the incidence and risk factors for breast cancer-related lymphedema based on cohort studies. METHODS: The study was guided by the Joanna Briggs Institute methodology and the Cochrane handbook for systematic reviews. PubMed, EMBASE, CINAHL, Scopus, Web of Science, The Cochrane Library, CNKI, SinoMed, and Wan Fang Database were searched from inception to November 15, 2021. Cohort studies reported adjusted risk factors were selected. PRISMA guideline was followed. Study quality were evaluated using the Newcastle-Ottawa scale. Random-effects models were adopted. The robustness of pooled estimates was validated by meta-regression and subgroup analysis. Lymphedema incidence and adjusted risk factors in the multivariable analyses with hazard / odds ratios and 95% CIs were recorded. RESULTS: Eighty-four cohort studies involving 58,358 breast cancer patients were included. The pooled incidence of lymphedema was 21.9% (95% CI, 19.8-24.0%). Fourteen factors were identified including ethnicity (black vs. white), higher body mass index, higher weight increase, hypertension, higher cancer stage (III vs. I-II), larger tumor size, mastectomy (vs. breast conservation surgery), axillary lymph nodes dissection, more lymph nodes dissected, higher level of lymph nodes dissection, chemotherapy, radiotherapy, surgery complications, and higher relative volume increase postoperatively. Additionally, breast reconstruction surgery, and adequate finance were found to play a protective role. However, other variables such as age, number of positive lymph nodes, and exercise were not correlated with risk of lymphedema. CONCLUSION: Treatment-related factors still leading the development of breast cancer-related lymphedema. Other factors such as postoperative weight increase and finance status also play a part. Our findings suggest the need to shift the focus from treatment-related factors to modifiable psycho-social-behavioral factors.

Air Pollution, Genetic Factors, and the Risk of Lung Cancer: A Prospective Study in the UK Biobank.

Rationale: Both genetic and environmental factors contribute to lung cancer, but the degree to which air pollution modifies the impact of genetic susceptibility on lung cancer remains unknown. Objectives: To investigate whether air pollution and genetic factors jointly contribute to incident lung cancer. Methods: We analyzed data from 455,974 participants (53% women) without previous cancer at baseline in the UK Biobank. The concentrations of particulate matter (PM) (PM ⩽2.5 µm in aerodynamic diameter [PM2.5], coarse PM between 2.5 µm and 10 µm in aerodynamic diameter [PMcoarse], and PM ⩽10 µm in aerodynamic diameter [PM10]), nitrogen dioxide (NO2), and nitrogen oxides (NOx) were estimated by using land-use regression models, and the association between air pollutants and incident lung cancer was investigated by using a Cox proportional hazard model. Furthermore, we constructed a polygenic risk score and evaluated whether air pollutants modified the effect of genetic susceptibility on the development of lung cancer. Measurements and Main Results: The results showed significant associations between the risk of lung cancer and PM2.5 (hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.33-2.01; per 5 µg/m3), PM10 (HR, 1.53; 95% CI, 1.20-1.96; per 10 µg/m3), NO2 (HR, 1.10; 95% CI, 1.05-1.15; per 10 µg/m3), and NOx (HR, 1.13; 95% CI, 1.07-1.18; per 20 µg/m3). There were additive interactions between air pollutants and the genetic risk. Compared with participants with low genetic risk and low air pollution exposure, those with high air pollution exposure and high genetic risk had the highest risk of lung cancer (PM2.5: HR, 1.71; 95% CI, 1.45-2.02; PM10: HR, 1.77; 95% CI, 1.50-2.10; NO2: HR, 1.77; 95% CI, 1.42-2.22; NOx: HR, 1.67; 95% CI, 1.43-1.95). Conclusions: Long-term exposure to air pollution may increase the risk of lung cancer, especially in those with high genetic risk.

Development and psychometric evaluation of a lymphoedema self-management behaviour questionnaire for breast cancer patients.

OBJECTIVES: The study was aimed to develop and evaluate a lymphoedema self-management behaviour questionnaire (LSMBQ) for breast cancer patients. METHODS: The initial version of the behaviour questionnaire was developed based on the framework of self-management and the evidence summary of lymphoedema self-management. Two rounds of expert consultation were conducted to validate the questionnaire's content validity. A cross-sectional survey was then conducted in breast wards of two hospitals in China to evaluate the reliability and validity of this scale. Exploratory structural equation model was used to test the construct validity. T-test was used to analyse the known group validity. Structural equation model was applied to verify the relationship between self-efficacy, social support, and lymphoedema self-management behaviour to test the convergent validity. Also, the internal consistency reliability and test-retest reliability were evaluated. RESULTS: The questionnaire's content validity was satisfactory. There were 22 items included in the LSMBQ for validation and 260 completed the survey. A six-factor structure with good construct validity was identified. The result of t-test verified that patients who knew the risk of lymphoedema and those who received lymphoedema health education had higher scores of lymphoedema self-management behaviours (P < 0.05), indicating that the questionnaire has good known group validity. The fitting results of the structural equation model indicated that the 22-item questionnaire had good convergent validity. Cronbach's alpha coefficients and test-retest reliability for the total questionnaire were 0.910 and 0.875, respectively. CONCLUSIONS: The 22-item LSMBQ appears to have adequate reliability and validity to assess the lymphoedema self-management behaviours for breast cancer patients.

Genome-wide gene-smoking interaction study identified novel susceptibility loci for non-small cell lung cancer in Chinese populations.

Gene-smoking interactions play important roles in the development of non-small cell lung cancer (NSCLC). To identify single-nucleotide polymorphisms (SNPs) that modify the association of smoking behavior with NSCLC risk, we conducted a genome-wide gene-smoking interaction study in Chinese populations. The genome-wide interaction analysis between SNPs and smoking status (ever- versus never-smokers) was carried out using genome-wide association studies of NSCLC, which included 13 327 cases and 13 328 controls. Stratified analysis by histological subtypes was also conducted. We used a genome-wide significance threshold of 5 × 10-8 for identifying significant gene-smoking interactions and 1 × 10-6 for identifying suggestive results. Functional annotation was performed to identify potential functional SNPs and target genes. We identified three novel loci with significant or suggestive gene-smoking interaction. For NSCLC, the interaction between rs2746087 (20q11.23) and smoking status reached genome-wide significance threshold [odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.54-0.74, P = 3.31 × 10-8], and the interaction between rs11912498 (22q12.1) and smoking status reached suggestive significance threshold (OR = 0.72, 95% CI: 0.63-0.82, P = 8.10 × 10-7). Stratified analysis by histological subtypes identified suggestive interactions between rs459724 (5q11.2) and smoking status (OR = 0.61, 95% CI: 0.51-0.73, P = 7.55 × 10-8) in the risk of lung squamous cell carcinoma. Functional annotation indicated that both classic and novel biological processes, including nicotine addiction and airway clearance, may modulate the susceptibility to NSCLC. These novel loci provide new insights into the biological mechanisms underlying NSCLC risk. Independent replication in large-scale studies is needed and experimental studies are warranted to functionally validate these associations.

Changes in the Content of Organic Acids and Expression Analysis of Citric Acid Accumulation-Related Genes during Fruit Development of Yellow (Passiflora edulis f. flavicarpa) and Purple (Passiflora edulis f. edulis) Passion Fruits.

Organic acids are key components that determine the taste and flavor of fruits and play a vital role in maintaining fruit quality and nutritive value. In this study, the fruits of two cultivars of passion fruit Yellow (Passiflora edulis f. flavicarpa) and purple (Passiflora edulis f. edulis) were harvested at five different developmental stages (i.e., fruitlet, green, veraison, near-mature and mature stage) from an orchard located in subtropical region of Fujian Province, China. The contents of six organic acids were quantified using ultra-performance liquid chromatography (UPLC), activities of citric acid related enzymes were determined, and expression levels of genes involved in citric acid metabolism were measured by quantitative real-time PCR (qRT-PCR). The results revealed that citric acid was the predominant organic acid in both cultivars during fruit development. The highest citric acid contents were observed in both cultivars at green stage, which were reduced with fruit maturity. Correlation analysis showed that citrate synthase (CS), cytosolic aconitase (Cyt-ACO) and cytosolic isocitrate dehydrogenase (Cyt-IDH) may be involved in regulating citric acid biosynthesis. Meanwhile, the PeCS2, PeACO4, PeACO5 and PeIDH1 genes may play an important role in regulating the accumulation of citric acid. This study provides new insights for future elucidation of key mechanisms regulating organic acid biosynthesis in passion fruit.

Ataxia telangiectasia mutated deficiency does not result in genetic susceptibility to 50 Hz magnetic fields exposure in mouse embryonic fibroblasts.

Extremely low frequency magnetic field (ELF-MF) has been classified as a possible carcinogen to humans by the International Agency for Research on Cancer [2002]. However, debate on the genotoxic effects of ELF-MF has continued due to lack of sufficient experimental evidence. Ataxia telangiectasia mutated (ATM) plays a central role in DNA damage repair; its deficiency can result in cellular sensitivity to DNA-damaging agents. To evaluate the genotoxicity of ELF-MF, we investigated the effects of 50 Hz MF on DNA damage in ATM-proficient (Atm+/+ ) mouse embryonic fibroblasts (MEFs) and ATM-deficient (Atm-/- ) MEFs, a radiosensitive cell line. Results showed no significant difference in average number of γH2AX foci per cell (9.37 ± 0.44 vs. 9.08 ± 0.28, P = 0.58) or percentage of γH2AX foci positive cells (49.22 ± 1.86% vs. 49.74 ± 1.44%, P = 0.83) between sham and exposure groups when Atm+/+ MEFs were exposed to 50 Hz MF at 2.0 mT for 15 min. Extending exposure duration to 1 or 24 h did not significantly change γH2AX foci formation in Atm+/+ MEFs. Similarly, the exposure did not significantly affect γH2AX foci formation in Atm-/- MEFs. Furthermore, 50 Hz MF exposure also did not significantly influence DNA fragmentation, cell viability, or cell cycle progression in either cell types. In conclusion, exposure to 50 Hz MF did not induce significant DNA damage in either Atm+/+ or Atm-/- MEFs under the reported experimental conditions. Bioelectromagnetics. 39:476-484, 2018. © 2018 Wiley Periodicals, Inc.

Binding Performance of Human Intravenous Immunoglobulin and 20(S)-7-Ethylcamptothecin.

A previous study showed that intravenous immunoglobulin (IVIG) could preserve higher levels of biologically active lactone moieties of topotecan, 7-ethyl-10-hydroxycamptothecin (SN-38) and 10-hydroxycamptothecin at physiological pH 7.40. As one of camptothecin analogues (CPTs), the interaction of 7-ethylcamptothecin and IVIG was studied in vitro in this study. It was shown that the main binding mode of IVIG to 7-ethylcamptothecin was hydrophobic interaction and hydrogen bonding, which is a non-specific and spontaneous interaction. The hydrophobic antigen-binding cavity of IgG would enwrap the drug into a host-guest inclusion complex and prevent hydrolysis of the encapsulated drug, while the drug is adjacent to the chromophores of IgG and may exchange energy with chromophores and quench the fluorescence of the protein. Also, the typical ß-sheet structure of IVIG unfolded partially after binding to 7-ethylcamptothecin. Additionally, the binding properties of IVIG and six CPTs with different substituents at A-ring and/or B-ring including camptothecin, topotecan, irinotecan, 10-hydroxycamptothecin, 7-ethylcamptothecin and SN-38 were collected together and compared each other. Synergizing with anti-cancer drugs, IVIG could be used as a transporter protein for 7-ethylcamptothecin and other CPTs, allowing clinicians to devise new treatment protocols for patients.

RF-EMF exposure at 1800 MHz did not elicit DNA damage or abnormal cellular behaviors in different neurogenic cells.

Despite many years of studies, the debate on genotoxic effects of radiofrequency electromagnetic fields (RF-EMF) continues. To systematically evaluate genotoxicity of RF-EMF, this study examined effects of RF-EMF on DNA damage and cellular behavior in different neurogenic cells. Neurogenic A172, U251, and SH-SY5Y cells were intermittently (5 min on/10 min off) exposed to 1800 MHz RF-EMF at an average specific absorption rate (SAR) of 4.0 W/kg for 1, 6, or 24 h. DNA damage was evaluated by quantification of γH2AX foci, an early marker of DNA double-strand breaks. Cell cycle progression, cell proliferation, and cell viability were examined by flow cytometry, hemocytometer, and cell counting kit-8 assay, respectively. Results showed that exposure to RF-EMF at an SAR of 4.0 W/kg neither significantly induced γH2AX foci formation in A172, U251, or SH-SY5Y cells, nor resulted in abnormal cell cycle progression, cell proliferation, or cell viability. Furthermore, prolonged incubation of these cells for up to 48 h after exposure did not significantly affect cellular behavior. Our data suggest that 1800 MHz RF-EMF exposure at 4.0 W/kg is unlikely to elicit DNA damage or abnormal cellular behaviors in neurogenic cells. Bioelectromagnetics. 38:175-185, 2017. © 2016 Wiley Periodicals, Inc.

BoneCeramic graft regenerates alveolar defects but slows orthodontic tooth movement with less root resorption.

INTRODUCTION: BoneCeramic (Straumann, Basel, Switzerland) can regenerate bone in alveolar defects after tooth extraction, but it is unknown whether it is feasible to move a tooth through BoneCeramic grafting sites. The objective of this study was to investigate 3-dimensional real-time root resorption and bone responses in grafted sites during orthodontic tooth movement. METHODS: Sixty 5-week-old rats were randomly assigned to 3 groups to receive BoneCeramic, natural bovine cancellous bone particles (Bio-Oss; Geistlich Pharma, Wolhusen, Switzerland), or no graft, after the extraction of the maxillary left first molar. After 4 weeks, the maxillary left second molar was moved into the extraction site for 28 days. Dynamic bone microstructures and root resorption were evaluated using in-vivo microcomputed tomography. Stress distribution and corresponding tissue responses were examined by the finite element method and histology. Mixed model analysis of variance was performed to compare the differences among time points with Bonferroni post-hoc tests at the significance level of P <0.05. RESULTS: The BoneCeramic group had the least amount of tooth movement and root resorption volumes and craters, and the highest bone volume fraction, trabecular number, and mean trabecular thickness, followed by the Bio-Oss and the control groups. The highest stress accumulated in the cervical region of the mesial roots. CONCLUSIONS: BoneCeramic has better osteoconductive potential and induces less root resorption compared with Bio-Oss grafting and naturally recovered extraction sites.

Dexmedetomidine ameliorates acute lung injury following orthotopic autologous liver transplantation in rats probably by inhibiting Toll-like receptor 4-nuclear factor kappa B signaling.

BACKGROUND: To investigate whether pretreatment with dexmedetomidine (Dex) has a protective effect against acute lung injury (ALI) in an orthotopic autologous liver transplantation (OALT) rat model and to explore the mechanisms responsible for the protective effect of Dex against lung injury. METHODS: Forty-eight rats underwent OALT and were randomly divided into six groups (n = 8 in each group) that received 10 µg/kg Dex, 50 µg/kg Dex, 50 µg/kg Dex + nonspecific α2-adrenergic receptor (AR) antagonist atipamezole, 50 µg/kg Dex + specific α2B/C-AR antagonist ARC-239, 50 µg/kg Dex + specific α2A-AR antagonist BRL-44408, or the same amount of normal saline. The sham rats (n = 8) underwent anesthesia induction, laparotomy, and separation of the portal vein without liver ischemia and reperfusion. Lung tissue sections were stained with hematoxylin and eosin (HE) to visualize the damage. The expression of Toll-like receptor 4 (TLR4) and the phospho-nuclear factor (NF)-κB p65 subunit as well as inflammatory cytokines was measured. RESULTS: Rats exhibited increased histological lung injury scores and pulmonary edema following OALT. Pretreatment with 50 µg/kg Dex attenuated OALT-induced lung injury in rats, probably by inhibiting the activation of the TLR4-NF-κB signaling pathway. The protective effect of Dex could be blocked by atipamezole or BRL-44408, but not by ARC-239, suggesting these effects of Dex were mediated, at least in part, by the α2A-AR. CONCLUSIONS: Dex exerts protective effects against ALI following OALT, and this protection is associated with the suppression of TLR4-NF-κB signaling. Thus, pretreatment with Dex may be a useful method for reducing lung damage caused by liver transplantation.