Nasopharyngeal carcinoma (NPC), the most common head and neck cancer, is characterized by distinct geographic distribution and familial aggregation. Multiple risk factors, including host genetics, ...environmental factor, and EBV infection, have been linked to the development of NPC, particularly in the familial clustering cases. However, the cause of NPC endemicity remains enigmatic due possibly to the complicated interplay between these risk factors. Recently, positive Epstein‐Barr virus (EBV) DNA loads at nasopharyngeal (NP) cavity has been found to reflect NPC development and applied in NPC screening. To examine whether the increased NP EBV loads could aggregate in the families and be affected by host genetics and environmental factor, EBV loads were obtained by 510 NP brushing samples from eligible unaffected individuals, who have two or more relatives affected with NPC, in 116 high‐risk NPC families. The correlation of relative pairs was estimated using S.A.G.E. (version 6.4, 2016), and host heritability of NP EBV loads was calculated with variance component models using SOLAR (version 8.4.2, 2019). In result, significant correlations of EBV loads were observed between parent‐offspring pairs and sibling‐sibling pairs (P < .001), but not in distant kin relationship pairs. Interestingly, after excluding the shared environmental factor within families, host genetics contributes significantly to NP EBV loads with a heritability of 56.41% (P = 1.00 × 10−7), and its effect was slightly elevated (68.86%, P = 3.40 × 10−6) in families with more NPC cases (≥3). These findings indicate that additional host‐genetic variants involved in the EBV local NP mucosal behavior may be especially important for the development of NPC.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Nasopharyngeal carcinoma (NPC), an Epstein–Barr virus (EBV) associated cancer, exhibits an extremely high incidence in southern Chinese. Given that human leukocyte antigen (HLA) plays ...critical roles in antigen presentation and relates to NPC susceptibility, it is speculated that certain HLA variants may affect EBV reactivation, which is a key pathogenic factor of NPC. Therefore, we attempted to identify HLA alleles associated with the indicator of EBV reactivation, Zta‐IgA, in healthy males from NPC endemic area.
Methods
HLA alleles of 1078 healthy males in southern China from the 21‐RCCP study were imputed using genome‐wide single nucleotide polymorphism data. EBV Zta‐IgA in blood samples were measured using an enzyme‐linked immunosorbent assay. Multiple logistic regression analysis was used to evaluate the effect of HLA allele on Zta‐IgA serological status and its potential joint association with smoking. The binding affinity for Zta‐peptide was predicted using NetMHCIIpan 4.0.
Results
HLA‐DRB1*09:01 was found to be associated with a higher risk of Zta‐IgA seropositivity (odds ratio = 1.80, 95% confidence interval = 1.32–2.45; p = 1.82 × 10−4). Compared with non‐smokers without HLA‐DRB1*09:01, the effect size increased to 2.19‐ and 3.70‐fold for the light and heavy smokers carrying HLA‐DRB1*09:01, respectively. Furthermore, HLA‐DRB1*09:01 showed a stronger binding affinity to Zta peptide than other HLA‐DRB1 alleles.
Conclusions
Our study highlighted the pivotal role of genetic HLA variants in EBV reactivation and the etiology of NPC. Smokers with HLA‐DRB1*09:01 have a significantly higher risk of being Zta‐IgA seropositive, which indicates the necessity of smoking cessation in certain high‐risk populations and also provide clues for further research on the etiology of NPC.
We conducted an association study for human leukocyte antigen (HLA) alleles and Epstein–Barr virus Zta‐IgA serological status in healthy males from a nasopharyngeal carcinoma endemic area. We found that HLA‐DRB1*09:01 was associated with a high risk of Zta‐IgA seropositivity and the effect increased when combined with smoking. In silico prediction indicated that HLA‐DRB1*09:01 had a distinctive binding motif pattern and a stronger binding affinity to Zta peptide in comparison with other HLA‐DRB1 alleles.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The presence of oral microbes in extra-oral sites is linked to gastrointestinal cancers. However, their potential ectopically colonization in the nasopharynx and impact on local cancer development ...remains uncertain. Our study involving paired nasopharyngeal-oral microbial samples from nasopharyngeal carcinoma (NPC) patients and controls unveils an aberrant oral-to-nasopharyngeal microbial translocation associated with increased NPC risk (OR = 4.51, P = 0.012). Thirteen species are classified as oral-translocated and enriched in NPC patients. Among these, Fusobacterium nucleatum and Prevotella intermedia are validated through culturomics and clonal strain identification. Nasopharyngeal biopsy meta-transcriptomes confirm these microbes within tumors, influencing local microenvironment and cytokine response. These microbes correlate significantly with the Epstein-Barr virus (EBV) loads in the nasopharynx, exhibiting an increased dose-response relationship. Collectively, our study identifies oral microbes migrating to the nasopharynx, infiltrating tumors, impacting microenvironments and linking with EBV infection. These results enhance our understanding of abnormal microbial communication and their roles in carcinogenesis.
Distant metastasis is the leading cause of death for esophageal squamous cell carcinoma (ESCC) with limited treatment options and unsatisfactory effectiveness. Bromodomain (BRD) containing proteins ...are emerging targets for cancer therapy with promising effects. As a unique member of BRD family, the function and molecular mechanism of ATAD2 in cancer development is seldomly investigated.
The clinical impact of ATAD2 was assessed both at RNA and protein level in 75 and 112 ESCC patients separately. The biological function of ATAD2 was investigated in vitro and in vivo. Signaling pathway and downstream effectors of ATAD2 were identified by RNA sequencing, luciferase reporter, co-immunoprecipitation, chromatin immunoprecipitation, immunofluorescence and western blot assay.
We found that elevated ATAD2 expression was significantly associated with lymph node metastasis, advanced clinical stage as well as poor survival of ESCC patients. Silencing ATAD2 significantly suppressed ESCC cell migration and invasion in vitro, and inhibited tumor growth and lung metastasis in vivo. Mechanically, we identified a new cofactor, C/EBPβ. ATAD2 directly interacted with C/EBPβ and promoted its nuclear translocation, which directly bound to the promoter region of TGF-β1 and activated its expression. Further, we demonstrated that TGF-β1 activated its downstream effectors in a Smad3 dependent manner. In addition, we further found that ATAD2 promoted ESCC metastasis through TGF-β signaling induced Snail expression and the subsequent epithelial-mesenchymal transition.
Our findings demonstrated the pro-metastatic function of ATAD2 and uncovered the new molecular mechanism by regulating C/EBPβ/TGF-β1/Smad3/Snail signaling pathway, thus providing a potential target for the treatment of ESCC metastasis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Screening is a confirmed way to reduce the incidence and mortality rates of CRC. This study aimed to identify a ...fecal-based, noninvasive, and accurate method for detection of colorectal cancer (CRC) and advanced adenoma (AA). Methods Through detection in tissue (n = 96) and fecal samples (n = 88) and tested in an independent group of fecal samples (n = 294), the methylated DNA marker ITGA4 and bacterial markers Fusobacterium nucleatum (Fn) and Pepetostreptococcusanaerobius (Pa) were identified from the candidate biomarkers for CRC and AA detection. A prediction score (pd-score) was constructed using the selected markers and fecal immunochemical test (FIT) for distinguishing AA and CRC from healthy subjects by logistic regression method. The diagnostic performance of the pd-score was compared with FIT and validated in the external validation cohort (n = 117) and in a large CRC screening cohort. Results The pd-score accurately identified AA and CRC from healthy subjects with an area under the curve (AUC) of 0.958, at a specificity of 91.37%; the pd-score showed sensitivities of 95.38% for CRC and 70.83% for AA, respectively. In the external validation cohort, the sensitivities of the pd-score for CRC and AA detection were 94.03% and 80.00%, respectively. When applied in screening, the pd-score identified 100% (11/11) of CRC and 70.83% (17/24) of AA in participants with both colonoscopy results and qualified fecal samples, showing an improvement by 41.19% compared to FIT. Conclusions The current study developed a noninvasive and well-validated approach for AA and CRC detection, which could be applied widely as a diagnostic and screening test. Keywords: Colorectal cancer, Advanced adenoma, Noninvasive test, Fecal biomarkers, Screening
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nasopharyngeal carcinoma (NPC) is closely associated with genetic factors and Epstein-Barr virus infection, showing strong familial aggregation. Individuals with a family history suffer elevated NPC ...risk, requiring effective genetic counseling for risk stratification and individualized prevention.
We performed whole-exome sequencing on 502 familial NPC patients and 404 unaffected relatives and controls. We systematically evaluated the established cancer predisposition genes and investigated novel NPC susceptibility genes, making comparisons with 21 other familial cancers in the UK biobank (N = 5218).
Rare pathogenic mutations in the established cancer predisposition genes were observed in familial NPC patients, including ERCC2 (1.39%), TP63 (1.00%), MUTYH (0.80%), and BRCA1 (0.80%). Additionally, 6 novel susceptibility genes were identified. RAD54L, involved in the DNA repair pathway together with ERCC2, MUTYH, and BRCA1, showed the highest frequency (4.18%) in familial NPC. Enrichment analysis found mutations in TP63 were enriched in familial NPC, and RAD54L and EML2 were enriched in both NPC and other Epstein-Barr virus-associated cancers. Besides rare variants, common variants reported in the studies of sporadic NPC were also associated with familial NPC risk. Individuals in the top quantile of common variant-derived genetic risk score while carrying rare variants exhibited increased NPC risk (odds ratio = 13.47, 95% confidence interval = 6.33 to 28.68, P = 1.48 × 10-11); men in this risk group showed a cumulative lifetime risk of 24.19%, much higher than those in the bottom common variant-derived genetic risk score quantile and without rare variants (2.04%).
This study expands the catalog of NPC susceptibility genes and provides the potential for risk stratification of individuals with an NPC family history.
The oral microbiota has been observed to be influenced by cigarette smoking and linked to several human diseases. However, research on the effect of cigarette smoking on the oral microbiota has not ...been systematically conducted in the Chinese population. We profiled the oral microbiota of 316 healthy subjects in the Chinese population by 16S rRNA gene sequencing. The alpha diversity of oral microbiota was different between never smokers and smokers (
P
= 0.002). Several bacterial taxa were first reported to be associated with cigarette smoking by LEfSe analysis, including
Moryella
(
q
= 1.56E-04),
Bulleidia
(
q
= 1.65E-06), and
Moraxella
(
q
= 3.52E-02) at the genus level and
Rothia dentocariosa
(
q
= 1.55E-02),
Prevotella melaninogenica
(
q
= 8.48E-08),
Prevotella pallens
(
q
= 4.13E-03),
Bulleidia moorei
(
q
= 1.79E-06),
Rothia aeria
(
q
= 3.83E-06),
Actinobacillus parahaemolyticus
(
q
= 2.28E-04), and
Haemophilus parainfluenzae
(
q
= 4.82E-02) at the species level. Two nitrite-producing bacteria that can increase the acidity of the oral cavity,
Actinomyces
and
Veillonella
, were also enriched in smokers with FDR-adjusted
q
-values of 3.62E-06 and 1.10E-06, respectively. Notably, we observed that two acid production-related pathways, amino acid-related enzymes (
q
= 6.19E-05) and amino sugar and nucleotide sugar metabolism (
q
= 2.63E-06), were increased in smokers by PICRUSt analysis. Finally, the co-occurrence analysis demonstrated that smoker-enriched bacteria were significantly positively associated with each other and were negatively correlated with the bacteria decreased in smokers. Our results suggested that cigarette smoking may affect oral health by creating a different environment by altering bacterial abundance, connections among oral microbiota, and the microbiota and their metabolic function.
During deep tunnel excavation, more than one rockburst sometimes occur in a particular area which seriously threatens construction safety. In this work, the characteristic microseismicity occurring ...during the development process of intermittent rockburst (more than one rockburst occurring in a particular area) and single rockburst (only one rockburst occurring in a particular area) and the associated mechanism of formation are studied. Data was collected during the construction of a railway tunnel in southwestern China. Microseismicity was recorded and analyzed before and after each rockburst (for both intermittent and single rockbursts). The Schmidt number declines heavily with time, the cumulative apparent volume rises sharply with time, and the Seismic activity is high before the rockburst. However, this characteristic microseismicity can also be found with no rockburst occurrence. Between each rockburst in an intermittent rockburst, the MS events mostly have low MS energy, i.e. whose logarithm (measured in Joules) is smaller than 3.5, and the energy stored in the rockmass of the rockburst zone is not adequately released. Therefore, there is likely to be another rockburst after the blast when high in situ stress is present. After the last rockburst of an intermittent rockburst and the single rockburst, some MS events of high MS energy, i.e. whose logarithm (measured in Joules) is larger than 3.5, occur in the deep surrounding rockmass and the energy stored in the rockmass of the rockburst zone is gradually released to a certain degree. The stress is transferred to the deep surrounding rockmass whose stability is relatively high. As a result, a subsequent rockburst is hardly likely to occur again.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
High stress induced by excavation disturbance in deep hard rock engineering can cause rockburst accidents. Microwave-induced borehole fracturing of hard rock is a promising technique for preventing ...rockbursts, the principle of which is to reduce energy and stress concentration levels in rock mass through microwave heating. The characteristics and mechanism of microwave-induced borehole fracturing of hard rock under different true triaxial stresses were experimentally investigated. After microwave-induced borehole fracturing under different σ1 and σ2 conditions, a complex crack network dominated by tensile cracks was generated in the rock specimen, which is consistent with the results obtained by AF and RA. According to the P-wave velocity before and after the test, the degree of thermal fracture is positively linearly correlated with σ1 and σ2 as a whole, and has good consistency with the length and number of thermal cracks. The results show that the technique will have better applicability and higher fracturing efficiency in high-stress areas. The thermal fracture process of basalt specimens under different σ1 and σ2 conditions is similar, which can be divided into a silent period, quiet period, dense period, and persistent period. In addition, thermal fracture exerts a significant threshold temperature effect, and fracture rate increases rapidly when the temperature reaches 150–192 °C (average about 172 °C). The relationship between thermal fracture and stress provides guidance for parameter design.
•Microwave-induced borehole fracturing of hard rock is a promising technique for preventing rockbursts.•Microwave-induced borehole fracturing tests are conducted under different true triaxial stress.•The characteristics and mechanism of microwave-induced borehole fracturing under different σ1 and σ2 conditions are investigated.•Microwave-induced borehole fracturing process is investigated by AE technique.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Anxiety, a common and devastating mental disorder, has raised widespread interests. The impacts of air pollution on physical health are well known, whereas few studies have explored the association ...of atmospheric pollution, especially short-term air pollution exposure, with the risk of anxiety disorders. In addition, there are increasing concerns in emerging evidence supporting a possible etiological link. Therefore, our aim was to evaluate the relationship between short-term exposure to atmospheric pollutants and anxiety outpatient visits in Xi'an, a city of northwestern China and a metropolis with relatively heavy air pollution. We collected the data of both daily outpatient visits and daily air pollution (SO2, NO2, and PM10) between January 1, 2010 and January 31, 2016 (2222 days). To clarify the association between short-term ambient atmospheric pollution exposure and anxiety outpatient visits, an over-dispersed Poisson generalized additive model was applied by adjusting the day of the week and weather conditions (including temperature, humidity, sunlight hours, and rainfalls). Positive association between gaseous air pollutants (SO2 and NO2) and anxiety daily outpatient visits was observed. Moreover, the largest estimated values of both SO2 and NO2 were evidence at lag 03 (4-day moving average lag), with 10 μg/m3 increase corresponded to the increase of outpatient anxiety visits at 4.11% (95% CI: 2.15%, 6.06%) for SO2 and 3.97% (95% CI: 1.90%, 6.06%) for NO2. However, there was no differences in susceptibility to air pollutants between different genders as well as different ages. Taken together, short-term exposure to ambient air pollutants, especially gaseous air pollutants (NO2 and SO2), can be related to higher risk of anxiety outpatient visits.
•Short-term ambient air pollution was associated with outpatient anxiety visits.•Positive association was evidenced for SO2 and NO2.•No gender and age difference were found in this association.
Short-term ambient air pollution and anxiety.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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