Caloric restriction disrupts the microbiota and colonization resistance.

Diet is a major factor that shapes the gut microbiome1, but the consequences of diet-induced changes in the microbiome for host pathophysiology remain poorly understood. We conducted a randomized human intervention study using a very-low-calorie diet (NCT01105143). Although metabolic health was improved, severe calorie restriction led to a decrease in bacterial abundance and restructuring of the gut microbiome. Transplantation of post-diet microbiota to mice decreased their body weight and adiposity relative to mice that received pre-diet microbiota. Weight loss was associated with impaired nutrient absorption and enrichment in Clostridioides difficile, which was consistent with a decrease in bile acids and was sufficient to replicate metabolic phenotypes in mice in a toxin-dependent manner. These results emphasize the importance of diet-microbiome interactions in modulating host energy balance and the need to understand the role of diet in the interplay between pathogenic and beneficial symbionts.

Impact of COVID-19 pandemic responses on tuberculosis incidence: insights from Shantou, China.

BACKGROUND: Various measures taken against the COVID-19 pandemic are not only effective in reducing the spread of the disease, but also lead to some unexpected results. This article regarded these measures as an intervention and explored their impact on the incidence of tuberculosis in Shantou, China. METHODS: The incidence rate and the surveillance data of tuberculosis from January 1st, 2018 to December 31st, 2021 were provided by the Shantou Tuberculosis Prevention and Control Institute. Data were divided into pre-pandemic period (January 1st, 2018 - December 31st, 2019) and pandemic periods (January 1st, 2020 - December 31st, 2021). The Interrupted Time Series (ITS) was used to analyze the trend of tuberculosis incidence prior to and during the COVID-19 epidemic. RESULTS: The results showed that the incidence of tuberculosis cases in Shantou decreased significantly (p < 0.05) during the pandemic as compared to that prior to the pandemic. Among them, the 45-64 age group and the 65 + age group have statistically significant declines. When patients were stratified by occupation, the unemployed and those working in agriculture reduced the most. CONCLUSIONS: In response to the pandemic, measures like lockdowns and quarantines seem to have reduced tuberculosis incidence. However, this does not imply a true decrease. Underlying causes for the reduced true incidence need further scrutiny. Findings offer a preliminary exploration of interventions designed for one disease but functioning as unexpected results for another.

Air pollution and upper respiratory diseases: an examination among medically insured populations in Wuhan, China.

Multiple evidence has supported that air pollution exposure has detrimental effects on the cardiovascular and respiratory systems. However, most investigations focus on the general population, with limited research conducted on medically insured populations. To address this gap, the current research was designed to examine the acute effects of inhalable particulate matter (PM2.5 and PM10), nitrogen dioxide (NO2), ground-level ozone (O3), and sulfur dioxide (SO2) on the incidence of upper respiratory tract infections (URTI), utilizing medical insurance data in Wuhan, China. Data on URTI were collected from the China Medical Insurance Basic Database for Wuhan covering the period from 2014 to 2018, while air pollutant data was gathered from ten national monitoring stations situated in Wuhan city. Statistical analysis was performed using generalized additive models for quasi-Poisson distribution with a log link function. The analysis indicated that except for ozone, higher exposure to four other pollutants (NO2, SO2, PM2.5, and PM10) were significantly linked to an elevated risk of URTI, particularly during the previous 0-3 days and previous 0-4 days. Additionally, NO2 and SO2 were found to be positively linked with laryngitis. Furthermore, the effects of air pollutants on the risk of URTI were more pronounced during cold seasons than hot seasons. Notably, females and the employed population were more susceptible to infection than males and non-employed individuals. Our findings gave solid proof of the link between ambient air pollution exposure and the risk of URTI in medically insured populations.

Association between ambient air pollution and daily hospital visits for cardiovascular diseases in Wuhan, China: a time-series analysis based on medical insurance data.

Although evidence showed the adverse effects of air pollution on cardiovascular disease (CVDs), few studies were based on medically insured populations. We applied a generalized additive Poisson model (GAM) to estimate the short-term effects of ambient air pollution on a group of medically insured population in Wuhan, China. We extracted daily air pollution data, meteorological data, and daily hospital visits for CVDs. We found that the ambient air pollutants sulfur dioxide (SO2), nitrogen dioxide (NO2), ground-level ozone (O3) particulate matter (PM) with an aerodynamic diameter ≤10 µm (PM10), and those ≤2.5 µm (PM2.5) all increased the risk of daily hospital visits for CVDs. We also found that the effect of air pollution on daily hospital visits for CVDs is greater in the cold season than in the warm season. Our findings can be used as evidence that supports the formulation of policies for air pollution and CVDs.

Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol.

Interferons (IFN) are essential antiviral cytokines that establish the cellular antiviral state through upregulation of hundreds of interferon-stimulated genes (ISGs), most of which have uncharacterized functions and mechanisms. We identified cholesterol-25-hydroxylase (CH25H) as a broadly antiviral ISG. CH25H converts cholesterol to a soluble antiviral factor, 25-hydroxycholesterol (25HC). 25HC treatment in cultured cells broadly inhibited growth of enveloped viruses including VSV, HSV, HIV, and MHV68 and acutely pathogenic EBOV, RVFV, RSSEV, and Nipah viruses under BSL4 conditions. It suppressed viral growth by blocking membrane fusion between virus and cell. In animal models, Ch25h-deficient mice were more susceptible to MHV68 lytic infection. Moreover, administration of 25HC in humanized mice suppressed HIV replication and reversed T cell depletion. Thus, our studies demonstrate a unique mechanism by which IFN achieves its antiviral state through the production of a natural oxysterol to inhibit viral entry and implicate membrane-modifying oxysterols as potential antiviral therapeutics.

Short-term effects of ambient air pollution on the incidence of influenza in Wuhan, China: A time-series analysis.

BACKGROUND: Evidence suggests that air pollution is associated with many adverse health outcomes such as cardiovascular diseases (CVD), respiratory diseases, cancer, and birth defects. Yet few studies dig into the relationship between air pollution and airborne infectious diseases. METHODS: Daily data on influenza incidence were obtained from Hubei Provincial Center for Disease Control and Prevention (Hubei CDC). Data on air pollutants including nitrogen dioxide (NO2), sulfur dioxide (SO2), ground-level ozone (O3), particulate matter (PM) with aerodynamic diameter ≤ 2.5 µm (PM2.5), and PM with aerodynamic diameter ≤ 10 µm (PM10) were retrieved from ten national air sampling stations located at Wuhan. We applied generalized additive model (GAM) to estimate the associations between air pollution and the risk of influenza in Wuhan, China during 2015-2017. RESULTS: In the single-day lag model, the largest effect estimates were observed at lag 0. An increased relative risk (RR) of influenza was significantly associated with a 10 µg/m3 increase in SO2 (RR: 1.099; 95% confidence interval [CI]: 1.011-1.195), NO2 (RR: 1.039; 95% CI: 1.013-1.065), and O3 (RR: 1.005; 95% CI: 0.994-1.016), respectively. In the multi-day lag model, concentrations of SO2, NO2, and O3 were statistically significantly associated with the risk of influenza at lag 0-1. The seasonal analysis suggests that the influence of air pollution on influenza is greater in the cold season as compared in the warm season in the early lag days. The multi-pollutant model indicates that NO2 may be a potential confounder for co-pollutants. CONCLUSIONS: Our study shows that air pollution may be associated with the risk of influenza in a broad sense. Therefore, when formulating policies to deal with influenza outbreaks in the future, factors regarding air pollution should be taken into consideration.

Effects of ambient temperature and precipitation on the risk of dengue fever: A systematic review and updated meta-analysis.

OBJECTIVES: We systematically reviewed the published studies on the relationship between dengue fever and meteorological factors and applied a meta-analysis to explore the effects of ambient temperature and precipitation on dengue fever. METHODS: We completed the literature search by the end of September 1st, 2019 using databases including Science Direct, PubMed, Web of Science, and Google Scholar. We extracted relative risks (RRs) in selected studies and converted all effect estimates to the RRs per 1 °C increase in temperature and 10 mm increase in precipitation, and combined all standardized RRs together using random-effect meta-analysis. RESULTS: Our results show that dengue fever was significantly associated with both temperature and precipitation. Our subgroup analyses suggested that the effect of temperature on dengue fever was most pronounced in high-income subtropical areas. The pooled RR of dengue fever associated with the maximum temperature was much lower than the overall effect. CONCLUSIONS: Temperature and precipitation are important risk factors for dengue fever. Future studies should focus on factors that can distort the effects of temperature and precipitation.

Associations between long-term exposure to air pollution and blood pressure and effect modifications by behavioral factors.

BACKGROUND: Studies on the hypertensive effect of long-term air pollution exposure were inconclusive and showed scarce evidence from rural areas in developing countries. In this context, we examined the associations of air pollution exposure with hypertension and blood pressure, and their effect modifiers in rural Chinese adults. METHODS: We studied 39,259 participants from a cohort established in five rural regions of central China. Individual exposures to PM2.5 and PM10 (particulate matter with an aerodynamic diameter less than or equal to 2.5 µm and 10 µm) and nitrogen dioxide (NO2) was evaluated using satellite-based spatiotemporal models. Mixed-effect regression models were applied to examine the associations of long-term exposure to air pollution with hypertension and four blood pressure component measurements, including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and pulse pressure (PP). Several potential effect modifiers related to demographic and behavioral factors were also examined. RESULTS: The results showed that for each 1 µg/m3 increase in PM2.5, PM10 and NO2, the adjusted odds ratio of hypertension was 1.029 (95%CI: 1.001,1.057), 1.015 (95%CI: 1.001, 1.029) and 1.069 (95%CI: 1.038, 1.100), respectively. These three air pollutants were also associated with increased SBP (except for PM10), DBP and MAP. The hypertensive effects of air pollution were more pronounced among males, smokers, drinkers, individuals with a high-fat diet, and those with high-level physical activity. CONCLUSION: Long-term exposure to PM2.5, PM10 and NO2 was associated with increased blood pressure and hypertension in rural Chinese adults, and the associations were modified by several behavioral factors.

Acute effect of ambient fine particulate matter on heart rate variability: an updated systematic review and meta-analysis of panel studies.

BACKGROUND: Decreased heart rate variability (HRV) is a predictor of autonomic system dysfunction, and is considered as a potential mechanism of increased risk of cardiovascular disease (CVD) induced by exposure to particulate matter less than 2.5 µm in diameter (PM2.5). Previous studies have suggested that exposure to PM2.5 may lead to decreased HRV levels, but the results remain inconsistent. METHODS: An updated systematic review and meta-analysis of panel studies till November 1, 2019 was conducted to evaluate the acute effect of exposure to ambient PM2.5 on HRV. We searched electronic databases (PubMed, Web of Science, and Embase) to identify panel studies reporting the associations between exposure to PM2.5 and the four indicators of HRV (standard deviation of all normal-to-normal intervals (SDNN), root mean square of successive differences in adjacent normal-to-normal intervals (rMSSD), high frequency power (HF), and low frequency power (LF)). Random-effects model was used to calculate the pooled effect estimates. RESULTS: A total of 33 panel studies were included in our meta-analysis, with 16 studies conducted in North America, 12 studies in Asia, and 5 studies in Europe. The pooled results showed a 10 µg/m3 increase in PM2.5 exposure which was significantly associated with a - 0.92% change in SDNN (95% confidence intervals (95%CI) - 1.26%, - 0.59%), - 1.47% change in rMSSD (95%CI - 2.17%, - 0.77%), - 2.17% change in HF (95%CI - 3.24%, - 1.10%), and - 1.52% change in LF (95%CI - 2.50%, - 0.54%), respectively. Overall, subgroup analysis suggested that short-term exposure to PM2.5 was associated with lower HRV levels in Asians, healthy population, and those aged ≥ 40 years. CONCLUSION: Short-term exposure to PM2.5 was associated with decreased HRV levels. Future studies are warranted to clarity the exact mechanism of exposure to PM2.5 on the cardiovascular system through disturbance of autonomic nervous function.

The association between short-term exposure to ambient air pollution and the incidence of mumps in Wuhan, China: A time-series study.

BACKGROUND: Previous studies have estimated the association between meteorological factors and mumps outbreaks without assessing the influence of air pollution. In this research, we explored the effects of short-term exposure to air pollution on the incidence of mumps. METHODS: Our time-series analysis was conducted using data collected in Wuhan, China from 2015 to 2017. Daily number of mumps cases was obtained from Disease Reporting System in Hubei Provincial Center for Disease Control and Prevention. Data on air pollution was obtained from 10 national air quality monitoring stations, including nitrogen dioxide (NO2), sulfur dioxide (SO2), ground-level ozone (O3), particulate matter less than or equal to 10 µm in aerodynamic diameter (PM10), and particulate matter less than or equal to 2.5 µm in aerodynamic diameter (PM2.5). Daily meteorological data including temperature and relative humidity were obtained from Hubei Meteorological Bureau. We performed a Poisson regression in generalized additive models (GAM) to explore the association between the incidence of mumps and exposure to air pollution. RESULTS: We observed that the effects of air pollutants were statistically significant mainly in two periods, lag 0 to lag 5 and lag 20 to lag 25, with the strongest effects appearing at lag 2 and lag 23. The cumulative effects were stronger than single-day lag effects. The stratified analysis showed the effect of pollutants during the hot season was stronger than that during the cold season, especially for NO2 and SO2. CONCLUSIONS: We found that exposure to NO2 and SO2 was significantly associated with higher risk of developing mumps. Our findings could help deepen the understanding of how air pollution exposure affects the incidence of mumps.

Cultivation of a human-associated TM7 phylotype reveals a reduced genome and epibiotic parasitic lifestyle.

The candidate phylum TM7 is globally distributed and often associated with human inflammatory mucosal diseases. Despite its prevalence, the TM7 phylum remains recalcitrant to cultivation, making it one of the most enigmatic phyla known. In this study, we cultivated a TM7 phylotype (TM7x) from the human oral cavity. This extremely small coccus (200-300 nm) has a distinctive lifestyle not previously observed in human-associated microbes. It is an obligate epibiont of an Actinomyces odontolyticus strain (XH001) yet also has a parasitic phase, thereby killing its host. This first completed genome (705 kb) for a human-associated TM7 phylotype revealed a complete lack of amino acid biosynthetic capacity. Comparative genomics analyses with uncultivated environmental TM7 assemblies show remarkable conserved gene synteny and only minimal gene loss/gain that may have occurred as TM7x adapted to conditions within the human host. Transcriptomic and metabolomic profiles provided the first indications, to our knowledge, that there is signaling interaction between TM7x and XH001. Furthermore, the induction of TNF-α production in macrophages by XH001 was repressed in the presence of TM7x, suggesting its potential immune suppression ability. Overall, our data provide intriguing insights into the uncultivability, pathogenicity, and unique lifestyle of this previously uncharacterized oral TM7 phylotype.

Evaluation of a consulting training course for international development assistance for health.

BACKGROUND: Development assistance for health (DAH) is an important component of foreign assistance. International health consultants usually play a key role in the international DAH field. However, there is still a shortage of consulting training in China. To address this issue and develop new backup force of DAH for China, the Global Health Institute of Wuhan University (GHIWHU) launched a training program called the "Consulting Training Course for International Development Assistance for Health". The purpose of this article is to evaluate the impact of the training on participants. METHODS: We conducted the analysis using Kirkpatrick's model. An evaluation survey examining participants' reaction (level 1) and learning (level 2) was carried out among trainees following the training, and a follow-up telephone interview of application (level 3) was made in three months after the training. RESULTS: A total of 25 participants from Chinese Consortium of Universities for Global Health (CCUGH) attended the training program. Results of satisfaction evaluation indicated that the training program was well received, with more than 85% of participants felt satisfied or relatively satisfied with the training. Trainees' self-ratings of the consulting knowledge and skills showed a significant increase (p < 0.001) from pre- to post-training. The follow-up interview revealed that the majority of participants applied the acquired knowledge and skills under various circumstances such as consulting program, teaching processes, writing reports, and et al. Meanwhile, participants considered that the lack of opportunities was one of the major application barriers. In addition, they expressed the willingness to participate in more relevant training and the need for more practice opportunities. CONCLUSIONS: This is the first study evaluating a consulting training program in China. The results show that the training course has been successfully implemented and participants have been given consulting knowledge and skills. Future research should use better-designed training methods based on demand surveys and consider providing participants with practice or practicum opportunities. Also, it is necessary to conduct both primary and advanced training courses and evaluate participants' long-term behavior changes resulting from the training.

Positive feedback regulation of type I IFN production by the IFN-inducible DNA sensor cGAS.

Rapid and robust induction of type I IFN (IFN-I) is a critical event in host antiviral innate immune response. It has been well demonstrated that cyclic GMP-AMP (cGAMP) synthase (cGAS) plays an important role in sensing cytosolic DNA and triggering STING dependent signaling to induce IFN-I. However, it is largely unknown how cGAS itself is regulated during pathogen infection and IFN-I production. In this study, we show that pattern recognition receptor (PRR) ligands, including lipid A, LPS, poly(I:C), poly(dA:dT), and cGAMP, induce cGAS expression in an IFN-I-dependent manner in both mouse and human macrophages. Further experiments indicated that cGAS is an IFN-stimulated gene (ISG), and two adjacent IFN-sensitive response elements (ISREs) in the promoter region of cGAS mediate the induction of cGAS by IFN-I. Additionally, we show that optimal production of IFN-ß triggered by poly (dA:dT) or HSV-1 requires IFNAR signaling. Knockdown of the constitutively expressed DNA sensor DDX41 attenuates poly(dA:dT)-triggered IFN-ß production and cGAS induction. By analyzing the dynamic expression of poly(dA:dT)-induced IFN-ß and cGAS transcripts, we have found that induction of IFN-ß is earlier than cGAS. Furthermore, we have provided evidence that induction of cGAS by IFN-I meditates the subsequent positive feedback regulation of DNA-triggered IFN-I production. Thus, our study not only provides a novel mechanism of modulating cGAS expression, but also adds another layer of regulation in DNA-triggered IFN-I production by induction of cGAS.

Functional Genomics Reveals Linkers Critical for Influenza Virus Polymerase.

UNLABELLED: Influenza virus mRNA synthesis by the RNA-dependent RNA polymerase involves binding and cleavage of capped cellular mRNA by the PB2 and PA subunits, respectively, and extension of viral mRNA by PB1. However, the mechanism for such a dynamic process is unclear. Using high-throughput mutagenesis and sequencing analysis, we have not only generated a comprehensive functional map for the microdomains of individual subunits but also have revealed the PA linker to be critical for polymerase activity. This PA linker binds to PB1 and also forms ionic interactions with the PA C-terminal channel. Nearly all mutants with five-amino-acid insertions in the linker were nonviable. Our model further suggests that the PA linker plays an important role in the conformational changes that occur between stages that favor capped mRNA binding and cleavage and those associated with viral mRNA synthesis. IMPORTANCE: The RNA-dependent RNA polymerase of influenza virus consists of the PB1, PB2, and PA subunits. By combining genome-wide mutagenesis analysis with the recently discovered crystal structure of the influenza polymerase heterotrimer, we generated a comprehensive functional map of the entire influenza polymerase complex. We identified the microdomains of individual subunits, including the catalytic domains, the interaction interfaces between subunits, and nine linkers interconnecting different domains. Interestingly, we found that mutants with five-amino-acid insertions in individual linkers were nonviable, suggesting the critical roles these linkers play in coordinating spatial relationships between the subunits. We further identified an extended PA linker that binds to PB1 and also forms ionic interactions with the PA C-terminal channel.

Genomic profiling of malignant phyllodes tumors reveals aberrations in FGFR1 and PI-3 kinase/RAS signaling pathways and provides insights into intratumoral heterogeneity.

Malignant phyllodes tumors of the breast are poorly understood rare neoplasms with potential for aggressive behavior. Few efficacious treatment options exist for progressed or metastatic disease. The molecular features of malignant phyllodes tumors are poorly defined, and a deeper understanding of the genetics of these tumors may shed light on pathogenesis and progression and potentially identify novel treatment approaches. We sequenced 510 cancer-related genes in 10 malignant phyllodes tumors, including 5 tumors with liposarcomatous differentiation and 1 with myxoid chondrosarcoma-like differentiation. Intratumoral heterogeneity was assessed by sequencing two separate areas in 7 tumors, including non-heterologous and heterologous components of tumors with heterologous differentiation. Activating hotspot mutations in FGFR1 were identified in 2 tumors. Additional recurrently mutated genes included TERT promoter (6/10), TP53 (4/10), PIK3CA (3/10), MED12 (3/10), SETD2 (2/10) and KMT2D (2/10). Together, genomic aberrations in FGFR/EGFR PI-3 kinase and RAS pathways were identified in 8 (80%) tumors and included mutually exclusive and potentially actionable activating FGFR1, PIK3CA and BRAF V600E mutations, inactivating TSC2 mutation, EGFR amplification and PTEN loss. Seven (70%) malignant phyllodes tumors harbored TERT aberrations (six promoter mutations, one amplification). For comparison, TERT promoter mutations were identified by Sanger sequencing in 33% borderline (n=12) and no (0%, n=8) benign phyllodes tumors (P=0.391 and P=0.013 vs malignant tumors, respectively). Genetic features specific to liposarcoma, including CDK4/MDM2 amplification, were not identified. Copy number analysis revealed intratumoral heterogeneity and evidence for divergent tumor evolution in malignant phyllodes tumors with and without heterologous differentiation. Tumors with liposarcomatous differentiation revealed more chromosomal aberrations in non-heterologous components compared with liposarcomatous components. EGFR amplification was heterogeneous and present only in the non-heterologous component of one tumor with liposarcomatous differentiation. The results identify novel pathways involved in the pathogenesis of malignant phyllodes tumors, which significantly increase our understanding of tumor biology and have potential clinical impact.

Systematic identification of type I and type II interferon-induced antiviral factors.

Type I and type II interferons (IFNs) are cytokines that establish the cellular antiviral state through the induction of IFN-stimulated genes (ISGs). We sought to understand the basis of the antiviral activity induced by type I and II IFNs in relation to the functions of their ISGs. Based on gene expression studies, we systematically identified antiviral ISGs by performing blinded, functional screens on 288 type I and type II ISGs. We assessed and validated the antiviral activity of these ISGs against an RNA virus, vesicular stomatitis virus (VSV), and a DNA virus, murine gammaherpes virus (MHV-68). Overall, we identified 34 ISGs that elicited an antiviral effect on the replication of either one or both viruses. Fourteen ISGs have uncharacterized antiviral functions. We further defined ISGs that affect critical life-cycle processes in expression of VSV protein and MHV-68 immediate-early genes. Two previously undescribed antiviral ISGs, TAP1 and BMP2, were further validated. TAP1-deficient fibroblasts were more susceptible to VSV infection but less so to MHV-68 infection. On the other hand, exogenous BMP2 inhibits MHV-68 lytic growth but did not affect VSV growth. These results delineate common and distinct sets of type I and type II IFN-induced genes as well as identify unique ISGs that have either broad or specific antiviral effects on these viruses.

Short-term impact of ambient temperature on the incidence of influenza in Wuhan, China.

Few studies have estimated the nonlinear association of ambient temperature with the risk of influenza. We therefore applied a time-series analysis to explore the short-term effect of ambient temperature on the incidence of influenza in Wuhan, China. Daily influenza cases were collected from Hubei Provincial Center for Disease Control and Prevention (Hubei CDC) from January 1, 2014, to December 31, 2017. The meteorological and daily pollutant data was obtained from the Hubei Meteorological Service Center and National Air Quality Monitoring Stations, respectively. We used a generalized additive model (GAM) coupled with the distributed lag nonlinear model (DLNM) to explore the exposure-lag-response relationship between the short-term risk of influenza and daily average ambient temperature. Analyses were also performed to assess the extreme cold and hot temperature effects. We observed that the ambient temperature was statistically significant, and the exposure-response curve is approximately S-shaped, with a peak observed at 23.57 ℃. The single-day lag curve showed that extreme hot and cold temperatures were both significantly associated with influenza. The extreme hot temperature has an acute effect on influenza, with the most significant effect observed at lag 0-1. The extreme cold temperature has a relatively smaller effect but lasts longer, with the effect exerted continuously during a lag of 2-4 days. Our study found significant nonlinear and delayed associations between ambient temperature and the incidence of influenza. Our finding contributes to the establishment of an early warning system for airborne infectious diseases.

Integrative Analysis of TP53INP2 in Head and Neck Squamous Cell Carcinoma.

TP53INP2 plays an important role in regulating gene transcription and starvation-induced autophagy, however, its function in head and neck squamous cell carcinoma (HNSCC) remains unclear. Therefore, we assessed the expression and prognostic value of TP53INP2. In addition, RNAseq, miRNAseq, copy number variation, and mutation profiles from The Cancer Genome Atlas (TCGA) dataset were applied to evaluate the distinctive genomic patterns related to TP53INP2 expression. We found that TP53INP2 expression was lower in HNSCC compared with normal controls. Patients with higher TP53INP2 expression had longer survival time. Knockdown of TP53INP2 promoted cell viability. Functional analysis exhibited that TP53INP2 was linked to DNA replication, DNA repair, cell cycle, and multiple metabolic pathways. Moreover, TP53INP2 might affect the expression of multiple genes via enhancing the transcriptional activity of nuclear hormone receptors. A competing endogenous RNA (ceRNA) network consisting of 33 lncRNAs, eight miRNAs, and 13 mRNAs was constructed based on the expression of TP53INP2. Taken together, our study highlights the potential value of TP53INP2 in predicting the survival of HNSCC and its important role in the genesis and development of HNSCC.

SPDEF suppresses head and neck squamous cell carcinoma progression by transcriptionally activating NR4A1.

SAM pointed domain containing E26 transformation-specific transcription factor (SPDEF) plays dual roles in the initiation and development of human malignancies. However, the biological role of SPDEF in head and neck squamous cell carcinoma (HNSCC) remains unclear. In this study, the expression level of SPDEF and its correlation with the clinical parameters of patients with HNSCC were determined using TCGA-HNSC, GSE65858, and our own clinical cohorts. CCK8, colony formation, cell cycle analysis, and a xenograft tumor growth model were used to determine the molecular functions of SPDEF in HNSCC. ChIP-qPCR, dual luciferase reporter assay, and rescue experiments were conducted to explore the potential molecular mechanism of SPDEF in HNSCC. Compared with normal epithelial tissues, SPDEF was significantly downregulated in HNSCC tissues. Patients with HNSCC with low SPDEF mRNA levels exhibited poor clinical outcomes. Restoring SPDEF inhibited HNSCC cell viability and colony formation and induced G0/G1 cell cycle arrest, while silencing SPDEF promoted cell proliferation in vitro. The xenograft tumor growth model showed that tumors with SPDEF overexpression had slower growth rates, smaller volumes, and lower weights. SPDEF could directly bind to the promoter region of NR4A1 and promoted its transcription, inducing the suppression of AKT, MAPK, and NF-κB signaling pathways. Moreover, silencing NR4A1 blocked the suppressive effect of SPDEF in HNSCC cells. Here, we demonstrate that SPDEF acts as a tumor suppressor by transcriptionally activating NR4A1 in HNSCC. Our findings provide novel insights into the molecular mechanism of SPDEF in tumorigenesis and a novel potential therapeutic target for HNSCC.

Density and proximity to hydraulic fracturing wells and birth outcomes in Northeastern British Columbia, Canada.

BACKGROUND: Hydraulic fracturing, a method used in Northeastern British Columbia (Canada) to extract natural gas, can release contaminants with potential deleterious health effects on fetal development. To date, the association between hydraulic fracturing activity and birth outcomes has not been evaluated in this region. OBJECTIVE: To evaluate the association between the hydraulic fracturing well density/proximity and birth outcomes (birthweight, head circumference, preterm birth and small for gestational age (SGA)). METHODS: We used birth records from the Fort St John hospital between December 30, 2006 and December 29, 2016 (n = 6333 births). To estimate gestational exposure, we used inverse distance weighting (IDW) to calculate the density/proximity of hydraulic fracturing wells to pregnant women's postal code centroid. For each birth, we calculated three IDWs using 2.5, 5, and 10 km buffer zones around women's postal code centroid. We used linear and logistic regressions to evaluate associations between quartiles of postal code well density/proximity and birth outcomes, controlling for relevant covariates. RESULTS: No associations were found between postal code well density/proximity and head circumference or SGA. A negative association was found between postal code well density/proximity and birthweight for infants born to women in the 2nd quartile of the 10 km buffer (ß [95% confidence interval (CI)]: -47.28 g [-84.30; -10.25]), and in the 2nd (ß [95% CI]: -40.87 g [-78.01; -3.73]) and 3rd (ß [95% CI]: -42.01 g [-79.15; -4.87]) quartiles of the 5 km buffer. Increased odds of preterm birth were observed among women in the 2nd quartile of the 2.5 km buffer (odds ratio (OR) [95% CI]: 1.60 [1.30; 2.43]). CONCLUSIONS: This is the first epidemiological study in Northeastern British Columbia evaluating associations between hydraulic fracturing and health outcomes. Our results show inconsistent patterns of association between hydraulic fracturing, preterm birth and reduced birthweight, and effect estimates did not match expected dose-response relationships.