Large-scale alternative polyadenylation-wide association studies to identify putative cancer susceptibility genes.

Alternative polyadenylation (APA) modulates mRNA processing in the 3' untranslated regions (3' UTR), affecting mRNA stability and translation efficiency. Research into genetically regulated APA has the potential to provide insights into cancer risk. Herein, we conducted large alternative polyadenylation-wide association studies (APA-WAS) to investigate associations of APA levels with cancer risk. Genetic models were built to predict APA levels in multiple tissues using genotype and RNA-sequencing data from 1,337 samples from the Genotype-Tissue Expression Project. Associations of genetically predicted APA levels with cancer risk were assessed by applying the prediction models to data from large genome-wide association studies of six common cancers among European-ancestry populations, including breast, ovary, prostate, colorectum, lung, and pancreas. A total of 58 risk genes (corresponding to 76 APA sites) were associated with at least one type of cancer, including 25 genes previously not linked to cancer susceptibility. Of the identified risk APAs, 97.4% and 26.3% were supported by 3' UTR APA quantitative trait loci and co-localization analyses, respectively. Luciferase reporter assays for four selected putative regulatory 3' UTR variants demonstrated that the risk alleles of 3' UTR variants, rs324015 (STAT6), rs2280503 (DIP2B), rs1128450 (FBXO38), and rs145220637 (LDHA), significantly increased the post-transcriptional activities of their target genes compared to reference alleles. Furthermore, knockdown of the target genes confirmed their ability to promote proliferation and migration. Overall, this study provides insights into the role of APA in the genetic susceptibility to common cancers.

Higher disease burden and lower utilization in mongolian with breast cancer: a 9-year retrospective cohort study of 18.19 million adults in China.

BACKGROUND: Whether health inequalities of disease burden and medical utilization exist by ethnicity in Asian breast cancer (BC) patients remains unclear. We aim to measure ethnic disparities in disease burden and utilization among Mongolian and Han female breast cancer patients in China. MATERIALS AND METHODS: Based on data extracted from Inner Mongolia Regional Health Information Platform, a retrospective cohort study was established during 2012-2021. Disease burden including incidence, 5-year prevalence, mortality, survival rate, and medical cost were analyzed and compared between Han and Mongolian patients. RESULTS: A total of 34,878 female patients (mean [SD] age, 52.34 [10.93] years) were included among 18.19 million Chinese, and 4,315 [12.03%] participants were Mongolian. Age-standardized rates of incidence are 32.68 (95% CI: 20.39-44.98) per 100,000. Higher age-specific incidence and 5-year prevalence were observed in Mongolian than in Han. The cost of breast cancer annually per capita was significantly lower for Mongolian than Han in FBC ($1,948.43 [590.11-4 776.42] vs. $2,227.35 [686.65-5,929.59], P<0.001). Mongolian females showed higher all-cause mortality (30.92, [95% CI: 28.15-33.89] vs. 27.78, [95% CI: 26.77-28.83] per 1,000, P=0.036) and breast cancer-specific mortality (18.78, [95% CI: 16.64-21.13] vs. 15.22, [95% CI: 14.47-16.00] per 1,000, P=0.002) than Han females. After adjusting covariates, Mongolian were associated with increased all-cause mortality (HR, 1.21, [95% CI, 1.09-1.34]; P<0.001) and breast cancer-specific mortality (HR, 1.31, [95% CI, 1.14-1.49]; P<0.001). CONCLUSION: The findings of this cohort study highlight a higher level of disease burden with unmet medical demand in Mongolian patients, suggesting that more practical efforts should be made for the minority. Further research is needed to explore the concrete mechanisms of the disparities as well as eliminate health disproportion.

The residues and health risk assessment of polychlorinated biphenyls (PCBs) in Pheretima (an earthworm-derived traditional medicine) from southeastern China.

Minimal research exists on polychlorinated biphenyl (PCB) exposure from traditional Chinese medicines (TCMs), despite their significant contributions to domestic and international health protection. This study is the first to investigate the levels, profiles, and health risks of PCB residue in Pheretima, a typical TCM produced from earthworm. Seventy-seven Pheretima samples from different regions of China were analyzed for 45 PCB congeners. PCBs were found in all samples exhibiting species-dependent discrepancies. ∑45PCBs was ranging from 0.532 to 25.2 µg/kg (mean 4.46 µg/kg), with CB-11 being the most abundant congener contributing 71.8% ± 10.8% to ∑45PCBs, followed by CB-47, which were all non-Aroclor congeners called unintentionally produced PCBs (UP-PCBs). The average estimated daily intake of ∑45PCBs, ∑7ID-PCBs (indicative polychlorinated biphenyls), and CB-11 were 0.71, 0.04, and 0.51 ng/kg bw/d, respectively. The ∑HQ of PCBs in Pheretima samples was 2.97 × 10-4-2.46 × 10-2 (mean 2.77 × 10-3, 95th 4.21 × 10-3), while the ∑RQ ranged from 1.19 × 10-8 to 2.88 × 10-6 (mean 4.87 × 10-7, 95th 2.31 × 10-6). These findings indicate that Pheretima ingestion does not pose significant non-carcinogenic risks. However, certain individual samples exhibit an acceptable level of potential risks, particularly when considering that PCBs are recognized as endocrine disruptors and classified as probable carcinogens. These results contribute to the safety evaluation of traditional medicines and suggest the potential use of Pheretima as a bioindicator for PCB pollution. It is advisable to monitor UP-PCBs as indicator congeners and gather additional toxicological data.

Large-scale alternative polyadenylation (APA)-wide association studies to identify putative susceptibility genes in human common cancers.

Alternative polyadenylation (APA) modulates mRNA processing in the 3' untranslated regions (3'UTR), which affect mRNA stability and translation efficiency. Here, we build genetic models to predict APA levels in multiple tissues using sequencing data of 1,337 samples from the Genotype-Tissue Expression, and apply these models to assess associations between genetically predicted APA levels and cancer risk with data from large genome-wide association studies of six common cancers, including breast, ovary, prostate, colorectum, lung, and pancreas among European-ancestry populations. At a Bonferroni-corrected P □<□0.05, we identify 58 risk genes, including seven in newly identified loci. Using luciferase reporter assays, we demonstrate that risk alleles of 3'UTR variants, rs324015 ( STAT6 ), rs2280503 ( DIP2B ), rs1128450 ( FBXO38 ) and rs145220637 ( LDAH ), could significantly increase post-transcriptional activities of their target genes compared to reference alleles. Further gene knockdown experiments confirm their oncogenic roles. Our study provides additional insight into the genetic susceptibility of these common cancers.

Targeted glycan degradation potentiates cellular immunotherapy for solid tumors.

Immune cell-based cancer therapies, such as chimeric antigen receptor T (CAR-T)-cell immunotherapy, have demonstrated impressive potency against hematological tumors. However, the efficacy of CAR-T cells against solid tumors remains limited. Herein, we designed tumor-targeting molecule-sialidase conjugates that potently and selectively stripped different sialoglycans from a variety of cancer cells. Desialylation enhanced induced pluripotent stem cell-derived chimeric antigen receptor-macrophage (CAR-iMac) infiltration and activation. Furthermore, the combination of cancer cell desialylation and CAR-iMac adoptive cellular therapy exerted a dramatic therapeutic effect on solid tumors and significantly prolonged the survival of tumor-bearing mice; these effects were mainly dependent on blockade of the checkpoint composed of sialic acid-binding immunoglobulin-like lectin (Siglec)-5 and Siglec-10 on the macrophages, and knockout of the glycoimmune checkpoint receptors could construct a CAR-iMac cell with stronger anticancer activity. This strategy that reverts the immune escape state ("cold tumor") to a sensitive recognition state ("hot tumor") has great significance for enhancing the effect of cellular immunotherapy on solid tumors. Therefore, desialylation combined with CAR-iMac cellular immunotherapy is a promising approach to enhance treatment with cellular immunotherapy and expand the valid indications among solid tumors, which provides inspiration for the development of cellular immunotherapies with glycoimmune checkpoint inhibition for the treatment of human cancer.

Self-Reported Primary Cooking Fuels Use and Risk of Chronic Digestive Diseases: A Prospective Cohort Study of 0.5 Million Chinese Adults.

BACKGROUND: Household air pollution (HAP) from inefficient combustion of solid fuels is a major health concern worldwide. However, prospective evidence on the health impacts of solid cooking fuels and risks of chronic digestive diseases remains scarce. OBJECTIVES: We explored the effects of self-reported primary cooking fuels on the incidence of chronic digestive diseases. METHODS: The China Kadoorie Biobank recruited 512,726 participants 30-79 years of age from 10 regions across China. Information on primary cooking fuels at the current and previous two residences was collected via self-reporting at baseline. Incidence of chronic digestive diseases was identified through electronic linkage and active follow-up. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of self-reported long-term cooking fuel patterns and weighted duration of self-reported solid cooking fuel use with chronic digestive diseases incidence. Linear trend was tested by assigning the medians of weighted duration in each group and then taking those as continuous variables in the models. Subgroup analyses were undertaken across the baseline characteristics of participants. RESULTS: During 9.1±1.6 y of follow-up, 16,810 new cases of chronic digestive diseases were documented, among which 6,460 were diagnosed as cancers. Compared with long-term cleaner fuel use, self-reported long-term use of solid cooking fuels (i.e., coal, wood) was associated with elevated risks of chronic digestive diseases (HR=1.08; 95% CI: 1.02, 1.13), including nonalcoholic fatty liver disease (NAFLD) (HR=1.43; 95% CI: 1.10, 1.87), hepatic fibrosis/cirrhosis (HR=1.35; 95% CI: 1.05, 1.73), cholecystitis (HR=1.19; 95% CI: 1.07, 1.32), and peptic ulcers (HR=1.15; 95% CI: 1.00, 1.33). The longer the weighted duration of self-reported solid cooking fuel use, the higher the risks of chronic digestive diseases, hepatic fibrosis/cirrhosis, peptic ulcers, and esophageal cancer (pTrend<0.05). The aforementioned associations were modified by sex and body mass index (BMI). Positive associations of always solid cooking fuel use with chronic digestive disease, hepatic fibrosis/cirrhosis, NAFLD, and cholecystitis were observed among women but not men. The longer the weighted duration of self-reported solid cooking fuel use, the higher the risk of NAFLD among those with a BMI ≥28 kg/m2. DISCUSSION: Long-term self-reported solid cooking fuels use was associated with higher risks of chronic digestive diseases. The positive association of HAP from solid cooking fuels with chronic digestive diseases indicates for an imminent promotion of cleaner fuels as public health interventions. https://doi.org/10.1289/EHP10486.

Integrated database-based Screening Cohort for Asian Nomadic descendants in China (Scan-China): Insights on prospective ethnicity-focused cancer screening.

Established in 2017, the Screening Cohort for Asian Nomadic descendants in China (Scan-China) has benefited over 180,000 members of a multi-ethnic population, particularly individuals of Mongolian descent compared with the general population (Han ethnicity), in the Inner Mongolia Autonomous Region, China. This cohort study aims to evaluate the effectiveness of cancer screening and serve as a real-world data platform for cancer studies. The 6 most prevalent cancers in China are considered-namely, breast, lung, colorectal, gastric, liver and esophageal cancer. After baseline cancer risk assessments and screening tests, both active and passive follow-up (based on the healthcare insurance database, cancer registry, the front page of hospital medical records, and death certificates) will be conducted to trace participants' onset and progression of cancers and other prevalent chronic diseases. Scan-China has preliminarily found a disproportionately lower screening participation rate and higher incidence/mortality rates of esophageal and breast cancer among the Mongolian population than among their Han counterparts. Further research will explore the cancer burden, natural history, treatment patterns, and risk factors of the target cancers.

Predictive value of admission CO2 combining power combined with serum sodium for the prognosis in acute Stanford type A aortic dissection patients.

Acute Stanford type A aortic dissection (ATAAD) with sudden onset and high mortality requiries a standard Bentall operation and a accurate prognosis in common, together with alteration of CO2 combining power (CO2CP) and serum sodium rase concern, hence, we evaluated the prognostic value of CO2CP combined with serum sodium in ATAAD patients. This retrospective study included 183 patients who underwent Bentall operation for ATAAD from 2015 to 2021 in the Fourth Hospital of Hebei Medical University, subsequently followed grouping by the levels of CO2CP and serum sodium. The study endpoint was 30-day all-cause mortality, and the prognostic value of CO2CP combined with serum sodium levels in ATAAD patients were evaluated with multivariate logistic regression method. The postoperative incidence of in-hospital death and adverse events in patients with ATAAD were 18% and 25.7%, respectively. Combination of CO2CP and serum sodium for predicting ATAAD death and adverse events presented a higher predictive value than each single indicator with ROC curve analysis (the AUC of CO2CP combined with serum sodium was 0.786, 95% CI 0.706-0.869, P < 0.001), along with CO2CP < 22.5 mmol/L + serum sodium > 138.5 mmol/L group had the worst prognostic. Multivariate regression analyse showed that CO2CP < 22.5 mmol/L combined with serum sodium > 138.5 mmol/L preferably predicted the prognosis of ATAAD (OR =6.073, 95% CI 2.557-14.425, P < 0.001). Consistently, the cumulative 30-day survival after surgery in ATAAD patients with the low CO2CP and high serum sodium simultaneously was the worst (log-rank P < 0.05). The combination of CO2CP and serum sodium increases the predictive value of prognosis, which is conducive to risk stratification of patients with ATAAD.

Association of Ethnicity, Sex, and Age With Cancer Diagnoses and Health Care Utilization Among Children in Inner Mongolia, China.

Importance: China is experiencing a sustained increase in childhood cancer. However, whether differences exist in disease burden by ethnicity remains unclear. Objective: To compare differences in cancer diagnoses and health care utilization in Inner Mongolia among children subgrouped by ethnicity (Han vs Mongolian), sex, and age. Design, Setting, and Participants: This retrospective cohort study in Inner Mongolia, China, used data on children aged 0 to 14 years with cancer from the Inner Mongolia Regional Health Information Platform, which comprises the National Basic Medical Insurance database and the Inner Mongolia cause-of-death reporting system, from January 1, 2013, to December 31, 2019. Ethnicities analyzed included Han and Mongolian; patients of other ethnicities were not included in the analysis because of the small sample size. Cancer was broadly defined as a primary malignant tumor or hematologic cancer; benign central nervous system tumors were also included. A 2-year washout period was used to exclude prevalent cases. After diagnosis, the patients were followed up until the date of death or the end of the insured status, whichever came first. Exposures: Ethnicity (Han vs Mongolian), sex (male vs female), and age (0-4, 5-9, and 10-14 years). Main Outcomes and Measures: Crude incidence, 5-year prevalence, and survival rates at 1 year and 3 years after diagnosis; health care utilization, represented by medical costs during the first year and first 3 years after diagnosis; and hospital attendance with level (tertiary vs secondary and lower-level hospitals) and location of each unique visit. Results: From 2013 to 2019, 1 106 684 (2013), 1 330 242 (2014), 1 763 746 (2015), 2 400 343 (2016), 2 245 963 (2017), 2 901 088 (2018), and 2 996 580 (2019) children aged 0 to 14 years were registered in the NBMI database. Among the 2 996 580 children enrolled in 2019, the mean (SD) age was 6.8 (4.3) years, of whom 1 572 096 (52.5%) were male, 2 572 091 (85.8%) were Han, and 369 400 (12.3%) were Mongolian. A total of 1910 patients with cancer were identified (1048 were male [54.9%]; 1559 were Han [81.6%], and 300 were Mongolian [15.7%]). There were 764 hematologic cancers (40.0%) and 1146 solid tumors (60.0%). The overall crude incidence of cancer from 2015 to 2019 was 129.85 per million children (95% CI, 123.63-136.06), with a higher incidence among Mongolian than among Han children (155.12 [95% CI, 136.81-173.43] vs 134.39 [95% CI, 127.46-141.32]). The 5-year prevalence was 428.97 per million (95% CI, 405.52-452.42) in 2020, with a higher prevalence among Mongolian than among Han children (568.49 [95% CI, 91.62-645.36] vs 404.34 [95% CI, 379.77-428.91]). The combined 1-year (2015-2019) and 3-year (2015-2017) survival rates were 72.5% (95% CI, 67.5%-77.5%) and 66.8% (95% CI, 61.6%-71.9%), respectively. The 1-year (median [IQR], $1991 [$912-$10 181] vs $3991 [$1171-$15 425]) and 3-year (median [IQR], $2704 [$954-$13 909] vs $5375 [$1283-$22 466]) postdiagnosis costs were lower among Mongolian than among Han children. A higher proportion of Mongolian patients attended low-level hospitals (45.9% vs 17.4%). Conclusions and Relevance: In this cohort study, Mongolian children had a higher incidence and prevalence of cancer but a lower demand for medical care, suggesting that further investigations are needed to identify mechanisms underlying ethnic disparities and ensure that care is equitable.

Circular RNA circDVL1 inhibits clear cell renal cell carcinoma progression through the miR-412-3p/PCDH7 axis.

Clear cell renal cell carcinoma (ccRCC) is a primary kidney cancer with high aggressive phenotype and extremely poor prognosis. Accumulating evidence suggests that circular RNAs (circRNAs) play pivotal roles in the occurrence and development of various human cancers. However, the expression, clinical significance and regulatory role of circRNAs in ccRCC remain largely unclear. Here we report that circDVL1 to be reduced in the serums and tissues from ccRCC patients, and to negatively correlate with ccRCC malignant features. Overexpression of circDVL1 inhibits proliferation, induces G1/S arrest, triggers apoptosis, and reduces migration and invasion in different ccRCC cells in vitro. Correspondingly, circDVL1 overexpression suppresses ccRCC tumorigenicity in a mouse xenograft model. Mechanistically, circDVL1 serves as a sponge for oncogenic miR-412-3p, thereby preventing miR-412-3p-mediated repression of its target protocadherin 7 (PCDH7) in ccRCC cells. Collectively, our results demonstrate that circDVL1 exerts tumor-suppressive function during ccRCC progression through circDVL1/miR-412-3p/PCDH7 axis, and suggest that circDVL1 could be a novel diagnostic and prognositc marker and therapeutic target for ccRCC.

Andrographolide, a diterpene lactone from the Traditional Chinese Medicine Andrographis paniculate, induces senescence in human lung adenocarcinoma via p53/p21 and Skp2/p27.

BACKGROUND: Senescence leads to permanent cell-cycle arrest and is a potential target for cancer therapy. Andrographolide (AD) is a diterpene lactone isolated from Traditional Chinese Medicine (TCM) Andrographis paniculate, which has been used as an anti-inflammatory drug in clinical practice with the potential to target senescence in recalcitrant lung cancer. PURPOSE: To determine whether AD can induce senescence in human lung adenocarcinoma in vitro and in vivo and to elucidate the underlying mechanisms. METHODS: SA-ß-Gal staining was used to detect the expression of senescence-associated ß-galactosidase (SA-ß-Gal) in human lung adenocarcinoma cells A549 and NCI-H1795. DNA damage was examined by the detection of γH2AX foci. Cell cycle was analyzed by flow cytometry. Cancer cell proliferation was determined by ATPlite assay and clonogenic survival assay in vitro. Tumor growth was determined in a mouse model of A549. The expression level of proteins and mRNA was estimated by Western blotting and Quantitative RT-PCR, respectively. Small interfering RNA (siRNA) was used to knock down p21, p27 and p53 to explore the potential mechanism of AD-induced senescence in human lung adenocarcinoma cells. RESULTS: AD-induced A549 and NCI-H1795 cell senescence determined by increased cell size, flattened morphology, DNA damage, cell cycle arrest as well as the increased expression of ß-galactosidase. AD inhibited cell proliferation in lung cells in vitro and lung cells xenograft growth in nude mice. p21 and p27, the major cell cycle regulators and mediators of senescence, were upregulated at the protein level in AD-treated A549 lung adenocarcinoma in vitro and in vivo. Further studies demonstrated that AD induced cell senescence via p53/p21 and Skp2/p27. CONCLUSION: In the present study, we found that the primary anti-inflammatory drug AD could have a potential antitumor effect in lung cancer. We demonstrated that AD induced lung adenocarcinoma senescence in vitro and in vivo via p53/p21 and Skp2/p27 for the first time. AD is therefore a promising senescence-inducing therapeutic for recalcitrant human lung adenocarcinoma.

Six Air Pollutants Associated With Increased Risk of Thyroid Nodules: A Study of 4.9 Million Chinese Adults.

Background: Thyroid nodules has become a significant public health issue worldwide with a rapidly increasing prevalence. However, its association with outdoor air pollution remains poorly understood. We aim to investigate the relationship between six outdoor air pollutants (PM2.5, PM10, NO2, SO2, CO, and O3) and the risk of thyroid nodules. Methods: We utilized a database including 4,920,536 participants who attended the annual physical examinations in the Meinian HealthCare Screening Center in 157 Chinese cities in 2017. City-specific concentrations of six pollutants (PM2.5, PM10, NO2, SO2, CO, and O3) from 2015 to 2017 were estimated based on the China's National Urban Air Quality Real Time Publishing Platform. Thyroid nodule was measured with ultrasound. Multivariable Logistic regression was used to examine the associations between air pollutants and thyroid nodules with adjustment for age, sex, education, smoking, body mass index, fasting blood glucose, triglyceride, low density lipoprotein cholesterol, high density lipoprotein cholesterol, urine iodine, gross domestic product, and thyroid stimulating hormone. We conducted stratified analyses to investigate potential effect modification by sex, age, and urine iodine groups. Results: Approximately 38% of the participants (1,869,742) were diagnosed with thyroid nodules. Each of the six air pollutants was significantly and linearly associated with the risk for thyroid nodules. The adjusted odds ratios [95% CI] for every increase of 10 µg/m3 for PM2.5, PM10, NO2, SO2, and O3 were 1.062 [1.061, 1.064], 1.04 [1.03, 1.04], 1.10 [1.09, 1.10], 1.11 [1.11, 1.12], and 1.151 [1.149, 1.154], respectively; The odds ratio for each increase of 1 mg/m3 for CO was 1.50 [1.49 to 1.52]. Furthermore, these associations were significantly higher in the participants who were men, younger, or having lower urine iodine level (p <0.001). Conclusion: The six air pollutants may contribute to the high prevalence of thyroid nodules in China.

The Value of Circulating Circular RNA in Cancer Diagnosis, Monitoring, Prognosis, and Guiding Treatment.

Liquid biopsy includes non-invasive analysis of circulating tumor-derived substances. It is a novel, innovative cancer screening tool that overcomes the limitations of current invasive tissue examinations in precision oncology. Circular RNA (circRNA) is a recent, novel, and attractive liquid biomarker showing stability, abundance, and high specificity in various diseases, especially in human cancers. This review focused on the emerging potential of human circRNA in body fluids as the liquid biopsy biomarkers for cancers and the methods used to detect the circRNA expression and summarized the construction of circRNA biomarkers in body fluids for treating human cancers and their limitations before they become part of routine clinical medicine. Furthermore, the future opportunities and challenges of translating circRNAs in liquid biopsy into clinical practices were explored.

Fangchinoline Inhibits Human Esophageal Cancer by Transactivating ATF4 to Trigger Both Noxa-Dependent Intrinsic and DR5-Dependent Extrinsic Apoptosis.

Esophageal squamous cell carcinoma (ESCC) is a recalcitrant cancer. The Chinese herbal monomer fangchinoline (FCL) has been reported to have anti-tumor activity in several human cancer cell types. However, the therapeutic efficacy and underlying mechanism on ESCC remain to be elucidated. In the present study, for the first time, we demonstrated that FCL significantly suppressed the growth of ESCC both in vitro and in vivo. Mechanistic studies revealed that FCL-induced G1 phase cell-cycle arrest in ESCC which is dependent on p21 and p27. Moreover, we found that FCL coordinatively triggered Noxa-dependent intrinsic apoptosis and DR5-dependent extrinsic apoptosis by transactivating ATF4, which is a novel mechanism. Our findings elucidated the tumor-suppressive efficacy and mechanisms of FCL and demonstrated FCL is a potential anti-ESCC agent.

Andrographolide Induces Noxa-Dependent Apoptosis by Transactivating ATF4 in Human Lung Adenocarcinoma Cells.

Lung adenocarcinoma is the most common pathological type of lung cancer with poor patient outcomes; therefore, developing novel therapeutic agents is critically needed. Andrographolide (AD), a major active component derived from the traditional Chinese medicine (TCM) Andrographis paniculate, is a potential antitumor drug, but the role of AD in lung adenocarcinoma remains poorly understood. In the present study, we demonstrated that AD inhibited the proliferation of broad-spectrum lung cancer cell lines in a dose-dependent manner. Meanwhile, we found that a high dose of AD induced Noxa-dependent apoptosis in human lung adenocarcinoma cells (A549 and H1299). Further studies revealed that Noxa was transcriptionally activated by activating transcription factor 4 (ATF4) in AD-induced apoptosis. Knockdown of ATF4 by small interfering RNA (siRNA) significantly diminished the transactivation of Noxa as well as the apoptotic population induced by AD. These results of the present study indicated that AD induced apoptosis of human lung adenocarcinoma cells by activating the ATF4/Noxa axis and supporting the development of AD as a promising candidate for the new era of chemotherapy.

Quality evaluation of HPV vaccine-related online messages in China: a cross-sectional study.

Since 2019, three types of HPV vaccine have been approved for use in mainland China. High quality messages are crucial for vaccine acceptance, but little is known about the online information quality concerning HPV vaccine in China. "HPV vaccine" and "cervical cancer vaccine" in the form of Chinese were used as keywords through search engines from personal computer (PC), portable mobile device (PMD), and WeChat Public Accounts in 2019. Readability, information content, as well as DISCERN scores were evaluated for each message included. Characteristics associated with quality indicators of the messages were also analyzed. A total of 294 messages from PC engines (104, 35%), PMD engines (128, 43%) and WeChat (62, 21%) were assessed. Most (269, 91%) messages required at least undergraduate readability level. The most frequently reported theme was HPV vaccine and its function (273, 93%), while the least was information regarding quality, safety and side effects (129, 44%). The frequency of messages with at least one error was 132 (45%). The median of sum DISCERN scores was 42 (IQR = 14), and only one (< 1%) message showed good DISCERN quality. Messages retrieved from PC engines and those with pictures were of better overall quality. The overall quality of HPV vaccine-related online messages in Chinese websites was not optimal. Government and health professionals should promote information quality construction to improve the status of HPV vaccination messages online.

Circular RNAs in renal cell carcinoma: implications for tumorigenesis, diagnosis, and therapy.

Renal cell carcinoma (RCC) is the most common malignant kidney tumor and has a high incidence rate. Circular RNAs (circRNAs) are noncoding RNAs with widespread distribution and diverse cellular functions. They are highly stable and have organ- and tissue-specific expression patterns. CircRNAs have essential functions as microRNA sponges, RNA-binding protein- and transcriptional regulators, and protein translation templates. Recent reports have shown that circRNAs are abnormally expressed in RCC and act as important regulators of RCC carcinogenesis and progression. Moreover, circRNAs have emerged as potential biomarkers for RCC diagnosis and prognosis and targets for developing new treatments. However, further studies are needed to better understand the functions of circRNAs in RCC. In this review, we summarize and discuss the recent research progress on RCC-associated circRNAs, with a focus on their potential for RCC diagnosis and targeted therapy.

The CRL3BTBD9 E3 ubiquitin ligase complex targets TNFAIP1 for degradation to suppress cancer cell migration.

Tumor necrosis factor alpha-induced protein 1 (TNFAIP1) modulates a plethora of important biological processes, including tumorigenesis and cancer cell migration. However, the regulatory mechanism of TNFAIP1 degradation remains largely elusive. In the present study, with a label-free quantitative proteomic approach, TNFAIP1 was identified as a novel ubiquitin target of the Cullin-RING E3 ubiquitin ligase (CRL) complex. More importantly, Cul3-ROC1 (CRL3), a subfamily of CRLs, was identified to specifically interact with TNFAIP1 and promote its polyubiquitination and degradation. Mechanistically, BTBD9, a specific adaptor component of CRL3 complex, was further defined to bind and promote the ubiquitination and degradation of TNFAIP1 in cells. As such, downregulation of BTBD9 promoted lung cancer cell migration by upregulating the expression of TNFAIP1, whereas TNFAIP1 deletion abrogated this effect. Finally, bioinformatics and clinical sample analyses revealed that BTBD9 was downregulated while TNFAIP1 was overexpressed in human lung cancer, which was associated with poor overall survival of patients. Taken together, these findings reveal a previously unrecognized mechanism by which the CRL3BTBD9 ubiquitin ligase controls TNFAIP1 degradation to regulate cancer cell migration.

Validation of NEDD8-conjugating enzyme UBC12 as a new therapeutic target in lung cancer.

BACKGROUND: The neddylation pathway is overactivated in human cancers. Inhibition of neddylation pathway has emerged as an attractive anticancer strategy. The mechanisms underlying neddylation overactivation in cancer remain elusive. MLN4924/Pevonedistat, a first-in-class NEDD8-activating enzyme (NAE, E1) inhibitor, exerts significant anti-tumor effects, but its mutagenic resistance remains unresolved. METHODS: The expression of NEDD8-conjugating enzyme UBC12/UBE2M (E2) and NEDD8 were estimated by bioinformatics analysis and western blot in human lung cancer cell lines. The malignant phenotypes of lung cancer cells were evaluated both in vitro and in vivo upon UBC12 knockdown. Cell-cycle arrest was evaluated by quantitative proteomic analysis and propidium iodide stain and fluorescence - activated cell sorting (FACS). The growth of MLN4924 - resistant H1299 cells was also evaluated upon UBC12 knockdown. FINDINGS: The mRNA level of UBC12 in lung cancer tissues was much higher than that in normal lung tissues, increased with disease deterioration, and positively correlated with NEDD8 expression. Moreover, the overexpression of UBC12 significantly enhanced protein neddylation modification whereas the downregulation of UBC12 reduced neddylation modification of target proteins. Functionally, neddylation inactivation by UBC12 knockdown suppressed the malignant phenotypes of lung cancer cells both in vitro and in vivo. The quantitative proteomic analysis and cell cycle profiling showed that UBC12 knockdown disturbed cell cycle progression by triggering G2 phase cell-cycle arrest. Further mechanistical studies revealed that UBC12 knockdown inhibited Cullin neddylation, led to the inactivation of CRL E3 ligases and induced the accumulation of tumor-suppressive CRL substrates (p21, p27 and Wee1) to induce cell cycle arrest and suppress the malignant phenotypes of lung cancer cells. Finally, UBC12 knockdown effectively inhibited the growth of MLN4924-resistant lung cancer cells. INTERPRETATION: These findings highlight a crucial role of UBC12 in fine-tuned regulation of neddylation activation status and validate UBC12 as an attractive alternative anticancer target against neddylation pathway. FUND: Chinese Minister of Science and Technology grant (2016YFA0501800), National Natural Science Foundation of China (Grant Nos. 81401893, 81625018, 81820108022, 81772470, 81572340 and 81602072), Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-10-E00056), Program of Shanghai Academic/Technology Research Leader (18XD1403800), National Thirteenth Five-Year Science and Technology Major Special Project for New Drug and Development (2017ZX09304001). The funders had no role in study design, data collection, data analysis, interpretation, writing of the report.

Peroral Endoscopic Myotomy with the Stag Beetle Knife (SB Knife): Feasibility and Follow-Up.

BACKGROUND Recently, a stag beetle (SB) knife was introduced to reduce the difficulty of peroral endoscopic myotomy (POEM). The objective of this study was to evaluate the efficacy and safety of the SB knife. MATERIAL AND METHODS A total of 71 patients undergoing POEM with the SB knife for esophageal achalasia were included. We used esophagography, manometry, esophagogastroduodenoscopy (EGD), and Eckardt score to assess the utility and safety. RESULTS All cases were completed for POEM. The incidence of adverse events during the operation were 2.8%; however, all cases were treated conservatively. There was a vast improvement in clinical symptoms and endoscopic findings. The average Eckardt score was 6.9 before and 0.6 at 1 year after POEM (p<0.05). The average lower esophageal sphincter (LES) pressure before and 6 months after POEM were 44.34±14.83 mmHg and 19.14±6.74 mmHg (p<0.05), respectively. The average LES relaxation pressure before and 6 months after POEM was 12.11±5.02 mmHg and 3.22±2.29 mmHg (p<0.05), respectively. CONCLUSIONS POEM with the SB Knife is technically efficient and safe in treating achalasia and is associated with favorable short-term outcomes.