Construction and validation of serum Metabolic Risk Score for early warning of malignancy in esophagus.

Using noninvasive biomarkers to identify high-risk individuals prior to endoscopic examination is crucial for optimization of screening strategies for esophageal squamous cell carcinoma (ESCC). We conducted a nested case-control study based on two community-based screening cohorts to evaluate the warning value of serum metabolites for esophageal malignancy. The serum samples were collected at enrollment when the cases had not been diagnosed. We identified 74 differential metabolites and two prominent perturbed metabolic pathways, and constructed Metabolic Risk Score (MRS) based on 22 selected metabolic predictors. The MRS generated an area under the receiver operating characteristics curve (AUC) of 0.815. The model performed well for the within-1-year interval (AUC: 0.868) and 1-to-5-year interval (AUC: 0.845) from blood draw to diagnosis, but showed limited ability in predicting long-term cases (>5 years). In summary, the MRS could serve as a potential early warning and risk stratification tool for establishing a precision strategy of ESCC screening.

Effectiveness of Endoscopic Screening on Esophageal Cancer Incidence and Mortality: A 9-Year Report of the Endoscopic Screening for Esophageal Cancer in China (ESECC) Randomized Trial.

PURPOSE: To evaluate the effectiveness of endoscopic screening against incidence of and mortality from esophageal squamous cell carcinoma (ESCC). METHODS: From January 2012 to September 2016, we conducted a community-based cluster randomized controlled trial involving permanent residents age 45-69 years in a high-risk region for ESCC in northern China. A total of 668 targeted villages were randomly assigned in a 1:1 ratio to the screening group (offered Lugol's chromoendoscopy) or control group (no screening). Intention-to-treat and per-protocol analyses were performed to compare esophageal cancer (EC) incidence and mortality between the two groups. The per-protocol analysis adjusted for nonadherence to the screening procedure. RESULTS: A total of 33,847 participants were included in the analysis: 17,104 in the screening group, 15,165 (88.7%) of whom underwent screening, and 16,743 in the control group. During a maximum follow-up of 9 years, EC incidence in the screening and control groups were 60.9 and 72.5 per 100,000 person-years, respectively; mortality in the screening and control groups were 29.7 and 32.4 per 100,000 person-years, respectively. Compared with the control group, the incidence and mortality of the screening group reduced by 19% (adjusted hazard ratio [aHR], 0.81 [95% CI, 0.60 to 1.09]) and 18% (aHR, 0.82 [95% CI, 0.53 to 1.26]), respectively, in the intention-to-treat analysis; and by 22% (aHR, 0.78 [95% CI, 0.56 to 1.10]) and 21% (aHR, 0.79 [95% CI, 0.49 to 1.30]), respectively, in the per-protocol analysis. CONCLUSION: With a 9-year follow-up, our trial suggests that chromoendoscopic screening induces modest reductions in EC incidence and mortality. A more efficient strategy for EC screening and subsequent patient management should be established to guarantee the effectiveness of endoscopic screening.

Clinical utility of keratin 14 expression measurement in reflecting the tumor properties and prognosis in patients with renal cell carcinoma: a study with long-term follow-up.

PURPOSE: Keratin 14 (KRT14) is hypothesized to be involved in the pathogenesis of renal cell carcinoma (RCC) based on its tumorigenic role in various cancers and its relationship with the prognosis of other urinary system malignancies. This study aimed to evaluate the correlation of KRT14 with tumor properties and prognosis in RCC patients. METHODS: Data from 180 RCC patients who received tumor resection were retrospectively reviewed. The KRT14 was assessed by immunohistochemistry (IHC) staining in tumor tissues and non-tumor tissues. RESULTS: KRT14 was insufficiently expressed in both tumor and non-tumor tissues, with median (interquartile range) IHC score of 2.0 (0.0-3.4) and 1.0 (0.0-2.0), respectively. While it was relatively higher in tumor versus non-tumor tissues (P < 0.001). Besides, tumor KRT14 was positively correlated with the pathological grade (P = 0.038), tumor size (P = 0.012), T stage (P = 0.006), and TNM stage (P = 0.018). Interestingly, tumor KRT14 high predicted shorter accumulating recurrence-free survival (RFS) (P = 0.003) and accumulating overall survival (OS) (P = 0.001), which was further verified by the multivariate Cox's regression analysis (both P < 0.05). Furthermore, tumor KRT14 high estimated shorter RFS and OS from the Gene Expression Profiling Interactive Analysis and Human Protein ATLAS databases (all P < 0.05). Subgroup analyses indicated that the correlation of tumor KRT14 with accumulating RFS and accumulating OS was more pronounced in RCC patients with better physical status (such as age < 65 years and better eastern cooperative oncology group performance status) and higher tumor stages (such as higher pathological grade). CONCLUSION: High KRT14 in tumor tissue could reflect an advanced tumor features and unsatisfying survival in RCC patients.

How should extra-large Lugol-unstained lesions of the esophagus be treated? Results from a population-based cohort study.

BACKGROUND: Current guidelines recommend only severe dysplasia and above (SDA) lesions of the esophageal squamous epithelium for clinical intervention. However, the histopathologic diagnosis derived from tissue biopsies may be subject to underestimation of severity. METHODS: 1073 participants from whom biopsies were taken at baseline chromoendoscopic examination in a population-based screening trial were enrolled in this study. The size of the Lugol-unstained lesions (LULs) was mainly analyzed. The outcome was defined as SDA lesions either identified at baseline screening, or during follow-up, collectively referred to as the cumulative risk of SDA. Multivariable logistic regression models were used to evaluate the cumulative risk of SDA. RESULTS: One hundred and forty-six SDA cases were identified in the study period. Participants with large LULs had a high cumulative incidence of SDA (cumulative incidence16-20mm : 55.88%; cumulative incidence>20mm : 76.92%) in the median of 7-year duration. LULs of large size were significantly associated with a higher cumulative risk of SDA, regardless of the pathologic diagnosis (adjusted OR16-20mmvs.≤5mm = 21.02, 95% CI: 7.56-58.47; adjusted OR>20mmvs.≤5mm = 33.62, 95% CI: 11.79-95.87). CONCLUSIONS: Results from this study suggest physician-patient shared decision-making regarding clinical treatment or intensive surveillance should be carried out for LULs >20 mm in the esophagus, regardless of the histologic diagnosis. For those with LULs of 16-20 mm, intensive surveillance would also best be considered.

Lugol-unstained lesions location in the esophagus affects the detection rate of malignancy: a population-based study.

INTRODUCTION: This study aimed to evaluate the impact of Lugol-unstained lesion (LUL) location on the detection yield, which may help the endoscopist select targets for biopsy. METHODS: We enrolled 1064 subjects who had LULs at the baseline screening of a population-based randomized controlled trial. There were 1166 LULs with recorded location and pathologic diagnosis, and these were used for analysis. The detection rate of severe dysplasia and above (SDA) was calculated as the number of LULs identified as SDA divided by the number of LULs biopsied. Logistic regression with a generalized estimating equation was applied to evaluate the association between the location of a given LUL and the risk of the LUL being SDA. RESULTS: The detection rate of SDA for LULs located in the lower, middle, and upper esophagus increased from 5.9% and 10.9% to 16.7%. LUL location was significantly associated with having SDA (adjusted odds ratio (OR)upper vs. lower  = 2.88, 95% confidential interval (CI) = 1.48-5.60; adjusted ORmiddle vs. lower  = 1.63, 95% CI = 0.96-2.76), and the association was stronger in subgroups with a family history of esophageal squamous cell carcinoma (ESCC) (adjusted ORupper vs. lower  = 9.72, 95% CI = 2.57-36.69; adjusted ORmiddle vs. lower  = 3.76, 95% CI = 0.93-15.21). CONCLUSIONS: Our results suggest that more attention should be paid by endoscopists to LULs in the upper and middle esophagus, particularly for individuals with a family history of ESCC.

Incidence of Inflammatory Bowel Disease in Urban China: A Nationwide Population-based Study.

BACKGROUND & AIMS: Limited studies have evaluated the burden of inflammatory bowel disease (IBD) in China. We aimed to estimate the incidence of IBD including ulcerative colitis (UC) and Crohn's disease (CD) in urban China. METHODS: The national urban incidence in 2016 was calculated based on urban basic medical insurance from 2012 to 2016 in China by using a 4-year washout period. The incidence in Yinzhou District estimated from the Yinzhou electronic health care record database was used to test the accuracy of the results from insurance data. RESULTS: A total of 95,555 patients with IBD were identified. The incidence in 2016 was 10.04 (95% confidence interval, 6.95-13.71) per 100,000 person-years. The incidence rates of both UC and CD were higher among males than among females. There was a sharp increase in UC incidence before the age of 30 years and stabilization in later years (50-79 years old), whereas CD incidence peaked at 30 to 34 years old and experienced decline subsequently. The incidence of UC was much greater than that of CD, with a UC-to-CD incidence ratio of 12.61. The results from the Yinzhou database confirmed these results. CONCLUSIONS: This study is the first to draw a portrait of the distribution of IBD in urban China. The difference in IBD incidence between urban China and other countries suggests an association between the IBD burden and industrialization process. The accelerating urbanization and industrialization process in China, a country with a population of 1.4 billion people, will likely increase the burden of IBD.

Oral Delivery of Anti-Parasitic Agent-Loaded PLGA Nanoparticles: Enhanced Liver Targeting and Improved Therapeutic Effect on Hepatic Alveolar Echinococcosis.

Background: Alveolar echinococcosis (AE) is a lethal parasitic disease caused by infection with the metacestode of the dog/fox tapeworm Echinococcus multilocularis, which primarily affects the liver. Although continued efforts have been made to find new drugs against this orphan and neglected disease, the current treatment options remain limited, with drug delivery considered a likely barrier for successful treatment. Methods: Nanoparticles (NPs) have gained much attention in the field of drug delivery due to their potential to improve delivery efficiency and targetability. In this study, biocompatible PLGA nanoparticles encapsulating a novel carbazole aminoalcohol anti-AE agent (H1402) were prepared to promote the delivery of the parent drug to liver tissue for treating hepatic AE. Results: H1402-loaded nanoparticles (H1402-NPs) had a uniform spherical shape and a mean particle size of 55 nm. Compound H1402 was efficiently encapsulated into PLGA NPs with a maximal encapsulation efficiency of 82.1% and drug loading content of 8.2%. An in vitro uptake assay demonstrated that H1402-NPs rapidly penetrated the in vitro cultured pre-cyst wall and extensively accumulated in the pre-cysts of E. multilocularis within only 1 h. The biodistribution profile of H1402-NPs determined through ex vivo fluorescence imaging revealed significantly enhanced liver distribution compared to unencapsulated H1402, which translated to improved therapeutic efficacy and reduced systemic toxicity (especially hepatotoxicity and cytotoxicity) in a hepatic AE murine model. Following a 30-day oral regimen (100 mg/kg/day), H1402-NPs significantly reduced the parasitic burden in both the parasite mass (liver and metacestode total weight, 8.8%) and average metacestode size (89.9%) compared to unmedicated infected mice (both p-values < 0.05); the treatment outcome was more effective than those of albendazole- and free H1402-treated individuals. Conclusion: Our findings demonstrate the advantages of encapsulating H1402 into PLGA nanoparticles and highlight the potential of H1402-NPs as a promising liver-targeting therapeutic strategy for hepatic AE.

The Role of Genetically Engineered Probiotics for Treatment of Inflammatory Bowel Disease: A Systematic Review.

BACKGROUND: Many preclinical studies have demonstrated the effectiveness of genetically modified probiotics (gm probiotics) in animal models of inflammatory bowel disease (IBD). OBJECTIVE: This systematic review was performed to investigate the role of gm probiotics in treating IBD and to clarify the involved mechanisms. METHODS: PubMed, Web of Science, Cochrane Library, and Medline were searched from their inception to 18 September 2022 to identify preclinical and clinical studies exploring the efficacy of gm probiotics in IBD animal models or IBD patients. Two independent researchers extracted data from the included studies, and the data were pooled by the type of study; that is, preclinical or clinical. RESULTS: Forty-five preclinical studies were included. In these studies, sodium dextran sulfate and trinitrobenzene sulfonic acid were used to induce colitis. Eleven probiotic species have been genetically modified to produce therapeutic substances, including IL-10, antimicrobial peptides, antioxidant enzymes, and short-chain fatty acids, with potential therapeutic properties against colitis. The results showed generally positive effects of gm probiotics in reducing disease activity and ameliorating intestinal damage in IBD models; however, the efficacy of gm probiotics compared to that of wild-type probiotics in many studies was unclear. The main mechanisms identified include modulation of the diversity and composition of the gut microbiota, production of regulatory metabolites by beneficial bacteria, reduction of the pro- to anti-inflammatory cytokine ratio in colonic tissue and plasma, modulation of oxidative stress activity in the colon, and improvement of intestinal barrier integrity. Moreover, only one clinical trial with 10 patients with Crohn's disease was included, which showed that L. lactis producing IL-10 was safe, and a decrease in disease activity was observed in these patients. CONCLUSIONS: Gm probiotics have a certain efficacy in colitis models through several mechanisms. However, given the scarcity of clinical trials, it is important for researchers to pay more attention to gm probiotics that are more effective and safer than wild-type probiotics to facilitate further clinical translation.

Phase Separation in cGAS-STING Signaling: Cytosolic DNA Sensing and Regulatory Functions.

Phase separation is a crucial biophysical process that governs cellular signaling and function. This process allows biomolecules to separate and form membraneless compartments in response to both extra- and intra-cellular stimuli. Recently, the identification of phase separation in different immune signaling pathways, including the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, has shed light on its tight association with pathological processes such as viral infections, cancers, and inflammatory diseases. In this review, we present the phase separation in cGAS-STING signaling, along with its related cellular regulatory functions. Furthermore, we discuss the introduction of therapeutics targeting cGAS-STING signaling, which plays a pivotal role in cancer progression.

Multiple Lugol-unstained lesions predict higher cumulative risk of malignance in the esophagus.

BACKGROUND AND AIM: The impact of the presence of multiple Lugol-unstained lesions (LULs) in the esophagus on the risk of having severe dysplasia and above (SDA) lesions among asymptomatic individuals is unknown. METHODS: We collected demographic factors, behavioral variables, and features of LULs from 1073 participants who were biopsied at baseline endoscopic screening in a population-based screening trial, and these individuals were followed over a median time of 7 years. Outcome events were defined as SDA identified at screening, at reexamination, or during follow-up. "Multiple LULs" were defined as ≥ 2 LULs found in the entirety of the esophagus. Multivariable logistic regression models were fitted to assess the effect of "multiple LULs" on the cumulative risk of SDA. RESULTS: There were 147 SDA cases in the current study. After adjustment for potential risk factors and endoscopic features of LULs, the presence of "multiple LULs" slightly increased the cumulative risk of having SDA with no statistical significance (adjusted odds ratio [OR] = 1.26; 95% confidence interval [CI] [0.85, 1.88]). Further stratified analysis showed that this association was strong among subjects with small LULs (≤ 5 mm) (adjusted OR = 3.29; 95% CI [1.39, 7.79]). However, no such association was observed in subjects with larger LULs (adjusted OR = 0.99; 95% CI [0.63, 1.55], P interaction  = 0.022). CONCLUSIONS: The presence of "multiple small LULs (≤ 5 mm)" in chromoendoscopy indicates a higher cumulative risk of having SDA in the esophagus. We recommend biopsies be taken and surveillance be maintained at a more active level in individuals with relatively small but multiple LULs.

The role of microbiota-mitochondria crosstalk in pathogenesis and therapy of intestinal diseases.

The interaction between mitochondria and gut microbiota plays a critical role in intestinal physiological homeostasis. In this kind of homeostasis, intestinal epithelial hypoxia helps microbiota to be dominated by obligate anaerobes, who provide their benefit metabolites for the host, such as short chain fatty acids (SCFAs). In addition, emerging studies suggest that microbial signals to the mitochondria of intestinal epithelial cells (IECs) could alter mitochondrial ultrastructure and its metabolic function, induce inflammasome activation and disrupt epithelial hypoxia. Conditions that alter the mitochondria could lead to intestinal epithelium inflammation and oxygenation, both of which would drive an expansion of facultative anaerobes and exacerbate the imbalance of mitochondria-microbiota crosstalk. This phenomenon has proved to be associated with the pathogenesis of gastrointestinal (GI) diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). Therefore, in this review, we summarized the recent process on the interaction between mitochondria of IECs and gut microbiota in the case of both GI physiological homeostasis and diseases, and potential therapeutic interventions targeting mitochondria-microbiota crosstalk in GI diseases.

Berberine Suppresses Lung Metastasis of Cancer via Inhibiting Endothelial Transforming Growth Factor Beta Receptor 1.

This study investigated the effects of berberine (BBR) on pancreatic cancer (PC) lung metastasis and explored the underlying mechanisms, using a BALB/C-nu/nu nude mouse model injected with PC cells (AsPC-1). Intragastric administration of BBR dose-dependently improves survival of mice intravenously injected with AsPC-1 cells, and reduces lung metastasis. Especially, BBR significantly reduces lung infiltration of circulating tumor cells (CTCs) 24 h after AsPC-1 cells injection. In vitro, tumor cells (TCs) trigger endothelial barrier disruption and promote trans-endothelial migration of CFSE-labeled TCs. BBR treatment effectively ameliorates TC-induced endothelial disruption, an effect that is diminished by inhibiting transforming growth factor-ß receptor 1 (TGFBR1). Blocking TGFBR1 blunts the anti-metastatic effect of BBR in vivo. Mechanistically, BBR binds to the intercellular portion of TGFBR1, suppresses its enzyme activities, and protects endothelial barrier disruption by TCs which express higher levels of TGF-ß1. Hence, BBR might be a promising drug for reducing PC lung metastasis in clinical practice.

Absence of NOTCH1 mutation and presence of CDKN2A deletion predict progression of esophageal lesions.

Currently, surveillance for esophageal squamous cell carcinoma (ESCC) runs a risk of underestimation of early lesions which show absence of iodine staining, with no or only mild histologic changes. The development of molecular markers that indicate risk of progression is thus warranted. We performed whole-exome sequencing on biopsies from two sequential endoscopies of a single esophageal lesion and matching blood samples. There were 27 pairs of age-, gender-, pathologic stage-, and sampling interval-matched progressors and non-progressors identified in a prospective community-based ESCC screening trial. Putative molecular progression markers for ESCC were first evaluated by comparing somatic mutation, copy number alteration (CNA), and mutational signature information among progressors and non-progressors. These markers were then validated with another 24 pairs of matched progressors and non-progressors from the same population using gene alteration status identified by target sequencing and quantitative PCR. Progressors had more somatic mutation and CNA burden, as well as apolipoprotein B mRNA editing catalytic polypeptide-like and age-related signature weights compared with non-progressors. A gene score consisting of somatic NOTCH1 mutation and CDKN2A deletion is predictive of risk of progression in lesions which show absence of iodine staining under endoscopy but have no or only mild dysplasia. This gene score was also validated in an external cohort of matched progressors and non-progressors. Absence of NOTCH1 mutation and presence of CDKN2A deletion are markers of progression in squamous lesions of the esophagus. This gene score would be an ideal indicator for assisting the pathologist in the identification of high-risk individuals who could be potentially 'missed' or subject to a risk underestimation by histologic analysis, and might improve the performance of ESCC surveillance. © 2022 The Pathological Society of Great Britain and Ireland.

More Positive or More Negative? Metagenomic Analysis Reveals Roles of Virome in Human Disease-Related Gut Microbiome.

Viruses are increasingly viewed as vital components of the human gut microbiota, while their roles in health and diseases remain incompletely understood. Here, we first sequenced and analyzed the 37 metagenomic and 18 host metabolomic samples related to irritable bowel syndrome (IBS) and found that some shifted viruses between IBS and controls covaried with shifted bacteria and metabolites. Especially, phages that infect beneficial lactic acid bacteria depleted in IBS covaried with their hosts. We also retrieved public whole-genome metagenomic datasets of another four diseases (type 2 diabetes, Crohn's disease, colorectal cancer, and liver cirrhosis), totaling 438 samples including IBS, and performed uniform analysis of the gut viruses in diseases. By constructing disease-specific co-occurrence networks, we found viruses actively interacting with bacteria, negatively correlated with possible dysbiosis-related and inflammation-mediating bacteria, increasing the connectivity between bacteria modules, and contributing to the robustness of the networks. Functional enrichment analysis showed that phages interact with bacteria through predation or expressing genes involved in the transporter and secretion system, metabolic enzymes, etc. We further built a viral database to facilitate systematic functional classification and explored the functions of viral genes on interacting with bacteria. Our analyses provided a systematic view of the gut virome in the disease-related microbial community and suggested possible positive roles of viruses concerning gut health.

Update and validation of a diagnostic model to identify prevalent malignant lesions in esophagus in general population.

Background: Previous risk prediction models taking esophageal malignant lesions detected during endoscopy as the primary outcome are not always sufficient to identify prevalent cases which are "overlooked" at screening. We aimed to update and externally validate our previous risk prediction model for malignant esophageal lesions by redefining the predicted outcome. Methods: 15,192 individuals from the Endoscopic Screening for Esophageal Cancer in China randomized controlled trial (ESECC trial, NCT01688908) were included as the training set, and 4576 participants from another population-based esophageal squamous cell carcinoma (ESCC) screening cohort (Anyang Esophageal Cancer Cohort Study, AECCS) served as the external validation set. Lesions with severe dysplasia or worse diagnosed at chromoendoscopy or identified via follow-up within 1 year after screening were defined as main outcome. Logistic regressions were applied to reconstruct the questionnaire-based prediction model using information collected before screening, with Akaike Information Criterion to determine the model structure. Findings: The final prediction model included age and its quadratic term, family history of ESCC, low body mass index (≤22 kg/m2), use of coal or wood as main fuel for cooking, eating rapidly, and ingestion of leftover food. The area under the curve was 0·77 (95% CI: 0·73-0·80) and 0·71 (95% CI: 0·65-0·78) in the training and validation set. When screening the top 50% or 10% of high-risk individuals within population, the detection rates can be increased in both cohorts, as compared to universal screening. Interpretation: The described tool may promote the efficiency of current national screening programs for ESCC and contribute to a precision screening strategy in high-risk regions in China. Funding: This work was supported by the National Natural Science Foundation of China (82073626, 81773501), the National Science & Technology Fundamental Resources Investigation Program of China (2019FY101102), the National Key R&D Program of China (2021YFC2500405), the Beijing-Tianjin-Hebei Basic Research Cooperation Project (J200016), the Digestive Medical Coordinated Development Center of Beijing Hospitals Authority (XXZ0204) and the Beijing Nova Program (Z201100006820093). Sponsors had no role in the study design, data collection, analysis, and interpretation of data.

Helicobacter pylori infection is associated with reduced risk of Barrett's esophagus: a meta-analysis and systematic review.

BACKGROUND: Helicobacter pylori (Hp) is a class I carcinogen in gastric carcinogenesis, but its role in Barrett's esophagus (BE) is unknown. Therefore, we aimed to explore the possible relationship. METHODS: We reviewed observational studies published in English until October 2019. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for included studies. RESULTS: 46 studies from 1505 potential citations were eligible for inclusion. A significant inverse relationship with considerable heterogeneity was found between Hp (OR = 0.70; 95% CI, 0.51-0.96; P = 0.03) and BE, especially the CagA-positive Hp strain (OR = 0.28; 95% CI, 0.15-0.54; P = 0.0002). However, Hp infection prevalence was not significantly different between patients with BE and the gastroesophageal reflux disease (GERD) control (OR = 0.99; 95% CI, 0.82-1.19; P = 0.92). Hp was negatively correlated with long-segment BE (OR = 0.47; 95% CI, 0.25-0.90; P = 0.02) and associated with a reduced risk of dysplasia. However, Hp had no correlated with short-segment BE (OR = 1.11; 95% CI, 0.78-1.56; P = 0.57). In the present infected subgroup, Hp infection prevalence in BE was significantly lower than that in controls (OR = 0.69; 95% CI, 0.54-0.89; P = 0.005); however, this disappeared in the infection history subgroup (OR = 0.88; 95% CI, 0.43-1.78; P = 0.73). CONCLUSIONS: Hp, especially the CagA-positive Hp strain, and BE are inversely related with considerable heterogeneity, which is likely mediated by a decrease in GERD prevalence, although this is not observed in the absence of current Hp infection.

Tumor-associated autoantibodies in ESCC screening: Detecting prevalent early-stage malignancy or predicting future cancer risk?

BACKGROUND: To assess potential roles for tumor-associated autoantibodies (TAAs) in esophageal squamous cell carcinoma (ESCC) screening: detecting early-stage malignancy, and predicting future cancer risk. METHOD: Thirteen candidate autoantibodies identified in previous literatures were measured using multiplex serological assays in sera from cases and matched controls nested in two population-level screening cohorts in China. To evaluate the role of TAAs in detecting prevalent esophageal malignant lesions, an identification set (150 cases vs. 560 controls) and an external validation set (34 cases vs. 121 controls) were established with pre-screening sera collected ≤ 12 months prior to screening-related diagnosis. To explore the role of TAAs in predicting future ESCC risk, an exploration set (105 cases vs. 416 controls) with pre-diagnostic sera collected > 12 months before clinical diagnosis was established. Two models, the questionnaire-based model and full model additionally incorporating TAA markers, were constructed. Area under the receiver operating characteristic curve (AUC) and net reclassification improvement (NRI) were calculated to compare the performance of the two models. FINDINGS: In the identification set, NY-ESO-1 (OR=2·12, 95% CI=1·02-4·40) and STIP1 (OR=1·83, 95% CI=1·10-3·05) were positively associated with higher risk of esophageal malignancy. Elevated MMP-7 was associated with higher risk of malignancy in females (ORfemale=5·07, 95% CI=1·30-19·71). The estimates in validation set were consistent with these results, but were close to null in exploration set. Integration of selected TAAs improved the performance of questionnaire-based models in detecting prevalent esophageal malignancy (female: AUCfull model=0·745, 95% CI=0·675-0·814, AUCquestionnaire-based model=0·658, 95% CI=0·585-0·732, NRI=0·604, P<0·0001; male: AUCfull model=0·662, 95% CI=0·596-0·728, AUCquestionnaire-based model=0·619, 95% CI=0·548-0·690, NRI=0·357, P=0·0028). This improvement was also seen in validation set, but was not similarly effective in distinguishing long-term incident cases from healthy controls. INTERPRETATION: Serological autoantibodies against NY-ESO-1, STIP1, and MMP-7 perform well in detecting early-stage esophageal malignancy, but are less effective in predicting future ESCC risks. FUNDING: This work was supported by the National Science & Technology Fundamental Resources Investigation Program of China (2019FY101102), the National Natural Science Foundation of China (82073626), the National Key R&D Program of China (2016YFC0901404), the Beijing-Tianjin-Hebei Basic Research Cooperation Project (J200016), the Digestive Medical Coordinated Development Center of Beijing Hospitals Authority (XXZ0204), and the Natural Science Foundation of Beijing Municipality (7182033).

Effects of inhalation and propofol anaesthesia on postoperative cognitive dysfunction in elderly noncardiac surgical patients: A systematic review and meta-analysis.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a very common event in elderly noncardiac surgical patients. The effects of inhalational anaesthetics and propofol on the incidence of POCD and postoperative cognitive status at different time points after surgery are currently unclear. METHODS: We searched the Embase, Medline, Cochrane Library, and Web of Science databases for randomized controlled trials (RCTs), in which inhalation anaesthesia and propofol anaesthesia were compared. The incidence of POCD or postoperative cognitive status was assessed in elderly patients undergoing noncardiac surgery. RESULTS: Fifteen RCTs with 1854 patients were included in this meta-analysis. The incidence of POCD on postoperative Days 2-6 after propofol anaesthesia was markedly lower than that after inhalation anaesthesia (risk ratio (RR): 0.37, 95% confidence interval (CI): 0.15-0.88, P = .025), and Mini-Mental State Examination (MMSE) scores after propofol anaesthesia were substantially higher than those after inhalation anaesthesia (standard mean difference (SMD): 0.59, 95% CI: 0.07-1.11, P = .026). The levels of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were much lower after propofol anaesthesia than after inhalation anaesthesia (SMD: -2.027, 95% CI: -3.748- -0.307, P = .021; SMD: -0.68, 95% CI: -0.93- -0.43, P < .001). CONCLUSIONS: The moderate evidence from this meta-analysis shows that, in elderly noncardiac surgical patients, propofol anaesthesia is superior to inhalation anaesthesia for attenuating of early POCD incidence, and low-level evidence shows that cognitive status is higher and systemic inflammation is less severe after propofol anaesthesia in the early days after surgery. LIMITATIONS: The sample size was not sufficiently large for systemic inflammation, and the tools to identify POCD were not uniform in the included studies.

Transcriptome analysis uncovers the key pathways and candidate genes related to the treatment of Echinococcus granulosus protoscoleces with the repurposed drug pyronaridine.

BACKGROUND: Cystic echinococcosis (CE) is a life-threatening zoonosis caused by the larval form of Echinococcus granulosus tapeworm. Our previous study showed that an approved drug pyronaridine (PND) is highly effective against CE, both in vitro and in an animal model. To identify possible target genes, transcriptome analysis was performed with E. granulosus sensu stricto protoscoleces treated with PND. RESULTS: A total of 1,321 genes were differentially expressed in protoscoleces treated with PND, including 541 upregulated and 780 downregulated genes. Gene ontology and KEGG analyses revealed that the spliceosome, mitogen-activated protein kinase (MAPK) pathway and ATP-binding cassette (ABC) transporters were the top three enriched pathways. Western blot analysis showed that PND treatment resulted in a dose-dependent increase in protein expression levels of EgMKK1 (MKK3/6-like) and EgMKK2 (MEK1/2-like), two members of MAPK cascades. Interestingly, several heat shock protein (HSP) genes were greatly downregulated including stress-inducible HSPs and their constitutive cognates, and some of them belong to Echinococcus-specific expansion of HSP70. CONCLUSIONS: PND has a great impact on the spliceosome, MAPK pathway and ABC transporters, which may underline the mechanisms by which PND kills E. granulosus protoscoleces. In addition, PND downregulates HSPs expression, suggesting a close relationship between the drug and HSPs.

Comparison of Outcomes After Breast Cancer Surgery Between Inhalational and Propofol-Based Intravenous Anaesthesia: A Systematic Review and Meta-Analysis.

BACKGROUND: General anaesthesia is the commonly provided for breast cancer surgery, but the effects of inhalational anaesthesia and propofol-based intravenous anaesthesia on short- and long-term outcomes after breast cancer surgery are not clear. In this study, we conduct a meta-analysis of randomized controlled trials (RCTs) to explore the superior anaesthetic for breast cancer surgery patients. METHODS: We searched the Embase, Medline, Cochrane Library, Web of Science, CNKI, and Wanfang databases (up to January, 2021) for RCTs in which inhalational anaesthesia and propofol-based intravenous anaesthesia were compared and short- and long-term outcomes were assessed in breast cancer surgical patients. The meta-analysis was performed by Stata 12.0. RESULTS: Twenty RCTs with a total of 2201 patients were included. Compared with inhalational anaesthesia, propofol-based intravenous anaesthesia was associated with more postoperative rescue analgesia (I2 =0%, RR: 1.18, 95% CI: 1.07-1.30, P=0.001) but a lower incidence of postoperative nausea and vomiting (PONV) (I2 =25.5%, RR: 0.71, 95% CI: 0.62-0.81, P<0.001) and postoperative rescue antiemetics (I2 =0%, RR: 0.69, 95% CI: 0.58-0.82, P<0.001). Propofol-based intravenous anaesthesia preserved nature killer cell cytotoxicity (I2 =86.2%, SMD: 0.76, 95% CI: 0.13-1.39, P=0.018), decreased IL-6 level (I2 =98.0%, SMD: -3.09, 95% CI: -5.70- -0.48, P=0.021) and neutrophil-to-lymphocyte ratio (I2 =0%, SMD: -0.28, 95% CI: -0.53- -0.03, P=0.030), and increased 2-year recurrence-free survival rate (I2 =0%, RR: 1.10, 95% CI: 1.00-1.20, P=0.043) but did not affect recurrence or the overall survival rate (P>0.05). CONCLUSION: Propofol-based intravenous anaesthesia increases postoperative rescue analgesia but reduces PONV compared with inhalational anaesthesia in breast cancer surgery. The benefit of propofol over inhalational anaesthetics in the preservation of anti-cancer immunity is obvious, but it is difficult to conclude that propofol can exert long-term benefits due to the small sample size.