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Background and Aims: Endoscopic submucosal dissection (ESD) has become a standard treatment for early-stage gastrointestinal (GI) cancer. Automated recognition for various ESD (endoscopic submucosal dissection) phase helps in ESD training and execution. The existing phase recognition systems are limited by their scope, focusing on specific types of ESD and lacking comprehensive phase identification. This study aims to develop a deep learning-based phase recognition system, named AI-ESD, that can accurately identify and categorize all phases of ESD for various gastrointestinal locations. Methods: Using 234 ESD videos from a single center, we trained AI-ESD to recognize 8 phases: preparation, estimation, marking, submucosal injection, incision, submucosal dissection, vessel treatment, and clips. Performance was evaluated on an independent validation set (n=69) and videos from novice endoscopists (n=34) using accuracy, sensitivity, specificity, F1-score and area under the receiver operating characteristic curve (AUROC). Subgroup analyses were performed by tumor location, endoscopist, and lesion size. Findings: The AUROC, accuracy, and specificity for all ESD phases was higher than 0.9 with sensitivity ranging from 0.880 (phase of incision) to 0.963 (phase of clips) and F1 score ranging from 0.823 (phase of incision) to 0.948 (phase of marking). The macro-average AUROC, accuracy, sensitivity, specificity, and F1 score were 0.987, 0.975, 0.919, 0.985, and 0.908, respectively. The AI-ESD model demonstrated nearly similar results in the subgroup analysis to overall analysis across all phases in the validation cohort. Similar results for novice cohort were obtained with macro-average AUROC, accuracy, sensitivity, specificity, and F1 score being 0.981, 0.971, 0.901, 0.981, and 0.897, respectively. Sensitivity was lowest for the preparation phase (0.881 validation, 0.848 novice). Interpretation: We developed AI-ESD for highly accurate automated phase recognition system for full gastrointestinal ESD, including gastric, esophageal, and colorectal ESD. Further external validation in diverse settings is warranted.

Abstract Small bowel vascular malformation disease (SBVM) commonly causes obscure gastrointestinal bleeding (OGIB). However, the pathogenetic mechanism and the role of lncRNAs in SBVM remain largely unknown. Here, we found that hypoxia and low-glucose environments co-augment angiogenesis and existed in SBVM. Mechanistically, hypoxia and low-glucose environments supported angiogenesis via activation of hypoxia and glucose deprivation-induced lncRNA (HGDILnc1) transcription by increasing binding of the NeuroD1 transcription factor to the HGDILnc1 promoter. Raised HGDILnc1 acted as a suppressor of α-Enolase 1 (ENO1) small ubiquitin-like modifier modification (SUMOylation)-triggered ubiquitination, and an activator of transcription of Aldolase C (ALDOC) via upregulation of Histone H2B lysine 16 acetylation (H2BK16ac) level in the promoter of ALDOC, and consequently promoting glycolysis and angiogenesis. Moreover, HGDILnc1 was clinically positively correlated with Neurogenic differentiation 1 (NeuroD1), ENO1, and ALDOC in SBVM tissues, and could function as a biomarker for SBVM diagnosis and therapy. These findings suggest that hypoxia and low-glucose environments were present in SBVM tissues, and co-augmented angiogenesis. Hypoxia and low-glucose environments co-induced HGDILnc1, which is higher expressed in SBVM tissue compared with normal tissue, could promoted glycolysis and angiogenesis.

Abstract Purpose The current study was designed to investigate the analgesic effect of esketamine on patients underwent thoracoscopic surgery and the underlying mechanism. Methods In this randomized, double blind, placebo-controlled study, 60 patients scheduled to undergo thoracoscopic lobectomy or segmentectomy were randomized to two groups to receive esketamine (group ESK) or saline (group SAL), respectively. 0.25 mg·kg−1 esketamine was given in group ESK for induction of anesthesia, and 0.12 mg·kg−1·h−1 esketamine for intraoperative maintenance. Group SAL received an equal volume of saline. The primary outcomes were the visual analogue scale (VAS) pain scores at rest and deep cough state which evaluated at departure from post-anesthesia care unit (PACU) (T1), 6 h, 24 h and 48 h after surgery (T2–T4). The secondary outcomes included the levels of white blood cell (WBC) count, absolute neutrophil count (ANC), interleukin-6 (IL-6), procalcitonin (PCT), anxiety/depression scores at T3, oxygen saturation (SpO2), and adverse reactions. Results Esketamine significantly decreased both rest and cough VAS pain scores at T1, and rest pain scores at T1, T2 and T4. Patients in ESK group had significantly lower WBC and ANC levels than SAL group, while the alteration of IL-6 and PCT levels between groups showed no significance. The anxiety scores of patients in both groups were significantly decreased after surgery. However, the depression scores of patients in ESK group did not decrease after surgery when compared with the preoperation. The postoperative SpO2 and the incidence of adverse reaction including postoperative nausea, vomiting, dizziness and dissociative symptom showed no significant difference between two groups (p > 0.05). Conclusion Esketamine can alleviate the acute postoperative pain of patients undergoing thoracoscopic surgery without increasing adverse reactions, and the underlying mechanism may be associated with the reduction of postoperative inflammation. Trial registration Registered at Chinese Clinical Trial Registry on February 7, 2022 (ChiCTR 2200056524). Graphical Abstract

Abstract Objectives Gastrointestinal stromal tumors (GISTs) carrying different KIT exon 11 (KIT-11) mutations exhibit varying prognoses and responses to Imatinib. Herein, we aimed to determine whether computed tomography (CT) radiomics can accurately stratify KIT-11 mutation genotypes to benefit Imatinib therapy and GISTs monitoring. Methods Overall, 1143 GISTs from 3 independent centers were separated into a training cohort (TC) or validation cohort (VC). In addition, the KIT-11 mutation genotype was classified into 4 categories: no KIT-11 mutation (K11-NM), point mutations or duplications (K11-PM/D), KIT-11 557/558 deletions (K11-557/558D), and KIT-11 deletion without codons 557/558 involvement (K11-D). Subsequently, radiomic signatures (RS) were generated based on the arterial phase of contrast CT, which were then developed as KIT-11 mutation predictors using 1408 quantitative image features and LASSO regression analysis, with further evaluation of its predictive capability. Results The TC AUCs for K11-NM, K11-PM/D, K11-557/558D, and K11-D ranged from 0.848 (95% CI 0.812–0.884), 0.759 (95% CI 0.722–0.797), 0.956 (95% CI 0.938–0.974), and 0.876 (95% CI 0.844–0.908), whereas the VC AUCs ranged from 0.723 (95% CI 0.660–0.786), 0.688 (95% CI 0.643–0.732), 0.870 (95% CI 0.824–0.918), and 0.830 (95% CI 0.780–0.878). Macro-weighted AUCs for the KIT-11 mutant genotype ranged from 0.838 (95% CI 0.820–0.855) in the TC to 0.758 (95% CI 0.758–0.784) in VC. TC had an overall accuracy of 0.694 (95%CI 0.660–0.729) for RS-based predictions of the KIT-11 mutant genotype, whereas VC had an accuracy of 0.637 (95%CI 0.595–0.679). Conclusions CT radiomics signature exhibited good predictive performance in estimating the KIT-11 mutation genotype, especially in prediction of K11-557/558D genotype. RS-based classification of K11-NM, K11-557/558D, and K11-D patients may be an indication for choice of Imatinib therapy.

IntroductionThe burden of colorectal cancer (CRC) plays a pivotal role in the global cancer epidemic. Our study reported the incidence trends in CRC and the associated effects of age, period, and birth cohort in 204 countries and territories over the past 30 years.MethodsThe incidence data of CRC were extracted from the Global Burden of Disease Study (GBD) 2019. We performed the age–period–cohort (APC) model to estimate the overall annual percentage change (net drift) in the incidence rate, the annual percentage change by age group (local drift), and the relative risk (period and cohort effects) of the period and cohort in CRC during 1990–2019. This approach allows examining and distinguishing age, period, and cohort effects in incidence and potentially distinguishing colorectal cancer gaps in prevention and screening.ResultsIn 2019, the incidence of CRC was 2.17 (95% UI 2.00–2.34) million, of which China, the United States of America, and Japan had the highest incidence population, accounting for 45.9% of the global population. The age–standardized incidence rate (ASIR) was 26.7 (95% UI 28.9–24.6) per 100,000 people, of which 30 countries had an incidence rate greater than 40.0 per 100,000 people. From 1990 to 2019, the middle SDI region had the largest increase in incidence rate, with a net drift of 2.33% (95% CI 2.2–2.46%, p 2%), mostly concentrated in the middle SDI region, such as China, Mexico, and Brazil, and the risk of period and birth cohort was unfavorable.ConclusionGlobally, the incidence of CRC has shown an overall upward trend over the past 30 years, with the exception of some countries with higher SDI values. Significant age–period–cohort differences were observed in the risk of incidence in CRC worldwide. Effective prevention and control policies need to take into account the age–period–cohort effect characteristics of different regions.

Summary: Artificial intelligence (AI) has been found to assist in optical differentiation of hyperplastic and adenomatous colorectal polyps. We investigated whether AI can improve the accuracy of endoscopists’ optical diagnosis of polyps with advanced features. We introduced our AI system distinguishing polyps with advanced features with more than 0.870 of accuracy in the internal and external validation datasets. All 19 endoscopists with different levels showed significantly lower diagnostic accuracy (0.410–0.580) than the AI. Prospective randomized controlled study involving 120 endoscopists into optical diagnosis of polyps with advanced features with or without AI demonstration identified that AI improved endoscopists’ proportion of polyps with advanced features correctly sent for histological examination (0.960 versus 0.840, p

BackgroundIschemic heart disease (IHD) is the leading cause of death among noncommunicable diseases worldwide, but data on current epidemiological patterns and associated risk factors are lacking. ObjectiveThis study assessed the global, regional, and national trends in IHD mortality and attributable risks since 1990. MethodsMortality data were obtained from the Global Burden of Disease 2019 Study. We used an age-period-cohort model to calculate longitudinal age curves (expected longitudinal age-specific rate), net drift (overall annual percentage change), and local drift (annual percentage change in each age group) from 15 to >95 years of age and estimate cohort and period effects between 1990 and 2019. Deaths from IHD attributable to each risk factor were estimated on the basis of risk exposure, relative risks, and theoretical minimum risk exposure level. ResultsIHD is the leading cause of death in noncommunicable disease–related mortality (118.1/598.8, 19.7%). However, the age-standardized mortality rate for IHD decreased by 30.8% (95% CI –34.83% to –27.17%) over the past 30 years, and its net drift ranged from –2.89% (95% CI –3.07% to –2.71%) in high sociodemographic index (SDI) region to –0.24% (95% CI –0.32% to –0.16%) in low-middle–SDI region. The greatest decrease in IHD mortality occurred in the Republic of Korea (high SDI) with net drift –6.06% (95% CI –6.23% to –5.88%), followed by 5 high-SDI nations (Denmark, Norway, Estonia, the Netherlands, and Ireland) and 2 high-middle–SDI nations (Israel and Bahrain) with net drift less than –5.00%. Globally, age groups of >60 years continued to have the largest proportion of IHD-related mortality, with slightly higher mortality in male than female group. For period and birth cohort effects, the trend of rate ratios for IHD mortality declined across successive period groups from 2000 to 2004 and birth cohort groups from 1985 to 2000, with noticeable improvements in high-SDI regions. In low-SDI regions, IHD mortality significantly declined in female group but fluctuated in male group across successive periods; sex differences were greater in those born after 1945 in middle- and low-middle–SDI regions and after 1970 in low-SDI regions. Metabolic risks were the leading cause of mortality from IHD worldwide in 2019. Moreover, smoking, particulate matter pollution, and dietary risks were also important risk factors, increasingly occurring at a younger age. Diets low in whole grains and legumes were prominent dietary risks in both male and female groups, and smoking and high-sodium diet mainly affect male group. ConclusionsIHD, a major concern, needs focused health care attention, especially for older male individuals and those in low-SDI regions. Metabolic risks should be prioritized for prevention, and behavioral and environmental risks should attract more attention to decrease IHD mortality.

Abstract Background Gastric cancer (GC) is one of most common cancers worldwide. Several studies have suggested that Rab31 functions as a membrane vesicle transport regulator; however, the mechanism by which RAB31 regulates exosome secretion and promotes metastasis remains to be clarified. Methods We examined the expression of RAB31 protein and mRNA in GC tissue samples via immunohistochemistry and reverse transcription‐polymerase chain reaction assays, respectively. We elucidated the function of RAB31 in GC cells by constructing a cell model and a pulmonary metastatic model of GC with overexpression of RAB31. Protein mass spectrometry was used to identify the exosomal protein. Results RAB31 expression increased at both the protein and mRNA levels with the development of GC. Cells overexpressing RAB31 showed an enhanced ability to migrate in both the in vitro cell model and the pulmonary metastatic model of GC. Exosome nanoparticle tracking analysis and electron microscopy revealed that the both the number and size of the exosomes secreted by GC cells were reduced when RAB31 expression was depleted. Injection of exosomes derived from RAB31 overexpressing cells promoted pulmonary metastasis in vivo. Analysis of the exosomal proteins revealed that PSMA1 was overexpressed in GC tissue in accordance with RAB31 expression. PSMA1 overexpression was highly associated with poor prognosis of GC patients. Conclusion Our findings revealed a key role for RAB31 in GC metastasis through regulation of exosome secretion.

Background & Aims: Approximately one-third of colorectal cancers develop from serrated lesions (SLs), including hyperplastic polyp (HP), sessile serrated lesion (SSL), traditional serrated adenoma (TSA), and SSL with dysplasia (SSLD) through the serrated neoplasia pathway, which progresses faster than the conventional adenoma-carcinoma pathway. We sought to depict the currently unclarified molecular and immune alterations by the single-cell landscape in SLs. Methods: We performed single-cell RNA sequencing of 16 SLs (including 4 proximal HPs, 5 SSLs, 2 SSLDs, and 5 TSAs) vs 3 normal colonic tissues. Results: A total of 60,568 high-quality cells were obtained. Two distinct epithelial clusters with redox imbalance in SLs were observed, along with upregulation of tumor-promoting SerpinB6 that regulated ROS level. Epithelial clusters of SSL and TSA showed distinct molecular features: SSL-specific epithelium manifested overexpressed proliferative markers with Notch pathway activation, whereas TSA-specific epithelium showed Paneth cell metaplasia with aberrant lysozyme expression. As for immune contexture, enhanced cytotoxic activity of CD8+ T cells was observed in SLs; it was mainly attributable to increased proportion of CD103+CD8+ tissue-resident memory T cells, which might be regulated by retinoic acid metabolism. Microenvironment of SLs was generally immune-activated, whereas some immunosuppressive cells (regulatory T cells, anti-inflammatory macrophages, MDK+IgA+ plasma cells, MMP11-secreting PDGFRA+ fibroblasts) also emerged at early stage and further accumulated in SSLD. Conclusion: Epithelial, immune, and stromal components in the serrated pathway undergo fundamental alterations. Future molecular subtypes of SLs and potential immune therapy might be developed.

Background Population growth, aging, and major alterations in epidemiologic trends inadvertently modulate the status of rheumatic heart disease (RHD) epidemiology. This investigation predicted RHD burden pattern and temporal trends to provide epidemiologic evidence. Methods and Results Prevalence, mortality, and disability‐adjusted life‐years data for RHD were obtained from the GBD (Global Burden of Disease) study. We performed decomposition analysis and frontier analysis to assess variations and burden in RHD from 1990 to 2019. In 2019, there were >40.50 million RHD cases worldwide, along with nearly 0.31 million RHD‐related deaths and 10.67 million years of healthy life lost to RHD. The RHD burden was commonly concentrated within lower sociodemographic index regions and countries. RHD primarily affects women (22.52 million cases in 2019), and the largest age‐specific prevalence rate was at 25 to 29 years in women and 20 to 24 years in men. Multiple reports demonstrated prominent downregulation of RHD‐related mortality and disability‐adjusted life‐years at the global, regional, and national levels. Decomposition analysis revealed that the observed improvements in RHD burden were primarily due to epidemiological alteration; however, it was negatively affected by population growth and aging. Frontier analysis revealed that the age‐standardized prevalence rates were negatively linked to sociodemographic index, whereas Somalia and Burkina Faso, with lower sociodemographic index, showed the lowest overall difference from the frontier boundaries of mortality and disability‐adjusted life‐years. Conclusions RHD remains a major global public health issue. Countries such as Somalia and Burkina Faso are particularly successful in managing adverse outcomes from RHD and may serve as a template for other countries.

Abstract Chidamide is the first oral subtype-selective histone deacetylase inhibitor approved in China for the treatment of relapsed and refractory peripheral T cell lymphoma. Due to the existence of isomers, many articles or patents have mistaken its structure. Herein we explored the synthesis of the key intermediate (E)-4-((3-(pyridin-3-yl)acrylamido)methyl)benzoic acid (A-3) and chidamide, using the condensing agent HBTU, instead of the unstable N,N'-carbonyldiimidazole. The single crystal of chidamide was determined by X-ray diffraction study. The optimized preparation process was easy to operate, and the purity of the final product can be up to 99.76%. Moreover, the structure of chidamide was established to be (E)-N-(2-amino-4-fluorophenyl)-4-((3-(pyridin-3-yl)acrylamido)methyl)benzamide.

Construction of chiral organosilicon compounds could have implications in photophysical, biological, and chemical fields, as silicon is isoelectronic with carbon, and can mimic carbon atoms while providing slightly different properties. Here the authors present an intermolecular, enantioselective C–H silylation of heterocycles via rhodium catalysis.

Abstract Background Endoscopic treatment methods for early colorectal cancer (ECRC) mainly depend on the size and morphology. It is unclear whether different endoscopic resection methods could achieve curative resection for ECRC confined in the mucosa. The study was designed to compare the rate of positive vertical margin (VM) of ECRC with advanced adenomas (AAs) including adenoma > 1 cm, villous adenoma, high-grade intraepithelial neoplasia/dysplasia stratified by different endoscopic resection methods. Methods Rate of positive VM for 489 ECRCs including Intramucosal (pTis) and superficial submucosal invasion (pT1) carcinomas were compared with those of 753 AAs stratified by different endoscopic resection methods using Chi-squared test. Multivariate logistic model was performed to investigate the risk factors of positive VM for different endoscopic resection methods. Results The pTis ECRC exhibited a similar rate of positive VM as that of AAs for en bloc hot snare polypectomy (HSP, 0% Vs. 0.85%, P = 0.617), endoscopic mucosal resection (EMR, 0.81% vs. 0.25%, P = 0.375) and endoscopic submucosal dissection (ESD, 1.82% Vs. 1.02%, P = 0.659). The pTis carcinoma was not found to be a risk factor for positive VM by en bloc EMR (P = 0.349) or ESD (P = 0.368). The en bloc resection achieved for pT1a carcinomas exhibited similar to positive VM achieved through ESD (2.06% Vs. 1.02%, P = 1.000) for AAs. Nonetheless, EMR resulted in higher risk of positive VM (5.41% Vs. 0.25%, P

Abstract Chiral piperidine scaffolds are prevalent as the common cores of a large number of active pharmaceuticals in medical chemistry. This review outlined the diversity of chiral piperidine scaffolds in recently approved drugs, and also covers the scaffolds in leads and drug candidates. The significance of chiral piperidine scaffolds in drug design is also discussed in this article. With the introduction of chiral piperidine scaffolds into small molecules, the exploration of drug-like molecules can be benefitted from the following aspect: (1) modulating the physicochemical properties; (2) enhancing the biological activities and selectivity; (3) improving pharmacokinetic properties; and (4) reducing the cardiac hERG toxicity. Given above, chiral piperidine-based discovery of small molecules will be a promising strategy to enrich our molecules' library to fight against diseases.

BackgroundThe burden of chronic respiratory diseases has changed over the three decades. This study aims to describe the spatiotemporal trends of prevalence, mortality, and disability-adjusted life years (DALY) due to chronic respiratory diseases (CRDs) worldwide during 1990–2019 using data from the Global Burden of Disease Study 2019 (GBD 2019).MethodsThe prevalence, mortality, and DALY attributable to CRDs and risk factors from 1990 to 2019 were estimated. We also assessed the driving factors and potentiality for improvement with decomposition and frontier analyses, respectively.ResultsIn 2019, 454.56 [95% uncertainty interval (UI): 417.35–499.14] million individuals worldwide had a CRD, showing a 39·8% increase compared with 1990. Deaths due to CRDs were 3.97 (95%UI: 3.58–4.30) million, and DALY in 2019 was 103.53 (95%UI: 94.79–112.27) million. Declines by average annual percent change (AAPC) were observed in age-standardized prevalence rates (ASPR) (0.64% decrease), age-standardized mortality rates (ASMR) (1.92%), and age-standardized DALY rates (ASDR) (1.72%) globally and in 5 socio-demographic index (SDI) regions. Decomposition analyses represented that the increase in overall CRDs DALY was driven by aging and population growth. However, chronic obstructive pulmonary disease (COPD) was the leading driver of increased DALY worldwide. Frontier analyses witnessed significant improvement opportunities at all levels of the development spectrum. Smoking remained a leading risk factor (RF) for mortality and DALY, although it showed a downward trend. Air pollution, a growing factor especially in relatively low SDI regions, deserves our attention.ConclusionOur study clarified that CRDs remain the leading causes of prevalence, mortality, and DALY worldwide, with growth in absolute numbers but declines in several age-standardized estimators since 1990. The estimated contribution of risk factors to mortality and DALY demands the need for urgent measures to improve them.Systematic review registrationhttp://ghdx.healthdata.org/gbd-results-tool.

AIM: To investigate the incidence of preoperative dry eye and related factors in patients undergoing corneal refractive surgery to correct myopia. METHODS: A total of 141 patients with myopia who underwent corneal refractive surgery were surveyed by questionnaires, tear film break-up time (BUT) test, Schimer I test (SIt), corneal fluorescein staining (FL) test and diagnosed according to the currently recognized domestic diagnostic criteria for dry eye. Correlation analysis of factors such as age, gender, regular wearing of contact lens (CL), diopter (spherical equivalent), corneal thickness, and corneal curvature that may affect the onset of dry eye was carried out to clarify the main influencing factors. RESULTS: There were 64 patients (45.39%) diagnosed with dry eye. The male patients (20.31%) was significantly less than that of non-dry eye subjects (41.56%; χ2=7.260, P=0.007); the proportion of patients with dry eye wearing CL (81.25%) was significantly higher than that of non-dry eye subjects (51.95%; χ2=13.234, P

Abstract Background Due to negative results in clinical trials of postoperative chemoradiation for gastric cancer, at present, there is a tendency to move chemoradiation therapy forward in gastric and gastroesophageal junction (GEJ) adenocarcinoma. Several randomized controlled trials (RCTs) are currently recruiting subjects to investigate the effect of neo-adjuvant radiotherapy (NRT) in gastric and GEJ cancer. Large retrospective studies may be beneficial in clarifying the potential benefit of NRT, providing implications for RCTs. Methods We retrieved the clinicopathological and treatment data of gastric and GEJ adenocarcinoma patients who underwent surgical resection and chemotherapy between 2004 and 2015 from Surveillance, Epidemiology, and End Results (SEER) database. We compared survival between NRT and non-NRT patients among four clinical subgroups (T1–2N−, T1–2N+, T3–4N−, and T3–4N+). Results Overall, 5272 patients were identified, among which 1984 patients received NRT. After adjusting confounding variables, significantly improved survival between patients with and without NRT was only observed in T3–4N+ subgroup [hazard ratio (HR) 0.79, 95% confidence interval (CI): 0.66–0.95; P = 0.01]. Besides, Kaplan-Meier plots showed significant cause-specific survival advantage of NRT in intestinal type (P

Abstract Background Marital status proves to be an independent prognostic factor in a variety of cancers. However, its prognostic impact on gastric neuroendocrine neoplasms (G-NEN) has not been investigated. Methods We identified 3947 G-NEN patients from the Surveillance, Epidemiology, and End Results (SEER) database. Meanwhile, propensity scores for marital status were used to match 506 unmarried patients with 506 married patients. We used Kaplan–Meier method and multivariate Cox regression to analyse the association between marital status and the overall survival (OS) and G-NEN cause-specific survival (CSS) before matching and after matching. Results Married patients enjoyed better OS and CSS, compared with divorced/separated, single, and widowed patients. Multivariate Cox regression analysis indicated that unmarried status was associated with higher mortality hazards for both OS and CSS among G-NEN patients. Additionally, widowed individuals had the highest risks of overall (adjusted hazard ratio (HR): 1.56, 95% confidence interval (CI): 1.35–1.81, P

Abstract Targeting histone deacetylases (HDACs) has become an important focus in cancer inhibition. The pharmacophore of HDAC inhibitors (HDACis) reported so far is composed of three parts: a zinc-binding group (ZBG), a hydrophobic cavity-binding linker, and a surface-recognition cap interacting with HDAC surface located at the rim of active site cavity. This study aims to discover novel HDAC1 inhibitors with potent antitumor activities through modifying the cap and ZBG based on the structures of two marketed oral HDACis: chidamide and entinostat (MS-275). In this work, a series of benzamide derivatives were designed, synthesized, and evaluated for their antitumor activity. The structures of novel compounds were confirmed by 1H NMR (nuclear magnetic resonance) and ESI-MS (electrospray ionization mass spectrometry), and all target compounds were tested in both HDAC1 enzymatic inhibitory activity and cellular antiproliferative activity. Our data showed that the potent compound 3j exhibited good HDAC1 enzyme inhibitory activity and high antitumor cell proliferation activity against a selected set of cancer cells (PC-3, HCT-116, HUT-78, Jurkat E6–1, A549, Colo205, and MCF-7 cells) with no observed effects on human normal cells. In particular, compound 3j inhibited HDAC1 over the other tested HDAC isoforms (HDAC2, HDAC6, and HDAC8). Encouraged by this, the safety characteristics, molecular docking, preliminary pharmacokinetic characteristics, and antitumor effect in vivo of compound 3j were further investigated. Our data showed that compound 3j demonstrated acceptable safety profiles and favorable oral pharmacokinetic properties. Moreover, compound 3j could bind well with HDAC1 and showed significant antitumor activity in a PC-3 tumor xenograft model in vivo, though not as potent as positive control entinostat (MS-275). In summary, 3j might have therapeutic potential for the treatment of human cancers.

BackgroundFollow-up guidelines for serrated polyps (SPs) are mainly based on factors such as histology and size with limited evidence. The underlying genomic mechanism of SPs in relation to recurrence risks is utterly unknown.MethodsWe applied targeted next-generation sequencing (NGS) approach on two groups of SPs [polyp-relapsed SPs (PRSPs) vs. polyp-free SPs (PFSPs)] based on the surveillance outcomes to compare differences of DNA variants in 71 colorectal cancer-associated genes. A multicenter validation cohort was established longitudinally from 2016 to 2019 to confirm the relevant results.ResultsAmong the 96 NGS samples, at least one mutant after filtration was detected in 90 samples (94%). Molecular profiling presented BRAF, KRAS, and APC as top 3 mutated genes. FBXW7, MSH2, and ERBB2 might be recurrence-relevant, while DMD, BRCA1, and BRCA2 might be negatively correlated with recurrence. Notably, ERBB2 mutants (R678Q and V842I) (n = 5) had higher risks of polyp recurrence than the wild types (n = 85), with a median polyp-free interval of 15 months compared to 26 months [P < 0.001; hazard ratio (HR) = 4.9; 95% confidence interval (CI) = 1.9–12.8]. Furthermore, a multicenter cohort composed by 321 SPs verified that ERBB2-mutated SPs had increased risks of polyp recurrence (P < 0.001; HR = 3.7; 95% CI = 2.3–6.0) and advanced neoplastic lesion (ANL) recurrence (P < 0.001; HR = 10.0; 95% CI = 2.7–36.9) compared with wild-type SPs, respectively.ConclusionsOur results are emphasizing that SP individuals with ERBB2 mutants are at higher risks of subsequent colorectal neoplasms. ERBB2 mutants might work as facilitated markers for prediction of high-risk SPs and might implicate a potential mechanism in the serrated pathway to colorectal carcinoma (CRC).

Abstract In this study, the synthesis and biological evaluation of a variety of benzoheterocyclic-containing benzamide derivatives were described. Some of these compounds were proved to inhibiting the activity of histone deacetylase 1 (HDAC1) with IC50 values below the micromolar range, retarding proliferation of several human cancer cells, and surprisingly, not possessing toxicity to human normal cells and hERG K+ ion channels. Among those compounds, 3c was the most potent and efficacious derivative. Compound 3c was orally active and displayed excellent in vivo antitumor activity in a HCT-116 xenograft mice model.

Abstract Background and Aim To develop and validate radiomic prediction models using contrast-enhanced computed tomography (CE-CT) to preoperatively predict Ki-67 expression in gastrointestinal stromal tumors (GISTs). Method A total of 339 GIST patients from four centers were categorized into the training, internal validation, and external validation cohort. By filtering unstable features, minimum redundancy, maximum relevance, Least Absolute Shrinkage and Selection Operator (LASSO) algorithm, a radiomic signature was built to predict the malignant potential of GISTs. Individual nomograms of Ki-67 expression incorporating the radiomic signature or clinical factors were developed using the multivariate logistic model and evaluated regarding its calibration, discrimination, and clinical usefulness. Results The radiomic signature, consisting of 6 radiomic features had AUC of 0.787 [95% confidence interval (CI) 0.632–0.801], 0.765 (95% CI 0.683–0.847), and 0.754 (95% CI 0.666–0.842) in the prediction of high Ki-67 expression in the training, internal validation and external validation cohort, respectively. The radiomic nomogram including the radiomic signature and tumor size demonstrated significant calibration, and discrimination with AUC of 0.801 (95% CI 0.726–0.876), 0.828 (95% CI 0.681–0.974), and 0.784 (95% CI 0.701–0.868) in the training, internal validation and external validation cohort respectively. Based on the Decision curve analysis, the radiomics nomogram was found to be clinically significant and useful. Conclusions The radiomic signature from CE-CT was significantly associated with Ki-67 expression in GISTs. A nomogram consisted of radiomic signature, and tumor size had maximum accuracy in the prediction of Ki-67 expression in GISTs. Results from our study provide vital insight to make important preoperative clinical decisions.

AIM: To explore whether the same corneal curvature parameters and anterior chamber depth measured by Pentacam and VX120 have a good consistency and can replace each other. METHODS: This study enrolled 140 eyes of 70 patients ranging in age from 19 to 53y. All eyes underwent a comprehensive ophthalmologic examination including an anterior segment analysis with the VX120 system (Visionix-Luneau Technologies, Chartres, France) and Pentacam (Oculus Optikgerate GmbH) respectively. The comparison on corneal curvature parameters was done between Pentacam and VX120 using clustered signed rank test; the interclass correlation coefficients (ICC) with 95% confidence intervals (CI) was calculated for each parameter between Pentacam and VX120; the Bland-Altman plot of each parameter was supplemented. RESULTS: The anterior corneal curvature measured by VX120 was Ks: 44.00±1.78 D, KsAt: 89.45±22.18, Kf: 42.84±1.58 D, KfAt: 93.91±79.34; which measured by Pentacam was Ks: 43.80±1.82 D, KsAt: 91.17±21.40, Kf: 42.61±1.64 D, KfAt: 91.16±78.69. There was statistical difference between Pentacam and VX120 for anterior corneal curvature parameter (P

Abstract This study reported an asymmetric synthesis of 1,2-limonene epoxides. The absolute stereochemistry was controlled by a Jacobsen epoxidation of cis-1,2-limonene epoxide (with diastereomeric excess of 98%) and trans-1,2-limonene epoxide (with diastereomeric excess of 94%), which could be used as important raw materials for the preparation of related cannabinoid drugs.

Background and study aims The aim of the study was to evaluate short- and long-term outcomes of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in China because no study has yet been conducted to confirm its effectiveness in EGC in China. Patients and methods A total of 570 EGC samples from 537 patients were collected for evaluation of en bloc, complete, and curative resection using ESD. Data from 302 patients with at least 3 years of active follow-up were collected for analysis of recurrence of EGC and occurrence of metachronous GC (MGC). Short- and long-outcomes of mixed-type and pure differentiated EGC were also compared. Results En bloc resection rates of 96.0 %, 98.7 %, and 95.2 %, complete resection rates of 91.2 %, 96.6 % and 90.8 %, and curative resection rates of 83.0 %, 96.2 % and 88.2 % were achieved in all EGCs included in the study, those with absolute indication, and those with expanded indication, respectively. As a long-term outcome, recurrence was observed in 1.3 % of patients, 3-year and 5-year recurrence rates being 0.7 % and 1.2 %, respectively. Thirteen patients (4.3 %) exhibited MGCs during follow-up, all of which were resected in a second ESD. Conclusions The effectiveness of ESD for EGC in China was confirmed, with satisfactory short- and long-term outcomes. With scheduled follow-up, the outcomes for mixed-type EGC can be similar to those for pure differentiated EGC after complete resection without development of lymphovascular invasion.

Guidelines have differed in their opinion regarding the indications for endoscopic resection of gastric-neuroendocrine neoplasms (g-NENs) and duodenal-NENs (d-NENs). We examined the association between size and lymph node metastasis (LNM) to identify candidates most suitable for endoscopic resection. We identified 706 patients with T1/T2 g-NENs and 621 patients with T1/T2 d-NENs from the SEER database. The prevalence of LNM and risk factors associated with LNM were analyzed. LNM was present in 8.1% of patients with gastroduodenal neuroendocrine tumors (NETs) and 31.6% of patients with neuroendocrine carcinomas (NECs). Multivariate logistic regression indicated that tumor size >10mm, greater invasion depth, and poor differentiation were independently associated with LNM. In addition, the percentage of g-NETs invading submucosa with LNM increased with tumor size (≤10 mm,3.9%;11–20 mm,8.6%;>20 mm,16.1%). However, in contrast to the low LNM risk in patients with small g-NETs (≤10 mm), we found that LNM rate exceeded 5% even for patients with small submucosal-infiltrating d-NETs. Among patients with nodal-negative g-NETs, the cause specific survival (CSS) was similar for those who received surgical resection and endoscopic resection. Among patients with d-NETs, the CSS was better for those who received endoscopic resection. In conclusion, patients with d-NETs had a higher probability of LNM than those with g-NETs. Endoscopic resection can be utilized for curative treatment of submucosa-infiltrating g-NETs and intramucosal d-NETs when the size is 10 mm or less. These results reinforce the need to search for LNM in lesions that are larger than 10 mm.

Abstract A novel series of quinazoline derivatives were designed, synthesized, and evaluated as multikinase inhibitors. Most of these compounds showed antiproliferation activities of several human cancer cell lines and exhibited inhibition efficacy against the estimated glomerular filtration rate (EGFR) in the nanomolar level. Among those compounds, compound B5 (also named SIPI6473) displayed the maximum effect, and thus was chosen for further study. Our data revealed that B5 inhibited the activity of several kinases (such as EGFR, VEGFR2, and PDGFRα) that contributed to the development of non-small cell lung cancer (NSCLC). Besides, an in vivo study also showed that B5 inhibited tumor growth without signs of adverse effects in the A549 xenograft model. In conclusion, B5 may represent a new and promising drug for the treatment of NSCLC.

Background: Log odds of positive lymph nodes (LODDS) classification showed superiority over 8th edition N staging in predicting survival of small bowel adenocarcinoma (SBA) patients. The aim of this study was to develop and validate the Tumor, LODDS, and Metastasis (TLM) staging of SBA. Methods: Totally 1789 SBA patients from the Surveillance, Epidemiology, and End Results (SEER) database between 1988–2010, 437 patients from SEER database between 2011–2013 and 166 patients from multicenters were categorized into development, validation and test cohort, respectively. The TLM staging was developed in the development cohort using Ensemble Algorithm for Clustering Cancer Data (EACCD) method. C-index was used to assess the performance of the TLM staging in predicting cancer-specific survival (CSS) and was compared with the traditional 8th edition TNM staging. Findings: Four-category TLM staging designed for the development cohort showed higher discriminatory power than TNM staging in predicting CSS in the development cohort (0.682 vs. 0.650, P

Abstract This work seeks the development and validation of radiomics signatures from nonenhanced computed tomography (CT, NE‐RS) to preoperatively predict the malignancy degree of gastrointestinal stromal tumors (GISTs) and the comparison of these signatures with those from contrast‐enhanced CT. A dataset for 370 GIST patients was collected from four centers. This dataset was divided into cohorts for training, as well as internal and external validation. The minimum‐redundancy maximum‐relevance algorithm and the least absolute shrinkage and selection operator (LASSO) algorithm were used to filter unstable features. (a) NE‐RS and radiomics signature from contrast‐enhanced CT (CE‐RS) were built and compared for the prediction of malignancy potential of GIST based on the area under the receiver operating characteristic curve (AUC). (b) The radiomics model was also developed with both the tumor size and NE‐RS. The AUC values were comparable between NE‐RS and CE‐RS in the training (.965 vs .936; P = .251), internal validation (.967 vs .960; P = .801), and external validation (.941 vs .899; P = .173) cohorts in diagnosis of high malignancy potential of GISTs. We next focused on the NE‐RS. With 0.185 selected as the cutoff of NE‐RS for diagnosis of the malignancy potential of GISTs, accuracy, sensitivity, and specificity for diagnosis high‐malignancy potential GIST was 90.0%, 88.2%, and 92.3%, respectively, in the training cohort. For the internal validation set, the corresponding metrics are 89.1%, 94.9%, and 80.0%, respectively. The corresponding metrics for the external cohort are 84.6%, 76.1%, and 91.0%, respectively. Compared with only NE‐RS, the radiomics model increased the sensitivity in the diagnosis of GIST with high‐malignancy potential by 5.9% (P = .025), 2.5% (P = .317), 10.5% (P = .008) for the training set, internal validation set, and external validation set, respectively. The NE‐RS had comparable prediction efficiency in the diagnosis of high‐risk GISTs to CE‐RS. The NE‐RS and radiomics model both had excellent accuracy in predicting malignancy potential of GISTs.

The current histologically based grading system for glioma does not accurately predict which patients will have better outcomes or benefit from adjuvant chemotherapy. We proposed that combining the expression profiles of multiple long non-coding RNAs (lncRNAs) into a single model could improve prediction accuracy. We included 1,094 glioma patients from three different datasets. Using the least absolute shrinkage and selection operator (LASSO) Cox regression model, we built a multiple-lncRNA-based classifier on the basis of a training set. The predictive and prognostic accuracy of the classifier was validated using an internal test set and two external independent sets. Using this classifier, we classified patients in the training set into high- or low-risk groups with significantly different overall survival (OS, HR = 8.42, 95% CI = 4.99–14.2, p < 0.0001). The prognostic power of the classifier was then assessed in the other sets. The classifier was an independent prognostic factor and had better prognostic value than clinicopathological risk factors. The patients in the high-risk group were found to have a favorable response to adjuvant chemotherapy (HR = 0.4, 95% CI = 0.25–0.64, p < 0.0001). We built a nomogram that integrated the 10-lncRNA-based classifier and four clinicopathological risk factors to predict 3 and 5 year OS. Gene set variation analysis (GSVA) showed that pathways related to tumorigenesis, undifferentiated cancer, and epithelial–mesenchymal transition were enriched in the high-risk groups. Our classifier built on 10-lncRNAs is a reliable prognostic and predictive tool for OS in glioma patients and could predict which patients would benefit from adjuvant chemotherapy.

Background: The prognostic roles of three common lymph node staging schemes, number of positive lymph nodes (pN), lymph node ratio (LNR) and log odds of positive lymph nodes (LODDS) in small bowel adenocarcinoma (SBA) are unclear. We assessed their prognostic ability in SBA. Methods: A total of 2128 patients diagnosed with SBA between 1988 and 2010 from the Surveillance, Epidemiology, and End Results (SEER) database and 186 patients from 15 hospitals in France and China were identified. We evaluated the prognostic ability of the schemes in both continuous and stratified patterns using R2, Harrell's C, and time-dependent receiver operating characteristic curve analyses. Findings: For continuous pattern, the LODDS had a better capacity of discrimination and higher accuracy of prognosis than pN and LNR. Similarly, the stratified LODDS classification had a better performance of discrimination and higher accuracy of prognosis than the pN and LNR classification. The multivariable model using the LODDS classification also showed superiorly predictive accuracy and discriminatory capacity to those of the 7th and, 8th TNM node and LNR classification. These results were fully validated in an independent international multicentre cohort. Interpretation: The LODDS scheme showed a better prognostic performance than the LNR or pN schemes in patients with SBA regardless of continuous or stratified pattern. The LODDS scheme could serve as an auxiliary to lymph node staging systems in future revisions of the American Joint Committee on Cancer (AJCC) manual. Fund: This work was funded by the Zhejiang Province Natural Science Fund of China. Keywords: Small bowel adenocarcinoma, Log odds of positive lymph nodes, Lymph node ratio, Number of positive lymph nodes, Prognosis, Multicentre cohort

Background: Current methods of lymph node (LN) staging are controversial in predicting the survival of SBA. We aimed to develop an alternative LN-classification-based nomogram to individualize SBA prognosis. Methods: Based on the data from the Surveillance, Epidemiology, and End Results (SEER) database of patients diagnosed with SBA between 2004 and 2014, we identified the cut-off points for the number of LNs examined and the number found to be metastatic using the K-adaptive partitioning (KAPS) algorithm. Using metastatic LNs, a nomogram predicting the survival of SBA was derived, internally and externally validated, and measured by calibration curve, C-index, and decision curve analysis (DCA), and compared to the 8th TNM stage. Results: A total of 1516 patients were included. The cut-off of 17 was the optimal examined LN number. For metastatic LN numbers, the cut-off points were 0, 2, and 8. The C-index for the nomogram was higher than the 8th TNM staging (internal: 0.734; 95% CI, 0.693 to 0.775 vs. 0.677; 95% CI, 0.652 to 0.702, P 8 metastatic LNs and set the least examined LN number to 17. A nomogram based on this staging showed great clinical usability than TNM staging for predicting the survival of SBA patients. Keywords: Small bowel carcinoma, Metastatic lymph node, Survival predicting model, TNM staging

Background: There existed limited evidence about prognosis of young-onset early colorectal cancer (ECRC). In the present study, we aimed to compare prognosis between patients with young-onset ECRCs and patients with conventional ECRCs.Method: Patients with surgically resected, histologically diagnosed ECRCs were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Young-onset ECRC was defined as ECRC occurring in patients aged

Background: This study was designed to validate the prognostic significance of the ratio of positive to examined lymph nodes (LNR) in patients with colorectal cancer.Methods: 218,314 patients from the SEER database and 1,811 patients from the three independent multicenter were included in this study. The patients were divided into 5 groups on a basis of previous published LNR: LNR0, patients with no metastatic lymph nodes; LNR1, patients with the LNR between 0.1 and 0.17; LNR2, patients with the LNR between 0.18 and 0.41; LNR3, patients with the LNR between 0.42 and 0.69; LNR4, patients with the LNR >0.7. The 5-year OS and CSS rate were estimated using Kaplan-Meier method and the survival difference was tested using log-rank test. Multivariate Cox analysis was used to further assess the influence of the LNR on patients' outcome.Results: The 5-year OS rate of patients within LNR0 to LNR4 group was 71.2, 55.8, 39.3, 22.6, and 14.6%, respectively (p < 0.001) in the SEER database. While the 5-year OS rate of those with LNR0 to LNR4 was 75.2, 66.1, 48.0, 34.0, and 17.7%, respectively (p < 0.001) in the international multicenter cohort. In the multivariate analysis, LNR was demonstrated to be a strong prognostic factor in patients with < 12 and ≥12 metastatic lymph nodes. Furthermore, the LNR had a similar impact on the patients' prognosis in colon cancer and rectal cancer.Conclusion: The LNR allowed better prognostic stratification than the positive node (pN) in patients with colorectal cancer and the cut-off values were well validated.