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Abstract Background Pancreatic adenocarcinoma (PAAD) is the most frequent kind of pancreatic cancer (PC). Recent studies suggest that lipid metabolism facilitates tumorigenesis, disease progression, and resistance to therapy by promoting lipid synthesis, accumulation, and breakdown. Thus, exploring the lipid metabolism network could unveil novel therapeutic avenues for early detection, precision medicine, and prognostication in PAAD. This project intends to develop new lipid metabolism-related biomarkers for PAAD diagnosis and investigate the link between important genes and immune cell infiltration (ICI). Methods Tissue samples from 20 PAAD patients and 20 healthy controls were obtained. Analysis were focused on the datasets GSE71729 and GSE16515, which include samples of PAAD (n = 161) and those from healthy human tissue (n = 61), derived from the GEO database. Knockdown of PCSK9 on PC cells were conducted by si-RNA and sh-RNA. Migration and cell functional experiments were performed to assess the role of PCSK9 in cell multiplication. Furthermore, a xenograft mouse model was employed to confirm PCSK9's function in vivo. Results The expression level of Proprotein convertase subtilisin/kexin type 9 (PCSK9) is significantly elevated in tissues affected by PAAD when compared to normal tissues. Survival analyses indicated that increased PCSK9 levels are inversely related to overall and disease-free survival (DFS). PCSK9’s functional annotation associated it with the cell cycle and metabolism, especially energy metabolism. Examination of ICI data determined that PCSK9 expression demonstrated an unambiguous association with the M0 macrophages, T follicular helper cells (Tfh), gamma delta T cells and activated DC, and an inverse relationship with Monocytes, CD8+ T cells, memory B cells, resting CD4+ memory T cells, activated NK cells and resting DC abundance. PCSK9 expression knockdown has the ability to impede PC cells’ migration and proliferation. Conclusion Our study identified PCSK9 as a critical gene in PAAD. Expression levels of PCSK9 varied between PAAD and normal samples. ROC analysis verified PCSK9's strong capacity to differentiate PC from normal samples. Importantly, PCSK9 expression was considerably elevated in PC cell lines and tissues. Furthermore, PCSK9 stimulates the migration and proliferation of tumor cells in vivo and vitro.

The pollution of indoor environments and the consequent health risks associated with thirdhand smoke (THS) are increasingly recognized in recent years. However, the carcinogenic potential of THS and its underlying mechanisms have yet to be thoroughly explored. In this study, we examined the effects of short-term THS exposure on the development of gastric cancer (GC) in vitro and in vivo. In a mouse model of spontaneous GC, CC036, we observed a significant increase in gastric tumor incidence and a decrease in tumor-free survival upon THS exposure as compared to control. RNA sequencing of primary gastric epithelial cells derived from CC036 mice showed that THS exposure increased expression of genes related to the extracellular matrix and cytoskeletal protein structure. We then identified a THS exposure-induced 91-gene expression signature in CC036 and a homologous 84-gene signature in human GC patients that predicted the prognosis, with secreted phosphoprotein 1 (SPP1) and tribbles pseudokinase 3 (TRIB3) emerging as potential targets through which THS may promote gastric carcinogenesis. We also treated human GC cell lines in vitro with media containing various concentrations of THS, which, in some exposure dose range, significantly increased their proliferation, invasion, and migration. We showed that THS exposure could activate the epithelial-mesenchymal transition (EMT) pathway at the transcript and protein level. We conclude that short-term exposure to THS is associated with an increased risk of GC and that activation of the EMT program could be one potential mechanism. Increased understanding of the cancer risk associated with THS exposure will help identify new preventive and therapeutic strategies for tobacco-related disease as well as provide scientific evidence and rationale for policy decisions related to THS pollution control to protect vulnerable subpopulations such as children.

Abstract Background Human endogenous retrovirus subfamily H long terminal repeat associating protein 2, (HHLA2), a member of B7 family, exhibits heightened expression in various malignant tumors. However, the exact functions of HHLA2 in pancreatic cancer (PC) remain incompletely elucidated. Methods We initially conducted an analysis of the B7 family members’ expression pattern in pancreatic tumor samples and adjacent normal tissues using The Cancer Genome Atlas (TCGA) database. Subsequently, immunohistochemistry, RT-qPCR and western blot methods were used to assess HHLA2 expression levels in PC tissues and cell lines. Furthermore, after silencing HHLA2 in PC cell lines, cell migration and proliferation of PC cells were detected by wound healing and CCK-8 assays, and cell invasion of PC cells was detected by transwell assays. We also investigated the regulation of epithelial-mesenchymal transition (EMT) markers and levels of EGFR, MEK, ERK1/2, mTOR and AKT via western blot analysis. Finally, the correlation between HHLA2 expression and immune infiltration was further explored. Results Silencing of HHLA2 resulted in the inhibition of PC cell proliferation, migration and invasion, potentially through the suppression of the EGFR/MAPK/ERK and mTOR/AKT signaling pathway. Additionally, silencing HHLA2 led to the inhibition of M2-type polarization of tumor associated macrophages (TAMs). Conclusion The knockdown of HHLA2 was observed to inhibit the migration and invasion of PC cells through the regulation of the EMT process and EGFR/MAPK/ERK and mTOR/AKT pathway. Furthermore, silencing HHLA2 was found to modulate M2 polarization of TAMs. These finding suggest that HHLA2 could be a promising therapeutic target for Pancreatic cancer.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is recognized as the most aggressive and fatal malignancy. A previous study reported that PDAC patients who exhibit elevated levels of DDX3X have a poor prognosis and low overall survival rate. However, the underlying molecular mechanism remains unclear. This study aimed to investigate the specific roles of DDX3X in PDAC. Multiple bioinformatics analyses were used to evaluate DDX3X expression and its potential role in PDAC. In vitro and in vivo studies were performed to assess the effects of DDX3X on PDAC cell growth. Furthermore, Western blotting, quantitative PCR, immunohistochemistry, immunofluorescence, mass spectrometry, coimmunoprecipitation and multiplexed immunohistochemical staining were conducted to identify the specific regulatory mechanism in PDAC. The results verified that DDX3X expression is notably upregulated in the tumor tissue vs. normal tissue of PDAC patients. DDX3X knockdown markedly suppressed the proliferation, invasion and migration of PDAC cells in vitro and inhibited tumor growth in vivo. Conversely, overexpression of DDX3X induced the opposite effect. Further studies supported that the DDX3X protein can associate with sirtuin 7 (SIRT7) to stimulate PDAC carcinogenesis and progression. Furthermore, SIRT7 inhibition significantly impeded DDX3X-mediated tumor growth both ex vivo and in vivo. The results also revealed that programmed death ligand 1 (PD-L1) expression is positively correlated with DDX3X expression. These results reveal significant involvement of the DDX3X-SIRT7 axis in the initiation and advancement of PDAC and offer previously undiscovered therapeutic options for PDAC management.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease refractory to all targeted and immune therapies. However, our understanding of PDAC microenvironment especially the metastatic microenvironment is very limited partly due to the inaccessibility to metastatic tumor tissues. Here, we present the single-cell transcriptomic landscape of synchronously resected PDAC primary tumors and matched liver metastases. We perform comparative analysis on both cellular composition and functional phenotype between primary and metastatic tumors. Tumor cells exhibit distinct transcriptomic profile in liver metastasis with clearly defined evolutionary routes from cancer cells in primary tumor. We also identify specific subtypes of stromal and immune cells critical to the formation of the pro-tumor microenvironment in metastatic lesions, including RGS5+ cancer-associated fibroblasts, CCL18+ lipid-associated macrophages, S100A8+ neutrophils and FOXP3+ regulatory T cells. Cellular interactome analysis further reveals that the lack of tumor-immune cell interaction in metastatic tissues contributes to the formation of the immunosuppressive microenvironment. Our study provides a comprehensive characterization of the transcriptional landscape of PDAC liver metastasis.

Abstract BRD4 is a member of the BET protein family involved in chromatin remodeling and transcriptional regulation. Several BET inhibitors (BETi) have entered clinical trials, demonstrating potential in inducing cancer cell apoptosis and tumor regression. However, resistance to BETi is common in solid tumors. In pancreatic cancer, it is found that cancer‐associated fibroblasts (CAFs) in the tumor microenvironment reduce the BET inhibitor JQ1 sensitivity by inducing BRD4 expression. Moreover, CAFs play a crucial role in the formation of a dense stromal barrier. Therefore, targeting CAFs in the tumor microenvironment of pancreatic cancer not only enhances cancer cells sensitivity to JQ1 but also increases drug perfusion and improves oxygen supply, thus reducing glycolysis and limiting energy supply. To address this challenge, a homologous targeting mechanism utilizing activated fibroblast membrane‐coated liposomes is proposed for specific drug precise target to CAFs‐rich pancreatic cancer. Additionally, TAT peptides enable liposomes penetration, delivering PFD for targeted anti‐fibrotic therapy, reducing extracellular matrix generation and glycolysis, and enhancing JQ1 delivery and sensitivity. In conclusion, the findings indicate the tremendous potential of this CAFs‐targeting liposomal delivery system in pancreatic cancer.

Monitoring and control of humidity is important for industry, agriculture and human activities. Currently, it is achallengeto develop highly sensitive humidity sensors with both the response time and recovery time less than 1 s.Therefore, it isdifficult to dynamically monitor rapid changes in humidity. Here, we report a resistive humidity sensor based on an ultrathin graphene oxide (GO) film, which is formed by stacked single-layered GO. Both the response and recovery time of the sensor is less than 1 s in the range of 10 %–95 % relative humidity (RH). The shortest response and recovery time of the reported GO-based resistive humidity sensor can be 0.33 s at 10 % RH, indicating the fastest response and recovery property to date. Moreover, the sensor is sensitive, and it can accurately detect the distance between the sensor and the human finger as well as the strength of the human breath. The simple preparation, microscale structure, and extremely fast response make the GO-based sensor a new alternative for integrated humidity sensors with real-time monitoring functions.

Objective. Abnormal lipid metabolism is known to influence the malignant behavior of gastric cancer. However, the underlying mechanism remains elusive. In this study, we comprehensively analyzed the biological significance of genes involved in lipid metabolism in advanced gastric cancer (AGC). Methods. We obtained gene expression profiles from The Cancer Genome Atlas (TCGA) database for early and advanced gastric cancer samples and performed differential expression analysis to identify specific lipid metabolism-related genes in AGC. We then used consensus cluster analysis to classify AGC patients into molecular subtypes based on lipid metabolism and constructed a diagnostic model using least absolute shrinkage and selection operator- (LASSO-) Cox regression analysis and Gene Set Enrichment Analysis (GSEA). We evaluated the discriminative ability and clinical significance of the model using the Kaplan-Meier (KM) curve, ROC curve, DCA curve, and nomogram. We also estimated immune levels based on immune microenvironment expression, immune checkpoints, and immune cell infiltration and obtained hub genes by weighted gene co-expression network analysis (WGCNA) of differential genes from the two molecular subtypes. Results. We identified 6 lipid metabolism genes that were associated with the prognosis of AGC and used consistent clustering to classify AGC patients into two subgroups with significantly different overall survival and immune microenvironment. Our risk model successfully classified patients in the training and validation sets into high-risk and low-risk groups. The high-risk score predicted poor prognosis and indicated low degree of immune infiltration. Subgroup analysis showed that the risk model was an independent predictor of prognosis in AGC. Furthermore, our results indicated that most chemotherapeutic agents are more effective for AGC patients in the low-risk group than in the high-risk group, and risk scores for AGC are strongly correlated with drug sensitivity. Finally, we performed qRT-PCR experiments to verify the relevant results. Conclusion. Our findings suggest that lipid metabolism-related genes play an important role in predicting the prognosis of AGC and regulating immune invasion. These results have important implications for the development of targeted therapies for AGC patients.

Introduction: Hypoxia is one of the important reasons for the poor therapeutic efficacy of current pancreatic cancer treatment, and the dense stroma of pancreatic cancer restricts the diffusion of oxygen within the tumor. Methods: A responsive oxygen-self-supplying adv-miRT-CAT-KR (adv-MCK) cascade reaction system to improve hypoxia in pancreatic cancer is constructed. We utilized various experiments at multiple levels (cells, organoids, in vivo) to investigate its effect on pancreatic cancer and analyzed the role of immune microenvironment changes in it through high-throughput sequencing. Results: The adv-MCK system is an oncolytic adenovirus system expressing three special components of genes. The microRNA (miRNA) targets (miRTs) enable adv-MCK to selectively replicate in pancreatic cancer cells. Catalase catalyzes the overexpressed hydrogen peroxide in pancreatic cancer cells to generate endogenous oxygen, which is catalyzed by killerRed to generate singlet oxygen (1O2) and further to enhance the oncolytic effect. Meanwhile, the adv-MCK system can specifically improve hypoxia in pancreatic cancer, exert antitumor effects in combination with photodynamic therapy, and activate antitumor immunity, especially by increasing the level of γδ T cells in the tumor microenvironment. Conclusion: The responsive oxygen-self-supplying adv-MCK cascade reaction system combined with photodynamic therapy can improve the hypoxic microenvironment of pancreatic cancer and enhance antitumor immunity, which provides a promising alternative treatment strategy for pancreatic cancer.

Lithium compounds, a classic class of metal complex medicine that target GSK 3β and are widely known as mood-stabilizer, have recently been reported as potential anti-tumor drugs. The objective of this investigation was to explore the anticancer potential of lithium chloride (LiCl) and elucidate its mode of action in pancreatic cancer cells. The MTT, colony formation, and Edu assay were used to evaluate the impact of LiCl on pancreatic cancer cell proliferation. Various methods were employed to investigate the anti-tumor activity of LiCl and its underlying mechanisms. Cell cycle analysis and apoptosis detection assays were utilized for in vitro experiments, while the orthotopic pancreatic cancer mouse model was employed to evaluate the effectiveness of LiCl treatment in vivo. Furthermore, the impact of LiCl on the proliferation of patient-derived organoids was also studied. The results demonstrated that LiCl inhibited the proliferation of pancreatic cancer (PC) cells, induced G2/M phase arrest, and activated apoptosis. Notably, the triggering of endoplasmic reticulum (ER) stress by LiCl was observed, leading to the activation of the PERK/CHOP/GADD34 pathway, which subsequently promoted apoptosis in PC cells. In the future, Lithium compounds could become an essential adjunct in the treatment of human pancreatic cancer.

Objective To identify a case of antibody against highly prevalent antigen through molecular biology technology. Methods Blood group typing, unexpected antibody identification and cross matching were performed by serological test, and genetic testing of Diego blood group was performed by molecular biology technology. Results Serological test showed that there was a high prevalence of anti-Dib in the serum of the patient. Gene sequencing showed that the genotype of the patient was Di(a+b-) . Two cases with Di(a+b-) matched with the patient were screened from 856 blood donors. Conclusion The combined detection method based on serological test supplemented by molecular biology technology is beneficial to the detection of antibody against highly prevalent antigens, and is of great significance for ensuring the safety of clinical blood transfusion.

The mortality rates of gastric cancer remain high due to limited therapeutic strategies. As a highly selective inhibitor of the BD2 domain of BET family proteins, ABBV-744 has potent chemotherapeutic activity against various human solid tumors. However, whether ABBV-744 has potential anti-tumor effects in gastric cancer remain largely unknown. In this study, we evaluated the effect of ABBV-744 on gastric cancer cells and explored the possible underlying mechanisms. We found that ABBV-744 inhibited the growth of gastric cancer cells and patient-derived tumor organoids in a dose-dependent manner. Cellular experiments revealed that ABBV-744 induced mitochondria damage, reactive oxygen species accumulation, cell cycle arrest and apoptotic cell death in gastric cancer cells. Transcriptomic analysis using RNA-sequencing data identified autophagy as a crucial pathway involved in the cell death caused by ABBV-744. Mechanically, further studies showed that ABBV-744 induced autophagy flux in gastric cancer cells by inactivating PI3K/AKT/mTOR/p70S6k and activating the MAPK signaling pathways. In vivo mouse xenograft studies demonstrated that ABBV-744 significantly suppressed the growth of gastric cancer cells via inducing autophagy. Taken together, our results suggest that ABBV-744 is a novel drug candidate for gastric cancer.

Background: Chemoresistance is a common event after cancer chemotherapy, including gastric cancer (GC). Cisplatin has been reported to induce the DNA damage response (DDR), thus leading to chemoresistance. VE-821, a specific inhibitor of ATR, has been proven to suppress a variety of solid malignancies effectively. Our study aimed to explore the effect of VE-821 on enhancing the chemical sensitivity to cisplatin and clarify the potential molecular mechanisms. Methods: Cell viability and apoptosis of MKN-45 and AGS were measured by CCK8 and flow cytometry assay respectively. Western blotting was used to detect the expression of target proteins. TCGA database was used to analyze the correlation between the ATR expression with the prognosis of GC patients. The viability of GC organoids was detected by Cell Titer Glo (CTG) through luminescence. Results: Cisplatin inhibited the proliferation and induced apoptosis of GC cells with a relatively high IC50 value, and increased the phosphorylation levels of ATR-CHK1 and H2AX. VE-821 achieved the same effects but by downregulating the phosphorylation levels of the ATR-CHK1 pathway. Besides, higher ATR expression in GC tissues was positively correlated with higher pathological stage in GC patients. Interestingly, ATR inhibition reversed cisplatin-induced STAT3 activation and enhanced H2AX levels. Moreover, VE-821 significantly sensitized GC cells to cisplatin, and these two drugs had synergistic effects in GC cell lines, organoids, and in vivo. Conclusion: Our results suggested VE-821 sensitized GC cells to cisplatin via reversing DDR activation. And VE-821 treatment may be a promising therapeutic strategy for GC patients with cisplatin resistance.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is characterised by accelerated lipid deposition, aberrant inflammation, and excessive extracellular matrix production in the liver. Short of effective intervention, NAFLD can progress to cirrhosis and hepatocellular carcinoma. In the present study we investigated the involvement of the C–C motif ligand 11 (CCL11) in NAFLD pathogenesis. Methods: NAFLD was induced by feeding mice with a high-fat high-carbohydrate diet. CCL11 targeting was achieved by genetic deletion or pharmaceutical inhibition. The transcriptome was analysed using RNA-seq. Results: We report that CCL11 expression was activated at the transcription level by free fatty acids (palmitate) in hepatocytes. CCL11 knockdown attenuated whereas CCL11 treatment directly promoted production of pro-inflammatory/pro-lipogenic mediators in hepatocytes. Compared with wild-type littermates, CCL11 knockout mice displayed an ameliorated phenotype of NAFLD when fed a high-fat high-carbohydrate diet as evidenced by decelerated body weight gain, improved insulin sensitivity, dampened lipid accumulation, reduced immune cell infiltration, and weakened liver fibrosis. RNA-seq revealed that interferon regulatory factor 1 as a mediator of CCL11 induced changes in hepatocytes. Importantly, CCL11 neutralisation or antagonism mitigated NAFLD pathogenesis in mice. Finally, a positive correlation between CCL11 expression and NAFLD parameters was identified in human patients. Conclusions: Our data suggest that CCL11 is a novel regulator of NAFLD and can be effectively targeted for NAFLD intervention. Impact and implications: Non-alcoholic fatty liver disease (NAFLD) precedes cirrhosis and hepatocellular carcinoma. In this paper we describe the regulatory role of CCL11, a C–C motif ligand chemokine, in NAFLD pathogenesis. Our data provide novel insights and translational potential for NAFLD intervention.

Abstract No fully validated risk-stratification strategies have been established in China where colonoscopies resources are limited. We aimed to develop and validate a fecal immunochemical test (FIT)-based risk-stratification model for colorectal neoplasia (CN); 10,164 individuals were recruited from 175 centers nationwide and were randomly allocated to the derivation (n = 6776) or validation cohort (n = 3388). Multivariate logistic analyses were performed to develop the National Colorectal Polyp Care (NCPC) score, which formed the risk-stratification model along with FIT. The NCPC score was developed from eight independent predicting factors and divided into three levels: low risk (LR 0–14), intermediate risk (IR 15–17), and high risk (HR 18–28). Individuals with IR or HR of NCPC score or FIT+ were classified as increased-risk individuals in the risk-stratification model and were recommended for colonoscopy. The IR/HR of NCPC score showed a higher prevalence of CNs (21.8%/32.8% vs. 11.0%, P

Abstract Infiltration of eosinophils is associated with and contributes to liver regeneration. Chemotaxis of eosinophils is orchestrated by the eotaxin family of chemoattractants. We report here that expression of eotaxin-1 (referred to as eotaxin hereafter), but not that of either eotaxin-2 or eotaxin-3, were elevated, as measured by quantitative PCR and ELISA, in the proliferating murine livers compared to the quiescent livers. Similarly, exposure of primary murine hepatocytes to hepatocyte growth factor (HGF) stimulated eotaxin expression. Liver specific deletion of Brahma-related gene 1 (Brg1), a chromatin remodeling protein, attenuated eosinophil infiltration and down-regulated eotaxin expression in mice. Brg1 deficiency also blocked HGF-induced eotaxin expression in cultured hepatocytes. Further analysis revealed that Brg1 could directly bind to the proximal eotaxin promoter to activate its transcription. Mechanistically, Brg1 interacted with nuclear factor kappa B (NF-κB)/RelA to activate eotaxin transcription. NF-κB knockdown or pharmaceutical inhibition disrupted Brg1 recruitment to the eotaxin promoter and blocked eotaxin induction in hepatocytes. Adenoviral mediated over-expression of eotaxin overcame Brg1 deficiency caused delay in liver regeneration in mice. On the contrary, eotaxin depletion with RNAi or neutralizing antibodies retarded liver regeneration in mice. More important, Brg1 expression was detected to be correlated with eotaxin expression and eosinophil infiltration in human liver specimens. In conclusion, our data unveil a novel role of Brg1 as a regulator of eosinophil trafficking by activating eotaxin transcription.

Abstract Background and aims Risk stratification to identify patients with high risk of variceal rebleeding is particularly important in patients with decompensated cirrhosis. In clinical practice, eliminating gastroesphageal varices thoroughly after sequential endoscopic treatment reduces the rebleeding rate, however, no simple method has been build to predict high risk of variceal rebleeding. We conducted this study to explore the value of the number of endoscopic sessions required to eradicate gastroesphageal varices in identifying high risk of rebleeding. Patients and methods Consecutive cirrhotic patients received sequential endoscopic therapy between January 2015 and March 2020 were enrolled. Endoscopic treatment was performed every 1–4 weeks until the eradication of varices. The primary endpoint was variceal rebleeding. Results A total of 146 patients were included of which 60 patients received standard therapy and 86 patients underwent sequential endoscopic treatment alone. The cut-off value of the number of sequential endoscopic sessions is 3.5 times. Variceal rebleeding was significant higher in patients with endoscopic sessions > 3 times versus ≤ 3 times (61.5% vs. 17.5%, p 3 times in group of standard therapy (19.6% vs. 88.9%, p

Tin-based perovskites are promising for realizing lead-free perovskite solar cells; however, there remains a significant challenge to achieving high-performance tin-based perovskite solar cells. In particular, the device fill factor was much lower than that of other photovoltaic cells. Therefore, understanding how the fill factor was influenced by device physical mechanisms is meaningful. In this study, we reported a method to improve the device fill factor using a thin cesium iodide layer modification in tin-based perovskite cells. With the thin passivation layer, a high-quality perovskite film with larger crystals and lower charge carrier densities was obtained. As a result, the series resistance of devices was decreased; the shunt resistance of devices was increased; and the non-radiative recombination of devices was suppressed. Consequently, the fill factor, and the device efficiency and stability were greatly enhanced. The champion tin-based perovskite cells showed a fill factor of 63%, an efficiency of 6.1% and excellent stability. Our study reveals that, with a moderate thin layer modification strategy, the long-term stability of tin-based PSCs can be developed.

Abstract Background Prevalence of inflammatory bowel disease (IBD) is increasing in China. The EXPLORE study evaluated the incidence and indicators of suboptimal responses to first-line anti-tumor necrosis factor (TNF) in patients with ulcerative colitis (UC) or Crohn’s disease (CD). We present results for the mainland China subgroup. Methods A retrospective chart review was performed in adults with IBD at 10 centers in mainland China who initiated anti-TNF therapy between 01 March 2010 and 01 March 2015. The cumulative incidence of suboptimal response to first-line anti-TNF therapy was assessed over 24 months using the Kaplan–Meier method. Indicators of suboptimal response were: dose escalation, discontinuation, augmentation with non-biologic therapy, or IBD-related surgery/hospitalization. At site initiation, a survey was conducted with participating physicians to identify barriers to anti-TNF use. Results Of 287 patients (72% male) examined, 16/35 (45.7%) with UC and 123/252 (48.8%) with CD experienced a suboptimal response to first-line anti-TNF therapy at any point during the observation period (median 27.6 and 40.0 months, respectively). At 1 and 2 years post anti-TNF initiation, the cumulative incidence of suboptimal response was 51.4% and 75.7% for UC and 45.4% and 57.0% for CD, respectively. Median time to first suboptimal response was 7.2 months for UC and 14.3 months for CD. The most frequent indicator of suboptimal response was discontinuation of anti-TNF therapy (9/16, 56.3%) for UC and IBD-related hospitalization for CD (69/123, 56.1%) followed by augmentation with non-biologic therapy for both cohorts (5/16, 31.3% for UC and 28/123, 22.8% for CD). Dose escalation was the least frequent indicator of suboptimal response to anti-TNF therapy (CD: 4/123, 3.3%; UC: not cited as an indicator). The cumulative incidence of suboptimal response within 4 months of first-line anti-TNF therapy (primary non-response) was over 30% in both cohorts. Financial reasons and reimbursement were identified by surveyed physicians as the most common barriers to prescribing an anti-TNF therapy. Conclusions Over one-half of patients with IBD are at risk of experiencing a suboptimal response to first-line anti-TNF therapy at 2 years post-initiation in China. This study highlights a substantial unmet need associated with anti-TNF therapies in China. (Clinicaltrials.gov identifier: NCT03090139).

Persistent hepatic cellular metabolic stress and liver inflammatory stimuli are key signatures of nonalcoholic steatohepatitis (NASH). DDX3X is a vital molecule involved in cell fate decisions in both pro-survival stress granule (SG) and pro-death NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome assembly in response to stress signals. However, the role of DDX3X in NASH remains unclear. We characterized the cell type-specific roles of DDX3X in NASH. Human liver tissues from NASH patients and normal control subjects were collected to assess DDX3X expression and distribution. Nutritional steatohepatitis models were constructed by feeding macrophage-specific DDX3X knockout (DDX3XΔMφ), hepatocyte-specific DDX3X knockout (DDX3XΔhep), and wild-type control (DDX3Xfl/fl) mice a high-fat and high-cholesterol (HFHC) diet, a methionine- and choline-deficient (MCD) diet, and a high-fat/high-iron/high-fructose/high-cholesterol, low-methionine, and choline-deficient (HFHIHFHC-MCD) diet. The study demonstrated that DDX3X was predominantly expressed in macrophages and hepatocytes in control liver tissues, and its expression was down-regulated in patients or mice with NASH. Compared to DDX3Xfl/fl littermates, DDX3XΔMφ mice showed improved liver histology in nutritional steatohepatitis models. Loss of macrophage DDX3X inhibited NLRP3 inflammasome-mediated pyroptosis, causing anti-inflammatory M2 polarization and alleviating hepatocyte steatohepatitic changes. DDX3XΔhep mice developed marked steatohepatitis in multiple nutritional steatohepatitis models compared to DDX3Xfl/fl littermates. DDX3X-deleted hepatocytes showed impaired SG assembly, leading to increased sensitivity and intolerance to metabolic stimulation and resultant steatohepatitis. In conclusion, DDX3X plays opposite roles in different cell types during the progression of NASH. A better understanding of the cell-specific differences in the crosstalk between SG formation and NLRP3 activation is crucial for developing prospective targeted DDX3X inhibitors for the treatment of NASH.

Background and Aims. Currently sedation is a common practice in colonoscopy to reduce pain of patients and improve the operator satisfaction, whereas its impact on examination quality, especially adenoma detection rate (ADR) is still controversial. Thus, we aimed to investigate the association of sedation with ADR. Methods. Consecutive patients receiving colonoscopy between January 2017 and January 2020 at the Nanjing Drum Tower Hospital, Nanjing, China, were collected. Univariate and multivariate logistic regression models were performed to investigate the association between sedation and ADR. Subgroup analysis and propensity score matching (PSM) analysis, as sensitivity analysis, were performed to validate the independent effect. Results. The ADR was significantly higher in cases with sedation (ADR: 36.9% vs. 29.1%, odds ratio [OR]: 1.42, 95% confidence interval [CI]: 1.31–1.55, P0.05) and PSM analysis (ADR: 37.6% vs. 29.1%, OR: 1.47, 95% CI: 1.33–1.63, P

Abstract Metformin, traditionally regarded as a hypoglycemic drug, has been studied in other various fields including inflammation. The specific mechanism of metformin’s effect on immune cells remains unclear. Herein, it is verified that LPS-induced macrophages are characterized by enhanced endogenous fatty acid synthesis and the inhibition of fatty acid synthase (FASN) downregulates proinflammatory responses. We further show that metformin could suppress such elevation of FASN as well as proinflammatory activation in macrophages. In vivo, metformin treatment ameliorates dextran sulfate sodium (DSS)-induced colitis through impairing proinflammatory activation of colonic lamina propria mononuclear cells (LPMCs). The reduction of FASN by metformin hinders Akt palmitoylation, which further disturbs Akt membrane attachment and its phosphorylation. Metformin-mediated suppression of FASN/Akt pathway and its downstream MAPK signaling contributes to its anti-inflammatory role in macrophages. From the perspective of immunometabolism, our work points towards metformin utilization as an effective and potential intervention against macrophages-involved inflammatory diseases.

Abstract Chemotherapeutics remain the first choice for advanced gastric cancers (GCs). However, drug resistance and unavoidable severe toxicity lead to chemotherapy failure and poor prognosis. Long noncoding RNAs (lncRNAs) play critical roles in tumor progression in many cancers, including GC. Here, through RNA screening, an apoptotic protease‐activating factor 1 (APAF1)‐binding lncRNA (ABL) that is significantly elevated in cancerous GC tissues and an independent prognostic factor for GC patients is identified. Moreover, ABL overexpression inhibits GC cell apoptosis and promotes GC cell survival and multidrug resistance in GC xenograft and organoid models. Mechanistically, ABL directly binds to the RNA‐binding protein IGF2BP1 via its KH1/2 domain, and then IGF2BP1 further recognizes the METTL3‐mediated m6A modification on ABL, which maintains ABL stability. In addition, ABL can bind to the WD1/WD2 domain of APAF1, which competitively prevent cytochrome c from interacting with APAF1, blocking apoptosome assembly and caspase‐9/3 activation; these events lead to resistance to cell death in GC cells. Intriguingly, targeting ABL using encapsulated liposomal siRNA can significantly enhance the sensitivity of GC cells to chemotherapy. Collectively, the results suggest that ABL can be a potential prognostic biomarker and therapeutic target in GC.

Objective To investigate the distribution frequency of RBC rare blood group among blood donors in Chongqing, so as to provide basic data for the establishment of regional rare blood group donor database. Methods A total of 14 805 voluntary blood donors of Chongqing Blood Center from December 2020 to May 2021 were screened for Jk(a-b-) phenotype of Kidd blood group system by urea hemolysis test and confirmed by saline agglutination test. The indirect anti-globulin test was used to screen the Fy(a-) phenotype of Duffy blood group system, s-phenotype of the MNS blood group system and k- phenotype of Kell blood group system in 1 466 O type blood donors. The polyamine test was used to screen the Di(b-) phenotype of Diego blood group system in 856 voluntary blood donors, and confirmed by anti-globulin test. Results Among the voluntary blood donors in Chongqing, the proportion of Jk(a-b-) phenotype was 0.0203% (3/14 805). The ratio of both Fy(a-b+ ) and S+ s- phenotype among type O blood donors was 0.136 4% (2/1 466), and k- phenotype was not seen. The proportion of Di(a+ b-) phenotype among 856 blood donors was 0.233 6% (2/826). Conclusion The distribution frequency of rare blood group antigens in the above five blood group systems in Chongqing voluntary blood donors presents regional characteristics.

Summary: Background: We aimed to develop a deep learning-based segmentation system for rapid on-site cytopathology evaluation (ROSE) to improve the diagnostic efficiency of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsy. Methods: A retrospective, multicenter, diagnostic study was conducted using 5345 cytopathological slide images from 194 patients who underwent EUS-FNA. These patients were from Nanjing Drum Tower Hospital (109 patients), Wuxi People's Hospital (30 patients), Wuxi Second People's Hospital (25 patients), and The Second Affiliated Hospital of Soochow University (30 patients). A deep convolutional neural network (DCNN) system was developed to segment cell clusters and identify cancer cell clusters with cytopathological slide images. Internal testing, external testing, subgroup analysis, and human–machine competition were used to evaluate the performance of the system. Findings: The DCNN system segmented stained cells from the background in cytopathological slides with an F1-score of 0·929 and 0·899–0·938 in internal and external testing, respectively. For cancer identification, the DCNN system identified images containing cancer clusters with AUCs of 0·958 and 0·948–0·976 in internal and external testing, respectively. The generalizable and robust performance of the DCNN system was validated in sensitivity analysis (AUC > 0·900) and was superior to that of trained endoscopists and comparable to cytopathologists on our testing datasets. Interpretation: The DCNN system is feasible and robust for identifying sample adequacy and pancreatic cancer cell clusters. Prospective studies are warranted to evaluate the clinical significance of the system. Funding: Jiangsu Natural Science Foundation; Nanjing Medical Science and Technology Development Funding; National Natural Science Foundation of China.

Abstract Background Endoscopic submucosal dissection (ESD) has been accepted as a standard treatment for early gastric cardiac cancer (EGCC). Here, we investigate the clinical outcomes of the EGCC patients who underwent ESD in different indications. Methods From January 2011 to October 2019, we enrolled 502 EGCC lesions from 495 patients which were resected by ESD at our center. We retrospectively analyzed the short-term and long-term clinical outcomes among different indication groups. Results The number of the patients in the absolute indication (AI), expanded indication (EI) and beyond the expanded indication (BEI) groups was 265, 137 and 93, respectively. The en bloc resection rate was 100%, 100% and 98.9% (P = 0.185). The complete resection rate was 99.3%, 98.5% and 74.5%, respectively (P

Background and ObjectiveTransjugular intrahepatic portosystemic shunt (TIPS) is a well-established procedure for treating complications of portal hypertension. Due to the complexity of anatomy and difficulty of the puncture technique, the procedure itself might brought potential complications, such as puncture failure, bleeding, infection, and, rarely, death. The aim of this study is to explore the incidence, management, and outcome of TIPS procedure-related major complications using covered stents.MethodsPatients who underwent TIPS implantation from January 2015 to December 2020 were recruited retrospectively. Major complications after TIPS were screened and analyzed.ResultsNine hundred and forty-eight patients underwent the TIPS procedure with 95.1% (n = 902) technical success in our department. TIPS procedure-related major complications occurred in 30 (3.2%) patients, including hemobilia (n = 13; 1.37%), hemoperitoneum (n = 7; 0.74%), accelerated liver failure (n = 6; 0.63%), and rapidly progressive organ failure (n = 4; 0.42%). Among them, 8 patients died because of hemobilia (n = 1), accelerated liver failure (n = 4), and rapidly progressive organ failure (n = 3).ConclusionThe incidence of major complications related to TIPS procedure is relatively low, and some of them could recover through effective medical intervention. In our cohort, the overall incidence is about 3%, which causes 0.84% death. The most fatal complication is organ failure and hemobilia.

Gastric cancer is a heterogeneous group of diseases with only a fraction of patients responding to immunotherapy. The relationships between tumor DNA damage response, patient immune system and immunotherapy have recently attracted attention. Accumulating evidence suggests that DNA repair landscape is a significant factor in driving response to immune checkpoint blockade (ICB) therapy. In this study, to explore new prognostic and predictive biomarkers for gastric cancer patients who are sensitive and responsive to immunotherapies, we developed a novel 15-DNA repair gene signature (DRGS) and its related scoring system and evaluated the efficiency of the DRGS in discriminating different molecular and immune characteristics and therapeutic outcomes of patients with gastric adenocarcinoma, using publicly available datasets. The results demonstrated that DRGS high score patients showed significantly better therapeutic outcomes for ICB compared to DRGS low score patients (p < 0.001). Integrated analysis of multi-omics data demonstrated that the patients with high DRGS score were characteristic of high levels of anti-tumor lymphocyte infiltration, tumor mutation burden (TMB) and PD-L1 expression, and these patients exhibited a longer overall survival, as compared to the low-score patients. Results obtained from HPA and IHC supported significant dysregulation of the genes in DRGS in gastric cancer tissues, and a positive correlation in protein expression between DRGS and PD-L1. Therefore, the DRGS scoring system may have implications in tailoring immunotherapy in gastric cancers. A preprint has previously been published (Yuan et al., 2021).

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease with poor prognosis. Our previous study found that peroxisome proliferator activated receptor gamma (PPARγ) was capable of enhancing glycolysis in PDAC cells. However, whether PPARγ could promote PDAC progression remains unclear. In our present study, PPARγ was positively associated with tumor size and poor prognosis in PDAC patients. Functional assays demonstrated that PPARγ could promote the proliferation of pancreatic cancer cells in vitro and in vivo. Additionally, flow cytometry results showed that PPARγ decreased mitochondrial reactive oxygen species (mitochondrial ROS) production, stabilized mitochondrial membrane potential (MMP) and inhibited cell apoptosis via up-regulating superoxide dismutase 2 (SOD2), followed by the inhibition of ATG4D-mediated mitophagy. Meanwhile, the activation of PPARγ might reduce pancreatic cancer cell stemness to improve PDAC chemosensitivity via down-regulating ATG4D. Thus, these results revealed that PPARγ/SOD2 might protect against mitochondrial ROS-dependent apoptosis via inhibiting ATG4D-mediated mitophagy to promote pancreatic cancer proliferation, further improving PDAC chemosensitivity.

Inflammatory bowel disease (IBD) is a chronic disease and has become a global concern, which greatly reduces the quality of patients’ life. It is generally believed that enhanced production of reactive oxygen species (ROS) contributes to the progression of IBD. Therefore, the modulation of ROS concentration is an efficient path to relief IBD symptoms. In this work, ultrathin niobium carbide (UNC) nanosheets have been developed as a superoxide dismutase (SOD)-like antioxidant to harvest ROS. Compared with bulk Nb2C (BNC), UNC possesses the surface without the –F, -O, –OH suspension parts which provides abundant oxidized vacancies to trap the hydroxyl groups. Moreover, theoretical calculation has been adopted to explain the absorption mechanism and stability of UNC. In this work, it is revealed that UNC exhibits benign therapeutic functions both in vitro and in vivo. UNC not only inhibits hydroperoxide-induced cell death in vitro through reducing intracellular ROS levels, but also improves the severity and survival rates of colitis mice in vivo. We believe that this work can expand a new horizon on IBD treatment by adjusting ROS concentration and broaden the biological application of MXenes as well.

The rapidly developing organic–inorganic hybrid chalcogenide solar cells have now become a hot topic of interest. However, the bandgap of inorganic ferroelectric materials with a typical chalcogenide structure is too wide to match the solar spectrum, while the ferroelectricity of organic-inorganic hybrid chalcogenide materials with a narrow bandgap, meth amide–lead–iodine, is not obvious, and the lead element causes environmental pollution. The recently discovered organic–inorganic hybrid material [C6N2H18]BiI5 with good ferroelectricity and the narrowest bandgap of molecular ferroelectrics can absorb visible light in the range of 380 nm to 660 nm, and compound [C6N2H18]SbI5 with the Bi cognate element Sb was also synthesized. In this paper, we designed the first experiment to prepare thin films by mixing and doping the above two materials in five different molar ratios, and we comparatively studied the changes in crystal structure, surface morphology, and photophysical properties of the prepared multicomponent hybrid films according to the mixing ratio. A theoretical model was developed to calculate and analyze the bandgap of the hybrid doped compounds and compare it with the experimental values. It was found that the absorption spectra of the multicomponent hybrid films were red-shifted relative to the original material, indicating that the forbidden bandwidth was reduced to absorb a wider range of visible light, and the reason for this was thought to be the narrowing of the bandgap due to doping. When the mixing ratio was 0.4:0.6, the bandgap was the narrowest and the light absorption was the best; the highest quality of the film was obtained when the mixing ratio was 0.5:0.5.

Given the problems of the high trash content and loss rate for mechanized sugarcane harvesting, taking the HN4GDL-194 sugarcane chopper harvester extractor developed by South China Agricultural University as the research object, three types of extractor negative pressure structures were designed and internal flow field simulation analysis was conducted. Simulation results showed that the aerodynamic performance of the flow field in the negative pressure area of the extractor negative pressure structure two is the best and the wind velocity and negative pressure are the largest. The measurement results of wind velocity, wind pressure, and flow showed that the changing trend in the actual value of wind velocity and wind pressure is basically consistent with the simulation value. The relative error between the actual flow of the air outlet and the simulation value is less than 10% under different speeds, indicating that the simulation has high accuracy. Field tests of the original extractor and the optimal extractor were conducted. The test results for the trash content showed that when the feeding rate was 1.5 kg/s, there was no significant difference in the trash content between the optimal extractor and the original extractor under various fan speeds. When the feeding rate increased to 7.5 kg/s and the fan speed was low (950 r/min) and medium (1100 r/min), the trash content of the optimal extractor was significantly lower than that of the original extractor, decreasing 2.5% and 1.63%, respectively. The loss rate test results showed that when the fan speed is low and high (1250 r/min), there is no significant difference between the loss rate of the optimal extractor and the original extractor. When the fan speed was 1100 r/min and the feeding rate was 1.5, 4.5, and 7.5 kg/s, compared with the original extractor, the loss rate of the optimal extractor decreased by 0.53%, 0.21%, and 0.19%, respectively.

Since their discovery, ferroelectric materials have shown excellent dielectric responses, pyroelectricity, piezoelectricity, electro-optical effects, nonlinear optical effects, etc. They are a class of functional materials with broad application prospects. Traditional pure inorganic piezoelectric materials have better piezoelectricity but higher rigidity; pure organic piezoelectric materials have better flexibility but havetoo small a piezoelectric coefficient. The material composite, on the other hand, can combine the advantages of both, so that it has both flexibility and a high piezoelectric coefficient. In this paper, a new molecular piezoelectric material (C5H11NO)2PbBr4 with a high Curie temperature Tc and a large piezoelectric voltage constant g33, referred to as (ATHP)2PbBr4, was used to prepare a 0-3 type piezoelectric composite film by compounding with an organic polymer material polyvinylidene fluoride (PVDF), and its ferroelectricity was investigated. The results show that the 0-3 type (ATHP)2PbBr4 piezoelectric composite film has good ferroelectricity and piezoelectricity, and the calculated piezoelectric voltage constant g33 after polarization is about 358.6 × 10−3 Vm/N, which is higher than that of PVDF material, and is important for the fabrication of high-performance piezoelectric sensors.

Abstract Background Endoscopic transpapillary cannulation of the gallbladder is useful but challenging. This study aimed to investigate cystic duct anatomy patterns, which may guide cystic duct cannulation. Methods A total of 226 patients who underwent endoscopic transpapillary cannulation of the gallbladder were analyzed retrospectively. Results According to the cystic duct take-off, 226 cystic duct patterns were divided into 3 patterns: Type I (193, 85.4%), located on the right and angled up; Type II (7, 3.1%), located on the right and angled down; and Type III (26, 11.5%), located on the left and angled up. Type I was further divided into three subtypes: Line type, S type (S1, not surrounding the common bile duct; S2, surrounding the common bile duct), and α type (α1, forward α; α2, reverse α). Types I and III cystic ducts were easier to be cannulated with a higher success rate (85.1 and 86.4%, respectively) compared with Type II cystic duct (75%) despite no statistically significant difference. The reasons for the failure of gallbladder cannulation included invisible cyst duct take-off, severe cyst duct stenosis, impacted stones in cyst duct or neck of the gallbladder, sharply angled cyst duct, and markedly dilated cyst duct with the tortuous valves of Heister. Conclusion Classification of cystic duct patterns was helpful in guiding endoscopic transpapillary gallbladder cannulation.

Abstract Cholangiocarcinoma (CCA) is an extremely invasive malignancy with late diagnosis and unfavorable prognosis. Surgery and chemotherapy are still not effective in improving outcomes in CCA patients. It is crucial to explore a novel therapeutic target for treating CCA. An NAD‐dependent deacetylase also known as Sirtuin‐3 (SIRT3) has been shown to regulate cellular metabolism in various cancers dynamically. However, the biological function of SIRT3 in CCA remains unclear. In this study, bioinformatics analyses were performed to identify the differentially expressed genes and pathways enriched. CCA samples were collected for immunohistochemical analysis. Three human CCA cell lines (HuCCT1, RBE, and HCCC9810) were used to explore the molecular mechanism of SIRT3 regulation of metabolic reprogramming and malignant behavior in CCA. A CCA xenograft model was then established for further validation in vivo. The data showed that SIRT3 expression was decreased and glycolysis was enhanced in CCA. Similar metabolic reprogramming was also observed in SIRT3 knockout mice. Furthermore, we demonstrated that SIRT3 could play an anti‐Warburg effect by inhibiting the hypoxia‐inducible factor‐1α (HIF1α)/pyruvate dehydrogenase kinase 1 (PDK1)/pyruvate dehydrogenase (PDHA1) pathway in CCA cells. CCA cell proliferation and apoptosis were regulated by SIRT3‐mediated metabolic reprogramming. These findings were further confirmed in CCA clinical samples and the xenograft model. Collectively, this study suggests that in the inhibition of CCA progression, SIRT3 acts through an anti‐Warburg effect on the downstream pathway HIF1α/PDK1/PDHA1.

Cholangiocarcinoma (CCA) is a malignant cancer with an unknown etiology and an unfavorable prognosis. Most patients are diagnosed at an advanced stage, thus making it essential to find novel curative targets for CCA. Metabolic reprogramming of the tumor cells includes metabolic abnormalities in glucose (known as the Warburg effect) and other substances such as amino acids and fats. Metabolic reprogramming produces anti-oxidant substances, reduces tumor oxidative stress, and finally promotes the proliferation of tumors. There is increasing evidence to imply that SIRT2, a histone deacetylase, and its downstream target cMYC, play metabolic regulatory roles in tumor cells. However, the role of the SIRT2/cMYC pathway in CCA is unclear. To assess the metabolic reprogramming function of the SIRT2/cMYC pathway in CCA and to determine the downstream targets as well as evaluate the therapeutic effect, the CCA RNA-Seq data were downloaded from the TCGA database. Differentially expressed genes were confirmed and KEGG pathway enrichment analysis was performed. Overall, 48 paired CCA samples were collected and subjected to immunohistochemical detection, and the clinical characteristics of participants were summarized. The CCA cells were suppressed or overexpressed with different downstream targets of SIRT2 and then subjected to apoptosis, immunoblotting, seahorse, and metabolites tracing analysis. In vivo experiments were also performed. We found that the SIRT2/cMYC pathway contributed to the proliferation of CCA cells and confirmed that the downstream target is PHDA1 and the serine synthesis pathway. The up-regulated SIRT2 and cMYC levels resulted in low levels of mitochondrial oxidative phosphorylation and increased conversion of glucose to serine and led to poor patient survival. The highly active SIRT2/cMYC pathway up-regulated the serine synthesis pathway pyruvate and increased antioxidant production, thus consequently protecting the CCA cells from oxidative stress-induced apoptosis. Our data revealed that the SIRT2/cMYC pathway plays a critical role in transforming glucose oxidative metabolism to serine anabolic metabolism, thus providing antioxidants for stress resistance. SIRT2/cMYC-induced metabolic reprogramming may represent a new therapeutic target for treating CCA.

Abstract Background Cancer cells avidly consume glucose and convert it to lactate, resulting in a low pyruvate level. This phenomenon is known as the Warburg effect, and is important for cell proliferation. Although cMyc has often been described as an oncoprotein that preferentially contributes to the Warburg effect and tumor proliferation, mechanisms of action remain unclear. Histone deacetylase 3 (HDAC3) regulates gene expression by removing acetyl groups from lysine residues, as well as has an oncogenic role in apoptosis and contributes to the proliferation of many cancer cells including cholangiocarcinoma (CCA). HDAC inhibitors display antitumor activity in many cancer cell lines. Cancer cells maintain low levels of pyruvate to prevent inhibition of HDAC but the mechanisms remain elusive. The purpose of our study was to explore the role of cMyc in regulating pyruvate metabolism, as well as to investigate whether the inhibitory effect of pyruvate on HDAC3 could hold promise in the treatment of cancer cells. Methods We studied pyruvate levels in CCA cell lines using metabolite analysis, and analyzed the relationship of pyruvate levels and cell proliferation with cell viability analysis. We cultivated CCA cell lines with high or low levels of pyruvate, and then analyzed the protein levels of HDAC3 and apoptotic markers via Western Blotting. We then explored the reasons of low levels of pyruvate by using seahorse analysis and 13C6 metabolites tracing analysis, and then confirmed the results using patient tissue protein samples through Western Blotting. Bioinformatics analysis and transfection assay were used to confirm the upstream target of the low levels of pyruvate status in CCA. The regulation of cMyc by HDAC3 was studied through immunoprecipitation and Western Blotting. Results We confirmed downregulated pyruvate levels in CCA, and defined that high pyruvate levels correlated with reduced cell proliferation levels. Downregulated pyruvate levels decreased the inhibition to HDAC3 and consequently protected CCA cells from apoptosis. Synergistically upregulated LDHA, PKM2 levels resulted in low levels of pyruvate, as well as poor patient survival. We also found that low levels of pyruvate contributed to proliferation of CCA cells and confirmed that the upstream target is cMyc. Conversely, high activity of HDAC3 stabilized cMyc protein by preferential deacetylating cMyc at K323 site, which further contributed to the low pyruvate levels. Finally, this creates a positive feedback loop that maintained the low levels of pyruvate and promoted CCA proliferation. Conclusions Collectively, our findings identify a role for promoting the low pyruvate levels regulated by c-Myc, and its dynamic acetylation in cancer cell proliferation. These targets, as markers for predicting tumor proliferation in patients undergoing clinical treatments, could pave the way towards personalized therapies.

Abstract Background Lipid profiles disorders frequently occur in patients with chronic liver diseases, and the mortality of cirrhosis complicated with portal vein thrombosis (PVT) remains high. Research identifying simple and objective prognosis indicators for cirrhotic PVT has been limited. The aim of the present study was to investigate the association between lipid profiles and liver function, which may help predict the 1-year mortality in non-malignant cirrhosis with PVT. Methods A retrospective cohort of 117 subjects with non-malignant cirrhotic PVT was conducted. The primary indicators of lipid profiles included triglyceride, cholesterol, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol. Correlations of lipid profiles with liver function tests, the Child-Turcotte-Pugh (CTP) score and the model for end-stage liver disease (MELD) score were investigated. The relationship between lipid profiles and 1-year mortality was assessed using the area under the receiver operating characteristic curves (AUROC). Logistic regression models were established to confirm the association between HDL-C and mortality. Results The level of HDL-C was significantly decreased in non-survivors (p

The seed filling of a seed-metering device is a critical process in sugarcane cultivation operations. To analyze the contact between billets, the related mechanical components, and the law of billets movement in the seed-metering device, a simulation of the seed-filling process based on EDEM was proposed, and a geometric model of the seed-metering device, a particle model, and a contact model were established by EDEM software. The physical experimental results and simulation results of the angle of repose were compared. The experimental results showed that the relative error of the angle of repose experiment was 6.67%, which verified the effectiveness of the material parameters of single-bud billet; the linear correlation coefficient of the seed-filling experiment was 0.762 for Sq and 0.869 for Se, which demonstrated the validity of using EDEM software to simulate the seed-filling process. Finally, the velocity and force of the particles in the seed-filling process were analyzed in EDEM. The analysis results indicated that there are two circulation circles in the seed box, and the larger the circulation circle, the easier the billets enter the rake bar. The EDEM simulation provides a basis for optimizing the structure and parameters of the sugarcane billet planter in future work.

Planting uniformity is a key evaluation index for planters. This paper investigated the effect of rotational speed, the angle of the rake bar chain, and the number of billets on the planting uniformity of a seed-metering device in the laboratory. The experimental results showed that the optimal planting uniformity can be achieved under a rake bar chain angle of 117°, a number of billets of 500, and a rotational speed of the rake bar chain of 70 rpm. Under this condition, the quality index Zq was 97.22% and the multiple index Zm was 0%, while the miss index Ze was 2.78%. Based on the above parameters, a single-bud planter was improved with three rake bar chains per seed box. Field experiments with different operation parameters (rotational speed, forward speed) were conducted. Results indicated that when the rotational speed was 40 rpm and the forward speed was 2.26 km/h, the planting uniformity was the best and the quality index Zq was 93.38%. The research results provide a basis for the application of single-bud billet planters in the field.

BackgroundPancreatic cancer (PC) has a dismal prognosis due to its insidious early symptoms and poor early detection rate. Exosomes can be released by various cell types and tend to be a potential novel biomarker for PC detection. In this study, we explored the proteomic profiles of plasma exosomes collected from patients with PC at different stages and other pancreatic diseases.MethodsPlasma samples were collected from six groups of patients, including PC at stage I/II, PC at stage III/IV, well-differentiated pancreatic neuroendocrine tumor (P-NET), pancreatic cystic lesions (PCLs), chronic pancreatitis (CP), and healthy controls (HCs). Plasma-derived exosomes were isolated by ultracentrifugation and identified routinely. Isobaric tags for relative and absolute quantification (iTRAQ) based proteomic analysis along with bioinformatic analysis were performed to elucidate the biological functions of proteins. The expression of exosomal ALIX was further confirmed by enzyme-linked immunosorbent assay in a larger cohort of patients. Furthermore, receiver operating characteristic curve analysis was applied to evaluate the potential of ALIX as a novel diagnostic biomarker.ResultsThe proteomic profile revealed a total of 623 proteins expressed among the six groups, and 16 proteins with differential degrees of abundance were found in PC vs. other pancreatic diseases (including P-NET, PCLs, and CP). Based on the results of proteomic and bioinformatic analyses, exosomal ALIX was subsequently selected as a novel biomarker for PC detection and validated in another clinical cohort. We noticed that ALIX expression was elevated in PC patients compared with patients with other pancreatic diseases or HC, and it was also closely associated with TNM stage and distant metastasis. Interestingly, the combination of exosomal ALIX and serum CA199 has greater values in differentiating both early vs. late PC (AUC value 0.872) and PC vs. other pancreatic diseases (AUC value 0.910) than either ALIX or CA199 alone.ConclusionIn summary, our study demonstrated that based on proteomic profiling, proteins isolated from the plasma-derived exosomes may function as ideal non-invasive biomarkers for the clinical diagnosis of PC. Importantly, exosomal ALIX combined with CA199 has great potentials in detection of PC, especially in distinguishing PC patients at early stages from advanced stages.

Background and AimsPrediction of intramucosal gastric cancer (GC) is a big challenge. It is not clear whether artificial intelligence could assist endoscopists in the diagnosis.MethodsA deep convolutional neural networks (DCNN) model was developed via retrospectively collected 3407 endoscopic images from 666 gastric cancer patients from two Endoscopy Centers (training dataset). The DCNN model’s performance was tested with 228 images from 62 independent patients (testing dataset). The endoscopists evaluated the image and video testing dataset with or without the DCNN model’s assistance, respectively. Endoscopists’ diagnostic performance was compared with or without the DCNN model’s assistance and investigated the effects of assistance using correlations and linear regression analyses.ResultsThe DCNN model discriminated intramucosal GC from advanced GC with an AUC of 0.942 (95% CI, 0.915–0.970), a sensitivity of 90.5% (95% CI, 84.1%–95.4%), and a specificity of 85.3% (95% CI, 77.1%–90.9%) in the testing dataset. The diagnostic performance of novice endoscopists was comparable to those of expert endoscopists with the DCNN model’s assistance (accuracy: 84.6% vs. 85.5%, sensitivity: 85.7% vs. 87.4%, specificity: 83.3% vs. 83.0%). The mean pairwise kappa value of endoscopists was increased significantly with the DCNN model’s assistance (0.430–0.629 vs. 0.660–0.861). The diagnostic duration reduced considerably with the assistance of the DCNN model from 4.35s to 3.01s. The correlation between the perseverance of effort and diagnostic accuracy of endoscopists was diminished using the DCNN model (r: 0.470 vs. 0.076).ConclusionsAn AI-assisted system was established and found useful for novice endoscopists to achieve comparable diagnostic performance with experts.

Background: We aimed to develop and validate a real-time deep convolutional neural networks (DCNNs) system for detecting early gastric cancer (EGC). Methods: All 45,240 endoscopic images from 1364 patients were divided into a training dataset (35823 images from 1085 patients) and a validation dataset (9417 images from 279 patients). Another 1514 images from three other hospitals were used as external validation. We compared the diagnostic performance of the DCNN system with endoscopists, and then evaluated the performance of endoscopists with or without referring to the system. Thereafter, we evaluated the diagnostic ability of the DCNN system in video streams. The accuracy, sensitivity, specificity, positive predictive value, negative predictive value and Cohen's kappa coefficient were measured to assess the detection performance. Finding: The DCNN system showed good performance in EGC detection in validation datasets, with accuracy (85.1%–91.2%), sensitivity (85.9%–95.5%), specificity (81.7%–90.3%), and AUC (0.887–0.940). The DCNN system showed better diagnostic performance than endoscopists and improved the performance of endoscopists. The DCNN system was able to process oesophagogastroduodenoscopy (OGD) video streams to detect EGC lesions in real time. Interpretation: We developed a real-time DCNN system for EGC detection with high accuracy and stability. Multicentre prospective validation is needed to acquire high-level evidence for its clinical application. Funding: This work was supported by the National Natural Science Foundation of China (grant nos. 81672935 and 81871947), Jiangsu Clinical Medical Center of Digestive System Diseases and Gastrointestinal Cancer (grant no. YXZXB2016002), and Nanjing Science and Technology Development Foundation (grant no. 2017sb332019).

This study was conducted to explore the potential genes and proteins associated with esophagus benign hyperplasia induced by esophageal stents. Five patients with esophageal cancer subjected to esophageal stent placement were enrolled in this study. Long non-coding RNA (lncRNA) sequencing and tandem mass tag quantitative proteomics analysis were performed by using the collected hyperplastic samples and adjacent non-hyperplastic tissues. Differentially expressed (DE) RNAs and proteins were analyzed, followed by functional enrichment analysis, protein-protein interaction (PPI) network analysis, and competitive endogenous RNA (ceRNA) network construction. Venn analysis was performed to extract the overlaps between DE mRNAs and DE proteins and the expression correlations between DE mRNA and proteins were analyzed. Results showed that total 642 DE RNAs (457 mRNA and 185 lncRNAs) and 256 DE proteins were detected. DE mRNAs (such as MAOB, SDR16C5, and FOSL1) were enriched in oxidation-reduction process-associated functions. PPI network was comprised of 175 nodes and 425 edges. VEGFA was a significant node with the highest degree. LncRNA-mRNA network with three subnetworks (C1, C2, C3) was constructed for lncRNAs with more than 15 gene targets. RP11-58O9.2 was a significant lncRNA with the most target genes and RP11-667F14.1 regulated more than 20 targets. FOSL1 was a common target of the two lncRNAs. Function analysis showed that DE lncRNAs were involved in the HTLV-I infection (RP11-58O9.2 and RP11-667F14.1) and IL-17 signaling pathways (RP11-5O24.1 and RP11-58O9.2). Total 11 DE mRNAs were overlapped with DE proteins, among which MAOB and SDR16C5 showed positive correlations between mRNA and protein expression. Function analysis showed that MAOB was enriched in oxidation-reduction process and its protein was closely related with response to lipopolysaccharide. VEGFA, FOSL1, MAOB, SDR16C5, RP11-58O9.2, RP11-667F14.1, and RP11-288A5.2 may be served as genetic targets for preventing stent restenosis in esophageal cancer.

Background and study aims Gastric outlet obstruction (GOO) is common in the late stage of many malignant tumors of the digestive system. Endoscopic ultrasound (EUS)-guided gastroenterostomy (EUS-GE) is commonly used for palliative treatment of malignant GOO. The objective of this study was to investigate the safety, efficacy, and prognosis of EUS-GE in treatment of malignant GOO in Chinese patients. Patients and methods This was a retrospective, single-center study with 36 consecutive patients with malignant GOO who were treated with EUS-GE. The main outcome measures were technical success rate, clinical success rate, incidence of adverse events (AEs), and median survival time. Results A total of 36 patients with malignant GOO underwent double-balloon-assisted EUS-GE between March 2017 and June 2019 in our hospital. GOO occurred mainly in elderly men (mean age 69.0 years, M:F 0.89). The most common etiology of GOO was pancreatic cancer (41.7 %). The most common obstruction site was the second part of the duodenum (63.9 %). The technical success rate was 100 % (36/36). The clinical success rate was 94.4 % (34/36). Median time for the total procedure was 52 minutes (range 34 – 156 min). Median time for determination of puncture site was 20 minutes (range 15 – 28 min). Median time between puncture and successful delivery of the stent was 38 minutes (range 19 – 128 min). The GOOSS score was 0.2 before EUS-GE. The GOO Scoring System (GOOSS) score was 2.2 at 15 days after the EUS-GE (P = 0.001). The GOOSS score was still higher than 2 during a median follow-up period of 89 days. AEs were observed in nine patients (25.0 %) and 13 total AEs occurred. One patient died as a result of delayed stent migration and bleeding. Mean length of hospital stay was 5.8 ± 4.7 days. The median survival period was 103 days. The rate of GOO recurrence was 2.7 % (1/36). Conclusion EUS-GE was associated with increased safety and efficacy for treatment of malignant GOO in Chinese Mainland.

Aims: Early gastric cardiac cancer (EGCC) has a low risk of lymph node metastasis with the potential for endoscopic therapy. We aimed to evaluate the short- and long-term outcomes of endoscopic submucosal dissection (ESD)-resected EGCCs in a large cohort of Chinese patients and compare endoscopic and clinicopathologic features between EGCC and early gastric non-cardiac cancer (EGNC). Methods: We retrospectively studied 512 EGCCs in 499 consecutive patients and 621 EGNCs in 555 consecutive patients between January 2011 and March 2018 at our center. We investigated clinicopathological characteristics of EGCC tumors, ESD treatment results, adverse events, and postresection patient survival. Results: Compared with EGNC patients, EGCC patients were significantly older (average age: 66 years versus 62 years, p

Background: Transcatheter arterial chemoembolization (TACE) is extensively used in the treatment of advanced hepatocellular carcinoma (HCC). However, the efficacy of TACE is usually limited to secondary tumor hypoxia and hypoxia-related tumor angiogenesis. Methods: In this study, poly(lactic-co-glycolic acid) (PLGA) microspheres (SOR-CAT-PLGA MSs) encapsulating sorafenib (SOR) and catalase (CAT) were prepared by double-emulsion solvent diffusion method. Sorafenib inhibits tumor angiogenesis, and catalase decomposes hydrogen peroxide (H2O2) to generate oxygen in the tumor. Results: In vitro and in vivo, SOR -CAT-PLGA MSs could significantly improve the efficacy of hepatic artery embolization in the treatment of rabbit VX2 liver tumors, regulate tumor hypoxia and immunosuppressive microenvironment, then achieved near-complete and rapid necrosis of liver tumors. Conclusions: The application of new SOR -CAT-PLGA MSs in hepatic artery chemoembolization of rabbit VX2 liver tumor is a promising approach to improve the therapeutic effect of liver tumors and has a broad clinical application prospect.