Search

Abstract Background The progression of gallbladder cancer (GBC) is accompanied by abnormal fatty acid β-oxidation (FAO) metabolism. Different types of lipids perform various biological functions. This study aimed to determine the role of acyl carnitines in the molecular mechanisms of GBC progression. Methods Distribution of lipids in GBC was described by LC–MS-based lipidomics. Cellular localization, expression level and full-length of lncBCL2L11 were detected using fluorescence in situ hybridization (FISH) assays, subcellular fractionation assay and 5′ and 3′ rapid amplification of the cDNA ends (RACE), respectively. In vitro and in vivo experiments were used to verify the biological function of lncBCL2L11 in GBC cells. Methylated RNA Immunoprecipitation (MeRIP) was performed to detect the methylation levels of lncBCL2L11. RNA pull-down assay and RNA immunoprecipitation (RIP) assay were used to identify lncBCL2L11 interacting proteins. Co-Immunoprecipitation (Co-IP) and Western blot assay were performed to validate the regulatory mechanism of lncBCL2L11 and THO complex. Results Acylcarnitines were significantly up-regulated in GBC tissues. High serum triglycerides correlated to decreased survival in GBC patients and promoted tumor migration. LncBCL2L11 was identified in the joint analysis of highly metastatic cells and RNA sequencing data. LncBCl2L11 prevented the binding of THOC6 and THOC5 and causes the degradation of THOC5, thus promoting the accumulation of acylcarnitines in GBC cells, leading to the malignant progression of cancer cells. In addition, highly expressed acylcarnitines stabilized the expression of lncBCL2L11 through N6-methyladenosine methylation (m6A), forming a positive feedback regulation in tumor dissemination. Conclusions LncBCL2L11 is involved in gallbladder cancer metastasis through FAO metabolism. High lipid intake is associated with poor prognosis of GBC. Therefore, targeting lncBCL2L11 and its pathway-related proteins or reducing lipid intake may be significant for the treatment of GBC patients.

Abstract. Biliary tract cancers (BTC), a heterogeneous disease with poor prognosis, including gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC). Although surgery is currently the primary regimen to treat BTC, most BTC patients are diagnosed at an advanced stage and miss the opportunity of surgical eradication. As a result, non-surgical therapy serves as the main intervention for advanced BTC. In recent years, immunotherapy has emerged as one of the most promising therapies in a number of solid cancers, and it includes immune checkpoint inhibitors (ICIs) monotherapy or combined therapy, tumor vaccines, oncolytic virus immunotherapy, adoptive cell therapy (ACT), and cytokine therapy. However, these therapies have been practiced in limited clinical settings in patients with BTC. In this review, we focus on the discussion of latest advances of immunotherapy in BTC and update the progress of multiple current clinical trials with different immunotherapies.

Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system with the worst prognosis. Even after radical surgery, the majority of patients with GBC have difficulty achieving a clinical cure. The risk of tumor recurrence remains more than 65%, and the overall 5-year survival rate is less than 5%. The gut microbiota refers to a variety of microorganisms living in the human intestine, including bacteria, viruses and fungi, which profoundly affect the host state of general health, disease and even cancer. Over the past few decades, substantial evidence has supported that gut microbiota plays a critical role in promoting the progression of GBC. In this review, we summarize the functions, molecular mechanisms and recent advances of the intestinal microbiota in GBC. We focus on the driving role of bacteria in pivotal pathways, such as virulence factors, metabolites derived from intestinal bacteria, chronic inflammatory responses and ecological niche remodeling. Additionally, we emphasize the high level of correlation between viruses and fungi, especially EBV and Candida spp., with GBC. In general, this review not only provides a solid theoretical basis for the close relationship between gut microbiota and GBC but also highlights more potential research directions for further research in the future.

Segmental lining structures constructed by shields/tunnel boring machines are often subjected to uneven longitudinal cross-section torsion as a result of eccentric external loads, which is extremely adverse to tunnel safety but has not received sufficient attention for a long time. To figure out the torsional performance of segmental tunnels, it is essential to assess the longitudinal torsional stiffness and active-torsion-rejection capability of a segmented tunnel. The aim of the paper is to derive an analytical solution to the longitudinal torsional stiffness of a segmental tunnel with existing elliptical deformation. The longitudinal torsional stiffness under different internal force combinations is deduced considering the longitudinal axial force and bending moment based on the equivalent continuous model and force balance equation. The validity of the analytical solution is verified by comparing it with finite element method results. Then, a parametric analysis, using the new analytical solution, is included to investigate the effect of the key parameters on torsional behaviors, including the segment size, the bolt size and the transverse bending stiffness, etc. It is found that: (1) the longitudinal torsional stiffness efficiency (LTSE) of the segmental tunnel decreases with the rise of segment thickness to diameter ratio but increases with the ring width to diameter ratio; (2) the LTSE reduces with the increase of the effective shear length but rises with the diameter of bolts; (3) the LTSE increases rapidly with the ratio of compression-torsion or bending-torsion. Furthermore, the envelope curve of the critical load (N0, M0) for a tunnel to actively resist a certain internal torque is given. The proposed solution can be easily utilized to determine the longitudinal torsional stiffness of segmental tunnels and is an effective tool for tunnel design and maintenance.

Summary: In recent years, significant advancements have been made in the synthesis and application of 1,3-dienes. This specific structural motif has garnered significant attention from researchers in materials science and biology due to its unique aggregation-induced emission (AIE) properties and extensive conjugation systems. The luminescent characteristics of these compounds are notably influenced by the geometry of the two double bonds. Therefore, it is essential to consolidate stereoselective synthetic strategies for 1,3-dienes. This comprehensive review seeks to elucidate the diverse techniques employed to attain stereo-control in the synthesis of 1,3-diene-based AIE luminogens (AIEgens). Particular emphasis is placed on comprehending the determinants of stereoselectivity and exploring the array of substrates amenable to these methods. Furthermore, the review underscores the AIE properties exhibited by these compounds and their extensive utility in organic light-emitting diodes (OLEDs), stimuli-responsive materials, sensors, bioimaging, and photodynamic therapy (PDT).

Bile acids (BAs) constitute essential components of cholesterol metabolites that are synthesized in the liver, stored in the gallbladder, and excreted into the intestine through the biliary system. They play a crucial role in nutrient absorption, lipid and glucose regulation, and the maintenance of metabolic homeostasis. In additional, BAs have demonstrated the ability to attenuate disease progression such as diabetes, metabolic disorders, heart disease, and respiratory ailments. Intriguingly, recent research has offered exciting evidence to unveil their potential antitumor properties against various cancer cell types including tamoxifen-resistant breast cancer, oral squamous cell carcinoma, cholangiocarcinoma, gastric cancer, colon cancer, hepatocellular carcinoma, prostate cancer, gallbladder cancer, neuroblastoma, and others. Up to date, multiple laboratories have synthesized novel BA derivatives to develop potential drug candidates. These derivatives have exhibited the capacity to induce cell death in individual cancer cell types and display promising anti-tumor activities. This review extensively elucidates the anticancer activity of natural BAs and synthetic derivatives in cancer cells, their associated signaling pathways, and therapeutic strategies. Understanding of BAs and their derivatives activities and action mechanisms will evidently assist anticancer drug discovery and devise novel treatment.

Traditional Chinese Medicine (TCM) introduces a potentially effective strategy in the realm of cancer therapy, whereas network pharmacology provides a reliable mechanism for clarifying the complex interplay between active constituents and their corresponding targets. Although Dan-Shen-Yin (DSY) has demonstrated remarkable efficacy in the treatment of various diseases, its potential anti-pancreatic cancer effects and underlying mechanisms remain unexplored. The present study aims to validate the anti-pancreatic cancer efficacy of DSY both in vivo and in vitro, while also elucidating its mechanism through a combination of network pharmacology, molecular docking, and related experiments. The in vivo effectiveness of DSY was validated using the patient-derived xenograft (PDX) model, which was chosen due to its remarkable capacity to maintain the essential histological and genetic attributes of the primary tumor. Network pharmacology predicted the anti-pancreatic cancer efficacy of DSY, which was confirmed by in vitro experiments showing inhibitory effects on proliferation, pro-apoptosis, migration, and colony formation of PC cells. Molecular docking studies further confirmed that the active components of DSY exhibited good nucleophilicity for the selected target proteins through their ability to interact via hydrogen bonding and Van der Waals forces. The PDX model showed that DSY effectively inhibited tumor growth and improved prognosis. Experiments conducted both in vivo and in vitro have demonstrated that DSY is an effective treatment for PC. Moreover, mechanistic investigations have provided evidence of the ability to impede the EGFR/SRC/STAT3 signaling pathway.

The stainless steel/aluminum multilayer composites were prepared by one-step explosive welding using ammonium nitrate explosive with two different thicknesses. The microstructure and mechanical properties of the multilayer composites were examined. There is a thin metallurgical melting zone at each bonding interface, consisting mostly of iron and aluminum elements. However, the micro-crack appears in the second metallurgical bonding zone obtained using the explosive of 24 mm thickness. The micro-hardness values at the four bonding interfaces are higher than those of bulk 1060 aluminum and 304 stainless steel. The yield strength of the multilayer composites obtained in the two cases is higher than that of the original 304 stainless steel while the tensile strength is between those of the original 1060 aluminum and 304 stainless steel. Meanwhile, the tensile strength and yield strength of multilayer composites obtained by explosive welding with explosive of 20 mm thickness are relatively higher.

Abstract. Background:. Gallbladder cancer (GBC) is the most common malignant tumor of biliary tract. Isoliquiritigenin (ISL) is a natural compound with chalcone structure extracted from the roots of licorice and other plants. Relevant studies have shown that ISL has a strong anti-tumor ability in various types of tumors. However, the research of ISL against GBC has not been reported, which needs to be further investigated. Methods:. The effects of ISL against GBC cells in vitro and in vivo were characterized by cytotoxicity test, RNA-sequencing, quantitative real-time polymerase chain reaction, reactive oxygen species (ROS) detection, lipid peroxidation detection, ferrous ion detection, glutathione disulphide/glutathione (GSSG/GSH) detection, lentivirus transfection, nude mice tumorigenesis experiment and immunohistochemistry. Results:. ISL significantly inhibited the proliferation of GBC cells in vitro. The results of transcriptome sequencing and bioinformatics analysis showed that ferroptosis was the main pathway of ISL inhibiting the proliferation of GBC, and HMOX1 and GPX4 were the key molecules of ISL-induced ferroptosis. Knockdown of HMOX1 or overexpression of GPX4 can reduce the sensitivity of GBC cells to ISL-induced ferroptosis and significantly restore the viability of GBC cells. Moreover, ISL significantly reversed the iron content, ROS level, lipid peroxidation level and GSSG/GSH ratio of GBC cells. Finally, ISL significantly inhibited the growth of GBC in vivo and regulated the ferroptosis of GBC by mediating HMOX1 and GPX4. Conclusion:. ISL induced ferroptosis in GBC mainly by activating p62-Keap1-Nrf2-HMOX1 signaling pathway and down-regulating GPX4 in vitro and in vivo. This evidence may provide a new direction for the treatment of GBC.

Introduction: The value of extended lymphadenectomy in pancreatoduodenectomy (PD) has been discussed by five randomized controlled studies. However, the limitations in the studies made their conclusions not sufficiently reliable. Objectives: This multi-center randomized controlled study was designed to clarify the efficacy of extended lymphadenectomy in PD for pancreatic ductal adenocarcinoma (PDAC). Methods: From December 2016 to October 2018, 170 consecutive patients undergoing PD were enrolled and randomized to standard or extended lymphadenectomy for the treatment of PDAC from three high-volume institutions in China. Demographic, pathological characteristics and survival data of these patients were collected and analyzed. No neoadjuvant treatment was performed. The primary endpoint was the 3-year overall survival. Results: For all patients, the 3-year survival rate was 25.88 %. There was no between-group difference in 3-year survival rate (27.16 % vs 24.72 % p = 0.717). The median survival time for the standard group was 18 months, while for the extended group it was 15 months. The demographic and pathological characteristics were similar between groups. More positive lymph nodes could be found in the extended group (2.34 ± 3.46 vs 1.41 ± 2.12, p = 0.035), which led to nodule stage migration. All patients received chemotherapy. But patients in extended group were more likely to fail in completion of all-cycles chemotherapy before recurrence (31.46 % vs 17.28 %, p = 0.032). Incomplete chemotherapy before recurrence, higher N status and abnormal CA125 were independent risk factors for 1-year survival (p

Abstract Background Gallbladder cancer (GBC) is the most prevalent and invasive biliary tract malignancy. As a GTPase-activating protein, Neurofibromin 1 (NF1) is a tumor suppressor that negatively regulates the RAS signaling pathway, and its abnormality leads to neurofibromatosis type 1 (NF-1) disease. However, the role of NF1 playing in GBC and the underlying molecular mechanism has not been defined yet. Methods A combination of NOZ and EH-GB1 cell lines as well as nude mice, were utilized in this study. mRNA expression and protein levels of NF1 and YAP1 were evaluated by quantitative real-time PCR (qRT-PCR), western blot (WB), and immunohistochemistry (IHC). In vitro and in vivo assays were performed to explore the biological effects of NF1 in NOZ and EH-GB1 cells via siRNA or lv-shRNA mediated knockdown. Direct interaction between NF1 and YAP1 was detected by confocal microscopy and co-immunoprecipitation (Co-IP), and further confirmed by GST pull-down assay and isothermal titration calorimetry assay (ITC). The stability of proteins was measured by western blot (WB) in the presence of cycloheximide. Results This study showed that a higher level of NF1 and YAP1 was found in GBC samples than in normal tissues and associated with worse prognoses. The NF1 knockdown impaired the proliferation and migration of NOZ in vivo and in vitro by downregulating YAP1 expression. Moreover, NF1 co-localized with YAP1 in NOZ and EH-GB1 cells, and the WW domains of YAP1 specifically recognized the PPQY motif of NF1. The structural modeling also indicated the hydrophobic interactions between YAP1 and NF1. On the other hand, YAP1 knockdown also impaired the proliferation of NOZ in vitro, phenocopying the effects of NF1 knockdown. Overexpression of YAP1 can partially rescue the impaired proliferation in NF1 stably knockdown cells. In mechanism, NF1 interacted with YAP1 and increased the stability of YAP1 by preventing ubiquitination. Conclusions Our findings discovered a novel oncogenic function of NF1 by directly interacting with YAP1 protein and stabilizing YAP1 to protect it from proteasome degradation in NOZ cells. NF1 may serve as a potential therapeutic target in GBC.

Abstract Molecular aggregation affects the electronic interactions between molecules and has emerged as a powerful tool in material science. Aggregate effect finds wide applications in the research of new physical phenomena; however, its value for chemical reaction development has been far less explored. Herein, we report the development of aggregation‐enabled alkene insertion into carbon–halogen bonds. The spontaneous cleavage of C–X (X = Cl, Br, or I) bonds generates an intimate ion pair, which can be quickly captured by alkenes in an aggregated state. Additional catalysts or promoters are not necessary under such circumstances, and solvent quenching experiments indicate that the aggregated state is critical for achieving such sequences. The ionic insertion mode is supported by mechanistic studies, density functional theory calculations, and symmetry‐adapted perturbation theory analysis. Results also show that the non‐aggregated state may quench the transition state and terminate the insertion process.

Background and purposeTo provide a comprehensive overview of epidemiological features and temporal trends of pancreatic cancer in urban Shanghai from 1973 to 2017.MethodsData on pancreatic cancer in urban Shanghai were obtained through the Shanghai Cancer Registry and the Vital Statistics System. Joinpoint analysis was used to describe the temporal trends and annual percent changes (APCs) and age-period-cohort analysis were used to estimate the effects of age, period, and birth cohort on pancreatic cancer.ResultsThere were a total of 29,253 cases and 27,105 deaths of pancreatic cancer in urban Shanghai over the 45-year study period. The overall average annual age-standardized incidence and mortality rates were 5.45/100,000 and 5.02/100,000, respectively. Both the incidence and mortality rates demonstrated fluctuating upward trends, with an average annual increase rate of 1.51% (APC = 1.51, P < 0.001) and 1.04% (APC = 1.04, P < 0.001), respectively. The upward trend in incidence was greater for females than for males, while the trend in mortality was seen in both sexes equally and continuously. In recent years (2013-2017), the age-specific incidence rates increased further than before, with statistically significant changes in the 35-year, 45- to 55-year and 70- to 85-year age groups (P < 0.05). The age-specific mortality rates also showed obvious upward trends, which in the 50- to 55-year, and 75- to 85-year age groups increased significantly. The results of the age-period-cohort analysis suggested significant effects of age, period, and cohort on the prevalence of pancreatic cancer.ConclusionThe prevalence of pancreatic cancer, dramatically influenced by socioeconomic development and lifestyles, demonstrated a significant upward trend from 1973 to 2017 in urban Shanghai and underscored the necessity and urgency for additional efforts in primary and secondary prevention measures.

Abstract. Background:. Hepatopancreatoduodenectomy (HPD) has been considered the only curative treatment for metastatic cholangiocarcinoma and some locally advanced gallbladder cancers (GBCs). However, HPD has not yet been included in treatment guidelines as a standard surgical procedure in consideration of its morbidity and mortality rates. The aim of this study was to evaluate the safety and effectiveness of HPD in treating biliary malignancies. Methods:. The medical records of 57 patients with advanced biliary cancer undergoing HPD from January 2009 to December 2019 were retrospectively retrieved. A case-control analysis was conducted at our department. Patients with advanced GBC who underwent HPD (HPD-GBC group) were compared with a control group (None-HPD-GBC group). Baseline characteristics, preoperative treatments, tumor pathologic features, operative results, and prognosis were assessed. Results:. Thirteen patients with cholangiocarcinoma and 44 patients with GBC underwent HPD at our department. Significant postoperative complications (grade III or greater) and postoperative pancreatic fistula were observed in 24 (42.1%) and 15 (26.3%) patients, respectively. One postoperative death occurred in the present study. Overall survival (OS) was longer in patients with advanced cholangiocarcinoma than in those with GBC (median survival time [MST], 31 months vs. 11 months; P

Abstract Background tRNA-derived fragments (tRFs) are newly discovered noncoding RNAs and regulate tumor progression via diverse molecular mechanisms. However, the expression and biofunction of tRFs in gallbladder cancer (GBC) have not been reported yet. Methods The expression of tRFs in GBC was detected by tRF and tiRNA sequencing in GBC tissues and adjacent tissues. The biological function of tRFs was investigated by cell proliferation assay, clonal formation assay, cell cycle assay, and xenotransplantation model in GBC cell lines. The molecular mechanism was discovered and verified by transcriptome sequencing, fluorescence in situ hybridization (FISH), target gene site prediction, and RNA binding protein immunoprecipitation (RIP). Results tRF-3013b was significantly downregulated in GBC compared with para-cancer tissues. Decreased expression of tRF-3013b in GBC patients was correlated with poor overall survival. Dicer regulated the production of tRF-3013b, and its expression was positively correlated with tRF-3013b in GBC tissues. Functional experiments demonstrated that tRF-3013b inhibited GBC cell proliferation and induced cell-cycle arrest. Mechanically, tRF-3013b exerted RNA silencing effect on TPRG1L by binding to AGO3, and then inhibited NF-κB. TPRG1L overexpression could rescue the effects of tRF-3013b on GBC cell proliferation. Conclusions This study indicated that Dicer-induced tRF-3013b inhibited GBC proliferation by targeting TPRG1L and repressed NF-κB, pointing to tRF-3013b as a novel potential therapeutic target of GBC.

Summary: The role of innate lymphoid cells (ILCs)—including natural killer cells, helper-like ILC1s, ILC2s, ILC3s, and lymphoid tissue inducers—in human cancer is still poorly understood due to the scarcity of cell number. To address this, we present a protocol to analyze or purify ILCs from human blood, adjacent intestine, and colorectal tumor tissue. We describe steps for tissue and blood treatment, density centrifugation, antibody staining, and cell sorting.For complete details on the use and execution of this protocol, please refer to Qi et al. (2021).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Biliary tract cancer (BTC) that contains cholangiocarcinoma, gallbladder cancer, and ampullary cancer is highly malignant and mostly diagnosed in elderly patients. Over the past decades, human life has globally risen; thus, aging emerges as the primary risk factor for BTC. However, an effective treatment for this vulnerable population remains a large clinical challenge. As a result, the incidence and mortality of TBC remains high. Here, we discuss the potential link between aging and BTC from the aspects of molecular and cellular mechanisms, surgical resection, and chemotherapy. In addition, we update a number of clinical trials that are currently ongoing in elderly patients. The overview of BTC in elderly patients is expected to help develop a new therapeutic strategy tailored to this elderly population, ultimately improving their life quality.

Tumour microenvironment profiling during colorectal cancer progression may enable the discovery of therapeutic targets. Here, single cell and spatial RNA sequencing of tumour and adjacent normal tissues reveals an interaction between FAP + fibroblasts and SPP1 + macrophages that could be disrupted as an immunotherapy strategy.

Introduction Gallbladder cancer (GBC) is an aggressive type of digestive system cancer with a dismal outcome. Given the lack of effective treatment options, the disease rapidly reoccurs and 5-year survival rate is

ObjectiveTo develop and validate an MRI-radiomics nomogram for the prognosis of pancreatic ductal adenocarcinoma (PDAC).Background“Radiomics” enables the investigation of huge amounts of radiological features in parallel by extracting high-throughput imaging data. MRI provides better tissue contrast with no ionizing radiation for PDAC.MethodsThere were 78 PDAC patients enrolled in this study. In total, there were 386 radiomics features extracted from MRI scan, which were screened by the least absolute shrinkage and selection operator algorithm to develop a risk score. Cox multivariate regression analysis was applied to develop the radiomics-based nomogram. The performance was assessed by discrimination and calibration.ResultsThe radiomics-based risk-score was significantly associated with PDAC overall survival (OS) (P < 0.05). With respect to survival prediction, integrating the risk score, clinical data and TNM information into the nomogram exhibited better performance than the TNM staging system, radiomics model and clinical model. In addition, the nomogram showed fine discrimination and calibration.ConclusionsThe radiomics nomogram incorporating the radiomics data, clinical data and TNM information exhibited precise survival prediction for PDAC, which may help accelerate personalized precision treatment.Clinical trial registrationclinicaltrials.gov, identifier NCT05313854.

The mesenchymal subtype of glioblastoma (mGBM), which is characterized by rigorous vasculature, resists anti-tumor immune therapy. Here, we investigated the mechanistic link between tumor vascularization and the evasion of immune surveillance. Clinical datasets with GBM transcripts showed that the expression of the mesenchymal markers YKL-40 (CHI3L1) and Vimentin is correlated with elevated expression of PD-L1 and poor disease survival. Interestingly, the expression of PD-L1 was predominantly found in vascular endothelial cells. Orthotopic transplantation of glioma cells GL261 over-expressing YKL-40 in mice showed increased angiogenesis and decreased CD8+ T cell infiltration, resulting in a reduction in mouse survival. The exposure of recombinant YKL-40 protein induced PD-L1 and VE-cadherin (VE-cad) expression in endothelial cells and drove VE-cad-mediated nuclear translocation of β-catenin/LEF, where LEF upregulated PD-L1 expression. YKL-40 stimulated the dissociation of VE-cad from PD-L1, rendering PD-L1 available to interact with PD-1 from CD8+-positive TALL-104 lymphocytes and inhibit TALL-104 cytotoxicity. YKL-40 promoted TALL-104 cell migration and adhesion to endothelial cells via CCR5-dependent chemotaxis but blocked its anti-vascular immunity. Knockdown of VE-cad or the PD-L1 gene ablated the effects of YKL-40 and reinvigorated TALL-104 cell immunity against vessels. In summary, our study demonstrates a novel vascular immune escape mechanism by which mGBM promotes tumor vascularization and malignant transformation.

Connexins are membrane expressed proteins, which could assemble into hexamers to transfer metabolites and secondary messengers. However, its roles in pancreatic cancer metastasis remains unknown. In this study, by comparing the gene expression patterns in primary pancreatic cancer patients primary and liver metastasis specimens, we found that Gap Junction Protein Beta 3 (GJB3) significantly increased in Pancreatic ductal adenocarcinoma (PDAC) liver metastasis. Animal experiments verified that GJB3 depletion suppressed the hepatic metastasis of PDAC cancer cells. Further, GJB3 over expression increased the neutrophil infiltration. Mechanistic study revealed that GJB3 form channels between PDAC tumor cells and accumulated neutrophil, which transfer cyclic adenosine monophosphate (cAMP) from cancer to neutrophil cells, which supports the survival and polarization. Taken together, our data suggesting that GJB3 could act as a potential therapeutic target of PDAC liver metastasis.

BackgroundAlthough a plethora of studies have employed multiple gallbladder cancer (GBC) cell lines, it is surprisingly noted that there is still lack of a normal gallbladder epithelial cell line as a normal counterpart, thus impeding substantially the progress of mechanistic studies on the transformation of normal epithelial cells to cancer. Here, we created a normal gallbladder epithelial cell line named L-2F7 from human gallbladder tissue.MethodsGallbladder tissues from a diagnosed cholecystitis female patient were collected, and epithelial cells were enriched by magnetic cell sorting. Then, the cells were immortalized by co-introduction of human telomerase reverse transcriptase (hTERT) and Simian virus 40 large T antigen (LT-SV40) via a lentivirus infection system. After clonal selection and isolation, L-2F7 cells were tested for epithelial markers CK7, CK19, CK20, and CD326, genomic feature, cell proliferation, and migration using Western blot, immunofluorescence, whole genome sequencing, karyotyping, and RNA sequencing. L-2F7 cells were also transplanted to Nude (nu/nu) mice to determine tumorigenicity.ResultsWe successfully identified one single-cell clone named L-2F7 which highly expressed epithelial markers CD326, CK7, CK19, and CK20. This cell line proliferated with a doubling time of 23 h and the epithelial morphology sustained over 30 passages following immortalization. Transient gene transduction of L-2F7 cells led to expression of exogenous GFP and FLAG protein. L-2F7 cells exhibited both distinct non-synonymous mutations from those of gallbladder cancer tissues and differential non-cancerous gene expression patterns similar to normal tissue. Although they displayed unexpected mobility, L-2F7 cells still lacked the ability to develop tumors.ConclusionWe developed a non-cancerous gallbladder epithelial cell line, offering a valuable system for the study of gallbladder cancer and other gallbladder-related disorders.

Abstract Background Liver cancer remains the leading cause of cancer death globally, and the treatment strategies are distinct for each type of malignant hepatic tumors. However, the differential diagnosis before surgery is challenging and subjective. This study aims to build an automatic diagnostic model for differentiating malignant hepatic tumors based on patients’ multimodal medical data including multi-phase contrast-enhanced computed tomography and clinical features. Methods Our study consisted of 723 patients from two centers, who were pathologically diagnosed with HCC, ICC or metastatic liver cancer. The training set and the test set consisted of 499 and 113 patients from center 1, respectively. The external test set consisted of 111 patients from center 2. We proposed a deep learning model with the modular design of SpatialExtractor-TemporalEncoder-Integration-Classifier (STIC), which take the advantage of deep CNN and gated RNN to effectively extract and integrate the diagnosis-related radiological and clinical features of patients. The code is publicly available at https://github.com/ruitian-olivia/STIC-model . Results The STIC model achieved an accuracy of 86.2% and AUC of 0.893 for classifying HCC and ICC on the test set. When extended to differential diagnosis of malignant hepatic tumors, the STIC model achieved an accuracy of 72.6% on the test set, comparable with the diagnostic level of doctors’ consensus (70.8%). With the assistance of the STIC model, doctors achieved better performance than doctors’ consensus diagnosis, with an increase of 8.3% in accuracy and 26.9% in sensitivity for ICC diagnosis on average. On the external test set from center 2, the STIC model achieved an accuracy of 82.9%, which verify the model’s generalization ability. Conclusions We incorporated deep CNN and gated RNN in the STIC model design for differentiating malignant hepatic tumors based on multi-phase CECT and clinical features. Our model can assist doctors to achieve better diagnostic performance, which is expected to serve as an AI assistance system and promote the precise treatment of liver cancer.

Abstract Background Gemcitabine plus platinum as the first-line chemotherapy for cholangiocarcinoma (CCA) has limited efficacy. The aim of this study was to evaluate the effectiveness of modified FOLFIRINOX (mFOLFIRINOX) compared to that of gemcitabine plus oxaliplatin (Gemox) for patients with locally advanced or metastatic CCA. Methods From January 2016 to December 2019, consecutive patients who were diagnosed with locally advanced or metastatic CCA were treated with either mFOLFIRINOX or Gemox as a first-line chemotherapy. The main endpoint was Progression free survival (PFS). The second endpoints were Overall survival (OS), Disease control rate (DCR) and incidence of severe toxicity (grade 3–4). Tumors were evaluated at baseline and thence every 4–6 weeks. The study was designed and carried out in accordance with the principles of the declaration of Helsinki, approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine (XHEC-D-2020-154) and registered with ClinicalTrials.gov , number NCT04305288 (registration date: 12/03/2020). Results Of 49 patients in this study, 27 were in the FOLFIRINOX regimen group and 22 in the Gemox regimen group. There were no significant differences between groups in baseline characteristics. The DCR was 77.8% in the mFOLFIRINOX group and 63.5% in the Gemox group. The corresponding median PFS was 9.9 months (95% confidence interval [CI], 7.3–12.4) in the mFOLFIRINOX group versus 6.4 months (95% CI,3.6–9.2, p = 0.040) in the Gemox group. The corresponding median OS was 15.7 months (95% CI, 12.5–19.0) versus 12.0 months (95% CI, 9.3–14.8, p = 0.099). Significantly more grade 3–4 vomiting occurred in the mFOLFIRINOX than the Gemox groups (7 (25.9%) vs 1 (4.5%), p = 0.044). Conclusions First-line mFOLFIRINOX offered more promising results in patients with advanced or metastatic CCA.

Abstract Cholangiocarcinoma (CCA) is a type of solid tumor derived from the bile duct epithelium that features universal gemcitabine resistance. Here, we utilized a gene-encoded ROS biosensor probe (HyPer3 probe) to sort subpopulations with different redox statuses from CCA cells. The isolated HyPer-low subpopulation CCA cells, which exhibited relatively lower cellular ROS levels, exhibited higher chemoresistance to gemcitabine than HyPer-high subpopulation CCA cells in vitro and in vivo. Mechanistically, increased expression of MTHFD1 was found in HyPer-low cells. Knocking down MTHFD1 in HyPer-low cells enhanced cellular ROS and restored sensitivity to gemcitabine. Furthermore, the MTHFD1 inhibitor antifolate compound methotrexate (MTX) increased cellular ROS, and combining gemcitabine with MTX effectively suppressed cholangiocarcinoma cell growth. In summary, the MTHFD1 level mediated the heterogeneous cellular redox status in CCA, which resulted in chemoresistance to gemcitabine. Our data suggest a novel strategy for CCA chemotherapy.

Aberrant expression of lysyl oxidase-like 1 (LOXL1) reportedly leads to fibrous diseases. Recent studies have revealed its role in cancers. In this study, we observed an elevated level of LOXL1 in the tissues and sera of patients with intrahepatic cholangiocarcinoma (ICC) compared with levels in nontumor tissues and sera of unaffected individuals. Overexpression of LOXL1 in RBE and 9810 cell lines promoted cell proliferation, colony formation, and metastasis in vivo and in vitro and induced angiogenesis. In contrast, depletion of LOXL1 showed the opposite effects. We further showed that LOXL1 interacted with fibulin 5 (FBLN5), which regulates angiogenesis, through binding to the αvβ3 integrin in an arginine-glycine-aspartic (Arg-Gly-Asp) domain-dependent mechanism and enhanced the focal adhesion kinase (FAK)-mitogen-activated protein kinase (MAPK) signaling pathway inside vascular endothelial cells. Our findings shed light on the molecular mechanism underlying LOXL1 regulation of angiogenesis in ICC development and indicate that the LOXL1-FBLN5/αvβ3 integrin/FAK-MAPK axis might be the critical pathological link leading to angiogenesis in ICC.

Abstract Neuroendocrine carcinoma (NEC) of the gallbladder (GB-NEC) is a rare but extremely malignant subtype of gallbladder cancer (GBC). The genetic and molecular signatures of GB-NEC are poorly understood; thus, molecular targeting is currently unavailable. In the present study, we applied whole-exome sequencing (WES) technology to detect gene mutations and predicted somatic single-nucleotide variants (SNVs) in 15 cases of GB-NEC and 22 cases of general GBC. In 15 GB-NECs, the C > T mutation was predominant among the 6 types of SNVs. TP53 showed the highest mutation frequency (73%, 11/15). Compared with neuroendocrine carcinomas of other organs, significantly mutated genes (SMGs) in GB-NECs were more similar to those in pulmonary large-cell neuroendocrine carcinomas (LCNECs), with driver roles for TP53 and RB1. In the COSMIC database of cancer-related genes, 211 genes were mutated. Strikingly, RB1 (4/15, 27%) and NAB2 (3/15, 20%) mutations were found specifically in GB-NECs; in contrast, mutations in 29 genes, including ERBB2 and ERBB3, were identified exclusively in GBC. Mutations in RB1 and NAB2 were significantly related to downregulation of the RB1 and NAB2 proteins, respectively, according to immunohistochemical (IHC) data (p values = 0.0453 and 0.0303). Clinically actionable genes indicated 23 mutated genes, including ALK, BRCA1, and BRCA2. In addition, potential somatic SNVs predicted by ISOWN and SomVarIUS constituted 6 primary COSMIC mutation signatures (1, 3, 30, 6, 7, and 13) in GB-NEC. Genes carrying somatic SNVs were enriched mainly in oncogenic signaling pathways involving the Notch, WNT, Hippo, and RTK-RAS pathways. In summary, we have systematically identified the mutation landscape of GB-NEC, and these findings may provide mechanistic insights into the specific pathogenesis of this deadly disease.

Abstract Apart from primary tumor development and metastasis, cancer-associated thrombosis is the second cause of cancer death in solid tumor malignancy. However, the mechanistic insight into the development of gallbladder cancer (GBC) and cancer-associated thrombosis remains unclear. This study aimed to investigate the mechanistic role of Sciellin (SCEL) in GBC cell proliferation and the development of venous thromboembolism. The expression level of SCEL was determined by immunohistochemical staining. Roles of SCEL in gallbladder cancer cell were determined by molecular and cell biology methods. SCEL was markedly upregulated in GBC and associated with advanced TNM stages and a poor prognosis. Furthermore, SCEL interacted with EGFR and stabilized EGFR expression that activates downstream PI3K and Akt pathway, leading to cell proliferation. In addition, SCEL induces tumor cell IL-8 production that stimulates the formation of neutrophil extracellular traps (NETs), accelerating thromboembolism. In xenografts, SCEL-expressing GBCs developed larger tumors and thrombosis compared with control cells. The present results indicate that SCEL promotes GBC cell proliferation and induces NET-associated thrombosis, thus serving as a potential therapeutic target.

Global climate change affects biodiversity patterns, especially in arid and semi-arid regions such as the Mongolian plateau, one of the most ecologically fragile regions in the world. Three dynamic habitat indices (DHIs) were related to the productivity hypothesis and calculated based on FAPAR, including cumulative productivity (DHIcum indicates the availability of resources such as food supply and habitat in a year, representing available energy), minimum productivity (DHImin indicates the limitations of food and habitat resources in a year, representing environmental stress), and seasonal productivity (DHIsea denotes the change in productivity in a year, representing environmental stability). In this paper, we investigated the distribution pattern of species richness on the Mongolian Plateau based on the productivity hypothesis. We constructed models of the richness of three species (mammals, birds, and amphibians) using DHIs and climate variables to explain patterns of species richness on the Mongolian Plateau. The results revealed that, on the Mongolian plateau, there is a relatively high correlation between DHIs and species richness, especially with DHIcum (R = 0.59 for mammals, R = 0.73 for birds, and R = 0.58 for amphibians). There was a significant non-linear relationship between DHIs and species richness, as the model predictive power was significantly enhanced with GAM and RF. The inclusion of climate variables significantly improved the explanatory power of various models for the mammal, bird, and amphibian species richness on the Mongolian Plateau, with the best results for RF (0.89, 0.94, and 0.91, respectively). The influence of climate variables on species richness patterns in the importance ranking was higher than that of DHIs. Climate also has an influence on species richness. Vegetation productivity and climatic factors are good determinants of species richness on the Mongolian Plateau and should be carefully considered in future studies.

Summary: Background: Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with an extremely poor prognosis. Effective targets for anticancer therapy confirmed in PDAC are limited. However, the characteristics of genomics have not been fully elucidated in large-scale patients with PDAC from China. Methods: We collected both blood and tissue samples from 1080 Chinese patients with pancreatic cancer and retrospectively investigated the genomic landscape using next-generation sequencing (NGS). Findings: We found recurrent somatic mutations in KRAS (83.2%), TP53 (70.6%), CDKN2A (28.8%), SMAD4 (23.0%), ARID1A (12.8%) and CDKN2B (8.9%) in Chinese PDAC patients. Compared with primary pancreatic cancers, more genomic alterations accumulated especially cell cycle regulatory gene variants (45.4% vs 31.6%, P < 0.001) were observed in metastatic tumors. The most common mutation site of KRAS is p.G12D (43.6%) in pancreatic cancer. Patients with KRAS mutations were significantly associated with older age and mutations in the other three driver genes, while KRAS wild-type patients contained more fusion mutations and alternative mechanisms of RTK/Ras/MAPK pathway including a number of clinically targetable mutations. KRAS mutations in Chinese cohort were significantly lower than those in Western cohorts (all P < 0.05). A total of 252 (23.3%) patients with the core DNA damage response (DDR) gene mutations were detected. ATM (n =59, 5.5%) was the most frequent mutant DDR gene in patients with pancreatic cancer from China. Patients with germline DDR gene mutations were younger (P = 0.018), while patients with somatic DDR gene mutations were more likely to accumulate in metastatic lesions (P < 0.001) and had higher TMB levels (P < 0.001). In addition, patients with mutant DDR genes and patients carrying TP53 mutation were observed mutually exclusive (P < 0.001). Interpretation: We demonstrated the real-world genomic characteristics of large-scale patients with pancreatic cancer from China which may have promising implications for further clinical significance and drug development. Funding: The funders are listed in the Acknowledgement.

Over the past decades, the aberrant epigenetic modification, apart from genetic alteration, has emerged as dispensable events mediating the transformation of pancreatic cancer (PC). However, the understanding of molecular mechanisms of methylation modifications, the most abundant epigenetic modifications, remains superficial. In this review, we focused on the mechanistic insights of DNA, histone, and RNA methylation that regulate the progression of PC. The methylation regulators including writer, eraser and reader participate in the modification of gene expression associated with cell proliferation, invasion and apoptosis. Some of recent clinical trials on methylation drug targeting were also discussed. Understanding the novel regulatory mechanisms in the methylation modification may offer alternative opportunities to improve therapeutic efficacy to fight against this dismal disease.

In high-resolution remote sensing image retrieval (HRRSIR), convolutional neural networks (CNNs) have an absolute performance advantage over the traditional hand-crafted features. However, some CNN-based HRRSIR models are classification-oriented, they pay no attention to similarity, which is critical to image retrieval; whereas others concentrate on learning similarity, failing to take full advantage of information about class labels. To address these issues, we propose a novel model called classification-similarity network (CSN), which aims for image classification and similarity prediction at the same time. In order to further improve performance, we build and train two CSNs, and two kinds of information from them, i.e., deep features and similarity scores, are consolidated to measure the final similarity between two images. Besides, the optimal fusion theorem in biometric authentication, which gives a theoretical scheme to make sure that fusion will definitely lead to a better performance, is used to conduct score fusion. Extensive experiments are carried out over publicly available datasets, demonstrating that CSNs are distinctly superior to usual CNNs and our proposed “two CSNs + feature fusion + score fusion” method outperforms the state-of-the-art models.

First of all, the explosion-welding method was adopted to prepare steel fiber-reinforced steel-aluminum composite plates. Secondly, the smooth particle hydrodynamic (SPH) method was used to investigate the effect of introducing steel fibers to a vortex region created at the bonding interface of the steel-aluminum composite plate. Thirdly, the following conclusions were drawn through an analysis of the vortex region with the assistance of scanning electron microscopy and energy-dispersive X-ray spectroscopy. A brittle intermetallic compound FeAl was produced in the vortex region in an environment characterized by high temperature, high pressure, and high strain rate, resulting in cracks, holes and pores. In addition, the hardness of the vortex area was less than the estimated value, which is mainly because the main element in the vortex area was 2A12 aluminum with low hardness, and there were cracks, holes, pores and other defects that caused hardness reduction. Although the addition of steel fibers caused defects at the bond interface, the addition of steel fibers was effective in improving the tensile resistance performance of steel-aluminum composite panels to a certain extent. In addition, the larger the fiber diameter, the more significant the increase in tensile resistance.

This paper presents a study on mechanical response of porous aluminum skeleton/rigid polyurethane foam interpenetrating phase composites (IPCs) at different strain rates. Mechanical properties and failure mechanisms of IPC were identified. Results shown that the strain rate sensitivity of IPC is mostly caused by foamed filler while the deformation mechanisms are still dominated by aluminum skeleton. The aluminum skeleton exhibited lower total energy absorption at high strain rates because of the decrease in dynamic compressibility. However, the two constituent phases simultaneously contributed their high toughness and outstanding dynamic response to the IPCs. Also, compared with IPCs composed of solid polymers, the foamed filler significantly improved the compressibility, mechanical properties and strain rate sensitivity of IPCs. The suggested constitutive model adequately captured dynamic response of IPCs by comparisons with experiments. All results show that the metallic/polymeric interpenetrating phase composite foam is of high potential in energy dissipation and impact protection.

Abstract Background Gallbladder cancer (GBC) is the most common cancer type of the biliary tract, and an association has been found between chronic calculous cholecystitis (CCC) and an increased incidence of GBC mortality. An understanding of the relationship between CCC and its carcinogenesis may enable us to prevent and cure GBC. In this study, we attempted to explore changes in the microbiome profile that take place during the transition from chronic cholecystitis mucosa to malignant lesions. Results Seven paired human GBC and CCC samples were provided by patients who had undergone laparoscopic cholecystectomy or radical cholecystectomy. Mucosal DNA extraction and metagenomic sequencing were performed to evaluate changes in the microbiota between the two groups. We found that GBC patients and CCC patients shared similar stable and permanent dominant species and showed apparent differences in their biliary microbial composition and gene function. Peptostreptococcus stomatis and Enterococcus faecium may potentially play a role in GBC progression. In addition, the metagenomic species profiles, co‐abundance and co‐exclusion correlations, and CAZyme prevalence showed significant differences between the CCC and GBC groups. Conclusion Our data suggested that changes in the microbiota between CCC and GBC may help deepen our understanding of the complex spectrum of different microbiotas involved in the development of GBC. Although the cohort size was small, this study has presented the first evidence of the existence of an altered biliary microbiota in GBC, which is clearly different from that in CCC patients.

To determine the ballistic limit velocity of titanium–titanium tri-aluminide (Ti/Al 3 Ti)-laminated composites under the action of tungsten alloy spherical fragments, a type of 12.7 mm ballistic gun loading system was used to test the tungsten alloy spherical fragments vertically impacting the Ti/Al 3 Ti-laminated composite targets with different thickness. The relationship between the ballistic limit velocity and the target area density of the Ti/Al 3 Ti-laminated composite was obtained. As the area density increased, the ballistic limit velocity and the ballistic energy absorbed by the target plate also enhanced. Based on the dimensional analysis and similarity theory, a simulation law of tungsten alloy spherical fragments penetrating Ti/Al 3 Ti-laminated composite targets with different thickness was studied and an empirical formula for the ballistic limit velocity was obtained. The research results had an important application value for the optimal design of the light armor protection structure.

Background/Aims: The role of ZFX in tumourigenesis is unclear. We aimed to study ZFX expression, regulation, and function and the clinical implications of this protein in human pancreatic cancer (PCa). Methods: One hundred and twenty patients with histologically confirmed PCa who underwent surgery were recruited for this study. Tumour samples and PCa cell lines were used to examine ZFX. Various cell functions related to tumourigenesis were assessed. In vivo mouse tumour xenografts were used to confirm the in vitro results. Results: Patients with ZFX-positive tumours had worse overall survival than patients with ZFX-negative tumours. The depletion of ZFX using lentiviral shRNAs significantly inhibited cell proliferation by inducing cell cycle arrest in G0/G1 phase and resulted in increased cell apoptosis and invasive repression. In vivo studies confirmed that ZFX promoted tumour growth. Mechanistically, MAPK pathway activation was involved in the oncogenic functions of ZFX. Conclusions: ZFX acts as a putative oncogene in PCa and could be a novel therapeutic target for this disease.

Abstract We report a shockwave method for altering the properties of the superconductor material Bi2Sr2CaCu2O8+δ (Bi2212). We find that the superconducting transition temperature (T c) increases from 84 K for the pristine sample to 94 K for the sample treated at a temperature and pressure of ~1200 K and ~31 GPa, respectively. X-ray diffraction and transmission electron microscopy characterizations indicate that this T c enhancement arises from a phase transition from pristine Bi2212 to a mixture of superconducting Bi2212 and semiconducting Bi2Sr2CuO6+δ (Bi2201) during the shockwave treatment. The shockwave-treated sample exhibits n-type semiconductor properties (with an on-off ratio ~5), in contrast to the pure metallic pristine sample. Our study offers an alternative route for modifying the superconducting properties via a shockwave treatment. Furthermore, this method may provide a new approach for studying other temperature- and pressure-sensitive materials.

Abstract Background Patients with metastatic or relapsed gallbladder cancer generally have a poor prognosis. Therefore, targeting metastasis is one arm of therapeutic strategies to treat gallbladder cancer. Methods Levels of translationally controlled tumor protein (TCTP) were measured in samples of gallbladder cancer by immunohistochemical staining. Wound healing, migration and invasion assays were used to investigate the motility of cells. Western blot assay was used to investigate the levels of TCTP and other proteins. Liver metastasis models and lung metastasis models were established to investigate the inhibitory effect of Dihydroartemisinin on gallbladder cancer metastasis. Results TCTP is aberrantly expressed in gallbladder cancer patients and associated with metastasis and a poor prognosis. Depleting TCTP significantly inhibited gallbladder cancer cell migration and invasion. We found that Dihydroartemisinin as a potent inhibitor of TCTP inhibited TCTP-dependent cell migration and invasion by reducing cell division control protein 42 homolog (Cdc42) activation. In addition, in mice with xenografted tumors, treatment with Dihydroartemisinin decreased gallbladder cancer cell metastases and improved survival. Conclusions These findings provide new insights into the therapeutic activity of Dihydroartemisinin as a treatment for gallbladder cancer metastasis.

In wireless networks, the performance is degraded by the intensity of the interference received from concurrent transmissions. Considering a stochastic cache-enabled network where some users have caching ability to store the most popular packets, we propose a novel interference management scheme to eliminate the interference by exploiting the content diversity. First, cache-enabled users can exploit cached packets as side information to cancel the interference. Second, considering that different access points may transmit the same contents to different users simultaneously, they should be regarded as useful signals rather than interference. The performance improvement with these two content diversity schemes is theoretically analyzed in this paper. The probabilities for the interference cancellation case and the signal enhancement case are derived, respectively, followed by the investigation of the signal to interference plus noise ratio improvement with our proposed content diversity schemes. Based on this, the effective content capacity of the system is analyzed. In addition to the simulations to validate the accuracy of the theoretical analysis, the impacts of caching ability and the proposed interference management schemes on the effective content capacity are investigated.

Rail surface scratching occurs with increasing frequency, seriously threatening the safety of vehicles and humans. Online repair of rail-surface scratches on damaged rails with scratch depths >1 mm is of increased importance, because direct rail-replacement has the disadvantages of long operation time, high manpower and high material costs. Advanced online repair of rail-surface scratch using three-dimensional (3D) metal printing technology such as laser cladding has become an increasing trend, desperately demanding a solution for the fast and precise establishment of a complete closed mesh model of rail-surface scratch data. However, there have only been limited studies on the topic so far. In this paper, the complete closed mesh model is well established based on a novel triangulation algorithm relying on the topological features of the point-cloud model (PCM) of scratch-data, which is obtained by implementing a scratch-data-computation process following a rail-geometric-feature-fused algorithm of random sample consensus (RANSAC) performed on the full rail-surface PCM constructed by 3D laser vision. The proposed method is universal for all types of normal-speed rails in China. Experimental results show that the proposed method can accurately acquire the complete closed mesh models of scratch data of one meter of 50 Kg/m-rails within 1 min.

Gallbladder cancer (GBC) is the most common malignancy in the biliary tract. Without effective treatment, its prognosis is notoriously poor. Tea polyphenols (TPs) have many pharmacological and health benefits, including antioxidant, anti-inflammatory, anti-tumor, anti-thrombotic, antibacterial, and vasodilatory properties. However, the anti-cancer effect of TPs in human gallbladder cancer has not yet been determined. Cell viability and colony formation assay were used to investigate the cell growth. Cell cycle and apoptosis were evaluated by flow cytometry analysis. Western blot assay was used to detect the expression of proteins related to cell cycle and apoptosis. Human tumor xenografts were used to examine the effect of TPs on gallbladder cancer cells in vivo. TPs significantly inhibited cell growth of gallbladder cancer cell lines in a dose- and time-dependent manner. Cell cycle progression in GBC cells was blocked at the S phase by TPs. TPs also induced mitochondrial-related apoptosis in GBC cells by upregulating Bax, cleaved caspase-3, and cleaved PARP expressions and downregulating Bcl-2, cyclin A, and Cdk2 expressions. The effects of TPs on GBC were further proven in vivo in a mouse xenograft model. Our study is the first to report that TPs inhibit GBC cell growth and these compounds may have potential as novel therapeutic agents for treating gallbladder cancer.

In the original publication of this article [1], there are mistakes in Fig. 3A and Fig. 3D.

Gastrointestinal stromal tumors originate from interstitial cells of Cajal, the pacemaker cells of the gut. Ca 2+ regulates the pacemaker activity of interstitial cells of Cajal. Store-operated Ca 2+ entry mediates the majority of Ca 2+ entry in most cancer cells and may be a factor in regulating intracellular Ca 2+ in interstitial cells of Cajal and gastrointestinal stromal tumors. Therefore, a blockade of this mechanism may affect the progression of gastrointestinal stromal tumors. Orai1 is the pore subunit of store-operated Ca 2+ channels. Here, we reported that Orai1 was overexpressed in gastrointestinal stromal tumor tissues and was positively correlated with a high-risk grade in gastrointestinal stromal tumor patients. Furthermore, upon Orai1 silencing, the functional store-operated Ca 2+ entry in gastrointestinal stromal tumor cells was decreased, indicating that the function of store-operated Ca 2+ entry was mediated by Orai1. Inhibition of Orai1-mediated store-operated Ca 2+ entry by Orai1 silencing or store-operated Ca 2+ entry blockers (SKF-96365 and 2-aminoethyl diphenylborate) induced obvious cell proliferation suppression, cell-cycle distribution, and apoptosis stimulation in GIST-T1 cells. Conversely, Orai1 overexpression increased store-operated Ca 2+ entry and cell proliferation in GIST882 cells. In addition, we found that activation of c-KIT and the extracellular signal–regulated kinase pathway participated in the oncogenic functions of Orai1-mediated store-operated Ca 2+ entry in gastrointestinal stromal tumor cells. These results revealed that Orai1-mediated store-operated Ca 2+ entry is critical for gastrointestinal stromal tumor cell proliferation via c-KIT and ERK signaling pathway activation. Orai1-mediated store-operated Ca 2+ entry plays an oncogenic role and may be a novel prognostic factor and therapeutic target for patients with gastrointestinal stromal tumors.

In this work, T2 red copper and high nitrogen austenitic stainless steel (HNASS) were explosively welded for the first time. The welding window was theoretically developed, and the experiment was designed by considering the effect of explosive loading on welding quality. To evaluate the welding quality, the microstructure and mechanical properties of the composite material were systematically investigated. The results showed that the welding quality was in good agreement with the results predicted by the welding window. The micromorphology of the welding interface changed with a varied welding parameter, and no intermetallic compounds were found at the welding interface by EDS analysis. The microhardness of the two raw materials both increased near the welding interface, and the enhancement increased with the explosive loading. The failure pattern of the welding interface in the tension-shear experiments was dominated by the strength failure of the red copper.

Energetic structural materials (ESMs) have many potential military applications due to their unique functions. In this work, the reactivity and penetration performance of ESMs have been examined as a shaped charge liner material. The penetration experiments of nickel-aluminum (Ni-Al) and copper-nickel-aluminum (Cu-Ni-Al)-shaped charge liners (SCLs) have been designed and fired into 45# steel. The targets were recovered and analyzed by optical microscopy, electron microscopy, energy dispersive spectroscopy, and Vickers microhardness measurements. The head and tail of the crater walls penetrated by two reactive jets demonstrated unique microstructures. The jet rapidly decayed with the penetration process, but the “white„ zone (a mixture of martensite and austenite) was more prominent in the tail, and the microhardness of the tail was much higher than that of the head. The results showed the continued exotherm of Ni-Al reactive jet when it was fired into the target. The addition of Cu reduced the exotherm of Ni-Al, Cu could not only increase the average crater size, but also raise the average penetration depth by 42%. These results offer valuable insight for utilizing ESM as shaped charge liner materials.