Ten-Eleven Translocation 1 Promotes Malignant Progression of Cholangiocarcinoma With Wild-Type Isocitrate Dehydrogenase 1.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is a highly lethal disease without effective therapeutic approaches. The whole-genome sequencing data indicate that about 20% of patients with CCA have isocitrate dehydrogenase 1 (IDH1) mutations, which have been suggested to target 2-oxoglutarate (OG)-dependent dioxygenases in promoting CCA carcinogenesis. However, the clinical study indicates that patients with CCA and mutant IDH1 have better prognosis than those with wild-type IDH1, further complicating the roles of 2-OG-dependent enzymes. APPROACH AND RESULTS: This study aimed to clarify if ten-eleven translocation 1 (TET1), which is one of the 2-OG-dependent enzymes functioning in regulating 5-hydroxymethylcytosine (5hmC) formation, is involved in CCA progression. By analyzing The Cancer Genome Atlas (TCGA) data set, TET1 mRNA was found to be substantially up-regulated in patients with CCA when compared with noncancerous bile ducts. Additionally, TET1 protein expression was significantly elevated in human CCA tumors. CCA cells were challenged with α-ketoglutarate (α-KG) and dimethyl-α-KG (DM-α-KG), which are cosubstrates for TET1 dioxygenase. The treatments with α-KG and DM-α-KG promoted 5hmC formation and malignancy of CCA cells. Molecular and pharmacological approaches were used to inhibit TET1 activity, and these treatments substantially suppressed 5hmC and CCA carcinogenesis. Mechanistically, it was found that knockdown of TET1 may suppress CCA progression by targeting cell growth and apoptosis through epigenetic regulation. Consistently, targeting TET1 significantly inhibited CCA malignant progression in a liver orthotopic xenograft model by targeting cell growth and apoptosis. CONCLUSIONS: Our data suggest that expression of TET1 is highly associated with CCA carcinogenesis. It will be important to evaluate TET1 expression in CCA tumors before application of the IDH1 mutation inhibitor because the inhibitor suppresses 2-hydroxyglutarate expression, which may result in activation of TET, potentially leading to CCA malignancy.

Targeting Aspartate Beta-Hydroxylase with the Small Molecule Inhibitor MO-I-1182 Suppresses Cholangiocarcinoma Metastasis.

BACKGROUND: Cholangiocarcinoma is a devastating disease with a 2% 5-year survival if the disease has spread outside the liver. The enzyme aspartate beta-hydroxylase (ASPH) has been demonstrated to be highly expressed in cholangiocarcinoma but not in normal bile ducts and found to stimulate tumor cell migration. In addition, it was found that targeting ASPH inhibits cholangiocarcinoma malignant progression. However, it is not clear whether targeting ASPH with the small molecule inhibitor MO-I-1182 suppresses cholangiocarcinoma metastasis. The current study aims to study the efficacy of MO-I-1182 in suppressing cholangiocarcinoma metastasis. METHODS: The analysis was performed in vitro and in vivo with a preclinical animal model by using molecular and biochemical strategies to regulate ASPH expression and function. RESULTS: Knockdown of ASPH substantially inhibited cell migration and invasion in two human cholangiocarcinoma cell lines. Targeting ASPH with a small molecule inhibitor suppressed cholangiocarcinoma progression. Molecular mechanism studies demonstrated that knockdown of ASPH subsequently suppressed protein levels of the matrix metalloproteinases. The ASPH knockdown experiments suggest that this enzyme may modulate cholangiocarcinoma metastasis by regulating matrix metalloproteinases expression. Furthermore, using an ASPH inhibitor in a rat cholangiocarcinoma intrahepatic model established with BED-Neu-CL#24 cholangiocarcinoma cells, it was found that targeting ASPH inhibited intrahepatic cholangiocarcinoma metastasis and downstream expression of the matrix metalloproteinases. CONCLUSION: ASPH may modulate cholangiocarcinoma metastasis via matrix metalloproteinases expression. Taken together, targeting ASPH function may inhibit intrahepatic cholangiocarcinoma metastasis and improve survival.

ASPH-notch Axis guided Exosomal delivery of Prometastatic Secretome renders breast Cancer multi-organ metastasis.

BACKGROUND: Aspartate ß-hydroxylase (ASPH) is silent in normal adult tissues only to re-emerge during oncogenesis where its function is required for generation and maintenance of malignant phenotypes. Exosomes enable prooncogenic secretome delivering and trafficking for long-distance cell-to-cell communication. This study aims to explore molecular mechanisms underlying how ASPH network regulates designated exosomes to program development and progression of breast cancer. METHODS: Stable cell lines overexpressing or knocking-out of ASPH were established using lentivirus transfection or CRISPR-CAS9 systems. Western blot, MTT, immunofluorescence, luciferase reporter, co-immunoprecipitation, 2D/3-D invasion, tube formation, mammosphere formation, immunohistochemistry and newly developed in vitro metastasis were applied. RESULTS: Through physical interactions with Notch receptors, ligands (JAGs) and regulators (ADAM10/17), ASPH activates Notch cascade to provide raw materials (especially MMPs/ADAMs) for synthesis/release of pro-metastatic exosomes. Exosomes orchestrate EMT, 2-D/3-D invasion, stemness, angiogenesis, and premetastatic niche formation. Small molecule inhibitors (SMIs) of ASPH's ß-hydroxylase specifically/efficiently abrogated in vitro metastasis, which mimics basement membrane invasion at primary site, intravasation/extravasation (transendothelial migration), and colonization/outgrowth at distant sites. Multiple organ-metastases in orthotopic and tail vein injection murine models were substantially blocked by a specific SMI. ASPH is silenced in normal adult breast, upregulated from in situ malignancies to highly expressed in invasive/advanced ductal carcinoma. Moderate-high expression of ASPH confers more aggressive molecular subtypes (TNBC or Her2 amplified), early recurrence/progression and devastating outcome (reduced overall/disease-free survival) of breast cancer. Expression profiling of Notch signaling components positively correlates with ASPH expression in breast cancer patients, confirming that ASPH-Notch axis acts functionally in breast tumorigenesis. CONCLUSIONS: ASPH-Notch axis guides particularly selective exosomes to potentiate multifaceted metastasis. ASPH's pro-oncogenic/pro-metastatic properties are essential for breast cancer development/progression, revealing a potential target for therapy.

Pharmacokinetic comparison of two phenolic acids after oral administration of Typhae pollen to normal rats and rats with acute cold blood stasis.

Typhae Pollen, dried pollen of Typha angustifolia L., Typha orientalis Presl or other plants of the same genus (Typhaeceae), has the effect of activating the circulation to cure blood stasis in traditional Chinese Medicine. The purpose of this study was to set up an ultra-high performance liquid chromatography method that could determine p-hydroxybenzoic acid and vanillic acid simultaneously in rat plasma, and to compare their pharmacokinetics in normal rats and rats with acute cold blood stasis, and further to investigate the influence of different dosages of oral administration. The pharmacokinetic parameters obtained showed that both of the phenolic acids had a higher bioavailability in rats with cold blood stasis than that in normal rats with a higher area under the concentration-time curve and longer mean residence time, and the high dose oral administration group had a higher capacity in blood stasis rats than in normal rats. These results reminded us that changes in health condition could alter the absorption and elimination of both phenolic acids in vivo, and the pharmacokinetic study under pathological conditions provides important information for more rational drug use in clinical situations.

Hydrogen sulphide exacerbates acute pancreatitis by over-activating autophagy via AMPK/mTOR pathway.

Previously, we have shown that hydrogen sulphide (H2 S) might be pro-inflammatory during acute pancreatitis (AP) through inhibiting apoptosis and subsequently favouring a predominance of necrosis over apoptosis. In this study, we sought to investigate the detrimental effects of H2 S during AP specifically with regard to its regulation on the impaired autophagy. The incubated levels of H2 S were artificially intervened by an administration of sodium hydrosulphide (NaHS) or DL-propargylglycine (PAG) after AP induction. Accumulation of autophagic vacuoles and pre-mature activation of trypsinogen within acini, which indicate the impairment of autophagy during AP, were both exacerbated by treatment with NaHS but attenuated by treatment with PAG. The regulation that H2 S exerted on the impaired autophagy during AP was further attributed to over-activation of autophagy rather than hampered autophagosome-lysosome fusion. To elucidate the molecular mechanism that underlies H2 S-mediated over-activation of autophagy during AP, we evaluated phosphorylations of AMP-activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR). Furthermore, Compound C (CC) was introduced to determine the involvement of mTOR signalling by evaluating phosphorylations of downstream effecters including p70 S6 kinase (P70S6k) and UNC-51-Like kinase 1 (ULK1). Our findings suggested that H2 S exacerbated taurocholate-induced AP by over-activating autophagy via activation of AMPK and subsequently, inhibition of mTOR. Thus, an active suppression of H2 S to restore over-activated autophagy might be a promising therapeutic approach against AP-related injuries.

Systematic characterization of the metabolites of echinacoside and acteoside from Cistanche tubulosa in rat plasma, bile, urine and feces based on UPLC-ESI-Q-TOF-MS.

Echinacoside (ECH) and acteoside (ACT), as the most and major active components of Cistanche tubulosa, were reported to possess cardioactive, neuroprotective and hepatocyte protective effects, as well as antibacterial, antioxidative effects. Recently, more studies have focused on their pharmacological activities. However, their metabolic profiles in vivo have not been sufficiently investigated. This study proposes an approach for rapidly identifying the complicated and unpredictable metabolites of ECH and ACT in rat plasma, bile, urine and feces, and systematically and comprehensively revealing their major metabolic pathways, based on powerful ultra-high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. Plasma, bile, urine and feces were collected from rats after a single 200 mg/kg oral dose. A total of 49 metabolites were detected in rat biological samples. Through analyzing metabolites in bile samples, it was found that ECH and ACT were subjected to a marked hepatic first-pass effect in liver. Copyright © 2016 John Wiley & Sons, Ltd.

[Impact of octreotide on pancreatic fistula after pancreaticoduodenectomy: a prospective study].

OBJECTIVE: To investigate the effect of utilizing octreotide during perioperative period on pancreatic fistula after pancreaticoduodenectomy (PD). METHODS: Three hundreds and six patients admitted from January 2010 to October 2014, who prepared to undergo pancreaticoduodenectomy (PD) were randomly divided into octreotide group (147 cases) and control group (159 cases). In octreotide group, octreotide was used in subcutaneous injection instantly after PD, each 8 hours until postoperative 10(th) day, and patients in control group were injected with the same volume of saline. Differences of pancreatic fistula (Grade A, Grade B, Grade C), hospitalization days and treatment cost were compared. χ(2) test, t-test and Fisher exact test were used to analyzed to the data, respectively. RESULTS: No statistical significance (P>0.05) between two groups in the incidence of pancreatic fistula after PD (Grade A: 8.8% vs. 10.2%, Grade B: 2.7% vs. 4.4%, Grade C: 0.7% vs. 1.3%; χ(2)=0.197, 0.700, 0.288; P=0.657, 0.403, 0.591), the length of hospitalization((12.1±1.2)days vs. (13.0±1.2)days)(t=1.711, P=0.104) and treatment cost (79 700±6 700 vs. 77 600±5 200)(t=1.378, P=0.185). When accompanied with high risk factors, such as soft texture of pancreas, pancreatic duct size less than 3 mm, BMI≥25 kg/m(2) and diabetes, compared with control group, octreotide group had the lower incidence rate of pancreatic fistula and clinical correlative pancreatic fistula(all P<0.05) after PD. CONCLUSIONS: Generally, octreotide makes no contribution to reduce the incidence of pancreatic fistula after PD. However, for patients who is accompanied with high risk factors, such as soft texture of pancreas, pancreatic duct size less than 3 mm, BMI≥25 kg/m(2) and diabetes, octreotide can effectively prevent pancreatic fistula after PD.

[The clinical analysis of autoimmune pancreatitis: a report of 21 cases].

OBJECTIVE: To investigate the clinical feature, diagnostic and therapeutic experience of autoimmune pancreatitis (AIP). METHODS: Twenty-one patients with AIP treated in the First Affiliated Hospital, Harbin Medical University from January 2006 to July 2014 were analyzed retrospectively. There were 15 men and 6 women among the 21 cases and the age ranged from 36 to 64 years. The characters of diagnosis and treatment of AIP were explored through clinical symptoms, imaging features, serologic test results, diagnostic treatment, and histopathologic characteristics. RESULTS: All the patients showed obstructive jaundice and upper abdominal pain to different extents as major manifestations and the levels of serum IgG4, CA19-9, CEA were elevated in 16 cases (76.2%), 6 cases (28.5%) and 3 cases (14.2%), respectively. CT showed diffuse enlargement of the pancreas in 9 cases, localized pancreatic head enlargement in 3 cases and focally pancreatic mass in 9 cases. AIP was confirmed by extrapancreatic involvement, radiological and serological results plus biopsy in 11 cases (52.4%), interpretation of response to steroid in 3 cases (14.3%) and open laparotomy in 7 cases (33.3%). Surgery included choledochojejunostomy in 3 cases, cholecystojejunostomy in 1 case, pancreaticoduodenectomy in 2 cases and distal pancreatectomy combined with splenectomy in 1 case. The pathologic results displayed massive lymphocytes and plasma cells infiltration in the pancreatic tissues as well as parenchymal fibrosis. Except for 1 patient who had no symptom, the regular steroid therapy was performed (oral prednisone) and all the patients were cured. The follow-up time range was from 3 to 93 months, 4 cases (19.0%) were recurrent followed by the symptoms alleviated after the steroid was applied again. CONCLUSIONS: AIP is rare and characterized by non-specific clinical manifestations so that the early diagnosis is difficult with a high misdiagnosis rate. The clinicians should strengthen the recognition of AIP and the definite diagnosis depends on the combination of clinical manifestations, radiological, serological and histopathological results so as to avoid the unnecessary operation.

The apoptosis of peripheral blood lymphocytes promoted by hyperbaric oxygen treatment contributes to attenuate the severity of early stage acute pancreatitis in rats.

The aim of this study was to investigate the immunoregulatory effects of hyperbaric oxygen (HBO) via promoting the apoptosis of peripheral blood lymphocytes (PBLs) to attenuate the severity of early stage acute pancreatitis (AP) in rats. Additionally, the persistence of the HBO treatment effects was evaluated. One hundred and twenty male Wistar rats were randomized into four groups: sham, AP, AP + normobaric oxygen (NBO), and AP + HBO. Each group consisted of 30 rats. Four hours after the induction of AP, the 30 rats in the AP + NBO group were given normobaric oxygen treatment with 100 % oxygen at 1 atm for 90 min. The 30 rats in the AP + HBO group received 100 % oxygen at 2.5 atm for 90 min, with a compression/decompression time of 15 min. The 30 rats in the AP group remained untreated. At 6, 12, and 24 h after the induction of AP, surviving rats from each group were sacrificed, and the blood and tissue samples were collected for the following measurements: the partial pressure of oxygen (PaO2) and oxygen saturation (SaO2) of the arterial blood, the levels of serum amylase, lipase, interleukin-2 (IL-2), interferon-γ (IFN-γ), interleukin-10 (IL-10), hepatocyte growth factor (HGF), and reactive oxygen species (ROS), and the mitochondrial membrane potential (∆Ψm) of the PBLs. The expression levels of procaspase-3, caspase-3, procaspase-9, and caspase-9 were also evaluated in the PBLs. Additionally, the apoptosis of PBLs was assessed, and the pancreatic tissues were subjected to a histopathological analysis by pathological grading and scoring. The histopathology of the lung, liver, kidney, duodenum, and heart was also analyzed at 12 h after the induction of AP. Significant differences were found at 6 and 12 h after AP induction. The HBO treatment significantly elevated the PaO2 and SaO2 levels, and the ROS levels in the PBLs. Additionally, HBO downregulated the levels of amylase and lipase. The HBO treatment also reduced the ∆Ψm levels, upregulated the expression of caspase-3 and caspase-9, and increased the apoptosis rate of the PBLs. Moreover, the HBO treatment decreased the serum concentrations of IL-2, IFN-γ and HGF, and reduced the pathological scores of the pancreatic tissue. The histopathological changes of the lung, liver, kidney, duodenum, and heart were also improved. A significant elevation of IL-10 occurred only at the 12-h time point. However, no obvious differences were found at the 24-h time point. This study demonstrated that the HBO treatment can promote the apoptosis of PBLs via a mitochondrial-dependent pathway and inhibit the inflammatory response. These immunoregulatory effects may play an important therapeutic role in attenuating the severity of early stage AP. The repeated administration of HBO or the use of HBO in combination with other approaches may further improve outcomes.

Elevated 2-oxoglutarate antagonizes DNA damage responses in cholangiocarcinoma chemotherapy through regulating aspartate beta-hydroxylase.

Cholangiocarcinoma (CCA) is resistant to systemic chemotherapies that kill malignant cells mainly through DNA damage responses (DDRs). Recent studies suggest that the involvement of 2-oxoglutarate (2-OG) dependent dioxygenases in DDRs may be associated with chemoresistance in malignancy, but how 2-OG impacts DDRs in CCA chemotherapy remains elusive. We examined serum 2-OG levels in CCA patients before receiving chemotherapy. CCA patients are classified as progressive disease (PD), partial response (PR), and stable disease (SD) after receiving chemotherapy. CCA patients classified as PD showed significantly higher serum 2-OG levels than those defined as SD and PR. Treating CCA cells with 2-OG reduced DDRs. Overexpression of full-length aspartate beta-hydroxylase (ASPH) could mimic the effects of 2-OG on DDRs, suggesting the important role of ASPH in chemoresistance. Indeed, the knockdown of ASPH improved chemotherapy in CCA cells. Targeting ASPH with a specific small molecule inhibitor also enhanced the effects of chemotherapy. Mechanistically, ASPH modulates DDRs by affecting ATM and ATR, two of the major regulators finely controlling DDRs. More importantly, targeting ASPH improved the therapeutic potential of chemotherapy in two preclinical CCA models. Our data suggested the impacts of elevated 2-OG and ASPH on chemoresistance through antagonizing DDRs. Targeting ASPH may enhance DDRs, improving chemotherapy in CCA patients.

[The clinical analysis of a step-up approach for severe acute pancreatitis: report of 121 cases].

OBJECTIVE: To investigate the feasibility and clinical value of the step-up approach for severe acute pancreatitis (SAP). METHODS: Clinical data of 121 SAP patients admitted between January 2002 and December 2011 were retrospectively analyzed. Fifty-eight patients (37 males and 21 females, aged from 20 to 72 years, mean 47.6 years) in the group of direct open necrosectomy from January 2002 to December 2006 were performed laparotomy through removal of all necrotic tissue. Sixty-three patients (42 males and 21 females, aged from 19 to 78 years, mean 46.2 years) of step-up approach from January 2007 to December 2011 underwent percutaneous catheter drainage through retroperitoneum or omental bursa guided by B-type ultrasonography for the first therapy, and then, according to the pathogenetic condition, if necessary, followed by a small incisional necrosectomy along the drainage tube. The two groups were compared for the rates of postoperative complications, death, transfusion and length of stay, medical costs. RESULTS: The rates of total postoperative complications, organ dysfunction, alimentary tract fistula and incisional hernia in step-up approach group were significantly lower than those of direct open necrosectomy group (31.7% vs. 62.1%, 14.3% vs. 37.5%, 6.3% vs. 19.0%, 9.5% vs. 29.3%; χ(2) = 4.43 to 11.17, P = 0.001 to 0.035). The other complications had no significant differences between the two groups (P > 0.05). Patients in step-up approach group had a lower rates of transfusion (44.4% vs. 70.7%, χ(2) = 8.488, P = 0.004), fewer medical costs of transfusion and hospital stay, compared with those in direct open necrosectomy group ((2525 ± 4573) yuan vs. (4770 ± 6867) yuan, t = 2.131, P = 0.035; (171 213 ± 50 917) yuan vs. (237 874 ± 67 832) yuan, t = 2.496, P = 0.014). There were no significant differences of length of stay and mortality between two groups (P > 0.05). CONCLUSION: Step-up approach for SAP which can reduce the rates of postoperative complications, transfusion and medical costs has significant feasibility and great clinical value.

The Prediction of Steel Bar Corrosion Based on BP Neural Networks or Multivariable Gray Models.

The corrosion of steel bars in concrete has a significant impact on the durability of constructed structures. Based on the gray relational analysis (GRA) of the accelerated corrosion data and practical engineering data using MATLAB, a back propagation neural network (BPNN) model, a multivariable gray prediction model (GM (1, N)), and an optimization multivariable gray prediction model (OGM (1, N)) of steel corrosion were established by using a sequence of the key affecting factors. By comparing the prediction results of the three models, it is found that the GM (1, N) model has larger fitting and prediction errors for steel corrosion, while the OGM (1, N) model has smaller prediction errors in the accelerated corrosion data; the BPNN model offers more accurate predictions of the practical engineering data. The results show that the BPNN and OGM (1, N) models are all suitable for the prediction of steel bar corrosion in concrete structures.

Molecular profiling reveals potential targets in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is a devastating malignancy and has a very poor prognosis if tumors spread outside the liver. Understanding the molecular mechanisms underlying the CCA progression will likely yield therapeutic approaches toward treating this deadly disease. AIM: To determine the molecular pathogenesis in CCA progression. METHODS: In silico analysis, in vitro cell culture, CCA transgenic animals, histological, and molecular assays were adopted to determine the molecular pathogenesis. RESULTS: The transcriptomic data of human CCA samples were retrieved from The Cancer Genome Atlas (TGCA, CHOL), European Bioinformatics Institute (EBI, GAD00001001076), and Gene Expression Omnibus (GEO, GSE107943) databases. Using Gene set enrichment analysis, the cell cycle and Notch related pathways were demonstrated to be significantly activated in CCA in TCGA and GEO datasets. We, through differentially expressed genes, found several cell cycle and notch associated genes were significantly up-regulated in cancer tissues when compared with the non-cancerous control samples. The associated genes, via quantitative real-time PCR and western blotting assays, were further examined in normal human cholangiocytes, CCA cell lines, mouse normal bile ducts, and mouse CCA tumors established by specifically depleting P53 and expressing KrasG12D mutation in the liver. Consistently, we validated that the cell cycle and Notch pathways are up-regulated in CCA cell lines and mouse CCA tumors. Interestingly, targeting cell cycle and notch pathways using small molecules also exhibited significant beneficial effects in controlling tumor malignancy. More importantly, we demonstrated that several cell cycle and Notch associated genes are significantly associated with poor overall survival and disease-free survival using the Log-Rank test. CONCLUSION: In summary, our study comprehensively analyzed the gene expression pattern of CCA samples using publicly available datasets and identified the cell cycle and Notch pathways are potential therapeutic targets in this deadly disease.

Comparison of Fecal Antimicrobial Resistance Genes in Captive and Wild Asian Elephants.

The Asian elephant (Elephas maximus) is a flagship species of tropical rainforests, and it has generated much concern. In this case, the gut bacterial communities of captive and wild Asian elephants are particularly noteworthy. We aim to compare the differences in bacterial diversity and antibiotic resistance gene (ARG) subtypes in fecal samples of Asian elephants from different habitats, which may affect host health. Analyses reveal that differences in the dominant species of gut bacteria between captive and wild Asian elephants may result in significant differences in ARGs. Network analysis of bacterial communities in captive Asian elephants has identified potentially pathogenic species. Many negative correlations in network analysis suggest that different food sources may lead to differences in bacterial communities and ARGs. Results also indicate that the ARG levels in local captive breeding of Asian elephants are close to those of the wild type. However, we found that local captive elephants carry fewer ARG types than their wild counterparts. This study reveals the profile and relationship between bacterial communities and ARGs in different sources of Asian elephant feces, providing primary data for captive breeding and rescuing wild Asian elephants.

Tumor Cell Derived Lnc-FSD2-31:1 Contributes to Cancer-Associated Fibroblasts Activation in Pancreatic Ductal Adenocarcinoma Progression through Extracellular Vesicles Cargo MiR-4736.

Pancreatic ductal adenocarcinoma (PDAC) presents with high mortality and short overall survival. Cancer-associated fibroblasts (CAFs) act as refuge for cancer cells in PDAC. Mechanisms of intracelluar communication between CAFs and cancer cells need to be explored. Long noncoding RNAs (lncRNAs) are involved in the modulation of oncogenesis and tumor progression of PDAC; however, specific lncRNAs and their mechanism of action have not been clarified clearly in tumoral microenvironment. This work aims to identify novel lncRNAs involved in cellular interaction between cancer cells and CAFs in PDAC. To this end, differentially expressed lncRNAs between long-term and short-term survival PDAC patients are screened. Lnc-FSD2-31:1 is found to be significantly increased in long-term survival patients. This work then discovers that tumor-derived lnc-FSD2-31:1 restrains CAFs activation via miR-4736 transported by extracellular vesicles (EVs) in vitro and in vivo. Mechanistically, EVs-derived miR-4736 suppresses autophagy and contributes to CAFs activation by targeting ATG7. Furthermore, blocking miR-4736 suppresses tumor growth in genetically engineered KPC (LSL-KrasG12D/+, LSL-Trp53R172H/+, and Pdx-1-Cre) mouse model of PDAC. This study demonstrates that intratumoral lnc-FSD2-31:1 modulates autophagy in CAFs resulting in their activation through EVs-derived miR-4736. Targeting miR-4736 may be a potential biomarker and therapeutic target for PDAC.

Gut microbiota aggravates neutrophil extracellular traps-induced pancreatic injury in hypertriglyceridemic pancreatitis.

Hypertriglyceridemic pancreatitis (HTGP) is featured by higher incidence of complications and poor clinical outcomes. Gut microbiota dysbiosis is associated with pancreatic injury in HTGP and the mechanism remains unclear. Here, we observe lower diversity of gut microbiota and absence of beneficial bacteria in HTGP patients. In a fecal microbiota transplantation mouse model, the colonization of gut microbiota from HTGP patients recruits neutrophils and increases neutrophil extracellular traps (NETs) formation that exacerbates pancreatic injury and systemic inflammation. We find that decreased abundance of Bacteroides uniformis in gut microbiota impairs taurine production and increases IL-17 release in colon that triggers NETs formation. Moreover, Bacteroides uniformis or taurine inhibits the activation of NF-κB and IL-17 signaling pathways in neutrophils which harness NETs and alleviate pancreatic injury. Our findings establish roles of endogenous Bacteroides uniformis-derived metabolic and inflammatory products on suppressing NETs release, which provides potential insights of ameliorating HTGP through gut microbiota modulation.

Solution-processable carbon dots with efficient solid-state red/near-infrared emission.

Carbon dots (CDs) emerge as promising luminescent materials for potential applications in optoelectronics on basis of their merits including low cost, eco-friendliness and strong, color-tunable photoluminescence (PL). However, the research on solid-state emissive CDs is still at the primary stage because of the aggregation-caused quenching (ACQ) of PL and their poor film-formation ability. In this work, we produce CDs with branched-polyethylenimine (b-PEI) chemically functionalized on the surfaces. The thus newly synthesized P-CDs successfully overcome the bottleneck of ACQ effect and display efficient red and NIR emission in aggregate state. Under the excitation of 520 nm, a strong red emission (maxima of 640 nm) with a high photoluminescence quantum yield (PLQY) of 21% was observed for the P-CDs in neat film. Moreover, this design strategy endows the P-CDs with good film-formation ability via solution spin-coating, which significantly increases its value for the film-based optoelectronic devices.

Adaptive antitumor immune response stimulated by bio-nanoparticle based vaccine and checkpoint blockade.

BACKGROUND: Interactions between tumor and microenvironment determine individual response to immunotherapy. Triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) have exhibited suboptimal responses to immune checkpoint inhibitors (ICIs). Aspartate ß-hydroxylase (ASPH), an oncofetal protein and tumor associated antigen (TAA), is a potential target for immunotherapy. METHODS: Subcutaneous HCC and orthotopic TNBC murine models were established in immunocompetent BALB/c mice with injection of BNL-T3 and 4 T1 cells, respectively. Immunohistochemistry, immunofluorescence, H&E, flow cytometry, ELISA and in vitro cytotoxicity assays were performed. RESULTS: The ASPH-MYC signaling cascade upregulates PD-L1 expression on breast and liver tumor cells. A bio-nanoparticle based λ phage vaccine targeting ASPH was administrated to mice harboring syngeneic HCC or TNBC tumors, either alone or in combination with PD-1 blockade. In control, autocrine chemokine ligand 13 (CXCL13)-C-X-C chemokine receptor type 5 (CXCR5) axis promoted tumor development and progression in HCC and TNBC. Interactions between PD-L1+ cancer cells and PD-1+ T cells resulted in T cell exhaustion and apoptosis, causing immune evasion of cancer cells. In contrast, combination therapy (Vaccine+PD-1 inhibitor) significantly suppressed primary hepatic or mammary tumor growth (with distant pulmonary metastases in TNBC). Adaptive immune responses were attributed to expansion of activated CD4+ T helper type 1 (Th1)/CD8+ cytotoxic T cells (CTLs) that displayed enhanced effector functions, and maturation of plasma cells that secreted high titers of ASPH-specific antibody. Combination therapy significantly reduced tumor infiltration of immunosuppressive CD4+/CD25+/FOXP3+ Tregs. When the PD-1/PD-L1 signal was inhibited, CXCL13 produced by ASPH+ cancer cells recruited CXCR5+/CD8+ T lymphocytes to tertiary lymphoid structures (TLSs), comprising effector and memory CTLs, T follicular helper cells, B cell germinal center, and follicular dendritic cells. TLSs facilitate activation and maturation of DCs and actively recruit immune subsets to tumor microenvironment. These CTLs secreted CXCL13 to recruit more CXCR5+ immune cells and to lyse CXCR5+ cancer cells. Upon combination treatment, formation of TLSs predicts sensitivity to ICI blockade. Combination therapy substantially prolonged overall survival of mice with HCC or TNBC. CONCLUSIONS: Synergistic antitumor efficacy attributable to a λ phage vaccine specifically targeting ASPH, an ideal TAA, combined with ICIs, inhibits tumor growth and progression of TNBC and HCC.

Impact of COVID-19 pandemic on acute pancreatitis presentations, management, and in-hospital outcomes: a single-center, retrospective observational study from the northeast of China.

Background: Since initially detected in late December 2019, the novel coronavirus disease 2019 (COVID-19) outbreak rapidly swept the world, which has profoundly affected healthcare system and clinical practice in the management of gastrointestinal diseases. Objectives: We aimed to evaluate the impact of COVID-19 pandemic on the pattern of hospital admissions and healthcare services for acute pancreatitis (AP). Design: We conducted a retrospective observational cohort study using the anonymized electronic medical records. Methods: This single-center, retrospective observational study from a regional medical center in the northeast of China included all consecutively admitted patients with AP from 23 January to 10 June 2020 (during the COVID-19 outbreak in Harbin), compared with the equivalent period of the previous year, in terms of demographics, clinical characteristics, and in-hospital outcomes. Results: In this article, we observed a reduction in AP admissions after the beginning of COVID-19 outbreak. With the prolonged time from symptom onset to hospitalization [32.0 (22.0-72.0) versus 18.0 (12.0-24.0) h; p < 0.001], a higher proportion of AP patients developed acute renal failure (14.0% versus 7.4%, p = 0.004) and acute necrotic collection (16.5% versus 11.2%; p = 0.038) in the COVID-19 era. The percentage of alcohol etiology significantly decreased after the implementation of social restriction measures (11.5% versus 20.4%; p = 0.002), whereas biliary etiology was numerically more common amidst the COVID-19 era (41.6% versus 32.6%; p = 0.014). No significant differences were found in the rates of intensive care unit admission and mortality between the two groups. Conclusion: This study preliminarily demonstrated the descending trend and delay in hospital presentations for AP during the outbreak of COVID-19. Given that the pandemic may persist for several years, adjustments of medical services according to the varying degrees of local breakouts are imperative to provide appropriate care for AP patients and diminish the risk of viral transmission. Registration: ClincialTrials.gov number ChiCTR2100043350.