Showing papers by "Li Yang published in 2018"

Prognostic significance of frequent CLDN18-ARHGAP26/6 fusion in gastric signet-ring cell cancer

Abstract: Signet-ring cell carcinoma (SRCC) has specific epidemiology and oncogenesis in gastric cancer, however, with no systematical investigation for prognostic genomic features. Here we report a systematic investigation conducted in 1868 Chinese gastric cancer patients indicating that signet-ring cells content was related to multiple clinical characteristics and treatment outcomes. We thus perform whole-genome sequencing on 32 pairs of SRC samples, and identify frequent CLDN18-ARHGAP26/6 fusion (25%). With 797 additional patients for validation, prevalence of CLDN18-ARHGAP26/6 fusion is noticed to be associated with signet-ring cell content, age at diagnosis, female/male ratio, and TNM stage. Importantly, patients with CLDN18-ARHGAP26/6 fusion have worse survival outcomes, and get no benefit from oxaliplatin/fluoropyrimidines-based chemotherapy, which is consistent with the fact of chemo-drug resistance acquired in CLDN18-ARHGAP26 introduced cell lines. Overall, this study provides insights into the clinical and genomic features of SRCC, and highlights the importance of frequent CLDN18-ARHGAP26/6 fusions in chemotherapy response for SRCC.

An Endogenous Vaccine Based on Fluorophores and Multivalent Immunoadjuvants Regulates Tumor Micro-Environment for Synergistic Photothermal and Immunotherapy.

Abstract: Recently, near-infrared (NIR) light-based photothermal therapy (PTT) has been widely applied in cancer treatment. However, in most cases, the tissue penetration depth of NIR light is not sufficient and thus photothermal therapy is unable to completely eradicate deep, seated tumors inevitably leading to recurrence of the tumor. Due to this significant limitation of NIR, improved therapeutic strategies are urgently needed. Methods: We developed an endogenous vaccine based on a novel nanoparticle platform for combinatorial photothermal ablation and immunotherapy. The design was based on fluorophore-loaded liposomes (IR-7-lipo) coated with a multivalent immunoadjuvant (HA-CpG). In vitro PTT potency was assessed in cells by LIVE/DEAD and Annexin V-FITC/PI assays. The effect on bone marrow-derived dendritic cells (BMDC) maturation and antigen presentation was evaluated by flow cytometry (FCM) with specific antibodies. After treatment, the immune cell populations in tumor micro-environment and the cytokines in the serum were detected by FCM and Elisa assay, respectively. Finally, the therapeutic outcome was investigated in an animal model. Results: Upon irradiation with 808 nm laser, IR-7-lipo induced tumor cell necrosis and released tumor-associated antigens, while the multivalent immunoadjuvant improved the expression of co-stimulatory molecules on BMDC and promoted antigen presentation. The combination therapy of PTT and immunotherapy regulated the tumor micro-environment, decreased immunosuppression, and potentiated host antitumor immunity. Most significantly, due to an enhanced antitumor immune response, combined photothermal immunotherapy was effective in eradicating tumors in mice and inhibiting tumor metastasis. Conclusion: This endogenous vaccination strategy based on synergistic photothermal and immunotherapy may provide a potentially effective approach for treatment of cancers, especially those difficult to be surgically removed.

Inhibition of Stat3 signaling pathway by nifuroxazide improves antitumor immunity and impairs colorectal carcinoma metastasis.

Abstract: Colorectal carcinoma (CRC) is the one of the most common cancers with considerable metastatic potential, explaining the need for new drug candidates that inhibit tumor metastasis. The signal transducers and activators of the transcription 3 (Stat3) signaling pathway has an important role in CRC and has been validated as a promising anticancer target for CRC therapy. In the present study, we report our findings on nifuroxazide, an antidiarrheal agent identified as an inhibitor of Stat3. Our studies showed that nifuroxazide decreased the viability of three CRC cell lines and induced apoptosis of cancer cells in a concentration-dependent manner. Moreover, western blot analysis demonstrated that the occurrence of its apoptosis was correlated with the activation of Bax and cleaved caspase-3, and decreased the expression of Bcl-2. In addition, nifuroxazide markedly impaired CRC cell migration and invasion by downregulating phosphorylated-Stat3Tyr705, and also impaired the expression of matrix metalloproteinases (MMP-2 and MMP-9). Furthermore, our studies showed that nifuroxazide also significantly inhibited the tumor metastasis in lung and abdomen metastasis models of colon cancer. Meanwhile, nifuroxazide functionally reduced the proliferation index, induced tumor apoptosis and impaired metastasis. Notably, nifuroxazide reduced the number of myeloid-derived suppressor cells in the blood, spleens and tumors, accompanied by the increased infiltration of CD8+ T cells in the tumors. Importantly, a marked decrease in the number of M2-type macrophages in tumor in the abdomen metastasis model was also observed. Taken together, our results indicated that nifuroxazide could effectively inhibit tumor metastasis by mediating Stat3 pathway and it might have a therapeutic potential for the treatment of CRC.

MicroRNA-214 promotes hepatic stellate cell activation and liver fibrosis by suppressing Sufu expression.

Abstract: MicroRNAs (miRNAs) have been demonstrated to modulate cellular processes in the liver. However, the role of miRNAs in liver fibrosis is poorly understood. Because the activation of hepatic stellate cells (HSCs) is a pivotal event in the initiation and progression of hepatic fibrosis, we investigate the differential expression of miRNAs in activated and quiescent rat HSCs by microarray analysis and find that miR-214 (miR-214-3p) is significantly upregulated during HSC activation. Moreover, the robust induction of miR-214 is correlated with liver fibrogenesis in carbon tetrachloride (CCl4)-treated rats and mice, high-fat diet-induced non-alcoholic steatohepatitis in mice, and cirrhosis in humans. We identify that miR-214 expression is driven by the helix–loop–helix transcription factor Twist1 via the E-box element. The increased miR-214 inhibits the expression of suppressor-of-fused homolog (Sufu), a negative regulator of the Hedgehog signaling pathway, thereby contributing to HSC activation to promote the accumulation of fibrous extracellular matrix and the expression of profibrotic genes in HSCs and LX2 cells. Furthermore, miR-214 expression is inversely correlated with the expression of Sufu in clinical cirrhosis samples. To explore the clinical potential of miR-214, we inject antagomiR-214 oligos into mice to induce hepatic fibrosis. The knockdown of miR-214 in vivo enhances Sufu expression and reduces fibrosis marker expression, which ameliorates liver fibrosis in mice. In conclusions, the Twist1-regulated miR-214 promotes the activation of HSC cells through targeting Sufu involved in the Hedgehog pathway and participates in the development of hepatic fibrosis. Hence, the knockdown of miR-214 expression may be a promising therapeutic strategy for liver fibrosis.

Comparison of Concanavalin a-Induced Murine Autoimmune Hepatitis Models

Abstract: Background/aims Autoimmune hepatitis (AIH) is a chronic necroinflammatory disease of the liver whose pathogenic mechanisms have not yet been elucidated. Moreover, the current treatment used for the vast majority of AIH patients is largely dependent on immunosuppressant administration and liver transplantation. However, research on the pathogenesis of AIH and effective new treatments for AIH have been hampered by a lack of animal models that accurately reproduce the human condition. Methods AIH models created by concanavalin A (ConA) injections at different times and doses. The levels of ALT, AST, LDH and inflammatory cytokines were examined at various times after 20 mg/kg ConA was administered by ELISA using commercially available kits. Moreover, liver pathological changes were observed by flow cytometry (FCM) and H&E staining. Results Our experiments demonstrated that the levels of ALT, AST, LDH and several inflammatory cytokines, including TNF-α, IFN-γ, and IL-6, were higher in the 20 mg/kg 12 h ConA group than in the other groups. Importantly, the numbers of activated CD4+ and CD8+ T lymphocytes in the blood, spleen and liver were calculated. These results showed that ConA (20 mg/kg for 12 h)-induced hepatitis was similar to that in clinical AIH patients. Furthermore, we found that the number of MDSCs in the blood was significantly increased in the ConA (20 mg/kg for 12 h) group compared with controls. Our findings indicated that ConA (20 mg/kg for 12 h)-induced hepatitis could be used as an experimental murine model that mirrors most of the pathogenic properties of human type I AIH. Conclusion This model [ConA (20 mg/kg for 12 h)] provides a valuable tool for studying AIH immunopathogenesis and rapidly assessing novel therapeutic approaches.

Modified Fe3O4 Magnetic Nanoparticle Delivery of CpG Inhibits Tumor Growth and Spontaneous Pulmonary Metastases to Enhance Immunotherapy.

Abstract: As a novel toll-like receptor 9 (TLR9) agonist, synthetic unmethylated cytosine-phosphate-guanine (CpG) oligodeoxynucleotides can stimulate a Th1 immune response and potentially be used as therapeutic agents or vaccine adjuvants for the treatment of cancer. However, some drawbacks of CpG limit their applications, such as rapid elimination by nuclease-mediated degradation and poor cellular uptake. Therefore, repeat high-dose drug administration is required for treatment. In this work, a CpG delivery system based on 3-aminopropyltriethoxysilane (APTES)-modified Fe3O4 nanoparticles (FeNPs) was designed and studied for the first time to achieve better bioactivity of CpG. In our results, we designed FeNP-delivered CpG particles (FeNP/CpG) with a small average size of approximately 50 nm by loading CpG into FeNPs. The FeNP/CpG particle delivery system, with enhanced cell uptake of CpG in bone marrow-derived dendritic cells (BMDCs) in vitro and through intratumoral injection, showed significant antitumor ability by stimulating better humoral and cellular immune responses in C26 colon cancer and 4T1 breast cancer xenograft models in vivo over those of free CpG. Moreover, mice treated by FeNP/CpG particles had delayed tumor growth with an inhibitory rate as high as 94.4%. In addition, approximately 50% of the tumors in the C26 model appeared to regress completely. Similarly, there were lower pulmonary metastases and a 69% tumor inhibitory rate in the 4T1 breast cancer tumor model than those in the untreated controls. In addition to their effectiveness, the easy preparation, safety, and high stability of FeNP/CpG particles also make them an attractive antitumor immunotherapy.

Delivery of a Modified mRNA Encoding IL-22 Binding Protein (IL-22BP) for Colon Cancer Gene Therapy.

Abstract: As an alternative form of genetic material, mRNA lacks a CpG island and can function without crossing the nuclear membrane. These properties make mRNA less of a potential immune stimulant than plasmid DNA. Therefore, chemically modified mRNA is an effective alternative to plasmid DNA for gene therapy. In this study, cationic liposomes were used as a vector to transport mRNA complexes that had been compressed using protamine and to obtain high mRNA transport and expression efficiency. The liposome-protamine-IL-22BP mRNA complex can strongly inhibit the growth of C26 tumour cells by inducing apoptosis, inhibiting tumour angiogenesis and increasing the number of immune cells that infiltrate the tumour microenvironment. The obvious tumour regression and safety of this approach were observed in peritoneal metastasis and subcutaneous xenograft models. The antitumour effect of the liposome protamine mRNA complex was as good as that for a plasmid DNA complex, and demonstrated the potential for mRNA-based gene therapy.

Novel Self-Assembled Micelles Based on Cholesterol-Modified Antimicrobial Peptide (DP7) for Safe and Effective Systemic Administration in Animal Models of Bacterial Infection.

Abstract: Owing to their broad-spectrum antibacterial properties, multitarget effects, and low drug resistance, antimicrobial peptides (AMPs) have played critical roles in the clinical therapy of drug-resistant bacterial infections. However, the potential hazard of hemolysis following systemic administration has greatly limited their application. Here, we developed a novel AMP derivative, DP7-C, by modifying a formerly identified highly active AMP (DP7) with cholesterol to form an amphiphilic conjugate. The prepared DP7-C easily self-assembled into stable nanomicelles in aqueous solution. The DP7-C micelles showed lower hemolytic activity than their unconjugated counterparts toward human red blood cells and a maximum tolerated dose of 80 mg/kg of body weight in mice via intravenous injection, thus demonstrating improved safety. Moreover, by eliciting specific immunomodulatory activities in immune cells, the DP7-C micelles exerted distinct therapeutic effects in zebrafish and mouse models of infection. In conclusion, DP7-C micelles may be an excellent candidate for the treatment of bacterial infections in the clinic.

Combination of common and novel rare NUDT15 variants improves predictive sensitivity of thiopurine-induced leukopenia in children with acute lymphoblastic leukemia.

Abstract: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer in the world, with treatment outcomes improving dramatically in the past several decades due to the combined usage of multiple drugs and sophisticated therapeutic protocols. Thiopurine (e.g., 6-mercaptopurine) is primarily used in ALL treatment, but can induce severe adverse drug reactions (ADR), including leukopenia and hepatotoxicity. Inherited predispositions to both ALL susceptibility and treatment outcomes have been noticed. Pharmacogenetics studies have indicated that cases of leukopenia can be largely explained by single nucleotide polymorphisms (SNPs) in TPMT and NUDT15 with varied variant allele frequencies among different ethnicities. In particular, the common missense variant in NUDT15 (i.e., rs116855232) has been reported to be consistently associated with thiopurineinduced leukopenia, either through genome-wide association studies or candidate replications in several independent patient cohorts, made up for the most part by East Asians and Hispanics. Subsequently, several less frequent and rare variants have also been identified that negatively impact on NUDT15 function, and which can further increase the predictive sensitivity of the eventual dosage of thiopurine. As a consequence, it is necessary to sequence the full length of NUDT15 in order to determine the initial clinical dosage of thiopurine, which, unlike TPMT, has had a limited number of functional variants identified thus far. In the study herein, which is a CCCG-ALL-2015 protocol based trial of Chinese pediatric ALL patients aged from one to fifteen years old (N = 188), we systematically investigated the association of thiopurine-induced ADRs with all NUDT15 variants in the West China Second Hospital between 2015 and 2016. 6-mercaptopurine (6MP) was used in multiple phases of ALL therapy: remission induction (standard dosage of 60mg/m in the last two weeks), consolidation (25mg/m), and maintenance (50mg/m). Forty-eight patients in total experienced thiopurine-induced leukopenia, requiring an obligatory reduction of the dosage of 6-MP, an interruption of the therapy, and/or the prescription of human granulocyte colony-stimulating factor (G-CSF). Thirty-seven patients experienced thiopurine-induced hepatotoxicity, which was characterized by an increase in aspartate transaminase and/or alanine transaminase by more than five times following the introduction of thiopurine. Firstly, we estimated the correlation of thiopurineinduced leukopenia/hepatotoxicity events with clinical characteristics, and found no significant association (Table 1). Next, the impact of the reported NUDT15 and TPMT SNPs on leukopenia was evaluated, including rs116855232 (p. R139C), rs186364861 (p. V18I), and rs554405994 (p. V18_V19insGV) in NUDT15, and rs1142345 (inducing p. Y240C) in TPMT. Not surprisingly, the genotypes of rs116855232, rs554405994 and rs1142345 were significantly associated with 6-MPinduced leukopenia (Table 1). However, rs554405994 completely lost its significance in a multivariate model after adjusting for rs116855232, due to the linkage dise-

Discovery of a self-assembling and self-adjuvant lipopeptide as a saccharide-free peptide vaccine targeting EGFRvIII positive cutaneous melanoma

Abstract: Recently, tumor immunotherapy has achieved great progress in the treatment of hematological and solid neoplasms. The DC vaccines, KLH-conjugated vaccines or glycosylated peptide vaccines can efficiently induce immune responses against tumors. In the current study, we have discovered cholesteryl PADRE-EGFRvIII epitope-conjugated lipopeptide self-assembled micelles as a potential self-adjuvant vaccine against cutaneous melanoma. The lipopeptide vaccines were synthesized using a standard solid phase peptide synthesis method, and these vaccines could elicit both a humoral and a cellular immune response to EGFRvIII positive melanoma cells. Their high humoral immunoreaction stimulation properties in combination with their cytotoxic T-cell eliciting properties provide them with potent tumor inhibitory capacity. In therapeutic and preventive xenograft models of B16-EGFRvIII melanoma cells, the self-adjuvant lipopeptide vaccine micelles efficiently prevented tumor growth as well as tumorigenesis. Our results provide a novel platform for eliciting immune responses to non-antigenic cancer-related epitopes in peptide cancer vaccine discovery and development.

Local and Systemic Delivery of Interleukin-12 Gene by Cationic Micelles for Cancer Immunogene Therapy.

Abstract: Immunogene therapy is an alternative strategy for cancer gene therapy. By stimulating the activities of immune cells in the tumor microenvironment, the genetic materials boost the immune response to attack cancer cells resulting in therapeutic effects. Interleukin-12 is an important regulator with great potential in modulating both innate and adaptive immunities. Here, a cancer immunogene therapy strategy was established and evaluated by delivering the IL-12 gene with a novel non-viral gene vector DMP. The DMP cationic micelles were prepared by modifying monomethoxy poly(ethylene glycol)-poly(e-caprolactone) with the DOTAP lipid via self-assembly. The anti-cancer efficacy of the DMP/IL-12 complex was studied on multiple murine cancer models via both local and systemic administration. Our results demonstrated that the secretory expressed IL-12 cytokine effectively enhanced lymphocytes activities resulting in strong inhibition of cancer cell growth in vitro. Meanwhile, there were obvious tumor regressions achieved in tumor models of C26 colon carcinoma and LL/2 lung cancer in vivo. Multiple anti-cancer mechanisms including T cell infiltration, TNF-α secretion, apoptosis induction and angiogenesis inhibition are involved; no pathology changes were observed in healthy tissues. These results suggest that the DMP/IL-12 complex is a potential candidate for cancer immunogene therapy.

Efficacy and safety of balloon-occluded retrograde transvenous obliteration of gastric varices with lauromacrogol foam sclerotherapy: initial experience

Abstract: Balloon-occluded retrograde transvenous obliteration (BRTO) is a widely-accepted treatment for gastric varices (GVs). The purpose of this study was to evaluate the efficacy and safety of BRTO with lauromacrogol foam sclerotherapy. Between May 2014 and June 2015, 32 patients were treated with lauromacrogol foam. Lauromacrogol foam was made using a combination of agents, with a 2:1:1 ratio of room air: lauromacrogol: contrast media. Patients were followed up using contrast-enhanced computed tomography (CT) and endoscopy. Technical success was achieved in 31 of 32 patients (96.9%). Portal vein thrombosis occurred in two patients and resolved spontaneously. No other major complications were observed. The overall mean dose of lauromacrogol used was 12.4 mL (range, 8–20 mL). Complete obliteration of GVs was confirmed in all 31 patients (100%) on follow-up CT. Seven of the 31 patients (22.6%) experienced worsening of esophageal varices. Rupture of esophageal varices occurred in three patients and was treated successfully with band ligation. Five patients (16.1%) experienced worsening of ascites and responded well to diuretic therapy. BRTO utilizing lauromacrogol foam appears to be a safe and useful treatment option in patients with GVs in the short term.

Clinical and Pathological Characteristics of Autoimmune Hepatitis with Acute Presentation

Abstract: Aim. To study the differences between acute presentation-autoimmune hepatitis (A-AIH) and chronic autoimmune hepatitis (C-AIH). Methods. Through long-term follow-up, 80 patients were included in our study by using the revised international autoimmune hepatitis group (IAIHG) score and were divided into acute and chronic groups for comparison. Results. No significant difference was found in the gender, age, IAIHG score (pretreatment/posttreatment), definite diagnosis rate, extrahepatic autoimmune disease, onset time, or treatment before biopsy between the acute and chronic groups. In terms of clinical symptoms, A-AIH patients were more prone to jaundice, anorexia, yellow urine, and detesting oil than C-AIH patients, but melena only occurred in chronic group (P < 0.05). The acute group exhibited more severe injury upon histological evaluation, with lobular inflammation and bile duct injury, especially central necrosis of the lobule, more pronounced in this group (P < 0.05). Conclusion. A-AIH had manifestations of acute hepatitis and presented cholestasis. Serum indicators could preliminarily distinguish A-AIH and C-AIH. Histologically, the primary manifestation of A-AIH was lobular inflammation, which was usually accompanied by lobular central necrosis. For the diagnosis of A-AIH, more attention should be paid to long-term follow-up. This study was registered at ClinicalTrials.gov (identifier: NCT02994537).

Transjugular intrahepatic portosystemic shunt creation: three-dimensional roadmap versus CO2 wedged hepatic venography.

Abstract: The blind portal vein puncture remains the most challenging step during transjugular intrahepatic portosystemic shunt (TIPS) creation. We performed a prospective randomised clinical trial to compare three-dimensional (3D) roadmap with CO2 wedged hepatic vein portography for portal vein puncture guidance. Between March 2017 and May 2017, 30 patients were enrolled and randomly allocated to the study group (3D roadmap) or the control group (CO2 wedged hepatic vein portography). Technical success of TIPS procedures was achieved in all 30 patients. The mean number of needle passes was significantly lower in the study group (2.0 ± 1.0) compared to the control group (3.7 ± 2.5; p = 0.021). A total of six (40%) patients in the study group and three (20%) in the control group required only one puncture for the establishment of TIPS. There were no significant differences in total fluoroscopy time (p = 0.905), total procedure time (p = 0.199) and dose-area product (p = 0.870) between the two groups. 3D roadmap is a safe and technically feasible means for portal vein puncture guidance during TIPS creation, equivalent in efficacy to CO2 wedged hepatic vein portography. This technique could reduce the number of needle passes, thereby simplifying the TIPS procedure. • 3D roadmap can be used to guide portal vein puncture. • Compared with CO 2 venography, 3D roadmap reduced the number of needle passes. • 3D roadmap has a potential to simplify the TIPS procedure.

Delivery of modified mRNA encoding vesicular stomatitis virus matrix protein for colon cancer gene therapy

Abstract: Plasmid DNA based gene delivery has been widely utilized among both pre-clinical and clinical gene therapy studies. However, therapeutic efficiency is usually limited by the size and potential immune-stimulation issue of plasmid backbone. As an alternative form of genetic material, chemically modified messenger RNA (mRNA) provides a promising alternative to plasmid DNA. In this work, an in vitro transcription mRNA encoding vesicular stomatitis virus matrix protein (VSVMP) was delivered by a cationic liposome–protamine complex, resulting in high mRNA transporting and expression efficiency. The liposome–protamine complex delivered VSVMP mRNA strongly inhibits the growth of C26 tumor cells through inducing apoptosis, while obvious tumor regressions were achieved on both abdominal cavity metastatic and subcutaneous xenograft models in vivo with high safety. Our results also demonstrated that the liposome–protamine–mRNA complex was as potent as its plasmid DNA counterpart, showing strong potential in further colon cancer therapy.

Delivery of interleukin-22 binding protein (IL-22BP) gene by cationic micelle for colon cancer gene therapy

Abstract: Gene therapy has provided an alternative strategy for cancer therapy. As an important cytokine, interleukin-22 (IL-22) is not only critical in reinforcing innate immune defenses and tissue regeneration, but also involved in the initial establishment of tumors. A soluble-secreted receptor of the cytokine IL-22, IL-22 binding protein (IL-22BP), binds IL-22 and prevents its binding to the functional transmembrane receptor IL-22R1 complex, inhibiting IL-22-based intracellular cancer proliferation signal. In this work, a novel IL-22BP-based cancer gene therapy strategy was reported for the first time. It was established by delivering IL-22BP gene with a newly developed non-viral gene vector DMP. The DMP cationic micelles were prepared by modifying monomethoxy poly(ethylene glycol)-poly(e-caprolactone) with DOTAP lipid through self-assembling. The anti-cancer efficacy of the DMP/IL-22BP complex was studied on a colon cancer model by intraperitoneal administration. Our results demonstrated that the secretory expressed IL-22BP cytokine effectively inhibited cancer growth both in vitro and in vivo. Multiple anti-cancer mechanisms including IL-22 blocking, apoptosis inducing, lymphocyte infiltration and angiogenesis inhibition were indicated to be involved while no pathology changes were observed in healthy tissues. These results suggest the DMP/IL-22BP complex to be a potential candidate for cancer gene therapy.

A novel BF 2 –curcumin-based fluorescent chemosensor for detection of Cu 2+ in aqueous solution and living cells

Abstract: A novel BF2–curcumin-based chemosensor 1, namely monopicolinate of BF2–curcumin complex, was designed, synthesized and applied for the detection of Cu2+ in aqueous buffer solution and living cells. Sensor 1 exhibited sensitive naked-eye color change toward Cu2+ from blue to pink in TBS solution and the detection limit was estimated to be 0.12 µM. The selectivity of sensor 1 for Cu2+ was high over competing metal ions (Ag+, Cu+, Hg2+, Mg2+, Ca2+, Co2+, Zn2+, Mn2+, Ni2+, Fe2+ and Fe3+). Based on the experimental results, the sensing mechanism was proposed for the Cu2+ triggered hydrolysis of 1 to BF2–curcumin which has unique chromogenic and fluorogenic properties. Compared with other chemosensors with a similar mechanism, chemosensor 1 had a comparatively large Stokes shift and the emission wavelength was close to NIR. Moreover, cell imaging investigations indicated that sensor 1 has the potential to be applied for practical Cu2+ detection in biological systems.

Letter: tacrolimus may be hazardous in decompensated autoimmune liver disease with hyperbilirubinaemia.

Abstract: N. Youssef A. El Tahan M. Elbadry A. M. Farid Y. El Shazly W. Doss G. Esmat A. Fontanet Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt Emerging Disease Epidemiology Unit, Institut Pasteur, Paris, France Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt Medical Surgical Nursing Department, Faculty of Nursing, Cairo University, Cairo, Egypt New Cairo Viral Hepatitis Treatment Unit, Cairo, Egypt Tropical Medicine and Gastroenterology Department, Faculty of Medicine, Aswan University, Sahary City, Egypt Egyptian National Committee for Control of Viral Hepatitis, Cairo, Egypt Institut Pasteur, Conservatoire National des Arts et M etiers, Unit e PACRI, Paris, France Email: m_elkassas@yahoo.com

Efficacy and Safety of Immunosuppressive Therapy for PBC-AIH Overlap Syndrome Accompanied by Decompensated Cirrhosis: A Real-World Study.

Abstract: Aim. To explore the efficacy and safety of immunosuppressive therapy for the treatment of primary biliary cirrhosis-autoimmune hepatitis (PBC-AIH) overlap syndrome accompanied by decompensated cirrhosis. Methods. A cohort study was performed to evaluate the usefulness of immunosuppressive therapy in this unique group. This cohort study was performed between October 2013 and June 2017 and included 28 biopsy-proven patients diagnosed according to the Paris criteria. The therapies included ursodeoxycholic acid (UDCA) alone (N=14) or in combination with immunosuppression (IS) therapy (N=14). The primary endpoints were biochemical remission, liver-related adverse events, transplant-free survival, and drug side-effects. Results. The frequency of biochemical remission for the AIH features was significantly higher in the UDCA+IS group than in the UDCA-only group (60.0 versus 9.1%, P=0.024) after 12 months of therapy but not after 3 and 6 months (28.6 versus 0%, P=0.165; 35.7 versus 7.1%, P=0.098). The rates of liver-related adverse events were lower in the combined group (2/14 versus 9/14, P=0.018). The Kaplan-Meier estimate showed that the transplant-free survival was distinct between the two groups (P=0.019). In the UDCA+IS group, mild and transient leukopenia occurred in two patients receiving azathioprine (AZA), and an infection was observed in one patient receiving mycophenolate mofetil (MMF). Conclusions. PBC-AIH patients with decompensated cirrhosis receiving a combination of UDCA and immunosuppressors presented with higher biochemical remission rates and experienced fewer liver-related adverse events, implying that the combined treatment might be a better therapeutic option for strictly defined decompensated PBC-AIH overlap syndrome.

Establishment and evaluation of a Beagle model of grade III pancreatic trauma.

Abstract: Pancreatic trauma (PT) is a severe abdominal injury that is often combined with multiple organ injury. It is a severe disease that is difficult to diagnose and has a high mortality rate, particularly for grade III PT. The pathogenesis, disease progress and complications have not been fully investigated due to the lack of a reliable animal model. To address this, a Beagle model of grade III PT was established in the present study using a procedure involving rupture of the main pancreatic duct. Peripancreatic effusions and the degree of pancreatic damage were examined by routine ultrasound and contrast-enhanced ultrasound (CEUS). Also, ascites were collected for the examination of amylase and lipase levels, and whole blood samples were collected for the analysis of amylase, lipase, C-reactive protein (CRP), interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels in the serum. Urine samples were also collected for the examination of trypsinogen activation peptide (TAP). In addition, the pancreas was sectioned and stained with hematoxylin and eosin. In comparison with routine ultrasound, CEUS showed a large area of focal trauma, with a depth greater than half of the anteroposterior diameter of the pancreas, with a clear boundary, clear capsular rupture and trauma induced by active bleeding. The volume of ascites peaked at 48 h post-trauma and decreased thereafter. Amylase and lipase levels in the ascites were elevated at 24 h post-trauma and significantly decreased at 48 and 72 h post-trauma (P<0.01). In addition, serum amylase and lipase levels increased to peak levels at 48 h post-trauma and then decreased (P<0.05), while serum CRP, IL-6 and TNF-α levels peaked at 24 h post-trauma and then decreased (P<0.05). Urinary TAP levels also peaked at 24 h post-trauma and subsequently decreased (P<0.05). At 72 h post-trauma, the pancreatic cells were loosely distributed, with damaged acini, hyperchromatic nuclei and severe inflammatory cell invasion. These results indicated that the Beagle model of grade III PT was satisfactorily established, and that CEUS is potentially useful as an auxiliary diagnosis method for PT. This animal model may be useful for studying the pathogenesis, disease progress and complications of PT.

Anticoagulant hydrogel coating capable of catalyzing release of nitric oxide and preparation method of anticoagulant hydrogel coating capable of catalyzing release of nitric oxide

Abstract: The invention discloses an anticoagulant hydrogel coating capable of catalyzing the release of nitric oxide and a preparation method of the anticoagulant hydrogel coating capable of catalyzing releaseof nitric oxide. The method comprises the following steps: (1) pretreating a substrate material; (2) sequentially placing the pretreated substrate material in a polycation electrolyte, a mixed solution of polyphenol and a compound A, and a polyanion electrolyte at room temperature to react for 20 minutes, and washing for 3 to 5 times; (3) using a product obtained in step (2) as a substrate at room temperature, repeating the operation of step (2) for 5 to 20 times, after drying by nitrogen, obtaining the anticoagulant hydrogel coating capable of catalyzing the release of nitric oxide. The hydrogel coating prepared by the method disclosed by the invention has the advantages of simple method, stable structure, and good biocompatibility, can stably catalyze NO to release for a long time to protect endothelial cells and has an anticoagulant effect. The coating can be used for surface modification of cardiovascular stent materials and heart valves.

Coating with anticoagulation-antiinflammatory-antihyperplasia functions and preparation method thereof

Abstract: The invention discloses a coating with anticoagulation-antiinflammatory-antihyperplasia functions and a preparation method thereof. The preparation method comprises the following steps of: (1) pretreating a substrate material; (2) placing the substrate material in polycationic electrolyte, after reaction, taking out and cleaning; (3) placing a product obtained in the step (2) into mixed liquid ofa polyphenol compound and an antihyperplasia medicine, after reaction, taking out and cleaning; (4) placing a product obtained in the step (3) in a polyanionic electrolyte, after reaction, taking outand cleaning; (5) repeating the steps (2)-(4) for 10-50 times; (6) equivalently replacing the antihyperplasia medicine in the step (3) with an antiinflammatory medicine and repeating the steps (2)-(4)for 10-50 times and obtaining a target coating. The coating prepared by the method can be used for surface functionalization of blood implanting materials, and can endow the materials or instrumentswith anticoagulation-antiinflammatory-antihyperplasia functions.

Short-Term Outcome of Patients with Cirrhosis and Concurrent Portal Cavernoma Presenting with Acute Variceal Bleeding.

Abstract: Background and Aim. The outcome of cirrhotic patients with main portal vein occlusion and portal cavernoma after the first episode of acute variceal bleeding (AVB) is unknown. We compared short-term outcomes after AVB in cirrhotic patients with and without portal cavernoma. Methods. Between January 2009 and September 2014, 28 patients with cirrhosis and portal cavernoma presenting with the first occurrence of AVB and 56 age-, sex-, and Child-Pugh score-matched cirrhotic patients without portal cavernoma were included. The primary endpoints were 5-day treatment failure and 6-week mortality. Results. The 5-day treatment failure rate was higher in the cavernoma group than in the control group (32.1% versus 12.5%; ). The 6-week mortality rate did not differ between the cavernoma and control group (25% versus 12.5%, ). Multivariable Cox proportional hazard regression analyses revealed that 5-day treatment failure (HR = 1.223, 95% CI = 1.082 to 1.384; ) independently predicted 6-week mortality. Conclusions. Cirrhotic patients with AVB and portal cavernoma have worse short-term prognosis than patients without portal cavernoma. The 5-day treatment failure was an independent risk factor for 6-week mortality in patients with cirrhosis and portal cavernoma.