Search

Context: Distinguishing different types of diabetes is important in directing optimized treatment strategies and correlated epidemiological studies., Objective: Through detailed analysis of hormone responses to mixed meal tolerance test (MMTT), we aimed to find representing characteristics of post-acute pancreatitis diabetes mellitus (PPDM-A) and post-chronic pancreatitis diabetes mellitus (PPDM-C)., Methods: Participants with PPDM-A, PPDM-C, type 1 diabetes, type 2 diabetes, and normal controls (NCs) underwent MMTT. Fasting and postprandial responses of serum glucose, C-peptide, insulin, glucagon, pancreatic polypeptide (PP), ghrelin, gastric inhibitory peptide (GIP), glucagon like peptide-1 (GLP-1), and peptide YY (PYY) were detected and compared among different groups. Focused analysis on calculated insulin sensitivity and secretion indices were performed to determine major causes of hyperglycemia in different conditions., Results: Participants with PPDM-A were characterized by increased C-peptide, insulin, glucagon, and PP, but decreased ghrelin, GIP, and PYY compared with NCs. Patients with PPDM-C showed secretion insufficiency of C-peptide, insulin, ghrelin, and PYY, and higher postprandial responses of glucagon and PP than NCs. In particular, both fasting and postprandial levels of ghrelin in PPDM-C were significantly lower than other diabetes groups. PYY responses in patients with PPDM-A and PPDM-C were markedly reduced. Additionally, the insulin sensitivity of PPDM-A was decreased, and the insulin secretion for PPDM-C was decreased., Conclusion: Along with the continuum from acute to chronic pancreatitis, the pathological mechanism of PPDM changes from insulin resistance to insulin deficiency. Insufficient PYY secretion is a promising diagnostic marker for distinguishing PPDM from type 1 and type 2 diabetes. Absent ghrelin secretion to MMTT may help identify PPDM-C., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Noninvasive and early assessment of liver fibrosis is of great significance and is challenging. We aimed to evaluate the predictive performance and cost-effectiveness of the LiverRisk score for liver fibrosis and liver-related and diabetes-related mortality in the general population., Methods: The general population from the NHANES 2017-March 2020, NHANES 1999-2018, and UK Biobank 2006-2010 were included in the cross-sectional cohort (n = 3,770), along with the NHANES follow-up cohort (n = 25,317) and the UK Biobank follow-up cohort (n = 17,259). The cost-effectiveness analysis was performed using TreeAge Pro software. Liver stiffness measurements ≥10 kPa were defined as compensated advanced chronic liver disease (cACLD)., Findings: Compared to conventional scores, the LiverRisk score had significantly better accuracy and calibration in predicting liver fibrosis, with an area under the receiver operating characteristic curve (AUC) of 0.76 (0.72-0.79) for cACLD. According to the updated thresholds of LiverRisk score (6 and 10), we reclassified the population into three groups: low, medium, and high risk. The AUCs of LiverRisk score for predicting liver-related and diabetes-related mortality at 5, 10, and 15 years were all above 0.8, with better performance than the Fibrosis-4 score. Furthermore, compared to the low-risk group, the medium-risk and high-risk groups in the two follow-up cohorts had a significantly higher risk of liver-related and diabetes-related mortality. Finally, the cost-effectiveness analysis showed that the incremental cost-effectiveness ratio for LiverRisk score compared to FIB-4 was USD $18,170 per additional quality-adjusted life-year (QALY) gained, below the willingness-to-pay threshold of $50,000/QALY., Conclusions: The LiverRisk score is an accurate, cost-effective tool to predict liver fibrosis and liver-related and diabetes-related mortality in the general population., Funding: The National Natural Science Foundation of China (nos. 82330060, 92059202, and 92359304); the Key Research and Development Program of Jiangsu Province (BE2023767a); the Fundamental Research Fund of Southeast University (3290002303A2); Changjiang Scholars Talent Cultivation Project of Zhongda Hospital of Southeast University (2023YJXYYRCPY03); and the Research Personnel Cultivation Program of Zhongda Hospital Southeast University (CZXM-GSP-RC125)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The changes of inflammation and metabolism are two features in nonalcoholic steatohepatitis (NASH). However, how they interact to regulate NASH progression remains largely unknown. Our works have demonstrated the importance of solute carrier family 7 member 11 (SLC7A11) in inflammation and metabolism. Nevertheless, whether SLC7A11 regulates NASH progression through mediating inflammation and metabolism is unclear. In this study, we found that SLC7A11 expression was increased in liver samples from patients with NASH. Upregulated SLC7A11 level was also detected in two murine NASH models. Functional studies showed that SLC7A11 knockdown or knockout had augmented steatohepatitis with suppression of inflammatory markers in mice. However, overexpression of SLC7A11 dramatically alleviated diet-induced NASH pathogenesis. Mechanically, SLC7A11 decreased reactive oxygen species (ROS) level and promoted α-ketoglutarate (αKG)/prolyl hydroxylase (PHD) activity, which activated AMPK pathway. Furthermore, SLC7A11 impaired expression of NLRP3 inflammasome components through AMPK-mitophagy axis. IL-1β release through NLRP3 inflammasome recruited myeloid cells and promoted hepatic stellate cells (HSCs) activation, which contributed to the progression of liver injury and fibrosis. Anti-IL-1β and anakinra might attenuate the hepatic inflammatory response evoked by SLC7A11 knockdown. Moreover, the upregulation of SLC7A11 in NASH was contributed by lipid overload-induced JNK-c-Jun pathway. In conclusions, SLC7A11 acts as a protective factor in controlling the development of NASH. Upregulation of SLC7A11 is protective by regulating oxidation, αKG and energy metabolism, decreasing inflammation and fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Polyunsaturated fatty acids (PUFAs) are vital nutrients in human physiology and are implicated in various chronic diseases. However, the relationship between PUFAs and gastric polyps remains unclear. This study employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess PUFA levels in the serum of 350 patients, along with analyzing the ω-6 to ω-3 ratio. The results revealed significant differences in the levels of C16:1, C18:1, C18:2, α-C18:3, γ-C18:3, C20:1, C20:4, C20:5, ω-3-C22:5, ω-6-C22:5, and C22:6, as well as ω-6 to ω-3 ratio between the control and gasteic polyp groups. Moreover, setting the threshold for ω-6: ω-3 at 10 revealed a close correlation between polyp occurrence and this ratio. These findings suggest that PUFAs and the ω-6 to ω-3 ratio hold promise as potential early screening markers for gastric polyps. However, further research is imperative to elucidate the underlying mechanisms and therapeutic potential of PUFAs in managing gastric polyps., Competing Interests: The authors declare that they have no competing interests., (© 2024 Li et al.)

Introduction: Circular RNAs (CircRNA) have emerged as an interest of research in recent years due to its regulatory role in various kinds of cancers of human body. Esophageal squamous cell carcinoma (ESCC) is one of the major disease subtype in Asian countries, including China. CircRNAs are formed by back-splicing covalently joined 3'- and 5'- ends rather than canonical splicing and are found to have binding affinity with miRNAs that conjointly contribute to oncogenesis., Materials and Methods: 4 pairs of normal, cancer adjacent tissues and cancer tissues were analyzed by high-throughput RNA sequencing and 84 differentially upregulated circRNAs were detected in cancer tissues. hsa_circ_0032746 was silenced by siRNA and lentivirus and then further proliferation, migration and invasion were performed by CCK-8 and transwell assays. Bioinformatic analysis  predicted binding affinity of circRNA/miRNA/mRNA axis., Results: After qPCR validation, we selected a novel upregulated hsa_circ_0032746 to explore its biogenetic functions which showed high expression in cancer tissues but not in cancer adjacent tissues. The clinicopathological relation of hsa_circ_0032746 showed positive correlation with the tumor location (P = 0.026) and gender (P = 0.05). We also predicted that hsa_circ_0032746 could sponge with microRNA. Bioinformatic analysis predicted 11 microRNA response element (MRE) sequences of hsa_circ_0032746 and dual luciferase reporter assay confirmed binding affinity with miR4270 evidencing further study of circRNA/miRNA role. The knockdown of hsa_circ_0032746 by siRNA and lentivirus demonstrated that proliferation, invasion and migration of ESCC were inhibited in vitro and vivo experiments. Bioinformatic analysis further predicted MCM3 as a target of miR-4270 and was found upregulated in ESCC upon validation. miR4270 mimic decreased the level of hsa_circ_0032746 and MCM3 while further rescue experiments demonstrated that hsa_circ_0032746 was dependent on miR4270/MCM3 axis on the development process of ESCC., Conclusion: We revealed for the first time that circ_0032746/mir4270/MCM3 contributes in proliferation, migration and invasion of ESCC and could have potential prognostic and therapeutic significance., (© 2024. The Author(s).)

Objectives: Endoscopic diagnosis of invasion depth of superficial esophageal squamous cell carcinoma (SESCC) by white-light imaging (WLI) modality remains difficult. This study aims to clarify WLI-based features which are predictive for invasion depth of SESCC., Methods: A two-phase study was performed by enrolling 1288 patients with 1396 SESCC lesions. Endoscopic appearances, clinical characteristics and post-operative pathological outcomes were collected and reviewed. The association between lesion features and invasion depth were analyzed. A predictive nomogram was constructed for prediction of invasion depth., Results: Among 1396 lesions in derivation and validation cohort, 1139 (81.6%), 194 (13.9%) and 63 (4.5%) lesions were diagnosed as lesions confined into the intraepithelium or the lamina propria mucosa (T1a-EP/LPM), lesions invading the muscularis mucosa (T1a-MM) or superficial submucosa (T1b-SM1) and tumor with moderate invasion into the submucosa or deeper submucosal invasion (≥ T1b-SM2), respectively. Lesion length > 2 cm (p < 0.001), wider circumferential extension (p < 0.001, 0.002 and 0.048 for > 3/4, 1/2-3/4 and 1/4-1/2 circumferential extension, respectively), surface unevenness (p < 0.001 for both type 0-IIa/0-IIc lesions and mixed type lesions), spontaneous bleeding (p < 0.001), granularity (p < 0.001) and nodules (p < 0.001) were identified as significant factors predictive for lesion depth. A nomogram based on these factors was constructed and the values of area under the Receiver Operating Characteristics curve were 0.89 and 0.90 in the internal and external patient cohort., Conclusions: Our study provides six WLI-based morphological features predicting for lesion depth of SESCC. Our findings will make endoscopic evaluation of invasion depth for SESCC more convenient by assessing these profiles., (© 2023. The Author(s).)

Background: Numerous studies have revealed that long noncoding RNAs (lncRNAs) are closely related to the development of many diseases and carcinogenesis. However, their specific biological function and molecular mechanism in oesophageal squamous cell carcinoma (ESCC) remains unclear., Methods: RNA-Seq was performed to determine the differential expressions of lncRNAs in ESCC, and the level of SNHG16 expression was detected in ESCC and intraepithelial neoplasia (IEN) samples. In vitro and in vivo experiments were performed to explore the role of SNHG16 and the interaction of EIF4A3 and Ras homologue family member U (RhoU) signalling., Results: One hundred and seventy-five upregulated and 134 downregulated lncRNAs were identified by RNA-Seq. SNHG16 was highly expressed in ESCC and intraepithelial neoplasia (IEN) samples, and its expression level was correlated with tumour differentiation and T stage. Overexpression of SNHG16 can facilitate ESCC cell proliferation and metastasis. Mechanistically, we noticed that SNHG16 could bind RNA binding protein (RBP)-eukaryotic translation initiation factor (EIF4A3) and interact with it to form a complex. Importantly, the coalition of SNHG16 and EIF4A3 ultimately regulated Ras homologue family member U (RhoU). SNHG16 modulated RhoU expression by recruiting EIF4A3 to regulate the stability of RhoU mRNA. Knockdown of RhoU further alleviated the effect of the SNHG16 oncogene in ESCC cells., Conclusions: The newly identified SNHG16-EIF4A3-RhoU signalling pathway directly coordinates the response in ESCC pathogenesis and suggests that SNHG16 is a promising target for potential ESCC treatment., (© 2022. The Author(s).)

Objective: To conduct a systematic review and meta-analysis on the prediction of severity of gastric intestinal metaplasia (GIM) in localized and entire gastric mucosa using endoscopy. Methods: The authors searched Web of Science, PubMed, Embase and Cochrane Central Register of Controlled Trials and performed systematic searches on endoscopic grading of GIM of the entire stomach using Meta-DiSc and Stata. Results: Sensitivity and specificity for the stratified prediction of overall GIM were 0.91 (95% CI: 0.85-0.95) and 0.91 (95% CI: 0.88-0.93), respectively. Sensitivity in predicting the different grades of GIM was higher in operative link on GIM assessment grades 0, III and IV but lower in grades I and II. Conclusion: Digital chromoendoscopy is well suited to predicting the severity of localized and overall GIM.

Peroral endoscopic myotomy (POEM) is a rapidly evolving technique for the treatment of esophageal diverticulum. The aim of this study was to perform a systematic review and meta-analysis of the literature focusing on POEM for symptomatic esophageal diverticula, including an in-depth evaluation of its efficacy, safety, and limitations. A comprehensive literature search was completed to identify articles that examined the efficacy and safety of POEM for esophageal diverticula. Heterogeneity among studies was assessed using the I2 statistic. Meta-regression and sensitivity analyses were performed to explore the sources of heterogeneity and assess potentially important covariates influencing the main outcomes. Primary endpoints such as rates of success, adverse events, and recurrences were evaluated. P values of ≤0.05 were considered statistically significant. Nine studies with a total of 153 patients were enrolled. Pooled technical success, clinical success, adverse events, and recurrence rates were 99% [95% confidence interval (CI), 97-100%; I2 = 0%), 94% (95% CI, 89-97%; I2 = 24%), 2% (95% CI, 0-6%, I2 = 0%), and 0% (95% CI, 0-1%; I2 = 0%), respectively. The pooled perforation rate was 6% (95% CI, 1-11%; I2 = 0%). Meta-regression analysis indicated that esophageal diverticula types and motility disorders were not associated with the clinical success rate (P > 0.05). POEM is a feasible, safe, and effective treatment for symptomatic esophageal diverticula, with low adverse events and recurrence rates., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The use of nonradiation endoscopic retrograde cholangiopancreatography (NR-ERCP) for choledocholithiasis is still limited. Hereby, we introduced our experience of digital cholangioscopy (DCS)-assisted NR-ERCP for retrieval of common bile duct stones., Methods: Altogether, data of 132 patients who underwent DCS-assisted NR-ERCP for choledocholithiasis were collected. Procedure details, complications, and short-term follow-up were reviewed and analyzed and were compared with those of conventional endoscopic retrograde cholangiopancreatography (ERCP)., Results: Routine stone extraction and laser lithotripsy were planned in 116 and 16 patients, respectively. Biliary access was successfully achieved by standard biliary cannulation and by advanced techniques in 99 and 33 patients, respectively. Complete stone removal was achieved in a single session in all patients. Routine stone extraction was performed in 117 patients, and laser lithotripsy was applied in 15 patients, among whom 14 patients with planned lithotripsy and 1 unexpected impacted stone found during the procedure. Unexpected right localized intrahepatic stones and purulent cholecystitis were found in 1 and 3 patients, respectively. Three mild and 1 moderate pancreatitis, 5 cases of hyperamylasemia, and 2 cases of leukocytosis occurred as complications. Short-term follow-up revealed no stone residual. Procedure details, technical success, and complications were not statistically different than conventional ERCP., Conclusions: DCS-assisted NR-ERCP is technically feasible, efficient, and safe for retrieval of common bile duct stones. This novel method is superior to conventional ERCP on detecting unexpected concomitant biliary diseases., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Combination therapy such as photodynamic therapy (PDT)-enhanced chemotherapy is regarded as a promising strategy for cancer treatment. Boron-dipyrromethene (BODIPY), as close relatives of porphyrins, was widely used in PDT. However, poor water solubility, rapid metabolism by the body and lack of targeting limits its clinical application. Lenvatinib, as the first-line drug for molecular-targeted therapy of liver cancer, restricted its clinical application for its side effects. Herein, to achieve the synergy between PDT and chemotherapy, we synthesized two halogenated BODIPY, BDPBr 2 and BDPCl 2 , which were prepared into self-assembly nanoparticles with lenvatinib, and were encapsulated with Pluronic F127 through the nanoprecipitation method, namely, LBPNPs (LBBr 2 NPs and LBCl 2 NPs). The fluorescence quantum yields of LBPNPs were 0.73 and 0.71, respectively. The calculated loading rates of lenvatinib for LBBr 2 NPs and LBCl 2 NPs were 11.8 and 10.2%, respectively. LBPNPs can be hydrolyzed under weakly acidic conditions (pH 5.0) to generate reactive oxygen species (ROS), and the release rate of lenvatinib reached 88.5 and 82.4%. Additionally, LBPNPs can be effectively taken up by Hep3B and Huh7 liver cancer cells, releasing halogenated BODIPY and lenvatinib in the acidic environment of tumor cells to enhance the targeting performance of chemotherapeutics. Compared with free lenvatinib and separate halogenated BODIPY, LBPNPs can inhibit tumor growth more effectively through pH-responsive chemo/photodynamic synergistic therapy and significantly promote the cascade of caspase apoptotic protease. This study shows that LBPNPs can be a promising nanotheranostic agent for synergetic chemo/photodynamic liver cancer therapy., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

In a continuous effort to develop effective vaccines against hepatitis E (HE), oral vaccine nanoparticles using the truncated capsid protein p146 (aa460-605) are formulated and characterized. To improve the immunogenicity of p146, chitosan nanoparticles (CSNPs) are used as a mucosal delivery system. Next, the physical-chemical properties, cytotoxic effects in vitro, and immunogenicity in mice of the produced NPs are analyzed. The results show that the produced CS/p146 NPs are stable and well dispersive and display a near-spherical shape with a mean size of 200-300 nm. The findings also demonstrate high encapsulation efficiency (65-73.9%) and loading capacity (27.7-67.5%) of the formulated nanoparticles. Further, the CS/p146 NPs exhibit low cytotoxicity and an obvious sustained-release effect in vitro. Immunogenicity experiments in mice indicate that CS/p146 NPs can induce antigen-specific systemic and mucosal immune responses higher than the purified p146 do. Besides, the expression levels and mRNA transcription of Interleukin (IL)-4 in spleen cells of CS/p146 NPs-immunized mice are higher than those of p146, indicating that a Th2-mediated cellular immune response is activated by the CS/p146 NPs. Overall, the synthesized CS/p146 NPs display promising properties as a potential HE oral vaccine candidate., (© 2021 Wiley-VCH GmbH.)

Aim: Although Clopidogrel is safe in healthy volunteers, it can induce recurrence of gastric ulcers in high-risk patients. Here, we investigated the protective effect of the natural product, stable gastric pentadecapeptide 157 (BPC 157) on Clopidogrel-induced gastric injury., Methods: We used acetic acid to induce gastric ulcer in Sprague Dawley rats. Clopidogrel alone or in combination with BPC 157 or L-NAME (nitric oxide system blockade) were administered after healing of acetic acid-induced ulcer. One percent methylcellulose solution was used as control. Ulcer recurrence rate and the ulcer index were compared between these groups. Gastric mucosal apoptosis rate, microscopic inflammation activity and angiogenesis markers vascular endothelial growth factor A ( VEGF-A ) and CD34 were examined by TUNEL, histological evaluations (HE) and immunohistochemistry (IHC). Pathways involved, expressions of endoplasmic reticulum (ER) stress apoptosis marker CHOP , angiogenic markers VEGF-A and its receptor VEGFR1 , and endothelial NO synthase ( eNOS ) were all analyzed by Western blot., Results: This study indicated that Clopidogrel significantly induced the gastric ulcers recurrence, severe inflammation and ER stress related apoptosis of the gastric mucosa, suppressed the synthesis of angiogenic markers and eNOS . Furthermore, Clopidrogel intervention resulted in the activation of protein kinase B ( AKT ) and p38 mitogen-activated protein kinase ( p38/MAPK ). BPC 157 attenuated the gastric mucosal damage caused by Clopidogrel and reversed these molecular effects. However, NO blockade L-NAME weakened the protective effect and thus the molecular effects of BPC 157 on gastric mucosa., Conclusion: In conclusion, these results suggest that BPC 157 inhibited Clopidogrel-induced gastric mucosa injury partially by inhibition of gastric mucosa cell ER stress-mediated apoptosis and inflammation, and promoting gastric mucosa angiogenesis via VEGF-A/VEGFR1 mediated- AKT/p38/MAPK signaling pathways., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Wu et al.)

Recently, the long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was reported to be involved in the pathogenesis of several cancers, including human colorectal cancer (CRC). However, the molecular basis for cancer initiation, development, and progression remains unclear. In this study, we observe that upregulated PVT1 is associated with poor prognosis and bad clinicopathological features of CRC patients. In vitro means of PVT1 loss in a CRC cell line inhibit cell proliferation, migration, and invasion. Furthermore, dual-luciferase reporter and RNA pull-down assays indicated that PVT1 binds to miR-16-5p, which has been shown to play strong tumor suppressive roles in CRC. Targeted loss of miR-16-5p partially rescues the suppressive effect induced by PVT1 knockdown. Vascular endothelial growth factor A (VEGFA), a direct downstream target of miR-16-5p, was suppressed by PVT1 knockdown in CRC cells. Overexpression of VEGFA is known to modulate the AKT signaling cascade by activating vascular endothelial growth factor receptor 1 (VEGFR1). We, therefore, show that PVT1 loss combined with miR-16-5p overexpression reduces tumor volume maximally when propagated within a mouse xenograft model. We conclude that the PVT1-miR-16-5p/VEGFA/VEGFR1/AKT axis directly coordinates the response in CRC pathogenesis and suggest PVT1 as a novel target for potential CRC therapy., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Bleeding and delayed healing of gastric ulcer are well-recognized in patients following Clopidorgrel treatment. Our previous studies have shown that endoplasmic reticulum stress (ER) is involved in Clopidogrel-induced gastric mucosal damage through activating p38 mitogen-activated protein kinases (MAPK) pathway. This present study aims to further investigate the role of MAP kinase phosphatase 5 (MKP-5), a MKP known to dephosphorylate and inactivate p38/MAPK, in Clopidogrel-induced gastric mucosal injury and the underlying mechanisms. It shows that MKP-5 is down-regulated at both mRNA and protein levels in the gastric mucosa from bleeding patients who took Clopidogrel over one year. In vitro study using human gastric epithelial cell line GES-1 demonstrates that exposure to Clopidorgrel (1.0-2.0 mM) increases phosphorylation of p38/MAPK and decreases MKP-5 expression simultaneously. Overexpression of MKP-5 promotes GES-1 cell proliferation and reduces apoptosis following Clopidogrel exposure. Interestingly, overexpression of MKP-5 also attenuates Clopidorgrel-induced tight junction (TJ) destruction by down-regulating expression of ER stress-related protein C/EBP homologous protein (CHOP) and tribbles pseudokinase 3 (TRIB3). These three effects, increased proliferation, reduced apoptosis and attenuated TJ destruction, are regulated through inhibited phosphorylation of p38/MAPK signaling pathway. We conclude that MKP-5 is down-regulated in Clopidogrel-induced gastric mucosa injury in vivo and in vitro via phosphorylation and activation of p38/MAPK signaling pathway. Overexpression of MKP-5 reverses Clopidogrel-induced gastric mucosal injury. These findings imply that MKP-5 may be a potential therapeutic target in Clopidogrel-induced gastric mucosal injury and bleeding., Competing Interests: None., (AJTR Copyright © 2020.)

Introduction: The targeted delivery of anti-cancer drugs to tumor tissue has been recognized as a promising strategy to increase their therapeutic efficacy and reduce side effects. Mesoporous silica-coated superparamagnetic Fe3O4 nanoparticles (NH2-MSNs), a kind of nanocarrier, can passively enter tumor tissues to enhance the permeability and retention of drugs. However, NH2-MSNs do not specifically bind to cancer cells. This drawback encouraged us to develop a more efficient nanocarrier for cancer therapy. Methods: Herein, we describe the development of an effective nanocarrier based on NH2-MSNs, which were modified with hyaluronic acid on their surface (HA-MSNs) and loaded with doxorubicin (DOX). We have successfully fabricated uniform spherical HA-MSNs nanocarriers. The targeting ability of this delivery system was evaluated through specific uptake by cells and IVIS imaging. Results: DOX-HA-MSNs nanocarriers displayed more dramatic cytotoxic activity against 4T1 breast cancer cells compared to GES-1 gastric mucosa cells. In vivo results revealed that once DOX-HA-MSNs nanocarriers are exposed to an external magnetic field, they could be rapidly attracted to the magnet and effectively cross the cytoplasmic membrane via CD44 receptor-mediated transcytosis. This allows them to access the cancer cell cytoplasm and release DOX based on changes in the physiological environment. Both in vitro and in vivo results demonstrated that the HA-MSNs nanocarriers provided better therapeutic efficacy. Conclusion: The HA-MSNs nanocarriers represent an effective new paradigm to treat cancers due to active targeting to the tumor cells. Moreover, the specific uptake by the tumor effectively protects normal tissues to reduce off-target side effects. The reported findings support further investigation of HA-MSNs for cancer therapy., Competing Interests: The authors report no conflicts of interest in this work.

Objective: To evaluate the feasibility of two types of segmented biodegradable esophageal stents in treatment of refractory benign esophagus strictures. Methods: Uncovered biodegradable segmented stent and fully-covered biodegradable segmented stent were implanted into the porcine esophagus (6 for each). Data on biodegradation, complications, and tissue reactions were compared between two groups. Results: All animals kept good general conditions; no death, decreased food intake, weight loss and malnutrition were observed. No perforation, ulcer, hemorrhage, stent migration and severe complications occurred. Stents degradation commenced at week 3. Stents structure breakage and complete stents absorption occurred at week 7-8 and week 9-10 in uncovered stents. While in fully-covered stents, stents structure breakage and complete stents absorption occurred at week 8-9 and week 10-11. Hyperplasia was prominent at week 1-3 and ameliorated at week 6 after stent implantation. A longer degradation period was present in fully-covered stents than in uncovered stents, while fully-covered stents induced tissue reactions at early stage were mild. Conclusions: The application of biodegradable esophageal stents with a segmented trunk in refractory benign esophagus strictures worth further investigation. The fully-covered stent has longer degradation period, which may be more suitable for clinical use.

Purpose: To investigate the correlations of magnetic resonance, perfusion-weighed imaging (PWI) parameters and microvessel density (MVD) in meningioma., Methods: 48 patients with pathologically confirmed meningioma (grade I, 38 cases; grade II+III, 10 cases) completed preoperative routine magnetic resonance imaging (MRI) and PWI. The cerebral blood volume (CBV) map of solid tumor region and the mean of maximum relative cerebral blood volume (rCBV) were then calculated. Immunohistochemical staining was performed in all specimens to measure the MVD., Results: On the CBV map, benign meningiomas showed a high perfusion signal, while malignant meningiomas exhibited a slightly higher one. The rCBV of benign meningiomas was 9.61±4.76, which was significantly higher than 3.61±0.25 of malignant meningiomas (t=7.165, p=0.000). The MVD of benign meningioma strips was 21.16 ± 11.32, which was also significantly higher than 10.71 ± 5.53 strips of malignant meningiomas (t=2.325, p=0.026). The correlation analysis showed that the mean of maximum rCBV and MVD of meningiomas had significant positive correlations (r=0.718, p=0.000)., Conclusions: The CBV map of benign meningiomas is different to that of malignant meningiomas, and the mean of maximum rCBV and MVD have significant positive correlations.

Objective: To evaluate the potential roles of MR perfusion weighted imaging (PWI) in preoperative assessment of vascularity of meningiomas., Methods: 9 patients with meningiomas underwent conventional MR and PWI before operation (Grade I 32 cases, Grade II+III 7 cases). Immunohistochemical stain methods were used to quantitatively measure the microvessel density (MVD) values in meningiomas after operation. The pulse sequence of PWI was single shot GRE-EPI-T2*WI, the cerebral blood volume (CBV) maps were calculated from the original data of perfusion images and the maximum CBV values of meningiomas was acquired from CBV maps through measurement on the region of interest (ROI). The mean maximal relative cerebral blood volume (rCBV) values were calculated by dividing the maximum CBV of a tumor by that of the contralateral white matter. The differences of the mean maximal rCBV values between benign and malignant groups were analysed and commpared with the MVD values., Results: The mean maximal rCBV values of benign and malignant groups were 9.76±4.68 and 3.57±0.27, respectively. The MVD values of benign and malignant groups were 22±12 and 11±5, respectively. The difference in mean maximal rCBV values between the two groups was statistically significant (t=7.166, P<0.01). Correlation analysis demonstrated that the mean maximal rCBV values and MVD values had significantly positive correlation (r=0.715, P<0.01)., Conclusion: The mean maximal rCBV values are feasible for evaluation of microvessel angiogenesis of meningiomas in vivo and useful for predicting tumor grade.

Dysregulation of microRNAs (miRNAs) has been linked to virulence factors of Helicobacter pylori and shown to contribute to the progression of gastric cancer. However, the mechanisms of these processes remain poorly understood. The aim of this study was to investigate the mechanisms by which lipopolysaccharide (LPS), a virulence factor of H. pylori, regulates miR-375 and miR-106b expression in gastric epithelial cells. The results show that LPS from H. pylori 26695 downregulated the expression of miR-375 and miR-106b in gastric epithelial cells, and low levels of Dicer were also observed. Downregulation of miR-375 was found to increase expression of MDM2 with SP1 activation. Overexpression of MDM2 inhibited Dicer by repressing p63 to create a positive-feedback loop involving SP1/MDM2/p63/Dicer that leads to inhibition of miR-375 and miR-106b expression. In addition, we demonstrated that JAK1 and STAT3 were downstream target genes of miR-106b. H. pylori LPS also enhanced the tyrosine phosphorylation of JAK1, JAK2 and STAT3. Together, these results provide insight into the regulatory mechanisms of MDM2 on H. pylori LPS-induced specific miRNAs, and furthermore, suggest that gastric epithelial cells treated with H. pylori LPS may be susceptible to JAK/STAT3 signal pathway activation via inhibition of miR-375 and miR-106b., (© 2014 UICC.)

Objective: To evaluate the expression of FBXW7 in esophageal squamous cell carcinoma (ESCC) and to explore the correlation of FBXW7 expression with clinicopathologic features and prognosis of ESCC., Methods: Ninety cases of ESCC and twenty cases of tumor-adjacent normal tissues and forty intraepithelial neoplasia tissues were detected by immunohistochemistry methods. The expression of FBXW7 in 40 surgical ESCC tissues and tumor-adjacent normal tissues was detected by Western blotting and RT-PCR. The relationship between the expression of FBXW7, clinicopathological characteristics and prognosis was analyzed., Results: The positive rate of FBXW7 protein was significantly lower in the ESCC and high-grade intraepithelial neoplasia tissues than in the tumor-adjacent normal tissues and low grade intraepithelial neoplasia tissues (40.0% and 33.3% vs. 85.0% and 77.3%, χ² = 21.923, P < 0.001). The FBXW7 protein was down-regulated in ESCC tissues (P < 0.05), whereas the FBXW7 mRNA was down-regulated in ESCC tissues compared with that in the paracancerous tissues. The expression of FBXW7 was significantly correlated with TNM stage, degree of differentiation, invasion depth and lymph node metastasis (χ² =9.643, 14.908, 16.294, 10.222, respectively, P = 0.002, 0.001, 0.000, 0.001). In the ninety patients, the 5-year survival rates of cases with positive and negative expression of FBXW7 protein was 67.6% and 39.3%, respectively (χ² =6.699, P = 0.01)., Conclusions: The results of this study demonstrate that FBXW7 expression is significantly declined in ESCC and high grade intraepithelial neoplasia tissues, and is closely correlated with poor prognosis of this disease. FBXW7 as a tumor suppressor gene may play an important role in the carcinogenesis, development and metastasis of ESCC. These results suggest that FBXW7 may become a valuable marker for the severity and prognosis in ESCC.

Unlabelled: Cholangiocarcinoma (CCA) is an often fatal primary malignancy of the intra- and extrahepatic biliary tract that is commonly associated with chronic cholestasis and significantly elevated levels of primary and conjugated bile acids (CBAs), which are correlated with bile duct obstruction (BDO). BDO has also recently been shown to promote CCA progression. However, whereas there is increasing evidence linking chronic cholestasis and abnormal bile acid profiles to CCA development and progression, the specific mechanisms by which bile acids may be acting to promote cholangiocarcinogenesis and invasive biliary tumor growth have not been fully established. Recent studies have shown that CBAs, but not free bile acids, stimulate CCA cell growth, and that an imbalance in the ratio of free to CBAs may play an important role in the tumorigenesis of CCA. Also, CBAs are able to activate extracellular signal-regulated kinase (ERK)1/2- and phosphatidylinositol-3-kinase/protein kinase B (AKT)-signaling pathways through sphingosine 1-phosphate receptor 2 (S1PR2) in rodent hepatocytes. In the current study, we demonstrate S1PR2 to be highly expressed in rat and human CCA cells, as well as in human CCA tissues. We further show that CBAs activate the ERK1/2- and AKT-signaling pathways and significantly stimulate CCA cell growth and invasion in vitro. Taurocholate (TCA)-mediated CCA cell proliferation, migration, and invasion were significantly inhibited by JTE-013, a chemical antagonist of S1PR2, or by lentiviral short hairpin RNA silencing of S1PR2. In a novel organotypic rat CCA coculture model, TCA was further found to significantly increase the growth of CCA cell spheroidal/"duct-like" structures, which was blocked by treatment with JTE-013., Conclusion: Our collective data support the hypothesis that CBAs promote CCA cell-invasive growth through S1PR2., (Copyright © 2014 The Authors. Hepatology published by Wiley on behalf of the American Association for the Study of Liver Diseases.)

Pancreatic cancer is highly invasive and is currently the fourth leading cause of cancer death worldwide. CXC chemokine receptor-4 (CXCR4) is a G protein-coupled receptor for CXC chemokine ligand 12/stromal cell-derived factor-1α (SDF-1α), a member of a large family of small, structurally related, heparin-binding chemokine proteins. SDF-1α/CXCR4 plays an important role in tumor growth, invasion, metastasis, and angiogenesis. SDF-1α and CXCR4 are upregulated in many tumors, including pancreatic cancer tissues, and preliminary data indicate that the SDF-1/CXCR4 axis plays an important role in tumor invasion. However, their precise role and the mechanism through which they function remain largely unknown. In this study, analysis of SDF-1α, CXCR4 and MMP-2 expression in pancreatic cancer and adjacent tissue samples from ten patients revealed that all three proteins are overexpressed in human pancreatic cancer. SDF-1α induced MMP-2 and MMP-9 upregulation in PANC-1 and SW-1990 cells, which was associated with increased pancreatic cancer cell proliferation and invasion. Furthermore, SDF-1α induced p38 phosphorylation and p38 inhibition reduced both the level of SDF-1α-stimulated MMP-2 expression and PANC-1 cell invasion. Overall, our results demonstrate that SDF-1α/CXCR4 upregulates MMP-2 expression and induces pancreatic cancer cell invasion in PANC-1 and SW-1990 cell lines by activating p38 MAPK.

In order to find the correlation between transgelin gene (TAGLN) and colorectal carcinoma occurrence, we investigated the expression of TAGLN in colorectal carcinoma tissue samples and colorectal carcinoma LoVo cells. Meanwhile, the effects of TAGLN on the characteristics of LoVo cells were also examined. The expressions of TAGLN in colorectal carcinoma tissues, adjacent normal tissues, and LoVo cells were detected by the Western blot method. The recombinant plasmid pcDNA3.1-TAGLN was established and transfected into LoVo cells with the help of Lipofectamine™ 2000. At the same time, the TAGLN siRNA was transfected into LoVo cells in another group. Forty-eight hours later, the expressions of TAGLN in all groups were assayed by Western blot, and the cell viability was analyzed by MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay. The cell cycle and cell apoptosis were examined by flow cytometry, and the cell invasive ability was analyzed by Transwell invasion experiment. The effect of TALGN on the expression of matrix metalloproteinase 9 (MMP9) was detected by Western blot. Western blot analysis showed that the expressions of TALGN in colorectal carcinoma tissues and LoVo cells were significantly decreased compared with colorectal carcinoma adjacent normal tissues (p < 0.01). In the overexpression or RNAi experiments, the plasmid pcDNA3.1-TAGLN significantly enhanced TALGN expression (p < 0.01), and TAGLN siRNA significantly decreased TAGLN expression (p < 0.01) in LoVo cells 48 h after transfection. In addition, MTT assay indicated that the cell viability of LoVo cells in the pcDNA3.1-TAGLN transfection group was significantly lower than that in the untransfected control group (p < 0.05). Furthermore, the overexpression of TAGLN significantly lowered the cell proliferation index (p < 0.05) and improved cell apoptosis (p < 0.01) in LoVo cells. In Transwell invasive experiments, the cell number, which had migrated through the chamber membrane, significantly decreased in the pcDNA3.1-TAGLN transfection group (p < 0.05) and significantly increased in the TAGLN knockdown group (p < 0.05) compared to the untransfected control group. At the same time, the expression of MMP9 was notably inhibited in the pcDNA3.1-TAGLN transfection group (p < 0.01). The expressions of TAGLN were inhibited in colorectal carcinoma tissues and colorectal carcinoma LoVo cells. The study also demonstrated that TAGLN could attenuate the proliferation and invasive ability of LoVo cells and enhance LoVo cell apoptosis. Furthermore, the expression of MMP9 was also inhibited by TAGLN. All these results could bring us a new perspective for biological therapy in colorectal carcinoma.

Here we investigated whether the cellular accumulation of p53 protein caused by over-expression of small ubiquitin-related modifier-1 (SUMO-1) could be used as a predictive marker for prognosis in colon cancer. We detected SUMO-1 and p53 protein levels in 46 cases of colon cancer and adjacent tissues by immunohistochemistry and found that SUMO-1 was expressed at much higher levels in colon cancer compared with that in normal colon tissue. Immunoprecipitation and Western blot analysis revealed that the tumor suppressor p53 was present predominantly in the sumoylated rather than the non-sumoylated form in the colon cancer cell lines. A small interfering RNA targeted to SUMO-1 mRNA sequences was used to observe the levels of the p53 protein. Patients who showed high dual expressions of SUMO-1 and p53 tended to experience metastasis more frequently. These results suggest that the cellular accumulation of p53 protein caused by over-expression of SUMO-1 may be involved in tumor aggressiveness. Multivariate analysis confirmed that the high dual expression of SUMO-1 and p53 was an independent factor for evaluating prognosis. SUMO-1 may be useful as a novel target for therapy in colon cancer as well as a clinical indicator for tumor aggressiveness.

Background: Bismuthyl ecabet is a combination of sulfodehydroabietic acid and bismuth, which forms a new type of salt that is useful in treating peptic ulcers and gastritis., Objective: This study was designed to assess the safety and tolerability of bismuthyl ecabet suspension in healthy Chinese subjects., Methods: For the study 77 volunteers were randomized into single- or multiple-dose groups for oral administration of bismuthyl ecabet 200-1600 mg once daily or 1200 mg twice daily for 7 days. Safety and tolerability were assessed by adverse events, physical examination and serum biochemistry., Results: In both the single- and multiple-dose studies, no severe adverse events were observed in any of the volunteers. The main adverse events caused by the drug in single-dose groups were an increase in serum alanine transaminase (ALT), γ-glutamyl transpeptidase, blood urea nitrogen, total bilirubin and skin rash. The numbers of adverse events judged to be possibly related to the drug were 2/18 in the 400 mg, 2/18 in the 800 mg, 1/8 in the 1200 mg, and none in the 200 or 1600 mg dose groups. In the multiple-dose studies, an increased serum ALT and aspartate transaminase (AST) was found in one subject after 7 days of administration of the drug. All serum biochemistry returned to normal levels and skin rash resolved after 7 days without any special treatment., Conclusion: Bismuthyl ecabet was shown to be safe and well tolerated in healthy Chinese subjects. The oral dosing regimen selected for subsequent phase II/III clinical trials was 800 mg twice daily., (© 2012 Adis Data Information BV. All rights reserved.)

Background/aims: We have previously shown that long-term consumption of 10% beef tallow diet promotes colon carcinogenesis in both saline- and azoxymethane (AOM)-treated rats. Here, we investigated the effects of mofezolac, a selective COX-1 inhibitor, on beef tallow-fed rats with saline- or AOM treatment., Methodology: Male SD rats were intraperitoneally injected with saline or AOM and fed 10% beef tallow diet with or without 1200 ppm mofezolac. At 12 weeks, aberrant crypt foci (ACF) were examined. At 44 weeks, tumors were counted, the proliferation and expression of COX-1 and 8-catenin on normal-appearing colonic mucosa was evaluated using the BrdU incorporation assay and Western blotting respectively., Results: Mofezolac decreased the number of ACF at 12 weeks (p < 0.05) and reduced tumor multiplicity and incidence at 44 weeks in beef tallow-fed rats with AOM treatment (p < 0.05). At 44 weeks, reduction of the BrdU-positive cells (p < 0.05) and beneficial distribution changes of these cells within the colon crypts in both groups with mofezolac supplementation were observed. The expression of COX-1 and beta-catenin also reduced in mofezolac-added groups simultaneously (p < 0.05)., Conclusions: This study suggested that mofezolac suppressed beef tallow-promoted colon carcinogenesis in rats, which probably was, appropriate for populations with high fat intake.