Research Progress on the Experimental Model and Underlying Mechanistic Studies of Tension-Type Headaches.

PURPOSE OF REVIEW: Tension-type headaches (TTH) significantly diminish patients' quality of life and increase absenteeism, thereby imposing a substantial economic burden. Animal models are essential tools for studying disease mechanisms and drug development. However, until now, little focus has been placed on summarizing the animal models of TTH and associated mechanistic studies. This narrative review discusses the current animal models of TTH and related mechanistic studies to provide insights into the pathophysiological mechanisms of and treatments for TTH. RECENT FINDINGS: The primary method for constructing an animal model of TTH involves injecting a solution of pain relievers, such as adenosine triphosphate, nerve growth factor, or a high concentration of salt solution, into the neck to initiate harmful cervical muscle responses. This model enables the examination of the interaction between peripheral muscles and central sensitization, which is crucial for understanding the pathophysiology of TTH. Mechanistic studies based on this model have investigated the effect of the P2X receptor antagonist, P2X7 receptor blockade, the P2Y1 receptor agonist 2-MESADP, P2Y1 receptor antagonist MRS2179, nitric oxide synthase inhibitors, and acetylsalicylic acid. Despite notable advancements, the current model of TTH has limitations, including surgical complexity and the inability to replicate chronic tension-type headache (CTTH). To gain a more comprehensive understanding and develop more effective treatment methods, future studies should focus on simplifying surgical procedures, examining other predisposing factors, and establishing a model for chronic TTH. This will offer a deeper insight into the pathophysiological mechanism of TTH and pave the way for improved treatment approaches.

Hollow SnO2/CdS QDs/CdCO3 heterostructured nanocubes coupled with hollow PtPd/MnCo-CeO2 nanozyme-mediated synergistic amplification for ultrasensitive PEC immunoanalysis of lung cancer biomarker.

Nowadays, lung cancer is one of the most dangerous cancers threatening human life all over the world. As a crucial biomarker, cytokeratin 19 fragment 21-1 (CYFRA 21-1) is extraordinary important for diagnosis of non-small cell lung cancer (NSCLC). In this work, we synthesized hollow SnO2/CdS QDs/CdCO3 heterostructured nanocubes with high and stable photocurrents, which applied to construction of a sandwich-typed photoelectrochemical (PEC) immunosensor for detection of CYFRA 21-1, integrated by in-situ catalytic precipitation strategy with home-built PtPd alloy anchored MnCo-CeO2 (PtPd/MnCo-CeO2) nanozyme for synergistic amplification. The interfacial electron transfer mechanism upon visible-light irradiation was investigated in details. Further, the PEC responses were seriously quenched by the specific immunoreaction and precipitation catalyzed by the PtPd/MnCo-CeO2 nanozyme. The established biosensor showed a wider linear range of 0.001-200 ng mL-1 and a lower limit of detection (LOD = 0.2 pg mL-1, S/N = 3), coupled by exploring such analysis even in diluted human serum sample. This work opens a constructive avenue to develop ultrasensitive PEC sensing platforms for detecting diverse cancer biomarkers in clinic.

Integration of CuS/ZnIn2S4 flower-like heterojunctions and (MnCo)Fe2O4 nanozyme for signal amplification and their application to ultrasensitive PEC aptasensing of cancer biomarker.

Vascular endothelial growth factor 165 (VEGF165) is a crucial regulator of angiogenesis and works as a major protein biomarker of cancer metastasis. Therefore, its quantitative detection is pivotal in clinic. In this work, CuS/ZnIn2S4 flower-like heterojunctions had strong and stable photocurrents, which behaved as photoactive material to construct a photoelectrochemical (PEC) aptasensor for detecting VEGF165, combined by home-prepared (MnCo)Fe2O4 nanozyme-mediated signal amplification. The interfacial photo-induced electron transfer mechanism was chiefly discussed by UV-vis diffuse reflectance spectroscopy in details. Specifically, the (MnCo)Fe2O4 modified VEGF165 aptamer was released from the PEC aptasensing platform for its highly specific affinity to target VEGF165, which terminated the color precipitation reaction, ultimately recovering the PEC signals. The developed sensor displayed a wider linear range from 1 × 10-2 to 1 × 104 pg mL-1 with a smaller limit of detection (LOD) of 0.1 fg mL-1. This study provides some valuable insights for building other ultrasensitive aptasensors for clinical assays of cancer biomarkers in practice.

Ultrasensitive PEC cytosensor for breast cancer cells detection and inhibitor screening based on plum-branched CdS/Bi2S3 heterostructures.

Breast cancer is the most common malignant tumor in women, which seriously threatens the life and health of patients. Therefore, facile and sensitive detection of human breast cancer cells is crucial for cancer diagnosis. In this work, plum-branched CdS/Bi2S3 heterostructures (CdS/Bi2S3 HSs) were synthesized under hydrothermal condition, whose photoelectrochemical (PEC) property and biocompatibility were scrutinously investigated. In parallel, a signal amplification strategy was designed based on immune recognition between epidermal growth factor receptor (EGFR) overexpressed on membrane of breast cancer cells MDA-MB-231 and its aptamer. Integration of the above together, a highly sensitive PEC cytosensor was developed for analysis of target MDA-MB-231 cells, exhibiting a wider linear range of 1 × 102 âˆ¼ 3 × 105 cells mL-1 with a limit of detection (LOD) down to 6 cells mL-1 (S/N = 3). Further, the biosensor was explored for anticancer drug (e.g., dacomitinib) screening by monitoring the variations in the PEC signals of the expressed EGFR upon drug stimulation. The obtained CdS/Bi2S3 HSs are identified as promising and feasible photoactive material for determination of cancer cells and drug screening in clinic and related research.

N-3 polyunsaturated fatty acids protect esophageal epithelial cells from acid exposure.

Our previous study showed that n-3 PUFAs inhibited inflammation in rats with esophagitis. This study aimed to observe the protective effect of n-3 PUFAs against acid damage to esophageal epithelial cells (Het-1A cells) and to explore its mechanism. The level of malondialdehyde (MDA) was increased by acid exposure, while that of superoxide dismutase (SOD) was decreased. In groups with different ratios of n-6/n-3 PUFAs, the expression levels of nuclear factor E2 related factor 2 (Nrf2) and SOD were increased with increasing proportions of n-3 PUFAs and were highest in the 1:1 group. Compared with those in the 9:1 group, the expression of NOD like receptor pyrin domain-containing protein 3 (NLRP3) and caspase-1 and the pyroptosis rate in the 1:1 group were decreased. Intervention with an Nrf2 agonist increased the expression of Nrf2 and decreased the expression of NLRP3 and caspase-1 and the pyroptosis rate. However, inhibiting Nrf2 expression led to the opposite result. In conclusion, n-3 PUFAs protected esophageal epithelial cells from acid damage by upregulating Nrf2 expression, which disrupted oxidative stress and NLRP3 inflammasome activation and inhibited pyroptosis.

Novel Ultrasensitive Photoelectrochemical Cytosensor Based on Hollow CdIn2S4/In2S3 Heterostructured Microspheres for HepG2 Cells Detection and Inhibitor Screening.

Hepatocellular carcinoma is a life-threatening malignant tumor found around the world for its high morbidity and mortality. Therefore, it is of great importance for sensitive analysis of liver cancer cells (HepG2 cells) in clinical diagnosis and biomedical research. To fulfill this demand, hollow CdIn2S4/In2S3 heterostructured microspheres (termed CdIn2S4/In2S3 for clarity) were prepared by a two-step hydrothermal strategy and applied for building a novel photoelectrochemical (PEC) cytosensor for ultrasensitive and accurate detection of HepG2 cells through specific recognition of CD133 protein on the cell surface with the respective aptamer. The optical properties of CdIn2S4/In2S3 were investigated by UV-vis diffuse reflectance spectroscopy (DRS) and PEC technology. By virtue of their appealing PEC characteristics, the resultant PEC sensor exhibited a wider dynamic linear range from 1 × 102 to 2 × 105 cells mL-1 with a lower limit of detection (LOD, 23 cells mL-1), combined by evaluating the expression level of CD133 protein stimulated by metformin as a benchmarked inhibitor. This work opens a valuable and feasible avenue for sensitive detection of diverse tumor cells, holding great potential in early clinical diagnosis and treatment coupled by screening inhibitors.

Heterostructured BiVO4/CoPi nanoarrays as high-efficiency photoanode and AuPt nanodendrites as nanozyme for sensitive sensing of miRNA 141.

MicroRNA (miRNA) is a new class of tumor biomarkers in human body for early diagnosis and therapy of cancers, whose detection has scientific significance and potential applications. Herein, a sensitive heterostructured BiVO4/CoPi photoelectrochemical (PEC) biosensor was established for sensing miRNA 141 with assistance of home-synthesized AuPt nanodendrites (NDs) as nanozyme. Specifically, the BiVO4/CoPi heterostructures displayed rough worm-like internetworks, as characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). In parallel, the PEC and UV-vis diffuse reflectance spectroscopy tests confirmed their excellent optical property, combined by discussing the interfacial electron transfer mechanism. Additionally, the AuPt NDs displayed superior peroxidase-like property in the presence of H2O2 as identified by benchmarked tetramethylbenzidine (TMB) oxidation, coupled by showing remarkable catalysis for 3-amino-9-ethylcarbazole (AEC) oxidation to form biocatalytic precipitation (BCP). Integrated by a cyclic enzyme strategy, the developed PEC biosensor exhibited a wider linear range of 5 fM ∼1 pM and a lower limit of detection (LOD) as low as 0.17 fM (S/N = 3). This work provides some valuable insights for sensitive analysis of tumor-associated miRNA in clinic.

Comparison of Pull and Introducer Techniques for Percutaneous Endoscopic Gastrostomy.

Objective: To compare indications, success rates and complications of pull [P] and introducer [I] techniques for percutaneous endoscopic gastrostomy (PEG). Methods: In this retrospective study, inpatients who underwent primary PEG tube insertion between January 2015 and February 2020 at the Endoscopy Center of the First Affiliated Hospital of Fujian Medical University were included. Results: A total of 103 inpatients were included in this study (P group, n = 67; I group, n = 36). The rates of tube replacement within first six months in the P and I groups were 1.5% and 11.1%, respectively (P = 0.049). The most common primary indication of PEG was malignancy. The proportion of patients with esophageal cancer was significantly lower in the P group (24.4% vs 54.2%, P = 0.015). No significant difference was found in the overall, major, or minor complications between the two groups. In patients with esophageal stenosis, the pull method was a risk factor for complications (P = 0.03; odds ratio [OR] = 12, 95% confidence interval [CI]: 1.164-123.684). Logistic regression analysis showed that the risk factors for major and minor complications were the admission-to-gastrostomy interval (OR = 1.078, 95% CI: 1.016-1.145, P = 0.014) and lack of antibiotic use (OR = 4.735, 95% CI: 1.247-17.979, P = 0.022), respectively. Conclusion: Both PEG techniques have high clinical success rates. The introducer technique is more suitable for patients with esophageal stricture, which has lower minor complications, but higher rate of tube replacement compared to the pull technique. Use of antibiotics may reduce minor complications following PEG. Early PEG insertion may help to reduce post-PEG major complications.

[Effects of cigarette smoke extract on mitochondrial function of macrophages].

Objective: To investigate the effects of cigarette smoke extract (CSE) on the mitochondrial function of macrophages. Methods: RAW264.7 macrophages were used for the experiment in this study. When the cell density was about 70%, the old culture medium was abandoned, and the 100% CSE stock solution was diluted with serum-free DMEM and FBS into 1%, 5%, 15%, 25% and 90% CSE and added to the well plate. The cell activity of RAW264.7 cells treated with CSE at different concentrations for 24 h was detected by CCK-8 method. Then the optimal CSE concentration was selected to treat cells for 0 h, 24 h, 48 h or 72 h respectively, and CCK-8 assay was used to detect the cell activity of CSE treated cells at different time groups. After the cells were treated with 0%, 5% and 25% CSE for 24 hours, cell necrosis and apoptosis was detected by Annexin V-FITC /PI staining; Mitochondrial membrane damage of RAW 264.7 was detected by mitochondrial membrane potential assay kit with JC-1; Macrophages were stained with ROS-specific dye DCFH-DA, and then Flow cytometer was used to determine the fluorescence and the proportion of ROS-positive macrophages; the enhanced ATP assay kit was used to detect the intracellular ATP concentration. Results: ①Compared with 0% CSE, cell viability was increased significantly in 1% CSE group (P＜0.01), cell viability was decreased significantly when CSE concentration was above 5% (P＜0.05); Macrophages were treated with 5% CSE, and cell viability was decreased significantly with the increase of treatment time (P＜0.01). ②Compared with 0% CSE, 5% CSE and 25% CSE mainly caused macrophage necrosis, decreased mitochondrial membrane potential, increased ROS production and decreased ATP significantly (P＜0.05 or P＜0.01), and the changes were more significant in 25% CSE treatment group(P＜0.05 or P＜0.01). Conclusion: CSE may affect mitochondrial function of macrophages, leading to decreased cell viability and necrosis.

Effect of Endoscopic Appendix Intubation and Irrigation on Acute Uncomplicated Appendicitis.

OBJECTIVE: To investigate the efficacy and safety of endoscopic appendix intubation and irrigation (EAI) on acute uncomplicated appendicitis. METHODS: This prospective non-randomized study examined 169 patients with suspected acute uncomplicated appendicitis at The First Affiliated Hospital of Fujian Medical University from October 2015 to 2017. Patients were divided into three groups: endoscopic appendix intubation and irrigation (EAI, n = 18), laparoscopic appendectomy (LA, n = 87), and antibiotic alone (A, n = 64). The treatment success rate, duration of hospitalization, medical costs, operation time, duration of abdominal pain, fasting time, complications, and recurrence were analyzed. RESULTS: The three groups had no significant differences in baseline characteristics (age, gender, Alvarado score, white blood cell count, and neutrophil count; all P > 0.05). Compared to the LA group, the EAI group had shorter durations of the operation, fasting, and abdominal pain; less use of oral and intravenous antibiotics; and lower medical costs (all P < 0.05). Compared to the A group, the EAI group had shorter durations of abdominal pain and hospitalization, and less use of intravenous antibiotics (all P < 0.05). The EAI group had no complications, but 3 patients (3.4%) in the LA group had surgery-related complications. CONCLUSION: EAI is a safe and effective treatment for acute uncomplicated appendicitis. Patients who received EAI had shorter durations of abdominal pain and hospitalization than those who received LA or conservative antibiotic treatment. TRIAL REGISTRATION NUMBER AND AGENCY: ChiCTR-IPN-15006565, Chinese Clinical Trial Registry.

Over-the-scope-clip applications for perforated peptic ulcer.

AIM: To investigate the effectiveness of over-the-scope-clip (OTSC)-based endoscopic closure in patients with perforated peptic ulcer (PPU). METHODS: One hundred six patients diagnosed with PPU were treated with either OTSC (n = 26) or conservative treatments (n = 80), respectively. The outcome assessments included technical success rate, clinical success rate, post-treatment complications after 1 month, mortality rate, time to resume oral feeding, length of hospital stay, and the administration of antibiotics. RESULTS: In the OTSC group, technical and clinical success was achieved in 100% of patients without any complications, including death, incomplete closure, duodenal obstruction, and gastrointestinal bleeding, with a median operation time of 10 min. All patients in the OTSC group were discharged, while the mortality rate in the control group was 13.8%. Subsequent surgeries were required in 30% of patients in the control group. The median times to resume oral feeding were 3.5 (interquartile range [IQR] 2.0-5.25) days in the OTSC group and 7.0 (IQR 5.0-9.0) days in the control group (p < 0.001). One month post-procedure, 30% (24/80) of patients in the control group and 0 (0/26) in the OTSC group required additional operations (p < 0.001). No significant difference was found in the length of the hospital stay and the administration of antibiotics between the two groups (p > 0.05). CONCLUSIONS: OTSC-based endoscopic technique, with a high clinical success rate and a shorter time to resume oral feeding, was effective in achieving closure of PPU with a diameter < 15 mm.

TGF-ß1 and TNF-α synergistically induce epithelial to mesenchymal transition of breast cancer cells by enhancing TAK1 activation.

TGF-ß1 is a main inducer of epithelial to mesenchymal transition (EMT). However, many breast cancer cells are not sensitive to the EMT induction by TGF-ß1 alone. So far, the mechanisms underlying the induction of TGF-ß1-insensitive breast cancer cells remains unclear. Here we report that TNF-α can induce EMT and invasiveness of breast cancer cells which are insensitive to TGF-ß1. Intriguingly, TGF-ß1 could cooperate with TNF-α to promote the EMT and invasiveness of breast cancer cells. The prolonged co-stimulation with TGF-ß1 and TNF-α could enhance the sustained activation of Smad2/3, p38 MAPK, ERK, JNK and NF-κB pathways by enhancing the activation of TAK1, which was mediated by the gradually up-regulated TßRs. Except for JNK, all of these pathways were required for the effects of TGF-ß1 and TNF-α. Importantly, the activation of p38 MAPK and ERK pathways resulted in a positive feed-back effect on TAK1 activation by up-regulating the expression of TßRs, favoring the activation of multiple signaling pathways. Moreover, SLUG was up-regulated and required for the TGF-ß1/TNF-α-induced EMT and invasiveness. In addition, SLUG could also enhance the activation of signaling pathways by promoting TßRII expression. These findings suggest that the up-regulation of TßRs contributes to the sustained activation of TAK1 induced by TGF-ß1/TNF-α and the following activation of multiple signaling pathways, resulting in EMT and invasiveness of breast cancer cells.

Carotane-type sesquiterpenes from cultures of the insect pathogenic fungus Isaria fumosorosea.

Two new carotane-type sesquiterpenes named trichocaranes E (1) and F (2), along with two known ones CAF-603 (3) and trichocarane C (4), were isolated from cultures of the insect pathogenic fungus Isaria fumosorosea. Their structures and relative configurations were elucidated by extensive spectroscopic analysis and X-ray crystallography. Compounds 1-3 showed potent cytotoxic activities against six tumor cell lines MDA, MCF-7, SKOV-3, Hela, A549, HepG2 with IC50 values in a concentration range of 0.1-6.0 µg/ml.

Simvastatin, but not pravastatin, inhibits the proliferation of esophageal adenocarcinoma and squamous cell carcinoma cells: a cell-molecular study.

BACKGROUND AND OBJECTIVE: Long-term statin therapy has been shown to protect against several cancers, including esophageal cancer (EC). While the mechanisms underlying this effect are not clear. We investigated the effect of hydrophobic simvastatin and hydrophilic pravastatin on the proliferation of EC cells and sought to explore the underlying mechanisms. METHODS: Esophageal adenocarcinoma OE-19 cells and esophageal squamous cell carcinoma Eca-109 cells were treated with different concentrations of simvastatin or pravastatin for 24 h and 48 h. Cell proliferation was assessed by Cell Counting Kit-8 assay. Malondialdehyde (MDA) levels were measured by thiobarbituric acid (TBA) assay. mRNA and protein expression of COX-2 were determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot, respectively; The expression of prostaglandin E2 (PGE2) was measured by ELISA. RESULTS: Simvastatin, but not pravastatin, significantly inhibited the proliferation of OE-19 and Eca-109 cells in a dose- and time-dependent manner, accompanying with the increasing of the MDA level. Moreover, simvastatin suppressed the expression of COX-2 and PGE2 in both OE-19 and Eca-109 cells in a dose-dependent manner. CONCLUSIONS: Lipophilic simvastatin, but not hydrophilic pravastatin, had significant inhibitory effects on the proliferation of Eca-109 and OE-19 cells. The reduction of COX-2 and PGE2 by simvastatin suggested that the inhibitory effect of simvastatin on the proliferation of EC cells may be independent of its lipid-lowering effect. Simvastatin may be a promising agent for the prevention and treatment of EC.

Balloon-assisted ultrasonic localization: a novel technique for direct percutaneous endoscopic jejunostomy.

Direct percutaneous endoscopic jejunostomy (DPEJ) is a useful method for the establishment of enteral nutrition (EN) pathway. However, the identification of stomal puncture points for DPEJ is difficult. Here we present a case treated with an improved technique for DPEJ puncture-point localization, which was named DPEJ with balloon-assisted ultrasonic localization (DPEJ-BAUL). There were four steps after insertion of an endoscope into the jejunum: (1) a balloon dilatation catheter was inserted through the endoscope working channel; (2) the balloon was fully filled with water; (3) the site of puncture was selected with an ultrasonic probe percutaneously locating the water-filled balloon; and (4) a jejunostomy tube was placed by introducer technique. Rapid localization of a puncture site was possible with BAUL and the DPEJ procedure was successful. The patient's nutritional status was improved with EN and no postoperative complications were observed. DPEJ-BAUL is a feasible and effective technique to increase the technical success rate of DPEJ in patients with negative transillumination test results.

PTP1B Inhibitors from the Entomogenous Fungi Isaria fumosorosea.

Protein tyrosine phosphatase 1B (PTP1B) is implicated as a negative regulator of insulin receptor (IR) signaling and a potential drug target for the treatment of type II diabetes and other associated metabolic syndromes. Thus, small molecule inhibitors of PTP1B can be considered as an attractive approach for the design of new therapeutic agents of type II diabetes and cancer diseases. In a continuing search for new PTP1B inhibitors, a new tetramic acid possessing a rare pyrrolidinedione skeleton named fumosorinone A (1), together with five known ones 2-6 were isolated from the entomogenous fungus Isaria fumosorosea. The structures of 2-6 were elucidated by extensive spectroscopic analysis. Fumosorinone A (1) and beauvericin (6) showed significant PTP1B inhibitory activity with IC50 value of 3.24 µM and 0.59 µM.

The effect of n-3/n-6 polyunsaturated fatty acids on acute reflux esophagitis in rats.

BACKGROUND: Polyunsaturated fatty acids (PUFAs) play various roles in inflammation. However, the effect of PUFAs in the development of reflux esophagitis (RE) is unclear. This study is to investigate the potential effect of n-3/n-6 PUFAs on acute RE in rats along with the underlying protective mechanisms. METHODS: Forty Sprague Dawley rats were randomly divided into four groups (n = 10 in each group). RE model was established by pyloric clip and section ligation. Fish oil- and soybean oil-based fatty emulsion (n-3 and n-6 groups), or normal saline (control and sham operation groups) was injected intraperitoneally 2 h prior to surgery and 24 h postoperatively (2 mL/kg, respectively). The expressions of interleukin (IL)-1ß, IL-8, IL-6 and myeloid differentiation primary response gene 88 (MyD88) in esophageal tissues were evaluated by Western blot and immunohistochemistry after 72 h. The malondialdehyde (MDA) and superoxide dismutase (SOD) expression in the esophageal tissues were determined to assess the oxidative stress. RESULTS: The mildest macroscopic/microscopic esophagitis was found in the n-3 group (P < 0.05). The expression of IL-1ß, IL-8, IL-6 and MyD88 were increased in all RE groups, while the lowest and highest expression were found in n-3 and n-6 group, respectively (P < 0.05). The MDA levels were increased in all groups (P < 0.05), in an ascending trend from n-3, n-6 groups to control group. The lowest and highest SOD levels were found in the control and n-3 group, respectively (P < 0.05). CONCLUSION: n-3 PUFAs may reduce acute RE in rats, which may be due to inhibition of the MyD88-NF-kB pathway and limit oxidative damage.

Decreased n-6/n-3 polyunsaturated fatty acid ratio reduces chronic reflux esophagitis in rats.

AIM: To investigate the effect of dietary ratio of n-6/n-3 PUFAs on chronic reflux esophagitis (RE) and lipid peroxidation. METHOD: Rat RE model were established and then fed on a diet contained different n-6/n-3 PUFA ratios (1:1.5, 5:1, 10:1) or received pure n-6 PUFA diet for 14 days. Esophageal pathological changes were evaluated using macroscopic examination and hematoxyline-eosin staining. IL-1ß, IL-8, and TNFα mRNA and protein levels of were determined using RT-PCR and Western blotting, respectively. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were determined using ELISA. RESULTS: The severity of esophagitis was lowest in the PUFA(1:1.5) group (P<0.05). IL-1ß, IL-8, and TNFα mRNA and protein and MDA levels were significantly increased in model groups with the increasing n-6/n-3 PUFA ratios. SOD levels were significantly decreased in all RE PUFA groups (P<0.05). CONCLUSION: Esophageal injury and lipid peroxidation appeared to be ameliorated by increased n-3 PUFAs intake.

Association of Endoscopic Esophageal Variceal Ligation with Duodenal Ulcer.

OBJECTIVE: To determine the frequency of duodenal ulcer (DU), as well as other clinical characteristics occurring after endoscopic variceal ligation (EVL) of the esophagus. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: The First Affiliated Hospital of Fujian Medical University, Fuzhou, China, from April 2012 to April 2013. METHODOLOGY: A total of 47 patients with esophageal varices (EVr) who had also undergone EVL and gastroscopic follow-up within 3 months of the procedure was retrospectively analyzed. The status of Helicobacter pylori(Hp) infection, Child-Pugh classification, and the grades of portal hypertensive gastropathy (PHG) were collected. Sixty EVr patients without EVL treatment, but with clinical data available, served as the control group. RESULTS: The frequency of DU in the EVL group (29.8%, 14/47) was higher than the control group (6.7%, 4/60) (p=0.02). Hp infection rate in EVLgroup was 19.15% (9/47), while in control group was 21.67% (13/60) (p=0.813). Hp positive rate (12.5%, 1/8) in patients exhibited new DUs after EVL was comparable to the patients without DU in the EVL group (12.1%, 4/33) (p=1.00). Patients with DU after EVL received 18.79 &plusmn;8.48 of ligating bands, while in those who did not exhibit DUs received 13.85 &plusmn;6.47 (z = -2.042, p = 0.041). Logistic regression analysis showed that the occurrence of DU was not associated with age, gender, Child-Pugh classification, or the grade of PHG (p &gt; 0.05). CONCLUSION: Esophageal EVL is associated with a higher frequency of developing DU, which is related to a larger number of applied bands but is not correlated with Hp infection status or other variables.

TLR4 ligand/H2O2 enhances TGF-ß1 signaling to induce metastatic potential of non-invasive breast cancer cells by activating non-Smad pathways.

TGF-ß1 has the potential to activate multiple signaling pathways required for inducing metastatic potential of tumor cells. However, TGF-ß1 was inefficient in inducing metastatic potential of many non-invasive human tumor cells. Here we report that the enhancement of TGF-ß1 signaling is required for inducing metastatic potential of non-invasive breast cancer cells. TGF-ß1 alone could not efficiently induce the sustained activation of Smad and non-Smad pathways in non-invasive breast cancer cells. TLR4 ligand (LPS) and H2O2 cooperated with TGF-ß1 to enhance the sustained activation of non-Smad pathways, including p38MAPK, ERK, JNK, PI3K, and NF-κB. The activation of MAPK and PI3K pathways resulted in a positive feed-back effect on TGF-ß1 signaling by down-regulating Nm23-H1 expression and up-regulating the expression of TßRI and TßRII, favoring further activation of multiple signaling pathways. Moreover, the enhanced TGF-ß1 signaling induced higher expression of SNAI2, which also promoted TßRII expression. Therefore, the sustained activation levels of both Smad and non-Smad pathways were gradually increased after prolonged stimulation with TGF-ß1/H2O2/LPS. Consistent with the activation pattern of signaling pathways, the invasive capacity and anoikis-resistance of non-invasive breast cancer cells were gradually increased after prolonged stimulation with TGF-ß1/H2O2/LPS. The metastatic potential induced by TGF-ß1/H2O2/LPS was sufficient for tumor cells to extravasate and form metastatic foci in an experimental metastasis model in nude mice. The findings in this study suggested that the enhanced signaling is required for inducing higher metastatic capacity of tumor cells, and that targeting one of stimuli or signaling pathways might be potential approach in comprehensive strategy for tumor therapy.