Regulators, functions, and mechanotransduction pathways of matrix stiffness in hepatic disease.

The extracellular matrix (ECM) provides physical support and imparts significant biochemical and mechanical cues to cells. Matrix stiffening is a hallmark of liver fibrosis and is associated with many hepatic diseases, especially liver cirrhosis and carcinoma. Increased matrix stiffness is not only a consequence of liver fibrosis but is also recognized as an active driver in the progression of fibrotic hepatic disease. In this article, we provide a comprehensive view of the role of matrix stiffness in the pathological progression of hepatic disease. The regulators that modulate matrix stiffness including ECM components, MMPs, and crosslinking modifications are discussed. The latest advances of the research on the matrix mechanics in regulating intercellular signaling and cell phenotype are classified, especially for hepatic stellate cells, hepatocytes, and immunocytes. The molecular mechanism that sensing and transducing mechanical signaling is highlighted. The current progress of ECM stiffness's role in hepatic cirrhosis and liver cancer is introduced and summarized. Finally, the recent trials targeting ECM stiffness for the treatment of liver disease are detailed.

Nanomolar Potency Aminophenyltriazine CFTR Activator Reverses Corneal Epithelial Injury in a Mouse Model of Dry Eye.

Purpose: Dry eye disorders are a major health care burden. We previously reported the identification of N-methyl-N-phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine [cystic fibrosis transmembrane conductance regulator (CFTR)act-K267], which activated human wild-type CFTR chloride conductance with EC50 ∼ 30 nM. Here, we report in vivo evidence for CFTRact-K267 efficacy in an experimental mouse model of dry eye using a human compatible ophthalmic vehicle. Methods: CFTR activation in mice in vivo was demonstrated by ocular surface potential difference (OSPD) measurements. Ocular surface pharmacodynamics was measured in tear fluid samples obtained at different times after topical administration of CFTRact-K267. Dry eye was produced by lacrimal duct cautery (LDC) and corneal epithelial injury and was assessed by Lissamine green (LG) staining. Results: OSPD measurements demonstrated a hyperpolarization of -8.6 ± 3 mV (standard error of the mean, 5 mice) in response to CFTRact-K267 exposure in low chloride solution that was reversed by a CFTR inhibitor. Following single-dose topical administration of 2 nmol CFTRact-K267, tear fluid CFTRact-K267 concentration was >500 nM for more than 6 h. Following LDC, corneal surface epithelial injury, as assessed by LG staining, was substantially reversed in 10 of 12 eyes receiving 2 nmol CFTRact-K267 3 times daily starting on day 2, when marked epithelial injury had already occurred. Improvement was seen in 3 of 12 vehicle-treated eyes. Conclusion: These studies provide in vivo evidence in mice for the efficacy of a topical, human use compatible CFTRact-K267 formulation in stimulating chloride secretion and reversing corneal epithelial injury in dry eye.

Inhibition of CFTR-mediated intestinal chloride secretion as potential therapy for bile acid diarrhea.

Bile acid diarrhea (BAD) is common with ileal resection, Crohn's disease, and diarrhea-predominant irritable bowel syndrome. Here, we demonstrate the efficacy of cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor (R)-benzopyrimido-pyrrolo-oxazine-dione-27 (BPO-27) in reducing bile acid-induced fluid and electrolyte secretion in colon. Short-circuit current measurements in human T84 colonic epithelial cells and planar colonic enteroid cultures showed a robust secretory response following mucosal but not serosal addition of chenodeoxycholic acid (CDCA) or its taurine conjugate, which was fully blocked by CFTR inhibitors, including (R)-BPO-27. (R)-BPO-27 also fully blocked CDCA-induced secretory current in murine colon. CFTR activation by CDCA primarily involved Ca2+ signaling. In closed colonic loops in vivo, luminal CDCA produced a robust secretory response, which was reduced by ∼70% by (R)-BPO-27 or in CFTR-deficient mice. In a rat model of BAD produced by intracolonic infusion of CDCA, (R)-BPO-27 reduced the elevation in stool water content by >55%. These results implicate CFTR activation in the colon as a major prosecretory mechanism of CDCA, a bile acid implicated in BAD, and support the potential therapeutic efficacy of CFTR inhibition in bile acid-associated diarrheas.-Duan, T., Cil, O., Tse, C. M., Sarker, R., Lin, R., Donowitz, M., Verkman, A. S. Inhibition of CFTR-mediated intestinal chloride secretion as potential therapy for bile acid diarrhea.

Intestinal epithelial potassium channels and CFTR chloride channels activated in ErbB tyrosine kinase inhibitor diarrhea.

Diarrhea is a major side effect of ErbB receptor tyrosine kinase inhibitors (TKIs) in cancer chemotherapy. Here, we show that the primary mechanism of ErbB TKI diarrhea is activation of basolateral membrane potassium (K+) channels and apical membrane chloride (Cl-) channels in intestinal epithelia and demonstrate the efficacy of channel blockers in a rat model of TKI diarrhea. Short-circuit current in colonic epithelial cells showed that the TKIs gefitinib, lapatinib, and afatinib do not affect basal secretion but amplify carbachol-stimulated secretion by 2- to 3-fold. Mechanistic studies with the second-generation TKI afatinib showed that the amplifying effect on Cl- secretion was Ca2+ and cAMP independent, was blocked by CF transmembrane conductance regulator (CFTR) and K+ channel inhibitors, and involved EGFR binding and ERK signaling. Afatinib-amplified activation of basolateral K+ and apical Cl- channels was demonstrated by selective membrane permeabilization, ion substitution, and channel inhibitors. Rats that were administered afatinib orally at 60 mg/kg/day developed diarrhea with increased stool water from approximately 60% to greater than 80%, which was reduced by up to 75% by the K+ channel inhibitors clotrimazole or senicapoc or the CFTR inhibitor (R)-BPO-27. These results indicate a mechanism for TKI diarrhea involving K+ and Cl- channel activation and support the therapeutic efficacy of channel inhibitors.

[Comparison of the efficacy and safety between endoscopic submucosal dissection and radical surgery for large colorectal laterally spreading tumors larger than 5 cm in diameter].

OBJECTIVE: To compare the safety and efficacy between endoscopic submucosal dissection (ESD) and radical surgery (RS) for the treatment of large colorectal laterally spreading tumors (LST) larger than 50 mm in diameter. 
 Methods: From January 2011 to January 2016, a total of 82 patients were diagnosed as large LST without deep submucosal invasion (T1 SM2, ≥1 000 µm) in the Second Xiangya Hospital of Central South University. Among them, 52 patients were treated by ESD and the other 30 patients were treated by RS [laparoscopic-assisted colectomy (LAC)/open colectomy (OC)]. The clinic data were retrospectively analyzed and the en-bloc resection rate, en-bloc R0 resection rate, local recurrence, complication, procedure time and hospital stay were collected and analyzed.
 Results: The lesion sizes were (5.80±1.20) cm and (5.53±0.69) cm in diameter for ESD and RS groups, respectively (P>0.05). En-bloc resection rates, en-bloc R0 resection rates and recurrence rates showed no significant difference between the ESD group and RS group (P>0.05). Complication rate of the ESD group (7.69%, 4/52) was much lower than that in the RS group (33.33%, 10/30; P<0.01). The ESD group also had a shorter hospital stay and operation time than the RS group (P<0.05).
 Conclusion: ESD appears to be a safe, minimal invasive and effective strategy for treating large LST and it is obviously better than RS in the aspects of hospital stay, operation time and short-term complication.

A comparison of submucosal tunneling endoscopic resection and endoscopic full-thickness resection for gastric fundus submucosal tumors.

AIM: Both submucosal tunneling endoscopic resection (STER) and endoscopic full-thickness resection (EFTR) are effective methods for gastric fundus submucosal tumors (SMTs). However, there is little data that compares the two methods. The aim of this study was to compare the safety and efficacy of STER and EFTR for the treatment of SMTs in the gastric fundus. METHODS: Clinical data was retrospectively collected from patients with gastric fundus SMTs who underwent STER or EFTR at our hospital from April 2011 to May 2016. Epidemiological data (gender, age), tumor size, procedure-related parameters, complications, postoperative hospital stay, cost and follow-up data were compared. RESULTS: A total of 43 patients were enrolled: 15 underwent STER and the remaining 28 cases underwent EFTR. There were no significant differences between the two groups with regard to gender, age, tumor size, en bloc resection rate, operation time, pathohistological results and cost (p > 0.05). However, patients who underwent EFTR had a longer suture time, required a larger number of clips for closure and a prolonged postoperative hospital stay (p < 0.05). No recurrence was noted in either the STER or the EFTR group during a mean follow-up of 12.1 and 22.8 months, respectively. CONCLUSIONS: The treatment efficacy of STER and EFTR for the treatment of gastric fundus SMTs was comparable. However, STER has some advantages over EFTR in terms of suture time, the number of clips required for closure and postoperative hospital stay.

A Retrospective Study of Peroral Endoscopic Full-Thickness Myotomy in Patients with Severe Achalasia.

OBJECTIVES: Selective circular myotomy (CM) is recommended in peroral endoscopic myotomy (POEM) for achalasia, but completeness of myotmoy is the prerequisite for excellent long-term results of conventional surgical myotomy. The aim of our study was to compare the efficacy and safety between peroral endoscopic full-thickness and simple CM for the treatment of severe achalasia. MATERIALS AND METHODS: A total of 123 severe achalasia patients who underwent POEM from August 2011 to May 2013 were included. They were divided into circular or full-thickness myotomy (FTM) groups according to the depth of myotomy. Demographics, Eckardt score, procedure-related parameters, perioperative adverse events, pre- and postoperative esophageal diameter, esophageal manometry, and follow-up results were retrospectively collected and compared between the two groups. RESULTS: All the 123 patients underwent POEM successfully, and the mean operation time was significantly shorter in FTM group compared with CM group (57.4 ± 8.2 minutes versus 63.2 ± 12.3 minutes, P < .05). There was no significant difference between the two groups in terms of treatment success, pre- and postoperative Eckardt score, esophageal diameter, esophageal manometry, and perioperative adverse events (P > .05). Twenty-four-hour pH monitoring was performed in 19 patients (11 in FTM, 8 in CM). Although no statistical difference was detected in rate of abnormal esophageal acid exposure between groups, this rate was higher in FTM group than CM group (60% versus 40%, P > .05). CONCLUSION: Treatment efficacy in short-to-medium term are comparable between circular or FTM. FTM significantly reduce the operative duration, but it may increase potential risk of gastroesophageal reflux disease incidence.

Comparison between submucosal tunneling endoscopic resection and endoscopic full-thickness resection for gastric stromal tumors originating from the muscularis propria layer.

BACKGROUND: Both submucosal tunneling endoscopic resection (STER) and endoscopic full-thickness resection (EFTR) are effective method for treating gastric gastrointestinal stromal tumors (GISTs); however, little is known about the comparison between STER and EFTR. The aim of the study was to compare the safety and efficacy of STER and EFTR for treating gastric GIST. METHODS: We retrospectively collected the clinical data about patients with gastric GISTs who received STER or EFTR at our hospital from April 2011 to June 2016. Epidemiological data (gender, age), tumor size, procedure-related parameters, complications, length of stay, cost and follow-up data were compared between STER and EFTR. RESULTS: A total of 52 patients were enrolled, and 20 of them received STER, while the other 32 cases received EFTR. There was no significant difference between the two groups in terms of gender, age, concomitant diseases, tumor size, en bloc resection rate, operation time, complications, pathohistological grade of GIST, hospital stay and cost (P > 0.05). However, patients who received EFTR had a longer suture time and needed more clips to close the gastric-wall defect (STER vs EFTR, 291.5 ± 68.7 vs 380.6 ± 96.9s and 6.0 ± 1.2 vs 7.6 ± 1.6, P < 0.05). No recurrence was noted in the STER and EFTR groups during a mean follow-up of 10.9 and 23.8 months, respectively. CONCLUSIONS: The treatment efficacy between STER and EFTR for treating gastric GISTs was comparable, and a large-scale, randomized study is necessary for a more confirmed conclusion.

Comparison between submucosal tunneling endoscopic resection and video-assisted thoracoscopic surgery for large esophageal leiomyoma originating from the muscularis propria layer.

BACKGROUND: Submucosal tunneling endoscopic resection (STER) has been proved to be safe and effective for removal of esophageal leiomyoma originating from the muscularis propria (MP) layer. However, there are still technical challenges for tumors ≥35 mm due to the limited space of the submucosal tunnel. The aim of the study was to estimate the safety and efficacy of STER for large esophageal leiomyoma originating from the MP layer as well as compare its efficacy with video-assisted thoracoscopic surgery (VATS), which is a standard procedure for treating esophageal leiomyoma. METHODS: We retrospectively collected the clinical data of the patients with esophageal leiomyoma of 35-55 mm who underwent STER or VATS at our hospital between January 2010 and December 2014. Epidemiological data (gender, age), tumor location, tumor size, procedure-related parameters, complications, length of stay and cost were compared between STER and VATS. RESULTS: A total of 31 patients were enrolled, and 18 patients underwent STER and the other 13 received VATS. There was no significant difference between the two groups in gender, age, tumor location, tumor size, complications and rate of en bloc resection (P > 0.05). However, patients in the STER groups had a shorter operation time, a less decrease in hemoglobin level, a shorter length of hospital stay and a decreased cost (P < 0.05). No recurrence was noted in the STER and VATS groups during a mean follow-up of 10.9 and 30.8 months, respectively. CONCLUSIONS: The treatment efficacy was comparable between the STER and VATS for esophageal leiomyoma of 35-55 mm. However, STER is superior to VATS in a shorter operation time, a less decrease in hemoglobin level, a shorter length of hospital stay and a decreased cost.

The Outcomes and Quality of Life of Patients with Achalasia after Peroral Endoscopic Myotomy in the Short-Term.

PURPOSE: To assess the short-term efficacy and quality of life (QOL) of patients with achalasia after peroral endoscopic myotomy (POEM). METHODS: Thirty-five achalasia patients underwent POEM from May 2013 to December 2013. The data on clinical evaluation and QOL before therapy, at 1 month and 6 months postoperation were collected and analyzed. RESULTS: All the thirty-five patients underwent POEM successfully. By comparing the data of the preoperative with that of 1 month and 6 months after POEM respectively, we found that: mean Eckardt score decreased (6.83 vs 0.51, 6.83 vs 0.46, all P <0.05), esophagus diameter reduced (47.97 mm vs 32.00 mm, 47.97 mm vs 28.50 mm, all P <0.05), and esophageal manometry declined (29.5 mmHg vs 11.5 mmHg, 29.5 mmHg vs 10.3 mmHg, all P <0.05). Complications occurred in 14.3% (5/35) of the cases, and no recurrence was observed. At each time point, postoperative QOL scores were higher than those of preoperative (P <0.05). CONCLUSIONS: POEM is safe and effective for treating achalasia in the short-term, it can relieve clinic symptoms as well as improve patients' QOL.

Submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors originating from the muscularis propria layer.

OBJECTIVE: To estimate the safety and efficacy of submucosal tunneling endoscopic resection (STER) for upper gastrointestinal submucosal tumors (SMTs) originating from the muscularis propria layer. METHODS: During October 2011 and May 2014, a total of 80 patients with SMTs underwent STER at our hospital. A submucosal tunnel was created from 3-5 cm above the tumor. Endoscopic submucosal dissection of the SMT was performed, and then the mucosal incision was closed with several clips after the tumor was removed. RESULTS: All the 80 patients underwent STER successfully, with a mean operation time of 61.2 min. Eighty-three SMTs were removed; among these, 67 were located in the esophagus and 16 in the gastric cardia, 68 were leiomyoma, and 15 were gastrointestinal stromal tumors, and 13 had a diameter no less than 35 mm. The mean tumor size was 23.2 mm; en-bloc resection was performed in 97.6% (81/83) of the tumors. Complications were noted in 8.75% (7/80) of the cases, and all of them resolved without the need for additional surgery. No recurrence was noted during a mean follow-up of 10.2 months. CONCLUSION: STER appears to be a feasible, safe, and effective method for upper gastrointestinal SMTs originating from the muscularis propria layer, even when the size of the tumor was larger than 35 mm.

Endoscopic Incision for the Treatment of Refractory Esophageal Anastomotic Strictures in Children.

OBJECTIVES: The aim of the present study was to assess the safety and efficacy of endoscopic incision (EI) for the treatment of refractory anastomotic esophageal strictures in pediatric patients. METHODS: We retrospectively reviewed the medical records of pediatric patients with refractory anastomotic strictures after surgical repair of esophageal atresia who underwent ≥3 sessions of endoscopic treatments (dilation and/or stenting). They were treated with EI alone or together with esophageal stenting. Efficacy and safety were evaluated during periodical follow-up. RESULTS: All of the 7 children received the procedure successfully with the operation time of 15 to 60 minutes. Four of them received EI alone, whereas the other 3 received EI with esophageal stenting (EIES). The symptoms remitted in all of the patients, and the dysphagia score decreased from 3-4 to 0-1 during follow-up from 1 to 21 months. The average diameter of stricture was enlarged from 3 mm (range 2-5 mm) to 10.6 mm (range 8-12 mm). One patient suffered from chest pain, which resolved within 3 days. Patient 1 had recurrence 11 months after EIES, and patient 6 had recurrence 3 months after EI. They all underwent an additional EI to maintain patency. No severe complications were observed during operation and periodical follow-up. CONCLUSIONS: EI is safe and appears effective for refractory esophageal anastomotic strictures in children in the short term. Large comparative studies are warranted to further confirm our findings. The long-term follow-up is necessary for assessing the long-term efficacy of the new technique.