Implanted, Wireless, Self-Powered Photodynamic Therapeutic Tablet Synergizes with Ferroptosis Inducer for Effective Cancer Treatment.

The effective and targeted treatment of resistant cancer cells presents a significant challenge. Targeting cell ferroptosis has shown remarkable efficacy against apoptosis-resistant tumors due to their elevated iron metabolism and oxidative stress levels. However, various obstacles have limited its effectiveness. To overcome these challenges and enhance ferroptosis in cancer cells, we have developed a self-powered photodynamic therapeutic tablet that integrates a ferroptosis inducer (FIN), imidazole ketone erastin (IKE). FINs augment the sensitivity of photodynamic therapy (PDT) by increasing oxidative stress and lipid peroxidation. Furthermore, they utilize the Fenton reaction to supplement oxygen, generating a greater amount of reactive oxygen species (ROS) during PDT. Additionally, PDT facilitates the release of iron ions from the labile iron pool (LIP), accelerating lipid peroxidation and inducing ferroptosis. In vitro and in vivo experiments have demonstrated a more than 85% tumor inhibition rate. This synergistic treatment approach not only addresses the limitations of inadequate penetration and tumor hypoxia associated with PDT but also reduces the required medication dosage. Its high efficiency and specificity towards targeted cells minimize adverse effects, presenting a novel approach to combat clinical resistance in cancer treatment.

Automatic Measuring of Finger Joint Space Width on Hand Radiograph using Deep Learning and Conventional Computer Vision Methods.

Hand osteoarthritis (OA) severity can be assessed visually through radiographs using semi-quantitative grading systems. However, these grading systems are subjective and cannot distinguish minor differences. Joint space width (JSW) compensates for these disadvantages, as it quantifies the severity of OA by accurately measuring the distances between joint bones. Current methods used to assess JSW require users' interaction to identify the joints and delineate initial joint boundary, which is time-consuming. To automate this process and offer a more efficient and robust measurement for JSW, we proposed two novel methods to measure JSW: 1) The segmentation-based (SEG) method, which uses traditional computer vision techniques to calculate JSW; 2) The regression-based (REG) method, which is a deep learning approach employing a modified VGG-19 network to predict JSW. On a dataset with 3,591 hand radiographs, 10,845 DIP joints were cut as regions of interest and served as input to the SEG and REG methods. The bone masks of the ROI images generated by a U-Net model were sent as input in addition to the ROIs. The ground truth of JSW was labeled by a trained research assistant using a semi-automatic tool. Compared with the ground truth, the REG method achieved a correlation coefficient of 0.88 and mean square error (MSE) of 0.02 mm on the testing set; the SEG method achieved a correlation coefficient of 0.42 and MSE of 0.15 mm. Results show the REG method has promising performance in automatic JSW measurement and in general, Deep Learning approaches can facilitate the automatic quantification of distance features in medical images.

The Application of Probe-Based Confocal Laser Endomicroscopy as a Diagnostic Tool in Choledochoscopic Gallbladder-Preserving Surgery.

BACKGROUND AND AIMS: Choledochoscopic gallbladder-preserving surgery (CGPS) has the advantage of treating benign gallbladder diseases on the premise of gallbladder preservation. However, it has no reliable preoperative diagnosis if the gallbladder is benign. Probe-based confocal laser endomicroscopy (pCLE) can obtain real-time and clear endoscopic images at the cell level in vivo. It is widely used in the diagnosis of digestive system diseases, but not in gallbladder diseases yet. We applied these two technologies in a complementary way into the diagnosis of gallbladder diseases and thereby lifted the reliability of CGPS. METHODS: We retrospectively analyzed the total 28 patients with the indication of CGPS with intraoperative pCLE scan referred to the Second Affiliated Hospital of Baotou Medical College between October 2019 and July 2020. The intraoperative pCLE results were compared with the postoperative pathology in various gallbladder diseases. RESULTS: We compared the intraoperative pCLE diagnosis with the postoperative pathological diagnosis and found a complete match without exception in both sensitivity and specificity. CONCLUSIONS: Based on our investigation, pCLE can provide the same accuracy as the traditional pathology in the diagnosis of gallbladder diseases with the additional advantages like noninvasive, real time, and instancy. This study serves to validate the correlation between CLE and histology. It holds a broad prospect in the application of pCLE as an intraoperative diagnosis in CGPS.

CCN1 suppresses cell proliferation of esophageal squamous cell carcinoma through amyloid precursor protein without DR6 participation.

Esophageal cancer is commonly seen as either squamous cell carcinoma (ESCC) or adenocarcinoma (EAC), two very different cancers. CCN1 is a matricellular protein that induces apoptosis in EAC cells through upregulation of DR5, a death receptor, while its role in ESCC is unclear. DR6 is another death receptor, which has been reported to induce apoptosis, necroptosis, or pyroptosis in various cell systems with or without the engagement of its putative ligand amyloid precursor protein (APP). In this study, we found that CCN1 and DR6 were both highly expressed in ESCC but downregulated in EAC. Overexpression of CCN1 in ESCC cells inhibited cell proliferation through upregulation of APP and its association with p53 without DR6 involvement. Overexpression of APP stopped cell growth, but overexpression of DR6 did not affect cell growth or cell death whatsoever.

TNF upregulates peptidoglycan recognition protein 1 in esophageal cancer cells to clear the path to its signaling: Making the "enemy" a friend.

TNF, CCN1, and peptidoglycan recognition protein 1 (PGLYRP1) are often found together in the inflammatory tissue. While TNF and CCN1 promote tissue regeneration, PGLYRP1 protects it from bacterial infection. In fibroblasts, CCN1 was reported to support TNF in apoptosis induction while PGLYRP1 was found to compete with TNF for binding to TNFR1. When PGLYRP1 binds to TNFR1 by itself, it silences the receptor, but if HSP70 joins them, it leads to cell death. In cancer cells, however, CCN1 was found to antagonize TNF signaling by increasing the extracellular pool of TNFR1. In this study, we assessed their relationship in the esophageal cancer cells and found a more complex liaison among them. At first, TNF highly upregulated PGLYRP1 expression but downregulated CCN1. Secondly, PGLYRP1 bound TNFR1 and HSP70 both intracellularly and extracellularly, but TNF only promoted their extracellular interaction. Lastly, the knockdown of PGLYRP1 impaired TNF signaling. Taken together, this study shows that CCN1 interrupts TNF signaling by increasing the extracellular TNFR1 species while TNF fights back by upregulating PGLYRP1 to absorb them.

The Role of CCN1 in Esophageal Adenocarcinoma: What We Have Learned From the Lab.

Background: Esophageal cancer is one of the most common and deadliest cancers in the world, particularly esophageal adenocarcinoma. There has never been a special drug to treat it.Purpose: This article summarizes the work that we have done in our laboratory about the role of CCN1 in esophageal cancer and gives a new perspective of CCN1 biology.Research Design: This is a review article. Study Sample: The work was done using validated cell lines and fixed human tissue slides.Data Collection and Analysis: This is a review article, therefore, no data collection or analysis was involved.Results: CCN1 is a matricellular protein supporting adhesion, migration, and survival in normal cells, but in the esophageal cancer cells, it induces TRAIL-mediated apoptosis. CCN1 promotes TRAIL and its death receptor expression but downregulates the decoy receptors and survivin in a p53-dependant manner. It was thought that CCN1 relies on TNF to induce apoptosis, but our study found that these two molecules antagonize each other. CCN1 promotes TNFR1 cleavage and uses the soluble product to block TNF signaling, while TNF upregulates PGLYRP1 to overcome this obstacle because PGLYRP1 is a secreted protein that competes with TNF for TNFR1 binding. As a result, when CCN1 and TNF are present together in the vicinity of esophageal tumors, they cancel each other out.Conclusions: Based on our laboratory study, CCN1 has much potential to be a candidate for the treatment of esophageal cancer.

TNF antagonizes CCN1 in apoptosis in esophageal adenocarcinoma.

TNF signaling mostly supports cell growth by activating NFκB and only induces cell death when NFκB activation fails. CCN1 is a matricellular protein that has been reported capable to convert TNF from a pro-survival factor into a stimulus for cell death without interfering with NFκB signaling. In this study, we examined the relationship between CCN1 and TNF in the context of esophageal adenocarcinoma and found that CCN1 did not help TNF to induce cell death when they were together, instead, it inhibited TNF expression, as well as TNF-induced JNK activation and apoptosis. CCN1 induced apoptosis in the cancer cells by itself through upregulation of TRAIL and its death receptors. The presence of TNF significantly lowered CCN1 expression and its capability in apoptosis induction. Furthermore, we found that CCN1 boosted ADAM17-mediated cleavage of TNF receptors through ITGA11 and the soluble decoy receptors generated by this action neutralized TNF activity. Taken together, CCN1 and TNF antagonize each other in esophageal cancer cells.

Detachable string magnetically controlled capsule endoscopy for detecting high-risk varices in compensated advanced chronic liver disease (CHESS1801): A prospective multicenter study.

BACKGROUND: Gastroesophageal varices is a serious complication of compensated advanced chronic liver disease (cACLD). Primary prophylaxis to reduce the risk of variceal hemorrhage is recommended if high-risk varices (HRV) are detected. We performed this study to compare the accuracy, patients' satisfaction and safety of detection of HRV by detachable string magnetically controlled capsule endoscopy (DS-MCCE) with esophagogastroduodenoscopy (EGD) as the reference. METHODS: We prospectively recruited participants with cACLD from 12 university hospitals (11 in China and one in the United Kingdom) between November 2018 and December 2019 (ClinicalTrials.gov, NCT03749954). All participants underwent DS-MCCE, followed by EGD within a week in a blinded fashion. Following endoscopy, and on the same day, participants were asked to fill in a satisfaction questionnaire regarding their experience. FINDINGS: A total of 105 eligible participants were enrolled. With EGD as the reference standard, the concordance index, sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of DS-MCCE in diagnosis of HRV were 0•90 (95% confidence interval [CI]: 0•83-0•95), 92% (95% CI: 78-98%), 88% (95% CI: 78-95%), 80% (95% CI: 70-92%), 95% (95% CI: 90-100%), 7•91 (95% CI: 4•10-15•30), and 0•09 (95% CI: 0•03-0•30), respectively. The kappa score of 0•78 (95% CI: 0•65-0•90) suggested substantial agreement between DS-MCCE and EGD. Moreover, in participants undergoing EGD without sedation, the satisfaction of DS-MCCE was significantly better than that of EGD (p < 0•0001, d = 1•15 [95%CI: 0•88-1•42]). All participants confirmed the excretion of the capsule, and no adverse events occurred. INTERPRETATION: DS-MCCE is an accurate alternative to EGD for detecting HRV in cACLD, which is safe and associated with better satisfaction. FUNDING: A full list of funding can be found in the Funding Support section.

Esophageal cancer cells convert the death signal from TRAIL into a stimulus for survival during acid/bile exposure.

BACKGROUND: TRAIL is best known for killing cancer cells selectively, however, some cancers resist TRAIL treatment for various reasons. Esophageal adenocarcinoma is such an example. Previously, we reported that the tumor cells interrupted TRAIL-mediated apoptosis by overexpressing the decoy receptors and survivin. AIMS: To investigate TRAIL resistance in esophageal adenocarcinoma during GERD. METHODS: We simulated GERD episodes in vitro by exposing cancer cells to the acid/bile conditions acutely as well as chronically. TRAIL and its receptors were examined for expression, interaction, and induction of cell death. RESULTS: We found that acid/bile exposure drove the tumor cells to express TRAIL and TRAILR2 robustly, but did not lead to apoptosis, because the tumor cells overexpressed TRADD to replace FADD as the adaptor molecule to trigger NFκB activation instead of caspases, and thereby convert a death signal from TRAIL into a stimulus for survival. The tumor cells also overexpressed c-FLIP to keep caspases away from TRAILR2 in case FADD finds a way back to the death receptor. CONCLUSION: Multiple reasons contribute to TRAIL resistance in esophageal adenocarcinoma, including overexpression of the decoy receptors to block the death receptors, using TRADD to replace FADD, and using c-FLIP to replace caspase-8.

Acid/bile exposure triggers TRAIL-mediated apoptosis in esophageal cancer cells by suppressing the decoy receptors and c-FLIPR.

Esophageal adenocarcinoma essentially develops from esophageal inflammation caused by chronic GERD. During GERD episodes, the lower esophageal epithelium is repeatedly exposed to stomach acid, which often contains duodenal bile salts that prompt malignant transformation. TRAIL is one of the cytokines produced in response to such insults and targets the transformed cells exclusively. In this study, we simulated GERD episodes in vitro by exposing the cancer cells to acid or acid/bile combination and found that the cancer cells lived through acid attacks by expression of the decoy receptors and c-FLIPR but died of TRAIL-mediated apoptosis when bile salts were present. Further investigation revealed that acid/bile exposure downregulated the decoy receptors and thereby facilitated TRAIL signaling; meantime, it inhibited protein kinase C activity and thus expedited c-FLIPR degradation, allowing apoptosis to take place.

Confocal laser endomicroscopy distinguishing benign and malignant gallbladder polyps during choledochoscopic gallbladder-preserving polypectomy: A case report.

BACKGROUND: In the last decade, confocal laser endomicroscopy (CLE) has emerged as a new endoscopic imaging modality for real-time in vivo histological examination at the microscopic level. CLE has been shown to be useful for distinguishing benign and malignant lesions and has been widely used in many digestive diseases. In our study, we used CLE for the first time to examine the morphology of cholesterol polyps as well as the different parts of normal gallbladder mucosa. CASE SUMMARY: A 57-year-old woman was diagnosed by ultrasound with a polyp of 21 mm in the gallbladder wall. She consented to polyp removal by laparoscopic choledo-choscopy. During laparoscopic cholecystectomy combined with choledochoscopic polyp resection, CLE was used to observe the morphology of the polyp surface cells. The appearance of the mucosa and microvessels in various parts of the gallbladder were also observed under CLE. Through comparison between postoperative pathology and intraoperative CLE diagnosis, the reliability of intraoperative CLE diagnosis was confirmed. CLE is a reliable method to examine living cell pathology during cholecystectomy. Based on our practice, CLE should be prioritized in the diagnosis of gallbladder polyps. CONCLUSION: Compared with traditional histological examination, CLE has several advantages. We believe that CLE has great potential in this field.

Overexpression of CCN1 in Het1A cells attenuates bile-induced esophageal metaplasia through suppressing non-canonical NFκB activation.

GERD is the most common gastrointestinal diagnosis given during office visit. People who suffer from a long history of GERD eventually develop Barrett's esophagus, a premalignant intestinal metaplasia due to NFκB activation. Previous studies focused on the contribution of TNF-triggered canonical NFκB pathway to this event. In this study, we demonstrated in vitro that it was LTA, rather than TNF, initiated canonical NFκB activation at the beginning of acid/bile attacks, but later it switched to CD40-activated non-canonical pathway, which played a bigger part in esophageal metaplasia. CCN1 attenuated this cellular transformation by suppressing CD40 and its associated proteins involved in non-canonical signaling.

Clinical study on the prevention of post-ERCP pancreatitis by pancreatic duct stenting.

Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is one of the most common and serious complications of ERCP, which has become a major concern for digestive endoscopists. In the present study, we examine whether pancreatic duct stenting can reduce the incidence of PEP. Forty patients who underwent an ERCP in our hospital were selected according to their risk factors for PEP. They were randomly divided into two groups: (1) 20 subjects received a pancreatic duct stenting after ERCP to prevent pancreatitis (stent group, S); and (2) the other 20 subjects did not receive pancreatic duct stenting after ERCP (non-stent group, NS). Urine and serum amylase, and serum lipase were determined after the operation; symptoms of abdominal pain were monitored; cost of hospitalization was evaluated for the comparison. The results show that (1) 18 cases developed PEP, and they were significantly less in S group than in NS group (4 vs. 14 cases; P < 0.01); (2) Serum amylase was significantly lower in S group than in NS group (197.8 ± 339.7 vs. 825.4 ± 1253.4 U/l, respectively; P < 0.05); (3) The intensity of abdominal pain was 3.4 ± 0.8 in S group, compared to 4.1 ± 1.2 in NS group; (4) Duration of pharmaceutical treatment was not significantly different between the two groups (4.2 ± 1.4 vs. 6.1 ± 2.3 days, in S and NS group, respectively); and (5) The total hospitalization cost was significantly less in S group (8928 ± 2635 RMB) than in NS group (11288 ± 4325 RMB; P < 0.05). It is concluded that pancreatic duct stenting can reduce the incidence of PEP, shorten the duration of hospitalization, and therefore, lessen patients' financial burden. It is shown to be an effective way to prevent PEP.