Endoscopic landmarks corresponding to anatomical landmarks for esophageal subsite classification.

Objectives: Individual treatment strategies for esophageal cancer have been investigated based on the anatomical subsite classification. Accurate subsite classification based on these anatomical landmarks is thus important. We investigated the suitability of the existing endoscopic classification and explored alternative landmarks for esophageal subsite classification. Methods: Patients who received endoscopic ultrasonography (and computed tomography scans for surveillance of esophageal cancer treatment or esophageal submucosal tumors were included. Distances between anatomical landmarks, including the inferior cricoid cartilage border, superior border of the sternum, and tracheal bifurcation, were measured using a combination of endoscopic ultrasonography, computed tomography, and other information. Results: The mean (standard deviation) distances from the superior incisor dentition to the pharynx-esophagus, cervical-upper thoracic esophagus, and upper-middle thoracic esophagus boundaries were 16.9 (1.7), 21.7 (1.9), and 29.0 (1.9) cm, respectively. However, variances in the differences between the mean and individual distances were large (2.8, 3.4, and 3.7, respectively), mainly because of differences in body height. However, variances in the differences between individual distances and novel endoscopic landmarks, including the lower end of the pyriform sinus and lower end of compression of the left main bronchus, were lower (1.7, 1.2, and 0.6, respectively). Conclusions: Existing indicators of esophageal subsite boundaries were not consistent with anatomical boundaries. Modification of the distance from the superior incisor dentition based on average distances from anatomical landmarks or the use of alternative endoscopic landmarks is recommended to provide more suitable anatomical boundaries.

Endoscopic ultrasound-guided hepaticogastrostomy versus choledochoduodenostomy for malignant biliary obstruction: A meta-analysis.

Objectives: Endoscopic ultrasound (EUS)-guided biliary drainage encompasses techniques such as EUS-guided hepaticogastrostomy (EUS-HGS) and EUS-guided choledochoduodenostomy (EUS-CDS). This meta-analysis compared the efficacy of EUS-CDS with that of EUS-HGS for the treatment of biliary obstruction. Methods: A systematic meta-analysis of all relevant articles listed was performed by searching the Cochrane Library, PubMed, and Google Scholar databases. We used random effects or fixed effects models to compare success rates, adverse events, procedure times, and time to recurrent biliary obstruction after EUS-CDS and EUS-HGS. Results: This meta-analysis included 18 eligible studies. There was no significant difference between EUS-CDS and EUS-HGS with respect to technical success rate (odds ratio [OR] 1.04; 95% confidence interval [CI] 0.62-1.73) and clinical success rate (OR 0.66; 95% CI 0.43-1.04), or with respect to total procedure-related adverse events (OR 1.39; 95% CI 1.00-1.93). Subgroup analysis of adverse events revealed that the rate of recurrent biliary obstruction (RBO) was significantly higher for EUS-HGS (OR 2.95; 95% CI 1.54-5.64). There was no significant difference between the two methods with respect to time to recurrent biliary obstruction (mean difference -11.93 days; 95% CI -47.77-23.91). However, the procedure time was longer for EUS-HGS (mean difference, 3.21 min; 95% CI 1.24-5.19). Conclusion: EUS-CDS and EUS-HGS are comparable in terms of technical success, clinical success, and rate of adverse events; however, EUS-CDS is superior with respect to procedure time and preventing RBO.

Development of a new gastrointestinal endoscope forceps plug that can minimize gas leakage.

Background and aims: In our previous study, we visualized and systematically evaluated gas leakage from the forceps plug of the gastrointestinal endoscope system using the Schlieren system. In order to minimize the potential risk of infection from gas leakage from the gastrointestinal endoscope, the development of a new forceps plug was considered urgent. In this study, we analyzed the structure of commercially available forceps plugs and attempted to develop new forceps plugs with improvements. Methods: Microfocus computed tomography was used to nondestructively analyze the structural changes that occur when forceps are inserted into a commercially available forceps plug. Based on the findings, the basic structure of the newly developed forceps plug was set. We examined the airtightness of these newly developed plugs using the Schlieren system and also compared their fractional resistance with those of commercially available plugs. Results: As a result of the nondestructive analysis, all of the commercially available plugs had a single valve, and the cleavage created in the valve during forceps, insertion was large in the case of plugs with slit-type entrances. In the newly developed forceps plugs, all four types of plugs showed less gas leakage and similar or better usability compared to the commercially available plugs. Conclusions: The structural weaknesses of the existing gastrointestinal endoscopic forceps plugs were identified. Based on the findings, we froze the design of a prototype of a new forceps plug that was airtight and not inferior in usability compared to commercially available plugs.

Current status of artificial intelligence analysis for the treatment of pancreaticobiliary diseases using endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography.

Pancreatic and biliary diseases encompass a range of conditions requiring accurate diagnosis for appropriate treatment strategies. This diagnosis relies heavily on imaging techniques like endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography. Artificial intelligence (AI), including machine learning and deep learning, is becoming integral in medical imaging and diagnostics, such as the detection of colorectal polyps. AI shows great potential in diagnosing pancreatobiliary diseases. Unlike machine learning, which requires feature extraction and selection, deep learning can utilize images directly as input. Accurate evaluation of AI performance is a complex task due to varied terminologies, evaluation methods, and development stages. Essential aspects of AI evaluation involve defining the AI's purpose, choosing appropriate gold standards, deciding on the validation phase, and selecting reliable validation methods. AI, particularly deep learning, is increasingly employed in endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography diagnostics, achieving high accuracy levels in detecting and classifying various pancreatobiliary diseases. The AI often performs better than doctors, even in tasks like differentiating benign from malignant pancreatic tumors, cysts, and subepithelial lesions, identifying gallbladder lesions, assessing endoscopic retrograde cholangiopancreatography difficulty, and evaluating the biliary strictures. The potential for AI in diagnosing pancreatobiliary diseases, especially where other modalities have limitations, is considerable. However, a crucial constraint is the need for extensive, high-quality annotated data for AI training. Future advances in AI, such as large language models, promise further applications in the medical field.

Successful endoscopic sclerotherapy for anastomotic tumor hemorrhage: A case report.

A 71-year-old male developed anastomotic tumor bleeding after subtotal gastrectomy (Billroth II), and the surgery was refused due to coronary atherosclerotic heart disease. Endoscopic sclerotherapy (ES) in the treatment of esophagogastric variceal bleeding has been commonly reported, but few in non-variceal upper gastrointestinal bleeding. As far as we know, endoscopic sclerotherapy for malignant tumor hemorrhage has not been reported. Here a valuable case is presented: endoscopic sclerotherapy was performed on the anastomotic tumor bleeding, which is an effective try in a particular period.

Impact of pre-operative weight loss on non-alcoholic fatty liver disease histopathology and insulin resistance in individuals undergoing bariatric surgery: a propensity matched cross-sectional comparison.

BACKGROUND: The effect of weight loss (WL) on histopathological aspects of non-alcoholic fatty liver disease (NAFLD) may provide further insights into the dynamics of hepatic recovery after WL. OBJECTIVE: To analyze the effects of pre-operative WL on insulin resistance- and NAFLD-related histology in individuals undergoing bariatric surgery (BS) with or without pre-operative WL. DESIGN AND SETTING: A matched cross-sectional study was conducted at a public university hospital and a private clinic in Campinas, Brazil. METHODS: An analytical, observational, cross-sectional study was conducted using prospectively collected databases of individuals who underwent BS and liver biopsy at either a public tertiary university hospital (with pre-operative WL) or a private clinic (without pre-operative WL). Random electronic matching by gender, age, and body mass index (BMI) was performed and two paired groups of 24 individuals each were selected. RESULTS: Of the 48 participants, 75% were female. The mean age was 37.4 ± 9.6. The mean BMI was 38.9 ± 2.6 kg/m2. Fibrosis was the most common histopathological abnormality (91.7%). Glucose was significantly lower in the WL group (92 ± 19.1 versus 111.8 ± 35.4 mg/dL; P = 0.02). Significantly lower frequencies of macrovesicular steatosis (58.3% versus 95.8%; P = 0.004), microvesicular steatosis (12.5% versus 87.5%; P < 0.001), and portal inflammation (50% versus 87.5%; P = 0.011) were observed in the WL group. CONCLUSION: Pre-operative WL was significantly associated with lower frequencies of macro- and mi- crovesicular steatosis, portal inflammation, and lower glycemia, indicating an association between the recent trajectory of body weight and histological aspects of NAFLD.

Correction to "Red blood cell distribution width as a novel marker for predicting bleeding after endoscopic resection for early gastric cancer".

[This corrects the article DOI: 10.1002/deo2.123.].

Zinc finger protein 831 promotes apoptosis and enhances chemosensitivity in breast cancer by acting as a novel transcriptional repressor targeting the STAT3/Bcl2 signaling pathway.

Emerging evidence suggested that zinc finger protein 831 (ZNF831) was associated with immune activity and stem cell regulation in breast cancer. Whereas, the roles and molecular mechanisms of ZNF831 in oncogenesis remain unclear. ZNF831 expression was significantly diminished in breast cancer which was associated with promoter CpG methylation but not mutation. Ectopic over-expression of ZNF831 suppressed breast cancer cell proliferation and colony formation and promoted apoptosis in vitro, while knockdown of ZNF831 resulted in an opposite phenotype. Anti-proliferation effect of ZNF831 was verified in vivo. Bioinformatic analysis of public databases and transcriptome sequencing both showed that ZNF831 could enhance apoptosis through transcriptional regulation of the JAK/STAT pathway. ChIP and luciferase report assays demonstrated that ZNF831 could directly bind to one specific region of STAT3 promoter and induce the transcriptional inhibition of STAT3. As a result, the attenuation of STAT3 led to a restraint of the transcription of Bcl2 and thus accelerated the apoptotic progression. Augmentation of STAT3 diminished the apoptosis-promoting effect of ZNF831 in breast cancer cell lines. Furthermore, ZNF831 could ameliorate the anti-proliferation effect of capecitabine and gemcitabine in breast cancer cell lines. Our findings demonstrate for the first time that ZNF831 is a novel transcriptional suppressor through inhibiting the expression of STAT3/Bcl2 and promoting the apoptosis process in breast cancer, suggesting ZNF831 as a novel biomarker and potential therapeutic target for breast cancer patients.

A novel FGFR1 inhibitor CYY292 suppresses tumor progression, invasion, and metastasis of glioblastoma by inhibiting the Akt/GSK3ß/snail signaling axis.

Glioblastoma (GBM) is a malignant brain tumor that grows quickly, spreads widely, and is resistant to treatment. Fibroblast growth factor receptor (FGFR)1 is a receptor tyrosine kinase that regulates cellular processes, including proliferation, survival, migration, and differentiation. FGFR1 was predominantly expressed in GBM tissues, and FGFR1 expression was negatively correlated with overall survival. We rationally designed a novel small molecule CYY292, which exhibited a strong affinity for the FGFR1 protein in GBM cell lines in vitro. CYY292 also exerted an effect on the conserved Ser777 residue of FGFR1. CYY292 dose-dependently inhibited cell proliferation, epithelial-mesenchymal transition, stemness, invasion, and migration in vitro by specifically targeting the FGFR1/AKT/Snail pathways in GBM cells, and this effect was prevented by pharmacological inhibitors and critical gene knockdown. In vivo experiments revealed that CYY292 inhibited U87MG tumor growth more effectively than AZD4547. CYY292 also efficiently reduced GBM cell proliferation and increased survival in orthotopic GBM models. This study further elucidates the function of FGFR1 in the GBM and reveals the effect of CYY292, which targets FGFR1, on downstream signaling pathways directly reducing GBM cell growth, invasion, and metastasis and thus impairing the recruitment, activation, and function of immune cells.

Mechanism of PARP inhibitor resistance and potential overcoming strategies.

PARP inhibitors (PARPi) are a kind of cancer therapy that targets poly (ADP-ribose) polymerase. PARPi is the first clinically approved drug to exert synthetic lethality by obstructing the DNA single-strand break repair process. Despite the significant therapeutic effect in patients with homologous recombination (HR) repair deficiency, innate and acquired resistance to PARPi is a main challenge in the clinic. In this review, we mainly discussed the underlying mechanisms of PARPi resistance and summarized the promising solutions to overcome PARPi resistance, aiming at extending PARPi application and improving patient outcomes.

Autophagy-related lncRNAs in tumor progression and drug resistance: A double-edged sword.

The incidence and mortality rates of cancer are increasing every year worldwide but the survival rate of cancer patients is still unsatisfactory. Therefore, it is necessary to further elucidate the molecular mechanisms involved in tumor development and drug resistance to improve cancer cure or survival rates. In recent years, autophagy has become a hot topic in the field of oncology research, which plays a double-edged role in tumorigenesis, progression, and drug resistance. Meanwhile, long non-coding RNA (lncRNA) has also been shown to regulate autophagy, and the two-sided nature of autophagy determines the dual regulatory role of autophagy-related lncRNAs (ARlncRNAs). Therefore, ARlncRNAs can be effective therapeutic targets for various cancers. Furthermore, the high abundance and stability of ARlncRNAs in tumor tissues make them promising biomarkers. In this review, we summarized the roles and mechanisms of ARlncRNAs in tumor cell proliferation, apoptosis, migration, invasion, drug resistance, angiogenesis, radiation resistance, and immune regulation. In addition, we described the clinical significance of these ARlncRNAs, including as biomarkers/therapeutic targets and their association with clinical drugs.

Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin.

Therapeutic targeting FOXO3A (a forkhead transcription factor) represents a promising strategy to suppress acute myeloid leukemia (AML). However, the effective inhibitors that target FOXO3A are lacking and the adaptive response signaling weakens the cytotoxic effect of FOXO3A depletion on AML cells. Here, we show that FOXO3A deficiency induces a compensatory response involved in the reactive activation of mTOR that leads to signaling rebound and adaptive resistance. Mitochondrial metabolism acts downstream of mTOR to provoke activation of JNK/c-JUN via reactive oxygen species (ROS). At the molecular level, FOXO3A directly binds to the promoter of G protein gamma subunit 7 (GNG7) and preserves its expression, while GNG7 interacts with mTOR and restricts phosphorylated activation of mTOR. Consequently, combinatorial inhibition of FOXO3A and mTOR show a synergistic cytotoxic effect on AML cells and prolongs survival in a mouse model of AML. Through a structure-based virtual screening, we report one potent small-molecule FOXO3A inhibitor (Gardenoside) that exhibits a strong effect of anti-FOXO3A DNA binding. Gardenoside synergizes with rapamycin to substantially reduce tumor burden and extend survival in AML patient-derived xenograft model. These results demonstrate that mTOR can mediate adaptive resistance to FOXO3A inhibition and validate a combinatorial approach for treating AML.

Ribonucleotide reductase M2 (RRM2): Regulation, function and targeting strategy in human cancer.

Ribonucleotide reductase M2 (RRM2) is a small subunit in ribonucleotide reductases, which participate in nucleotide metabolism and catalyze the conversion of nucleotides to deoxynucleotides, maintaining the dNTP pools for DNA biosynthesis, repair, and replication. RRM2 performs a critical role in the malignant biological behaviors of cancers. The structure, regulation, and function of RRM2 and its inhibitors were discussed. RRM2 gene can produce two transcripts encoding the same ORF. RRM2 expression is regulated at multiple levels during the processes from transcription to translation. Moreover, this gene is associated with resistance, regulated cell death, and tumor immunity. In order to develop and design inhibitors of RRM2, appropriate strategies can be adopted based on different mechanisms. Thus, a greater appreciation of the characteristics of RRM2 is a benefit for understanding tumorigenesis, resistance in cancer, and tumor microenvironment. Moreover, RRM2-targeted therapy will be more attention in future therapeutic approaches for enhancement of treatment effects and amelioration of the dismal prognosis.

Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia.

CDC42 controls intestinal epithelial (IEC) stem cell (IESC) division. How aberrant CDC42 initiates intestinal inflammation or neoplasia is unclear. We utilized models of inflammatory bowel diseases (IBD), colorectal cancer, aging, and IESC injury to determine the loss of intestinal Cdc42 upon inflammation and neoplasia. Intestinal specimens were collected to determine the levels of CDC42 in IBD or colorectal cancer. Cdc42 floxed mice were crossed with Villin-Cre, Villin-CreERT2 and/or Lgr5-eGFP-IRES-CreERT2, or Bmi1-CreERT2 mice to generate Cdc42 deficient mice. Irradiation, colitis, aging, and intestinal organoid were used to evaluate CDC42 upon mucosal inflammation, IESC/progenitor regenerative capacity, and IEC repair. Our studies revealed that increased CDC42 in colorectal cancer correlated with lower survival; in contrast, lower levels of CDC42 were found in the inflamed IBD colon. Colonic Cdc42 depletion significantly reduced Lgr5+ IESCs, increased progenitors' hyperplasia, and induced mucosal inflammation, which led to crypt dysplasia. Colonic Cdc42 depletion markedly enhanced irradiation- or chemical-induced colitis. Depletion or inhibition of Cdc42 reduced colonic Lgr5+ IESC regeneration. In conclusion, depletion of Cdc42 reduces the IESC regeneration and IEC repair, leading to prolonged mucosal inflammation. Constitutive monogenic loss of Cdc42 induces mucosal inflammation, which could result in intestinal neoplasia in the context of aging.

RNA m6A reader YTHDF2 facilitates precursor miR-126 maturation to promote acute myeloid leukemia progression.

As the most common internal modification of mRNA, N6-methyladenosine (m6A) and its regulators modulate gene expression and play critical roles in various biological and pathological processes including tumorigenesis. It was reported previously that m6A methyltransferase (writer), methyltransferase-like 3 (METTL3) adds m6A in primary microRNAs (pri-miRNAs) and facilitates its processing into precursor miRNAs (pre-miRNAs). However, it is unknown whether m6A modification also plays a role in the maturation process of pre-miRNAs and (if so) whether such a function contributes to tumorigenesis. Here, we found that YTHDF2 is aberrantly overexpressed in acute myeloid leukemia (AML) patients, especially in relapsed patients, and plays an oncogenic role in AML. Moreover, YTHDF2 promotes expression of miR-126-3p (also known as miR-126, as it is the main product of precursor miR-126 (pre-miR-126)), a miRNA that was reported as an oncomiRNA in AML, through facilitating the processing of pre-miR-126 into mature miR-126. Mechanistically, YTHDF2 recognizes m6A modification in pre-miR-126 and recruits AGO2, a regulator of pre-miRNA processing, to promote the maturation of pre-miR-126. YTHDF2 positively and negatively correlates with miR-126 and miR-126's downstream target genes, respectively, in AML patients, and forced expression of miR-126 could largely rescue YTHDF2/Ythdf2 depletion-mediated suppression on AML cell growth/proliferation and leukemogenesis, indicating that miR-126 is a functionally important target of YTHDF2 in AML. Overall, our studies not only reveal a previously unappreciated YTHDF2/miR-126 axis in AML and highlight the therapeutic potential of targeting this axis for AML treatment, but also suggest that m6A plays a role in pre-miRNA processing that contributes to tumorigenesis.