Introduction

The NLRP3 inflammasome is crucial in regulating innate immune responses, balancing inflammation and homeostasis. It acts as a sensor for danger signals, facilitates the release of pro-inflammatory cytokines and plays a role in TGFβ, NF-κB, and IL-6/JAK/STAT3 signaling. Although the NLRP3 inflammasome is well known for its role in inflammation, recent studies suggest that it may also influence liver regeneration by modulating hepatocyte proliferation and tissue remodeling. This study investigates the role of the NLRP3 inflammasome and its related pathways in liver regeneration over time.

Aims & Methods

Using a partial hepatectomy mouse model, this research examines mRNA expression dynamics of NLRP3 and associated components post-surgery through RNA sequencing (RNA-seq). Liver tissue was analyzed at different time points after partial hepatectomy. Pathway analysis investigated the regulation of related signaling pathways, such as TGFβ, NF-κB, IL-6/JAK/STAT3, and endoplasmic reticulum stress responses.

Results

NLRP3 and Caspase-1 mRNA levels remained unchanged during liver regeneration. In contrast, mRNA expression of NLRP3 inhibitors, including Hsp90 and Sugt1 were significantly upregulated. Pathway analysis revealed substantial upregulation of TGFβ pathway during early proliferation phase, increased NF-κB signaling throughout the process, and consistent activation of the IL-6/JAK/STAT3 signaling pathway and endoplasmic reticulum stress responses.

Conclusion

These findings indicate the complex regulatory mechanisms of the NLRP3 inflammasome in liver regeneration and the varying pathway activation at different stages. Understanding the role of the NLRP3 inflammasome in liver regeneration could offer new insights into potential therapeutic approaches for patients with chronic liver disease or impaired hepatic recovery after surgery.

Introduction

Gastric hyperplastic polyps (GHPs) carry a neoplastic transformation risk of up to 5%, with previous studies indicating an increased risk with larger polyp size. We aimed to evaluate the frequency and risk factors of its malignant transformation in a Portuguese cohort.

Aims & Methods

A multicenter retrospective cohort study was conducted including all patients undergoing endoscopic resection of GHPs ≥10mm from January 2013 to January 2024 in Portuguese tertiary reference centers. Patients with hereditary polyposis syndromes were excluded. Demographic, clinical, endoscopic, and histopathological data were collected.

Results

A total of 782 GHPs from eight centers were evaluated. The median age was 68 years (IQR 60-75), and 58.8% were female. Evidence of advanced gastritis stage (OLGIM≥3) and synchronous gastric neoplasia were present in 57 (10.2%) and 37 (4.7%) cases, respectively. The median lesion size was 15 mm (IQR 12-20), and most presented a polypoid morphology (96.8%). Most GHPs were removed by endoscopic mucosal resection (86.6%), followed by cold snare polypectomy (8.1%) endoscopic submucosal dissection (3.6%), and cold snare EMR (1.7%), achieving en-bloc resection in 677 cases (86.6%). Neoplastic transformation was observed in 33 polyps (4.2%) – 25 (3.2%) low/high-grade dysplasia and 8 (1.0%) adenocarcinoma; the resection was non-curative in 30.3% of cases.
In the multivariate analysis, OLGIM≥3 (OR 4.994, 95%CI 1.036-24.065), lesion size ≥25 mm (OR 7.973, 95%CI 7.973 (1.242-51.180), flat/depressed morphology (OR 9.57, 95%CI 1.096-83.712) and synchronous gastric neoplasia (OR 16.956, 95%CI 2.737-105.045) were independently associated with a higher risk of malignant transformation.

Conclusion

The risk of malignant transformation of GHPs in non-neglectable, with lesion size and morphology and concomitant precancerous gastric conditions/lesions being associated with a higher risk. Nevertheless, the rate of non-curative endoscopic resection is high. The identification of these features may help for optimizing and tailoring the selection of adequate endoscopic resection techniques and surveillance strategies in high-risk patients.

Introduction

Colorectal cancer, the third most prevalent malignancy globally[1], exhibits strong associations with aberrant DNA methylation patterning. While DNA methyltransferase inhibitors (DNMTis) demonstrate therapeutic efficacy in hematologic malignancies, their clinical application in solid tumors remains constrained by dose-limiting genomic instability secondary to genome-wide hypomethylation[2]. Recent mechanistic studies have established methyl-CpG-binding domain protein 2 (MBD2) as a pivotal mediator of methylation-dependent transcriptional repression; however, its potential involvement in context-dependent oncogene activation remains unresolved. This study elucidates that pharmacological MBD2 inhibition achieves dual epigenetic rectification – reactivating tumor suppressor genes through promoter demethylation while selectively attenuating WNT16 overexpression via methylation-sensitive suppression, thereby establishing a targeted therapeutic paradigm that circumvents the pleiotropic toxicity associated with conventional DNMTis.

Aims & Methods

A multi-dimensional platform encompassing clinical specimens, cell lines, patient-derived organoids, and PDX models was employed. Integrative whole-genome bisulfite sequencing and RNA-seq analyses delineated methylation-driven transcriptional networks. Chromatin immunoprecipitation sequencing characterized MBD2 binding at differentially methylated regions, with CRISPR interference validating functional regulatory elements.

Results

CRC cells exhibited pronounced hypomethylation at the WNT16 promoter accompanied by diminished MBD2 occupancy. MBD2 inhibitor treatment downregulated WNT16 expression at both RNA and protein levels, concomitant with suppression of Wnt/β-catenin signaling. In PDX models, MBD2 inhibition reduced tumor burden without inducing genomic instability—a hallmark toxicity of conventional DNMTis.

Conclusion

This study unveils a novel epigenetic mechanism wherein MBD2 facilitates oncogenic WNT16 activation via its "methylation reader" function. Compared to broad-spectrum DNMTis, MBD2-targeted therapy achieves precise correction of carcinogenic epigenetic lesions while avoiding genome-wide hypomethylation risks, advancing a paradigm for targeted CRC treatment.

References

[1] Jiexi Li, Xingdi Ma, Deepavali Chakravarti, Shabnam Shalapour, Ronald A DePinho. Genetic and biological hallmarks of colorectal cancer. Genes Dev.
2021;35(11-12):787-820
[2] Marie Lopez, Julie Gilbert, Jean Contreras, Ludovic Halby, Paola B Arimondo. Inhibitors of DNA Methylation. Adv Exp Med Biol. 2022;1389:471-513
[3] Yang Xie, Feng Wang, Jun Yu, Jing Zhang, Yuting Liu, Mengying Li, Jian Qi. Silencing of MBD2 and EZH2 inhibits the proliferation of colorectal carcinoma cells by rescuing the expression of SFRP. Oncol Rep. 2021;46(6):250.

Introduction

Self-expandable metallic stent (SEMS) placement is a palliative treatment for inoperable esophageal malignancies to improve the quality of life. Traditional methods rely on fluoroscopy and endoscopy, but anatomical landmarks can simplify the procedure.

Aims & Methods

To evaluate the technical success, safety and reproducibility of using vertebral column and diaphragm landmarks for SEMS placement.
This retrospective observational study included 801 patients with inoperable esophageal malignancies undergoing SEMS placement for dysphagia due to malignant esophageal strictures, by using vertebral column and diaphragm as landmarks, from 1^st January 2006 to 31^st December 2024. The primary endpoint was to assess the technical success, safety and reproducibility of this unique technique for SEMS placement.
Methodology for Stent Placement in Esophageal Tumors:
1. For Proximal or Mid-Esophageal Tumor, following algorithm was followed: Step 1: Identify key anatomical landmarks using fluoroscopy. Step 2: With the scope in place, under fluoroscopic guidance, identify the vertebra in line with the distal extent of the tumor using the diaphragm as a reference, followed by identification of vertebra at the proximal extent of the tumor. Count the vertebrae between the distal and proximal extent of the tumor. Assign a length of 2.5 cm per vertebral body. Ascertain the desired size of SEMS by calculating the total length of the stricture by counting the vertebrae, adding one vertebral body above and below the tumor for proper stent placement. Step 3: Using fluoroscopy, position the stent. Place the distal end of the stent at the distal vertebral marker. Position the proximal end of the stent at the proximal vertebral marker. Release the stent at the appropriate position to ensure full coverage of the stricture.
2. For Tumor Extending Beyond the Gastro-Esophageal Junction (GEJ), following algorithm was followed: Step 1: Identify the proximal extent of the tumor. Align the proximal extent of the tumor with the vertebra, using the diaphragm as a reference for precise alignment. Measure the distance from the proximal end of the tumor to the proximal stomach using the scope to decide the required size of the stent. Step 2: Place the stent under fluoroscopic guidance. Position the upper end of the stent at the identified vertebra. Extend the distal end of the stent into the stomach, past the GE junction to ensure proper coverage. Release the stent.

Results

408 (50.9%) patients were females. The age range was 18-95 years (mean50±Standard deviation15). Predominant presenting complaint was dysphagia (85.39%). Average duration of dysphagia was 3.84 months. 594 (74.16%) patients had squamous cell carcinoma, whereas 207 (25.84%) patients were diagnosed with adenocarcinoma on histopathology. 365 (45.57%) patients had tumor confined to the lower one-third of esophagus. Major cause of inoperability was distant metastasis (52.81%). 240 (30%) patients had involvement of GEJ. Average length of malignant stricture was 8.4 cm. 139 (17.40%) patients required dilatation by using savary gilliard dilators before SEMS placement. TEF was present in 48 (6%) patients. Range of length of SEMS was 8-18 cm (12.5±2.26). Technical success was achieved in 100% cases. No major immediate complications occurred. Minor complications were rare.

Conclusion

Using vertebral column and diaphragm landmarks is a reliable, safe, simplified and reproducible approach for SEMS placement in patients with inoperable esopahgeal malignancies.

References

1. Lander S, Lander E, Gibson MK. Esophageal Cancer: Overview, Risk Factors, and Reasons for the Rise. Curr Gastroenterol Rep. 2023 Nov;25(11):275-279. doi: 10.1007/s11894-023-00899-0. Epub 2023 Oct 9. PMID: 37812328.

2. Li J, Xu J, Zheng Y, Gao Y, He S, Li H, Zou K, Li N, Tian J, Chen W, He J. Esophageal cancer: Epidemiology, risk factors and screening. Chin J Cancer Res. 2021 Oct 31;33(5):535-547. doi: 10.21147/j.issn.1000-9604.2021.05.01. PMID: 34815628; PMCID: PMC8580797.

3. Asghar MS, Khan NA, Kazmi SJH, Hassan M, Rasheed U, Jawed R, Yaseen R, Naqvi SAA. Clinical, epidemiological, and diagnostic characteristics of esophageal carcinoma in a Pakistani population. Ann Saudi Med. 2021 Mar-Apr;41(2):91-100. doi: 10.5144/0256-4947.2021.91. Epub 2021 Apr 1. PMID: 33818145; PMCID: PMC8020643.

Introduction

The impact of antral preservation versus antral resection in sleeve gastrectomy remains a subject of debate due to its potential effects on weight loss, metabolic outcomes, and gastrointestinal function. This meta-analysis aims to provide a comparative assessment of these surgical techniques.

Aims & Methods

The Meta-Analysis aims to provide a comprehensive analysis between ​these two surgical techniques.
A systematic review and meta-analysis were conducted using 10 studies published between 2014 and 2025 that compared sleeve gastrectomy with antral preservation versus antral resection. The primary outcomes included excess weight loss (EWL) at different time points, while secondary outcomes assessed metabolic parameters (C-peptide, GLP-1, HbA1c), gastric emptying, gastroesophageal reflux disease (GERD), and resolution of comorbidities.

Results

A total of 10 studies were included. Patients undergoing antral resection exhibited greater excess weight loss at 6 and 12 months (MD: -4.50, 95% CI: -5.98 to -3.02; MD: -6.11, 95% CI: -7.74 to -4.47, respectively; p<0.00001), though the difference diminished by 24 months (MD: -3.37, 95% CI: -7.04 to 0.30; p=0.07). No significant differences were observed in overall GERD incidence (RR: 1.00, 95% CI: 0.75–1.33) or complications (RR: 1.00, 95% CI: 0.74–1.42). Metabolic outcomes showed marginal differences, with C-peptide (SMD: 0.02, 95% CI: -0.38 to 0.42) and GLP-1 (SMD: -0.22, 95% CI: -0.90 to 0.47) exhibiting minimal changes between groups.

Conclusion

Antral resection in sleeve gastrectomy is associated with superior short-term weight loss, but long-term differences remain inconclusive. Metabolic outcomes and postoperative complications appear comparable between techniques. Further randomized controlled trials with extended follow-up are warranted to refine surgical recommendations.

References

Disclosure

The author(s) declare no conflict of interest

Introduction

Defecatory dysfunction (DD) is a common cause of chronic constipation resulting from functional abnormalities or structural pelvic pathologies. Accurate diagnosis requires combining anorectal manometry (ARM), balloon expulsion test (BET), and defecography. This study evaluates the diagnostic utility of these modalities and explores uncertainties in their performance and interpretation.

Aims & Methods

This retrospective study included 325 adult patients assessed for DD between 2020 and 2023. All patients went through ARM, BET in the left lateral position, and defecography. Statistical associations between test outcomes were analyzed to assess diagnostic concordance and significance.

Results

A strong correlation was observed between ARM and defecography, with 65% of patients with normal anal relaxation on ARM achieving normal rectal evacuation on defecography (p < 0.0001). Conversely, patients with paradoxical contraction during ARM demonstrated a higher likelihood of evacuation failure. BET demonstrated high specificity but limited sensitivity in association with relaxation on ARM and evacuation on defecography. BET failure did not demonstrate a significant association with the presence of pelvic floor pathologies.

Conclusion

Combining ARM, BET, and defecography provides a comprehensive framework for diagnosing DD, addressing its functional and structural components. This integrated approach facilitates targeted interventions, ultimately improving clinical outcomes.

References

Chronic constipation is a common disorder with multifactorial pathophysiology, including pelvic floor dysfunction (Bharucha & Lacy, 2020). Symptomatic pelvic floor disorders affect a significant proportion of women (Nygaard et al., 2008). High-resolution anorectal manometry (HRAM) and rectal balloon expulsion tests are critical for diagnosing defecatory disorders (Prichard et al., 2017; Bharucha & Coss-Adame, 2022). Standardized protocols, including the London Classification, have improved the diagnostic accuracy of anorectal functional tests (Carrington et al., 2020; Carrington et al., 2018). Imaging modalities such as magnetic resonance defecography complement functional testing (Reiner et al., 2011; Carter et al., 2020). Variations in body position influence anorectal test results (Su et al., 2019; Wu et al., 2017; Tsunoda et al., 2022; Ratuapli et al., 2013). Comparative studies emphasize the complementary role of manometry, balloon expulsion, and defecography (Blackett et al., 2022; Heinrich et al., 2015). Recent advances suggest HRAM improves detection of specific defecatory mechanisms (Deb et al., 2022; Sharma et al., 2020), supported by international consensus guidelines (Wald et al., 2021; Rao & Tetangco, 2020; Lee & Bharucha, 2016).

Disclosure

no conflict of interest