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Nature Immunology Jun 2024Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic...
Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100 mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an HLA-DQ2/HLA-DQ8 stratification based on gene doses to maximally eliminate the interferon-γ-induced mucosal damage triggered by gluten.
PubMed: 38914866
DOI: 10.1038/s41590-024-01867-0 -
Archives of Biochemistry and Biophysics Jun 2024Bovine intestinal alkaline phosphatase (biALP), a membrane-bound plasma metalloenzyme, maintains intestinal homeostasis, regulates duodenal surface pH, and protects...
Bovine intestinal alkaline phosphatase (biALP), a membrane-bound plasma metalloenzyme, maintains intestinal homeostasis, regulates duodenal surface pH, and protects against infections caused by pathogenic bacteria. The N-glycans of biALP regulate its enzymatic activity, protein folding, and thermostability, but their structures are not fully reported. In this study, the structures and quantities of the N-glycans of biALP were analyzed by liquid chromatography-electrospray ionization-high energy collision dissociation-tandem mass spectrometry. In total, 48 N-glycans were identified and quantified, comprising high-mannose [6 N-glycans, 33.1% (sum of relative quantities of each N-glycan)], hybrid (6, 11.9%), and complex (36, 55.0%) structures [bi- (13, 26.1%), tri- (16, 21.5%), and tetra-antennary (7, 7.4%)]. These included bisecting N-acetylglucosamine (33, 56.6%), mono- to tri-fucosylation (32, 53.3%), mono- to tri-α-galactosylation (16, 20.7%), and mono- to tetra-β-galactosylation (36, 58.5%). No sialylation was identified. N-glycans with non-bisecting GlcNAc (9, 10.3%), non-fucosylation (10, 13.6%), non-α-galactosylation (26, 46.2%), and non-β-galactosylation (6, 8.4%) were also identified. The activity (100%) of biALP was reduced to 37.3 ± 0.2% (by de-fucosylation), 32.7 ± 2.9% (by de-α-galactosylation), and 0.2 ± 0.2% (by de-β-galactosylation), comparable to inhibition by 10 to 10 mM EDTA, a biALP inhibitor. These results indicate that fucosylated and galactosylated N-glycans, especially β-galactosylation, affected the activity of biALP. This study is the first to identify 48 diverse N-glycan structures and quantities of bovine as well as human intestinal ALP and to demonstrate the importance of the role of fucosylation and galactosylation for maintaining the activity of biALP.
PubMed: 38914216
DOI: 10.1016/j.abb.2024.110069 -
The Indian Journal of Radiology &... Jul 2024The aim of this study was to examine the imaging manifestations of post-endoscopic retrograde cholangiopancreatography (ERCP) specific complications by computed...
The aim of this study was to examine the imaging manifestations of post-endoscopic retrograde cholangiopancreatography (ERCP) specific complications by computed tomography to aid in its early and successful diagnosis and timely intervention. Forty-one cases of imaging having post-ERCP were complications were retrospectively collected and the spectrum of complications and their key imaging features and methods to improve their detection were analyzed. The most common complication detected in computed tomography (CT) post-ERCP was the presence of intra-abdominal collections seen in 21 patients (51.2%). Pancreatitis was seen in 20 of 41 patients (48.7%), while bowel perforation was present in 9 patients (21%). Pleural effusion was present in 8 patients (19.5%), liver abscess in 6 patients (14.6%), cholangitis in 4 patients (9.7%), gallbladder perforation in 4 patients (9.7%), displaced common bile duct stent in 3 patients (7.3%), possibility of main pancreatic duct cannulation in 2 patients (4.8%), vascular injury resulting in right hepatic artery pseudoaneurysm in 1 patient (2.4%), thrombosis of portal vein or its branches in 2 patients (4.8%), superior mesenteric vein thrombosis in 1 patient (2.4%), right hepatic vein thrombosis in 1 patient (2.4%), pulmonary thromboembolism in 2 patients (4.8%), duodenal inflammation in 1 patient (2.4%), bowel ileus in 4 patients (9.6%), and bowel obstruction in 1 patient (2.4%). Complications after ERCP can cause significant morbidity and mortality if not diagnosed early and treated appropriately. Familiarity with normal findings post-ERCP and knowledge of the imaging appearance of these complications are vital in the early management of these conditions.
PubMed: 38912237
DOI: 10.1055/s-0044-1779585 -
International Medical Case Reports... 2024In this case we report a rare presentation of a ruptured gastroduodenal artery aneurysm (GDA) accompanied by a duodenal perforation. It contributes to the scientific...
PURPOSE
In this case we report a rare presentation of a ruptured gastroduodenal artery aneurysm (GDA) accompanied by a duodenal perforation. It contributes to the scientific literature by discussing the management approach and results in a patient with dual complications and emphasizes the importance of early diagnosis and appropriate treatment.
CASE PRESENTATION
A 50-year-old male presented with severe abdominal pain, anemia, and signs of hemodynamic instability. Diagnostic imaging including CTA revealed a large, thrombosed gastroduodenal artery aneurysm with evidence of rupture. The patient underwent open surgical exploration and repair to address both the aneurysm and the duodenal perforation. The patient's recovery was satisfactory and was discharged home in stable condition.
CONCLUSION
Early diagnosis and appropriate management in gastroduodenal artery aneurysms is crucial. There is a need for individualized surgical interventions based on the patient's hemodynamic status and associated complications. Dual complications required open surgical exploration and repair, resulting in favorable outcomes.
PubMed: 38911607
DOI: 10.2147/IMCRJ.S468278 -
Frontiers in Pharmacology 2024Anaprazole, an innovative drug, has shown promise in initial clinical trials for patients with duodenal ulcers (DU) in China. This study aimed to evaluate the potential...
OBJECTIVE
Anaprazole, an innovative drug, has shown promise in initial clinical trials for patients with duodenal ulcers (DU) in China. This study aimed to evaluate the potential effects, safety, and cost-effectiveness of Anaprazole compared to Ilaprazole in the treatment of DU and the budgetary impact on the healthcare system.
METHODS
Two multicentre, randomized controlled trials were used as data sources. The efficacy and safety of Anaprazole and Ilaprazole were compared using an anchored matching-adjusted indirect comparison (MAIC). A cost-utility analysis (CUA) was performed using a Markov model. A budget impact analysis (BIA) was conducted to evaluate the impact on the expenditure of the Chinese healthcare system. Deterministic and probabilistic sensitivity analyses were undertaken to test the uncertainty.
RESULTS
The study findings indicated that Anaprazole and Ilaprazole have similar efficacy and safety in treating DU (OR = 1.05; 95% CI, 0.94-1.01; = 0.35; OR = 0.63; 95% CI, 0.39-1.08; = 0.12). The ICUR was 2,995.41¥/QALY, which is below the WTP threshold. The CUA results showed that Anaprazole is a cost-effective intervention with a probability of 85% at a given threshold. The results demonstrated strong robustness in the sensitivity analysis. Anaprazole imposed a low burden on the Chinese healthcare budget in the BIA.
CONCLUSION
Compared with Ilaprazole, Anaprazole has similar efficacy, safety, and high cost-effectiveness, while also impacting the total expenditure of the healthcare system.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, identifier NCT04215653 and NCT02847455.
PubMed: 38910891
DOI: 10.3389/fphar.2024.1407435 -
Cureus May 2024Background Gastric adenocarcinoma (GCA) poses a significant global health burden due to its prevalence and high morbidity and mortality rates. GCA is classified into...
Background Gastric adenocarcinoma (GCA) poses a significant global health burden due to its prevalence and high morbidity and mortality rates. GCA is classified into three main histological types: well-differentiated (intestinal type), poorly differentiated (diffuse type), and mixed or indeterminate forms. These types vary in causes, epidemiology, and genetics, with the diffuse type often associated with the worst prognosis. Endoscopic biopsy is the primary method for characterization, but it has its limitations. There is potential in using contrast-enhanced computed tomography (CT) to differentiate between histological subtypes of gastric adenocarcinoma, which could aid subtype differentiation. Building on this, our study aims to assess CT's effectiveness in distinguishing between broad histological groups of gastric adenocarcinoma based on enhancement patterns, contributing to improved diagnostic accuracy Objective Our research focuses on evaluating the effectiveness of multiphasic contrast-enhanced computed tomography (CECT) in distinguishing between the three broad histopathological subtypes of gastrointestinal cancers. Methods This study was a prospective, analytical observational study that was approved and carried out in our institutional tertiary care hospital. Consecutive individuals who had undergone endoscopic-guided biopsy and demonstrated histological evidence of GCA were taken into consideration for participation in the study. In order to complete the clinical staging process, further multiphasic CT scans were carried out on each of the fifty patients and were categorised accordingly based on the findings of histopathology. Results In the differentiated type, segmental distribution was: 5.5% upper segment, 16.7% middle segment, 66.7% lower segment, and 11.1% diffuse type. Esophageal involvement was 5.6%, duodenal involvement was similar, and lymph node involvement was approximately 38.8%. TNM staging: 38.8% IIIB, 22.2% III, 27.8% IVA, and 11.1% IVB. In the undifferentiated type, segmental distribution: 6.2% upper segment, 31.2% middle segment, 50.0% lower segment, and 12.5% diffuse type. Esophageal involvement was around 6.25%, duodenal involvement was 18.75%, and lymph node involvement was about 71.8%. TNM staging: 34.4% IIIB, 21.8% III, 28.1% IVA, and 15.6% IVB. Conclusion Multiphasic CT evaluations provide valuable insights into the prognostic aspects of gastric carcinomas by assessing peak enhancement. Differentiated tumors typically exhibit arterial phase enhancement, while undifferentiated tumors show venous phase enhancement, reflecting their microvascular architecture. Recent studies emphasize the importance of understanding gastric carcinoma characteristics for diagnosis and prognosis. Our research aligns with this, revealing distinct contrast enhancement patterns between differentiated and undifferentiated types. However, discrepancies in histological classifications and contrast enhancement patterns across studies warrant further investigation. Integrating histopathological and radiological insights is essential for accurate diagnosis and treatment planning.
PubMed: 38910671
DOI: 10.7759/cureus.60841 -
Cureus May 2024Superior mesenteric artery syndrome is a rare vascular compression syndrome in which the duodenum is compressed between the aorta and the overlying superior mesenteric...
Superior mesenteric artery syndrome is a rare vascular compression syndrome in which the duodenum is compressed between the aorta and the overlying superior mesenteric artery. This condition is often chronic and secondary to cachexia. It can trigger further weight loss due to the subsequent proximal intestinal obstruction, causing a positive feedback loop. We report a case of acute presentation of superior mesenteric artery syndrome, complicated by gastric necrosis and treated surgically using the principles of a novel bariatric procedure.
PubMed: 38910630
DOI: 10.7759/cureus.60971 -
Gastroenterology Jun 2024Pancreatic ducts form an intricate network of tubules that secrete bicarbonate and drive acinar secretions into the duodenum. This network is formed by centroacinar...
BACKGROUND AND AIMS
Pancreatic ducts form an intricate network of tubules that secrete bicarbonate and drive acinar secretions into the duodenum. This network is formed by centroacinar cells, terminal, intercalated, intracalated ducts, and the main pancreatic duct. Ductal heterogeneity at the single-cell level has been poorly characterized; therefore, our understanding of the role of ductal cells in pancreas regeneration and exocrine pathogenesis has been hampered by the limited knowledge and unexplained diversity within the ductal network.
METHODS
We used scRNA-seq to comprehensively characterize mouse ductal heterogeneity at single-cell resolution of the entire ductal epithelium from centroacinar cells to the main duct. Moreover, we used organoid cultures, injury models and pancreatic tumor samples to interrogate the role of novel ductal populations in pancreas regeneration and exocrine pathogenesis.
RESULTS
We have identified the coexistence of 15 ductal populations within the healthy pancreas and characterized their organoid formation capacity and endocrine differentiation potential. Cluster isolation and subsequent culturing let us identify ductal cell populations with high organoid formation capacity and endocrine and exocrine differentiation potential in vitro, including Wnt-responsive-population, ciliated-population and FLRT3 cells. Moreover, we have characterized the location of these novel ductal populations in healthy pancreas, chronic pancreatitis, and tumor samples. The expression of WNT-responsive, IFN-responsive and EMT-population markers increases in chronic pancreatitis and tumor samples.
CONCLUSIONS
In light of our discovery of previously unidentified ductal populations, we unmask potential roles of specific ductal populations in pancreas regeneration and exocrine pathogenesis. Thus, novel lineage tracing models are needed to investigate ductal specific populations in vivo.
PubMed: 38908487
DOI: 10.1053/j.gastro.2024.06.008 -
European Radiology Jun 2024To assess 3-Tesla (3-T) ultra-small superparamagnetic iron oxide (USPIO)-enhanced MRI in detecting lymph node (LN) metastases for resectable adenocarcinomas of the...
OBJECTIVES
To assess 3-Tesla (3-T) ultra-small superparamagnetic iron oxide (USPIO)-enhanced MRI in detecting lymph node (LN) metastases for resectable adenocarcinomas of the pancreas, duodenum, or periampullary region in a node-to-node validation against histopathology.
METHODS
Twenty-seven consecutive patients with a resectable pancreatic, duodenal, or periampullary adenocarcinoma were enrolled in this prospective single expert centre study. Ferumoxtran-10-enhanced 3-T MRI was performed pre-surgery. LNs found on MRI were scored for suspicion of metastasis by two expert radiologists using a dedicated scoring system. Node-to-node matching from in vivo MRI to histopathology was performed using a post-operative ex vivo 7-T MRI of the resection specimen. Sensitivity and specificity were calculated using crosstabs.
RESULTS
Eighteen out of 27 patients (median age 65 years, 11 men) were included in the final analysis (pre-surgery withdrawal n = 4, not resected because of unexpected metastases peroperatively n = 2, and excluded because of inadequate contrast-agent uptake n = 3). On MRI 453 LNs with a median size of 4.0 mm were detected, of which 58 (13%) were classified as suspicious. At histopathology 385 LNs with a median size of 5.0 mm were found, of which 45 (12%) were metastatic. For 55 LNs node-to-node matching was possible. Analysis of these 55 matched LNs, resulted in a sensitivity and specificity of 83% (95% CI: 36-100%) and 92% (95% CI: 80-98%), respectively.
CONCLUSION
USPIO-enhanced MRI is a promising technique to preoperatively detect and localise LN metastases in patients with pancreatic, duodenal, or periampullary adenocarcinoma.
CLINICAL RELEVANCE STATEMENT
Detection of (distant) LN metastases with USPIO-enhanced MRI could be used to determine a personalised treatment strategy that could involve neoadjuvant or palliative chemotherapy, guided resection of distant LNs, or targeted radiotherapy.
REGISTRATION
The study was registered on clinicaltrials.gov NCT04311047. https://clinicaltrials.gov/ct2/show/NCT04311047?term=lymph+node&cond=Pancreatic+Cancer&cntry=NL&draw=2&rank=1 .
KEY POINTS
LN metastases of pancreatic, duodenal, or periampullary adenocarcinoma cannot be reliably detected with current imaging. This technique detected LN metastases with a sensitivity and specificity of 83% and 92%, respectively. MRI with ferumoxtran-10 is a promising technique to improve preoperative staging in these cancers.
PubMed: 38907886
DOI: 10.1007/s00330-024-10838-w -
Journal of Medical Case Reports Jun 2024Due to rarity of duodenal GISTs, clinicians have few information about its clinical features, diagnosis, management and prognosis. (Review)
Review
BACKGROUND
Due to rarity of duodenal GISTs, clinicians have few information about its clinical features, diagnosis, management and prognosis.
CASE REPORT
We report a case of promptly diagnosed duodenal GIST in a 61-year-old Egyptian man presented shocked with severe attack of hematemesis and melena. Upper gastroduodenal endoscopy was done and revealed a large ulcerating bleeding mass at first part of duodenum 4 hemo-clips were applied with good hemostasis. An exploratory laparotomy and distal gastrectomy, duodenectomy and gastrojejunostomy were performed. The morphology of the mass combined with immunohistochemistry was consistent with duodenal gastrointestinal stromal tumours (GISTs) of high risk type. The patient is on amatinib one tablet daily and he was well with no evidence of tumor recurrence.
CONCLUSION
despite being rare, emergency presentation with sudden severe, life-threatening hemorrhagic shock duodenal GISTs might be a cause of potentially lethal massive combined upper and lower gastrointestinal bleeding which is the key feature of this rare and challenging tumor.
Topics: Humans; Gastrointestinal Stromal Tumors; Male; Middle Aged; Gastrointestinal Hemorrhage; Duodenal Neoplasms; Shock, Hemorrhagic; Melena; Hematemesis; Gastrectomy
PubMed: 38907357
DOI: 10.1186/s13256-024-04597-x