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Gastrointestinal Endoscopy May 2024Juvenile Polyposis Syndrome (JPS) is a rare hereditary autosomal dominant cancer-predisposition syndrome caused by germline pathogenic variants (PV) located in SMAD4 or...
BACKGROUND AND AIMS
Juvenile Polyposis Syndrome (JPS) is a rare hereditary autosomal dominant cancer-predisposition syndrome caused by germline pathogenic variants (PV) located in SMAD4 or BMPR1A genes. Precise clinical and endoscopic presentation as the evolution of gastric lesions remain ill-known.
METHODS
Clinical, endoscopic, genetic, pathological data from patients with SMAD4 or BMPR1A PVs included between 2007 and 2020 in the French network on rare digestive polyposis (RENAPOL) database were prospectively collected to address uncertainties regarding gastric involvement.
RESULTS
Thirty-six patients were included: 25 (69.5%) had SMAD4 PVs, 11 had BMPR1A PVs. For SMAD4 PV carriers, median age at inclusion was 43.0 years [range 10-78]. At baseline esophagogastroduodenoscopy (EGD), 22/25 (88%) exhibited at least one gastric juvenile polyp, 5/25 (20%) had macroscopic signs of inflammatory gastritis. Early gastric disease was mostly located under the cardia, then progressed to gastric antrum and body. During a mean follow-up period of 55.0 months, 12/25 had gastric disease progression (i.e. new juvenile polyps (91.6%), diffuse gastric involvement (41.6%), inflammatory flat progression (25%)). Among 62 biopsies, low-grade dysplasia was observed in 5 (7.5%) samples from 2 patients. Nine carriers (36%) underwent gastrectomy (mean age of 47.2 years) due to diffuse gastric involvement or worsening clinical symptoms. Gastric adenocarcinoma (T1) was found in one gastrectomy specimen. Among the 11 patients with BMPR1A PVs, 2 had gastric hamartomatomas at baseline EGD, none with dysplasia or symptoms.
CONCLUSION
Gastric involvement in JPS appears to be progressive during life, initiating in the cardia area, and mostly concerns SMAD4 PV carriers.
PubMed: 38777277
DOI: 10.1016/j.gie.2024.05.015 -
Molecular Plant Pathology May 2024The movement of potyviruses, the largest genus of single-stranded, positive-sense RNA viruses responsible for serious diseases in crops, is very complex. As potyviruses...
The movement of potyviruses, the largest genus of single-stranded, positive-sense RNA viruses responsible for serious diseases in crops, is very complex. As potyviruses developed strategies to hijack the host secretory pathway and plasmodesmata (PD) for their transport, the goal of this study was to identify membrane and/or PD-proteins that interact with the 6K2 protein, a potyviral protein involved in replication and cell-to-cell movement of turnip mosaic virus (TuMV). Using split-ubiquitin membrane yeast two-hybrid assays, we screened an Arabidopsis cDNA library for interactors of 6K2. We isolated AtHVA22a (Hordeum vulgare abscisic acid responsive gene 22), which belongs to a multigenic family of transmembrane proteins, homologous to Receptor expression-enhancing protein (Reep)/Deleted in polyposis (DP1)/Yop1 family proteins in animal and yeast. HVA22/DP1/Yop1 family genes are widely distributed in eukaryotes, but the role of HVA22 proteins in plants is still not well known, although proteomics analysis of PD fractions purified from Arabidopsis suspension cells showed that AtHVA22a is highly enriched in a PD proteome. We confirmed the interaction between 6K2 and AtHVA22a in yeast, as well as in planta by using bimolecular fluorescence complementation and showed that 6K2/AtHVA22a interaction occurs at the level of the viral replication compartment during TuMV infection. Finally, we showed that the propagation of TuMV is increased when AtHVA22a is overexpressed in planta but slowed down upon mutagenesis of AtHVA22a by CRISPR-Cas9. Altogether, our results indicate that AtHVA22a plays an agonistic effect on TuMV propagation and that the C-terminal tail of the protein is important in this process.
Topics: Potyvirus; Arabidopsis; Arabidopsis Proteins; Plant Diseases; Viral Proteins; Virus Replication; Nicotiana
PubMed: 38767756
DOI: 10.1111/mpp.13466 -
World Journal of Clinical Cases May 2024Cronkhite-Canada syndrome (CCS) is a rare disease of unknown etiology. The optimal treatment for CCS remains unknown. Treatment with corticosteroids is considered the...
BACKGROUND
Cronkhite-Canada syndrome (CCS) is a rare disease of unknown etiology. The optimal treatment for CCS remains unknown. Treatment with corticosteroids is considered the mainstay treatment because of its high efficacy, but the therapeutic strategy for steroid-resistant CCS is not yet established.
CASE SUMMARY
This is the case of an 81-year-old woman who was diagnosed with CCS. Given her severe diarrhea, nausea, vomiting, and hypoproteinemia, hormone therapy (40 mg/d) was administered, and the symptoms improved within 1 wk. After 3 mo, the patient had no obvious symptoms. The polyps were significantly reduced on review gastroscopy and colonoscopy, thus hormone reduction gradually began. The hormone level was maintained at 10 mg/d after 6 mo. Despite the age of the patient and the side effects of hormones, the patient had no obvious discomfort. However, hormone drugs were discontinued, and mesalazine was administered orally at 3 g/d. The patient's symptoms continued to improve after a follow-up of 5 years.
CONCLUSION
Corticosteroids and mesalazine are potential treatment options for CCS.
PubMed: 38765740
DOI: 10.12998/wjcc.v12.i14.2431 -
Neoplasia (New York, N.Y.) Jul 2024Colorectal cancer (CRC) stands as a prevalent malignancy globally. A pivotal event in CRC pathogenesis involves the loss-of-function mutation in the APC gene, leading to...
Colorectal cancer (CRC) stands as a prevalent malignancy globally. A pivotal event in CRC pathogenesis involves the loss-of-function mutation in the APC gene, leading to the formation of benign polyps. Despite the well-established role of APC, the contribution of CUL4B to CRC initiation in the pre-tumorous stage remains poorly understood. In this investigation, we generated a murine model by crossing Apc mice with Cul4b mice to achieve specific deletion of Cul4b in the gut epithelium against an Apc background. By employing histological methods, RNA-sequencing (RNA-seq), and flow cytometry, we assessed alterations and characterized the immune microenvironment. Our results unveiled that CUL4B deficiency in gut epithelium expedited Apc adenoma formation. Notably, CUL4B in adenomas restrained the accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). In vivo inhibition of MDSCs significantly delayed the growth of CUL4B deleted Apc adenomas. Furthermore, the addition of MDSCs to in vitro cultured Apc; Cul4b adenoma organoids mitigated their alterations. Mechanistically, CUL4B directly interacted with the promoter of Csf3, the gene encoding granulocyte-colony stimulating factor (G-CSF) by coordinating with PRC2. Inhibiting CUL4B epigenetically activated the expression of G-CSF, promoting the recruitment of MDSCs. These findings offer novel insights into the tumor suppressor-like roles of CUL4B in regulating Apc adenomas, suggesting a potential therapeutic strategy for CRC initiation and progression in the context of activated Wnt signaling.
Topics: Animals; Cullin Proteins; Mice; Myeloid-Derived Suppressor Cells; Adenoma; Disease Models, Animal; Adenomatous Polyposis Coli Protein; Humans; Tumor Microenvironment; Colorectal Neoplasms; Gene Deletion; Intestinal Mucosa
PubMed: 38761506
DOI: 10.1016/j.neo.2024.101005 -
JPGN Reports May 2024Mucosal prolapse syndrome (MPS) is a rare group of benign conditions characterized by a set of unifying histologic findings thought to be the result of repeated mucosal...
Mucosal prolapse syndrome (MPS) is a rare group of benign conditions characterized by a set of unifying histologic findings thought to be the result of repeated mucosal shearing and submucosal vascular congestion caused by straining. This set of conditions is often misdiagnosed as other polyposis syndromes, inflammatory bowel disease, or malignancy due to its clinical presentation, appearance, and rarity. We report a case of a 15-year-old male who presented with painless rectal bleeding. He was found to have four rectal polyps thought to be due to Peutz-Jeghers syndrome. A repeat colonoscopy with biopsies a year later revealed a diagnosis of MPS. Our case highlights the morphologic similarity between hamartomatous polyp and mucosal prolapse histology. Since MPS is a rare diagnosis even among the adult population, it has not been well described in pediatrics. This syndrome should be on the differential diagnosis for pediatric rectal polyps to prevent unnecessary invasive testing and a delay in treatment.
PubMed: 38756112
DOI: 10.1002/jpr3.12022 -
BMC Gastroenterology May 2024Serrated polyposis syndrome is the most common polyposis syndrome that has neoplastic potential. However, the natural history, genetic basis, and risk of dysplasia and...
BACKGROUND
Serrated polyposis syndrome is the most common polyposis syndrome that has neoplastic potential. However, the natural history, genetic basis, and risk of dysplasia and neoplasia of serrated polyposis syndrome are incompletely understood. The objective of this study is to define the epidemiology of serrated polyposis syndrome. Using this data, we aim to evaluate candidate variables for predicting the risk of dysplasia and neoplasia in sessile serrated lesions found in serrated polyposis syndrome patients. Finally, we aim to use this data to create and evaluate clinical prediction models for accuracy in predicting dysplastic sessile serrated lesions in serrated polyposis syndrome patients.
METHODS
This was a regional Australian single-centre retrospective cohort study. Data was prospectively collected data from the clinical record database of a regional Australian gastroenterology practice. All patients undergoing colonoscopy at Port Macquarie Gastroenterology between January 2015 and September 2021 were screened for this study. Collected data included patient demographic, endoscopic, and histopathological findings. Clinical and endoscopic multivariate logistic regression models were created to predict dysplastic sessile serrated lesions. Model performance was examined using the area under the receiver operating curve.
RESULTS
In total 8401 patients underwent a colonoscopy procedure during the study period. Serrated polyposis syndrome was diagnosed in 247, representing a prevalence of 2.94% (mean age 67.15 years, 62.75% female). Logistic regression identified; older age at serrated polyposis syndrome diagnosis, a personal history of colorectal cancer, size of the largest sessile serrated lesions removed, and total sessile serrated lesions count as predictors of dysplastic sessile serrated lesions. The clinical and endoscopic model had an area under the receiver operating curve of 0.75.
CONCLUSION
Serrated polyposis syndrome is more common than previously described. The clinical and endoscopic variables identified in logistic regression have acceptable accuracy in predicting the risk of dysplasia, however other populations need to be studied to achieve generalisability and improve model performance.
Topics: Humans; Female; Male; Colonoscopy; Retrospective Studies; Aged; Middle Aged; Australia; Risk Factors; Colonic Polyps; Colorectal Neoplasms; Logistic Models; Prevalence; Syndrome
PubMed: 38755550
DOI: 10.1186/s12876-024-03247-2 -
Asian Journal of Neurosurgery Mar 2024Desmoid tumors are locally aggressive, benign neoplasms originating in connective tissues. Although the exact pathophysiology remains unknown, antecedent trauma or...
Desmoid tumors are locally aggressive, benign neoplasms originating in connective tissues. Although the exact pathophysiology remains unknown, antecedent trauma or surgery are believed to be important contributing factors. The occurrence of paraspinal desmoid tumor in pediatric patients is extremely uncommon. Here, we present an exceedingly rare case of a pediatric patient with no surgical or family history who developed a paraspinal desmoid tumor. A 9-year-old female patient presented with 4 months of progressive back pain, right lower extremity weakness, and numbness. Spinal imaging revealed a left epidural paraspinal mass compressing her thoracic spinal cord and extending into the left thoracic cavity. A multidisciplinary approach with neurosurgery and thoracic surgery enabled gross total resection of the lesion. The patient had complete resolution of her symptoms with no signs of residual tumor on postoperative imaging. Pathology revealed a desmoid tumor that avidly stained for beta-catenin. On her last follow-up, she developed a recurrence, to which she was started on sorafenib therapy. Desmoid tumors are rare connective tissue neoplasms that often occur after local tissue trauma, such as that caused by surgery. This report presents a rare case of a pediatric paraspinal desmoid tumor that occurred in a patient with no surgical or family history. Such tumors should undergo surgical resection for symptomatic relief and tissue diagnosis. Close clinical and radiographic surveillance are essential in these patients due to the high recurrence rates of desmoid tumor.
PubMed: 38751393
DOI: 10.1055/s-0043-1771366 -
BMJ Open May 2024Chronic rhinosinusitis with nasal polyps (CRSwNP) is a frequent condition affecting approximately 2% of the population. Medical treatment consists long-term use of...
INTRODUCTION
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a frequent condition affecting approximately 2% of the population. Medical treatment consists long-term use of intranasal corticosteroids and short-term use of oral corticosteroids, in adjunct with saline solution rinses. Surgical management is proposed in patients who failed after medical treatment. In France, two biologics are reimbursed in case of severe uncontrolled CRSwNP despite medical treatment and endoscopic sinus surgery. Waiting for head-to-head biologics comparison, studies should report the efficacy and safety of biologics in large real-life cohorts. This study protocol describes the aims and methods of a prospective, observational, national, multicentric cohort of patients with CRSwNP treated with biologics.
METHODS AND ANALYSIS
The BIOlogics in severe nasal POlyposis SurvEy is a French multicentre prospective observational cohort study. The main aim is to assess the efficacy and tolerance of biologics in patients with CRSwNP, with or without association with other type 2 diseases, and to determine the strategies in case of uncontrolled disease under biologics. Patients over 18 years old requiring biologics for CRSwNP in accordance with its marketing approval in France (ie, severe nasal polyposis, with lack of control under nasal corticosteroid, systemic corticosteroids and surgery) are invited to participate. Collected data include topical history of surgical procedures and biologics, medication and use of systemic corticosteroids, visual analogical scales for specific symptoms, Sino-Nasal Outcome Test-22 questionnaire, nasal polyp score, asthma control test, Lund-Mackay score on CT scan and IgE concentration and eosinophilic count on blood sample.
TRIAL REGISTRATION
NCT05228041/DRI_2021/0030.
Topics: Humans; Nasal Polyps; Sinusitis; Chronic Disease; Rhinitis; Prospective Studies; Biological Products; France; Observational Studies as Topic; Omalizumab; Multicenter Studies as Topic; Rhinosinusitis
PubMed: 38749694
DOI: 10.1136/bmjopen-2023-083112 -
Frontiers in Oncology 2024Colorectal cancer is the second leading cause of cancer-related deaths. In 2018, there were an estimated 1.8 million cases, and this number is expected to increase to...
evaluation of anti-colorectal cancer inhibitors by Resveratrol derivatives targeting Armadillo repeats domain of APC: molecular docking and molecular dynamics simulation.
Colorectal cancer is the second leading cause of cancer-related deaths. In 2018, there were an estimated 1.8 million cases, and this number is expected to increase to 2.2 million by 2030. Despite its prevalence, the current therapeutic option has a lot of side effects and limitations. Therefore, this study was designed to employ a computational approach for the identification of anti-cancer inhibitors against colorectal cancer using Resveratrol derivatives. Initially, the pass prediction spectrum of 50 derivatives was conducted and selected top seven compounds based on the maximum pass prediction score. After that, a comprehensive analysis, including Lipinski Rule, pharmacokinetics, ADMET profile study, molecular orbitals analysis, molecular docking, molecular dynamic simulations, and MM-PBSA binding free energy calculations. The reported binding affinity ranges of Resveratrol derivatives from molecular docking were -6.1 kcal/mol to -7.9 kcal/mol against the targeted receptor of human armadillo repeats domain of adenomatous polyposis coli (APC) (PDB ID: 3NMW). Specifically, our findings reported that two compounds [(03) Resveratrol 3-beta-mono-D-glucoside, and (29) Resveratrol 3-Glucoside] displayed the highest level of effectiveness compared to all other derivatives (-7.7 kcal/mol and -7.9 kcal/mol), and favorable drug-likeness, and exceptional safety profiles. Importantly, almost all the molecules were reported as free from toxic effects. Subsequently, molecular dynamic simulations conducted over 100ns confirmed the stability of the top two ligand-protein complexes. These findings suggest that Resveratrol derivatives may be effective drug candidate to manage the colorectal cancer. However, further experimental research, such as / studies, is essential to validate these computational findings and confirm their practical value.
PubMed: 38746675
DOI: 10.3389/fonc.2024.1360745 -
MedRxiv : the Preprint Server For... May 2024Pathogenic constitutional variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant...
Systematic large-scale application of ClinGen InSiGHT -specific ACMG/AMP variant classification criteria substantially alleviates the burden of variants of uncertain significance in ClinVar and LOVD databases.
BACKGROUND
Pathogenic constitutional variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant classification and resolve the interpretative challenges of variants of uncertain significance (VUS), APC-specific ACMG/AMP variant classification criteria were developed by the ClinGen-InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP).
METHODS
A streamlined algorithm using the -specific criteria was developed and applied to assess all variants in ClinVar and the InSiGHT international reference LOVD variant database.
RESULTS
A total of 10,228 unique variants were analysed. Among the ClinVar and LOVD variants with an initial classification of (Likely) Benign or (Likely) Pathogenic, 94% and 96% remained in their original categories, respectively. In contrast, 41% ClinVar and 61% LOVD VUS were reclassified into clinically actionable classes, the vast majority as (Likely) Benign. The total number of VUS was reduced by 37%. In 21 out of 36 (58%) promising variants that remained VUS despite evidence for pathogenicity, a data mining-driven work-up allowed their reclassification as (Likely) Pathogenic.
CONCLUSIONS
The application of -specific criteria substantially reduced the number of VUS in ClinVar and LOVD. The study also demonstrated the feasibility of a systematic approach to variant classification in large datasets, which might serve as a generalisable model for other gene-/disease-specific variant interpretation initiatives. It also allowed for the prioritization of VUS that will benefit from in-depth evidence collection. This subset of variants was approved by the VCEP and made publicly available through ClinVar and LOVD for widespread clinical use.
PubMed: 38746299
DOI: 10.1101/2024.05.03.24306761