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Journal of Medical Genetics Apr 2024Both hereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) are known to be caused by pathogenic variants, with overlapping symptoms for...
BACKGROUND
Both hereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) are known to be caused by pathogenic variants, with overlapping symptoms for both disorders in some patients. Additional connective tissue disorders have also been reported. Here, we describe carriers of variants followed in an HHT reference centre to further delineate the phenotype.
METHODS
Observational study based on data collected from the Clinical Investigation for the Rendu-Osler Cohort database.
RESULTS
Thirty-three participants from 15 families, out of 1114 patients with HHT, had an variant (3%).Regarding HHT, 26 out of 33 participants (88%) had a definite clinical diagnosis based on Curaçao criteria. Complication frequencies were as follows: epistaxis (n=27/33, 82%), cutaneous telangiectases (n=19/33, 58%), pulmonary arteriovenous malformations (n=17/32, 53%), hepatic arteriovenous malformations (AVMs) (n=7/18, 39%), digestive angiodysplasia (n=13/22, 59%). No cerebral AVMs were diagnosed.Regarding juvenile polyposis, 25 out of 31 participants (81%) met the criteria defined by Jass for juvenile polyposis syndrome. Seven patients (21%) had a prophylactic gastrectomy due to an extensive gastric polyposis incompatible with endoscopic follow-up, and four patients (13%) developed a digestive cancer.Regarding connective tissue disorders, 20 (61%) had at least one symptom, and 4 (15%) participants who underwent echocardiography had an aortic dilation.
CONCLUSION
We describe a large cohort of variant carriers in the context of HHT. Digestive complications are frequent, early and diffuse, justifying endoscopy every 2 years. The HHT phenotype, associating pulmonary and hepatic AVMs, warrants systematic screening. Connective tissue disorders broaden the phenotype associated with gene variants and justify systematic cardiac ultrasound and skeletal complications screening.
PubMed: 38575304
DOI: 10.1136/jmg-2023-109632 -
Polish Archives of Internal Medicine May 2024
Topics: Humans; Adenomatous Polyposis Coli; Proctocolectomy, Restorative; Colonic Pouches; Adenocarcinoma; Male; Female; Adult; Ileal Neoplasms
PubMed: 38573197
DOI: 10.20452/pamw.16722 -
GE Portuguese Journal of... Apr 2024The role of capsule endoscopy in the evaluation of the small bowel is well established, and current guidelines position it as a first-line test in a variety of clinical... (Review)
Review
BACKGROUND
The role of capsule endoscopy in the evaluation of the small bowel is well established, and current guidelines position it as a first-line test in a variety of clinical scenarios. The advent of double-headed capsules further enabled the endoscopic assessment of colonic mucosa and the opportunity for a one-step noninvasive examination of the entire bowel (pan-enteric capsule endoscopy [PCE]).
SUMMARY
We reviewed the technical procedure and preparation of patients for PCE, as well as its current clinical applications and future perspectives. In non-stricturing and non-penetrating Crohn's disease affecting the small bowel and colon, PCE monitors disease activity by assessing mucosal healing, a major treatment outcome, with a higher diagnostic yield than cross-sectional imaging or conventional colonoscopy. Also in ulcerative colitis, double-headed capsules have been used to monitor disease activity noninvasively. Currently, validated scoring systems have been specifically devised for these double-headed capsules and permit a standardized assessment of the inflammatory burden. In suspected mid-lower digestive bleeding, some exploratory studies have demonstrated the feasibility and high diagnostic yield of PCE, which may work as a filter indicating which patients may benefit of further invasive procedures, namely, for planned hemostatic procedures. The possibility of using PCE is also discussed in the context of polyposis syndromes with simultaneous involvement of the small intestine and colon.
KEY MESSAGES
PCE is a feasible, effective, and safe diagnostic procedure to evaluate the small bowel and colon. It has been increasingly explored in the setting of inflammatory bowel diseases and, more recently, in suspected mid-lower digestive bleeding. PCE is expected to reduce the demand for invasive procedures and expand the scope of noninvasive intestinal evaluation in the coming future.
PubMed: 38572440
DOI: 10.1159/000533960 -
Cancer Science Jun 2024ABCC3 (also known as MRP3) is an ATP binding cassette transporter for bile acids, whose expression is downregulated in colorectal cancer through the Wnt/β-catenin...
ABCC3 (also known as MRP3) is an ATP binding cassette transporter for bile acids, whose expression is downregulated in colorectal cancer through the Wnt/β-catenin signaling pathway. However, it remained unclear how downregulation of ABCC3 expression contributes to colorectal carcinogenesis. We explored the role of ABCC3 in the progression of colorectal cancer-in particular, focusing on the regulation of bile acid export. Gene expression analysis of colorectal adenoma isolated from familial adenomatous polyposis patients revealed that genes related to bile acid secretion including ABCC3 were downregulated as early as at the stage of adenoma formation. Knockdown or overexpression of ABCC3 increased or decreased intracellular concentration of deoxycholic acid, a secondary bile acid, respectively, in colorectal cancer cells. Forced expression of ABCC3 suppressed deoxycholic acid-induced activation of MAPK signaling. Finally, we found that nonsteroidal anti-inflammatory drugs increased ABCC3 expression in colorectal cancer cells, suggesting that ABCC3 could be one of the targets for therapeutic intervention of familial adenomatous polyposis. Our data thus suggest that downregulation of ABCC3 expression contributes to colorectal carcinogenesis through the regulation of intracellular accumulation of bile acids and activity of MAPK signaling.
Topics: Humans; Colorectal Neoplasms; Multidrug Resistance-Associated Proteins; Deoxycholic Acid; Down-Regulation; MAP Kinase Signaling System; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Adenomatous Polyposis Coli
PubMed: 38566304
DOI: 10.1111/cas.16132 -
JCO Precision Oncology Mar 2024Patients with germline pathogenic variants (PVs) in develop tens (attenuated familial adenomatous polyposis [AFAP]) to innumerable (classic FAP) adenomatous polyps in...
PURPOSE
Patients with germline pathogenic variants (PVs) in develop tens (attenuated familial adenomatous polyposis [AFAP]) to innumerable (classic FAP) adenomatous polyps in their colon and are at significantly increased lifetime risk of colorectal cancer. Up to 10% of FAP and up to 50% of patients with AFAP who have undergone DNA-only multigene panel testing (MGPT) do not have an identified PV in . We seek to demonstrate how the addition of RNA sequencing run concurrently with DNA can improve detection of germline PVs in individuals with a clinical presentation of AFAP/FAP.
METHODS
We performed a retrospective query of individuals tested with paired DNA-RNA MGPT from 2021 to 2022 at a single laboratory and included those with a novel PV located in intronic regions infrequently covered by MGPT, a personal history of polyposis, and family medical history provided. All clinical data were deidentified in this institutional review board-exempt study.
RESULTS
Three novel variants were identified in six families and were shown to cause aberrant splicing because of the creation of a deep intronic cryptic splice site that leads to an RNA transcript subject nonsense-mediated decay. Several carriers had previously undergone DNA-only genetic testing and had received a negative result.
CONCLUSION
Here, we describe how paired DNA-RNA MGPT can be used to solve missing heritability in FAP families, which can have important implications in family planning and treatment decisions for patients and their families.
Topics: Humans; Retrospective Studies; Adenomatous Polyposis Coli; Genetic Testing; Colorectal Neoplasms; DNA
PubMed: 38564685
DOI: 10.1200/PO.23.00404 -
Journal of Asthma and Allergy 2024Severe eosinophilic asthma (SEA) patients often present overlapping inflammatory features rendering them eligible for multiple biologic therapies; switching biologic...
PURPOSE
Severe eosinophilic asthma (SEA) patients often present overlapping inflammatory features rendering them eligible for multiple biologic therapies; switching biologic treatment is a strategy adopted to optimize asthma control when patients show partial or no response to previous biologics.
PATIENTS AND METHODS
ANANKE is a retrospective, multicenter Italian study (NCT04272463). Here, we outline the characteristics and long-term clinical outcomes in naïve-to-biologics and biologics-experienced patients treated with benralizumab for up to 96 weeks. Bio-experienced patients were split into omalizumab and mepolizumab subsets according to the type of biologic previously used.
RESULTS
A total of 124 (76.5%) naïve and 38 (23.5%) bio-experienced patients were evaluated at index date; 13 patients (34.2%) switched from mepolizumab, 21 patients (55.3%) switched from omalizumab, and four patients (10.5%) received both biologics. The mepolizumab subset was characterized by the longest SEA duration (median of 4.6 years), the highest prevalence of chronic rhinosinusitis with nasal polyposis (CRSwNP) (76.5%), and the greatest oral corticosteroid (OCS) daily dosage (median of 25 mg prednisone equivalent). The omalizumab group showed the highest severe annual exacerbation rate (AER) (1.70). At 96 weeks, treatment with benralizumab reduced any and severe AER by more than 87% and 94%, respectively, across all groups. Lung function was overall preserved, with major improvements observed in the mepolizumab group, which also revealed a 100% drop of the median OCS dose. Asthma Control Test (ACT) score improved in the naïve group while its increment was more variable in bio-experienced patients; among these, a marked difference was noticed between omalizumab and mepolizumab subsets (median ACT score of 23.5 and 18, respectively).
CONCLUSION
Benralizumab promotes durable and profound clinical benefits in naïve and bio-experienced groups, indicating that a nearly complete depletion of eosinophils is highly beneficial in the control of SEA, independently of previous biologic use.
PubMed: 38562251
DOI: 10.2147/JAA.S438981 -
Frontiers in Cell and Developmental... 2024chaffeensis: TRP120 is a multifunctional effector that acts as a ligand mimic to activate evolutionary conserved eukaryotic signaling pathways Notch, Wnt, Hedgehog and...
chaffeensis: TRP120 is a multifunctional effector that acts as a ligand mimic to activate evolutionary conserved eukaryotic signaling pathways Notch, Wnt, Hedgehog and Hippo. In addition, TRP120 is also a HECT E3 ubiquitin ligase known to ubiquitinate several host cell regulatory proteins (FBW7, PCGF5 and ENO-1) for degradation. We previously determined that TRP120 ubiquitinates the Notch negative regulator, FBW7, to maintain Notch signaling and promote infection. In this study, we investigated a potential mechanism used by to maintain Hippo and Wnt signaling by ubiquitinating the tumor suppressor, adenomatous polyposis coli (APC), a negative regulator of Wnt and Hippo signaling. We determined that APC was rapidly degraded during infection despite increased APC transcription. Moreover, RNAi knockdown of significantly increased infection and coincided with increased active Yap and β-catenin in the nucleus. We observed strong nuclear colocalization between TRP120 and APC in infected THP-1 cells and after ectopic expression of TRP120 in HeLa cells. Additionally, TRP120 interacted with both APC full length and truncated isoforms via co-immunoprecipitation. Further, TRP120 ubiquitination of APC was demonstrated and confirmed by ectopic expression of a TRP120 HECT Ub ligase catalytic site mutant. This study identifies APC as a TRP120 HECT E3 Ub ligase substrate and demonstrates that TRP120 ligase activity promotes ehrlichial infection by degrading tumor suppressor APC to positively regulate Hippo and Wnt signaling.
PubMed: 38562145
DOI: 10.3389/fcell.2024.1327418 -
Scientific Reports Mar 2024Chronic rhinosinusitis (CRS) can be traditionally classified as CRSwNP [with nasal polyps (NPs)] and CRSsNP (without NPs) based on the clinical phenotypes but recently...
The cyclooxygenase-2 upregulation mediates production of PGE2 autacoid to positively regulate interleukin-6 secretion in chronic rhinosinusitis with nasal polyps and polyp-derived fibroblasts.
Chronic rhinosinusitis (CRS) can be traditionally classified as CRSwNP [with nasal polyps (NPs)] and CRSsNP (without NPs) based on the clinical phenotypes but recently suggested to be classified by the endotypes. We have identified overexpression of the cyclooxygenase-2 (COX-2) gene in NP tissues of Taiwanese CRSwNP patients. Therefore, in this study, we sought to investigate its protein expression/location/distribution in NP specimens and explore its roles in nasal polyposis. The COX-2 protein and mRNA expression was found higher in NPs than that in the control and CRSsNP patients' nasal tissues, mainly located at the epithelium and subepithelial stroma. Consistently, the CRS-related peptidoglycan (PGN) and bradykinin provoked COX-2 mRNA and protein upregulation in the human NP-derived fibroblasts and caused PGE, thromboxane A (TXA), and interleukin (IL-6) secretion in culture medium. Further analysis revealed that the PI3K/Akt activation and COX-2 induction were necessarily required for PGN-induced IL-6 production/secretion and the induced PGE, but not TXA, was speculated to affect IL-6 protein trafficking and production. Finally, the IL-6 increase observed in vitro could also be detected in NP tissues. Collectively, we demonstrated here that COX-2 protein and IL-6 are overexpressed in human NP tissues. In response to PGN challenge, the PI3K/Akt activation and COX-2-mediated PGE autacoid correlates with extracellular IL-6 protein trafficking/production in NP-derived fibroblasts, which can additionally contribute to the production of Th17-related cytokines such as IL-17 and TNF-α. This study also suggests COX-2 as a special biomarker for CRSwNP endotyping and may highlight the importance of COX-2 inhibitors in treating CRSwNP.
Topics: Humans; Chronic Disease; Cyclooxygenase 2; Dinoprostone; Fibroblasts; Interleukin-6; Nasal Polyps; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rhinitis; Rhinosinusitis; RNA, Messenger; Up-Regulation
PubMed: 38555391
DOI: 10.1038/s41598-024-58143-2 -
Human Genome Variation Mar 2024A young patient diagnosed with advanced colon cancer and liver metastasis was found to have familial adenomatous polyposis (FAP) through comprehensive genomic analysis....
A young patient diagnosed with advanced colon cancer and liver metastasis was found to have familial adenomatous polyposis (FAP) through comprehensive genomic analysis. Whole-genome array comparative genomic hybridization (aCGH) revealed germline deletions at chromosome 5q22.1-22.2 encompassing the entire APC gene. The patient and her son exhibited mild intellectual disability without developmental delay. This case highlights the need for further exploration of the characteristics associated with whole APC deletions. aCGH is a valuable tool for studying FAP and provides a detailed analysis of large deletions.
PubMed: 38548799
DOI: 10.1038/s41439-024-00270-3 -
Molecular Cancer Research : MCR Jun 2024The pathogenesis of duodenal tumors in the inherited tumor syndromes familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) is poorly understood. This...
UNLABELLED
The pathogenesis of duodenal tumors in the inherited tumor syndromes familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) is poorly understood. This study aimed to identify genes that are significantly mutated in these tumors and to explore the effects of these mutations. Whole exome and whole transcriptome sequencing identified recurrent somatic coding variants of phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) in 19/70 (27%) FAP and MAP duodenal adenomas, and further confirmed the established driver roles for APC and KRAS. PIGA catalyzes the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Flow cytometry of PIGA-mutant adenoma-derived and CRISPR-edited duodenal organoids confirmed loss of GPI anchors in duodenal epithelial cells and transcriptional profiling of duodenal adenomas revealed transcriptional signatures associated with loss of PIGA.
IMPLICATIONS
PIGA somatic mutation in duodenal tumors from patients with FAP and MAP and loss of membrane GPI-anchors may present new opportunities for understanding and intervention in duodenal tumorigenesis.
Topics: Humans; Glycosylphosphatidylinositols; Duodenal Neoplasms; Mutation; Adenomatous Polyposis Coli; Membrane Proteins; Carcinogenesis; Male; Female
PubMed: 38546397
DOI: 10.1158/1541-7786.MCR-23-0810