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World Journal of Gastroenterology Feb 2024Cronkhite-Canada syndrome (CCS) is a rare, noninherited disease characterized by gastrointestinal polyposis with diarrhea and ectodermal abnormalities. CCS polyps are...
BACKGROUND
Cronkhite-Canada syndrome (CCS) is a rare, noninherited disease characterized by gastrointestinal polyposis with diarrhea and ectodermal abnormalities. CCS polyps are distributed through the whole digestive tract, and they are common in the stomach and colon but very uncommon in the esophagus.
CASE SUMMARY
Here, we present a case of a 63-year-old man with skin hyperpigmentation accompanied by diarrhea, alopecia, and loss of his fingernails. Laboratory data indicated anemia, hypoalbuminemia, hypocalcemia, hypokalemia, and positive fecal occult blood. Endoscopy showed numerous polyps scattered throughout the digestive tract, including the esophagus. He was treated with nutritional support and glucocorticoids with remission of his symptoms.
CONCLUSION
Comprehensive treatment led by hormonal therapy can result in partial or full remission of clinical symptoms. Treatment should be individualized for each patient according to their therapy response. Surveillance endoscopy is necessary for assessing mucosal disease activity and detecting malignant transformation.
Topics: Male; Humans; Middle Aged; Endoscopy, Gastrointestinal; Glucocorticoids; Esophagus; Intestinal Polyposis; Diarrhea
PubMed: 38516236
DOI: 10.3748/wjg.v30.i8.984 -
Clinical Endoscopy Mar 2024Helicobacter pylori infection-negative gastric cancer (HPNGC) has not been systematically investigated in consecutive patients. Hence, this study aimed to investigate...
BACKGROUND/AIMS
Helicobacter pylori infection-negative gastric cancer (HPNGC) has not been systematically investigated in consecutive patients. Hence, this study aimed to investigate the clinicopathological and endoscopic features of HPNGC.
METHODS
This single-center retrospective study selected participants from patients with gastric cancer who were treated at the Fukuoka University Chikushi Hospital between January 2013 and December 2021. Only patients diagnosed with HPNGC were enrolled, and their clinicopathological and endoscopic features were analyzed in detail.
RESULTS
The prevalence of HPNGC in the present study was 2.6% (54/2112). The types of HPNGC observed in each gastric region were as follows: advanced gastric cancer was observed in the cardia; gastric adenocarcinoma of fundic-gland differentiation, gastric adenocarcinoma of foveolar-type presenting with whitish elevation and raspberry-like foveolar-type gastric adenocarcinoma, gastric adenocarcinoma arising in polyposis, and gastric adenocarcinoma with autoimmune gastritis were observed in the fundic gland region ranging from the gastric fornix to the gastric body; signet-ring cell carcinoma was observed in the gastric-pyloric transition region ranging from the lower gastric body to the gastric angle; and well-differentiated tubular adenocarcinoma with low-grade atypia was observed in the antrum.
CONCLUSIONS
This study revealed that tumors from each gastric region exhibited distinct macroscopic and histological types in HPNGC.
PubMed: 38514987
DOI: 10.5946/ce.2023.258 -
European Journal of Cell Biology Jun 2024Cell shape and motility are determined by the cytoskeleton, an interpenetrating network of actin filaments, microtubules, and intermediate filaments. The biophysical...
Cell shape and motility are determined by the cytoskeleton, an interpenetrating network of actin filaments, microtubules, and intermediate filaments. The biophysical properties of each filament type individually have been studied extensively by cell-free reconstitution. By contrast, the interactions between the three cytoskeletal networks are relatively unexplored. They are coupled via crosslinkers of the plakin family such as plectin. These are challenging proteins for reconstitution because of their giant size and multidomain structure. Here we engineer a recombinant actin-vimentin crosslinker protein called 'ACTIF' that provides a minimal model system for plectin, recapitulating its modular design with actin-binding and intermediate filament-binding domains separated by a coiled-coil linker for dimerisation. We show by fluorescence and electron microscopy that ACTIF has a high binding affinity for vimentin and actin and creates mixed actin-vimentin bundles. Rheology measurements show that ACTIF-mediated crosslinking strongly stiffens actin-vimentin composites. Finally, we demonstrate the modularity of this approach by creating an ACTIF variant with the intermediate filament binding domain of Adenomatous Polyposis Coli. Our protein engineering approach provides a new cell-free system for the biophysical characterization of intermediate filament-binding crosslinkers and for understanding the mechanical synergy between actin and vimentin in mesenchymal cells.
Topics: Vimentin; Actins; Humans; Intermediate Filaments; Actin Cytoskeleton; Animals; Protein Binding
PubMed: 38503131
DOI: 10.1016/j.ejcb.2024.151403 -
Cureus Feb 2024The presence of double mesiodens or mesiodentes, i.e., two supernumerary teeth in the maxillary midline, presents unique challenges in mixed dentition. Common clinical...
The presence of double mesiodens or mesiodentes, i.e., two supernumerary teeth in the maxillary midline, presents unique challenges in mixed dentition. Common clinical manifestations include delayed eruption, midline diastema, and occlusal disturbances, leading to complications such as root resorption, pathological migration of tooth, crowding, cyst formation, and malocclusion. Mesiodens can be associated with several syndromes, like cleidocranial dysplasia, familial adenomatous polyposis, trichorhinophalangeal syndrome, type I, Rubinstein-Taybi syndrome, and Nance-Horan syndrome, among others. It can also be secondary to trauma, hyperactivity of the dental lamina, and a combination of genetic and environmental factors, but its etiology continues to be idiopathic. Double mesiodens are relatively rare, so this clinical observation aimed to highlight five such cases of double mesiodens in mixed dentition in non-syndromic children and adolescents. Additionally, a literature search reporting cases of double mesiodens in the mixed dentition was done, and the results were tabulated. Clinicians should be able to identify indications of supernumerary teeth, specifically deviations in the eruption pattern. Appropriate investigations and timely intervention are essential to reducing complications that may arise in the developing dentition.
PubMed: 38500940
DOI: 10.7759/cureus.54161 -
Current Research in Toxicology 2024Colorectal cancer (CRC) is the third leading cause of cancer-related mortalities in the USA and around 52,550 people were expected to die from this disease by December...
Colorectal cancer (CRC) is the third leading cause of cancer-related mortalities in the USA and around 52,550 people were expected to die from this disease by December 2023. The objective of this study was to investigate the effect of diet type on benzo(a)pyrene [B(a)P]-induced colon cancer in an adult male rat model, the Polyposis In the Rat Colon (PIRC) kindred type. Groups of PIRC rats (n = 10) were fed with AIN-76A regular diet (RD) or Western diet (WD) and received 25, 50 and 100 µg B(a)P/kg body wt. via oral gavage for 60 days. Rats fed diets alone, but no B(a)P, served as controls. After exposure, rats were euthanized; colon and liver samples were analyzed for activation of drug metabolizing enzymes (DMEs) CYP1A1, CYP1B1, SULT and GST. Plasma and tissue samples were analyzed by reverse phase-HPLC for B(a)P metabolites. In addition to these studies, DNA isolated from colon and liver tissues was analyzed for B(a)P-induced DNA adducts by the P-postlabeling method using a thin-layer chromatography system. Western diet consumption resulted in a marked increase in DME expression and B(a)P metabolite concentrations in rats that were administered 100 µg/kg B(a)P + WD (p < 0.05) compared to other treatment groups. Our findings demonstrate that WD accelerates the development of colon tumors induced by B(a)P through enhanced biotransformation, and the products of this process (metabolites) were found to bind with DNA and form B(a)P-DNA adducts, which may have given rise to colon polyps characterized by gain in tumor number, sizes, and dysplasia.
PubMed: 38496007
DOI: 10.1016/j.crtox.2024.100162 -
Acta Pharmaceutica Sinica. B Mar 2024Sulfation is a crucial and prevalent conjugation reaction involved in cellular processes and mammalian physiology. 3'-Phosphoadenosine 5'-phosphosulfate (PAPS) synthase...
Sulfation is a crucial and prevalent conjugation reaction involved in cellular processes and mammalian physiology. 3'-Phosphoadenosine 5'-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the primary enzyme to generate the universal sulfonate donor PAPS. The involvement of PAPSS2-mediated sulfation in adenomatous polyposis coli (APC) mutation-promoted colonic carcinogenesis has not been reported. Here, we showed that the expression of PAPSS2 was decreased in human colon tumors along with cancer stages, and the lower expression of PAPSS2 was correlated with poor prognosis in advanced colon cancer. Gut epithelial-specific heterozygous deficient and -knockout () mice were created, and the phenotypes were compared to the spontaneous intestinal tumorigenesis of mice. mice were more sensitive to gut tumorigenesis, which was mechanistically accounted for by the activation of Wnt/-catenin signaling pathway due to the suppression of chondroitin sulfation and inhibition of the farnesoid X receptor (FXR)-transducin-like enhancer of split 3 (TLE3) gene regulatory axis. Chondroitin sulfate supplementation in mice alleviated intestinal tumorigenesis. In summary, we have uncovered the protective role of PAPSS2-mediated chondroitin sulfation and bile acids-FXR-TLE3 activation in the prevention of gut carcinogenesis the antagonization of Wnt/-catenin signaling. Chondroitin sulfate may be explored as a therapeutic agent for Papss2 deficiency-associated colonic carcinogenesis.
PubMed: 38487006
DOI: 10.1016/j.apsb.2023.12.006 -
Frontiers in Oncology 2024Pancreatoblastoma (PB) is a rare malignant pancreatic epithelial tumor that mostly occurs in children and occasionally occurs in adults. The tumor has acinar cell...
Pancreatoblastoma (PB) is a rare malignant pancreatic epithelial tumor that mostly occurs in children and occasionally occurs in adults. The tumor has acinar cell differentiation and squamous corpuscles/squamous epithelial islands, which are frequently separated by fibrous bundles. Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disease characterized by the presence of numerous adenomatous polyps in the colon and rectum. Cases of pancreatoblastoma combined with familial adenomatous polyposis (FAP) are rarely reported. A review of a rare case of adult pancreatoblastoma with atypical histological morphology combined with familial adenomatous polyposis is presented herein. In this case, the patient was first diagnosed with familial adenomatous polyposis and subsequently found to have pancreatoblastoma 1 year and 3 months later. This suggests pancreatoblastoma may occur in patients with familial adenomatous polyposis or a family history of the condition, indicating a possible association between the two tumors. Therefore, pancreatoblastoma should be included in a differential diagnosis for FAP patients with a pancreatic mass. The final diagnosis of pancreatoblastoma depends on the pathological diagnosis. Acinar-like cells and squamous corpuscles/squamous epithelial cell islands under light microscopy are the key diagnostic points. This case report also can improve the awareness of clinicians, radiologists, and pathologists on the presence of rare tumor-adult pancreatoblastoma in patients with familial adenomatous polyposis.
PubMed: 38482206
DOI: 10.3389/fonc.2024.1346964 -
Cancers Mar 2024Glioblastoma multiforme (GBM) is the most common and deadly type of brain tumor originating from glial cells. Despite decades of clinical trials and research, there has...
Haploinsufficiency of Adenomatous Polyposis Coli Coupled with Kirsten Rat Sarcoma Viral Oncogene Homologue Activation and P53 Loss Provokes High-Grade Glioblastoma Formation in Mice.
Glioblastoma multiforme (GBM) is the most common and deadly type of brain tumor originating from glial cells. Despite decades of clinical trials and research, there has been limited success in improving survival rates. However, molecular pathology studies have provided a detailed understanding of the genetic alterations associated with the formation and progression of glioblastoma-such as Kirsten rat sarcoma viral oncogene homolog (KRAS) signaling activation (5%), P53 mutations (25%), and adenomatous polyposis coli (APC) alterations (2%)-laying the groundwork for further investigation into the biological and biochemical basis of this malignancy. These analyses have been crucial in revealing the sequential appearance of specific genetic lesions at distinct histopathological stages during the development of GBM. To further explore the pathogenesis and progression of glioblastoma, here, we developed the glial-fibrillary-acidic-protein (GFAP)-Cre-driven mouse model and demonstrated that activated KRAS and p53 deficiencies play distinct and cooperative roles in initiating glioma tumorigenesis. Additionally, the combination of APC haploinsufficiency with mutant Kras activation and p53 deletion resulted in the rapid progression of GBM, characterized by perivascular inflammation, large necrotic areas, and multinucleated giant cells. Consequently, our GBM models have proven to be invaluable resources for identifying early disease biomarkers in glioblastoma, as they closely mimic the human disease. The insights gained from these models may pave the way for potential advancements in the diagnosis and treatment of this challenging brain tumor.
PubMed: 38473403
DOI: 10.3390/cancers16051046 -
Accounts of Chemical Research Apr 2024Base excision repair (BER) enzymes are genomic superheroes that stealthily and accurately identify and remove chemically modified DNA bases. DNA base modifications erode... (Review)
Review
Base excision repair (BER) enzymes are genomic superheroes that stealthily and accurately identify and remove chemically modified DNA bases. DNA base modifications erode the informational content of DNA and underlie many disease phenotypes, most conspicuously, cancer. The "OG" of oxidative base damage, 8-oxo-7,8-dihydroguanine (OG), is particularly insidious due to its miscoding ability that leads to the formation of rare, pro-mutagenic OG:A mismatches. Thwarting mutagenesis relies on the capture of OG:A mismatches prior to DNA replication and removal of the mis-inserted adenine by MutY glycosylases to initiate BER. The threat of OG and the importance of its repair are underscored by the association between inherited dysfunctional variants of the MutY human homologue (MUTYH) and colorectal cancer, known as MUTYH-associated polyposis (MAP). Our functional studies of the two founder MUTYH variants revealed that both have compromised activity and a reduced affinity for OG:A mismatches. Indeed, these studies underscored the challenge of the recognition of OG:A mismatches that are only subtly structurally different than T:A base pairs. Since the original discovery of MAP, many MUTYH variants have been reported, with most considered to be "variants of uncertain significance." To reveal features associated with damage recognition and adenine excision by MutY and MUTYH, we have developed a multipronged chemical biology approach combining enzyme kinetics, X-ray crystallography, single-molecule visualization, and cellular repair assays. In this review, we highlight recent work in our laboratory where we defined MutY structure-activity relationship (SAR) studies using synthetic analogs of OG and A in cellular and assays. Our studies revealed the 2-amino group of OG as the key distinguishing feature of OG:A mismatches. Indeed, the unique position of the 2-amino group in the major groove of OG:A mismatches provides a means for its rapid detection among a large excess of highly abundant and structurally similar canonical base pairs. Furthermore, site-directed mutagenesis and structural analysis showed that a conserved C-terminal domain β-hairpin "FSH'' loop is critical for OG recognition with the "His" serving as the lesion detector. Notably, MUTYH variants located within and near the FSH loop have been associated with different forms of cancer. Uncovering the role(s) of this loop in lesion recognition provided a detailed understanding of the search and repair process of MutY. Such insights are also useful to identify mutational hotspots and pathogenic variants, which may improve the ability of physicians to diagnose the likelihood of disease onset and prognosis. The critical importance of the "FSH" loop in lesion detection suggests that it may serve as a unique locus for targeting probes or inhibitors of MutY/MUTYH to provide new chemical biology tools and avenues for therapeutic development.
Topics: Humans; DNA Repair; Adenine; Escherichia coli; DNA Damage; DNA; Colorectal Neoplasms; Follicle Stimulating Hormone; Guanine
PubMed: 38471078
DOI: 10.1021/acs.accounts.3c00759 -
European Journal of Human Genetics :... May 2024In the Danish Polyposis Register, patients with over 100 cumulative colorectal adenomas of unknown genetic etiology, named in this study colorectal polyposis (CP), is...
In the Danish Polyposis Register, patients with over 100 cumulative colorectal adenomas of unknown genetic etiology, named in this study colorectal polyposis (CP), is registered and treated as familial adenomatous polyposis (FAP). In this study, we performed genetic analyses, including whole genome sequencing (WGS), of all Danish patients registered with CP and estimated the detection rate of pathogenic variants (PV). We identified 231 families in the Polyposis Register, 31 of which had CP. A polyposis-associated gene panel was performed and, if negative, patients were offered WGS and screening for mosaicism in blood and/or adenomas. Next-generation sequencing (NGS) was carried out for 27 of the families (four declined). PVs were detected in 11 families, and WGS revealed three additional structural variants in APC. Mosaicism of a PV in APC was detected in two families. As the variant detection rate of eligible families was 60%, 93% of families in the register now have a known genetic etiology.
Topics: Humans; Adenomatous Polyposis Coli; Female; Adenomatous Polyposis Coli Protein; Male; Denmark; Adult; Genotype; Middle Aged; Genetic Testing; Mosaicism; Registries
PubMed: 38467732
DOI: 10.1038/s41431-024-01585-z