Radiation-induced gastritis is a rare cause of gastrointestinal bleeding. The aim of this study was to evaluate the clinical features associated with radiation-induced gastritis in cirrhosis treated ...with radiation therapy for hepatocellular carcinoma. Radiation-induced gastritis was observed in 6 of 12 patients showing endoscopic findings of diffuse antral vascular ectasia and correlated significantly with radiation therapy for recurrence of hepatocellular carcinoma in abdominal lymph nodes. Argon plasma coagulation was performed in 4 patients with radiation-induced hemorrhagic gastritis and 3 patients with radiation therapy for abdominal lymph nodes showed refractory radiation-induced hemorrhagic gastritis. We suggest that radiation therapy for abdominal lymph nodes in cirrhosis could be associated with refractory radiation-induced hemorrhagic gastritis.
Recently, endoscopic submucosal dissection (ESD) has been widely used as a therapeutic procedure for mucosal cancer of the digestive tract, including esophageal disease. However, ESD may result in ...bleeding, perforation and post-treatment stenosis of the esophagus. In high-risk patients with underlying disease, ESD should be avoided for treatment of superficial esophageal carcinoma. Argon plasma coagulation (APC) has been reported to be a safe and useful procedure for the management of gastric mucosal cancer. We report here two cases of superficial esophageal carcinoma and high-grade dysplasia of the esophagus which were treated using APC. Case 1 : An 84-year-old man─with malignant lymphoma─was diagnosed with superficial squamous cell carcinoma of the esophagus. Since he had been receiving steroid therapy and had renal dysfunction, he underwent APC in preference to endoscopic resection to treat the esophageal carcinoma. After ablation of the lesion by APC, the ablated epithelial layer was removed by endoscopic distal attachment (soft hood) and additional APC was performed on the lesion. The esophageal carcinoma disappeared. Case 2 : A 55-year-old man─who had lower pharyngeal cancer─was diagnosed with early esophageal cancer. Since he had multiple tiny lesions unstained by iodine, he underwent chemoradiotherapy for the esophageal cancer. High-grade dysplasia of the esophagus developed 20 months after CRT. After repeated APC therapy, the esophageal dysplasia disappeared. No complications were observed in either case. This suggests that APC is a safe and effective treatment for superficial esophageal carcinoma that cannot be resected endoscopically because of underlying severe disease, as well as treatment of local recurrence after chemoradiotherapy.
A 77-year-old man underwent extended right hepatectomy due to suspicion of gallbladder cancer invading the right hepatic artery and bile duct. The patient developed post-ERCP pancreatitis and ...pancreatic pseudocyst formation before the surgical procedure. Debridement was performed and a drainage tube inserted at the time of surgery to treat the pancreatic pseudocyst. After the procedure, we continued to irrigate the drain with normal saline. Sixty-eight days post-surgery, the patient had bleeding from the pseudocyst. Enhanced CT and angiography showed no extravasations, but the source appeared to be irregularity of the right gastroepiploic artery. We performed transcatheter arterial embolization (TAE) to treat the bleeding. After TAE, bleeding from the pseudocyst recurred and the source was thought to be small vessels in the cyst wall. Argon plasma coagulation (APC) was performed using a small-caliber endoscope through the fistula. After this procedure, bleeding was controlled and the patient discharged 136 days later. Percutaneous endoscopic APC appears to be a useful procedure for treatment of pseudocyst bleeding.
Various preclinical and clinical studies have demonstrated the robust wound healing capacity of the natural anticoagulant activated protein C (APC). A bioengineered APC variant designated 3K3A‐APC ...retains APC's cytoprotective cell signalling actions with <10% anticoagulant activity. This study was aimed to provide preclinical evidence that 3K3A‐APC is efficacious and safe as a wound healing agent. 3K3A‐APC, like wild‐type APC, demonstrated positive effects on proliferation of human skin cells (keratinocytes, endothelial cells and fibroblasts). Similarly it also increased matrix metollaproteinase‐2 activation in keratinocytes and fibroblasts. Topical 3K3A‐APC treatment at 10 or 30 μg both accelerated mouse wound healing when culled on Day 11. And at 10 μg, it was superior to APC and had half the dermal wound gape compared to control. Further testing was conducted in excisional porcine wounds due to their congruence to human skin. Here, 3K3A‐APC advanced macroscopic healing in a dose‐dependent manner (100, 250 and 500 μg) when culled on Day 21. This was histologically corroborated by greater collagen maturity, suggesting more advanced remodelling. A non‐interference arm of this study found no evidence that topical 3K3A‐APC caused either any significant systemic side‐effects or any significant leakage into the circulation. However the female pigs exhibited transient and mild local reactions after treatments in week three, which did not impact healing. Overall these preclinical studies support the hypothesis that 3K3A‐APC merits future human wound studies.
O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is the sole enzyme that catalyzes all O-GlcNAcylation reactions intracellularly. Previous investigations have found that OGT levels ...oscillate during the cell division process. Specifically, OGT abundance is downregulated during mitosis, but the underlying mechanism is lacking. Here we demonstrate that OGT is ubiquitinated by the ubiquitin E3 ligase, anaphase promoting complex/cyclosome (APC/C)-cell division cycle 20 (Cdc20). We show that APC/CCdc20 interacts with OGT through a conserved destruction box (D-box): Arg-351/Leu-354, the abrogation of which stabilizes OGT. As APC/CCdc20-substrate binding is often preceded by a priming ubiquitination event, we also used mass spectrometry and mapped OGT Lys-352 to be a ubiquitination site, which is a prerequisite for OGT association with APC/C subunits. Interestingly, in The Cancer Genome Atlas, R351C is a uterine carcinoma mutant, suggesting that mutations of the D-box are linked with tumorigenesis. Paradoxically, we found that both R351C and the D-box mutants (R351A/L354A) inhibit uterine carcinoma in mouse xenograft models, probably due to impaired cell division and proliferation. In sum, we propose a model where OGT Lys-352 ubiquitination primes its binding with APC/C, and then APC/CCdc20 partners with OGT through the D-box for its mitotic destruction. Our work not only highlights the key mechanism that regulates OGT during the cell cycle, but also reveals the mutual coordination between glycosylation and the cell division machinery.
Therapeutic strategies that promote read-through of a mutant gene have proved effective for certain non-neoplastic diseases. However, the efficacy of this approach is unproven regarding neoplastic ...diseases with germline nonsense mutations, including familial adenomatous polyposis. Here we examined the cancer-preventive efficacy of the macrolide antibiotic azithromycin, with a reported read-through effect, on intestinal tumorigenesis in C3B6F1 ApcMin/+ mice harboring a nonsense Apc mutation resulting in a truncated Apc protein. Mice were given drinking water lacking azithromycin or containing 0.0125–0.2 mg/mL azithromycin from 3 weeks of age. The small intestine and cecum were analyzed for pathological changes and alterations of intestinal flora. Azithromycin suppressed the number of tumors and the proportion of adenocarcinomas, with the most effective drinking-water concentration being 0.0125 mg/mL. Furthermore, azithromycin recovered the cellular level of full-length Apc, resulting in downregulation of β-catenin and cyclin D1. Conversely, the effect of azithromycin on the diversity of the intestinal microbiota depended on the drinking-water concentration. These results suggest that the balance between azithromycin-mediate read-through of mutant Apc mRNA and antibacterial effects influences intestinal tumorigenesis. Thus, azithromycin is a potential anticancer agent for familial adenomatous polyposis patients harboring nonsense mutations.
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Mutation of tumor suppressor gene adenomatous polyposis coli (APC) is an initiating step in most colon cancers. This review summarizes Apc models in mice and rats, with particular concentration on ...those most recently developed, phenotypic variation among different models, and genotype/phenotype correlations.
Early-life immune development is critical to long-term host health. However, the mechanisms that determine the pace of postnatal immune maturation are not fully resolved. Here, we analyzed ...mononuclear phagocytes (MNPs) in small intestinal Peyer’s patches (PPs), the primary inductive site of intestinal immunity. Conventional type 1 and 2 dendritic cells (cDC1 and cDC2) and RORgt+ antigen-presenting cells (RORgt+ APC) exhibited significant age-dependent changes in subset composition, tissue distribution, and reduced cell maturation, subsequently resulting in a lack in CD4+ T cell priming during the postnatal period. Microbial cues contributed but could not fully explain the discrepancies in MNP maturation. Type I interferon (IFN) accelerated MNP maturation but IFN signaling did not represent the physiological stimulus. Instead, follicle-associated epithelium (FAE) M cell differentiation was required and sufficient to drive postweaning PP MNP maturation. Together, our results highlight the role of FAE M cell differentiation and MNP maturation in postnatal immune development.
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•Peyer’s patch (PP) CD4+ T cells exhibit delayed maturation after birth•cDC1 and RORgt+ APC are increased whereas cDC2 are diminished in the neonatal PP•PP APCs exhibit halted maturation and cDC2 show reduced T cell priming capacity•M cell development is required and sufficient to drive APC maturation
Despite the critical importance of immune development in early life, our mechanistic understanding of this process is limited. Torow et al. demonstrate that postnatal establishment of intestinal microbe-host interaction is not expressly driven by early microbial colonization, but rather the maturation of Peyer’s patch M cells and antigen-presenting cells.
Neuromuscular junctions (NMJs) are peripheral synapses between motoneurons and skeletal muscle fibers that are critical for the control of muscle contraction. Dysfunction of these synapses has been ...implicated in congenital myasthenic syndrome (CMS). In vertebrates, agrin‐LRP4‐MuSK signaling plays a critical role in acetylcholine receptor (AChR) clustering and NMJ formation. The adaptor protein DOK7 is the downstream substrate of MuSK and also a cytoplasmic activator of MuSK. The role of DOK7 in the promotion of AChR clustering and the mechanisms involved have been well studied; however, the negative regulation of DOK7 after MuSK activation remains unknown. Anaphase‐promoting complex 2 (APC2), the core subunit of APC/C E3 ligase complex, was originally believed to regulate cell‐cycle transitions. Here, we show that APC2 is enriched at post‐synapse of NMJs in postmitotic myotubes. In response to agrin stimulation, APC2 negatively regulates AChR clustering by promoting the ubiquitination of DOK7 at lysine 243 for its proteolytic degradation, which relies on MuSK kinase activity and the phosphorylation of tyrosine 106 in DOK7. Thus, this study provides a mechanism whereby agrin signaling is negatively regulated as part of vertebrate NMJ homeostasis.
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