SEMA7A-mediated juxtacrine stimulation of IGFBP-3 upregulates IL-17RB at pancreatic cancer invasive front.

Tumor invasion is the hallmark of tumor malignancy. The invasive infiltration pattern of tumor cells located at the leading edge is highly correlated with metastasis and unfavorable patient outcomes. However, the regulatory mechanisms governing tumor malignancy at the invasive margin remain unclear. The IL-17B/IL-17RB pathway is known to promote pancreatic cancer invasion and metastasis, yet the specific mechanisms underlying IL-17RB upregulation during invasion are poorly understood. In this study, we unveiled a multistep process for IL-17RB upregulation at the invasive margin, which occurs through direct communication between tumor cells and fibroblasts. Tumor ATP1A1 facilitates plasma membrane expression of SEMA7A, which binds to and induces IGFBP-3 secretion from fibroblasts. The resulting gradient of IGFBP-3 influences the direction and enhances IL-17RB expression to regulate SNAI2 in invasion. These findings highlight the importance of local tumor-fibroblast interactions in promoting cancer cell invasiveness, potentially leading to the development of new therapeutic strategies targeting this communication.

Resolution of Laryngeal Ulceration with Prednisolone Therapy in a Patient with Crohn's Disease.

A 23-year-old man diagnosed with Crohn's disease (CD) was treated with infliximab. He developed new-onset sore throat and dysphagia during admission, and nasopharyngoscopy revealed epiglottic ulceration. Laryngeal ulceration was considered as an extraintestinal manifestation of CD owing to treatment failure with antibiotics and hydrocortisone. This strongly suggested that laryngeal ulceration was a complication of CD because of the rapid improvement in the symptoms and lesions after prednisolone administration. Furthermore, this treatment process demonstrated the superior anti-inflammatory effect of prednisolone over that of hydrocortisone and supported the assumption of inflammation related to CD.

Observation of the drainage process of the residual lipoma after endoscopic unroofing technique during colonoscopic evaluation of post-procedural hematochezia.

A 57-year-old man was referred to our hospital for further management of a subepithelial lesion noted on colonoscopy. He underwent endoscopic treatment of unroofing technique, in which the protruding portion of the tumor was partially resected. Due to a small amount of hematochezia, colonoscopy was performed to re-evaluate the lesion post-treatment. This enabled the observation of the drainage process of the residual lipoma. Remission was achieved and confirmed 8 months after the treatment. Endoscopic unroofing technique has been reported as a safe and effective method of treating lipomas, particularly large ones. To the best of our knowledge, this is the first endoscopic unroofing case in which the drainage process of the residual lipoma was observed and the remission of the lesion was confirmed.

Unresectable Ectopic Hepatocellular Carcinoma Treated with Sorafenib.

Ectopic hepatocellular carcinoma (HCC) is a rare malignancy, which manifests similar morphology and immunohistochemistry to intrahepatic HCC. Herein, we report a case of ectopic HCC in a 73-year-old male. The patient presented to our hospital with gradually progressing right lower abdominal pain, and enhanced computed tomography revealed multiple nodules in the peritoneum without intrahepatic mass. A diagnostic laparoscopy was performed, and the final pathology result confirmed that it was HCC. Additional laboratory tests showed elevated serum alpha-fetoprotein and protein induced by vitamin K absence-II (PIVKA-II) levels, suggesting our diagnosis. The patient received sorafenib, a tyrosine kinase inhibitor (TKI), for unresectable ectopic HCC. However, the tumor progressed, and because of tarry stools and hemorrhagic anemia, sorafenib was ceased after 7 months of therapy. One month after the cessation of sorafenib, the PIVKA-II level increased abruptly, and the patient died 1 year after diagnosis. The effective treatment for unresectable ectopic HCC is still unknown. Additional cases should be accumulated to determine the effect of TKI on ectopic HCC.

NPGPx-Mediated Adaptation to Oxidative Stress Protects Motor Neurons from Degeneration in Aging by Directly Modulating O-GlcNAcase.

Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, usually occurs in middle-aged people. However, the molecular basis of age-related cumulative stress in ALS pathogenesis remains elusive. Here, we found that mice deficient in NPGPx (GPx7), an oxidative stress sensor, develop ALS-like phenotypes, including paralysis, muscle denervation, and motor neurons loss. Unlike normal spinal motor neurons that exhibit elevated O-GlcNAcylation against age-dependent oxidative stress, NPGPx-deficient spinal motor neurons fail to boost O-GlcNAcylation and exacerbate ROS accumulation, leading to cell death. Mechanistically, stress-activated NPGPx inhibits O-GlcNAcase (OGA) through disulfide bonding to fine-tune global O-GlcNAcylation. Pharmacological inhibition of OGA rescues spinal motor neuron loss in aged NPGPx-deficient mice. Furthermore, expression of NPGPx in ALS patients is significantly lower than in unaffected adults. These results suggest that NPGPx modulates O-GlcNAcylation by inhibiting OGA to cope with age-dependent oxidative stress and protect motor neurons from degeneration, providing a potential therapeutic axis for ALS.

IL28B gene polymorphism is correlated with changes in low-density lipoprotein cholesterol levels after clearance of hepatitis C virus using direct-acting antiviral treatment.

BACKGROUND: Direct-acting antivirals (DAAs) rapidly clear hepatitis C virus (HCV), but the lipid dynamics after DAA treatment remain unknown. Low-density lipoprotein (LDL) cholesterolemia is the predicting factor for the onset and death of atherosclerotic cardiovascular diseases. Thus, in this study, we examined the frequency and risk of hyper-LDL cholesterolemia in HCV patients who achieved sustained virologic response (SVR) with DAA treatment. METHODS: A total of 121 patients with HCV genotype 1b, who achieved SVR with DAA treatment, were examined for serum levels of total cholesterol, LDL-cholesterol (LDL-C), high-density lipoprotein, and triglycerides from the start of treatment until 2 years after SVR (SVR-2y). ΔLDL-C was defined as the change in LDL-C levels from treatment initiation to SVR-2y. Hyper-LDL cholesterolemia was defined as ≥ 140 mg/dL LDL-C at SVR-2y. Stepwise multiple regression analysis was performed to determine whether ΔLDL-C and hyper-LDL cholesterolemia are associated with other factors, including viral kinetics. RESULTS: A total of 63, 3, and 55 patients were administered daclatasvir + asunaprevir, ombitasvir + paritaprevir + ritonavir, and ledipasvir + sofosbuvir, respectively. ΔLDL-C in patients with the IL28B (rs8099917) TG/GG genotype was significantly higher than in those with IL28B TT (27.3 ± 27.0 and 9.6 ± 27.3 mg/dL; P < 0.001). In addition, IL28B TG/GG was an independent risk factor for hyper-LDL cholesterolemia (odds ratio: 8.47; P < 0.001). CONCLUSIONS: An IL28B polymorphism is associated with ΔLDL-C and hyper-LDL cholesterolemia after achieving SVR. Thus, lipid markers should be carefully monitored in patients who achieve SVR with DAA.

Factors Attenuating Zinc Deficiency Improvement in Direct-Acting Antiviral Agent-Treated Chronic Hepatitis C Virus Infection.

Zinc deficiency is frequently observed in chronic liver diseases. However, no studies have focused on the zinc status in chronic hepatitis C (HCV)-infected patients receiving direct-acting antiviral agents (DAAs). In this retrospective study, we assessed the serum zinc status in DAA-treated HCV patients with sustained virologic response for over two years (Zn-2y). Ninety-five patients were enrolled, whose baseline characteristics and blood parameters at DAA therapy initiation were collected. Baseline Zn < 65 µg/dL (odds ratio (OR) = 10.56, p < 0.001) and baseline uric acid (UA) > 5.5 mg/dL (OR = 9.99, p = 0.001) were independent risk factors for Zn-2y deficiency. A decision-tree algorithm classified low-baseline Zn and high-baseline UA as the first two variables, suggesting that baseline hypozincemia and hyperuricemia are prognosticators for long-term zinc deficiency. Baseline Zn was negatively correlated with the Fibrosis-4 (FIB-4) index, while baseline UA was significantly higher in habitual alcohol drinkers. In conclusion, serum zinc levels should be closely monitored, considering that zinc status improvement is related to liver fibrosis regression. Hyperuricemia indicates risks of developing metabolic disorders and subsequent zinc deficiency, for which an adjustment of personal lifestyle or dietary habits should be recommended clinically.

An essential role of cAMP response element-binding protein in epidermal growth factor-mediated induction of sodium/glucose cotransporter 1 gene expression and intestinal glucose uptake.

The sodium/glucose cotransporter 1 (SGLT1) is responsible for glucose uptake in intestinal epithelial cells. Its expression is decreased in individuals with intestinal inflammatory disorders and is correlated with the pathogenesis of disease. The aim of this study was to understand the regulatory mechanism of the SGLT1 gene. Using the trinitrobenzene sulfonic acid-induced mouse models of intestinal inflammation, we observed decreased SGLT1 expression in the inflamed intestine was positively correlated with the mucosal level of epidermal growth factor (EGF) and activated CREB. Overexpression of EGF demonstrated that the effect of EGF on intestinal glucose uptake was primarily due to the increased level of SGLT1. We identified an essential cAMP binding element (CRE) confers EGF inducibility in the human SGLT1 gene promoter. ChIP assay further demonstrated the increased binding of CREB and CBP to the SGLT1 gene promoter in EGF-treated cells. In addition, the EGFR- and PI3K-dependent CREB phosphorylations are involved in the EGF-mediated SGLT1 expression. This is the first report to demonstrate that CREB is involved in EGF-mediated transcription regulation of SGLT1 gene in the normal and inflamed intestine, which can provide potential therapeutic applications for intestinal inflammatory disorders.

A new classification system for pregnancy prognosis of tubal factor infertility.

UNLABELLED: The aim of the present study was to assess the objectivity and accuracy of a new system to evaluate pregnancy prognosis in tubal factor infertility (TFI) patients. Retrospective study in 469 TFI patients were pre- and postoperatively scored using the new system as mild, moderate or severe TFI, based on tubal adhesions, patency, morphology and structure. Follow-up was assessed to determine pregnancy outcomes. Laparoscopic salpingoplasty and hydrotubation, hysteroscopic-laparoscopic salpingoplasty and hydrotubation, and laparoscopic hydrotubation all decreased TFI scores to a similar extent. The pre- and postoperative TFI classification was significantly associated with intrauterine pregnancy (mild: 43.6% vs. moderate: 34.0% vs. severe: 19.4%, P < 0.0001) and live births (mild: 35.9% and moderate: 31.5% vs. severe: 16.8%, P = 0.0002) rates. Multivariate analysis showed that the preoperative disease course (P = 0.02), preoperative TFI score (P < 0.0001), and postoperative TFI score (P = 0.0007) were independently associated with the rate of intrauterine pregnancy rate. Multivariate analysis also showed that the postoperative TFI score (P = 0.001), pelvic inflammatory disease (P = 0.03) and age (P = 0.03) were independently associated with the rate of live births. CONCLUSION: We devised a new classification system for TFI prognosis. Salpingoplasty improved these scores. Both pre- and postoperative TFI assessments using this new system are associated with pregnancy prognosis in TFI patients.