Precancerous Pyloric Gland Metaplasia in the Biliary Epithelium Associated with Congenital Biliary Dilatation in a Three-Month-Old Infant

Pyloric gland metaplasia in the biliary epithelium is a precancerous lesion and has been confirmed in patients with congenital biliary dilatation presenting with overt biliary tract cancer. A patient was found to have an intra-abdominal cyst on fetal ultrasonography and was born at 37 weeks of gestation with a body weight of 2,636 g. Abdominal distension and repeated vomiting appeared 2 days after birth. Congenital biliary dilatation was diagnosed by imaging, wherein the common bile duct was enlarged to 9–10 cm in size, and the surrounding organs were extensively compressed; however, there was no sign of pancreatitis or cholangitis. Biliary drainage was performed through the gallbladder at 6 days of age, but it was insufficient because of the narrow and twisted cystic duct and changed to common bile duct at 18 days to relieve the compression. Because the body weight gain was poor due to loss of large amount of bile, the dilated bile duct and gallbladder were resected and hepatic duct Roux-Y jejunostomy was performed at 115 days of age with 4,500 g of body weight. Intraoperative imaging showed a pancreaticobiliary maljunction, and the pancreatic enzyme activities of the bile in the biliary system were remarkably elevated. Histopathological examination revealed pyloric gland metaplasia in the gallbladder epithelium and cystic duct. The patient is now over 2 years old and has been doing well without any complications. Based on our experience, precancerous pyloric gland metaplasia of the biliary epithelium may already occur even in a 3-month-old infant presenting with congenital biliary dilatation

Absum: Simple Regularization Method for Reducing Structural Sensitivity of Convolutional Neural Networks

We propose Absum, which is a regularization method for improving adversarial robustness of convolutional neural networks (CNNs). Although CNNs can accurately recognize images, recent studies have shown that the convolution operations in CNNs commonly have structural sensitivity to specific noise composed of Fourier basis functions. By exploiting this sensitivity, they proposed a simple black-box adversarial attack: Single Fourier attack. To reduce structural sensitivity, we can use regularization of convolution filter weights since the sensitivity of linear transform can be assessed by the norm of the weights. However, standard regularization methods can prevent minimization of the loss function because they impose a tight constraint for obtaining high robustness. To solve this problem, Absum imposes a loose constraint; it penalizes the absolute values of the summation of the parameters in the convolution layers. Absum can improve robustness against single Fourier attack while being as simple and efficient as standard regularization methods (e.g., weight decay and L1 regularization). Our experiments demonstrate that Absum improves robustness against single Fourier attack more than standard regularization methods. Furthermore, we reveal that robust CNNs with Absum are more robust against transferred attacks due to decreasing the common sensitivity and against high-frequency noise than standard regularization methods. We also reveal that Absum can improve robustness against gradient-based attacks (projected gradient descent) when used with adversarial training.Comment: 16 pages, 39 figure

Age- and sex-specific associations between sarcopenia severity and poor cognitive function among community-dwelling older adults in Japan: The IRIDE Cohort Study

IntroductionThis study examined whether the association between sarcopenia severity and cognitive function differed according to sex and age in community-dwelling older adults in Japan.MethodsThis is a cross-sectional study of older adults (age ≥ 65 years) consisting of five regional cohorts integrated as the Integrated Research Initiative for Living Well with Dementia (IRIDE) Cohort Study. Sarcopenia severity was determined based on the Asian Working Group for Sarcopenia 2019, which assessed grip strength, walking speed, and skeletal muscle mass index. Poor cognitive function was defined as a Mini-Mental State Examination score of ≤ 23. Odds ratios (ORs) and 95% confidence intervals (CIs) for poor cognitive function were calculated by sex and age group (65–74 and ≥75 years) using binomial logistic regression models, which were adjusted for age, educational attainment, history of non-communicable diseases, smoking and drinking habits, living alone, frequency of going outdoors, exercise habits, and depressive symptom.ResultsOf the 8,180 participants, 6,426 (1,157 men aged 65–74 and 1,063 men aged 75 or older; 2,281 women aged 65–74 and 1,925 women aged 75 or older) were analyzed. The prevalence ratio of sarcopenia and severe sarcopenia were 309 (13.9%) and 92 (4.1%) among men and 559 (13.3%) and 166 (3.7%) among women, respectively. A total of 127 (5.8%) men and 161 (3.9%) women had a poor cognitive function. Setting non-sarcopenia as a reference, the adjusted ORs (95% CI) of poor cognitive function were 2.20 (1.54, 3.15) for sarcopenia and 3.56 (2.20, 5.71) for severe sarcopenia. A similar trend was observed in analyses stratified by sex and age, with linear associations (P for trend <0.05) in both categories. Furthermore, there was a significant interaction (P < 0.05) between sex and sarcopenia severity, indicating a stronger linear association of sarcopenia severity with poor cognitive function in women compared with men.Discussion and conclusionSarcopenia severity was linearly associated with poor cognitive function in adults aged ≥ 65 years, with a stronger association in women compared with men

Percutaneous sclerotherapy for venous malformations using polidocanol under fluoroscopy.

This retrospective study evaluated the safety and efficacy of using polidocanol with X-ray fluoroscopy for percutaneous sclerotherapy of venous malformations of the limbs, head, and neck. The subjects were 16 of 18 patients who presented to our department with venous malformations. Two patients were excluded because they were unlikely to benefit from the treatment. Of the 16 included in the study, 1 could not be treated because of inaccessibility, and another was lost to follow-up. Among the 14 cases that we were able to follow-up, 11 cases had had pain as their primary symptom. Following treatment, this symptom remained unchanged in 1 patient, was improved in 4, and had disappeared in 6; however, there was a recurrence of pain for 3 of these patients. Two patients had sought treatment for cosmetic purposes; following treatment, the lesion disappeared in one and showed a significant reduction in the other. The remaining patient presented with a primary symptom of mouth bleeding, which disappeared following treatment. There were no critical complications. Percutaneous sclerotherapy of venous malformations using polidocanol is safe and effective, and permits repeat treatments. The efficacy is especially good for resolving pain, and complications are minor. It is desirable to use fluoroscopy for these procedures</p

Extracellular vesicles shed from gastric cancer mediate protumor macrophage differentiation

Background Peritoneal dissemination often develops in gastric cancer. Tumor-associated macrophages (TAMs) are present in the peritoneal cavity of gastric cancer patients with peritoneal dissemination, facilitating tumor progression. However, the mechanism by which macrophages differentiate into tumor-associated macrophages in the peritoneal cavity is not well understood. In this study, the interplay between gastric cancer-derived extracellular vesicles (EVs) and macrophages was investigated. Methods The association between macrophages and EVs in peritoneal ascitic fluid of gastric cancer patients, or from gastric cancer cell lines was examined, and their roles in differentiation of macrophages and potentiation of the malignancy of gastric cancer were further explored. Results Immunofluorescent assays of the ascitic fluid showed that M2 macrophages were predominant along with the cancer cells in the peritoneal cavity. EVs purified from gastric cancer cells, as well as malignant ascitic fluid, differentiated peripheral blood mononuclear cell-derived macrophages into the M2-like phenotype, which was demonstrated by their morphology and expression of CD163/206. The macrophages differentiated by gastric cancer-derived EVs promoted the migration ability of gastric cancer cells, and the EVs carried STAT3 protein. Conclusion EVs derived from gastric cancer play a role by affecting macrophage phenotypes, suggesting that this may be a part of the underlying mechanism that forms the intraperitoneal cancer microenvironment

Inhibitory Effect of a Tankyrase Inhibitor on Mechanical Stress-Induced Protease Expression in Human Articular Chondrocytes

We investigated the effects of a Tankyrase (TNKS-1/2) inhibitor on mechanical stress-induced gene expression in human chondrocytes and examined TNKS-1/2 expression in human osteoarthritis (OA) cartilage. Cells were seeded onto stretch chambers and incubated with or without a TNKS-1/2 inhibitor (XAV939) for 12 h. Uni-axial cyclic tensile strain (CTS) (0.5 Hz, 8% elongation, 30 min) was applied and the gene expression of type II collagen a1 chain (COL2A1), aggrecan (ACAN), SRY-box9 (SOX9), TNKS-1/2, a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), and matrix metalloproteinase-13 (MMP-13) were examined by real-time PCR. The expression of ADAMTS-5, MMP-13, nuclear translocation of nuclear factor-κB (NF-κB), and β-catenin were examined by immunocytochemistry and Western blotting. The concentration of IL-1β in the supernatant was examined by enzyme-linked immunosorbent assay (ELISA). TNKS-1/2 expression was assessed by immunohistochemistry in human OA cartilage obtained at the total knee arthroplasty. TNKS-1/2 expression was increased after CTS. The expression of anabolic factors were decreased by CTS, however, these declines were abrogated by XAV939. XAV939 suppressed the CTS-induced expression of catabolic factors, the release of IL-1β, as well as the nuclear translocation of NF-κB and β-catenin. TNKS-1/2 expression increased in mild and moderate OA cartilage. Our results demonstrated that XAV939 suppressed mechanical stress-induced expression of catabolic proteases by the inhibition of NF-κB and activation of β-catenin, indicating that TNKS-1/2 expression might be associated with OA pathogenesis

Role of the VEGF-Flt-1-FAK pathway in the pathogenesis of osteoclastic bone destruction of giant cell tumors of bone

BACKGROUND: Giant cell tumors (GCTs) of bone are primary benign bone tumors that are characterized by a high number of osteoclast-like multinuclear giant cells (MNCs). Recent studies suggest that the spindle-shaped stromal cells in GCTs are tumor cells, while monocyte-like cells and MNCs are reactive osteoclast precursor cells (OPCs) and osteoclasts (OCs), respectively. In this study, we investigated the pathogenesis of osteoclastic bone destruction in GCTs by focusing on the role of the vascular endothelial growth factor (VEGF)-Flt-1 (type-1 VEGF receptor)-focal adhesion kinase (FAK) pathway. METHODS: The motility of OPCs cells was assessed by a chemotaxis assay and the growth of OPCs was examined using a cell proliferation assay. The expression of VEGF and activation of Flt-1 and FAK in clinical GCT samples and in OPCs were detected by immunohistochemistry and immunoblotting. The correlation between the expression levels of activated Flt-1 and FAK and clinical stages of GCTs was investigated by immunohistochemistry. RESULTS: In GCT samples, CD68, a marker of OPCs and OCs, co-localized with Flt-1. Conditioned media from GCT tissue (GCT-CM) enhanced the chemotaxis and proliferation of OPCs. GCT-CM also stimulated FAK activation in OPCs in vitro. Moreover, there was a correlation between the clinical stage of GCTs and the expression of tyrosine-phosphorylated Flt-1 and FAK. CONCLUSIONS: Our results suggest that the VEGF-Flt-1-FAK pathway is involved in the pathogenesis of bone destruction of GCTs

Targeting neutrophil extracellular traps with thrombomodulin prevents pancreatic cancer metastasis

Surgery is the only curative treatment option for pancreatic cancer, but patients often develop postoperative recurrence. Surgical invasiveness might be involved in the mechanism of recurrence. The associations among inflammation caused by surgery, neutrophils, and cancer metastasis were investigated. At first, neutrophil extracellular traps (NETs) were examined in clinical specimens, and NETs were observed around metastatic tumors. To explore how NETs were induced, neutrophils were cultured with pancreatic cancer or in cancer-conditioned medium. Neutrophils formed NETs when they were cultured with pancreatic cancer or even its conditioned medium. The effects of NETs on cancer cells were further investigated in vitro and in vivo. NETs induced the epithelial to mesenchymal transition in cancer cells and thereby promoted their migration and invasion. HMGB1 derived from NETs appeared to potentiate the malignancy of cancer cells. In a mouse model of liver metastasis with inflammation, NETs participated in the metastatic process by enhancing extravasation. Interestingly, thrombomodulin degraded HMGB1 and consequently inhibited the induction of NETs, thereby preventing pancreatic cancer metastasis to the liver. In conclusion, NETs interact reciprocally with pancreatic cancer cells, which play a pivotal role in inflammation-associated metastasis. Targeting NETs with thrombomodulin can be a novel strategy to improve the surgical outcome of pancreatic cancer patients