Gemcitabine alters sialic acid binding of the glycocalyx and induces inflammatory cytokine production in cultured endothelial cells.

Gemcitabine (GEM) is an anticancer drug inhibiting DNA synthesis. Glomerular thrombotic microangiopathy (TMA) has been reported as an adverse effect. However, the precise mechanism of GEM-induced endothelial injury remains unknown. Cultured human umbilical vein endothelial cells (HUVECs) in the confluent phase were exposed to GEM (5-100 µM) for 48 h and evaluated cell viability and morphology, lectin binding concerning sialic acid of endothelial glycocalyx (GCX), and immunofluorescent staining of platelet-endothelial cell adhesion molecule (PECAM) and vascular endothelial growth factor receptor 2 (VEGFR2). The mRNA expression of α2,6-sialyltransferase (ST6Gal1), sialidase (neuraminidase-1: NEU-1), and interleukin (IL)-1ß and IL-6 was also evaluated. GEM exposure at 5 µM induced cellular shrinkage and intercellular dissociation, accompanied by slight attenuation of PECAM and VEGFR2 immunostaining, although cell viability was still preserved. At this concentration, lectin binding showed a reduction of terminal sialic acids in endothelial GCX, probably associated with reduced ST6Gal1 mRNA expression. IL-1ß and IL-6 mRNA expression was significantly increased after GEM exposure. GEM reduced terminal sialic acids in endothelial GCX through mRNA suppression of ST6Gal1 and induced inflammatory cytokine production in HUVECs. This phenomenon could be associated with the mechanism of GEM-induced TMA.

A case of ß-catenin-positive hepatocellular adenoma with MR imaging sign of diffuse intratumoral fat deposition.

Hepatocellular adenoma (HCA) is a rare primary benign tumor of the liver, which occurs predominantly in young and middle-aged women. Recently, the subclassification of HCA was proposed by the Bordeaux group. Subsequently, characteristic radiological and clinical features have been revealed in each HCA subtype. According to the previous literature, diffuse intratumoral fat deposition is a very common finding in hepatocyte nuclear factor 1α-negative HCA, but this finding has been reported in ß-catenin-positive HCA in the literature for only one case. In this case report, we report the second case of ß-catenin-positive HCA with MR imaging sign of diffuse intratumoral fat deposition, confirmed immunohistologically on the basis of a surgical specimen. In addition, our case showed hypovascularity and isointensity on the hepatobiliary phase which have been reported as characteristic findings in ß-catenin-positive HCA. Diffuse intratumoral fat deposition can be observed in ß-catenin-positive HCA, which has a greater probability of malignant transformation than other types of HCA.

Perceived Future Outcomes of Unsuccessful Treatment and Their Association with Treatment Persistence Among Type-2 Diabetes Patients: A Cross-Sectional Content Analysis.

INTRODUCTION: Despite the known strong association between patients' knowledge of outcomes of type 2 diabetes mellitus (T2DM) and treatment persistence, this knowledge in this patient population requires further clarification. The aim of our study was to reveal the perception of unsuccessful treatment outcomes among patients with T2DM and its association with treatment persistence by analysing answers to open-ended questions. METHODS: In this cross-sectional study, 106 patients with T2DM who lived in Fukushima Prefecture, Japan, had a medical record in the Fukushima National Health Insurance Organisation database and had no cognitive problems were enrolled by purposive sampling. Treatment status was defined as "non-persistent" when a participant's treatment medical record was absent for a continuous period of ≥ 6 months; otherwise, it was referred to as "persistent". We asked about the possible future problems of untreated T2DM, inductively classified the open answers into 15 codes and then statistically examined the association between these codes and treatment persistence using logistic regression analysis adjusted for age and sex. RESULTS: Persistent treatment was prevalent among participants who mentioned the code "treatment", which encompasses the terms that indicated invasiveness, such as dialysis, insulin injection, and shots (odds ratio 4.339; 95% confidence interval 1.104-17.055). CONCLUSION: Persistent treatment was prevalent among patients with T2DM who mentioned the code "treatment", suggesting that these patients may anticipate a threat due to the invasiveness of diabetes and thus participate in persistent treatment to avoid this threat. Healthcare professionals should provide appropriate information and supportive conditions to achieve both a reduced feeling of threat and persistent treatment engagement.

Crohn's disease may promote inflammation in IgA nephropathy: a case-control study of patients undergoing kidney biopsy.

Intestinal immunity has been closely associated with the pathogenesis and progression of renal diseases, a relationship known as the "gut-kidney axis." To determine the association between immunoglobulin A nephropathy (IgAN) and Crohn's disease (CD), a clinico-pathological study was performed on patients who had IgAN with CD (CD-IgAN) and without CD (NOS-IgAN). We enrolled 29 patients diagnosed with IgAN via renal biopsy at the Tokyo Yamate Medical Center from 2009 to 2017. The patients were divided into CD-IgAN (n = 18) and NOS-IgAN (n = 11) and evaluated for clinical and pathological findings. IgA subclasses and galactose-deficient IgA1 (Gd-IgA1) were examined via immunohistochemistry using formalin-fixed paraffin-embedded sections from renal biopsy. Our results showed no significant difference in the extent of mesangial IgA subclasses or Gd-IgA1 deposition according to the presence or absence of CD. Pathologically, however, those with CD-IgAN had remarkably higher percentage of global glomerulosclerosis and extent of interstitial fibrosis and tubular atrophy (IF/TA) compared to those with NOS-IgAN. Moreover, the extent of macrophage infiltration in the glomerulus and interstitium was significantly higher in CD-IgAN than in NOS-IgAN. Clinically, the CD-IgAN group had significantly worse responsiveness to steroid treatment compared to the NOS-IgAN group. In conclusion, the similar immunological characteristics of deposited IgA molecules in the glomeruli between the CD-IgAN and NOS-IgAN groups might suggest their etiological similarity. However, a renal pathology showing advanced glomerular and tubulointerstitial sclerosis accompanying increased macrophage infiltration and highly resistant clinical features in patients with CD-IgAN suggests that some pathophysiological factors in CD, including abnormal intestinal immunity, may promote and activate the inflammatory process in IgAN via undetermined mechanisms.

High concentration of extracellular nucleotides suppresses cell growth via delayed cell cycle progression in cancer and noncancer cell lines.

Tumor necrosis frequently occurs in malignant tumors, showing rapid growth and invasion. This phenomenon is generally regarded as simple ischemic necrosis due to insufficient tumor vessels and blood supply. However, the necrotic tissue contains high amount of nuclear substances, DNA, and nucleoproteins that may affect the surrounding tumor cells by promoting or suppressing the tumor cell growth in vivo. This study focused on the effects of an externally administered water-soluble nuclear crude extract (SNE) containing nuclear protein and oligonucleotides on several human cancer and noncancer cell lines. The results demonstrated that the SNE suppressed cell growth in cancer and noncancer cells in vitro. Through the flow cytometry analysis of the nuclear DNA content, it was observed that the SNE increased and decreased cell proportion in the S and G2/M phases, respectively, thereby suggesting that the cell growth inhibition was due to cell cycle delay, and not due to apoptosis. These studies suggest that the high-concentration of extracellular nucleotides generated as a result of tumor necrosis and/or released from infiltrated neutrophils could suppress the growth of surrounding cancer and intrinsic cells, which provides us some insights into an alternative anticancer strategy for patients with highly malignant necrotic tumor.

Brain metastasis effectively treated with erlotinib following the acquisition of resistance to gefitinib: a case report.

INTRODUCTION: Non-small-cell lung cancer harboring an activated epidermal growth factor receptor mutation exhibits a good response to epidermal growth factor receptor-tyrosine kinase inhibitors; however, clinicians often experience treatment failure following the development of resistance to epidermal growth factor receptor-tyrosine kinase inhibitor. CASE PRESENTATION: We here report a case of a 56-year-old Japanese woman with non-small-cell lung carcinoma with a secondary T790M mutation associated with resistance to epidermal growth factor receptor-tyrosine kinase inhibitor that maintained sensitivity of brain metastases to epidermal growth factor receptor-tyrosine kinase inhibitor. An autopsy showed that the primary focus had a T790M mutation; however, no mutations of T790M were found in the brain metastases. CONCLUSION: This case demonstrates the detection of T790M was associated with the clinical responsiveness to epidermal growth factor receptor-tyrosine kinase inhibitor.