18F-Fluorodeoxyglucose PET/CT in a Patient with Esophageal and Genital Leiomyomatosis

Diffuse esophageal leiomyomatosis is a rare benign tumor, which can be associated with leiomyoma in female genital tracts involving the uterus, vagina, and vulva. Alport syndrome, an inherited disorder that includes the kidneys, eyes, and sensorineural hearing loss, is also rarely associated with these multiple leiomyomatosis. In our case, 18F-fluoroseoxyglucose positron emission tomography/computed tomography was used to distinguish esophageal and genital leiomyomatosis from malignant masses

MMP9 Processing of HSPB1 Regulates Tumor Progression

Matrix metalloproteinases regulate pathophysiological events by processing matrix proteins and secreted proteins. Previously, we demonstrated that soluble heat shock protein B1 (HSPB1) is released primarily from endothelial cells (ECs) and regulates angiogenesis via direct interaction with vascular endothelial growth factor (VEGF). Here we report that MMP9 can cleave HSPB1 and release anti-angiogenic fragments, which play a key role in tumorprogression. We mapped the cleavage sites and explored their physiological relevance during these processing events. HSPB1 cleavage by MMP9 inhibited VEGF-induced ECs activation and the C-terminal HSPB1 fragment exhibited more interaction with VEGF than did full-length HSPB1. HSPB1 cleavage occurs during B16F10 lung progression in wild-type mice. Also, intact HSPB1 was more detected on tumor endothelium of MMP9 null mice than wild type mice. Finally, we confirmed that secretion of C-terminal HSPB1 fragment was significantly inhibited lung and liver tumor progression of B16F10 melanoma cells and lung tumor progression of CT26 colon carcinoma cells, compared to full-length HSPB1. These data suggest that in vivo MMP9-mediated processing of HSPB1 acts to regulate VEGF-induced ECs activation for tumor progression, releasing anti-angiogenic HSPB1 fragments. Moreover, these findings potentially explain an anti-target effect for the failure of MMP inhibitors in clinical trials, suggesting that MMP inhibitors may have pro-tumorigenic effects by reducing HSPB1 fragmentation

The heme oxygenase-1 genotype is a risk factor to renal impairment of IgA nephropathy at diagnosis, which is a strong predictor of mortality

The induction of heme oxygenase-1 (HO-1) ameliorates oxidative stress and inflammatory process, which play important roles in IgA nephropathy. We hypothesized length polymorphism in the promoter region of the HO-1 gene, which is related to the level of gene transcription, is associated with disease severity of IgA nephropathy. The subjects comprised 916 patients with IgA nephropathy and gene data. Renal impairment was defined as an estimated glomerular filtration rate less than 60 mL/min/1.73 m(2) at diagnosis. The short (S: 28) (GT) repeats in the HO-1 gene was determined. The frequencies of S/S, S/M, M/M, S/L, L/M, and L/L genotypes were 7.2%, 6.9%, 3.1%, 30.8%, 22.7%, and 29.4%, respectively. The baseline characteristics were not different. In the S/S genotypic group, the renal impairment rate was 18.2%, which was lower than 32.2% in the group with M/M, L/M, or L/L genotype. The odds ratio of renal impairment in S/S genotype, compared to that in M/M, L/M, or L/L genotype, was 0.216 (95% confidence interval, 0.060-0.774, p=0.019). The HO-1 gene promoter length polymorphism was related to the renal impairment of IgA nephropathy at diagnosis, which is an important risk factor for mortality in IgA nephropathy patients

Association of Angiotensin II Type 2 Receptor Gene A1818T Polymorphism with Progression of Immunoglobulin A Nephropathy in Korean Patients

We determined the relationship between the progression of immunoglobulin A nephropathy (IgAN) and the A1818T polymorphism in intron 2 of Angiotensin II type 2 receptor (AT2R) gene, which might play protective roles in the pathogenesis of IgAN. Patients with biopsy-proven IgAN were recruited from the registry of the Progressive REnal disease and Medical Informatics and gEnomics Research (PREMIER) which was sponsored by the Korean Society of Nephrology. A1818T polymorphism of AT2R gene was analyzed with PCR-RFLP method and the association with the progression of IgAN, which was defined as over 50% increase in baseline serum creatinine level, was analyzed with survival analysis. Among the 480 patients followed for more than 10 months, the group without T allele had significantly higher rates of progression of IgAN than the group with T allele (11.4% vs. 3.9%, p=0.024), although there were no significant differences in the baseline variables such as initial serum creatinine level, the degree of proteinuria, and blood pressure. In the Cox's proportional hazard model, the hazard ratio of disease progression in the patients with T allele was 0.221 (95% confidence interval for Exp(B): 0.052-0.940, p=0.041) compared to that of without T allele. In conclusion, A1818T polymorphism of AT2R gene was associated with the progression of IgAN

NAD(P)-dependent steroid dehydrogenase-like is involved in breast cancer cell growth and metastasis

The cholesterol biosynthesis pathway is typically upregulated in breast cancer. The role of NAD(P)-dependent steroid dehydrogenase-like (NSDHL) gene, which is involved in cholesterol biosynthesis, in breast cancer remains unknown. This study aimed to uncover the role of NSDHL in the growth and metastasis of breast cancer. After NSDHL knockdown by transfection of short interfering RNA into human breast cancer cell lines (MCF-7, MDA-MB-231 and BT-20) and human breast epithelial cell line (MCF10A), cell proliferation assay, cell cycle analysis, three-dimensional cell culture, clonogenic assay, transwell migration and invasion assays, and wound healing assay were performed. Erlotinib was used as the target drug for epidermal growth factor receptor. Immunodeficient mice (NOD.Cg-Prkdcscid Il2rgtm1wjl /SzJ) were used as orthotropic breast tumor models by injecting them with NSDHL-knockdown MDA-MB-231 cells using lentivirus-carrying NSDHL short hairpin RNA. Clinical data from 3951 breast cancer patients in Gene Expression Omnibus databases were used to investigate the potential prognostic role of NSDHL by survival analysis. NSDHL knockdown in BT-20, and MDA-MB-231 resulted in a significant decrease in their viability, colony formation, migration, and invasion abilities (p < 0.05). Total cholesterol levels were observed to be significantly decreased in NSDHL-knockdown BT-20 and MDA-MB-231 (p < 0.0001). NSDHL knockdown significantly increased the rate of erlotinib-induced cell death, especially in MDA-MB-231 (p = 0.01). NSDHL knockdown led to significantly decreased tumor growth and lung metastasis in the MDA-MB-231 xenograft model (p < 0.01). Clinically, high NSDHL expression in tumors of patients with breast cancer was associated with significantly reduced recurrence-free survival (p < 0.0001). NSDHL might have a role in promoting breast cancer progression. The usage of NSDHL as a therapeutic target in breast cancer needs to be clarified in further studies.This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2018R1A2A2A05022732). The funding body had no role in the design of the study and collection, analysis, and interpretation of data, nor in writing the manuscrip

The Mildly Elevated Serum Bilirubin Level is Negatively Associated with the Incidence of End Stage Renal Disease in Patients with IgA Nephropathy

Oxidative stress plays various roles in the development and progression of IgA nephropathy, while bilirubin is known as a potent antioxidant. We therefore hypothesized that serum bilirubin would be associated with renal prognosis in IgA nephropathy. The study subjects comprised 1,458 adult patients with primary IgA nephropathy in Korea. We grouped patients according to the following quartile levels of bilirubin: <0.4 mg/dL (Q1), 0.4-0.5 mg/dL (Q2), 0.6-0.7 mg/dL (Q3), and >0.8 mg/dL (Q4). The outcome data were obtained from the Korean Registry of end-stage renal disease (ESRD). Eighty patients (5.5%) contracted ESRD during a mean follow-up period of 44.9 months. The ESRD incidences were 10.7% in Q1, 8.2% in Q2, 2.8% in Q3, and 2.8% in Q4 (p<0.001). The relative risk of ESRD compared to that in Q1 was 0.307 (95% confidence interval [CI], 0.126-0.751) in Q3 and 0.315 (95% CI, 0.130-0.765) in Q4. The differences of ESRD incidence were greater in subgroups of males and of patients aged 35 yr or more, with serum albumin 4.0 g/dL or more, with normotension, with eGFR 60 mL/min/1.73 m2 or more, and with proteinuria less then 3+ by dipstick test. In conclusion, higher bilirubin level was negatively associated with ESRD incidence in IgA nephropathy

A novel gene mutation in a fatal neonate case with type 2 familial hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) occurs in the primary form (genetic or familial) or secondary form (acquired). The familial form of HLH (FHL) is a potentially fatal autosomal recessive disorder that occurs because of constitutional defects in cell-mediated cytotoxicity. Here, we report a fatal neonatal case of type 2 FHL (FHL2) that involved a novel frameshift mutation. Clinically, the newborn presented with severe sepsis-like features and required mechanical ventilation and continuous venovenous hemodiafiltration. Flow cytometry analysis showed marked HLH and complete absence of intracytoplasmic perforin expression in cytotoxic cells; therefore, we performed molecular genetic analyses for PRF1 mutations, which showed that the patient had a compound heterozygous mutation in PRF1, that is, c.65delC (p.Pro22Argfs*2) and c.1090_1091delCT (p.Leu364Glufs*93). Clinical and genetic assessments for FHL are required for neonates with refractory fever and progressive multiple organ failure, particularly when there is no evidence of microbiological or metabolic cause