MRI Features May Predict Molecular Features of Glioblastoma in Isocitrate Dehydrogenase Wild-Type Lower-Grade Gliomas.

BACKGROUND AND PURPOSE: Isocitrate dehydrogenase (IDH) wild-type lower-grade gliomas (histologic grades II and III) with epidermal growth factor receptor (EGFR) amplification or telomerase reverse transcriptase (TERT) promoter mutation are reported to behave similar to glioblastoma. We aimed to evaluate whether MR imaging features could identify a subset of IDH wild-type lower-grade gliomas that carry molecular features of glioblastoma. MATERIALS AND METHODS: In this multi-institutional retrospective study, pathologically confirmed IDH wild-type lower-grade gliomas from 2 tertiary institutions and The Cancer Genome Atlas constituted the training set (institution 1 and The Cancer Genome Atlas, 64 patients) and the independent test set (institution 2, 57 patients). Preoperative MRIs were analyzed using the Visually AcceSAble Rembrandt Images and radiomics. The molecular glioblastoma status was determined on the basis of the presence of EGFR amplification and TERT promoter mutation. Molecular glioblastoma was present in 73.4% and 56.1% in the training and test sets, respectively. Models using clinical, Visually AcceSAble Rembrandt Images, and radiomic features were built to predict the molecular glioblastoma status in the training set; then they were validated in the test set. RESULTS: In the test set, a model using both Visually AcceSAble Rembrandt Images and radiomic features showed superior predictive performance (area under the curve = 0.854) than that with only clinical features or Visually AcceSAble Rembrandt Images (areas under the curve = 0.514 and 0.648, respectively; P < . 001, both). When both Visually AcceSAble Rembrandt Images and radiomics were added to clinical features, the predictive performance significantly increased (areas under the curve = 0.514 versus 0.863, P < .001). CONCLUSIONS: MR imaging features integrated with machine learning classifiers may predict a subset of IDH wild-type lower-grade gliomas that carry molecular features of glioblastoma.

Whole-Tumor Histogram and Texture Analyses of DTI for Evaluation of IDH1-Mutation and 1p/19q-Codeletion Status in World Health Organization Grade II Gliomas.

BACKGROUND AND PURPOSE: Prediction of the isocitrate dehydrogenase 1 (IDH1)-mutation and 1p/19q-codeletion status of World Health Organization grade ll gliomas preoperatively may assist in predicting prognosis and planning treatment strategies. Our aim was to characterize the histogram and texture analyses of apparent diffusion coefficient and fractional anisotropy maps to determine IDH1-mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas. MATERIALS AND METHODS: Ninety-three patients with World Health Organization grade II gliomas with known IDH1-mutation and 1p/19q-codeletion status (18 IDH1 wild-type, 45 IDH1 mutant and no 1p/19q codeletion, 30 IDH1-mutant and 1p/19q codeleted tumors) underwent DTI. ROIs were drawn on every section of the T2-weighted images and transferred to the ADC and the fractional anisotropy maps to derive volume-based data of the entire tumor. Histogram and texture analyses were correlated with the IDH1-mutation and 1p/19q-codeletion status. The predictive powers of imaging features for IDH1 wild-type tumors and 1p/19q-codeletion status in IDH1-mutant subgroups were evaluated using the least absolute shrinkage and selection operator. RESULTS: Various histogram and texture parameters differed significantly according to IDH1-mutation and 1p/19q-codeletion status. The skewness and energy of ADC, 10th and 25th percentiles, and correlation of fractional anisotropy were independent predictors of an IDH1 wild-type in the least absolute shrinkage and selection operator. The area under the receiver operating curve for the prediction model was 0.853. The skewness and cluster shade of ADC, energy, and correlation of fractional anisotropy were independent predictors of a 1p/19q codeletion in IDH1-mutant tumors in the least absolute shrinkage and selection operator. The area under the receiver operating curve was 0.807. CONCLUSIONS: Whole-tumor histogram and texture features of the ADC and fractional anisotropy maps are useful for predicting the IDH1-mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas.

Prediction of IDH1-Mutation and 1p/19q-Codeletion Status Using Preoperative MR Imaging Phenotypes in Lower Grade Gliomas.

BACKGROUND AND PURPOSE: WHO grade II gliomas are divided into three classes: isocitrate dehydrogenase (IDH)-wildtype, IDH-mutant and no 1p/19q codeletion, and IDH-mutant and 1p/19q-codeleted. Different molecular subtypes have been reported to have prognostic differences and different chemosensitivity. Our aim was to evaluate the predictive value of imaging phenotypes assessed with the Visually AcceSAble Rembrandt Images lexicon for molecular classification of lower grade gliomas. MATERIALS AND METHODS: MR imaging scans of 175 patients with lower grade gliomas with known IDH1 mutation and 1p/19q-codeletion status were included (78 grade II and 97 grade III) in the discovery set. MR imaging features were reviewed by using Visually AcceSAble Rembrandt Images (VASARI); their associations with molecular markers were assessed. The predictive power of imaging features for IDH1-wild type tumors was evaluated using the Least Absolute Shrinkage and Selection Operator. We tested the model in a validation set (40 subjects). RESULTS: Various imaging features were significantly different according to IDH1 mutation. Nonlobar location, larger proportion of enhancing tumors, multifocal/multicentric distribution, and poor definition of nonenhancing margins were independent predictors of an IDH1 wild type according to the Least Absolute Shrinkage and Selection Operator. The areas under the curve for the prediction model were 0.859 and 0.778 in the discovery and validation sets, respectively. The IDH1-mutant, 1p/19q-codeleted group frequently had mixed/restricted diffusion characteristics and showed more pial invasion compared with the IDH1-mutant, no codeletion group. CONCLUSIONS: Preoperative MR imaging phenotypes are different according to the molecular markers of lower grade gliomas, and they may be helpful in predicting the IDH1-mutation status.

Risk factors to predict the development of chronic kidney disease in patients with lupus nephritis.

Objectives We analyzed the clinical follow-up results of 88 lupus nephritis patients to find prognostic factors for the development of chronic kidney disease in ethnically homogeneous Korean patients with biopsy-proven lupus nephritis. Methods Sociodemographic, clinical, laboratory, and treatment-related data at the time of kidney biopsy and during follow-up were obtained. Renal biopsy specimens were reclassified according to the International Society of Pathology/Renal Pathology Society classification, separately, by two renal pathologists blinded to the previous classification. Univariate and multivariate analyses were performed using the Cox proportional hazard regression model to identify independent risk factors for chronic kidney disease in lupus nephritis patients. Results Eighteen of 88 patients (20.5%) developed chronic kidney disease during a mean follow-up of 47.6 months (range: 12-96 months). Patients who developed chronic kidney disease were older at onset of lupus nephritis, had less education, and were more likely to have hypertension; they had lower serum albumin levels, lower platelet levels, higher serum creatinine levels, lower estimated glomerular filtration rate, higher chronicity index, and lower frequency of anti-ribosomal P antibodies, and they were less likely to be in complete remission in the first year. In stepwise multivariable analyses, hypertension, lower glomerular filtration rate, and failure to achieve complete remission in the first year of treatment were significant predictors of the development of chronic kidney disease in lupus nephritis patients. Conclusions These findings suggest that patients with hypertension and decreased kidney function at the onset of lupus nephritis and showing a poor response to immunosuppressive drugs in the first year should be monitored carefully and managed aggressively to avoid deterioration of kidney function.

Diet-induced obesity reduces the production of influenza vaccine-induced antibodies via impaired macrophage function.

Obesity is a metabolic disease characterized by low-level chronic inflammation. Obese individuals are susceptible to infection by viruses, and vaccination against these pathogens is less effective than in nonobese individuals. Here, we sought to explore the immunological environment in a mouse model of obesity induced by a high-fat diet (HFD). HFD treatment increased the body weight and epididymal fat mass. The proportion of activated B cells, T cells, and macrophages was similar between mice in the HFD group and the regular-fat diet (RFD) group. The Th1 cell subpopulation in the HFD group was increased, whereas the proportion of Treg cells was reduced compared with the RFD group. Moreover, T-cell proliferation and cytokine production did not differ between the groups when cells were stimulated with anti-CD3 and anti-CD28 antibodies in vitro. In macrophages, phagocytic activity was higher in mice fed an HFD than in those fed an RFD, but expression levels of CD86 and MHC class II antigens were similar. When macrophages were cultured in vitro, the proportion of CD86-expressing macrophages was lower in those isolated from mice in the HFD group than in those isolated from the RFD group. Furthermore, lipopolysaccharide-induced interleukin 6 (IL-6) and tumor necrosis factor alpha secretions were significantly reduced in macrophages isolated from the HFD group. In addition, influenza vaccine-induced antibodies in the HFD group diminished more rapidly than in the RFD group. These results suggest that poor functionality of macrophages during obesity might contribute to a reduction in vaccine efficacy.

Lhx2 regulates bone remodeling in mice by modulating RANKL signaling in osteoclasts.

The LIM homeobox 2 (Lhx2) transcription factor Lhx2 has a variety of functions, including neural induction, morphogenesis, and hematopoiesis. Here we show the involvement of Lhx2 in osteoclast differentiation. Lhx2 was strongly expressed in osteoclast precursor cells but its expression was significantly reduced during receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis. Overexpression of Lhx2 in bone marrow-derived monocyte/macrophage lineage cells (BMMs), which are osteoclast precursor cells, attenuated RANKL-induced osteoclast differentiation by inhibiting the induction of nuclear factor of activated T cells c1 (NFATc1). Interestingly, interaction of Lhx2 proteins with c-Fos attenuated the DNA-binding ability of c-Fos and thereby inhibited the transactivation of NFATc1. Furthermore, Lhx2 conditional knockout mice exhibited an osteoporotic bone phenotype, which was related with increased osteoclast formation in vivo. Taken together, our results suggest that Lhx2 acts as a negative regulator of osteoclast formation in vitro and in vivo. The anti-osteoclastogenic effect of Lhx2 may be useful for developing a therapeutic strategy for bone disease.

Identification of a pivotal endocytosis motif in c-Met and selective modulation of HGF-dependent aggressiveness of cancer using the 16-mer endocytic peptide.

Since c-Met has an important role in the development of cancer, it is considered as an attractive target for cancer therapy. Although molecular mechanisms for oncogenic property of c-Met have been actively investigated, regulatory elements for c-Met endocytosis and its effect on c-Met signaling remain unclear. In this study, we identified a pivotal endocytic motif in c-Met and tested it for selective modulation of HGF-induced c-Met response. Using various chimeric constructs with the cytoplasmic tail of c-Met, we were able to demonstrate that a dileucine motif located in the C-terminus of c-Met acts to regulate its endocytosis. Synthetic peptide Ant-3S, consisting of antennapedia-derived protein transduction domain (designated as Ant) and c-Met-derived 16 amino-acids (designated as 3S, spanning amino-acids 1378 to 1393), rapidly moved into cancer cells and disrupted c-Met trafficking. Importantly, an extension of c-Met retention time on the membrane by Ant-3S peptide significantly decreased phosphorylation-dependent c-Met signal transduction. Additionally, the peptide effectively inhibited HGF-induced cell growth, scattering and migration. The underlying molecular mechanism for these observations has been investigated and revealed that the dileucine motif interacts with endocytic machinery, including adaptin ß and caveolin-1, for sustained and enhanced signal transduction. Finally, Ant-3S peptide specifically blocked internalization of interleukin-2 receptor α-subunit/3S chimeric protein, but not the other receptors, including Glut4, Glut8 and transferrin receptor. Such results indicate the presence of a selective endocytic assembly for c-Met. It also suggests a potential for c-Met-specific anti-cancer therapy using the identified endocytic motif in this study.

Successful treatment using cyclosporine in a patient with rhupus complicated by aplastic anemia: a case report and review of the literature.

Systemic lupus erythematosus (SLE) co-morbid with rheumatoid arthritis (RA) is known as 'Rhupus syndrome' and is estimated to be present in between 0.01 and 2% of SLE and RA patients. The occurrence of aplastic anaemia in a patient with rhupus is very rare and a treatment for this condition has not been reported. A 52-year-old woman presented complaining of nausea and dizziness during the preceding month. She had been treated for rheumatoid arthritis for 16 years. At the time of presentation, she had a malar rash, multiple arthritis, pancytopenia, pleural effusion, proteinuria, and positive anti-nuclear and anti-dsDNA antibodies. A kidney biopsy revealed ISN/RPS class IV-G (A) lupus nephritis. Bone marrow aspiration and biopsy showed aplastic anaemia with no evidence of viral infection. The patient was successfully treated using cyclosporine and prednisolone and she remained symptom-free at the one-and-a-half-year follow-up. To our knowledge, this is the first report of a successful treatment using cyclosporine in a patient with rhupus complicated by aplastic anaemia.

A unit-coordinator system: an effective method of reducing inappropriate hospital stays.

BACKGROUND: Many hospitals would benefit from a reduction in the length of inpatient hospital stays; in this regard, nursing approaches require complementation to ensure optimized nursing care. Such action is particularly important in general hospitals in Korea, where the ratio of patients to nurses is more than 10:1. OBJECTIVES: This study aimed to determine the effectiveness of a unit-coordinator system in complementing primary nursing in general hospitals as a means of reducing inappropriate hospital stays. METHODS: The unit-coordinator system was implemented in seven wards in a hospital in Seoul for 8 weeks. The existing primary nursing system was maintained, and newly placed unit-coordinators organized the activities within each ward. The numbers of early admissions and early discharges were determined by assessing the electronic administrative records of the hospital. Further, the number of patients who had undergone check-ups and chemotherapy on the day of admission was confirmed from the daily reports of each ward. The effect of the unit-coordinator system on nurse satisfaction was assessed through direct interviews. FINDINGS: Early-discharge and early-admission numbers increased significantly after implementation of the unit-coordinator system. Early admission allowed check-ups and treatments to be performed on the day of admission. Thus, this system reduced the length of hospital stay by 1 day, and the total reduction of inappropriate hospital stays over the 8-week study period was 66 days. Further, the unit-coordinator system also increased nurse satisfaction. CONCLUSION: The unit-coordinator system is an effective method of complementing primary nursing and reducing inappropriate hospital stays.

Pancreatic adenocarcinoma upregulated factor promotes metastasis by regulating TLR/CXCR4 activation.

Pancreatic adenocarcinoma upregulated factor (PAUF) is overproduced in certain types of cancer. However, little is known of the tumorigenic function of PAUF. In this study, we report the X-ray crystal structure of PAUF and reveal that PAUF is a mammalian lectin normally found in plant lectins. We also identify PAUF as an endogenous ligand of Toll-like receptor 2 (TLR2) and TLR4 by screening extracellular domain receptor pools. We further confirmed the specificity of the PAUF-TLR2 interaction. PAUF induces extracellular signal-regulated kinase (ERK) phosphorylation and activates the IKK-ß-mediated TPL2/MEK/ERK signaling pathway through TLR2. In agreement with the result of TLR2-mediated ERK activation by PAUF, PAUF induces increased expression of the protumorigenic cytokines RANTES and MIF in THP-1 cells. However, PAUF does not fully activate Iκ-B-α signaling pathways in THP-1 cells, and fails to translocate the p65 subunit of the nuclear factor-κB (NF-κB) complex into the nucleus, resulting in no NF-κB activation. Surprisingly, we found that PAUF also associated with the CXC chemokine receptor (CXCR4)-TLR2 complex and inhibited CXCR4-dependent, TLR2-mediated NF-κB activation. Together, these findings suggest that the new cancer-associated ligand, PAUF, may activate TLR-mediated ERK signaling to produce the protumorigenic cytokines, but inhibits TLR-mediated NF-κB signaling, thereby facilitating tumor growth and escape from innate immune surveillance.

De novo appearance of primitive neuroectodermal tumor in a patient with systemic lupus erythematosus and moyamoya disease.

Primitive neuroectodermal tumor is a rare brain tumor composed of undifferentiated or poorly differentiated neuroepithelial cells with a high malignant potential that usually occurs in children, and which is only occasionally encountered in adults. A 19-year-old female with systemic lupus erythematosus presented with right hemiparesis and a headache of 10 days duration. Brain magnetic resonance imaging showed a large solid mass with necrotic portions in the left frontoparietal lobe. Primitive neuroectodermal tumor was confirmed by a neuronavigator-guided brain biopsy. This is the first case report of primitive neuroectodermal tumor associated with systemic lupus erythematosus and moyamoya disease. This case demonstrates that brain tumors, such as primitive neuroectodermal tumor, should be included in the differential diagnosis of neurological manifestations in children and adolescent patients with systemic lupus erythematosus.

Lupus-associated pancreatitis complicated by pancreatic pseudocyst and central nervous system vasculitis.

Pancreatitis is an uncommon manifestation of systemic lupus erythematosus (SLE), but this can occasionally cause major complications. We report in this article, a case of 33-year-old female patient who developed lupus-associated pancreatitis that was subsequently complicated by pancreatic pseudocyst and central nervous system (CNS) vasculitis. Abdominal computed tomography (CT) showed an oedematous swelling of the pancreas and a pseudocyst measuring 4 x 3 cm2. Brain magnetic resonance imaging (MRI) showed multiple high-signal intensity lesions in both cerebral hemispheres. The pseudocyst did not completely resolve with high-dose steroid therapy, and it was later complicated by infection and rupture. After a surgical drainage for the complicated pseudocyst, her clinical symptoms and signs were markedly improved. This case shows the importance of performing early drainage rather than conservative treatment for a pancreatic pseudocyst in a patient with lupus-associated pancreatitis.

Moyamoya syndrome associated with systemic lupus erythematosus.

Moyamoya disease is a rare, progressive cerebrovascular disorder that is characterized by a stenosis or occlusion of the bilateral internal carotid arteries and the development of collateral vessels. Transient ischemic attacks or seizures are the usual presentation of moyamoya disease in children, whereas cerebral hemorrhage is the most common symptom in adults. We report an 18-year-old female patient with active lupus nephritis who presented with the sudden onset of left hemiparesis. Brain magnetic resonance imaging showed acute infarctions in the right basal ganglia and subcortical white matter of the right frontal lobe. Cerebral angiography showed the stenosis of the bilateral internal carotid arteries with rich basal collateral vessels (moyamoya vessels). There was no evidence of atherosclerosis or antiphospholipid syndrome. Glucocorticoid therapy was used to control the systemic lupus erythematosus. Prophylactic bypass surgery was performed to prevent recurrent ischemic attacks. This case report shows that an underlying cerebrovascular lesion of moyamoya vessels in a patient with systemic lupus erythematosus is susceptible to cerebrovascular accidents.

TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial-mesenchymal transition.

TMPRSS4 is a novel type II transmembrane serine protease found at the cell surface that is highly expressed in pancreatic, colon and gastric cancer tissues. However, the biological functions of TMPRSS4 in cancer are unknown. Here we show, using reverse transcription-PCR, that TMPRSS4 is highly elevated in lung cancer tissues compared with normal tissues and is also broadly expressed in a variety of human cancer cell lines. Knockdown of TMPRSS4 by small interfering RNA treatment in lung and colon cancer cell lines was associated with reduction of cell invasion and cell-matrix adhesion as well as modulation of cell proliferation. Conversely, the invasiveness, motility and adhesiveness of SW480 colon carcinoma cells were significantly enhanced by TMPRSS4 overexpression. Furthermore, overexpression of TMPRSS4 induced loss of E-cadherin-mediated cell-cell adhesion, concomitant with the induction of SIP1/ZEB2, an E-cadherin transcriptional repressor, and led to epithelial-mesenchymal transition events, including morphological changes, actin reorganization and upregulation of mesenchymal markers. TMPRSS4-overexpressing cells also displayed markedly increased metastasis to the liver in nude mice upon intrasplenic injection. Taken together, these studies suggest that TMPRSS4 controls the invasive and metastatic potential of human cancer cells by facilitating an epithelial-mesenchymal transition; TMPRSS4 may be a potential therapeutic target for cancer treatment.

Expression profile of tight junction protein claudin 3 and claudin 4 in ovarian serous adenocarcinoma with prognostic correlation.

Tight junction proteins claudin 3 (CLDN3) and claudin 4 (CLDN4) are frequently altered in several human cancers, including ovarian carcinomas. Here, we examined the gene expression of CLDN3 and CLDN4 in various tumors, including 19 normal ovaries and 47 ovarian carcinomas by analyzing Affymetrix HG-U133 array data. Furthermore, a total of 114 ovarian serous tumors, including 10 adenomas, 20 borderline tumors and 84 carcinomas, were analyzed immunohistochemically to confirm the expression of two proteins and we assessed the association of their expression with the clinicopathological characteristics and survival of the patients. The microarray experiment revealed CLDN3 and CLDN4 transcripts were significantly up-regulated by 5-fold or more in most subtypes of ovarian epithelial carcinomas while the immunohistochemical analyses indicated that each protein was expressed in 68 (81.0%) and 72 (85.7%) of 84 serous adenocarcinomas, respectively. Borderline serous tumors and adenomas showed significantly lower expression of these proteins than the adenocarcinomas. Kaplan-Meier survival analysis showed that serous adenocarcinoma patients with high CLDN3 expression had substantially shorter survival (P=0.027). Multivariate analysis demonstrated that CLDN3 overexpression is an independent negative prognostic factor. Our findings suggest that CLDN3 overexpression can be used as a prognostic indicator in ovarian serous carcinomas. Moreover, CLDN3 may be a promising target for antibody-based therapy of ovarian carcinomas.

The novel -G646A polymorphism of the TNFalpha promoter is associated with the HLA-B51 allele in Korean patients with Behçet's disease.

OBJECTIVE: This study was performed to examine the influence of tumour necrosis factor-alpha (TNFalpha) promoter polymorphisms on disease susceptibility and clinical features of Behçet's disease (BD) and the association between TNFalpha polymorphisms and human leucocyte antigen (HLA)-B51. METHODS: We examined 115 patients with BD and 114 healthy subjects. Six single nucleotide polymorphisms (SNPs) of the TNFalpha promoter at positions -1031, -863, -857, -308, -238, and -646 were analysed using automated sequencing. We compared the frequencies of alleles and genotypes in patients with BD and controls using the chi(2)-test or Fisher's exact test. Haplotype frequency was also assessed using the chi(2)-test. RESULTS: We found no significant differences in the frequencies of polymorphic genotypes and alleles of the TNFalpha promoter region between BD patients and controls. The resulting haplotype frequencies of the BD patients were also not significantly different from those of controls. None of the TNFalpha promoter polymorphisms analysed here were associated with clinical features. Patients with the novel -646A allele of the TNFalpha promoter region were significantly associated with the expression of the HLA-B51 allele (p(corr) = 0.006), although this novel polymorphic allele was not associated with BD susceptibility. CONCLUSION: The novel -646A TNFalpha allele was associated with the expression of HLA-B51 in Korean BD, although we found no genetic role of TNFalpha promoter polymorphisms in the susceptibility to BD. Further studies to examine the contributions of this gene polymorphism and HLA-B51 to the susceptibility to BD in large populations are required.

Enzymatic interesterification of tripalmitin with vegetable oil blends for formulation of caprine milk infant formula analogs.

The structure of triacylglycerols in vegetable oil blends was enzymatically modified, and the blends were incorporated into skim caprine milk to produce goat milk-based infant formula analogs, homologous to human milk. A modified lipid containing palmitic, oleic, and linoleic acids, resembling the composition of human milk fat, was synthesized by enzymatic interesterification reactions between tripalmitin and a vegetable oil blend containing a 2.5:1.1:0.8 ratio of coconut, safflower, and soybean oils. A commercial sn-1,3-specific lipase obtained from Rhyzomucor miehei, Lipozyme RM IM, was used as the biocatalyst. The effects of substrate molar ratio and reaction time on the incorporation of palmitic, oleic, and linoleic acids at the sn-2 position of the triacylglycerols were investigated. The fatty acid composition and sn-2 position of the experimental formulas were analyzed using gas chromatography. Results showed that the highest incorporation of palmitic acid was obtained at 12 h of incubation at 55 degrees C with a substrate molar ratio of 1:0.4 of tripalmitin to vegetable oil blend. However, the modified milk interesterified for 12 h at a 1:1 molar ratio had a greater resemblance to human milk compared with the other formulas. The level of oleic acid incorporation at the sn-2 position increased with the molar ratio of tripalmitin to vegetable oil blend. It was concluded that, unlike the original goat milk and other formulas, the formulated caprine milk with a molar ratio of 1:1 and a 12-h incubation was similar to the fatty acid composition of human milk.