Efficacy and Mechanism of Antitumor Activity of an Antibody Targeting Transferrin Receptor 1 in Mouse Models of Human Multiple Myeloma.

The transferrin receptor 1 (TfR1) is an attractive target for Ab-mediated cancer therapy. We previously developed a mouse/human chimeric IgG3 Ab (ch128.1) targeting human TfR1, which exhibits direct in vitro cytotoxicity against certain human malignant B cells through TfR1 degradation and iron deprivation. ch128.1 also demonstrates exceptional antitumor activity against the B cell malignancy multiple myeloma (MM) in xenograft models of SCID-Beige mice bearing either disseminated ARH-77 or KMS-11 cells in an early disease setting. Interestingly, this activity is observed even against KMS-11 cells, which show no sensitivity to the direct cytotoxic activity of ch128.1 in vitro. To understand the contributions of the Fc fragment, we generated a ch128.1 mutant with impaired binding to FcγRs and to the complement component C1q, which retains binding to the neonatal Fc receptor. We now report that this mutant Ab does not show antitumor activity in these two MM models, indicating a crucial role of the Fc fragment in the antitumor activity of ch128.1, which can be attributed to effector functions (Ab-dependent cell-mediated cytotoxicity, Ab-dependent cell-mediated phagocytosis, and/or complement-dependent cytotoxicity). Interestingly, in the KMS-11 model, complement depletion does not affect protection, whereas macrophage depletion does. Consistent with this observation, we found that ch128.1 induces Ab-dependent cell-mediated cytotoxicity and Ab-dependent cell-mediated phagocytosis against KMS-11 cells in the presence of murine bone marrow-derived macrophages. Finally, we found that ch128.1 therapy effectively increases survival in a late MM disease setting. Our results suggest that macrophages play a major role in ch128.1-mediated antitumor protection in our models and that ch128.1 can be effective against human B cell malignancies such as MM.

Asp30 of Aspergillus oryzae cutinase CutL1 is involved in the ionic interaction with fungal hydrophobin RolA.

Aspergillus oryzae hydrophobin RolA adheres to the biodegradable polyester polybutylene succinate-co-adipate (PBSA) and promotes PBSA degradation by interacting with A. oryzae polyesterase CutL1 and recruiting it to the PBSA surface. In our previous studies, we found that positively charged amino acid residues (H32, K34) of RolA and negatively charged residues (E31, D142, D171) of CutL1 are important for the cooperative ionic interaction between RolA and CutL1, but some other charged residues in the triple mutant CutL1-E31S/D142S/D171S are also involved. In the present study, on the basis of the 3D-structure of CutL1, we hypothesized that D30 is also involved in the CutL1-RolA interaction. We substituted D30 with serine and performed kinetic analysis of the interaction between wild-type RolA and the single mutant CutL1-D30S or quadruple mutant CutL1-D30S/E31S/D142S/D171S by using quartz crystal microbalance. Our results indicate that D30 is a novel residue involved in the ionic interaction between RolA and CutL1.

Nestin Expression in the Adult Mouse Retina with Pharmaceutically Induced Retinal Degeneration.

The present study investigated the temporal pattern and cellular localization of nestin in the adult mouse retina with pharmaceutically induced retinal degeneration using N-methyl-N-nitrosourea (MNU). After a single intraperitoneal injection of MNU in 8-week-old C57BL/6 mice, the animals were sacrificed at 1, 3, 5, 7, and 21 days (n = 6, in each stage). The eyes were examined by means of immunohistochemical tests using nestin, ionized calcium-binding adaptor molecule (Iba-1), CD11b, F4/80, and glial fibrillary acidic protein (GFAP). Western blot analysis and manual cell counting were performed for quantification. Nestin expression was increased after MNU administration. Nestin+/Iba-1+ cells were migrated into outer nuclear layer (ONL) and peaked at day 3 post injection (PI). Nestin+/CD11b+ cells were also mainly identified in ONL at day 3 PI and peaked at day 5. Nestin+/F4/80+ cells were shown in the subretinal space and peaked at day 3 PI. Nestin+/GFAP+ cells were distinctly increased at day 1 PI and peaked at day 5 PI. The up-regulation of nestin expression after MNU administration in adult mouse retinal microglia, and monocyte/macrophage suggests that when retinal degeneration progresses, these cells may revert to a more developmentally immature state. Müller cells also showed reactive gliosis and differentiational changes.

Changes in Corneal Curvature After Upper Eyelid Surgery Measured by Corneal Topography.

PURPOSE: To analyze corneal curvature changes (eg, central corneal power and corneal astigmatism) after upper eyelid surgery, and to compare the effects of different upper eyelid procedures on corneal curvature. METHODS: Fifty eyes of 34 patients with various degrees of dermatochalasis or ptosis underwent corneal topography before surgery, and at 6 weeks after blepharoplasty or levator resection. Patients were divided into groups according to the method of surgery. Preoperative and postoperative changes in corneal curvature of each operated eye were compared within each group. RESULTS: At 6 weeks after levator resection, 50% of the eyes showed an increase in corneal power, 34.6% showed a decrease, and 15.4% showed no change. The corneal astigmatism in 50% of eyes with levator resection decreased, increased in 19.2% of eyes, and showed no change in 30.8% of eyes. At 6 weeks after blepharoplasty, 12.5% of the eyes showed an increase in corneal power, 37.5% showed a decrease, and 66.7% showed no change. Regarding corneal astigmatism in patients who underwent blepharoplasty, 16.7% of the eyes decreased, 16.7% increased, and 66.6% showed no change. Comparing eyes treated with the 2 surgical techniques, there was a statistical difference in the percentage eye which showed corneal diopter and astigmatism change using these 2 techniques (P < 0.05). CONCLUSION: Repositioning of the upper eyelid after levator resection showed greater changes of corneal curvature (eg, central corneal power and corneal astigmatism) than blepharoplasty. The advanced aponeurosis technique may have a greater effect on the lid/cornea interface, by lifting the eyelids pressing against the eyeball to affect corneal curvature.

Ultra-Low-Dose CT of the Thorax Using Iterative Reconstruction: Evaluation of Image Quality and Radiation Dose Reduction.

OBJECTIVE: The purpose of this study is to assess the image quality and radiation dose reduction of ultra-low-dose CT using sinogram-affirmed iterative reconstruction (SAFIRE). SUBJECTS AND METHODS: This prospective study enrolled 25 patients who underwent three consecutive unenhanced CT scans including low-dose CT (120 kVp and 30 mAs) and two ultra-low-dose CT protocols (protocol A, 100 kVp and 20 mAs; protocol B, 80 kVp and 30 mAs) with image reconstruction using SAFIRE. The image quality and radiation dose reduction were assessed. RESULTS: The mean (± SD) effective radiation dose was 1.06 ± 0.11, 0.44 ± 0.05, and 0.31 ± 0.03 mSv for low-dose CT, ultra-low-dose CT protocol A, and ultra-low-dose CT protocol B, respectively. Overall image quality was determined as diagnostic in 100% of low-dose CT scans, 96% of ultra-low-dose CT protocol A scans, and 88% of ultra-low-dose CT protocol B scans. All patients with nondiagnostic quality images had a body mass index (weight in kilograms divided by the square of height in meters) greater than 25. There was no statistically significant difference in detection frequencies of 14 lesion types among the three CT protocols, but pulmonary emphysema was detected in fewer patients (3/25) in ultra-low-dose CT protocol B scans compared with ultra-low-dose CT protocol A scans (5/25) or low-dose CT scans (6/25). We measured the longest dimensions of 33 small solid nodules (3.8-12.4 mm in long diameter) and found no statistically significant difference in the values afforded by the three CT protocols (p = 0.135). CONCLUSION: Iterative reconstruction allows ultra-low-dose CT and affords acceptable image quality, allowing size measurements of solid pulmonary nodules to be made.

Ghost in the left ventricle on electrocardiogram-gated cardiac computed tomography by turbulent flow.

We report on an extremely rare case of a fake lesion in the left ventricle on electrocardiogram-gated cardiac computed tomography simulating thrombus or tumor by turbulent flow in a 14-year-old boy. Cardiac magnetic resonance imaging with contrast-enhanced myocardial perfusion and delayed enhancement images were helpful in excluding true thrombus or tumor. Awareness of this potential pitfall is critical in order to avoid unnecessary anticoagulation or surgery.

Development of an efficient soymilk cream production method by papain digestion, heat treatment, and low-speed centrifugation.

We developed the simple method of soymilk cream production from the high-fat soymilk, which was prepared by papain digestion and heat treatment. As a result of the treatment, high-fat soymilk was aggregated and it became possible to separate soymilk cream as the surface fraction by low-speed centrifugation (6000 × g, 10 min).

Reduced radiation exposure of the female breast during low-dose chest CT using organ-based tube current modulation and a bismuth shield: comparison of image quality and radiation dose.

OBJECTIVE: The objective of our study was to evaluate the effect of organ-based tube current modulation and bismuth shielding on image quality and breast radiation dose in women undergoing low-dose chest CT. SUBJECTS AND METHODS: From March 2011 through July 2011, 80 women prospectively underwent low-dose chest CT to screen for lung cancer. The patients were randomly assigned to a control group (n = 20), organ-based tube current modulation group (n = 20), breast shield group (n = 20), or breast shield plus organ-based tube current modulation group (n = 20). Axial slice images of the aortic arch, carina, and inferior pulmonary vein were used to analyze image quality. Three radiologists scored the image quality in terms of artifact and noise and then characterized the overall image quality as optimal (does not affect the diagnostic accuracy) or suboptimal (affects the diagnostic accuracy). Noise levels were measured in the anterior and posterior lung in each image. A phantom dose study was conducted to measure radiation dose. RESULTS: Images with artifacts or noise were more frequently obtained in the breast shield groups; however, the overall image quality was not significantly different among the four groups. Measured noise levels in the anterior lung were significantly higher in the breast shield groups than the control group; however, no statistical significance was found among the four groups with regard to noise level in the posterior lung. In the phantom dose study, a 16-37.5% dose reduction in the breast was achieved using the breast shield, organ-based tube current modulation protocol, or both. CONCLUSION: The radiation dose in the female breast may be reduced using a breast shield or organ-based tube current modulation during low-dose chest CT with acceptable image quality. The use of organ-based tube current modulation reduced the radiation dose in the breast without inducing image quality deterioration.

The value of chest CT for prediction of breast tumor size: comparison with pathology measurement.

BACKGROUND: Little information is available on the use of chest computed tomography (CT) to predict breast tumor size in breast cancer, despite the fact that chest CT examinations are being increasingly used. The purpose of this study was to evaluate the value of chest CT for predicting breast tumor size using pathology measurements as reference standards. METHODS: Tumor sizes (defined as greatest diameter) were retrospectively measured on the preoperative chest CT images of 285 patients with surgically proven unifocal, invasive breast carcinoma. Greatest tumor diameters as determined by chest CT and pathologic examinations were compared by linear regression and Spearman's rho correlation analysis. Concordance between CT and pathology results was defined as a diameter difference of <5 mm. Subgroup analyses were also performed with respect to tumor size (<20 mm or ≥20 mm) and histological subtype (invasive ductal carcinoma(IDC) or non-IDC). RESULTS: CT and pathology measured diameters were found to be linearly related (size at pathology = 1.086 × CT determined tumor size - 1.141; Spearman's rho correlation coefficient = 0.84, P<0.001). Most tumors (n = 228, 80.0%) were concordant by chest CT and pathology, but 36 tumors (12.7%) were underestimated by CT (average underestimation, 11 mm; range, 6-36 mm) and 21 tumors (7.4%) were overestimated (average overestimation by CT, 10 mm; range, 6-19 mm). The concordance rate between the two sets of measurements was greater for tumor of <20 mm and for IDC (P<0.001 and P = 0.011, respectively). CONCLUSIONS: Tumor size by chest CT is well correlated with pathology determined tumor size in breast cancer patients, and the diameters of the majority of tumors by chest CT and pathology differed by <5 mm. In addition, the concordance rate was higher for breast tumors of <20 mm and for tumors of the IDC histologic subtype.

Corrosion and in vitro biocompatibility properties of cryomilled-spark plasma sintered commercially pure titanium.

Ti alloys, such as Ti6Al4V, are currently used in biomedical and dental implant applications. Ti alloys are used because they are stronger than commercially pure (CP) Ti due to the presence of alloying elements. However, toxicity of alloying elements during long-term use of implants is of concern. Another means of increasing the strength of materials is grain size refinement. In this study, ultrafine-grained (UFG, ~250 nm to 1 µm) CP Ti was produced by cryomilling followed by spark plasma sintering (SPS). Electrochemical impedance spectroscopy (EIS) and cell culture experiments were performed to compare the corrosion and biocompatibility properties of coarse grained (CG) Ti and UFG Ti. It was found that UFG Ti exhibited corrosion resistance comparable to CG Ti in Ringers solution. In addition, UFG Ti exhibited a reduced inflammatory response and enhanced cell adhesion compared to CG Ti. Investigation of surface roughness provided an explanation for enhanced cell adhesion.

Maternal Attribution, Perceptions of Parenting, and Behavior Management Strategies as Predictors of Mother-Teacher Discrepancies in Rating Behavior Problems of Korean Preschoolers.

The present study aimed to investigate mother-teacher discrepancies in reports of preschoolers' behavior problems and to examine whether maternal attribution to behavior problems, perception of parenting, and behavior management strategies predicted the discrepancies. The mothers and teachers of 384 preschoolers aged 3-6 years from 16 preschools of Seoul, South Korea, completed the Child Behavior Checklist and the Caregiver-Teacher Report Form. Based on their ratings, they were classified into three groups: (a) mother-teacher Agreement Group, (b) Disagreement Group with Mother only reporting at Risk (Disagreement Group-MR), and (c) Disagreement Group with Mother only reporting No Risk (Disagreement Group-MNR). The results showed marginal similarities between mothers' and teachers' reports of behavior problems, indicating both low correlations and differences in percentages of at-risk children. Multinomial logistic regressions revealed that maternal attribution and maternal perception of parenting difficulties predicted group membership regarding mother-teacher discrepancies. For both internalizing and externalizing problems, mothers who attributed environmental factors as primary causes of children's behavior problems were more likely to be in the Agreement Group than the Disagreement Group-MNR. With regard to externalizing problems, the more the mothers perceived parenting difficulties, the more likely they were to belong to either of the Disagreement Groups. The outcomes suggest the importance of considering that mothers' reports of children's behavior and mother-teacher discrepancies partly mirror mothers' beliefs and perceptions regarding children's behavior and parenting. Professionals need to be aware that information from mother-teacher discrepancies can be of help in understanding mothers as well as children in practice.

[Radiologic Approach for Pulmonary Vasculitis]. / 폐혈관염의 ì˜ìƒì˜í•™ì  ì ‘ê·¼.

Vasculitis is a systemic disease, characterized by inflammation of the vascular wall. Although rare, it is sometimes life-theatening due to diffuse pulmonary hemorrhage or acute glomerulonephritis. Besides primary vasculitis, whose cause is unknown, numerous conditions such as autoimmune diseases, drugs, infections, and tumors can cause secondary vasculitis. Vasculitis displays various non-specific symptoms, signs, and laboratory findings; hence, diagnosis of the disease requires integration of various results including clinical features, imaging findings, autoantibody tests, and pathological findings. In this review, we have discussed the clinical, radiologic, and pathological features of vasculitis. Further, we elaborated the imaging findings and differential diagnosis of typical vasculitis that frequently involves the lung and introduced a new international classification of vasculitis, the Diagnostic and Classification Criteria in Vasculitis.

Separation and recovery of nucleic acids with improved biological activity by acid-degradable polyacrylamide gel electrophoresis.

One of the fundamental challenges in studying biomacromolecules (e.g. nucleic acids and proteins) and their complexes in a biological system is isolating them in their structurally and functionally intact forms. Electrophoresis offers convenient and efficient separation and analysis of biomacromolecules but recovery of separated biomacromolecules is a significant challenge. In this study, DNAs of various sizes were separated by electrophoresis in an acid-degradable polyacrylamide gel. Almost 100% of the nucleic acids were recovered after the identified gel bands were hydrolyzed under a mildly acidic condition and purified using anion exchange resin. Further concentration by centrifugal filtration and a second purification using ion exchange column chromatography yielded 44-84% of DNA. The second conventional (non-degradable) gel electrophoresis confirmed that the nucleic acids recovered from acid-degradable gel bands preserved their electrophoretic properties through acidic gel hydrolysis, purification, and concentration processes. The plasmid DNA recovered from acid-degradable gel transfected cells significantly more efficiently than the starting plasmid DNA (i.e. improved biological activity via acid-degradable PAGE). Separation of other types of nucleic acids such as small interfering RNA using this convenient and efficient technique was also demonstrated.

Can MR Imaging contribute in characterizing well-circumscribed breast carcinomas?

Most well-circumscribed breast masses are benign lesions such as cysts, fibroadenomas, and intramammary lymph nodes. Nevertheless, 10%-20% of breast malignancies are well-circumscribed masses, and these malignancies include papillary, mucinous, medullary, and metaplastic carcinomas, as well as malignant phyllodes tumors. Therefore, it is important to differentiate these well-circumscribed breast malignancies from benign breast lesions, but it is not easy to do so with conventional imaging modalities such as mammography and ultrasonography (US). As an emerging adjunctive imaging method, magnetic resonance (MR) imaging has substantial potential in characterizing well-circumscribed breast carcinomas. Analysis of the lesion signal intensity on nonenhanced T2-weighted MR images, determination of the enhancement pattern, and kinetic curve assessment can greatly help differentiate malignant from benign well-circumscribed breast lesions. Therefore, breast MR imaging can play a substantial role in distinguishing between well-circumscribed benign and malignant breast lesions, especially in cases that are difficult to diagnose by using conventional imaging. In this article, the MR imaging findings of the subtypes of well-circumscribed malignant breast lesions-intracystic papillary carcinoma, invasive papillary carcinoma, mucinous carcinoma, medullary carcinoma, metaplastic carcinoma, and malignant phyllodes tumor-are described and correlated with the histopathologic, mammographic, and US findings.

Isolation of intact proteins from acid-degradable polyacrylamide gel.

Elucidating native structure-function relationships of proteins identified using PAGE has been impeded by limitations in the isolation of intact proteins from the gel. By hydrolyzing polyacrylamide gel band under mildly acidic conditions rather than digesting entrapped proteins approximately 70% of a large native protein, mouse IgG1 (molecular weight 150 kDa), was isolated. Further analysis indicated that the isolated antibodies had preserved specific binding capability to target antigens as well as intact molecular weights. This new technology may contribute to functional proteomic studies through the isolation of proteins in their native state after PAGE, and other technologies requiring simultaneous separation and isolation of other macromolecules and complexes.

Thoracic complications of liver cirrhosis: radiologic findings.

Patients with chronic liver disease exhibit various cardiovascular and pulmonary complications. Hepatopulmonary syndrome results in dyspnea due to intrapulmonary arteriovenous shunting and ventilation-perfusion mismatch. Portopulmonary hypertension occurs in patients with portal hypertension. Intrathoracic portosystemic collateral vascular pathways develop in patients with portal hypertension to allow decompression of the portal vein into the systemic circulation. Hepatic hydrothorax may develop in patients with cirrhosis and ascites. Massive necrosis of the liver from any cause may be associated with acute hypoxic respiratory failure, necessitating ventilatory support. Bacterial infection is common in cirrhotic patients because of a compromised host defense system. Hepatocellular carcinoma may produce hematogenous lung metastases, intrathoracic lymph node metastases, direct intracardiac extension, and pulmonary embolism. Interferon therapy for treatment of chronic active hepatitis C may disturb cellular immune activation in some patients and contribute to the onset and progression of sarcoidosis. Awareness of the various thoracic manifestations in chronic liver disease can be helpful for making a differential diagnosis and planning proper management.

Nodal metastasis in non-small cell lung cancer: accuracy of 3.0-T MR imaging.

PURPOSE: To prospectively evaluate the diagnostic accuracy of 3.0-T magnetic resonance (MR) imaging in the detection of non-small cell lung cancer nodal metastasis, with histopathologic analysis as the reference standard. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. From July 2005 to May 2006, 113 patients (91 men, 22 women; age range, 34-82 years; mean age, 61 years) with non-small cell lung cancer underwent thoracic 3.0-T MR imaging followed by surgery or mediastinoscopy. The lymph node-to-tumor ratios (LTRs) of signal intensity and nodal morphologic characteristics (such as eccentric cortical thickening or obliteration of the fatty hilum) were assessed on T2-weighted triple-inversion black-blood fast spin-echo images. Nodal short-axis diameter was assessed on T1-weighted three-dimensional fast field-echo images. Receiver operating characteristic and multivariate logistic regression analyses were used for statistical evaluation. RESULTS: The cutoff value (LTR > 0.84) proved to be most appropriate (area under the receiver operating characteristic curve = 0.735, P < .001) in the detection of a nodal metastasis. Of the various parameters examined, morphologic characteristics appeared to be the most significant (P < .001) parameters for depicting a malignant node (multivariate logistic regression analyses; odds ratio, 7.5). Nodal morphology was analyzed, and diagnostic sensitivity, specificity, and accuracy were 53% (39 of 74 nodal stations), 91% (453 of 496 nodal stations), and 86% (492 of 570 nodal stations), respectively. CONCLUSION: Morphologic details of lymph nodes on T2-weighted triple-inversion black-blood fast spin-echo MR images are significant for detection of mediastinal or hilar nodal metastasis at 3.0-T MR imaging.

Infrared plus visible light and heat from natural sunlight participate in the expression of MMPs and type I procollagen as well as infiltration of inflammatory cell in human skin in vivo.

BACKGROUND: Compared with the detailed characterization of the ultraviolet (UV) response in human skin, the effects of infrared (IR) and other regions of the sunlight are scarce. OBJECTIVES: To determine the participation of IR/visible light and heat components of the sunlight on matrix metalloproteinases (MMPs) and type I procollagen expression, and inflammatory cell infiltration in human skin in vivo. METHODS: The buttocks of 16 healthy volunteers (aged 24-43 years, 10 male and 6 female) were irradiated with a 1.1-3 minimal erythema dose (MED) of natural sunlight. To determine the differential effects of UV, IR/visible rays and solar heat alone, the exposed sites were covered with either a UV filter or black cloth, respectively, during irradiation. Skin samples were taken 24h later. RESULTS: IR/visible light spectrum of sunlight significantly increased MMP-1 and MMP-9 expression and decreased type I procollagen expression. Solar heat also contributed to the increased MMP-1 expression. Only the UV region recruited neutrophils into the dermis, while UV, IR/visible light and heat contributed to macrophage infiltration. CONCLUSIONS: IR/visible light and heat of natural sunlight, in addition to UV, play a role in modulating the expressions of MMPs and procollagen, and inflammatory cell infiltration in human skin.

Prognostic significance of CT-determined emphysema in patients with small cell lung cancer.

BACKGROUND: Although emphysema and small cell lung cancer (SCLC) are prevalent in smokers, no previous study has investigated the prognostic impact of computed tomography (CT)-determined emphysema in SCLC. This study was undertaken to analyze the prognostic value of emphysema scores as determined by baseline CT scans in patients with SCLC. METHODS: The data of 149 consecutive patients with SCLC were analyzed. Emphysema severity was semi-quantitatively scored on baseline chest CT images using the Goddard scoring system (possible scores for individual patients ranged from 0 to 24). Data on clinical characteristics and survival were retrospectively collected. Survivals were estimated using the Kaplan-Meier method and compared using the log-rank test. A multivariable Cox proportional hazard model was used to identify prognostic factors. RESULTS: Most of the 149 patients were male (85.2%) and current/ex-smokers (87.2%). The median CT emphysema score was 4 (range, 0 to 23). Univariable analysis, patients with a higher CT emphysema score (≥8) had significantly poorer overall survivals (OS) than those with lower scores (5.0 vs. 12.3 months, P<0.001). Multivariable analysis showed a higher CT emphysema score (treated as a continuous variable) was a significant independent prognostic factor of poor survival [hazard ratio (HR), 1.85; 95% confidence interval (CI), 1.14 to 3.00; P=0.012], along with extensive stage (HR, 2.27; 95% CI, 1.45-3.53; P<0.001), elevated lactate dehydrogenase (LDH) (HR, 1.52; 95% CI, 1.03-2.23; P=0.034), and supportive care only (HR, 6.46; 95% CI, 3.64-11.48; P<0.001). CONCLUSIONS: Emphysema severity, as determined by baseline CT, is significantly associated with poor prognosis in SCLC.