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Fibroblast activation protein (FAP) is expressed on activated fibroblast. Its role in fibrosis and desmoplasia is controversial, and data on pharmacological FAP inhibition are lacking. We aimed to better define the role of FAP in liver fibrosis in vivo and in vitro.FAP expression was analyzed in mice and patients with fibrotic liver diseases of various etiologies. Fibrotic mice received a specific FAP inhibitor (FAPi) at 2 doses orally for 2 weeks during parenchymal fibrosis progression (6 weeks of carbon tetrachloride) and regression (2 weeks off carbon tetrachloride), and with biliary fibrosis (Mdr2-/-). Recombinant FAP was added to (co-)cultures of hepatic stellate cells (HSC), fibroblasts, and macrophages. Fibrosis- and inflammation-related parameters were determined biochemically, by quantitative immunohistochemistry, polymerase chain reaction, and transcriptomics.FAP+ fibroblasts/HSCs were α-smooth muscle actin (α-SMA)-negative and located at interfaces of fibrotic septa next to macrophages in murine and human livers. In parenchymal fibrosis, FAPi reduced collagen area, liver collagen content, α-SMA+ myofibroblasts, M2-type macrophages, serum alanine transaminase and aspartate aminotransferase, key fibrogenesis-related transcripts, and increased hepatocyte proliferation 10-fold. During regression, FAP was suppressed, and FAPi was ineffective. FAPi less potently inhibited biliary fibrosis. In vitro, FAP small interfering RNA reduced HSC α-SMA expression and collagen production, and FAPi suppressed their activation and proliferation. Compared with untreated macrophages, FAPi regulated macrophage profibrogenic activation and transcriptome, and their conditioned medium attenuated HSC activation, which was increased with addition of recombinant FAP.Pharmacological FAP inhibition attenuates inflammation-predominant liver fibrosis. FAP is expressed on subsets of activated fibroblasts/HSC and promotes both macrophage and HSC profibrogenic activity in liver fibrosis.

The histological growth pattern of liver metastases (desmoplastic, pushing, and replacement patterns) at the tumor-liver parenchymal interface is a prognostic factor in patients with colorectal cancer. However, data regarding its association with the primary tumor characteristics and molecular alterations are limited. This study evaluated the histological growth pattern in 136 cases of colorectal cancer liver metastases without preoperative treatment, comparing it with the clinicopathological features of the primary tumor. Liver metastasis exhibiting predominantly non-desmoplastic pattern (50%), observed in 74 cases (54%), was associated with hepatic vein invasion (P = 0.025), worse recurrence-free survival (P 0.001) and overall survival (P = 0.008). In multivariate analyses, multiple tumors (P 0.001) and non-desmoplastic patterns (P = 0.009) were associated with worse recurrence-free survival, and tumor size (P = 0.025) and non-desmoplastic pattern (P = 0.025) were associated with worse overall survival. In 88 patients with available primary tumor tissue slides, non-desmoplastic pattern in the liver metastasis was associated with high-grade tumor budding (P = 0.002), high-grade poorly differentiated cluster (P = 0.021), absence of mucinous histology (P = 0.016), and aberrant p53 expression (complete loss or overexpression; P 0.001) of the primary colorectal cancer. In conclusion, the histological growth pattern in liver metastasis was a strong and independent prognostic factor for colorectal cancer. Our observations highlight the significant associations between histological growth patterns in liver metastases and histopathological features of the primary tumor, especially invasive front morphology and p53 aberration.

Nonalcoholic steatohepatitis (NASH) is a disease entity with an increasing incidence, with involvement of several metabolic pathways. Various organs, including the liver, kidneys, and the vasculature, are damaged in NASH, indicating the urgent need to develop a standard therapy. Therefore, this study was conducted to investigate the effects of drugs targeting various metabolic pathways and their combinations on a high-fat diet (HFD)-induced NASH medaka model.To investigate the effects of drugs on vascular structures, the NASH animal model was developed using the fli::GFP transgenic medaka fed with HFD at 20 mg/fish daily. The physiological changes, histological changes in the liver, vascular structures in the fin, and serum biochemical markers were evaluated in a time-dependent manner after treatment with selective peroxisome proliferator-activated receptor α modulator (pemafibrate), statin (pitavastatin), sodium-glucose cotransporter 2 inhibitor (tofogliflozin), and their combinations. Furthermore, to determine the mechanisms underlying the effects, whole transcriptome sequencing was conducted using medaka liver samples.Histological analyses revealed significant suppression of fat accumulation and fibrotic changes in the liver after treatment with drugs and their combinations. The expression levels of steatosis- and fibrosis-related genes were modified by the treatments. Moreover, the HFD-induced vascular damages in the fin exhibited milder changes after treatment with the drugs.The effects of treating various metabolic pathways on the medaka body, liver, and vascular structures of the NASH medaka model were evidenced. Moreover, to our knowledge, this study is the first to report whole genome sequence and gene expression evaluation of medaka livers, which could be helpful in clarifying the molecular mechanisms of drugs.

Multi-source data fusion, in which multiple data sources are jointly analyzed to obtain improved information, has considerable research attention. For the datasets of multiple medical institutions, data confidentiality and cross-institutional communication are critical. In such cases, data collaboration (DC) analysis by sharing dimensionality-reduced intermediate representations without iterative cross-institutional communications may be appropriate. Identifiability of the shared data is essential when analyzing data including personal information. In this study, the identifiability of the DC analysis is investigated. The results reveals that the shared intermediate representations are readily identifiable to the original data for supervised learning. This study then proposes a non-readily identifiable DC analysis only sharing non-readily identifiable data for multiple medical datasets including personal information. The proposed method solves identifiability concerns based on a random sample permutation, the concept of interpretable DC analysis, and usage of functions that cannot be reconstructed. In numerical experiments on medical datasets, the proposed method exhibits a non-readily identifiability while maintaining a high recognition performance of the conventional DC analysis. For a hospital dataset, the proposed method exhibits a nine percentage point improvement regarding the recognition performance over the local analysis that uses only local dataset., Comment: 19 pages, 3 figures, 7 tables

Postmortem computed tomography (CT) is currently a well-known procedure and helps in postmortem investigations. In this case report, we report a unique postmortem CT finding: delayed cerebral enhancement associated with the antemortem infusion of contrast medium. A 72-year-old female lost consciousness at a restaurant and was taken to a hospital in an ambulance. Despite resuscitation efforts, she died of hypoxic–ischemic encephalopathy caused by cardiac arrest. About 6 h before her death, she underwent enhanced antemortem CT of the head. No abnormal enhancement was observed in the cerebral parenchyma. Then, 11 h after her death, she underwent unenhanced postmortem CT, which showed bilateral hyperdense caudate nucleus and putamina, due to residual iodinated contrast medium, in addition to other characteristic findings of hypoxic–ischemic encephalopathy. The mechanism underlying this phenomenon could be the destruction of the blood–brain barrier, and/or selective vulnerability, due to hypoxic–ischemic changes in the gray matter. Enhancement of basal ganglia on postmortem CT due to antemortem infusion of iodinated contrast medium might suggest hypoxic–ischemic encephalopathy, which should be noted in postmortem CT interpretations.

Introduction Although hepatitis B virus infection is well-described, the additional risk posed by oral bleeding in individuals with chronic hepatitis B virus infection has not been determined. This study aimed to determine the quantity of hepatitis B virus in the saliva of carriers in Japan, as a means of understanding the potential risk for horizontal transmission. Methods Saliva samples from 48 confirmed hepatitis B virus carriers were included in the analysis. Hepatitis B virus concentrations and the presence of occult blood as periodontal disease were evaluated in each sample. Results Hepatitis B surface antigen was identified in 46 of the 48 samples (98%), with hepatitis B virus DNA identified in 19 of the 48 saliva samples (40%). Occult blood was detected in 32 (67%) samples with the prevalence increasing as a function of age (r = 0.413; P = 0.003). There was a significantly positive correlation between hepatitis B virus DNA levels in the serum and saliva specimens (r = 0.895; P Conclusions Occult blood in saliva was detected in most participants. The detection of hepatitis B virus DNA correlated positively with hepatitis B virus in the serum and occult blood in the saliva. Therefore, improved care of periodontal disease among older people is important for preventing horizontal transmission of hepatitis B virus.

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) accounts for 10%-20% of the total HCC numbers. Its clinical features include the occurrence in the younger generation, large tumors, and poor prognosis. The contribution of hepatitis B virus X (HBx) protein in hepatocytes during activation of various oncogenic pathways has been reported. We aimed to assess the possible association between HBx and Yes-associated protein (YAP) expression in the liver tissue and the clinical features of HBV-related HCC.The relationship between HBx and YAP expression was examinedAmong 19 cases of HBV-related, 17 cases of hepatitis C virus (HCV)-related, and 19 cases of nonviral-related HCC, the HBV-related tumor showed the largest size. The HBx-stained area in the tumor and peritumor tissue showed a significant correlation with tumor size and serum α-fetoprotein level. YAP expression was higher in HBV-related tumor tissue than in the peritumor tissue and HCV-related tumor. Additionally, HBx and YAP protein expressions are correlated and both expressions in the tumor contributed to the poor prognosis. AnOur study demonstrated that YAP expression in the liver of HBV-infected patients might be the key factor in HBV-related HCC development and control of tumor-related features.

As postmortem imaging has gained prominence as a supplement to traditional autopsy, it is important to understand the normal postmortem changes to enable the accurate evaluation of postmortem imaging. No studies have evaluated the postmortem changes in cardiothoracic ratio (CTR) compared with antemortem images in the same subjects. We studied 147 consecutive subjects who underwent antemortem and postmortem CT, and autopsy. Postmortem CT was performed23h after death and was followed by autopsy. The subjects were divided into three groups: normal heart, old myocardial infarction, and CPR-treated hearts. CTR was compared between antemortem and postmortem CT using paired t tests, which revealed that the CTR was greater on postmortem CT than on antemortem CT in all groups (mean CTR: 0.53±0.06vs. 0.50±0.06, respectively; P0.01). Sex, age, time elapsed since death, and the causes of death were examined as potential confounding factors for the postmortem changes in CTR, but no significant associations were found. Receiver-operating characteristic (ROC) curves were used to determine CTR values for cardiomegaly, which was defined according to the autopsy weight of the heart. The area under the ROC curve was 0.71 (95% confidence interval 0.63-0.79). The CTR threshold of 0.54 identified cardiomegaly with the greatest accuracy, compared with the general threshold of 0.50. In conclusion, the CT-determined CTR increases after death, irrespective of the heart's condition. We should be cautious of overdiagnosis of cardiomegaly on postmortem CT, and new criteria for interpreting cardiomegaly on postmortem CTR are needed.

To extend the applications of optical coherence tomography (OCT) to the fields of physiology and clinical medicine, less invasive, robust, and reliable optical probes are required. Thus, we demonstrate an ultrathin forward-imaging short multimode fiber (SMMF) optical coherence microscopy (OCM) probe with a 50 μm core diameter, 125 μm total diameter, and 5.12 mm length. Imaging conditions and magnification were analyzed, and they correspond closely to the measured results. The dispersion of the SMMF was investigated, and the modal dispersion coefficient was found to be 2.3% of the material dispersion coefficient. The axial resolution was minimized at 2.15 μm using a 0.885-mm-thick dispersion compensator. The lateral resolution was evaluated to be 4.38 μm using a test pattern. The contrast of the OCM images was 5.7 times higher than that of the signal images owing to the coherence gate. The depth of focus and diameter of the field of view were measured to be 60 μm and 40–50 μm, respectively. OCM images of the dried fins of small fish (Medaka) were measured and internal structures could be recognized.

Highlights • Few guidelines describe routine surveillance of small bowel cancer in Lynch syndrome. • A male patient with Lynch syndrome underwent surgery for ascending colon cancer. • Next year, metachronous cancer was found by colonoscopy inserted to the ileum. • He survived disease-free for five years after resection of the ileal cancer. • Our case suggested the importance of inspecting the small bowel in Lynch syndrome., Introduction and importance Colorectal surveillance via colonoscopy in patients with Lynch syndrome reduces the mortality of colorectal cancer. On the other hand, it is unclear whether surveillance for other malignancies, including small bowel cancer, is beneficial. We report a patient with Lynch syndrome who developed ileal cancer after surgery for ascending colon cancer. Case presentation A 47-year-old man visited our hospital for a check-up for positive fecal occult blood. He was diagnosed with ascending colon cancer and met the clinical criteria for the diagnosis of Lynch syndrome based on his past and family history. The Bethesda markers demonstrated high-frequent microsatellite instability. Laparoscopy-assisted right hemicolectomy was performed. He received follow-up colonoscopy the next year, which revealed ileal cancer near the anastomosis. He underwent resection of the second cancer via a laparoscopic approach, and has been free from recurrence for five years. Clinical Discussion Small bowel cancer has a dismal prognosis because a high percentage of patients were diagnosed at advanced stages. The diagnosis of metachronous ileal cancer by the first follow-up colonoscopy after surgery for ascending colon cancer offered a long disease-free survival in our patient. Conclusion The clinical course suggested the importance of inspecting the small bowel in Lynch syndrome patients, especially when colorectal cancer is diagnosed.

Objective To investigate the changes in ascites attenuation between antemortem (AMCT) and postmortem computed tomography (PMCT) analyses of the same subjects. Methods Thirty-five subjects who underwent unenhanced or enhanced AMCT within 7 days before death, unenhanced PMCT, and autopsy were evaluated. In each subject, ascites attenuation was measured at similar sites on AMCT and PMCT. Attenuation changes were evaluated in 42 unenhanced AMCT/PMCT site pairs (23 subjects) and 20 enhanced AMCT/PMCT site pairs (12 subjects). Factors contributing to CT attenuation changes were also assessed, including the time interval between AMCT and PMCT, serum albumin level, estimated glomerular filtration rate, and ascites volume. Results Significantly elevated CT attenuation was observed between enhanced AMCT and PMCT (12.2 ± 6.3 vs. 18.7 ± 10.4 Hounsfield units; paired t-test, p = 0.006), but not between unenhanced AMCT and PMCT (13.5 ± 8.9 vs. 13.4 ± 9.3; p = 0.554). A significant inverse association was observed between the degree of CT attenuation change and the time interval between enhanced AMCT and PMCT (Spearman’s rank correlation coefficient, r = −0.56, p = 0.01). Conclusions We confirmed an elevated level of ascites attenuation on PMCT relative to AMCT in subjects who underwent enhanced AMCT shortly before death.

Rationale and Objectives The study aimed to evaluate the feasibility and advantages of a combined high temporal and high spatial resolution protocol for dynamic contrast-enhanced magnetic resonance imaging of the breast. Materials and Methods Twenty-three patients with enhancing lesions were imaged at 3T. The acquisition protocol consisted of a series of bilateral, fat-suppressed “ultrafast” acquisitions, with 6.9- to 9.9-second temporal resolution for the first minute following contrast injection, followed by four high spatial resolution acquisitions with 60- to 79.5-second temporal resolution. All images were acquired with standard uniform Fourier sampling. A filtering method was developed to reduce noise and detect significant enhancement in the high temporal resolution images. Time of arrival (TOA) was defined as the time at which each voxel first satisfied all the filter conditions, relative to the time of initial arterial enhancement. Results Ultrafast images improved visualization of the vasculature feeding and draining lesions. A small percentage of the entire field of view ( Conclusions Ultrafast imaging in the first minute of dynamic contrast-enhanced magnetic resonance imaging of the breast has the potential to add valuable information on early contrast dynamics. Ultrafast imaging could allow radiologists to confidently identify lesions in the presence of marked background parenchymal enhancement.

We provide a systematic way of dimensional reduction for ( 4 + 2 n ) -dimensional U ( N ) supersymmetric Yang–Mills (SYM) theories ( n = 0 , 1 , 2 , 3 ) and their mixtures compactified on two-dimensional tori with background magnetic fluxes, which preserve a partial N = 1 supersymmetry out of full N = 2 , 3 or 4 in the original SYM theories. It is formulated in an N = 1 superspace respecting the unbroken supersymmetry, and the four-dimensional effective action is written in terms of superfields representing N = 1 vector and chiral multiplets, those arise from the higher-dimensional SYM theories. We also identify the dilaton and geometric moduli dependence of matter Kahler metrics and superpotential couplings as well as of gauge kinetic functions in the effective action. The results would be useful for various phenomenological/cosmological model buildings with SYM theories or D-branes wrapping magnetized tori, especially, with mixture configurations of them with different dimensionalities from each other.

Titanium oxide nanotube thin films formed by anodic oxidation of titanium metal exhibit high reactivity towards various gases at high temperatures. To date, various types of gas sensors using titanium oxide nanotube films have been proposed. Previously, we proposed a microscale gas sensor with titanium oxide nanotube thin films fabricated by local anodization of titanium microelectrodes. In this study, to improve the response characteristics of titanium oxide nanotube-based microscale gas sensors, we decorated titanium oxide nanotube films with catalytic noble metals of platinum nanoparticles using atomic layer deposition technique. We confirmed that due to Pt decoration the sensitivity was significantly improved for hydrogen and carbon monoxide gases. The detection limit of hydrogen gas was found to be in the sub-ppm range. The response characteristics of hydrogen and carbon monoxide gases were analyzed in detail based on the Langmuir adsorption model. It was found that when the concentration of gas increased, the adsorption mode changed from adsorption on the top surface of the film to that on the inner wall of the titanium oxide nanotubes. We also show that the trace amounts of carbon monoxide gas in a mixed gas containing oxygen and nitrogen can be detected.

In this study, we compared the postmortem computed tomography (PMCT) findings among nonpathological lungs, lungs with bacterial pneumonia, and lungs with pulmonary edema in patients following non-traumatic in-hospital death. We studied 104 consecutive adult patients (208 lungs) who died in our tertiary care hospital and underwent PMCT and pathological autopsy (both within 2.5 days after death), and were pathologically diagnosed with nonpathological lungs, bacterial pneumonia, and pulmonary edema. Thirteen pulmonary features were assessed on the CT scans. We also examined the association between the time elapsed since death and the pulmonary findings. We observed increased lung opacities with horizontal plane formation, diffuse opacities, diffuse bronchovascular bundle thickening, symmetric opacities to the contralateral lung, and decreased segmental opacities with time elapsed since death (Cochran–Armitage test for trend). Multiple logistic regression revealed that the presence of opacities without horizontal plane formation or centrilobular opacities, and the absence of diffuse bronchovascular bundle thickening were associated with histopathological pneumonia, whereas the presence of opacities with horizontal plane formation, diffuse opacities, and interlobular septal thickening were associated with histopathological pulmonary edema. In conclusion, specific pulmonary PMCT findings increased with time elapsed since death, and some lung findings may facilitate the diagnosis of bacterial pneumonia and pulmonary edema.

In this paper, we report a fatal case of multiple intracerebral hemorrhages associated with lipohyalinosis. A woman in her sixties was admitted to the hospital, where she was subsequently diagnosed with intracerebral hemorrhage. While hospitalized, she suffered several intracerebral hemorrhages and died 67 days after admission. During her hospital stay, she was also diagnosed with cerebral amyloid angiopathy (CAA). The results of autopsy and postmortem computed tomography indicated that the cause of death was a fourth hemorrhage from the cortex to the subcortex in the left parietal lobe. Microscopy further revealed eosinophilic and structureless material in the vessel walls of the brain surface. In addition, these blood vessel walls did not stain by Congo Red stain or immunohistochemical staining using the anti-amyloid β-protein antibody, but they were stained blue with the azocarmine stain. Thus, the decedent was considered to be in a state of lipohyalinosis. To the best of our knowledge, this is the first case report of a death after multiple intracerebral hemorrhages as a result of lipohyalinosis. Based on these findings, the possibility cannot be excluded that there may be a case that has been clinically diagnosed as CAA despite the true cause of multiple intracerebral hemorrhages being small vessel disease such as lipohyalinosis. Therefore, it is important to conduct brain tissue examinations to make a correct diagnosis.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare cancer-related complication leading to hypoxia, pulmonary hypertension, and heart failure. The standard treatment for PTTM is not established. However, imatinib, a tyrosine kinase inhibitor of platelet-derived growth factor receptor (PDGFR), may cause regression of pulmonary hypertension and pulmonary artery remodeling in PTTM. We report a case of a 61-year-old woman in whom PTTM developed during chemotherapy for metastatic breast cancer. Although imatinib alleviated pulmonary hypertension, she died because of progression of metastatic breast cancer 54 days after her initial admission to our hospital. It would be advisable to conduct a well-designed clinical trial using chemotherapy regimens combined with imatinib for PTTM.

Oxygen consumption rate of in vivo-derived porcine embryos was measured, and its value as an objective method for the assessment of embryo quality was evaluated. Embryos were surgically collected 5 or 6 days after artificial insemination (AI), and oxygen consumption rate of embryos was measured using an embryo respirometer. The average oxygen con- sumption rate (F � 10 14 /mol s � 1 ) of the embryos that developed to the compacted morula stage on Day 5 (Day 0 ¼ the day of artificial insemination) was 0.58 � 0.03 (meanstandard error of the mean). The Day-6 embryos had consumption rates of 0.56 � 0.13, 0.87 � 0.06, and 1.13 � 0.07 at the early blastocyst, blastocyst, and expanded blastocyst stages, respectively, showing a gradual increase as the embryos developed. Just after collection, the average oxygen consumption rates of embryos that hatched and of those that did not hatch after culture were 0.60 � 0.04 and 0.50 � 0.04 for Day 5 (P ¼ 0.08) and 1.05 � 0.09 and 0.77 � 0.05 for Day 6 (P < 0.05), respectively. The value and proba- bility of discrimination by measuring the oxygen consumption rates of embryos to predict their hatching ability after culture were 0.56 and 63.6% for Day-5 embryos and 0.91 and 68.4% for Day-6 blastocysts, respectively. When Day-5 embryos were classified based on the oxygen consumption rate and then transferred non-surgically to recipient sows, three of the seven sows, to which embryos having a high oxygen consumption rate (� 0.59) were transferred, became pregnant and farrowed a total of 20 piglets. However, none of the four sows, to which embryos having low oxygen consumption rate (

Acinic cell carcinoma is a rare malignant salivary gland tumor. Most cases of acinic cell carcinoma occur in the parotid gland and acinic cell carcinoma arising in the minor salivary glands is extremely rare; it accounts for 3–16% of cases. Pathologically, it is well known that tumor cellular features can be identified as acinar, intercalated ductal, vacuolated, clear and nonspecific glandular, and architectural patterns of acinic cell carcinoma are divided into four types: solid, microcystic, papillary-cystic and follicular. The papillary-cystic pattern is generally characterized by prominent cystic lumens that are partially filled with papillary epithelial proliferations. We report a case of acinic cell carcinoma arising in the left buccal mucosa of a 45-year-old male. On MRI findings, the tumor showed an oval, solid mass; however, during the surgical operation, a part of the tumor easily raptured by only finger pressure and the contents leaked out. The contents exhibited a grayish-brown color and mud-like consistency. Pathologically, the tumor showed a large cystic space. Some tumor cells included in the luminal side of cyst wall and the tumor cells partially protruded into the luminal space. The mud-like specimen revealed also tumor cells. These tumor cells were identified as typical serous acinar differentiated cells; therefore, the final diagnosis was acinic cell carcinoma with a papillary-cystic growth pattern that consisted of typical acinar cells. We report the details of this specific type of acinic cell carcinoma and discuss the prognostic factors.

We discuss an N = 2 supergravity model that interpolates the full and the partial supersymmetry breakings. In particular, we find the conditions for an N = 0 Minkowski vacuum, which is continuously connected to the partial-breaking ( N = 1 preserving) one. The model contains multiple (Abelian) vector multiplets and a single hypermultiplet, and is constructed by employing the embedding tensor technique. We compute the mass spectrum on the Minkowski vacuum, and find some non-trivial mass relations among the massive fields. Our model allows us to choose the two supersymmetry-breaking scales independently, and to discuss the cascade supersymmetry breaking for the applications to particle phenomenology and cosmology.

Purpose To compare magnetic resonance imaging (MRI) and ultrasound (US) for axillary lymph node (LN) staging in breast cancer patients in an observer-performance study. Materials and Methods An observer-performance study was conducted with five breast radiologists reviewing 50 consecutive patients of newly diagnosed invasive breast cancer with the use of ipsilateral axillary MRI and US. LN status was pathologically proved in all patients. Each observer reviewed the images in two separate sessions: one for MRI and the other for US. Observers were asked to indicate their confidence of the presence of at least one ipsilateral metastatic LN on a quasi-continuous rating scale and whether they recommend percutaneous biopsy preoperatively. Receiver operating characteristic (ROC) analysis and area under the ROC curve were used to characterize diagnostic performance. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated from whether observers recommended biopsy. Results There were no statistically significant differences in each observer's performance between MRI and US, or in the performance of all observers as a group, in terms of ROC analysis. There were no statistically significant differences in sensitivity, specificity, PPV, or NPV between MRI and US, but there were statistically significant improvements in specificity and PPV from either MRI or US alone to MRI and US combined. Conclusions Observer performance on MRI and US are comparable for axillary LN staging. When US and MRI are concordant for positive findings, higher specificity and PPV can be obtained.

Hydrodynamic gene delivery is a common method for gene transfer to the liver of small animals, and its clinical applicability in large animals has been demonstrated. Previous studies focused on functional analyses of therapeutic genes in animals with normal livers and little, however, is known regarding its effectiveness and safety in animals with liver fibrosis. Therefore, this study aimed to examine the effects of liver fibrosis on hydrodynamic gene delivery efficiency using a rat liver fibrosis model. We demonstrated for the first time, using pCMV-Luc plasmid, that this procedure is safe and that the amount of fibrotic tissue in the liver decreases gene delivery efficiency, resulting in decrease in luciferase activity depending on the volume of fibrotic tissue in the liver and the number of hepatocytes that are immunohistochemically stained positive for transgene product. We further demonstrate that antifibrotic gene therapy with matrix metalloproteinase-13 gene reduces liver fibrosis and improves efficiency of hydrodynamic gene delivery. These results demonstrate the negative effects of fibrotic tissue on hydrodynamic gene delivery and its recovery by appropriate antifibrotic therapy.

We present a four-dimensional (4D) ${\cal N}=1$ superfield description of supersymmetric Yang-Mills (SYM) theory in ten-dimensional (10D) spacetime with certain magnetic fluxes in compactified extra dimensions preserving partial ${\cal N}=1$ supersymmetry out of full ${\cal N}=4$. We derive a 4D effective action in ${\cal N}=1$ superspace directly from the 10D superfield action via dimensional reduction, and identify its dependence on dilaton and geometric moduli superfields. A concrete model for three generations of quark and lepton superfields are also shown. Our formulation would be useful for building various phenomenological models based on magnetized SYM theories or D-branes., Comment: 19pages, no figures

Rationale and Objectives The aims of this study were to evaluate high spectral and spatial resolution (HiSS) magnetic resonance imaging (MRI) for the diagnosis of breast cancer without the injection of contrast media by comparing the performance of precontrast HiSS images to that of conventional contrast-enhanced, fat-suppressed, T1-weighted images on the basis of image quality and in the task of classifying benign and malignant breast lesions. Materials and Methods Ten benign and 44 malignant lesions were imaged at 1.5 T with HiSS (precontrast administration) and conventional fat-suppressed imaging (3–10 minutes after contrast administration). This set of 108 images, after randomization, was evaluated by three experienced radiologists blinded to the imaging technique. Breast Imaging Reporting and Data System morphologic criteria (lesion shape, lesion margin, and internal signal intensity pattern) and final assessment were used to measure reader performance. Image quality was evaluated on the basis of boundary delineation and quality of fat suppression. An overall probability of malignancy was assigned to each lesion for HiSS and conventional images separately. Results On boundary delineation and quality of fat suppression, precontrast HiSS scored similarly to conventional postcontrast MRI. On benign versus malignant lesion separation, there was no statistically significant difference in receiver-operating characteristic performance between HiSS and conventional MRI, and HiSS met a reasonable noninferiority condition. Conclusions Precontrast HiSS imaging is a promising approach for showing lesion morphology without blooming and other artifacts caused by contrast agents. HiSS images could be used to guide subsequent dynamic contrast-enhanced MRI scans to maximize spatial and temporal resolution in suspicious regions. HiSS MRI without contrast agent injection may be particularly important for patients at risk for contrast-induced nephrogenic systemic fibrosis or allergic reactions.

Pasteurella multocida toxin (PMT) is a virulence factor responsible for the pathogenesis of some forms of pasteurellosis. The toxin activates G(q)- and G(12/13)-dependent pathways through the deamidation of a glutamine residue in the alpha-subunit of heterotrimeric GTPases. We recently reported the crystal structure of the C terminus (residues 575-1285) of PMT (C-PMT), which is composed of three domains (C1, C2, and C3), and that the C1 domain is involved in the localization of C-PMT to the plasma membrane, and the C3 domain possesses a cysteine protease-like catalytic triad. In this study, we analyzed the membrane-targeting function of the C1 domain in detail. The C1 domain consists of seven helices of which the first four (residues 590-670), showing structural similarity to the N terminus of Clostridium difficile toxin B, were found to be involved in the recruitment of C-PMT to the plasma membrane. C-PMT lacking these helices (C-PMT DeltaC1(4H)) neither localized to the plasma membrane nor stimulated the G(q/12/13)-dependent signaling pathways. When the membrane-targeting property was complemented by a peptide tag with an N-myristoylation motif, C-PMT DeltaC1(4H) recovered the PMT activity. Direct binding between the C1 domain and liposomes containing phospholipids was evidenced by surface plasmon resonance analyses. These results indicate that the C1 domain of C-PMT functions as a targeting signal for the plasma membrane.

We study non-abelian discrete flavor symmetries, which can appear in magnetized brane models. For example, $D_4$, $\Delta(27)$ and $\Delta(54)$ can appear and matter fields with several representations can appear. We also study the orbifold background, where non-abelian flavor symmetries are broken in a certain way., Comment: 20 pages

Increases in electric current density and temperature due to scaling down of IC deteriorate the reliability of the metal line. Electromigration might be one of the main damage mechanisms of the interconnecting metal line. Electromigration is a phenomenon that metallic atoms are transported by electron wind. The metal lines in IC are often connected by vias and multi-level interconnections are constructed. In such lines, it is well known that there is a threshold current density of electromigration damage. When the metal line is subjected to the electric current beyond the threshold current density, electromigration damage occurs as a drift of cathode edge of the line. Recently, a parameter governing electromigration damage at the ends of passivated polycrystalline line, AFDgen|end∗, was expressed for reliability evaluation of the polycrystalline line connected with via. In this study, velocity of the edge drift is theoretically expressed by utilizing AFDgen|end∗ to construct the derivation method of film characteristic constants. By this derivation method, the film characteristic constants included in the parameter formula can be determined only from the measurement of the drift velocity. Next, the test specimen modeled on the via-connected line is treated, and the drift velocity in the line is actually measured under accelerated condition. By equating the theoretical drift velocity expressed by AFDgen|end∗ with experimental one, the film characteristic constants are obtained. Through the discussion on the validity of film characteristics obtained based on AFDgen|end∗, the adequateness of the parameter is verified. And, the usefulness of the derivation method of the film characteristic constants is shown.

The detection of oxygen consumption as an indicator of the bovine embryo activity has attracted much attention. A microfluidic chip with the built-in amperometric detector array was successfully constructed to transport, immobilize, and in situ measure a single bovine embryo for the evaluation of oxygen consumption characteristics. The microfluidic chip consisted of a poly(dimethylsiloxane) slab containing a size-limited transportation microchannel and a glass substrate with a 4-working-electrode amperometric detector array located on the bottom of a groove. A single embryo could be transported along the groove and be safely immobilized at the gate position of the microchannel due to the size limitation by using the flow rate of 10 μl/min. Subsequently, the oxygen consumption characteristics of the embryo were in situ measured with the amperometric detector array. The average value of oxygen concentration difference (Δ C ) between the bulk solution and the Day-6 embryo surface based on the analysis of spherical diffusion theory was 2.80 ± 0.72 μM at room temperature. Moreover, the correlation coefficient of more than 0.92 indicates that the spherical diffusion theory could be suitable for depicting the oxygen consumption layer of an embryo at the morula stage in the microchannel. The success of the presently used microfluidic chip not only greatly simplifies the expensive instrument requirements such as scanning electrochemical microscope and stereo-positioning manipulator but also makes the transportation, immobilization, and detection of a single embryo feasible within a microchip.

Rationale and Objectives The aim of the study is to investigate the effect of a computer-aided diagnostic (CAD) scheme on radiologist performance in the detection of lung cancers on chest radiographs. Materials and Methods We combined two independent CAD schemes for the detection and classification of lung nodules into one new CAD scheme by use of a database of 150 chest images, including 108 cases with solitary pulmonary nodules and 42 cases without nodules. For the observer study, we selected 48 chest images, including 24 lung cancers, 12 benign nodules, and 12 cases without nodules, from the database to investigate radiologist performance in the detection of lung cancers. Nine radiologists participated in a receiver operating characteristic (ROC) study in which cases were interpreted first without and then with computer output, which indicated locations of possible lung nodules, together with a five-color scale illustrating the computer-estimated likelihood of malignancy of the detected nodules. Results Performance of the CAD scheme indicated that sensitivity in detecting lung nodules was 80.6%, with 1.2 false-positive results per image, and sensitivity and specificity for classification of nodules by use of the same database for training and testing the CAD scheme were 87.7% and 66.7%, respectively. Average area under the ROC curve value for detection of lung cancers improved significantly ( P = .008) from without (0.724) to with CAD (0.778). Conclusion This type of CAD scheme, which includes two functions, namely detection and classification, can improve radiologist accuracy in the diagnosis of lung cancer.

In Bordetella bronchiseptica, the functional type III secretion system (TTSS) is required for the induction of necrotic cell death in infected mammalian cells. To identify the factor(s) involved in necrotic cell death, type III-secreted proteins from B. bronchiseptica were analyzed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and electrospray ionization tandem mass spectrometry. We identified a 69-kDa secreted protein designated BopC. The gene encoding BopC is located outside of the TTSS locus and is also highly conserved in both Bordetella parapertussis and Bordetella pertussis. The results of a lactate dehydrogenase release assay and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling assay demonstrated that BopC is required for necrotic cell death. It has been reported that tyrosine-phosphorylated proteins (PY) of host cells are dephosphorylated during B. bronchiseptica infection in a TTSS-dependent manner. We found that BopC is also involved in PY dephosphorylation in infected host cells. It appears that the necrotic cell death triggered by BopC occurs prior to the PY reduction in host cells, because Bordetella-induced cell death was not affected even in the presence of a dephosphorylation inhibitor. Furthermore, a translocation assay showed that the signal sequence for both secretion into culture supernatant and translocation into the host cell is located in 48 amino acid residues of the BopC N terminus. This report reveals for the first time that a novel type III effector, BopC, is required for the induction of necrotic cell death during Bordetella infection.

Computer-aided diagnosis (CAD) provides a computerized diagnostic result as a "second opinion" to assist radiologists in the diagnosis of various diseases by use of medical images. CAD has become a practical clinical approach in diagnostic radiology, although, at present, primarily in the area of detection of breast cancer in mammograms. Currently, a large research effort has been devoted to the detection and classification of various lung diseases in thoracic computed tomography (CT) images. We describe in this article the current status of the development of CAD schemes in thoracic CT, including nodule detection, distinction between benign and malignant nodules, and detection, characterization, and differential diagnosis of diffuse lung disease. Observer performance studies indicate that these CAD schemes would be useful in clinical practice by providing radiologists with computer output as a "second opinion."

Respiration, photosynthesis and peroxidase activities of living spherical samples, such as algal protoplasts, breast cancer spheroids and bovine embryos, were characterized with scanning electrochemical microscopy (SECM). The concentration profile of the metabolic product around the spherical sample was directly measured by scanning with a probe microelectrode. According to the spherical diffusion theory, the total mass transfer rate per spherical sample is linear to the multiplication of the sample radius and the concentration difference between the sample surface and the bulk of the solution. Therefore, the sample radius is a key parameter to assess the viability of the living samples. For example, we investigated the respiration and photosynthesis activities as a function of the size of the protoplast (Bryopsis plumosa). The respiration rate was linear to the cube of the sample radius. On the contrary, the photosynthesis rate was linear to the square of the sample radius, suggesting that the former is controlled by the volume of the protoplast, and the latter is controlled by the surface area of the protoplast. We will also discuss the size-dependent activity of the breast cancer spheroids and the bovine embryos. Furthermore, relations between the sample size, the concentration difference, and the oxygen consumption rate of the cryo-preserved bovine blastocysts were investigated.

Rationale and objective We developed a technique that uses a multiple massive-training artificial neural network (multi-MTANN) to reduce the number of false-positive results in a computer-aided diagnostic (CAD) scheme for detecting nodules in chest radiographs. Materials and methods Our database consisted of 91 solitary pulmonary nodules, including 64 malignant nodules and 27 benign nodules, in 91 chest radiographs. With our current CAD scheme based on a difference-image technique and linear discriminant analysis, we achieved a sensitivity of 82.4%, with 4.5 false positives per image. We developed the multi-MTANN for further reduction of the false positive rate. An MTANN is a highly nonlinear filter that can be trained with input images and corresponding teaching images. To reduce the effects of background levels in chest radiographs, we applied a background-trend-correction technique, followed by contrast normalization, to the input images for the MTANN. For enhancement of nodules, the teaching image was designed to contain the distribution for a “likelihood of being a nodule.” Six MTANNs in the multi-MTANN were trained by using typical nodules and six different types of non-nodules (false positives). Results Use of the trained multi-MTANN eliminated 68.3% of false-positive findings with a reduction of one true-positive result. The false-positive rate of our original CAD scheme was improved from 4.5 to 1.4 false positives per image, at an overall sensitivity of 81.3%. Conclusion Use of a multi-MTANN substantially reduced the false-positive rate of our CAD scheme for lung nodule detection on chest radiographs, while maintaining a level of sensitivity.

The photocatalytic degradation of chloroform was studied in a tubular photoreactor packed with TiO2 pellets prepared by sol–gel method. Concentrations of chloroform and CO2 in the gas stream and Cl− ion which was dissolved from the pellets into water after the photodegradation experiments were detected quantitatively. Chloroform was completely mineralized to CO2 and HCl but the conversion decreased drastically with an increase in the irradiation time. Such a decrease in the catalytic activity was attributable to the accumulation of Cl− on the TiO2 surface and was recovered by washing the pellets with water. The presence of Cu and Ca(OH)2 increased the concentration of Cl− accumulated on the surface. The deterioration of the catalytic activity was suppressed with Ca(OH)2 whereas no appreciable effect was observed with Cu. The TiO2 prepared by sol–gel method exhibited a higher catalytic activity than commercially available Degussa P-25.

Rationale and Objectives. To evaluate the effect of temporal subtraction images on the radiologists’ detection of early primary lung cancer in computed tomography (CT) scans. Materials and Methods. Fourteen cases with primary lung cancer and 16 normal cases were used for this study from a database of low-dose CT images, which were obtained from a lung cancer screening program in Nagano, Japan. Images were obtained with a single-detector helical CT scanner using 10 mm collimation and 2:1 pitch. Each case had both previous and current CT scans. Temporal subtraction images were obtained by subtracting the warped previous images from the current images. Seven radiologists, including four attendings and three residents, provided their confidence levels for the presence or absence of lung cancers with use of film CT images without and with temporal subtraction images. Receiver operating characteristic analysis was used to compare their performance without and with temporal subtraction images. Results. The mean Az values (area under the receiver operating characteristic curve) of seven observers without and with temporal subtraction images were 0.868 and 0.930, respectively. Diagnostic accuracy was significantly improved by using temporal subtraction images (P .007). Temporal subtraction images were especially useful when a nodule was present near the pulmonary hilum, where radiologists tended to overlook it. Conclusion. The temporal subtraction technique can significantly improve the sensitivity and specificity for detection of lung cancer on CT scans. © AUR, 2004

Chest radiography is still a useful examination in various situations, although CT has become a modality of choice as a diagnostic examination in many cases. Current computer-aided diagnosis (CAD) schemes for chest radiographs include nodule detection, interstitial disease detection, temporal subtraction, differential diagnosis of interstitial disease, and distinction between benign and malignant pulmonary nodules. All of these schemes are demonstrated as providing potentially useful tools for radiologists when the output of these schemes is used as a "second opinion." There are some commercially available products for these schemes and more are expected to be available in the near future. The current status of CAD for CT is also discussed briefly in this article.

Rationale and objectives A computerized scheme for automated detection of unruptured intracranial aneurysms in magnetic resonance angiography was developed based on the use of a three-dimensional selective enhancement filter for dots (aneurysms). Materials and methods Twenty-nine cases with 36 unruptured aneurysms (diameter, 3 to 26 mm; mean, 6.6 mm) and 31 non-aneurysm cases were used in this study. The isotropic 3-dimensional magnetic resonance angiography images with 400 × 400 × 128 voxels (voxel size, 0.5 mm) were processed by use of the selective enhancement filter. The initial candidates were identified by use of a multiple gray-level thresholding technique on the dot-enhanced images and a region-growing technique with monitoring some image features. All candidates were classified into four types of candidates according to the size and local structures based on the effective diameter and skeleton image of each candidate (ie, large candidates and three types of small candidates including short-branch type, single-vessel type, and bifurcation type). In each group, a number of false-positives were removed by use of different rules on localized image features related to gray levels and morphology. Linear discriminant analysis was used for further removal of false-positives. Results With this computer-aided diagnostic scheme, all of 36 aneurysms were correctly detected with 2.4 false-positives per patient based on a leave-one-out-by-patient test method. Conclusion This computer-aided diagnostic system would be useful in assisting radiologists for the detection of intracranial aneurysms in magnetic resonance angiography.

We have developed a computer-aided diagnostic (CAD) scheme for automated detection of intracranial aneurysms in magnetic resonance angiography (MRA). A total of 29 cases with 36 aneurysms and 31 non-aneurysm cases were processed by use of the selective enhancement filter for dots (aneurysms). All candidates were classified into four types according to the size and local structures based on the effective diameter and the skeleton image of each candidate. A number of false positives were removed in each group by use of rule-based schemes and linear discriminant analysis. All of 36 aneurysms were correctly detected with 0.55 false positives per patient. The CAD scheme would be useful in assisting radiologists for detection of intracranial aneurysms in MRA.

In the present study, direct numerical simulation of turbulent heat transfer in a channel flow has been carried out in order to investigate the characteristics of surface heat-flux fluctuations. The Reynolds numbers based on the friction velocity and the channel half width are 180, 395, 640 and 1020, and the molecular Prandtl numbers are 0.025 and 0.71. A local peak for Pr=0.71 and large peaks for Pr=0.025 appear in the spanwise-wavenumber power spectra at low wavenumbers, and these peaks become more significant with increasing Reynolds number. This suggests that the effect of large-scale structures extends even to the surface heat-flux fluctuations, and increases with increasing Reynolds number. In addition, it was found that the surface heat-flux fluctuations for Pr=0.71 are mostly similar to the streamwise wall shear-stress fluctuations, while a noticeable dissimilarity can be seen in the large positive and negative fluctuations.

Rationale and Objectives. To evaluate the performance of an artificial neural network (ANN) scheme with use of consecutive clinical cases and its effect on radiologists with an observer test. Materials and Methods. Artificial neural networks were designed to distinguish among 11 interstitial lung diseases on the basis of 26 inputs (16 radiologic findings, 10 clinical parameters). Chest radiographs of 96 consecutive cases with interstitial lung disease were used. Five radiologists independently rated their radiologic findings on the 96 chest radiographs. Based on their ratings of radiologic findings and clinical parameters obtained from the hospital information system, the output values indicating the likelihood of each of the 11 interstitial lung diseases were determined. Subsequently, 30 cases were selected from these 96 cases for an observer test. Five radiologists marked their confidence levels for diagnosis of 11 possible diseases in each case without and with ANN output. The performance of ANNs and radiologists was evaluated by receiver operating characteristic analysis based on their outputs and on confidence levels, respectively. Results. The average AZ value (area under the receiver operating characteristic curve) indicating ANN performance for the 96 consecutive cases was 0.85 ± 0.03. The average AZ values indicating radiologists’ performance without and with ANN outputs were 0.81 ± 0.11 and 0.87 ± 0.06, respectively. The diagnostic accuracy was improved significantly when radiologists read chest radiographs with ANN outputs (P

Rationales and Objectives. This study investigated the effect of a high sensitivity in computer-aided diagnosis (CAD) for detecting lung nodules in chest radiographs when extremely subtle cases were presented to radiologists. Material and Methods. The chest radiographs used in this study consisted of 36 normal images and 54 abnormals containing solitary lung nodules, of which 25 were extremely subtle and 29 were very subtle. Receiver operating characteristic analysis for detecting lung nodules was performed without and with CAD. The levels of CAD output were simulated with a hypothetical ideal performance of 100% sensitivity, but with three or four false positives per image. Six radiologists participated in an observer study in which cases were interpreted first without and then with the use of CAD. Results. The average A Z values for radiologists without and with CAD were 0.682 and 0.808, respectively. The performance of radiologists was improved significantly when high sensitivity was used ( P = .0003). However, the radiologists were not able to recognize some extremely subtle nodules (5 of 54 nodules by all radiologists), even with the correct CAD output; these nodules were then considered as non-actionable. None of 306 computer-false positives was incorrectly regarded as a nodule by all radiologists, but 63 false positives were incorrectly identified by one or more radiologists. Conclusion. The accuracy of radiologists in the detection of some extremely subtle solitary pulmonary nodules can be improved significantly when the sensitivity of a CAD scheme can be made to be at an extremely high level. However, all of the six radiologists failed to identify some nodules (about 10%), even with the correct output of the CAD.

Rationale and Objectives. To report the detection rate for lung cancers in computed tomography (CT) screening in Japanese adults, and to analyze differences in the appearance of the cancers in non-smokers versus smokers. Materials and Methods. Subjects consisted of 7,847 Japanese adults who received low-dose CT screening at least once in a 3-year period. The detection rate of lung cancers and the correlation of imaging, clinical, and pathologic findings of cancers in non-smokers versus smokers were examined. Results. The detection rate for lung cancer was 1.1% for both non-smokers (45 of 4,251) and smokers (39 of 3,596). The prevalence of well-differentiated adenocarcinomas was greater in non-smokers (88%; 22 of 25) than in smokers (29%; 4 of 14) ( P P P P Conclusion. Most of the lung cancers in non-smokers were slow-growing adenocarcinomas appearing as faint ground-glass opacities on CT, whereas rapidly growing cancers appearing as solid nodules were more commonly seen in smokers.

Identification of insulin-responsive glucose transporter proteins, GLUT4 and GLUT8, was attempted in chickens that characteristically are hyperglycemic and insulin resistant. Northern blot analysis using rat GLUT4 cDNA probe and RT-PCR using primers designed against the conserved regions in mammalian GLUT4 cDNA were not successful in identifying GLUT4 homologue(s) in various chicken tissues. Furthermore, GLUT4 homologues could not be detected in chicken tissues by genomic Southern blot analyses using a rat GLUT4 cDNA probe. These data, therefore, suggest that the GLUT4 homologous gene is deficient in chicken tissues. However, GLUT8, another insulin-responsive glucose transporter in the blastocyst, was identified with the aid of RACE (rapid amplification of cDNA ends) reactions in the chicken testis. Chicken GLUT8 was composed of 1449 bp with a coding region for a 482 amino acid protein. The deduced amino acid sequence was 58.8, 56.3, and 56.8% identical with human, rat, and mouse GLUT8, respectively. By RT-PCR, GLUT8 mRNA expressions were detected in chicken brain, kidney, adrenal, spleen, lung, testis, and pancreas; and barely detectable in skeletal muscle, liver, adipose tissue, and heart. Here we firstly report that GLUT8 was identified in chickens, while GLUT4, a major insulin-responsive transporter in mammals, is deficient in these animals. We propose the hypothesis that the hyperglycemia and insulin resistance observable in chickens is associated with their possible deficiency of GLUT4.