An Optochemical Oxygen Scavenger Enabling Spatiotemporal Control of Hypoxia.

We present an optochemical O2 scavenging system that enables precise spatiotemporal control of the level of hypoxia in living cells simply by adjusting the light intensity in the illuminated region. The system employs rhodamine containing a selenium or tellurium atom as an optochemical oxygen scavenger that rapidly consumes O2 by photochemical reaction with glutathione as a coreductant upon visible light irradiation (560-590 nm) and has a rapid response time, within a few minutes. The glutathione-consuming quantum yields of the system were calculated as about 5 %. The spatiotemporal O2 consuming in cultured cells was visualized with a hypoxia-responsive fluorescence probe, MAR. Phosphorescence lifetime imaging was applied to confirmed that different light intensities could generate different levels of hypoxia. To illustrate the potential utility of this system for hypoxia research, we show that it can spatiotemporally control calcium ion (Ca2+ ) influx into HEK293T cells expressing the hypoxia-responsive Ca2+ channel TRPA1.

Anaphylaxis after vaccination for cats in Japan.

Severe adverse reactions in cats after vaccination were examined from 316 cases reported to the Ministry of Agriculture, Forestry and Fisheries (MAFF) in Japan during 15-year period from April 2004 to March 2019. We found that 130 (41%) showed anaphylaxis, and 99 (76%) of the 130 cases of anaphylaxis resulted in death. Veterinarians should be well prepared to deal with vaccine-associated anaphylaxis in cats. Bovine serum albumin (BSA) as indicator of purification was detected at high levels in commercially available feline vaccines. BSA might derive from fetal calf serum in culture media. This study provides useful information about anaphylaxis including critical details of the potential clinical signs associated with adverse events to feline vaccination.

Detectability of the diagonal direction in the assessment of medical images using a high-brightness liquid crystal display monitor.

Liquid crystal display (LCD) monitors show a homogenous quadratic pattern in the number of pixels, size, and dimensions. However, their modulation transfer function (MTF) has a non-isotropic effect in the vertical, horizontal, and diagonal directions on the screen from the shape and pattern of arrangement of pixels. Moreover, the MTF of the human eye differs in spatial frequency response directivity among individuals. In this study, the high-brightness LCD monitor detectability was physically simulated and visually examined throughout the system, including the imaging system. Furthermore, the influence of anisotropy of the LCD monitor was evaluated. The MTF of the LCD monitor was measured by acquiring a bar pattern using a digital camera with sufficiently small pixels in the vertical, horizontal, and diagonal directions and by performing interpolation processing through waveform reproduction and frequency analysis. The detectability of the LCD monitor was verified throughout the system, including the imaging system. Radiographs of the rectangular wave chart (0.5-10 LP/mm) were obtained in the vertical, horizontal, and diagonal (45°) directions to assess the perceivable limit of the human eye (LP/mm). The spatial resolution of the LCD monitor in the diagonal direction was higher than that in the vertical or horizontal direction, which was in good agreement with the results of the profile analysis and visual evaluation.

Anaphylaxis after rabies vaccination for dogs in Japan.

Severe adverse reactions after rabies vaccination in dogs were examined from 317 cases reported to the Ministry of Agriculture, Forestry and Fisheries (MAFF) in Japan during 15-year period from April 2004 to March 2019. We found that 109 of the 317 dogs showed anaphylaxis (0.15/100,000 vaccinated dogs), and 71 of the 109 cases of anaphylaxis resulted in death (0.10/100,000 vaccinated dogs). We measured bovine serum albumin (BSA) in four commercially available rabies vaccines and found the levels ranged from 0.1 to 16.6 µg/dose. Our survey showed that the rate of anaphylaxis to rabies vaccines in dogs is rare, although some cases of anaphylaxis resulted in death. Veterinarians should be well prepared to deal with vaccine-associated anaphylaxis.

A Potent Blood-Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model.

Gliomas are the second most common primary brain tumors in adults. They are treated with combination therapies, including surgery, radiotherapy, and chemotherapy. There are currently limited treatment options for recurrent gliomas, and new targeted therapies need to be identified, especially in glioblastomas, which have poor prognosis. Isocitrate dehydrogenase (IDH) mutations are detected in various tumors, including gliomas. Most patients with IDH mutant glioma harbor the IDH1R132H subtype. Mutant IDH catalyzes the conversion of α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG), which induces aberrant epigenetic status and contributes to malignant progression, and is therefore a potential therapeutic target for IDH mutant tumors. The present study describes a novel, orally bioavailable selective mutant IDH1 inhibitor, DS-1001b. The drug has high blood-brain barrier (BBB) permeability and inhibits IDH1R132H. Continuous administration of DS-1001b impaired tumor growth and decreased 2-HG levels in subcutaneous and intracranial xenograft models derived from a patient with glioblastoma with IDH1 mutation. Moreover, the expression of glial fibrillary acidic protein was strongly induced by DS-1001b, suggesting that inhibition of mutant IDH1 promotes glial differentiation. These results reveal the efficacy of BBB-permeable DS-1001b in orthotopic patient-derived xenograft models and provide a preclinical rationale for the clinical testing of DS-1001b in recurrent gliomas.

Nodular thymic lymphoid follicular hyperplasia mimicking thymoma.

In this report, we describe a case of thymic lymphoid follicular hyperplasia that was incidentally found as a small thymic nodule in the health screening program including a low-dose chest CT. The CT and MRI findings of the nodule were similar to those of thymoma, and it was difficult to differentiate the lesion from thymoma.

Autocrine pathway of angiopoietins-Tie2 system in AML cells: association with phosphatidyl-inositol 3 kinase.

Hematopoietic cells and endothelial cells are mutually correlated in their development and growth. Various angiogenic factors, such as vascular endothelial growth factor (VEGF) and angiopoietins (Angs), are thought to be associated with leukemia cell growth. In this study, we examined if the Angs-Tie2 autocrine pathway works in primary AML cells or not by using soluble Tie2-Fc, which inhibits Angs from binding to Tie2 receptor. After 48 h of culture with Tie2-Fc, nine AML cells from 19 examined samples were not influenced by Tie2-Fc (group A), while AML cells from remaining 10 patients demonstrated remarkable reduction of cell number by Tie2-Fc treatment (group B). Tie2 receptor, upon binding to Angs, are known to activate phosphatidyl-inositol 3 kinase (PI3 kinase). Then, we examined the effect of LY294002, a potent PI3 kinase inhibitor, on primary AML cells. Cell number reduction effect by the treatment of LY294002 was much more prominent in cells of group B than of group A. In addition, extent of cell number reduction by Tie2-Fc and LY294002 was quite well correlated. These observations demonstrated that cells from a part of AML were dependent on autocrine Angs-Tie2 pathway. This notion was further supported by the study of two AML cell lines, KG-1 and HL-60: the growth of KG-1 was suppressed by Tie2-Fc, and also by anti-Tie2 antibody, which inhibits receptor-ligand interaction, while that of HL-60 was not suppressed by Tie2-Fc or anti-Tie2 antibody. Our results will help to explore the angiogenesis-oriented or endothelial cell-mediated therapy for leukemia.

A problem in diagnosing N3 disease using FDG-PET in patients with lung cancer--high false positive rate with visual assessment.

OBJECTIVE: To evaluate the accuracy of diagnosing N3 disease using positron emission tomography (PET) with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) in patients with pulmonary disease. SUBJECTS AND METHODS: Twenty patients diagnosed as FDG-PET N3 were enrolled. On FDG-PET, lymph nodes were considered to be positive when increased uptake as compared with that of the surrounding mediastinum was visually observed, or the mean standardized uptake ratio (SUR) was more than 2, 2.5, or 3. On CT, lymph nodes exceeding 1 cm in the shortest diameter were regarded as positive. RESULTS: The PET result was true positive (TP) in 2 patients and false positive (FP) in 18 with an overall accuracy (OA) of 10% using visual criteria. Using an SUR of more than 2.5, the result was TP in 2, FP in 3, and true negative (TN) in 15, the false negative (FN) in 0, with an OA of 85%. CT diagnosis was TP in 2, FP in 9, and TN in 9 with an OA of 55%. The accuracy using the SUR criteria of more than 2.5 was superior to that of CT. CONCLUSION: Of 20 patients with the diagnosis of PET N3, we found frequent over-diagnosis in nodal staging using the visual criteria.

Radiographic findings of aberrant right subclavian artery initially depicted on CT.

PURPOSE: To evaluate the radiographic findings of aberrant right subclavian artery (ARSCA) initially depicted on CT. METHODS: Twenty-five cases incidentally diagnosed during CT between June 1993 and May 2001, were examined. They included 13 men and 12 women aged from 29 to 84 years old (mean, 63 years). Three findings were evaluated on posteroanterior radiographs: 1) oblique edge, 2) vessel through the trachea, and 3) mass effect. On lateral radiographs, the following findings were evaluated: 1) posterior tracheal imprint, 2) retrotracheal opacity, and 3) aortic arch obscuration. RESULTS: On the posteroanterior radiographs, oblique edge, vessel through the trachea, and mass effect were observed in 32% (8/25), 44% (11/25), and 20% (5/25) of cases, respectively. On the lateral radiographs, posterior tracheal imprint, retrotracheal opacity, and aortic arch obscuration were observed in 95% (18/19), 58% (11/19), and 37% (7/19), respectively. On posteroanterior radiographs, normal cases were most frequent (40%). In contrast, lateral radiographs demonstrated at least one abnormality in all cases. As a variation of posterior tracheal imprint, the long-segment type of compression was observed in 32%. CONCLUSIONS: We consider detailed interpretation of the posterior tracheal edge on lateral radiographs to be important in diagnosing cases of mild ARSCA.

Primary ureteral mucosa-associated lymphoid tissue (MALT) lymphoma--pathological and radiological findings.

In this report we describe the pathological and radiological findings in a patient with primary ureteral MALT lymphoma. We suggest that it is useful for the differential diagnosis of ureter masses that some MALT lymphomas may show a low signal intensity on T2-weighted MR images.

Concurrent periosteal chondroma and enchondroma of the fibula mimicking chondrosarcoma.

We present a rare concurrence of enchondroma and periosteal chondroma in the right distal fibula that mimicked chondrosarcoma in a 13-year-old boy. Radiographs and CT scans showed a periosteal lesion producing saucerization without periosteal reaction and calcification in the distal metaphysis of the right fibula. MRI showed an intramedullary lesion adjacent to the periosteal lesion, although it was invisible at CT. There was no cortical breach on imaging and gross examination. Because both lesions represented benign cartilaginous tumors on histology, concurrent periosteal chondroma and enchondroma of the fibula was diagnosed. This combination in the same bone in a patient without enchondromatosis is exceedingly rare. Such imaging features may be confused with those of chondrosarcoma.

t(8;21) acute myeloid leukaemia cells are dependent on vascular endothelial growth factor (VEGF)/VEGF receptor type2 pathway and phosphorylation of Akt.

Several anti-angiogenic drugs have recently been clinically tested for haematological malignancies. To improve the efficacy of molecular target therapy against angiogenic molecules in acute myeloid leukaemia (AML), we examined the dependency of AML cells on the vascular endothelial growth factor (VEGF)/VEGF receptor type2 (VEGFR2) system by using VEGFR2 kinase inhibitor. Nineteen patient AML samples were cultured with or without VEGFR2 kinase inhibitor. All four t(8;21) viable AML cells showed significant reductions when treated with VEGFR2 kinase inhibitor, although VEGFR2 kinase inhibitor did not affect the cell proliferation of five t(15;17) AML samples. Other AML cases showed variable responses. VEGFR2 kinase inhibitor greatly suppressed the growth of Kasumi-1, a t(8;21) cell line in a dose-dependent manner through induction of apoptosis, but did not show any significant influence on NB4, a t(15;17) cell line. In addition, VEGFR2 kinase inhibitor potentiated the growth inhibitory effect of cytarabine in Kasumi-1. Finally, it was shown that the Akt phosphorylation was augmented by VEGF(165) in Kasumi-1, which was abrogated by VEGFR2 kinase inhibitor. NB4 showed undetectable Akt phosphorylation even with VEGF(165). These data demonstrated that t(8;21) AML cells are dependent on VEGF through VEGFR2, resulting in the phosphorylation of Akt.

Placenta growth factor stimulates the growth of Philadelphia chromosome positive acute lymphoblastic leukemia cells by both autocrine and paracrine pathways.

Vascular endothelial growth factor (VEGF) and its associated molecule, placenta growth factor (PlGF) are now known to support normal hematopoiesis, and leukemia cell growth. In this study, expression of VEGF and PlGF in acute lymphoblastic leukemia (ALL) cells was examined by real time reverse transcription-polymerase chain reaction in 20 patient samples. Expression of PlGF was more intense in Philadelphia chromosome positive (Ph(+)) ALL than in Ph(-) ALL cases. On the other hand, expression level of VEGF was not different between Ph(+) and Ph(-) cases. Then, PlGF was added to the two ALL cell lines, CRL1929 (Ph(+)), and Nalm6 (Ph(-)). The PlGF stimulated the growth of CRL1929 in time- and dose-dependent manners, although the growth of Nalm6 was not affected by PlGF. The growth stimulation of CRL1929 by PlGF was confirmed by the increase of S phase cells. And the growth promoting effect of PlGF on CRL1929 was cancelled by simultaneous addition of VEGFR1/Fc (which binds to PlGF and abrogates its function), but was not cancelled by VEGFR2/Fc (which does not bind to PlGF). Then, addition of VEGFR1/Fc to the simple culture of CRL1929 demonstrated growth inhibitory effect. These observations demonstrated that PlGF stimulates the growth of Ph(+) ALL cells by both autocrine and paracrine pathways. Finally, PlGF-VEGFR1 loop might be a therapeutic target to improve the prognosis of Ph(+) ALL.