tbuckley/cabot-search huggingface dataset:
ANNEXIN A2 REGULATES ANGIOGENESIS AND INVASION PHENOTYPES OF MALIGNANT GLIOMA
Authors: T. Ichikawa, M. Onishi, K. Kurozumi, T. Maruo, S. Inoue, H. Michiue, K. Yoshida, K. Fuji, J. Ishida, Y. Shimazu, T. Oka, E. A. Chiocca, I. Date
Journal: Neuro-Oncology (2014)

BACKGROUND: Despite advances in multimodal therapy, patients with malignant glioma have a dismal prognosis. Aberrant angiogenesis and diffuse glioma cell invasion are major obstacles for effective treatment. Therefore, investigation of angiogenesis and invasion is essential for the development of a curative therapy. We established animal models that histologically mimic two invasive and angiogenic phenotypes of glioma, ie, angiogenesis-dependent invasion (J3T-1) and angiogenesis-independent invasion (J3T-2). In our previous study, comparative proteomic analysis showed that annexin A2 was more highly expressed in J3T-1 than in J3T-2. In this study, the function of annexin A2 in malignant glioma in relation to angiogenesis and invasion was investigated using these animal models. METHODS: Annexin A2-downregulated J3T-1 cells (J3T-1shA) and annexin A2-upregulated J3T-2 cells (J3T-2A) were generated by gene transfection. Quantitative reverse transcription polymerase chain reaction (QRT-PCR) and immunohistochemical staining of annexin A2 and vascular endothelial growth factor (VEGF) were performed on cultured cells. J3T-1, J3T-1shA, J3T-2, and J3T-2A brain tumors were established in athymic rats. Brain sections were evaluated histopathologically. Human glioblastoma specimens were stained for annexin A2, VEGF, and platelet-derived growth factor (PDGF). RESULTS: QRT-PCR and immunohistochemical staining of cultured cells revealed that expression of VEGF was upregulated in accordance with the expression of annexin A2 in J3T-1 and J3T-2A cells. J3T-1 tumors showed remarkable angiogenic activity and invasion around neovasculature, whereas J3T-1shA tumors, including J3T-2 tumors, showed no angiogenic activity, but diffuse single-cell infiltration of tumor cells into normal parenchyma. J3T-2A tumors were highly angiogenic and showed angiogenesis-dependent invasion. Human glioblastoma specimens revealed that annexin A2 was positive in clusters of tumor cells around dilated vessels (25/30 cases). The intensity of VEGF and PDGF staining corresponded to the expression of annexin A2 (correlation coefficients: annexin A2/VEGF: R = 0.73, P < 0.05; annexin A2/PDGF: R = 0.37, P < 0.05). CONCLUSIONS: Our results revealed that the phenotype of glioma invasion is closely related to angiogenesis, and annexin A2 is one of the factors that regulates angiogenesis and invasion phenotype of malignant glioma. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.
Cardiovascular Disease in Early Stages of Chronic Kidney Disease in a Chinese Population
Authors: LuXia Zhang, Li Zuo, Fang Wang, Mei Wang, ShuYu Wang, JiCheng Lv, LiSheng Liu, HaiYan Wang
Journal: Journal of the American Society of Nephrology (2006)

Cardiovascular disease (CVD) is one of the most serious complications of kidney disease, yet studies of CVD in early stage of chronic kidney disease (CKD) in Asian patients are very limited. Therefore, this study determined the prevalence and the spectrum of CVD in individuals with early-stage CKD and compared them with data of individuals without CKD. Compared with individuals with estimated GFR (eGFR) >90 ml/min per 1.73 m2, the prevalence of myocardial infarction, stroke, and total CVD of individuals with eGFR 60 to 89 ml/min per 1.73 m2 was increased by 91.4, 71.7, and 67.6%, respectively. For individuals with eGFR 30 to 59 ml/min per 1.73 m2, the percentage was 105.2, 289.1, and 200.7%, respectively. For each eGFR category, stroke was more prevalent than myocardial infarction. Compared with individuals with eGFR >90 ml/min per 1.73 m2, participants with eGFR 60 to 89 and 30 to 59 ml/min per 1.73 m2 tended to have more cardiovascular risk factors, and there were strong unadjusted and adjusted associations between CVD with different stages of eGFR (eGFR >90 ml/min per 1.73 m2 as reference). This is the first report on the prevalence and the spectrum of CVD in early stages of CKD in a community-based Chinese population. The spectrum of CVD in this Chinese population is different from reports of Western countries. Individuals with subtle decreased renal function seem much more likely to have multiple cardiovascular risk factors and have higher prevalence of CVD than those without CKD.
Molecular Pathways: The Hedgehog Signaling Pathway in Cancer
Authors: Ross McMillan, William Matsui
Journal: Clinical Cancer Research (2012)

Abstract The Hedgehog (Hh) signaling pathway regulates embryonic development and may be aberrantly activated in a wide variety of human cancers. Efforts to target pathogenic Hh signaling have steadily progressed from the laboratory to the clinic, and the recent approval of the Hh pathway inhibitor vismodegib for patients with advanced basal cell carcinoma represents an important milestone. On the other hand, Hh pathway antagonists have failed to show significant clinical activity in other solid tumors. The reasons for these negative results are not precisely understood, but it is possible that the impact of Hh pathway inhibition has not been adequately measured by the clinical endpoints used thus far or that aberrancies in Hh signal transduction limits the activity of currently available pathway antagonists. Further basic and correlative studies to better understand Hh signaling in human tumors and validate putative antitumor mechanisms in the clinical setting may ultimately improve the success of Hh pathway inhibition to other tumor types. Clin Cancer Res; 18(18); 4883–8. ©2012 AACR.
S75 Is a practice incremental shuttle walk test always necessary and is it influenced by MRC dyspnoea grade?
Authors: A. K. Dhaliwal, L. Sewell, R. Collier, S. J. Singh
Journal: Thorax (2010)

<h3>Introduction</h3> The Incremental Shuttle Walk Test (ISWT) is a common assessment tool used to assess exercise capacity in patients with Chronic Obstructive Pulmonary Disease (COPD). Healthcare professionals conducting this test will ask patients to perform a practice Incremental Shuttle Walk Test (PISWT). The aim was to explore whether a PISWT is needed and to examine whether variance between PISWT and the second shuttle walk test (ISWT2) is influenced by MRC dyspnoea grade. <h3>Method</h3> This is a retrospective audit of 441 COPD patients: male 194 female 297 mean (SD) age 68.9 (10.13) years who were assessed for outpatient pulmonary rehabilitation (PR). Patients undertook a PISWT and rested for 30 min before performing ISWT2. Distance covered (m), MRC grade, heart rate (HR), forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and body mass index (BMI) were recorded. <h3>Results</h3> The mean (SD) change between both shuttle walk tests and significance levels were analysed using a paired t test. These results are detailed in Abstract S75 Table 1. Overall, there was a statistically significant increase in mean walking distance between PISWT and ISWT2. In each patient subgroup, a significant increase was seen for all, except for those of MRC grade 1; however this group consisted only of eight patients. Furthermore, no patient subgroup achieved the minimum clinically important distance for the ISWT &gt;47.5 m (Singh <i>et al</i>, 2008). Patients in MRC grades 2 and 3 showed more variance between each shuttle walk test. The least mean change was seen in patients of MRC grade 5. <h3>Conclusion</h3> Overall, there was a statistical significant increase in distance walked in all patients. These data confirm the need for a PISWT to be conducted within the COPD population. Patients in MRC grades 2 and 3 show a larger variance in walking distance between both shuttle walk tests.
Breathing pattern during acute respiratory failure and recovery
Authors: N Del Rosario, CS Sassoon, KG Chetty, SE Gruer, CK Mahutte
Journal: European Respiratory Journal (1997)

The objective of this study was to compare the breathing pattern of patients who failed to wean from mechanical ventilation to the pattern during acute respiratory failure. We hypothesized that a similar breathing pattern occurs under both conditions. Breathing pattern, mouth occlusion pressure (P[0.1]) and maximum inspiratory pressure (P[I,max]) were measured in 15 patients during acute respiratory failure, within 24 h of the institution of mechanical ventilation, and in 49 patients during recovery, when they were ready for discontinuation from mechanical ventilation. The following indices were calculated: rapid shallow breathing index (respiratory frequency/tidal volume (fR/VT)); rapid shallow breathing-occlusion pressure index (ROP = P[0.1 x fR/VT]); P(0.1)/P(I,max); and effective inspiratory impedance (P[0.1]/VT/(inspiratory time (tI)). Patients who failed to wean (n=11) had a similar ROP,fR/VT and P(0.1)/P(I,max) to those with acute respiratory failure despite a significantly reduced P(0.1)/VT/tI, the value of which was comparable to that of patients who weaned successfully (n=38). The P(I,max) of patients who failed to wean was similar to that of patients who weaned successfully. We conclude that patients who failed to wean had a breathing pattern similar to that during acute respiratory failure, despite a reduced mechanical load on the respiratory muscles and a relatively adequate inspiratory muscle strength. This suggests that strategies that enhance respiratory muscle endurance may facilitate weaning.
Deoxycytidine Kinase Modulates the Impact of the ABC Transporter ABCG2 on Clofarabine Cytotoxicity
Authors: Shinjiro Nagai, Kazumasa Takenaka, Deepa Nachagari, Charles Rose, Kali Domoney, Daxi Sun, Alex Sparreboom, John D. Schuetz
Journal: Cancer Research (2011)

Purine nucleoside antimetabolites, such as clofarabine, are effective antileukemic agents. However, their effectiveness depends on an initial activation step in which they are monophosphorylated by deoxycytidine kinase (dCK). Some purine nucleoside antimetabolites and their monophosphate derivatives are exported by the ABC transporter ABCG2. Because clofarabine is a dCK substrate, and we show substantial variation in dCK and ABCG2 in myeloid leukemia, we hypothesized that the activity of dCK may modulate ABCG2-mediated resistance to clofarabine by regulating the formation of clofarabine monophosphate. We show that ABCG2 influence on clofarabine cytotoxicity was markedly influenced by dCK activity. When dCK expression was reduced by siRNA, clofarabine cytotoxicity was strongly reduced by enhanced ABCG2-mediated efflux. Conversely, dCK overexpression blunted ABCG2-mediated efflux of clofarabine by increasing the formation of clofarabine nucleotides. The use of an ABCG2 inhibitor confirmed that ABCG2 export of clofarabine is maximal when dCK levels are minimal. Analysis of intracellular clofarabine metabolites suggested that ABCG2 exported clofarabine more readily than clofarabine monophosphate. That ABCG2 primarily effluxes clofarabine, but not chlorfarabine-monophosphate, was confirmed by HPLC analysis of drug exported from ABCG2-overexpressing cells. Because the level and function of dCK and ABCG2 vary substantially among other types of cancer, these findings have important implications not only for clofarabine therapy but for purine nucleoside therapy in general. Therefore, we propose that addition of ABCG2 inhibitors would effectively increase the antitumor efficacy of purine nucleosides by blocking drug efflux that may be a significant mode of resistance when dCK levels are low.
RABBIT POX
Authors: Paul D. Rosahn, Ch'uan-K'uei Hu
Journal: The Journal of Experimental Medicine (1935)

Observations on an epidemic of rabbit pox occurring in an isolated animal room during the winter of 1933-34 are reported. The clinical manifestations, consisting of a generalized papular eruption involving the skin and mucous membranes, together with blepharitis, ophthalmia, nasal discharge and lymphadenopathy were essentially similar to those noted in a pox epidemic of the previous year. This was true in general also of the pathological findings except that vacuolization, local necrosis and vesicle formation were seen in the epidermis, while in the previous year the microscopic pathology in the skin was confined to the corium. Evidence was presented indicating that the infection can be transmitted through the medium of a personal carrier, and that transmission in this manner can occur during the incubation period or before a definite diagnosis is possible. The findings also demonstrated that the etiological agents responsible for the disease reported here and that of the previous year were immunologically related, and that the immunity in recovered animals effectively persisted during the entire period for which data are available, 9 to 12 months. It appeared also that young animals suckling an immune doe were more refractory to the development of the lesions of rabbit pox than were the young of susceptible does.
Propylthiouracil-induced alveolar haemorrhage associated with antineutrophil cytoplasmic antibody
Authors: M Ohtsuka, Y Yamashita, M Doi, S Hasegawa
Journal: European Respiratory Journal (1997)

Propylthiouracil (PTU) is known to cause vasculitis as a rare complication. We report the case of a patient who developed alveolar haemorrhage and haematuria whilst treated with PTU. The serum was positive for antineutrophil cytoplasmic antibody (ANCA) with myeloperoxidase (MPO) specificity (MPO-ANCA). All symptoms resolved completely after discontinuation of PTU. Alveolar haemorrhage or pulmonary-renal syndrome associated with antineutrophil cytoplasmic antibody with myeloperoxidase specificity may be a new complication of propylthiouracil therapy.
Histologic transformation of follicular lymphoma to diffuse lymphoma represents tumor progression by a single malignant B cell.
Authors: A D Zelenetz, T T Chen, R Levy
Journal: The Journal of Experimental Medicine (1991)

To investigate the clonal relationship between follicular lymphoma (FL) and transformed diffuse lymphoma (tDL), we examined the expression of tumor idiotype, immunoglobulin (Ig) gene rearrangements and sequence of Ig variable genes in paired tissue specimens. All 16 cases analyzed expressed surface immunoglobulin (sIg) on both the FL and the tDL, though the immunophenotype of one case of FL could not be definitively determined. In 14 of 15 cases, the surface immunophenotype was preserved; the exception was likely secondary to a class switch from IgM to IgG. In 12 of 13 cases, antiidiotypic monoclonal antibodies prepared against the FL reacted with the paired tDL. Analysis of Ig gene rearrangements in four cases by Southern blot hybridization showed evidence of clonal relationships in all cases though concordance was not seen with all probes tested (C kappa, C lambda, JH, PFL1, and PFL2). In the one case that had a discordant L chain rearrangement, sequence analysis of the L chain demonstrated a common mature B cell origin for both the FL and tDL. To determine whether tDL arose from one or more FL cells, the sequences of the H chain variable genes were analyzed. Individual clones of the V region gene of the FL showed a random distribution of changes throughout the sequence. In contrast, individual clones of the V region gene from tDL shared numerous nonrandom sequence alterations, implying a common single cell origin. In conclusion, tDL is a mature B cell and arises by transformation of a single FL cell.
Government got its NHS workforce plans wrong, say experts
Authors: Adrian O'Dowd
Journal: BMJ (2007)

Poor NHS workforce planning a few years ago by the government has led to the current climate of staff cutbacks and redundancies, say workforce experts. 

The government should have warned the NHS to start trimming its growing staff back in 2004, the parliamentary health select committee was told at a meeting on 13 December, in the latest evidence session of its inquiry into workforce planning. 

John Sargent, a workforce development consultant and former chief executive of the Greater Manchester Workforce Development Confederation, told the MPs that warnings could and should have come sooner. 

He said, “The [health] department has an important …
Importance of timing of post-contrast MRI in rheumatoid arthritis: what happens during the first 60 minutes after IV gadolinium-DTPA?
Authors: M Ostergaard
Journal: Annals of the Rheumatic Diseases (2001)

<h3>BACKGROUND</h3> Volumes of inflamed synovial membrane determined by magnetic resonance imaging (MRI) are closely related to histopathological synovitis and may predict erosive progression in rheumatoid arthritis (RA). However, after IV injection, leakage of MRI contrast from the synovium gradually compromises the differentiation of synovium from joint fluid. <h3>OBJECTIVE</h3> To determine the time period after IV MRI contrast (gadolinium-DTPA (Gd)) injection in which synovial membrane volume determination is reliable. <h3>METHODS</h3> MRI of five RA knees with clinical synovitis was carried out, with axial, T<sub>1</sub> weighted, spin echo images before IV Gd injection and every 1.75 minutes for 60 minutes post-Gd. By a semiautomated "signal enhancement threshold" method, including voxels with &gt;35% or &gt;45% relative post-Gd enhancement, synovial membrane volumes were estimated at each time point. At 4.25 minutes post-Gd, volumes were also determined by a more accurate but time consuming "manual method". <h3>RESULTS</h3> The initially observed synovium-effusion borderline remained clearly visible, and on the same location, within at least the initial 11 minutes post-Gd (that is, within the normal time frame of post-Gd imaging in RA) but started blurring and moving centripetally thereafter. Compared with volumes at all other time points, synovial membrane volumes at 0.75 and 2.50 minutes post-Gd were significantly lower (Wilcoxon-Pratt), suggesting that some synovial membrane areas had not yet exceeded the enhancement threshold. Thereafter, the measured volumes remained practically unchanged. <h3>CONCLUSION</h3> This study suggests that MR image acquisition in arthritic knee joints should be performed within the initial approximately 10 minutes after gadolinium contrast injection to achieve the most accurate distinction between synovium and joint fluid but that small time variations are not of major importance to the measured synovial membrane volumes.
Physical Activity and Television Viewing in Relation to Risk of Undiagnosed Abnormal Glucose Metabolism in Adults
Authors: David W. Dunstan, Jo Salmon, Neville Owen, Timothy Armstrong, Paul Z. Zimmet, Timothy A. Welborn, Adrian J. Cameron, Terence Dwyer, Damien Jolley, Jonathan E. Shaw
Journal: Diabetes Care (2004)

OBJECTIVE—The goal of this study was to assess the associations of physical activity time and television (TV) time with risk of “undiagnosed” abnormal glucose metabolism in Australian adults. RESEARCH DESIGN AND METHODS—This population-based cross-sectional study using a stratified cluster design involving 42 randomly selected Census Collector Districts across Australia included 8,299 adults aged 25 years or older who were free from new type 2 diabetes and self-reported ischemic disease and did not take lipid-lowering or antihypertensive drugs. Abnormal glucose metabolism (impaired fasting glycemia [IFG], impaired glucose tolerance [IGT], or new type 2 diabetes) was based on an oral glucose tolerance test. Self-reported physical activity time and TV time (previous week) were assessed using interviewer-administered questionnaires. RESULTS—After adjustment for known confounders and TV time, the odds ratio (OR) of having abnormal glucose metabolism was 0.62 (95% CI 0.41–0.96) in men and 0.71 (0.50–1.00) in women for those engaged in physical activity ≥2.5 h/week compared with those who were sedentary (0 h/week). The ORs of having abnormal glucose metabolism were 1.16 (0.79–1.70) in men and 1.49 (1.12–1.99) in women who watched TV &amp;gt;14 h/week compared with those who watched ≤7.0 h/week. Higher TV viewing (&amp;gt;14 h/week) was also associated with an increased risk of new type 2 diabetes in men and women and IGT in women compared with those watching &amp;lt;14 h/week. Total physical activity of ≥2.5 h/week was associated with a reduced risk of IFG, IGT, and new type 2 diabetes in both sexes; however, only the association with IGT in women was statistically significant. CONCLUSIONS—These findings suggest a protective effect of physical activity and a deleterious effect of TV time on the risk of abnormal glucose metabolism in adults. Population strategies to reduce risk of abnormal glucose metabolism should focus on reducing sedentary behaviors such as TV time, as well as increasing physical activity.
Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells
Authors: Kathyjo A. Jackson, Susan M. Majka, Hongyu Wang, Jennifer Pocius, Craig J. Hartley, Mark W. Majesky, Mark L. Entman, Lloyd H. Michael, Karen K. Hirschi, Margaret A. Goodell
Journal: Journal of Clinical Investigation (2001)

Myocyte loss in the ischemically injured mammalian heart often leads to irreversible deficits in cardiac function. To identify a source of stem cells capable of restoring damaged cardiac tissue, we transplanted highly enriched hematopoietic stem cells, the so-called side population (SP) cells, into lethally irradiated mice subsequently rendered ischemic by coronary artery occlusion for 60 minutes followed by reperfusion. The engrafted SP cells (CD34–/low, c-Kit+, Sca-1+) or their progeny migrated into ischemic cardiac muscle and blood vessels, differentiated to cardiomyocytes and endothelial cells, and contributed to the formation of functional tissue. SP cells were purified from Rosa26 transgenic mice, which express lacZ widely. Donor-derived cardiomyocytes were found primarily in the peri-infarct region at a prevalence of around 0.02% and were identified by expression of lacZ and α-actinin, and lack of expression of CD45. Donor-derived endothelial cells were identified by expression of lacZ and Flt-1, an endothelial marker shown to be absent on SP cells. Endothelial engraftment was found at a prevalence of around 3.3%, primarily in small vessels adjacent to the infarct. Our results demonstrate the cardiomyogenic potential of hematopoietic stem cells and suggest a therapeutic strategy that eventually could benefit patients with myocardial infarction.