tbuckley/cabot-search huggingface dataset:
Correlation of high-frequency ultrasound backscatter with tumor microstructure in iris melanoma
Authors: Roxana Ursea, D.Jackson Coleman, Ronald H Silverman, Frederic L Lizzi, Suzanne M Daly, Winston Harrison
Journal: Ophthalmology (1998)

ObjectiveThis study aimed to correlate histologic characteristics with high-frequency ultrasound backscatter spectra in malignant melanomas of the iris.DesignThe study design was a cohort (case series) study of patients diagnosed with iris melanoma in the authors' clinic.ParticipantsSixteen patients with iris melanoma participated.InterventionThe patients were scanned with a 50-MHz ultrasound unit equipped for digitization of raw echo data. Spectral parameter images representing the spatial distribution of size and concentration of tissue inhomogeneities were produced.Main outcome measuresThe variation of spectral properties within and between tumors was determined. In the two tumors in this series for which histologic material was available, the authors compared scatterer concentration and size with histology and mathematically modeled the effect of melanocyte distribution on spectra.ResultsUltrasound scattering characteristics differed considerably among tumors. Where histology was available, acoustic parameters correlated with the size and number of melanocytes present.ConclusionsIris melanomas exhibited a wide range in acoustic backscatter properties. Whereas characteristics such as vascularity and necrosis might contribute to this, in the two cases examined here, backscatter characteristics could be largely accounted for by melanocyte distribution. A better understanding of the relationship of histology to noninvasive ultrasound data will enhance the diagnostic utility of this technique.
Fli1 Acts Downstream of Etv2 to Govern Cell Survival and Vascular Homeostasis via Positive Autoregulation
Authors: Md J. Abedin, Annie Nguyen, Nan Jiang, Cameron E. Perry, John M. Shelton, Dennis K. Watson, Anwarul Ferdous
Journal: Circulation Research (2014)

Rationale: Cardiovascular health depends on proper development and integrity of blood vessels. Ets variant 2 (Etv2), a member of the E26 transforming–specific family of transcription factors, is essential to initiate a transcriptional program leading to vascular morphogenesis in early mouse embryos. However, endothelial expression of the Etv2 gene ceases at midgestation; therefore, vascular development past this stage must continue independent of Etv2. Objective: To identify molecular mechanisms underlying transcriptional regulation of vascular morphogenesis and homeostasis in the absence of Etv2. Methods and Results: Using loss- and gain-of-function strategies and a series of molecular techniques, we identify Friend leukemia integration 1 ( Fli1 ), another E26 transforming–specific family transcription factor, as a downstream target of Etv2. We demonstrate that Etv2 binds to conserved Ets-binding sites within the promoter region of the Fli1 gene and governs Fli1 expression. Importantly, in the absence of Etv2 at midgestation, binding of Etv2 at Ets-binding sites in the Fli1 promoter is replaced by Fli1 protein itself, sustaining expression of Fli1 as well as selective Etv2-regulated endothelial genes to promote endothelial cell survival and vascular integrity. Consistent with this, we report that Fli1 binds to the conserved Ets-binding sites within promoter and enhancer regions of other Etv2-regulated endothelial genes, including Tie2 , to control their expression at and beyond midgestation. Conclusions: We have identified a novel positive feed-forward regulatory loop in which Etv2 activates expression of genes involved in vasculogenesis, including Fli1 . Once the program is activated in early embryos, Fli1 then takes over to sustain the process in the absence of Etv2.
Dying for attention: Microparticles and angiogenesis
Authors: C BOULANGER, A TEDGUI
Journal: Cardiovascular Research (2005)

See article by Brill et al.  [18]  (pages 30–38) in this issue. 

Microparticles, which were initially described as cell dust, have revealed over the past few years several exciting and unexpected properties. Microparticles are submicron vesicles shed from plasma membranes following cell activation or apoptosis, whose protein and lipid profile may be considered as a snapshot of the phenotype of the cell they stem from. The molecular mechanisms of microparticle formation and shedding are not yet fully understood, but seem to involve the changes in the cytoskeleton and exposure of phosphatidylserine on the outer leaflet of the plasma membrane [1,2]. Nevertheless, microparticles can easily be generated in vitro from aggregating platelets or from cultured cells following activation or apoptosis.

Microparticles are also found circulating in the blood. Their numbers increase in patients exhibiting hypercoagulability and decrease in those with bleeding disorders [2,3]. Presence of microparticles has also been documented at sites of inflammation such as the acellular lipid core of the atherosclerotic plaque or the synovial fluid from patients with rheumatoid arthritis [3–6]. Furthermore, increased numbers … 

*Corresponding author. Tel.: +33 1 4463 1864; fax: +33 1 4281 3128. Email address: chantal.boulanger{at}larib.inserm.fr
Elevated Placental Soluble Vascular Endothelial Growth Factor Receptor-1 Inhibits Angiogenesis in Preeclampsia
Authors: Shakil Ahmad, Asif Ahmed
Journal: Circulation Research (2004)

Preeclampsia is an inflammatory disorder in which serum levels of vascular endothelial growth factor (VEGF) and its soluble receptor-1 (sVEGFR-1, also known as sFlt-1) are elevated. We hypothesize that VEGF and placenta growth factor (PlGF) are dysregulated in preeclampsia due to high levels of sVEGFR-1, which leads to impaired placental angiogenesis. Analysis of supernatants taken from preeclamptic placental villous explants showed a four-fold increase in sVEGFR-1 than normal pregnancies, suggesting that villous explants in vitro retain a hypoxia memory reflecting long-term fetal programming. The relative ratios of VEGF to sVEGFR-1 and PlGF to sVEGFR-1 released from explants decreased by 53% and 70%, respectively, in preeclampsia compared with normal pregnancies. Exposure of normal villous explants to hypoxia increased sVEGFR-1 release compared with tissue normoxia (P<0.001), as did stimulation with tumor necrosis factor-alpha (P<0.01). Conditioned medium (CM) from normal villous explants induced endothelial cell migration and in vitro tube formation, which were both attenuated by pre-incubation with exogenous sVEGFR-1 (P<0.001). In contrast, endothelial cells treated with preeclamptic CM showed substantially reduced angiogenesis compared with normal CM (P<0.001), which was not further decreased by the addition of exogenous sVEGFR-1, indicating a saturation of the soluble receptor. Removal of sVEGFR-1 by immunoprecipitation from preeclamptic CM significantly restored migration (P<0.001) and tube formation (P<0.001) to levels comparable to that induced by normal CM, demonstrating that elevated levels of sVEGFR-1 in preeclampsia are responsible for inhibiting angiogenesis. Our finding demonstrates the dysregulation of the VEGF/PlGF axis in preeclampsia and offers an entirely new therapeutic approach to its treatment.
Visceral leishmaniasis causes fever and decompensation in patients with cirrhosis
Authors: P. Pagliano, N. Carannante, M. Gramiccia, T. Ascione, G. Stornaiuolo, L. Gradoni, F. S Faella, G. B Gaeta
Journal: Gut (2007)

Infections and fever due to bacterial infections are well-known complications of liver cirrhosis, and often trigger decompensation and death.1 Visceral leishmaniasis (VL), a protozoan infection endemic in the Mediterranean area, causes a febrile disease, the clinical and laboratory features (splenomegaly, pancytopenia, reduced serum albumin and increased γ-globulin concentrations) of which largely overlap with those of cirrhosis.2,3 Although the areas where VL is endemic coincide with areas where the prevalence of cirrhosis is high, no study has described VL in patients with cirrhosis.

During a 12-year period, all patients with cirrhosis admitted for decompensation and fever lasting more than 1 week, unresponsive to broad-spectrum antibiotics, underwent diagnostic procedures for VL. For each case diagnosed as VL, three consecutive cases of bacterial infection observed in the same period were enrolled. Cirrhosis was defined …
Potential Use of Quantitative Tissue Phenotype to Predict Malignant Risk for Oral Premalignant Lesions
Authors: Martial Guillaud, Lewei Zhang, Catherine Poh, Miriam P. Rosin, Calum MacAulay
Journal: Cancer Research (2008)

Abstract The importance of early diagnosis in improving mortality and morbidity rates of oral squamous cell carcinoma (SCC) has long been recognized. However, a major challenge for early diagnosis is our limited ability to differentiate oral premalignant lesions (OPL) at high risk of progressing into invasive SCC from those at low risk. We investigated the potential of quantitative tissue phenotype (QTP), measured by high-resolution image analysis, to identify severe dysplasia/carcinoma in situ (CIS; known to have an increased risk of progression) and to predict progression to cancer within hyperplasia or mild/moderate dysplasia. We generated a nuclear phenotype score (NPS), a combination of five nuclear morphometric features that best discriminate 4,027 “normal” nuclei (selected from 29 normal oral biopsies) from 4,298 “abnormal” nuclei (selected from 30 SCC biopsies). This NPS was then determined for a set of 69 OPLs. Severe dysplasia/CIS showed a significant increase in NPS compared with hyperplasia or mild/moderate dysplasia. However, within the latter group, elevated NPS was strongly associated with the presence of high-risk loss of heterozygosity (LOH) patterns. There was a statistical difference between NPS of hyperplasia or mild/moderate dysplasia that progressed to cancer and those that did not. Individuals with a high NPS had a 10-fold increase in relative risk of progression. In the multivariate Cox model, LOH and NPS together were the strongest predictors for cancer development. These data suggest that QTP could be used to identify lesions that require molecular evaluation and should be integrated with such approaches to facilitate the identification of hyperplasia or mild/moderate dysplasia OPLs at high risk of progression. [Cancer Res 2008;68(9):3099–107]
Schizophrenia Is a Cognitive Illness
Authors: René S. Kahn, Richard S. E. Keefe
Journal: JAMA Psychiatry (2013)

Schizophrenia is currently classified as a psychotic disorder. This article posits that this emphasis on psychosis is a conceptual fallacy that has greatly contributed to the lack of progress in our understanding of this illness and hence has hampered the development of adequate treatments. Not only have cognitive and intellectual underperformance consistently been shown to be risk factors for schizophrenia, several studies have found that a decline in cognitive functioning precedes the onset of psychosis by almost a decade. Although the question of whether cognitive function continues to decline after psychosis onset is still debated, it is clear that cognitive function in schizophrenia is related to outcome and little influenced by antipsychotic treatment. Thus, our focus on defining (and preventing) the disorder on the basis of psychotic symptoms may be too narrow. Not only should cognition be recognized as the core component of the disorder, our diagnostic efforts should emphasize the changes in cognitive function that occur earlier in development. Putting the focus back on cognition may facilitate finding treatments for the illness before psychosis ever emerges.
New year resolutions
Authors: A. Bush, I. Pavord
Journal: Thorax (2011)

We have deliberately not published these in January, so they will be intact beyond the first week of the New Year. This is in essence a six month report of where we are, and where we hope to go. It is also a formal invitation to the readership to be pro-active with suggestions for improvement.

We received 1839 submissions in 2010. Outright rejections were 41% and eventual acceptance rate was 16%. Time from submission to first decision was 26 days (54 days for reviewed papers). We received submissions from all round the world, reflecting our International standing, and the main areas were UK 27%, USA 10%, Italy 6%, Netherlands 5%, China 5% and Japan 4%. We are particularly grateful to the Associate and Deputy Editors and the reviewers, without whom the Journal would not function. A particular thanks to our statistical team, Drs Gibson, McKeever and Tata from Nottingham. They have provided superb and prompt reviews, and majorly contributed to keeping the manuscript quality high. Thanks also to Dr Jenny Quint who has done such an excellent job with ‘lung alerts’ and Mark FitzGerald who has kept the flow of fascinating Images, Case reports and Pulmonary puzzles going. We have appointed an entirely new Editorial Board and have had two excellent editorial meetings in Barcelona, with lots of energy and ideas. We want to take these forward in 2011. Our aim is to keep getting the content right, and see that reflected in a rising impact factor. We are also grateful to our Journal support staff, in particular Claire …
Time dependent risk of gastrointestinal complications induced by non-steroidal anti-inflammatory drug use: a consensus statement using a meta-analytic approach
Authors: F Richy
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objectives:</b> To provide an updated document assessing the global, NSAID-specific, and time dependent risk of gastrointestinal (GI) complications through meta-analyses of high quality studies. <b>Methods:</b> An exhaustive systematic search was performed. Inclusion criteria were: RCT or controlled study, duration of 5 days at least, inactive control, assessment of minor or major NSAID adverse effects, publication range January 1985 to January 2003. The publications retrieved were assessed during a specifically dedicated WHO meeting including leading experts in all related fields. Statistics were performed conservatively. Meta-regression was performed by regressing NSAID adjusted estimates against study duration categories. <b>Results:</b> Among RCT data, indolic derivates provided a significantly higher risk of GI complications related to NSAID use than for non-users: RR = 2.25 (1.00; 5.08) than did other compounds: naproxen: RR = 1.83 (1.25; 2.68); diclofenac: RR = 1.73 (1.21; 2.46); piroxicam: RR = 1.66 (1.14; 2.44); tenoxicam: RR = 1.43 (0.40; 5.14); meloxicam: RR = 1.24 (0.98; 1.56), and ibuprofen: RR = 1.19 (0.93; 1.54). Indometacin users had a maximum relative risk for complication at 14 days. The other compounds presented a better profile, with a maximum risk at 50 days. Significant additional risk factors included age, dose, and underlying disease. The controlled cohort studies provided higher estimates: RR = 2.22 (1.7; 2.9). Publication bias testing was significant, towards a selective publication of deleterious effects of NSAIDs from small sized studies. <b>Conclusion:</b> This meta-analysis characterised the “compound” and “time” aspects of the GI toxicity of non-selective NSAIDs. The risk/benefit ratio of such compounds should thus be carefully and individually evaluated at the start of long term treatment.
ESRD Impairs Nonrenal Clearance of Fexofenadine but not Midazolam
Authors: Thomas D. Nolin, Reginald F. Frye, Phuong Le, Hooman Sadr, Judith Naud, Francois A. Leblond, Vincent Pichette, Jonathan Himmelfarb
Journal: Journal of the American Society of Nephrology (2009)

ESRD can affect the pharmacokinetic disposition of drugs subject to nonrenal clearance. Cytochrome P450 (CYP) enzymes, including CYP3A, and multiple intestinal and hepatic drug transporters are thought to mediate this process, but the extent to which kidney disease alters the function of these proteins in humans is unknown. We used midazolam and fexofenadine to assess CYP3A (intestinal and hepatic) and drug transport, respectively, in patients with ESRD and healthy control subjects. We evaluated the effect of uremia on CYP3A and transporter expression in vitro by incubating normal rat hepatocytes and enterocytes with serum drawn from study participants. ESRD dramatically reduced nonrenal transporter function, evidenced by a 63% decrease in clearance (P < 0.001) and a 2.8-fold increase in area under the plasma concentration-time curve for fexofenadine (P = 0.002), compared with control subjects. We did not observe significant differences in midazolam or 1'-hydroxymidazolam clearance or area under the curve after oral administration, suggesting that CYP3A function is not changed by ESRD. Changes in hepatocyte and enterocyte protein expression in the presence of uremic serum were consistent with in vivo results. These findings demonstrate a mechanism for altered drug disposition in kidney disease, which may partially account for the high rates of drug toxicity in this population.
Association of plasma lipoproteins with postheparin lipase activities.
Authors: I J Goldberg, J J Kandel, C B Blum, H N Ginsberg
Journal: Journal of Clinical Investigation (1986)

Studies were designed to explore the association of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities with lipoproteins in human postheparin plasma (PHP). The major peak of LPL activity after gel filtration of PHP eluted after the triglyceride-rich lipoproteins and just before the peak of low density lipoprotein (LDL) cholesterol. When PHP contained chylomicrons, an additional peak of LPL activity eluted in the void volume of the column. Most HTGL activity eluted after the LDL and preceded the elution of high density lipoprotein cholesterol. LPL activity in preheparin plasma eluted in the same position, relative to lipoproteins, as did LPL in PHP. Gel filtration of purified human milk LPL mixed with plasma or isolated LDL produced a peak of activity eluting before LDL. During gel filtration of PHP in high salt buffer (1 M NaCl) or after isolation of lipoproteins by ultracentrifugation in high salt density solutions, most of the lipase activity was not associated with lipoproteins. LPL activity was removed from PHP by elution through immunoaffinity columns containing antibodies to apolipoprotein (apo) B and apo E. Since lipoproteins in PHP have undergone prior in vivo lipolysis, LPL activity in PHP may be bound to remnants of chylomicrons and very low density lipoproteins.
Cooperation between Th1 and Th2 cells in a murine model of eosinophilic airway inflammation
Authors: David A. Randolph, Robin Stephens, Cynthia J.L. Carruthers, David D. Chaplin
Journal: Journal of Clinical Investigation (1999)

We have studied the actions of helper T lymphocyte-1 and -2 (Th1 and Th2) cells in an acute model of eosinophilic airway inflammation by infusing chicken ovalbumin-specific (OVA-specific) Th1 cells, Th2 cells, or both into unsensitized mice and challenging the mice with an OVA aerosol. OVA challenge after infusion of Th1 cells alone resulted in airway inflammation with lymphocytes and monocytes. Challenge after the infusion of Th2 cells alone resulted in minimal inflammation. In contrast, when Th1 and Th2 cells were transferred together, they cooperated to promote a robust eosinophil-predominant inflammatory response. Th1 cells alone were readily recruited to the airways after challenge, but in the absence of Th1 cells, Th2 cells did not accumulate in the airways. When transferred together, both Th1 and Th2 cells, as well as endogenous eosinophils, were effectively recruited. This recruitment was correlated with increased VCAM-1 expression in the medium- and large-sized vessels of the lung and could be inhibited by treating the mice with neutralizing antibodies to TNF-α or VCAM-1. These data indicate that Th2 cells require signals in addition to antigen for their effective recruitment to the airways. Th1 cells can provide these signals.
Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment
Authors: Puneeth Iyengar, Virginia Espina, Terence W. Williams, Ying Lin, David Berry, Linda A. Jelicks, Hyangkyu Lee, Karla Temple, Reed Graves, Jeffrey Pollard, Neeru Chopra, Robert G. Russell, Ram Sasisekharan, Bruce J. Trock, Marc Lippman, Valerie S. Calvert, Emanuel F. Petricoin, Lance Liotta, Ekaterina Dadachova, Richard G. Pestell, Michael P. Lisanti, Paolo Bonaldo, Philipp E. Scherer
Journal: Journal of Clinical Investigation (2005)

The interactions of transformed cells with the surrounding stromal cells are of importance for tumor progression and metastasis. The relevance of adipocyte-derived factors to breast cancer cell survival and growth is well established. However, it remains unknown which specific adipocyte-derived factors are most critical in this process. Collagen VI is abundantly expressed in adipocytes. Collagen–/– mice in the background of the mouse mammary tumor virus/polyoma virus middle T oncogene (MMTV-PyMT) mammary cancer model demonstrate dramatically reduced rates of early hyperplasia and primary tumor growth. Collagen VI promotes its growth-stimulatory and pro-survival effects in part by signaling through the NG2/chondroitin sulfate proteoglycan receptor expressed on the surface of malignant ductal epithelial cells to sequentially activate Akt and β-catenin and stabilize cyclin D1. Levels of the carboxyterminal domain of collagen VIα3, a proteolytic product of the full-length molecule, are dramatically upregulated in murine and human breast cancer lesions. The same fragment exerts potent growth-stimulatory effects on MCF-7 cells in vitro. Therefore, adipocytes play a vital role in defining the ECM environment for normal and tumor-derived ductal epithelial cells and contribute significantly to tumor growth at early stages through secretion and processing of collagen VI.
Clinical and Theoretical Consequences of the Misuse of Basic Behavior Therapy Concepts
Authors: DAVID L. BRAFF
Journal: American Journal of Psychiatry (1973)

The basic behavioral terms "aversive stimulation" and "negative reinforcement" are defined and the frequent misuse of these terms in the current literature is illustrated. The author notes the theoretical and clinical consequences of this misapplication, emphasizing the point that unclear thinking about these terms may lead to an unnecessary restriction of the techniques available to the clinician.