tbuckley/cabot-search huggingface dataset:
Antiangiogenic Therapies: Going beyond Their Limits
Authors: Lidia Moserle, Gabriela Jiménez-Valerio, Oriol Casanovas
Journal: Cancer Discovery (2013)

Tumor growth requires induction of an angiogenic program, and targeting of this program with antiangiogenic drugs shows an impact on tumor progression. However, although they are effective at reducing angiogenesis, these therapies have not produced widespread or enduring clinical benefit, which openly exposes their limitations. Here, we describe the current limitations of these therapies, including the known mechanisms and current controversies. Further, we present some of the recent approaches to predict these limitations and strategies to overcome them. With the development of meaningful predictive biomarkers and effective treatments that impede these limitations, longer and more robust efficacies will be achieved for a wider population of patients.
Thrombin generation test - As a potential marker of severity and outcome of severe pneumonia with pulmonary sepsis
Authors: Tatiana Martynenko, Irina Balatskaya, Shoychet Yakov, Momot Aleksey, Olga Rusakova, Anastasia Grebenyuk
Journal: European Respiratory Journal (2012)

Background. There is an important interaction between inflammatory mechanisms and coagulopathy in severe pneumonia (SP) with pulmonary sepsis.  The aim. Determine the prognostic role of thrombin generation test (TGT) as a marker of severity in patients with SP with sepsis.  Materials and Methods. 35 adults (18 years old or above) with SP and pulmonary sepsis were enrolled in the study. All patients were divided into two groups: survivors – 30 patients (85,7%, group 1) and died – 5 (14.3%, group 2) and stratified according to APACHE II score.  Results. According to TGT, the greater number of patients (84.6%) showed reduction in intensity of thrombin generation. We observed lengthening of Lag time of thrombin, reduction of Peak thrombin, and increase in ttPeak, and in general - reducing endogenous thrombin potential (ETP) (table 1). Analysis of the average of the absolute values of thrombin generation curve showed that mean values of ETP and Peak thrombin remain below the reference in both groups, and Lag time and ttPeak - higher than in control. In group 2, in comparison with the first one, peak thrombin was lower at 82,9%, ttPeak was shorter by 15.1%, and ETP was reduced 3.9-fold.  When comparing patients according to severity, in group with APACHE II >20 (compared with APACHE II   Conclusion. According to our preliminary data, reducing the intensity of TGT in SP with pulmonary sepsis is associated with more severe course of the disease and can be regarded as a predictor of poor outcome.
Effects of coronary arterial pressure on left ventricular end-systolic pressure-volume relation of isolated canine heart.
Authors: K Sunagawa, W L Maughan, G Friesinger, P Guzman, M S Chang, K Sagawa
Journal: Circulation Research (1982)

In the excised canine left ventricle, the end-systolic pressure-volume relationship (ESPVR) has been shown to be approximately linear over the working range of loading conditions when coronary arterial pressure (CAP) is maintained constant, independent of loading conditions. To investigate the ESPVR under the more intact physiological condition in which the CAP varies with loading on the left ventricle, we studied the effect of changes in CAP on the ESPVR in 10 excised cross-circulated canine ventricles which were contracting isovolumically. The ESPVR, determined from isovolumic contractions at four different volumes, was reasonably independent of CAP as long as CAP remained above a critical pressure (67.0 +/- 22.1 mm Hg). Below this pressure, the slope of ESPVR decreased although the volume axis intercept (V0) remained unaltered. These findings indicate that under physiological conditions, where there is a close coupling of CAP to systolic left ventricular pressure, the ESPVR should become nonlinear in the low preload or afterload regions. When CAP was varied with the left ventricular pressure in five ventricles, the ESPVR indeed became nonlinear in the low-load region. We conclude that the ESPVR in intact conditions is reasonably linear in the physiological load range, but it can be nonlinear in the low-load range.
Cathepsin B in osteoarthritis: zonal variation of enzyme activity in human femoral head cartilage.
Authors: A Baici, D Hörler, A Lang, C Merlin, R Kissling
Journal: Annals of the Rheumatic Diseases (1995)

To determine the quantitative topographical distribution of cathepsin B in human femoral head cartilage by measuring the zonal variation of enzyme activity in specimens taken from various anatomical regions of normal and osteoarthritic (OA) tissues, and to correlate this parameter with the severity of the OA lesions. OA articular cartilage was obtained at surgery for total hip replacement and control cartilage obtained at postmortem. Cylinders of full thickness cartilage with underlying bone were retrieved with a biopsy trephine. Sections of cartilage were produced by cryocutting the tissue as slices parallel to the articular surface and assayed for cathepsin B with a specific, highly sensitive fluorogenic substrate. The severity of the OA lesions was graded according to the histopathological-histochemical method of Mankin. Zonal cathepsin B activity of normal cartilage was uniform and low in all regions of the femoral head. In apparently intact OA cartilage and in severely degraded tissue the zonal distribution and the amounts of enzyme were similar to control values. At sites with active disease, cathepsin B activity was much greater than in controls and its irregular zonal distribution correlated with tissue degeneration, hypercellularity, or cloning of chondrocytes as determined histochemically. Particularly high enzyme levels were observed at sites with regenerating cartilage, where some zonal peaks attained 20-fold activity with respect to controls. Cathepsin B may play a role in sustaining the chronicity of OA, not as an initiator, but rather as a perpetuator of the disease and as an antagonist of regeneration.
Histamine receptor 2 is a key influence in immune responses to intestinal histamine-secreting microbes
Authors: Ruth Ferstl, Remo Frei, Elisa Schiavi, Patrycja Konieczna, Weronika Barcik, Mario Ziegler, Roger P. Lauener, Christophe Chassard, Christophe Lacroix, Cezmi A. Akdis, Liam O'Mahony
Journal: Journal of Allergy and Clinical Immunology (2014)
Roles of IGH and L Chains and of Surrogate H and L Chains in the Development of Cells of the B Lymphocyte Lineage
Authors: F Melchers, D Haasner, U Grawunder, C Kalberer, H Karasuyama, T Winkler, A G Rolink
Journal: Annual Review of Immunology (1994)

Proteins expressed from productively rearranged H and L chain gene loci have been implied in the regulation of Ig gene rearrangements during B lymphopoiesis. However, recent findings suggest that early B cell development can occur without expression of surrogate L chain, without deposition of microH chains into membranes, without productive H chain gene rearrangements, and even without any rearrangements of Ig gene loci. In bone marrow, 2-5% of all B220-, sIgM-, c-kit+ cells are pro B cells that undergo differentiation from B220- via B220+, c-kit+, CD43+, clonable long-term proliferating pre B-I cells to B220+, c-kit-, CD43-, IL-2 receptor+ pre B-II cells and immature B cells, only to die by apoptosis in situ within less than 4 days. A membrane-bound complex of surrogate H chain (gp130/gp35-65) and surrogate L chain expressed on pro B and pre B-I cells has apparently no influence on this early development. Pre B-I cells carrying DHJH-rearrangements in reading frame (rf) II are counter-selected, probably because they can express an Ig-like complex of truncated DHJHC mu-protein and surrogate L chain, while pre B-I cells DHJH-rearranged in rf I or III are not suppressed. Immature sIg+ B cells, also from bcl-2 transgenic mice, can continue to rearrange L chain gene loci. Thus, mere membrane deposition of Ig, even with concomitant expression of bcl-2, terminates neither expression of RAG-1 and 2, nor secondary L chain gene rearrangements, nor does it allow the development of mature B cells. Membrane-bound expression of an Ig-like complex of microH chains and surrogate L chains appears to be needed to generate the 50-70 million pre B-II cells in bone marrow. However, the membrane-bound expression of Ig is mandatory for negative and positive selection of immature B cells. Autoantigens delete or anergize self-reactive B cells. We speculate that all mature, resting, primary antigen-reactive B cells in the periphery have been selected from immature sIg+ B cells by unknown antigens and have, thereby, changed their lifestyle from rapid death by apoptosis to longevity.
HIV-1 Vaccines and Adaptive Trial Designs
Authors: Lawrence Corey, Gary J. Nabel, Carl Dieffenbach, Peter Gilbert, Barton F. Haynes, Margaret Johnston, James Kublin, H. Clifford Lane, Giuseppe Pantaleo, Louis J. Picker, Anthony S. Fauci
Journal: Science Translational Medicine (2011)

Developing a vaccine against the human immunodeficiency virus (HIV) poses an exceptional challenge. There are no documented cases of immune-mediated clearance of HIV from an infected individual, and no known correlates of immune protection. Although nonhuman primate models of lentivirus infection have provided valuable data about HIV pathogenesis, such models do not predict HIV vaccine efficacy in humans. The combined lack of a predictive animal model and undefined biomarkers of immune protection against HIV necessitate that vaccines to this pathogen be tested directly in clinical trials. Adaptive clinical trial designs can accelerate vaccine development by rapidly screening out poor vaccines while extending the evaluation of efficacious ones, improving the characterization of promising vaccine candidates and the identification of correlates of immune protection.
An evaluation of echography in the diagnosis of pancreatic disease.
Authors: G Fontana, L Bolondi, M Conti, G Plicchi, L Gullo, G C Caletti, G Labo
Journal: Gut (1976)

In the present study an attempt to evaluate the efficacy of echography as a diagnostic tool has been made. A total of 52 patients (chronic pancreatitis (42); pancreatic cysts (three); and carcinoma of the pancreas (seven)) were studied and the results compared with those from other diagnostic techniques. In 65.7% of chronic pancreatitis patients, and in all cases of carcinoma of the pancreas, echography provided evidence of pancreatic abnormality but in no case could an unambiguous diagnosis of the disease be made. However, in all cases of pancreatic cyst, echography gave precise and unequivocal diagnostic information. There was good agreement between the echographic picture and surgical findings. Cholangiography and duodenography indicated duodenal and choledochal compression in a high proportion of cases in which echography revealed enlargement of the head of the pancreas. It is concluded that echography is a simple, safe, and valuable addition to the techniques available for studying the pancreas.
Left ventricular chamber size predicts the race time of Japanese participants in a 100 km ultramarathon * Commentary
Authors: J Nagashima, H Musha, H Takada, M Murayama
Journal: British Journal of Sports Medicine (2006)

As a subanalysis of an echocardiographic study performed on 291 Japanese participants in a 100 km ultramarathon, to estimate predictors of race time.A total of 247 male participants in a 100 km ultramarathon (age 20-73 years) were examined by echocardiography. Correlations between age, body surface area, monthly running distance, or echocardiographic variables and the race time were examined.According to simple regression analysis, age (r = 0.299, p < 0.0001), monthly running distance (r = -0.388, p < 0.0001), left ventricular end diastolic diameter (r = -0.300, p < 0.0001), and left ventricular end systolic diameter (r = -0.325, p < 0.0001) correlated significantly with the race time. When multiple regression analysis was performed, age (f = 2.364), monthly running distance (f = -0.113), and left ventricular end systolic diameter (f = -2.361) remained significant predictors of the race time.Left ventricular diameter predicts the race time for a 100 km ultramarathon, in addition to age and amount of training.
The Single Positive T Cells Found in CD3-ζ/η−/− Mice Overtly React with Self–Major Histocompatibility Complex Molecules upon Restoration of Normal Surface Density of T Cell Receptor–CD3 Complex
Authors: Shih-Yao Lin, Laurence Ardouin, Anne Gillet, Marie Malissen, Bernard Malissen
Journal: The Journal of Experimental Medicine (1997)

CD3-ζ/η–deficient mice have small thymuses containing cells that show a profound reduction in the surface levels of T cell receptors and terminate their differentiation at the CD4+CD8+ stage. Rather unexpectedly, CD3− or very low single positive T cells accumulate over time in the spleen and lymph nodes of CD3-ζ/η–deficient mice after a process dependent on MHC expression. Fusion of these peripheral T cells with a CD3-ζ–positive derivative of the BW5147 TCR-α−/β− thymoma resulted in hybridomas that do express an heterogeneous set of T cell receptor α/β dimers at their surface and at density comparable to those found in hybridomas derived from wild-type peripheral T cells. We have investigated the specificities of these T cell receptors using spleen cells from congenic and mutant mouse strains, and showed that the majority of them readily recognized self-MHC class I or class II molecules. These results demonstrate that by increasing the density and/or output of the T cell receptors expressed in peripheral T cells, one can confer them with the capacity to respond to normal density of self-MHC molecules.
Indocyanine Green Clearance and Estimated Hepatic Blood Flow during Mild to Maximal Exercise in Upright Man *
Authors: Loring B. Rowell, John R. Blackmon, Robert A. Bruce
Journal: Journal of Clinical Investigation (1964)

Krogh in 1912 (1) postulated the necessity for a large capacity venous reservoir capable of quickly delivering an autotransfusion of blood into the right heart during exercise, particularly in upright man, where Krogh felt venous return may at times be inadequate.Bock and co-workers (2) in their classical work reasoned that increased blood flow to working muscle, related in part to local vasodilation, must be partially effected by de- creased splanchnic blood flow.Since the splanch- nic region receives 20 to 25% of the total left ven- tricular output but extracts only 10 to 25% of the available oxygen (3), the splanchnic bed is ideally suited for rapid correction for any residual in- balance between left ventricular output and peripheral distribution of flow.The experimental evaluation of the influence of exercise on splanchnic blood flow, however, has produced conflicting results.Herrick, Grindlay, Baldes, and Mann (4), and more recently Rush- mer, Franklin, Van Citters, and Smith (5) did not find a decrease in splanchnic blood flow in dogs undergoing an intensity of exercise far below their maximal capacities.Also plethysmographic studies in man by Sj6strand (6) led him to con- clude that intrathoracic rather than splanchnic blood depots are functionally important in exer- cise.In contrast, a study by Bradley (7) and by Wade and co-workers (8), utilizing the sulfo- bromophthalein sodium (BSP) extraction method, demonstrated that significant decreases in splanch-
Revisit complexation between DNA and polyethylenimine — Effect of length of free polycationic chains on gene transfection
Authors: Yanan Yue, Fan Jin, Rui Deng, Jinge Cai, Zhuojun Dai, Marie C.M. Lin, Hsiang-Fu Kung, Maria A. Mattebjerg, Thomas L. Andresen, Chi Wu
Journal: Journal of Controlled Release (2011)
Ancient Recruitment by Chromists of Green Algal Genes Encoding Enzymes for Carotenoid Biosynthesis
Authors: R. Frommolt, S. Werner, H. Paulsen, R. Goss, C. Wilhelm, S. Zauner, U. G. Maier, A. R. Grossman, D. Bhattacharya, M. Lohr
Journal: Molecular Biology and Evolution (2008)

Chromist algae (stramenopiles, cryptophytes, and haptophytes) are major contributors to marine primary productivity. These eukaryotes acquired their plastid via secondary endosymbiosis, whereby an early-diverging red alga was engulfed by a protist and the plastid was retained and its associated nuclear-encoded genes were transferred to the host genome. Current data suggest, however, that chromists are paraphyletic; therefore, it remains unclear whether their plastids trace back to a single secondary endosymbiosis or, alternatively, this organelle has resulted from multiple independent events in the different chromist lineages. Both scenarios, however, predict that plastid-targeted, nucleus-encoded chromist proteins should be most closely related to their red algal homologs. Here we analyzed the biosynthetic pathway of carotenoids that are essential components of all photosynthetic eukaryotes and find a mosaic evolutionary origin of these enzymes in chromists. Surprisingly, about one-third (5/16) of the proteins are most closely related to green algal homologs with three branching within or sister to the early-diverging Prasinophyceae. This phylogenetic association is corroborated by shared diagnostic indels and the syntenic arrangement of a specific gene pair involved in the photoprotective xanthophyll cycle. The combined data suggest that the prasinophyte genes may have been acquired before the ancient split of stramenopiles, haptophytes, cryptophytes, and putatively also dinoflagellates. The latter point is supported by the observed monophyly of alveolates and stramenopiles in most molecular trees. One possible explanation for our results is that the green genes are remnants of a cryptic endosymbiosis that occurred early in chromalveolate evolution; that is, prior to the postulated split of stramenopiles, alveolates, haptophytes, and cryptophytes. The subsequent red algal capture would have led to the loss or replacement of most green genes via intracellular gene transfer from the new endosymbiont. We argue that the prasinophyte genes were retained because they enhance photosynthetic performance in chromalveolates, thus extending the niches available to these organisms. The alternate explanation of green gene origin via serial endosymbiotic or horizontal gene transfers is also plausible, but the latter would require the independent origins of the same five genes in some or all the different chromalveolate lineages.
To express or suppress may be function of others' distress
Authors: Geert Crombez, Chris Eccleston
Journal: Behavioral and Brain Sciences (2002)

We argue that pain behaviour cannot be wholly accounted for within the operant model of Fordyce (1976). Many pain behaviours, including facial expression, are not socially reinforced but are evolutionarily predetermined. We urge researchers to take into consideration other learning accounts. Building on the idea that pain sufferers learn to suppress the expression of pain, we begin the development of a framework for a relational understanding of pain complaint.
Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems
Authors: Kevin P. Hill
Journal: JAMA (2015)

As of March 2015, 23 states and the District of Columbia had medical marijuana laws in place. Physicians should know both the scientific rationale and the practical implications for medical marijuana laws.To review the pharmacology, indications, and laws related to medical marijuana use.The medical literature on medical marijuana was reviewed from 1948 to March 2015 via MEDLINE with an emphasis on 28 randomized clinical trials of cannabinoids as pharmacotherapy for indications other than those for which there are 2 US Food and Drug Administration-approved cannabinoids (dronabinol and nabilone), which include nausea and vomiting associated with chemotherapy and appetite stimulation in wasting illnesses.Use of marijuana for chronic pain, neuropathic pain, and spasticity due to multiple sclerosis is supported by high-quality evidence. Six trials that included 325 patients examined chronic pain, 6 trials that included 396 patients investigated neuropathic pain, and 12 trials that included 1600 patients focused on multiple sclerosis. Several of these trials had positive results, suggesting that marijuana or cannabinoids may be efficacious for these indications.Medical marijuana is used to treat a host of indications, a few of which have evidence to support treatment with marijuana and many that do not. Physicians should educate patients about medical marijuana to ensure that it is used appropriately and that patients will benefit from its use.
A morphometric study of mucins and small airway plugging in cystic fibrosis
Authors: P.-R. Burgel, D. Montani, C. Danel, D. J Dusser, J. A Nadel
Journal: Thorax (2006)

Little knowledge exists on structural changes and plugging in small airways in cystic fibrosis.To characterise the extent of plugging and contribution of secreted mucins to the plugs.Small airways in patients with cystic fibrosis at transplantation (n = 18) were compared with control non-smokers (n = 10). Tissue sections were stained with Alcian blue (AB)/periodic acid-Schiff (PAS), for mucins MUC5B and MUC5AC, and for neutrophils and its chemoattractant interleukin (IL) 8. Epidermal growth factor receptor (EGFR) and its ligand pro-transforming growth factor alpha were also identified using immunohistochemical staining. Epithelial and luminal contents were assessed morphometrically.Plugs occupying >50% of total luminal volume were found in 147 of 231 (63.6%) airways in patients with cystic fibrosis, but only in 1 of 39 (2.6%) airways in controls. In the epithelium of patients with cystic fibrosis, AB/PAS, MUC5B, and MUC5AC-stained volume densities were increased 10-fold (p < 0.01), indicating increased mucin production. In airway lumens, staining for mucins was also increased in cystic fibrosis, indicating increased mucin secretion. In the epithelium of patients with cystic fibrosis, neutrophil numbers were markedly increased and were inversely correlated with volume densities of mucous glycoconjugates (r = -0.66, p < 0.005). IL8 staining was increased in the epithelium of patients with cystic fibrosis and colocalised with mucins. Staining for EGFR and for pro-transforming growth factor alpha were increased in the epithelium of patients with cystic fibrosis; positive correlations were found between EGFR-stained volume density and both AB/PAS and IL8-stained volume densities.Most of the small airways are plugged in cystic fibrosis at the time of transplantation. Mucins contribute to airway plugging. Recruited neutrophils may be involved in mucin secretion in the plugs. Increased expression of EGFR and its ligand suggests roles in mucin synthesis and neutrophil recruitment.