tbuckley/cabot-search huggingface dataset:
Quantification, self-renewal, and genetic tracing of FL1+ tumor-initiating cells in a large cohort of human gliomas
Authors: V. Clement-Schatlo, D. Marino, K. Burkhardt, P. Teta, F. Leyvraz, B. Schatlo, S. Frank, K. Schaller, V. Castella, I. Radovanovic
Journal: Neuro-Oncology (2012)

Evidence has emerged that the initiation and growth of gliomas is sustained by a subpopulation of cancer-initiating cells (CICs). Because of the difficulty of using markers to tag CICs in gliomas, we have previously exploited more robust phenotypic characteristics, including a specific morphology and intrincic autofluorescence, to identify and isolate a subpopulation of glioma CICs, called FL1(+). The objective of this study was to further validate our method in a large cohort of human glioma and a mouse model of glioma. Seventy-four human gliomas of all grades and the GFAP-V(12)HA-ras B8 mouse model were analyzed for in vitro self-renewal capacity and their content of FL1(+). Nonneoplastic brain tissue and embryonic mouse brain were used as control. Genetic traceability along passages was assessed with microsatellite analysis. We found that FL1(+) cells from low-grade gliomas and from control nonneoplasic brain tissue show a lower level of autofluorescence and undergo a restricted number of cell divisions before dying in culture. In contrast, we found that FL1(+) cells derived from many but not all high-grade gliomas acquire high levels of autofluorescence and can be propagated in long-term cultures. Moreover, FL1(+) cells show a remarkable traceability over time in vitro and in vivo. Our results show that FL1(+) cells can be found in all specimens of a large cohort of human gliomas of different grades and in a model of genetically induced mouse glioma as well as nonneoplastic brain. However, their self-renewal capacity is variable and seems to be dependent on the tumor grade.
On the Biomechanics of Vaginal Birth and Common Sequelae
Authors: James A. Ashton-Miller, John O.L. DeLancey
Journal: Annual Review of Biomedical Engineering (2009)

Approximately 11% of U.S. women undergo surgery for pelvic floor dysfunction, including genital organ prolapse and urinary and fecal incontinence. The major risk factor for developing these conditions is giving vaginal birth. Vaginal birth is a remarkable event about which little is known from a biomechanical perspective. We first review the functional anatomy of the female pelvic floor, the normal loads acting on the pelvic floor in activities of daily living, and the functional capacity of the pelvic floor muscles. Computer models show that the stretch ratio in the pelvic floor muscles can reach an extraordinary 3.26 by the end of the second stage of labor. Magnetic resonance images provide evidence that show that the pelvic floor regions experiencing the most stretch are at the greatest risk for injury, especially in forceps deliveries. A conceptual model suggests how these injuries may lead to the most common form of pelvic organ prolapse, a cystocele.
Validity of the polymyalgia rheumatica activity score in primary care practice
Authors: A Binard, B Lefebvre, M De Bandt, J-M Berthelot, A Saraux
Journal: Annals of the Rheumatic Diseases (2008)

Objective: To evaluate the validity and reliability of the polymyalgia rheumatica (PMR) activity score (PMR-AS) for relapse diagnosis by general practitioners (GPs) who manage a large proportion of patients with PMR. Methods: Seven clinical vignettes of PMR were used, for which 35 rheumatologists previously made a diagnosis of relapse or no relapse with greater than 80% agreement. These vignettes were submitted to 163 GPs, who were asked to assess disease activity using a visual analogue scale (VASph), this being the only physician-dependent component of the PMR-AS. The 1116 available vignette–GP combinations were used to assess differences in VASph assessed by GPs versus rheumatologists. Statistical associations linking a relapse diagnosis by the rheumatologists (the reference standard) to the value of the GP-assessed PMR-AS or its components (GP-assessed VASph, visual analogue scale pain score, C-reactive protein, morning stiffness and elevation of upper limbs) were evaluated. Results: No significant differences were found between VASph scores by GPs versus rheumatologists for any of the vignettes. A relapse diagnosis was strongly associated with PMR-AS values of 7 or more (sensitivity 99.4%; specificity 93.3%; agreement 95.9% (95% CI 94.5% to 97.0%) with κ = 0.92). Of the 590 GP–vignette combinations with PMR-AS values lower than 7, all but three (0.5%) had no relapse diagnosis. Of 510 combinations with PMR-AS values of 7 or more, only 42 (8%) had no flare diagnosis. Conclusions: This study supports the validity of the PMR-AS in primary care practice and provides evidence that a good scoring system can be useful to guide clinical and therapeutic decisions.
A Novel Tankyrase Small-Molecule Inhibitor Suppresses <i>APC</i> Mutation–Driven Colorectal Tumor Growth
Authors: Ted Lau, Emily Chan, Marinella Callow, Jo Waaler, Jason Boggs, Robert A. Blake, Steven Magnuson, Amy Sambrone, Melissa Schutten, Ron Firestein, Ondrej Machon, Vladimir Korinek, Edna Choo, Dolores Diaz, Mark Merchant, Paul Polakis, Daniel D. Holsworth, Stefan Krauss, Mike Costa
Journal: Cancer Research (2013)

Abstract Most colorectal cancers (CRC) are initiated by mutations of APC, leading to increased β-catenin–mediated signaling. However, continued requirement of Wnt/β-catenin signaling for tumor progression in the context of acquired KRAS and other mutations is less well-established. To attenuate Wnt/β-catenin signaling in tumors, we have developed potent and specific small-molecule tankyrase inhibitors, G007-LK and G244-LM, that reduce Wnt/β-catenin signaling by preventing poly(ADP-ribosyl)ation-dependent AXIN degradation, thereby promoting β-catenin destabilization. We show that novel tankyrase inhibitors completely block ligand-driven Wnt/β-catenin signaling in cell culture and display approximately 50% inhibition of APC mutation–driven signaling in most CRC cell lines. It was previously unknown whether the level of AXIN protein stabilization by tankyrase inhibition is sufficient to impact tumor growth in the absence of normal APC activity. Compound G007-LK displays favorable pharmacokinetic properties and inhibits in vivo tumor growth in a subset of APC-mutant CRC xenograft models. In the xenograft model most sensitive to tankyrase inhibitor, COLO-320DM, G007-LK inhibits cell-cycle progression, reduces colony formation, and induces differentiation, suggesting that β-catenin–dependent maintenance of an undifferentiated state may be blocked by tankyrase inhibition. The full potential of the antitumor activity of G007-LK may be limited by intestinal toxicity associated with inhibition of Wnt/β-catenin signaling and cell proliferation in intestinal crypts. These results establish proof-of-concept antitumor efficacy for tankyrase inhibitors in APC-mutant CRC models and uncover potential diagnostic and safety concerns to be overcome as tankyrase inhibitors are advanced into the clinic. Cancer Res; 73(10); 3132–44. ©2013 AACR.
Distribution of fibroblast surface antigen in the developing chick embryo.
Authors: E Linder, A Vaheri, E Ruoslahti, J Wartiovaara
Journal: The Journal of Experimental Medicine (1975)

Fibroblast surface (SE) antigen is present in fibrillar surface structures of cultured normal fibroblasts, shed to the extracellular medium, and is also found in circulation (serum and plasma). Malignant fibroblasts (transformed by viruses) do not express SF antigen on the cell surface. In this study the in vivo differentiation and distribution of SF antigen has been investigated in the developing chick embryo using cryostat sections and immunofluorescence. The major findings were: (a) SF antigen was detectable in the loose connective tissue of very early (2-to 3-day old) embryos. (b) Condensation of SF antigen was seen in various boundary membranes such as the glomerular and tubular basement membranes of the kidney, the boundary membranes of the notochord, yolk sac, and vitelline membranes and liver sinusoids. (c) SF antigen was found to be cell-type specific. It was seen as a fibrillar network in the loose connective tissue of different organs but not in the parenchymal cells. It was not found in muscle cells at any stage of development. (d) The antigen was present in the undifferentiated mesenchymal cells of the kidney; but not found after their development into epithelial cells of the secretory tubules. (e) Both in vivo and in fibroblast cultures SF antigen was distributed as a fibrillar network. These data indicate that SF antigen is a "differentiation antigen" restricted to certain cells of mesenchymal origin and character, and that is accumulates in the connective tissue during embryogenesis.
Improving the Efficacy of Photoimmunotherapy (PIT) using a Cocktail of Antibody Conjugates in a Multiple Antigen Tumor Model
Authors: Takahito Nakajima, Kohei Sano, Peter L. Choyke, Hisataka Kobayashi
Journal: Theranostics (2013)

Tumors are characterized by a high degree of diversity and heterogeneity in receptor expression.Monoclonal antibodies (mAbs) are an established therapeutic method of targeting cell surface receptors.However, high affinity antibodies targeting highly expressed receptors are often prevented from distributing evenly throughout the tumor due to the "binding site barrier" whereby antibody is trapped peripherally before it can reach deeper into the tumor that leads inhomogeneous micro-distribution.When employing armed antibodies it is important that the toxin (in this case, phototoxin) be distributed evenly to more effectively treat the cancer.By adding an additional antibody conjugate, targeting a secondary, unsaturated receptor with lower expression, a more uniform distribution of the phototoxin can be achieved.In this study, panitumumab (Pan) and basiliximab (Bas) were conjugated with the phthalocyanine dye, IRDye700DX (IR700).Upon exposure to near infrared light, these armed antibodies produce rapid cell death only when bound to their respective receptors, a treatment termed photo-immunotherapy (PIT).ATAC4 cells which demonstrate high expression of human epidermal growth factor receptor (EGFR) and low expression of interleukin-2 receptor-alpha (CD25) were treated by PIT using a cocktail of Pan-IR700 and Bas-IR700.An in vivo study showed that the cocktail Pan-Bas-IR700 resulted in significantly reduced tumor growth and prolonged survival in ATAC4 tumor-bearing mice compared with either Pan-IR700 or Bas-IR700 alone.In conclusion, a cocktail injection of two different antibody-IR700 conjugates created a more homogeneous microdistribution of antibody-conjugates resulting in enhanced therapeutic effects after PIT, compared to the use of either antibody-IR700 conjugate.
Predominant expression of 950delCAG of IL-18R α chain cDNA is associated with reduced IFN-γ production and high serum IgE levels in atopic Japanese children
Authors: Mizuho Watanabe, Hideo Kaneko, Hiroaki Shikano, Minako Aoki, Heima Sakaguchi, Eiko Matsui, Ryosuke Inoue, Zenichiro Kato, Kimiko Kasahara, Osamu Fukutomi, Tomio Kondo, Naomi Kondo
Journal: Journal of Allergy and Clinical Immunology (2002)
Mammalian conserved ADAR targets comprise only a small fragment of the human editosome
Authors: Yishay Pinto, Haim Y Cohen, Erez Y Levanon
Journal: Genome biology (2014)

Abstract Background ADAR proteins are among the most extensively studied RNA binding proteins. They bind to their target and deaminate specific adenosines to inosines. ADAR activity is essential, and the editing of a subset of their targets is critical for viability. Recently, a huge number of novel ADAR targets were detected by analyzing next generation sequencing data. Most of these novel editing sites are located in lineage-specific genomic repeats, probably a result of overactivity of editing enzymes, thus masking the functional sites. In this study we aim to identify the set of mammalian conserved ADAR targets. Results We used RNA sequencing data from human, mouse, rat, cow, opossum, and platypus to define the conserved mammalian set of ADAR targets. We found that the conserved mammalian editing sites are surprisingly small in number and have unique characteristics that distinguish them from non-conserved ones. The sites that constitute the set have a distinct genomic distribution, tend to be located in genes encoding neurotransmitter receptors or other synapse related proteins, and have higher editing and expression levels. We also found a high consistency of editing levels of this set within mice strains and between human and mouse. Tight regulation of editing in these sites across strains and species implies their functional importance. Conclusions Despite the discovery of numerous editing targets, only a small number of them are conserved within mammalian evolution. These sites are extremely highly conserved and exhibit unique features, such as tight regulation, and probably play a pivotal role in mammalian biology.
Severity of ventilator induced lung injury does not contribute to ventilator induced diaphragmatic dysfunction
Authors: Christian Bruells, Kathy Reiss, Ashley Smuder, Matthew Hudson, Bradley Nelson, Stefan Uhlig, Scott Powers
Journal: European Respiratory Journal (2012)

Mechanical ventilation (MV) is a life-saving intervention for patients with respiratory failure. Even 12h of MV can promote diaphragmatic contractile dysfunction and atrophy (referred to as ventilator-induced diaphragmatic dysfunction, VIDD).The pathophysiology remains unclear but could be linked to inactivity, the physiological impact of positive pressure ventilation (PPV) on the diaphragm and/or ventilator-induced lung injury (VILI).  We tested the hypothesis, if negative pressure ventilation (NPV) compared to PPV will diminish VIDD.  The concomitant influence of VILI on VIDD was also examined.  Rats were ventilated with either PPV or NPV or breathed spontaneously (control) for 12h.  We measured diaphragmatic contractile properties, fiber size and markers of oxidative damage. Lungs were histologically examined and cytokine levels were assayed in bronchoalveolar lavage for evidence of VILI.  Compared to control, both PPV and NPV resulted in significant oxidative damage to the diaphragm along with fiber atrophy and contractile dysfunction. No significant differences existed in these measures between PPV and NPV groups. Both the PPV and NPV groups experienced VILI, graded by histologic scores or cytokines. Note, that the severity of VILI varied between animals within both the PPV and NPV groups. Nonetheless, the severity of VILI was not significantly correlated with the degree of VIDD.  Both PPV and NPV promote VIDD and VILI. The magnitude of VILI is not correlated with the degree of VIDD. Although these findings do not eliminate the possibility that VILI may play a role in VIDD, our results are consistent with the concept that diaphragmatic inactivation as major contributor to VIDD.
Study of Luminal Coronary Collateral Circulation in the Beating Canine Heart
Authors: THOMAS W. MOIR
Journal: Circulation Research (1969)

Coronary collateral circulation from the cardiac lumen was studied in 36 anesthetized, open-chest dogs with hearts beating in situ. The coronary arteries were cannulated and perfused from an isolated, nonradioactive blood source while 131 I-labeled blood circulated through the cardiac lumen for 2 minutes. Ventricular fibrillation was then produced, and luminal blood samples and myocardial tissue samples were obtained for radioactive assay and calculation of the amount of luminal blood appearing as a part of the myocardial blood volume. These volumes were obtained from both ventricles and the atria under (1) normal antegrade coronary flow conditions, (2) myocardial ischemia, (3) left and right ventricular hypertension, and (4) coronary occlusion. Small quantities of luminal blood appeared in the left ventricular myocardium under normal coronary flow conditions while considerably larger amounts were found in the right ventricle and atria. There was no significant increase of the luminal contribution to the myocardial blood volume in response to the various experimental conditions except that of coronary occlusion. Although in the latter, the amount of left ventricular luminal blood was greater than with normal coronary flow conditions, right ventricular and atrial myocardial blood volumes remained greater than the left.
Methodologic Advances and Ongoing Challenges in Designing Community-Based Health Promotion Programs
Authors: Beti Thompson, Gloria Coronado, Shedra A. Snipes, Klaus Puschel
Journal: Annual Review of Public Health (2003)

Community intervention trials continue to attract researchers as potential ways to achieve widespread, long-term change in health behaviors. The first generations of community studies were somewhat unsophisticated in design and analysis, and their promise may have been overstated. As design and analysis issues were better defined, as secular trends caught up with the behaviors that researchers were trying to change, or as other unknown variables affected community studies, small effects of interventions were observed in community trials. Discussions were held in professional meetings and reported in the literature: Should community trials be discontinued? In general, the answer was a qualified no. In this paper, we briefly review some of the many advances made in community intervention trials, and address in more detail the challenges ahead.
Predicting chromatin organization using histone marks
Authors: Jialiang Huang, Eugenio Marco, Luca Pinello, Guo-Cheng Yuan
Journal: Genome biology (2015)

Genome-wide mapping of three dimensional chromatin organization is an important yet technically challenging task. To aid experimental effort and to understand the determinants of long-range chromatin interactions, we have developed a computational model integrating Hi-C and histone mark ChIP-seq data to predict two important features of chromatin organization: chromatin interaction hubs and topologically associated domain (TAD) boundaries. Our model accurately and robustly predicts these features across datasets and cell types. Cell-type specific histone mark information is required for prediction of chromatin interaction hubs but not for TAD boundaries. Our predictions provide a useful guide for the exploration of chromatin organization.
Cooperative B7-1/2 (CD80/CD86) and B7-DC Costimulation of CD4+ T Cells Independent of the PD-1 Receptor
Authors: Tahiro Shin, Gene Kennedy, Kevin Gorski, Haruo Tsuchiya, Haruhiko Koseki, Miyuki Azuma, Hideo Yagita, Lieping Chen, Jonathan Powell, Drew Pardoll, Franck Housseau
Journal: The Journal of Experimental Medicine (2003)

B7-DC is a recently discovered member of the B7 family that binds to PD-1 and is selectively expressed by dendritic cells (DCs). It has been shown to either costimulate or inhibit T cell responses. To assess the role of B7-DC in DC–T cell interactions, DCs from B7-DC knockout (KO) mice were generated and compared with DCs from wild-type (WT) and B7–1/B7–2 double KO mice. B7–1/B7–2–deficient DCs, while strongly diminished in their ability to stimulate naive CD4+ T cells, nonetheless retain partial activity. DCs from B7-DC KO mice are diminished in their ability to activate CD4+ T cells, demonstrating that DC-expressed B7-DC serves a predominantly stimulatory rather than inhibitory function in the initiation of T cell responses. B7-DC costimulates expression of CD40L with faster kinetics than B7–1 and displays potent synergy with B7–1 and B7–2 for T cell proliferation and cytokine production, indicating that these B7 family members work in concert to stimulate T cells. Finally, costimulation with B7-DC alone or in conjunction with B7–1 is PD-1 independent, indicating that B7-DC costimulates T cells via a second receptor.
Point-of-care urine test for assessing adherence to isoniazid treatment for tuberculosis
Authors: Mohammad Roshan Soobratty, Ruth Whitfield, Krithika Subramaniam, Grace Grove, Anthony Carver, Grace V. O'Donovan, Houdini H.T. Wu, Oona Y-C. Lee, Ramasamyiyer Swaminathan, Graham F. Cope, Heather J. Milburn
Journal: European Respiratory Journal (2014)

To the Editor: 

Good adherence to treatment for tuberculosis (TB) is essential, both to cure disease and prevent development of drug resistance. Adherence to chemoprophylaxis (preventive therapy) for latent TB infection (LTBI) is particularly poor [1].

Methods for measuring adherence to TB medication include detecting urine colour change due to the presence of rifampicin. However, this effect is short lived, peaking at 2–6 h and is only seen in <50% of patients [2]. Directly observed therapy (DOT) will ensure adherence to antituberculous treatment, but this can be unacceptable and many patients do not tolerate a three times a week regimen. DOT is costly in terms of personnel and is seldom employed in chemoprophylaxis patients [1]. The highly reliable Arkansas method for detecting isoniazid metabolites in urine relies on a laboratory colorimetric assay, involving adding drops of prepared solutions of reagents, including potassium cyanide, to a urine sample [3]. There are obvious risks involved in handling and storing the reagents.

IsoScreen (GFC Diagnostics, Bicester, UK) uses the reagents of the Arkansas Method but in an enclosed plastic testing device (SafeTube; GFC Diagnostics), allowing safe and rapid point-of-care testing in clinics and patients’ homes [2]. The urine colour change is apparent within a few seconds but 5 min is allowed to ensure stable colour development. Purple or blue samples are deemed positive, green intermediate and yellow negative. High sensitivities and specificities have been reported, but without a consistent relationship to the timing of the previous dose of isoniazid or measurement of acetylator status [2, 4].

In this prospective study, we analysed the relationship over time of the colour change seen with IsoScreen over 72 h to determine whether different colours could accurately inform when the last dose was taken, …