tbuckley/cabot-search huggingface dataset:
Transient Receptor Potential Channels and Mechanosensation
Authors: Niels Eijkelkamp, Kathryn Quick, John N. Wood
Journal: Annual Review of Neuroscience (2013)

Transient receptor potential (TRP) channels act as sensors for a range of stimuli as diverse as light, sound, touch, pheromones, and tissue damage. Their role in mechanosensation in the animal kingdom, identified by gene ablation studies, has raised questions about whether they are directly mechanically gated, whether they act alone or in concert with other channels to transduce mechanical stimuli, and their relative importance in various functions and disease states in humans. The ability of these channels to form heteromultimers and interact with other ion channels underlies a range of cell-specific functions in different cell types. Here we overview recent advances in this rapidly expanding field, focusing on somatosensation, hearing, the cardiovascular system, and interactions between TRP channels and other proteins involved in mechanoelectrical signaling.
Bevacizumab Beyond First Progression Is Associated With Prolonged Overall Survival in Metastatic Colorectal Cancer: Results From a Large Observational Cohort Study (BRiTE)
Authors: Axel Grothey, Mary M. Sugrue, David M. Purdie, Wei Dong, Daniel Sargent, Eric Hedrick, Mark Kozloff
Journal: Journal of Clinical Oncology (2008)

Bevacizumab provides a survival benefit in first- and second-line metastatic colorectal cancer (mCRC). In a large, observational, bevacizumab treatment study (Bevacizumab Regimens: Investigation of Treatment Effects and Safety [BRiTE]) in patients who had mCRC, a longer-than-expected overall survival (OS) of 25.1 months was reported. The association between various pre- and post-treatment factors (including the use of bevacizumab beyond first progression [BBP]) and survival was examined.The 1,445 of 1,953 previously untreated patients with mCRC who were enrolled in BRiTE and who experienced disease progression (PD) were classified into three groups: no post-PD treatment (n = 253), post-PD treatment without bevacizumab (no BBP; n = 531), and BBP (n = 642). Relevant baseline and on-study variables, including BBP, were analyzed with a Cox model with respect to their independent effect on survival beyond first PD.Median OS was 25.1 months (95% CI, 23.4 to 27.5 months), and median progression-free survival was 10.0 months in the overall BRiTE population. Baseline and postbaseline factors were well balanced between the BBP and no-BBP groups. Median OS rates were 12.6, 19.9, and 31.8 months in the no post-PD treatment, no-BBP, and BBP groups, respectively. In multivariate analyses, compared with no BBP, BBP was strongly and independently associated with improved survival (HR, 0.48; P < .001). Hypertension that required medication was the only bevacizumab-related safety event that occurred more frequently in the BBP group (24.6% v 19.2%).These results from a large, prospective, observational study suggest that continued vascular endothelial growth factor inhibition with bevacizumab beyond initial PD could play an important role improving the overall success of therapy for patients who have mCRC.
Mounting and storage of gastrocamera films.
Authors: J R Kirkpatrick, R J Marshall
Journal: Gut (1969)

The various models of the Olympus gastrocamera use film of either 4 or 5 mm size, with 32 exposures per roll of film. The developed film is returned from the processing laboratory, therefore, as a film strip, 4 or 5 mm in width, and approximately 34 cm in length. The Olympus Camera Company supply a viewer with a magnifying power of x 10 with each instrument, and this is of some value in examining the returned film, although not suitable for demonstration purposes. They also produce, as an accessory, a projector, complete with a small screen 14-5 x 23-7 cm in size, which can be used for studying films, and for demonstrating them to a small group of people. The lens and lighting system of this projector are not, however, equal to the task of projecting on a large screen, such as in a lecture room, and only a few exposures can be seen at any given time. A further disadvantage of both these instruments is that they involve repeated handling of the film strips which become defaced very easily by finger marks and dust. In addition, in our experience, the film is readily scratched, particularly with the use of the projector. Gastrocamera film is usually stored and filed by using a special filing book obtainable from the Olympus Company, in which each film strip is filed in a slotted plastic envelope. Each page of envelopes is interleaved with a ruled page (with Japanese headings) in which details of each film may be recorded opposite the slot in which the film strip is filed. There is, therefore, a great need for a means of easy projection for demonstrating and teaching, and for a method of filing and handling which avoids damage to these small film strips. Griffiths (1967) described a method whereby the films were cut into five small pieces, each containing five or six exposures, and mounted in a paper mask as a composite lantern slide between 2 x 2 in. cover glasses. This technique fulfils the requirements as regards easy projection using a standard 2 x 2 in. slide projector, and storage, safe from dust and scratches. Its disadvantage lies in the use of 2 x 2 in. cover glasses. The films are returned from the processing laboratory as a roll, and consequently when cut up for mounting the segments are still curled in their long axis. They are difficult to handle on this account, and to mount them neatly in parallel strips by Griffiths' method requires considerable patience, dexterity, and time. It is necessary for the clinician conducting the gastric photography to select personally those exposures which can be expended in the course of cutting the film for mounting. He must, therefore, either be present to supervise the process, or do
RIGHT TO LEFT VENTRICULAR APICAL CONTRACTION INTERVAL&amp;ndash;A NEW INDEX OF VENTRICULAR DYSSYNCHRONY DERIVED FROM SPECT GATED BLOOD POOL RADIONUCLIDE VENTRICULOGRAPHY
Authors: Andrew Van Tosh, Kenneth J. Nichols, Mark Goldman, Kathy Muratore, Christopher J. Palestro, Nathaniel Reichek
Journal: Journal of the American College of Cardiology (2012)
Multiple Sclerosis: New Insights in Pathogenesis and Novel Therapeutics
Authors: Daniel Ontaneda, Megan Hyland, Jeffrey A. Cohen
Journal: Annual Review of Medicine (2011)

Concepts of multiple sclerosis (MS) have shifted from the traditional view of a T cell-mediated, demyelinating disease of the white matter to include a broad range of immunopathogenic mechanisms, axonal damage, and widespread gray matter pathology. The cause of MS remains unknown, but recent epidemiological work has focused on genetic factors; environmental factors such as vitamin D, sunlight, and Epstein-Barr virus; and the controversial theory of chronic cerebrospinal venous insufficiency. Revised criteria facilitate making the diagnosis of MS. Emerging therapies are rapidly expanding treatment options, including both parenterally administered and oral medications. Strategies to preserve tissue, promote repair, and restore function are under development, and it is anticipated that they will provide better options for patients with progressive disease.
How We Hear
Authors: Merle Lawrence
Journal: JAMA (1966)

It must be stated at the outset of this discussion that there are still missing in the physiological processes of hearing enough details to make it impossible to describe, with finality, how we hear. About the best that can be accomplished is a description of the different processes known to be involved, and a rough approximation of how these processes contribute to the overall sensitivity and frequency discrimination ability of the ear. It is essential, first of all, to have a fairly clear understanding of the capabilities of the ear, ie, what can one hear? The ear responds to a remarkably wide range of frequencies extending from 16 to well over 16,000 cycles per second. As a matter of fact, a young child can hear a frequency as high as 24,000 cps, but presbycusis starts to set in soon and by the time this individual is 70 years old he
Vitamin D as a Neurosteroid Affecting the Developing and Adult Brain
Authors: Natalie J. Groves, John J. McGrath, Thomas H.J. Burne
Journal: Annual Review of Nutrition (2014)

Vitamin D deficiency is prevalent throughout the world, and growing evidence supports a requirement for optimal vitamin D levels for the healthy developing and adult brain. Vitamin D has important roles in proliferation and differentiation, calcium signaling within the brain, and neurotrophic and neuroprotective actions; it may also alter neurotransmission and synaptic plasticity. Recent experimental studies highlight the impact that vitamin D deficiency has on brain function in health and disease. In addition, results from recent animal studies suggest that vitamin D deficiency during adulthood may exacerbate underlying brain disorders and/or worsen recovery from brain stressors. An increasing number of epidemiological studies indicate that vitamin D deficiency is associated with a wide range of neuropsychiatric disorders and neurodegenerative diseases. Vitamin D supplementation is readily available and affordable, and this review highlights the need for further research.
Another LAP in the Race
Authors: Sylvia M. Lee, Cassian Yee
Journal: Cancer Discovery (2012)

Abstract The unique promise of latency-associated peptide resides in its selective presence on regulatory T cells (Treg) in the activated setting after patients are treated with immunomodulators such as anti–CTLA-4. The improved ability to track, scrutinize, and potentially target Tregs in this manipulated environment will be increasingly critical in developing immune-based therapies for patients with cancer. Cancer Discovery; 2(2); 107–9. ©2012 AACR. Commentary on Sun et al., p. 122.
Mice with AS160/TBC1D4-Thr649Ala Knockin Mutation Are Glucose Intolerant with Reduced Insulin Sensitivity and Altered GLUT4 Trafficking
Authors: Shuai Chen, David H. Wasserman, Carol MacKintosh, Kei Sakamoto
Journal: Cell Metabolism (2011)

AS160 has emerged as a key player in insulin-mediated glucose transport through controlling GLUT4 trafficking, which is thought to be regulated by insulin-stimulated phosphorylation of sites including the 14-3-3 binding phospho-Thr649 (equivalent to Thr642 in human AS160). To define physiological roles of AS160-Thr649 phosphorylation and 14-3-3 binding in glucose homeostasis, we substituted this residue by a nonphosphorylatable alanine by knockin mutation in mice. The mutant protein was expressed at normal levels, while insulin-stimulated AS160 binding to 14-3-3s was abolished in homozygous knockin mice. These animals displayed impaired glucose disposal and insulin sensitivity, which were associated with decreased glucose uptake in vivo. Insulin-stimulated glucose transport and cell surface GLUT4 content were reduced in isolated muscles, but not in adipocytes. These results provide genetic evidence that insulin-induced AS160-Thr649 phosphorylation and/or its binding to 14-3-3 play an important role in regulating whole-body glucose homeostasis, at least in part through regulating GLUT4 trafficking in muscle.
Purification and partial characterization of the nephritis strain-associated protein from Streptococcus pyogenes, group A.
Authors: K H Johnston, J B Zabriskie
Journal: The Journal of Experimental Medicine (1986)

We report the isolation and purification of the nephritis strain-associated protein (NSAP) first described by Villareal et al. (8). Amino acid analysis, and determination of the first 21 amino-terminal amino acids indicated that this 46 kD protein is a streptokinase. Biochemical analysis confirmed that NSAP could act as a plasminogen activator; immunological investigations indicated that NSAP is antigenically different from streptokinase from group C streptococcus, and possibly represents a unique streptokinase. It is this uniqueness that may contribute to the role of NSAP in the pathogenesis of acute poststreptococcal glomerulonephritis.
Enhanced bronchial expression of vascular endothelial growth factor and receptors (Flk-1 and Flt-1) in patients with chronic obstructive pulmonary disease
Authors: A R Kranenburg, W I de Boer, V K T Alagappan, P J Sterk, H S Sharma
Journal: Thorax (2005)

Ongoing inflammatory processes resulting in airway and vascular remodelling characterise chronic obstructive pulmonary disease (COPD). Vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) could play a role in tissue remodelling and angiogenesis in COPD.The cellular expression pattern of VEGF, Flt-1, and KDR/Flk-1 was examined by immunohistochemistry in central and peripheral lung tissues obtained from ex-smokers with COPD (forced expiratory volume in 1 second (FEV(1)) <75% predicted; n = 14) or without COPD (FEV(1) >85% predicted; n = 14). The immunohistochemical staining of each molecule was quantified using a visual scoring method with grades ranging from 0 (no) to 3 (intense).VEGF, Flt-1, and KDR/Flk-1 immunostaining was localised in vascular and airway smooth muscle (VSM and ASM) cells, bronchial, bronchiolar and alveolar epithelium, and macrophages. Pulmonary endothelial cells expressed Flt-1 and KDR/Flk-1 abundantly but not VEGF. Bronchial VEGF expression was higher in microvascular VSM cells and ASM cells of patients with COPD than in patients without COPD (1.7 and 1.6-fold, p<0.01, respectively). VEGF expression in intimal and medial VSM (1.7 and 1.3-fold, p<0.05) of peripheral pulmonary arteries associated with the bronchiolar airways was more intense in COPD, as was VEGF expression in the small pulmonary vessels in the alveolar region (1.5 and 1.7-fold, p<0.02). In patients with COPD, KDR/Flk-1 expression was enhanced in endothelial cells and in intimal and medial VSM (1.3, 1.9 and 1.5-fold, p<0.02) while endothelial Flt-1 expression was 1.7 times higher (p<0.03). VEGF expression was significantly increased in bronchiolar and alveolar epithelium as well as in bronchiolar macrophages (1.5-fold, p<0.001). The expression of VEGF in bronchial VSM and mucosal microvessels as well as bronchiolar epithelium was inversely correlated with FEV(1) (r<-0.45; p<0.01).VEGF and its receptors Flt-1 and KDR/Flk-1 may be involved in peripheral vascular and airway remodelling processes in an autocrine and/or paracrine manner. This system may also be associated with epithelial cell viability during airway wall remodelling in COPD.
Effects of STX209 (Arbaclofen) on Neurobehavioral Function in Children and Adults with Fragile X Syndrome: A Randomized, Controlled, Phase 2 Trial
Authors: Elizabeth M. Berry-Kravis, David Hessl, Barbara Rathmell, Peter Zarevics, Maryann Cherubini, Karen Walton-Bowen, Yi Mu, Danh V. Nguyen, Joseph Gonzalez-Heydrich, Paul P. Wang, Randall L. Carpenter, Mark F. Bear, Randi J. Hagerman
Journal: Science Translational Medicine (2012)

Administration of a selective GABA B agonist to individuals with fragile X syndrome improves their deficits in social avoidance, a core symptom of the disease.
Receptor Channel TRPC6 Is a Key Mediator of Notch-Driven Glioblastoma Growth and Invasiveness
Authors: Srinivasulu Chigurupati, Rajarajeswari Venkataraman, Daniel Barrera, Anusha Naganathan, Meenu Madan, Leena Paul, Jogi V. Pattisapu, George A. Kyriazis, Kiminobu Sugaya, Sergey Bushnev, Justin D. Lathia, Jeremy N. Rich, Sic L. Chan
Journal: Cancer Research (2009)

Glioblastoma multiforme (GBM) is the most frequent and incurable type of brain tumor of adults. Hypoxia has been shown to direct GBM toward a more aggressive and malignant state. Here we show that hypoxia increases Notch1 activation, which in turn induces the expression of transient receptor potential 6 (TRPC6) in primary samples and cell lines derived from GBM. TRPC6 is required for the development of the aggressive phenotype because knockdown of TRPC6 expression inhibits glioma growth, invasion, and angiogenesis. Functionally, TRPC6 causes a sustained elevation of intracellular calcium that is coupled to the activation of the calcineurin-nuclear factor of activated T-cell (NFAT) pathway. Pharmacologic inhibition of the calcineurin-NFAT pathway substantially reduces the development of the malignant GBM phenotypes under hypoxia. Clinically, expression of TRPC6 was elevated in GBM specimens in comparison with normal tissues. Collectively, our studies indicate that TRPC6 is a key mediator of tumor growth of GBM in vitro and in vivo and that TRPC6 may be a promising therapeutic target in the treatment of human GBM.
Explanatory models are needed to integrate RCT and observational data with the patient's unique biology
Authors: Vijay Sharma, Rubin Minhas
Journal: Journal of the Royal Society of Medicine (2012)

In this review, we make the case for evidence-based medicine (EBM) to include models of disease underscored by evidence in order to integrate evidence, as it is currently defined, with the patient's unique biology. This would allow clinicians to use a pathophysiologic rationale, but underscoring the pathophysiological model with evidence would create an objective evidence base for extrapolating randomized controlled trial evidence. EBM encourages practitioners not to be passive receivers of information, but to question the information. By the same token, practitioners should not be passive executors of the process by which information is generated, appraised and applied, but should question the process. We use the historical examples of the evolution of EBM to show that its subordination of a pathophysiological perspective was unintentional, and of essential hypertension to illustrate the importance of disease models and the fact that evidence supporting them comes from many sources. We follow this with an illustration of the benefits a pathophysiological perspective can bring and a suggested model of how inclusion of pathophysiological models in the EBM approach would work. From a practical perspective, information cannot be integrated with the patient's unique biology without knowledge of that biology; this is why EBM is currently so silent on how to carry out its fourth stage. It is also clear that, regardless of whether a philosophical or practical definition of evidence is used, pathophysiology is evidence and should be regarded as such.
Lung Surfactant Microbubbles Increase Lipophilic Drug Payload for Ultrasound-Targeted Delivery
Authors: Shashank R. Sirsi, Chinpong Fung, Sumit Garg, Mary Y. Tianning, Paul A. Mountford, Mark A. Borden
Journal: Theranostics (2013)

The cavitation response of circulating microbubbles to targeted ultrasound can be used for noninvasive, site-specific delivery of shell-loaded materials.One challenge for microbubble-mediated delivery of lipophilic compounds is the limitation of drug loading into the microbubble shell, which is commonly a single phospholipid monolayer.In this study, we investigated the use of natural lung surfactant extract (Survanta ® , Abbott Nutrition) as a microbubble shell material in order to improve drug payload and delivery.Pulmonary surfactant extracts such as Survanta contain hydrophobic surfactant proteins (SP-B and SP-C) that facilitate lipid folding and retention on lipid monolayers.Here, we show that Survanta-based microbubbles exhibit wrinkles in bright-field microscopy and increased lipid retention on the microbubble surface in the form of surface-associated aggregates observed with fluorescence microscopy.The payload of a model lipophilic drug (DiO), measured by flow cytometry, increased by over 2-fold compared to lipid-coated microbubbles lacking SP-B and SP-C.Lung surfactant microbubbles were highly echogenic to contrast enhanced ultrasound imaging at low acoustic intensities.At higher ultrasound intensity, excess lipid was observed to be acoustically cleaved for localized release.To demonstrate targeting, a biotinylated lipopolymer was incorporated into the shell, and the microbubbles were subjected to a sequence of radiation force and fragmentation pulses as they passed through an avidinated hollow fiber.Lung surfactant microbubbles showed a 3-fold increase in targeted deposition of the model fluorescent drug compared to lipid-only microbubbles.Our results demonstrate that lung surfactant microbubbles maintain the acoustic responsiveness of lipid-coated microbubbles with the added benefit of increased lipophilic drug payload.
Patient-Centered Outcomes Research Institute: The Intersection of Science and Health Care
Authors: Carolyn Clancy, Francis S. Collins
Journal: Science Translational Medicine (2010)

The Patient Protection and Affordable Care Act created the Patient-Centered Outcomes Research Institute (PCORI), a nonprofit corporation that is neither an agency nor an establishment of the U.S. government. PCORI's mission is to support the production of well-validated scientific evidence to assist the nation in making informed decisions about a broad range of health care-related issues. In this Commentary, the directors of the Agency for Healthcare Research and Quality and the National Institutes of Health discuss PCORI's opportunities to contribute to a robust portfolio of scientific inquiry that builds on their agencies' investment in comparative effectiveness research.
BDNF Gene-Modified Mesenchymal Stem Cells Promote Functional Recovery and Reduce Infarct Size in the Rat Middle Cerebral Artery Occlusion Model
Authors: Kazuhiko Kurozumi, Kiminori Nakamura, Takashi Tamiya, Yutaka Kawano, Masayoshi Kobune, Sachie Hirai, Hiroaki Uchida, Katsunori Sasaki, Yoshinori Ito, Kazunori Kato, Osamu Honmou, Kiyohiro Houkin, Isao Date, Hirofumi Hamada
Journal: Molecular Therapy (2003)

Examination of the clinical therapeutic efficacy of using bone marrow stromal cells, including mesenchymal stem cells (MSC), has recently been the focus of much investigation. MSC were reported to ameliorate functional deficits after stroke in rats, with some of this improvement possibly resulting from the action of cytokines secreted by these cells. To enhance such cytokine effects, we transfected telomerized human MSC with the BDNF gene using a fiber-mutant F/RGD adenovirus vector and investigated whether these cells contributed to improved functional recovery in a rat transient middle cerebral artery occlusion (MCAO) model. BDNF production by MSC-BDNF cells was 23-fold greater than that seen in uninfected MSC. Rats that received MSC-BDNF showed significantly more functional recovery than did control rats following MCAO. Specifically, MRI analysis revealed that the rats in the MSC-BDNF group exhibited more significant recovery from ischemia after 7 and 14 days. The number of TUNEL-positive cells in the ischemic boundary zone was significantly smaller in animals treated with MSC-BDNF compared to animals in the control group. These data suggest that MSC transfected with the BDNF gene may be useful in the treatment of cerebral ischemia and may represent a new strategy for the treatment of stroke.