tbuckley/cabot-search huggingface dataset:
<i>In vivo</i> Imaging of the Systemic Recruitment of Fibroblasts to the Angiogenic Rim of Ovarian Carcinoma Tumors
Authors: Dorit Granot, Yoseph Addadi, Vyacheslav Kalchenko, Alon Harmelin, Leoni A. Kunz-Schughart, Michal Neeman
Journal: Cancer Research (2007)

Abstract Tumor-associated stroma, in general, and tumor fibroblasts and myofibroblasts, in particular, play a role in tumor progression. We previously reported that myofibroblast infiltration into implanted ovarian carcinoma spheroids marked the exit of tumors from dormancy and that these cells contributed to vascular stabilization in ovarian tumors by expression of angiopoietin-1 and angiopoietin-2. Ex vivo labeling of fibroblasts with either magnetic resonance or optical probes rendered them detectable for in vivo imaging. Thus, magnetic resonance imaging (MRI) follow-up was feasible by biotin-bovine serum albumin-gadolinium diethylenetriaminepentaacetic acid or iron oxide particles, whereas labeling with near-IR and fluorescent vital stains enabled in vivo visualization by near-IR imaging and two-photon microscopy. Using this approach, we show here that prelabeled fibroblasts given i.p. to CD-1 nude mice can be followed in vivo by MRI and optical imaging over several days, revealing their extensive recruitment into the stroma of remote s.c. MLS human epithelial ovarian carcinoma tumors. Two-photon microscopy revealed the alignment of these invading fibroblasts in the outer rim of the tumor, colocalizing with the angiogenic neovasculature. Such angiogenic vessels remained confined to the stroma tracks within the tumor and did not penetrate the tumor nodules. These results provide dynamic evidence for the role of tumor fibroblasts in maintenance of functional tumor vasculature and offer means for image-guided targeting of these abundant stroma cells to the tumor as a possible mechanism for cellular cancer therapy. [Cancer Res 2007;67(19):9180–9]
Learning While Caring: Medicine's Epistemology
Authors: Samuel Hellman
Journal: Journal of Clinical Oncology (2014)

An essential epistemic consideration is the conditional nature of medical knowledge. This uncertainty must be understood when acquiring new knowledge or designing treatments. We must value all sources of information, neither discarding those deemed lower on the current value scale, nor slavishly accepting randomized clinical trials or their meta-analyses as the fount of all knowledge. Generally, the tension between clinical investigation and individual care can be framed in a utilitarian versus deontologic or rights-based philosophy. The utilitarian is clearly appropriate to public health considerations, but what is learned for public health may not necessarily be in the best interest of an individual patient. In utilitarianism, the distribution of goods-in this case, health-is not important; rather, it is the amount of total good gained that is to be maximized. Too often we assume that survival or cure is a sufficient metric, with no similar quantitative measure of other factors. This often leads to the so-called best treatment being not what the patient wants. All personal care requires consideration of both the helpful and harmful consequences of treatment in the context of individual patient comorbidity, preferences, and fears. Knowledge of patients in general is not what is required; rather, it is how to apply the information to the particular patient that is the heart of medical practice. Each patient's episode of illness is the consequence of a unique interaction of that individual with the disease. Good patient care considers the disease and its management in the context of each patient's values.
The Ebola Outbreak, Fragile Health Systems, and Quality as a Cure
Authors: Andrew S. Boozary, Paul E. Farmer, Ashish K. Jha
Journal: JAMA (2014)

SecurityCouncil unanimously approved a resolution establishing the UN Mission for Ebola Emergency Response (UNMEER) with 134 cosponsors-the most support for any resolution since the founding of the United Nations in 1946.This commitment, however, comes many months into an outbreak that has already become one of the most devastating health crises of the 21st century.And the need is immense: the World Health Organization (WHO) now reports more than 5300 infections and 2600 deaths across Guinea, Liberia, and Sierra Leone, 1 with broad consensus that the true burden of disease is far greater.Yet if the Ebola virus surfaced in Boston or Toronto, there is little doubt that their health systems, despite shortcomings, could effectively contain and then eliminate the disease with far lower case-fatality rates than those reported now in West Africa.Why the disparity when there is no proven drug or vaccine available?The answer lies not with the virus, but in the collective failure to ensure the availability of adequate health care staff, resources, and systems required for the delivery of high-quality health care
FROM GABA<sub>A</sub> RECEPTOR DIVERSITY EMERGES A UNIFIED VISION OF GABAergic INHIBITION
Authors: E. Costa
Journal: The Annual Review of Pharmacology and Toxicology (1998)

Transmitter receptor diversity often indicates differences in transmitter receptor transduction mechanisms. This is not the case for gamma-aminobutyric acid subtype A (GABAA) receptor subtypes despite the presence of 16 genes to encode the 5 families of native GABAA receptor subtypes. Similar considerations apply to GABAC receptors and GABAB receptors. Both GABAA and GABAB receptors cause hyperpolarization of neuronal membranes and inhibition of neuronal excitability, but their mechanisms differ. GABAB receptors involve an efflux of K+ rather than an influx of Cl-, as in the case of GABAA and GABAC receptors. The stimulation of GABAA receptors can sometimes cause depolarization by Cl- efflux; this efflux is not the result of a transduction mechanism modification, but of Cl(-)-concentration gradient modification. Presumably, GABAA receptor diversity is directly linked to the inhibitory activity of basket cells and other interneuron axons, each innervating several postsynaptic neurons (cortical and hippocampal pyramidal cells for instance). Since the role of this inhibition is to entrain hippocampal and cortical pyramidal neurons into columnary activity, the GABAA receptor diversification may be a mechanism expressed by these postsynaptic neuron populations that uses different GABA potencies to synchronize pyramidal neurons into columnary activity. Thus, GABA potency variability, which emerges from GABAA receptor diversity, plays a unifying role in the intrinsic functional mechanism of laminated structures. GABAA receptor structural differences also play a role in diazepam tolerance, which is a mechanism operative in neuronal circuit adaptation to the extreme amplification of GABA-gated Cl- current intensities. Partial agonists (such as imidazenil), which modestly amplify GABA action at many GABAA receptor subtypes, fail to cause tolerance, dependence, ataxia, or ethanol and barbiturate potentiation. Partial agonists might become a new class of anxiolytic and anticonvulsant drugs that are virtually devoid of the side effects that cause serious concerns in the clinical use of full allosteric positive modulators of GABA action, such as diazepam, alprazolam, triazolam, and others. None of the above can be used as anticonvulsants because of an extremely high tolerance liability. When there is tolerance to diazepam, signs of sensitization to proconvulsive action are exhibited simultaneously. After tolerance, associated changes in GABAA recepter subtype expression are virtually reversed in 72 h. Also, 96 h after termination of long-term diazepam treatment, rats exhibit anxiety and are more sensitive to kainic acid-elicited convulsions. At the same time, these rats have an increase in brain expression of GLuR1, R2, and R3. It is believed that the supersensitivity to kainic acid, convulsions and anxiety, and the increased expression of GLuR1, R2, and R3 may be parts of the mechanism of diazepam dependence.
Reflex Circulatory Effects Elicited by Hypertonic and Hypotonic Solutions Injected into Femoral and Brachial Arteries of Dogs
Authors: RICHARD P. LASSER, MYRON R. SCHOENFELD, DOUGLAS F. ALLEN, CHARLES K. FRIEDBERG, Dimitri Lalosi
Journal: Circulation Research (1960)

Rapid injection of 40 ml. of 5 per cent saline into the femoral or brachial arteries of 24 dogs resulted in an average elevation of arterial blood pressure of +42/+20 mm. Hg, an increase in the heart rate of +20 beats/min., and an acceleration of the respiratory rate of +140 per cent. The response began 6 to 10 seconds after the onset of injection and lasted for 5 to 30 minutes. It occurred with the injection of hypertonic solution of saline, dextrose, and urea. The magnitude of the response was related to the degree of hypertonicity. Responses could be provoked by 10 ml. of 1.25 per cent saline. Rapid intra-arterial injection of isotonic saline, dextrose, and urea solutions, and of whole blood in volumes up to 80 ml. had no circulatory effect. Rapid injection of distilled water, 0.225 per cent and 0.45 per cent saline into the femoral or brachial arteries resulted in a slight degree of hypotension and a rise in the respiratory rate. The appearance of circulating catechol amines following the response to intra-arterial injection of hypertonic solutions was suggested by the demonstration of hypotensive response to intravenous injection of phentolamine. These responses to injection of hypertonic and hypotonic solutions in the femoral artery were abolished by section of the sciatic nerve in animals with an ipsilateral partially-transected hind limb, a preparation which left intact only the femoral artery, femoral vein, and femur. Sciatic section in the intact limb reduced but did not abolish the response. Removal of the sympathetic chain from the eleventh thoracic through the third lumbar ganglia had no apparent effect. It is concluded that the response to femoral aud brachial intra-arterial injection of hypertonic and hypotonic solutions is initiated by peripherally located "osmoreceptors" in the distribution of these arteries and is mediated via a reflex whose afferent fibers travel in the peripheral somatic nerves and enter the spinal cord without passing through the sympathetic chain. The efferent are is the sympathetic nervous system.
Manifestations of Chronic Disease During Pregnancy
Authors: Risto J Kaaja, Ian A Greer
Journal: JAMA (2005)

Physiologic changes of pregnancy include insulin resistance, thrombophilia, immunosuppression, and hypervolemia. These changes may herald the development of disease in later life.To summarize current evidence on how pregnancy reveals risk of chronic disease.MEDLINE was searched for articles published between 1990 and 2005 relating pregnancy conditions to the development of chronic disease. Bibliographies and the Web sites of the International Society of Obstetric Medicine and International Society for the Study of Hypertension in Pregnancy were also reviewed.Pregnancy exaggerates atherogeniclike responses, including insulin resistance and dyslipidemia, manifesting as preeclampsia or gestational diabetes. These complications herald an increased risk of postpartum cardiovascular disease, with a 2-fold increased risk of coronary artery disease and stroke. Women with gestational diabetes mellitus can progress to type 2 diabetes mellitus. The rate of progression varies from 6% to 92% depending on diagnostic criteria, race/ethnicity, and duration of surveillance (from 6 months to 28 years). Pregnancy increases risk of venous thrombosis by 7- to 10-fold. Heritable thrombophilia is present in at least 15% of Western populations and underlies at least 50% of gestational venous thromboses. Thus, the procoagulant changes during pregnancy can unmask hereditary thrombophilia. An important adaptation leading to immunotolerance of the fetoplacental unit is a switch from helper T-cell (T(H)) 1 dominance to T(H)2 dominance. Patients with a T(H)1-dominant immune disease, such as rheumatoid arthritis or multiple sclerosis, improve during pregnancy. However, rheumatoid arthritis is 5 times more likely to develop after delivery than at any other time. During pregnancy, there is a 50% increase in plasma volume, which can unmask glomerulopathies, peripartum cardiomyopathy, arterial aneurysms, or arteriovenous malformations. Development of intrahepatic cholestasis of pregnancy predicts increased risk of later cholelithiasis.The physiologic changes of pregnancy can reveal risk of chronic diseases. Exaggerated responses reflective of the metabolic syndrome are seen in preeclampsia and gestational diabetes and can herald future cardiovascular and metabolic disease. Pregnancy is therefore an important screening opportunity for cardiovascular and metabolic disease risk factors, with the possibility of early intervention.
Heparin and Air Filters Reduce Embolic Events Caused by Intra-Arterial Cerebral Angiography
Authors: Martin Bendszus, Martin Koltzenburg, Andreas J. Bartsch, Roland Goldbrunner, Thomas Günthner-Lengsfeld, Franz X. Weilbach, Klaus Roosen, Klaus V. Toyka, László Solymosi
Journal: Circulation (2004)

Background— Intra-arterial cerebral angiography is associated with a low risk for neurological complications, but clinically silent ischemic events after angiography have been seen in a substantial number of patients. Methods and Results— In a prospective study, diffusion-weighted magnetic resonance imaging (DW-MRI) before and after intra-arterial cerebral angiography and transcranial Doppler sonography during angiography were used to evaluate the frequency of cerebral embolism. One hundred fifty diagnostic cerebral angiographies were randomized into 50 procedures, each using conventional angiographic technique, or systemic heparin treatment throughout the procedure, or air filters between the catheter and both the contrast medium syringe and the catheter flushing. There was no neurological complication during or after angiography. Overall, DW-MRI revealed 26 new ischemic lesions in 17 patients (11%). In the control group, 11 patients showed a total of 18 lesions. In the heparin group, 3 patients showed a total of 4 lesions. In the air filter group, 3 patients exhibited a total of 4 lesions. The reduced incidence of ischemic events in the heparin and air filter groups compared with the control group was significantly different ( P =0.002). Transcranial Doppler sonography demonstrated a large number of microembolic signals that was significantly lower in the air filter group compared with the heparin and control groups ( P &lt;0.01), which did not differ from each other. Conclusions— Air filters and heparin both reduce the incidence of silent ischemic events detected by DW-MRI after intra-arterial cerebral angiography and can potentially lower clinically overt ischemic complications. This may apply to any intra-arterial angiographic procedure.
Oscillation of Blood Flow and Vascular Resistance During Mayer Waves
Authors: Thomas Killip
Journal: Circulation Research (1962)

In cats anesthetized with chloralose, Mayer waves developed following graded hemorrhage and, in some, partial carotid occlusion. The average Mayer wave was 56 mm. Hg in amplitude rising from a base systemic pressure of 70 mm. Hg at a frequency of 3.0 per minute. Rhythmic fluctuation of respiratory depth and frequency paralleled but slightly preceded the blood pressure change. There was no significant variation in heart rate during Mayer waves. Flow in the abdominal aorta and vena cava varied inversely with systemic pressure. A flow lag of four to six seconds in the vena cava behind that in the aorta during Mayer waves was probably related to circulation time. Blood flow was measured in muscle, small intestine, skin, and kidney. During the pressure rise of each Mayer wave, blood flow decreased in muscle more than in gut. Cutaneous flow increased moderately. Renal flow varied directly with the arterial pressure. Changes vascular resistance were evaluated by holding perfusion pressure constant and measuring regional blood flow. During Mayer waves, muscle vascular resistance increased 276 per cent, intestinal resistance increased 210 per cent, and cutaneous resistance rose 136 per cent. Renal vascular resistance did not change. Since Mayer waves are apparently reflexogenic in origin, the data are interpreted as evidence for regional differences in the pattern of central reflex control of the peripheral vascular system.
Comparison of histamine and methacholine for use in bronchial challenge tests in community studies.
Authors: B G Higgins, J R Britton, S Chinn, T D Jones, A S Vathenen, P G Burney, A E Tattersfield
Journal: Thorax (1988)

Measurement of bronchial reactivity is widely used in epidemiological surveys. Histamine has been compared with methacholine inhalation challenge in two samples of adults from a small town to determine which is the better agent for use in community studies. Increasing doses of histamine and methacholine were given, up to a maximum of 4 and 12 mumol respectively, according to the method of Yan et al, the provocative dose of agonist causing a 20% fall in FEV1 (PD20) being measured. More subjects had a measurable PD20 with methacholine than with histamine, both in a random sample of 108 subjects (25 v 11 subjects, p less than 0.01) and in an additional 95 subjects selected because of wheeze in the last 12 months (67 v 48 subjects, p less than 0.01). Side effects were mild with both agents but histamine caused voice change in more subjects (21% v 11%). Repeatability was assessed in a further group of subjects with wheeze in the last year. The 95% range for a single estimation of PD20 in subjects with a measured PD20 on at least one occasion was +/- 2.5 doubling doses for histamine (n = 25) and +/- 2.1 doubling doses for methacholine (n = 33). Thus methacholine has advantages over histamine for community studies of bronchial reactivity as it is possible to use doses that produce more PD20 measurements with fewer side effects.
Takotsubo Syndrome Secondary to Adrenal Adenocarcinoma: Cortisol as a Possible Culprit
Authors: Nadine Wickboldt, Jean-Claude Pache, Pierre-Yves Dietrich, Christian Toso, Christophe Gallay, Laurent Brochard, Paolo Merlani, Deborah Pugin
Journal: American Journal of Respiratory and Critical Care Medicine (2012)
FOXO1A Is a Candidate for the 13q14 Tumor Suppressor Gene Inhibiting Androgen Receptor Signaling in Prostate Cancer
Authors: Xue-Yuan Dong, Ceshi Chen, Xiaodong Sun, Peng Guo, Robert L. Vessella, Ruo-Xiang Wang, Leland W.K. Chung, Wei Zhou, Jin-Tang Dong
Journal: Cancer Research (2006)

Abstract Chromosomal deletion is frequent at the region between BRCA2 and RB1 in the q14 band of chromosome 13 (13q14) in human cancers, including prostate cancer, suggesting the presence of a tumor suppressor gene. However, no reasonable candidate has been identified thus far. In this study, we did genetic and functional analyses to identify and evaluate the 13q14 tumor suppressor gene. Hemizygous and homozygous deletions in cell lines/xenografts of prostate cancer mapped the deletion locus to 919 kb, which harbors only one known gene, the FOXO1A transcription factor. Deletion at FOXO1A was detected in 31% to 34% in 6 cell lines, 27 xenografts, and 72 clinical specimens of prostate cancer, and was significantly more frequent than deletions at surrounding loci. In addition, FOXO1A was transcriptionally down-regulated in some prostate cancers. Functionally, ectopic expression of FOXO1A inhibited, and its knockdown promoted, cell proliferation or survival. Furthermore, FOXO1A inhibited androgen- and androgen receptor–mediated gene regulation and cell proliferation. Consistent with the understanding of FOXO1A biology, our findings suggest that FOXO1A is the 13q14 tumor suppressor gene, at least in prostate cancer. As a well-established negative effector in the phosphatidylinositol 3-kinase/AKT signaling pathway, FOXO1A inactivation in cancer would impair the therapeutic effect of phosphatidylinositol 3-kinase/AKT inhibitors in cancer treatment. (Cancer Res 2006; 66(14): 6998-7006)
Lupus relapse after prostaglandin E1 administration: activation of a cytokine cascade?
Authors: M de la Torre
Journal: Annals of the Rheumatic Diseases (2002)

A variety of abnormalities in cytokine production occur in human and murine lupus, but their specific role in lupus pathogenesis is unknown.1 Recent in vitro studies emphasise the role of prostaglandins in the cytokine induction and modulation of the humoral immune response.2,3 We present a patient with systemic lupus erythematosus (SLE) who had a relapse after prostaglandin E1 (PGE1) administration, which to our knowledge has not been previously reported.

A 25 year old woman was admitted to hospital to receive treatment with IV PGE1 owing to severe Raynaud's phenomenon. Fifteen years previously SLE had been diagnosed according to American Rheumatism Association …
The Use of Specimen Roentgenography to Detect Small Carcinomas Not Found by Routine Pathologic Examination
Authors: R. H. Koehl, R. E. Snyder, R. V. P. Hutter
Journal: CA A Cancer Journal for Clinicians (1971)

CA: A Cancer Journal for Clinicians publishes information about the prevention, early detection, and treatment of cancer, as well as nutrition, palliative care, survivorship, and additional topics of interest related to cancer care.
Erlotinib resistance in EGFR-amplified glioblastoma cells is associated with upregulation of EGFRvIII and PI3Kp110 
Authors: A. Schulte, K. Liffers, A. Kathagen, S. Riethdorf, S. Zapf, A. Merlo, K. Kolbe, M. Westphal, K. Lamszus
Journal: Neuro-Oncology (2013)

Background.The treatment efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors like erlotinib has not met expectations for glioblastoma therapy, even for EGFR-overexpressing tumors.We determined possible mechanisms of therapy resistance using the unique BS153 glioblastoma cell line, which has retained amplification of the egfr gene and expression of EGFR variant (v)III.Methods.Functional effects of erlotinib, gefitinib, and cetuximab on BS153 proliferation, migration, and EGFR-dependent signal transduction were systematically compared in vitro.The tumor-initiating capacity of parental and treatment-resistant BS153 was studied in Naval Medical Research Institute/Foxn1 nu mice.Potential mediators of resistance were knocked down using small interfering (si)RNA.Results.Erlotinib and gefitinib inhibited proliferation and migration of BS153 in a dose-dependent manner, whereas cetuximab had no effect.BS153 developed resistance to erlotinib (BS153 resE ) but not to gefitinib.Resistance was associated with strong upregulation of EGFRvIII and subsequent activation of the phosphatidylinositol-3-OH kinase (PI3K) pathway in BS153 resE and an increased expression of the regulatory 110-kDa delta subunit of PI3K (p110d).Knockdown of EGFRvIII in BS153 resE largely restored sensitivity to erlotinib.Targeting PI3K pharmacologically caused a significant decrease in cell viability, and specifically targeting p110d by siRNA partially restored erlotinib sensitivity in BS153 resE .In vivo, BS153 formed highly invasive tumors with an unusual growth pattern, displaying numerous satellites distant from the initial injection site.Erlotinib resistance led to delayed onset of tumor growth as well as prolonged overall survival of mice without changing tumor morphology.Conclusions.EGFRvIII can mediate resistance to erlotinib in EGFR-amplified glioblastoma via an increase in PI3Kp110d.Interfering with PI3Kp110d can restore sensitivity toward the tyrosine kinase inhibitor.