tbuckley/cabot-search huggingface dataset:
Silencing of p130Cas in Ovarian Carcinoma: A Novel Mechanism for Tumor Cell Death
Authors: Alpa M. Nick, Rebecca L. Stone, Guillermo Armaiz-Pena, Bulent Ozpolat, Ibrahim Tekedereli, Whitney S. Graybill, Charles N. Landen, Gabriel Villares, Pablo Vivas-Mejia, Justin Bottsford-Miller, Hye Sun Kim, Ju-Seog Lee, Soo Mi Kim, Keith A. Baggerly, Prahlad T. Ram, Michael T. Deavers, Robert L. Coleman, Gabriel Lopez-Berestein, Anil K. Sood
Journal: JNCI Journal of the National Cancer Institute (2011)

We investigated the clinical and biological significance of p130cas, an important cell signaling molecule, in ovarian carcinoma.Expression of p130cas in ovarian tumors, as assessed by immunohistochemistry, was associated with tumor characteristics and patient survival. The effects of p130cas gene silencing with small interfering RNAs incorporated into neutral nanoliposomes (siRNA-DOPC), alone and in combination with docetaxel, on in vivo tumor growth and on tumor cell proliferation (proliferating cell nuclear antigen) and apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling) were examined in mice bearing orthotopic taxane-sensitive (HeyA8 and SKOV3ip1) or taxane-resistant (HeyA8-MDR) ovarian tumors (n = 10 per group). To determine the specific mechanisms by which p130cas gene silencing abrogates tumor growth, we measured cell viability (MTT assay), apoptosis (fluorescence-activated cell sorting), autophagy (immunoblotting, fluorescence, and transmission electron microscopy), and cell signaling (immunoblotting) in vitro. All statistical tests were two-sided.Of 91 ovarian cancer specimens, 70 (76%) had high p130cas expression; and 21 (24%) had low p130cas expression. High p130cas expression was associated with advanced tumor stage (P < .001) and higher residual disease (>1 cm) following primary cytoreduction surgery (P = .007) and inversely associated with overall survival and progression-free survival (median overall survival: high p130cas expression vs low expression, 2.14 vs 9.1 years, difference = 6.96 years, 95% confidence interval = 1.69 to 9.48 years, P < .001; median progression-free survival: high p130cas expression vs low expression, 1.04 vs 2.13 years, difference = 1.09 years, 95% confidence interval = 0.47 to 2.60 years, P = .01). In mice bearing orthotopically implanted HeyA8 or SKOV3ip1 ovarian tumors, treatment with p130cas siRNA-DOPC in combination with docetaxel chemotherapy resulted in the greatest reduction in tumor growth compared with control siRNA therapy (92%-95% reduction in tumor growth; P < .001 for all). Compared with control siRNA therapy, p130cas siRNA-DOPC reduced SKOV3ip1 cell proliferation (31% reduction, P < .001) and increased apoptosis (143% increase, P < .001) in vivo. Increased tumor cell apoptosis may have persisted despite pan-caspase inhibition by the induction of autophagy and related signaling pathways.Increased p130cas expression is associated with poor clinical outcome in human ovarian carcinoma, and p130cas gene silencing decreases tumor growth through stimulation of apoptotic and autophagic cell death.
Biphasic flow reaction after nitroglycerine provocation in patients with myocardial bridging demostrated by intracoronary doppler flow measurement
Authors: J. Go, D. Baumgart, F. Liu, G. Gorge, M. Haude, G. Caspan, R. Hammentgen, R. Erbel
Journal: Journal of the American College of Cardiology (1998)
Delayed Progression of Pancreatic Intraepithelial Neoplasia in a Conditional KrasG12D Mouse Model by a Selective Cyclooxygenase-2 Inhibitor
Authors: Hitoshi Funahashi, Makoto Satake, David Dawson, Ngoc-An Huynh, Howard A. Reber, Oscar J. Hines, Guido Eibl
Journal: Cancer Research (2007)

Pancreatic ductal adenocarcinomas are thought to arise from noninvasive, intraductal precursor lesions called pancreatic intraepithelial neoplasias (PanIN). The study of PanINs holds great promise for the identification of early detection markers and effective cancer-preventing strategies. Cyclooxygenase-2 (COX-2) represents an intriguing target for therapeutic and preventive approaches in various human malignancies. The aim of the present study was to evaluate the efficacy of a selective COX-2 inhibitor to prevent the progression of PanINs in a conditional Kras(G12D) mouse model. Offspring of LSL-KRAS(G12D) x PDX-1-Cre intercrosses were randomly allocated to a diet supplemented with the selective COX-2 inhibitor nimesulide (400 ppm) or a control diet. After 10 months, animals were sacrificed. Successful recombination in the pancreas was evaluated by PCR. The pancreas of KRAS(G12D);PDX-1-Cre mice was analyzed for the presence of murine PanINs. Animals fed the COX-2 inhibitor had significantly fewer PanIN-2 and PanIN-3 lesions than control animals (P < 0.05). Ten percent of all pancreatic ducts in the nimesulide-fed animals showed PanIN-2 or PanIN-3 lesions, whereas 40% of the pancreatic ducts in the control animals had PanIN-2 or PanIN-3 lesions. Intrapancreatic prostaglandin E(2) levels were reduced in nimesulide-fed animals. Immunohistochemistry confirmed COX-2 expression in early and late PanINs. In summary, we found that the selective COX-2 inhibitor nimesulide delays the progression of pancreatic cancer precursor lesions in a preclinical animal model. These data highlight the importance of COX-2 in the development of pancreatic cancer. Inhibition of COX-2 may represent an intriguing strategy to prevent pancreatic cancer in high-risk patients.
Isolated Growth Hormone Deficiency and Related Disorders
Authors: T J Merimee
Journal: Annual Review of Medicine (1974)

This brief discussion wm consider those forms of dwarfism characterized either by a mono tropic deficiency of human growth hormone (HGH) (a defect in synthesis and/or release), a defect in the ability of HGH to generate sulfation factor, or end organ sub responsiveness to exogenous or endogenous HGH. Although there is controversy over what term should be used to describe such dwarfs, the term ateliosis is historically correct, and a somewhat neutral term is useful if it is rigor­ ously defined as in the preceding sentence. Although interest in dwarfism has existed for centuries, it was not until 1902 that Guilford (1) proposed the first systematic classification based upon the simple observation that dwarfs appear to be of two major types: those with and those without obvious physical abnormalities. For the latter group, now known more popularly as midgets, Guilford used the term ateliosis (ateliosis = not arriving at perfection), since he considered this form of dwarfism a disorder in which growth and development were not arrested but in which both were retarded. He recognized, likewise, that some of these patients attained  maturity whereas others re­ mained infantile, and for the former he coined the term sexual ateliosis. The most complete collection of familial cases of  ateliotic dwarfism prior to 1967 was compiled in 1912 by Rischbieth & Barrington (2). Rimoin was able to add to this collection when he recorded 64 individuals and 19 kindreds who could be classified as  ateliotics (3). In most of the kindred reviewed, autosomal recessive inheritance was suggested by the occurrence of affected siblings, both male and female, from unaffected parents. Using the Proband-Sib method for estimating the segregation ratio, data also indicated an autosomal recessive trait. The high frequency of consanguinity in the kindred studies was, likewise, consistent with this interpretation. Con sanguinous matings occurred in 5 of 19 kindreds (26%) with  ateliosis (3). Although our own data indicate that  ateliosis is usually inherited as a
Obesity: the elephant in the corner
Authors: David Ogilvie, Neil Hamlet
Journal: BMJ (2005)

In 2055, everybody knew that obesity was a problem, but what did they do about it? 

The year is 2055. Socrates is discussing the history of the western obesity epidemic with Panacea, the goddess of healing.

Socrates: Do you recall the days when people were still allowed to smoke?

Panacea: Indeed, Socrates. It seems unthinkable now. Of course in those days smoking was the leading preventable cause of chronic disease. It is remarkable how times have changed.

Socrates: In the past 50 years, obesity has come to account for more health problems than any other single factor. I can't help thinking, Panacea, that something could have been done to prevent this. What on earth was going on at the beginning of the 21st century?

Panacea: Well, it was common knowledge that more and more people were becoming overweight. Obesity was well established as a risk factor for all kinds of diseases. There was even talk of epidemics and time bombs.1 2

Socrates: So why were people becoming obese?

Panacea: Surely that's obvious. They were consuming more energy than they were expending.

Socrates: It was that simple?

Panacea: Absolutely.

Socrates: I suppose this was a recent scientific discovery?

Panacea: Oh no, Socrates. Even in the 20th century, the concept was well understood.3

Socrates: Is the human body not designed to regulate itself?

Panacea: Indeed. It has sophisticated mechanisms for controlling hunger and appetite.

Socrates: So why did some people not achieve a balance between their energy inputs and energy outputs?

Panacea: Well, Socrates, it was all to do with their lifestyle choices.4

Socrates: Some followed a lifestyle of gluttony?

Panacea: Or a lifestyle of sloth. Or both.

Socrates: Your explanation implies a very neat, rational prescription, Panacea. If people consume more energy than they expend, they will gain …
Activation of PKN Mediates Survival of Cardiac Myocytes in the Heart During Ischemia/Reperfusion
Authors: Hiromitsu Takagi, Chiao-Po Hsu, Katsuya Kajimoto, Dan Shao, Yanfei Yang, Yasuhiro Maejima, Peiyong Zhai, Ghassan Yehia, Chikaomi Yamada, Daniela Zablocki, Junichi Sadoshima
Journal: Circulation Research (2010)

The function of PKN, a stress-activated protein kinase, in the heart is poorly understood.We investigated the functional role of PKN during myocardial ischemia/reperfusion (I/R).PKN is phosphorylated at Thr774 in hearts subjected to ischemia and reperfusion. Myocardial infarction/area at risk (MI/AAR) produced by 45 minutes of ischemia and 24 hours of reperfusion was significantly smaller in transgenic mice with cardiac-specific overexpression of constitutively active (CA) PKN (Tg-CAPKN) than in nontransgenic (NTg) mice (15+/-5 versus 38+/-5%, P<0.01). The number of TUNEL-positive nuclei was significantly lower in Tg-CAPKN (0.3+/-0.2 versus 1.0+/-0.2%, P<0.05). Both MI/AAR (63+/-9 versus 45+/-8%, P<0.05) and the number of TUNEL-positive cells (7.9+/-1.0 versus 1.3+/-0.9%, P<0.05) were greater in transgenic mice with cardiac-specific overexpression of dominant negative PKN (Tg-DNPKN) than in NTg mice. Thr774 phosphorylation of PKN was also observed in response to H(2)O(2) in cultured cardiac myocytes. Stimulation of PKN prevented, whereas inhibition of PKN aggravated, cell death induced by H(2)O(2), suggesting that the cell-protective effect of PKN is cell-autonomous in cardiac myocytes. PKN induced phosphorylation of alpha B crystallin and increased cardiac proteasome activity. The infarct reducing effect in Tg-CAPKN mice was partially inhibited by epoxomicin, a proteasome inhibitor.PKN is activated by I/R and inhibits apoptosis of cardiac myocytes, thereby protecting the heart from I/R injury. PKN mediates phosphorylation of alpha B crystallin and stimulation of proteasome activity, which, in part, mediates the protective effect of PKN in the heart.
The evolution of the body size and shape in children: causes and consequences
Authors: Hans de Ridder
Journal: British Journal of Sports Medicine (2010)

Childhood obesity is becoming a worldwide public health concern. Research studies from the International Obesity Task Force reveal that an estimated 155 million school-age children and adolescents worldwide show symptoms of obesity and being overweight. Among those, 30–45 million children and adolescents aged 5–17 are obese. According to the Centers for Disease Control and Prevention, 18.8% of children aged 6–11 in the USA are obese. Recent studies have shown that the current generation of children in the USA and UK are projected to have shorter life spans than the previous generations – for the first time in history. According to recent studies, the costs of obesity to health systems and individuals are increasing by alarming rates. Since 2000, costs from childhood obesity-associated illnesses in the USA have risen from $35 to $127 million. The decrease in physical activity is found to be associated with the epidemic of obesity in children. There is therefore no better time for parents, educators, children and communities to promote healthy lifestyles and learning opportunities for students and to examine how we are preparing health and physical education (PE) teachers. It is important that all children have access to daily health and PE programmes. Physical educators at all school levels should remain abreast of current research, committed to further professional development, open-minded and committed to advancing the field. Life-long active living must be the primary goal of the health and PE curriculum. PE must be part of the school curriculum and not a subject that continues to be marginalised. Health must be a very important focus point in the PE curriculum with a strong emphasis on how to handle the worldwide obesity problem in children.
Malignant perivascular epithelioid cell tumor: A case report of a cutaneous tumor on the cheek of a male patient
Authors: Karin Greveling, Veronique J.L. Winnepenninckx, Ivo F. Nagtzaam, Martin Lacko, Stephania M.H. Tuinder, Jos M.A. de Jong, Nicole W.J. Kelleners-Smeets
Journal: Journal of the American Academy of Dermatology (2013)
Dry cough and dyspnoea rapidly increasing to respiratory failure in a male smoker
Authors: I. Sigala
Journal: European Respiratory Journal (2005)

A 65-yr-old male, current smoker of .30cigarettes?day -1 (total smoking history 150 pack-yrs), who was working as a bus driver, presented at the Evangelismos Hospital (Athens, Greece) complaining of increasing breathlessness on exertion and dry cough during the past 2 months.He had no animal exposure and he hadn't travelled abroad during the last few years.His medical history showed arterial hypertension, for which he was receiving treatment with an angiotension-converting enzymeinhibitor (ramipril) plus hydrochlorothiazide, as well as asymptomatic cholelithiasis and prostate hypertrophy for which he was receiving tamsulosin hydrochloride.He did not mention suffering from fever in the last few months.On admission, the patient was mildly tachypnoeic (22 breaths?min -1 ), but apparently in discrete health, with a body temperature of 36.8˚C,pulse rate 85 beats?min -1 and blood pressure 130/70 mmHg.On chest auscultation, rare fine inspiratory rales were audible over both hemithoraces.He had no clubbing.The tuberculin test was negative.The routine blood analysis and chemistry was normal.Arterial blood gas analysis while breathing room air gave results as follows: arterial oxygen tension (Pa,O 2 ) 7.95 kPa; carbon dioxide arterial tension (Pa,CO 2 ) 3.94 kPa; pH: 7.45.Chest radiography on admission is shown in figure 1.
Incidence of Reactions Following Administration of Antirabies Serum
Authors: Joel S. Karliner
Journal: JAMA (1965)

<h3>But where the greater malady is fix'd The lesser is scarce felt.</h3> Shakespeare:<i>King Lear</i>, Act III, scene 4 Rabies in man is a uniformly fatal disease once clinical symptoms appear. In a human bitten by a potentially rabid animal, the only hope of rabies prevention lies in effective postexposure prophylaxis, which at the present time consists in the administration of antirabies serum (equine origin) followed, if indicated, by a course of duckembryo or nervous-tissue vaccine. Our hospital is located in an area with the greatest concentration of enzootic and epizootic rabies in the United States.<sup>1</sup>In 1963, over 31% of all rabid dogs in this country were reported from the US-Mexico border; of these 186 animals, 44 were from the city of El Paso alone.<sup>2</sup>Because of the high risk of rabies in the area, we have evolved a vigorous program of rabies prophylaxis, following the criteria
Accuracy of Data in Abstracts of Published Research Articles
Authors: Roy M. Pitkin
Journal: JAMA (1999)

The section of a research article most likely to be read is the abstract, and therefore it is particularly important that the abstract reflect the article faithfully.To assess abstracts accompanying research articles published in 6 medical journals with respect to whether data in the abstract could be verified in the article itself.Analysis of simple random samples of 44 articles and their accompanying abstracts published during 1 year(July 1, 1996-June 30, 1997) in each of 5 major general medical journals (Annals of Internal Medicine, BMJ, JAMA, Lancet, and New England Journal of Medicine) and a consecutive sample of 44 articles published during 15 months (July 1, 1996-August 15, 1997) in the CMAJ.Abstracts were considered deficient if they contained data that were either inconsistent with corresponding data in the article's body (including tables and figures) or not found in the body at all.The proportion of deficient abstracts varied widely (18%-68%) and to a statistically significant degree (P<.001) among the 6 journals studied.Data in the abstract that are inconsistent with or absent from the article's body are common, even in large-circulation general medical journals.
TLR2 activation causes no morbidity or cardiovascular failure, despite excessive systemic nitric oxide production
Authors: Anje Cauwels, Benjamin Vandendriessche, Jennyfer Bultinck, Benedicte Descamps, Elke Rogge, Tom Van Nieuwenhuysen, Magdalena Sips, Christian Vanhove, Peter Brouckaert
Journal: Cardiovascular Research (2013)

Septic shock is the leading cause of death in intensive care units worldwide, resulting from a progressive systemic inflammatory reaction causing cardiovascular and organ failure. Nitric oxide (NO) is a potent vasodilator and inhibition of NO synthases (NOS) can increase blood pressure in septic shock. However, NOS inhibition does not improve outcome, on the contrary, and certain NO donors may even provide protection. In addition, NOS produce superoxide in case of substrate or cofactor deficiency or oxidation. We hypothesized that excessive systemic iNOS-derived NO production is insufficient to trigger cardiovascular failure and shock.We found that the systemic injection with various synthetic Toll-like receptor-2 (TLR2), TLR3, or TLR9 agonists triggered systemic NO production identical to that of lipopolysaccharide (LPS) or tumour necrosis factor. In contrast to the latter, however, these agonists did not cause hypothermia or any other signs of discomfort or morbidity, and inflammatory cytokine production was low. TLR2 stimulation with the triacylated lipopeptide Pam3CSK4 not only caused identical NO levels in circulation, but also identical iNOS expression patterns as LPS. Nevertheless, Pam3CSK4 did not cause hypotension, bradycardia, reduced blood flow, or inadequate tissue perfusion in the kidney or the liver.We demonstrate that excessive iNOS-derived NO in circulation is not necessarily linked to concomitant cardiovascular collapse, morbidity, or mortality. As such, our data indicate that the central role of iNOS-derived NO in inflammation-associated cardiovascular failure may be overestimated.
Definition of Molecular Determinants of Prostate Cancer Cell Bone Extravasation
Authors: Steven R. Barthel, Danielle L. Hays, Erika M. Yazawa, Matthew Opperman, Kempland C. Walley, Leonardo Nimrichter, Monica M. Burdick, Bryan M. Gillard, Michael T. Moser, Klaus Pantel, Barbara A. Foster, Kenneth J. Pienta, Charles J. Dimitroff
Journal: Cancer Research (2012)

Advanced prostate cancer commonly metastasizes to bone, but transit of malignant cells across the bone marrow endothelium (BMEC) remains a poorly understood step in metastasis. Prostate cancer cells roll on E-selectin(+) BMEC through E-selectin ligand-binding interactions under shear flow, and prostate cancer cells exhibit firm adhesion to BMEC via β1, β4, and αVβ3 integrins in static assays. However, whether these discrete prostate cancer cell-BMEC adhesive contacts culminate in cooperative, step-wise transendothelial migration into bone is not known. Here, we describe how metastatic prostate cancer cells breach BMEC monolayers in a step-wise fashion under physiologic hemodynamic flow. Prostate cancer cells tethered and rolled on BMEC and then firmly adhered to and traversed BMEC via sequential dependence on E-selectin ligands and β1 and αVβ3 integrins. Expression analysis in human metastatic prostate cancer tissue revealed that β1 was markedly upregulated compared with expression of other β subunits. Prostate cancer cell breaching was regulated by Rac1 and Rap1 GTPases and, notably, did not require exogenous chemokines as β1, αVβ3, Rac1, and Rap1 were constitutively active. In homing studies, prostate cancer cell trafficking to murine femurs was dependent on E-selectin ligand, β1 integrin, and Rac1. Moreover, eliminating E-selectin ligand-synthesizing α1,3 fucosyltransferases in transgenic adenoma of mouse prostate mice dramatically reduced prostate cancer incidence. These results unify the requirement for E-selectin ligands, α1,3 fucosyltransferases, β1 and αVβ3 integrins, and Rac/Rap1 GTPases in mediating prostate cancer cell homing and entry into bone and offer new insight into the role of α1,3 fucosylation in prostate cancer development.
Ipratropium Bromide (Atrovent®) as Inhalation Powder
Authors: F. P. V. Maesen, J. J. Smeets, R. Bernsen, P. J. G. Cornelissen
Journal: Allergy (1986)

The bronchospasmolytic effects of 40 μg ipratropium bromide (Atrovent®) given either as an aerosol (2 puffs of 20 μg) or as a powder inhalation were compared in a double‐blind cross‐over study. Following a randomisation list the drug was given on 2 successive days to 20 patients with stable bronchospasm in whom it had previously been shown that the bronchial obstruction was reversible after administration of 40 μg ipratropium bromide as an aerosol (with an increase over‐ the baseline value of the FEV 1 of at least 15% 1 h after drug administration). The effects of the two presentations of ipratropium bromide were followed by respiratory function tests from 15 min to 6 h after administration of the drug. With both formulations excellent bronchospasmolytic effects were noted in each of the parameters measured. The peak of the effects was noted approximately 1 h alter the inhalations. Six hours later there was still a significant improvement in comparison with the baseline values. There was no significant difference between the results with the two different formulations. Inhalation powder of ipratropium bromide was well tolerated and there were no complaints of irritation or coughing. It would appear, therefore, to be a valuable alternative to the pressure aerosol.