tbuckley/cabot-search huggingface dataset:
Abstract 2789: Interaction of (+)-discodermolide-Taxol hybrids with microtubules
Authors: Chia-Ping H. Yang, Keizo Sugasawa, Onur Atasoylu, Amos B. Smith, Susan B. Horwitz
Journal: Cancer Research (2012)

Abstract Taxol and discodermolide are both microtubule stabilizing agents that bind to the β-tubulin subunit of microtubules. Based on our results that the hydrophobic binding pocket of β-tubulin is occupied by the Taxol side chain but not by (+)-discodermolide, and that the two drugs act synergistically in cancer cell lines, a small library of (+)-discodermolide-Taxol hybrids was synthesized (J. Med. Chem. 54:6319, 2011). Cytotoxicity assays demonstrated a 2-9-fold increase in antiproliferative activity by the hybrids compared to discodermolide in the human cancer cell lines, A549 and MCF-7. Hybrids containing a tether of 3 carbons that connect discodermolide with the Taxol side chain, exhibited the best activity. Tubulin assembly assays were performed with the two most potent hybrid molecules. Like discodermolide, these two hybrids increased tubulin assembly rapidly without a lag period. Tubulin polymerization studies using purified bovine brain tubulin demonstrated that they also had the greatest effect on the formation of polymerized microtubules. These results also were observed in intact A549 cells and in 100,000 x g supernatants prepared from these cells. We have previously shown that [3H]2-(m-azidobenzoyl)Taxol photolabels a peptide containing amino acid residues 217-231 of β-tubulin. A 5-fold molar excess of unlabeled compound inhibited the photolabeling of purified bovine brain tubulin by 94%, demonstrating the specificity of this photolabeling. Microtubule stabilizing agents (MSAs), such as Taxol, epothilone B, discodermolide and ixabepilone, each at a 5-fold molar excess, inhibited the photolabeling by 24%, 92%, 100% and 41%, respectively, indicating that discodermolide is the most potent inhibitor of the photolabeling. In contrast, two other MSAs, laulimalide and peloruside that are known to bind to a different site in β-tubulin, exhibited stimulatory effects on the photolabeling. Both drugs, at a 5-fold molar excess, increased the labeling by 30-40%. [3H]2-(m-azidobenzoyl)Taxol (0.5 - 20 µM) was used to study the kinetics of the inhibitory effects of the hybrid molecules on photoaffinity labeling of tubulin. Discodermolide-Taxol hybrids inhibited the photolabeling of bovine brain tubulin in a dose dependent manner. The concentrations that inhibited by 50% were lowest for the two most potent hybrid molecules. Therefore, the tubulin polymerization activity and the binding affinity of the hybrids to β-tubulin correlated with their antiproliferative activity. Other biological properties of the discodermolide-Taxol hybrids including senescence and antitumor activity are being evaluated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2789. doi:1538-7445.AM2012-2789
P620Alterations in cardiac levels and activities of toll-like receptor 9 and circulating levels of it's putative ligand, mitochondrial DNA, in human heart failure
Authors: Y D Holmen, A Yndestad, CP Dahl, A Fiane, L Gullestad, P Aukrust, LE Vinge
Journal: Cardiovascular Research (2014)

Background: Experimental studies have shown a central role for Toll-like receptor 9 (TLR9) in the pathogenesis of heart failure (HF). There is also evidence that mitochondrial DNA (mtDNA) not confined within the mitochondrion may act as a TLR9 ligand. However, it is unknown whether these findings also have a human correlate.
Significance of microhaematuria in young adults.
Authors: P Froom, J Ribak, J Benbassat
Journal: BMJ (1984)

The medical records of 1000 asymptomatic male air force personnel were examined retrospectively for the results of 15 yearly examinations of urinary sediment. The study covered the period 1968-82, beginning with the subjects aged 18-33 years. The cumulative incidence of two to four or more red blood cells per high power field found at one or more examinations was 38.7% after an average of 12.2 yearly examinations per person. In 161 subjects two to four or more red blood cells per high power field were found at two or more yearly examinations within a five year period. Intravenous pyelography in 58 cases disclosed asymptomatic nephrolithiasis in six. Cystoscopy performed in 11 cases identified one patient with urethritis, one with a vesical calculus, and one with transitional cell carcinoma of the bladder. Two years before diagnosis the patient with carcinoma had had a single transient finding of 10-12 red blood cells per high power field which was not investigated further. Cystoscopy was performed after an episode of macroscopic haematuria. Renal biopsy in one subject with recurrent microhaematuria and trace proteinuria disclosed focal glomerulonephritis. None of the remaining subjects with microhaematuria developed hypertension or proteinuria, and at the end of the study period all were active and free of urinary symptoms. The observed cumulative incidence of urological neoplasms at 15 years (0.1%) was consistent with that expected in Israeli men aged 18-40 (0.09%). Hence microhaematuria detected during a screening examination probably should not be regarded as a specific sign of a significant lesion and does not of itself warrant urological investigation in adults aged 40 or less.
The unwanted diagnosis
Authors: Sue Warren
Journal: BMJ (2005)

He was a fit intelligent 74 year old accountant who walked five miles every day, lived for his family and dogs, and had worked hard for his comfortable life. He was afraid of doctors and never saw one until absolutely necessary—as demonstrated by his two strangulated inguinal hernias.

As I drove to his house, I had the feeling that my life was about to change. It was a bitter February day with a biting north wind blowing flurries of snow. I entered the house and breathed a sigh of relief when everything seemed normal. Then his words: …
Donor Simvastatin Treatment Abolishes Rat Cardiac Allograft Ischemia/Reperfusion Injury and Chronic Rejection Through Microvascular Protection
Authors: Raimo Tuuminen, Simo Syrjälä, Rainer Krebs, Mikko A.I. Keränen, Katri Koli, Usama Abo-Ramadan, Pertti J. Neuvonen, Jussi M. Tikkanen, Antti I. Nykänen, Karl B. Lemström
Journal: Circulation (2011)

Background— Ischemia/reperfusion injury may have deleterious short- and long-term consequences for cardiac allografts. The underlying mechanisms involve microvascular dysfunction that may culminate in primary graft failure or untreatable chronic rejection. Methods and Results— Here, we report that rat cardiac allograft ischemia/reperfusion injury resulted in profound microvascular dysfunction that was prevented by donor treatment with peroral single-dose simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase and Rho GTPase inhibitor, 2 hours before graft procurement. During allograft preservation, donor simvastatin treatment inhibited microvascular endothelial cell and pericyte RhoA/Rho-associated protein kinase activation and endothelial cell–endothelial cell gap formation; decreased intragraft mRNA levels of hypoxia-inducible factor-1α, inducible nitric oxide synthase, and endothelin-1; and increased heme oxygenase-1. Donor, but not recipient, simvastatin treatment prevented ischemia/reperfusion injury–induced vascular leakage, leukocyte infiltration, the no-reflow phenomenon, and myocardial injury. The beneficial effects of simvastatin on vascular stability and the no-reflow phenomenon were abolished by concomitant nitric oxide synthase inhibition with N -nitro- l -arginine methyl ester and RhoA activation by geranylgeranyl pyrophosphate supplementation, respectively. In the chronic rejection model, donor simvastatin treatment inhibited cardiac allograft inflammation, transforming growth factor-β1 signaling, and myocardial fibrosis. In vitro, simvastatin inhibited transforming growth factor-β1–induced microvascular endothelial-to-mesenchymal transition. Conclusions— Our results demonstrate that donor simvastatin treatment prevents microvascular endothelial cell and pericyte dysfunction, ischemia/reperfusion injury, and chronic rejection and suggest a novel, clinically feasible strategy to protect cardiac allografts.
Decreased frequency of exercise-induced ventricular ectopic activity in the second of two consecutive treadmill tests.
Authors: D S Sheps, J C Ernst, F R Briese, L V Lopez, C A Conde, A Castellanos, R J Myerburg
Journal: Circulation (1977)

Two exercise tests were performed with an intervening rest period of 45 minutes in a group of 13 subjects with previously identified exercise-induced ventricular arrhythmias and no resting arrhythmias. Both normal subjects and patients with heart disease were included in the group. The level of stresss was equal in both tests as judged by similar rate-pressure products at peak exercise. There was a significant decrease (P less than 0.05) in the number of VPCs induced by exercise during and after the second test. When the number of VPCs on test I and test II in the same patients were compared, a regression line fitted the data well (r = 0.92). Analysis of the recovery periods revealed significant (P less than 0.01) decreases in systolic blood pressure at one and three minutes post exercise, comparing the second to the first test. The underlying mechanism may be decreased myocardial oxygen demand during the second test as the lowered rate-pressure products during recovery (P less than 0.01) reflect. The results of this study indicate that tests of effectiveness of an antiarrhythmic drug should not be based solely on a decrease in the amount of severity of ventricular irritability between two successive exercise tests, one immediately before and the other following administration of the drug.
High expression of protein phosphatase 4 is associated with the aggressive malignant behavior of colorectal carcinoma
Authors: Xinxiang Li, Lei Liang, Liyong Huang, Xiaoji Ma, Dawei Li, Sanjun Cai
Journal: Molecular Cancer (2015)

Recent evidence suggests an important role of protein phosphatase 4 (PP4C) in the progression of several cancers, including breast cancer, lung cancer and pancreatic ductal adenocarcinoma. However, the contribution of PP4C to colorectal carcinoma (CRC) remains elusive.The expression of PP4C in CRC tissues compared with matched non-tumor tissues and CRC cells was detected using quantitative RT-PCR, immunohistochemistry and western blotting assays. Through univariate and Kaplan-Meier analysis, we correlated the PP4C expression with clinicopathological features and patient survival. A series of experiments, including cell proliferation, lentiviral infection, cell invasion and MMP gelatinase activity assays, were performed to investigate the underlying mechanisms. Through further experiments, tumor growth and metastasis were evaluated in vivo using a xenogenous subcutaneously implant model and a tail vein metastasis model.In the present study, we found that PP4C expression is frequently increased in human CRC and that the upregulation of PP4C correlates with a more invasive tumor phenotype and poor prognosis. The ectopic expression of PP4C promoted CRC cell proliferation, migration and invasion in vitro and tumor growth and lung metastasis in vivo. Silencing the expression of PP4C resulted in the inhibition of cell proliferation and invasion. Further investigations showed that phosphorylated Akt (p-AKT) is required for the PP4C-mediated upregulation of MMP-2 and MMP-9, which promotes cell invasion.Our data suggested a potential role of PP4C in tumor progression and provided novel insights into the mechanism of how this factor positively regulated cell proliferation and invasion in CRC cells.
An English Country Practice
Authors: John Lister
Journal: New England Journal of Medicine (1952)

An English Country PracticeAugust being the traditional holiday month in England, I was recently spending a few days in a small town on our South West Coast. My host was driving me in his car one evening and pointed out a new building, which, he explained, was his doctor's surgery (English for a doctor's office). When I said I was interested to know how a country practice was working under present conditions, my host suggested I call up the doctor and ask him to show me around. The result was a cordial invitation to visit him next evening, when . . .
Limitations of Direct-to-Consumer Advertising for Clinical Genetic Testing
Authors: Sarah E. Gollust
Journal: JAMA (2002)

Although direct-to-consumer (DTC) advertisements for pharmaceuticals have been appearing in the mass media for 20 years, DTC advertisements for genetic testing have only recently appeared. Advertisements for genetic testing can provide both consumers and physicians with information about test availability in an expanding market. However, 3 factors limit the value and appropriateness of advertisements: complex information, a complicated social context surrounding genetics, and a lack of consensus about the clinical utility of some tests. Consideration of several advertisements suggests that they overstate the value of genetic testing for consumers' clinical care. Furthermore, advertisements may provide misinformation about genetics, exaggerate consumers' risks, endorse a deterministic relationship between genes and disease, and reinforce associations between diseases and ethnic groups. Advertising motivated by factors other than evidence of the clinical value of genetic tests can manipulate consumers' behavior by exploiting their fears and worries. At this time, DTC advertisements are inappropriate, given the public's limited sophistication regarding genetics and the lack of comprehensive premarket review of tests or oversight of advertisement content. Existing Federal Trade Commission and Food and Drug Administration regulations for other types of health-related advertising should be applied to advertisements for genetic tests.
Maintaining Low HIV Seroprevalence Among Injecting Drug Users
Authors: C. L. Morrison, S. M. Ruben
Journal: JAMA (1996)

<h3>To the Editor.</h3> —Dr Des Jarlais and colleagues<sup>1</sup>have concluded that as a result of establishing HIV prevention measures (needle exchange, outreach) for drug users, some cities have escaped from epidemic levels of HIV in IDUs and that simply the continued existence of such facilities will avert a future epidemic. Their conclusion is based on the observation that those cities with established HIV prevention measures currently have low HIV rates in the IDU population. The authors, how ever, assume rather than test any relationship between establishing HIV prevention measures and low-risk behavior in the associated drug-using community. In effect, their report has failed to include important performance indicators and outcome measures of health care provision to IDU populations by concentrating on the HIV infection incidence alone; a more relevant and predictive indicator would be to measure sharing risk. Health policy in England has recognized this and has set targets
Polycystin-1 expression in PKD1, early-onset PKD1, and TSC2/PKD1 cystic tissue
Authors: Albert C.M. Ong, Peter C. Harris, David R. Davies, Lynn Pritchard, Sandro Rossetti, Simon Biddolph, David J.T. Vaux, Nicola Migone, Christopher J. Ward
Journal: Kidney International (1999)
Competing goals draw attention to effort, which then enters cost-benefit computations as input
Authors: Marie Hennecke, Alexandra M. Freund
Journal: Behavioral and Brain Sciences (2013)

Abstract Different to Kurzban et al., we conceptualize the experience of mental effort as the subjective costs of goal pursuit (i.e., the amount of invested resources relative to the amount of available resources). Rather than being an output of computations that compare costs and benefits of the target and competing goals, effort enters these computations as an input .
Intestinal hypersecretion of the refed starved rat: a model for alimentary diarrhoea.
Authors: A Young, R J Levin
Journal: Gut (1992)

Fluid transport was gravimetrically measured in vivo in the duodenum, jejunum, and ileum of anaesthetised fed, 72 hour starved and 72 hour starved rats refed for up to five days after starvation. Basal unstimulated fluid transport was monitored by instilling 0.9% NaCl into the lumen and measuring the gain or loss in weight of the closed intestinal loop. Fluid was absorbed in all the areas of the intestine in the fed rats. Increasing basal fluid absorption was observed in the duodenum over the three days of starvation but in the jejunum there was no significant change. In the ileum, the pattern was very different, on day 1 the fluid was absorbed but on days 2 and 3 there was an increasing secretion of fluid. Refeeding the rats with their normal diet restored the basal absorption of fluid in the duodenum within 24 hours, had no effect in the jejunum but in the case of the ileum the hypersecretion of fluid observed in the day 3 starved rat was maintained on day 1 of refeeding, increased further on day 2, decreased on day 3 but returned to absorption on day 4. The normal absorption was restored to the ileum on day 5 of refeeding. Fluid secretion was induced in all the rat groups by bethanechol (ip 60 micrograms/kg bw) a stable cholinergic agonist, PGE2 (ip 10 micrograms/kg (bw) and E coli STa (luminally instilled, 500 ng/ml) a secretory enterotoxin. All the secretagogues gave enhanced secretion compared with the fed by day 2 of starvation which increased considerably on day 3. Refeeding returned their secretion back to the fed level in the duodenum within 24 hours, in the jejunum within 48 hours but in the ileum their induced secretion on day 2 of refeeding was greater than that of the day 2 of refeeding was greater than that of day 3 starved and took until day 4 to return to the fed levels for behanechol and PGE2 and until day 5 for E. coli STa. This behaviour of rat small intestine showing even greater hypersecretion in the refed state than the starved mimics the human condition of alimentary induced diarrhoea where incautious feeding of starved humans induces severe, often lethal diarrhoea. The refed starved rat appears to be a possible model for this condition.
Diminished Airway Inflammation against Double-stranded RNA in Mast Cell-Deficient Mice
Authors: H. Nagase, K. Noda, M. Yamaguchi, H. Yoshihara, K. Yamamura, T. Yano, S. Ueki, H. Ishida, O. Ohbayashi, M. Nakajima, T. Adachi, K. Ohta
Journal: Journal of Allergy and Clinical Immunology (2007)
STUDIES ON PARATYPHOID C BACILLI ISOLATED IN CHINA
Authors: Carl Tenbroeck, C. P. Li, H. Yü
Journal: The Journal of Experimental Medicine (1931)

A brief clinical history of five patients from whom paratyphoid C was isolated and a description of the cultures are given. It is pointed out that the purely non-specific forms are more nearly related to the hog cholera bacillus than are those containing both specific and non-specific forms.
Driving and dish-washing: Failure of the correspondence metaphor for memory
Authors: Keith S. Karn, Gregory J. Zelinsky
Journal: Behavioral and Brain Sciences (1996)

Abstract Koriat &amp; Goldsmith restrict their definition of memory to “being about some past event,” which causes them to ignore the most common use of memory: everyday visual-motor tasks. New techniques make it possible to study memory in the context of these natural tasks with which memory is so tightly coupled. Memory can be more fully understood in the context of these actions.
Simplified Assessment of Pituitary-Adrenal Reserve
Authors: RICHARD F. SPARK
Journal: Annals of Internal Medicine (1971)

The metyrapone test has been improved by specific measurement of plasma 11-deoxycortisol. This simplified method measures 11-deoxycortisol and cortisol in a sample of 0.1 ml of plasma after a standard dose of metyrapone. In normal patients, after metyrapone ingestion, plasma 11-deoxycortisol rises from a base line of 0.8 ± 0.8 µg/100 ml to 16.8 ± 4.4 µg/100 ml, and plasma cortisol falls from 13.5 ± 5.1 µg/100 ml to 3.3 ± 2.8 µg/100 ml. After metyrapone 11-deoxycortisol is reduced only in adrenocorticotrophin (ACTH) deficiency. Patients with hypopituitarism or chronic corticoid therapy and 9 of 12 acromegalics had subnormal levels. Patients with the "empty sella" syndrome or trophic hormone deficiency other than ACTH had normal levels. In primary hypothyroidism postmetyrapone 11-deoxycortisol is significantly greater than in normals. This difference is thought to be caused by delayed metabolic clearance of the steroid. Simultaneous measurement of serum cortisol affords an internal standard for the degree of 11-hydroxylation block achieved by the amount of administered metyrapone.
Response to Fraser
Authors: Giorgio Mello, Elena Parretti, Riccardo Cioni
Journal: Diabetes Care (2002)

In relation to our recent paper (1) on third trimester glucose levels in nondiabetic pregnant women, Dr. Fraser (2) reports some data on glucose profiles from nondiabetic nonobese pregnant women in the third trimester. We believe that these data are interesting first because there are few contributions on this topic and second because Dr. Fraser’s study relies on glucose profiles consisting of 17 determinations per day. However, there are some important differences in the two studies. Our study involved 51 pregnant women undergoing home …