tbuckley/cabot-search huggingface dataset:
Mesp1
Authors: Antoine Bondue, Cédric Blanpain
Journal: Circulation Research (2010)

In mammals, the heart arises from the differentiation of 2 sources of multipotent cardiovascular progenitors (MCPs). Different studies indicated that an evolutionary conserved transcriptional regulatory network controls cardiovascular development from flies to humans. Whereas in Drosophila, Tinman acts as a master regulator of cardiac development, the identification of such a master regulator in mammals remained elusive for a long time. In this review, we discuss the recent findings suggesting that Mesp1 acts as a key regulator of cardiovascular progenitors in vertebrates. Lineage tracing in mice demonstrated that Mesp1 represents the earliest marker of cardiovascular progenitors, tracing almost all the cells of the heart including derivatives of the primary and second heart fields. The inactivation of Mesp1/2 indicated that Mesp genes are essential for early cardiac mesoderm formation and MCP migration. Several recent studies have demonstrated that Mesp1 massively promotes cardiovascular differentiation during embryonic development and pluripotent stem cell differentiation and indicated that Mesp1 resides at the top of the cellular and transcriptional hierarchy that orchestrates MCP specification. In primitive chordates, Mesp also controls early cardiac progenitor specification and migration, suggesting that Mesp arises during chordate evolution to regulate the earliest step of cardiovascular development. Defining how Mesp1 regulates the earliest step of MCP specification and controls their migration is essential to understand the root of cardiovascular development and how the deregulation of these processes can lead to congenital heart diseases. In addition, these findings will be very useful to boost the production of cardiovascular cells for cellular therapy, drug and toxicity screening.
Novel Mitogenic Effect of Adenosine on Coronary Artery Smooth Muscle Cells
Authors: Jianzhong Shen, Stephen P. Halenda, Michael Sturek, Peter A. Wilden
Journal: Circulation Research (2005)

Adenosine is a vascular endothelial cell mitogen, but anti-mitogenic for aortic smooth muscle cells and fibroblasts when acting via the A2B adenosine receptor. However, we show that adenosine increases porcine coronary artery smooth muscle cell (CASMC) number, cellular DNA content, protein synthesis, and PCNA staining. RT-PCR analysis indicates that porcine CASMC express A1, A2A, A3, and barely detectable levels of A2B receptor mRNAs. The mitogenic effect of adenosine is mimicked by NECA, CCPA, and R-PIA, but not by CGS21680and 2-Cl-IB-MECA, and is inhibited by DPCPX, indicating a prominent role for the A1 receptor. This interpretation is supported by the finding that adenosine- and CCPA-induced DNA synthesis is significantly inhibited by pertussis toxin, but substantially potentiated by PD81723, an allosteric enhancer of the A1 receptor. When a cDNA encoding the porcine A1 receptor was cloned and expressed in COS-1 cells, A1 receptor pharmacology is confirmed. Anti-sense oligonucleotides to the cloned sequence dramatically suppress the mitogenic effect of adenosine and CCPA. Conversely, over-expression of the cloned A1 receptor in CASMC increases adenosine- and CCPA-induced DNA synthesis. Furthermore, stimulation with adenosine or CCPA of intact coronary arteries in an organ culture model of vascular disease increases cellular DNA synthesis, which was abolished by DPCPX. We conclude that adenosine acts as a novel mitogen in porcine CASMC that express the A1 adenosine receptor, possibly contributing to the development of coronary artery disease.
CpG Island Methylator Phenotype Predicts Progression of Malignant Melanoma
Authors: Atsushi Tanemura, Alicia M. Terando, Myung-Shin Sim, Anneke Q. van Hoesel, Michiel F.G. de Maat, Donald L. Morton, Dave S.B. Hoon
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The CpG island methylator phenotype (CIMP) may be associated with development of malignancy through coordinated inactivation of tumor suppressor and tumor-related genes (TRG) and methylation of multiple noncoding, methylated-in-tumor (MINT) loci. These epigenetic changes create a distinct CIMP pattern that has been linked to recurrence and survival in gastrointestinal cancers. Because epigenetic inactivation of TRGs also has been shown in malignant melanoma, we hypothesized the existence of a clinically significant CIMP in cutaneous melanoma progression. Experimental Design: The methylation status of the CpG island promoter region of TRGs related to melanoma pathophysiology (WIF1, TFPI2, RASSF1A, RARβ2, SOCS1, and GATA4) and a panel of MINT loci (MINT1, MINT2, MINT3, MINT12, MINT17, MINT25, and MINT31) in primary and metastatic tumors of different clinical stages (n = 122) was assessed. Results: Here, we show an increase in hypermethylation of the TRGs WIF1, TFPI2, RASSF1A, and SOCS1 with advancing clinical tumor stage. Furthermore, we find a significant positive association between the methylation status of MINT17, MINT31, and TRGs. The methylation status of MINT31 is associated with disease outcome in stage III melanoma. Conclusions: These findings show the significance of a CIMP pattern that is associated with advancing clinical stage of malignant melanoma. Future prospective large-scale studies may determine if CIMP-positive primary melanomas are at high risk of metastasis or recurrence.
Randomised controlled trial of adenine arabinoside 5'-monophosphate (ARA-AMP) in chronic hepatitis B virus infection.
Authors: I V Weller, A S Lok, A Mindel, P Karayiannis, S Galpin, J Monjardino, S Sherlock, H C Thomas
Journal: Gut (1985)

A randomised controlled trial was conducted in 29 HBV carriers who had been HBs and HBe antigen positive for more than six months. Fifteen patients were treated with ARA-AMP 10 mg/kg/day given as intramuscular injections 12 hours apart for five days followed by 5 mg/kg/day for 23 days. The 14 controls received no treatment. Serum HBV-DNA polymerase, and HBV-DNA decreased in all patients during therapy. Six treated patients lost serum HBV-DNA polymerase, HBV-DNA and HBeAg, HBsAg concentrations decreased, and five developed anti-HBe. One of these six patients lost HBsAg and developed anti-HBs. No such changes were observed in the control group over a similar 18 month period of observation. A four week course of ARA-AMP inhibits HBV replication and in a significant minority of patients this is long lasting and is associated with a reduced level of inflammatory activity in the liver.
Chondromatous Hamartoma of the Lung
Authors: C. J. Carlsen, W. Kiaer
Journal: Thorax (1950)

Chondromatous hamartoma of the lung is a pulmonary "tumour" which, as a result of the progress made in thoracic surgery during the last decade, is now being reported as not particularly uncommon.Since a lack of familiarity with this tumour may give rise to clinical as well as to pathological errors, it seems justified to describe it in some detail.At the same time we will report our experience based on nine cases.The term hamartoma (&uocp'r&uet =to fail or to err) was first used in 1904 by the German pathologist Albrecht, who defined it as a tumour-like malformation of an organ, made up of the normal elements of that organ, but with abnormal mixing and quantity of the components and perhaps an abnormal degree of differentiation.The hamartomata originally described by Albrecht were cavernomata of the liver, cavernomata of the spleen, and tuberous fibromata of the medullary substance of the kidney.Goldsworthy (1934) andJaeger (1934) were the first to realize that the previously reported " chondromata " of the lung were not pure chondromata, but that they should be classified as hamartomas.The word " chondromatous" designated that cartilage was the dominant element.The first reports of hamartomata of the lung were published in 1845 and 1847, when Lebert and Bleu described one typical case each.Both called them primary chondromata, but they realized that the growths did not look like typical chondro- mata.All the subsequently reported primary " chondromata " of the lung parenchyma-for which we have been able to procure the original reports with adequate histological descriptions-have proved to be hamartomata.Cornil and Ranvier (1884) denied the existence of ordinary chondromata in the lung parenchyma, but an exception is that reported by Edling (1938), who has kindly lent us his preparations.In this instance none of the sections showed changes suggesting chondromatous hamartoma with certainty, and the histological appearance does not differ from that of a chondroma.More than 100 hamartomata of the lung have been reported so far, and all show a typical histological picture with slight variations which correspond to the findings in our nine cases.Hamartoma may occur anywhere in the lung; in the hilus (sometimes in relation to the large bronchi); in peripheral or subpleural situations, being sometimes attached to the pleura by a pedicle (Matras, 1929;Jaeger, 1934).They may in rare cases be encountered in the form of endobronchial polypi, but in this site they are not as common as true chondromata.The size may vary within wide limits, from that of a hemp-seed (McDonald, Harrington, and Clagett, 1945) to a mass occupying the entire pleural cavity (Busse, 4 Publication has been delayed because of our difficulty in importing radiographs from abroad.-ED.
Improving Active Compression-Decompression Cardiopulmonary Resuscitation With an Inspiratory Impedance Valve
Authors: Keith G. Lurie, Paul Coffeen, Jeffrey Shultz, Scott McKnite, Barry Detloff, Kate Mulligan
Journal: Circulation (1995)

Background Active compression-decompression (ACD) cardiopulmonary resuscitation (CPR) has recently been demonstrated to provide significantly more blood flow to vital organs during cardiac arrest. To further enhance the effectiveness of this technique, we tested the hypothesis that intermittent impedance to inspiratory gas exchange during the decompression phase of ACD CPR enhances vital organ blood flow. Methods and Results ACD CPR was performed with a pneumatically driven automated compression-decompression device in a porcine model of ventricular fibrillation (VF). Nine pigs were randomized to receive ACD CPR alone, while 8 pigs received ACD CPR plus intermittent impedance to inspiratory gas exchange with a threshold valve set to 40 cm H 2 O. Results comparing 2 minutes of ACD CPR alone versus ACD CPR with the inspiratory impedance threshold valve (ITV) revealed significantly higher mean (±SEM) coronary perfusion pressures (diastolic aortic minus diastolic right atrial pressures) in the ITV (31.0±2.3 mm Hg) group versus with ACD CPR alone (21±3.6 mm Hg) ( P &lt;.05). Total left ventricular and cerebral blood flows, determined by radiolabeled microspheres, were 0.77±0.095 and 0.47±0.06 mL/min per gram, respectively, with ACD CPR plus the ITV versus 0.45±0.1 and 0.32±0.016 mL/min per gram, respectively, with ACD CPR alone ( P &lt;.05). Similar improvements in the ITV group were observed after 7 minutes of ACD CPR. After 16 minutes of VF and 13 minutes of ACD CPR, 6 of 8 pigs in the ITV group were successfully resuscitated with less than three successive 150-J shocks, whereas only 2 of 9 pigs with ACD CPR alone were resuscitated with equivalent energy levels ( P &lt;.02). With up to three additional and successive 200-J shocks, all pigs in the ITV group and 7 of 9 pigs with ACD CPR alone were resuscitated ( P =.18). Conclusions Intermittent impedance to inspiratory flow of respiratory gases during ACD CPR significantly improves coronary perfusion pressures and vital organ blood flow and lowers defibrillation energy requirements in a porcine model of VF.
DECIPHERING THE GENETIC BASIS OF SPEECH AND LANGUAGE DISORDERS
Authors: Simon E. Fisher, Cecilia S.L. Lai, Anthony P. Monaco
Journal: Annual Review of Neuroscience (2003)

▪ Abstract A significant number of individuals have unexplained difficulties with acquiring normal speech and language, despite adequate intelligence and environmental stimulation. Although developmental disorders of speech and language are heritable, the genetic basis is likely to involve several, possibly many, different risk factors. Investigations of a unique three-generation family showing monogenic inheritance of speech and language deficits led to the isolation of the first such gene on chromosome 7, which encodes a transcription factor known as FOXP2. Disruption of this gene causes a rare severe speech and language disorder but does not appear to be involved in more common forms of language impairment. Recent genome-wide scans have identified at least four chromosomal regions that may harbor genes influencing the latter, on chromosomes 2, 13, 16, and 19. The molecular genetic approach has potential for dissecting neurological pathways underlying speech and language disorders, but such investigations are only just beginning.
How To Give a Cell a Heart Attack
Authors: Michael D. Stern
Journal: Circulation Research (2006)

ardiac ischemia is the leading killer in the developed world.It is a complex pathology, with myriad factors-electrical, chemical, metabolic, mechanical, and immunological-manifesting on scales ranging from the molecular to the whole organism.So it is not surprising that, despite decades of study, we cannot succinctly identify "the" injury that is central to this disorder.But, ultimately, the fate of millions of people comes down to what happens to a cardiac myocyte when it is deprived of its blood supply.It can die-by necrosis, apoptosis, or mechanical self-destruction.It isn't always easy to decide when it is "dead."It can lose its contractile function, its relaxation function, and/or its electrical function.It can hibernate and, if provoked by earlier nonlethal episodes of ischemia, it can "learn" to protect itself on time scales from minutes to weeks.It would make sense, then, to study cardiac ischemia at the single-cell level.This turns out to be surprisingly difficult to do.The isolated cardiac myocyte in the laboratory is normally bathed in an ocean of moving fluid.In contrast, even under the best of conditions, the myocyte in its native habitat is secluded from its sources of nutrition.The pO 2 at the myocyte surface is normally no more than 20 torr.The extracellular space, in which the cell must dispose of its metabolic waste, is tiny.In the heart, it is very easy to make a myocyte ischemic.In a petri dish, it is almost impossible.When studying cardiac myocytes on a patch-clamp apparatus, it is customary to bubble the perfusing solution with oxygen.If you use nitrogen instead, you will see no change in physiology!To make matters worse, present-day methods of measuring the electrical activity of a myocyte require that it be freely accessible from above by a long micropipette.Some 18 years ago, Howard Silverman and I developed a crude fix for this problem. 1 By establishing an upward laminar flow of a heavier-than-air inert gas (argon is the only practical choice) in a conical well, it was possible to exclude oxygen from cells in a dish at the bottom of the well, even while allowing open access above for instrumentation.The practical problems didn't end there.It was necessary to perfuse the dish with anoxic buffer.Because all plastics are permeable to oxygen (the best is polyvinylidene chloride-Saran, with PVC; Tygon, a close second), it was necessary to
DR-01 * NOVEL PEDIATRIC EPENDYMOMA MODELS SHOW HIGH CHEMOTHERAPY-RESISTANCE AND HYPERACTIVATION OF ABC-TRANSPORTERS
Authors: J. Gojo, D. Lotsch, C. Pirker, A. Araki, A. Peyrl, M. Chocholous, H. Stefanits, T. Czech, C. Haberler, I. Slavc, W. Berger
Journal: Neuro-Oncology (2014)

Malignant ependymoma is one of the most frequent CNS-tumors in childhood characterized by a poor outcome owing to low effects of chemotherapy accompanied by high rates of recurrence. However, the underlying mechanisms are still poorly understood. Aim of this study is to investigate the role of ABC-transporters - a well-known resistance mechanism of cancer cells - in primary and recurrent ependymomas. In a collaborative approach primary adherent and neurospheroid cell cultures of four tumors were established of which two developed stable cell lines. The impact of ABC-transporters on chemotherapy-resistance of pediatric ependymoma cells was then analyzed by cytotoxicity assays, Western blot, Microarray and FACS. All tested cells were highly resistant against etoposide and vincristine, both well-known substrates of ABC-transporters. In contrast, treatment with either cisplatin or temozolomide was more effective. With respect to primary versus recurrent as well as supratentorial versus infratentorial tumors no significant difference in chemosensitivity was observed. The analysis of ABC-transporter expression revealed that ABCG2 was highly expressed throughout the cell panel at both protein and RNA level. Moreover, ependymoma cells exhibited the same ABCG2 activity as A549 cells, a well described ABC-transporter resistance model. In contrast to ABCG2, expression of ABCB1 and ABCC1 differed among the tested cells. Combination of chemotherapeutics with the ABC-transporter inhibitors imatinib, erlotinib, cyclosporine A and verapamil had only minor effects on cytotoxic response of ependymoma cells. Interestingly, a synergistic effect of etoposide and vincristine with erlotinib was seen. Taken together primary as well as recurrent ependymomas are highly resistant against classical chemotherapeutics. Furthermore, we could show that ependymoma cells express highly active ABC-transporters. This fact might also have an impact on chemotherapy-resistance towards the therapeutic regimens currently applied in ependymoma therapy. The cellular mechanisms underlying these results will be investigated in further studies.
Color-order systems: A guide for the perplexed
Authors: C. L. Hardin
Journal: Behavioral and Brain Sciences (1997)

If, as Saunders &amp; van Brakel assert, hue, lightness, and saturation characterize artificial color spaces and not the colors of everyday life, one would expect those color spaces to have limited relevance to our understanding of color phenomena and to be of little practical application. This is not the case. Although people perceive these and equivalent color dimensions holistically rather than analytically, they are able to use such triples to categorize the colors of their environment.
Model-Guided Determination of Maximum Tolerated Dose in Phase I Clinical Trials: Evidence for Increased Precision
Authors: R. Mick, M. J. Ratain
Journal: JNCI Journal of the National Cancer Institute (1993)

Background : A widely used phase I design in clinical trials of chemotherapy for cancer and for AIDS (acquired immunodeficiency syndrome) allows for dose escalation in cohorts of three to six patients. Escalation continues until a predefined percentage of patients experience unacceptable toxic effects at a given dose level. A safe and maximum tolerated dose (MTD) for phase II study is then determined. This standard phase I study design has serious inadequacies. MTD is not a model-based estimate of the true dose that would yield the targeted dose-limiting toxicity rate. Moreover, this simplistic study design allows some patients in the phase I study to be treated at doses unlikely to have therapeutic efficacy. Purpose : We constructed a novel quantitative assessment design that repetitively evaluates accumulating dose-toxicity data by repeatedly fitting and updating a pharmacodynamic model after small cohorts of patients are treated. The goal was to more accurately estimate the MTD. Methods : One hundred phase I studies were simulated by both the standard and quantitative assessment phase I designs. We compared determination of MTD, frequency of grade 0 leukopenia (no toxicity), and study size in the studies simulated using the standard design with those in the studies simulated using the quantitative assessment design. Results : The median MTD determined from the 100 studies was nearly identical for the two designs: 100 and 95 mg/m 2 per day for standard and quantitative assessment designs, respectively. However, the interstudy variation in the MTD was decreased in the quantitative assessment design. Moreover, the study size was significantly reduced ( P <.0001), and the median percentage of patients treated at subtoxic doses (no leukopenia) was significantly lower for the quantitative assessment design (44% versus 48%; P <.0001). Conclusion : Our results show clear evidence that a phase I study design using dose and toxicity data in a repetitive and quantitative manner can identify the MTD with more accuracy than the standard design. Implications : New approaches must be explored to improve our ability to identify the optimal dose for phase II studies of chemotherapy for cancer and for AIDS. There is evidence that the quantitative assessment design will identify the MTD with fewer patients, more precision, and fewer patients exposed to suboptimal doses. [J Natl Cancer Inst 85:217–223, 1993]
CD36 Mediates the Cardiovascular Action of Growth Hormone-Releasing Peptides in the Heart
Authors: V. Bodart, M. Febbraio, A. Demers, N. McNicoll, P. Pohankova, A. Perreault, T. Sejlitz, E. Escher, R.L. Silverstein, D. Lamontagne, H. Ong
Journal: Circulation Research (2002)

Growth hormone-releasing peptides (GHRPs) are known as potent growth hormone secretagogues whose actions are mediated by the ghrelin receptor, a G protein-coupled receptor cloned from pituitary libraries. Hexarelin, a hexapeptide of the GHRP family, has reported cardiovascular activity. To identify the molecular target mediating this activity, rat cardiac membranes were labeled with a radioactive photoactivatable derivative of hexarelin and purified using lectin affinity chromatography and preparative gel electrophoresis. A binding protein of M(r) 84 000 was identified. The N-terminal sequence determination of the deglycosylated protein was identical to rat CD36, a multifunctional glycoprotein, which was expressed in cardiomyocytes and microvascular endothelial cells. Activation of CD36 in perfused hearts by hexarelin was shown to elicit an increase in coronary perfusion pressure in a dose-dependent manner. This effect was lacking in hearts from CD36-null mice and hearts from spontaneous hypertensive rats genetically deficient in CD36. The coronary vasoconstrictive response correlated with expression of CD36 as assessed by immunoblotting and covalent binding with hexarelin. These data suggest that CD36 may mediate the coronary vasospasm seen in hypercholesterolemia and atherosclerosis.