tbuckley/cabot-search huggingface dataset:
Circulating tumour cells go green
Authors: Robert M Hoffman
Journal: Gut (2014)

Circulating tumour cells (CTCs) are being used for the prediction of disease progression and drug sensitivity for various types of cancers. Current CTC isolation depends on epithelial cell surface proteins which can therefore miss CTCs that are non-epithelial.

Shigeyasu et al 1 describe technology to capture, sort and characterise epithelial and non-epithelial CTCs using a green fluorescent protein (GFP)-expressing attenuated adenovirus, in which the telomerase promoter regulates viral replication (OBP-401). OBP-401 selectively labels cancer cells, including CTCs, that express telomerase, which should include the vast majority of any type of cancer cell, since cancer cells in general express telomerase.2 Shigeyasu et al isolated CTCs from patients with colon cancer using their adenoviral GFP labelling technology but have not yet tested the technology on normal patients to demonstrate specificity. This study is published in Gut .1 

Shigeyasu et al 1 capture, image and characterise epithelial and mesenchymal CTCs in contrast to currently used methods which depend on the epithelial cells adhesion molecule (EpCAM) for capture. After sorting the GFP-expressing CTCs, direct sequencing or mutation-specific PCR detected various mutations in KRAS, BRAF and KIT genes in epithelial, mesenchymal or epithelial–mesenchymal transition-induced CTCs using model human cancer cell lines, as well as in blood samples from patients with colorectal cancer.

CTCs can have epithelial and mesenchymal characteristics. EpCAM-positive and EpCAM-negative CTCs from patients with breast cancer have been shown to have a high potential to metastasise to the lung and …
Lactate dehydrogenase A silencing in IDH mutant gliomas
Authors: Charles Chesnelong, Myriam M. Chaumeil, Michael D. Blough, Mohammad Al-Najjar, Owen D. Stechishin, Jennifer A. Chan, Russell O. Pieper, Sabrina M. Ronen, Samuel Weiss, H. Artee Luchman, J. Gregory Cairncross
Journal: Neuro-Oncology (2013)

Mutations of the isocitrate dehydrogenase 1 and 2 gene (IDH1/2) were initially thought to enhance cancer cell survival and proliferation by promoting the Warburg effect. However, recent experimental data have shown that production of 2-hydroxyglutarate by IDH mutant cells promotes hypoxia-inducible factor (HIF)1α degradation and, by doing so, may have unexpected metabolic effects. We used human glioma tissues and derived brain tumor stem cells (BTSCs) to study the expression of HIF1α target genes in IDH mutant (mt) and IDH wild-type (wt) tumors. Focusing thereafter on the major glycolytic enzyme, lactate dehydrogenase A (LDHA), we used standard molecular methods and pyrosequencing-based DNA methylation analysis to identify mechanisms by which LDHA expression was regulated in human gliomas. We found that HIF1α-responsive genes, including many essential for glycolysis (SLC2A1, PDK1, LDHA, SLC16A3), were underexpressed in IDHmt gliomas and/or derived BTSCs. We then demonstrated that LDHA was silenced in IDHmt derived BTSCs, including those that did not retain the mutant IDH1 allele (mIDHwt), matched BTSC xenografts, and parental glioma tissues. Silencing of LDHA was associated with increased methylation of the LDHA promoter, as was ectopic expression of mutant IDH1 in immortalized human astrocytes. Furthermore, in a search of The Cancer Genome Atlas, we found low expression and high methylation of LDHA in IDHmt glioblastomas. To our knowledge, this is the first demonstration of downregulation of LDHA in cancer. Although unexpected findings, silencing of LDHA and downregulation of several other glycolysis essential genes raise the intriguing possibility that IDHmt gliomas have limited glycolytic capacity, which may contribute to their slow growth and better prognosis.
The Potential Relevance of Cytokines to Ovarian Physiology: The Emerging Role of Resident Ovarian Cells of the White Blood Cell Series
Authors: ELI Y. ADASHI
Journal: Endocrine Reviews (1990)

ELUCIDATING the secrets of intraovarian intercellular communication constitutes a central area of investigation. Whereas most attention has been directed thus far at the somatic cellular components of the ovary, the potential role(s) and relative importance of resident ovarian white blood cell types have received relatively limited attention. Efforts are currently underway to reconcile traditional ovarian physiology with observations relevant to intraovarian components of the white blood cell series. In so doing, the already formidable task of analyzing intraovarian interactions stands to be further complicated. In many ways, the paradigms explored at the level of the ovary have broad implications for endocrinology, in general, in that similar phenomena are likely to be operational in other highly regulated systems. Although the present scientific literature may only provide limited information as it pertains to resident ovarian white blood cell types, the mere implications of these relatively new developments appear worthy of further discussion.
Intravenous Iron
Authors: Tilman B. Dru[Combining Diaeresis]eke, Ziad A. Massy
Journal: Journal of the American Society of Nephrology (2005)

Anemia is associated with poor cardiovascular and global outcome in patients with chronic kidney disease (CKD) ([1][1]). The correction of anemia requires epoetin in most instances. This in turn generally requires intravenous iron supplementation to avoid iron-deficiency and to achieve optimal
Paradoxical Vessel Remodeling of the Proximal Segment of the Left Anterior Descending Artery Predicts Long-Term Mortality After Heart Transplantation
Authors: Kozo Okada, Hideki Kitahara, Hyoung-Mo Yang, Shigemitsu Tanaka, Yuhei Kobayashi, Takumi Kimura, Helen Luikart, Paul G Yock, Alan C Yeung, Hannah A Valantine, Peter J Fitzgerald, Kiran K Khush, Yasuhiro Honda, William F Fearon
Journal: JACC Heart Failure (2015)
Homocysteine, a marker of cardiovascular disease risk, is markedly elevated in patients with gout: Table 1
Authors: Ole Slot
Journal: Annals of the Rheumatic Diseases (2012)

Homocysteine (Hcy) is an amino acid formed by demethylation of methionine. Impaired renal function, enzymatic polymorphisms, and low levels of B-group vitamins dispose to hyperhomocysteinaemia (HHcy).1 ,2 HHcy as well as hyperurecaemia induce reactive oxygen species and impair endothelial function1 ,3 and are associated with increased risk of cardiovascular disease (CVD).1–4 Hcy and urate possibly have additive effects on the endothelial function.5

Studies in normal populations have shown positive correlations between p-Hcy and p-urate,6 ,7 but reports on the prevalence of HHcy in gout patients have shown conflicting results.8–10

To study the prevalence of HHcy in gout—133 …
Expression Pattern of Connexin Gene Products at the Early Developmental Stages of the Mouse Cardiovascular System
Authors: Bruno Delorme, Edgar Dahl, Thérèse Jarry-Guichard, Jean-Paul Briand, Klaus Willecke, Daniel Gros, Magali Théveniau-Ruissy
Journal: Circulation Research (1997)

The synchronized contraction of myocytes in cardiac muscle requires the structural and functional integrity of the gap junctions present between these cells. Gap junctions are clusters of intercellular channels formed by transmembrane proteins of the connexin (Cx) family. Products of several Cx genes have been identified in the mammalian heart (eg, Cx45, Cx43, Cx40, and Cx37), and their expression was shown to be regulated during the development of the myocardium. Cx43, Cx40, and Cx45 are components of myocyte gap junctions, and it has also been demonstrated that Cx40 was expressed in the endothelial cells of the blood vessels. The aim of the present work was to investigate the expression and regulation of Cx40, Cx43, and Cx37 during the early stages of mouse heart maturation, between 8.5 days post coitum (dpc), when the first rhythmic contractions appear, and 14.5 dpc, when the four-chambered heart is almost completed. At 8.5 dpc, only the reverse-transcriptase polymerase chain reaction technique has allowed identification of Cx43, Cx40, and Cx37 gene transcripts in mouse heart, suggesting a very low activity level of these genes. From 9.5 dpc, all three transcripts became detectable in whole-mount in situ-hybridized embryos, and the most obvious result was the labeling of the vascular system with Cx40 and Cx37 anti-sense riboprobes. Cx40 and Cx37 gene products (transcript and/or protein) were demonstrated to be expressed in the vascular endothelial cells at all stages examined. By contrast, only Cx37 gene products were found in the endothelial cells of the endocardium. In heart, Cx37 was expressed exclusively in these cells, which rules out any direct involvement of this Cx in the propagation of electrical activity between myocytes and the synchronization of contractions. Between 9.5 and 11.5 dpc, Cx40 gene activation in myocytes was demonstrated to proceed according to a caudorostral gradient involving first the primitive atrium and the common ventricular chamber (9.5 dpc) and then the right ventricle (11.5 dpc). During this period of heart morphogenesis, there is clearly a temporary and asymmetrical regionalization of the Cx40 gene expression that is superimposed on the functional regionalization. In addition, comparison of Cx40 and Cx43 distribution at the above developmental stages has shown that these Cxs have overlapping (left ventricle) or complementary (atrial tissue and right ventricle) expression patterns.
Is multidrug-resistant tuberculosis on the rise in Mozambique? Results of a national drug resistance survey
Authors: P. Samo Gudo, Z. Cuna, E. Coelho, S. Maungate, E. Borroni, P. Miotto, S. Ahmadova, M. Brouwer, G.B. Migliori, M. Zignol, D.M. Cirillo
Journal: European Respiratory Journal (2011)

takes place only once the tubes are in the laboratory.If we consider only the samples sent from regional or remote sources, the rate of indeterminate test result is still very low (one (0.3%) out of 317).The use of T-Cell Xtend TM for all samples shipped overnight is likely to have had a beneficial effect on older samples.The cold weather conditions had no influence on the rate of indeterminate results (all samples were sent and processed in winter).The number of tests performed in very young or very old patients being small, we cannot assess the rate of indeterminate in these population groups.The slightly higher rate of positivity in samples referred from Vaud county (17% versus 10% in other groups) can be explained since these samples were mostly from recent immigrants from countries with a high prevalence of tuberculosis, whereas the samples from the city or from remote places were more often taken for contact tracing investigations where the rate of infection may be expected to be lower.In conclusion, these results demonstrate that the use of lithium heparinate blood collection tubes for all samples and T-Cell Xtend TM for samples shipped overnight allows the processing of samples from all over Switzerland while maintaining the rate of indeterminate test results at a very low level in spite of longer travel time (8-36 h).In our experience, the only indeterminate test results are observed in patients with some immune abnormality and do not represent a laboratory failure.
PROSTAGLANDINS AND CANCER
Authors: D Wang
Journal: Gut (2005)

Chemoprevention has been considered as a possible approach for cancer prevention. A significant effort has been made in the development of novel drugs for both cancer prevention and treatment over the past decade. Recent epidemiological studies and clinical trials indicate that long term use of aspirin and similar agents, also called non-steroidal anti-inflammatory drugs (NSAIDs), can decrease the incidence of certain malignancies, including colorectal, oesophageal, breast, lung, and bladder cancers. The best known targets of NSAIDs are cyclooxygenase (COX) enzymes, which convert arachidonic acid to prostaglandins (PGs) and thromboxane. COX-2 derived prostaglandin E(2)(PGE(2)) can promote tumour growth by binding its receptors and activating signalling pathways which control cell proliferation, migration, apoptosis, and/or angiogenesis. However, the prolonged use of high dosages of COX-2 selective inhibitors (COXIBs) is associated with unacceptable cardiovascular side effects. Thus it is crucial to develop more effective chemopreventive agents with minimal toxicity. Recent efforts to identify the molecular mechanisms by which PGE(2) promotes tumour growth and metastasis may provide opportunities for the development of safer strategies for cancer prevention and treatment.
The molecular targets of approved treatments for pulmonary arterial hypertension
Authors: Marc Humbert, Hossein-Ardeschir Ghofrani
Journal: Thorax (2015)

Until recently, three classes of medical therapy were available for the treatment of pulmonary arterial hypertension (PAH)—prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 (PDE5) inhibitors. With the approval of the soluble guanylate cyclase stimulator riociguat, an additional drug class has become available targeting a distinct molecular target in the same pathway as PDE5 inhibitors. Treatment recommendations currently include the use of all four drug classes to treat PAH, but there is a lack of comparative data for these therapies. Therefore, an understanding of the mechanistic differences between these agents is critical when making treatment decisions. Combination therapy is often used to treat PAH and it is therefore important that physicians understand how the modes of action of these drugs may interact to work as complementary partners, or potentially with unwanted consequences. Furthermore, different patient phenotypes mean that patients respond differently to treatment; while a certain monotherapy may be adequate for some patients, for others it will be important to consider alternating or combining compounds with different molecular targets. This review describes how the four currently approved drug classes target the complex pathobiology of PAH and will consider the distinct target molecules of each drug class, their modes of action, and review the pivotal clinical trial data supporting their use. It will also discuss the rationale for combining drugs (or not) from the different classes, and review the clinical data from studies on combination therapy.
Anthrolysin O and Other Gram-positive Cytolysins Are Toll-like Receptor 4 Agonists
Authors: Jin Mo Park, Vincent H. Ng, Shin Maeda, Richard F. Rest, Michael Karin
Journal: The Journal of Experimental Medicine (2004)

Exposure of bone marrow–derived macrophages (BMDMs) to low concentrations of Bacillus anthracis lethal toxin (LT), whose catalytic subunit is lethal factor (LF), results in induction of a robust apoptotic response dependent on activation of Toll-like receptor (TLR)4. A similar TLR4-dependent apoptotic response is observed when BMDMs are infected with live B. anthracis (Sterne strain). However, TLR4 is considered to be a specific signaling receptor for lipopolysaccharide (LPS), a typical product of gram-negative bacteria, whereas B. anthracis is gram-positive. To understand how B. anthracis can activate TLR4, we analyzed its culture supernatants and found them to contain a potent TLR4-stimulating activity that can also induce apoptosis in macrophages in which the antiapoptotic p38 MAP kinase (whose activation is prevented by LF) was inhibited. Purification of this activity suggested it consists of anthrolysin O (ALO), a member of the cholesterol-dependent cytolysin (CDC) family. We show that recombinant ALO can activate TLR4 in a manner independent of LPS contamination and, together with LT, can induce macrophage apoptosis. We also provide genetic evidence that ALO is required for induction of macrophage apoptosis in response to infection with live B. anthracis and that other CDC family members share the ability to activate TLR4.
Prospective Study of Pathogen Burden and Risk of Myocardial Infarction or Death
Authors: Jianhui Zhu, F. Javier Nieto, Benjamin D. Horne, Jeffrey L. Anderson, Joseph B. Muhlestein, Stephen E. Epstein
Journal: Circulation (2001)

We previously demonstrated that the risk of coronary artery disease (CAD) increased in relation to the number of pathogens (the "pathogen burden") in a cross-sectional study. In the present prospective study with a different patient cohort, we evaluated the effect of pathogen burden on the risk of myocardial infarction (MI) or death among CAD patients.IgG antibodies to cytomegalovirus (CMV), hepatitis A virus (HAV), herpes simplex virus type 1 (HSV1), HSV type 2 (HSV2), Chlamydia pneumoniae and Helicobacter pylori, and C-reactive protein (CRP) levels were tested in baseline blood samples from 890 patients who had significant CAD on angiography. The mean follow-up period was 3 years. The baseline prevalence of antibodies directed against CMV, HAV, HSV1, or HSV2, but not C pneumoniae and H pylori, was significantly higher among patients who subsequently developed MI or death than among control subjects. After adjustment for traditional risk factors, number of diseased vessels, and clinical presentation, relative hazards (95% confidence limits) for MI or death were 2.0 (1. 4 to 3.2) for CMV, 1.6 (1.1 to 2.3) for HAV, and 1.5 (1.0 to 2.2) for HSV2. Increasing pathogen burden was significantly associated with increasing risk of MI or death in a dose-response fashion. Adjusted relative hazards of MI or death associated with pathogen burden were significant among individuals with low or high CRP levels.The results suggest that infection plays an important role in incident MI or death and that the risk posed by infection is independently related to the pathogen burden.
The pulmonary physician in critical care 3: Critical care management of community acquired pneumonia
Authors: S V Baudouin
Journal: Thorax (2002)

Severe community acquired pneumonia carries a high mortality. Early recognition of the severity of the illness, rapid and appropriate resuscitation, targeted antibiotic treatment, and the critical care support of multiple failing organ systems are all important in this group of patients. Only by improving all these aspects of care is it likely that survival will increase.
STREPTOCOCCAL NUCLEASES
Authors: Lewis W. Wannamaker, Walid Yasmineh
Journal: The Journal of Experimental Medicine (1967)

Streptococcal DNAse C is more resistant to heat inactivation than the A or B enzyme. DNAses A and C are indifferent to the bacterial ribonucleic acid inhibitor whereas the B enzyme is markedly inhibited. Prolonged digestion with relatively large amounts of DNAse B results in chemical and biological destruction of the inhibitor. Ribonuclease as well as deoxyribonuclease activity is associated with the B enzyme. Both activities require divalent cations and both are inhibited by bacterial ribonucleic acid. The ratios of the two activities are constant in various preparations and after partial heat inactivation. Mutual inhibition of the two activities can be demonstrated in mixed substrate systems. The evidence presented is consistent with the view that the B enzyme is a single nuclease which can attack both deoxyribonucleic and ribonucleic acids.
Monocyte chemotactic protein 3 is a homing factor for circulating angiogenic cells
Authors: Mélanie Bousquenaud, Chantal Schwartz, Frédérique Léonard, Magali Rolland-Turner, Daniel Wagner, Yvan Devaux
Journal: Cardiovascular Research (2012)

Circulating angiogenic cells (CAC) participate in cardiac repair. CAC recruitment to the ischaemic heart is mainly induced by the chemokine (C–X–C motif) receptor 4 (CXCR4)/stromal-cell derived factor-1α axis. However, CAC mobilization is only partly prevented by CXCR4 blockade, indicating that other mechanisms are involved. Since the expression of monocyte chemotactic protein 3 (MCP3) is increased in ischaemic hearts, we hypothesized that it may participate in CAC mobilization. CAC were obtained from peripheral blood mononuclear cells of healthy volunteers. In vitro migration of CAC was concentration-dependently increased by recombinant MCP3 (one-fold increase, P= 0.001), and this effect was inhibited by antibodies neutralizing the chemokine (C–C motif) receptor 1 (CCR1). CCR1 expression at the surface of CAC was confirmed by flow cytometry. Conditioned medium from heparan sulfate-activated macrophages, which contained MCP3, induced the migration of CAC (one-fold increase, P= 0.01). This increase was partly inhibited by CCR1 antibodies. The migration of CAC was also stimulated by macrophage inflammatory protein 3β. This effect was blocked by CCR7 antibodies and was of lower magnitude than that of MCP3. MCP3 induced the formation of blood vessels in Matrigel plugs implanted in mice (1.5-fold increase, P< 0.001). This effect was abrogated by anti-CCR1 antibodies. This study shows that MCP3 stimulates the migration of CAC and angiogenesis, suggesting that MCP3 may be useful to improve cardiac repair.
THE USE OF PSYCHOTROPIC DRUGS IN THE REHABILITATION OF SEX-DEVIATED CRIMINALS
Authors: RUDOLPH A. BUKI
Journal: American Journal of Psychiatry (1964)

Combinations of 25 mg. or 10 mg. amitriptyline and 4, 2, or 1 mg. perphenazine, 3 or 4 times daily, were administered to 40 hospitalized adult males with sociopathic personality characterized by sexual deviation. The treatment period ranged between one and 5 months. These patients also received group psychotherapy. Results of treatment were graded as satisfactory in 15 patients who can now be considered for release, promising in 16 patients who were greatly improved but who require additional hospitalization, and unsatisfactory in 9 patients who showed no appreciable change. Mild side effects occurred in most patients during the first few days of treatment but these usually disappeared spontaneously without reduction of dosage. Laboratory studies revealed no variations from the pretreatment values. This combination of an antidepressant and a tranquilizer was of considerable value in the treatment of agitated depression, anxiety, and aggressiveness in severely neurotic patients. The drugs enabled these patients to function better within the hospital community and to become more accessible to psychotherapy which offers the only hope of permanent cure.
The association between smoking and the development of psoriatic arthritis among psoriasis patients
Authors: Lihi Eder, Sutha Shanmugarajah, Arane Thavaneswaran, Vinod Chandran, Cheryl F Rosen, Richard J Cook, Dafna D Gladman
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Aim</h3> To investigate the association between smoking and psoriatic arthritis (PsA) among patients with psoriasis and its interaction with the HLA-C*06 allele. <h3>Methods</h3> In this exploratory case–control study, smoking status was determined at the time of the diagnosis of arthritis for PsA patients and at their first study visit for psoriasis patients, when they were confirmed not to have PsA. The proportions of patients exposed to smoking were compared in patients with PsA to those with psoriasis alone. A logistic regression model was constructed to test the independent association of smoking and PsA after adjusting for potential confounders. The statistical interaction between HLA-C*06 and smoking was tested through a regression model. <h3>Results</h3> The proportions of current and past smokers were higher in the psoriasis group compared with the PsA group (30.2% vs 23.4% and 26.7% vs 22.3%, p=0.001, respectively). On multivariate analysis being a current smoker versus a lifetime non-smoker remained inversely associated with PsA (OR 0.57, p=0.002), while past smoker versus lifetime non-smoker status was no longer significant. In a subgroup analysis, smoking remained inversely associated with PsA only among patients who were HLA-C*06 negative. Regression analysis revealed that the interaction between smoking status (ever smoked vs lifetime non-smoker) and HLA-C*06 was statistically significant (p=0.01). <h3>Conclusion</h3> Smoking may be inversely associated with PsA among psoriasis patients. This association is not present among HLA-C*06-positive individuals.