tbuckley/cabot-search huggingface dataset:
Epigenetic Mechanisms of Depression and Antidepressant Action
Authors: Vincent Vialou, Jian Feng, Alfred J. Robison, Eric J. Nestler
Journal: The Annual Review of Pharmacology and Toxicology (2011)

Epigenetic mechanisms, which control chromatin structure and function, mediate changes in gene expression that occur in response to diverse stimuli. Recent research has established that environmental events and behavioral experience induce epigenetic changes at particular gene loci and that these changes help shape neuronal plasticity and function and hence behavior. Some of these changes can be stable and can even persist for a lifetime. Increasing evidence supports the hypothesis that aberrations in chromatin remodeling and subsequent effects on gene expression within limbic brain regions contribute to the pathogenesis of depression and other stress-related disorders such as post-traumatic stress disorder and other anxiety syndromes. Likewise, the gradually developing but persistent therapeutic effects of antidepressant medications may be achieved in part via epigenetic mechanisms. This review discusses recent advances in our understanding of the epigenetic regulation of stress-related disorders and focuses on three distinct aspects of stress-induced epigenetic pathology: the effects of stress and antidepressant treatment during adulthood, the lifelong effects of early-life stress on subsequent stress vulnerability, and the possible transgenerational transmission of stress-induced abnormalities.
A mutated HLA-A2 molecule recognized by autologous cytotoxic T lymphocytes on a human renal cell carcinoma.
Authors: D Brändle, F Brasseur, P Weynants, T Boon, B Van den Eynde
Journal: The Journal of Experimental Medicine (1996)

Many human tumor cells have been shown to express antigens that are recognized by autologous cytotoxic T lymphocytes (CTL) and the molecular nature of a number of melanoma antigens has been defined recently. Here we describe the characterization of an antigen recognized on a renal cell carcinoma by autologous CTL clones. This antigen is encoded by the HLA-A2 gene present in the tumor cells. The sequence of this gene differs from the HLA-A2 sequence found in autologous peripheral blood lymphocytes by a point mutation that results in an arginine to isoleucine exchange at residue 170, which is located on the alpha-helix of the alpha 2 domain. Transfection experiments with the normal and mutated HLA-A2 cDNA demonstrated that this amino acid replacement was responsible for the recognition of the HLA-A2 molecule expressed on the tumor cells. The mutant HLA-A2 gene was also detected in the original tumor tissue from the patient, excluding the possibility that the mutation had appeared in vitro. Thus, HLA class I molecules carrying a tumor-specific mutation can be involved in the recognition of tumor cells by autologous CTL.
BRAF inhibitor–associated ERK activation drives development of chronic lymphocytic leukemia
Authors: Niuscha Yaktapour, Frank Meiss, Justin Mastroianni, Thorsten Zenz, Hana Andrlova, Nimitha R. Mathew, Rainer Claus, Barbara Hutter, Stefan Fröhling, Benedikt Brors, Dietmar Pfeifer, Milena Pantic, Ingrid Bartsch, Timo S. Spehl, Philipp T. Meyer, Justus Duyster, Katja Zirlik, Tilman Brummer, Robert Zeiser
Journal: Journal of Clinical Investigation (2014)

Patients with BRAFV600E/K-driven melanoma respond to the BRAF inhibitor vemurafenib due to subsequent deactivation of the proliferative RAS/RAF/MEK/ERK pathway. In BRAF WT cells and those with mutations that activate or result in high levels of the BRAF activator RAS, BRAF inhibition can lead to ERK activation, resulting in tumorigenic transformation. We describe a patient with malignant melanoma who developed chronic lymphocytic leukemia (CLL) in the absence of RAS mutations during vemurafenib treatment. BRAF inhibition promoted patient CLL proliferation in culture and in murine xenografts and activated MEK/ERK in primary CLL cells from additional patients. BRAF inhibitor-driven ERK activity and CLL proliferation required B cell antigen receptor (BCR) activation, as inhibition of the BCR-proximal spleen tyrosine kinase (SYK) reversed ERK hyperactivation and proliferation of CLL cells from multiple patients, while inhibition of the BCR-distal Bruton tyrosine kinase had no effect. Additionally, the RAS-GTP/RAS ratio in primary CLL cells exposed to vemurafenib was reduced upon SYK inhibition. BRAF inhibition increased mortality and CLL expansion in mice harboring CLL xenografts; however, SYK or MEK inhibition prevented CLL proliferation and increased animal survival. Together, these results suggest that BRAF inhibitors promote B cell malignancies in the absence of obvious mutations in RAS or other receptor tyrosine kinases and provide a rationale for combined BRAF/MEK or BRAF/SYK inhibition.
Antimitogenic effects of HDL and APOE mediated by Cox-2–dependent IP activation
Authors: Devashish Kothapalli, Ilia Fuki, Kamilah Ali, Sheryl A. Stewart, Liang Zhao, Ron Yahil, David Kwiatkowski, Elizabeth A. Hawthorne, Garret A. FitzGerald, Michael C. Phillips, Sissel Lund-Katz, Ellen Puré, Daniel J. Rader, Richard K. Assoian
Journal: Journal of Clinical Investigation (2004)

HDL and its associated apo, APOE, inhibit S-phase entry of murine aortic smooth muscle cells. We report here that the antimitogenic effect of APOE maps to the N-terminal receptor–binding domain, that APOE and its N-terminal domain inhibit activation of the cyclin A promoter, and that these effects involve both pocket protein–dependent and independent pathways. These antimitogenic effects closely resemble those seen in response to activation of the prostacyclin receptor IP. Indeed, we found that HDL and APOE suppress aortic smooth muscle cell cycle progression by stimulating Cox-2 expression, leading to prostacyclin synthesis and an IP-dependent inhibition of the cyclin A gene. Similar results were detected in human aortic smooth muscle cells and in vivo using mice overexpressing APOE. Our results identify the Cox-2 gene as a target of APOE signaling, link HDL and APOE to IP action, and describe a potential new basis for the cardioprotective effect of HDL and APOE.
Label-Free Luminescent Mesoporous Silica Nanoparticles for Imaging and Drug Delivery
Authors: Hongmin Chen, Zipeng Zhen, Wei Tang, Trever Todd, Yen-Jun Chuang, Lianchun Wang, Zhengwei Pan, Jin Xie
Journal: Theranostics (2013)

We report herein a straightforward and label-free approach to prepare luminescent mesoporous silica nanoparticles. We found that calcination at 400 °C can grant mesoporous organosilica nanoparticles with strong fluorescence of great photo- and chemical stability. The luminescence is found to originate from the carbon dots generated from the calcination, rather than the defects in the silica matrix as was believed previously. The calcination does not impact the particles' abilities to load drugs and conjugate to biomolecules. In a proof-of-concept study, we demonstrated that doxorubicin (Dox) can be efficiently encapsulated into these fluorescent mesoporous silica nanoparticles. After coupled to c(RGDyK), the nanoconjugates can efficiently home to tumors through interactions with integrin αvβ3 overexpressed on the tumor vasculature. This calcination-induced luminescence is expected to find wide applications in silica-based drug delivery, nanoparticle coating, and immunofluorescence imaging.
Active Tamoxifen Metabolite Plasma Concentrations After Coadministration of Tamoxifen and the Selective Serotonin Reuptake Inhibitor Paroxetine
Authors: Vered Stearns, Michael D. Johnson, James M. Rae, Alan Morocho, Antonella Novielli, Pankaj Bhargava, Daniel F. Hayes, Zeruesenay Desta, David A. Flockhart
Journal: JNCI Journal of the National Cancer Institute (2003)

Tamoxifen, a selective estrogen receptor modulator (SERM), is converted to 4-hydroxy-tamoxifen and other active metabolites by cytochrome P450 (CYP) enzymes. Selective serotonin reuptake inhibitors (SSRIs), which are often prescribed to alleviate tamoxifen-associated hot flashes, can inhibit CYPs. In a prospective clinical trial, we tested the effects of coadministration of tamoxifen and the SSRI paroxetine, an inhibitor of CYP2D6, on tamoxifen metabolism.Tamoxifen and its metabolites were measured in the plasma of 12 women of known CYP2D6 genotype with breast cancer who were taking adjuvant tamoxifen before and after 4 weeks of coadministered paroxetine. We assessed the inhibitory activity of pure tamoxifen metabolites in an estradiol-stimulated MCF7 cell proliferation assay. To determine which CYP isoforms were involved in the metabolism of tamoxifen to specific metabolites, we used CYP isoform-specific inhibitors. All statistical tests were two-sided.We separated, purified, and identified the metabolite 4-hydroxy-N-desmethyl-tamoxifen, which we named endoxifen. Plasma concentrations of endoxifen statistically significantly decreased from a mean of 12.4 ng/mL before paroxetine coadministration to 5.5 ng/mL afterward (difference = 6.9 ng/mL, 95% confidence interval [CI] = 2.7 to 11.2 ng/mL) (P =.004). Endoxifen concentrations decreased by 64% (95% CI = 39% to 89%) in women with a wild-type CYP2D6 genotype but by only 24% (95% CI = 23% to 71%) in women with a variant CYP2D6 genotype (P =.03). Endoxifen and 4-hydroxy-tamoxifen inhibited estradiol-stimulated MCF7 cell proliferation with equal potency. In vitro, troleandomycin, an inhibitor of CYP3A4, inhibited the demethylation of tamoxifen to N-desmethyl-tamoxifen by 78% (95% CI = 65% to 91%), and quinidine, an inhibitor of CYP2D6, reduced the subsequent hydroxylation of N-desmethyl-tamoxifen to endoxifen by 79% (95% CI = 50% to 108%).Endoxifen is an active tamoxifen metabolite that is generated via CYP3A4-mediated N-demethylation and CYP2D6-mediated hydroxylation. Coadministration of paroxetine decreased the plasma concentration of endoxifen. Our data suggest that CYP2D6 genotype and drug interactions should be considered in women treated with tamoxifen.
Promoter methylation of IGFBP-3 and p53 expression in ovarian endometrioid carcinoma
Authors: Pao-Ling Torng, Ching-Wei Lin, Michael WY Chan, Hui-Wen Yang, Su-Cheng Huang, Chin-Tarng Lin
Journal: Molecular Cancer (2009)

Abstract Background Insulin-like growth factor binding protein (IGFBP-3) is an antiproliferative, pro-apoptotic and invasion suppressor protein which is transcriptionally regulated by p53. Promoter methylation has been linked to gene silencing and cancer progression. We studied the correlation between IGFBP-3 and p53 expression as well as IGFBP-3 promoter methylation in ovarian endometrioid carcinoma (OEC) by immunohistochemical staining and quantitative methylation-specific PCR (qMSP). Additionally, we assessed the molecular regulatory mechanism of wild type (wt) p53 on IGFBP-3 expression using two subclones of OEC, the OVTW59-P0 (low invasive) and P4 (high invasive) sublines. Results In 60 cases of OEC, 40.0% showed lower IGFBP-3 expression which was significantly correlated with higher IGFBP-3 promoter methylation. p53 overexpression was detected in 35.0% of OEC and was unrelated to clinical outcomes and IGFBP-3. By Kaplan-Meier analysis, patients with lower IGFBP-3, higher IGFBP-3 promoter methylation, and normal p53 were associated most significantly with lower survival rates. In OEC cell line, IGFBP-3 expression was correlated with IGFBP-3 promoter methylation. IGFBP-3 expression was restored after treatment with a DNA methy-transferase inhibitors (5-aza-deoxycytidine) and suppressed by a p53 inhibitor (pifithrin-α). The putative p53 regulatory sites on the promoter of IGFBP-3 were identified at -210, -206, -183 and -179 bases upstream of the transcription start site. Directed mutagenesis at these sites quantitatively reduced the transcription activity of IGFBP-3. Conclusion Our data suggests that IGFBP-3 silencing through IGFBP-3 promoter methylation in the absence of p53 overexpression is associated with cancer progression. These results support a potential role of IGFBP-3 methylation in the carcinogenesis of OEC.
Bronchial Carcinoma With Autovagotomy and Bezoar Formation
Authors: T. Noël K. Allan
Journal: JAMA (1977)

AUTOVAGOTOMY, except as a manifestation of diabetic autonomic neuropathy, is a rare occurrence. Esophageal carcinoma causing autovagotomy and gastric bezoar has been recorded.1The present communication concerns the association of bronchial carcinoma with autovagotomy, gastric outlet obstruction, and bezoar formation.  Report of a Case  A 54-year-old man was hospitalized for recurrent pneumonia of the left side. During the previous six months he had experienced dysphagia, hemoptysis, anorexia, and an 18-kg weight loss. A chest roentgenogram showed a persistent infiltrate in the lingula and the superior segment of the left lower lobe. Bronchial cytology and biopsy specimens showed atypical squamous metaplasia. An upper gastrointestinal tract x-ray film showed a midesophageal stricture caused by an extrinsic lesion (Fig 1), an atonic stomach with gastric outlet obstruction, and a large intragastric mass simulating an extensive fundal carcinoma (Fig 2). A second film, taken after carbon dioxide producing tablets had been ingested to
Abstract 19081: Renal Insufficiency as a Marker for Stroke Risk in Patients with Atrial Fibrillation
Authors: Brian D Powell, Masayoshi Kinoshita, Naser M Ammash, Regina M Herges, David O Hodge, Charles J Bruce, Virend K Somers, Joseph F Maalouf, Bernard J Gersh, Paul A Friedman
Journal: Circulation (2010)

Background: Renal function is closely associated with cardiovascular disease. However, there are limited data about the relationship between renal function and stroke risk in patients with atrial fibrillation. Methods: Consecutive patients who underwent cardioversion for nonvalvular atrial fibrillation or flutter between January 2000 and December 2005 were studied. Clinical and laboratory data on risk factors, renal function, and a history of stroke was collected at the time of the cardioversion. Multivariate analysis for risk factors associated with a history of stroke was adjusted for age, gender, hypertension, diabetes, and CHF. Patients with normal glomerular filtration rate (GFR) > 60 mL/min were used as the comparison group. Results: A total of 1,424 patients, with a mean age 70 ± 12 years were identified. 140 (11.7%) had a history of stroke or transient ischemic attack (TIA). Patients with renal insufficiency, defined as GFR<60 mL/min, were older, more likely to have hypertension and CHF (p<0.001)....
THE ACTION OF CHLORINATED ANTISEPTICS ON BLOOD CLOT
Authors: Herbert D. Taylor, Marianne G. Stebbins
Journal: The Journal of Experimental Medicine (1919)

This work demonstrates that the chlorinated antiseptics have no power to penetrate blood clots and destroy bacteria therein contained. Correspondingly, blood clots may protect virulent bacteria for a long period of time and the organisms properly planted will be able to proliferate in a normal manner.
Comment on Tone et al. Six-Week Versus Twelve-Week Antibiotic Therapy for Nonsurgically Treated Diabetic Foot Osteomyelitis: A Multicenter Open-Label Controlled Randomized Study. Diabetes Care 2015;38:302–307
Authors: Leonie Nijenhuis-Rosien, Titia M. Vriesendorp, Gijs W.D. Landman
Journal: Diabetes Care (2015)

Tone et al. (1) are to be awarded for performing the first randomized trial that compares 6-week and 12-week antibiotic treatment duration in patients with diabetes and osteomyelitis with neuropathy without vascular disease. The study has two strong points: cultures of transcutaneous bone biopsy material were obligatory for inclusion and, in almost all cases, there was an antibiotic-free period between suspicion …
A Short Treatment with Galactomannan GM-CT-01 Corrects the Functions of Freshly Isolated Human Tumor–Infiltrating Lymphocytes
Authors: Nathalie Demotte, René Bigirimana, Grégoire Wieërs, Vincent Stroobant, Jean-Luc Squifflet, Javier Carrasco, Kris Thielemans, Jean-François Baurain, Patrick Van Der Smissen, Pierre J. Courtoy, Pierre van der Bruggen
Journal: Clinical Cancer Research (2014)

Several galectins are released by tumor cells and macrophages and accumulate in the tumor microenvironment. Galectin-1 and -3 were found to bind to glycosylated receptors at the surface of tumor-infiltrating lymphocytes (TIL), forming glycoprotein-galectin lattices that could reduce the motility and therefore the functionality of surface molecules. In contrast to blood T cells, human TIL show defective IFN-γ secretion upon ex vivo stimulation. We have previously shown that extracellular galectin-3 participates in the impairment of TIL functions. Indeed, disruption of glycoprotein-galectin-3 lattices using anti-galectin-3 antibodies, or N-acetyllactosamine as a competing sugar, boosted cytokine secretion by TIL. Here we have tested a clinical grade galectin antagonist: GM-CT-01, a galactomannan obtained from guar gum reported to be safe in more than 50 patients with cancer.TIL were isolated from human tumor ascites, treated for 2 to 20 hours with galectin antagonists and tested for function.We found that GM-CT-01 boosts cytotoxicity of CD8(+) TIL and their IFN-γ secretion in a dose-dependent manner. Treating TIL obtained from patients with various cancers, during a few hours, resulted in an increased IFN-γ secretion in up to 80% of the samples.These observations pave the way for investigating the potential benefit of this galectin antagonist in patients with cancer, alone or combined with cancer vaccination, in order to correct in vivo impaired functions of TIL.
The conscious and the unconscious: A package deal
Authors: Martin Kurthen
Journal: Behavioral and Brain Sciences (2002)

Parsimony and simplicity in cognition theory are not achieved by excluding either the “cognitive unconscious” or consciousness from theoretical modeling, but rather, by eliminating redundant constructs independent of their location on the conscious-unconscious axis. Hence, Perruchet &amp; Vinter's (P&amp;V's) case against the “cognitive unconscious” does not work as an argument for consciousness, but rather as a rejection of the redundant background computational processes postulated in traditional cognition theory.
GP surgery recommends private treatment to patients after cutbacks
Authors: A. O'Dowd
Journal: BMJ (2011)

A GP surgery in Yorkshire is being questioned by the local primary care trust after writing to patients to propose they use private care for some minor procedures, which the doctors claim the NHS will no longer fund.

The Haxby and Wigginton Health Centre says it has offered patients treatment alternatives as a consequence of cutbacks caused by the ongoing £20bn (€23bn; $30bn) worth of efficiency savings that the NHS has to make by 2015.

In July, the health centre’s Haxby Group Practice wrote to 30 patients to tell them eight minor procedures, including removal of skin tags, moles, and warts or cysts, and treatment of ingrowing toenails, were now things the NHS was no longer able to provide. …
Pericardial influences on right and left ventricular filling dynamics.
Authors: B D Hoit, N Dalton, V Bhargava, R Shabetai
Journal: Circulation Research (1991)

The influence of the pericardium on right and left ventricular filling was studied using two-dimensional and Doppler echocardiography in 14 open-chest dogs. Doppler echo parameters of filling included early (E) and late (A) velocities and their ratio (E/A) for the mitral and tricuspid valves. Right and left ventricular volumes were calculated from orthogonal two-dimensional echocardiographic images. Data were compared at three levels of left ventricular end-diastolic pressure (6 +/- 2, 13 +/- 3, and 21 +/- 4 mm Hg) at matched heart rates before and after pericardiectomy. The instantaneous diastolic pressure gradient was measured in 12 of the dogs. Pericardiectomy resulted in an increase in early mitral velocity, peak early diastolic pressure gradient, and E/A but not early mitral velocity normalized for end-diastolic volume. In contrast, for the tricuspid valve flow, pericardiectomy did not change E but caused a marked increase in A and a decrease in E/A. Right ventricular end-diastolic volumes at matched left ventricular end-diastolic volumes were similar before and after the pericardium was removed. However, removal of the pericardium caused a significant decrease of the slope for the right (86.0 +/- 27.0 x 10(-4) versus 50.0 +/- 19.5 x 10(-4) mm Hg/ml, p less than 0.01), but not left, ventricular ln end-diastolic pressure-volume relation (21.2 +/- 9.2 x 10(-3) versus 21.4 +/- 5.3 x 10(-3) mm Hg/ml, p = NS), and a decrease of the pressure intercept for the left (3.0 +/- 2.0 versus 1.6 +/- 0.9 mm Hg, p less than 0.05), but not right, ventricular ln end-diastolic pressure-volume relation (2.8 +/- 1.4 versus 1.4 +/- 0.8 mm Hg, p = NS). In conclusion, filling of the two ventricles is affected by the pericardium over a wide range of physiological ventricular volumes and pressures. At matched left ventricular end-diastolic volume, pericardiectomy causes a fundamental alteration in right, but not left, ventricular filling.
Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics
Authors: Joanne T. Brindle, Henrik Antti, Elaine Holmes, George Tranter, Jeremy K. Nicholson, Hugh W.L. Bethell, Sarah Clarke, Peter M. Schofield, Elaine McKilligin, David E. Mosedale, David J. Grainger
Journal: Nature Medicine (2002)
Bilateral adrenal masses: phaeochromocytoma or melanoma?
Authors: Isla S Mackenzie, Michael J Ashby, Tim Donovan, Demetrius D Voutnis, Morris J Brown
Journal: Journal of the Royal Society of Medicine (2006)

Adrenal masses vary in importance from being incidental findings of no clinical significance to having sinister consequences through malignancy.The importance in integrating the clinical history, biochemical findings and results of modern imaging techniques is illustrated in this case.
High resolution magic angle spinning 1H NMR of childhood brain and nervous system tumours
Authors: Martin Wilson, Nigel P Davies, Marie-Anne Brundler, Carmel McConville, Richard G Grundy, Andrew C Peet
Journal: Molecular Cancer (2009)

Brain and nervous system tumours are the most common solid cancers in children. Molecular characterisation of these tumours is important for providing novel biomarkers of disease and identifying molecular pathways which may provide putative targets for new therapies. 1H magic angle spinning NMR spectroscopy (1H HR-MAS) is a powerful tool for determining metabolite profiles from small pieces of intact tissue and could potentially provide important molecular information. Forty tissue samples from 29 children with glial and primitive neuro-ectodermal tumours were analysed using HR-MAS (600 MHz Varian gHX nanoprobe). Tumour spectra were fitted to a library of individual metabolite spectra to provide metabolite values. These values were then used in a two tailed t-test and multi-variate analysis employing a principal component analysis and a linear discriminant analysis. Classification accuracy was estimated using a leave-one-out analysis and B632+ bootstrapping. Glial tumours had significantly (two tailed t-test p < 0.05) higher creatine and glutamine and lower taurine, phosphoethanolamine, phosphorylcholine and choline compared with primitive neuro-ectodermal tumours. Classification accuracy was 90%. Medulloblastomas (n = 9) had significantly (two tailed t-test p < 0.05) higher creatine, glutamine, phosphorylcholine, glycine and scyllo-inositol than neuroblastomas (n = 7), classification accuracy was 94%. Supratentorial primitive neuro-ectodermal tumours had metabolite profiles in keeping with other primitive neuro-ectodermal tumours whilst ependymomas (n = 2) had metabolite profiles intermediate between pilocytic astrocytomas (n = 10) and primitive neuro-ectodermal tumours. HR-MAS identified key differences in the metabolite profiles of childhood brain and nervous system improving the molecular characterisation of these tumours. Further investigation of the underlying molecular pathways is required to assess their potential as targets for new agents.