tbuckley/cabot-search huggingface dataset:
Androgen-regulated genes differentially modulated by the androgen receptor coactivator L-dopa decarboxylase in human prostate cancer cells
Authors: Katia Margiotti, Latif A Wafa, Helen Cheng, Giuseppe Novelli, Colleen C Nelson, Paul S Rennie
Journal: Molecular Cancer (2007)

Abstract Background The androgen receptor is a ligand-induced transcriptional factor, which plays an important role in normal development of the prostate as well as in the progression of prostate cancer to a hormone refractory state. We previously reported the identification of a novel AR coactivator protein, L-dopa decarboxylase (DDC), which can act at the cytoplasmic level to enhance AR activity. We have also shown that DDC is a neuroendocrine (NE) marker of prostate cancer and that its expression is increased after hormone-ablation therapy and progression to androgen independence. In the present study, we generated tetracycline-inducible LNCaP-DDC prostate cancer stable cells to identify DDC downstream target genes by oligonucleotide microarray analysis. Results Comparison of induced DDC overexpressing cells versus non-induced control cell lines revealed a number of changes in the expression of androgen-regulated transcripts encoding proteins with a variety of molecular functions, including signal transduction, binding and catalytic activities. There were a total of 35 differentially expressed genes, 25 up-regulated and 10 down-regulated, in the DDC overexpressing cell line. In particular, we found a well-known androgen induced gene, TMEPAI , which wasup-regulated in DDC overexpressing cells, supporting its known co-activation function. In addition, DDC also further augmented the transcriptional repression function of AR for a subset of androgen-repressed genes. Changes in cellular gene transcription detected by microarray analysis were confirmed for selected genes by quantitative real-time RT-PCR. Conclusion Taken together, our results provide evidence for linking DDC action with AR signaling, which may be important for orchestrating molecular changes responsible for prostate cancer progression.
Myocardin Induces Cardiomyocyte Hypertrophy
Authors: Weibing Xing, Tong-Cun Zhang, Dongsun Cao, Zhigao Wang, Christopher L. Antos, Shijie Li, Yibin Wang, Eric N. Olson, Da-Zhi Wang
Journal: Circulation Research (2006)

In response to stress signals, postnatal cardiomyocytes undergo hypertrophic growth accompanied by activation of a fetal gene program, assembly of sarcomeres, and cellular enlargement. We show that hypertrophic signals stimulate the expression and transcriptional activity of myocardin, a cardiac and smooth muscle-specific coactivator of serum response factor (SRF). Consistent with a role for myocardin as a transducer of hypertrophic signals, forced expression of myocardin in cardiomyocytes is sufficient to substitute for hypertrophic signals and induce cardiomyocyte hypertrophy and the fetal cardiac gene program. Conversely, a dominant-negative mutant form of myocardin, which retains the ability to associate with SRF but is defective in transcriptional activation, blocks cardiomyocyte hypertrophy induced by hypertrophic agonists such as phenylephrine and leukemia inhibitory factor. Myocardin-dependent hypertrophy can also be partially repressed by histone deacetylase 5, a transcriptional repressor of myocardin. These findings identify myocardin as a nuclear effector of hypertrophic signaling pathways that couples stress signals to a transcriptional program for postnatal cardiac growth and remodeling.
General practitioners' perceptions of chronic fatigue syndrome and beliefs about its management, compared with irritable bowel syndrome: qualitative study
Authors: Rosalind Raine, Simon Carter, Tom Sensky, Nick Black
Journal: BMJ (2004)

<b>Objectives</b> To compare general practitioners9 perceptions of chronic fatigue syndrome and irritable bowel syndrome and to consider the implications of their perceptions for treatment. <b>Design</b> Qualitative analysis of transcripts of group discussions. <b>Participants and setting</b> A randomly selected sample of 46 general practitioners in England. <b>Results</b> The participants tended to stereotype patients with chronic fatigue syndrome as having certain undesirable traits. This stereotyping was due to the lack of a precise bodily location; the reclassification of the syndrome over time; transgression of social roles, with patients seen as failing to conform to the work ethic and “sick role” and conflict between doctor and patient over causes and management. These factors led to difficulties for many general practitioners in managing patients with chronic fatigue syndrome. For both conditions many participants would not consider referral for mental health interventions, even though the doctors recognised social and psychological factors, because they were not familiar with the interventions or thought them unavailable or unnecessary. <b>Conclusions</b> Barriers to the effective clinical management of patients with irritable bowel syndrome and chronic fatigue syndrome are partly due to doctors9 beliefs, which result in negative stereotyping of patients with chronic fatigue syndrome and the use of management strategies for both syndromes that may not take into account the best available evidence.
Metatarsalgia caused by derangement of the second, third, and fourth metatarsal joints.
Authors: J M Fitton
Journal: Annals of the Rheumatic Diseases (1970)

PROF.BYWATERS (Taplow) The life of this type of presentation is becoming shorter with rapidly advancing knowledge and changing concepts.This is one of the great drawbacks of all these types of pre-recorded teach- ing.I do not quite see how that can ever be got over.DR. HOL ROYD E The question is a philosophical one.It relates to whether the quality of a lecture such as this is haphazard.The lecturer may be extremely good one week and bad the next week.How much better to have a presentation when the lecturer is on top form, and for this to be available at the end or beginning of term.Metatarsalgia caused by Derangement of the Second, Third, and Fourth Metatarsal Joints.By J. M. FmON
The LMP2 polymorphism is associated with susceptibility to acute anterior uveitis in HLA-B27 positive juvenile and adult Mexican subjects with ankylosing spondylitis
Authors: W. P Maksymowych, G. S Jhangri, C. Gorodezky, M. Luong, C. Wong, R. Burgos-Vargas, M. Morenot, J. Sanchez-Corona, C. Ramos-Remus, A. S Russell
Journal: Annals of the Rheumatic Diseases (1997)

<h3>INTRODUCTION</h3> An association between polymorphism of the HLA linked LMP2 locus and the development of acute anterior uveitis (AAU) has previously been described in B27 positive white subjects with ankylosing spondylitis (AS). This study evaluated LMP2 alleles in two HLA-B27 positive Mexican populations of patients with spondyloarthropathy known to have a different clinical spectrum of disease from white people. <h3>PATIENTS AND METHODS</h3> The study populations consisted of 90 AS patients from Guadalajara with predominantly adult onset disease and 80 AS patients from Mexico City with predominantly juvenile onset disease. LMP2-CfoI amplified fragment length polymorphisms were determined after polymerase chain reaction amplification and digestion with CfoI restriction enzyme. <h3>RESULTS</h3> There was an increased LMP2A allelic frequency in patients who had had AAU in both Guadalajara (31.8%) and Mexico City (33.3%) when compared with non-AAU patients (15.2% and 17.7% of Guadalajara and Mexico City populations, respectively). The odds ratio relating LMP2A allelic frequency and AAU for the combined population, stratified by age at onset of disease, was 2.51 (p=0.01). LMP2 alleles did not influence the age at onset of disease or the development of peripheral arthritis. <h3>CONCLUSIONS</h3> These data support the view that polymorphism at the LMP2 locus is associated with the development of AAU in B27 positive subjects with AS. The requirement for both the less common LMP2 allele and HLA-B27 is consistent with the low prevalence of AAU in Mexican patients with spondyloarthritis.
Equipoise and the Ethics of Clinical Research
Authors: Benjamin Freedman
Journal: New England Journal of Medicine (1987)

The ethics of clinical research requires equipoise--a state of genuine uncertainty on the part of the clinical investigator regarding the comparative therapeutic merits of each arm in a trial. Should the investigator discover that one treatment is of superior therapeutic merit, he or she is ethically obliged to offer that treatment. The current understanding of this requirement, which entails that the investigator have no "treatment preference" throughout the course of the trial, presents nearly insuperable obstacles to the ethical commencement or completion of a controlled trial and may also contribute to the termination of trials because of the failure to enroll enough patients. I suggest an alternative concept of equipoise, which would be based on present or imminent controversy in the clinical community over the preferred treatment. According to this concept of "clinical equipoise," the requirement is satisfied if there is genuine uncertainty within the expert medical community--not necessarily on the part of the individual investigator--about the preferred treatment.
Subcutaneous glucose measurements and glucose regulation (?)
Authors: Jack J. Ligtenberg, Hella F. Borggreve, Arjanne Stemerdink, Jan G. Zijlstra
Journal: Intensive Care Medicine (2010)

Sir: Andrea Stoszkova et al. [1] conclude, based on a correlation coefficient of 0.69 comparing subcutaneous glucose values (Guardian RT) and blood glucose values (Central Laboratory) in 15 patients, that subcutaneous devices should not be used in critically ill patients. However, Holzinger et al. [2] in the August issue report a good correlation between subcutaneous and arterial glucose values, even in critically ill patients treated with norepinephrine.

We also evaluated the accuracy and feasibility of a comparable continuous subcutaneous glucose monitoring system (CGMS System Gold, Medtronic Minimed) and found a correlation coefficient of 0.87 with the point-of-care blood gas/glucose analyzer ABL 715 (Radiometer Medical, Copenhagen, Denmark), which we validated in ICU patients previously [3]. We drew 786 arterial blood samples from 60 consecutive ICU patients, of whom 37 patients received vaso-active medication (only norepinephrine) and 13 patients were treated with steroids. Blood glucose ranged from 2.2 to 20.1 mmol/l. In the Clarke error grid (Fig. 1), 85.1% of measurements were in zone A (clinically accurate, leading to correct and safe treatment decisions), 13.2% were in zone B (clinically acceptable), 0.13% were in zone C, and 1.5% were in zone D. Zone D means failure-to-detect (high or low blood glucose) errors, resulting in failure to treat either low or high blood glucose results appropriately. The readings in zone D were found in nine patients, of whom eight were treated with vasopressors. One could argue that—with a correlation coefficient of 0.87 and 98.3% of glucose values in the clinically acceptable zones—rejection of s.c. glucose determination in the ICU seems premature.



Fig. 1

Clarke error-grid analysis



On the other hand, looking more precisely at zone D of the Clarke error grid (Fig. 1), a difference of nearly 4 mmol/l in the lower glucose zone (reference 2.8 mmol/l versus s.c. sensor 6.5 mmol/l) observed in one patient could have severe consequences in this individual patient, if this results in an inappropriate rise in insulin dose. Unlike other diagnostic procedures, which usually are interpreted in conjunction with additional findings, a single glucose measurement has direct consequences for treatment, with potentially detrimental effects.

In other words, tight glucose regulation in ICU patients using a subcutaneous device may lead to more severe adverse events than the zone interpretation of the error grid suggests. The fact that we now have safe computerized protocols, which give excellent glucose regulation with a very low chance of hypoglycemic events [4], adds to the feeling that for glucose regulation in critically ill patients only the best point-of-care glucose analyzer and protocol should be used [5]. In an era where the beneficial effect of tight glucose regulation is questioned we cannot afford the introduction of treatment-related morbidity.
Sports doctors' resuscitation skills under examination: do they take it seriously?
Authors: M Lavis, J Rose, T Jenkinson
Journal: British Journal of Sports Medicine (2001)

As 64% of sports medicine doctors were unable to show proficiency at basic life support and assessment and management of a seriously injured patient with a potential spinal injury in the last two examinations for a University of Bath diploma in sports and exercise medicine, it was decided that a reminder is required of the importance of acquiring, at the very least, some basic resuscitation skills. An analysis and comment on the results from the first aid component of the examination is also presented.
Different Prognostic Value of Cytokeratin-19 mRNA–Positive Circulating Tumor Cells According to Estrogen Receptor and HER2 Status in Early-Stage Breast Cancer
Authors: Michail Ignatiadis, Nikos Xenidis, Maria Perraki, Stella Apostolaki, Eleni Politaki, Maria Kafousi, Efstathios N. Stathopoulos, Aliki Stathopoulou, Evi Lianidou, Grigorios Chlouverakis, Christos Sotiriou, Vassilis Georgoulias, Dimitris Mavroudis
Journal: Journal of Clinical Oncology (2007)

To examine the prognostic value of cytokeratin-19 (CK-19) mRNA-positive circulating tumor cells (CTCs) in early-stage breast cancer patients focusing on clinically relevant subgroups based on estrogen receptor (ER) and HER2 expression.CK-19 mRNA-positive CTCs were detected by real-time reverse transcriptase polymerase chain reaction in the blood of 444 consecutive, stage I-III, breast cancer patients before initiation of adjuvant chemotherapy. The association between detection of CK-19 mRNA-positive CTCs and clinical outcome was analyzed for patients with ER-positive, ER-negative, triple-negative, HER2-positive, and ER-positive/HER2-negative tumors.CK-19 mRNA-positive CTCs were detected in 181 (40.8%) of 444 patients; 109 (41.9%) of 260 patients with ER-positive tumors; 71 (40.6%) of 175 patients with ER-negative tumors; 27 (35%) of 77 patients with triple-negative tumors; 35 (39.8%) of 88 patients with HER2-positive tumors; and 82 (44.1%) of 186 patients with ER-positive/HER2-negative tumors. After a median follow-up of 53.5 months, patients with CK-19 mRNA-positive CTCs experienced reduced disease-free survival (DFS; P < .001) and overall survival (OS; P < .001); this was mainly observed in patients with ER-negative (P < .001 and P < .001, respectively) but not ER-positive tumors (P = .172 and P = .425, respectively) and in patients with triple-negative (P = .008 and P = .001, respectively) and HER2-positive (P = .023 and P = .040, respectively) but not ER-positive/HER2-negative tumors (P = .210 and P = .578, respectively). In multivariate analysis, the interaction between CK-19 mRNA-positive CTCs and ER status was the strongest independent prognostic factor for reduced DFS (hazard ratio [HR], 3.808; 95% CI, 2.415 to 6.003; P < .001) and OS (HR, 4.172; 95% CI, 2.477 to 9.161; P < .001).Detection of CK-19 mRNA-positive CTCs before adjuvant chemotherapy predicts poor clinical outcome mainly in patients with ER-negative, triple-negative, and HER2-positive early-stage breast cancer.
Use of Tc-99m HMPAO Brain SPECT to Evaluate Cerebral Collateral Circulation During Matas Test
Authors: HAN-JUNG CHEN, HUEI-YUNG CHEN
Journal: Clinical Nuclear Medicine (1995)

Five patients with traumatic carotid-cavernous fistulae and two patients with internal carotid artery aneurysms inside the cavernous sinus are presented. A quantitative method was used for the evaluation of brain collateral circulation in the anterior and middle cerebral artery territories by using Tc-99m HMPAO SPECT before and during the Matas test. It affords a more reliable quantitative measurement of reduced activity than conventional carotid angiography during the Matas test. In this study, a reduction of radioactivity of less than 15% during the Matas test did not reveal any postoperative neurological deficit after a carotid artery trapping procedure. This noninvasive method seems to be useful to determine the appropriate surgical treatment.
Sheep Mitochondrial DNA Variation in European, Caucasian, and Central Asian Areas
Authors: Miika Tapio, Nurbiy Marzanov, Mikhail Ozerov, Mirjana Ćinkulov, Galina Gonzarenko, Tatyana Kiselyova, Maciej Murawski, Haldja Viinalass, Juha Kantanen
Journal: Molecular Biology and Evolution (2006)

Three distinct mitochondrial maternal lineages (haplotype Groups A, B, and C) have been found in the domestic sheep. Group B has been observed primarily in European domestic sheep. The European mouflon carries this haplotype group. This could suggest that European mouflon was independently domesticated in Europe, although archaeological evidence supports sheep domestication in the central part of the Fertile Crescent. To investigate this question, we sequenced a highly variable segment of mitochondrial DNA (mtDNA) in 406 unrelated animals from 48 breeds or local varieties. They originated from a wide area spanning northern Europe and the Balkans to the Altay Mountains in south Siberia. The sample included a representative cross-section of sheep breeds from areas close to the postulated Near Eastern domestication center and breeds from more distant northern areas. Four (A, B, C, and D) highly diverged sheep lineages were observed in Caucasus, 3 (A, B and C) in Central Asia, and 2 (A and B) in the eastern fringe of Europe, which included the area north and west of the Black Sea and the Ural Mountains. Only one example of Group D was detected. The other haplotype groups demonstrated signs of population expansion. Sequence variation within the lineages implied Group A to have expanded first. This group was the most frequent type only in Caucasian and Central Asian breeds. Expansion of Group C appeared most recently. The expansion of Group B involving Caucasian sheep took place at nearly the same time as the expansion of Group A. Group B expansion for the eastern European area started approximately 3,000 years after the earliest inferred expansion. An independent European domestication of sheep is unlikely. The distribution of Group A variation as well as other results are compatible with the Near East being the domestication site. Groups C and D may have been introgressed later into a domestic stock, but larger samples are needed to infer their geographical origin. The results suggest that some mitochondrial lineages arrived in northern Europe from the Near East across Russia.
THE LUPUS ANTICOAGULANT/ANTIPHOSPHOLIPID SYNDROME
Authors: Sandor S. Shapiro, M.D
Journal: Annual Review of Medicine (1996)

▪ Abstract Lupus anticoagulants and anticardiolipin antibodies have been strongly associated with the risk of thrombosis, recurrent fetal loss, thrombocytopenia, and a number of other clinical manifestations that together have been referred to as the antiphospholipid syndrome. Despite growing evidence of the significance of this relationship, the pathogenetic mechanisms involved are largely unknown. Recent data suggest strongly that lupus anticoagulants (LACs) and anticardiolipin antibodies (ACAs) are antibodies to protein-phospholipid complexes rather than to phospholipids, as had originally been thought, and that other protein-phospholipid complexes, not recognized by standard assays for LACs or ACAs, may also exist in patients with the antiphospholipid syndrome. Although very recent experimental data may lead to new therapeutic approaches in this syndrome, at present we can only deal with the thrombotic risk by the use of long-term anticoagulation. This chapter reviews current methods of diagnosis, concepts of pathogenesis, and the basis for an approach to anticoagulation in patients at risk for thrombosis or other manifestations of the antiphospholipid syndrome.
Enhancement of the ATP-Sensitive K <sup>+</sup> Current by Extracellular ATP in Rat Ventricular Myocytes
Authors: Andrey Babenko, Guy Vassort
Journal: Circulation Research (1997)

Abstract ATP-sensitive K + (K ATP ) channels are present at high density in membranes of cardiac cells, where they regulate cardiac function during metabolic impairment. The present study analyzes the effects of extracellular ATP (ATP e ), a P 2 -purinergic agonist that can be released under various conditions in the myocardial cell bed, on K ATP current (I K-ATP ) in rat ventricular myocytes. Under the whole-cell patch-clamp configuration at a physiological level of intracellular ATP, applying ATP e in the micromolar range did not activate I K-ATP . However, dialyzing the cell with a low-ATP (100 μmol/L) pipette solution elicited a slowly, quasilinearly increasing I K-ATP that was markedly enhanced by applying ATP e in the presence of a P 1 -purinergic antagonist. The effect was reversible on washing out the agonist. The I K-ATP enhancement was inhibited by cholera toxin treatment of the myocytes, suggesting that a G s protein was involved to mediate the effect. Experiments on excised patches allowed us to exclude a membrane-delimited G protein–dependent pathway. Rather, the results suggested that ATP e activates the adenylyl cyclase, since its inhibition by 2′-deoxyadenosine 3′-monophosphate and SQ-22536, which respectively interact with the purine and catalytic site of the cyclase, strongly reduced the ATP e -induced I K-ATP enhancement, whereas neither compound affected I K-ATP in inside-out patches. Inhibition of cAMP-dependent protein kinase by protein kinase inhibitor peptide 5-24 did not alter the purinergic effect. The findings suggests that ATP e triggers the activation of adenylyl cyclase, which causes a subsarcolemmal ATP depletion sufficient to enhance I K-ATP as it develops during low-ATP dialysis of rat ventricular myocytes.
Inhibition of <i>NANOG/NANOGP8</i> Downregulates MCL-1 in Colorectal Cancer Cells and Enhances the Therapeutic Efficacy of BH3 Mimetics
Authors: Abid R. Mattoo, Jingyu Zhang, Luis A. Espinoza, J. Milburn Jessup
Journal: Clinical Cancer Research (2014)

Abstract Purpose: High levels of BCL-2 family members in colorectal carcinoma cause resistance to treatment. Inhibition of NANOG or its paralog NANOGP8 reduces the proliferation, stemness, and tumorigenicity of colorectal carcinoma cells. Our hypothesis was that inhibition of NANOG/NANOGP8 enhances the cytotoxic effect of BH3 mimetics targeting BCL-2 family members in colorectal carcinoma cells through reducing expression of MCL-1, a prosurvival BCL-2 protein. Experimental Design: Lentiviral vector (LV) shRNA to NANOG (shNG-1) or NANOGP8 (shNp8-1) transduced colorectal carcinoma cells that were also exposed to the BH3 mimetics ABT-737 or ABT-199 in vivo in colorectal carcinoma xenografts and in vitro where proliferation, protein and gene expression, and apoptosis were measured. Results: Clone A and CX-1 were sensitive to ABT-737 and ABT-199 at IC50s of 2 to 9 μmol/L but LS174T was resistant with IC50s of 18 to 30 μmol/L. Resistance was associated with high MCL-1 expression in LS174T. LVshNG-1 or LVshNp8-1 decreased MCL-1 expression, increased apoptosis, and decreased replating efficiency in colorectal carcinoma cells treated with either ABT-737 or ABT-199 compared with the effects of either BH3 mimetic alone. Inhibition or overexpression of MCL-1 alone replicated the effects of LVshNG-1 or LVshNp8-1 in increasing or decreasing the apoptosis caused with the BH3 mimetic. The combination therapy inhibited the growth of LS174T xenografts in vivo compared with untreated controls or treatment with only LV shRNA or ABT-737. Conclusions: Inhibition of NANOGP8 or NANOG enhances the cytotoxicity of BH3 mimetics that target BCL-2 family members. Gene therapy targeting the NANOGs may increase the efficacy of BH3 mimetics in colorectal carcinoma. Clin Cancer Res; 20(21); 5446–55. ©2014 AACR.