tbuckley/cabot-search huggingface dataset:
Effect of white-matter lesions on the risk of periprocedural stroke after carotid artery stenting versus endarterectomy in the International Carotid Stenting Study (ICSS): a prespecified analysis of data from a randomised trial
Authors: Jörg Ederle, Indran Davagnanam, H Bart van der Worp, Graham S Venables, Philippe A Lyrer, Roland L Featherstone, Martin M Brown, H Rolf Jäger
Journal: The Lancet Neurology (2013)

Findings from randomised trials have shown a higher early risk of stroke after carotid artery stenting than after carotid endarterectomy. We assessed whether white-matter lesions affect the perioperative risk of stroke in patients treated with carotid artery stenting versus carotid endarterectomy.Patients with symptomatic carotid artery stenosis included in the International Carotid Stenting Study (ICSS) were randomly allocated to receive carotid artery stenting or carotid endarterectomy. Copies of baseline brain imaging were analysed by two investigators, who were masked to treatment, for the severity of white-matter lesions using the age-related white-matter changes (ARWMC) score. Randomisation was done with a computer-generated sequence (1:1). Patients were divided into two groups using the median ARWMC. We analysed the risk of stroke within 30 days of revascularisation using a per-protocol analysis. ICSS is registered with controlled-trials.com, number ISRCTN 25337470.1036 patients (536 randomly allocated to carotid artery stenting, 500 to carotid endarterectomy) had baseline imaging available. Median ARWMC score was 7, and patients were dichotomised into those with a score of 7 or more and those with a score of less than 7. In patients treated with carotid artery stenting, those with an ARWMC score of 7 or more had an increased risk of stroke compared with those with a score of less than 7 (HR for any stroke 2·76, 95% CI 1·17-6·51; p=0·021; HR for non-disabling stroke 3·00, 1·10-8·36; p=0·031), but we did not see a similar association in patients treated with carotid endarterectomy (HR for any stroke 1·18, 0·40-3·55; p=0·76; HR for disabling or fatal stroke 1·41, 0·38-5·26; p=0·607). Carotid artery stenting was associated with a higher risk of stroke compared with carotid endarterectomy in patients with an ARWMC score of 7 or more (HR for any stroke 2·98, 1·29-6·93; p=0·011; HR for non-disabling stroke 6·34, 1·45-27·71; p=0·014), but there was no risk difference in patients with an ARWMC score of less than 7.The presence of white-matter lesions on brain imaging should be taken into account when selecting patients for carotid revascularisation. Carotid artery stenting should be avoided in patients with more extensive white-matter lesions, but might be an acceptable alternative to carotid endarterectomy in patients with less extensive lesions.Medical Research Council, the Stroke Association, Sanofi-Synthélabo, the European Union Research Framework Programme 5.
Reduced expression of multiple gap junction proteins is a feature of cervical dysplasia
Authors: Trond Aasen, Sheila V Graham, Mike Edward, Malcolm B Hodgins
Journal: Molecular Cancer (2005)

Abstract Cervical dysplasia is a premalignant lesion associated with human papillomavirus (HPV) infection which, over time, can turn cancerous. Previous studies have indicated that loss of gap junctions may be a feature of cervical cancer and premalignant dysplasia. Loss of the gap junction protein connexin43 has been demonstrated in dysplastic cervix, but other connexins have not been investigated. In contrast we previously showed that HPV-associated cutaneous warts – and other hyperproliferative skin conditions – display a dramatic upregulation of certain connexins, in particular connexin26. By performing immunofluorescence staining after antigen retrieval of paraffin-embedded cervical tissue samples, this study reports for the first time that connexin26 and connexin30, in addition to connexin43, are expressed in differentiating cells of normal human cervical epithelia. Moreover, in dysplastic ectocervix, all connexins studied display a dramatic loss of expression compared to adjacent normal epithelia. The role of connexins in keratinocyte differentiation and carcinogenesis is discussed.
The multiple contributions of thyroid hormone to heat production
Authors: J. Enrique Silva
Journal: Journal of Clinical Investigation (2001)

The advent of homeothermy during evolution brought with it the need of mechanisms to produce heat to maintain body temperature in environments usually colder than the body. Thermogenic mechanisms are customarily classified as either obligatory or facultative. Obligatory thermogenesis (OT) represents the energy dissipated as heat in the many energetic transformations inherent to life. As discussed below, OT may be higher in warm-blooded species, possibly reflecting a lower thermodynamic efficiency of homeothermic machine compared with the poikilothermic machine. Facultative, or adaptive, thermogenesis (FT) is the additional heat production that the body activates in response to cold or overfeeding. The magnitude of OT determines the thermoneutrality temperature — the environmental temperature at which FT is activated, at which point neither heat-producing nor heat-dissipating mechanisms are activated, and body temperature is maintained solely on the basis of OT.
Evolutionary potentials: structure specific knowledge-based potentials exploiting the evolutionary record of sequence homologs
Authors: Alejandro Panjkovich, Francisco Melo, Marc A Marti-Renom
Journal: Genome biology (2008)

Abstract We introduce a new type of knowledge-based potentials for protein structure prediction, called 'evolutionary potentials', which are derived using a single experimental protein structure and all three-dimensional models of its homologous sequences. The new potentials have been benchmarked against other knowledge-based potentials, resulting in a significant increase in accuracy for model assessment. In contrast to standard knowledge-based potentials, we propose that evolutionary potentials capture key determinants of thermodynamic stability and specific sequence constraints required for fast folding.
Inflammatory Biomarkers for Persistent Fatigue in Breast Cancer Survivors
Authors: Alicia Collado-Hidalgo, Julienne E. Bower, Patricia A. Ganz, Steve W. Cole, Michael R. Irwin
Journal: Clinical Cancer Research (2006)

Abstract Purpose: This study seeks to define immunologic and inflammatory variables associated with persistent post-treatment fatigue in breast cancer survivors. Experimental Design: Leukocyte subsets, plasma inflammatory markers, and ex vivo proinflammatory cytokine production were assessed in 50 fatigued and nonfatigued breast cancer survivors recruited ≥2 years after successful primary therapy. Multivariate statistical analyses were used to define a composite immunologic biomarker of fatigue risk. Results: Fatigued breast cancer survivors were distinguished from nonfatigued survivors by increased ex vivo monocyte production of interleukin (IL)-6 and tumor necrosis factor-α following lipopolysaccharide stimulation, elevated plasma IL-1ra and soluble IL-6 receptor (sIL-6R/CD126), decreased monocyte cell-surface IL-6R, and decreased frequencies of activated T lymphocytes and myeloid dendritic cells in peripheral blood (all P &amp;lt; 0.05). An inverse correlation between sIL-6R and cell-surface IL-6R was consistent with inflammation-mediated shedding of IL-6R, and in vitro studies confirmed that proinflammatory cytokines induced such shedding. Multivariate linear discriminant function analysis identified two immunologic markers, the ratio of sIL-6R to monocyte-associated IL-6R and decreased circulating CD69+ T lymphocytes, as highly diagnostic of fatigue (P = 0.0005), with cross-validation estimates indicating 87% classification accuracy (sensitivity = 0.83; specificity = 0.83). Conclusion: These results extend links between fatigue and inflammatory markers to show a functional alteration in proinflammatory cytokine response to lipopolysaccharide and define a prognostic biomarker of behavioral fatigue.
ERG/AKR1C3/AR Constitutes a Feed-Forward Loop for AR Signaling in Prostate Cancer Cells
Authors: Katelyn Powell, Louie Semaan, M. Katie Conley-LaComb, Irfan Asangani, Yi-Mi Wu, Kevin B. Ginsburg, Julia Williams, Jeremy A. Squire, Krishna R. Maddipati, Michael L. Cher, Sreenivasa R. Chinni
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Intratumoral androgen synthesis in prostate cancer contributes to the development of castration-resistant prostate cancer (CRPC). Several enzymes responsible for androgen biosynthesis have been shown to be overexpressed in CRPC, thus contributing to CRPC in a castrated environment. The TMPRSS2–ERG transcription factor has been shown to be present in primary prostate cancer tumors as well as CRPC tumors. We hypothesize that TMPRSS2–ERG fusions regulate androgen biosynthetic enzyme (ABE) gene expression and the production of androgens, which contributes to the development of CRPC. Experimental design: We used a panel of assays, including lentivirus transduction, gene expression, chromatin immunoprecipitation and sequencing, liquid chromatography-mass spectrometric quantitation, immunocytochemistry, immunohistochemistry, and bioinformatics analysis of gene microarray databases, to determine ERG regulation of androgen synthesis. Results: We found that ERG regulated the expression of the ABE AKR1C3 in prostate cancer cells via direct binding to the AKR1C3 gene. Knockdown of ERG resulted in reduced AKR1C3 expression, which caused a reduction in both DHT synthesis and PSA expression in VCaP prostate cancer cells treated with 5α-androstanedione (5α-Adione), a DHT precursor metabolite. Immunohistochemical staining revealed that ERG was coexpressed with AKR1C3 in prostate cancer tissue samples. Conclusions: These data suggest that AKR1C3 catalyzes the biochemical reduction of 5α-Adione to DHT in prostate cancer cells, and that ERG regulates this step through upregulation of AKR1C3 expression. Elucidation of ERG regulation of ABEs in CRPC may help to stratify TMPRSS2–ERG fusion-positive prostate cancer patients in the clinic for anti–androgen receptor–driven therapies; and AKR1C3 may serve as a valuable therapeutic target in the treatment of CRPC. Clin Cancer Res; 21(11); 2569–79. ©2015 AACR.
Estrogen-Mediated Post transcriptional Down-regulation of Breast Cancer Resistance Protein/ABCG2
Authors: Yasuo Imai, Etsuko Ishikawa, Sakiyo Asada, Yoshikazu Sugimoto
Journal: Cancer Research (2005)

Breast cancer resistance protein (BCRP)/ABCG2 mediates concurrent resistance to chemotherapeutic agents, such as 7-ethyl-10-hydroxycamptothecin (SN-38), mitoxantrone, and topotecan, by pumping them out of cells. We previously reported that BCRP transports sulfated estrogens. In the present study, we show that at physiologic levels, estrogens markedly decrease endogenous BCRP expression in the estrogen-responsive and estrogen receptor alpha (ERalpha)-positive human breast cancer MCF-7 cells, but not in estrogen-nonresponsive human cancer cells. 17 beta-Estradiol (E(2)) also significantly reduces exogenous BCRP expression, driven by a constitutive promoter, in BCRP-transduced estrogen-responsive and ERalpha-positive MCF-7 (MCF-7/BCRP) and T-47D cells, but not in BCRP-transduced estrogen-nonresponsive MDA-MB-231 and SKOV-3 cells. E(2) potentiates the cytotoxicity of SN-38, but not vincristine, in MCF-7/BCRP cells significantly, and increases cellular topotecan uptake in MCF-7 and MCF-7/BCRP cells. Antiestrogen tamoxifen partially reverses E(2)-mediated BCRP down-regulation in MCF-7 and MCF-7/BCRP cells and treatment of MCF-7/BCRP cells with an ERalpha small interfering RNA abolished E(2)-mediated BCRP down-regulation, suggesting that interaction of E(2) and ERalpha is necessary for BCRP down-regulation. E(2) does not affect endogenous BCRP mRNA levels in MCF-7 cells or exogenous BCRP mRNA levels in MCF-7/BCRP cells. The results from pulse-chase labeling experiments with MCF-7/BCRP cells suggest that decreased protein biosynthesis and maturation, but not alterations in protein turnover, might underlie E(2)-mediated BCRP down-regulation. These data indicate that estrogen down-regulates BCRP expression by novel posttranscriptional mechanisms. This is the first report of small molecules that can affect BCRP protein expression in cells and may therefore assist in establishing new strategies for regulating BCRP expression.
Effect of a participatory intervention with women's groups on birth outcomes in Nepal: cluster-randomised controlled trial
Authors: Dharma S Manandhar, David Osrin, Bhim Prasad Shrestha, Natasha Mesko, Joanna Morrison, Kirti Man Tumbahangphe, Suresh Tamang, Sushma Thapa, Dej Shrestha, Bidur Thapa, Jyoti Raj Shrestha, Angie Wade, Josephine Borghi, Hilary Standing, Madan Manandhar, Anthony M de L Costello
Journal: The Lancet (2004)
Current Methods in Medical Image Segmentation
Authors: Dzung L. Pham, Chenyang Xu, Jerry L. Prince
Journal: Annual Review of Biomedical Engineering (2000)

▪ Abstract Image segmentation plays a crucial role in many medical-imaging applications, by automating or facilitating the delineation of anatomical structures and other regions of interest. We present a critical appraisal of the current status of semiautomated and automated methods for the segmentation of anatomical medical images. Terminology and important issues in image segmentation are first presented. Current segmentation approaches are then reviewed with an emphasis on the advantages and disadvantages of these methods for medical imaging applications. We conclude with a discussion on the future of image segmentation methods in biomedical research.
The Development of Psychopathy
Authors: Donald R. Lynam, Lauren Gudonis
Journal: Annual Review of Clinical Psychology (2004)

In this review, we explore two aspects of the development of psychopathy. First, we examine what psychopathy looks like across time. Second, we ask where psychopathy comes from. Much recent empirical work supports the idea that psychopathy in childhood and adolescence looks much like psychopathy in adulthood. Research utilizing recently created juvenile psychopathy indices demonstrates that juvenile psychopathy can be assessed reliably and that the nomological network surrounding the construct is quite similar to the one around adult psychopathy. Juvenile psychopathy is robustly related to offending, other externalizing problems, low levels of Agreeableness and Conscientiousness, and deficits in emotional processing and inhibition. Juvenile psychopathy is also relatively stable across adolescence. Much less research has examined from whence psychopathy comes, although several theories are reviewed. We close with a discussion of recent objections to the downward developmental extension of psychopathy to juveniles and some suggestions for additional research.
Function and heterogeneity of human Fc receptors for immunoglobulin G.
Authors: J C Unkeless
Journal: Journal of Clinical Investigation (1989)

The recognition of foreign antigens by receptors on the surface of cells of the immune system is a fundamental feature of immune defenses.The receptor systems involved include the T cell receptor complex, surface Ig of B cells, class I and II histocompatibility antigens, CD4, CD8, complement recep- tors, and receptors for the Fc domain of IgG (FcYR).1It is
Defenseless against the common cold
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

Epithelial cell dysfunction may explain why people with asthma fare worse than most when infected with common cold viruses. Wark and colleagues show on page 937 that bronchial epithelial cells from asthma sufferers fail to invoke critical antiviral defenses but still provoke inflammation when infected with rhinoviruses—an ideal combination for asthma induction.

Respiratory virus infections often trigger asthma attacks, and these infections are more severe in asthma sufferers than in healthy individuals. Past studies have demonstrated increased virus replication in asthmatic versus healthy subjects and suggested that alterations in cytokine production that favor asthma-promoting T helper (Th)-2 responses might be to blame.

Wark and colleagues now uncover a defect that may provide the initial trigger for virus-induced asthma. They found that bronchial epithelial cells—the primary targets of viral infection—from asthma sufferers supported more virus replication than did cells from healthy controls. The reason for this was twofold: epithelial cells from asthmatic subjects failed to produce the potent anti-viral cytokine interferon-β (IFN-β) and also failed to initiate apoptosis, mechanisms employed by healthy cells to limit virus replication and eliminate infected cells. These defects may be linked, as IFN-β was recently shown to induce apoptosis in virus-infected cells.

How does this enhanced viral replication lead to asthma? The authors show that epithelial cells from asthma sufferers, although unable to produce IFN-β, could still secrete pro-inflammatory cytokines, which can recruit asthma-inducing eosinophils and Th2 cells to the lungs. Future experiments are planned to identify the mutation that causes the IFN-β defect. Although several genetic markers have been linked to asthma in the past, so far none are related to IFNs.
Polymyalgia and low back pain: a common cause not to be missed
Authors: N Hopkinson, A A Myint, S Benjamin
Journal: Annals of the Rheumatic Diseases (1999)

### PATIENT 1

A 65 year old man was admitted with a one month history of increasingly severe left sided sciatica. He had one previous episode of low back pain 40 years earlier. Four months before admission, a left inguinal hernia was repaired and following this he had complained of pain in the left testicle. His pain had rapidly increased day and night despite chiropractic treatment, and he complained of anorexia and weight loss, but no night sweats.

On examination he appeared unwell and was in very severe pain, although with no focal spinal tenderness. All movements of the lumbar spine were reduced, with straight leg raising reduced on the left to 60°, with a positive sciatic stretch test. The left ankle jerk was absent. There were no abnormalities in the heart, lungs or abdomen.

Blood tests showed a high erythrocyte sedimentation rate (ESR) of 91 mm 1st h with an anaemia of chronic disease. C reactive protein (CRP) was high at 70 mg/l, liver function tests, including alkaline phosphatase, and urea and electrolytes were normal, as were calcium and prostate specific antigen. Urine analysis on dipstick testing was normal. Although initial radiographs of the lumbar spine were unremarkable, apart from disc space narrowing only at level L5/S1, magnetic resonance imaging of the lumbar spine showed extensive abnormal signal within L5/S1 consistent with a malignancy (fig 1) and abnormal tissue surrounding the left L5 and S1 nerve roots. …
The Era of Cancer Discovery
Authors: Lewis C. Cantley, José Baselga
Journal: Cancer Discovery (2011)

Realization of the need for a forum that would bring basic and translational scientists and clinical trials specialists together inspired the launch of Cancer Discovery .

A growing optimism that cancer research and treatment are entering a new era is taking hold. Since the late 1950s, when the first real cancer cures were achieved with combination therapies, progress in treating cancers has been painfully slow, and with a few notable exceptions, breakthroughs came from empirical observations in the clinic rather than from detailed understanding of the disease. We did not understand why certain therapies were successful in some subsets of cancers and failures in others. Most cancer drugs were being developed on the basis of their ability to kill cancer cells grown on plastic or in nude mice, with no real understanding of the mechanism of drug action. It is therefore not surprising that the majority of these investigational drugs ultimately failed when tested in large and expensive randomized trials, and those that did succeed typically extended lives by only a few months. In 1996, the 25th anniversary of the declaration of war on cancer, it was difficult to point to a single breakthrough in treatment that emerged from the tens of billions of dollars that had been spent on basic and clinical research.

Nevertheless, we learned a lot during those first 25 years. We discovered that cancer was, for the most part, caused by mutations in genes (oncogenes) that control cell proliferation, cell growth, cell survival, and cell differentiation. Importantly, we discovered that the types of cancers that had been historically defined based on tissue of origin and classical techniques of pathology could be further divided into dozens of subtypes when analyzed at the molecular level. This knowledge began to explain why 2 patients with the same disease diagnosis …
In Search of Beneficial Coding RNA Editing
Authors: Guixia Xu, Jianzhi Zhang
Journal: Molecular Biology and Evolution (2014)

RNA editing is a posttranscriptional modification that can lead to a change in the encoded protein sequence of a gene. Although a few cases of mammalian coding RNA editing are known to be functionally important, the vast majority of over 2,000 A-to-I editing sites that have been identified from the coding regions of the human genome are likely nonadaptive, representing tolerable promiscuous targeting of editing enzymes. Finding the potentially tiny fraction of beneficial editing sites from the sea of mostly nearly neutral editing is a difficult but important task. Here, we propose and provide evidence that evolutionarily conserved or "hardwired" residues that experience high-level nonsynonymous RNA editing in a species are enriched with beneficial editing. This simple approach allows the prediction of sites where RNA editing is functionally important. We suggest that priority be given to these candidates in future characterizations of the functional and fitness consequences of RNA editing.
Plasminogen Activator Inhibitor-1 as a Potential Marker for the Malignancy of Esophageal Squamous Cell Carcinoma
Authors: Takumi Sakakibara, Kenji Hibi, Yasuhiro Kodera, Katsuki Ito, Seiji Akiyama, Akimasa Nakao
Journal: Clinical Cancer Research (2004)

To test whether plasminogen activator inhibitor-1 (PAI-1) can serve as a candidate marker for the malignancy of esophageal squamous cell carcinoma (SCC), we performed a quantitative reverse transcription-PCR for PAI-1 gene and evaluated the possible relationship between PAI-1 gene expression levels and clinicopathological findings in esophageal SCC.Significant increases in PAI-1 scores were observed in metastasis-positive esophageal SCCs (3.08 +/- 0.80) compared with metastasis-negative ones (-0.31 +/- 0.62; P = 0.0042). PAI-1 expression scores significantly increased with tumor stage (P = 0.05, ANOVA).These results suggested that PAI-1 might serve as a new parameter for prediction of prognosis in esophageal SCC.