tbuckley/cabot-search huggingface dataset:
miR-21: an oncomir on strike in prostate cancer
Authors: Marco Folini, Paolo Gandellini, Nicole Longoni, Valentina Profumo, Maurizio Callari, Marzia Pennati, Maurizio Colecchia, Rosanna Supino, Silvia Veneroni, Roberto Salvioni, Riccardo Valdagni, Maria Grazia Daidone, Nadia Zaffaroni
Journal: Molecular Cancer (2010)

Abstract Background Aberrant expression of microRNAs, small non-coding RNA molecules that post-transcriptionally repress gene expression, seems to be causatively linked to the pathogenesis of cancer. In this context, miR-21 was found to be overexpressed in different human cancers (e.g. glioblastoma, breast cancer). In addition, it is thought to be endowed with oncogenic properties due to its ability to negatively modulate the expression of tumor-suppressor genes (e.g. PTEN ) and to cause the reversion of malignant phenotype when knocked- down in several tumor models. On the basis of these findings, miR-21 has been proposed as a widely exploitable cancer-related target. However, scanty information is available concerning the relevance of miR-21 for prostate cancer. In the present study, we investigated the role of miR-21 and its potential as a therapeutic target in two prostate cancer cell lines, characterized by different miR-21 expression levels and PTEN gene status. Results We provide evidence that miR-21 knockdown in prostate cancer cells is not sufficient per se i) to affect the proliferative and invasive potential or the chemo- and radiosensitivity profiles or ii) to modulate the expression of the tumor-suppressors PTEN and Pdcd4, which in other tumor types were found to be regulated by miR-21. We also show that miR-21 is not differently expressed in carcinomas and matched normal tissues obtained from 36 untreated prostate cancer patients subjected to radical prostatectomy. Conclusions Overall, our data suggest that miR-21 is not a central player in the onset of prostate cancer and that its single hitting is not a valuable therapeutic strategy in the disease. This supports the notion that the oncogenic properties of miR-21 could be cell and tissue dependent and that the potential role of a given miRNA as a therapeutic target should be contextualized with respect to the disease.
Breast Density and Benign Breast Disease: Risk Assessment to Identify Women at High Risk of Breast Cancer
Authors: Jeffrey A. Tice, Diana L. Miglioretti, Chin-Shang Li, Celine M. Vachon, Charlotte C. Gard, Karla Kerlikowske
Journal: Journal of Clinical Oncology (2015)

Purpose Women with proliferative breast lesions are candidates for primary prevention, but few risk models incorporate benign findings to assess breast cancer risk. We incorporated benign breast disease (BBD) diagnoses into the Breast Cancer Surveillance Consortium (BCSC) risk model, the only breast cancer risk assessment tool that uses breast density. Methods We developed and validated a competing-risk model using 2000 to 2010 SEER data for breast cancer incidence and 2010 vital statistics to adjust for the competing risk of death. We used Cox proportional hazards regression to estimate the relative hazards for age, race/ethnicity, family history of breast cancer, history of breast biopsy, BBD diagnoses, and breast density in the BCSC. Results We included 1,135,977 women age 35 to 74 years undergoing mammography with no history of breast cancer; 17% of the women had a prior breast biopsy. During a mean follow-up of 6.9 years, 17,908 women were diagnosed with invasive breast cancer. The BCSC BBD model slightly overpredicted risk (expected-to-observed ratio, 1.04; 95% CI, 1.03 to 1.06) and had modest discriminatory accuracy (area under the receiver operator characteristic curve, 0.665). Among women with proliferative findings, adding BBD to the model increased the proportion of women with an estimated 5-year risk of 3% or higher from 9.3% to 27.8% (P &lt; .001). Conclusion The BCSC BBD model accurately estimates women's risk for breast cancer using breast density and BBD diagnoses. Greater numbers of high-risk women eligible for primary prevention after BBD diagnosis are identified using the BCSC BBD model.
The lysophospholipid mediator sphingosine-1-phosphate promotes angiogenesis in vivo in ischaemic hindlimbs of mice
Authors: O. Oyama, N. Sugimoto, X. Qi, N. Takuwa, K. Mizugishi, J. Koizumi, Y. Takuwa
Journal: Cardiovascular Research (2008)

The lysophospholipid mediator sphingosine-1-phosphate (S1P) acts on vascular endothelial cells to stimulate migration, proliferation, and capillary-like tube formation in vitro. It is unknown whether S1P stimulates in vivo angiogenesis induced under tissue ischaemia. We investigated the effects of both exogenously and endogenously overproduced S1P on post-ischaemic angiogenesis in murine hindlimbs.The effects of locally injected S1P on blood flow recovery, angiogenesis, and vascular permeability in mouse ischaemic hindlimbs that underwent femoral arteriectomy were assessed by a laser Doppler blood flow (LDBF) analysis, anti-CD31 immunohistochemistry, and Miles assay, respectively, and compared with those induced by fibroblast growth factor (FGF)-2. Blood flow recovery and angiogenesis in sphingosine kinase 1-transgenic mice that overproduce S1P endogenously were also assessed and compared with wild-type mice. The LDBF analysis showed that daily intramuscular administration of S1P dose-dependently stimulated blood flow recovery, resulting in up to twice as much blood flow when compared with vehicle control, which was accompanied by 1.7-fold increase in the capillary density. The optimal S1P effects were comparable with those obtained with FGF-2. S1P injection did not increase vascular permeability. The post-ischaemic blood flow recovery and angiogenesis were accelerated in sphingosine kinase 1-transgenic mice, which showed 40-fold higher sphingosine kinase activity and 1.8-fold higher S1P content in skeletal muscle than in wild-type (WT) mice, without an increase in the vascular permeability when compared with WT mice.These results indicate that either local exogenous S1P administration or endogenous S1P overproduction promotes post-ischaemic angiogenesis and blood flow recovery. These observations suggest potential therapeutic usefulness of S1P for tissue ischaemia.
The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04
Authors: Rachelle Salomon, John Franks, Elena A. Govorkova, Natalia A. Ilyushina, Hui-Ling Yen, Diane J. Hulse-Post, Jennifer Humberd, Michel Trichet, Jerold E. Rehg, Richard J. Webby, Robert G. Webster, Erich Hoffmann
Journal: The Journal of Experimental Medicine (2006)

H5N1 influenza viruses transmitted from poultry to humans in Asia cause high mortality and pose a pandemic threat. Viral genes important for cell tropism and replication efficiency must be identified to elucidate and target virulence factors. We applied reverse genetics to generate H5N1 reassortants combining genes of lethal A/Vietnam/1203/04 (VN1203), a fatal human case isolate, and nonlethal A/chicken/Vietnam/C58/04 (CH58) and tested their pathogenicity in ferrets and mice. The viruses' hemagglutinins have six amino acids differences, identical cleavage sites, and avian-like α-(2,3)–linked receptor specificity. Surprisingly, exchanging hemagglutinin and neuraminidase genes did not alter pathogenicity, but substituting CH58 polymerase genes completely attenuated VN1203 virulence and reduced viral polymerase activity. CH58's NS gene partially attenuated VN1203 in ferrets but not in mice. Our findings suggest that for high virulence in mammalian species an avian H5N1 virus with a cleavable hemagglutinin requires adaptive changes in polymerase genes to overcome the species barrier. Thus, novel antivirals targeting polymerase proteins should be developed.
Critically Ill Patients With Severe Acute Respiratory Syndrome
Authors: Robert A. Fowler
Journal: JAMA (2003)

ContextSevere acute respiratory syndrome (SARS) is a newly recognized infectious disease capable of causing severe respiratory failure.ObjectiveTo determine the epidemiological features, course, and outcomes of patients with SARS-related critical illness.Design, Setting, and PatientsRetrospective case series of 38 adult patients with SARS-related critical illness admitted to 13 intensive care units (ICUs) in the Toronto area between the onset of the outbreak and April 15, 2003. Data were collected daily during the first 7 days in the ICUs, and patients were followed up for 28 days.Main Outcome MeasuresThe primary outcome was mortality at 28 days after ICU admission. Secondary outcomes included rate of SARS-related critical illness, number of tertiary care ICUs and staff placed under quarantine, and number of health care workers (HCWs) contracting SARS secondary to ICU-acquired transmission.ResultsOf 196 patients with SARS, 38 (19%) became critically ill, 7 (18%) of whom were HCWs. The median (interquartile range [IQR]) age of the 38 patients was 57.4 (39.0-69.6) years. The median (IQR) duration between initial symptoms and admission to the ICU was 8 (5-10) days. Twenty-nine (76%) required mechanical ventilation and 10 of these (34%) experienced barotrauma. Mortality at 28 days was 13 (34%) of 38 patients and for those requiring mechanical ventilation, mortality was 13 (45%) of 29. Six patients (16%) remained mechanically ventilated at 28 days. Two of these patients had died by 8 weeks' follow-up. Patients who died were more often older, had preexisting diabetes mellitus, and on admission to hospital were more likely to have bilateral radiographic infiltrates. Transmission of SARS in 6 study ICUs led to closure of 73 medical-surgical ICU beds. In 2 university ICUs, 164 HCWs were quarantined and 16 (10%) developed SARS.ConclusionsCritical illness was common among patients with SARS. Affected patients had primarily single-organ respiratory failure, and half of mechanically ventilated patients died. The SARS outbreak greatly strained regional critical care resources.
Users' Guides to the Medical Literature
Authors: Roman Jaeschke
Journal: JAMA (1994)

<h3>CLINICAL SCENARIO</h3> You are a medical consultant asked by a surgical colleague to see a 78-year-old woman, now 10 days after abdominal surgery, who has become increasingly short of breath over the last 24 hours. She has also been experiencing what she describes as chest discomfort, which is sometimes made worse by taking a deep breath (but sometimes not). Abnormal findings on physical examination are restricted to residual tenderness in the abdomen and scattered crackles at both lung bases. Chest roentgenogram reveals a small right pleural effusion, but this is the first roentgenogram since the operation. Arterial blood gases show a Po<sub>2</sub>of 70 mm Hg, with a saturation of 92%. The electrocardiogram shows only nonspecific changes. You suspect that the patient, despite receiving 5000 U of heparin twice a day,
How should COPD patients exercise during respiratory rehabilitation? Comparison of exercise modalities and intensities to treat skeletal muscle dysfunction
Authors: M A Puhan, H J Schünemann, M Frey, M Scharplatz, L M Bachmann
Journal: Thorax (2005)

<b>Background:</b> Physical exercise is an important component of respiratory rehabilitation because it reverses skeletal muscle dysfunction, a clinically important manifestation of COPD associated with reduced health-related quality of life (HRQL) and survival. However, there is controversy regarding the components of the optimal exercise protocol. A study was undertaken to systematically evaluate and summarise randomised controlled trials (RCTs) comparing different exercise protocols for COPD patients. <b>Methods:</b> Six electronic databases, congress proceedings and bibliographies of included studies were searched without imposing language restrictions. Two reviewers independently screened all records and extracted data on study samples, interventions and methodological characteristics of included studies. <b>Results:</b> The methodological quality of the 15 included RCTs was low to moderate. Strength exercise led to larger improvements of HRQL than endurance exercise (weighted mean difference for Chronic Respiratory Questionnaire 0.27, 95% CI 0.02 to 0.52). Interval exercise seems to be of similar effectiveness as continuous exercise, but there are few data on clinically relevant outcomes. One small RCT which included patients with mild COPD compared the effect of high and low intensity exercise (at 80% and 40% of the maximum exercise capacity, respectively) and found larger physiological training effects from high intensity exercise. <b>Conclusions:</b> Strength exercise should be routinely incorporated in respiratory rehabilitation. There is insufficient evidence to recommend high intensity exercise for COPD patients and investigators should conduct larger high quality trials to evaluate exercise intensities in patients with moderate to severe COPD.
False-positive results with PCR to detect leukaemia-specific transcript
Authors: Timothy Hughes, J.W.G Janssen, Gareth Morgan, Philippe Martiat, Guiseppe Saglio, J.M Pignon, FrancoPier Pignatti, Ken Mills, Armand Keating, Eliane Gluckman, C.R Bartram, J.M Goldman
Journal: The Lancet (1990)
Expression of the soluble vascular endothelial growth factor receptor-1 in cutaneous melanoma: role in tumour progression
Authors: F. Ruffini, C.M. Failla, A. Orecchia, M.R. Bani, A.S. Dorio, C. Fortes, G. Zambruno, G. Graziani, R. Giavazzi, S. D’Atri, P.M. Lacal
Journal: British Journal of Dermatology (2010)

Vascular endothelial growth factor (VEGF)-A, placenta growth factor (PlGF) and their corresponding membrane receptors are involved in autocrine and paracrine regulation of melanoma growth and metastasis. Besides the membrane receptors, a soluble form of the VEGF receptor (VEGFR)-1 (sVEGFR-1) has been identified, that behaves both as a decoy receptor, sequestering VEGF-A and PlGF, and as an extracellular matrix (ECM) molecule, promoting endothelial cell adhesion and migration through the interaction with α5β1 integrin.To analyse whether sVEGFR-1 plays a role during melanoma progression.sVEGFR-1 expression was evaluated in a panel of 36 melanoma cell lines and 11 primary human melanocyte cultures by quantitative real-time polymerase chain reaction analysis and in specimens of primary or metastatic melanoma lesions from 23 patients by immunohistochemical analysis.sVEGFR-1 expression was highly upregulated in melanoma cell lines with respect to human melanocytes. Interestingly, cell lines obtained from cutaneous metastases showed a significant reduction of sVEGFR-1 expression, as compared with cell lines derived from primary tumours. These results were confirmed by immunohistochemical analysis of sections from primary skin melanomas and the corresponding cutaneous metastases, suggesting that modulation of sVEGFR-1 expression influences ECM invasion by melanoma cells and metastasis localization. Moreover, we provide evidence that adhesion of melanoma cells to sVEGFR-1 is favoured by the activation of a VEGF-A/VEGFR-2 autocrine loop.Our data strongly suggest that sVEGFR-1 plays a role in melanoma progression and that low sVEGFR-1/VEGF-A and sVEGFR-1/transmembrane VEGFR-1 ratios might predict a poor outcome in patients with melanoma.
The A<sub>3</sub>Adenosine Receptor: History and Perspectives
Authors: Pier Andrea Borea, Katia Varani, Fabrizio Vincenzi, Pier Giovanni Baraldi, Mojgan Aghazadeh Tabrizi, Stefania Merighi, Stefania Gessi
Journal: Pharmacological Reviews (2014)

By general consensus, the omnipresent purine nucleoside adenosine is considered a major regulator of local tissue function, especially when energy supply fails to meet cellular energy demand. Adenosine mediation involves activation of a family of four G protein–coupled adenosine receptors (ARs): A<sub>1</sub>, A<sub>2A</sub>, A<sub>2B</sub>, and A<sub>3</sub>. The A<sub>3</sub> adenosine receptor (A<sub>3</sub>AR) is the only adenosine subtype to be overexpressed in inflammatory and cancer cells, thus making it a potential target for therapy. Originally isolated as an orphan receptor, A<sub>3</sub>AR presented a twofold nature under different pathophysiologic conditions: it appeared to be protective/harmful under ischemic conditions, pro/anti-inflammatory, and pro/antitumoral depending on the systems investigated. Until recently, the greatest and most intriguing challenge has been to understand whether, and in which cases, selective A<sub>3</sub> agonists or antagonists would be the best choice. Today, the choice has been made and A<sub>3</sub>AR agonists are now under clinical development for some disorders including rheumatoid arthritis, psoriasis, glaucoma, and hepatocellular carcinoma. More specifically, the interest and relevance of these new agents derives from clinical data demonstrating that A<sub>3</sub>AR agonists are both effective and safe. Thus, it will become apparent in the present review that purine scientists do seem to be getting closer to their goal: the incorporation of adenosine ligands into drugs with the ability to save lives and improve human health.
An Assessment of Prostatectomy for Benign Urinary Tract Obstruction
Authors: John E. Wennberg
Journal: JAMA (1988)

IN MAINE, the efforts of practicing urologists to understand how their clinical decisions contribute to the striking variations in rates of prostatectomy from one community to another led to a critical evaluation of the theories under See also pp 3010 and 3018. lying the decision to operate. Specific aspects of our work have been described elsewhere.<sup>1-3</sup>The purpose of this report is to provide an overview of the prostatectomy assessment project—its background and relevance, the methods used, the principal findings and recommendations—and to comment on the applicability of the approach to the evaluation of other common medical practices. <h3>BACKGROUND</h3> The project was an initiative of the Maine Medical Assessment Program,<sup>4,5</sup>an ongoing program sponsored by the Maine Medical Association to respond to the small-area variations in medical practice patterns seen among Maine communities. Striking geographic variations in use are characteristic of many operations, diagnostic procedures, and causes of
Flexible bronchoscopy in children: an open airway
Authors: J. Gerritsen
Journal: European Respiratory Journal (2003)

About 35 yrs ago the airways of neonates, infants and children were predominantly the working space of ear, nose and throat physicians and a sporadic paediatrician. The main indications, at that time, for rigid bronchoscopy were: aspiration of a corpus alienum, congenital web of the larynx or trachea, exploration of abnormalities of the airways, etc . This technique was only available in a limited number of institutes, and mostly in academic settings. From that time many paediatric pulmonologists learned the technique of rigid bronchoscopy at the department of E. Szekely, the Pediatric Institute, Svabhegy, Budapest, Hungary 1. This centre was specialised in rigid bronchoscopy and fluoroscopy. Back at home it was often very difficult to compete with the already existing departments.

The introduction of the special paediatric bronchoscopes, with a smaller diameter and a suction channel changed this dramatically within a period of 10–20 yrs. One of the leading publications with the challenging title: “Spelunking in the paediatric airways: Explorations with the flexible fiberoptic bronchoscope” by Wood 2 demonstrated that this technique was useful in …
The Lipoxin Receptor ALX: Potent Ligand-Specific and Stereoselective Actions in Vivo
Authors: Nan Chiang, Charles N. Serhan, Sven-Erik Dahlén, Jeffrey M. Drazen, Douglas W. P. Hay, G. Enrico Rovati, Takao Shimizu, Takehiko Yokomizo, Charles Brink
Journal: Pharmacological Reviews (2006)

Lipoxins (LXs) and aspirin-triggered LX (ATL) are trihydroxytetraene-containing eicosanoids generated from arachidonic acid that are distinct in structure, formation, and function from the many other proinflammatory lipid-derived mediators. These endogenous eicosanoids have now emerged as founding members of the first class of lipid/chemical mediators involved in the resolution of the inflammatory response. Lipoxin A<sub>4</sub> (LXA<sub>4</sub>), ATL, and their metabolic stable analogs elicit cellular responses and regulate leukocyte trafficking in vivo by activating the specific receptor, ALX. ALX was the first receptor cloned and identified as a G protein-coupled receptor (GPCR) for lipoxygenase-derived eicosanoids with demonstrated cell type-specific signaling pathways. ALX at the level of DNA has sequence homology to the <i>N</i>-formylpeptide receptor and as an orphan GPCR was initially referred to as the <i>N</i>-formylpeptide receptor-like 1. Although LXA<sub>4</sub> is the endogenous potent ligand for ALX activation, a number of peptides can also activate this receptor to stimulate calcium mobilization and chemotaxis in vitro. In contrast with LXA<sub>4</sub>, the counterparts of many of these peptides in vivo remain to be established. The purpose of this review is to highlight the molecular characterization of the ALX receptor and provide an overview of the ALX-LXA<sub>4</sub> axis responsible for anti-inflammatory and proresolving signals in vivo. The information in this review provides further support for the initial nomenclature proposition for this GPCR as ALX.
Compressed Sensing, Sparsity, and Dimensionality in Neuronal Information Processing and Data Analysis
Authors: Surya Ganguli, Haim Sompolinsky
Journal: Annual Review of Neuroscience (2012)

The curse of dimensionality poses severe challenges to both technical and conceptual progress in neuroscience. In particular, it plagues our ability to acquire, process, and model high-dimensional data sets. Moreover, neural systems must cope with the challenge of processing data in high dimensions to learn and operate successfully within a complex world. We review recent mathematical advances that provide ways to combat dimensionality in specific situations. These advances shed light on two dual questions in neuroscience. First, how can we as neuroscientists rapidly acquire high-dimensional data from the brain and subsequently extract meaningful models from limited amounts of these data? And second, how do brains themselves process information in their intrinsically high-dimensional patterns of neural activity as well as learn meaningful, generalizable models of the external world from limited experience?
High-Cost Generic Drugs — Implications for Patients and Policymakers
Authors: Jonathan D. Alpern, William M. Stauffer, Aaron S. Kesselheim
Journal: New England Journal of Medicine (2014)

Some older generic drugs have become very expensive, owing to factors including drug shortages, supply disruptions, and consolidations in the generic-drug industry. But generics manufacturers that legally obtain a market monopoly can also unilaterally raise prices.