tbuckley/cabot-search huggingface dataset:
Another fine mess
Authors: L. Farrell
Journal: BMJ (1999)

“Who would have thought the old man to have had so much blood in him,” said Lady Macbeth; we sense her unrelenting ambition beginning to ebb and I reckon that Shakespeare must have been painfully conversant with both the spiritual and practical import of spilt blood. It can be a cathartic sight, and it makes a spectacle totally disproportionate to the amount bled.

Just the smallest drop can masquerade as a life threatening haemorrhage. “Don't …
Breast conservation therapy for stage I or stage II breast cancer: a meta-analysis of randomized controlled trials
Authors: S.H. Yang, K.H. Yang, Y.P. Li, Y.C. Zhang, X.D. He, A.L. Song, J.H. Tian, L. Jiang, Z.G. Bai, L.F. He, Y.L. Liu, B. Ma
Journal: Annals of Oncology (2008)
Inhaled nitric oxide in cardiology practice
Authors: C Hayward
Journal: Cardiovascular Research (1999)

Inhaled nitric oxide allows selective pulmonary vasodilatation with rapidity of action. It is effective in the acute post-operative management of pulmonary hypertension in cardiac surgical patients and is also valuable in assessing the pulmonary vasodilator capacity in patients with chronic pulmonary hypertension. This review examines the current role of inhaled nitric oxide in cardiac medicine, discussing issues concerning its administration and toxicity, as well as a summary of clinical studies in cardiac patients. New roles, as a modifier of platelet and leukocyte function, post-thrombolysis and following lung transplantation are described. New agents and alternative therapies, which prolong pulmonary activity, are also discussed.
Modulation of Human Immunodeficiency Virus 1 Replication by Interferon Regulatory Factors
Authors: Marco Sgarbanti, Alessandra Borsetti, Nicola Moscufo, Maria C. Bellocchi, Barbara Ridolfi, Filomena Nappi, Giulia Marsili, Giovanna Marziali, Eliana M. Coccia, Barbara Ensoli, Angela Battistini
Journal: The Journal of Experimental Medicine (2002)

Transcription of the human immunodeficiency virus (HIV)-1 is controlled by the cooperation of virally encoded and host regulatory proteins. The Tat protein is essential for viral replication, however, expression of Tat after virus entry requires HIV-1 promoter activation. A sequence in the 5′ HIV-1 LTR, containing a binding site for transcription factors of the interferon regulatory factors (IRF) family has been suggested to be critical for HIV-1 transcription and replication. Here we show that IRF-1 activates HIV-1 LTR transcription in a dose-dependent fashion and in the absence of Tat. This has biological significance since IRF-1 is produced early upon virus entry, both in cell lines and in primary CD4+ T cells, and before expression of Tat. IRF-1 also cooperates with Tat in amplifying virus gene transcription and replication. This cooperation depends upon a physical interaction that is blocked by overexpression of IRF-8, the natural repressor of IRF-1, and, in turn is released by overexpression of IRF-1. These data suggest a key role of IRF-1 in the early phase of viral replication and/or during viral reactivation from latency, when viral transactivators are absent or present at very low levels, and suggest that the interplay between IRF-1 and IRF-8 may play a key role in virus latency.
Consensus Report of the National Cancer Institute Clinical Trials Planning Meeting on Pancreas Cancer Treatment
Authors: Philip A. Philip, Margaret Mooney, Deborah Jaffe, Gail Eckhardt, Malcolm Moore, Neal Meropol, Leisha Emens, Eileen O'Reilly, Murray Korc, Lee Ellis, Jacqueline Benedetti, Mace Rothenberg, Christopher Willett, Margaret Tempero, Andrew Lowy, James Abbruzzese, Diane Simeone, Sunil Hingorani, Jordan Berlin, Joel Tepper
Journal: Journal of Clinical Oncology (2009)

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality, despite significant improvements in diagnostic imaging and operative mortality rates. The 5-year survival rate remains less than 5% because of microscopic or gross metastatic disease at time of diagnosis. The Clinical Trials Planning Meeting in pancreatic cancer was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to discuss the integration of basic and clinical knowledge in the design of clinical trials in PDAC. Major emphasis was placed on the enhancement of research to identify and validate the relevant targets and molecular pathways in PDAC, cancer stem cells, and the microenvironment. Emphasis was also placed on developing rational combinations of targeted agents and the development of predictive biomarkers to assist selection of patient subsets. The development of preclinical tumor models that are better predictive of human PDAC must be supported with wider availability to the research community. Phase III clinical trials should be implemented only if there is a meaningful clinical signal of efficacy and safety in the phase II setting. The emphasis must therefore be on performing well-designed phase II studies with uniform sets of basic entry and evaluation criteria with survival as a primary endpoint. Patients with either metastatic or locally advanced PDAC must be studied separately.
Pancoast's syndrome due to Pseudomonas aeruginosa infection of the lung apex.
Authors: O Vandenplas, C Mercenier, J P Trigaux, L Delaunois
Journal: Thorax (1991)

Abstract A case of Pancoast's syndrome was caused by Pseudomonas aeruginosa infection of the lung apex. The infection extended to extrapleural structures of the thoracic inlet.
Carbon‐Dot‐Based Two‐Photon Visible Nanocarriers for Safe and Highly Efficient Delivery of siRNA and DNA
Authors: Liqin Wang, Xiaoyong Wang, Ashwinkumar Bhirde, Jianbo Cao, Yun Zeng, Xinglu Huang, Yaping Sun, Gang Liu, Xiaoyuan Chen
Journal: Advanced Healthcare Materials (2014)

A simple and versatile nanoparticulate siRNA and DNA delivery vehicle is reported, based on photonic Cdots by using Alkyl–PEI2k for surface passivation.
Cellular Mechanisms Underlying Complete Hematological Response of Chronic Myeloid Leukemia to BRAF and MEK1/2 Inhibition in a Patient with Concomitant Metastatic Melanoma
Authors: Miles C. Andrews, Natalie Turner, Janis Boyd, Andrew W. Roberts, Andrew P. Grigg, Andreas Behren, Jonathan Cebon
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Targeted MEK inhibition is an emerging therapy in a number of solid tumors. It holds particular promise in BRAF V600E mutation–positive malignant melanoma, where constitutive activation and cell growth through the MAP kinase (MAPK) pathway is well established. In vitro and preclinical research indicates that MAPK pathway activation is important in chronic myeloid leukemia (CML) leukemogenesis; however, the potential of MEK inhibition has not yet been investigated clinically in the setting of such hematologic malignancies. Experimental Design: We report a case of complete hematologic response of CML to MEK inhibition in a patient with synchronous metastatic melanoma, who received treatment with combination BRAF and MEK1/2 inhibitors. We studied the effects of these agents on proliferation and outgrowth of myeloid precursors, and longitudinal shifts in peripheral blood phenotyping during the course of treatment. A model cell line system was used to examine the effects of dabrafenib and trametinib on MAPK and BCR–ABL1 signaling. Results: After 35 weeks on treatment with BRAF and MEK inhibitors, complete hematologic response was observed without recourse to BCR–ABL1–targeted therapy. MEK inhibition was principally responsible for impaired proliferation of both mature and primitive myeloid precursors, as well as growth and hemoglobinization of erythroid precursors. Paradoxical activation of the MAPK pathway was seen in response to BRAF inhibitor therapy but this was easily overcome by clinically relevant doses of concurrent MEK inhibitor. Conclusions: These studies suggest that further evaluation of the optimal MAPK targeting approach is warranted to extend therapeutic options in CML. Clin Cancer Res; 21(23); 5222–34. ©2015 AACR.
Local Recurrence in Mismatch Repair–Proficient Colon Cancer Predicted by an Infiltrative Tumor Border and Lack of CD8+ Tumor-Infiltrating Lymphocytes
Authors: Inti Zlobec, Luigi M. Terracciano, Alessandro Lugli
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The identification of colon cancer patients at high risk of local recurrence is necessary to improve the selection of patients for more tailored treatment protocols. The aim of this study was to develop a predictive model of local recurrence by assessing the independent predictive effect of 7 clinicopathologic features, 24 protein markers of tumor progression, and their multifeature combinations in mismatch repair–proficient colon cancers. Experimental Design: Immunohistochemistry for 24 protein markers was done on 269 patients with complete clinicopathologic data. After univariate and multivariable analyses, independent predictors of local recurrence were identified and their multifeature combinations were analyzed. Kaplan-Meier and Cox proportional hazards regression were done for survival analysis. Results: Local recurrence was observed in 119 patients (55.8%). Independent predictors of tumor recurrence were lymph node involvement (P = 0.006), absence of CD8+ tumor-infiltrating lymphocytes (TIL; P &amp;lt; 0.001), and infiltrative tumor margin (P &amp;lt; 0.001). This independent effect persisted after adjusting for adjuvant therapy. Risk of recurrence was 0.75 and the 5-year survival rate was 8.8% in patients with these three adverse features. Node-negative patients with an infiltrative tumor margin and absence of CD8+ TILs were identified as high risk with a probability of 0.55 for recurrence and a 60% 5-year survival rate. The remaining node-negative cases fared significantly better with risks ranging from 8% to 26% and 5-year survival rates reaching 97.6%. Conclusions: An infiltrative tumor margin and absence of CD8+ TILs are highly predictive of local recurrence in node-negative mismatch repair–proficient colon cancer and may help to identify high-risk patients who may benefit from adjuvant chemotherapy.
Skin Electroporation of a Plasmid Encoding hCAP-18/LL-37 Host Defense Peptide Promotes Wound Healing
Authors: Lars Steinstraesser, Martin C Lam, Frank Jacobsen, Paolo E Porporato, Kiran Kumar Chereddy, Mustafa Becerikli, Ingo Stricker, Robert EW Hancock, Marcus Lehnhardt, Pierre Sonveaux, Véronique Préat, Gaëlle Vandermeulen
Journal: Molecular Therapy (2014)

Host defense peptides, in particular LL-37, are emerging as potential therapeutics for promoting wound healing and inhibiting bacterial growth. However, effective delivery of the LL-37 peptide remains limiting. We hypothesized that skin-targeted electroporation of a plasmid encoding hCAP-18/LL-37 would promote the healing of wounds. The plasmid was efficiently delivered to full-thickness skin wounds by electroporation and it induced expression of LL-37 in the epithelium. It significantly accelerated reepithelialization of nondiabetic and diabetic wounds and caused a significant VEGFa and interleukin (IL)-6 induction. IL-6 was involved in LL-37-mediated keratinocyte migration in vitro and IL-6 neutralizing antibodies delivered to mice were able to suppress the wound healing activity of the hCAP-18/LL-37 plasmid. In a hindlimb ischemia model, electroporation of the hCAP-18/LL-37 plasmid increased blood perfusion, reduced muscular atrophy, and upregulated the angiogenic chemokines VEGFa and SDF-1a, and their receptors VEGF-R and CXCR-4. These findings demonstrate that a localized gene therapy with LL-37 is a promising approach for the treatment of wounds.
<i>ERCC5</i> Is a Novel Biomarker of Ovarian Cancer Prognosis
Authors: Christine S. Walsh, Seishi Ogawa, Hisae Karahashi, Daniel R. Scoles, James C. Pavelka, Hang Tran, Carl W. Miller, Norihiko Kawamata, Charles Ginther, Judy Dering, Masashi Sanada, Yasuhito Nannya, Dennis J. Slamon, H. Phillip Koeffler, Beth Y. Karlan
Journal: Journal of Clinical Oncology (2008)

To identify a biomarker of ovarian cancer response to chemotherapy. PATIENTS AND METHODS Study: participants had epithelial ovarian cancer treated with surgery followed by platinum-based chemotherapy. DNA and RNA were isolated from frozen tumors and normal DNA was isolated from matched peripheral blood. A whole-genome loss of heterozygosity (LOH) analysis was performed using a high-density oligonucleotide array. Candidate genomic areas that predicted enhanced response to chemotherapy were identified with Cox proportional hazards methods. Gene expression analyses were performed through microarray experiments. Candidate genes were tested for independent effects on survival using Cox proportional hazards models, Kaplan-Meier survival curves, and the log-rank test.Using a whole-genome approach to study the molecular determinants of ovarian cancer response to platinum-based chemotherapy, we identified LOH of a 13q region to predict prolonged progression-free survival (PFS; hazard ratio, 0.23; P = .006). ERCC5 was identified as a candidate gene in this region because of its known function in the nucleotide excision repair pathway, the unique DNA repair pathway that removes platinum-DNA adducts. We found LOH of the ERCC5 gene locus and downregulation of ERCC5 gene expression to predict prolonged PFS. Integration of genomic and gene expression data shows a correlation between 13q LOH and ERCC5 gene downregulation.ERCC5 is a novel biomarker of ovarian cancer prognosis and a potential therapeutic target of ovarian cancer response to platinum chemotherapy.
Impairment of organ-specific T cell negative selection by diabetes susceptibility genes: genomic analysis by mRNA profiling.
Authors: Adrian Liston, Kristine Hardy, Yvonne Pittelkow, Susan R Wilson, Lydia E Makaroff, Aude M Fahrer, Christopher C Goodnow
Journal: Genome biology (2007)

Abstract Background T cells in the thymus undergo opposing positive and negative selection processes so that the only T cells entering circulation are those bearing a T cell receptor (TCR) with a low affinity for self. The mechanism differentiating negative from positive selection is poorly understood, despite the fact that inherited defects in negative selection underlie organ-specific autoimmune disease in AIRE -deficient people and the non-obese diabetic (NOD) mouse strain Results Here we use homogeneous populations of T cells undergoing either positive or negative selection in vivo together with genome-wide transcription profiling on microarrays to identify the gene expression differences underlying negative selection to an Aire -dependent organ-specific antigen, including the upregulation of a genomic cluster in the cytogenetic band 2F. Analysis of defective negative selection in the autoimmune-prone NOD strain demonstrates a global impairment in the induction of the negative selection response gene set, but little difference in positive selection response genes. Combining expression differences with genetic linkage data, we identify differentially expressed candidate genes, including Bim , Bnip3 , Smox , Pdrg1 , Id1 , Pdcd1 , Ly6c , Pdia3 , Trim30 and Trim12 . Conclusion The data provide a molecular map of the negative selection response in vivo and, by analysis of deviations from this pathway in the autoimmune susceptible NOD strain, suggest that susceptibility arises from small expression differences in genes acting at multiple points in the pathway between the TCR and cell death.
Cytokine Therapy for Crohn's Disease: Advances in Translational Research
Authors: Theresa T. Pizarro, Fabio Cominelli
Journal: Annual Review of Medicine (2007)

Crohn's disease (CD) and ulcerative colitis (UC), the two idiopathic inflammatory bowel diseases (IBDs), affect almost two million individuals in North America and several million worldwide. Cytokines are important in the pathogenesis of CD, and their manipulation has successfully reduced disease severity and maintained remission. Following the discovery of novel cytokines and the role they may play in gut mucosal immunity, as well as the emergence of new concepts and changing paradigms in CD pathogenesis, the roles of several cytokines have been elucidated and tested in both preclinical animal models and clinical trials of patients with IBD. Complementary to this, proof of concept for new cytokine targets is rapidly developing, with the possibility of future cytokine-based therapies that may offer greater specificity and decreased toxicity for the treatment of CD. This review discusses novel concepts in CD pathogenesis and the roles of cytokines in the initiation and perpetuation of disease. In addition, we review applications of cytokine-based therapies in human clinical trials and preclinical animal studies. Finally, we discuss novel cytokine targets not yet investigated in vivo and describe their potential contribution to CD pathogenesis.
Volume targeted versus pressure support non-invasive ventilation in patients with super obesity and chronic respiratory failure: a randomised controlled trial
Authors: Patrick Brian Murphy, Craig Davidson, Matthew David Hind, Anita Simonds, Adrian J Williams, Nicholas S Hopkinson, John Moxham, Michael Polkey, Nicholas Hart
Journal: Thorax (2012)

<h3>Introduction</h3> Automatic titration modes of non-invasive ventilation, including average volume assured pressure support (AVAPS), are hybrid technologies that target a set volume by automated adjustment of pressure support (PS). These automated modes could offer potential advantages over fixed level PS, in particular, in patients who are super obese. <h3>Methods</h3> Consecutive patients with obesity hypoventilation syndrome were enrolled in a two-centre prospective single-blind randomised controlled trial of AVAPS versus fixed-level PS using a strict protocolised setup. <h3>Measurements</h3> The primary outcome was change in daytime arterial PCO<sub>2</sub> (PaCO<sub>2</sub>) at 3 months. Body composition, physical activity (7-day actigraphy) and health-related quality of life (severe respiratory insufficiency questionnaire, SRI) were secondary outcome measures. <h3>Results</h3> 50 patients (body mass index 50±7 kg/m<sup>2</sup>; 55±11 years; 53% men) were enrolled with a mean PaCO<sub>2</sub> of 6.9±0.8 kPa and SRI of 53±17. 46 patients (23 AVAPS and 23 PS) completed the trial. At 3 months, improvements in PaCO<sub>2</sub> were observed in both groups (AVAPS ∆0.6 kPa, 95% CI 0.2 to 1.1, p&lt;0.01 vs PS ∆0.6 kPa, 95% CI 0.1 to 1.1, p=0.02) but no between-group difference (∆−0.1 kPa, 95% CI −0.7 to 0.6, p=0.87). SRI also improved in both groups (AVAPS ∆11, 95% CI 6 to 17, p&lt;0.001 vs PS ∆7, 95% CI 1 to 12, p=0.02; between groups ∆5, 95% CI −3 to 12, p=0.21). Secondary analysis of both groups combined showed improvements in daytime physical activity that correlated with reduction in fat mass (r=0.48; p=0.01). <h3>Conclusion</h3> The study demonstrated no differences between automated AVAPS mode and fixed-level PS mode using a strict protocolised setup in patients who were super obese. The data suggest that the management of sleep-disordered breathing may enhance daytime activity and promote weight loss in super-obese patients. Trial registration details available at http://www.controlled-trials.com/ISRCTN63940700
Radiolabeled Cell Distribution After Intramyocardial, Intracoronary, and Interstitial Retrograde Coronary Venous Delivery
Authors: Dongming Hou, Eyas Al-Shaykh Youssef, Todd J. Brinton, Ping Zhang, Pamela Rogers, Erik T. Price, Alan C. Yeung, Brian H. Johnstone, Paul G. Yock, Keith L. March
Journal: Circulation (2005)

Background— Several clinical studies are evaluating the therapeutic potential of delivery of various progenitor cells for treatment of injured hearts. However, the actual fate of delivered cells has not been thoroughly assessed for any cell type. We evaluated the short-term fate of peripheral blood mononuclear cells (PBMNCs) after intramyocardial (IM), intracoronary (IC), and interstitial retrograde coronary venous (IRV) delivery in an ischemic swine model. Methods and Results— Myocardial ischemia was created by 45 minutes of balloon occlusion of the left anterior descending coronary artery. Six days later, 10 7 111 indium-oxine–labeled human PBMNCs were delivered by IC (n=5), IM (n=6), or IRV (n=5) injection. The distribution of injected cells was assessed by γ-emission counting of harvested organs. For each delivery method, a significant fraction of delivered cells exited the heart into the pulmonary circulation, with 26±3% (IM), 47±1% (IC), and 43±3% (IRV) of cells found localized in the lungs. Within the myocardium, significantly more cells were retained after IM injection (11±3%) compared with IC (2.6±0.3%) ( P &lt;0.05) delivery. IRV delivery efficiency (3.2±1%) trended lower than IM infusion for PBMNCs, but this difference did not reach significance. The IM technique displayed the greatest variability in delivery efficiency by comparison with the other techniques. Conclusions— The majority of delivered cells is not retained in the heart for each delivery modality. The clinical implications of these findings are potentially significant, because cells with proangiogenic or other therapeutic effects could conceivably have effects in other organs to which they are not primarily targeted but to which they are distributed. Also, we found that although IM injection was more efficient, it was less consistent in the delivery of PBMNCs compared with IC and IRV techniques.
Elevated alanine aminotransferase (ALT) in blood donors: an assessment of the main causes and its relationship to the development of hepatitis
Authors: F.L. Gonçales, R.S.B. Stucchi, PM.O. Papaiordanou, M.H.P. Pavan, M.C. Chiovitti, C.A.F. Escanhoela, N.S.L. Gonçales, J.R.R. Pinho
Journal: Journal of Hepatology (1998)
Effect of HLA-B and HLA-DR genes on susceptibility to and severity of spondyloarthropathies in Mexican patients
Authors: G Vargas-Alarcon
Journal: Annals of the Rheumatic Diseases (2002)

<b>Objective:</b> To investigate the role of HLA-B and HLA-DR genes as contributors to genetic susceptibility and clinical expression of the spondyloarthropathies (SpA) in the Mexican population. <b>Methods:</b> The study included 172 patients with SpA (undifferentiated SpA 83, ankylosing spondylitis (AS) 64, and reactive arthritis 25) and 99 healthy controls. The HLA-B and HLA-DR alleles were detected by the polymerase chain reaction with sequence-specific primers technique. Patient assessment included demographic data, diagnostic categories, and disease patterns. Statistical methods included the Mantel-Haenzel χ<sup>2</sup> test, Fisher9s exact test, and Woolf method for odds ratio (OR). Differences of continuous variables between HLA allele groups were calculated by Student9s <i>t</i> test. <b>Results:</b> Increased frequencies of HLA-B27 (pCh10<sup>−3</sup>, OR=28.7), HLA-DR1 (pC=0.045, OR=2.77), and HLA-B15 (p=0.034, pC=NS, OR=2.04) alleles in the whole group were found. HLA-B27 strength of association (OR) was 41.4 in AS; 20.9 in undifferentiated SpA; 27.2 in reactive arthritis. HLA-DR1 and HLA-B15 were increased in undifferentiated SpA (pC=0.045, OR=2.98 and p=0.004, pC=NS, OR=2.75). By analysing 58 HLA-B27 negative patients it was found that HLA-B15 and HLA-DR1 associations with SpA were independent of HLA-B27; increased frequencies of HLA-B15 were found in the whole SpA group and in patients with undifferentiated SpA (pC=0.03, OR=3.09 and pCh0.01, OR=3.77) and of HLA-DR1 in the latter (p=0.04, pC=NS, OR=3.15). HLA-B27 positive patients were younger than HLA-B27 negative patients at onset (p=0.03), but HLA-DR1 positive patients were older than HLA-DR1 negative patients (p=0.03). Bath indices for disease activity and functioning were higher in HLA-B27 positive patients (p=0.006 and p=0.004 <i>v</i> HLA-B27 negative patients). In contrast, neither HLA-DR1 nor HLA-B15 influenced these indices. <b>Conclusion:</b> Apart from HLA-B27, there is a significant association of HLA-DR1 and HLA-B15 with SpA in Mexicans which is independent of B27. HLA-B27 is associated with younger age at onset and increased disease severity and HLA-DR1 with older age at onset. The strength of HLA-B15, HLA-B27, and HLA-DR1 associations varied in different forms of SpA.