tbuckley/cabot-search huggingface dataset:
SG2285, a novel C2-aryl-substituted pyrrolobenzodiazepine dimer prodrug with potent antitumor activity
Authors: John Hartley, Christopher Martin, Anzu Hamaguchi, Marissa Coffils, Zhizhi Chen, Stephen Gregson, Christopher Pepper, Thet Thet Lin, Christopher Fegan, David Thurston, Philip Howard
Journal: Cancer Research (2008)

3302  The pyrrolobenzodiazepines (PBDs) are a family of naturally occurring antitumor antibiotics. Many of the most potent family members contain a C2-endo-exo unsaturated motif associated with the pyrrolo C-ring of the PBD. SG2202 is a PBD dimer consisting of two PBD monomer units, which retain the endo-exo unsaturation motif in the form of a C2-aryl substituent conjugated to a 2,3 double bond, joined via their C8/C8’ positions through a propyldioxy linker. SG2285 is a prodrug of SG2202 whereby two bisulphite groups inactivate the N10-C11 imines of the PBD units. Once the bisulphite groups are eliminated to produce SG2202 the two PBD imine moieties are able to bind covalently in the minor groove of DNA to the N2-positions of guanine on opposite strands of DNA to form an interstrand crosslink (ICL).  SG2285 is highly potent in vitro, with sub-nM GI50 values in most human tumour cell lines tested using the Alamar blue assay following continuous exposure. A modification of the single cell gel electrophoresis (comet) assay has shown SG2285 to be highly efficient at producing ICLs in cells, which form more slowly than those produced by SG2202. Using DNA repair-deficient cell lines cellular sensitivity to SG2285 was shown to be dependent on the ERCC1/XPF heterodimer and homologous recombination. In 20 primary chronic lymphocytic leukaemia (B-CLL) samples the mean LD50 value (Annexin V / propidium iodide assay) was 8.3(±3.4) nM. Although there was a trend towards increased resistance to SG2285 in cells from previously treated (n=10) compared to untreated (n=10) patients this did not reach significance (p=0.07). LD50 values in normal age-matched B- and T-lymphocytes were significantly higher (p
Treatment of Cholangiocarcinoma
Authors: Kelly M. McMasters, Steven A. Curley
Journal: Liver Cancer (1998)

Cholangiocarcinomas, malignant tumors that arise from the intrahepatic or extrahepatic bile ducts, are rare, comprising fewer than 10% of primary malignancies of the liver.1 There are only about 4000 new cases of cholangiocarcinoma per year in the United States, being diagnosed most frequently during the fifth and sixth decades of life.2 The prognosis for patients with this disease remains dismal despite advances in the operative and nonoperative management.3–7
Flagellin suppresses experimental asthma by generating regulatory dendritic cells and T cells
Authors: Jae-Uoong Shim, Shee Eun Lee, Won Hwang, Changhon Lee, Jung-Won Park, Jung-Ho Sohn, Jong Hee Nam, Young Kim, Joon Haeng Rhee, Sin-Hyeog Im, Young-Il Koh
Journal: Journal of Allergy and Clinical Immunology (2015)
A human metapneumovirus outbreak at a community hospital in England, July to September 2010
Authors: M A Degail, G J Hughes, C Maule, C Holmes, M Lilley, R Pebody, J Bonnet, A Bermingham, S Bracebridge
Journal: Eurosurveillance (2012)

We describe an outbreak of human metapneumovirus (hMPV) which occurred in July-September 2010 at a community hospital in the East of England. Based on the medical and nursing records, cases were retrospectively defined as suspected if they had had an influenza-like illness (ILI), and probable if they had had an ILI and an epidemiological link to a laboratory-confirmed case. Of a total of 17 symptomatic inpatients, five were classified as probable cases, five were laboratory confirmed and seven were suspected. The attack rate was 29.4% for confirmed and probable cases combined. The median age of symptomatic inpatients was 85 years-old (range 68-96) and the majority (16/17) of symptomatic inpatients had an underlying medical condition. Control measures introduced appeared to restrict further exposure of susceptible patients to infection although modelling suggested that up to four of 10 confirmed and probable cases (40%) could have been prevented through more timely diagnosis and recognition of an outbreak. These findings suggest that there should be increased awareness of hMPV infection within healthcare settings, particularly when the population at risk has a high prevalence of underlying co-morbidities.
Localised prostate cancer: can we do better?
Authors: T. Prior
Journal: BMJ (2000)

Prostate cancer is now the commonest male cancer and the second commonest cause of male cancer deaths. Death rates have doubled over the past 20 years, and mortality is predicted to exceed that for lung cancer in 15 years' time. This increased incidence of prostate cancer has led to considerable efforts to improve on local treatments and boost survival. In the United Kingdom 60% of patients with prostate cancer are diagnosed with metastatic disease. Screening for prostate specific antigen (PSA) in North America has led to increased detection of the disease at an earlier stage, but not yet to increased survival.1 Screening has, however, meant that more patients have become candidates for radical local treatments. What evidence do we have that we are doing any better for localised prostate cancer?

Localised prostate cancer may be treated surgically or with radiotherapy or managed by “watchful waiting,” with treatment only when disease progresses. Surgery has been suggested as offering the best chance of cure for patients with poorly differentiated tumours, with survival figures of 70-80% compared with 15% for radiotherapy.2 The survival figures for patients with well and moderately differentiated tumours are identical whether they are managed by radiotherapy or by watchful waiting.3–5 …
Cervical screening for women with learning disability Editorial by Aspray et al : Numbers screened can be optimised by using a focused initiative
Authors: Peter Hall, Elizabeth Ward
Journal: BMJ (1999)

Editor—Pearson et al were concerned to find that only a quarter of eligible women with learning disability in Exeter and District Community Health Services NHS Trust had undergone cervical screening in the previous five years, compared with 82% of the rest of the eligible population.1 In 1997, Horizon NHS Trust, Hertfordshire Health Promotion, and the Women’s Nationwide Cancer Control Campaign cooperated over an intensive programme to screen the 126 eligible women in the learning disability hospital. As previous experience had shown the importance of securing carers’ support, staff and some patients participated in educational sessions. The members of the trust’s sex education team provided advice and educational models and made themselves available in case the process should provoke disturbing memories, as might happen in the case of previous sexual abuse.

Given the screening—as opposed to curative—nature of the procedure, no resident was tested who withheld consent (whether valid or not) or failed to cooperate passively. Despite the procedure being a routine public health measure, relatives were, as a matter of good practice, informed unless the patient indicated on direct questioning that they should not be.

Of the 128 eligible women, 40 were withdrawn because they were considered to be behaviourally or physically unable to participate. Of the remainder, 25 proved to be virgins or behaviourally unsuitable or refused consent; 18 did not cooperate. Forty five (35%) underwent cervical screening; 39 smears gave negative results, five were inadequate, and one showed an abnormality. The difficulties encountered because of the high proportion of psychiatric cases and cases of challenging behaviour and of physical disability in the trust’s population compared with people living in the community may to an extent be offset by the logistically easier task of arranging the resource intensive programme in a relatively small organisation.

The lessons learnt from this programme were that the numbers screened can be optimised by a focused initiative that includes education of carers to support the programme and the patients; the procedure should be carried out only by women staff to avoid embarrassment; it is not possible to predict who has had sexual experience; and the doctor taking the smears must be skilled and flexible enough to be able to take them in any position offered.
Abstract 5907: Development of Left Ventricular Dysfunction During Progression of Infant Right Ventricular Hypertrophy
Authors: Kazuo Kitahori, Huamei He, Douglas B Cowan, Ingeborg Friehs, Pedro J Nido, Francis X McGowan
Journal: Circulation (2008)

Background: Progressive left ventricular (LV) dysfunction can be a major late complication in patients with chronic right ventricular (RV) pressure overload (e.g. tetralogy of Fallot). The mechanisms remains unclear. We therefore examined LV function (serial echocardiography and ex vivo Langendorff) and histology in a model of infant pressure-load RV hypertrophy (RVH). Methods and Results: Ten-day-old rabbits (N=6 per time point, total =48) underwent pulmonary artery banding (PAB), were sacrificed at 2–8 weeks after PAB, and compared to age-matched sham controls. Both RV and LV performance (myocardial performance index, MPI; fractional area change, FAC), measured by echocardiography, decreased during the progression of RVH (Table ). In addition, RVH caused significant septal displacement, reduced septal contractility, and decreased LV end-systolic (LVDs) and diastolic (LVDd) dimensions. Significant septal and LV free wall apoptosis (myocyte-specific TUNEL and activated caspase-3), fibrosis (Masson’s Trichrome), and reduced capillary density (CD31 immunostaining) occurred in the left ventricles of the PAB group after 6 – 8 wks (all p&lt;0.05). Conclusion: This study for the first time shows that pressure overload resulting in RVH causes LV dysfunction by both mechanical and molecular effects upon the septum and LV myocardium. In particular, the development of RVH is associated with septal and LV apoptosis, pathologic LV remodeling, and reduced LV capillary density. Potential mediators and mechanisms (e.g. paracrine vs. circulating stimuli) merit further investigation LV performance during the progression of RVH
Abstract 520: Changes in Plasma Von Willebrand Factor-cleaving Protease(ADAMTS13) Levels in Patients with Unstable Angina
Authors: Shunichiro Fuchigami, Koichi Kaikita, Kenji Soejima, Mitsutoshi Miura, Masakazu Matsukawa, Tsuyoshi Honda, Kenichi Tsujita, Seigo Sugiyama, Hisao Ogawa
Journal: Circulation (2007)

Background : Increased plasma levels of von Willebrand factor (VWF) has been reported in acute myocardial infarction (AMI), which indicates the injured endothelial damage in occluded coronary arteries. The larger VWF multimers are known to be more active biologically, and are more potent mediators of platelet thromubus formations. Recently, a metalloprotease that cleaves VWF multimers has been identified, namely, VWF-cleaving protease (ADAMTS13). We recently reported reduced ADAMTS13 activity in AMI patients and the importance of this protease in the prognosis after AMI. However, whether ADAMTS13 may affect the pathogenesis of unstable angina (UA) has not been fully elucidated. The purpose of this study is to examine changes in plasma VWF and ADAMTS13 levels in patients with UA. Methods and Results : Plasma VWF and ADAMTS13 levels (mU/ml) were measured in 39 patients with UA, 55 patients with stable exertional angina (SEA) and 47 patients with chest pain syndrome (CPS) at the time of coronary angiography by enzyme-linked immunosorbent assay. We measured these antigen levels after 6 months follow-up period in patients with UA. Plasma VWF antigen levels (mU/ml) increased significantly in patients with UA compared with SEA and CPS (2118.5 ± 810.5, 1571.8 ± 494.2 and 1536.0 ± 526.4, respectively; P &lt; 0.0001 in UA vs. SEA or CPS). Plasma ADAMTS13 antigen levels (mU/ml) decreased significantly in patients with UA than SEA or CPS (741.2 ± 150.9, 875.3 ± 229.0 and 877.3 ± 199.7mU/ml, respectively; P &lt; 0.01 in UA vs. SEA or CPS). Furthermore, there were significant inverse correlations between VWF and ADAMTS13 antigen levels (r = −0.320, P &lt; 0.0001). Plasma VWF and ADAMTS13 antigen levels did not change compared to each level in acute phase in 15 UA patients that the blood samples could be obtained at 6 months follow-up periods. Conclusions : These findings suggested the prolonged endothelial damage in UA and tendency toward platelet thrombus formation at the injury sites after the attacks in patients with UA. The long-term antithrombotic therapy might be needed in those patients.
A combinatorial approach using sorafenib and liposomal ceramide to inhibit malignant melanoma
Authors: Melissa Tran, Arati Sharma, Charles Smith, Mark Kester, Gavin Robertson
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4754 

Melanoma is the deadliest form of skin cancer killing one person in the US every hour. Current treatments for advanced disease are ineffective necessitating development of rationally based combinatorial approaches with a solid mechanistic underpinning. Thus, combinatorial therapeutics, targeting multiple processes regulating tumorigenesis are being explored. One protein under intense investigation as a therapeutic target in melanoma is B-Raf, which is mutated to a constitutively active form in ~60% of sporadic melanomas leading to MAP kinase activation. While targeting this protein using a nonspecific Raf kinase inhibitor called sorafenib (BAY 43-9006) is relatively ineffective in human patients, in combination with carboplatin and paclitaxel it can be beneficial. However, there is no rational basis for this combination of agents. In order to develop rational based combinatorial agents, we have evaluated the preclinical effectiveness and mechanistic basis for combining sorafenib with ceramide encapsulated in a liposomal formulation. Sorafenib alone decreases cell proliferation and vascular development in xenografted melanoma tumors by reducing signaling through the MAP kinase-signaling cascade. In contrast, ceramide is a lipid-derived second messenger that preferentially induces tumor apoptosis by inhibiting Akt3, which is a second kinase activated in ~70% of melanomas through amplification and/or PTEN loss. We have developed a liposomal delivery system for ceramide that increases cellular permeability and prevents degradation by ceramidases in the circulatory system. Combining sorafenib and liposomal ceramide increased rates of apoptosis (by 9 fold) and decreased cellular proliferation (by 16 fold) compared to control cells. The combined treatment resulted in a significant reduction in tumor development compared to single agents alone. Specifically, the drug combination led to a 30% reduction in tumor development compared to sorafenib treatment alone and a 58% decrease in tumor size compared to liposomal ceramide treatment. This combination of agents is also effective at inhibiting breast cancer tumor development to a similar extent. Thus, targeted inhibition of the MAP kinase and Akt signaling cascades using sorafenib and liposomal ceramide has potential to more effectively inhibit melanoma and breast cancer development than either agent alone.
Abstract 13158: Development of Reporter Gene Techniques for Long-Term Assessment of Transplanted Human Circulating Progenitor Cells with Positron Emission Tomography
Authors: Yan Zhang, Drew Kuraitis, Patrick Burgon, Suzanne Crowe, Branka Vulesevic, Stephanie Thorn, Joseph C Wu, Jean N DaSilva, Robert A deKemp, Rob S Beanlands, Erik J Suuronen, Marc Ruel
Journal: Circulation (2011)

Background: PET with direct cell radiolabeling can only track transplanted cells for several hours. To further investigate cell fate in vivo, we transduced human circulating progenitor cells (CPCs) with reporter genes for long-term assessment of cell therapy. Methods: A lentiviral vector, carrying a triple-fusion reporter (TFR) construct consisting of PET (herpes simplex virus type 1 truncated thymidine kinase; HSV1-sr39tk), fluorescence (monomeric red fluorescence protein; mRFP), and bioluminescence (firefly luciferase) reporter genes, was produced by a transient transfection in 293FT cells. Human CPCs were transduced with the created viral particle. The transduction efficiency was determined by flow cytometry analysis of RFP expression. The expression of HSV1-tk was examined by Western blot. Transduced CPC morphology, viability, migration and angiogenic capacities were assessed. Transduced cells were isolated by FACS and transduction stability was measured. Results: A dose-response effect was achieved b...
Abstract 12377: Prognostic Impact of Myocardial Fibrosis in Patients with Heart Failure -Comparison between Preserved and Reduced Ejection Fraction Heart Failure
Authors: Tatsuo Aoki, Yoshihiro Fukumoto, Koichiro Sugimura, Kimio Satoh, Yutaka Miura, Kotaro Nochioka, Shunsuke Tatebe, Saori Miyamichi-Yamamoto, Masaharu Nakayama, Hiroaki Shimokawa
Journal: Circulation (2011)
Engraftment of Severe Combined Immune Deficient Mice Receiving Allogeneic Bone Marrow Via In Utero or Postnatal Transfer
Authors: Bruce R. Blazar, Patricia A. Taylor, Ron McElmurry, Lina Tian, Angela Panoskaltsis-Mortari, Sylvia Lam, Chris Lees, Thomas Waldschmidt, Daniel A. Vallera
Journal: Blood (1998)
Coronary Risk Stratification, Discrimination, and Reclassification Improvement Based on Quantification of Subclinical Coronary Atherosclerosis
Authors: Raimund Erbel, Stefan Möhlenkamp, Susanne Moebus, Axel Schmermund, Nils Lehmann, Andreas Stang, Nico Dragano, Dietrich Grönemeyer, Rainer Seibel, Hagen Kälsch, Martina Bröcker-Preuss, Klaus Mann, Johannes Siegrist, Karl-Heinz Jöckel
Journal: Journal of the American College of Cardiology (2010)
4-Hydroxynonenal (HNE) inhibits Mrp1-mediated transport in vitro
Authors: Paiboon Jungsuwadee, Marcie Cole, Allan Butterfield, Daret St. Clair, Mary Vore
Journal: Cancer Research (2006)

596   Multidrug resistant-associated protein 1 (MRP1, 190 kDa) mediates ATP-dependent efflux of endo- and xenobiotics and metabolites of phase II biotransformation, such as leukotriene C4, estradiol 17-(β-D-glucuronide) (E 2 17G), and the GSH conjugate of HNE (GS-HNE), a highly reactive product of lipid peroxidation. Adriamycin (ADR) induces oxidative stress, and production of HNE in cardiac tissue, which may contribute to cardiomyopathy. We postulate that ADR-induced cardiotoxicity is due, in part, to inhibition of MRP1. To investigate the pivotal role of Mrp1 in cardiac tissues, mice were injected with ADR (20 mg/kg, i.p.) and heart homogenate was subjected to Mrp1 immunoblot. Mrp1 expression in the heart at 6 and 24 hr after ADR treatment was increased 1.3** and 1.2* fold as compare to saline control (** p  Mrp1 ) and plasma membranes isolated for ATP-dependent transport of [ 3 H]E 2 -17G. Mrp1 activity was increased significantly (9-fold, p  Mrp1  membranes with DMSO or HNE (10 μM) for 20 min at 37°C, decreased transport activity (pmole/min/mg protein) from 115 to 94.1 (DMSO) and 63.2* (HNE), respectively. Taken together, these results suggest that the upregulation of Mrp1 in heart following ADR treatment has physiologic relevance in protecting the heart by mediating the efflux of toxic products of oxidative stress. However, adduction of Mrp1 with HNE under conditions of high oxidative stress likely causes dysfunction of Mrp1, and hence, may exacerbate ADR-induced cardiotoxicity.
The International Medical Prevention Registry on Venous Thromboembolism (IMPROVE): Venous Thromboembolism Prophylaxis Practices in Acutely Ill Medical Patients.
Authors: Victor F. Tapson, Herve Decousus, Jean-Fran[ccedi]ois Bergmann, Beng H. Chong, James B. Froehlich, Ajay K. Kakkar, Geno J. Merli, Manuel Monreal, Mashio Nakamura, Riccardo Pavanello, Mario Pini, Franco Piovella, Alex C. Spyropoulos, Alexander G.G. Turpie, Rainer B. Zotz, Gordon FitzGerald, Frederick A. Anderson
Journal: Blood (2004)
Abstract 3440: Frequency and Predictors of Post-Procedural Myonecrosis in Saphenous Vein Graft Intervention in the Stent Era: A Meta-Regression
Authors: William B Hillegass, Michael J Lyerly, Nishant J Patel, Gilbert J Zoghbi, Vijay K Misra, Brigitta C Brott
Journal: Circulation (2006)

Background: Evaluations of the frequency and predictors of peri-procedural myonecrosis in saphenous vein graft (SVG) percutaneous coronary intervention (PCI) have been hampered by limited sample si...
S100 proteins induce MUC5AC production in airway epithelial cells
Authors: Jin Hyun Kang, Sae Mi Hwang, Il Yup Chung
Journal: European Respiratory Journal (2014)

S100A8, S100A9, and S100A12 are damage-associated molecular pattern (DAMP) molecules that are mainly released by neutrophils. They initiate and modulate local inflammation and innate immune responses. Airway mucus hyperproduction is a paramount feature of chronic airway obstructive diseases such as severe asthma, chronic obstructive pulmonary disease, and cystic fibrosis, which are closely associated with neutrophilic airway inflammation. In the present study, we report a new role for S100A8, S100A9, and S100A12 for producing MUC5AC, a major mucin protein in the respiratory tract. All three S100 proteins induced  MUC5AC  mRNA and protein expression in normal human bronchial epithelial (NHBE) cells as well as NCI-H292 cells. A TLR4 inhibitor almost completely abolished MUC5AC expression by all the three S100 proteins, while neutralization of the receptor for advanced glycation end-products (RAGE) inhibited only S100A12-mediated production of MUC5AC. Treatment with various pharmacological inhibitors showed that MUC5AC production by these three S100 proteins was achieved through activation of multiple signaling molecules, including MAPKs and NF-κB. Biochemical analyses demonstrated that S100A8, S100A9, and S100A12 equally elicited both phosphorylation of ERK and nuclear translocation of NF-κB/degradation of cytosolic IκB with similar kinetics through TLR4. In contrast, S100A12 preferentially activated the ERK pathway rather than the NF-κB pathway through RAGE. Collectively, our results suggest that S100A8 S100A9, and S100A12 all serve as key mediators linking neutrophil-dominant airway inflammation to mucin hyperproduction, thereby contributing to the pathophysiology of obstructive airway diseases.
Noninvasive Evaluation of the Aortic Root With Multislice Computed Tomography
Authors: Laurens F. Tops, David A. Wood, Victoria Delgado, Joanne D. Schuijf, John R. Mayo, Sanjeevan Pasupati, Frouke P.L. Lamers, Ernst E. van der Wall, Martin J. Schalij, John G. Webb, Jeroen J. Bax
Journal: JACC. Cardiovascular imaging (2008)
Novel Chimeric Antigen Receptor T Cells for the Treatment of CD19-Negative Relapses Occurring after CD19-Targeted Immunotherapies
Authors: Marco Ruella, David Barrett, Saad S. Kenderian, Olga Shestova, Ted J. Hofmann, John Scholler, Simon F. Lacey, Jan J Melenhorst, Farzana Nazimuddin, Michael Kalos, David L. Porter, Carl H. June, Stephan A. Grupp, Saar I. Gill
Journal: Blood (2014)