tbuckley/cabot-search huggingface dataset:
Olaparib Monotherapy in Patients With Advanced Cancer and a Germline <i>BRCA1/2</i> Mutation
Authors: Bella Kaufman, Ronnie Shapira-Frommer, Rita K. Schmutzler, M. William Audeh, Michael Friedlander, Judith Balmaña, Gillian Mitchell, Georgeta Fried, Salomon M. Stemmer, Ayala Hubert, Ora Rosengarten, Mariana Steiner, Niklas Loman, Karin Bowen, Anitra Fielding, Susan M. Domchek
Journal: Journal of Clinical Oncology (2014)

Purpose Olaparib is an oral poly (ADP-ribose) polymerase inhibitor with activity in germline BRCA1 and BRCA2 (BRCA1/2) –associated breast and ovarian cancers. We evaluated the efficacy and safety of olaparib in a spectrum of BRCA1/2-associated cancers. Patients and Methods This multicenter phase II study enrolled individuals with a germline BRCA1/2 mutation and recurrent cancer. Eligibility included ovarian cancer resistant to prior platinum; breast cancer with ≥ three chemotherapy regimens for metastatic disease; pancreatic cancer with prior gemcitabine treatment; or prostate cancer with progression on hormonal and one systemic therapy. Olaparib was administered at 400 mg twice per day. The primary efficacy end point was tumor response rate. Results A total of 298 patients received treatment and were evaluable. The tumor response rate was 26.2% (78 of 298; 95% CI, 21.3 to 31.6) overall and 31.1% (60 of 193; 95% CI, 24.6 to 38.1), 12.9% (eight of 62; 95% CI, 5.7 to 23.9), 21.7% (five of 23; 95% CI, 7.5 to 43.7), and 50.0% (four of eight; 95% CI, 15.7 to 84.3) in ovarian, breast, pancreatic, and prostate cancers, respectively. Stable disease ≥ 8 weeks was observed in 42% of patients (95% CI, 36.0 to 47.4), including 40% (95% CI, 33.4 to 47.7), 47% (95% CI, 34.0 to 59.9), 35% (95% CI, 16.4 to 57.3), and 25% (95% CI, 3.2 to 65.1) of those with ovarian, breast, pancreatic, or prostate cancer, respectively. The most common adverse events (AEs) were fatigue, nausea, and vomiting. Grade ≥ 3 AEs were reported for 54% of patients; anemia was the most common (17%). Conclusion Responses to olaparib were observed across different tumor types associated with germline BRCA1/2 mutations. Olaparib warrants further investigation in confirmatory studies.
ret/PTC-1 expression alters the immunoprofile of thyroid follicular cells
Authors: Karen Denning, Paul Smyth, Susanne Cahill, Jinghuan Li, Richard Flavin, Sinead Aherne, John J O' Leary, Orla Sheils
Journal: Molecular Cancer (2008)

Abstract Background Hashimoto Thyroiditis (H.T.) is a destructive autoimmune thyroid condition whose precise molecular pathogenesis remains unclear. ret /PTC-1 is a chimeric transcript which has been described in autoimmune thyroid disease (AITD) and thyroid neoplasia. The purpose of this study was to observe the immunogenic effect exposure to H.T. and control lymphocyte supernatant would have on normal (Nthy-ori) and ret /PTC-1 (TPC-1) expressing thyroid cell line models. Results A 2 × 2 matrix comprising Nthy-ori and TPC-1 cell lines and H.T. and control lymphocyte supernatant was designed and utilised as follows; activated lymphocytic supernatant from a H.T. and normal control were co-cultured with a cell line derived from normal thyroid (Nthy-ori) and also a cell line derived from a papillary thyroid carcinoma that endogenously expresses ret /PTC-1 (TPC-1). The co-cultures were harvested at 0, 6 and 18 hour time points. Gene expression analysis was performed on RNA extracted from thyrocytes using TaqMan ® Immune profiling Low-Density Arrays (Applied Biosystems, CA, USA) comprising gene expression markers for 93 immune related targets plus 3 endogenous controls. Stimulation of the normal thyroid cell line model with activated T cell supernatant from the H.T. donor yielded global up-regulation of immune targets when compared with control supernatant stimulation. In particular, a cohort of targets (granzyme B, CD3, CD25, CD152, CD45) associated with cytotoxic cell death; T cell receptor (TCR) and T cell signaling were up-regulated in the normal cell line model. When the ret /PTC-1 expressing thyroid cell line was co-cultured with H.T. lymphocyte supernatant, in comparison to control supernatant stimulation, down-regulation of the same subset of immune targets was seen. Conclusion Co-culturing H.T. lymphocyte supernatant with a normal thyroid cell line model leads to over-expression of a subset of targets which could contribute to the pathogenesis of H.T. via cytotoxic cell death and TCR signalling. Stimulation of the ret /PTC-1 positive cell line with the same stimulus led to a down-regulated shift in the gene expression pattern of the cohort of immune targets. We hypothesize that ret /PTC-1 activation may dampen immunogenic responses in the thyroid, which could possibly facilitate papillary thyroid carcinoma development.
A9.16 Synovial Fibroblasts from Patients with Rheumatoid Arthritis Differentiate into Distinct Fibroblast Subsets in the Presence of Cartilage
Authors: Adam P Croft, Amy Naylor, Birgit Zimmermann, Debbie Hardie, Guillaume Desanti, Maria Jaurez, Ulf Muller-Ladner, Andrew Filer, Elena Neumann, Christopher Buckley
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatoid arthritis synovial fibroblasts (RASF) migrate to distant tissue sites and damage articular cartilage. Using novel markers of RASF subsets to identify lining and sub-lining layer RASF we investigated the ability of RASF to undergo self-assembly, transmigration and cartilage degradation in vivo. <h3>Methods</h3> Healthy human cartilage was co-implanted subcutaneously into the flank of SCID mice together with RASF. On the contralateral flank, cartilage was implanted without cells. After 60 days, implants and blood were analysed. Human cells were detected using immunohistochemistry for species-specific antibodies. For in vitro studies, RASF were isolated from patients with established RA and healthy controls and the expression of cellular markers were defined. <h3>Results</h3> RASF at the ipsilateral implant differentiated into distinct fibroblast subsets in the presence of cartilage. Cells proximal to cartilage expressed markers of a lining layer phenotype (GP38, FAP, VCAM-1 and Cadherin-11). These cells attached to, invaded and degraded cartilage. Cells more distal to cartilage expressed sub-lining layer phenotype markers including CD248 and CD90. Cells expressing CD248 and CD90 were never observed in the lining layer (proximal to cartilage) and never invaded cartilage. The development of this stromal architecture mirrored that observed in vivo in the inflamed synovial membrane. This stromal pattern of distinct lining layer and sub lining layer differentiation was recapitulated in the contralateral implant that contained only cartilage. In addition, we demonstrate that RASF in vitro can be directed towards either a lining layer (GP38, FAP, VCAM-1 and Cadherin-11) or sub-lining layer phenotype (CD248 and CD90) following cytokine treatment. The lining layer, but not sub lining cell phenotype is associated with increased cartilage degradation in vitro. <h3>Conclusions</h3> RASF have an activated cell phenotype ex vivo<i>.</i> In vitro and in vivo they display plasticity with the capacity to differentiate into distinct cell sub-populations that morphologically distinguish between the lining and sub-lining layer of the human joint. In vivo cell sub-population differentiation occurs locally at the site of engraftment and recapitulates the lining anatomy observed at the site of origin. This phenomenon is dependent on the release of tissue factors found present in the joint microenvironment following cartilage damage. This inflammatory microenvironment is required for cartilage destruction by RASF. Cellular therapies targeting RASF specific subsets are an unexplored but important therapeutic target to modulate inflammation and may provide an avenue to minimise joint damage in patients with RA.
Relationship Between Medicare’s Hospital Compare Performance Measures and Mortality Rates
Authors: Rachel M. Werner, Eric T. Bradlow
Journal: JAMA (2006)

THE quality of health care in the UnitedStates is uneven and often inadequate. 1,2In the outpatient setting, quality of care varies across individuals depending on age, sex, race, and socioeconomic status. 3 Overall, only half of US individuals receive recommended care. 1 In hospitals, quality of care is also variable.Compliance with hospital performance measures varies not only across US hospitals but also across regions, conditions, and performance measures. 4ecause it is assumed that measuring quality of care is a key component in improving care, quality measurement is playing an increasingly prominent role in quality improvement.][16] These efforts are designed to provide an incentive to improve the quality of the care delivered and to influence consumer choice of providers. 17,18][21] Recently, the US Centers for Medicare & Medicaid Services (CMS), along with other health care organiza-See also p 2731.
Rampant Gene Loss in the Underground Orchid Rhizanthella gardneri Highlights Evolutionary Constraints on Plastid Genomes
Authors: E. Delannoy, S. Fujii, C. Colas des Francs-Small, M. Brundrett, I. Small
Journal: Molecular Biology and Evolution (2011)

Since the endosymbiotic origin of chloroplasts from cyanobacteria 2 billion years ago, the evolution of plastids has been characterized by massive loss of genes. Most plants and algae depend on photosynthesis for energy and have retained ∼110 genes in their chloroplast genome that encode components of the gene expression machinery and subunits of the photosystems. However, nonphotosynthetic parasitic plants have retained a reduced plastid genome, showing that plastids have other essential functions besides photosynthesis. We sequenced the complete plastid genome of the underground orchid, Rhizanthella gardneri. This remarkable parasitic subterranean orchid possesses the smallest organelle genome yet described in land plants. With only 20 proteins, 4 rRNAs, and 9 tRNAs encoded in 59,190 bp, it is the least gene-rich plastid genome known to date apart from the fragmented plastid genome of some dinoflagellates. Despite numerous differences, striking similarities with plastid genomes from unrelated parasitic plants identify a minimal set of protein-encoding and tRNA genes required to reside in plant plastids. This prime example of convergent evolution implies shared selective constraints on gene loss or transfer.
Efficacy and Quality-of-Life Data Are Related in a Phase II Trial of Oral Chemotherapy in Previously Untreated Patients With Metastatic Colorectal Carcinoma
Authors: Timothy J. Hobday, John W. Kugler, Michelle R. Mahoney, Daniel J. Sargent, Jeff A. Sloan, Tom R. Fitch, James E. Krook, Michael J. O’Connell, James A. Mailliard, Maria Tria Tirona, Loren K. Tschetter, Charles D. Cobau, Richard M. Goldberg
Journal: Journal of Clinical Oncology (2002)

To evaluate quality of life (QOL) and tumor response after administration of an oral chemotherapy regimen in patients with previously untreated metastatic colorectal cancer.Seventy-eight patients received a mean number of 5.8 cycles of therapy. QOL data were analyzed at baseline, after every two cycles of therapy, and at the time of treatment discontinuation. The Uniscale and the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 were both utilized.The confirmed response rate was 26% (95% confidence interval [CI], 17% to 37%). Median survival was 11.3 months (95% CI, 9.6 to 15.1 months). Global QOL scores were unchanged over the course of therapy by either tool. Only the physical function subscale score had worsened at the end of therapy. In an analysis of responding patients, significant and durable improvements in both global QOL measures as well as select subscale scores were observed. Diarrhea and physical function QOL scores had declined at the time of treatment discontinuation. Patients who did not respond to therapy had preserved QOL scores when they were evaluated after two cycles of therapy.This oral treatment strategy preserved QOL in treated patients. Global QOL measures as well as several QOL subscale scores significantly improved in patients with a documented response to therapy. The profile of improved QOL components indicated that patient well-being was related to tumor response in specific and perceivable ways. Nonresponding patients reported preserved QOL during the first two cycles of therapy. QOL analysis was feasible and informative in this moderately sized multicenter phase II trial.
Factors Associated With Severe Late Toxicity After Concurrent Chemoradiation for Locally Advanced Head and Neck Cancer: An RTOG Analysis
Authors: Mitchell Machtay, Jennifer Moughan, Andrew Trotti, Adam S. Garden, Randal S. Weber, Jay S. Cooper, Arlene Forastiere, K. Kian Ang
Journal: Journal of Clinical Oncology (2008)

Purpose Concurrent chemoradiotherapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) increases both local tumor control and toxicity. This study evaluates clinical factors that are associated with and might predict severe late toxicity after CCRT. Methods Patients were analyzed from a subset of three previously reported Radiation Therapy Oncology Group (RTOG) trials of CCRT for locally advanced SCCHN (RTOG 91-11, 97-03, and 99-14). Severe late toxicity was defined in this secondary analysis as chronic grade 3 to 4 pharyngeal/laryngeal toxicity (RTOG/European Organisation for the Research and Treatment of Cancer late toxicity scoring system) and/or requirement for a feeding tube ≥ 2 years after registration and/or potential treatment-related death (eg, pneumonia) within 3 years. Case-control analysis was performed, with a multivariable logistic regression model that included pretreatment and treatment potential factors. Results A total of 230 patients were assessable for this analysis: 99 patients with severe late toxicities and 131 controls; thus, 43% of assessable patients had a severe late toxicity. On multivariable analysis, significant variables correlated with the development of severe late toxicity were older age (odds ratio 1.05 per year; P = .001); advanced T stage (odds ratio, 3.07; P = .0036); larynx/hypopharynx primary site (odds ratio, 4.17; P = .0041); and neck dissection after CRT (odds ratio, 2.39; P = .018). Conclusion Severe late toxicity after CCRT is common. Older age, advanced T-stage, and larynx/hypopharynx primary site were strong independent risk factors. Neck dissection after CCRT was associated with an increased risk of these complications.
Salinomycin treatment reduces metastatic tumor burden by hampering cancer cell migration
Authors: Florian Kopp, Adam Hermawan, Prajakta Shirish Oak, Annika Herrmann, Ernst Wagner, Andreas Roidl
Journal: Molecular Cancer (2014)

Tumor spreading is the major threat for cancer patients. The recently published anti-cancer drug salinomycin raised hope for an improved treatment by targeting therapy-refractory cancer stem cells. However, an unambiguous role of salinomycin against cancer cell migration and metastasis formation remains elusive. We report that salinomycin effectively inhibits cancer cell migration in a variety of cancer types as determined by Boyden chamber assays. Additionally, cells were treated with doxorubicin at a concentration causing a comparable low cytotoxicity, emphasizing the anti-migratory potential of salinomycin. Moreover, single-cell tracking by time-lapse microscopy demonstrated a remarkable effect of salinomycin on breast cancer cell motility. Ultimately, salinomycin treatment significantly reduced the metastatic tumor burden in a syngenic mouse tumor model. Our findings clearly show that salinomycin can strongly inhibit cancer cell migration independent of the induction of cell death. We furthermore demonstrate for the first time that salinomycin treatment reduces metastasis formation in vivo, strengthening its role as promising anti-cancer therapeutic.
OC-078 Cost Savings and Outpatient Clinic Appointments Saved: A 2 Year Review of a Nurse Led Telephone Advice Line for Inflammatory Bowel Disease
Authors: T Price, K Lithgo, M W Johnson
Journal: Gut (2013)

<h3>Introduction</h3> In 2008 the Luton &amp; Dunstable University Hospital set up a nurse led telephone advice line for inflammatory bowel disease (IBD) patients. This service was set up to provide specialist assistance for GPs, IBD patients and their carers in the community. A recent national audit looking into the role of the IBD specialist nurses highlighted the value patients attribute to easy access specialist advice at the point of need [1]. The patients can call for a range of issues including general advice, their blood results, to change clinic appointments or to discuss patient self management of flares in their IBD. The advice line has become a major component of the IBD nursing post. <h3>Objective</h3> To assess the cost savings and number of outpatient appointments (OPAs) saved through nursing intervention using the IBD advice line. <h3>Methods</h3> For a 2 year period every phone call to the advice line was logged and recorded. If the advice given help prevent or expedite a patient request for an urgent OPA, then this was recorded. Both the patients' GPs and IBD Consultants were informed of any changes in the patients' clinical management. A cost analysis was made using the national tariff of £85 for a routine OPA clinic visit. <h3>Results</h3> In 2011 a total of 1252 phone calls were received. This led to 305 OPAs being saved and 44 being expedited. This saved our local primary care trust (PCT) £25,925. In 2012 a total of 2205 phone calls were received. This led to 194 OPAs being saved and 58 being expedited. This saved our local PCT £16,490. <h3>Conclusion</h3> There has been a year on year increase in the number of patients using the IBD advice line. In the last 2 years 3457 calls have been received, 499 OPAs have been saved and 102 OPAs have been expedited. Over 2011 and 2012 this nurse led advice line has saved our local PCT £42,415. As a result of our audit we have managed to secure funding for the advice line where clinical management has been shown to saved a clinic appointment. <h3>Disclosure of Interest</h3> None Declared <h3>Reference</h3> Mason, I. Holbrook, K. Garrick, V. Johns, K. Kane, M. 2012 Inflammatory Bowel Disease Nursing, results of an audit exploring the roles and activity of nurses with specialist/advanced roles. London. Royal College of Nursing.
Fluorescence Imaging of Membrane Dynamics
Authors: Jay T. Groves, Raghuveer Parthasarathy, Martin B. Forstner
Journal: Annual Review of Biomedical Engineering (2008)

Imaging membrane dynamics is an important goal, motivated by the abundance of biochemical and biophysical events that are orchestrated at, or by, cellular membranes. The short length scales, fast timescales, and environmental requirements of membrane phenomena present challenges to imaging experiments. Several technical advances offer means to overcome these challenges, and we describe here three powerful techniques applicable to membrane imaging: total internal reflection fluorescence (TIRF) microscopy, fluorescence interference contrast (FLIC) microscopy, and fluorescence correlation spectroscopy (FCS). For each, we discuss the physics underpinning the approach, its practical implementation, and recent examples highlighting its achievements in exploring the membrane environment.
Proneural Transcription Factors Regulate Different Steps of Cortical Neuron Migration through Rnd-Mediated Inhibition of RhoA Signaling
Authors: Emilie Pacary, Julian Heng, Roberta Azzarelli, Philippe Riou, Diogo Castro, Mélanie Lebel-Potter, Carlos Parras, Donald M. Bell, Anne J. Ridley, Maddy Parsons, François Guillemot
Journal: Neuron (2011)

Little is known of the intracellular machinery that controls the motility of newborn neurons. We have previously shown that the proneural protein Neurog2 promotes the migration of nascent cortical neurons by inducing the expression of the atypical Rho GTPase Rnd2. Here, we show that another proneural factor, Ascl1, promotes neuronal migration in the cortex through direct regulation of a second Rnd family member, Rnd3. Both Rnd2 and Rnd3 promote neuronal migration by inhibiting RhoA signaling, but they control distinct steps of the migratory process, multipolar to bipolar transition in the intermediate zone and locomotion in the cortical plate, respectively. Interestingly, these divergent functions directly result from the distinct subcellular distributions of the two Rnd proteins. Because Rnd proteins also regulate progenitor divisions and neurite outgrowth, we propose that proneural factors, through spatiotemporal regulation of Rnd proteins, integrate the process of neuronal migration with other events in the neurogenic program.
GEOGRAPHICAL VARIATION IN ISCHEMIA SEVERITY IN PATIENTS REFERRED FOR STRESS IMAGING STUDIES: SCREENING DATA FROM THE ISCHEMIA TRIAL
Authors: Berger S. Jeffrey, Jonathan D. Newman, Jean Gregoire, Roxy Senior, Marcin Demkow, Denis Phaneuf, Andras Vertes, Jorge Escobedo, Sasko Kedev, Andrea Mortara, Ira M. Dauber, Lorenzo Monti, Gerard Devlin, James Cha, Peter Stone, Harmony R. Reynolds, Nicola Johnston, Grzegorz Gajos, Kreton Mavromatis, Jose Luis Lopez-Sendon, Mandeep Sidhu, William E. Boden, Francesco Orso, David J. Maron, Judith S. Hochman
Journal: Journal of the American College of Cardiology (2014)
Altered gut–liver axis and hepatic adiponectin expression in OSAS: novel mediators of liver injury in paediatric non-alcoholic fatty liver
Authors: Valerio Nobili, Anna Alisi, Renato Cutrera, Guido Carpino, Cristiano De Stefanis, Valentina D'Oria, Rita De Vito, Salvatore Cucchiara, Eugenio Gaudio, Giovanni Musso
Journal: Thorax (2015)

Background Mechanism(s) connecting obstructive sleep apnoea syndrome (OSAS) to liver injury in paediatric non-alcoholic fatty liver disease (NAFLD) are unknown. We hypothesised alterations in gut–liver axis and in the pool and phenotype of hepatic progenitor cells (HPCs) may be involved in OSAS-associated liver injury in NAFLD. Methods Eighty biopsy-proven NAFLD children (age, mean±SD, 11.4±2.0 years, 56% males, body mass index z -score 1.95±0.57) underwent a clinical–biochemical assessment, with measurement of insulin sensitivity, plasma cytokines, lipopolysaccharide (LPS), an intestinal permeability test and a standard polysomnography. Hepatic toll-like receptor (TLR)-4 expression by liver-resident cells and overall number and expression of resistin and adiponectin by HPCs were assessed by immunofluorescence and immunohistochemistry. OSAS was defined by an apnoea/hypopnoea index ≥1. Results OSAS was characterised by an increased intestinal permeability and endotoxemia, coupled with TLR-4 upregulation in hepatocytes, Kupffer and hepatic stellate cells (HSCs) and by an expansion of an adiponectin-deficient HPC pool, key features of steatohepatitis and fibrosis. The duration of haemoglobin desaturation (SaO 2 &lt;90%) independently predicted intestinal permeability (β: 0.396; p=0.026), plasma LPS (β: 0.358; p=0.008) and TLR-4 expression by hepatocytes (β: 0.332; p=0.009), Kupffer cells (β: 0.357; p=0.006) and HSCs (β:0.445; p=0.002). SaO 2 &lt;90% predicted also HPC number (β: 0.471; p=0.001) and impaired adiponectin expression by HPC pool (β: −0.532; p=0.0009). These relationships were observed in obese and non-obese children. Conclusions In paediatric NAFLD, OSAS is associated with increased endotoxemia coupled with impaired gut barrier function, with increased TLR-4-mediated hepatic susceptibility to endotoxemia and with an expansion of an adiponectin-deficient HPC pool. These alterations may represent a novel pathogenic link and a potential therapeutic target for OSAS-associated liver injury in NAFLD.