tbuckley/cabot-search huggingface dataset:
Increased cell motility and invasion upon siRNA knockdown of LSR in bladder cancer
Authors: Malene Herbsleb, Thomas Thykj r, Karin Demtroeder, Carsten Wiuf, Torben Orntoft, Lars Dyrskjot
Journal: Cancer Research (2007)

2013  Bladder cancer is the ninth most common cancer world wide with an incidence of 357,000 and 145,000 deaths annually. The disease presents in two different forms: a superficial form, which often recur and in some cases progress to an invasive stage, and an invasive form with a poor survival rate despite radical cystectomy and systemic therapy. The molecular mechanisms involved in disease progression are still poorly understood. Identification of target molecules involved in the disease development and progression would have great impact on the future understanding and treatment of the disease.  Using HG-U133A oligonucleotide microarray analyses on tumor specimens from 90 patients (55 Ta, 3 T1, 23 T2-T4, 9 normal samples) we identified an elevated expression of LSR in all stages of bladder cancer compared to normal samples. IHC on tumor specimens showed that the LSR expression was found in the malignant urothelial cells.  In an effort to identify the function and effect of this cancer specific overexpression we knocked down the expression of LSR in a bladder cancer cell line (SW780). Cells were transfected using five different constructs: mock-siRNA, two LSR-siRNA variants, TP53-siRNA and LSR+TP53 siRNAs. Cells were harvested at three different time points; 18h (one replicate), 48h (four replicates) and 72h (two replicates). siRNA knock down was QPCR verified and global gene expression consequences of the knockdown were analysed using 35 HG-U133 Plus 2.0 microarrays. The microarray gene expression levels of three genes (EMP3, AGR2, CTGF) were verified by QPCR. Microarray data was analysed with the novel bioinformatic software application, Ingenuity Pathway Analysis. Using this approach we found that cellular movement, including cell motility and invasion, were the main cellular functions affected by the knockdown of LSR using both siRNAs against LSR. This result was experimentally verified in a matrigel based assay demonstrating that the cell’s invasive capacity was elevated 3-fold in cells transfected with LSR-siRNAs compared to mock transfected cells. The molecular changes and affected molecular pathways identified from the cell line experiments will be correlated to the the gene expression data from clinical samples and the results will be presented at the meeting. Consequently, our results indicate that LSR is involved in disease progression in bladder cancer. Future studies will be needed to further delineate the role of LSR in bladder cancer progression.
VCAM-1 targeted alpha-particle therapy for early brain metastases
Authors: Aurélien Corroyer-Dulmont, Samuel Valable, Nadia Falzone, Anne-Marie Frelin-Labalme, Ole Tietz, Jérôme Toutain, Manuel Sarmiento Soto, Didier Divoux, Laurent Chazalviel, Elodie A Pérès, Nicola R Sibson, Katherine A Vallis, Myriam Bernaudin
Journal: Neuro-Oncology (2019)

Abstract Background Brain metastases (BM) develop frequently in patients with breast cancer. Despite the use of external beam radiotherapy (EBRT), the average overall survival is short (6 months from diagnosis). The therapeutic challenge is to deliver molecularly targeted therapy at an early stage when relatively few metastatic tumor cells have invaded the brain. Vascular cell adhesion molecule 1 (VCAM-1), overexpressed by nearby endothelial cells during the early stages of BM development, is a promising target. The aim of this study was to investigate the therapeutic value of targeted alpha-particle radiotherapy, combining lead-212 (212Pb) with an anti–VCAM-1 antibody (212Pb-αVCAM-1). Methods Human breast carcinoma cells that metastasize to the brain, MDA-231-Br-GFP, were injected into the left cardiac ventricle of nude mice. Twenty-one days after injection, 212Pb-αVCAM-1 uptake in early BM was determined in a biodistribution study and systemic/brain toxicity was evaluated. Therapeutic efficacy was assessed using MR imaging and histology. Overall survival after 212Pb-αVCAM-1 treatment was compared with that observed after standard EBRT. Results 212Pb-αVCAM-1 was taken up into early BM with a tumor/healthy brain dose deposition ratio of 6 (5.52e108 and 0.92e108) disintegrations per gram of BM and healthy tissue, respectively. MRI analyses showed a statistically significant reduction in metastatic burden after 212Pb-αVCAM-1 treatment compared with EBRT (P &amp;lt; 0.001), translating to an increase in overall survival of 29% at 40 days post prescription (P &amp;lt; 0.01). No major toxicity was observed. Conclusions The present investigation demonstrates that 212Pb-αVCAM-1 specifically accumulates at sites of early BM causing tumor growth inhibition.
Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials
Authors: Claus Bachert, Joseph K Han, Martin Desrosiers, Peter W Hellings, Nikhil Amin, Stella E Lee, Joaquim Mullol, Leon S Greos, John V Bosso, Tanya M Laidlaw, Anders U Cervin, Jorge F Maspero, Claire Hopkins, Heidi Olze, G Walter Canonica, Pierluigi Paggiaro, Seong H Cho, Wytske J Fokkens, Shigeharu Fujieda, Mei Zhang, Xin Lu, Chunpeng Fan, Steven Draikiwicz, Siddhesh A Kamat, Asif Khan, Gianluca Pirozzi, Naimish Patel, Neil M H Graham, Marcella Ruddy, Heribert Staudinger, David Weinreich, Neil Stahl, George D Yancopoulos, Leda P Mannent
Journal: The Lancet (2019)
Daily Walking among Commuters: A Cross-Sectional Study of Associations with Residential, Work, and Regional Accessibility in Melbourne, Australia (2012–2014)
Authors: Alison Barr, Koen Simons, Suzanne Mavoa, Hannah Badland, Billie Giles-Corti, Jan Scheurer, Elizabeth Korevaar, Josh Stewart, Rebecca Bentley
Journal: Environmental Health Perspectives (2019)

Most research on walking for transport has focused on the walkability of residential neighborhoods, overlooking the contribution of places of work/study and the ease with which destinations outside the immediate neighborhood can be accessed, referred to as regional accessibility.We aimed to examine if local accessibility/walkability around place of work/study and regional accessibility are independently and interactively associated with walking.A sample of 4,913 adult commuters was derived from a household travel survey in Melbourne, Australia (2012-2014). Local accessibility was measured as the availability of destinations within an 800-m pedestrian network from homes and places of work/education using a local living index [LLI; 0-3 (low), 4-6, 7-9, and 10-12 (high) destinations]. Regional accessibility was estimated using employment opportunity, commute travel time by mode, and public transport accessibility. Every individual's potential minutes of walking for each level of exposure (observed and counter to fact) were predicted using multivariable regression models including confounders and interaction terms. For each contrast of exposure levels of interest, the corresponding within-individual differences in predicted walking were averaged across individuals to estimate marginal effects.High LLI at home and work/education was associated with more minutes walking than low LLI by 3.9 [95% confidence interval (CI): 2.3, 5.5] and 8.3 (95% CI: 7.3, 9.3) min, respectively, in mutually adjusted models. Across regional accessibility measures, an independent association with walking and an interactive association with LLI at work/education was observed. To take one example, the regional accessibility measure of "Jobs within 30 min by public transport" was associated with 4.3 (95% CI: 2.9, 5.7) more mins walking for high (≥30,000 jobs) compared with low (<4,000 jobs) accessibility in adjusted models. The estimated difference for high vs. low LLI (work/education) (among those with low regional accessibility) was 3.6 min (95% CI: 2.3, 4.8), while the difference for high vs. low regional accessibility (among those with low LLI) was negligible (-0.01; 95% CI: -1.2, 1.2). However, the combined effect estimate for high LLI and high regional accessibility, compared with low on both, was 12.8 min (95% CI: 11.1, 14.5), or 9.3 (95% CI: 6.7, 11.8) min/d walking more than expected based on the separate effect estimates.High local living (work/education) and regional accessibility, regardless of the regional accessibility measure used, are positively associated with physical activity. High exposure to both is associated with greater benefit than exposure to one or the other alone. https://doi.org/10.1289/EHP3395.
Effect of the iExaminer Teaching Method on Fundus Examination Skills
Authors: Kiyoshi Shikino, Shingo Suzuki, Yusuke Hirota, Makoto Kikukawa, Masatomi Ikusaka
Journal: JAMA Network Open (2019)

In this randomized clinical trial, the iExaminer teaching method led to improved diagnostic accuracy and reduced examination time for the fundus examination.The results suggest that the iExaminer teaching method may be superior to the traditional teaching method.
The necessity of using direct measures of child development
Authors: Lia C H Fernald, Helen O Pitchik
Journal: The Lancet Global Health (2019)

More than half of the world's poor are children,1 and one crushing consequence of growing up in poverty is the subsequent loss of human potential.2 A common metric used to quantify the effects of poverty on human capital is the use of child growth, or stunting, as a proxy measure for poor cognitive development.3 This crucially important approach allows researchers and advocates to push for government action. However, despite the standard assumption that improvements in growth lead to improvements in cognitive development, the associations between these two variables are not consistent.
Association Between Current and Future Annual Hospital Percutaneous Coronary Intervention Mortality Rates
Authors: Alexander T. Sandhu, Shun Kohsaka, Jay Bhattacharya, William F. Fearon, Robert A. Harrington, Paul A. Heidenreich
Journal: JAMA Cardiology (2019)

<h3>Importance</h3> Multiple states publicly report a hospital's risk-adjusted mortality rate for percutaneous coronary intervention (PCI) as a quality measure. However, whether reported annual PCI mortality is associated with a hospital's future performance is unclear. <h3>Objective</h3> To evaluate the association between reported risk-adjusted hospital PCI-related mortality and a hospital's future PCI-related mortality. <h3>Design, Setting, and Participants</h3> This study used data from the New York Percutaneous Intervention Reporting System from January 1, 1998, to December 31, 2016, to assess hospitals that perform PCI. <h3>Exposures</h3> Public-reported, risk-adjusted, 30-day mortality after PCI. <h3>Main Outcomes and Measures</h3> The primary analysis evaluated the association between a hospital's reported risk-adjusted PCI-related mortality and future PCI-related mortality. The correlation between a hospital's observed to expected (O/E) PCI-related mortality rates each year and future O/E mortality ratios was assessed. Multivariable linear regression was used to examine the association between index year O/E mortality and O/E mortality in subsequent years while adjusting for PCI volume and patient severity. <h3>Results</h3> This study included 67 New York hospitals and 960 hospital-years. Hospitals with low PCI-related mortality (O/E mortality ratio, ≤1) and high mortality (O/E mortality ratio, &gt;1) had inverse associations between their O/E mortality ratio in the index year and the subsequent change in the ratio (hospitals with low mortality,<i>r</i> = −0.45; hospitals with high mortality,<i>r</i> = −0.60). Little of the variation in risk-adjusted mortality was explained by prior performance. An increase in the O/E mortality ratio from 1.0 to 2.0 in the index year was associated with a higher O/E mortality ratio of only 0.15 (95% CI, 0.02-0.27) in the following year. <h3>Conclusions and Relevance</h3> At hospitals with high or low PCI-related mortality rates, the rates largely regressed to the mean the following year. A hospital's risk-adjusted mortality rate was poorly associated with its future mortality. The annual hospital PCI-related mortality may not be a reliable factor associated with hospital quality to consider in a practice change or when helping patients select high-quality hospitals.
Abstract 17354: Aortic Stenosis in Women vs. Men: Differential Severity to Calcification Load Relationship
Authors: Shivani R Aggarwal, David Messika-Zeitoun, Caroline Cueff, Joseph Maalouf, Philip A Araoz, Alec Vahanian, Maurice E Sarano
Journal: Circulation (2011)

Introduction: Aortic Stenosis (AS) is a common valve disease of the adult, caused by calcification of aortic cusps. The relationship between cusp calcification and severity of AS has been established mostly in men and it is unclear whether the calcification process and its relation to AS severity is similar in women Hypothesis: We hypothesized that the physiologic relation between aortic valve calcification (AVC) load and AS severity is different in men and women and that lower calcification loads may lead to severe AS in women Methods: We prospectively performed high resolution computed tomography (CT) without contrast in 679 patients with AS (Aortic valve area (AVA) &lt;2cm 2 , Mean gradient ≥10 mmHg) at two academic centers (Rochester, MN; Paris, France) to measure AVC scores and compare these to the hemodynamic obstruction measured by Echo-Doppler. Results: Women vs. men were older (76±11 vs 74±11, p&lt;0.0001) with slightly higher ejection fraction (62±12 vs 59±13, p=0.001) but AS severity was similar (AVA/body surface area 0.55±0.2 vs 0.56±0.2 cm 2 /m 2 ; Peak velocity 4±1 vs 3.9±1 m/s; Mean gradient 41±21 vs 38±18 mmHg, all p≥0.1). Yet, AVC load was lower in women vs men, score absolute or normalized for LVOT area (551±383 vs 626±399 all p&lt;0.0001). For those with severe AS (Mean gradient &gt;40 mmHg), AVC scores were 2433±1412 in women vs 3805±1587 in men. Multivariate analysis adjusting for age, BSA, LVOT area and mean gradient, confirmed that severe AS was achieved with lower AVC load in women (all p&lt;0.0001). Conclusions: In this large multicenter AS population, women reached similar AS severity than males for lower calcium loads, even after adjustment for lower body and LVOT size. Hence the relation between valvular calcification process and severity of AS differs in women vs. men. Thus, future studies are needed to determine the differential mechanism of aortic calcification in men and women and diagnostic consideration must be given to gender in the interpretation of AS severity by AVC load.
Abstract 16073: A Whole Blood Transcriptional Signature in Women With Myocardial Infarction With Non-Obstructive Coronary Artery Disease (MINOCA)
Authors: Tessa J Barrett, Angela H Lee, Anais Hausvater, Nathaniel Smilowitz, Glenn Fishman, Judith Hochman, Harmony R Reynolds, Jeffrey S Berger
Journal: Circulation (2018)

Introduction: Myocardial infarction (MI) with non-obstructive coronary artery disease (MINOCA) occurs in 5-20% of patients with MI. Blood transcriptional profiling has improved diagnosis and unders...
Mechanisms and Antitumor Activity of a Binary EGFR/DNA–Targeting Strategy Overcomes Resistance of Glioblastoma Stem Cells to Temozolomide
Authors: Zeinab Sharifi, Bassam Abdulkarim, Brian Meehan, Janusz Rak, Paul Daniel, Julie Schmitt, Nidia Lauzon, Kolja Eppert, Heather M. Duncan, Kevin Petrecca, Marie-Christine Guiot, Bertrand Jean-Claude, Siham Sabri
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Glioblastoma (GBM) is a fatal primary malignant brain tumor. GBM stem cells (GSC) contribute to resistance to the DNA-damaging chemotherapy, temozolomide. The epidermal growth factor receptor (EGFR) displays genomic alterations enabling DNA repair mechanisms in half of GBMs. We aimed to investigate EGFR/DNA combi-targeting in GBM. Experimental Design: ZR2002 is a “combi-molecule” designed to inflict DNA damage through its chlorethyl moiety and induce irreversible EGFR tyrosine kinase inhibition. We assessed its in vitro efficacy in temozolomide-resistant patient-derived GSCs, mesenchymal temozolomide-sensitive and resistant in vivo–derived GSC sublines, and U87/EGFR isogenic cell lines stably expressing EGFR/wild-type or variant III (EGFRvIII). We evaluated its antitumor activity in mice harboring orthotopic EGFRvIII or mesenchymal TMZ-resistant GSC tumors. Results: ZR2002 induced submicromolar antiproliferative effects and inhibited neurosphere formation of all GSCs with marginal effects on normal human astrocytes. ZR2002 inhibited EGF-induced autophosphorylation of EGFR, downstream Erk1/2 phosphorylation, increased DNA strand breaks, and induced activation of wild-type p53; the latter was required for its cytotoxicity through p53-dependent mechanism. ZR2002 induced similar effects on U87/EGFR cell lines and its oral administration significantly increased survival in an orthotopic EGFRvIII mouse model. ZR2002 improved survival of mice harboring intracranial mesenchymal temozolomide-resistant GSC line, decreased EGFR, Erk1/2, and AKT phosphorylation and was detected in tumor brain tissue by MALDI imaging mass spectrometry. Conclusions: These findings provide the molecular basis of binary EGFR/DNA targeting and uncover the oral bioavailability, blood–brain barrier permeability, and antitumor activity of ZR2002 supporting potential evaluation of this first-in-class drug in recurrent GBM.
A Novel Gene Expression Classifier Enriches for Single Agent Clinical Activity of CC-122, a Cereblon Modulator, Administered Orally to Relapsed or Refractory Diffuse Large B-Cell Lymphoma Subjects: Results from the Phase I CC-122-ST-001 Study
Authors: Cecilia Carpio, Reda Bouabdallah, Loic Ysebaert, Juan-Manuel Sancho, Gilles Salles, Raul Cordoba, Antonio Pinto, Mecide Gharibo, Drew W. Rasco, Carlos Panizo, Jose A. Lopez-Martin, Armando Santoro, Antonio Salar, Silvia Damian, Alejandro Martín, Gregor Verhoef, Xin Wei, Patrick R. Hagner, Kristen Hege, Alberto Risueño, Anita K. Gandhi, Tonia J. Buchholz, Michael Pourdehnad, Vincent Ribrag
Journal: Blood (2017)
Antithrombotic Effects of Recombinant Human, Active Site–Blocked Factor VIIa in a Rabbit Model of Recurrent Arterial Thrombosis
Authors: PaoloGolino, MassimoRagni, PlinioCirillo, DavideD’Andrea, AnnalisaScognamiglio, AmeliaRavera, ChiaraBuono, MirellaEzban, NicolaCorcione, FrancescoVigorito, MarioCondorelli, MassimoChiariello
Journal: Circulation Research (1998)

Abstract—The extrinsic coagulation pathway is activated when circulating factor VII (FVII) gains access to tissue factor (TF) exposed as a consequence of vascular injury. Increasing evidence indicates that this TF-dependent activation of the coagulation plays an important role in the pathophysiology of intravascular thrombus formation. In the present study, we tested the effects of recombinant human, active site–blocked activated FVII (FVIIai) in a rabbit model of carotid artery thrombosis. Cyclic flow variations (CFVs), due to recurrent thrombus formation, were obtained in stenotic rabbit carotid arteries with endothelial injury. Carotid blood flow velocity was measured by a Doppler flow probe. After 30 minutes of CFVs, the animals received FVIIai (100 μg · kg−1 · min−1 intracarotid infusion for 10 minutes, n=9). If CFVs were abolished, animals were followed for 30 additional minutes, after which recombinant human activated FVII (FVIIa) was infused into the carotid artery (100 μg · kg−1 · min−1 for 10 mi...
Asylum seeker whose breast cancer treatment was delayed over eligibility has died
Authors: Clare Dyer
Journal: BMJ (2019)

An Ethiopian asylum seeker with advanced breast cancer who was denied treatment for several weeks amid confusion about whether she should be charged by the NHS has died at the age of 39.

Kelemua Mulat, whose breast cancer had spread to her abdomen and spine, was refused treatment after Home Office and NHS officials decided that she was ineligible for free care.

She fell foul of a combination of Home Office rules on asylum and NHS regulations introduced in 2017 requiring NHS trusts to check patients’ eligibility for free treatment and to charge …
Exclusive high dose rate brachytherapy (HDR-BT) for early stage non-small cell lung carcinoma: Results of a retrospective study in 226 patients
Authors: M. Aumont, M. A. Mahe, B. Prevost, M. P. Sunyach, D. Peiffert, P. Maingon, L. Thomas, M. Begue, D. Willaume, D. Lerouge, L. Campion
Journal: Journal of Clinical Oncology (2007)

7688 Objective: To evaluate efficacy and toxicity of HDR BT in non operable endobronchial carcinoma from a retrospective multicentric study. Patients and Methods: Criteria for selection: non small cell carcinoma accessible to fiberoptic bronchoscopy, no extrabronchial extension on CT, contraindication to surgery and external radiation therapy (ERT). Statistical analysis: survival curves calculated with the Kaplan-Meier method and compared with the Logrank test; Cox model to evaluate in uni and multivariate analysis the impact on survival and complications of these parameters: location of tumor: lobar or segmental vs main stem bronchus, previous ERT vs no, total dose:= 30 Gy vs less, dose per fraction:= 5 Gy vs more, number of catheter(s):1 vs = 2. Results: Between 1991 and 2006, 226 patients from 9 radiotherapy departments were included. Main characteristics of tumors: squamous-cell histology: 96%, stage Tis: 60, T1: 153, T2: 9, Tx 4; lobar or segmental location: 91%. 51 patients (22.5%) had received ERT for previous lung cancer(s). Characteristics of HDR BT were: total dose = 30 Gy: 70%, dose per fraction = 5 Gy: 66%, 1 catheter: 46%. Dose was prescribed at 1 cm from the radius. Mean follow-up was 30.4 months (9- 116). Histologic evaluation was performed at 3 months in 137 patients. 92% had a complete response. 128 patients were died: intercurrent disease 45, local failure 35, complications 13. Two and 5-year survival: overall: 57%, 29%; specific (death of lung cancer) 81%, 56%; local- relapse free (LRF) 68%, 50%. Toxicity included 1.3% pneumothorax, hemoptysis 6.6% (5% fatal), bronchitis 20%. In univariate analysis: overall, specific and LRF survival were better for lobar or segmental location vs main stem bronchus (p=0.0001), overall and specific survival were higher with no previous ERT (p=0.006). In multivariate analysis, lobar or segmental location was associated with improved overall (p=0.0001) and LRF (p=0.003) survival. LRF survival was better in patients treated with = 2 catheters (p=0.007). No factor influence frequency of complications. Conclusion: This large retrospective study confirmed that HDRBT is efficient and safe in medically inoperable patients particulary with lobar or segmental endobronchial carcinoma. No significant financial relationships to disclose.
Asymptomatic Patients With Abnormal Fractional Flow Reserve Treated With Medication Alone or With PCI
Authors: Stephane Fournier, Yuhei Kobayashi, William F. Fearon, Carlos Collet, Bruno Roza da Costa, Gilles Rioufol, Nico H.J. Pijls, Peter Jüni, Bernard De Bruyne
Journal: Journal of the American College of Cardiology (2019)