tbuckley/cabot-search huggingface dataset:
Rac1-mediated cytoskeleton rearrangements induced by intersectin-1s deficiency promotes lung cancer cell proliferation, migration and metastasis
Authors: Niranjan Jeganathan, Dan Predescu, Jin Zhang, Fei Sha, Cristina Bardita, Monal Patel, Stephen Wood, Jeffrey A. Borgia, Robert A. Balk, Sanda Predescu
Journal: Molecular Cancer (2016)

The mechanisms involved in lung cancer (LC) progression are poorly understood making discovery of successful therapies difficult. Adaptor proteins play a crucial role in cancer as they link cell surface receptors to specific intracellular pathways. Intersectin-1s (ITSN-1s) is an important multidomain adaptor protein implicated in the pathophysiology of numerous pulmonary diseases. To date, the role of ITSN-1s in LC has not been studied.Human LC cells, human LC tissue and A549 LC cells stable transfected with myc-ITSN-1s construct (A549 + ITSN-1s) were used in correlation with biochemical, molecular biology and morphological studies. In addition scratch assay with time lapse microscopy and in vivo xenograft tumor and mouse metastasis assays were performed.ITSN-1s, a prevalent protein of lung tissue, is significantly downregulated in human LC cells and LC tissue. Restoring ITSN-1s protein level decreases LC cell proliferation and clonogenic potential. In vivo studies indicate that immunodeficient mice injected with A549 + ITSN-1s cells develop less and smaller metastatic tumors compared to mice injected with A549 cells. Our studies also show that restoring ITSN-1s protein level increases the interaction between Cbl E3 ubiquitin ligase and Eps8 resulting in enhanced ubiquitination of the Eps8 oncoprotein. Subsequently, downstream unproductive assembly of the Eps8-mSos1 complex leads to impaired activation of the small GTPase Rac1. Impaired Rac1 activation mediated by ITSN-1s reorganizes the cytoskeleton (increased thick actin bundles and focal adhesion (FA) complexes as well as collapse of the vimentin filament network) in favor of decreased LC cell migration and metastasis.ITSN-1s induced Eps8 ubiquitination and impaired Eps8-mSos1 complex formation, leading to impaired activation of Rac1, is a novel signaling mechanism crucial for abolishing the progression and metastatic potential of LC cells.
Long-term use of pegfilgrastim in children with severe congenital neutropenia: clinical and pharmacokinetic data
Authors: Francesca Fioredda, Tiziana Lanza, Federica Gallicola, Francesca Riccardi, Marina Lanciotti, Elena Mastrodicasa, Sara Signa, Sabrina Zanardi, Michaela Calvillo, Carlo Dufour
Journal: Blood (2016)
P0943 : Beneficial effects of IL-1 cytokine inactivation and the role of the serine/threonine kinase MK-2 in hepatic steatosis in a murine obesity model
Authors: J. Wohlfahrt, A. Fettelschoss, T. Kündig, H. Hermanns, B. Müllhaupt, J. Schmitt, A. Geier
Journal: Journal of Hepatology (2015)
Senior doctors urge public inquiry over Hunt’s claims of excess weekend mortality
Authors: Anne Gulland
Journal: BMJ (2016)

A group of prominent doctors and scientists, including Stephen Hawking and Robert Winston, has called on the UK prime minister to set up an independent inquiry into claims made by England’s health secretary, Jeremy Hunt, over excess deaths among patients admitted to NHS hospitals at weekends.1

The group, which includes Margaret McCartney, the GP and BMJ columnist, and Neena Modi, president of the Royal College of Paediatrics and Child Health, has written to the Guardian newspaper urging Theresa May to act in the public’s interest and “take immediate …
A7-02: Identification of polymorphisms in the Caspase-3 gene and their association with lung cancer risk
Authors: Heejung Jun, Kyungmi Kim, Jinsung Jang, Sungbeom Han, Eunjin Kim, Seungick Cha, Changho Kim, Taehoon Jung, Jaeyong Park
Journal: Journal of Thoracic Oncology (2007)
Innovative quality initiative measurement using Web-based drug dispensing technology with interactive physician queries to evaluate bisphosphonate use across community oncology practices nationwide.
Authors: C. G. Baker, G. Grabavoy, I. Aksamit, H. J. McKenzie, K. A. Bergstrom
Journal: Journal of Clinical Oncology (2010)

9070 Background: Published data suggest suboptimal compliance rates with Quality Oncology Practice Initiative (QOPI) criteria for use of intravenous bisphosphonates in breast cancer patients with bone metastasis. We implemented a quality initiative across our nationwide community oncology practice membership to measure intravenous bisphosphonate compliance and provide clinical education using Web-based drug dispensing technology, with interactive physician queries. Methods: Patients within participating oncology practices using our Web-based drug dispensing technology receiving treatment for breast, lung, or prostate cancers with newly diagnosed bone metastases, or newly diagnosed multiple myeloma were identified between 6/21/2009 and 8/31/2009 and categorized as not receiving (arm A) or receiving (arm B) intravenous bisphosphonate therapy. Intravenous bisphosphonate use for the total population was evaluated. Physicians were queried regarding reason for declining to initiate therapy for each specific patient in arm A. Through the query process clinical education regarding use of intravenous bisphosphonate therapy was provided. Results: A total of 182 patients from 56 practices in 27 states were evaluated; arm A included 25 (14%) patients and arm B included 157 (86%) patients. For reasons identified by physicians for not initiating therapy, see Table. Conclusions: Practices demonstrated high rates of compliance with use of intravenous bisphosphonate therapy in patients with breast, lung, or prostate cancers with bone metastases, or multiple myeloma. In most patients for whom intravenous bisphosphonates were not prescribed, acceptable contraindications to therapy were present. Using Web-based drug dispensing technology supported with interactive queries is a viable method of measuring adherence to quality criteria. Number of patients (%) Severe renal insufficiency or renal failure 7 (28%) Indolent multiple myeloma 6 (24%) Patient deceased 3 (12%) Other 3 (12%) Side effect profile 2 (8%) Cost to patient 1 (4%) Poor performance status/frailty 1 (4%) No response to question 2 (8%) Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration McKesson, Novartis Amgen, McKesson, Novartis
Final results from a phase I study of TRC093 (humanized anti-cleaved collagen antibody) in patients with solid cancer.
Authors: F. Robert, M. S. Gordon, L. S. Rosen, D. S. Mendelson, M. Mulay, B. J. Adams, D. Alvarez, C. P. Theuer, B. R. Leigh
Journal: Journal of Clinical Oncology (2010)

3038 Background: TRC093 is a humanized IgG1 monoclonal antibody to cryptic collagen epitopes that are exposed during angiogenesis and tumor growth. These epitopes are recognized by integrin receptors on endothelial and cancer cells during angiogenesis and tumor progression. Intravenous TRC093 localizes to the subendothelial basement membranes in tumor tissues (but not normal tissues) and inhibits angiogenesis and tumor growth as monotherapy and in combination with bevacizumab. Methods: This phase I study evaluated the safety and PK of i.v. TRC093 monotherapy for advanced refractory cancer. Patients were required to have an ECOG PS ≤ 2 and adequate organ function. TRC093 was administered by 90 min i.v. infusion on days 1 and 15 of each 28-day cycle. Results: A total of 19 patients were treated including 3 each at 0.5, 1.5, and 5 mg/kg, 9 at 12 mg/kg, and 1 at 24 mg/kg. The median number of prior cancer regimens was 4 (range: 1 to 10). Dose-limiting toxicity was not observed. The 12 mg/kg dose level was considered the maximum feasible dose due to limited drug supply. The most common possibly related adverse event was grade 1/2 fatigue. Possibly related grade 3/4 adverse events were not observed. One patient experienced grade 1 infusion reaction with the initial dose that did not recur with diphenhydramine premedication. TRC093 demonstrated linear dose-dependent PK typical of a humanized antibody. Target TRC093 serum concentrations based on preclinical efficacy studies were achieved throughout the 2-week dosing interval at 12 mg/kg (mean Cmax=467 ug/mL, T1/2=10.9 days). Human antihuman antibody (HAHA) formation was not observed. Evidence of clinical activity included one ovarian cancer patient with a mixed response, five patients with stable disease lasting up to 10 months, and an overall decline in mean circulating VEGF levels with treatment. Conclusions: TRC093 was well-tolerated at clinically relevant doses with early evidence of activity. Phase Ib/II trials are planned to evaluate TRC093 in combination with bevacizumab in patients with glioblastoma. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration TRACON Pharma TRACON Pharma TRACON Pharma
Patients With Nonpolypoid (Flat and Depressed) Colorectal Neoplasms at Increased Risk for Advanced Neoplasias, Compared With Patients With Polypoid Neoplasms
Authors: Sarah K. McGill, Roy Soetikno, Robert V. Rouse, Hobart Lai, Tonya Kaltenbach
Journal: Clinical Gastroenterology and Hepatology (2016)
Influence of NKG2D/DNAM-1 interaction with tumor cell ligands on the ability of lenalidomide to enhance ADCC of antibody-coated solid tumor cells.
Authors: L. Wu, M. Adams, S. Parton, L. Lu, P. Schafer, J. B. Bartlett
Journal: Journal of Clinical Oncology (2010)

e21008 Background: Lenalidomide has been shown to enhance the antibody- dependent cellular cytotoxicity (ADCC) of rituximab-treated B cell chronic lymphocytic leukemia (B-CLL) and non-Hodgkin lymphoma (NHL) tumor cells. The combination appears to be especially active in patients so we sought to build on these observations by determining lenalidomide's ability to enhance ADCC of solid tumor cells. Methods: Purified NK cells were used as effector cells and tumor cell lines were used as targets after pre-treatment with cetuximab or trastuzumab. 23 tumor cell lines were used; 11 colorectal (CRC), 3 breast, 3 ovary, 2 lung, 2 head and neck and 2 bone sarcoma. Cytotoxicity was assessed using a standard lactate dehydrogenase release assay and specific lysis calculated. NK cell expression of activating receptors from 30 donors and tumor cell expression of NK cell ligands were assessed by flow cytometry. Results: Lenalidomide increased NK cell-specific lysis of cetuximab-coated CRC cells; HCT- 116, from 19% to 39% (p < 0.01), HT-29, 32% to 50% (p < 0.05) and also of trastuzumab-coated breast cancer cells; SKBR-3, 32% to 44% (p < 0.01), MCF-7, 30% to 70% (p < 0.01). Variable sensitivity of CRC cell lines was dependent on EGFR expression (range 5%-96%) but independent of either KRAS or BRAF mutational status or FCγRIIIa genotype. CRC cell line expression of NK cell ligands, PVR, MIC-A, ULBP2 and ULBP3 correlated with sensitivity to ADCC. NK cell expression of DNAM-1, NKG2D, but not NKp46, correlated with the extent of ADCC and its enhancement by lenalidomide. Antibody blocking of NKG2D, and to a lesser extent DNAM-1, inhibited CRC cell killing from 70% to 31% and 48% respectively (both p < 0.05), whereas blocking of individual cognate ligands had minimal effect. Lenalidomide enhanced NK cell production of gmcsf, IL-8, MIP-1α/βm RANTES, MCP-1 and IP-10 but reversed phosphorylation of Src family kinases induced by antibody alone. Conclusions: Lenalidomide enhances the ADCC of solid tumor cells, the extent of which is largely dependent on NKG2D/NKG2D ligand interactions, providing a rationale for exploratory clinical studies and assessment of potential biomarkers predictive lenalidomide-mediated ADCC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene Celgene
P2-279: Outcome of advanced nonsmall cell lung cancer patients receiving gemcitabine and weekly paclitaxel as first–line treatment
Authors: Zhong-Zhe Lin, Chiun Hsu, Yeun-Chung Chang, Chong-Jen Yu, Chih-Hung Hsu, Chia-Chi Lin, Ann-Lii Cheng, Pan-Chyr Yang, Chih-Hsin Yang
Journal: Journal of Thoracic Oncology (2007)
MAGE-A3 GENE EXPRESSION FREQUENCY AND DEMOGRAPHY DATA OF STAGE IB-IIIA NSCLC PATIENTS FROM ONGOING MAGRIT PHASE III TRIAL EVALUATING MAGE-A3 ANTIGEN SPECIFIC CANCER IMMUNOTHERAPEUTIC (ASCI) AS ADJUVANT TREATMENT
Authors: J. H Kim, J Jassem, H Tada, M Yoshimura, F Piantedosi, P Zatloukal, G Krakorova, M Debois, C Debruyne, Johan Vansteenkiste
Journal: Annals of Oncology (2010)
P2-100: Real time RT-PCR based 3-gene expression signature predicts survival in early-stage squamous cell lung cancer (SqCLC)
Authors: Marcin Skrzypski, Ewa Jassem, Pedro Mendez, Imane Chaib, Amelia Szymanowska, Witold Rzyman, Grazyna K. Gulida, Jacek Jassem, Miguel Taron, Rafael Rosell
Journal: Journal of Thoracic Oncology (2007)
Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of Age or Older
Authors: Anthony L. Cunningham, Himal Lal, Martina Kovac, Roman Chlibek, Shinn-Jang Hwang, Javier Díez-Domingo, Olivier Godeaux, Myron J. Levin, Janet E. McElhaney, Joan Puig-Barberà, Carline Vanden Abeele, Timo Vesikari, Daisuke Watanabe, Toufik Zahaf, Anitta Ahonen, Eugene Athan, Jose F. Barba-Gomez, Laura Campora, Ferdinandus de Looze, H. Jackson Downey, Wayne Ghesquiere, Iris Gorfinkel, Tiina Korhonen, Edward Leung, Shelly A. McNeil, Lidia Oostvogels, Lars Rombo, Jan Smetana, Lily Weckx, Wilfred Yeo, Thomas C. Heineman
Journal: New England Journal of Medicine (2016)

A trial involving adults 50 years of age or older (ZOE-50) showed that the herpes zoster subunit vaccine (HZ/su) containing recombinant varicella-zoster virus glycoprotein E and the AS01B adjuvant system was associated with a risk of herpes zoster that was 97.2% lower than that associated with placebo. A second trial was performed concurrently at the same sites and examined the safety and efficacy of HZ/su in adults 70 years of age or older (ZOE-70).This randomized, placebo-controlled, phase 3 trial was conducted in 18 countries and involved adults 70 years of age or older. Participants received two doses of HZ/su or placebo (assigned in a 1:1 ratio) administered intramuscularly 2 months apart. Vaccine efficacy against herpes zoster and postherpetic neuralgia was assessed in participants from ZOE-70 and in participants pooled from ZOE-70 and ZOE-50.In ZOE-70, 13,900 participants who could be evaluated (mean age, 75.6 years) received either HZ/su (6950 participants) or placebo (6950 participants). During a mean follow-up period of 3.7 years, herpes zoster occurred in 23 HZ/su recipients and in 223 placebo recipients (0.9 vs. 9.2 per 1000 person-years). Vaccine efficacy against herpes zoster was 89.8% (95% confidence interval [CI], 84.2 to 93.7; P<0.001) and was similar in participants 70 to 79 years of age (90.0%) and participants 80 years of age or older (89.1%). In pooled analyses of data from participants 70 years of age or older in ZOE-50 and ZOE-70 (16,596 participants), vaccine efficacy against herpes zoster was 91.3% (95% CI, 86.8 to 94.5; P<0.001), and vaccine efficacy against postherpetic neuralgia was 88.8% (95% CI, 68.7 to 97.1; P<0.001). Solicited reports of injection-site and systemic reactions within 7 days after injection were more frequent among HZ/su recipients than among placebo recipients (79.0% vs. 29.5%). Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two study groups.In our trial, HZ/su was found to reduce the risks of herpes zoster and postherpetic neuralgia among adults 70 years of age or older. (Funded by GlaxoSmithKline Biologicals; ZOE-50 and ZOE-70 ClinicalTrials.gov numbers, NCT01165177 and NCT01165229 .).
P2-169: Carboplatin and Gemcitabine as adjuvant therapy in completely resected stage I-IIIA non small cell lung cancer patients
Authors: Andriani G. Charpidou, Evgenia Katirtzoglou, Antonis Zalonis, Kosmas Pantazopoulos, Ifigenia Tzanou, Nikolaos Katirtzoglou, Niki Georgatou, Mina Gaga, Kostas N. Syrigos
Journal: Journal of Thoracic Oncology (2007)
Signal Integration by the IκB Protein Pickle Shapes Drosophila Innate Host Defense
Authors: Otto Morris, Xi Liu, Celia Domingues, Christopher Runchel, Andrea Chai, Shaherin Basith, Tencho Tenev, Haiyang Chen, Sangdun Choi, Giuseppa Pennetta, Nicolas Buchon, Pascal Meier
Journal: Cell Host & Microbe (2016)
P2-163: Concurrent Chemoradiation for Stage III Non-Small Cell Lung Cancer (NSCLC): A Single Institution Canadian Experience
Authors: Shantanu Banerji, Amit Chowdhury, Ahmet Leylek, Naseer Ahmed, Shahida Ahmed, A.L. Tan, Helmut W. Unruh, Andrew W. Maksymiuk, Srisala Navaratnam
Journal: Journal of Thoracic Oncology (2007)
Patterns of treatment (trx) with angiogenesis inhibitors (AIs) in patients (pts) with metastatic renal cell carcinoma (mRCC) in France.
Authors: A. Levy, M. Gross-Goupil, S. P. Sarda, C. Korves, L. Antràs, A. Luka, P. Ramamurthy, M. Neary, M. S. Duh, B. Escudier
Journal: Journal of Clinical Oncology (2010)

e15139 Background: This study evaluated trx patterns of AIs sunitinib (SU), sorafenib (SOR), and bevacizumab (BEV) in a clinical practice setting in France. Methods: Data from medical records were retrospectively reviewed at a tertiary oncology center in France for mRCC pts who were >18 yrs and received SU, SOR or BEV as 1st AI. Proportions of pts with trx discontinuation (d/c), interruption, or dose change were computed. Reasons for trx modifications and AI trx sequences were examined. Results: 121 pts were included (SU n=71, 12 in clinical trial [CT], 5 in expanded access program [EAP]; SOR n=33, 6 in CT, 4 in EAP; BEV n=17, 1 in CT). 8.5% (SU), 24.2% (SOR) and 64.7% (BEV) of pts had received prior cytokine therapy. 88.7% (SU), 97.0% (SOR) and 88.2% (BEV) of pts initiated on the recommended dose. Median 1st-line AI trx duration was 9.1 months (m) (SU), 11.3 m (SOR) and 9.9 m (BEV). Trx d/c occurred in 74.6% (SU), 90.9% (SOR) and 41.2% (BEV) of pts, mostly due to progressive disease (PD) or adverse events (AEs). AEs were the most common reasons for trx interruptions and dose reductions and led to trx modifications in 52.1% (SU), 27.3% (SOR) and 35.3% (BEV) of pts. 38.0% (SU), 54.5% (SOR) and 23.5% (BEV) of pts received 2nd-line AI trx (Table). Conclusions: In clinical practice, toxicity associated with AIs, particularly SU, led to high rates of trx modifications. This study is limited by its retrospective nature and small sample sizes from only a single center. Further exploration of new agents with improved tolerability profiles that may also contribute to improved clinical outcomes is needed for mRCC. Trx patterns, n (%) SU N=71 SOR N=33 BEV N=17 Pts with 1st-line trx d/c 53 (74.6) 30 (90.9) 7 (41.2) Due to PD 36 (50.7) 25 (75.8) 5 (29.4) Due to AEs 11 (15.5) 4 (12.1) 2 (11.8) Pts with 1st-line trx interruption 6 (8.5) 1 (3.0) 2 (11.8) Due to AEs 5 (7.0) 1 (3.0) 2 (11.8) Patients with 1st-line trx dose reduction 28 (39.4) 8 (24.2) 2 (11.8) Due to AEs 28 (39.4) 8 (24.2) 2 (11.8) Pts with ≥1 1st-line trx modification due to AEs 37 (52.1) 9 (27.3) 6 (35.3) Pts with 2nd-line trx 27 (38.0) 18 (54.5) 4 (23.5) Sunitinib 1 (1.4) 18 (54.5) 1 (5.9) Sorafenib 18 (25.4) 0 (0.0) 3 (17.6) Temsirolimus 8 (11.3) 0 (0.0) 0 (0.0) Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline, Novartis, Pfizer, Roche GlaxoSmithKline GlaxoSmithKline
P18 The effects of acute and repeated bouts of unilateral Neuromuscular Electrical Stimulation on quadriceps muscle inflammation in COPD: Abstract P18 Table 1
Authors: A Gray, L Latimer, A Parmar, P Bradding, NJ Greening, MC Steiner
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> Impaired skeletal muscle function is an important systemic manifestation of COPD which can be improved by exercise training. Non-volitional training using neuromuscular electrical stimulation (NMES) may be an effective training technique in situations where voluntary exercise may be difficult or impractical (e.g. peri-exacerbation or severe ventilatory limitation). Exercise is known to result in both intramuscular and systemic inflammation. However, the cellular response to NMES, which directly depolarises the motor units, is unclear. We investigated the impact of acute and repeated bouts of unilateral NMES in COPD patients. <h3>Methods</h3> 16 patients underwent 6 weeks of unilateral NMES 5 times a week for 30 min at 50 Hz at Glenfield Hospital, Leicester. Mean (SD) age was 65 (9) years, FEV<sub>1</sub>: 50 (22)% predicted, BMI 26.5 (5.2) Kg/m<sup>2</sup>). Isometric quadriceps strength, regional muscle mass (DEXA) and quadriceps thickness (ultrasound) were recorded at baseline and at the end of the intervention. Vastus lateralis muscle biopsies were obtained from both the trained and untrained limbs at baseline, 24 h after the first bout of NMES and at 6 weeks. Venous blood was taken at the same time. Biopsies were analysed for neutrophil (neutrophil elastase) and macrophage (CD163) density using immunohistochemistry. ELISA measurements of inflammatory cytokines (IL-6 and TNFα) were performed on blood samples. <h3>Results</h3> Quadriceps strength increased by 7.6% (p = 0.024), thigh mass by 2.8% (p = 0.185), and quadriceps thickness by 11% (p = 0.002). Muscle biopsies for 11 patients were analysed. Neutrophil density 24 h after a single bout of unilateral NMES significantly increased in both the trained and untrained limb, with larger increase in the stimulated muscle (Table 1). Neutrophil density returned to baseline in the trained limb following training. No changes were seen in muscle macrophage density, serum IL-6 or serum TNFα. <h3>Conclusion</h3> A single bout of unilateral NMES provokes an intramuscular neutrophilic inflammatory response in both the trained and untrained limb, which are not mediated by changes in circulating IL-6 or TNFα. Neutrophil infiltration returned to baseline in the stimulated leg following training.