tbuckley/cabot-search huggingface dataset:
Abstract 182: Dual inhibition of the MEK5 and PI3K pathways most effectively reduces proliferation and migration in triple negative breast cancer cells
Authors: Thomas Wright, Christopher Raybuck, Katheryn Wendekier, Jane E. Cavanaugh
Journal: Cancer Research (2016)

Abstract Aberrations in the MAPK/extracellular signal-regulated kinase (MEK/ERK) and phosphoinositide-3-kinase (PI3K) pathways have been linked to increased proliferation and survival in triple negative breast cancer (TNBC) cells. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. Promising combinations of MEK and PI3K inhibition have been evaluated in phase I clinical trials for various cancer types. However, these clinical trials have had limited efficacy and have yet to encompass the MEK5/ERK5 pathway, which has been shown to promote cell survival. The goal of this study was to examine the crosstalk between the MEK1/2, MEK5, and PI3K pathways and determine the most promising combination of the MEK1/2, ERK5, and PI3K inhibitors, U0126, XMD8-92, and LY294002, respectively, in a diverse panel of triple negative breast cancer cell lines: BT549, MDA-MB-231, and MDA-MB-468. Our results indicate that dual inhibition of the MEK5 and PI3K pathways significantly reduced both proliferation (45.53%) and migration (39.37%) in MDA-MB-231 TNBC cells. In contrast, inhibition of ERK1/2 alone or in combination with PI3K or ERK5 inhibition yielded mixed responses. Interestingly, dual inhibition of the MEK5 and PI3K pathways increased the activity of the MEK1/2 pathway. These data suggest that crosstalk between these kinases occurs and dual inhibition of PI3K and ERK5 may be a novel therapeutic approach for treating TNBC. Citation Format: Thomas Wright, Christopher Raybuck, Katheryn Wendekier, Jane E. Cavanaugh. Dual inhibition of the MEK5 and PI3K pathways most effectively reduces proliferation and migration in triple negative breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 182.
A pilot study of unemployment in patients with hidradenitis suppurativa in Denmark
Authors: P. Theut Riis, L. Thorlacius, E. Knudsen List, G.B.E. Jemec
Journal: British Journal of Dermatology (2016)

Hidradenitis Suppurativa (HS) is a chronic, inflammatory and relapsing skin disease, characterized by repeated outbreaks of painful inflamed nodules in the apocrine gland-bearing regions (armpits, genital area, groin, breasts and perianal region). These nodules can progress to abscesses, sinus tracts (tunnels) and scarring. (1) The estimated prevalence is 1-4% worldwide and HS is approximately three times more common in women than in men. (1)

HS is associated with significant disability and handicap. The lesions are often painful and lead to loss of mobility.

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MRI With Liver-Specific Contrast for Surveillance of Patients With Cirrhosis at High Risk of Hepatocellular Carcinoma
Authors: So Yeon Kim, Jihyun An, Young-Suk Lim, Seungbong Han, Ji-Young Lee, Jae Ho Byun, Hyung Jin Won, So Jung Lee, Han Chu Lee, Yung Sang Lee
Journal: JAMA Oncology (2016)

<h3>Importance</h3> Current recommendations for patients with cirrhosis are to undergo surveillance for hepatocellular carcinoma (HCC) with ultrasonography (US) every 6 months. However, the sensitivity of US screening to detect early-stage HCC is suboptimal. Magnetic resonance imaging (MRI) with liver-specific contrast may detect additional HCCs missed by US in high-risk patients with cirrhosis. <h3>Objective</h3> To compare the HCC detection rate of US and MRI in patients with cirrhosis who are at high risk for HCC. <h3>Design, Setting, and Participants</h3> A prospective surveillance study of 407 patients with cirrhosis and an estimated annual risk of HCC greater than 5% who underwent 1 to 3 biannual screening examinations with paired US and liver-specific contrast-enhanced MRI at a tertiary care hospital between November 2011 and August 2014. All patients were followed-up with dynamic computed tomography (CT) at 6 months after the study. The confirmation of HCC was based on the results of histologic examination and/or typical CT images of HCC. <h3>Main Outcomes and Measures</h3> HCC detection rates and false-positive findings of US vs MRI. <h3>Results</h3> A total of 407 eligible patients received 1100 screenings with paired US and MRI. Hepatocellular carcinomas were diagnosed in 43 patients: 1 detected by US only, 26 by MRI only, 11 by both, and 5 were missed by both. The HCC detection rate of MRI was 86.0% (37/43), significantly higher than the 27.9% (12/43) of US (<i>P</i> &lt; .001). Magnetic resonance imaging showed a significantly lower rate of false-positive findings than US (3.0% vs 5.6%;<i>P</i> = .004). Of the 43 patients with HCC, 32 (74.4%) had very early-stage HCC (a single nodule &lt;2 cm), and 29 (67.4%) received curative treatments. The 3-year survival rate of the patients with HCC (86.0%) was not inferior to those without HCC (94.2%; hazard ratio, 2.26; 95% CI, 0.92-5.56;<i>P</i> = .08). <h3>Conclusions and Relevance</h3> In patients with cirrhosis at high-risk of HCC, screening that used MRI with liver-specific contrast resulted in a higher HCC detection rate and lower false-positive findings compared with US. With MRI screening, most of the cancers detected were at very early stage, which was associated with a high chance of curative treatments and favorable survival of patients. Whether surveillance with MRI would reduce mortality from HCC in high-risk patients requires further investigation. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT01446666
Abstract 3269: Recapitulating the BETH adjuvant breast cancer trial (NCT00625898) using clinically accurate orthotopic surgical resection models
Authors: Liam S. Shiels, Ian S. Miller, Clare Morgan, Mattia Cremona, Robert Kerbel, Bryan Hennessey, Norma O’Donovan, John Crown, Annette T. Byrne
Journal: Cancer Research (2016)

Abstract Background: An overwhelming majority of phase III clinical trials in the oncology setting fail as promising results observed in the ‘pre-clinic’ are not successfully translated to patients. As such, improved models which more accurately predict outcomes are now required. Herein, we have established orthotopic surgical resection models of Her2+ breast cancer, which replicate the phenotype of clinical post-resection metastasis [1,2]. Using these models we have recapitulated the BETH adjuvant breast cancer trial (NCT00625898) where the addition of bevacizumab (BVZ) to chemotherapy plus trastuzumab (TRAST) failed to provide additional benefit in the adjuvant setting. Methods: SCID mice were orthotopically implanted with bioluminescent Her2+ MDA-MB-231or HCC1954 cells and palpable tumors resected approximately 5 weeks later. 3 weeks after resection, mice were treated with 10 mg/kg TRAST + 5mg/kg paclitaxel IP once weekly for 6 cycles with or without weekly BVZ (5mg/kg IP). Metastasis was monitored by weekly bioluminescence imaging. Results: Tumor growth and imaging data confirmed that the addition of BVZ to adjuvant TRAST + chemotherapy provided no additional benefit compared with TRAST + chemotherapy alone. Previous pre-clinical studies using inappropriate non-resection models failed to predict this response. Furthermore, Reverse Phase Protein Array analysis of treated tumors implicated HER2, VEGF, mTOR and the intrinsic mitochondrial cell death apoptotic pathways in treatment resistance. Conclusion: In summary, our data provides evidence for pre-clinical models which better predict clinical outcome in the breast cancer adjuvant setting, and which represent an important resource for interrogating resistance pathways and identifying novel biomarker signatures. [1]. Breast. 2013 Aug;22 Suppl 2:S57-65; [2]. Cancer Res. 2013 May 1;73(9):2743-8.This work was performed under Irish HPRA Authorization AE18982 and was supported by the Clinical Cancer Research Trust. ATB receives funding from the Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT Grant (CCRC13GAL). Citation Format: Liam S. Shiels, Ian S. Miller, Clare Morgan, Mattia Cremona, Robert Kerbel, Bryan Hennessey, Norma O’Donovan, John Crown, Annette T. Byrne. Recapitulating the BETH adjuvant breast cancer trial (NCT00625898) using clinically accurate orthotopic surgical resection models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3269.
A Phase 1 Study of the BET-Bromodomain Inhibitor OTX015 in Patients with Advanced Acute Leukemia
Authors: Hervé Dombret, Claude Preudhomme, Céline Berthon, Emmanuel Raffoux, Xavier Thomas, Norbert Vey, Carlos Gomez-Roca, Mark Ethell, Karen Yee, Fabrice Bourdel, Patrice Herait, Mauricette Michallet, Christian Recher, Christophe Roumier, Bruno Quesnel
Journal: Blood (2014)
High-Resolution Genomic Profiles Identify Novel Genes and/or Chromosomal Regions with Prognostic and Oncogenic Significance in Myeloma Patients.
Authors: Herve Avet Loiseau, Nikhil C. Munshi, Cheng Li, Florence Magrangeas, Wilfried Gouraud, Catherine Charbonnel, Jean-Luc Harousseau, Michel Attal, Gerald Marit, Claire Mathiot, Thierry Facon, Philippe Moreau, Kenneth C. Anderson, Stephane Minvielle
Journal: Blood (2007)
Detection of antineutrophil cytoplasmic antibodies (ANCAs): a multicentre European Vasculitis Study Group (EUVAS) evaluation of the value of indirect immunofluorescence (IIF) versus antigen-specific immunoassays
Authors: Jan Damoiseaux, Elena Csernok, Niels Rasmussen, Frank Moosig, Pieter van Paassen, Bo Baslund, Pieter Vermeersch, Daniel Blockmans, Jan-Willem Cohen Tervaert, Xavier Bossuyt
Journal: Annals of the Rheumatic Diseases (2016)

Objective This multicentre study was performed to evaluate the diagnostic accuracy of a wide spectrum of novel technologies nowadays available for detection of myeloperoxidase (MPO) and proteinase 3 (PR3)-antineutrophil cytoplasmic antibodies (ANCAs). Methods Sera (obtained at the time of diagnosis) from 251 patients with ANCA-associated vasculitis (AAV), including granulomatosis with polyangiitis and microscopic polyangiitis, and from 924 disease controls were tested for the presence of cytoplasmic pattern/perinuclear pattern and atypical ANCA (A-ANCA) by indirect immunofluorescence (IIF) (at two sites) and for the presence of PR3-ANCA and MPO-ANCA by eight different immunoassays. Results The area under the curve (AUC) of the receiver operating characteristic curve to discriminate AAV from controls was 0.923 (95% CI 0.902 to 0.944) and 0.843 (95% CI 0.814 to 0.871) for the two IIF methods. For the antigen-specific immunoassays, the AUC varied between 0.936 (95% CI 0.912 to 0.960) and 0.959 (95% CI 0.941 to 0.976), except for one immunoassay for which the AUC was 0.919 (95% CI 0.892 to 0.945). Conclusions Our comparison of various ANCA detection methods showed (i) large variability between the two IIF methods tested and (ii) a high diagnostic performance of PR3-ANCA and MPO-ANCA by immunoassay to discriminate AAV from disease controls. Consequently, dual IIF/antigen-specific immunoassay testing of each sample is not necessary for maximal diagnostic accuracy. These results indicate that the current international consensus on ANCA testing for AAV needs revision.
P1250 : Low incidence of reinfection with hepatitis C virus after successful treatment in montreal
Authors: N. Machouf, B. Trottier, C. Galanakis, E. Huchet, M. Poliquin, S. Vézina, S. Lavoie, D. Longpré, D. Legault, R. Thomas
Journal: Journal of Hepatology (2015)
Abstract 836: Effect of voluntary running on metastasis in a mouse model of breast cancer
Authors: Sara Mijwel, Helene Rundqvist, Carolin Lindholm, Carina Strell, Pernilla Roswall, Kristian Pietras, Randall S. Johnson, Arne Östman
Journal: Cancer Research (2016)

Abstract Introduction: Emerging evidence states that regular physical exercise provides a risk reduction for breast cancer by approximately 25%. In addition, recent studies suggest that physical activity may also have an effect on recurrence and mortality. Mouse models are suitable tools to study anti-neoplastic mechanisms. Aim: to evaluate the effect of voluntary running on tumor initiation, growth and metastasis in the Polyoma Middle T (PyMT) model of breast cancer. Methods: PyMT mice were housed with access either to wirelessly recording running wheels or locked control wheels. Running distances and tumor volumes were recorded. At 12 weeks, mice were sacrificed. Mammary glands were histologically staged and pulmonary metastases were quantified. In a follow up study, pre-trained mice were injected intravenously with tumor cells derived from the PyMT model and after an additional 10 weeks of voluntary running, pulmonary metastases were quantified. Results: PyMT mice ran significantly more than wildtype mice (6.4 vs 3.4 km/day). No significant effects of voluntary running on tumor- initiation, volume or stage were found. However, a trend for reduced metastasis was observed. After intravenous injections of tumor cells, runners had a significantly lower pulmonary metastasis frequency than non-runners. Conclusion: In this aggressive breast cancer model, an average of 6 km/day of voluntary running did not induce any effect on tumor formation or growth. However, the findings suggest that physical activity has impact on the metastatic process. Citation Format: Sara Mijwel, Helene Rundqvist, Carolin Lindholm, Carina Strell, Pernilla Roswall, Kristian Pietras, Randall S. Johnson, Arne Östman. Effect of voluntary running on metastasis in a mouse model of breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 836.
Efficacy and safety of aclidinium/formoterol <i>versus</i> salmeterol/fluticasone: a phase 3 COPD study
Authors: Claus Vogelmeier, Pier Luigi Paggiaro, Jordi Dorca, Pawel Sliwinski, Marcel Mallet, Anne-Marie Kirsten, Jutta Beier, Beatriz Seoane, Rosa Maria Segarra, Anne Leselbaum
Journal: European Respiratory Journal (2016)

The efficacy and safety of twice-daily aclidinium bromide/formoterol fumarate was compared with that of salmeterol/fluticasone propionate in patients with stable, moderate-to-severe chronic obstructive pulmonary disease (COPD). AFFIRM COPD (Aclidinium and Formoterol Findings in Respiratory Medicine COPD) was a 24-week, double-blind, double-dummy, active-controlled study. Patients were randomised (1:1) to aclidinium/formoterol 400/12 µg twice-daily via Genuair/Pressair or salmeterol/fluticasone 50/500 µg twice-daily via Accuhaler. The primary end-point was peak forced expiratory volume in 1 s (FEV 1 ) at week 24. Other end-points included Transition Dyspnoea Index (TDI) focal score at week 24, TDI and St George's Respiratory Questionnaire (SGRQ) responders, COPD Assessment Test and SGRQ scores, assessment of COPD symptoms and exacerbations, use of reliever medication, and device preference. Adverse events were monitored throughout. In total, 933 patients were eligible (mean age 63.4 years, 65.1% male). Aclidinium/formoterol was superior to salmeterol/fluticasone in peak FEV 1 and noninferior in TDI. Health status and reduction in exacerbation risk were similar in both groups. While both treatments were well tolerated, pneumonia occurred less frequently with aclidinium/formoterol than salmeterol/fluticasone. In stable COPD, aclidinium/formoterol significantly improved bronchodilation versus salmeterol/fluticasone, with equivalent benefits in symptom control and reduction in exacerbation risk. Both treatments were well tolerated and treatment-related adverse events were less common with aclidinium/formoterol.
Abstract 525: Higher mutation rate is associated with more frequent expression of cancer/testis antigens in human tumors
Authors: Junping Jing, Patrick Mayes, Yan Degenhardt, James R. Brown, Philippe Sanseau
Journal: Cancer Research (2016)

Abstract Tumors with high mutation rate such as those of melanoma and non-small cell lung cancers (NSCLC) have shown greatest response to the emerging immune therapies. These tumors harbor a large number of somatic mutations, some of which could be translated into neoantigens, potentially evoking host immune response. To what degree self antigens, many of which are cancer testis (CT) antigens, contribute to enhanced immune response in these tumors has never been systematically studied. Here we show that cancers with higher mutation rate frequently express a larger number of CT antigens than cancers with fewer mutations. In NSCLC, tumors with more than 300 non-synonymous mutations (75th percentile, n = 158) express more than 3 times as many CT antigens as those tumors with fewer than 100 mutations (25th percentile, n = 162), with a P-value of 1.6e-13. In head and neck cancers, tumors with more than 140 non-synonymous mutations (75th percentile, n = 79) express nearly twice as many CT antigens as those tumors with fewer than 60 mutations (25th percentile, n = 80), with a P-value of 0.004. Additionally, in NSCLC, tumors with high mutation rate are associated with higher expression of CD8B and granzyme B, markers representing cytotoxic lymphocytes. Tumors with more expressed CT antigens are also associated with higher expression of these markers. These data suggest that CT antigens, along with neoantigens, may contribute to a stronger host immune response in these hypermutative tumors. Citation Format: Junping Jing, Patrick Mayes, Yan Degenhardt, James R. Brown, Philippe Sanseau. Higher mutation rate is associated with more frequent expression of cancer/testis antigens in human tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 525.
Abstract A12: Combination of the anti-CD38 monoclonal antibody daratumumab and all-trans retinoic acid.
Authors: Inger S. Nijhof, Henk M. Lokhorst, Berris van Kessel, Parul Doshi, Kate Sasser, Tuna Mutis, Niels WCJ van de Donk
Journal: Clinical Cancer Research (2015)

Abstract Background: Daratumumab (DARA) is an anti-CD38 monoclonal antibody (mAb) with lytic activity on multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). In current clinical phase I/II trials, DARA induced anti-MM activity; however, the depth of the response varied between patients. Further improvement of DARA-treatment can be achieved by modulating the mechanisms hampering DARA responsiveness. Results: In a sub-analysis of 16 MM patients treated with DARA monotherapy (GEN501 trial), we observed that response to DARA was associated with baseline CD38 expression levels on the MM cells (R2= 0.40; P= 0.009). We also observed a significant decrease of CD38 expression on MM cells during DARA-treatment (median MFI decreased from 900 to 83). Consistent with this idea, in vitro experiments with isogenic MM cell lines expressing different levels of CD38 have revealed that the level of CD38 expression correlates with DARA-mediated ADCC and CDC. Similarly, in bone marrow samples from 125 and 56 MM patients, we observed a significant correlation between CD38 expression and DARA-mediated ADCC (Pearson R= 0.34; P= 0.&amp;lt;0001) as well as CDC (Pearson R= 0.35; P= 0.0038) respectively. Altogether, this suggested that upregulation of CD38 expression, before and during DARA-treatment, may improve the anti-MM activity of DARA. Indeed, all-trans retinoic acid (ATRA) induced a ~5-fold increase in CD38 expression both in 4 MM cell lines and primary MM cells from 5 DARA-naive patients, which resulted in synergistic improvement of DARA-mediated ADCC and CDC. The synergy between ATRA and DARA was observed not only in DARA-naive patients, but also in 2 DARA-treated patients, whose residual MM cells had lower CD38 expression following therapy. Conclusion: Our results provide evidence that CD38 expression levels may predict response to DARA. Furthermore, we show that ATRA increases CD38 expression on MM cells, resulting in enhanced DARA-mediated lysis of MM cells. Our results provide the preclinical rationale for further evaluation of DARA combined with ATRA in MM patients. Citation Format: Inger S. Nijhof, Henk M. Lokhorst, Berris van Kessel, Parul Doshi, Kate Sasser, Tuna Mutis, Niels WCJ van de Donk. Combination of the anti-CD38 monoclonal antibody daratumumab and all-trans retinoic acid. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A12.
Abstract 3835: An anti-MET IgG2 monoclonal antibody degrades both wild-type and exon 14 mutant MET receptor tyrosine kinase through a novel exon 14-independent mechanism and inhibits tumor growth
Authors: Brett S. Robinson, Sreekala Mandiyan, Gerald McMahon, Yan Yang
Journal: Cancer Research (2016)

Abstract MET gene amplification and exon 14 mutations have been reported and implicated as oncogenic drivers in several types of cancer representing approximately 5-7% of NSCLC, 4-10% of gastric cancer, and 5-10% of colon cancers. Preclinical research and clinical data derived from patients with tumors containing MET gene amplification and exon 14 mutations showed significant growth inhibition and meaningful clinical benefit after treatment with MET-targeting tyrosine kinase inhibitors (TKIs), supporting the hypothesis that MET gene amplification and exon 14 mutations are actionable biomarkers. We have identified several anti-MET monoclonal antibodies that block MET-dependent signaling and tumor growth through: (1) binding to the Sema/PSI domain, (2) preventing HGF interaction with MET and (3) inducing receptor ubiqutination and degradation. One of the anti-MET antibodies, KTN0073, induces potent degradation of oncogenic exon 14 mutant MET, which has been reported to propagate prolonged MET signaling due to a defect in receptor degradation. Our data suggest that KTN0073 engages a pathway different from HGF-induced receptor degradation and protease-mediated shedding, which is independent of the 47 amino acids that are encoded by exon 14 in the intracellular juxtamembrane region and only partially inhibited by the TKI crizotinib. In summary, we report the use of an anti-MET monoclonal antibody to elucidate an exon 14-independent mechanism of MET degradation that could provide a novel way to design anti-MET therapeutics to inhibit growth of human tumors that are driven by HGF, MET amplification and exon 14 mutations. Based on this work, KTN0073-IgG2 anti-MET antibody has been humanized for further preclinical development to explore its potential as a therapeutic for the treatment of human MET expressing cancers. Citation Format: Brett S. Robinson, Sreekala Mandiyan, Gerald McMahon, Yan Yang. An anti-MET IgG2 monoclonal antibody degrades both wild-type and exon 14 mutant MET receptor tyrosine kinase through a novel exon 14-independent mechanism and inhibits tumor growth. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3835.