tbuckley/cabot-search huggingface dataset:
Growth inhibitory effects of trastuzumab, erlotinib, and bevacizumab are proportional to average cellular levels of HER2 expression in breast cancer cell lines, and the effects of combinations of the three are additive in cell lines with high HER2 expression
Authors: David R. Emlet, Agnese Pollice, Charles Smith, Kathryn Brown, Deborah Kociban, Stanley E. Shackney
Journal: Cancer Research (2006)

1229   MCF-7 cells were transfected with HER2 and cell sublines were selected for graded levels of HER2 overexpression. Dose response curves for trastuzumab, erlotinib, and bevacizumab were obtained in each of these sublines, and in established breast cancer cell lines expressing low levels (parental MCF-7, MDA-231), and high levels (SKBR-3, BT474, NH27) of HER2, using tumor growth inhibition as an endpoint. At all drug concentrations tested, growth inhibition by each drug was proportional to the average levels of HER2 expression in the different cell lines. Using drug concentrations estimated to be in the clinically relevant range (1 mg/ml for trastuzumab and bevacizumab, and 500nM for erlotinib) each targeted agent inhibited the high HER2-expressing cell lines by 30-50%. All two-agent combinations inhibited these cell lines by 50-70%, and the three-agent combination inhibited these cell lines by 70-85%. Serial flow cytometry studies showed that the triple combination inhibited >20% of cells in G1, and led to delayed S phase progression in an additional ∼30% of cells. By comparison, the correlation of response with HER2 expression level was not observed with anti-IGF1 receptor therapy. Rb dysfunctional tumors (MDA-468, BT549, DU4475, and MDA-436) which do not overexpress HER2, were unresponsive to trastuzumab, erlotinib, and bevacizumab, singly or in any combination, except for EGFR-amplified MDA-468 cells, which exhibited ∼25% growth inhibition with erlotinib and erlotinib-containing combinations. Drug effect in MDA-468 cells was not associated with G1 arrest or S phase progression delay. These findings indicate that the combination of trastuzumab, erlotinib, and bevacizumab is more potent than any of these targeted agents individually, and that its growth inhibitory effects are highly selective for tumor cells with high levels of HER2 expression.
Personalized treatment outcomes in never smokers with advanced non-small cell lung cancer (NSCLC) in the Princess Margaret Cancer Centre.
Authors: Grzegorz Korpanty, Suzanne Kamel-Reid, Ming Sound Tsao, David M Hwang, Alona Zer, Geoffrey Liu, Natasha B. Leighl, Ronald Feld, Bethany Gill, Melania Pintilie, Frances A. Shepherd
Journal: Journal of Clinical Oncology (2015)

e19006 Background: Lung cancer in never smokers represents a distinct clinical and molecular entity characterized by frequent actionable driver mutations. Methods: Clinical and demographic data of 503 never smokers with advanced NSCLC were retrieved from patient records in order to characterize treatment outcome, survival, demographics, pathology and molecular profile. Results: There were 203 patients treated with targeted therapy (T-pts) and 300 patients without (NT-pts). Median age at diagnosis in T- and NT-pts was 59.7 & 61.6 yrs, respectively. Most patients in both groups were female (75%), with 49% & 37% Asians among T- and NT-pts, respectively. Most tumors in T-pts (193/203, 95%) had a single mutation (MUT): EGFR 167/193 (87%), ALK 23/193 (12%), and HER-2 3/193 (1%). In T-pts, 10 had tumors with multiple MUTs: (EGFR 9, and ALK 1). NT-pts did not receive targeted therapy because of unknown mutation status (55%), absence of any MUT (29%), lack of “druggable” MUT (6%) or resected or asymptomatic stable disease in patients with tumors harboring targetable MUTs (10%). Median overall survival (mOS) in T-pts was 47 months (mo) compared with 23 mo in NT-pts (HR 0.56, 95% CI: 0.44-0.71, P < 0.001). Patients with EGFR- or ALK-mutant tumors who did not require systemic treatment because of clinically and radiologically stable disease had the longest survival (median > 47 mo). Caucasian vs. Asian ethnicity (p = 0.014) and ECOG PS 0 vs. 1 (p = 0.004) in T-pts and ECOG PS 0-1 vs 2-3 (p < 0.001) in NT-pts were associated with longer survival. EGFR Exon 21 MUT was associated with a trend towards shorter survival than Exon 19 (HR 1.48, 95% CI: 0.95-2.3, P = 0.083). Patients with EGFR MUTs and brain metastases at diagnosis had similar survival to those without (HR 1.16, 95% CI: 0.74-1.8, P = 0.514). However, in the 74 patients with CNS metastases at diagnosis EGFR Exon 21 compared to Exon 19 was associated with significantly shorter survival (med 21 vs 57 mo; HR 3.96, 95% CI: 1.73-9.05, P < 0.001). Conclusions: Never smokers with advanced NSCLC can achieve long survival when treated with targeted therapy. Our observation of poorer survival in patients with EGFR Exon 21 and brain metastases warrants further study.
Copanlisib in patients with relapsed or refractory follicular lymphoma.
Authors: Martin H. Dreyling, Armando Santoro, Sirpa Leppa, Judit Demeter, George Follows, Georg Lenz, Won Seog Kim, Luigina Mollica, Arnon Nagler, Colin Phipps Diong, Mariano Provencio, Don A. Stevens, David Trevarthen, Massimo Magagnoli, Lisa Cupit, Shuxin Yin, Florian Hiemeyer, Jose E. Garcia-Vargas, Barrett H. Childs, Pier Luigi Zinzani
Journal: Journal of Clinical Oncology (2017)

7535 Background: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (iNHL) subtype, yet treatment options in the relapsed/refractory (r/r) setting are limited. Copanlisib is a pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α and PI3K-δ activity. We report results from the FL subset of a large phase II study (n=141) in iNHL patients (pts) (NCT01660451, part B). Methods: A total of 104 pts with indolent FL (grade 1-3a) relapsed/refractory to ≥2 prior lines of treatment were treated with copanlisib (60 mg IV infusion) administered on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was objective tumor response rate (ORR) per independent radiologic review (Cheson et al., JCO 20:579, 2007). Results: Of the 104 pts treated, 62% were refractory; median prior lines 3 (range 2-8), median time from progression 8 wks (range 1-73 wks). 52% were male, 83% white, median age 62 yrs, and 62% ECOG 0. At the time of primary analysis the ORR was 58.7%, comprising 15 pts (14.4%) with complete response (CR) and 46 (44.2%) with partial response. Stable disease was observed in 35 (33.7%) pts and progression of disease as best response in 2 pts. The median duration of response was 370 days (range 0-687), with 43 responders censored at data cut-off. Median duration of treatment was 22 wks (range 1-105); 33 (32%) pts remained on treatment. For all pts, the most common treatment-emergent AEs occurring in &gt;25% of pts included (all grade/grade 3+): diarrhea (34%/5%), reduced neutrophil count (30%/24%), fatigue (30%/2%), and fever (25%/4%). Hyperglycemia (50%/41%) and hypertension (30%/24%) were transient. The incidence of pneumonitis (8%/1.4%), hepatic enzymopathy (AST 28%/1.4%; ALT 23%/1.4%), opportunistic infection (1.4%) and colitis (0.7%) were low. Six deaths were observed, 3 of which were attributed to copanlisib: one lung infection, one respiratory failure, and one thromboembolic event. Conclusions: Copanlisib was highly active as a single agent in heavily pretreated r/r FL pts and resulted in durable responses in the majority of pts. Toxicities were manageable, with a low incidence of severe AEs associated with other PI3K inhibitors, especially hepatic enzymopathy, opportunistic infections, and colitis. Clinical trial information: NCT01660451.
Impermeable Robust Hydrogels via Hybrid Lamination
Authors: German A. Parada, Hyunwoo Yuk, Xinyue Liu, Alex J. Hsieh, Xuanhe Zhao
Journal: Advanced Healthcare Materials (2017)

Hydrogels have been proposed for sensing, drug delivery, and soft robotics applications, yet most of these materials suffer from low mechanical robustness and high permeability to small molecules, limiting their widespread use. This study reports a general strategy and versatile method to fabricate robust, highly stretchable, and impermeable hydrogel laminates via hybrid lamination of an elastomer layer bonded between hydrogel layers. By controlling the layers' composition and thickness, it is possible to tune the stiffness of the impermeable hydrogels without sacrificing the stretchability. These hydrogel laminates exhibit ultralow surface coefficients of friction and, unlike common single-material hydrogels, do not allow diffusion of various molecules across the structure due to the presence of the elastomer layer. This feature is then used to release different model drugs and, in a subsequent experiment, to sense different pH conditions on the two sides of the hydrogel laminate. A potential healthcare application is shown using the presented method to coat medical devices (catheter, tubing, and condom) with hydrogel, to allow for drug release and sensing of environmental conditions for gastrointestinal or urinary tract.
Identifying Health Information Technology Needs of Oncologists to Facilitate the Adoption of Genomic Medicine: Recommendations From the 2016 American Society of Clinical Oncology Omics and Precision Oncology Workshop
Authors: Kevin S. Hughes, Edward P. Ambinder, Gregory P. Hess, Peter Paul Yu, Elmer V. Bernstam, Mark J. Routbort, Jean Rene Clemenceau, John T. Hamm, Phillip G. Febbo, Susan M. Domchek, James L. Chen, Jeremy L. Warner
Journal: Journal of Clinical Oncology (2017)

At the ASCO Data Standards and Interoperability Summit held in May 2016, it was unanimously decided that four areas of current oncology clinical practice have serious, unmet health information technology needs. The following areas of need were identified: 1) omics and precision oncology, 2) advancing interoperability, 3) patient engagement, and 4) value-based oncology. To begin to address these issues, ASCO convened two complementary workshops: the Omics and Precision Oncology Workshop in October 2016 and the Advancing Interoperability Workshop in December 2016. A common goal was to address the complexity, enormity, and rapidly changing nature of genomic information, which existing electronic health records are ill equipped to manage. The subject matter experts invited to the Omics and Precision Oncology Workgroup were tasked with the responsibility of determining a specific, limited need that could be addressed by a software application (app) in the short-term future, using currently available genomic knowledge bases. Hence, the scope of this workshop was to determine the basic functionality of one app that could serve as a test case for app development. The goal of the second workshop, described separately, was to identify the specifications for such an app. This approach was chosen both to facilitate the development of a useful app and to help ASCO and oncologists better understand the mechanics, difficulties, and gaps in genomic clinical decision support tool development. In this article, we discuss the key challenges and recommendations identified by the workshop participants. Our hope is to narrow the gap between the practicing oncologist and ongoing national efforts to provide precision oncology and value-based care to cancer patients.
MAGE-a Mediate Resistance to Chemotherapy in Multiple Myeloma through Regulation of Bcl-2 Proteins
Authors: Hearn Jay Cho, Anna Mei, Jami Fukui, Kaity Tung, Violetta V Leshchenko, Alessandro Lagana, Manishkumar Patel, Seunghee Kim-Schulze, Deepak Perumal, Ajai Chari, Sundar Jagannath, Samir Parekh
Journal: Blood (2016)
In CLL, Myeloid-Derived Suppressor Cells and Their Monocytic and Granulocytic Varieties Differ in T-Cell Subset Association and Polarization Induction
Authors: Gerardo Ferrer, Brendan Franca, Pui Yan Chiu, Stefano Vergani, Andrea Nicola Mazzarello, Florencia Palacios, Davide Bagnara, Shih-Shih Chen, Sophia Yancopoulos, Yun Liu, Aliki Xochelli, Xiao-Jie Yan, Jacqueline C. Barrientos, Jonathan E. Kolitz, Steven L. Allen, Kostas Stamatopoulos, Kanti R. Rai, Barbara Sherry, Nicholas Chiorazzi
Journal: Blood (2016)
The Src family kinase inhibitor dasatinib (BMS-354825) blocks migration and invasion of human melanoma cells
Authors: Ralf Buettner, Tania Mesa, Sangkil Nam, Frank Lee, Richard Jove
Journal: Cancer Research (2007)

3248  Dasatinib (BMS-354825) is a potent inhibitor of multiple oncogenic protein kinases that has been approved by the FDA and European Union in all stages of CML and Ph+ ALL resistant or intolerant to prior therapy. On the basis of oral bioavailability, in vivo activity and pharmacokinetic profile, as well as its low toxicity, dasatinib has advanced to early-phase clinical trials for solid tumors harboring activated Src kinase. Although Src family kinases (SFK) are currently being investigated as potential targets for treatment strategies in various cancers, the effect of dasatinib on human melanoma cells has not been investigated in detail. In this study, we show that dasatinib blocks migration and invasion of human melanoma cells without affecting proliferation and survival. Moreover, dasatinib completely inhibits SFK kinase activity at low nanomolar concentrations in all 8 human melanoma cell lines examined. In addition, two known downstream targets of SFKs, focal adhesion kinase (FAK) and Crk-associated substrate (p130CAS), are inhibited with similar concentrations and kinetics. Consistent with inhibition of these signaling pathways and invasion, we show that dasatinib also down-regulates expression of matrix metalloproteinase-9 (MMP-9). We also provide evidence that dasatinib directly inhibits kinase activity of the EphA2 receptor tyrosine kinase, which is overexpressed and/or overactive in many solid tumors including melanoma. Since SFK/FAK/p130CAS as well as EphA2 signaling pathways are involved in tumor progression, our findings suggest that dasatinib is a promising agent for preventing melanoma metastasis.
Nanoparticle-mediated local depletion of tumour-associated platelets disrupts vascular barriers and augments drug accumulation in tumours
Authors: Suping Li, Yinlong Zhang, Jing Wang, Ying Zhao, Tianjiao Ji, Xiao Zhao, Yanping Ding, Xiaozheng Zhao, Ruifang Zhao, Feng Li, Xiao Yang, Shaoli Liu, Zhaofei Liu, Jianhao Lai, Andrew K. Whittaker, Gregory J. Anderson, Jingyan Wei, Guangjun Nie
Journal: Nature Biomedical Engineering (2017)
Predictive role of serum HBsAg and HBcrAg kinetics in patients with HBeAg-negative chronic hepatitis B receiving pegylated interferon–based therapy
Authors: N. Chuaypen, N. Posuwan, S. Chittmittraprap, N. Hirankarn, S. Treeprasertsuk, Y. Tanaka, N. Shinkai, Y. Poovorawan, P. Tangkijvanich
Journal: Clinical Microbiology and Infection (2017)
Cost-effectiveness analysis of afatinib vs gefitinib in EGFR-mutated population with advanced non-small-cell lung cancer.
Authors: Christos Chouaid, Laura Luciani, Katell Le Lay, Gerard De Pouvourville
Journal: Journal of Clinical Oncology (2017)

e20548 Background: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib were compared in the multicenter, international, randomized, head-to-head phase 2b LUX-Lung 7 trial (LL7) for first-line treatment of advanced EGFR mutation-positive non-small-cell lung cancer (EGFRm+ NSCLC). We aimed to assess the cost and health outcomes of afatinib and gefitinib in this setting. Methods: A partitioned survival model was designed to assess the cost-effectiveness of afatinib versus geftinib in the French context for EGFRm+ NSCLC.Outcomes and safety are taken primarily from the head-to-head LL7 trial. Only direct medical costs were considered. Resources use and utilities were derived from the trial, expert panel and published literature. Incremental cost-effectiveness ratios (ICER) were calculated in the common EGFR population and also, in the sub-groups with EGFR Exon 19 deletion (del 19) and EGFR Exon 21 L858R (L858R) mutation over a 10 year-time horizon. Deterministic and probabilistic sensitivity analyses were performed. Results: For common EGFR+ NSCLC, the ICER of afatinib versus gefitinib was €45,211 per QALY (with a gain of 0.170 QALYs, and an incremental cost of €7,697). The ICERs for del 19 and L858R populations were €38,970 and €52,518 respectively. Afatinib had a probability of 100% to be cost-effective at a willingness-to-pay threshold of €70,000 for patients with common EGFR mutation, and also in the del 19 and L858R subgroups. Conclusions: Afatinib is a cost-effective treatment compared to geftinib in patients with EGFRm+ NSCLC with an ICER varying between €38,970/QALYs and €52,518/QALYs.
Adherence to adjuvant hormone therapy (AHT) in early breast cancer (BC).
Authors: Ana Lohmann, Jasem Al Barrak, Renata D'Alpino Peixoto, Leo Chen, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2013)

e11522 Background: Randomized controlled trials of early BC consistently demonstrate a survival benefit from AHT. Some studies show that adherence to AHT is suboptimal, but data are conflicting. There are concerns that poor adherence can negatively impact survival. We conducted a systematic review to evaluate adherence to AHT in early BC and clinical factors associated with non-adherence. Methods: Using search terms such as 'adherence', ‘adjuvant treatment’ and ‘breast cancer’, we identified a total of 843 articles published between 1990 and 2012 of which 43 met our eligibility criteria (7 prospective and 36 retrospective). Pooled estimates of adherence and non-adherence were derived by random effects models. Heterogeneity was assessed by the Cochran's Q and I-squared statistics. To detect for potential publication bias, Egger’s test was conducted. Results: The median rates of adherence, compliance, continuation and persistence to AHT were 77%, 79%, 69% and 81%, respectively. Compared to individuals aged &lt;60 years, patients aged &gt;/=60 years had a significantly higher likelihood of non-adherence (RR 1.59, 95% CI 1.27-2.00, p&lt;0.001). Likewise, non-white patients were more likely to poorly adhere to AHT when compared to their white counterparts (RR 1.39, 95% CI 1.00-1.94, p=0.05). Additionally, prior or concurrent receipt of chemotherapy (RR 1.41, 95% CI 1.06-1.88, p=0.018) and radiation (RR 1.79, 95% CI 1.14-2.81, p=0.011) were independently associated with worse adherence. Interestingly, those with more than a moderate income level defined as &gt;$30,000 per annum had a greater likelihood of poor adherence to AHT when compared to low income earners (RR 1.12, 95% CI 1.01-1.24, p&lt;0.024). There was moderate to high heterogeneity across studies, but there was no evidence of publication bias. Conclusions: In this systematic review, adherence rates to AHT for early BC were suboptimal, underscoring the importance of increased vigilance and need for strategies that promote compliance with proven therapies. Poor adherence patterns were observed in specific patient subsets, but these were not limited to only marginalized populations. Prospective trials of adherence interventions that stratify by these patient subgroups are warranted.
Investigating the ways in which health information technology can promote antimicrobial stewardship: a conceptual overview
Authors: Abby King, Kathrin M Cresswell, Jamie J Coleman, Sarah K Pontefract, Ann Slee, Robin Williams, Aziz Sheikh
Journal: Journal of the Royal Society of Medicine (2017)

Antimicrobial resistance is now recognised as a threat to health worldwide. Antimicrobial stewardship aims to promote the responsible use of antibiotics and is high on international and national policy agendas. Health information technology has the potential to support antimicrobial stewardship in a number of ways, but this field is still poorly characterised and understood. Building on a recent systematic review and expert roundtable discussions, we take a lifecycle perspective of antibiotic use in hospitals and identify potential targets for health information technology-based interventions to support antimicrobial stewardship. We aim for this work to help chart a future research agenda in this critically important area.
N-Degradomic Analysis Reveals a Proteolytic Network Processing the Podocyte Cytoskeleton
Authors: Markus M. Rinschen, Ann-Kathrin Hoppe, Florian Grahammer, Martin Kann, Linus A. Völker, Eva-Maria Schurek, Julie Binz, Martin Höhne, Fatih Demir, Milena Malisic, Tobias B. Huber, Christine Kurschat, Jayachandran N. Kizhakkedathu, Bernhard Schermer, Pitter F. Huesgen, Thomas Benzing
Journal: Journal of the American Society of Nephrology (2017)

Regulated intracellular proteostasis, controlled in part by proteolysis, is essential in maintaining the integrity of podocytes and the glomerular filtration barrier of the kidney. We applied a novel proteomics technology that enables proteome-wide identification, mapping, and quantification of protein N-termini to comprehensively characterize cleaved podocyte proteins in the glomerulus in vivo . We found evidence that defined proteolytic cleavage results in various proteoforms of important podocyte proteins, including those of podocin, nephrin, neph1, α -actinin-4, and vimentin. Quantitative mapping of N-termini demonstrated perturbation of protease action during podocyte injury in vitro , including diminished proteolysis of α -actinin-4. Differentially regulated protease substrates comprised cytoskeletal proteins as well as intermediate filaments. Determination of preferential protease motifs during podocyte damage indicated activation of caspase proteases and inhibition of arginine-specific proteases. Several proteolytic processes were clearly site-specific, were conserved across species, and could be confirmed by differential migration behavior of protein fragments in gel electrophoresis. Some of the proteolytic changes discovered in vitro also occurred in two in vivo models of podocyte damage (WT1 heterozygous knockout mice and puromycin aminonucleoside–treated rats). Thus, we provide direct and systems-level evidence that the slit diaphragm and podocyte cytoskeleton are regulated targets of proteolytic modification, which is altered upon podocyte damage.
Lymphedema: Pathogenesis and Novel Therapies
Authors: Joseph H. Dayan, Catherine L. Ly, Raghu P. Kataru, Babak J. Mehrara
Journal: Annual Review of Medicine (2017)

Lymphedema affects up to 1 in 6 patients who undergo treatment for a solid tumor in the United States. Its prevalence has increased as more effective oncologic therapies have improved patient survival, but there remains no definitive cure. Recent research has elucidated new details in the pathogenesis of the disease and has demonstrated that it is fundamentally an immunologic process that ultimately results in inflammation, fibroadipose deposition, impaired lymphangiogenesis, and dysfunctional lymphatic pumping. These findings have allowed for the development of novel medical and surgical therapies that may potentially alter the standard of care for a disease that has largely been treated by compression. This review seeks to provide an overview of the emerging therapies and how they can be utilized for effective management of lymphedema.
Inflammatory mediators mediate airway smooth muscle contraction through a G protein-coupled receptor–transmembrane protein 16A–voltage-dependent Ca2+ channel axis and contribute to bronchial hyperresponsiveness in asthma
Authors: Pei Wang, Wei Zhao, Jie Sun, Tao Tao, Xin Chen, Yan-Yan Zheng, Cheng-Hai Zhang, Zhong Chen, Yun-Qian Gao, Fan She, Ye-Qiong Li, Li-Sha Wei, Ping Lu, Cai-Ping Chen, Ji Zhou, Da-Quan Wang, Liang Chen, Xiao-Hao Shi, Linhong Deng, Ronghua ZhuGe, Hua-Qun Chen, Min-Sheng Zhu
Journal: Journal of Allergy and Clinical Immunology (2017)
Abstract 4336: Acute Kidney Injury in Octogenarian Patients Undergoing Percutaneous Coronary Intervention: Predictors and Impact on Long Term Outcomes
Authors: Helena Tizon-Marcos, Jean-Pierre Dery, Pierre-Louis Bernard, Julie Plaisance, Cindy Boulanger-Gobeil, Eric Larose, Josep Rodes-Cabau, Stephane Rinfret, Gerald Barbeau, Bernard Noel, Guy Proulx, Onil Gleeton, Can M Nguyen, Louis Roy, Robert Delarochelliere, Olivier Bertrand
Journal: Circulation (2009)