tbuckley/cabot-search huggingface dataset:
Abstract 5435: A bioluminescent assay for measuring glucose uptake
Authors: Michael P. Valley, Mary Sobol, Jolanta Vidugiriene, James J. Cali
Journal: Cancer Research (2015)

Abstract Glucose management is a key biological process. In adipose tissue and skeletal muscle, decreased rates of glucose uptake commonly associated with diabetes mellitus lead to chronic hyperglycemia and a wide array of physiological damage. In contrast, the overexpression of glucose transporters in cancer cells results in increased rates of glucose uptake to support their high rates of proliferation. Thus, activators and inhibitors of glucose uptake are useful for both diabetes management and anticancer therapies. The standard method of assaying glucose uptake involves addition of a radioactive glucose analog (2-deoxyglucose) and measurement of the accumulation of the stable and impermeable phosphorylated derivative, 2-deoxyglucose-6-phosphate (2DG6P). However, radioactive assays are laborious, costly, and require special handling of radioactive materials and waste. A simpler assay can be made by measuring the production of NADPH through the oxidation of 2DG6P by glucose-6-phosphate dehydrogenase. We have developed a bioluminescent glucose uptake assay that is both rapid and convenient and exhibits a larger signal window than comparable fluorescent or colorimetric approaches. The utility of this assay will be demonstrated with both cancer cells and insulin-sensitive 3T3L1 adipocytes and L6 myotubes. Citation Format: Michael P. Valley, Mary Sobol, Jolanta Vidugiriene, James J. Cali. A bioluminescent assay for measuring glucose uptake. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5435. doi:10.1158/1538-7445.AM2015-5435
Phase 1 Results of ZUMA-1: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma
Authors: Frederick L. Locke, Sattva S. Neelapu, Nancy L. Bartlett, Tanya Siddiqi, Julio C. Chavez, Chitra M. Hosing, Armin Ghobadi, Lihua E. Budde, Adrian Bot, John M. Rossi, Yizhou Jiang, Allen X. Xue, Meg Elias, Jeff Aycock, Jeff Wiezorek, William Y. Go
Journal: Molecular Therapy (2017)

Outcomes for patients with refractory diffuse large B cell lymphoma (DLBCL) are poor. In the multicenter ZUMA-1 phase 1 study, we evaluated KTE-C19, an autologous CD3ζ/CD28-based chimeric antigen receptor (CAR) T cell therapy, in patients with refractory DLBCL. Patients received low-dose conditioning chemotherapy with concurrent cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days followed by KTE-C19 at a target dose of 2 × 106 CAR T cells/kg. The incidence of dose-limiting toxicity (DLT) was the primary endpoint. Seven patients were treated with KTE-C19 and one patient experienced a DLT of grade 4 cytokine release syndrome (CRS) and neurotoxicity. Grade ≥3 CRS and neurotoxicity were observed in 14% (n = 1/7) and 57% (n = 4/7) of patients, respectively. All other KTE-C19-related grade ≥3 events resolved within 1 month. The overall response rate was 71% (n = 5/7) and complete response (CR) rate was 57% (n = 4/7). Three patients have ongoing CR (all at 12+ months). CAR T cells demonstrated peak expansion within 2 weeks and continued to be detectable at 12+ months in patients with ongoing CR. This regimen of KTE-C19 was safe for further study in phase 2 and induced durable remissions in patients with refractory DLBCL. Outcomes for patients with refractory diffuse large B cell lymphoma (DLBCL) are poor. In the multicenter ZUMA-1 phase 1 study, we evaluated KTE-C19, an autologous CD3ζ/CD28-based chimeric antigen receptor (CAR) T cell therapy, in patients with refractory DLBCL. Patients received low-dose conditioning chemotherapy with concurrent cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days followed by KTE-C19 at a target dose of 2 × 106 CAR T cells/kg. The incidence of dose-limiting toxicity (DLT) was the primary endpoint. Seven patients were treated with KTE-C19 and one patient experienced a DLT of grade 4 cytokine release syndrome (CRS) and neurotoxicity. Grade ≥3 CRS and neurotoxicity were observed in 14% (n = 1/7) and 57% (n = 4/7) of patients, respectively. All other KTE-C19-related grade ≥3 events resolved within 1 month. The overall response rate was 71% (n = 5/7) and complete response (CR) rate was 57% (n = 4/7). Three patients have ongoing CR (all at 12+ months). CAR T cells demonstrated peak expansion within 2 weeks and continued to be detectable at 12+ months in patients with ongoing CR. This regimen of KTE-C19 was safe for further study in phase 2 and induced durable remissions in patients with refractory DLBCL.
Trust but Verify (Ideally With a Randomized Clinical Trial)
Authors: Mitchell H. Katz
Journal: JAMA Internal Medicine (2016)

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Dietary salt restriction is beneficial to the management of autosomal dominant polycystic kidney disease
Authors: Vicente E. Torres, Kaleab Z. Abebe, Robert W. Schrier, Ronald D. Perrone, Arlene B. Chapman, Alan S. Yu, William E. Braun, Theodore I. Steinman, Godela Brosnahan, Marie C. Hogan, Frederic F. Rahbari, Jared J. Grantham, Kyongtae T. Bae, Charity G. Moore, Michael F. Flessner
Journal: Kidney International (2016)
Abstract A2-53: Integrative systems analyses reveal addiction of HER2+ breast cancers to ERAD for survival
Authors: Navneet Singh, Rashika Joshi, Kakajan Komurov
Journal: Cancer Research (2015)

Abstract ERBB2/HER2-positive breast cancers are associated with poor prognosis; and resistance to HER2-targeted therapy is one of the significant clinical challenges. Trastuzumab and lapatinib are two agents that target the HER2 protein in the clinic and constitute the standard of care for HER2+ breast cancers (BCs). However, the clinical benefits of HER2-targeted therapies are limited due to significant de novo (&amp;gt;60%) and acquired resistance (~100%) to these agents during prolonged phases of treatment. No treatment options exist for metastatic HER2+ BCs that have progressed on HER2-targeted therapy. Therefore, targeting of non-oncogenic vulnerabilities is a promising therapeutic approach in tumors that are resistant to oncogene-targeted therapy. Using an evolutionary selection criterion, we computationally interrogated targetable non-oncogenic vulnerabilities in ERBB2/HER2+ breast cancers, which suffer from a high rate of de novo and acquired resistance to HER2-targeted therapy. We found that the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway is induced in HER2+ breast cancers, partly due to adaptive genomic rearrangements, to counter ER stress caused by increased proteotoxic burden due to heightened HER2/mTOR activity. Genetic and pharmacologic targeting of ERAD lead to irrecoverable ER stress and selectively killed HER2+ breast cancer cells, including those that are resistant to conventional therapy. Cell death due to ERAD inhibition was executed by the IRE1α/JNK pathway, which was suppressed in HER2+ breast cancers due to the activation of JNK phosphatases. Accordingly, inhibiting ERAD in combination with JNK phosphatases synergized in killing HER2+, but not HER2-, breast cancer cells. Our study supports exploiting oncogenic proteotoxicity as a novel therapeutic approach for therapy-refractory breast cancers, and presents an integrated strategy to identify non-oncogenic vulnerabilities in cancers. Citation Format: Navneet Singh, Rashika Joshi, Kakajan Komurov. Integrative systems analyses reveal addiction of HER2+ breast cancers to ERAD for survival. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-53.
Reconstruction of LPS Transfer Cascade Reveals Structural Determinants within LBP, CD14, and TLR4-MD2 for Efficient LPS Recognition and Transfer
Authors: Je-Kyung Ryu, Soo Jin Kim, Sang-Hyun Rah, Ji In Kang, Hi Eun Jung, Dongsun Lee, Heung Kyu Lee, Jie-Oh Lee, Beom Seok Park, Tae-Young Yoon, Ho Min Kim
Journal: Immunity (2016)
Therapeutic Targeting of the IL-6 Trans-Signaling/Mechanistic Target of Rapamycin Complex 1 Axis in Pulmonary Emphysema
Authors: Saleela M. Ruwanpura, Louise McLeod, Lovisa F. Dousha, Huei J. Seow, Sultan Alhayyani, Michelle D. Tate, Virginie Deswaerte, Gavin D. Brooks, Steven Bozinovski, Martin MacDonald, Christoph Garbers, Paul T. King, Philip G. Bardin, Ross Vlahos, Stefan Rose-John, Gary P. Anderson, Brendan J. Jenkins
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

The potent immunomodulatory cytokine IL-6 is consistently up-regulated in human lungs with emphysema and in mouse emphysema models; however, the mechanisms by which IL-6 promotes emphysema remain obscure. IL-6 signals using two distinct modes: classical signaling via its membrane-bound IL-6 receptor (IL-6R), and trans-signaling via a naturally occurring soluble IL-6R.To identify whether IL-6 trans-signaling and/or classical signaling contribute to the pathogenesis of emphysema.We used the gp130F/F genetic mouse model for spontaneous emphysema and cigarette smoke-induced emphysema models. Emphysema in mice was quantified by various methods including in vivo lung function and stereology, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to assess alveolar cell apoptosis. In mouse and human lung tissues, the expression level and location of IL-6 signaling-related genes and proteins were measured, and the levels of IL-6 and related proteins in sera from emphysematous mice and patients were also assessed.Lung tissues from patients with emphysema, and from spontaneous and cigarette smoke-induced emphysema mouse models, were characterized by excessive production of soluble IL-6R. Genetic blockade of IL-6 trans-signaling in emphysema mouse models and therapy with the IL-6 trans-signaling antagonist sgp130Fc ameliorated emphysema by suppressing augmented alveolar type II cell apoptosis. Furthermore, IL-6 trans-signaling-driven emphysematous changes in the lung correlated with mechanistic target of rapamycin complex 1 hyperactivation, and treatment of emphysema mouse models with the mechanistic target of rapamycin complex 1 inhibitor rapamycin attenuated emphysematous changes.Collectively, our data reveal that specific targeting of IL-6 trans-signaling may represent a novel treatment strategy for emphysema.
Through a glass darkly: inhaled corticosteroids, airway inflammation and COPD
Authors: Peter M.A. Calverley
Journal: European Respiratory Journal (2017)

It is 18 years since I last used the famous biblical phrase "through a glass darkly" to describe our uncertainties about the use of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) patients [1]. Subsequently, an enormous amount of research has been undertaken, which has clarified the role of ICS in clinical management [2]. There is general agreement that these drugs produce small improvements in lung function but that their main clinical benefit is to reduce exacerbation frequency, especially for events treated with oral corticosteroids [3]. The impact on COPD mortality of adding ICS to long-acting inhaled bronchodilators remains famously controversial, as does the potential of ICS to reduce the rate of decline of forced expiratory volume in 1 s (FEV1), the topic of my original editorial [1]. Recent data suggest that a small reduction in rate of decline may occur with ICS use [4], in keeping with meta-analysed data from previous studies [5]. The most important development has been the proposal that ICS are only beneficial in individuals with high normal blood eosinophil counts [6], although the threshold value to identify such an effect may reflect the level of background bronchodilator treatment [7]. ICS can reduce inflammation in COPD but this effect ceases after drug discontinuation; clinical effects are unclear <http://ow.ly/JgwT306sFn2>
Abstract CT319: Determination of FGF-19, 21, and 23 protein levels in a phase I clinical trial of ARQ 087, an oral pan-FGFR inhibitor
Authors: Terence Hall, Julia Kazakin, Brian Schwartz, Ronald Savage
Journal: Cancer Research (2015)

Abstract Background: Early biomarker development is vital in the current clinical landscape of targeted oncology therapies. Biomarkers that can be used to assess target engagement are increasingly being developed in parallel with novel agents. Fibroblast growth factors (FGFs) represent a potentially useful biomarker for use with pan-FGFR inhibitors such as ARQ 087. To evaluate this possibility, levels fibroblast growth factors 19, 21, and 23 were monitored using during the phase I trial of ARQ 087. Study Design: Plasma was collected from 61 pts (dose range 25-425mg QOD or QD). FGF levels were quantified using commercially available ELISA kits for FGF-19 and 21 (R&amp;D Systems, Minneapolis, MN), and FGF-23 (EMD-Millipore, Billerica, MA). The kits were validated at ArQule for use with human clinical samples. Experiments were designed based on the FDA guidance for bioanalytical method development, and conducted using standard curves and quality control samples prepared in plasma. Performance parameters included selectivity, specificity, precision, accuracy, stability, and effect of sample collection tube additives on measured protein levels. Results: The kits were successfully validated for all three FGFs. Changes from baseline levels of all three FGFs were observed in patients. Full data tables and results from our evaluation, along with clinical and preclinical data will be presented. Conclusions: Although there are previous reports of altered FGF-23 levels in patients treated with an FGFR inhibitor, FGF-19 and 21 represent novel biomarkers, which have not previously been reported in the literature. These biomarkers may assist in identifying ARQ 087 activity in patients, and contribute to defining an optimal clinical development strategy. Citation Format: Terence Hall, Julia Kazakin, Brian Schwartz, Ronald Savage. Determination of FGF-19, 21, and 23 protein levels in a phase I clinical trial of ARQ 087, an oral pan-FGFR inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT319. doi:10.1158/1538-7445.AM2015-CT319
PO48CHARACTERISING INTRATUMOUR HETEROGENEITY IN PAEDIATRIC GLIOBLASTOMA MULTIFORME USING A NOVEL ADVANCED MASS SPECTROMETRY TECHNIQUE
Authors: J.A. Wood, J.H. Ward, S.J. Smith, D.H. Kim, D.A. Barrett, R.G. Grundy, R. Rahman
Journal: Neuro-Oncology (2015)

INTRODUCTION: Intratumour heterogeneity (ITH) may account for therapy failure and tumour recurrence in adult glioblastoma multiforme (GBM). Low availability of fresh frozen tissue has hindered characterisation of ITH in paediatric GBM. Here, we propose the application of desorption electrospray ionisation mass spectrometry (DESI-MS) to assess spatial lipidomic profiles of formalin-fixed paraffin-embedded (FFPE) tissue of paediatric GBM. METHOD: Optimisation of DESI-MS has been conducted on FFPE tissue of normal adult brain prior to transfer of the technology to paediatric GBM tissue. Immunohistochemical analyses for proteins associated with lipid biosynthesis delineated distinct intratumour regions. Spatial characterisation of lipids synthesised by these metabolic proteins will permit optimisation of DESI-MS, prior to unbiased lipidomic analyses. RESULTS: Paediatric GBM cell lines grown under lipoprotein-deficient conditions demonstrated greater resilience compared to an adult cell line, indicating distinct lipid metabolism that will be revealed through lipidomic analyses. Proteins associated with lipid biosynthesis demonstrated evidence of ITH in paediatric GBM, with 69% of patients displaying heterogeneous expression of fatty acid synthase that correlated with areas of high cellularity. CONCLUSION: DESI-MS has the potential to characterise early indications of paediatric GBM ITH through characterisation of lipid markers associated with distinct intratumour regions. Proteins associated with the synthesis of identified lipid markers may represent potential therapeutic targets. We anticipate the establishment of an optimised DESI-MS method that will facilitate lipidomic studies of other paediatric brain tumours.
A Novel Missense Mutation in FGG (c.944C&gt;A) Encodes for An Amino Acid Change (p.Ala315Asp) in the Gamma Chain of Fibrinogen Causing Hypofibrinogenemia and a Thrombotic Phenotype
Authors: Larissa Bornikova, Gary Brodsky, Keith B Neeves, Rita Marchi, Donald S Backos, Philip Reigan, Alisa S. Wolberg, Marilyn J. Manco-Johnson, Jorge A Di Paola
Journal: Blood (2011)
Abstract 2841: A co-clinical assessment of patterns of BRAF inhibitor resistance
Authors: Lawrence N. Kwong, Genevieve Boland, Dennie Frederick, Timothy Helms, Ahmad Akid, John Miller, Shan Jiang, Zachary Cooper, Xingzhi Song, Sahil Seth, Jennifer Kamara, Alexei Protopopov, Gordon Mills, Keith Flaherty, Jennifer Wargo, Lynda Chin
Journal: Cancer Research (2015)

Abstract Multiple mechanisms conferring resistance of melanomas to BRAF inhibitors have been described, yet the basis of resistance in a sizeable portion of patient samples remains undefined. To address this gap, we characterized patients’ baseline, on-treatment, and resistant tumors on both the protein and RNA levels. By RNA-sequencing, we identified known resistance-conferring mutations in 50% (6/12) of the resistant samples. In parallel, targeted proteomic analysis by protein array categorized the resistant samples into three stable groups: two that reactivate MAPK signaling to different levels, and one that is MAPK-independent. The molecular relevance of these categories was supported by both mutation data and the similarity of resistance patterns that emerged in a co-clinical trial in a novel genetically engineered mouse model. Additionally, we have defined biomarkers in pre- and early-treatment patient samples that have potential for predicting clinical responses. On the basis of these observations, we suggest that BRAF inhibitor-resistant melanomas can be actionably categorized using protein patterns, even without the identification of the underlying genetic alteration. Citation Format: Lawrence N. Kwong, Genevieve Boland, Dennie Frederick, Timothy Helms, Ahmad Akid, John Miller, Shan Jiang, Zachary Cooper, Xingzhi Song, Sahil Seth, Jennifer Kamara, Alexei Protopopov, Gordon Mills, Keith Flaherty, Jennifer Wargo, Lynda Chin. A co-clinical assessment of patterns of BRAF inhibitor resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2841. doi:10.1158/1538-7445.AM2015-2841
Durable Remissions Observed in a Phase I/II Study of Clofarabine in Combination with Etoposide and Cyclophosphamide in Pediatric Patients with Refractory or Relapsed Acute Leukemia
Authors: Nobuko Hijiya, Paul S. Gaynon, Manuel Fernandez, Lewis B. Silverman, Blythe Thomson, Roland Chu, Todd Cooper, Richard Kadota, Michael Rytting, Peter G. Steinherz, Violet Shen, Sima Jeha, Elly Barry, William L. Carroll
Journal: Blood (2008)
Surgical treatment of patients (pts) with gastrointestinal stromal tumors (GIST) after imatinib mesylate (IM) therapy
Authors: P. Rutkowski, Z. Nowecki, P. Nyckowski, W. Dziewirski, A. Nasierowska-Guttmejer, U. Grzesiakowska, W. Michej, M. Krawczyk, W. Ruka
Journal: Journal of Clinical Oncology (2005)

9037 Background: Complete response (CR) during IM therapy due to unresectable/metastatic GIST is restricted to a few pts and progression rate is about 10%/year. The aim of the study was to analyze the surgical possibilities of unresectable/metastatic GIST CD117(+) pts during IM treatment. Methods: We analyzed the results of surgery in 118 consecutive pts (69 male - M, 49 female - F, median age 55) treated with IM for inoperable/metastatic GIST CD117(+) between 09/2001 and 09/2004 in 1 center. Median follow-up time was 7 months [m] (range: 1 - 18 m). Results: Surgery was used as adjuvant treatment in 16 pts (group I - 14%, 9M, 7F, median age 56) for R0/R1 resection of residual disease after CR/partial response (PR - according to RECIST) no longer responding to IM treatment (median duration of IM treatment 14 m, range: 4–30 m) and as salvage therapy in 7 pts (group II: 5M, 2F, median age 52), who progressed on initially successful IM (median duration of IM treatment 20 m, range: 10–31m). In group I the viable GIST cells were not detected histologically in resection specimens in only 3 pts. Surgical procedures in group I consisted of 5 extensive liver resections (in 2 cases combined with radiofrequency ablation), 7 resections of intraperitoneal lesions with omentectomy, 1 partial gastrectomy and 3 explorative laparotomies only (in CR). Initially 5 pts in group I did not received further IM and we observed 3/5 recurrences (IM reintroduction demonstrated again PR). In other 11 pts, who continue IM after surgery, we do not observe disease relapse. Complications comprised 3 prolonged ileus treated conservatively. In group II after resection of progressive lesions (resistant to IM) we continued IM therapy, but in 4/7 pts we observed subsequent progression. In this group surgery was associated with a high risk of complications: 1 perioperative death due to uncontrolled bleeding and 1 ileus treated surgically. Conclusions: Surgical removal of residual disease during IM treatment may allow for CR in selected GIST pts after PR, theoretically prolonging durable remission, but it is necessary to continue IM after R0/R1 surgery for maintaining CR. In case of progression during IM the indications for surgery should be individualized. No significant financial relationships to disclose.