tbuckley/cabot-search huggingface dataset:
Abstract 3565: Dinaciclib, a CDK inhibitor promotes proteasomal degradation of Mcl-1 and enhances ABT-737 mediated cell death in malignant human glioma cell lines
Authors: Esther P. Jane, Daniel Premkumar, Jonathon Cavaleri, Thatchana Rajasekar, Philip Sutera, Ian Pollack
Journal: Cancer Research (2016)

Abstract The prognosis of malignant glioma, the most common brain tumor, is still poor, thus underscoring the need to develop novel treatment strategies. Because glioma cells commonly exhibit genomic alterations involving genes that regulate cell cycle control, there is a strong rationale to examine the potential efficacy of strategies to counteract this process. In this study, we examined the antiproliferative effects of the cyclin-dependent kinase inhibitor dinaciclib in malignant human glioma cell lines, with intact or deleted or mutated p53 or PTEN or p14ARF, or EGFR amplification status. Dinaciclib was found to inhibit cell proliferation and induce cell cycle arrest at the G2/M checkpoint, independent of p53 mutational status. In a standard 72 h MTS assay, at clinically relevant concentrations, dose-dependent antiproliferative effects were observed but cell death was not induced. Moreover, the combination of conventional chemotherapeutic agents and various growth signaling inhibitors with dinaciclib did not yield synergistic cytotoxicity. In contrast, combination of the Bcl-2/Bcl-xL inhibitor ABT-263 or ABT-737 with dinaciclib potentiated the apoptotic response induced by each single drug. The synergistic killing by ABT-737 with dinaciclib led to cell death accompanied by the hallmarks of apoptosis, including an early loss of the mitochondrial transmembrane potential, the release of cytochrome c, smac/DIABLO and apoptosis-inducing factor (AIF), phosphatidylserine exposure on the plasma membrane surface and activation of caspases and PARP. Mechanistic studies revealed that dinaciclib promoted proteasomal degradation of Mcl-1. Citation Format: Esther P. Jane, Daniel Premkumar, Jonathon Cavaleri, Thatchana Rajasekar, Philip Sutera, Ian Pollack. Dinaciclib, a CDK inhibitor promotes proteasomal degradation of Mcl-1 and enhances ABT-737 mediated cell death in malignant human glioma cell lines. [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 3565.
Abstract 632: Establishment and characterization of xenografts and cell lines trom nasopharyngeal carcinoma
Authors: WT Lin, L Xia, Dan Dan Wen, CM Tsang, KW Lo, ML Lung, George Sai-Wah Tsao
Journal: Cancer Research (2016)

Abstract Nasopharyngeal carcinoma (NPC) is a common cancer among ethnic Cantonese living in Hong Kong and southern China. It is closely associated with Epstein-Barr virus (EBV) infection. Unfortunately, there are very few representative xenografts and cell lines established from NPC available for investigation. Most of the NPC xenografts established have been passaged in immune deficient animals for over 20 years and may not be representative of the original NPC in patients. For in vitro NPC cell lines, there is only one cell line which retains the EBV genomes. Other NPC cell lines have all lost their EBV episomes. Furthermore, many of these NPC cell lines are found to be contaminated with genetic components from HeLa cells (HPV16 genome) which raised issues on their origins and limited their uses as NPC cells. There is great urgency in establishment new NPC cell lines both in vivo and in vitro for various research investigations and for the study of pathogenic role of EBV infection in NPC. We have carried out continuous efforts since 2010 to attempt establishment of new NPC xenografts and cell lines from surgical and biopsies NPC tissues. NPC tissues from resected recurrent NPC and biopsies from primary NPC were explanted to subrenal capsular sites and maintained for four months to one year to observe for growth of new NPC xenografts. Attempts to establish new NPC celles were also carried out. At present, we have successfully established 3 NPC xenografts (Xeno 23, Xeno 32, Xeno 47) which could be passages at subcutaneously sites and one in vitro NPC cells (NPC43) which harbors EBV genomes. The growth properties and genetic alterations of these newly established NPC cell lines have been characterized. Novel genetic alterations and growth signaling pathways were observed in these newly established NPC cell lines and may represent driver mutations and signaling pathways essential for progression of NPC. Profiling of EBV gene expression of these newly established NPC cell lines revealed predominant latent EBV infection and expression of EBV-encoded mRNA from the BART transcripts which are characteristic of EBV infection in NPC. The establishment of new NPC cells will contribute to investigate the pathogenesis of NPC and its intimate relationship with EBV infection. Funding acknowledgement: University Grant Council (HK) grants (AoE NPC (AoE/M-06/08); TBRS (T12-401/13R); GRF); University of Hong Kong (CRCG and SRT cancer) Citation Format: WT Lin, L Xia, Dan Dan Wen, CM Tsang, KW Lo, ML Lung, George Sai-Wah Tsao. Establishment and characterization of xenografts and cell lines trom nasopharyngeal carcinoma. [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 632.
Small cell lung cancer: Why has it become an orphan disease?
Authors: Shakun M. Malik, Ed Korn, Anish Thomas
Journal: Journal of Clinical Oncology (2015)

7578 Background: Lung cancer remains the leading cause of death in US and worldwide. Substantial progress has recently been made in non-small cell lung cancer (NSCLC) with the discovery of molecular targets leading to the targeted drug development. Positive trials have led to the approval of a number of targeted therapies in NSCLC. However, therapies for small cell lung cancer (SCLC) have lagged behind with the current standard treatment reflecting the prevailing state-of-the-art from the early 1980s. We wanted to identify the reasons for the lack of progress in the treatment of SCLC. Methods: We searched all the randomized clinical trials of SCLC through a search of the National Cancer Institute Cancer Therapy Evaluation Program database (through June 31, 2014). We also conducted a search of Medline with the MeSH terms
Predictive factors of survival for patients with bladder cancer (BC) in phase I clinical trials.
Authors: Vasiliki Michalarea, Saeed Rafii, Rajiv Kumar, Karim Rihawi, Helen Nicole Toloui, Robert Anthony Huddart, Stanley B. Kaye, Johann Sebastian De Bono, Udai Banerji, L Rhoda Molife
Journal: Journal of Clinical Oncology (2014)

e15525 Background: There are limited anticancer therapies available for BC. Novel targeted therapies (TT) may offer more treatment options. Methods: Retrospective data was collected on clinical treatment and tumour characteristics on patients (pts) with BC treated in the Drug Development Unit, at the Royal Marsden Hospital (RMH) between August 1996 and September 2013.Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazards model, and associations were tested with Fischer’s Exact test. Results: 125 pts with BC were referred and 36 (29%) were treated. Median age was 58 yrs (range: 30-68). 7 female, 38% ECOG 0 and 62% ECOG 1-2. Histological types included: transitional cell (n=24), squamous cell (n=2), urachal (n=2), papillary cell (n=2) and adenocarcinoma (n=2). 51% pts had 1 line of prior treatment, 33% 2 lines and 16% ≥3 lines.Pts were treated on 20 phase 1 trials; 6 trials were combination chemotherapy and TT, and 14 trials were single agents, targeting: PI3K (n=3) , HDAC (n=3), EGFR/VEGFR (n=3), oncolytic viruses (n=2), mTOR (n=1), AKT (n=1), PARP (n=1), TS (n=1), c-MET (n=1), nucleoside (n=1), microtubule (n=1), Rho (n=1) and Bcl2 (n=1). Median time on trial was 1.8 months (m; range: 0.1 -15.6).Objective response rate was 14%, and the clinical benefit rate (CBR:CR+PR+SD) was 47%, as defined by RECIST 1.0. Median overall survival (OS) for pts with a CB was 9.2 m versus 3.3 m for pts with progressive disease (HR0.29,CI 0.07-0.037,P<0.0001). In univariate analysis, superior OS was favoured by RMH score 0-1 (HR0.33,CI 0.05-0.55,P=0.004), and white cell count (WCC) <10.5x109/L(HR 0.40,CI 0.08-0.80,P=0.047). Lines of prior treatment, platelet count and ECOG were not predictive of OS. In a multivariate model, CB and WCC <10.5x109/L remained predictive of OS, however RMH score did not. There was no interaction between RMH score and WCC. Conclusions: Predictors of OS for BC patients on phase I clinical trials include CB and WCC. The number of BC pts treated is low, although outcomes are comparable to the general phase I pt population. With the limited treatment options available for this group, phase 1 trial participation should be considered at an earlier stage for these pts.
Abstract 3162: Blood-based exosomal miRNAs as biomarkers for diagnosis and prognosis of clear cell renal cell cancer
Authors: Joana Heinzelmann, Sophie Baumgart, Sebastian Hoelters, Martin Janssen, Michael Stöckle, Kerstin Junker
Journal: Cancer Research (2016)

Abstract Introduction &amp; objectives: In previous studies we identified specific miRNA alterations in tumor tissues of clear cell renal cell cancer (ccRCC) with diagnostic and prognostic value relating to the presence of metastasis. For few years it has been known, that miRNAs are actively packed in exosomes which can be released into body fluids. Therefore, we hypothesize that in a simple blood based test we are able to use specific miRNA signatures as minimal invasive biomarkers for confirmation of the diagnosis and evaluation of the metastatic risk in ccRCC. Materials &amp; methods: Initially, exosomes were isolated from 1 ml serum of 10 ccRCC patients (metastatic and non metastatic tumors) and 10 healthy volunteers using appropriated exosome isolation kit protocol (Thermo Fisher Scientific). Quality of exosomes was proven using exosomal markers (CD63, CD81, Alix, Synthenin) and Nano Particle Tracking Analysis. Exosomal totalRNA was isolated using miRNeasy Mini Kit (Qiagen). For miRNA analyses total RNA was reverse transcribed using TaqMan Reverse Transcription Kit (Thermo Fisher Scientific), cDNA was preamplified using TaqMan® PreAmp Master Mix (Thermo Fisher Scientific) and real time PCR was performed using Gene Expression master mix (Thermo Fisher Scientific). Expression differences were calculated using REST Software and SPSS. Results: We have shown that 1 ml serum is sufficient to analyze miRNA expression in exosomes. Exosomes isolated from serum exhibit high amount of exosomal markers and possess the typical exosomal size (30-120 nm). CcRCC serum samples are characterized by downregulation of several miRNAs (including miR-10b and miR451). Furthermore, specific miRNAs (including miR-30c) differentiate patients with or without metastases as well as healthy volunteers. Conclusion: These initial data confirm our hypothesis that the tissue based miRNA signature could be used as biomarkers for detection of aggressive ccRCC analyzing exosomes from liquid biopsy. This minimal invasive blood based test is easy to handle in clinical practice and could be a powerful tool for early detection and monitoring of metastatic disease. To validate these results the expansion of the sample set is ongoing. Citation Format: Joana Heinzelmann, Sophie Baumgart, Sebastian Hoelters, Martin Janssen, Michael Stöckle, Kerstin Junker. Blood-based exosomal miRNAs as biomarkers for diagnosis and prognosis of clear cell renal cell 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 3162.
Next-Generation Sequencing Reveals Oncogenic Driver Mutations In Both Progressive and Non-Progressive Monoclonal B Lymphocytosis
Authors: Mark C. Lanasa, Doreen te Raa, Sallie D. Allgood, Paula Scotland, Cassie Love, Zhen Sun, Arend Jan van Houte, Douwe Biesma, Arnon P. Kater, Sandeep Dave
Journal: Blood (2013)
P134 Exercise Responses to One-legged Cycling in Patients with Idiopathic Pulmonary Fibrosis: Abstract P134 Table 1
Authors: TS Reilly, S Majd, B Popat, NJ Greening, TE Dolmage, S Agrawal, FA Woodhead, RA Evans
Journal: Thorax (2015)

<h3>Introduction</h3> Pulmonary Rehabilitation is recommended for patients with Idiopathic Pulmonary Fibrosis (IPF) although the magnitude of benefit appears less compared to those with other chronic lung diseases. Patients with IPF may not be able to sustain high-intensity training to induce physiological change due to a ventilatory limitation to exercise. One strategy to circumvent this in COPD has been to reduce the exercising muscle mass by cycling one leg at a time during the same exercise session. Randomised controlled trials have shown greater improvements in exercise capacity after training using one-legged cycling (OLC) compared to two-legged cycling (TLC).<sup>1,2</sup> We, therefore, compared OLC to TLC responses during incremental and constant work rate (CWR) exercise in patients with IPF. <h3>Methods</h3> Patients were recruited from a tertiary referral centre if they met the current NICE diagnostic criteria for IPF with a MRC dyspnoea grade ≥2. Exclusion criteria included a requirement for long-term oxygen therapy. Participants completed four Cardiopulmonary Exercise Tests (CPETs) to intolerance on a cycle ergometer with expired gas analysis. The tests were completed on separate days: 1) two-legged maximal incremental test (TLC-ICE); 2) one-legged maximal incremental test (OLC-ICE); 3) two-legged CWR (TLC-CWR) test at 70% peak power achieved on the TLC-ICE; 4) one-legged CWR (OLC-CWR) test at 35% TLC-ICE peak power. <h3>Results</h3> Twelve participants (11 male, mean [SD] 73 [8] yrs, BMI 30.6 [4.8] kg/m<sup>2</sup>, FVC% predicted 71.8 [20.3]%, resting SpO<sub>2</sub> 98 [1]%) completed all four CPETs demonstrating a ventilatory limitation to exercise (92 [14]% maximum voluntary ventilation [MVV]). Although the OLC-ICE peak oxygen uptake (peak VO­<sub>2</sub>) was significantly lower than the peak VO<sub>2</sub> TLC-ICE (p &lt; 0.001) the OLC: TLC was high at 0.85. The OLC-CWR was endured for more than twice the TLC-CWR (p &lt; 0.001) at the same muscle-specific power leading to almost double the work being performed (Table 1). <h3>Conclusion</h3> OLC at the same muscle-specific power compared to TLC enabled patients with IPF to achieve almost double the work in a simulated exercise training session. Future research should investigate OLC as a potentially efficacious aerobic training strategy for patients with IPF. <h3>References</h3> 1 Bjorgen SJ. <i>Eur J ApplPhysiol </i>2009;<b>106</b>:501–507 2 Dolmage TE. <i>Chest</i> 2008;<b>133</b>:370–376
Racial Differences in Utilization of Life-Sustaining vs Curative Inpatient Procedures After Stroke
Authors: Roland Faigle, Victor C. Urrutia, Lisa A. Cooper, Rebecca F. Gottesman
Journal: JAMA Neurology (2016)

Procedures After StrokeInpatient procedures are integral to routine stroke care.Common nondiagnostic procedures after stroke include intravenous thrombolysis (IVT), mechanical ventilation, hemicraniectomy, carotid revascularization (endarterectomy or stenting), gastrostomy, and tracheostomy.While some of these procedures are considered curative, aiming at improving functional status (IVT) or preventing further stroke (carotid revascularization), others are considered life-sustaining by preventing death in the short term (mechanical ventilation and hemicraniectomy) or long term (gastrostomy and tracheostomy).Race disparities among some stroke-related procedures have been described, 1 but a comprehensive comparison of procedure utilization by patients from different racial groups after stroke is lacking.In the present study, we compared racial differences in the use of 6 common nondiagnostic inpatient procedures after stroke; we hypothesized that curative procedures are underutilized while life-sustaining procedures are overutilized in minorities.Methods | Data were obtained from the Nationwide Inpatient Sample. 2 We identified cases with the primary diagnosis of ischemic stroke by using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 433.01, 433.11, 433.21, 433.31, 433.81, 433.91, 434.01, 434.11, 434.91, and 436 between 2007 and 2011. 3For hemicraniectomy analysis, we excluded posterior circulation strokes (ICD-9-CM codes 433.01 and 433.21).To determine carotid revascularization only among strokes associated with carotid disease, we restricted the analysis to cases with ICD-9-CM codes 433.11, 433.31, and 433.91.Procedures were identified with the following 96.70,96.71, 96.72, and 96.04 (mechanical ventilation); 31.1, 31.21, and 31.29 (tracheostomy); 99.10 (IVT); 01.24 and 01.25 (hemicraniectomy); and 38.12 and 00.63 (carotid revascularization).Endof-life care was identified by ICD-9-CM code V66.7.Because data from the Nationwide Inpatient Sample are publicly available and contain no personal identifying information, the Johns Hopkins institutional review board declared this study exempt from approval.Patients with and without each procedure were compared using the χ 2 test and the Wilcoxon rank sum test for categorical and continuous variables (Stata version 13; Stata-Corp), respectively.Logistic regression was used to assess the association between race and the respective procedure.P < .05 was considered to be statistically significant.Multivariable models for each procedure were adjusted for sociodemographic factors (age, sex, insurance status, and median household income per patient's zip code), hospital jamaneurology.com
Dehydroepiandrosterone (DHEA) in metastatic castration-resistant prostate cancer (mCRPC): Preliminary results from the SU2C/PCF/AACR West Coast Dream Team (WCDT).
Authors: Won Kim, Charles J. Ryan, Li Zhang, Jack Youngren, John Wilton, Joshi J. Alumkal, Tomasz M. Beer, Robert Baertsch, Josh Stuart, Kim N. Chi, Martin Gleave, Matthew Rettig, Robert Evan Reiter, Primo Lara, Christopher P. Evans, Eric Jay Small
Journal: Journal of Clinical Oncology (2016)

e16598 Background: Aberrant androgen receptor (AR) phenotypes (e.g. splice variants, amplification) are strongly correlated with abiraterone (Abi) and enzalutamide (Enz) resistance. Low serum DHEA is also associated with poor outcomes to AR-targeted therapy. Here, we investigate the relationship between serum DHEA, AR phenotype, and treatment efficacy in the WCDT. Methods: Men with progressive mCRPC enrolled to the WCDT were included in this preliminary analysis. Serum hormones were analyzed via liquid chromatography/tandem mass spectrometry. Limit of quantitation (LQ) of DHEA was 0.2ng/mL. Full-length AR and AR-v7 expression was obtained via RNAseq of metastatic tumor biopsies. PSA response (PSAr) was defined as ≥ 50% PSA decline. Results: 40 men were included in this analysis. 15 men had treatment-naïve mCRPC and 25 had prior AR-targeted therapy (17 Abi, 8 Enz; docetaxel-naive) before WCDT enrollment. 11 men had DHEA < LQ; of these, 9 had received prior AR-targeted therapy. In a mass array analysis, glucocorticoid levels (cortisol and cortisone) were higher in Enz-refractory men compared to Abi-refractory or treatment-naïve men (p = 0.001 for all). Subsequent treatment data was available on 35 men: 12 received chemotherapy and 23 received AR-targeted therapy (7 Abi, 16 Enz). In men with DHEA < LQ, 4/5 (80%) treated with chemotherapy had PSAr, while 1/6 (17%) treated with Abi/Enz had PSAr. In men with DHEA ≥ LQ, 2/7 (27%) treated with chemotherapy had PSAr, while 9/16 (56%) treated with Abi/Enz had PSAr. Thus, the relationship between DHEA and PSAr was significantly heterogeneous between treatment groups (p = 0.029). DHEA was higher in men with PSAr to Abi/Enz vs those without PSAr (median, 0.87 vs 0.28ng/mL, p = 0.006). In 31 men with RNAseq data, the AR-v7/AR ratio was not significantly different in men with DHEA < LQ vs men with DHEA ≥ LQ. Conclusions: In this exploratory analysis, there is significant heterogeneity in the relationship between DHEA and PSAr in chemotherapy- versus Abi/Enz-treated men. There was no significant relationship between DHEA and AR-v7/AR ratio. These results support a larger study to evaluate DHEA as a potential biomarker in mCRPC.
Abstract 4828: Enhanced cytotoxicity following sequential treatment with filanesib and melphalan in human myeloma cell lines
Authors: Darla Destephanis, Eric J. Norris, Brian Turnquist, Saad Usmani, Mahrukh Ganapathi, Ram Ganapathi
Journal: Cancer Research (2016)

Abstract As a single agent, melphalan is used as a preparative treatment prior to autologous stem cell transplant (ASCT) in patients with multiple myeloma (MM) given its myelosuppressive and anti-myeloma effects. While most patients achieve complete remission following ASCT, a majority will develop recurrent disease. Therefore, novel combinations that improve the anti-myeloma activity of melphalan may improve post-transplant outcomes. The first-in-class agent Filanesib (Fil) is a kinesin spindle protein inhibitor which induces mitotic arrest/apoptosis in proliferating cells and has demonstrated anti-myeloma activity in vitro and in vivo. In this study, we tested the effects of combination treatment with filanesib and melphalan in the human myeloma cell lines (HMCLs), U266, MM1S and NCI-H929. As single agents, melphalan and filanesib both inhibit myeloma cell proliferation as assessed by the MTS assay. However, when HMCLs were treated simultaneously with both drugs an antagonistic interaction was observed. This antagonism was in part due to cell cycle arrest in the S-phase, which prevented filanesib from downregulating the anti-apoptotic proteins, BCL-2 and MCL-1 and exerting its cytotoxic effect in the G2/M-phase.. To elucidate whether sequential treatment could enhance cytotoxicity, HMCLs were treated with either melphalan (1 hour) followed by filanesib (MelFil) for 48 hours or filanesib for 48 hours followed by 1 hour melphalan treatment (FilMel). Compared to the apoptosis observed with individual drugs, the MelFil sequence led to significantly lower apoptosis, whereas the the FilMel treatment led to enhanced apoptosis following 48 hours after drug washout. Furthermore examination of recovery of cell proliferation following seven days of recovery after drug removal revealed an increase in cell proliferation for the MelFil treatment compared to a decline in the number of viable cells for FilMel treatment. Taken together, our findings suggest that filanesib pretreatment prior to melphalan may be a clinically relevant therapeutic combination strategy. Moreover, our data underscore the importance of testing sequencing strategies for optimizing therapeutic efficacy of combination treatment. Citation Format: Darla Destephanis, Eric J. Norris, Brian Turnquist, Saad Usmani, Mahrukh Ganapathi, Ram Ganapathi. Enhanced cytotoxicity following sequential treatment with filanesib and melphalan in human myeloma cell lines. [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 4828.