tbuckley/cabot-search huggingface dataset:
Abstract 370: Expansion of CTCs from early stage lung cancer patients using a microfluidic co-culture model
Authors: Zhuo Zhang, Hiroe Shiratsuchi, Jules Lin, Guoan Chen, Rishindra M. Reddy, Ebrahim Azizi, Shamileh Fouladdel, Andrew C. Chang, Lin Lin, Hui Jiang, Meghna Waghray, Diane M. Simeone, Max S. Wicha, David G. Beer, Gary Luker, Nithya Ramnath, Sunitha Nagrath
Journal: Cancer Research (2015)

Abstract Establishing the role of circulating tumor cells (CTCs) in tumor progression and metastasis depends both on enumeration and on obtaining sufficient numbers of cells for downstream assays. The numbers of CTCs are few in early stages of cancer, limiting detailed molecular characterization. One approach to overcome this limitation is to expand CTCs, i.e. increase their numbers as a result of cell division. Herein, we have developed a novel in-situ capture and culture methodology for ex-vivo expansion of CTCs using a three dimensional co-culture model, simulating a tumor microenvironment to support tumor development. We have successfully identified CTCs isolated from 14 of 19 early stage lung cancer patients. Expanded lung CTCs expressed tumor specific markers and formed spheroids in culture. CTCs derived xenograft demonstrated tumorigenic capability of these cells. Furthermore, CTCs carried mutations of the TP53 gene identical to those observed in the matched primary tumors. Next-generation sequencing further revealed additional matched mutations between primary tumor and CTCs of cancer-related genes. This strategy sets the stage to further characterize the biology of CTCs derived from patients with early lung cancers, thereby leading to a better understanding of these putative drivers of metastasis. Citation Format: Zhuo Zhang, Hiroe Shiratsuchi, Jules Lin, Guoan Chen, Rishindra M. Reddy, Ebrahim Azizi, Shamileh Fouladdel, Andrew C. Chang, Lin Lin, Hui Jiang, Meghna Waghray, Diane M. Simeone, Max S. Wicha, David G. Beer, Gary Luker, Nithya Ramnath, Sunitha Nagrath. Expansion of CTCs from early stage lung cancer patients using a microfluidic co-culture model. [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 370. doi:10.1158/1538-7445.AM2015-370
Dynamic Contrast-Enhanced MRI Identifies a Distinct Group of Asymptomatic Myeloma Patients with Increased Bone Marrow Microcirculation.
Authors: Jens Hillengass, Christian Zechmann, Andreas Nadler, Stefan Delorme, Axel Benner, Christiane Heiss, Anthony D. Ho, Hartmut Goldschmidt, Thomas Moehler
Journal: Blood (2006)
Abstract 3515: RRx-001: A double action systemically non-toxic epigenetic agent for cancer therapy
Authors: Hongjuan Zhao, Shoucheng Ning, Jan Scicinski, Bryan Oronsky, Susan Knox, Donna M. Peehl
Journal: Cancer Research (2015)

Abstract RRx-001 (also known as ABDNAZ, 1-bromoacetyl-3,3-dinitroazetidine) is a novel aerospace-derived compound that demonstrated anticancer activity in the absence of systemic toxicities in a recent phase I clinical trial and is now in phase II studies. With a highly energetic heterocyclic scaffold, RRx-001 generates reactive oxygen species (ROS) and nitric oxide (NO), modulates intracellular redox status, and triggers caspase-independent apoptosis in cancer cells. Here we showed that RRx-001 as a single chemical entity regulates at least two epigenetic processes, histone acetylation and DNA demethylation. Specifically, RRx-001 at its therapeutic concentrations (0.5-5 μM) significantly decreased global DNA methylation, i.e., 5-methylcytosine levels, in SCC VII tumor cells as determined by ELISA. Consistently, treatment of SCC VII cells with 0.5-5 μM RRx-001 significantly decreased Dnmt1 and Dnmt3a protein expression in a dose- and time-dependent manner as determined by Western blots. In addition, global methylation profiling using Illumina Infinium HumanMethylation450 BeadChip® identified differentially methylated genes in SCC VII cells treated with 0.5, 2, and 5 μM RRx-001 compared to control cells. Of 111 genes demethylated by RRx-001 identified using GenomeStudio software, methylation levels of 3 genes (FAM20C, STON1-GTF2A1L and TRIAP1) were decreased by at least 2-fold across all three concentrations of RRx-001. Validation of these changes by pyrosequencing is underway. Pathway enrichment analysis by IPA suggested that RRx-001 demethylated genes involved in hepatic fibrosis, G protein signaling, leucine degradation and remodeling of epithelial adherens junctions. Moreover, RRx-001 at 2 μM significantly increased global acetylated histone H3 and H4 levels in SCC VII cells after 24 hour treatment as determined by a fluorometric assay, suggesting that RRx-001 regulates global acetylation in cancer cells. Western blot analysis also showed significant increases in acetylated histone H3 and H4 levels in SCC VII cells in a dose and time-dependent manner after RRx-001 treatment. Taken together, our results demonstrated that, in contrast to the traditional “one drug one target” paradigm, RRx-001 has multi(epi)target features, which contribute to its anticancer activity. Citation Format: Hongjuan Zhao, Shoucheng Ning, Jan Scicinski, Bryan Oronsky, Susan Knox, Donna M. Peehl. RRx-001: A double action systemically non-toxic epigenetic agent for cancer therapy. [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 3515. doi:10.1158/1538-7445.AM2015-3515
The Pharmacology of Autonomic Failure: From Hypotension to Hypertension
Authors: Italo Biaggioni
Journal: Pharmacological Reviews (2016)

Primary neurodegenerative autonomic disorders are characterized clinically by loss of autonomic regulation of blood pressure. The clinical picture is dominated by orthostatic hypotension, but supine hypertension is also a significant problem. Autonomic failure can result from impairment of central autonomic pathways (multiple system atrophy) or neurodegeneration of peripheral postganglionic autonomic fibers (pure autonomic failure, Parkinson's disease). Pharmacologic probes such as the ganglionic blocker trimethaphan can help us in the understanding of the underlying pathophysiology and diagnosis of these disorders. Conversely, understanding the pathophysiology is crucial in the development of effective pharmacotherapy for these patients. Autonomic failure patients provide us with an unfortunate but unique research model characterized by loss of baroreflex buffering. This greatly magnifies the effect of stimuli that would not be apparent in normal subjects. An example of this is the discovery of the osmopressor reflex: ingestion of water increases blood pressure by 30–40 mm Hg in autonomic failure patients. Animal studies indicate that the trigger of this reflex is related to hypo-osmolality in the portal circulation involving transient receptor potential vanilloid 4 receptors. Studies in autonomic failure patients have also revealed that angiotensin II can be generated through noncanonical pathways independent of plasma renin activity to contribute to hypertension. Similarly, the mineralocorticoid receptor antagonist eplerenone produces acute hypotensive effects, highlighting the presence of non-nuclear mineralocorticoid receptor pathways. These are examples of careful clinical research that integrates pathophysiology and pharmacology to advance our knowledge of human disease.
Significance of, and Difficulty in Diagnosing, Erythropoietin Deficiency in Sickle Cell Anemia
Authors: Santosh L Saraf, Seema Sidhwani, Mohammed Farooqui, Giovanni Infusino, Lani Krauz, Michael Gowhari, Stephen Vara, Louise Dorn, Joseph Desimone, Robert Molokie, Yogen Saunthararajah
Journal: Blood (2008)
Endobronchial valves for patients with heterogeneous emphysema and without interlobar collateral ventilation: open label treatment following the BeLieVeR-HIFi study
Authors: Zaid Zoumot, Claire Davey, Simon Jordan, William H McNulty, Denis H Carr, Matthew D Hind, Michael I Polkey, Pallav L Shah, Nicholas S Hopkinson
Journal: Thorax (2016)

Outcomes in early trials of bronchoscopic lung volume reduction using endobronchial valves for the treatment of patients with advanced emphysema were inconsistent. However improvements in patient selection with focus on excluding those with interlobar collateral ventilation and homogeneous emphysema resulted in significant benefits in the BeLieVeR-HIFi study compared with sham treated controls. In this manuscript we present data from the control patients in the BeLieVeR-HIFi study who went on to have open label endobronchial valve treatment after completion of the clinical trial (n=12), combined with data from those in the treatment arm who did not have collateral ventilation (n=19). Three months after treatment FEV<sub>1</sub> increased by 27.3 (36.4)%, residual volume reduced by 0.49 (0.76) L, the 6 min walk distance increased by 32.6 (68.7) m and the St George Respiratory Questionnaire for COPD score improved by 8.2 (20.2) points. These data extend the evidence for endobronchial valve placement in appropriately selected patients with COPD. <h3>Trial registration number:</h3> ISRCTN04761234; Results.
Determinants of chemotherapy administration and effects of chemotherapy on survival in elderly patients with small cell lung cancer (SCLC): A SEER-Medicare analysis.
Authors: L. C. Caprario, D. M. Kent, T. A. Trikalinos, G. M. Strauss
Journal: Journal of Clinical Oncology (2011)

7083 Background: The benefit of chemotherapy for elderly patients with SCLC in the community setting has not been quantified. The purpose of this retrospective cohort study is to analyze factors associated with the administration of chemotherapy and to examine the impact of chemotherapy on survival. Methods: Patients with SCLC diagnosed between 1992 and 2001 who were at least 65-years old were selected from the SEER-Medicare database. Logistic regression was used to evaluate which covariates influenced receipt of chemotherapy and to construct a propensity score. Cox proportional hazards regression was employed to examine the influence of clinical and demographic variables on survival. Quantile regression was utilized to examine the independent effect of chemotherapy on survival. Results: The final cohort included 10,428 patients. After diagnosis, 67.1% received chemotherapy, 39.1% received radiation, 3.4% received surgery, and 21.8% received no treatment. The most common chemotherapy regimens included etoposide combined with cisplatin or carboplatin. Patients ages 85 and older were less likely to receive chemotherapy compared to patients ages 65 to 69 (OR 0.17, 95% CI 0.14-0.21). Being black was associated with a decreased likelihood of receiving chemotherapy (OR 0.67, 95% CI 0.56-0.81) as was having distant stage disease compared to localized disease (OR 0.56, 95% CI 0.47-0.67). Median survival was 7 months. Factors associated with improved survival were female gender, black race, having localized stage disease, receiving any treatment, and having a lower comorbidity score. Propensity score analysis demonstrated a 6.9-month improvement in median survival for patients who received chemotherapy. Similarly, quantile regression demonstrated that chemotherapy provided a 6.4-month improvement in median survival (95% CI, 6.2–6.6, p<0.001). Conclusions: Statistically significant differences in the receipt of chemotherapy exist among elderly patients with SCLC. Even after extensive adjustments, treatment with chemotherapy is associated with a greater than 6-month improvement in median survival among elderly patients with SCLC.
Analysis of 120 Pediatric Patients with Non-Malignant Disorders Transplanted Using Unrelated Plasma Depleted Cord Blood and the Role of Post-Thaw Wash
Authors: Joseph Rosenthal, Tang-Her Jaing, Lee Lee Chan, Gretchen Eames, Michael L. Graham, Ah Moy Tan, Hai Peng Lin, Auayporn P. Nademanee, Chatchada Karanes, Brian Wang, Tina Wu, Tiffany Chow, Patrick Tan, David Gjertson, Lawrence Petz, Stephen J. Forman, Robert Chow
Journal: Blood (2008)
A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer
Authors: Matthew P. Humphries, Sreekumar Sundara Rajan, Alastair Droop, Charlotte A.B. Suleman, Carmine Carbone, Cecilia Nilsson, Hedieh Honarpisheh, Gabor Cserni, Jo Dent, Laura Fulford, Lee B. Jordan, J. Louise Jones, Rani Kanthan, Maria Litwiniuk, Anna Di Benedetto, Marcella Mottolese, Elena Provenzano, Sami Shousha, Mark Stephens, Rosemary A. Walker, Janina Kulka, Ian O. Ellis, Margaret Jeffery, Helene H. Thygesen, Vera Cappelletti, Maria G. Daidone, Ingrid A. Hedenfalk, Marie-Louise Fjällskog, Davide Melisi, Lucy F. Stead, Abeer M. Shaaban, Valerie Speirs
Journal: Clinical Cancer Research (2016)

Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar.Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico Biomarkers were immunohistochemically assessed in 697 MBCs (n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor.Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12-2.8 and P = 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed (P = 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P = 0.016; HR = 2.38 (1.18-4.8), eIF5 P = 0.022; HR = 2.55 (1.14-5.7); coexpression P = 0.001; HR = 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival.Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required. Clin Cancer Res; 23(10); 2575-83. ©2016 AACR.
Abstract 2298: Profiling of syngeneic models by anti-PD1, anti-CTLA4 immunotherapeutics and deep sequencing enables better selection of models for immune targeted combination therapy
Authors: Lan Zhang, Juan Zhang, Qian Shi
Journal: Cancer Research (2015)

Abstract Syngeneic tumor models have long been used in cancer research. Recently, the clinical success of anti-CTLA4 and anti-PD1 antibodies resulted in increased interests in using syngeneic models to evaluate cancer immunotherapeutics. Furthermore, as researchers discovered many of the existing or developing inhibitors of the canonical signaling pathways may interact with immune-environment, thus may synergize with cancer immunotherapies, they are looking for suitable models that may evaluate the combination of those therapies. To meet this demand, Crown has established a large collection of syngeneic models that covers most of the tumor types. Those models have been extensively profiled in vivo using anti-PD1, anti-CTLA4 antibodies, providing information necessary for selecting models and doses for combination therapy. Mostly recently, we have generated detailed maps of the expressional and mutational profiles of those models, as well as identified the alternative gene spliced transcripts, post-transcriptional modifications, gene fusion using RNA-seq. These data will enable selection of models based on researchers’ specific targets. Combining with the in vivo immunotherapy profiles of the models, our comprehensive syngeneic models with profiling data are useful tools in developing combinatory cancer immunotherapies that may one day benefit the patients. Citation Format: Lan Zhang, Juan Zhang, Qian Shi. Profiling of syngeneic models by anti-PD1, anti-CTLA4 immunotherapeutics and deep sequencing enables better selection of models for immune targeted combination therapy. [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 2298. doi:10.1158/1538-7445.AM2015-2298
479. An Optimized DNA Vaccine Formulation Protects Against Lethal Ebola Makona Virus Challenge in Non-Human Primates and Elicits Robust Immune Responses
Authors: Ami Patel, Emma L. Reuschel, Kimberly A. Kraynyak, Trina Racine, Daniel H. Park, Amelia A. Keaton, Muthumani Karuppiah, Devon Shedlock, Jian Yan, Amir Khan, Kevin Tierney, Niranjan Sardesai, Gary P. Kobinger, David B. Weiner
Journal: Molecular Therapy (2016)

The West African Ebola hemorrhagic fever virus outbreak is the most wide-spread occurrence of the virus to-date. Over 28 000 cases have been confirmed, however the actual figures are likely much higher. There are currently no approved vaccines but several clinical trials of viral vector candidates are underway and evidence suggests that the VSV-ZEBOVGP vaccine can prevent further transmission of the virus. However, the considerable drawback of anti-vector immunity still remains to be addressed and reports from human clinical trials observe the presence of adverse events including fever, blistering, and development of arthritis/joint pain which may limit some applications of this vaccine. Therefore, investigating alternative immunization approaches is important. We designed a DNA vaccine formulation expressing 3 synthetic Zaire Ebola virus (EBOV) glycoproteins (GP): 2 designed based on GP sequence alignments (1976-2014) and a 3rd construct matched to a 2014 outbreak strain. Plasmid IL-12 (pIL-12) was also included as an adjuvant to further enhance cellular immune responses. We administered this multivalent GP DNA vaccine formulation in macaques following a DNA-DNA prime-boost immunization regimen. Macaques (n=3 or 4/group) received the multivalent GP DNA formulation + pIL-12 by intramuscular delivery followed by electroporation. We assayed differences in immunogenicity and monitored protection between different doses, regimens (2, 3, 4, and 5 injections), and different spacing intervals between subsequent doses. Both antibody and T cell responses were observed in 83% of animals 2 weeks following the first injection and 100% of animals after the 2nd injection. The macaques were challenged with a lethal dose of the EBOV Guinea-Makona outbreak strain (1000pfu, 7-U virus) and monitored for 28 days following infection. 100% of animals receiving at least 3 injections at 4 week intervals survived lethal challenge. Animals were fully protected against signs of disease and did not exhibit elevated blood chemistry. Interestingly, 50% of animals receiving 2 injections survived lethal challenge. The surviving animals exhibited minimal signs of disease, suggesting that with further optimization complete protection with 2 injections is potentially achievable. In additional optimization studies in mice, single injections were found to be 100% protective and we observed that long-term immune responses 8 months post vaccination were induced. Further studies in NHP are now in progress.
Abstract 1358: Generation of induced pluripotent stem cells from tumor-infiltrating lymphocytes
Authors: Hidehito Saito, Keisuke Okita, Noemi Fusaki, Michael Sabel, Alfred Chang, Fumito Ito
Journal: Cancer Research (2015)

Abstract Human induced pluripotent stem cells (iPSCs) derived from somatic cells of patients hold great promise for autologous cell therapies. One of the possible applications of iPSCs is to use them as a cell source for producing autologous lymphocytes for cell-based therapy against cancer. Tumor-infiltrating lymphocytes (TILs) were found to have tumor-reactive T cells and have been used for adoptive cell therapy for metastatic melanoma. The objective in this study is to generate iPSCs from TILs and assess their pluripotency. Under the approved protocol by the Institutional Review Board and the Human Pluripotent Stem Cell Research Oversight Committee, we obtained melanomas from a patient who provided informed consent for tissue procurement and generation of iPSCs. TILs were reprogrammed by Sendai virus (SeV) vector encoding four pluripotency transcription factors (Oct3/4, Klf4, Sox2 and c-Myc). TIL-derived iPSCs (TIL-iPSCs) were characterized by their pluripotency. Within 3 weeks of infection with SeV to deliver pluripotency transcription factors, we identified colonies that resembled embryonic stem cells (ESCs) among the T cell derivatives. TIL-iPSCs displayed typical stem cell morphology and had a normal karyotype. Alkaline phosphatase and immunofluorescence staining with stem cell surface markers, OCT3/4, SSEA3, SSEA 4, TRA1-81 and TRA1-60 proteins suggested pluripotency of colonies. RT-PCR analyses revealed that TIL-iPSCs expressed pluripotent stem cell markers such as NANOG, OCT3/4 at levels comparable to those in ESCs. T cell receptor (TCR) gene rearrangement analysis in TIL-iPSCs confirmed that they originated from mature T cells and retained diversity of TCR gene rearrangement. In conclusion, human iPSCs with diverse TCR gene rearrangement can be generated from TILs efficiently by SeV encoding four pluripotency transcription factors. Future work will explore their differentiation potential to T cells for cancer immunotherapy. We acknowledge in DNAVEC Corporation for kindly providing Sendai virus vectors. This study was supported by the University of Michigan Start-up fund, American College of Surgeons and Central Surgical Association. Note: This abstract was not presented at the meeting. Citation Format: Hidehito Saito, Keisuke Okita, Noemi Fusaki, Michael Sabel, Alfred Chang, Fumito Ito. Generation of induced pluripotent stem cells from tumor-infiltrating lymphocytes. [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 1358. doi:10.1158/1538-7445.AM2015-1358
Preliminary Results of the Combination Rituximab, Fludarabine, Cyclophosphamide and Mitoxantrone (R-FCM) Followed by Rituximab Maintenance in Previously Untreated Chronic Lymphocytic Leukemia (CLL).
Authors: Francesc Bosch, Ana Muntañola, Neus Villamor, Maria Jose Terol, Elena Gonzalez-Barca, Josep Maria Ribera, Marcos Gonzalez, Eugenia Abella, Julio Delgado, Felix Carbonell, Jose A. Garcia-Marco, Lourdes Escoda, Secundino Ferrer, E. Monzo, Yolanda Gonzalez, Pau Abrisqueta, Olga Salamero, Eva Gine, Emili Montserrat
Journal: Blood (2007)