tbuckley/cabot-search huggingface dataset:
Comparative Effectiveness of Ofatumumab (O) in Combination with Chlorambucil (Chl) Versus Bendamustine (B), and Obinutuzumab (GA101) or Rituximab (R) in Combination with Chlorambucil for Chronic Lymphocytic Leukaemia (CLL)
Authors: Sorrel E Wolowacz, Sarah Mitchell, Amin Haiderali
Journal: Blood (2014)
Prospective Metabolic and Cardiovascular Assessment in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Nilotinib 300 Mg Bid Frontline in the Gimema 0811 Trial
Authors: Massimo Breccia, Fausto Castagnetti, Gabriele Gugliotta, Bruno Martino, Giuseppe Rossi, Angelo Michele Carella, Fabio Stagno, Diamante Turri, Paolo Avanzini, Elena Trabacchi, Ivana Pierri, Mario Tiribelli, Alessandro Isidori, Marzia Salvucci, Silvana Capalbo, Anna Merli, Luciano Levato, Gianni Binotto, Elena Maino, Serena Rupoli, Fabrizio Pane, Giuseppe Saglio, Michele Baccarani, Giuliana Alimena, Gianantonio Rosti
Journal: Blood (2015)
Lenalidomide (CC-5013; Revlimid®) Promotes Erythropoiesis in Myelodysplastic Syndromes (MDS) by CD45 Protein Tyrosine Phosphatase (PTP) Inhibition.
Authors: Alan F. List, Myka Estes, Ann Williams, Madhavi Sekharam, Ukiyasu Ozawa, Gui Gao, Jerry Wu, Gui Gao, Lubomir Sokol
Journal: Blood (2006)
Trastuzumab use at relapse after adjuvant trastuzumab therapy in HER2-positive breast cancer.
Authors: I. Lang, R. Bell, F. Feng, R. I. Lopez, J. Jassem, V. Semiglazov, N. Al-Sakaff, E. Carreras, J. Chang
Journal: Journal of Clinical Oncology (2011)

575 Background: Trastuzumab (H) is the standard of care for patients with early and advanced HER2-positive breast cancer. It is therefore important to investigate the benefit of retreatment with H for patients who experienced a relapse after adjuvant H. The RHEA trial assessed the efficacy and safety of H plus a taxane, as first-line treatment for patients with metastatic breast cancer (MBC) who relapsed following adjuvant H for HER2-positive early breast cancer. Methods: RHEA was a two-cohort, non-randomized, multicenter, open-label, Phase II study. Patients (N=43) with HER2-positive MBC who had received prior adjuvant H for ≥10 months, with a relapse-free interval of ≥6 months after the last H dose, were recruited. Eligible patients (N=41) were assigned to receive H either weekly (loading dose 4 mg/kg, then 2 mg/kg) or 3-weekly (loading dose 8 mg/kg, then 6 mg/kg) in combination with docetaxel (100 mg/m2 q3w × 6) or paclitaxel (175 mg/m2 q3w × 6 or 75 mg/m2 qw × 18). H was given until progression, unacceptable toxicity, withdrawal or death. Taxanes were given for 18 weeks, with additional cycles at the investigator’s discretion. The primary endpoint was response rate (complete response or partial response) assessed according to RECIST criteria. Results: Patients had a median age of 54 years (range: 31–78) and a median ECOG status of 0 (range: 0–2). Thirty-seven patients received docetaxel, three received paclitaxel and one received nab-paclitaxel. Partial response was observed in 25/41 patients (61%), stable disease in seven patients (17.1%), and progressive disease in six patients (14.6%). Median progression-free survival was 8.0 months (95% CI: 6–11 months). The most common adverse events (AEs, all grades) were alopecia (32%), diarrhea (32%), fatigue (24%), peripheral edema (17%) and asthenia (15%). Six patients (14.6%) developed at least one serious AE. There were no reports of congestive heart failure or any unexpected toxicities. Conclusions: H, in combination with a taxane, is an effective and well tolerated first-line treatment for MBC in patients who relapsed following H-based adjuvant therapy. These data support the concept of retreatment with H in the metastatic setting in patients with HER2-positive BC.
648. Mitigating Tumor Escape: Tandem Anti-CD20- and CD19 SCFV-Based Chimeric Antigen Receptors (CARs) in Leukemia/Lymphoma
Authors: Ying Xiong, Darong Wu, Boro Dropulic, Rimas Orentas, Dina Schneider
Journal: Molecular Therapy (2016)

In recent years, adoptive cell therapy using T cells engineered with chimeric antigen receptors (CAR T) specific for CD19 has shown marked clinical efficacy. Nevertheless, cases of tumor escape due to tumor escape in B cell malignancies could be mitigated by CAR T the loss of CD19 antigen have been reported. We hypothesized that approaches that target the CD19 and CD20 tumor antigens simultaneously. Second generation CARs containing scFv specific for CD19 and CD20 were generated by lentiviral transduction of human primary T cells. The configurations were: a) single targeting domain, b) tandem targeting domains, or c) two full-length CAR receptors co-expressed bicistronically in the same T cell. CAR T expression for all constructs confirmed by Western blotting and protein L flow cytometry. CAR T cytolytic activity and IFN gamma secretion were evaluated by killing assays and ELISA, respectively. Single, tandem, and bicistronic CAR T cells exhibited CAR surface expression of 50-70%. All anti- CD19, anti-CD20 CAR T cells demonstrated target-specific cells lysis and induction of IFN-gamma. Interestingly, bicistronic CAR19, CAR20 construct yielded high CAR T surface expression and IFN-gamma production, but inferior in vitro cytolytic activity. To confirm CAR T specificity, K562 CD19+ and K562 CD20+ cell lines were generated. In flow-based 1h killing assays, CAR19 and CAR20 lysed their respective target lines only, whereas tandem CAR constructs lysed both K562 CD19+ and K562 CD20+ cells, but not K562 control. In a subsequent series of co-culture experiments, Raji target cells were combined with very low ratios of CAR T cells, to allow for the evolution of escape variants. On day 5 of co-incubation in the presence of CAR19 T cells, the surviving Raji cells numbers were comparable to control (85,000 cells/well vs 77, 000 cells/well in sham transduction). In comparison, viable Raji numbers decreased drastically post co-incubation with CAR20-, CAR19_20- and CAR20_19-T cells (546, 1,355 and 1,543 cells/well, respectively). Among the surviving Raji population, CD19 surface expression was reduced to 1.6%, vs 93.29% for sham control, whereas the expression of CD20 and CD22 remained high (97% and 78%, respectively). By contrast, the CD20 surface marker was less prone to down-regulation by CAR-T cells expressing anti-CD20 scFv. Similar results were seen when experiments were of longer, 7 days, or shorter, 1 day, duration. Thus, targeting two tumor antigens simultaneously using tandem CAR T cells is a promising new strategy for mitigation of tumor escape via antigen down-regulation. Moreover, expression of two scFv in a single CAR format is superior to expression of two independent CARs from a bicitsronic vector. It also appears that the order of the targeting domains within the tandem CAR impacts anti-tumor activity. These findings are currently being explored further in animal model systems.
Abstract 3006: Hyperoxia may be a treatment option for NSCLC
Authors: Junko Hamamoto, Hiroyuki Yasuda, Ichiro Nakachi, Michael G. Edwards, Masayoshi Miyawaki, Makoto Nishino, Aoi Kuroda, Tetsuo Tani, Daisuke Arai, Kota Ishioka, Ichiro Kawada, Katsuhiko Naoki, Tomoko Betsuyaku, Kenzo Soejima
Journal: Cancer Research (2015)

Abstract Introduction: Many anti-tumor drugs have been developed, however, prognosis of NSCLC remains poor and new approaches for NSCLC treatment are expected. Lung is a unique organ whose epithelial cells are directly exposed to oxygen. Hyperoxia produces reactive oxygen species (ROS) and induces cell damage. Therefore we attempted to investigate the potential of hyperoxia as an anti-tumor treatment in NSCLC cells in this study. Methods: We used oxygen-concentration-adjustable incubators and validated effect of hyperoxia on various lung cancer cell lines in vitro. The effect of hyperoxia on cell proliferation, apoptosis and gene expression was evaluated using MTS assay, flowcytometry and cDNA microarray, respectively. Results: We found that the growth of lung cancer cell lines (A549, NCI-H1975) was inhibited by 50% of hyperoxia in a dose-dependent manner, while that of normal airway epithelial cells (NHBE, BEAS-2B) was not. Two independent pathway analysis using cDNA microarray revealed the activation of NF-kB and AMPK pathways, and the production of nitric oxide and ROS in hyperoxia (50%) treated lung cancer cell lines compared to untreated ones. The combined treatment with ABT-263, Bcl-2 inhibitor, and hyperoxia (50%) induced synergistic growth inhibition and apoptosis in NCI-H1975 and SK-MES-1 cells. Moreover, the combination of ABT-263 and activator of either ROS, NF-kB or AMPK also showed synergistic growth inhibition in those cells. Conclusions: Hyperoxia (50%) showed anti-tumor effect in NSCLC cell lines through the activation of NF-kB and AMPK pathways, and the production of ROS. The effect was augumented in combination with Bcl-2 inhibitor. Hyperoxia may be a treatment option for NSCLC patients. Citation Format: Junko Hamamoto, Hiroyuki Yasuda, Ichiro Nakachi, Michael G. Edwards, Masayoshi Miyawaki, Makoto Nishino, Aoi Kuroda, Tetsuo Tani, Daisuke Arai, Kota Ishioka, Ichiro Kawada, Katsuhiko Naoki, Tomoko Betsuyaku, Kenzo Soejima. Hyperoxia may be a treatment option for NSCLC. [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 3006. doi:10.1158/1538-7445.AM2015-3006
537. Comparing the Efficacy of Tat-Dependent and Tat-Independent Lentiviral Vectors
Authors: Chantelle McIntyre, Fiona Craig, Patricia Cmielewski, Martin Donnelley, Nigel Farrow, David Parsons
Journal: Molecular Therapy (2015)

The Tat HIV-1 accessory protein has been found to play a role in both transcriptional initiation and elongation of RNA transcripts and provirus. For historical "safety" reasons, clinical trials using HIV-1 vectors do not generally accept the use of Tat. The aim of this experiment was to compare the efficacy of Tat-dependent and Tat-independent vector systems, to ensure the most effective gene therapy can be achieved. Experiments were performed using our second-generation 5-plasmid Tat-dependent vector, and a third-generation 4-plasmid Tat-independent vector system that utilised an RSV internal promoter, to determine the effects of exchanging the helper plasmids from one system with the helper plasmids from the other system, and to directly compare the quality and the quantity of the virus made by each individual system. The p24 concentrations and viral RNA titres were obtained to determine packaging efficiency. Reporter gene expression of GFP and Luciferase was quantified by fluorescence microscopy, FACS, and IVIS fluorescence and bioluminescence imaging. The p24 concentrations of the Tat-dependent vectors were significantly greater than that of the Tat-independent vectors. However, the viral RNA titres of the Tat-dependent vectors were significantly lower than that of the Tat-independent vectors. Luciferase bioluminescence imaging determined that there was no difference in expression, relative to viral RNA titre, for the Tat-independent vector when using different helper plasmids and ratios, or when Tat was included in the system. The Tat-independent vector produced a greater number of correctly packaged viral particles (particles that contain the desired transgene). We conclude that vectors that are Tat-independent may be comparable in efficacy to Tat-dependent vectors. Further studies are needed to determine if transduction efficiency is comparable, or better, for use in in vivo animal models.
Abstract 2066: Aberrant upregulation of 14-3-3 gamma promotes mononucleated polyploidization in human lung cancers
Authors: Cecil J. Gomes, Michael Harman, Jesse Martinez, Sara Centuori
Journal: Cancer Research (2015)

Abstract Advanced non-small cell lung cancers (NSCLC), frequently display increased expression of 14-3-3 gamma (14-3-3γ); a scaffolding protein shown to have oncogenic capacity. This aberrant increase in expression has also been correlated with poorer survival, indicating that upregulation of 14-3-3γ results in a more aggressive tumor phenotype. Our lab is in pursuit of characterizing the mechanisms driving this more advanced cancer phenotype. One such mechanism currently being investigated is 14-3-3γ's ability to promote polyploidization in lung cancer cells. Polyploidization is a known mechanism observed to increase tumorigenicity, resistance to conventional therapies, and theorized to promote chromosomal instability. Our data shows that overexpression of 14-3-3γ results in a subpopulation of cells that harbor mono-nucleated tetraploid DNA content. This suggests that elevated expression of 14-3-3γ promotes aberrant cell cycle progression, either by mechanisms of an abortive mitosis known as endomitosis, or by means of endoreplication, a re-replication event occurring in the absence of mitosis. Further analyses have confirmed that these cells, in the absence of tumor suppressor p53, remain viable and undergo cellular division; supporting our hypothesis that upregulation of 14-3-3γ is resulting in an unstable, tumorigenic tetraploid cell state. Taken together, our data elucidates one role by which 14-3-3γ may be contributing to a more aggressive tumor phenotype in patients with advanced NSCLC. Citation Format: Cecil J. Gomes, Michael Harman, Jesse Martinez, Sara Centuori. Aberrant upregulation of 14-3-3 gamma promotes mononucleated polyploidization in human lung cancers. [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 2066. doi:10.1158/1538-7445.AM2015-2066
Premorbid Obesity, but Not the Nutritional Regimen during Critical Illness, Prevented Illness-Induced Lean Tissue Wasting in Mice
Authors: Mirna Marques, Thomas Janssens, Fabian Güiza, Sarah Vander Perre, Sarah Derde, Greet Van den Berghe, Lies Langouche
Journal: Endocrine Reviews (2014)
Abstract 347: Mechanism of c-Met TKI resistance and role of epithelial mesenchymal transition in melanoma
Authors: Supriya Rajanna, Ichwaku Rastogi, Sunil Palani, Neelu Puri
Journal: Cancer Research (2015)

Abstract Various tyrosine kinase inhibitors (TKI’s) are approved for the treatment of melanoma, but their efficacies are limited due to development of drug resistance. To analyze the resistance to c-Met inhibitors we used two melanoma cell lines: MU which has mutated BRAF (V600E +ve) and RU which has wild type BRAF. These cell lines were also made resistant to c-Met inhibitor, SU11274 by growing them in progressively increasing concentrations of drug. In earlier studies we observed activation of Wnt pathway in both of the aforementioned cell lines indicating the role of active β-Catenin in transcription and hence cell proliferation. β-Catenin levels when localized and accumulated in the nucleus binds to TCF/LEF and activates transcription. The level of β-Catenin in the cytosol is regulated by the adherens junction proteins (E-Cadherin) along with the Wnt pathway. Increased levels of β-Catenin might be a possible result of loss of E-Cadherin which is related to epithelial mesenchymal transition. During epithelial mesenchymal transition (EMT) cells transition from epithelial (attached, non-migratory) to mesenchymal (unattached and migratory) cells which promotes metastasis. We examined the role of EMT in the development of resistance in the c-Met TKI resistant melanoma cell lines. We quantified the β-Catenin activity using luciferase assay and observed a 5 fold upregulation in the SU11274 resistant MU cells when compared to MU parental cells in the presence of HGF. Additionally, we performed immunoblotting, where we observed modulation in EMT related proteins in MU and RU parental and resistant cells. E-Cadherin, ZO-1, Claudin-1 and Slug were found to be downregulated 1.5 - 2.7 fold, 1.5 - 2.0 fold, 2 - 9 fold and 1.5 - 2 fold respectively and N-Cadherin and β-Catenin were found to be upregulated 1.8 - 5.3 and 2.4 - 3.7 fold respectively in the SU11274 resistant MU cells in the presence and absence of HGF and SU11274 treatments. Similarily we observed upregulation of β-Catenin by 1.7 fold and downregulation of E-Cadherin and ZO-1 by 2 - 3.5 fold and 6 - 9 fold respectively in SU11274 resistant RU cells when compared to RU parental cells in the presence and absence of HGF and SU11274 treatments. Further studies are being carried to understand the role of EMT in the development of this acquired resistance. These results may help in development of novel therapies for melanoma patients or may help in increasing the efficacy and beneficence from the currently available therapeutics. Citation Format: Supriya Rajanna, Ichwaku Rastogi, Sunil Palani, Neelu Puri. Mechanism of c-Met TKI resistance and role of epithelial mesenchymal transition in melanoma. [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 347. doi:10.1158/1538-7445.AM2015-347
Cyanoacrylate injection versus band ligation for bleeding from cardiac varices along the lesser curvature of the stomach
Authors: Sang Jung Park, Yong Kwon Kim, Yeon Seok Seo, Seung Woon Park, Han Ah Lee, Tae Hyung Kim, Sang Jun Suh, Young Kul Jung, Ji Hoon Kim, Hyunggin An, Hyung Joon Yim, Jae Young Jang, Jong Eun Yeon, Kwan Soo Byun
Journal: Clinical and Molecular Hepatology (2016)

Background/Aims Practice guidelines recommend endoscopic band ligation (EBL) and endoscopic variceal obturation (EVO) for bleeding from esophageal varices and fundal varices, respectively. However, the optimal treatment for bleeding from cardiac varices along the lesser curvature of the stomach (GOV1) remains undefined. This retrospective study compared the efficacy between EBL and EVO for bleeding from GOV1. Methods Patients treated by EBL or EVO via cyanoacrylate injection for bleeding from GOV1 were enrolled. Patients diagnosed with hepatocellular carcinoma or treated with endoscopic injection sclerotherapy were excluded. Results The study included 91 patients treated for bleeding from GOV1. The mean age was 56.3±10.9 years (mean±SD), and 78 of them (85.7%) were men. Overall, 51 and 40 patients were treated with EBL and EVO, respectively. A trend for a higher hemostasis rate was noted in the EVO group (100%) than in the EBL group (82.6%, P=0.078). Varices rebled in 15 patients during follow-up. The rebleeding rate was significantly higher in the EBL group than in the EVO group (P=0.004). During follow-up, 13 patients died (11 in the EBL group and 2 in the EVO group); the survival rate was marginally significant between two groups (P=0.050). The rebleeding-free survival rate was significantly higher in the EVO group than in the EBL group (P=0.001). Conclusions Compared to EBL, EVO offered significantly lower rebleeding rates, significantly higher rebleeding-free survival rates, and a trend for higher hemostasis and survival rates. EVO appears to be the better therapeutic option for bleeding from GOV1. Keywords: Varices; Liver cirrhosis; Endoscopy; Cyanoacrylate; Band ligation
Inv(11)(q21q23) Fuses MLL to the NOTCH Co-Activator Mastermind-Like 2 in Secondary T Cell Acute Lymphoblastic Leukemia.
Authors: Markus Metzler, Jan Zuna, Martin S. Staege, Lana Harder, Claus Meyer, Thomas Flohr, Joerg Meerpohl, Eva Fronkova, Thorsten Langer, Jochen Harbott, Jan Trka, Reiner Siebert, Rolf Marschalek, Charlotte Marie Niemeyer, Wolfgang Rascher
Journal: Blood (2006)
Associations between Chromosomal Aberrations and Functional Impairment of the P53 Pathway in Chronic Lymphocytic Leukaemia.
Authors: Andrew R. Pettitt, Anthony Carter, Ke Lin, Paul D. Sherrington, Mark Atherton, Kevin Pearson, Angela Douglas, Anna Burford, V. Brito-Babapulle, Estella Matutes, Daniel Catovsky
Journal: Blood (2004)
Dose Intensive Administration of PR-047, a Novel Orally Bioavailable Inhibitor of the 20S Proteasome, Is Well Tolerated in Experimental Animals.
Authors: Tony Muchamuel, Shirin Kapur, Christopher J Kirk, Jing Jiang, Susan Lee, Mark K Bennett, Evan Lewis, Jinfu Yang, Mouhannad Jumaa, Eileen Ring, Pasit Phiasivongsa, Han-Jie Zhou, Zhengping Wang
Journal: Blood (2009)
PTH-047 Safety and tolerability of prucalopride (resolor) in patients with chronic constipation: pooled data from three pivotal phase 3 studies: Abstract PTH-047
Authors: J Tack, R Kerstens, J Ausma, G Beyens, L Vandeplassche
Journal: Gut (2010)

<h3>Introduction</h3> Prucalopride (PRU) is a selective high affinity 5-HT4 agonist. Studies have shown that PRU effectively improved bowel movements in patients with chronic constipation (CC). <h3>Methods</h3> Three pivotal phase III double-blind, randomised, placebo (PLA)-controlled studies were conducted, identical in design. Trials consisted of a 2-week run-in period followed by a 12-week treatment period in which patients were randomised to once daily treatment with PRU 2 mg, PRU 4 mg or PLA. Adverse events (AEs) were reported and vital signs, laboratory and ECG were recorded at baseline, weeks 4 and 12 of treatment. Combined analyses of the three trials are presented. <h3>Results</h3> Eighty-nine percent of a total of 1977 treated subjects were female, average age was 47 years, average history of constipation was 20 years and &gt;50% of patients reported to have no spontaneous complete bowel movements during the 2-week run-in period. PRU 2 mg, PRU 4 mg and PLA were administered to 659, 657 and 661 patients, respectively. AE incidence is summarised in Abstract 008 below. The higher incidence of headache, nausea and diarrhoea in the PRU groups can be explained by the pharmacodynamic effect of PRU and mainly occurred on the first day of treatment. Most AEs (≥5%) considered at least moderate in severity and possibly related to PRU were mainly related to the GI tract with a higher incidence in the PRU groups for nausea, diarrhoea, abdominal pain and headache ranging from 2.7% to 4.7% in PLA vs 5.1% to 11.8% in PRU 2 mg and 6.1% to 16.1% in PRU 4 mg. No deaths were reported. The only SAE reported in more than one patient was abdominoplasty for two patients in the PRU 4 mg group (not related to study medication). Most frequent AEs (≥2%) leading to discontinuation were also nausea, diarrhoea, abdominal pain and headache. No clinically relevant differences were observed between PRU and PLA in laboratory parameters, in vital signs or ECG values during the trial period (Abstract 047). <h3>Conclusion</h3> Treatment during 12 weeks with PRU 2 mg and 4 mg is safe and well tolerated by patients with CC.