tbuckley/cabot-search huggingface dataset:
A phase I schedule optimization study of pegylated glutaminase (PEG-PGA) plus 6-diazo-5-oxo-l-norleucine (DON) in patients (pts) with advanced solid tumors.
Authors: C. Unger, C. Mueller, M. P. Bausch, K. Krzemieniecki, S. Ochenduszko, B. Wilk, E. Jaeger, S. Al-Batran
Journal: Journal of Clinical Oncology (2011)

3049 Background: DON is a glutamine antagonist and inhibits irreversibly the purine/pyrimidine synthesis. Effectiveness of DON is greatly enhanced if plasma glutamine is depleted by PEG-PGA. Previous phase I studies suggested twice weekly administration. Methods: Pts with refractory metastatic colorectal (mCRC) or non-small cell lung cancer (NSCLC) were enrolled. After a single initial dose (150 IU/m2) prior to day 1, PEG-PGA (150 IU/m2) was infused 30 minutes before DON (280-470 mg/m2). Both were given as 15 min i.v. infusions on day 1, 8 and 15 every 21 days until disease progression or unacceptable toxicity. DON was escalated in 3 pt cohorts until MTD was reached. Dose limiting toxicity (DLT) was assessed for the first 21 days. The objectives were: determination of the maximal tolerable dose (MTD), safety (NCI-CTC v2.0), pharmacodynamics and tumor response (RECIST 1.0). Results: Sixteen pts (4f/12m, 13 mCRC, 3 NSCLC, median age 62 yrs, ECOG PS 0/1) were enrolled from June to Nov 2009. Every pt received ≥ 3 (2) PEG-PGA (DON) infusions with a mean of 10 (9). Plasma glutamine was depleted to a non-detectable level (< 1 mg/l) before first DON infusion and remained depleted in 16/16 pts. At 470 mg/m2 DON, two of six pts experienced nausea and vomiting grade 3 after the first DON infusion as DLTs. Since the other four pts tolerated the dose very well the MTD was defined with 470 mg/m2. Other non-hematological pos. rel. grade 3 adverse events (AEs) were asthenia (n=1), back pain (n=1) and decreased appetite (n=1). Most common (n≥3) AEs at any grade were nausea (n=8), diarrhea (n=5), vomiting (n=4), insomnia (n=3) and fatigue (n=3). No AEs grade 4 occurred. Hematological side effects (n=5) were not severe except in one pt with transient lymphopenia grade 3. Twelve pts with pre-treated (median 4.0) mCRC were evaluable for activity. One pt at 470 mg/m2 had a confirmed partial response lasting 8 months and another pt at the same dose had a minor response. Disease control rate was 58 % (7/12) including 4 pts stable for ≥ 5 months. Conclusions: PEG-PGA and DON given once weekly have a favorable safety profile. Interesting signs of activity were observed in patients with progressive mCRC.
673. Establishment of a National Reference Standard for Reverse Transcriptase Activity Assay and Its Applicability in Quality Control of Gene therapy Products
Authors: Yonghong Li, Chen Wang, Lei Yu, Chunming Rao, Junzhi Wang
Journal: Molecular Therapy (2015)

The reverse transcriptase (RT) activity assay is widely used in the quality control of biological products including gene therapy products for it can detect all infectious retroviruses in biological starting materials, cell banks and final products. But the lack of reference standard for RT activity results in significant systemic error and incomparability between laboratories. To standardize RT activity assay, this study established a sensitive real time PCR and developed the first national reference standard, which was prepared from a raw material of recombinant moloney murine leukemia virus reverse transcriptase. Our tests indicated that the candidate reference standard met relevant requirements of the national reference standard. The activity value of candidate RT standard was determined as 26.4 U per ampoule by a collaborative calibration among four laboratories, with the within-laboratory geometric coefficients of variation (GCVs) ranging from 2.7% to 9.6% and the between-laboratory GCV values being 9.8%. The thermal accelerated stability test showed that no loss of activity was observed when the candidate RT standard was stored at 4°C, 25°C and 37 °C compared with -20°C even after 9 months. The applicability study showed that the cell bank and viral bank of an adenovirus gene therapy product were positive and the final products were negative. As a conclusion, the candidate preparation was suitable to serve as a Chinese national standard for RT activity assay and can be used in the quality control of gene therapy products.
Value of Pretransplantation Minimal Residual Disease in Acute Myeloid Leukemia and Myeloablative Hematopoietic Cell Transplantation.
Authors: Leyre Bento, Mi Kwon, Ismael Buno, Carolina Martinez-Laperche, Javier Anguita, Ana M Pérez-Corral, Cristina Pascual, Pascual Balsalobre, David Serrano, Jorge Gayoso, Jose Luis Diez-Martin
Journal: Blood (2012)
PTU-016 Quality of ercp services in district hospitals in the northern region – a 3-month audit: Abstract PTU-016
Authors: D Nylander, S Chatterjee, L MacDougall, J Greenaway, D Dwarakanath, C MacDonald, R Barton, W Gregory, C Rees
Journal: Gut (2010)

<h3>Introduction</h3> ERCP is an important tool in the diagnosis and treatment of pancreaticobiliary disease. It is associated with complication rates between 4-30%. We assessed ERCP practice in the Northern Region (NR) against the results found in the BSG audit (BSGA).1 <h3>Methods</h3> Data were collected prospectively from all ERCPs performed in DGHs in the NR over a 3-month period, followed by a notes review &gt;30 days later to look for complications. These hospitals provided ERCP services for their local population only. A questionnaire about ERCP service in each trust and giving total number of procedures over 12 months was completed by a senior endoscopist. <h3>Results</h3> Data were obtained from eight acute trusts in which a total of 23 ERCP endoscopists performed procedures. Over 12 months these units undertook a median 280 procedures (range 150–372). During the period of the audit there were 467 procedures performed. 367 of these were first procedure the patient had encountered. 84% were ASA grade I or II, 14% grade III and 2% grade IV. All patients had radiology imaging before their first ERCP. All procedures were performed to achieve biliary therapy.First procedure details are shown in Abstract 016 (BSGA figures in brackets). All procedures performed using conscious sedation. 5.5% of patients had Midazolam dose &gt;5 mg (33% BSGA), and in all these cases this was combined with an opioid. Reversal agent was not used in any of these but in only 1 other case in entire series (7.6% BSGA). 30-day complication was reported in 25 cases (included pancreatitis -6; significant bleed-4; cholangitis-3, hepatic abcess-1). Includes 9 deaths; 1 definitely, and 2 possibly ERCP related (0.4% BSGA). <h3>Conclusion</h3> The Northern Region provides a high standard of ERCP performance exceeding results seen in BSGA. Complication rates were low. More information on comparative data from individual endoscopists possibly by greater use of ERCP quality network (Peter Cotton) will be used to encourage further improvement in standards. Abstract submitted on behalf of Northern Region Endoscopy Group.
Biological Features and Plasticity of CD56-Positive Dendritic-Like Cells: relationship to Blastic Plasmacytoid Dendritic Cell Neoplasm
Authors: Yohei Osaki, Akihiko Yokohama, Akio Saitoh, Kenichi Tahara, Kunio Yanagisawa, Yoshiyuki Ogawa, Takuma Ishizaki, Takeki Mitsui, Hiromi Koiso, Makiko Takizawa, Hideki Uchiumi, Hirokazu Murakami, Takayuki Saitoh, Norifumi Tsukamoto, Hiroshi Handa, Yoshihisa Nojima
Journal: Blood (2012)
Review of neoplastic brachial plexopathy at the Mater Misericordiae University Hospital, Ireland
Authors: A. M. Noonan, D. N. Carney, J. McCaffrey
Journal: Journal of Clinical Oncology (2009)

e20681 Background: Neoplastic brachial plexopathy (NBP) may occur with benign or malignant neoplasms. Symptomatic NBP is estimated to occur in about 0.4% of all patients with cancer. Despite therapy NBP is often irreversible. The aim of this review was to determine the incidence of brachial plexopathy occurring in patients with cancer at our centre. Methods: A retrospective review was done of the MRIs (magnetic resonance images) of brachial plexus performed at the Mater Misericordiae University Hospital over a 5 year period from 1 st January 2004 to 31 st December 2008. Results: A total of 66 MRIs of brachial plexus were performed during this period. 29 were performed for assessment of suspected traumatic injuries to the brachial plexus. 18 MRIs were performed in patients with a known cancer diagnosis, 1 was performed in a patient with a benign thymoma, 1 with a neurofibroma and the remaining 17 MRIs were ordered for other conditions. In total, 13 MRIs were positive for brachial plexopathy (7 traumatic, 5 due to cancer, 1 neurofibroma). Of the 20 MRIs performed (18 in patients with cancer, 2 in patients with a history of benign neoplasms), 6 (30%) confirmed a diagnosis of NBP. 27.8% (5/18) of patients with a diagnosis of cancer had NBP (3 had metastatic breast cancer, 2 had non-small cell lung cancer (NSCLC). Female to male ratio was 5:1. Median age at diagnosis was 67 years (range 35 to 86 years). 80% of patients had MRI of cervical spine also performed. Radiotherapy was the treatment of choice for 5 patients with cancer diagnosis, followed by chemotherapy also for one patient. Data was missing on treatment for the patient with neurofibroma. Some improvement in pain control was achieved with radiotherapy. However, there was no improvement in neurology. Conclusions: In our series in the past 5 years, 9% (6/66) of total number of MRIs of brachial plexus performed were positive for a diagnosis of NBP. NBP is devastating diagnosis. Physicians should have a high degree of suspicion for NBP in patients presenting with upper limb pain, paraesthesia and weakness. No significant financial relationships to disclose.
Abstract 667: Regorafenib inhibits colorectal tumor growth through PUMA-mediated apoptosis
Authors: Dongshi Chen, Liang Wei, Jian Yu, Lin Zhang
Journal: Cancer Research (2015)

Abstract Regorafenib, a multi-kinase inhibitor targeting the Ras/Raf/MEK/ERK pathway, has recently been approved for the treatment of metastatic colorectal cancer (CRC). However, the mechanisms of action of regorafenib in CRC cells have been unclear. We investigated how regorafenib suppresses CRC cell growth and potentiates effects of other chemotherapeutic drugs. We found that regorafenib treatment induces PUMA in CRC cells irrespective of p53 status through the NF-κB pathway following ERK inhibition and glycogen synthase kinase 3β (GSK3β) activation. Upregulation of PUMA is correlated with apoptosis induction in different CRC cell lines. PUMA is necessary for regorafenib-induced apoptosis in CRC cells. Chemosensitization by regorafenib is mediated by enhanced PUMA induction through different pathways. Furthermore, deficiency in PUMA abrogates the in vivo antitumor, antiangiogenic and chemosensitization effects of regorafenib. Our results demonstrate a key role of PUMA in mediating the anticancer effects of regorafenib in CRC cells. They suggest that PUMA induction can be used as an indicator of regorafenib sensitivity, and also provide a rationale for manipulating the apoptotic machinery to improve the therapeutic efficacy of regorafenib and other targeted drugs. Citation Format: Dongshi Chen, Liang Wei, Jian Yu, Lin Zhang. Regorafenib inhibits colorectal tumor growth through PUMA-mediated apoptosis. [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 667. doi:10.1158/1538-7445.AM2015-667
Abstract 2059: Novel roles for GNA13 and RHOA as tumor suppressor genes
Authors: Morgan O'hayre, Asuka Inoue, Katiuchia Sales, Irina Kufareva, Juan Luis Callejas Valera, Fukun Guo, Constantinos Mikelis, Giovanni DiPasquale, Kira Finkel, Junken Aoki, Yi Zheng, Thomas H. Bugge, J. Silvio Gutkind
Journal: Cancer Research (2015)

Abstract G-protein coupled receptors (GPCRs) and G-proteins are critical signal transduction molecules that regulate cell survival, proliferation, motility and differentiation. However, mutations and disruptions in the expression or function of these molecules have been linked to growth, progression and metastasis of various cancers. Recently, major efforts in the area of genome-wide sequencing of tumors have unveiled numerous previously uncharacterized mutations in G-proteins and GPCRs, which could have significant implications to cancer initiation and progression. In particular, mutations in the gene encoding the G-protein G13 (GNA13) and/or its downstream effector, RhoA, have been identified in B cell lymphomas (particularly Burkitt's lymphoma and Diffuse Large B cell Lymphoma), T cell lymphomas, and Head and Neck Squamous Cell Carcinomas (HNSCCs). Our analyses indicate that these mutations are highly statistically significant over background cancer gene mutation rate, and mutations in GNA13 alone occur in ∼10-15% of patients with Burkitt's lymphoma and Diffuse Large B cell Lymphoma. Surprisingly, although G13 and RhoA have previously been linked to cellular transformation and metastatic potential of epithelial cancers, our data suggests that the mutations in GNA13 and/or RHOA in these B cell lymphomas and HNSCC are inhibitory in nature. Furthermore, our results indicate a tumor suppressive function for wild-type GNA13 and RHOA in in vivo cancer models. Overall, our data suggest a novel function tumor suppressive function for the G13/RhoA axis in multiple human malignancies. Citation Format: Morgan O'hayre, Asuka Inoue, Katiuchia Sales, Irina Kufareva, Juan Luis Callejas Valera, Fukun Guo, Constantinos Mikelis, Giovanni DiPasquale, Kira Finkel, Junken Aoki, Yi Zheng, Thomas H. Bugge, J. Silvio Gutkind. Novel roles for GNA13 and RHOA as tumor suppressor genes. [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 2059. doi:10.1158/1538-7445.AM2015-2059
Abstract 1173: Extracellular ATP is internalized through not only macropinocytosis but also other endocytic process and promotes growth of human lung cancer cells with Ras mutations
Authors: Yanrong Qian, Xuan Wang, Yunsheng Li, Yanyang Cao, Shiyong Wu, Xiaozhuo Chen
Journal: Cancer Research (2015)

Abstract Within a tumor, extracellular ATP (exATP) concentrations are in the range of several hundred micromolars or higher, 103-104 times higher than those in normal tissues1. We recently showed that extracellular ATP, within the intratumoral concentrations, was internalized by Ras-mutated (Rasmut) A549 human lung cancer cells through macropinocytosis, elevated intracellular ATP levels and rescued cancer cells under various stresses2. However, macropinocytosis3 alone could not account for all the elevated intracellular ATP increase. Here, we show that other endocytic processes, in addition to macropinocytosis, also contributed to the internalization of exATP in A549 and H1299 human lung cancer cells. Cell viability assays, intracellular ATP luminescence measurement assays, fluorescent microscopy were used in this study. First, high-molecular-weight (HMW) dextran uptake assay indicated that A549 and H1299, both Rasmut cancer cells, exhibited a phenotype of macropinocytosis. The colocalization of the red fluorescent HMW dextran and green nonhydrolyzable ATP analog inside the cells indicated that extracellular ATP was internalized by macropinocytosis. In contrast, significantly fewer macropinosomes were found in NL-20 noncancerous lung cells. In addition, the colocalization of low-molecular-weight (LMW) dextran, an endocytic tracer, and ATP analog indicated the internalization of exATP through non-macropinocytic-endocytosis in both lung cancer cell lines. Interestingly, when both red HMW dextran and green LMW dextran were applied to cancer cells, not only colocalization, but also some green-only endosomes were observed, strongly suggesting that both endocytic processes were responsible for exATP internalization. Collectively, these data indicated for the first time that other endocytic processes in addition to macropinocytosis contributed to the internalization of exATP in human lung cancer cells with Rasmut. This finding may significantly enhance our understanding of energy hemostasis within cancer cells and the Warburg effect, which in turn facilitates the development of anticancer therapeutics targeting the endocytic processes and Ras mutations as well as novel anticancer strategies. 1. Pellegatti, et al. (2008). PLoS ONE 3, e2599. 2. Qian, et al. (2014). Cancer Letters 351, 242-251. 3. Commisso, et al. (2013). Nature 497, 633-637. Citation Format: Yanrong Qian, Xuan Wang, Yunsheng Li, Yanyang Cao, Shiyong Wu, Xiaozhuo Chen. Extracellular ATP is internalized through not only macropinocytosis but also other endocytic process and promotes growth of human lung cancer cells with Ras mutations. [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 1173. doi:10.1158/1538-7445.AM2015-1173
Abstract 2987: Next generation sequencing analysis of genetically engineered mouse models of human cancers
Authors: Wei-Jen Chung, Jason Long, Jason Cheng, Chris Tran, Anwesha Dey, Anneleen Daemen, Melissa Junttila
Journal: Cancer Research (2015)

Abstract Genetically engineered mouse models (GEMM) of cancer are invaluable tools for oncology research. They recapitulate critical aspects of tumor etiology and allow for unique interrogation of the tumor stroma interactions during tumorigenesis. In addition, these models are poised for assessing therapeutic drug efficacy and resistance mechanisms. Although these models are widely used, the mutational landscape and transcriptional profile of GEMMs have yet to be thoroughly characterized. In this study we sought to investigate the precise mutational landscape of four well-validated GEMMs representing three types of cancers, non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC) and melanoma. Using next generation sequencing techniques, we profiled one adenovirally-induced Kras mutant NSCLC model (KrasLSL.G12D; p53frt/frt), two Kras mutant models of spontaneous PDAC (KrasLSL.G12D; p16/p19fl/fl; Pdx1.Cre and KrasLSL.G12D; p16/p19fl/wt; p53LSL.R270H/wt; Pdx1.Cre) and one Braf mutant melanoma model (BrafV600E/wt; PTENfl/fl; TyrCreER). All four GEMMs incorporate mutations that are well documented to occur in the human patient population. Additionally these models have been documented to approximate histological and phenotypic aspects of their human correlate. We carried out whole exome sequencing for each model (NSCLC n = 120; PDAC n = 73 and n = 40, respectively; melanoma n = 17) to comprehensively characterize the baseline genomes. We also looked for additional recurrent driver mutations beyond those engineered within each model. Interestingly, both intra and intertumoral heterogeneity was evident. Furthermore, we performed RNA sequencing and identified significantly affected genes and gene sets. Finally, we compared our GEMMs to human tumors from TCGA (LUAD, LUSC, PAAD and SKCM) at the genomic and transcriptomic level. Taken together, the results we will present provide a clearer understanding of the genomic and transcriptional landscape of these GEMMs and their relationship with human patients. More importantly, these analyses will allow us to better interpret results from previous and future experiments using these GEMMs of cancer. Citation Format: Wei-Jen Chung, Jason Long, Jason Cheng, Chris Tran, Anwesha Dey, Anneleen Daemen, Melissa Junttila. Next generation sequencing analysis of genetically engineered mouse models of human 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 2987. doi:10.1158/1538-7445.AM2015-2987
Abstract 1777: The characterization of the effects of the strigolactones on the heat shock response
Authors: Victor S. Wang, Nu Nu Kyin, Claire Pollock, Hyjoung Lee, Xin Li, Cristina Prandi, Yoram Kapulnik, Hinanit Koltai, Luke Whitesell, Ronit Yarden
Journal: Cancer Research (2015)

Abstract Strigolactones (SLs) are a novel class of plant hormones that inhibit the self-renewal of undifferentiated meristem cells in shoots regulating above-ground plant architecture. Data from our lab have shown that SL analogues are able to inhibit the growth and survival of a wide array of cancer-derived cell lines including: prostate, colon, lung, breast and osteosarcoma (U2OS) while minimally affecting cultured normal cells. Treatment of cancer cells with SL analogues leads to the activation of stress-related signaling including p38MAPKs and JNK1/2, as well as the activation of the heat shock master regulator, heat shock transcription factor 1 (HSF1), and heat shock response (HSR) gene expression. We further show that SLs generate reactive oxygen species (ROS) and that SL treatments of cancer cells leads to the activation of GRP78, the master regulator of the unfolded protein response (UPR). To further characterize the relationship between SLs, HSR and UPR, several clones of HSF1 shRNA knockdown, in U2OS cells were generated and are currently being studied. Interestingly, while wild type mouse embryonic fibroblast (MEF) cells are refractory to SLs treatments, we demonstrate that HSF1 knockout in MEFs enhances the sensitivity of the cells to SLs treatments. Taken together, our data suggest that the HSR and UPR are recruited as cell survival mechanisms against the SLs treatments, giving rise to possible future chemotherapeutic combinatorial treatment options. Citation Format: Victor S. Wang, Nu Nu Kyin, Claire Pollock, Hyjoung Lee, Xin Li, Cristina Prandi, Yoram Kapulnik, Hinanit Koltai, Luke Whitesell, Ronit Yarden. The characterization of the effects of the strigolactones on the heat shock response. [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 1777. doi:10.1158/1538-7445.AM2015-1777