tbuckley/cabot-search huggingface dataset:
Early assessment of efficacy of ixabepilone (IXA) by analysis of the rate of tumor growth and decay using data from phase II and phase III clinical trials in metastatic breast cancer (MBC) patients (Pts).
Authors: L. Amiri-Kordestani, I. Jawed, J. Wilkerson, W. D. Stein, A. T. Fojo, S. M. Swain, S. E. Bates
Journal: Journal of Clinical Oncology (2011)

2527 Background: Early efficacy assessment in drug development should help find new cancer therapies. We have developed a novel method to analyze tumor response to therapy by quantifying the rate of tumor regression (d) and growth (g). We have shown g is slower when pts are on effective therapy and that g correlates with survival (Stein et al, Oncologist 2008). We utilized this method to evaluate a phase III trial of capecitabine (CAP) ± IXA in second line therapy (Tomas et al, JCO 2007) and a three-cohort phase II trial in second and subsequent lines of therapy in pts with MBC consisting of (1) Daily X 5 (DX5) IXA given to taxane (TAX)-naïve patients (Denduluri et al, JCO 2007); (2) DX5 IXA in pts previously treated with TAX (Low et al, JCO 2005); and (3) DX3 IXA in pts previously treated with TAX (Denduluri et al, Invest New Drug 2007). Methods:Using tumor measurements assessed by RECIST and a two-phase mathematical equation we determined d and g. Results: In the phase III study g was superior to PFS identifying a significant difference between the arms very early - before the 200th pt had enrolled. IXA + CAP in second line (g = 0.0018) was more effective than CAP (g = 0.0023) at reducing g, and more effective (p=0.0085) than single agent (SA)-IXA in the Phase II study (g = 0.0027). SA-IXA was comparably effective (p=0.814) in reducing the g of tumors previously exposed to a TAX (g = 0.0032) as in reducing the g of TAX-naïve tumors (g = 0.0035), consistent with its development as an agent active in TAX-refractory disease. Unlike differences in g, the d of SA-IXA (0.118) was comparable to that of IXA+CAP (0.0074) suggesting differences were primarily driven by effect on the growth of residual tumor. Conclusions: Unlike PFS, an incremental measure of efficacy, g is a continuous variable and can more accurately assess differences between treatments. Because calculations of g are indifferent to assessment intervals, estimating a tumor’s g allows comparison of efficacy across trials.
Abstract 1805: DUOX2: The key player for hyper-radiosensitivity in gastric cancer cells with low dose fractionation radio therapy (LDFRT)
Authors: Duc Nguyan, Palak R. Parekh, Elizabeth T. Chang, Navesh Sharma, France Carrier
Journal: Cancer Research (2015)

Abstract The most conventional therapy for solid tumors is radiotherapy. Still there is a challenge when it comes to managing highly disseminated gastrointestinal cancers because of the toxicity issues. Earlier, low dose fractionated radiotherapy (LDFRT) was considered to be ineffective for tumor removal, rather believed to cause cancer. There are few improvements with the use of novel approach in few cases of solid malignancy. This paradigm exploits the advantage of LDFRT with the combination of chemotherapy. Because now it's known that LDFRT causes hyper-radiosensitivity (HRS). The aim of our study is to determine the efficacy of LDFRT in combination with modified regimen of docetaxel, cisplatin and 5′-fluorouracil (mDCF) and their mechanism of action in gastric cancer cells. Our data indicate that consecutive three days radiation with daily fraction of 0.15 Gy produced HRS in gastric cancer cells and potentiated the effect of chemotherapeutic drugs (mDCF). Colony survival assays showed only 10% of gastric cancer cell survival when LDFRT was combined with mDCF while ten times higher dose (1.35 Gy) of radiation alone was required to achieve the same results. RT2-PCR profiler array analysis showed marked upregulation of dual oxidase-2 (DUOX2), an enzyme of NADPH- oxidase family, without inducing the genes involved in DNA repair. This was evident from 3.5 fold increase in reactive oxygen species (ROS) in cells exposed to LDFRT and mDCF. Further, this was confirmed by increase in cancer cell survival hence radioresistance with downregulation of DUOX2 expression. In addition to this inhibition of DUOX2 activity also abrogated the efficacy of the combination therapy. Taken together these data suggest that chemopotentiation by LDFRT in gastric cancer cells may be partly due to increased ROS production by DUOX2 without inducing the DNA repair machinery. These data thus provide a rationale for further explorations of potential clinical applications of LDFRT as a chemopotentiator for advanced and metastatic gastric cancers. (* = Equally Contributed) Citation Format: Duc Nguyan, Palak R. Parekh, Elizabeth T. Chang, Navesh Sharma, France Carrier. DUOX2: The key player for hyper-radiosensitivity in gastric cancer cells with low dose fractionation radio therapy (LDFRT). [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 1805. doi:10.1158/1538-7445.AM2015-1805
24. Targeted Anticancer Approach Through microRNA-Regulated Tumor-Specific RNA Replacement
Authors: Ju-hyun Kim, Jin-Sook Jeong, Seong-Wook Lee
Journal: Molecular Therapy (2015)

We have previously presented that trans-splicing ribozymes based on Tetrahymena group I intron could be potent anti-cancer devices through diminishing target RNA level and simultaneously triggering anti-cancer gene activity only in cancer cells expressing the target RNA. Particularly, hTERT-targeting ribozyme was shown to specifically and efficiently retard tumors in various xenograft carcinomatosis nude mouse models. However, concerns for the hTERT-targeting approach include potential side effects to proliferating hTERT+ normal cells. In this study, to improve cancer-specificity of the ribozyme, we developed cancer-specific ribozyme expression construct via microRNA regulation. To circumvent hepatocellular carcinoma (HCC) as target models, we created tissue-specific microRNA-regulated ribozyme system by incorporating perfect antisense sequence against normal hepatocyte-selective miRNA-122a that is down-regulated in HCC to the 3'-UTR region of ribozyme. Adenovirus encoding the modified hTERT-targeting ribozyme specifically and efficiently induced transgene and cytotoxicity in liver cancers through cancer-specific RNA replacement. Moreover, specificity of cancer regression was highly increased without compromising its anti-cancer efficacy in xenograft orthotopic HCC model. Furthermore, to assess the effect of this system in syngeneic model, we constructed mTERT-targeting ribozyme harboring miRNA-122a target sites. Adenoviral vector encoding the modified ribozyme selectively and efficiently regressed mTERT+ HCC with minimal liver toxicity due to least ribozyme expression in the normal livers in syngeneic orthotopic mouse model. Noticeably, cytotoxicity caused by the adenovirus induced specific immunogenic cancer cell death in the syngeneic model, thereby completely suppressing secondary tumor challenge in the mouse. Therefore, specifically targeted transgene induction through microRNA-regulated RNA replacement provides novel strategies for efficient and safe cancer gene therapy.
Abstract 814: Truncated HBx-dependent silencing of growth arrest-specific 2 promotes hepatocarcinogenesis through inhibition of p53-mediated apoptosis
Authors: Alfred S. L. Cheng, Ranxu Zhu, Myth T.S. Mok, Wai Kang, Ka-Fai To, Joseph J.Y. Sung, Henry L.Y. Chan
Journal: Cancer Research (2015)

Abstract Hepatocellular carcinoma (HCC) is a worldwide threat to public health, especially in China where chronic hepatitis B virus (HBV) infection is found in 80-90% of all HCCs. The HBV encoded X antigen (HBx) is a trans-regulatory protein involved in the virus-induced hepatocarcinogenesis. Although the carboxyl-terminus truncated HBx, rather than the full-length counterpart, is frequently overexpressed in human HCCs, its functional mechanisms have yet been fully defined. In this study, we investigated the molecular pathogenesis of a naturally-occurring HBx variant which has 35 amino acids deleted at C-terminus (HBxΔ35). By performing genome-wide scanning analysis and PCR validation, we identified growth arrest-specific 2 (GAS2) as a direct target of HBxΔ35 at transcriptional level in human immortalized liver cells. HBxΔ35 was found to bind the promoter region of GAS2 and suppress its expression to promote hepatocellular proliferation and tumorigenicity. Further functional assays showed that overexpression of GAS2 inhibited tumor growth both in vitro and in vivo by inducing p53-dependent apoptosis. Conversely, siRNA-mediated knockdown of GAS2 in hepatocytes attenuated apoptotic response and reduced cell susceptibility to etoposide-induced apoptosis. Notably, GAS2 expression was significantly down-regulated in truncated HBx-expressing HCCs compared with the corresponding normal tissues. In conclusion, our integrated study uncovered a novel viral mechanism in hepatocarcinogenesis, wherein HBxΔ35 ablates p53-driven apoptosis via direct silencing of GAS2, and thereby provides survival advantage for pre-neoplastic hepatocytes to facilitate cancer development. Citation Format: Alfred S. L. Cheng, Ranxu Zhu, Myth T.S. Mok, Wai Kang, Ka-Fai To, Joseph J.Y. Sung, Henry L.Y. Chan. Truncated HBx-dependent silencing of growth arrest-specific 2 promotes hepatocarcinogenesis through inhibition of p53-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 814. doi:10.1158/1538-7445.AM2015-814
Molecular, Epigenetic, and Phenotypic Repolarization of T Lymphocytes From Chronic Lymphocytic Leukemia Patients Using 5-Aza-2′-Deoxycytidine
Authors: Jason A Dubovsky, John Powers, Yang Gao, Luis F Mariusso, Eduardo M. Sotomayor, Javier Pinilla-Ibarz
Journal: Blood (2010)
602. Stem Cell Transplantation in a Novel, Long-Lived, and Highly Engraftable Immunodeficient Mouse Model of Mucopolysaccharidosis Type I
Authors: Daniel C. Mendez, Alexander E. Stover, Anthony D. Rangel, Omar Khalid, Steven Q. Le, Shih-hsin Kan, Patricia I. Dickson, Philip H. Schwartz
Journal: Molecular Therapy (2015)

Mucopolysaccharidosis type I (MPS I) is an inherited α-L-iduronidase (IDUA, I) deficiency in which glycosaminoglycan (GAG) accumulation causes progressive multi-system organ dysfunction, neurological impairment, and death. We developed a new MPS I model based on a NOD/SCID/Il2rγ (NSG) background. This model lives longer than one year and is tumor-free during that time. NSG MPS I (NSGI) mice exhibit the typical phenotypic features of MPS I including coarsened fur and facial features, reduced/abnormal gait, kyphosis, and corneal clouding. IDUA is undetectable in all tissues examined while GAG levels are dramatically higher in most tissues. NSGI brain shows a significant inflammatory response and prominent gliosis. Neurological MPS I manifestations are evidenced by impaired performance in behavioral tests. Human neural and hematopoietic stem cells (HSCs) were found to readily engraft, with human cells detectable for at least one year post-transplantation. HSC transplantation at birth gave rise to improvement in behavioral parameters that lasted at least 3 months after transplantation. By 6 months, however, these effects were no longer present. Biochemical and cytometric analyses at 9 months after HSC transplantation showed that iduronidase activity in the liver and hexosaminidase activity in the brain were correlated with levels of HSC engraftment. Behavior at 9 months, however, was not correlated with levels of HSC engraftment suggesting that HSC engraftment, in and of itself, was insufficient to give a prolonged behavioral effect. Future studies will examine the effects of neural stem cells engraftment, with and without concomitant HSC engraftment.
Abstract 651: Superior anti-tumor activity compared to T-DM1 in preclinical studies of targeted therapies for her2-positive cancers by a novel her2-ADC ZV0201
Authors: Hong Zhang, Zhaohui Li, Tong Zhu, Sheldon Cao, Gang Chen, David Miao
Journal: Cancer Research (2015)

Abstract ZV0201 is a her2-targeting ADC based on newly developed K-Lock technology at Concortis. Anti-her2 Antibody ZV02 was conjugated with highly cytotoxic auristatin analogue through a non-cleavable linker to form ZV0201,which mainly consists of DAR2 species. Biochemical analysis indicated that ZV0201 was homogeneous and displayed as a single population after purification. In cellular assay, enhanced anti-tumor activities were observed with this conjugate, compared to T-DM1 in a variety of tumor cell lines. ZV0201 was especially active in cells expressing medium to low level of Her-2. In PK study, ZV0201 had an IC50 about 3-4 days in mouse and was stable for up to 7 days in sera from different species. In xenograft models, a single dose of ZV0201 at low levels completely wiped out the tumors and kept it down for up to 100 days, outperformed T-DM1. Toxicity analysis in rats showed less or comparable toxic effect to that of T-DM1. ZV0201 is currently under further evaluation as a candidate for clinical treatment of her2-positive cancers. Citation Format: Hong Zhang, Zhaohui Li, Tong Zhu, Sheldon Cao, Gang Chen, David Miao. Superior anti-tumor activity compared to T-DM1 in preclinical studies of targeted therapies for her2-positive cancers by a novel her2-ADC ZV0201. [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 651. doi:10.1158/1538-7445.AM2015-651
Bevacizumab maintenance (BM) in first line treatment for metastatic breast cancer (MBC): a multicenter retrospective observational study
Authors: L. Mentuccia, A. Fabi, A. Cassano, P. Vici, A. Michelotti, I. Sperduti, G. Sarobba, P. Marchetti, M.T. Scognamiglio, A. Vaccaro, E. Rossi, D. Pellegrini, D. Nicoletta, A. Pellegrino, V. Sini, L. Pizzuti, M. Palleschi, L. Moscetti, G. Jamara, F. Ciancola, T. Gamucci
Journal: Annals of Oncology (2015)
Expression Profiling for MEIS1 and HOXA9/10 Identifies an Increased Incidence of MLL Rearrangements in T-ALL: A Children's Oncology Group Study.
Authors: Ksenia Matlawska-Wasowska, Richard C. Harvey, I-Ming Chen, Cheryl L Willman, Nyla A. Heerema, Andrew J. Carroll, Meenakshi Devidas, Mignon L. Loh, Stephen P. Hunger, Elizabeth Raetz, Charles G Mullighan, Barbara Asselin, Naomi Winick, William L. Carroll, Richard S. Larson, Kimberly P. Dunsmore, Stuart S. Winter
Journal: Blood (2012)
Plasmatic Levels of FLT-3 Ligand and SDF-1 and Expression of FLT-3 and CXCR4 in CD34+ Cells Population Prior and Post Mobilization of Peripheral Blood Stem Cell.
Authors: Karin Z. Cecyn, Dulce M. Schimieguel, Eliza Y. Kimura, Mihoko Yamamoto, José Salvador R. Oliveira
Journal: Blood (2007)
Abstract 2722: Characterization of human lung enzymes involved in the reduction of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)
Authors: Joseph Ashmore, Ying Liu, Amity Peterson, Sabrina Fechtner, Gang Chen, Philip Lazarus
Journal: Cancer Research (2015)

Abstract 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the primary tobacco-specific nitrosamine (TSNA) related to cancer. The major metabolic pathway for NNK is carbonyl reduction to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) which, like NNK, is a potent lung and pancreatic carcinogen in rodents, with it estimated that 39-100% of NNK is converted to NNAL in cigarette smokers. NNAL is formed as both (R)- and (S)-NNAL enantiomers; while (S)-NNAL is more readily formed from NNK, it is also more readily glucuronidated and detoxified by the phase II UGTs than is (R)-NNAL in monkeys and probably in humans. Therefore, both (S)- and (R)-NNAL are likely to be important metabolites in the NNK carcinogenic process. In the present study, we demonstrated that while (S)-NNAL is the major form (&amp;gt;90%) produced using lung cytosolic fractions, lung microsomes formed primarily (R)-NNAL (&amp;gt;95%). Consistent with previous studies using placenta-fractionated cytosolic enzymes, we demonstrated that several cytosolic enzymes including the aldo-keto reductases (AKRs) 1C1, 1C2, and 1C4, as well as carbonyl reductase I (CBR1) were active against NNK, with all of them forming primarily (&amp;gt;90%) (S)-NNAL. This pattern is consistent with that observed for lung cytosolic fractions. Using HEK293 cells over-expressing microsomal enzymes HSD11β1, HSD11β2, HSD17β12, SDR5A1, SDR5A3, HSD17β1, HSD17β2 or HSD3β7, only HSD11β1 and HSD17β12, all of which were reported to be expressed in lung, exhibited activity against NNK. Most interestingly, both enzymes formed primarily (R)-NNAL (&amp;gt;80%), which is consistent with that observed in lung microsomes. Real-time PCR showed that HSD17β12 was expressed at a level that, on average, was three-fold higher than that observed for HSD11β1 in a screening of normal lung tissue specimens from five individuals. These data suggest that both cytosolic and microsomal enzymes are active against NNK and that HSD11β1 and HSD17β12 are the active microsomal reductases in human lung microsomes, contributing to the exclusive formation of (R)-NNAL Citation Format: Joseph Ashmore, Ying Liu, Amity Peterson, Sabrina Fechtner, Gang Chen, Philip Lazarus. Characterization of human lung enzymes involved in the reduction of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). [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 2722. doi:10.1158/1538-7445.AM2015-2722
Abstract 1511: Identification of metastatic subsets of pancreatic cancer stem cells possessing metabolic features of pluripotent stem cells
Authors: Chi-Che Hsieh, Wen-Ying Liao, Chih-Lung Chen, Pei-Yu Lin, Chia-Ning Shen
Journal: Cancer Research (2015)

Abstract The current cancer chemotherapy can mainly cause pancreatic cancer remission but often fails to cure cancer due to the existence of cancer stem cells in pancreatic ductal adenocarcinomas (PDACs). Therefore, development of methods targeting pancreatic cancer stem cells could lead to improvement in PDAC therapeutic. However, the key characteristics of pancreatic cancer stem cells remain to be determined. Accumulating evidences revealed the similar features shared by pluripotent stem cells and cancer stem cells, we therefore hypothesize acquisition of pluripotent characteristics during the reprogramming process is superficially reminiscent of the dysplastic transformation proposed in cancers. In the current work, comparative genome-wide profiling analysis was conducted on embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and different subpopulation of pancreatic cancer cells. We initially revealed expression of pluripotent transcriptional factors and surface markers such as Oct4, Sox2, Lin28, CD133, ABCG2 and CD44 was significantly higher in ABCG2+ CD44+ pancreatic CSC subpopulation which was correlated with their drug resistance and high metastatic potentials. Metabolic pathway analysis was further performed and identified that, very similar to ESCs/iPSCs, the metastatic ABCG2+CD44+ subpopulations had evaluated levels of of GLUT5 and KHK and expressed higher levels of ST6Gal1. Utilizing tumor-engraft mice and spontaneous pancreatic cancer mice, we actually revealed fructose diet enhanced cancer drug resistance and CSC-mediated cancer metastasis possibly via up-regulating ST6Gal1 as knockdown of ST6Gal can affect self-renewal, invasion potential and ABCG2 efflux ability of ABCG2+CD44+ CSC subpopulations. In summary, the current work elucidated that pancreatic ABCG2+CD44+ CSC subpopulations possess metabolic features of pluripotent stem cells including the capability to efficiently to utilize fructose and to perform 2,6 sialylation via sialyltransferase ST6Gal1 which critically mediated cancer drug resistance and metastasis. Hopefully, the findings can lead to developing efficient treatments for patients of PDAC in the near future. Citation Format: Chi-Che Hsieh, Wen-Ying Liao, Chih-Lung Chen, Pei-Yu Lin, Chia-Ning Shen. Identification of metastatic subsets of pancreatic cancer stem cells possessing metabolic features of pluripotent stem cells. [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 1511. doi:10.1158/1538-7445.AM2015-1511
Reduced Intensity Conditioning with Fludarabine, BCNU and Melphalan (FBM) for Allogeneic Hematopoietic Cell Transplantation in Elderly AML Patients: Factors Predicting Outcome
Authors: Verena Wais, Stephan Bohl, Lukas Kündgen, Stephanie von Harsdorf, Katrina Scholl, Richard F. Schlenk, Susanne Hofmann, C. Philipp Maier, Konstanze Döhner, Maria-Veronica Teleanu, Lars Bullinger, Kathrin Drognitz, Jean-Charles Moulin, Martin Binnenhei, Martin Bentz, Hartmut Döhner, Donald Bunjes, Mark Ringhoffer, Florian Kuchenbauer
Journal: Blood (2015)
HLA-Identical Umbilical Cord Blood Transplantation from a Sibling Donor in Juvenile myelomonocytic Leukemia
Authors: Andrica de Vries, Robbert Bredius, Arjan Lankester, Marc Bierings, Monika Trebo, Jan Stary, Marco Zecca, Franco Locatelli, Charlotte Niemeyer, Marry Van Den Heuvel
Journal: Blood (2008)
Chronic obstructive pulmonary disease exacerbation and inhaler device handling: real-life assessment of 2935 patients
Authors: Mathieu Molimard, Chantal Raherison, Severine Lignot, Aurelie Balestra, Stephanie Lamarque, Anais Chartier, Cecile Droz-Perroteau, Regis Lassalle, Nicholas Moore, Pierre-Olivier Girodet
Journal: European Respiratory Journal (2016)

Acute exacerbations of chronic obstructive pulmonary disease (COPD) can be prevented by inhaled treatment. Errors in inhaler handling, not taken into account in clinical trials, could impact drug delivery and minimise treatment benefit. We aimed to assess real-life inhaler device handling in COPD patients and its association with COPD exacerbations. To this end, 212 general practitioners and 50 pulmonologists assessed the handling of 3393 devices used for continuous treatment of COPD in 2935 patients. Handling errors were observed in over 50% of handlings, regardless of the device used. Critical errors compromising drug delivery were respectively made in 15.4%, 21.2%, 29.3%, 43.8%, 46.9% and 32.1% of inhalation assessment tests with Breezhaler® (n=876), Diskus® (n=452), Handihaler® (n=598), pressurised metered-dose inhaler (pMDI) (n=422), Respimat® (n=625) and Turbuhaler® (n=420). The proportion of patients requiring hospitalisation or emergency room visits in the past 3 months for severe COPD exacerbation was 3.3% (95% CI 2.0–4.5) in the absence of error and 6.9% (95% CI 5.3–8.5) in the presence of critical error (OR 1.86, 95% CI 1.14–3.04, p&lt;0.05). Handling errors of inhaler devices are underestimated in real life and are associated with an increased rate of severe COPD exacerbation. Training in inhaler use is an integral part of COPD management.
Effectiveness of detecting the primary lesion of CUP using FDG-PET/CT: a case report
Authors: Yuki Miyai, Sho Tano, Kaname Uno, Masato Yoshihara, Michinori Mayama, Mayu Ukai, Shinya Kondo, Tetsuya Kokabu, Yasuyuki Kishigami, Hidenori Oguchi
Journal: Annals of Oncology (2015)