tbuckley/cabot-search huggingface dataset:
Abstract 5237: Protection of tocopherols against estrogen-induced breast cancer via mechanisms targeting cancer stem cells
Authors: Min Ji Bak, Soumyasri Das Gupta, Joseph Wahler, Mao-Jung Lee, Yong Lin, Weichung Joe Shih, Chung S Yang, Nanjoo Suh
Journal: Cancer Research (2016)

Abstract Estrogens have been implicated to be complete carcinogens through mechanisms involving increased proliferation, oxidative stress and DNA damage. Although the importance of estrogen in breast cancer is well established, the effects of estrogen on breast cancer stem cells are not fully understood. Due to the role of breast cancer stem cells in tumor initiation, maintenance, and progression, targeting cancer stem cells has become important for understanding estrogen-mediated breast carcinogenesis. The vitamin E family, which is consisted of four different forms of tocopherols and tocotrienols, has been shown to exert anti-tumor effects in animal models of various cancers. In the present study, we examined the protective effects of α-, γ-, δ-tocopherol as well as a natural γ-tocopherol rich mixture of tocopherols (γ-TmT) against estrogen-induced expansion of cancer stem-like cells and estrogen-mediated tumor growth. To determine the effects of tocopherols on breast cancer stem cells, the MCF-7 mammosphere cell culture system, which enriches for mammary progenitor cells and putative breast cancer stem cells, was utilized. Treatment of MCF-7 mammosphere with estrogen for six days resulted in an increase in CD44+/CD24- stem-like cell populations as well as the number and size of mammosphere. α-, γ-, δ-Tocopherol, and most significantly γ-TmT, inhibited estrogen-induced mammosphere formation, indicating that tocopherols reverse estrogen-induced expansion of breast cancer stem cells. In MCF-7 xenograft tumor study, MCF-7 cells (5 × 106 cells/mouse) were injected into the mammary fat pad in immunodeficient mice after subcutaneous implantation with 0.72 mg of estrogen pellet. Mice were then administered with diets containing 0.2% α-, γ-, δ-tocopherol and γ-TmT for 5 weeks. Treatment of α-, γ-, δ-tocopherol or γ-TmT reduced the tumor volume by 71% (p&amp;lt;0.05), 55% (p&amp;lt;0.05), 59% (p&amp;lt;0.05) and 42% (p&amp;lt;0.01) as well as tumor weight by 80%, 63% (p&amp;lt;0.05), 61% (p&amp;lt;0.05) and 48% (p&amp;lt;0.05), respectively. Our results suggest that tocopherols significantly repress the expansion of breast cancer stem cell-like population and tumor development. Tocopherols, in particular a naturally occurring tocopherol mixture rich in γ and δ-tocopherols, could thus be effective natural agents for the prevention and treatment of estrogen-induced breast cancer.(This work was supported by NIH R01 AT007036) Citation Format: Min Ji Bak, Soumyasri Das Gupta, Joseph Wahler, Mao-Jung Lee, Yong Lin, Weichung Joe Shih, Chung S Yang, Nanjoo Suh. Protection of tocopherols against estrogen-induced breast cancer via mechanisms targeting cancer stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5237.
A novel clip-assisted method for endoscopic removal of an impacted toothpick from the colon
Authors: Felipe da Mota, Thalles Lisboa, Breno da Costa, Fábio de Queiroz, Eliane Mansur, Rodrigo de Almeida Paiva, Paulo França Neto
Journal: Endoscopy (2016)

Perforated acute abdomen is a common syndrome among nontraumatic abdominal emergencies [1]. Bowel perforations may occur because of inflammatory, neoplastic, traumatic, or infectious processes in the digestive tract [2]. They can also be due to ingestion of foreign bodies or as a result of diagnostic and therapeutic medical procedures [2]. The bowel perforation can present as diffuse peritonitis, when it occurs in free peritoneum, or as an obstructive process [3].
Construction of the system of treatment for deep venous thrombosis with malignant tumor in Anjo Kosei Hospital
Authors: Yuichiro Inagaki, Takahiro Suzuki, Satomi Saeki, Natsuko Tsushita, Toshiyasu Sakai, Tomonori Kato, Hiroyuki Manshio, Junko Arima, Yoshitaka Ono, Masashi Sawa
Journal: Annals of Oncology (2015)
Abstract 2669: Glutaminase alternative splicing controls tumor growth and metabolism
Authors: Zachary Stine, Zandra E. Walton, Lin Zhang, Teresa MW Fan, Andrew N. Lane, Chi V. Dang
Journal: Cancer Research (2016)

Abstract Cancer cells reprogram their metabolism to meet their energetic and biosynthetic needs, with many cancer cells showing increased aerobic glycolysis and glutamine consumption. In addition to providing carbon to the TCA cycle to compensate for the diversion of glucose to lactate, glutamine is an important carbon and nitrogen donor for the synthesis of nucleotides, amino sugars and non-essential amino acids. Glutaminase (GLS) catalyzes the first step of glutamine metabolism, the hydrolysis of glutamine to glutamate, which can then be converted to alpha-ketoglutarate, glutathione or non-essential amino acids. GLS is alternatively spliced to make the KGA or more catalytically active GAC isoforms. Analysis of publicly available TCGA RNA-seq data from primary human tumors shows that GAC is the predominant splice form of GLS in many tumor types. However, the roles played by GAC versus KGA in tumor metabolism and progression are poorly understood. To facilitate the study of GLS alternative splicing, CRISPR/Cas9 mediated deletion of the GAC specific exon was used to convert predominantly GAC-expressing parental cell lines to solely KGA-expressing cell lines (ΔGAC). Despite showing decreased glutamine-derived glutamate and α-ketoglutarate, ΔGAC cells do not show impaired growth in nutrient-replete in vitro conditions compared to parental cells. 13C-isotopic labeling and metabolomics showed that ΔGAC cells have decreased levels of proline and alanine, both of which can be derived from glutamine-derived glutamate. This led us to ask if ΔGAC cells are dependent on exogenous non-essential amino acids. We found that depletion of non-essential amino acids slowed the growth of ΔGAC cells compared with parental cells, rescuable by exogenous proline and alanine. Importantly, the growth of lung (A549) and breast cancer (MDA-MB231) ΔGAC xenograft models was diminished compared with parental tumor xenografts in vivo, which is consistent with a role for GAC in nutrient challenged conditions. In summary, the GAC form of glutaminase fuels tumor growth partly through synthesis of non-essential amino acids, particularly under nutrient limiting conditions. As GLS inhibitors enter the clinic, a more thorough understanding of the role of GLS in tumor metabolism will aid in the development of treatment strategies to best make use of these drugs. Citation Format: Zachary Stine, Zandra E. Walton, Lin Zhang, Teresa MW Fan, Andrew N. Lane, Chi V. Dang. Glutaminase alternative splicing controls tumor growth and metabolism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2669.
Abstract 5030: Tumor necrosis serves as a prognostic predictor in operable and stage I lung adenocarcinoma
Authors: Pei-Ying Lin, Tzu-Hung Hsiao, Pan-Chyr Yang
Journal: Cancer Research (2016)

Abstract Background A relatively high proportion of stage I lung adenocarcinoma patients suffer from disease relapse after surgical resection. This highlights an unmet need in clinical risk assessment for this patient group. Several previous studies suggested adopting the feature tumor necrosis as a risk stratification parameter, but consensus has not been reached. Here we evaluated whether gene signatures that represented three biological processes, cell proliferation, tissue hypoxia and nutrient supplement, underlying their pathological sum tumor necrosis, supported the assumption that necrosis is a prognostic predictor. Methods and Results The three selected gene signatures, cell-cycle, hypoxia and mTOR, were revealed to have higher signature activities in necrosis-positive lung adenocarcinoma tissues than in necrosis-negative ones. This phenomenon was observed in a Japanese dataset and was verified in The Cancer Genome Atlas lung adenocarcinoma dataset. In these two datasets, both the feature tumor necrosis and the signatures were shown to stratify operable and/or stage I lung adenocarcinoma patients into different risk groups. We further validated this observation in a 130 surgically resected lung adenocarcinoma patient cohort. The results showed that tumor necrosis predicted shorter overall and relapse-free survival in patients with operable (P&amp;lt;0.001 and P = 0.007, respectively) and stage I (P = 0.003 and P = 0.03, respectively) lung adenocarcinomas. Conclusions Our study showed that tumor necrosis served as a prognostic predictor in operable and stage I lung adenocarcinomas. The findings supported the results from previous pure pathological studies. Citation Format: Pei-Ying Lin, Tzu-Hung Hsiao, Pan-Chyr Yang. Tumor necrosis serves as a prognostic predictor in operable and stage I lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5030.
Abstract 774: Proteogenomic characterization of high-grade serous ovarian cancer
Authors: Jason E. McDermott, Samuel Payne, Debjit Ray, Vladislav Petyuk, Ronald Moore, Marina Gritsenko, Richard Smith, Karin Rodland
Journal: Cancer Research (2016)

Abstract High grade serous ovarian carcinoma (HGSOC) is a highly lethal gynecological malignancy, in large part because most patients develop resistance to the standard of care chemotherapy with platinum and taxanes. We performed deep proteomic and phosphoproteomic characterization on ovarian high-grade serous carcinomas (HGSC) previously characterized genomically by the The Cancer Genome Atlas (TCGA) as part of the Clinical Proteomic Tumor Analysis Consortium (CPTAC; http://proteomics.cancer.gov/programs/cptacnetwork). We constructed an integrated proteogenomic landscape of HGSC and identified functional modules statistically associated with outcomes including platinum resistance and overall survival. Integration of genomic data such as copy number alterations (CNA) with global protein abundance data revealed several chromosomal regions that have significant trans effects on protein expression. These genetically affected proteins were used to construct statistical models capable of predicting survival outcomes. Trans-affected proteins were enriched in proliferation, cell motility and invasion, and immune regulation, hallmarks of cancer. We used statistical methods to identify functional pathways able to discriminate between short surviving and long surviving patients. We found that protein abundance and phosphorylation indicated pathway activity that was able to clearly discriminate between these two groups, but that transcriptional expression and CNAs were not. We integrated proteomic abundance and phosphorylation state to elucidate specific signaling interactions and pathways differentially active in tumors from patients with short overall survival as well as to predict novel kinase substrate relationships important in HGSC. Finally, we identified druggable pathways that are differentially active across proteomic subtypes. A key point arising from our multimodal analysis is that combining different types of molecular data from these tumors greatly increases the ability to identify biologically relevant differences between groups. Using a Lasso-based regression approach to integrate data we show that the most robustly predictive survival models can be obtained using integrated CNA, transcriptome, proteome, and phosphoproteome data than with any of the individual sources of data. Citation Format: Jason E. McDermott, Samuel Payne, Debjit Ray, Vladislav Petyuk, Ronald Moore, Marina Gritsenko, Richard Smith, Karin Rodland. Proteogenomic characterization of high-grade serous ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 774.
Abstract 1216: Assays for the selection and functional characterization of antibody-drug conjugates at the National Research Council of Canada
Authors: Maria L. Jaramillo, Luc Meury, Normand Jolicoeur, Myriam Banville, Limei Tao, Maureen O’Connor McCourt.
Journal: Cancer Research (2016)

Abstract One of the most promising and fastest growing classes of cancer therapeutics builds on the molecular targeting abilities of antibodies by combining them with drugs to generate highly specific antibody-drug conjugates (ADCs). However, the development of ADCs requires time-consuming selection of the antibody for every target and cancer type. Screening technologies based on the use of conjugated secondary antibodies provide a fast and efficient surrogate assay from which to identify which antibodies are best internalized and suitable for immunoconjugate development into ADCs. As part of its integrated antibody development initiative, NRC has isolated and characterized anti- mouse Fc and anti-human Fc monoclonal antibodies to serve as very selective detective reagents for various IgG isoforms. We have shown that these secondary antibodies are species specific, selective and of high affinity. Furthermore, they exhibit high specific potency and low background toxicity after conjugating them to drugs (DM1, MMAE) or immunotoxins(saporin) in cell viability studies. By combining this methodology with our proprietary mRNA and DNA expression database for the selection of appropriate cell lines, we plan on screening thousands of NRC antibodies generated against variety of cancer associated cell surface targets for ADC development. In addition to secondary conjugate cytotoxicity assays, we have developed a suite of assays based on cellular accumulation, endosomal routing and activation (intracellular drug release) of antibody drug conjugates. These assays can all contribute to our mechanistic understanding of ADCs under development. Combined with our strength in biologic production and characterization, this expertise promotes the integration and advancement of NRC's capabilities and strengths in the area of Antibody-Drug Conjugates (ADCs), and can be used to establish strategic collaborations with other Canadian or international partners to develop external or internal NRC antibodies into novel ADC biologics. Citation Format: Maria L. Jaramillo, Luc Meury, Normand Jolicoeur, Myriam Banville, Limei Tao, Maureen O’Connor McCourt. Assays for the selection and functional characterization of antibody-drug conjugates at the National Research Council of Canada. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1216.
Vincristine (V) and irinotecan (CPT): A highly active combination in metastatic rhabdomyosarcoma. A report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group (STSCOG)
Authors: A. S. Pappo, E. Lyden, P. Breitfeld, S. Donaldson, J. Anderson, S. Qualman, E. Wiener, K. Crews, P. Houghton, W. Meyer
Journal: Journal of Clinical Oncology (2005)

8509 Background: Children with metastatic RMS continue to fare poorly and new agents are needed. CPT is active in pediatric RMS xenografts when given in protracted schedules (JCO 17:1815, 1999). A previous study from the STSCOG demonstrated the activity of CPT, however a high progression rate (30%) precluded further development of this agent (ASCO 2002). Preclinical data suggests that the combination of V and camptothecins is synergistic (Clin Ca Res 5:3617, 1999). Methods: We tested this combination (V; 1.5mg/m2 weekly weeks 0,1), CPT (20mg/m2/dailyx5 weeks 0,1) in untreated pts with metastatic RMS. Pts with embryonal tumors < 10 yrs, those requiring day 0 radiotherapy, and those refusing window treatment received VAC [Vincristine (V;1.5mg/m2), actinomycin D (A;1.5mg/m2) and cyclophosphamide (C; 2.2 g/m2)]. After 2 V-CPT cycles, responders received V-CPT alternating with VAC; non-responders received VAC. Radiotherapy was delivered at week 15. Results: Median age of the 49 eligible pts was 14 yr (1–26 yr); 55% were male, 67% were white and most had extremity (40%) or retroperitoneal (15%) tumors. 86% had alveolar tumors, 52% had nodal disease, and 70% had ≥ 2 metastatic sites most commonly involving bone marrow (45%), bone (36%) and lung (34%) The CR/PR rate after 2 V-CPT cycles was 69% (95% CI 56%,82%) (see table below). The most common grade 3+ toxicities during the 2 V-CPT cycles were PRBC transfusion (35%), abdominal pain (22%), dehydration (22%), diarrhea (18%), neutropenia (16%), anemia (14%), and hyponatremia (12%). The CR/PR/PD rates of V-CPT were superior to other topoisomerase I inhibitors window trials and similar to VAC. Conclusions: V-CPT is highly active in high risk pediatric RMS. The different toxicity profile and comparable CR/PR/PD rate to VAC strongly argues in favor of developing future RMS trials that incorporate this combination. No significant financial relationships to disclose.
Survival of patients (pts) with metastatic bladder cancer (MBC) in the past quarter century: Sobering results from the California Cancer Registry (CCR).
Authors: Primo Lara, Ann Brunson, Ralph deVere White, Marc A. Dall'Era, Christopher P. Evans, Stanley A Yap, Frederick J. Meyers, Chong-xian Pan
Journal: Journal of Clinical Oncology (2016)

e16033 Background: Pts with MBC are often offered chemotherapy (CT) as initial treatment. Although studies have shown that CT is associated with improved survival, it is unclear if this benefit has translated into the population-at -large and whether survival has improved over time. We sought to identify baseline factors including receipt of frontline CT & their influence on outcomes in MBC pts. Methods: Pts (n = 111,800) diagnosed (dx'd) with BC in California between 1988 and 2012 were identified. Of these, 4,470 with MBC (SEER “distant stage”) were included. Primary outcome measures: overall & cause-specific survival (OS & CSS). Uni-and multivariate Cox models for OS and CSS were constructed. Results: Most MBC pts were male (66.3%), > 69 years (54.6%), White (75.7%), dx'd in 2000-‘12 (60.2%), urban (93.5%), and of lower socioeconomic status (SES scale 1-3: 59.5%). Median OS and CSS: 5 & 7 months, respectively. Only 1,867 (42%) received frontline CT. Although pts receiving CT had improved outcomes, there was no OS or CSS improvement when diagnosis year was considered (1988-99 vs 2000-12; HR 1.05, p = 0.15). Conclusions: In this large database spanning ~25 years, only 42% of MBC pts received frontline CT. Although CT receipt was associated with a > 40% reduction in the risk of death, no apparent improvement in outcomes over time was seen, highlighting the need to develop more active systemic agents in this space. Multivariate Models Select Variables OS CSS HR 95%CI P- Value HR 95%CI P- Value Gender (vs. Male) Female 0.94 (0.88, 1.0) 0.09 0.96 (0.89, 1.0) 0.32 Age (5 year increments) 1.06 (1.05, 1.1) < 0.001 1.05 (1.0, 1.1) < 0.001 Race/Ethnicity (vs White) Black 0.97 (0.8, 1.1) 0.65 1.04 (0.9, 1.2) 0.63 Hispanic 0.87 (0.8, 1) 0.005 0.82 (0.7, 0.9) < 0.001 Asian 0.86 (0.8, 1) 0.03 0.80 (0.7, 0.9) 0.008 Diagnosis year (vs 1988- 99) 2000-12 1.06 (1, 1.1) 0.07 1.05 (0.98, 1.1) 0.15 Histology (vs Transitional cell) Other Histologies 1.15 (1.07, 1.24) < 0.001 1.10 (1.0, 1.2) 0.023 Chemotherapy (vs No) Yes 0.53 (0.5, 0.6) < 0.001 0.54 (0.5, 0.6) < 0.001 Location (vs Urban) Rural 0.99 (0.9, 1.1) 0.87 0.98 (0.8, 1.1) 0.77 SES [vs High (4, 5)] Low SES (1, 2, 3) 1.15 (1.1, 1.2) < 0.001 1.13 (1.0, 1.2) 0.001
Abstract 2876: The androgen receptor utilizes protein kinase docking sites to constitutively activate Elk1
Authors: Rayna Rosati, Mugdha Patki, Selvakumar Dakshnamurthy, Venkatesh Chari, Thomas McFall, Manohar Ratnam
Journal: Cancer Research (2016)

Abstract The ETS domain transcription factor Elk1 tethers the androgen receptor (AR) to chromatin, enabling sustained activation of a set of genes critical for growth in established prostate cancer cell lines. This process does not entail the transient hyper-activation of immediate early genes typical of activation of Elk1 through phosphorylation by ERK1/2. We compared the structural requirements for the association of AR and Elk1 with that for activation of Elk1 by phosphorylation using mammalian one- and two-hybrid assays. The critical polypeptide segments were mapped by systematic deletion mutagenesis. The amino-terminal A/B domain of AR, which lacks the ligand-binding domain (LBD), was adequate for association with Elk1 and to activate Elk1-AR target genes in LNCaP prostate cancer cells. The AR A/B domain also supported hormone-independent growth of LNCaP cells reflecting the ability of overexpressed natural splice variants of AR, which also lack LBD, to support prostate tumor growth. The association of AR with Elk1 was optimal in the absence of ERK1/2 and serum response factor (SRF), which are the known binding partners of Elk1. We identified two sites on Elk1 that are critical for its association with the AR A/B domain as well as the whole AR molecule. One of those sites spans amino acid residues 307 to 330, overlapping the D box, which is one of two ERK docking sites. The other site on Elk1 mapped to amino acid residues 372 to 397, overlapping the FXFP motif, which comprises the downstream ERK docking site. The results suggest that AR utilizes ERK docking sites to associate with Elk1 and is exclusive of the interaction of Elk1 with ERK1/2 or SRF. A nuclear receptor could thus function as a transcription factor co-activator by binding at protein kinase docking sites. Citation Format: Rayna Rosati, Mugdha Patki, Selvakumar Dakshnamurthy, Venkatesh Chari, Thomas McFall, Manohar Ratnam. The androgen receptor utilizes protein kinase docking sites to constitutively activate Elk1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2876.