tbuckley/cabot-search huggingface dataset:
Abstract 1561: Detection of colorectal cancer-associated genetic and epigenetic alterations in urine of patients with CRC
Authors: Adam Winfield Clemens, Selena Lin, Surbhi Jain, Ying-Hsiu Su, Wei Song
Journal: Cancer Research (2015)

Abstract Colorectal cancer (CRC) has been the second leading cause of cancer-related deaths due in part to a low compliance rate (&amp;lt;50%) of the current screening method, an invasive colonoscopy, resulting in failure of detecting cancer early in its curative stages. 20% of CRC cases are only detected once the cancer has spread to a distant site, drastically reducing the 5-year survival rate from 90% to 12%. In order to improve the success of early detection methods of CRC, we have focused on developing non-invasive, multi-biomarker detection assays designed to identify CRC-associated genetic alterations. We have previously demonstrated that urine contains circulation-derived low molecular weight (LMW) DNA (&amp;lt;300 bp), which suggests that LMW urine DNA could be used to detect CRC-associated genetic alterations. Using previously identified stool and serum-based biomarkers for CRC, we have developed a panel of potential CRC markers for early detection for use in a non-invasive urine DNA test. Our panel contains genetic mutations and epigenetic alterations of nine genes: mutations of KRAS codons 12/13 and BRAF V600E and aberrant hypermethylation of VIM, SEPT9, BMP3, NDRG4, CDKN2A, TFPI2, and MGMT. The proof-of-concept of a CRC urine DNA test was demonstrated in a small pilot study investigating mVIM as a biomarker for CRC in matched tissue-urine samples. This led to the development of a PCR-based approach to quantify these markers in a prevalidation study with blinded CRC samples to identify the specificity and sensitivity of these genetic mutations and epigenetic alterations. In a concordant study using this blinded CRC sample set, our panel of markers was used in an amplicon NGS-based study. Results from these two studies will be used to confirm the sensitivity and specificity of each marker for early detection of CRC. Citation Format: Adam Winfield Clemens, Selena Lin, Surbhi Jain, Ying-Hsiu Su, Wei Song. Detection of colorectal cancer-associated genetic and epigenetic alterations in urine of patients with CRC. [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 1561. doi:10.1158/1538-7445.AM2015-1561
Variation of p21, P-Gp Expression in K562/A02 Cell Line with Tetrandrine
Authors: Bao-An Chen, Jing Li, Jian Cheng, Feng Gao, Wen-lin Xu, Hui-lin Shen, Jia-hua Ding, Chong Gao, Yun-Yu Sun, Jun Wang, Gang Zhao, Hui-hui Song, Wen Bao, Xin-chen Sun, Hong-yan Cheng, Yu-xia Deng, Guo-hong Li, Li-jie Liu, Wen-ji Chen, Jue-qiong Wang, Peng Yuan, Xiao-ping Pei, Ning-na Chen, Xue-mei Wang, Min-sheng Zhu
Journal: Blood (2008)
A global, multicenter phase II trial of lapatinib plus capecitabine in gastric cancer.
Authors: M. Pishvaian, D. Sakaeva, R. K. Hsieh, S. Y. Rha, G. Caderillo-Ruiz, W. H. Miller, A. M. Kemner, Y. M. Nagarwala, W. Zhang, H. Lenz
Journal: Journal of Clinical Oncology (2011)

88 Background: Advanced gastric cancer (GC) is an incurable disease. HER2 overexpression has been reportedin 6%–35% of gastric and gastroesophageal tumors, whereas the EGFR is upregulated in about 18%–28%. Clinical studies confirm that targeting HER2 in combination with chemotherapy is an effective strategy, achieving a median survival of ∼13.5 mos. Lapatinib, a dual tyrosine kinase inhibitor of HER2 and the EGFR, inhibits tumor growth and modulates expression of fluoropyrimidine-targeting genes. LPT109747 is an international, multicenter phase II study investigating the combination of lapatinib + capecitabine in patients with advanced gastric or gastroesophageal junction adenocarcinoma. Methods: Primary endpoints of the study included clinical response rate, 5 mo PFS and mRNA and protein expression levels of genes involved in the 5-FU and HER2 pathway. HER2 overexpression was not required at study entry. Oral lapatinib was administered (1,250 mg/d, continuously) during a monotherapy run-in period (day -7 to 0) and in combination with oral capecitabine (1,000 mg/m 2 BID, 14 of 21 days). Patients were treated until disease progression (PD) or study withdrawal. Biopsies were performed on days -7 and 0. Safety was assessed every 3 weeks and response every 6 weeks by RECIST. Results: Sixty-seven patients were included in the current analysis: 25% female, 75% male; 51% Caucasian, 45% Asian; median age 60 y (range: 22-89 y); 75% GC, 25% GEJ. All 67 patients were evaluable for response. The overall response rate was 22.4% (16.4% confirmed). 45% of patients had stable disease, and 24% had PD. No complete responses were observed. PD or death at &lt; 5 mo was 63%. At the time of data cut off, PFS at 5 mo was 28.4% (17.3%–40.5%); median follow up was 26.4 weeks (CI: 22.1; 55.9); 39% of patients remain in follow up. Most frequent grade 3/4 events were anemia (13%), hand-foot syndrome (12%), decreased appetite (10%), and nausea (9%). Conclusions: The combination of lapatinib + capecitabine shows promising efficacy and is well tolerated as 1st line treatment for advanced GC. An analysis of biomarker data may help identify who may benefit most from this regimen. [Table: see text]
220. Evaluation of the Efficacy of a New Oncolytic Vaccine Platform in Humanized Mice
Authors: Cristian Capasso, Mari Hirvinen, Mariangela Garofalo, Dmitrii Romaniuk, Lukasz Kuryk, Teea Sarvela, Andrea Vitale, Tapani Viitala, Maxim Antopolsky, Arto Urtti, Vincenzo Cerullo
Journal: Molecular Therapy (2015)

Cancer immunotherapy represents a promising approach for the treatment of malignancies. However, breaking the immunosuppressive micro-environment is still a difficult but necessary condition to improve modern therapies. Oncolytic Adenoviruses (OAds) are able to elicit some degree of anti-tumor response and we are now investigating how OAds can be turned in novel cancer-vaccine platforms by exploiting their natural immunogenicity. The key feature of our peptide-coated conditionally-replicating adenoviruses (PeptiCRAd) is the physical conjugation of the adjuvant (i.e. OAds) to the tumor epitopes, in order to achieve a better co-delivery to antigen presenting cells (APCs). We coated the negatively charged OAds with a positive lysine-extended version of the major histocompatibility complex (MHC) class-I model epitope SIINFEKL (polyK-SIIN), and we observed no significant changes in the oncolytic activity compared to naked viruses. Then, we confirmed the cross presentation on MHC-I of the modified polyK-SIIN in absence or presence of the virus. Afterwards, using B16-OVA tumor-bearing immunecompetent mice, we compared the administration of polyK-SIIN-coated OAds (PeptiCRAd) to the administration of an OAds-SIINFEKL mix solution. Mice treated with PeptiCRAd showed smaller tumor volumes and higher levels of OVA-specific CD8+ T-lymphocytes compared to all control groups. Interestingly, we observed a strong (negative) correlation between the size of the tumors and the anti-OVA immune response. Moreover, we evaluated whether or not the different activation of dendritic cells (DCs) could explain the advantage of PeptiCRAd over the OAds-SIINFEKL mix: consistent with our hypothesis, PeptiCRAd promoted the expansion of mature (CD86+) and SIINFEKL-cross presenting CD11c+ DCs. Then we tested our PeptiCRAd technology using a multipeptide vaccine approach to evaluate if a broader targeting could improve the anti-tumor immune response. In addition, by monitoring the effect of the treatment on uninjected tumors we were also able to assess the effect of PeptiCRAd on metastasis. Finally, to collect human-relevant data, PeptiCrad efficacy, specificity and immunogenicity were assessed in humanized mice bearing implanted human melanomas.
Abstract 3333: The expression of FKTN gene in gastric cancer related to radiation exposure: research on atomic bomb survivors
Authors: Trang T.B. Pham
Journal: Cancer Research (2015)

Abstract While radiation use increases, the Life Span Study (LSS) atomic bomb survivor cohort of Radiation Effects Reserach Foundation (RERF) from 1951-2003 shows a significant cancer risk for most major organs in the body, including stomach. To identify genes associated with gastric cancer, we utilize Escherichia coli ampicillin secretion trap (CAST) method, which is a powerful tool for novel cancer biomarkers. By this method, we found that FKTN (fukutin) was overexpressed in gastric cancer. Fukutin localizes to the Golgi apparatus and normally has low expression, but overexpresses in some cell lines. It is thought to forms a complex with protein POMGnT1, a glycosyltransferase involved in the synthesis of O-mannosyl glycan attached to mucin-like domain of alpha-dystroglycan. The POMGnT1 activity was also downregulated by fukutin mutation and resulted in Fukuyama congenital muscular dystrophy: brain malformation, one of the most common autosomal-recessive disorders in Japan. To elucidate the molecular mechanisms of radiation carcinogenesis, we analyzed FKTN expression from sporadic gastric cancer cohort and LSS cohort by immunohistochemistry. In the sporadic cohort of 695 gastric cancer samples, there was a significant correlation of FKTN expression in differentiated type gastric cancer. For mucin markers, a significant relationship was detected between FKTN and CD10 (p&amp;lt;0.0001). The LSS cohort of 86 gastric cancer samples showed FTKN expression downregulated in high-dose than in low-dose exposed patients (p&amp;lt;0.0001), but with no correlation between FKTN and mucin phenotype expression. This is the first analysis on the expression of fukutin protein in gastric cancers among atomic-bomb survivors and the radiation dose response, using immunohistochemistry. These results suggest that FTKN has a possible relationship with radiation exposure and gastric cancer among atomic bomb survivors. Citation Format: Trang T.B. Pham. The expression of FKTN gene in gastric cancer related to radiation exposure: research on atomic bomb survivors. [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 3333. doi:10.1158/1538-7445.AM2015-3333
Abstract 1658: Proteolytic processing pathways for topoisomerase covalent complexes
Authors: Yilun Sun, Karin C. Nitiss, John L. Nitiss
Journal: Cancer Research (2015)

Abstract DNA topoisomerase II (Top2) is the target of several important anti-cancer agents, including doxorubicin and etoposide. Clinically active Top2 agents, termed Top2 poisons, act by blocking the enzyme reaction at a step where the protein is covalently bound to DNA. This leads to the accumulation of Top2/DNA complexes that act as DNA damaging agents that can trigger cell death. Surviving Top2-induced damage likely requires the repair of the enzyme induced damage and has been hypothesized to include pathways that proteolyze the protein bound to DNA followed by nucleolytic removal of the remaining peptide that is bound to DNA by a phosphotyrosyl linkage. This model of repair suggests that inhibition of proteolysis would lead to elevated levels of intact Top2/DNA complexes, and increased sensitivity to Top2 poisons such as etoposide. We have tested this model using the proteasome inhibitor carfilzomib in a pediatric rhabdomyosarcoma cell line (Rh30). We found that carfilzomib enhanced cell killing by etoposide, and that co-treatment of Rh30 cells with carfilzomib led to increases in both Top2 alpha and Top2 beta covalent complexes. These results suggest that proteasomal degradation of both Top2 isoforms is important for repairing DNA damage arising from etoposide. We are also interested in identifying the determinants of Top2 degradation following treatment with etoposide, especially proteins that recognize the trapped enzyme as DNA damage. We used a yeast genetic model system to address this question. We showed that the proteasome inhibitor MG132 greatly enhanced the sensitivity of yeast cells to etoposide, and that co-treatment of MG132 and etoposide led to elevated levels of Top2/DNA complexes compared to etoposide alone. We found that deletion of the human RNF4 homolog Slx5/Slx8 (a SUMO dependent ubiquitin ligase) also leads to an increase in Top2 covalent complexes induced by etoposide. We found that deletion of the genes encoding either Slx5 or Slx8 along with the repair protein Tdp1 led to much higher levels of cell killing compared to single deletions. These results suggest that there are at least two independent pathways for repairing Top2 damage, one dependent on Slx5/Slx8 dependent protein degradation and a second pathway dependent on nucleolytic removal of Top2. We suggest that Slx5/Slx8 plays a role in targeting Top2 for degradation following etoposide treatment. Our results also provide a rationale for the combination of a proteasome inhibitor with etoposide as an approach of increasing the efficacy of etoposide. Citation Format: Yilun Sun, Karin C. Nitiss, John L. Nitiss. Proteolytic processing pathways for topoisomerase covalent complexes. [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 1658. doi:10.1158/1538-7445.AM2015-1658
Genetics of Patients with F-Refractory CLL or Early Relapse After FC or FCR: Results From the CLL8 Trial of the GCLLSG
Authors: Thorsten Zenz, Raymonde Busch, Anna Fink, Dirk Winkler, Kirsten Fischer, Andreas Bühler, Patrick Hoth, Gunter R. Fingerle-Rowson, Michael Kneba, Sebastian Boettcher, Ulrich Jäger, Myriam Mendila, Michael Wenger, Peter Lichter, Michael Hallek, Hartmut Döhner, Stephan Stilgenbauer
Journal: Blood (2010)
Abstract 4485: Anticancer effect of platinum(IV) complex against cisplatin-resistant human ovarian cancer
Authors: Yoshinori Okamoto, Takao Tobe, Koji Ueda, Nakao Kojima
Journal: Cancer Research (2015)

Abstract Background: Platinum(IV) [Pt(IV)] complexes are one of the attractive next-generation anticancer drugs. Beside Pt(II)-based drugs such as cisplatin, carboplatin, and oxaliplatin, Pt(IV) complexes show less adverse effects and can be administrated orally. In addition, because Pt(IV) complexes adopt octahedral coordination geometry, it also have an advantage that can be coordinated with more functional ligands than Pt(II) complexes. These different features prompted us to investigate the effectiveness of Pt(IV) complexes on cisplatin-resistant cancer cells with its mechanisms. This study aims to elucidate the anti-cancer effects of Pt(IV) complexes. Materials and Methods: The cytotoxicity of cis-diammine-tetrachloro-Pt(IV) [cis-Pt(IV)] and cisplatin was determined using human ovarian cancer cell lines (A2780), and its cisplatin-resistant subline (A2780cis), with their influx/efflux patterns using ICP-MS. Pt-DNA-crosslink formation was also determined by agarose gel electrophoresis, in which the crosslink was quantified by decrease of ethidium bromide staining of DNA. Results and Discussion: Cisplatin completely failed to decrease the survival of A2780cis cells at a concentration that killed A2780, whereas cis-Pt(IV) exerted cytotoxicity in both cell lines. Pt-DNA-crosslink formation assay showed cis-Pt(IV) bound to DNA only in the presence of reductant such as glutathione (GSH) or ascorbic acid, indicating cisplatin production. However, it is also known excess amount of GSH suppress DNA binding of cisplatin. Indeed, intracellular GSH level in A2780cis cells was about 3 times higher as compared with A2780 cells; therefore cisplatin would be inactivated in A2780cis cells. These findings suggest that cis-Pt(IV) is actually reduced to cisplatin in GSH-rich environment and then induce cytotoxicity by somehow escaping from GSH-dependent inactivation. Pt(IV)-specific subcellular distribution might contribute this paradoxical advantageous effect of GSH on cis-Pt(IV). Intracellular accumulation of Pt was reduced by competing a related transporter CTR1 by copper in cis-Pt(IV) treatment, whereas cytotoxicity was not suppressed. Therefore CTR1 is involved in the intake of Pt complexes including cis-Pt(IV), but the alternative pathway(s) could be responsible for anti-cancer effect of Pt(IV) complexes. Citation Format: Yoshinori Okamoto, Takao Tobe, Koji Ueda, Nakao Kojima. Anticancer effect of platinum(IV) complex against cisplatin-resistant human ovarian cancer. [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 4485. doi:10.1158/1538-7445.AM2015-4485
Chromosomal damage in LDsers
Authors: J. Egozcue
Journal: JAMA (1968)

An increase of chromosomal abnormalities was found in leukocytes of LSD users compared to drug-free controls. Elevated breakage rates were also found in children exposed to the drug in utero. The data showed no correlation between amount of drug per dose, number of doses, or total dosage and frequency of chromosomal breaks.
The potential predictive role of nuclear NHERF1 expression in advanced gastric cancer patients treated with epirubicin/oxaliplatin/capecitabine first line chemotherapy
Authors: A. Mangia, G. Simone, S. Dell'Endice, E. Scarpi, L. Saragoni, M. Monti, D. Santini, O. Brunetti, N. Silvestris
Journal: Annals of Oncology (2015)
Hodgkin lymphoma: Use of modern combined modality therapy and its effect on the risk of second malignancies: The M. D. Anderson Experience over five decades.
Authors: P. Allen, B. S. Dabaja, F. D. Shihadeh, P. Nickerson, L. K. Ballas
Journal: Journal of Clinical Oncology (2011)

e18529 Background: The treatment of Hodgkin’s Lymphoma has radically changed over the past five decades. The change involved the type and number of cycles of chemotherapy; as well as the dose, fields, and techniques of radiation therapy. We here report on the change of incidence of second malignancies with the use of modern therapy. Methods: The medical record of 1671 patients diagnosed with Hodgkin’s lymphoma between June 1956 and June 2009 was reviewed. The subjects of this study are 949 patients with available follow-up information. Using logistic regression analysis we have looked at the correlation between the following factors and the risk for second malignancy: Age at diagnosis (<30, 30-50, and >50 years), Gender, stage at diagnosis (early favorable, early unfavorable, and advanced), type of chemotherapy (MOPP containing versus none), type of field of radiation used (involved fields, mantle, or extended), The use of three dimensional radiation modality, era of diagnosis by decades (<1995 versus > 1995), and relapse. Results: In univariate analysis The incidence of developing second malignancy was significantly associated with younger age at diagnosis (<30 years) (p=0.0001), the use of MOPP containing chemotherapy (p=0.004), the use of non modern radiotherapy techniques (p=0.01), patients who relapsed (p=0.0001), patients who were treated before 1995 (p=0.0001). On multivariate analysis factors that kept their significance includes: the use of MOPP containing chemotherapy (p0.0001), the use of outdate non modern radiotherapy techniques (p=0.001), patients treated before 1995, patients younger than 30 years of age at diagnosis (p=0.0001), number of radiation courses for relapsed patients (p=0.0001), and radiation dose of > 36 Gy (0.041). Conclusions: Modern therapy (standard after 1995 at our institution) represented by the use of non-MOPP chemotherapy, and modern techniques and lower doses of radiation is associated with a significant decrease of the risk of second malignancy.
Inhibition of Fatty Acid Oxidation with Avocatin B Selectively Targets AML Cells and Leukemia Stem Cells
Authors: Eric A Lee, Leonard Angka, Sarah-Grace Rota, Thomas Hanlon, Rose Hurren, Xiao Ming Wang, Marcela Gronda, Dannie Bernard, Mark D. Minden, Andrew Mitchell, Andrea Edginton, Shrivani Sriskanthadevan, Alessandro Datti, Jeff Wrana, Jamie W Joseph, Joe Quadrilatero, Aaron D. Schimmer, Paul A Spagnuolo
Journal: Blood (2014)
Tumor suppressor effects for miR-215 identified through use of miRNA profiling in metastatic renal cell carcinoma.
Authors: Georg A. Bjarnason, Nicole MA White, Heba WZ Khella, Joerg Grigull, Sonja Adzovic, Youssef M. Youssef, R. John Honey, Robert Stewart, Kenneth T Pace, Michael A Jewett, Andrew Evans, Manal Gabril, George M. Yousef
Journal: Journal of Clinical Oncology (2012)

392 Background: Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. Metastatic RCC is difficult to treat. The five-year survival rate for metastatic RCC is &lt;10%. Recently, microRNAs (miRNAs) have been shown to have a role in cancer metastasis and potential as prognostic biomarkers in cancer. Methods: We preformed a miRNA microarray to identify a miRNA signature characteristic of metastatic compared to primary RCC. Results were validated by quantitative real time PCR. Target prediction analysis and gene expression profiling identified many of the dysregulated miRNAs could target genes involved in tumor metastasis. The effect of miR-215 on cellular migration and invasion was shown in a RCC cell line model. Results: We identified 65 miRNAs that were significantly altered in metastatic when compared to primary RCC. Nine (14%) miRNAs had increased expression while 56 (86%) miRNAs showed decreased expression. miR-10b, miR-196a, and miR-27b were the most downregulated while miR-638, miR-1915, and miR-149* were the most upregulated. A non-supervised 2D-cluster analysis showed that a sub-group of the primary tumors clustered under the metastatic arm with a group of miRNAs that follow the same pattern of expression suggesting they have an inherited aggressive signature. We validated our results by examining the expressions of miR-10b, miR-126, miR-196a, miR-204, and miR-215, in two independent cohorts of patients. We also showed that overexpression of miR-215 decreased cellular migration and invasion in a RCC cell line model. In addition, through gene expression profiling, we identified direct and indirect targets of miR-215 that can contribute to tumor metastasis. Conclusions: Our analysis showed that miRNAs are altered in metastatic RCC and can contribute to kidney cancer metastasis through different biological processes. Dysregulated miRNAs represent potential prognostic biomarkers and may have therapeutic applications in kidney cancer.