bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3505: Development of robust copy number assays for tumor FFPE tissues.
Authors: Huw Ling-Yuh , Patel Rajesh , O'Brien Carol , Fu Ling , Raja Rajiv , Amler Lukas , Hampton Garret , Lackner Mark 
Published: August 2014

Abstract
Somatic copy number variations (CNVs) are frequently observed in cancer, likely a result high genomic and structural instability characteristic of cancer. CNVs have been shown to be important drivers for many oncogenic pathways and are associated with drug sensitivity and resistance. Therefore, these genetic alterations are valuable candidate biomarkers for patient stratification and predictors for therapeutic responses to targeted therapies. A fundamental challenge for copy number determination in tumor FFPE DNA is that the material is often degraded and modified by fixation, processing and storage. Here we present a PCR-based copy number assay utilizing target specific pre-amplification and a microfluidics detection system. 45 genes were selected based on literature and their potential relevance to therapeutic targets. This high-throughput platform showed excellent specificity and dynamic range from 1 to 100ng input genomic DNA. A panel of matched frozen and FFPE DNAs from cell lines were used for cross -validation with copy number identified by array CGH. A medium-center method is employed to calculate copy number and assess the extent of degradation in sample DNAs. To evaluate clinical utility of the technology, copy number alteration from a collection of matched primary and metastatic breast tumors as well as correlation between copy number changes and gene expression will be reported. We will also report results from a survey of other tumor types, including gastric cancer, mesothelioma, and HER2+ breast cancer.
Citation Format: Ling-Yuh Huw, Rajesh Patel, Carol O'Brien, Ling Fu, Rajiv Raja, Lukas Amler, Garret Hampton, Mark Lackner. Development of robust copy number assays for tumor FFPE tissues. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3505. doi:10.1158/1538-7445.AM2013-3505
Abstract 3510: Evaluation of PI3K Inhibitor chemosensitivity in human tumor explants using the Mosaic Blue assay and relationship to biomarkers by immunohistochemistry.
Authors: Dauffenbach Lisa , Cash Patricia A. , Sia Gela C. , Girees Sherif K. , Lim Ryan S. , Zheng Jianping , Olsen Eric P. , Kerfoot Christopher A. 
Published: August 2014

Abstract
The AKT protein family plays an important role in cellular survival by inhibiting apoptotic processes and is one of the major downstream targets of the phosphatidylinositol 3-kinase (PI3K) pathway. Mammalian target of rapamycin (mTOR) is a key kinase acting downstream of the activation of PI3K. Several chemotherapeutic agents target this pathway and are in clinical trials to treat patients with solid tumors. The use of chemosensitivity testing using human cancer explants is very useful in identifying biomarkers that relate to the intrinsic sensitivity of the tumor to a chemotherapetuic agent. The Mosaic Blue assay is a soft agar, ex vivo tumor response assay that utilized non-expanded patient cancer cells.
Human tumors with matched fresh tissue and formalin-fixed, paraffin embedded (FFPE) tissue were used for this study. Fresh tissues were disaggregated into single cells and exposed to various inhibitors of the PI3K pathway. Samples were classified as resistant or sensitive. The corresponding FFPE tissue block was stained by immunohistochemistry for several phosphorylated proteins, which included AKT, PRAS40, 4EBP1, S6 kinase, S6 ribosomal protein, and PTEN in accordance with validated protocols. Additional fresh cells were also treated with inhibitors, harvested, and phophorylated proteins were evaluated in the pre and post-dose tumor cells. Results were compared the chemosensitivity results and 2 relationships were identified. First, biomarker status of the archival tissue was evaluated in order to understand the intrinsic chemosensitivity. Second, biomarker status upon treatment was evaluated to understand modulation of proteins due to therapy.
In summary, use of soft agar ex vivo tumor response assays such as the Mosaic Blue assay is a useful tool to predict relative sensitivity across tumor types and allow investigation of potential biomarkers.
Citation Format: Lisa Dauffenbach, Patricia A. Cash, Gela C. Sia, Sherif K. Girees, Ryan S. Lim, Jianping Zheng, Eric P. Olsen, Christopher A. Kerfoot. Evaluation of PI3K Inhibitor chemosensitivity in human tumor explants using the Mosaic Blue assay and relationship to biomarkers by immunohistochemistry. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3510. doi:10.1158/1538-7445.AM2013-3510
Abstract 3514: A dose-escalation study of anastrozole and everolimus in patients with advanced gynecologic and breast malignancies: tolerance, biological activity, and molecular alterations in the PI3K/AKT/mTOR pathway.
Authors: Wheler Jennifer J. , Moulder Stacey L. , Naing Aung , Janku Filip , Piha-Paul Sarina A. , Falchook Gerald S. , Zinner Ralph , Tsimberidou Apostolia M. , Fu Siqing , Hong David S. , Atkins Johnique T. , Cronin Maureen , Yelensky Roman , Stephens Phil 
Published: August 2014

Abstract
Background
Combining aromatase inhibitors with PI3K/AKT/mTOR inhibitors is synergistic and may overcome hormone resistance.
Patients and Methods
We evaluated anastrozole and everolimus in patients with metastatic estrogen receptor (ER) and/or progesterone receptor (PR)-positive breast and gynecologic tumors. Endpoints were safety, antitumor activity and molecular correlates.
Results
Fifty-five patients were enrolled. Full doses of anastrozole (1 mg PO daily) and everolimus (10 mg PO daily) were well tolerated. Fifty patients were evaluable for response with a median age of 57 (range: 24-82) and a median number of prior therapies of 3 (range: 0-13). Twelve of 50 patients (24%) achieved stable disease (SD) ≥ 6 months/partial response (PR)/complete response (CR), including 9 of 32 patients (28%) with breast cancer, 2 of 9 patients (22%) with ovarian cancer and 1 of 6 patients (17%) with uterine cancer. Six of 8 patients (75%) with SD ≥ 6 months/PR/CR with molecular testing demonstrated at least one alteration in the PI3K/AKT/mTOR pathway including mutations in PIK3CA (n=3) and AKT1 (n=1) or PTEN loss (n=3). All 3 patients who had next generation sequencing demonstrated additional alterations: amplifications in CCNE1, IRS2, MCL1, CCND1, FGFR1 and MYC and a rearrangement in PRKDC. Six of 22 patients (27%) with molecular alterations in the PI3K/AKT/mTOR pathway achieved SD ≥ 6 months/PR/CR.
Conclusion
Combination anastrozole and everolimus is well tolerated at full approved doses and active in heavily pretreated patients with ER and/or PR-positive breast, ovarian and endometrial cancers. Patients with SD ≥ 6 months/PR/CR frequently had alterations in the PI3K/AKT/mTOR pathway.
Citation Format: Jennifer J. Wheler, Stacey L. Moulder, Aung Naing, Filip Janku, Sarina A. Piha-Paul, Gerald S. Falchook, Ralph Zinner, Apostolia M. Tsimberidou, Siqing Fu, David S. Hong, Johnique T. Atkins, Maureen Cronin, Roman Yelensky, Phil Stephens. A dose-escalation study of anastrozole and everolimus in patients with advanced gynecologic and breast malignancies: tolerance, biological activity, and molecular alterations in the PI3K/AKT/mTOR pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3514. doi:10.1158/1538-7445.AM2013-3514
Abstract 3515: Pathway convergent evolution underscores treatment response to MTOR inhibitors in kidney cancers.
Authors: Voss Martin H. , Hakimi A Ari , Pham Can G. , Brannon A Rose , Chen Ying-Bei , Cunha Luis F. , Akin Oguz , Liu Han , Takeda Shugaku , Scott Sasinya N. , Socci Nicholas D. , Viale Agnes , Schultz Nikolaus , Sander Chris , Reuter Victor E. , Russo Paul , Cheng Emily H. , Motzer Robert J. , Berger Michael F. , Hsieh James J. 
Published: August 2014

Abstract
Despite the established role of MTOR inhibitors (rapalogs) in treating advanced kidney cancer, therapeutic benefit varies and predictive biomarkers are lacking. Intratumor branching heterogeneity, a recently discovered hallmark of this disease, has raised concerns about the feasibility of developing genomic biomarkers for targeted agents in kidney cancer. We undertook an outlier approach to interrogate the genetic determinants underlying long-term therapeutic response (&gt;20 months) to rapalogs in 6 patients. An integrated ultra-deep targeted-exome (∼500x) and standard whole-exome (∼100x) sequencing was performed. Additionally, to address intratumor and intertumor heterogeneity, spatially separated tumor specimens from the same individuals were analyzed whenever possible. Multiregional sequencing unveiled surprising MTOR pathway convergent evolution, manifested by MTOR pathway activation by means of distinct genomic events in spatially separate sites of disease within the same individual. Amongst the core components of the MTORC1 pathway, complete functional loss of TSC1 and TSC2, and a hyperactive MTOR mutant were discovered in 4 of 6 long-term responders. Mutations in MTOR Clustered at FAT and kinase domains confer hyperactivity and yet remain sensitive to rapamycin. Here, we affirm intratumor heterogeneity, identify genomic determinants of drug response, and discover pathway convergent evolution in the majority of long-term responders. We propose a “river” model in which intratumor and intertumor clonal heterogeneity in cancer patients evolves like a branching river that converges at critical nodes. These convergent points provide unique opportunities for the treatment of genetically diverged yet functionally converged cancers in any given patient.
Citation Format: Martin H. Voss, A Ari Hakimi, Can G. Pham, A Rose Brannon, Ying-Bei Chen, Luis F. Cunha, Oguz Akin, Han Liu, Shugaku Takeda, Sasinya N. Scott, Nicholas D. Socci, Agnes Viale, Nikolaus Schultz, Chris Sander, Victor E. Reuter, Paul Russo, Emily H. Cheng, Robert J. Motzer, Michael F. Berger, James J. Hsieh. Pathway convergent evolution underscores treatment response to MTOR inhibitors in kidney cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3515. doi:10.1158/1538-7445.AM2013-3515
Abstract 3521: B7-H3 associated with tumor progression and epigenetic regulatory activity in cutaneous melanoma.
Authors: Wang Jinhua , Chong Kelly , Huang Sharon , Hoon Dave 
Published: August 2014

Abstract
B7-H3 is a transmembrane glycoprotein and a member of the B7/CD28 immunoglobulin superfamily which plays an important functional role in tumor surveillance by T-cells. High expression of B7-H3 has been related to a poor prognosis in some tumor types. Melanoma is the most aggressive form of skin cancer. B7-H3 expression was evaluated by RT-qPCR and IHC analysis on individual melanoma specimens and then verified in clinically annotated melanoma stage III and stage IV metastasis tissue microarrays(TMA) in a double blind study. B7-H3 mRNA expression was shown to be significantly increased with stage of melanoma(P&lt;0.0001) and significantly associated with melanoma-specific survival(MSS) in both stage III(P&lt;0.0001) and stage IV(P&lt;0.012) melanoma patients. B7-H3 expression was related to migration and invasion of melanoma cells; overexpression B7-H3 increased migration and invasion while knockdown of B7-H3 reduced cell migration and invasion. MiR-29c expression was shown to inversely regulate B7-H3. Furthermore, we demonstrated that B7-H3 expression was related to p-STAT3 expression in melanoma. These results suggest B7-H3 may be a useful biomarker for melanoma progression and patients’ outcome.
Citation Format: Jinhua Wang, Kelly Chong, Sharon Huang, Dave Hoon. B7-H3 associated with tumor progression and epigenetic regulatory activity in cutaneous melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3521. doi:10.1158/1538-7445.AM2013-3521
Abstract 3522: Vincristine activates c-Jun N-terminal kinase in chronic lymphocytic leukemia in vivo.
Authors: Bates Darcy JP , Danilov Alexey V. , Beaulieu Bernard B. , Lewis Lionel D. , Eastman Alan 
Published: August 2014

Abstract
Chronic lymphocytic leukemia (CLL) is a cancer of B cell lymphocytes whose survival depends on the anti-apoptotic activity of Bcl-2 family proteins. Due to the low growth fraction of CLL cells, drugs that kill during mitosis, such as the microtubule-targeting vinca alkaloids, are not expected to be effective. However, we have found that vincristine and vinblastine can act independently of mitosis and induce acute apoptosis in freshly isolated CLL cells. The mechanism of this effect still depends on destabilization of microtubules as similar events occur with combretastatin A4 which destabilizes microtubules through binding to a different site on tubulin.
Vinca-mediated apoptosis in CLL cells can be enhanced by addition of the cyclin-dependent kinase (CDK) inhibitor dinaciclib, killing cells acutely within 6 h. Dinaciclib functions by inhibiting CDK9, suppressing transcription and preventing expression of Mcl-1. The combination of dinaciclib and vinca alkaloids depends on vinca-induced phosphorylation of c-Jun N-terminal kinase (JNK). Therefore, we investigated whether JNK phosphorylation occurs in peripheral blood CLL cells in patients receiving vincristine. Patients received 2 mg vincristine intravenously by infusion over 5 minutes. Venous blood samples were obtained at time zero (pre-treatment) and post drug administration for up to 6 h. Patients then continued to receive chemotherapy treatment as prescribed by their primary oncologist. Pre-treatment CLL cells were studied ex vivo for JNK phosphorylation on exposure to vincristine. These studies showed that CLL cells phosphorylated JNK in response to clinically relevant concentrations of vincristine (10-50 nM). In the CLL cells from all 4 patients studied thus far, vincristine led to rapid (≤ 1 h) JNK phosphorylation which was sustained for 4-6
h post vincristine administration. These proof-of-principle study results provide justification for the development of a Phase I study to define the effect of the combination of vinca alkaloids and dinaciclib in patients with CLL.
Citation Format: Darcy JP Bates, Alexey V. Danilov, Bernard B. Beaulieu, Lionel D. Lewis, Alan Eastman. Vincristine activates c-Jun N-terminal kinase in chronic lymphocytic leukemia in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3522. doi:10.1158/1538-7445.AM2013-3522
Abstract 3525: Functional analysis of epidermal growth factor receptor tyrosine kinase inhibitors: A comparison of Afatanib, Lapatinib, and Gefitinib in human tumor primary cultures.
Authors: Nagourney Robert Alan , Bernard Paula J. , Federico Eric , Nguyen Sophie , Evans Steven S. 
Published: August 2014

Abstract
Introduction:
Targeting epidermal growth factor receptor (EGFr) tyrosine kinases has provided effective therapies for NSCLC, breast & GI cancers. However, secondary mutations can confer resistance. New multi-targeted and/or irreversible inhibitors (TKI's) may overcome these mechanisms. We used the ex vivo analysis of programmed death (EVA/PCD) to compare the activity of the irreversible EGFr TKI, BIBW 2992 (Afatanib) with Gefitinib and Lapatinib and examined downstream signals with inhibitors of MEK/ERK & PI3K/mTOR. Methods: Human tumor 1° culture microspheroids isolated from 54 individual-patient specimens obtained at surgery or aspiration were examined for EGFr-TKI induced programmed cell death, using morphologic & metabolic endpoints as previously described (Nagourney R, Curr. Treat Opt in Oncol., 2006). Lethal concentration 50% (LC50’s) interpolated from 5-point dose response curves were compared and drug correlations were conducted by Pearson-Moment. Results: BIBW activity favored upper GI, NSCLC and ovary over breast and colorectal cancer. In NSCLC, EGFr mutation (+) tumors were significantly more sensitive than wild type to BIBW (P &lt; .05). Patients relapsing after Erlotinib who carried T790M mutations remained BIBW sensitive despite Gefitinib resistance. BIBW activity correlated with Gefitinib (r = 0.35, P= 0.05) and the MEK/ERK inhibitor AZD 6244 (r = 0.43, P &lt; 0.05) and trended to correlation with Lapatinib, but did correlate with mTOR or mTOR/PI3K inhibitors, Everolimus & BEZ235. Of 3 patients treated with Afatanib, 2 of 3 showed benefit, 1 durable SD & 1 durable PR. Conclusions: BIBW reveals activity in several tumor types including NSCLC, GI and ovary. In NSCLC LC50’s significantly favor EGFr mutation (+) ‘s with favorable results in T790M(+) patients. Correlations with
AZD 6244 but not Everolimus or BEZ235, suggest MEK/ERK pathway to be the operative survival signal. EVA/PCD analysis in human tumor 1°cultures offers a platform to study novel strategies for EGFr-targeted therapies. Supported by the Vanguard Cancer Foundation & the Nagourney Institute.
Citation Format: Robert Alan Nagourney, Paula J. Bernard, Eric Federico, Sophie Nguyen, Steven S. Evans. Functional analysis of epidermal growth factor receptor tyrosine kinase inhibitors: A comparison of Afatanib, Lapatinib, and Gefitinib in human tumor primary cultures. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3525. doi:10.1158/1538-7445.AM2013-3525
Abstract 3537: Serum cobalamin level and clinical outcome in patients with acute myeloid leukemia.
Authors: Bai Li-Yuan , Chen Tzu-Ting , Li Long-Yuan , Chiu Chang-Fang 
Published: August 2014

Abstract
Introduction: An elevated concentration of serum cobalamin was found in one third of patients with acute myeloid leukemia; however, the clinical implication of elevated level of cobalamin in disease prognosis is not clear.
Procedures: We performed a retrospective analysis of the patients who were diagnosed to have de novo acute myeloid leukemia at China Medical University Hospital from January 2003 to December 2011. Two hundred and six patients were diagnosed as de novo acute myeloid leukemia, and thirty-four patients (16.5%) had been checked the level of serum cobalamin at diagnosis. Patients were divided into two groups, one with serum cobalamin level less than 400 pg/mL (n=10), the other with serum cobalamin level 400 pg/mL or higher (n=24). The clinical and cytogenetic characteristics between each group were compared.
Findings: There was no difference in gender, age and cytogenetic risk between the two groups. Nine of ten patients in lower serum cobalamin group and eighteen of twenty-four patients in higher serum cobalamin group received intensive chemotherapy for acute myeloid leukemia (p=0.315). The patients with lower serum cobalamin had a trend to obtain complete remission (80.0 % vs. 45.8 %, p=0.072). For patients who reached complete remission after chemotherapy, those in the higher cobalamin group had a trend to have more disease relapse (81.8% vs. 37.5%, p=0.067). Interestingly, the relapse-free survival time after complete remission was 42.5 m and 9.2 m for patients with lower and higher cobalamin, respectively (p=0.010). Furthermore, serum cobalamin level remained significant in the multivariate analysis of risk factors for relapse-free survival (p=0.028). The median overall survival time was 18.3 m and 7.2 m for patients with lower and higher cobalamin, respectively. However, the difference in overall survival between the two groups did not reach statistical significance (p=0.140). In multivariate analysis, intensive chemotherapy for AML was the most important factor for overall survival.
Conclusions: AML patients with higher serum level of cobalamin have a trend of worse response to chemotherapy, higher relapse rate and significantly shorter relapse-free survival time. Targeted therapy to interfere the cobalamin uptake or related pathways is worth of further investigation in treating patient with acute myeloid leukemia.
Citation Format: Li-Yuan Bai, Tzu-Ting Chen, Long-Yuan Li, Chang-Fang Chiu. Serum cobalamin level and clinical outcome in patients with acute myeloid leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3537. doi:10.1158/1538-7445.AM2013-3537
Abstract 3546: S-Glutathionylation of buccal mucosal cell proteins as biomarkers of oxidative stress.
Authors: Grek Christina L. , Manevich Yefim , Townsend Danyelle M. , Tew Kenneth D. 
Published: August 2014

Abstract
Many anticancer drugs produce reactive oxygen species (ROS) that directly or indirectly lead to toxicities. As a conduit to drug development we have identified S-glutathionylated (post-translational addition of glutathione to susceptible cysteine residues) serine proteinase inhibitors (serpin's A1 and A3) as plausible biomarkers for drug exposure in both rodent and human blood. Commercial mouthwashes often contain redox-altering agents such as hydrogen peroxide (H2O2) and/or ethanol. Oxidative damage in buccal mucosa cells is associated with etiology of oral cancers and we hypothesized that these cells may also serve to provide a surrogate tissue source for biomarker analysis to measure S-glutathionylated proteins. Using an approved clinical protocol for exfoliated buccal cell samples, we have identified a number of S-glutathionylated proteins, including actin, in samples from volunteers following standard treatments with a commercial mouthwash containing H2O2 (1.5%). Their identities are similar to those discovered using in vitro experiments with the human buccal cell line TR146. Our current data show a time and dose-dependent increase in S-glutathionylation of buccal cell sample profiles in normal volunteers following four days of exposure dosing to H2O2 containing mouthwash. Increases in protein S-glutathionylation occurred immediately following exposure and remained for 30min following treatments. Higher levels of S-glutathionylation were maintained with each subsequent daily exposure. These increased levels of S-glutathionylation preceded the transcriptional activation of ROS sensitive genes, incuding ATF3. The identification of biomarkers that evaluate the effects of oxidative stress in the oral cavity may define at-risk populations for oral cancer and may be useful as direct biomarkers for the impact of drugs on general redox status.
Citation Format: Christina L. Grek, Yefim Manevich, Danyelle M. Townsend, Kenneth D. Tew. S-Glutathionylation of buccal mucosal cell proteins as biomarkers of oxidative stress. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3546. doi:10.1158/1538-7445.AM2013-3546