tbuckley/cabot-search huggingface dataset:
Abstract 2627: Molecular analyses of histopathologic morphologic features in breast cancer
Authors: Yu Jing Jan Heng, Jong Cheol Jeong, Deena M.A Gendoo, Benjamin Haibe-Kains, Giovanni Ciriello, Katherine A. Hoadley, Charles M. Perou, Andrew H. Beck
Journal: Cancer Research (2016)

Abstract Traditional histopathologic analysis of breast cancer phenotypes has played a central role in the diagnosis, prognosis and clinical management of breast cancer. This study integrated molecular data with breast cancer histopathologic annotations to elucidate the molecular basis of these common morphologic features. We constructed a large, comprehensive histopathologic database of 850 invasive breast cancer cases from The Cancer Genome Atlas (TCGA). We integrated the consensus assessments of 11 morphologic features (nuclear pleomorphism, mitotic count, epithelial tubule formation, inflammation, DCIS, LCIS, lymphovascular invasion, necrosis, fibrotic focus, apocrine features and proportion of epithelium in invasive portion by area) with TCGA's genomic, transcriptomic and proteomic data. Using this highly annotated dataset, we identified molecular profiles associated with morphologic features, constructed Omics-based multivariate models to predict morphologic features and provided insights into their molecular etiology. The association of morphologic features’ signatures with survival in ER-positive and ER-negative breast cancer was assessed using six independent datasets. All data are publicly accessible at http://pathology.ai/tcga_breast. Morphologic features were associated with PAM50 subtypes, PAM50 proliferation scores, genomic alterations and gene expression (p&amp;lt;0.05). Clustering of morphologic features and genomic alterations produced two clusters of morphologic features and their separate were driven by TP53, CDH1 and PIK3CA mutations and chr12p13.3, ch8q24.21 and chr3q26.3 amplifications. The clustering of morphologic features and gene sets/pathways also produced two clusters of morphologic features characterized by “proliferation” or “inflammation”. The transcriptomic signatures of nuclear pleomorphism and epithelial tubule formation were independently prognostic in ER-positive breast cancer. No signatures were prognostic in ER-negative. Our detailed morphologic data enrich and complement TCGA's existing molecular data, increase our understanding of the molecular basis of breast cancer pathologic phenotypes, can facilitate the refinement of breast cancer classification, and enhance our understanding of breast cancer biology. Citation Format: Yu Jing Jan Heng, TCGA Breast Cancer Expert Pathology Committee, Jong Cheol Jeong, Deena M.A Gendoo, Benjamin Haibe-Kains, Giovanni Ciriello, Katherine A. Hoadley, Charles M. Perou, Andrew H. Beck. Molecular analyses of histopathologic morphologic features in breast 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 2627.
Measurement of Individual p53-Specific Damage Formation and Repair Following In Vitro Exposure of Peripheral Mononuclear Cells to Melphalan May Predict Clinical Outcome in Patients with Multiple Myeloma (MM) Subsequently Treated with High Dose Melphalan (HDM) and Autologous Blood Stem Cell Transplantation (ASCT).
Authors: Meletios A. Dimopoulos, V. L. Souliotis, A. Anagnostopoulos, A. Pouli, I. Baltadakis, E. Terpos, Petros P. Sfikakis
Journal: Blood (2005)
Abstract 4416: Combination of HSP90 and proteasome inhibitor is effective in pancreatic cancer
Authors: Ganji Purnachandra Nagaraju, Balney Rajitha, Leah Benton, Bassel F. El-Rayes
Journal: Cancer Research (2016)

Abstract Background: Heat shock protein (HSP90) and proteasome play an important role in cellular protein trafficking and degradation in pancreatic cancer (PC). Given the overlap in the mechanism of action, we investigated the effects of the combination of pharmacological inhibitors of HSP90 (Ganetespib) and proteasome (Carfilzomib) on PC cells in vitro and in vivo. Methods: The combined effects of ganetespib and carfilzomib were evaluated in MIA PaCa-2 and HPAC cell lines using a cell proliferation assay. Effects on the expression of survival (PI3K/AKT, and ERK), cell cycle (Cdc-2 and cyclin B1), angiogenesis (HIF-1α and VEGF) and autophagy (LC3 A/B, and Atg7) pathways were examined by Western blot. Cell cycle analysis was performed by FACS assay. HPAC cell lines were tested for efficacy to ganetespib, carfilzomib, alone and in combination, using an in vivo tumor xenograft model. Results: The combination of ganetespib and carfilzomib significantly decreased cell proliferation, induced G2-M cell cycle arrest and induced autophagy in both MIA PaCa-2 and HPAC cell lines. Ganetespib and carfilzomib also decreased the activation of ERK, PI3K/AKT, and autophagy signaling molecules (LC3 A/B, and Atg7). In animal models, ganetespib potentiated the effects of carfilzomib, as measured by tumor volume. Western blot analysis from tumors removed from animals confirmed the effects of ganetespib and carfilzomib on survival, cell cycle, autophagy and angiogenesis. Conclusion: These observations provide preclinical proof-of-principle that combinatorial targeting of HSP90 and proteasome is a rational approach for development in PC clinical trials. Citation Format: Ganji Purnachandra Nagaraju, Balney Rajitha, Leah Benton, Bassel F. El-Rayes. Combination of HSP90 and proteasome inhibitor is effective in pancreatic 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 4416.
Abstract 2287: Final results of the pharmacodynamic (PD) data of PQR309-001, a first-in-human trial of a combined PI3K/mTOR inhibitor in advanced solid tumors
Authors: Andreas Wicki, Vincent Prêtre, Reto Ritschard, Nicholas Brown, Vincent Bize, Thomas Fabbro, Natasa Cmiljanovic, Sasa Dimitrijevic, Deborah Schmitz, Michael Stumm, Rebecca Kristeleit
Journal: Cancer Research (2016)

Abstract Background: PQR309 is a novel, oral, balanced pan-class 1 PI3K, mTORC1 and mTORC2 inhibitor. PQR309-001 was a first-in-man dose escalation study evaluating PQR309 in patients with advanced solid tumours. The primary objective of the study was to establish the maximum tolerated dose (MTD) of PQR309, its safety and tolerability. Secondary objectives included characterization of PQR309 pharmacokinetics (PK) and pharmacodynamics (PD). Methods: We investigated PQR309 treatment-induced PD, including changes of 16 PI3K-mTOR and MAPK associated phospho-proteins, and 84 mRNAs in serial tumor biopsies obtained from patients enrolled in study PQR309-001. 13 patients were eligible for PD analysis after histologic evaluation of fresh-frozen tissue. A solid-phase assay with phospho-specific antibodies was used for the investigation of PI3K/mTOR and MAPK signalling. RNA analysis was performed with an RTK/PI3K-specific RNA array. Results: Under treatment with PQR309, phospho-Akt (p_T308 and p_S473), phospho-mTOR and phospho-S6 were significantly downregulated compared to baseline (p&amp;lt;0.05, Wilcoxon signed-rank test). Moreover, patients with radiographic tumor shrinkage (n = 7) had significantly stronger phospho-Akt (p_T308), phospho-mTOR and phospho-S6 reduction than patients whose tumor was growing (n = 6) (p&amp;lt;0.05, Mann-Whitney test). Importantly, ERK1/2 phosphorylation, as the readout of MAPK activity, was decreased overall with no statistically significant difference between shrinking and growing tumors. The analysis of mRNAs showed a trend towards upregulation of PDGFRA (3.2 times, not statistically significant) after 21 days of therapy with PQR309. Intriguingly, no consistent changes of other PI3K-related RNAs was observed. Conclusion: PD assessments in tumour tissue samples from patients treated with PQR309 demonstrated a reduction of phosphorylation of direct targets for PQR309 (PI3K and mTOR) as well as downstream effectors of mTOR. Furthermore, the data indicate that downregulation of phospho-Akt (p_T308) and mTORC1 activity may be predictive of tumor shrinkage while upregulation of PDGFRA may represent a mechanism of resistance against PI3K/mTOR inhibition. Citation Format: Andreas Wicki, Vincent Prêtre, Reto Ritschard, Nicholas Brown, Vincent Bize, Thomas Fabbro, Natasa Cmiljanovic, Sasa Dimitrijevic, Deborah Schmitz, Michael Stumm, Rebecca Kristeleit. Final results of the pharmacodynamic (PD) data of PQR309-001, a first-in-human trial of a combined PI3K/mTOR inhibitor in advanced solid tumors. [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 2287.
Abstract 1687: KIF5B-RET fusion gene may induce EMT via the regulation of two transcription factors, FOXA2 and STAT5A
Authors: Min-Young Kim, Jung-Young Shin, Jeong-Oh Kim, Kyoung-Hwa Son, Jin Hyoung Kang
Journal: Cancer Research (2016)

Abstract Background &amp; Purpose In recent, KIF5B-RET gene rearrangement has been discovered as a driver oncogene in non-small cell lung cancers. This fusion gene was demonstrated to be able to induce tumorigenesis in vivo mouse model. Hereby, we investigated how KIF5B-RET fusion gene affect tumor differentiation and which transcription factors and signaling pathway are activated. Methods We analyzed cell proliferative activity in transformed HEK293T cells with KIF5B-RET fusion gene (K4) and empty vector (V5) using CCK8 assay. We used light microscopy and H&amp;E staining to observe morphological changes of transformed cells. We evaluated protein and mRNA expressions of four EMT markers (E-cadherin, N-cadherin, Snail, and Twist) and two transcription factors (FOXA2, p-STAT5A) using transcription factor PCR array, Western blot, RT-PCR, immunofluorescence staining. Results K4 cells showed decreased cell proliferative activity compared with V5 cells. V5 cells had spreading pattern alike mesenchymal phenotype when their density was lower. However, their morphology changed to epithelial phenotype as they were overgrown with higher density. On the other hands, K4 cells exhibited the island growing pattern similar to epithelial phenotype in lower density of tumor cells, but changed to mesenchymal phenotype as the density of tumor cells gradually increased. On H&amp;E staining, the cytoplasm of K4 cells was much smaller than that of V5 cells. We observed that E-cadherin mRNA was down-regulated, but N-cadherin and Twist were up-regulated in K4 cells. Based on the results of repeated screening assay, we finally selected two transcription factors, FOXA2 and STAT5A, which were significantly overexpressed in K4 cells. In K4 cells, phosphorylated-STAT5A was increased and FOXA2 was decreased compared to V5 cells. In addition, the expression of E-cadherin was reduced, but p-GSK3β, p-AKT, and p-ERK were markedly increased in K4 cells. The pattern of immunofluorescence staining of V5 and K4 cells were similar to the protein expressions of E-cadherin and p-STAT5A in Western blot analysis. Conclusion Taken together, FOXA2 and E-cadherin are down-regulated and p-STAT5A is up-regulated in HEK-293T cells stably expressing the KIF5B-RET. Our data suggest that KIF5B-RET fusion gene may induce EMT via the regulation of two transcription factors, FOXA2 and STAT5A. Citation Format: Min-Young Kim, Jung-Young Shin, Jeong-Oh Kim, Kyoung-Hwa Son, Jin Hyoung Kang. KIF5B-RET fusion gene may induce EMT via the regulation of two transcription factors, FOXA2 and STAT5A. [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 1687.
Prognostic significance of PIK3CA mutation in patients with muscle-invasive urothelial carcinoma (UC).
Authors: Vaibhav G. Patel, Russell Bailey McBride, Ana Collazo Lorduy, Mireia Castillo-Martin, Eugene K. Cha, Michael F. Berger, Li Wang, William K. Oh, Jun Zhu, Carlos Cordon-Cardo, David B. Solit, John Sfakianos, Matt D. Galsky
Journal: Journal of Clinical Oncology (2016)

e16002 Background: Missense mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), which encodes a subunit of PI3-kinase, are among the most common recurrent mutations in UC. Recently, PIK3CA mutations have been associated with improved outcomes in patients with muscle-invasive UC; we sought to validate these findings in an independent cohort. Methods: DNA was extracted from formalin fixed paraffin embedded tumor and normal tissue from 77 cystectomy specimens from patients with muscle-invasive UC of the bladder. PIK3CA mutations were detected using MSK-IMPACT, a hybridization capture-based next-generation sequencing platform. PIK3CA hotspot mutations with functional significance were summed for each case and dichotomized (any vs. none). Clinical information was complete on 63/77 cases, including age at diagnosis, sex, TNM stage, and the use of neo-adjuvant therapy. Recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) were estimated using Kaplan-Meier curve and cox proportional hazard models using SAS 9.3. Results: Among the 63 patients, the median age was 74 years (range 46-88), and 78% were male. ≤ T2, T3, T4, and N+ disease were present in 33%, 51%, 16%, and 27% of patients, respectively. PIK3CA mutations were detected in 15/63 (24%). A higher proportion of patients in the mutation group had received neoadjuvant chemotherapy (p = 0.01). PIK3CA mutation was associated with numerically inferior RFS (hazard ratio [HR]: 1.3; p = 0.48), DSS (HR: 2.1; p = 0.09), and OS (HR: 1.9; p = 0.07); similar results were obtained after excluding neoadjuvant patients. After controlling for nodal metastases, PIK3CA mutation remained associated with inferior RFS (HR: 1.2, p = 0.69), DSS (HR:1.7, p = 0.22), and OS (HR: 1.7, p = 0.13). Conclusions: We were unable to validate the favorable prognostic significance of PIK3CA mutations in invasive UC of the bladder post-cystectomy. PIK3CA mutations were associated with numerically inferior outcomes, as has been demonstrated in other solid tumors. Though limited by small sample size, these findings highlight the role for external validation of somatic-mutation based prognostic biomarkers.
Abstract 4392: Yes1 is the key molecule for the resistance to trastuzumab in breast cancer, and dasatinib overcomes the resistance
Authors: Hiromasa Yamamoto, Tatsuaki Takeda, Hirotaka Kanzaki, Ken Suzawa, Kei Namba, Hiroki Sato, Hidejiro Torigoe, Mototsugu Watanabe, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Yoshihisa Kitamura, Toshiaki Sendo, Shinichi Toyooka
Journal: Cancer Research (2016)

Abstract Background: Overexpression of human epidermal growth factor receptor 2 (HER2) was observed in approximately 15-23% of breast cancers and they are classified as HER2-positive breast cancer. Trastuzumab is a therapeutic drug for the first choice for HER2-positive breast cancer, showing good response. However, acquired resistance to trastuzumab is one of the critical clinical issues in breast cancer treatment, especially in the patients with recurrent breast cancer. Therefore, it is necessary to develop the effective therapy to overcome the resistance. In this study, we established a trastuzumab-resistant breast cancer cell line from a trastuzumab-sensitive cell line with HER2 amplification (BT-474). We analyzed the mechanisms of resistance to trastuzumab and demonstrated the anti-tumor effect of dasatinib. Methods: Trastuzumab-resistant breast cancer cell line (BT-474-R) was established by treating BT-474 cells for long-term exposure with increasing doses of trastuzumab (from 0.1 μg/mL up to 40 μg/mL). Expression and activation of HER2 and its related molecules were investigated using western blotting and real-time PCR. Cell viability was evaluated using MTS assay. Cell cycle was analyzed using flow cytometry. Results: Proto-oncogene tyrosine-protein kinase Yes1, which is one of the Src family members, was amplified, overexpressed and activated in BT-474-R. HER2 and Akt were also activated. Silencing of Yes1 by siRNA induced BT-474-R to recover sensitivity to trastuzumab. Pharmaceutical inhibition of Yes1 by Src inhibitor dasatinib was also effective to recovery sensitivity to trastuzumab in BT-474-R. Combination treatment of dasatinib and trastuzumab induced down-regulation of signaling molecules such as HER2 and Akt. Moreover, these combination treatments induced G1-phase cell-cycle arrest and apoptosis. Conclusion: Yes1 plays an important role in acquired resistance to trastuzumab in HER2-positive breast cancer. Our data also suggest that pharmacological inhibition of Yes1 may become the new strategy to overcome resistance to trastuzumab. Citation Format: Hiromasa Yamamoto, Tatsuaki Takeda, Hirotaka Kanzaki, Ken Suzawa, Kei Namba, Hiroki Sato, Hidejiro Torigoe, Mototsugu Watanabe, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Yoshihisa Kitamura, Toshiaki Sendo, Shinichi Toyooka. Yes1 is the key molecule for the resistance to trastuzumab in breast cancer, and dasatinib overcomes the resistance. [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 4392.
Abstract 322: Selective inhibition of MYC expression by a small molecule G-quadruplex stabilizer
Authors: Elena C. Leon, John K. Simmons, David Calabrese, Wendy DuBois, Kenneth Felsenstein, Lindsey B. Saunders, Shuling Zhang, Aleksandra Michalowski, Frank Gonzalez, Beverly A. Mock, John S. Schneekloth
Journal: Cancer Research (2016)

Abstract MYC overexpression or amplification is commonly seen in a wide variety of tumor types, including multiple myeloma. Although MYC appears to be an important driver of the oncogenic phenotype, the helix-loop-helix topology, short half-life, and rapid replenishment of its encoded protein make it a particularly challenging drug target. However, the promoter region of the MYC gene contains a G-quadruplex (G4) DNA secondary structure that can be stabilized to block transcription. Recently, we reported the identification of a compound from a small molecule microarray screen that selectively binds the MYC G4, compared with other oncogenes that also contain G4s, and inhibits MYC mRNA and protein expression, leading to cell cycle arrest in human multiple myeloma cell lines (ACS Chem Biol. 2015). Here we describe the in vitro and in vivo evaluation of a more potent analog that retains the selectivity of the original compound for the MYC G4 sequence. After observing strong growth inhibitory activity of this new compound in a diverse panel of human cancer cell lines, we evaluated its pharmacokinetic and toxicity profiles in mice. Preliminary pharmacokinetic studies showed promising serum bioavailability and exposure properties when administered either intravenously or intraperitoneally. The compound was well tolerated in a month long, dose-escalation toxicity study in mice receiving daily administration of the compound. No adverse effects were observed during the study. In an assessment of short term in vivo activity, MYC expression was inhibited in multiple myeloma xenografts. More long-term studies to evaluate the anti-tumor activity of the compound are currently in progress. Thus, our data provide evidence that small molecule stabilization of the MYC G4 can drive transcriptional silencing of oncogenic MYC expression both in vitro and in vivo. Citation Format: Elena C. Leon, John K. Simmons, David Calabrese, Wendy DuBois, Kenneth Felsenstein, Lindsey B. Saunders, Shuling Zhang, Aleksandra Michalowski, Frank Gonzalez, Beverly A. Mock, John S. Schneekloth. Selective inhibition of MYC expression by a small molecule G-quadruplex stabilizer. [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 322.
Abstract 3184: Genomic analyses reveal two distinct biologic entities of endometrial endometrioid carcinoma
Authors: Yuko Sugiyama, Nobuyuki Fukui, Osamu Gotoh, Katsuhiko Hasumi, Yutaka Takazawa, Tetsuo Noda, Seiichi Mori
Journal: Cancer Research (2016)

Abstract Endometrial carcinoma (EC) is classified into two types: type 1 (endometrioid type) and type 2 (non-endometrioid type). Type 1 endometrioid adenocarcinoma (EA) has been generally considered a single disease entity and was developed from endometrial hyperplasia as a precursor lesion. Recently we identified two distinct subgroups in type 1 EA; groups 1 and 2 as tumors with and without endometrial hyperplasia, respectively. The purpose of this study is to identify genes involved those differentially expressed by groups 1 and 2 EA. Genomic analyses including transcriptome and exome sequencing and immunohistochemistry were performed. For the validation, these data were projected to the TCGA (The Cancer Genome Atlas Research Network) data. In the results of transcriptome, group 1 and 2 EAs identified differential regulation of multiple genes and pathways. As an example, estrogen receptor (ER) related pathways were up-regulated in group 1 EA. Immunohistochemical analyses further confirmed overexpression of ER and PgR in the protein level. In the result of exome sequencing, mutation was observed more frequently in group 2 and sixteen driver genes were more frequently mutated in group 2. Citation Format: Yuko Sugiyama, Nobuyuki Fukui, Osamu Gotoh, Katsuhiko Hasumi, Yutaka Takazawa, Tetsuo Noda, Seiichi Mori. Genomic analyses reveal two distinct biologic entities of endometrial endometrioid carcinoma. [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 3184.
State and Regional Prevalence of Diagnosed Multiple Chronic Conditions Among Adults Aged ≥18 Years — United States, 2014
Authors: Brian W. Ward, Lindsey I. Black
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

The prevalence and care management of multiple (two or more) chronic conditions (MCC) are important public health concerns (1). Approximately 25% of U.S. adults have diagnoses of MCC (2). Care management of MCC presents a challenge to both patients and providers because of the substantial costs associated with treating more than one condition and the traditional care strategies that focus on single conditions as opposed to enhanced care coordination (3,4). Maintaining surveillance, targeting service delivery, and projecting resources are all important to meet this challenge, and these actions can be informed by identifying state and other regional variations in MCC prevalence (5,6). Data from the 2014 National Health Interview Survey (NHIS) were used to estimate prevalence of MCC (defined as two or more of 10 diagnosed chronic conditions) for each U.S. state and region by age and sex. Significant state and regional variation in MCC prevalence was found, with state-level estimates ranging from 19.0% in Colorado to 38.2% in Kentucky. MCC prevalence also varied by region, ranging from 21.4% in the Pacific region to 34.5% in the East South Central region. The prevalence of MCC was higher among women than among men within certain U.S. regions, and was higher in older persons in all regions. Such findings further the research and surveillance objectives stated in the U.S. Department of Health and Human Services (HHS) publication, Multiple Chronic Conditions: A Strategic Framework (1). Furthermore, geographic disparities in MCC prevalence can inform state-level surveillance programs and groups targeting service delivery or allocating resources for MCC prevention activities.