bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B45: Characterization of human fallopian tube epithelial stem-like cells.
Authors: Ding Dah-Ching , Chu Tang-Yuan 
Published: May 2016

Abstract
Purpose: Recent studies have suggested a large part of ovarian high grade serous carcinomas arise from the fallopian tube epithelium (FTE). The purpose of this study was to derive the stem-like cells of fallopian tube epithelium (FTESC).
Results: Immunohistochemistry of human fallopian tube revealed expression of Pax8 in secretory cells, Tubb4 in ciliated cells and Epcam in all the epithelial cells, whereas Lgr5 was expressed in a small subset of cells in the epithelial layer. The presumed FTESC were cultured from the fallopian tube fimbria epithelium exhibiting a cuboidal cell morphology and could be maintained at a constant proliferation rate up to P9. When cultured on matrigel, these cells formed spheroids with Pax8, Tubb4 and Lgr5 expression. Flowcytometry revealed decreasing expression of EpCAM, CD73, CD133 and CD105, and increasing of Pax 8 secretory cell marker (87% in P6, 78% in P3) with the advance of passage. Adding of estrogen to the culture resulted in an enlargement of cell body (4 nM) and differentiation toward ciliated cells (400 nM). When these FTESC were cultured on the mouse embryonic fibroblast feeder, or mixe-cultured with fallopian tube stromal cells and HUVECs, they formed tubal-like structures mimicking the fallopian tube.
Conclusion: We successfully derived a presumed FTESC with self-renewal and differentiation capability. These cells may provide new insight to investigate how FTE regenerate, respond to hormone and ROS injury and subjected to cancer initiation.
Citation Format: Dah-Ching Ding, Tang-Yuan Chu. Characterization of human fallopian tube epithelial stem-like cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B45.
Abstract IA01: The origins of ovarian cancer.
Authors: Cho Kathleen R. 
Published: May 2016

Abstract
Ovarian cancer is a generic term that can be used for any malignant ovarian tumor. The majority of ovarian cancers are carcinomas, i.e., malignancies with epithelial differentiation. Ovarian carcinomas represent a heterogeneous group of tumors that can be divided into five major types based largely on their light microscopic appearance. Notably, the origins of these different tumor types (high-grade serous carcinoma, low-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma, and mucinous carcinoma) remain incompletely understood. Indeed, many ovarian cancers may not actually originate in the ovaries, but instead involve the ovaries secondarily. Even those that develop in the ovaries may arise from cell types, for example endometrial- or fallopian tube-type epithelium, that are not considered intrinsic to normal ovaries.
Potential origins and putative precursors of the five major types of ovarian carcinoma will be reviewed and experimental data from mouse models supporting a role for the ovarian surface epithelium and/or fallopian tube epithelium will be presented. A more complete understanding of the origin(s) of each type of ovarian carcinoma is needed to inform the development of effective ovarian cancer prevention, early detection and treatment strategies.
Citation Format: Kathleen R. Cho. The origins of ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA01.
Abstract IA23: Ovarian cancer screening.
Authors: Menon Usha 
Published: May 2016

Abstract
Ovarian cancer is the 5th most common cause of cancer death among women in the UK, with ten-year survival rates of 35%. The continued high case fatality ratio has underpinned efforts to develop a screening strategy that could impact on mortality. In the UK large ovarian cancer screening trials have been completed both in the general (United Kingdom Collaborative Trial of Ovarian Cancer Screening - UKCTOCS) and high-risk (UK Familial Ovarian Cancer Screening Study UKFOCSS) population. Emerging evidence from UKCTOCS is encouraging with the multimodal strategy appearing to have detected double the number of invasive epithelial ovarian/fallopian tube cancer during incidence screening compared to a fixed cut-off for serum CA125 used previously. The key issue is impact on ovarian cancer mortality, which will be available from UKCTOCS in December 2015. Meanwhile new insights into carcinogenesis with a better understanding of the target lesion, improved design of biomarker discovery studies, a focus on detecting low volume disease using cancer specific markers, novel biospecimens such as endocervical samples, targeted imaging and time series algorithms for interpreting marker profile suggests that a new era in ovarian cancer screening is underway.
Citation Format: Usha Menon. Ovarian cancer screening. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA23.
Abstract 20: Mutation profiling reveals distinct signatures in hypopharyngeal squamous cell carcinoma
Authors: Liu Zhiye , Wei Lai , Zhao Dewei , Wang Ruoyu , Tong Kai , Zhang Yuewei , Yang Bin , Cao Hong , Li Nina , Liang Shanshan , Gu Jiahuan , Wang Zhiqiang , Ding Yan 
Published: May 2016

Abstract
The mutational profiles of hypopharyngeal squamous cell carcinoma (HSCC), an anatomical and clinical subtype of head and neck squamous cell carcinoma (HNSCC) was characterized in this study. Whole exome sequencing of HSCC tumors (n=15) and normal pairs (n=15) reveals distinct somatic gene mutations to HSCC (KDR, ABL-1, ATM, and HNF1A), while some others are common to HNSCC significantly mutated genes (e.g. TP53, HRAS, NOTCH1 and PIK3CA). Copy number analysis shows distinct signatures of HSCC gene amplifications(e.g. CCND1) or deletions(e.g. GSTT1). Furthermore, pathway analysis identified several statistically significant enriched pathways (e.g. VEGFR signaling) for genomic alterations specific to HSCC. We then performed targeted therapies to individual patients corresponding to their mutation profiles, and monitored their responses to the personalized treatment by enumerating the circulating tumor cells. These findings offer new insights into understanding fundamental tumorigenic mechanisms of HSCC and exploring precise therapies.
Citation Format: Zhiye Liu, Lai Wei, Dewei Zhao, Ruoyu Wang, Kai Tong, Yuewei Zhang, Bin Yang, Hong Cao, Nina Li, Shanshan Liang, Jiahuan Gu, Zhiqiang Wang, Yan Ding. Mutation profiling reveals distinct signatures in hypopharyngeal squamous cell carcinoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 20.
Abstract 36: Functional characterization of ERBB2 mutations and response to targeted therapies
Authors: Johnsen Hannah , Hanrahan Aphrothiti , Jones Alexis , Solit David 
Published: May 2016

Abstract
Amplification of HER2 (ERBB2) has been well characterized as an oncogenic driver, but only recently have mutations in ERBB2 also been shown to have activating and tumorigenic potential. We sought to characterize a large number of ERBB2 mutations seen in sequencing data from patients at MSKCC as well as the cBioPortal for Cancer Genomics, and determine the therapeutic response of these mutations to HER2 targeted therapies. HER2 is a transmembrane tyrosine kinase that is responsible for regulating cell growth and proliferation, among other cell processes. The ERBB2 gene is amplified in approximately 25% of breast cancers and in this disease, HER2 directed therapies are now a component of standard care. More recently, ERBB2 mutations were identified in a variety of cancers, most commonly cancers of the urinary tract but also at lower frequency in cancers of the breast, stomach, colon and lung, among others. Recent data has shown that select ERBB2 mutations activate HER kinase signaling and promote anchorage independent growth in vitro and tumor formation in mice. However, only a small number of ERBB2 mutations have been reported and biologically characterized as oncogenic in preclinical models. Moreover, the therapeutic impact of ERBB2 mutations has not been validated. To screen for activating potential of a large number of ERBB2 mutations, cells were transiently transfected to express ERBB2 mutants generated using site-directed mutagenesis. Expression of several mutations led to increased receptor activation and downstream signaling, as determined by levels of phosphorylated HER2, AKT, ERK, and S6 protein, whereas other mutations had little impact on activity compared to a wild type HER2 control. Stable cell lines were then generated to express the activating mutations and tested for transforming ability in soft agar. Mutations promoted colony formation, with certain mutations producing more colonies. Cells were also grown in the presence of the dual EGFR/HER2 inhibitor, neratinib. While certain mutations were more sensitive to lower doses of neratinib, addition of neratinib at higher doses abrogated colony formation in soft agar for all mutations. While a number of ERRB2 mutations have been shown to have tumorigenic potential, not all mutations respond similarly to HER2 targeted therapies. We hope to create an annotated database of alterations so that in the future, patients can be screened for specific mutations to minimize ineffective and unnecessary treatment options.
Citation Format: Hannah Johnsen, Aphrothiti Hanrahan, Alexis Jones, David Solit. Functional characterization of ERBB2 mutations and response to targeted therapies. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 36.
Abstract 41: XI-006 induces potent p53-independent apoptosis in Ewing sarcoma
Authors: Pishas Kathleen , Neuhaus Susan , Clayer Mark , Farshid Gelareh , Staudacher Alexander , Callen David 
Published: May 2016

Abstract
Despite aggressive multi-modal treatment strategies, limited improvement in overall survival rates for patients diagnosed with Ewing sarcoma, the second most prevalent solid bone tumor observed in children and young adolescents, has been achieved over the past thirty years. As such, new targeted therapies are urgently required particularly for those sarcoma patients with recurrent or metastatic disease. Overexpression of MDM4, a major transcriptional regulator of the TP53 tumour suppressor has been documented in a substantial proportion of Ewing, Synovial and Osteosarcomas (&gt;30%). For this reason, we have examined the molecular and cellular responses of cultured Ewing and Osteosarcoma cell lines following treatment with XI-006 (NSC207895), a small molecule 4-nitrobenzofuroxan derivative MDM4 transcriptional inhibitor.
XI-0006 treatment of Ewing and osteosarcoma cell lines (n=11) resulted in rapid and potent apoptosis at low nano-molar concentrations specifically in Ewing sarcoma cell lines (48hr IC50: 0.098-1.61µM). Importantly, the viability of normal human fibroblasts (IMR90) remained unaffected at these low nano-molar concentrations (48hr IC50: 6.80µM). Unexpectedly, apoptotic response was not dependent on MDMX mRNA and protein levels or TP53 status. Alkaline/neutral comet and γH2AX immunofluorescence assays revealed that the cytotoxic effects of XI-006 at low nano-molar concentrations could not be attributed to the induction of DNA damage. RNA expression analysis of XI-006 treated cell lines revealed that the mechanism of action of XI-006 could be attributed to the inhibition of cell division and cycle regulators such as KIF20A and GPSM2. XI-006 was also shown to synergise with current Ewing sarcoma chemotherapeutic protocols, Doxorubicin, Etoposide and Actinomycin D in vitro. Furthermore, combinatorial treatment with Olaparib led to a maximum 56.3% increase in apoptosis compared to XI-006 alone, due to the down-regulation of Mre11.
Our pre-clinical findings suggest that XI-006 represents a novel therapeutic intervention for the treatment of Ewing sarcoma, and warrants further pharmacokinetic and pharmacodynamic investigations of XI-006 in vivo.
Citation Format: Kathleen Pishas, Susan Neuhaus, Mark Clayer, Gelareh Farshid, Alexander Staudacher, David Callen. XI-006 induces potent p53-independent apoptosis in Ewing sarcoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 41.
Abstract IA12: Open-source, crowdsourcing-capable tools for N of 1 cancer genomics
Authors: Mardis Elaine R. 
Published: May 2016

Abstract
There are multiple challenges to implementing cancer genomics in a clinical setting to identify for individual patients and their oncologist, the potentially druggable targets in their disease. Our group has introduced several open-source informatics tools for the identification of known driver mutations, for identifying their vulnerabilities regarding small molecule- and/or antibody-based inhibitors. These are meant not only to negotiate databased information that resides in different formats and locations, but also to serve as crowdsourcing-based information intake points that permit the community of practicing cancer care physicians to participate in knowledge sharing. My talk will highlight these tools and their functionality in the context of several “N of 1” examples from our work.
Citation Format: Elaine R. Mardis. Open-source, crowdsourcing-capable tools for N of 1 cancer genomics. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr IA12.
Abstract A063: Cancer cell expression of CCR2 regulates the PD-L1/ PD-1 immune checkpoint in breast cancer
Authors: Fein Miriam R. , Almeida Ana S. , Eberhardt Anaïs , Egeblad Mikala 
Published: May 2016

Abstract
C-C chemokine receptor type 2 (CCR2) is highly expressed in human breast cancer tissue by both cancer cells and infiltrating immune cells. High expression of CCR2 is correlated with advanced tumor stage, metastasis, and early relapse. Studies in mice have suggested that CCR2 expression on infiltrating inflammatory monocytes promotes primary tumor growth and metastasis. However, the role of CCR2 expression on cancer cells has not been well studied.
To determine how CCR2 directly impacts tumor growth and metastasis, we used a murine model of luminal breast cancer, the mouse mammary tumor virus (MMTV) promoter polyoma middle T antigen (PyMT) model. We crossed MMTV-PyMT mice to Ccr2-/- mice and found that loss of CCR2 did not alter tumor onset. However, primary tumors of MMTV-PyMT;Ccr2+/+ mice grew significantly faster than tumors of MMTV-PyMT;Ccr2-/- mice. Lung metastases were also larger in MMTV-PyMT;Ccr2+/+ mice than in MMTV-PyMT;Ccr2-/- mice.
We determined by RNA in situ hybridization that CCR2 was indeed expressed by both host cells and cancer cells in MMTV-PyMT tumors. To differentiate between the contributions of CCR2 expression in the tumor and host, we transplanted primary cancer cells derived from MMTV-PyMT;Ccr2+/+ and MMTV-PyMT;Ccr2-/- mice to syngeneic Ccr2+/+ and Ccr2-/- hosts. Surprisingly, CCR2 expression in the host had no significant effect on tumor growth. However, deletion of CCR2 from cancer cells resulted in delayed tumor growth and increased survival. Furthermore, when Ccr2+/+ and Ccr2-/- cancer cells were transplanted to athymic nude mice (lacking T cells), the resulting tumors no longer showed a delayed growth. Consistent with this finding, flow cytometry of infiltrating leukocytes in tumors transplanted to syngeneic mice revealed increased levels of CD8+ cytotoxic T cells and antigen-presenting CD103+ dendritic cells into Ccr2-/- tumors compared to wild type tumors. These data suggest that CCR2 expression on cancer cells regulates an immune response to the tumors. Supporting this conclusion, expression of programmed cell death ligand 1 (PD-L1) on Ccr2-/- cancer cells was reduced to just 30% of the level on wild type cancer cells, indicating that CCR2 expression on cancer cells suppresses the anti-tumor immune response. Together, our results establish a novel role for cancer cell CCR2 expression in breast cancer progression by suppression of cytotoxic T cells through an immune checkpoint.
Citation Format: Miriam R. Fein, Ana S. Almeida, Anaïs Eberhardt, Mikala Egeblad. Cancer cell expression of CCR2 regulates the PD-L1/ PD-1 immune checkpoint in breast cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A063.
Abstract A163: Tertiary lymphoid structures: Prognostic significance and relationship with tumor-infiltrating lymphocytes in triple-negative breast cancer
Authors: Park In Ah , Lee Hee Jin , Song In Hye , Kim Joo Young , Yu Jong Han , Gong Gyungyub 
Published: May 2016

Abstract
Tumor-infiltrating lymphocytes (TILs) have a strong prognostic and predictive significance, particularly in triple-negative breast cancer (TNBC). One important source of TILs in breast cancer is tertiary lymphoid structures (TLSs). Here, we performed histologic analysis of surgically resected TNBC to identify the location of TLSs, the relationship between TLSs and TILs, and their prognostic significance in TNBC. We retrospectively analyzed 769 patients with TNBC. TILs were defined as the percentage of stroma of invasive carcinoma infiltrated by lymphocytes. TLSs were mainly present within adjacent terminal duct lobular units and around in situ components. TNBC with higher levels of TILs showed a higher nuclear grade, lower lymphovascular invasion rate, less accompanying in situ component, a homogeneous growth pattern, necrosis in invasive areas, low levels of tumor stroma, high levels of peritumoral lymphocytic infiltration, and moderate to abundant TLSs in adjacent tissue. TILs, degree of peritumoral lymphocytic infiltration, and adjacent TLSs were prognostic factors for disease-free and overall survival outcomes. Although the TIL level did not have a prognostic value in stage I, it added significant prognostic information for stages II and III. Conversely, patients with high levels of TILs did not show prognostic differences according to the pTNM stage. Patients with high levels of TILs (&gt;60%) and moderate to abundant TLSs had significantly better disease-free survival outcomes than those with high levels of TILs but none or few TLSs. TLSs are frequently present in TNBC and are closely associated with TILs. TILs provide additional prognostic information in TNBC patients with a higher pTNM stage.
Citation Format: In Ah Park, Hee Jin Lee, In Hye Song, Joo Young Kim, Jong Han Yu, Gyungyub Gong. Tertiary lymphoid structures: Prognostic significance and relationship with tumor-infiltrating lymphocytes in triple-negative breast cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A163.
Abstract A172: Allogeneic dendritic cells (AlloDCs) transduced with an infection-enhanced adenovirus as adjuvant for cancer immunotherapy
Authors: Fotaki Grammatiki , Jin Chuan , Karlsson-Parra Alex , Yu Di , Essand Magnus 
Published: May 2016

Abstract
AlloDC cancer immunotherapy utilizes the allogeneic reaction as an immunostimulatory adjuvant. Intratumoral alloDC vaccination reverses the immune suppressed tumor micro-environment and activates anti-tumor immune responses. Herein, we aim to examine the use of Ad5f35PTD, an infection-enhanced serotype 5 adenovirus containing fibers from serotype 35 and cell-penetrating peptides on the hexons, as a vector to deliver tumor-associated antigens to monocyte-derived immature DCs in combination with an established DC maturation cocktail. Ad5f35PTD-transduced, cocktail-matured DCs expressed co-stimulatory and activation molecules and secreted the Th-1 type cytokine IL-12, in vitro. Natural killer (NK) cells migrated better towards medium from Ad5f35PTD-transduced, cocktail-matured DCs than medium from only cocktail-matured DCs, which was in accordance with a higher CXCL-10 chemokine level. The alloDC effect was examined in vivo using mature murine DCs of BALB/c origin (D2SC/I), transduced with Ad5f35PTD encoding the melanoma-associated antigen gp100, injected subcutaneously into C57BL/6 mice. They induced a higher migration of host DCs in the draining lymph node, in comparison to the D2SC/I cells alone. The migrated host DCs efficiently presented the captured gp100 and activated gp100-specific CD8+ T-cells. Moreover, alloDCs transduced with the gp100-encoding Ad5f35PTD reduced the immunosuppressive environment when injected intratumoraly by reducing the ratio of monocytic to granulocytic myeloid-derived suppressor cell compartment and delay tumor growth in a B16 melanoma model, in comparison with the D2SC/I cells alone. Concluding, the Ad5f35PTD transduced alloDCs expressing gp100 showed potency in eliciting tumor-specific immune responses in comparison to the alloDCs alone.
Citation Format: Grammatiki Fotaki, Chuan Jin, Alex Karlsson-Parra, Di Yu, Magnus Essand. Allogeneic dendritic cells (AlloDCs) transduced with an infection-enhanced adenovirus as adjuvant for cancer immunotherapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A172.