bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2758: Cancer risk in relatives of nasopharyngeal carcinoma - A register-based cohort study in Sweden
Authors: Liu Zhiwei , Fang Fang , Chang Ellen T. , Ye Weimin 
Published: August 2015

Abstract
Background: Little is known about the cancer susceptibility among relatives of patients with nasopharyngeal carcinoma (NPC) in non-endemic areas. We conducted a register-based cohort study to assess the relative risks (RRs) of cancer in families (including both first- and second-degree relatives) of NPC patients, compared with other individuals of the general population in Sweden, a low-incidence area for NPC.
Method: The present study included 11,602,616 individuals that were identified from the Swedish Censuses in 1960, 1970, 1980, and 1990, and were born in Sweden (defined as “general population”). Cross-linking this population to the Swedish Cancer Register and the Swedish Multi-Generation Register, we identified 9,157 relatives (3,645 first-degree and 5,512 second-degree) of 1,211 NPC probands that were diagnosed between 1958 and 2009 and were the first NPC cases in their families. The occurrence of incident cancers in these relatives and other individuals of the general population during 1961-2009 was ascertained through the Swedish Cancer Register. RRs of cancer in the relatives of NPC probands, compared with other individuals from the general population were calculated from Poisson regression models.
Results: The RR of all cancers combined among the first- or second-degree relatives of NPC probands was 1.03 (95% confidence interval [CI] = 0.95 to 1.11, P = 0.50), compared with other individuals of the general population. First-degree relatives of NPC probands had higher risks of NPC (N = 2, RR = 4.29, 95% CI = 1.07 to 17.17), and cancers of the larynx (N = 5, RR = 2.53, 95% CI = 1.05 to 6.09), prostate (N = 76, RR = 1.35, 95% CI = 1.07 to 1.68), and thyroid (N = 10, RR = 2.44, 95% CI = 1.31 to 4.53). In addition, a higher risk of cancer of the salivary glands was observed among the first-degree relatives of NPC probands with undifferentiated carcinoma (N = 2, RR = 6.64, 95% CI = 1.66 to 26.57). In contrast, a decreased risk of colorectal cancer incidence among relatives of NPC probands has been observed (N = 43, RR = 0.71, 95% CI = 0.53 to 0.96).
Conclusion: The increased risk of NPC and some other cancers among the first-degree relatives of NPC patients may potentially be explained by shared genetic and environmental risk factors, the latter including Epstein-Barr virus infection and tobacco smoking. However, interpretation of these findings should be cautious given the small number of cancer cases observed among the relatives of NPC patients.
Citation Format: Zhiwei Liu, Fang Fang, Ellen T. Chang, Weimin Ye. Cancer risk in relatives of nasopharyngeal carcinoma - A register-based cohort study in Sweden. [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 2758. doi:10.1158/1538-7445.AM2015-2758
Abstract 2841: A co-clinical assessment of patterns of BRAF inhibitor resistance
Authors: Kwong Lawrence N. , Boland Genevieve , Frederick Dennie , Helms Timothy , Akid Ahmad , Miller John , Jiang Shan , Cooper Zachary , Song Xingzhi , Seth Sahil , Kamara Jennifer , Protopopov Alexei , Mills Gordon , Flaherty Keith , Wargo Jennifer , Chin Lynda 
Published: August 2015

Abstract
Multiple mechanisms conferring resistance of melanomas to BRAF inhibitors have been described, yet the basis of resistance in a sizeable portion of patient samples remains undefined. To address this gap, we characterized patients’ baseline, on-treatment, and resistant tumors on both the protein and RNA levels. By RNA-sequencing, we identified known resistance-conferring mutations in 50% (6/12) of the resistant samples. In parallel, targeted proteomic analysis by protein array categorized the resistant samples into three stable groups: two that reactivate MAPK signaling to different levels, and one that is MAPK-independent. The molecular relevance of these categories was supported by both mutation data and the similarity of resistance patterns that emerged in a co-clinical trial in a novel genetically engineered mouse model. Additionally, we have defined biomarkers in pre- and early-treatment patient samples that have potential for predicting clinical responses. On the basis of these observations, we suggest that BRAF inhibitor-resistant melanomas can be actionably categorized using protein patterns, even without the identification of the underlying genetic alteration.
Citation Format: Lawrence N. Kwong, Genevieve Boland, Dennie Frederick, Timothy Helms, Ahmad Akid, John Miller, Shan Jiang, Zachary Cooper, Xingzhi Song, Sahil Seth, Jennifer Kamara, Alexei Protopopov, Gordon Mills, Keith Flaherty, Jennifer Wargo, Lynda Chin. A co-clinical assessment of patterns of BRAF inhibitor resistance. [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 2841. doi:10.1158/1538-7445.AM2015-2841
Abstract 2849: The combination of the PARP inhibitor talazoparib (BMN 673) with the ATR inhibitor VE-821 overcomes the drug resistance of Schlafen 11-deficient cells
Authors: Murai Junko , Pommier Yves 
Published: August 2015

Abstract
Poly(ADP-ribose)polymerases (PARP) inhibitors work as catalytic inhibitors as well as PARP poisons by trapping PARP-DNA complexes (Murai et al., Cancer Res. 2012: 72:5588-99), and talazoparib is the most potent PARP inhibitor to date in terms of cytotoxicity and PARP trapping (Murai et al., Mol. Cancer Ther. 2014:13:433-43). Nevertheless, mining the NCI60 data shows that half of the 60 cell lines are tolerant to talazoparib. To elucidate the mechanisms of such tolerance, we searched for genes with expression levels correlated to talazoparib sensitivity using CellMiner (http://discover.nci.nih.gov/cellminer/). Schlafen 11 (SLFN11) turned out to be one of the most positively correlated genes whose expression is correlated with cellular sensitivity to talazoparib. Using genetically altered cells, we established that SLFN11 inactivation confers high resistance to talazoparib, revealing that SLFN11 inactivation, which is common in cancer cells (Zoppoli et al. PNAS 2014: 109:15030-5), is a novel mechanism of resistance for PARP inhibitors. Based on genetically engineered CRISPR/casp9 SLFN11-knockout cell lines and cell cycle analyses, we found that the parent SLFN11-proficient cells arrest in S phase without DNA replication, while SLFN11-knock out cells maintain their replication until entering G2 phase in the presence of talazoparib. Although ATR is the key regulator of intra-S phase check point, the addition of the ATR inhibitor (VE-821) (Josse et al., Cancer Res. 2014) does not rescue the replication arrest in SLFN11-proficient cells, suggesting the existence of a SLFN11-dependent replication arrest mechanism independently of ATR. On the other hand, the addition of the ATR inhibitor in SLFN11-knock out cells alters the arresting point from G2 to S phase, and eventually increases dead cells. This is probably because the prolonged replication block leads to the collapse of replication forks, resulting in DNA double-strand breaks. Consistent to these findings, the combination of the ATR inhibitor with talazoparib synergistically sensitizes SLFN11-knock out cells more efficiently than the parent SLFN11-proficient cells. Together, these results demonstrate that the combination of the ATR inhibitor with talazoparib can overcome the resistance of SLFN11-deficient cells to talazoparib.
Citation Format: Junko Murai, Yves Pommier. The combination of the PARP inhibitor talazoparib (BMN 673) with the ATR inhibitor VE-821 overcomes the drug resistance of Schlafen 11-deficient cells. [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 2849. doi:10.1158/1538-7445.AM2015-2849
Abstract 2857: Metastatic site and response to pembrolizumab (anti-PD1 antibody) in melanoma
Authors: Tumeh* Paul Camille , Rosenblum* Michael , Handley Nathan , Tsai Katy , Rodriguez Robert Rodriguez S. , Khurana Niharika , Harview Christina , Spasic Marko , Sanchez Phillip J. , Chang Jeremy , Shintaku I. Peter , Taylor Emma , Chmielowski Bartosz , Grogan Tristan , Elashoff David A. , Pierce Robert H. , Daud Adil 
Published: August 2015

Abstract
Therapies that block the PD-1/PD-L1 axis have shown significant clinical activity in melanoma and other cancers. Recent evidence has shown that pre-existing CD8 T cells infiltrates at the invasive tumor margin of metastatic melanoma are associated with the presence of the PD-1/PD-L1 immune axis and may predict response to therapy. We examined the relationship between site of metastatic disease, local immune response, and treatment outcome in patients with advanced melanoma treated with pembrolizumab. We studied patients enrolled in the pembrolizumab Phase I clinical trial in the intention to treat (ITT, N = 112) and full analysis set (FAS) cohorts (N = 96). Using quantitative immunohistochemistry and multi-parameter flow cytometry we analyzed the local immune response in pre-treatment metastatic samples according to organ site of metastasis and treatment outcome. The overall response rate was 40% with a median progression-free survival (PFS) of 5.58 months. The presence of melanoma metastatic to the liver (liver metastasis group) had an objective response rate (ORR) of 16% and median PFS of 2.79 months. The presence of melanoma metastatic to the lung (lung metastasis group) had an ORR of 64% and median PFS of 14.48 months. Preliminary analysis of samples obtained from patients with liver metastases showed reduced tumor infiltrating CD8+ T cells (TILs), PD-1 expression, and tumor PD-L1 expression in distant metastases. Phenotypic and functional analysis of TILs showed reduced percentages of partially exhausted PD-1+CTLA-4+CD8+ cells, which correlated with progression and with liver metastasis. These cells were shown to make IFNγ but not TNF or IL-2. Additionally, the presence of liver metastasis in melanoma patients prior to starting anti-PD1 therapy correlated with treatment failure. Liver metastasis was associated with fewer PD-1+ CTLA-4+ TILs in distant tumors. These preliminary results warrant further investigation into determining whether site of metastasis modulates the systemic immune response to PD-1/PD-L1 blocking therapies.
Citation Format: Paul Camille Tumeh*, Michael Rosenblum*, Nathan Handley, Katy Tsai, Robert Rodriguez S. Rodriguez, Niharika Khurana, Christina Harview, Marko Spasic, Phillip J. Sanchez, Jeremy Chang, I. Peter Shintaku, Emma Taylor, Bartosz Chmielowski, Tristan Grogan, David A. Elashoff, Robert H. Pierce, Adil Daud. Metastatic site and response to pembrolizumab (anti-PD1 antibody) in melanoma. [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 2857. doi:10.1158/1538-7445.AM2015-2857
Abstract 2868: SETDB1 accelerates non-small cell lung cancer (NSCLC) tumorigenesis through WNT signalling pathway
Authors: Sun Qiaoyang , Ding Lingwen , Xiao Jinfen , Goodglick Lee , Chia David , Mah Vei , Alavi Mohammad , Doan Ngan , Said Jonathan W. , Yang Henry , Koeffler H.Phillip 
Published: August 2015

Abstract
Histone methylation deregulation leads to disruption of chromatin structure and gene expression pattern in many human cancers. Histone H3 lysine K9 methyltransferase, SETDB1 (SET domain, bifurcated 1) is initially reported to control heterochromatin structure, repress gene expression and be essential in early embryogenesis. Studies have recently shown its involvement in boosting tumorigenesis in different kinds of human cancers, including lung cancer. However, the mechanism underlying its ability to promote tumorigenesis remains largely unknown. In our study, we sought to investigate the oncogenic role of SETDB1 in NSCLC. Our immunohistochemistry found that 72% out of 387-lung cancer cases stained positively for SETDB1, compared to 46% samples of normal bronchial epithelium (p&lt;0.0001). Moreover, the percent positive cells and their intensity of positivity correlated with cancer grades.
Ectopic expression of SETDB1 in NSCLC cell lines enhanced clonogenic growth in vitro and significantly enlarges tumor size in vivo; while depleting endogenous SETDB1 expression with shRNAs suppressed NSCLC cells proliferation and tumor formation. Analyzing the expression pattern of cells with forced expression of SETDB1 combined with TOP/FOP luciferase assay and western blotting showed that WNT/β-catenin signaling was activated upon overexpression of SETDB1, as well as upregulation of its downstream targets, c-Myc and Cyclin D1. ChIP assay showed that SETDB1 binds to WNT relevant genes, such as APOE, IGFBP4, FZD1 and LRP8 and upregulates their transcription, which is very distinct from its canonical suppressing function of H3K9 trimethylation. Interestingly, we also noted that SETDB1 was able to repress P53 expression, while diminishing P53 expression reciprocally enhanced SETDB1 expression.
In summary, our study demonstrates that SETDB1 enhances NSCLC tumorigenesis through activating WNT/β-catenin signaling and repressing tumor suppressor P53. Our novel findings provide new insight into a non-canonical function of SETDB1 in activating gene expression, and suggest therapeutic benefit of targeting SETDB1 in NSCLC having high expression level of this protein.
Citation Format: Qiaoyang Sun, Lingwen Ding, Jinfen Xiao, Lee Goodglick, David Chia, Vei Mah, Mohammad Alavi, Ngan Doan, Jonathan W. Said, Henry Yang, H.Phillip Koeffler. SETDB1 accelerates non-small cell lung cancer (NSCLC) tumorigenesis through WNT signalling pathway. [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 2868. doi:10.1158/1538-7445.AM2015-2868
Abstract 287: Specific delivery of immunostimulatory RNA via nanoparticles blocks growth of primary and disseminated ovarian tumors
Authors: Primiano Thomas , Chang Bey-ih 
Published: August 2015

Abstract
One important mechanism of immune evasion is the accumulation of tumor-infiltrating regulatory T cells creating an immunosuppressive microenvironment in situ. Many new therapies target immune checkpoint receptors, CTLA-4 and PD-1, on immunosuppressive T-cells to reverse tumor immune evasion. Small interfering RNAs (siRNAs) are double stranded, sequence-specific inhibitors of gene expression. The paradigm for using siRNA to block cancer is to target mRNA sequences of oncogenes. Several limitations have suppressed the use of siRNA in human cancer therapy, such as off-target effects and lack of tumor-specific delivery. Additionally, certain siRNA sequence motifs activate toll-like receptors that induce the systemic innate immune response, including induction of interferon and interleukin-6 release that is traditionally considered as an undesirable clinical outcome. The hypothesis proposed here is to control the innate immune response by directing it only to tumors and not other organs by delivering an immunostimulatory siRNA (isRNA) directly to tumors. An isRNA designed to silence no human genes was synthesized as an unmodified triphosphate 19-mer double-stranded RNA with a GUGA motif on the 5′ antisense end. This isRNA was delivered into human ovarian tumors grown from SK-OV-3 cells surgically implanted into the ovaries of immunosuppressed mice by an L1CAM-targeted elastin-like polypeptide (ELP-L) nanoparticle. The isRNA/ELP-L nanocomplex was dosed into ten mice by i.p. injection 14 times at 10 mg/kg with respect to the isRNA over 28 days. The isRNA was delivered to the tumors, not to liver, spleen, heart, or lungs. The total tumor mass and number of disseminated nodules both decreased by 50% with respect to vehicle control. Six ovaries harboring tumors were resected from isRNA/ELP-L nanocomplex-dosed mice and each displayed elevated levels of interferon alpha and interleukin 6 mRNA as determined by RT-PCR. Mean AST, ALT and BUN serum biomarkers of liver and kidney function were elevated by 68%, 128% and 14%, respectively, compared to vehicle dosed mice; none of which were outside average normal levels. These results indicate that specifically targeting isRNA to tumors using a targeted nanoparticle may provide an effective therapy for ovarian cancer, either alone or in combination with agents that affect immune check point pathways in tumors.
Citation Format: Thomas Primiano, Bey-ih Chang. Specific delivery of immunostimulatory RNA via nanoparticles blocks growth of primary and disseminated ovarian tumors. [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 287. doi:10.1158/1538-7445.AM2015-287
Abstract 2871: Allele-specific modulation of cancer metabolism by a long noncoding RNA
Authors: Redis Roxana S. , Ivan Cristina , Vela Luz , Lu Weiqin , Rodriguez-Aguayo Cristian , Ambrosio Andre LB , Gomes Dias Sandra M. , Berindan-Neagoe Ioana , Calin George A. 
Published: August 2015

Abstract
Altered energy metabolism is a cancer hallmark as malignant cells tailor their metabolic pathways to meet their energy requirements. Glucose and glutamine are the two major nutrients that fuel cellular metabolism and the pathways utilizing these nutrients are often altered in cancer. In this study we show that the long non-codingRNA CCAT2, located at 8q24 amplicon on cancer risk associated rs6983267 SNP, regulates cancer metabolism in vitro and in vivo, in an allele-specific manner by binding the cleavage factor I (CFIm) complex with distinct affinities, complementary to the risk for colon cancer. The newly formed RNA:protein complex, CCAT2:CFIm, regulates the alternative splicing of glutaminase 1 (GLS1) by selecting the poly(A) site in intron 14 of the precursor mRNA. This results in the preferential expression of the GAC, the more catalytically active GLS1 isoform. Our findings, supported by data in human colorectal cancer samples from multiple cohorts, including TCGA dataset, and multiple animal models, uncover complex mechanisms of cancer metabolism regulation controlled by a long non-codingRNA.
Citation Format: Roxana S. Redis, Cristina Ivan, Luz Vela, Weiqin Lu, Cristian Rodriguez-Aguayo, Andre LB Ambrosio, Sandra M. Gomes Dias, Ioana Berindan-Neagoe, George A. Calin. Allele-specific modulation of cancer metabolism by a long noncoding RNA. [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 2871. doi:10.1158/1538-7445.AM2015-2871
Abstract 2901: The role of basal and BRAF inhibitor-induced autophagy-driven secretion in remodeling the melanoma tumor secretome
Authors: Kraya Adam , Speicher David W. , Amaravadi Ravi 
Published: August 2015

Abstract
Autophagy is a homeostatic process of cellular self-digestion and is an adaptive therapy resistance mechanism in cancer. Emerging studies indicate that autophagy is involved in secretion through non-classical mechanisms. It is not well understood, however, how this secretory function modifies the molecular composition of the tumor secretome, which plays an important role in tumor growth and tumor immune responses. In this work, we focused on the role of both basal and BRAF inhibitor (BRAFi)-induced autophagy in melanoma cells harboring BRAF V600E, a missense mutation observed in ∼60% of melanoma tumors. Using quantitative proteomics we previously showed that a small number of proteins were differentially secreted by low and high autophagy melanoma cells grown in three-dimensional culture. Secreted proteins associated with high autophagy included IL-1β, IL-8, LIF, FAM3C, and DKK3, which have known roles in tumorigenesis. Further, serum collected from untreated metastatic melanoma patients with high tumor autophagy levels exhibited higher levels of these proteins than serum from low autophagy patients. In the current study, melanoma cells with high autophagy and the BRAF V600E mutation (1205Lu) were treated with the BRAF inhibitor PLX4720, the autophagy inhibitor hydroxychloroquine (HCQ), PLX4720+HCQ, and the autophagy inducer rapamycin. The increase in autophagic flux upon the addition of PLX4720 or rapamycin was confirmed by western blotting and tandem fluorescently tagged LC3 (mCherry-eGFP-LC3). Secretomes were compared using quantitative proteomics, which resulted in identification of 1154 proteins with a false discovery rate of less than 1%. Hierarchical clustering and principal components analysis showed that secretomes from cells treated with the autophagy inducers rapamycin or PLX4720 correlated more closely with each other than those treated with HCQ either alone or in combination. A panel of proteins involved in extracellular matrix modification, cell-cell adhesion, and inflammation (including FAM3C and LIF) significantly increased in the supernatants of cells treated with PLX4720 or rapamycin and decreased in supernatants from cells treated with HCQ or HCQ+PLX4720. These results demonstrate that autophagy plays an active role in modifying the molecular composition of the tumor secretome. Proteins specifically shed in response to BRAF inhibitors and/or autophagy inhibition may have utility in the clinic for diagnostic and pharmacodynamic applications.
Citation Format: Adam Kraya, David W. Speicher, Ravi Amaravadi. The role of basal and BRAF inhibitor-induced autophagy-driven secretion in remodeling the melanoma tumor secretome. [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 2901. doi:10.1158/1538-7445.AM2015-2901