bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5129: Delineating immune networks in colorectal cancers to predict effects of immune checkpoint inhibitors using CANScript platform technology preserving tumor immune microenvironment
Authors: Majumder Pradip K. , Brijwani Nilesh , Karandikar Nikita N. , Radhakrishna Vinod D. , Oliyarasi Muthusamy , Pinto Dency D. , Balakrishnan Babu , Sekar Vasathakumar , Rajappa Manoj , Mehrotra Debapriya G. , Chevur Priyanka , Chevur Priyanka , Ghosh Arkasubhra , Thyiagarajan Saravanan , Radhakrishnan Padhma , Majumder Biswanath 
Published: July 2016

Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer related mortality. Recent findings from clinical studies showed that immune checkpoint inhibitors are making good progress towards clinical practise. However, existing biomarkers and 3D platforms are not equipped to offer reliable prediction of response of these drugs. We recently engineered a personalized ex vivo systems biology based platform using patient tumors called CANScriptTM (Majumder B et al Nat. Commun. 2015, Goldman A et al Nat. Commun. 2015) and a companion in vivo patient derived immune reconstituted xenograft model (Mi-HTX) preserving multiple critical phenotypic profiles orchestrating tumor-immune cross talk and dysfunction. We further performed baseline characterization of immune markers (CD4, CD8, CD68, CXCR4 and CD45-RO). Intratumor heterogeneity of both M1 and M2 phenotypes were observed irrespective of clinico-pathological features. Baseline CD68 enrichment status was found to be correlated with therapy failure for some patients where clinical outcome (PERCIST) was available. Flow cytometry and microarray analysis showed preservation of diverse sets of functional CD4, CD8 and NK phenotypes along with degranulation markers (CD107a), IFN-γ and FoxP3 in both in vivo and ex vivo tumors reconstituted with ex vivo primed PBMC. The comparative response profiling of these models following treatment with immune checkpoint inhibitors suggested enhanced antitumor effects (as measured by multiple functional parameters like viability, proliferation, morphology and apoptosis). Together, these findings highlight the strengths of immune-competent functional testing tools to stratify patients for precision immunotherapy where direct response prediction biomarkers are still elusive.
1. Majumder B et al. Nat. Commun.6:6169 (2015).
2. Goldman A et al. Nat. Commun. 6:6139 (2015).
Citation Format: Pradip K. Majumder, Nilesh Brijwani, Nikita N. Karandikar, Vinod D. Radhakrishna, Muthusamy Oliyarasi, Dency D. Pinto, Babu Balakrishnan, Vasathakumar Sekar, Manoj Rajappa, Debapriya G. Mehrotra, Priyanka Chevur, Priyanka Chevur, Arkasubhra Ghosh, Saravanan Thyiagarajan, Padhma Radhakrishnan, Biswanath Majumder. Delineating immune networks in colorectal cancers to predict effects of immune checkpoint inhibitors using CANScript platform technology preserving tumor immune microenvironment. [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 5129.
Abstract 5149: A novel regulatory circuit involving STIM1 and HIF-1 mediates hypoxia-driven hepatocarcinogenesis
Authors: Li Yongsheng 
Published: July 2016

Abstract
Hypoxia and intracellular Ca2+ transient are fundamental traits of cancer. Signaling cascades initiated or regulated by HIF-1 is essential for hypoxic responses. Stromalinteraction molecule 1 (STIM1) is well known as a Ca2+ sensor on endoplasmic reticulum (ER) that mediates SOCE activation and promotes tumor invasion and migration. However, there was no general consensus about the relationship between HIF-1 and STIM1. Also, the significance of STIM1, as well as the Ca2+ mobilization route in cancer cells during hypoxia remains unknown. Our results show that STIM1 correlates with elevated hypoxia-inducible factor-1 alpha (HIF-1α) in hypoxic hepatocarcinoma cells (HCC) and is upregulated during hepatocarcinoma growth. HIF-1 directly transcripts STIM1 and contributes to store-operated Ca2+ entry (SOCE), while STIM1-mediated SOCE is also required for HIF-1 accumulation in hypoxic HCC, via activating Ca2+/calmodulin-dependent protein kinase II and p300. Administration of YC-1, a HIF-1 inhibitor, or knockdown of HIF1A significantly diminishes hypoxia-enhanced STIM1 and suppresses tumorigenesis. Moreover, ectopic expression of STIM1 or HIF-1α partially reverses the impaired growth of the tumor treated with YC-1. These results suggest a mutual dependency and regulation of STIM1 and HIF-1 in controlling Ca2+ mobilization and hypoxic tumor growth, and highlight a potential target for early hypoxia-related intervention.
Citation Format: Yongsheng Li. A novel regulatory circuit involving STIM1 and HIF-1 mediates hypoxia-driven hepatocarcinogenesis. [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 5149.
Abstract 5156: The roles of x-linked Midline 1 interacting protein 1 (MID1IP1) in gender disparity and development of hepatocellular carcinoma
Authors: Chiu Elley Yung Tuen , Ng. Irene Oi Lin 
Published: July 2016

Abstract
HBV-associated hepatocellular carcinoma (HCC) has a male predominance, with a male-to-female ratio of about 5:1, suggesting gender difference is one of the major risk factors for HCC development. However, up till now, no concrete evidence is obtained to elucidate the male predominance of HCC. It is believed that the gender-specific signaling pathway is critically involved and targeting this pathway may provide a significant treatment outcome.
To target candidates that are implicated in the male predominance in HCC, aberrant expression of sex-linked genes between HCC tumors and non-tumorous livers (NT-L) draws particular attention. Previously, we performed transcriptome sequencing on sixteen pairs of human HCC tumors and NT-Ls. Our preliminary data show that a potential target, Midline 1 interacting protein 1 (MID1IP1) which is involved in hepatic lipogenesis and microtubule stabilization, was remarkably overexpressed in HCC tumors as compared to the NT-Ls (fold change = 2.73; p = 0.017). Moreover, the expression of MID1IP1 was significantly higher in male non-tumorous liver tissue than that of female (fold change = 2.63; p = 0.001). In addition, the upregulation of MID1IP1 correlated with less tumor encapsulation, more tumor microsatellite formation, more venous and direct liver invasion, and poorer tumor stage, features of a more aggressive biological behavior in our clinicopathological correlation study. Moreover, upregulation of MID1IP1 in the tumors was associated with a poorer overall survival. In its functional study, upon knockdown of MID1IP1, HCC cells (BEL7402, SMMC7721 and HepG2) had reduced proliferation rates in the cell proliferation assay and colony formation assay. Here, we also showed that the migratory abilities of the HCC cell lines with MID1IP1 knockdown were remarkably reduced in the transwell assay. Furthermore, the STRING interaction network analysis suggests that MID1IP1 interacts with Suppressor of Fused (Sufu), which is a regulator of Gli in the hedgehog (HH) pathway. To examine its regulatory pathway, we showed that the mRNA expression of the negative regulator of HH pathway, Gli3, was increased in the MID1IP1 knockdown HCC cells. The downstream target of Gli, cyclin D, was also downregulated upon MID1IP1 knockdown. In summary, our data suggest that the MID1IP1 plays a significant role in the male predominance of human HCC. MID1IP1 may also play a novel role in the regulation of hedgehog signaling.
Citation Format: Elley Yung Tuen Chiu, Irene Oi Lin Ng. The roles of x-linked Midline 1 interacting protein 1 (MID1IP1) in gender disparity and development of hepatocellular 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 5156.
Abstract 5160: Establishment of in vitro carcinogenic model of high-grade serous ovarian carcinoma using immortalized fallopian tubal secretory epithelial cell
Authors: Nakamura Kohei , Nakayama Kentaro , Kiyono Tohru , Ishikawa Noriyoshi , Ishikawa Masako , Katagiri Hiroshi , Minamoto Toshiko , Ishibashi Tomoka , Sato Emi , Sanuki Kaori , Yamashita Hitomi , Iida Kouji , Sultana Razia , Kyo Satoru 
Published: July 2016

Abstract
High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy in the world. Recent studies suggest that fallopian tubal secretory epithelial cells (FTSECs) are candidates for the origin of HGSOC. Several genetic alterations involved in the carcinogenesis have been reported in HGSOC, but their minimal requirement and the specific combinations remained unclear. To clarify these points, we established an in vitro stepwise carcinogenesis model using immortalized FTSECs with overexpressed cyclinD1/cdk4 and hTERT, in which we additionally mimicked selected genetic abnormalities frequently observed in clinical samples. Mutational analysis using clinical samples of HGSOCs identified frequent p53 mutations (96%). Furthermore, RAS/PI3K pathway is important signaling pathway and was deregulated in 45% of HGSOCs. PI3K/AKT pathway is also important pathway in HGSOCs. Thus, we introduced dominant negative form of p53 alone or in combination with oncogenic mutant KRAS allele into immortalized cells, but both failed to exhibit tumorigenic phenotypes. Additional introduction of genetic factors were attempted, and overexpression of c-Myc or phosphorylated Akt (p-Akt) were independently found to confer tumorigenic phenotypes. Importantly, all transformed FTSECs exhibited high-grade serous carcinomas that were grossly, histologically, and immunohistochemically similar to human HGSOCs. Thus, p53/KRAS/c-Myc or p53/KRAS/PI3K-AKT pathways were determined to be minimal required for carcinogenesis. The strength of our study is the use of immortalized FTSECs that have original characteristics of fallopian tube as well as the introduction of genetic mutations clinically observed in human HGSOCs. This experimental model provides a foundation for future studies of early events in carcinogenesis of HGSOCs and the identification of candidate targets for drug development and secreted biomarkers for early detection. It is also likely that a similar model can be broadly applied to studying the normal biology of other epithelial cells where precursor lesions and malignant counterparts are not entirely understood.
Citation Format: Kohei Nakamura, Kentaro Nakayama, Tohru Kiyono, Noriyoshi Ishikawa, Masako Ishikawa, Hiroshi Katagiri, Toshiko Minamoto, Tomoka Ishibashi, Emi Sato, Kaori Sanuki, Hitomi Yamashita, Kouji Iida, Razia Sultana, Satoru Kyo. Establishment of in vitro carcinogenic model of high-grade serous ovarian carcinoma using immortalized fallopian tubal secretory epithelial cell. [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 5160.
Abstract 5163: Mitochondrial mutations and gene expression analysis in colorectal adenopolyps
Authors: Wallace LaShanale M. , Mehrabi Sharifeh , Yao Xuebiao , Aikhionbare Felix 
Published: July 2016

Abstract
Colorectal cancer (CRC) is the third most common diagnosed and cause of cancer related deaths in both men and women in the United States. Numerous studies have analyzed mitochondria DNA mutations in CRC and other tumors. Results from these studies have detected high mutation rates which may lead to mitochondrial deregulation and tumor progression. Most CRCs develop from adenopolyps via the adenoma-carcinoma sequence. Therefore, analysis of mitochondrial mutations and gene expression may provide a mechanism for inhibition of this tumoral sequence in individuals with a high risk of developing CRC. In the present study, PCR based sequencing and reverse transcription-quantitative PCR (RT-qPCR) were used to determine if mutations in mitochondrial encoded genes and levels of expression of these genes could influence the progression of the adenoma- carcinoma tumoral sequence. Genes analyzed included MT-RNR1, MT-COI, MT-ATP6, MT- MT-CYB, and mitochondrial ND genes that are involved in the normal metabolism of mitochondria. Measurements were made for 34 tissue sample pairs obtained from various types of colorectal adenomas and corresponding normal surrounding tissues. Additionally, mitochondrial complexes I (NADH: ubiquinone oxidoreductase) and III (CoQH2-cytochrome c reductase) protein was analyzed. There was progressive differential expression of mt-genes and complexes I and III proteins among the colorectal tumor stages relative to their paired normal samples. The level of complexes I and III were higher in tumor tissues relative to normal surrounding tissues. Noticeably, the expression of MT-COI was higher in late stage carcinomas among; all studied transcripts. We detected 54 point mutations in one region ranging from 11871-11877. The frequency of these mutations in all stages was as followed; 71.5% in tubular adenoma, 57% tubulovillous, and 43% in villous and carcinoma. Our results suggest that alterations in mt-gene expression play a role in the transformation of the colorectal tumoral stages.
Citation Format: LaShanale M. Wallace, Sharifeh Mehrabi, Xuebiao Yao, Felix Aikhionbare. Mitochondrial mutations and gene expression analysis in colorectal adenopolyps. [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 5163.
Abstract 5164: Protein kinase C epsilon is a mediator of KRAS-driven lung tumorigenesis
Authors: Garg Rachana , Kapoor Veena , Abba Martin , Feldser David M. , Albelda Steven M. , Kazanietz Marcelo G. 
Published: July 2016

Abstract
Exposure to a number of environmental carcinogens, such as polycyclic aromatic hydrocarbons (PAHs), are the major causative agents of lung cancer, the leading cause of cancer related deaths in the U.S. Oncogenic mutations in KRAS, one of the most common alteration found in non-small cell lung cancer (NSCLC), are induced in high frequency by PAHs and environmental carcinogens. Studies from many laboratories, including ours, established key roles for PKCϵ, a member of the protein kinase C (PKC) family, in mitogenesis and survival of cancer cells. Notably, PKCϵ is up-regulated in several epithelial cancers, including human NSCLC, suggesting a role in the development and/or maintenance of the malignant phenotype. We observed that PKCϵ inhibition/depletion blunt the proliferative, motile, and invasive properties of lung cancer cells with KRAS mutation (PLoS One;7(2):e31714,2012). More importantly, silencing PKCϵ reduced the ability of human NSCLC cells with KRAS mutation to form tumors in nude mice as well as impaired their metastatic potential (Oncogene 31(20):2593-600, 2011). As Ras-transformed cells have enhanced DAG levels and signaling, we hypothesized that genetic targeting of PKCϵ reverses lung tumorigenesis driven by oncogenic Ras. To address this, we intercrossed lung-specific mutant Ras mice (KrasLSL-G12D/+) with PKCϵ knockout mice. Notably, significant inhibition occurred in the formation of lung tumors upon loss of either one or both PKCϵ gene (PRKCE) alleles, with significant extension of mice lifespan, suggesting a role for PKCϵ in the initiation of lung tumorigenesis driven by oncogenic mutant KRas. Furthermore, in silico database analysis of KRAS mutated human lung adenocarcinomas revealed a significant association between high PRKCE expression and poor patient outcome. As environmental lung carcinogens (PAHs) induce mutations in Ras, we next intended to test the hypothesis that PKCϵ is implicated in the action of these carcinogens. Interestingly, alveolar hyperplasia as well as pulmonary adenomas induced by benzo(a)pyrene, a prototypical PAH, were significantly reduced upon loss of one or two PKCϵ alleles, suggesting that genetic ablation of PKCϵ impairs chemically-induced lung carcinogenesis. Overall, our results indicate that PKCϵ is a novel effector of KRAS in lung cancer that may represent a promising target for disease treatment.
Citation Format: Rachana Garg, Veena Kapoor, Martin Abba, David M. Feldser, Steven M. Albelda, Marcelo G. Kazanietz. Protein kinase C epsilon is a mediator of KRAS-driven lung tumorigenesis. [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 5164.
Abstract 5201: Identification of growth factors that promote the proliferation and drug resistance of human primary acute B lymphoblastic cells
Authors: Li Peng , Jiang Zhiwu 
Published: July 2016

Abstract
Bone marrow mesenchymal stem cells (BMMSCs) contribute the survival, expansion, and drug resistance of leukemic cells. However, how BMMSCs promote the proliferation and drug resistance of leukemia remains to be poorly understood. Here, we derived a BM-derived stromal cell line that supported unlimited growth of human primary acute B lymphoblastic leukemic cells (B-ALL) by physical contacts with B-ALL cells and secreting growth factors. Nevertheless, its capacity of promoting primary B-ALL proliferation was abolished once the cell line was induced to differentiate into adipocytes. In xenograft models, we demonstrate that the presence of adipocytes suppressed the engraftment of primary B-ALL cells while the decrease of adipocytes enhanced the reconstitution of B-ALL. Consistently, we observed that the increase of numbers and diameters of adipocytes was correlated with remission after chemotherapy treatments in B-ALL patients. By comparing the global transcription profiles between the BM stromal cells and the adipocytes that were derived from the cell line, we identified a combination of cytokines and adherent proteins that were able to support the long-term growth of human primary B-ALL cells and desensitize them to chemotherapy drugs in a stromal-free culture condition. Furthermore, we showed that the PI3K/AKT pathways were involved in chemotherapy-induced resistance because targeting these signaling pathways increased the chemotherapy sensitivity of B-ALL in xenografts. Collectively, our results uncovered the mechanisms of BMMSCs supporting the survival, expansion, and drug resistance of human B-ALL cells.
Citation Format: Peng Li, Zhiwu Jiang. Identification of growth factors that promote the proliferation and drug resistance of human primary acute B lymphoblastic cells. [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 5201.
Abstract 5205: Changes in trends in colorectal cancer incidence rate by anatomic site between 1978 and 2004 in Japan
Authors: Nakagawa Hiroko , Ito Hidemi , Hosono Satoyo , Oze Isao , Mikami Haruo , Hattori Masakazu , Nishino Yoshikazu , Sugiyama Hiromi , Nakata Kayo , Tanaka Hideo 
Published: July 2016

Abstract
Although colorectal cancer (CRC), a major cancer worldwide, has shown a proximal or right-sided shift in subsite distribution in western countries, trends in subsite incidence in Asian countries remain unclear. Here, we evaluated subsite-specific trends in CRC incidence rate between 1978 and 2004 in Japan using large data from 10 population-based cancer registries. The colorectal sites (C18-20) were categorized into three groups, proximal colon (C18.0-18.5), distal colon (C18.6-C18.7) and rectum (C19.9 and C20.9). Trends in age-standardized incidence rates (ASRs) were characterized by Joinpoint regression analysis. A total of 474,651 colorectal cancer cases were analyzed. Overall, ASRs increased remarkably until 1993, with an annual percent change (APC) of 4.9%, and then stabilized thereafter. By subsite, however, ASRs of proximal colon significantly increased, with APCs of 7.1% (1978∼1991), 3.8% (1991∼96) and 0.9% (1996∼2004); distal colon showed an initial significant increase, with an APC of 7.6%, but stabilized from 1991 until the end of observation; and rectal cancer showed an initial significant increase, with APCs of 1.9% (1978∼88) and 5.6% (1988∼92), but then decreased abruptly in 1992, the year colorectal cancer screening was introduced nationwide, with an APC of -1.0%. Thus, we revealed that changes in incidence trends for the three anatomic sites apparently began to differ in the 1990s, and this is a first report to our knowledge. We also discuss factors that could explain these changes in Japanese. Careful monitoring is necessary to confirm whether these trends are changing in the Japanese population.
Citation Format: Hiroko Nakagawa, Hidemi Ito, Satoyo Hosono, Isao Oze, Haruo Mikami, Masakazu Hattori, Yoshikazu Nishino, Hiromi Sugiyama, Kayo Nakata, Hideo Tanaka. Changes in trends in colorectal cancer incidence rate by anatomic site between 1978 and 2004 in Japan. [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 5205.
Abstract 5208: Trends in fatal prostate cancer incidence by race among US men
Authors: Kelly Scott P. , Rosenberg Philip S. , Anderson William F. , Cleary Sean D. , Younes Naji , Andreotti Gabriella , Cook Michael B. 
Published: July 2016

Abstract
Background: Prostate-specific antigen testing (PSA) has dramatically changed the composition of prostate cancer, making it difficult to assess incidence trends. By defining fatal prostate cancer as the underlying cause of death from disease within 10 years of diagnosis, we have been able to conduct an in-depth analysis of “clinically relevant” prostate cancer incidence trends.
Methods: We extracted incident prostate cancer cases, causes of death and survival among men aged 45-84 years using the US Surveillance, Epidemiology, and End Results (SEER) database (1975-2002). In addition to standard descriptive analyses, the ability to distinguish prostate cancer cases that were ultimately fatal enabled us to fit age-period-cohort models.
Results: Among 51,682 fatal prostate cancer cases, incidence increased 1% per year prior to 1992, declined 15% per year from 1992-1995, and further declined by 5% per year through 2002. Age-specific incidence rates of fatal disease decreased over 2% per year among men aged 55 years and older, yet increased up to 1% per year among younger men. Fatal disease rates were more than 2-fold higher in black men compared with white men, a racial disparity that increased to 3-6 fold among younger men.
Conclusion: In the United States, after widespread use of PSA screening and advances in prostate cancer treatment, fatal prostate cancer rates have substantially declined. Yet, rates of fatal prostate cancer among younger men have remained relatively stable, suggesting the need for additional attention to early-onset prostate cancer that has the potential to result in death. This study also highlights the persistent black-to-white racial disparity in fatal prostate cancer, underscoring the need for a greater understanding of the causes of this difference so that strategies may be implemented to reduce, and ultimately eliminate, racial disparities in prostate cancer.
Citation Format: Scott P. Kelly, Philip S. Rosenberg, William F. Anderson, Sean D. Cleary, Naji Younes, Gabriella Andreotti, Michael B. Cook. Trends in fatal prostate cancer incidence by race among US men. [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 5208.