bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5179: Development of a humanized mouse model for direct evaluation of anti-human PD-L1 antibodies
Authors: Qiao Meng , Zhang Juan , Ding Jian , Zhang Rui , Li Zhongliang , Zheng Jia , Lu Teng , Ning Jinjing , Shi Qian 
Published: July 2016

Abstract
Therapies that perturb the binding of programmed death-1 receptor ligand (PD-L1) to its receptor PD-1 achieved unprecedented rates of sustained clinical responses in patients with various types of cancer. Mouse surrogate antibodies were initially evaluated in syngeneic mouse models as the proof of concept for anti-PD-L1 therapy.
However, there's an urgent need to develop appropriate animal model to directly evaluate anti-human PD-L1 antibodies before clinical trial. Here we describe our ongoing efforts in developing a chimeric mouse/human cell line to test human anti PD-L1 antibody. We profiled PD-L1 expression by FACS using anti-mouse PD-L1 antibody and confirmed expression of PD-L1 in a series of murine cancer cell lines. H22, a liver cancer line with moderate expression level of PD-L1 was selected due to its in vivo sensitivity towards anti-PD1 and anti-PD-L1 antibodies. Crispr/cas9 system was employed to knockout murine PD-L1 and replace it with the human counterpart. The targeted knockout had been confirmed by sequencing, the expression of human PD-L1 is illustrated by FACS using antibody that specifically recognize human form and no cross reaction to mouse form. The engineered H22-hPD-L1 cell line was then inoculated subcutaneously to immune-competent BALB/c mice to establish the in vivo model that maintains complete murine immune system and harbor humanized PD-L1. The tumor growth curve of H22-hPD-L1 model and its sensitivity to anti-human PD-L1 antibody have been established.
In summary, our H22-hPD-L1 model may be a valuable tool to evaluate the in vivo activity of anti-human PD-L1 antibody therapies either as a single agent or combinational strategies. The similar engineering may be applied to more murine cell lines (e.g. EMT-6, B16F10 and MBT-2, etc) to provide a spectrum of cell lines with different diseases and genetic makeup for immunotherapies involving anti-hPD-L1 antibodies.
Citation Format: Meng Qiao, Juan Zhang, Jian Ding, Rui Zhang, Zhongliang Li, Jia Zheng, Teng Lu, Jinjing Ning, Qian Shi. Development of a humanized mouse model for direct evaluation of anti-human PD-L1 antibodies. [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 5179.
Abstract 518: Ionizing radiation-induced DNA damage response decreases during induced pluripotent and embryonic stem cell differentiation
Authors: Mujoo Kalpana , Pandita Raj K. , Tiwari Anjana , Charaka Vijay , Hittelman Walter N. , Hegde Murlidhar , Wang Haibo , Hunt Clayton R. , Dave Bhuvanesh , Chang Jenny , Butler E Brian , Pandita Tej K. 
Published: July 2016

Abstract
Embryonic as well as induced pluripotent stem cells (ESC/iPSC) have a robust DNA damage response to facilitate efficient repair of DNA strand breaks as well as interstrand cross-links (ICLs). Stem cell abundance in tumors can impact the efficacy of the therapeutic agents, and such agents also have an impact on the normal tissue toxicity. Therefore, it is important to compare DNA damage repair in progenitor stem cells and their differentiated lineages since the normal tissues surrounding the tumor predominantly contain differentiated cells. We therefore asked whether the DNA damage response is altered during differentiation of embryonic as well as induced pluripotent stem cells and found that sensing of ionizing radiations, interstrand cross-linking or hydroxyurea induced DNA damage was minimally altered by cellular differentiation. Furthermore, DNA DSB repair by non-homologous end joining was minimally impacted. However, the homologous recombination of DSB repair or ICL repair was significantly reduced in differentiated cells. In addition, differentiated cells showed a reduction in the frequency of new origins of replication and increased stalled replication forks. Interestingly, similar to ESC or iPSC lines, breast tumor stem cells also exhibited a decrease in DNA damage repair by homologous recombination in differentiated cells. The defect in DNA damage repair by homologous recombination was reversed in de-differentiated cells, supporting the argument that differentiation can influence homologous recombination repair of DSBs as well as repair of ICLs. These studies have implications in modulating the therapeutic efficacy of DNA damage inducing tumor-killing agents.
Citation Format: Kalpana Mujoo, Raj K. Pandita, Anjana Tiwari, Vijay Charaka, Walter N. Hittelman, Murlidhar Hegde, Haibo Wang, Clayton R. Hunt, Bhuvanesh Dave, Jenny Chang, E Brian Butler, Tej K. Pandita. Ionizing radiation-induced DNA damage response decreases during induced pluripotent and embryonic stem cell differentiation. [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 518.
Abstract 5180: Bayesian multi-endpoint analysis of syngeneic mouse immunotherapeutic trials
Authors: Gold David , Chen Ningning 
Published: July 2016

Abstract
Recent and notable immunotherapeutic successes for the treatments of melanoma and lung cancer have catalyzed wide-spread development of novel immunotherapies and combinations for a variety of cancers. While promising, responses to immunotherapies are a focal point of present investigations, being as of yet challenging to explain. Amongst the many translational challenges, pre-clinical in bred syngeneic mouse experiments often display heterogeneous tumor responses, whereby a fraction of tumors show resistance, partial, or complete response to the same immuno-intervention(s) implanted in identical in bred mouse strains.
We mathematically modeled heterogeneous tumor responses in syngeneic mouse trials with Bayesian statistical methodology. Our decision criteria for drugs and drug combinations can simultaneously evaluate two or more endpoints. At the heart of our methodology is Bayesian learning with prior information that did not compromise statistical performance; actually, we achieved statistical gains to identify superior immunotherapies, rendering quantifiable efficiencies by design. We illustrate an augmented approach to discovery by Bayesian learning in real syngeneic mouse studies. We propose our powerful multi-endpoint Bayesian statistical criteria to ascertain superior pre-clinical immunotherapeutic activity.
Citation Format: David Gold, Ningning Chen. Bayesian multi-endpoint analysis of syngeneic mouse immunotherapeutic trials. [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 5180.
Abstract 5185: Development of patient-derived xenograft (PDX) models for pancreatic carcinoma as a preclinical platform for drug development
Authors: Ricono Jill , Thatte Jayant , Scott Colleen , Broudy Thomas B. 
Published: July 2016

Abstract
Pancreatic ductal adenocarcinoma (PDA) remains one of the most aggressive tumors in humans. A notable feature of PDA is its innate resistance to many chemotherapies. In preclinical studies, Abraxane showed antitumor activity as a single agent and synergistic activity in combination with gemcitabine in murine models of pancreatic cancer. In this study, we have developed and characterized multiple models of patient derived xenograft (PDX) pancreatic models. These models recapitulate major structural and genetic features noted in patient populations. Developed PDX models are from both prior treated and non prior treated patients with varying levels of resistance to Gemcitibine. Here we have investigated efficacy of standard of care agents in these pancreatic models and demonstrate the potential utility of the pancreatic models in drug discovery efforts in oncology for the treatment of pancreatic cancer.
Citation Format: Jill Ricono, Jayant Thatte, Colleen Scott, Thomas B. Broudy. Development of patient-derived xenograft (PDX) models for pancreatic carcinoma as a preclinical platform for drug development. [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 5185.
Abstract 5188: Combination of radiofrequency ablation and Sunitinib in the treatment of experimental hepatocellular cancer
Authors: Qi Xiaoqiang , Li Guangfu , Liu Dai , F Staveley-O’Carroll Kevin , Kimchi Eric 
Published: July 2016

Abstract
Radiofrequency Ablation (RFA) is one of current clinical option in the treatment of hepatocellular cancer (HCC); however, RFA monotherapy is often not curative as a consequence of tumor micro-metastases and recurrence. Thus, induction of systemic response with additive treatment is required. In the present study, we are exploring the combination of RFA and sunitinib, an FDA-approved multiple tyrosine kinase inhibitor, in the treatment of HCC. Using our established strategy a clinically relevant murine model of HCC is prepared which mimics human disease and reflect its typical features. The follow-up magnetic resonance imaging (MRI) is applied to monitor tumor progression until the cumulative tumor volume reaches 2000 mm3. Size-matched tumor-bearing mice are assigned into 3 groups and receive the following treatments: no treatment, RFA alone with our improved machine and optimized parameters, combination of sunitinib and RFA. The therapeutic efficacy is evaluated by measuring tumor volume with MRI every twice weeks. We demonstrate that tumors grow substantially in the mice without treatment. RFA alone effectively destroys tumors, but unable to prevent tumor recurrence and micro-metastasis. In contrast, &gt; 50% size reduction in tumor size is detected in the combined group compared to that in control mice, even no detectable tumors are observed in some treated mice. In conclusion, combination of sunitinib and RFA powerfully suppress tumor growth and could be translate into clinic practice.
Citation Format: Xiaoqiang Qi, Guangfu Li, Dai Liu, Kevin F Staveley-O’Carroll, Eric Kimchi. Combination of radiofrequency ablation and Sunitinib in the treatment of experimental hepatocellular 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 5188.
Abstract 5199: An in vivo reporter to quantitatively and temporally analyze the effects of CDK4/6 inhibitor-based therapies in melanoma
Authors: Teh Jessica L. , Purwin Timothy , Greenawalt Evan J. , Chervoneva Inna , Goldberg Allison , Davies Michael E. , Aplin Andrew 
Published: July 2016

Abstract
Aberrant cell cycle progression is a hallmark feature of cancer cells. Cyclin-dependent kinase 4 and 6 (CDK4/6) drive progression through the G1 stage of the cell cycle, at least in part, by inactivating the tumor suppressor, retinoblastoma (RB). CDK4/6 are targetable and the selective CDK4/6 inhibitor, palbociclib (IBRANCE/PD-0332991), was recently FDA approved for the treatment of estrogen receptor-positive, HER2-negative advanced breast cancer. In cutaneous melanoma, driver mutations in NRAS and BRAF signal to promote CDK4/6 activation suggesting that inhibitors such as palbociclib are likely to provide therapeutic benefit most likely in combination with BRAF and/or MEK inhibitors that are FDA-approved. However, the determinants of the response to CDK4/6 inhibitors alone and in combination with other targeted inhibitors are poorly defined. Furthermore, in vivo systems to quantitatively and temporally measure the efficacy of CDK4/6 inhibitors and determine the extent that CDK activity is reactivated during acquired resistance are lacking. Here, we describe the heterogeneous effects of CDK4/6 inhibitors, the expression of anti-apoptotic proteins that associate with response to CDK4/6 and MEK inhibitors, and the development of a luciferase-based reporter system to determine the effects of CDK4/6 inhibitors alone and in combination with MEK inhibitors in melanoma xenografts. These findings are likely to inform on-going and future clinical trials utilizing CDK4/6 inhibitors in cutaneous melanoma.
Citation Format: Jessica L. Teh, Timothy Purwin, Evan J. Greenawalt, Inna Chervoneva, Allison Goldberg, Michael E. Davies, Andrew Aplin. An in vivo reporter to quantitatively and temporally analyze the effects of CDK4/6 inhibitor-based therapies in melanoma. [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 5199.
Abstract 52: NF-kB promotes a Warburg metabolic profile in pediatric sarcomas
Authors: Ijiri Yuichi , Londhe Priya , London Cheryl , Houghton Peter J. , Guttridge Denis C. 
Published: July 2016

Abstract
In contrast to normal cells that use mitochondrial oxidative phosphorylation for ATP production in aerobic conditions, many cancer cells depend on glycolysis even in the presence of sufficient oxygen. This process is known as aerobic glycolysis or the Warburg effect. Recent reports have shown that both the classical and alternative signaling pathways of NF-κB play important roles in controlling the metabolic profile of cancer and normal cells, respectively. However, how these signaling pathways affect the metabolism of pediatric sarcomas has not yet been explored. Here, we show NF-κB activity undergoes a shift in signaling from an alternative to a classical pathway in the genesis of sarcoma subtypes, rhabdomyosarcoma and osteosarcoma. Inhibition of classical NF-κB in sarcoma cells restores alternative signaling, as well as an oxidative metabolic phenotype in vitro and in vivo. In contrast, forced expression of the alternative pathway in rhabdomyosarcoma or in osteosarcoma cells is unable to reverse NF-κB classical activity, suggesting that the activation of the classical pathway in sarcomagenesis dominates over alternative signaling. Furthermore, we observed that inhibition of NF-κB in sarcoma cells reduced the expression of the glycolytic gene, hexokinase 2 (HK2). Through chromatin immunoprecipitation (ChIP) assays, we show that HK2 is a direct NF-κB target. Moreover, deletion of HK2 by using shRNA shifts the metabolic profile in sarcoma cells away from a warburg effect. These findings demonstrate a crucial role for classical NF-κB in sarcomagenesis and suggest that NF-κB metabolically reprograms sarcoma cells by regulating HK2.
Citation Format: Yuichi Ijiri, Priya Londhe, Cheryl London, Peter J. Houghton, Denis C. Guttridge. NF-kB promotes a Warburg metabolic profile in pediatric sarcomas. [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 52.
Abstract 5207: Comparison of subtype-specific incidence rates of lymphoid malignancies in Hong Kong and the United States
Authors: Rothman Nathaniel , Bassig Bryan A. , Au Wing-Yan , Mang Oscar , Ngan Roger , Morton Lindsay M. , K.M. Ip Dennis , Hu Wei , Zheng Tongzhang , Seow Wei Jie , Xu Jun , Lan Qing 
Published: July 2016

Abstract
Clinical studies of lymphoid malignancies (LMs) have suggested that the descriptive patterns of these neoplasms differ in East Asia compared to Western populations. However, there are very limited available data on population-based, subtype-specific incidence rates of LMs in the East Asian population, particularly in Chinese. Using data from the Hong Kong (HK) Cancer Registry and the United States (U.S.) Surveillance, Epidemiology, and End Results Program, we calculated and compared age-adjusted incidence rates of LM subtypes in HK to those in Whites and Asians living in the U.S. Overall and sex-specific rates were calculated for the period 2001-2010. In order to formally compare the incidence rates between HK and the U.S., standardized rate ratios (SRRs) were calculated comparing the age-adjusted rates of each subtype for U.S. Whites and U.S. Asians in the SEER 13 database to HK. The incidence of most subtypes was low in the HK population, with rates &lt;1 case per 100,000 for all subtypes except for diffuse large B-cell lymphoma (3.26/100,000) and plasma cell neoplasms (1.99/100,000). Age-adjusted incidence rates of all evaluated B-cell subtypes were significantly higher in U.S. Whites compared to HK, with SRRs ranging from 1.6 (Burkitt lymphoma) to 9.1 (chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)). Rates in U.S. Asians were generally intermediate to those in U.S. Whites and HK, with SRRs for B-cell subtypes ranging from 1.0 (Burkitt) to 2.0 (CLL/SLL) comparing Asians in the U.S. to HK. For T or NK-cell subtypes, rates of extranodal NK/T-cell lymphoma were significantly lower in both U.S. Whites (SRR = 0.2) and U.S. Asians (SRR = 0.5) compared to HK. However, incidence rates of other evaluated T-cell subtypes were comparable or slightly higher in the U.S. population compared to HK. Our findings, which are based on data from population-based disease registries, provide new insight into the subtype-specific patterns of LMs in the Chinese population, and suggest the need for etiological studies of LMs in the East Asian population to elucidate the factors responsible for these differences in the geographic incidence patterns.
Citation Format: Nathaniel Rothman, Bryan A. Bassig, Wing-Yan Au, Oscar Mang, Roger Ngan, Lindsay M. Morton, Dennis K.M. Ip, Wei Hu, Tongzhang Zheng, Wei Jie Seow, Jun Xu, Qing Lan. Comparison of subtype-specific incidence rates of lymphoid malignancies in Hong Kong and the United States. [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 5207.
Abstract 521: c-MYC as a differentiating marker between angiosarcoma and atypical vascular lesion
Authors: Kak Ipshita , Sadikovic Bekim , Pare Guillaume , Corbett Tom , Popovic Snezana 
Published: July 2016

Abstract
Introduction: Angiosarcoma is a rare, aggressive malignancy that accounts for less than 1% of all sarcomas, characterized by a dismal 5 year survival of 20-30% at best. In striking contrast, atypical vascular lesion (AVL), which typically occurs secondary to radiation, follows for the most part, a benign course. However, debate rages over the true nature of AVL with reports describing both benign and malignant behavior. Further compounding the issue is the fact that overlapping histological features make the important differentiation between AVL and angiosarcoma difficult, especially on limited biopsy specimens. There have been a number of recent studies of c-MYC expression in vascular tumors in relation to this question, yielding varied results.
Objectives: This pilot study aimed to investigate c-MYC expression in atypical vascular lesions and angiosarcomas (primary and secondary) to evaluate the clinical utility of c-MYC testing as an adjunct to the histological diagnosis.
Methods: A retrospective search for biopsy, resection specimens and internal consult cases with diagnosis of angiosarcoma and/or atypical vascular lesion from January 2008- February 2014 was performed. A total of 32 cases (including controls) obtained after review were stained by dual colour c-MYC copy number probe set. The expression of c-MYC was read by two independent evaluators and final data was collated along with histology findings, follow-up and survival data.
Results: c-MYC amplification was found to be a major differentiating factor (p value: 0.00002, 68% sensitivity, 96% specificity) between AVL and angiosarcoma(median c-MYC expression 1.0 vs. 12.14, 95% confidence interval: 0.8-1.9 vs. 9.2-22.3 respectively). The amplification levels of primary (median c-MYC expression:10.9, 95% confidence interval: 3.8-16.6) and secondary angiosarcoma (median c-MYC expression:13.2, 95% confidence interval: 9.0-25.5) were statistically not found to be significantly different (p = 0.07). Although no correlation was found between level of c-MYC amplification and outcome, the study was underpowered to accurately evaluate this relation.
Conclusion: Amplification of c-MYC can be used as a reliable ancillary test to differentiate between diagnostically challenging cases of angiosarcoma and AVL.
Citation Format: Ipshita Kak, Bekim Sadikovic, Guillaume Pare, Tom Corbett, Snezana Popovic. c-MYC as a differentiating marker between angiosarcoma and atypical vascular lesion. [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 521.
Abstract 5213: Remarkably stable sex-ratio in sporadic kidney cancer incidence
Authors: Scelo Ghislaine , Chanudet-van den Brink Estelle , Li Peng , Vinayanuwattikun Chanida , Muller David C. 
Published: July 2016

Abstract
Background: Patterns of sex-disparity in cancer incidence can provide clues on risk factors and susceptibility to the disease. While known kidney cancer genetic syndromes follow an autosomal dominant inheritance and equally affect males and females, kidney cancer occurs predominantly outside a syndromic context (97% of cases are sporadic) and more commonly in males than females.
Methods: We used cancer registry data from 10 registries around the world, from countries showing large variations in kidney cancer incidence in 2012 (from 5.2 to 16.7/100,000 person-years) and with at least 20 years of registration. Using age-standardized incidence rate (on the World population), we compared the male-to-female sex-ratio in incidence rates across registries and over time. We also evaluated whether the sex-ratio varied by categories of age at diagnosis. Finally, we compared the kidney cancer-specific mortality after diagnosis in males and females in 2,969 cases using Cox regression model.
Results and interpretation: From 1985 to 2005, the sex-ratio was on average 2.0 and showed little variation across countries: it was 1.7 in Iceland; 1.8 in Australia and Finland; 1.9 in the UK and Norway; 2.0 in Singapore, Estonia, the Czech Republic, and the USA; and 2.1 in Slovenia. The sex-ratios were also remarkably stable in all registries over time, arguing against the role of known risk factors such as tobacco smoking to which the proportion of exposed women has evolved drastically in the last 50 years. In line with the autosomal dominant inheritance, sex-ratio was on average 1.0 in younger ages and progressively increased to stabilize from around 40 years old on. In particular the ratio remained stable at older ages, which suggests that estrogen levels are unlikely to account for the lower risk experienced by women. In contrast to the observed difference in incidence, our survival analysis showed similar survival rates in both sexes after adjustment for age and stage at diagnosis.
Conclusion: Our results suggest that the difference in kidney cancer incidence rates between males and females are not due to varying prevalence of known risk factors or a protection by sex hormones. While the susceptibility to the disease varies, the tumor behavior seems similar in males and females as shown by similar survival rates.
Citation Format: Ghislaine Scelo, Estelle Chanudet-van den Brink, Peng Li, Chanida Vinayanuwattikun, David C. Muller. Remarkably stable sex-ratio in sporadic kidney cancer incidence. [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 5213.