bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2352: Vectorization in an oncolytic vaccinia virus of an antibody, a Fab and a scFv against programmed cell death -1 (PD-1) allow their intratumoral delivery and an improved tumor-growth inhibition
Authors: Marchand Jean-Baptiste , Kleinpeter Patricia , Fend Laetitia , Thioudellet Christine , Geist Michel , Sfrontato Nathalie , Koerper Véronique , Brandely Renée , Villeval Dominique , Rittner Karola , Silvestre Nathalie , Erbs Philippe , Zitvogel Laurence , Quemeneur Eric , Preville Xavier 
Published: July 2016

Abstract
We report here the successful vectorization of a hamster monoclonal IgG (namely J43) recognizing the murine Programmed cell death-1 (mPD-1) in Western Reserve (WR) oncolytic vaccinia virus. Three forms of mPD-1 binders have been inserted in the virus: whole antibody (mAb), Fragment antigen-binding (Fab) or single-chain variable fragment (scFv). MAb, Fab and scFv were produced and assembled with the expected patterns in supernatants of cells infected by the recombinant viruses. The 3 purified mPD-1 binders were able to block the binding of mPD-1 ligand to mPD-1 in vitro. Moreover, mAb was detected in tumor and in serum of C57BL/6 mice when the recombinant WR-mAb was injected intratumorally (IT) in B16F10 and MCA 205 tumors. The concentration of circulating mAb detected after IT injection was up to 1900-fold higher than the level obtained after a subcutaneous (SC) injection (i.e. without tumor) confirming the virus tropism for tumoral cells and/or that tumoral microenvironment allows virus escape from immune surveillance. Moreover, the overall tumoral accumulation of the mAb was higher and lasted longer after IT injection of WR-mPD-1, than after IT administration of 10 μg of J43. Interestingly, in the MCA 205 tumor model, WR-mPD-1 (both mAb and scFv) induced a therapeutic control of tumor growth similar to unarmed WR combined to systemically administered J43 and superior to that provided by an unarmed WR. These results pave the way for next generation of oncolytic vaccinia armed with immunomodulatory therapeutic proteins such as mAbs. New generation of oncolytic vaccinia virus that will express several transgenes simultaneously may also be designed with the goal of providing to the patients enhanced therapeutic/toxicity ratio.
Citation Format: Jean-Baptiste Marchand, Patricia Kleinpeter, Laetitia Fend, Christine Thioudellet, Michel Geist, Nathalie Sfrontato, Véronique Koerper, Renée Brandely, Dominique Villeval, Karola Rittner, Nathalie Silvestre, Philippe Erbs, Laurence Zitvogel, Eric Quemeneur, Xavier Preville. Vectorization in an oncolytic vaccinia virus of an antibody, a Fab and a scFv against programmed cell death -1 (PD-1) allow their intratumoral delivery and an improved tumor-growth inhibition. [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 2352.
Abstract 2391: Flow cytometric sorting of subpopulations followed by RNASeq reveals distinct phenotypes in PDX model of basal breast cancer
Authors: Porter Warren , Hahn Friedrich , Snowden Eileen , Ferguson Mitchell , Tong Frances , Dillmore Shannon , Parker Joel S. , Middlebrook Aaron , Ghanekar Smita , Blaesius Rainer 
Published: July 2016

Abstract
The recognition of tumor tissue as an interactive ecosystem of distinct cell types has recently emerged as a very promising basis for more successful treatment of cancer patients. While intratumor heterogeneity (ITH) as a phenomenon has been known for decades it is only recent that its functional significance can be investigated with effective tools. Starting with a correlation of cellular heterogeneity with aggressiveness, metastatic potential and drug susceptibility of a cancerous lesion the current focus on functional differences between various tumor cell compartments is revealing a number of distinct functions and interactions. The discovery of communication between various tumor cells through soluble factors as well as differences in implantation of homogeneous vs. heterogeneous cell populations into immune compromised mouse models suggest a “division of labor” among cell types within many tumor tissues.
We have investigated the surface marker distribution of more than 8 different PDX tumor models by flow cytometry and detected extensive immunophenotypic heterogeneity. Using a range of markers associated with cancer stem cells, EMT and invasiveness (e.g. CD 24, 44, 133, 184, 326 (EpCAM), and CD45) we find heterogeneity with respect to many surface markers as well as individual immunophenotypic signatures for each model. Building on this characterization we chose several markers for sorting of subpopulations and performed gene expression analysis. Transcriptome analysis of a breast cancer model revealed two phenotypic signatures which suggest a strong proliferative population alongside a second population which is far less proliferative but much more active in angiogenesis, ECM organization and secretion of various soluble factors. This observation suggests a very clear example of distinct roles of multiple cell types to form a tumor tissue.
Our findings could have implications for therapeutic strategies directed at more than one cell type as well as development of better diagnostic tools which take into account the presence of various phenotypically distinct cell populations.
Citation Format: Warren Porter, Friedrich Hahn, Eileen Snowden, Mitchell Ferguson, Frances Tong, Shannon Dillmore, Joel S. Parker, Aaron Middlebrook, Smita Ghanekar, Rainer Blaesius. Flow cytometric sorting of subpopulations followed by RNASeq reveals distinct phenotypes in PDX model of basal breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2391.
Abstract 2413: Cell type-specific deconvolution of heterogeneous tumor samples with immune infiltration using expression data
Authors: Wang Zeya , Morris Jeffrey S. , Holmes Chris C. , Ahn Jaeil , Li Bo , Lu Wei , Tang Ximing , Wistuba Ignacio I. , Wang Wenyi 
Published: July 2016

Abstract
Tumor tissue samples comprise a mixture of cancerous and surrounding stromal cells. Understanding tumor heterogeneity is crucial to analyzing gene signatures associated with cancer prognosis and treatment decisions. Compared with the experimental approach of using laser micro-dissection to isolate different tissue components, in silico dissection of mixed cell samples is faster and cheaper. Numerous computational approaches previously developed have limited ability to deconvolute heterogeneous tumor samples. We have developed a deconvolution model, DeMix-T, that can explicitly account for a third component such as infiltrating immune cells, and address this challenging problem when the observed signals are assumed to come from a mixture of three cell compartments, infiltrating immune cells, the tumor microenvironment and cancerous tissues. The optimization-based algorithm for DeMix-T finds a local optimum for our estimation problem and is computationally feasible when it needs to compute high-dimensional integrals. DeMix-T therefore involves a novel two-stage filtering method that yields accurate estimates of cell purities and compartment-specific expression profiles. Simulations and real data analyses have demonstrated the good performance of our method. Compared with other deconvolution tools, DeMix-T can be applied more widely and provides deeper insight for cancer biomarker studies. It allows for a further understanding of immune cell infiltration in cancer and assists in the development of novel prognostic markers and therapeutic strategies.
Citation Format: Zeya Wang, Jeffrey S. Morris, Chris C. Holmes, Jaeil Ahn, Bo Li, Wei Lu, Ximing Tang, Ignacio I. Wistuba, Wenyi Wang. Cell type-specific deconvolution of heterogeneous tumor samples with immune infiltration using expression data. [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 2413.
Abstract 243: Investigating microtubule growth dynamics in patient-derived metastatic prostate cancer cells
Authors: Matov Alexandre , de Rooij Johan , Gatlin Jay , Rohrberg Julia , Ahmad Nikta , Aggarwal Rahul , Simko Jeff , Goga Andrei , Ryan Charles , Wittmann Torsten 
Published: July 2016

Abstract
Advanced prostate cancer (PC) is treated primarily by means of chemotherapy with one of the clinically approved microtubule (MT)-targeting agents (MTAs): paclitaxel, docetaxel and cabazitaxel. The mechanism of action of the MTAs on the cellular level is to bind to MTs and inhibit MT-dependent intracellular pathways, ultimately leading to cell death. In PC, MTAs are the only chemotherapy class shown to improve survival, however, there is high variability of response to MTA chemotherapy among patients as well as emergence of resistance to drug action which hampers the clinical efficacy. Clinicians need additional information to match individual patient tumors to the most effective drugs or refrain from treating patients that will not respond. However, the precise mechanism of action or resistance development to MTAs is not understood, which represents a critical gap in our knowledge to select the best treatment. Our hypothesis is that there are inherent differences in tumor MT dynamics among individual patients which dictates their response to treatment with specific MTAs. To this end, we envision that a systematic characterization of PC MT dynamics and their response to MTAs will allow chemotherapy customization and prolong survival. Specifically, our approach consists of the analysis of metastatic castrate resistant PC (mCRPC) organoids (Gao D. et al, 2014) derived from bone (acetabulum, vertebrae), soft tissue (salvage prostatectomy, lymph nodes), pleural effusion and circulating tumor cells biopsy samples obtained from metastatic patients who have received hormonal therapy and the MTA docetaxel or hormonal therapy alone or no treatment. We apply a quantitative single-cell image analysis algorithm (ClusterTrack) to measure a panel of twelve distinct MT dynamics parameters (a MT dynamics signature). Preliminary analysis suggests differences between different mCRPC organoids. MT tracking results indicate a correlation of decreased MT growth rate with increased Op18/stathmin expression. In this context, we hypothesize that differential expression of MT regulating genes affects specific parameters of MT dynamics, thus determining the sensitivity to MTA treatment.
Citation Format: Alexandre Matov, Johan de Rooij, Jay Gatlin, Julia Rohrberg, Nikta Ahmad, Rahul Aggarwal, Jeff Simko, Andrei Goga, Charles Ryan, Torsten Wittmann. Investigating microtubule growth dynamics in patient-derived metastatic prostate cancer 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 243.
Abstract 2447: PIN1 protects GLI1 from ubiquitination and promotes Hedgehog-driven medulloblastoma tumorigenesis
Authors: Rual Jean-Francois M. , Xu Tao , Zhang Honglai , Park Sung-Soo , Venneti Sriram , Kuick Rork , Ha Kimberly , Michael Lowell , Santi Mariarita , Uchida Chiyoko , Uchida Takafumi , Srinivasan Ashok , Dlugosz Andrzej , Camelo-Piragua Sandra 
Published: July 2016

Abstract
Medulloblastoma is the most common malignant brain tumor of childhood. Therapeutic approaches to medulloblastoma have led to significant improvements, but are achieved at a high cost to quality of life. Aberrant upregulation of the hedgehog (Hh) pathway drives cerebellar tumorigenesis in ∼30% of medulloblastoma patients. Hh pathway inhibitors such as the SMO antagonist Vismodegib are currently being tested in Hh-activated medulloblastoma and the preliminary results are encouraging. However, resistance to SMO inhibition can be acquired, leading to relapse. Alternative therapeutic approaches are needed. We aim to uncover novel Hh signal modulators that are essential in medulloblastoma to maintain tumorigenic potential. Using our proteomic platform for systematic protein interaction mapping, we discovered a novel interaction between GLI1, a key transcription factor for the mediation of Hh signals, and PIN1, a peptidylprolyl cis/trans isomerase that regulates the post-phosphorylation conformation of its substrates. Our results support a molecular model in which PIN1 protects GLI1 from proteasomal degradation, thus contributing to the positive regulation of Hh signals. Most importantly, our in vivo functional analyses of PIN1 in mouse models of Hh-driven medulloblastoma demonstrate that the loss-of-PIN1 impairs tumor development and increases survival by 3 fold, from 57 to 158 days (P &lt; 0.0001), establishing PIN1 as a key factor in Hh-driven medulloblastoma tumorigenesis. Finally, in human medulloblastoma tumor samples, the GLI1 and PIN1 proteins are correlated in their expression, supporting the relevance of the GLI1/PIN1 interaction in this disease context. In summary, the discovery of the GLI1/PIN1 interaction uncovers PIN1 as a novel therapeutic target in medulloblastoma tumorigenesis. If our hypothesis is validated, i.e., PIN1 inhibitors can improve survival in mouse models of Hh-driven medulloblastoma, our project will strongly justify testing the clinical relevance of PIN1 blockade in medulloblastoma patients.
Citation Format: Jean-Francois M. Rual, Tao Xu, Honglai Zhang, Sung-Soo Park, Sriram Venneti, Rork Kuick, Kimberly Ha, Lowell Michael, Mariarita Santi, Chiyoko Uchida, Takafumi Uchida, Ashok Srinivasan, Andrzej Dlugosz, Sandra Camelo-Piragua. PIN1 protects GLI1 from ubiquitination and promotes Hedgehog-driven medulloblastoma 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 2447.
Abstract 2475: Bmi1 is a therapeutic target in recurrent medulloblastoma
Authors: Singh Sheila K. , Garg Neha , Manornajan Branavan , Bakhshinyan David , Venugopal Chitra , Hallett Robin , Wang Kevin Xin , Ramaswamy Vijay , Cho Yoon-Jae , Mitra Siddhartha , Kaplan David , Davis Thomas , Taylor Michael 
Published: July 2016

Abstract
We describe the epigenetic regulator Bmi1 as a novel therapeutic target for the treatment of recurrent human Group 3 medulloblastoma, a childhood brain tumor for which there is virtually no treatment option beyond palliation. Through comparative profiling of primary and recurrent medulloblastoma, we show that Bmi1 defines a treatment-refractory cell population that is uniquely targetable by a novel class of small molecule inhibitors. When administered to mice xenografted with patient tumors, we observed significant reduction in tumor burden and increased mouse survival, without neurotoxicity. As Group 3 medulloblastoma is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious targeted agent would be rapidly transitioned to clinical trials.
Current clinical trials for recurrent medulloblastoma patients who no longer respond to risk-adapted therapy are based on genomic profiles of primary, treatment-naïve tumors. These approaches will provide limited clinical benefit for patients since recurrent metastatic Group 3 medulloblastomas are highly genetically divergent from their primary tumor. Our experimental approach defines a tractable target, the epigenetic regulator Bmi1, which characterizes not only recurrent medulloblastoma, but many other metastatic and treatment-resistant cancers. As future clinical oncology trials will most likely begin with relapsed patients, therapeutic targets from comparative analyses in primary and matched-recurrent tumors offer the greatest clinical yield and may be readily translated to the patient bedside.
Citation Format: Sheila K. Singh, Neha Garg, Branavan Manornajan, David Bakhshinyan, Chitra Venugopal, Robin Hallett, Kevin Xin Wang, Vijay Ramaswamy, Yoon-Jae Cho, Siddhartha Mitra, David Kaplan, Thomas Davis, Michael Taylor. Bmi1 is a therapeutic target in recurrent medulloblastoma. [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 2475.
Abstract 2533: Interlukin-1 (IL-1) may induce prostate cancer (PCa) stem-like cells
Authors: Thomas Shayna , Merchant Sana , Meade Rachel , Nawas Afshan Fathima , Delk Nikki 
Published: July 2016

Abstract
Inflammation is implicated in prostate cancer initiation and progression. Our lab found that the inflammatory cytokine, interleukin-1 beta (IL-1β) concomitantly upregulates the pro-survival scaffold protein, Sequestome-1 (SQSTM1/p62) and represses androgen receptor accumulation in a relatively small cell subpopulation within various prostate cancer cell lines. Given that cancer stem cell subpopulations have been isolated from isogenic cell lines and given that prostate cancer stem cells are androgen receptor negative, we hypothesized that the IL-1β-responsive subpopulation might be stem-like cells. Cancer stem cells are significant in prostate cancer because they are resistant to chemo-radiation and androgen-targeted therapies and can contribute to the tumor cell pool through asymmetric division. Thus, we analyzed the mRNA and protein accumulation of several stem cell markers in various prostate cancer cells lines exposed to IL-1β. We also have experiments underway to analyze stem cell biology in order to determine the functional significance of the IL-1β-responsive subpopulation. Thus far, we have discovered that IL-1β can induce stem cell marker mRNA and protein accumulation, suggesting that IL-1β alters prostate cell fate and supports the notion that inflammation contributes to prostate cancer initiation and progression.
Citation Format: Shayna Thomas, Sana Merchant, Rachel Meade, Afshan Fathima Nawas, Nikki Delk. Interlukin-1 (IL-1) may induce prostate cancer (PCa) stem-like 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 2533.
Abstract 254: Lung cancer cells growing under prolonged period of serum starvation display increased stemness
Authors: Venkatadri Rajkumar , Yakisich Juan Sebastian , Azad Neelam , Iyer. Anand Krishnan V. 
Published: July 2016

Abstract
Purpose: Resistance to anticancer drugs is a common cause of failure in chemotherapy. We recently found that adherent cells growing under prolonged periods (7-12 days) of serum starvation become highly resistant to conventional anticancer drugs such as Paclitaxel, Hydroxyurea and Colchicine but retain sensitivity to therapeutic levels of the cardiac glycoside Digitoxin.
Objectives: The main goal of this study is to characterize the biological properties of cells growing under prolonged periods of serum starvation (PPSS), and to elucidate the underlying mechanism of chemoresistance to Paclitaxel and sensitivity to Digitoxin with particular emphasis on Sox2 and the PI3K/AKT signaling pathway.
Experimental setup: Distribution of cell cycle was characterized by flow cytometry. Cell viability was assessed using the MTT assay. Western blotting was employed to evaluate the expression of several key protein markers of cancer stemness (Sox2, Wnt), multidrug resistance (MDR1, ABCG2), epithelial mesenchymal transition (Vimentin), and cell survival (Bcl-2, XIAP, PI3K/AKT).
Results: Cells grown under PPSS showed a higher proportion of cells in G1/S and G2 compared to cells growing under routine culture conditions (RCCs). Western blot analysis showed that these cells expressed higher levels of Sox2, MDR1, ABCG2, Bcl-2 compared to cells growing under RCCs. Pretreatment of cells for 3 h with Verapamil or Sorafenib (MDR1 and ABCG2 inhibitors, respectively) followed by co-incubation with Paclitaxel for 72 h did not overcome Paclitaxel resistance. Obatoclax (a Bcl-2 inhibitor), Wortmannin or LY294002 (PI3K inhbitors) also failed to overcome Paclitaxel resistance. It was interesting to observe that cells growing under PPSS were highly resistant to Obatoclax, Wortmannin and LY294002 compared to cells growing under RCCs. However, these cells were highly sensitive to treatment with Digitoxin.
Conclusions: It is likely that multiple mechanisms (increased stemness, overexpression of multidrug resistance protein and prosurvival proteins) contributes to the resistance of cells under PPSS to Paclitaxel, Obatoclax and PI3K inhibitors. Preliminary results indicates that Digitoxin exerts its antiproliferative effect in part by downregulating Sox2. However, the lack of effect of Wortmannin and LY294002 on Paclitaxel resistance suggests that this effect is not via the PI3K/AKT pathway. Adherent cells growing under PPSS provide a simple yet powerful system to screen for drugs targeting cancer stemness.
Citation Format: Rajkumar Venkatadri, Juan Sebastian Yakisich, Neelam Azad, Anand Krishnan V. Iyer. Lung cancer cells growing under prolonged period of serum starvation display increased stemness. [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 254.
Abstract 2560: Significant association between a fatty acid-related genetic variant and the risk of lung cancer
Authors: Wang Cheng , Qin Na , Zhu Meng , Hu Zhibin , Shen Hongbing 
Published: July 2016

Abstract
Systematically study the metabolism can help us understand the etiology of diseases. Recent metabolism GWAS provided us a chance to explore the association between serum metabolites and risk of diseases through genetic instruments. Based on the idea of mendelian randomization, we studied the associations between metabolites-related SNPs and lung cancer risk in 13,945 cases and 12,939 controls. We identified a fatty acid (FA) related SNP that was significantly associated with lung cancer risk (odd ratio (OR) = 0.87, P = 1.76×10-15) and this effect was stronger in females. We further validated a significant association between this SNP and serum levels of this FA (Beta = -0.57, P = 1.68×10-3) in 253 Chinese healthy individuals by LC-MS system. The association between the SNP and the expression of FA-related gene was also observed in the liver tissues (Beta = -0.84, P = 6.49×10-3). Together, we organized a mendelian randomization study which provided a FA related SNP as a female concentrated and smoke independent genetic determinant of lung cancer from the aspect of metabolites and proposed that higher level of this FA was a causal risk factor of lung cancer.
Citation Format: Cheng Wang, Na Qin, Meng Zhu, Zhibin Hu, Hongbing Shen. Significant association between a fatty acid-related genetic variant and the risk of lung 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 2560.