bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-082: FLJ25439, a novel cytokinesis-associated protein, induces tetraploidization and maintains chromosomal stability via enhancing expression of endoplasmic reticulum stress chaperones
Authors: Ouyang Pin 
Published: August 2015

Abstract
Purpose of the study: Identify and characterize a novel D box-containing protein, FLJ25439 for tetraploid induction and maintenance of genomic stability.
Pertinent experimental procedures: Immunofluorescent microscopy and flow cytometry for cell cycle determination. Proteomics and bioinformatics approaches for protein category profiling.
Summary of the data: Investigation of the mechanisms leading to aneuploidy and polyploidy is critical to cancer research. Previous studies have provided strong evidence of the importance of tetraploidization as an early step in tumorigenesis. In cancer cells, tetraploid cells may contribute to abnormal mitotic progression, which may be associated with cytokinesis failure. Tetraploidy leads to genomic instability due to centrosome and chromosome over-replication. Until now, the mechanism by which cells maintain tetraploid status has been unknown. Here, we identified a novel D box-containing protein, FLJ25439, which displays a dynamic expression profile during mitosis/cytokinesis with the midbody as the most prominent associated structure. To understand the function of FLJ25439, we established stable cell lines overexpressing FLJ25439. FLJ25439-overexpression cells grew slower and displayed a tetraploid DNA content in comparison with diploid parental cells. They also showed aberrant mitosis and dysregulated expression of p53, pRb and p21, suggesting a defect in cell cycle progression. To explore the molecular mechanisms responsible for FLJ25439-induced tetraploidization, we conducted a comparative analysis of the global protein expression patterns of wild type and overexpressors using proteomics and bioinformatics approaches. Protein category profiling indicated that FLJ25439 is involved in pathways related to anti-apoptosis, protein folding, the cell cycle, and cytoskeleton regulation. Specifically, genotoxic-stress- and ER stress-related chaperone proteins greatly contributed to the FLJ25439 overexpression phenotypes.
Conclusion: The results of this study pave the way to our further understanding of the role of FLJ25439, a novel cytokinesis-related protein in protecting cells from environmental stress and tetraploid formation.
Note: This abstract was not presented at the meeting.
Citation Format: Pin Ouyang. FLJ25439, a novel cytokinesis-associated protein, induces tetraploidization and maintains chromosomal stability via enhancing expression of endoplasmic reticulum stress chaperones. [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 LB-082. doi:10.1158/1538-7445.AM2015-LB-082
Abstract LB-087: A facilitative role for caspase 3 in promoting genetic instability and carcinogenesis
Authors: LIU XINJIAN , Li Fang , Li Chuan-yuan 
Published: August 2015

Abstract
Apoptosis and apoptotic caspases are generally considered tumor-suppressive since there are involved in the elimination of unwanted or damaged cells. However, the relationship between caspases and carcinogenesis has not been thoroughly examined. In this study, we sought to determine the role of caspase 3 in chemical- and radiation-induced genetic instability and carcinogenesis. By use of a non-invasive caspase 3 reporter, we found that that a significant fraction of mammalian cells treated with ionizing radiation could survive, despite caspase 3 activation. Moreover, this sublethal activation of caspase 3 promoted persistent DNA damage, chromosome aberrations and oncogenic transformation. In addition, chemically-induced skin carcinogenesis was significantly reduced in mice genetically deficient in caspase 3. We provided strong evidence that activated caspase 3 can indeed promote oncogenic transformation in human cells and in mice by inducing persistent genetic instability. Since a wide array of environmental and endogenous stressors can trigger caspase 3 activation, our findings suggest that rather than acting as a broad inhibitor of carcinogenesis, caspase 3 activation may contribute to genome instability and play a pivotal role in tumor formation following damage.
Citation Format: XINJIAN LIU, Fang Li, Chuan-yuan Li. A facilitative role for caspase 3 in promoting genetic instability and carcinogenesis. [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 LB-087. doi:10.1158/1538-7445.AM2015-LB-087
Abstract LB-088: Ptch1 heterozygosity predisposes mice to developing IR-induced BCCs
Authors: Wang Grace Y. , Libove Eileen , Tucker Danielle , Epstein Ervin 
Published: August 2015

Abstract
Basal cells nevus syndrome (BCNS, Gorlin syndrome) patients carry heterozygous germline mutations in PATCHED1 (PTCH1) gene, which encodes a receptor of hedgehog (HH) ligands and represses HH signaling in the absence of ligands. Mutated PTCH1 leads to aberrant activation of the HH signaling pathway, which is the pivotal driver underlying BCC carcinogenesis in both sporadic and BCNS BCCs. BCNS (PTCH1+/-) individuals are very susceptible to developing more BCCs at an earlier age but the mechanism for this genetic predisposition to BCCs remains elusive. In this study, we assessed how heterozygosity of the murine Ptch1 gene contributes to IR-induced BCC carcinogenesis.
Specifically, we treated Ptch1fl/+ K14CreER2 mice with tamoxifen either at age 4 weeks (group A) or at 9 weeks (group B) to delete one copy of Ptch1 in K14-expressing keratinocytes. We irradiated both groups of mice with IR at mouse age 8 weeks so that at the time of IR, keratinocytes in group A mice, like those in BCNS patients, were Ptch1+/-, and mice in group B remained Ptch1+/+ but subsequent to recovery from acute damage all mice had Ptch1+/- keratinocytes. We found that mice in both groups developed similar amounts of microscopic BCCs at age either 7- or 9-months. However, only mice of group A (3 out of 13 mice) developed visible BCCs; none of the mice of group B (n = 30) developed visible BCCs by age 18-months, the longest time point monitored based on our studies of Ptch1+/- mice. The difference is statistically significant (p = 0.03). Histologically, these visible BCCs closely resemble human BCCs. This finding indicates (i) that heterozygosity of the Ptch1 gene limited to keratinocytes (without gene deletion in stromal cells) is sufficient to produce susceptibility to IR-induced visible BCC development and (ii) surprisingly that heterozygosity of the Ptch1 gene during acute mutagenic damage dramatically increases eventual conversion of microscopic to visible BCCs, probably by affecting acute repair of this damage. To gain further insights into this possible mechanism, we are culturing keratinocytes from these mice and performing cell cycle and apoptosis analysis upon IR treatment in vitro.
Citation Format: Grace Y. Wang, Eileen Libove, Danielle Tucker, Ervin Epstein. Ptch1 heterozygosity predisposes mice to developing IR-induced BCCs. [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 LB-088. doi:10.1158/1538-7445.AM2015-LB-088
Abstract LB-092: Programmed death-ligand 1 is overexpressed in bronchial preneoplastic lesions: can it be a risk indicator
Authors: Park Hee Sun , Park Bo Mi , Park Dong Il , Uk Chung Jae , Moon Jae Young , Soo Jung Sung , Lee Choong Sik , Kim Ju Ock , Kim Sun Young , Koo Jaseok Peter 
Published: August 2015

Abstract
Compared to the vigorous development of targeted drugs and some of them are already become one of the best treatment of choices in lung adenocarcinoma, squamous lung carcinoma has no definite targets and treatment outcome is not yet superior to lung adenocarcinoma. Demonstration of initial carcinogenesis is benefitial in two aspects: cancer prevention and development of its targets. Studying preneoplastic lesions of bronchus can answer those questions. Preneoplastic lesion, which is considered to have malignant potential, may develop into invasive cancer by escaping from host immune response. CD274 (programmed death-ligand 1, PD-L1) interacts with PD-1, is known to inhibit CD8+ cytotoxic T lymphocyte and induce apoptosis and, also to promote the differentiation of CD4+ T cells into regulatory T cells, so finally evade immune surveillance. We hypothesized that PD-L1 may work as an immune evader in preneoplastic lesion during its carcinogenesis. We performed white light and/or autofluorescence bronchoscopy in patients who have risk factor(s) of lung cancer or are suspected to have a lung cancer. Interestingly, PD-L1 was also overexpressed in preneoplastic lesions especially in severe dysplasia of the bronchus. This finding implies overexpression of PD-L1 can involve at early step of carcinogenesis. Further studies are needed to demonstrate the role of PD-L1 in preneoplastic bronchial lesion potential to develop invasive cancer.
Citation Format: Hee Sun Park, Bo Mi Park, Dong Il Park, Chung Jae Uk, Jae Young Moon, Jung Sung Soo, Choong Sik Lee, Ju Ock Kim, Sun Young Kim, Jaseok Peter Koo. Programmed death-ligand 1 is overexpressed in bronchial preneoplastic lesions: can it be a risk indicator. [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 LB-092. doi:10.1158/1538-7445.AM2015-LB-092
Abstract LB-094: Regorafenib and sildenafil interact to kill tumor cells
Authors: Tavallai Mehrad , Booth Laurence , Roberts Jane L. , Poklepovic Andrew , Dent Paul 
Published: August 2015

Abstract
The present studies were to determine whether the multi-kinase inhibitor sorafenib or its derivative regorafenib interacted with phosphodiesterase 5 (PDE5) inhibitors such as sildenafil (Viagra) to kill tumor cells. PDE5 and PDGFR (alpha and beta) were over-expressed in liver tumors compared to normal liver tissue. In multiple cell types in vitro sorafenib/regorafenib and PDE5 inhibitors interacted in a greater than additive fashion to cause tumor cell death. Knock down of PDE5 or of PDGFR (alpha and beta) recapitulated the effects of the individual drugs. The drug combination increased ROS/RNS levels that were causal in cell killing. RNS stimulated the activation of the death receptor CD95 as well as the formation of autophagosomes and autolysosomes. Inhibition of CD95 / FADD / caspase 8 signaling suppressed drug combination toxicity. Knock down of ULK-1, Beclin1 or ATG5 suppressed drug combination lethality. The drug combination inactivated ERK, AKT, p70 S6K and mTOR and activated JNK. The drug combination also reduced mTOR protein expression. Activation of ERK or AKT was modestly protective whereas re-expression of an activated mTOR protein or inhibition of JNK signaling almost abolished drug combination toxicity. Sildenafil and sorafenib / regorafenib interacted in vivo to suppress xenograft tumor growth using liver and colon cancer cells. PDE5 inhibitors and sorafenib / regorafenib are FDA approved agents, and our data is now being translated into the clinic for further determination as to whether this drug combination is a useful anti-tumor therapy for solid tumor patients.
Citation Format: Mehrad Tavallai, Laurence Booth, Jane L. Roberts, Andrew Poklepovic, Paul Dent. Regorafenib and sildenafil interact to kill tumor 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 LB-094. doi:10.1158/1538-7445.AM2015-LB-094
Abstract LB-095: Distribution and clearance of single-walled carbon nanotubes in mouse tissues: in situ detection, imaging and analysis
Authors: Barlas Afsar , Xu Ke , Romin Yevgeniy , Alidori Simone , Yarilin Dmitry , Fan Ning , Turkekul Mesruh , Fujisawa Sho , Scheinberg David A. , McDevitt Michael R. , Manova-Todorova Katia 
Published: August 2015

Abstract
Single-walled carbon nanotubes (SWCNT) are the subject of expanding research in the fields of targeted drug delivery and biosensors for disease treatment and monitoring. Functionalization of the SWCNT has proven to enhance the efficiency of distribution in the organism. The goal of this project was to establish and standardize methods of detection and characterization of the local tissue distribution of functionalized SWCNT in mouse models. We investigated the distribution and clearance of SWCNT in several tissues at various times after injection, up to one month. We also try to standardize methods of tracking SWCNT in both live and fixed tissues and image analysis protocols to quantify the distribution of the SWCNT in tissues. Another aim is to evaluate local immune response to SWCNT. We have analyzed liver, kidney, spleen, lung, brain, ovary, colon and small intestine from mice sacrificed 24 hours, 3 days, 7 days and 30 days following the injection of SWCNT. Our evaluation revealed that some organs, like kidney and small intestine, retain SWCNTs for at least a month. Slow rates of SWCNT removal from these organs do not appear to affect the overall health of the animals. We have made multiple attempts to image anesthetized live animals and detect SWCNTs in situ, however, the fluorescent signal emitted from SWCNT is too low to be reliably detected. The tissues must be fixed and signals amplified through immunodetection. Detection of immune markers, especially in immunologically active tissues such as spleen is a challenge for histological experiments, but is extremely important and such experiments is underway. Our findings of SWCNT persistence in certain organs 30 days post-injection is surprising and should be studied further. This observation opens further questions about the effect of long-term presence of SWCNT in some tissues and shows that careful investigation into the advantages and disadvantages of SWCNT retention is necessary.
Citation Format: Afsar Barlas, Ke Xu, Yevgeniy Romin, Simone Alidori, Dmitry Yarilin, Ning Fan, Mesruh Turkekul, Sho Fujisawa, David A. Scheinberg, Michael R. McDevitt, Katia Manova-Todorova. Distribution and clearance of single-walled carbon nanotubes in mouse tissues: in situ detection, imaging and analysis. [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 LB-095. doi:10.1158/1538-7445.AM2015-LB-095
Abstract LB-097: Targeted degradation of the androgen receptor in prostate cancer
Authors: Jin Meizhong , Winkler James D. , Coleman Kevin , Crew Andrew P. , Rossi AnnMarie K. , Willard Ryan R. , Dong Hanqing , Siu Kam , Wang Jing , Gordon Deborah A. , Chen Xin , Ferraro Caterina , Crews Craig M. , Neklesa Taavi K. 
Published: August 2015

Abstract
Progression of prostate cancer in patients treated with anti-androgen therapy usually involves several mechanisms of enhanced Androgen Receptor (AR) signaling, including increased intratumoral androgen synthesis, increased AR expression and AR mutations. We have developed a protein degradation technology called PROTACs (PROteolysis TArgeting Chimera), which uses bi-functional molecules that simultaneously bind a target of choice and an E3 ligase. PROTACs, via induced proximity, cause ubiquitination and degradation of the targeted, pathological protein. As opposed to traditional target inhibition, which is a competitive process, degradation is a progressive process. As such, it is less susceptible to increases in endogenous ligand, target expression, or mutations in the target. Thus this technology seems ideal for addressing the mechanisms of AR resistance in patients with prostate cancer.
AR PROTACs were shown to degrade AR in LNCaP and VCaP cells, with low nM to pM potency, and had a &gt;85% reduction in AR concentration (Dmax). Degradation was rapid, with 50% of AR lost within 15 minutes and maximal degradation observed by 4 hours. The degradation process in cells was specific, as the PROTAC activity can be competed with excess E3 ligand and PROTACs with an inactive epimer for E3 ligase binding did not degrade AR. AR PROTACs induced rapid apoptosis and cell death in VCaP cells. In LNCap and VCaP cell systems, AR PROTACs were anti-proliferative under conditions in which enzalutamide was inactive, such as increasing concentrations of the AR agonist R1881 and cells containing the ARF876L mutation. AR PROTACs typically exhibited good pharmacokinetic properties, with t1/2 values of several hours and bioavailability of &gt;50% after ip or sc injection. In mice, AR PROTACs demonstrate in vivo activity, including reduction of AR protein levels, prostate involution and tumor growth inhibition.
In summary, PROTACs designed to degrade AR are potent, specific, active in vitro and in vivo, and have cellular efficacy superior to enzalutamide. Targeted degradation of AR may provide a novel mechanism for providing efficacious therapy for patients with prostate cancer for whom current therapies have failed.
Citation Format: Meizhong Jin, James D. Winkler, Kevin Coleman, Andrew P. Crew, AnnMarie K. Rossi, Ryan R. Willard, Hanqing Dong, Kam Siu, Jing Wang, Deborah A. Gordon, Xin Chen, Caterina Ferraro, Craig M. Crews, Taavi K. Neklesa. Targeted degradation of the androgen receptor in prostate cancer. [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 LB-097. doi:10.1158/1538-7445.AM2015-LB-097
Abstract LB-129: Identifying tumor subpopulations and the functional consequences of intratumor heterogeneity using single-cell profiling of breast cancer patient-derived xenografts
Authors: Savage Paul , Saleh Sadiq M. , Iacucci Ernesto , Revil Timothe , Wang Yu-Chang , Bertos Nicholas , Monast Anie , Zhao Hong , Souleimanova Margarita , Szulwach Keith , Batchu Chandana , Omeroglu Atilla , Park Morag , Ragoussis Ioannis 
Published: August 2015

Abstract
Human breast tumors have been shown to exhibit extensive inter- and intra-tumor heterogeneity. While recent advances in genomic technologies have allowed us to deconvolute this heterogeneity, few studies have addressed the functional consequences of diversity within tumor populations. Here, we identified an index case for which we have derived a patient-derived xenograft (PDX) as a renewable tissue source to identify subpopulations and perform functional assays. On pathology, the tumor was an invasive ductal carcinoma which was hormone receptor-negative, HER2-positive (IHC 2+, FISH average HER2/CEP17 2.4), though the FISH signal was noted to be heterogeneous. On gene expression profiling of bulk samples, the primary tumor and PDX were classified as basal-like. We performed single cell RNA and exome sequencing of the PDX to identify population structure. Using a single sample predictor of breast cancer subtype, we have identified single basal-like, HER2-enriched and normal-like cells co-existing within the PDX tumor. Genes differentially expressed between these subpopulations are involved in proliferation and differentiation. Functional studies distinguishing these subpopulations are ongoing. Microfluidic whole genome amplification followed by whole exome capture of 81 single cells showed high and homogeneous target enrichment with &gt;75% of reads mapping uniquely on target. Variant calling using GATK and Samtools revealed founder mutations in key genes as BRCA1 and TP53, as well as subclonal mutations that are being investigated further. Loss of heterozygocity was observed in 16 TCGA cancer driver genes and novel mutations in 7 cancer driver genes. These findings may be important in understanding the functional consequences of intra-tumor heterogeneity with respect to clinically important phenotypes such as invasion, metastasis and drug-resistance.
Citation Format: Paul Savage, Sadiq M. Saleh, Ernesto Iacucci, Timothe Revil, Yu-Chang Wang, Nicholas Bertos, Anie Monast, Hong Zhao, Margarita Souleimanova, Keith Szulwach, Chandana Batchu, Atilla Omeroglu, Morag Park, Ioannis Ragoussis. Identifying tumor subpopulations and the functional consequences of intratumor heterogeneity using single-cell profiling of breast cancer patient-derived xenografts. [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 LB-129. doi:10.1158/1538-7445.AM2015-LB-129
Abstract LB-138: Use of cerebral organoids to model pediatric gliomas with H3.3K27M and H3.3G34R
Authors: Ismail Amin 
Published: August 2015

Abstract
Glioblastoma (GBM) is the most devastating brain cancer with dismal prognosis both in adults and children and accounts for 16% of primary brain tumors. Despite aggressive therapeutic approaches, the majority of patients die within one year after diagnosis. Giving the limitation of current GBM mouse models, which do not reflect the biological properties of human tumors, in particular, tumor heterogeneity and pathogenesis, there is a growing need for new models. Current in vitro 3D models involve the use of hydrogel scaffolds and cell lines, which do not represent a viable developmental context where the tumor mass interacts with and invades the surrounding brain tissues. Starting with pluripotent human embryonic stem cells we reproduced a 3D tissue structure (so-called cerebral organoid) representing a developing human brain in vitro. We engineered these mini-brains to express oncogenic hits responsible for the derivation of tumors in pediatric GBM patients. Pediatric GBM is driven by a combination of epigenetic and genetic hits including the expression of a mutant histone H3 variant H3F3A (mutated at K27M or G34R) or a gain of function mutant isocitrate dehydrogenase IDH1R132H in combination with the loss of the histone remodeling factor ATRX and/or p53 tumor suppressor. We used a combination of these oncogenic hits to create a model of tumor engineering representing the first 3D human tissue model of GBM. This model combines the accurate multi-lineage differentiation and physiology of human brain with the easiness of manipulation of in vitro systems.
H&E staining of the modified organoids shows remarkable dysplasia reminiscent of human primary glioma. Different genetic hits result in different type of dysplasia with IDH1R132H showing distinct morphology, suggestive of a broad range of applicability to model oncogenic-dependence in pediatric GBM.
Cerebral organoids may also be used as a model to study tumor invasion starting with glioma stem-like cells (GSCs, which are believed to be the tumor-initiating cells in GBM). Indeed 923 GSCs (which are not invasive in mice brain) quickly and spontaneously (within few days) invade a co-cultured cerebral organoid.
This study is the first to engineer a human CNS tumor in vitro. The model carries a tremendous potential to uncover the pathogenesis and initiation of brain cancer in pediatric settings.
Citation Format: Amin Ismail. Use of cerebral organoids to model pediatric gliomas with H3.3K27M and H3.3G34R. [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 LB-138. doi:10.1158/1538-7445.AM2015-LB-138