bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B06: Single-cell RNA-seq profiling of transcriptional transition states during human retinoblastoma development
Authors: Lee Sunhye , Singh Hardeep , Cobrinik David 
Published: November 2016

Abstract
Retinoblastoma is a rare childhood tumor initiated by biallelic inactivation of the RB1 gene and loss of function of retinoblastoma (Rb) protein. Although Rb loss is a key-initiating event, the molecular mechanisms controlling the transformation into malignancy remain unclear. In this project, we seek to define the cell state transitions that follow RB1 inactivation in a defined cell of origin, the cone photoreceptor precursor. Previously we revealed that Rb knockdown could induce cone precursors to proliferate in vitro and to form retinoblastoma-like tumors in orthotopic xenografts. Using post-mitotic cone precursors from normal human fetal retina, we describe the generation, isolation, and single-cell RNA sequencing (RNA-seq) on RB1-knockdown cells at multiple time points to profile the levels of all polyadenylated transcripts. We then use “Monocle” to pseudo-temporally order cells according to their transcriptome profiles into distinct states through which the cells pass during cell cycle entry and tumor progression. Through this single cell RNA-seq approach, we will define the transcriptional alteration events of each cell state transition, and identify potential mediators of such transitions during retinoblastoma development. In addition, we define effects of inhibitors targeting potential mediators of each cell state transition as therapeutic candidates, currently focusing on Nutlin-3a (targeting MDM2), JQ1 (targeting MYCN), and SNS-032 and SU9516 (targeting CDK2). Taken together, this study seeks to identify transformation-related events that can be pharmacologically targeted to suppress tumorigenesis in genetically predisposed children.
Citation Format: Sunhye Lee, Hardeep Singh, David Cobrinik. Single-cell RNA-seq profiling of transcriptional transition states during human retinoblastoma development. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B06.
Abstract B15: Synergistic functions of E2F7 and E2F8 are critical to suppress stress induced skin cancer
Authors: Westendorp Bart , Thurlings Ingrid , Martinez-Lopez Lina , Zijp Marjolein , Kuiper Raoul , Tooten Peter , Vos HarmJan , Burgering Boudewijn , Bruin Alain de 
Published: November 2016

Abstract
E2F transcription factors are important regulators of the cell cycle, and unrestrained activation of E2F-dependent transcription is considered to be an important driver of tumor formation and progression. Although highly expressed in normal skin and skin cancer, the role of the atypical E2Fs, E2F7 and E2F8, in keratinocyte homeostasis, regeneration and tumorigenesis is unknown. Surprisingly, keratinocyte-specific deletion of E2F7 and E2F8 in mice did not interfere with skin development and wound healing. However, the rate for successful isolation and establishment of E2f7/8-deficient primary keratinocyte cultures was much higher than for wild-type keratinocytes. Moreover, E2f7/8-deficient primary keratinocytes proliferate more efficiently under stress conditions, such as low/high confluence or DNA damage. Application of in vivo stress using the DMBA/TPA skin carcinogenesis protocol revealed that combined inactivation of E2f7/8 enhanced tumorigenesis and accelerated malignant progression. Loss of atypical E2Fs resulted in increased expression of E2F target genes, including E2f1. Additional loss of E2f1 did not rescue, but worsened skin tumorigenesis. We show that loss of E2F7/8 triggers apoptosis via induction of E2F1 in response to stress, indicating that the tumor-promoting effect of E2F7/8 inactivation can be partially compensated via E2F1-dependent apoptosis. Importantly, E2F7/8 repressed a large set of E2F target gene that are highly expressed in human patients with skin cancer. Together, our studies demonstrate that atypical E2Fs act as tumor suppressors, most likely via transcriptional repression of cell cycle genes in response to stress.
Citation Format: Bart Westendorp, Ingrid Thurlings, Lina Martinez-Lopez, Marjolein Zijp, Raoul Kuiper, Peter Tooten, HarmJan Vos, Boudewijn Burgering, Alain de Bruin. Synergistic functions of E2F7 and E2F8 are critical to suppress stress induced skin cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B15.
Abstract B30: Resistance to Photodynamic Therapy in Non-Melanoma Skin Cancer Cells
Authors: Leon Daniela , Silva Ramon , Inada Natalia , Kurachi Cristina , Ili Carmen Gloria , Brebi Priscilla , Roa Juan Carlos 
Published: November 2016

Abstract
Introduction: Squamous skin cancer is one of the most common neoplasia worldwide and may be preceded by Bowen's disease (BD) and Actinic Keratosis (AK). These preneoplastic lesions can be treated with photodynamic therapy (PDT). PDT causes cell death mainly by reactive oxygen species (ROS) produced through a combination of O2, a photosensitizer and light. BD and AK have well overcomes after PDT. However, high recurrence rates of some lesions have been reported.
Objective: To generate resistant cells to PDT as an in vitro model for future studies.
Methodology: HSC-1 cells from human squamous cell cancer (SCC) of skin were used. Cells were treated with a total of 16 cycles of PDT. Every PDT cycle was carried out incubating cells with methyl aminolevulinate (MAL), as a protoporphyrin IX (PpIX) precursor, for 4 hours in the dark. Then, cells were irradiated with red light (630 nm). The light fluence used for the four first cycles was 1 J/cm2, for subsequent cycles light fluence increased to 2, 3 and 4 J/cm2. Cell viability was evaluated 1 and 24 hours after PDT by flow cytometry and MTT assay respectively. Intracellular PpIX was detected by flow cytometry and the PpIX content was quantified using a standard curve. By flow cytometry using a CM-H2DCFDA probe intracellular ROS was detected.
Results: After 24 hours of PDT (4 J/cm2), viability in parental HSC-1 cells was 5%, meanwhile in resistant cells was 70% (P &lt; 0.05). On the other hand, 88% of parental cells produced PpIX (40 ng/mg protein) and 18% of resistant cells produced PpIX (17 ng/mg protein) (P &lt; 0.05). No significant differences were found in ROS detection in both parental and resistant cells.
Conclusion: The results indicate that it was possible to obtain HSC-1 cells two-fold resistant to PDT compared to their parental cells.
Acknowledgments: Financial support by CONICYT. CONICYT-PCHA/Doctorado Nacional/2012-21120665, CORFO 09CN14-5960, Corfo N°12IDL2-18157, FONDECYT N° 11150802, FONDECYT N°11150622.
Citation Format: Daniela Leon, Ramon Silva, Natalia Inada, Cristina Kurachi, Carmen Gloria Ili, Priscilla Brebi, Juan Carlos Roa. Resistance to Photodynamic Therapy in Non-Melanoma Skin Cancer Cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B30.
Abstract IA02: Neomorphic functions of cyclin D1 during neoplastic development
Authors: Diehl J. Alan 
Published: November 2016

Abstract
Cyclin D1 is a cell cycle recipient of diverse oncogenic signals and a multifunctional transcriptional modulator. Extensive studies have characterized mutational disruption of p53 signaling in human cancers. However, the mechanisms underlying retention of wild-type p53 during neoplastic outgrowth have remained ambiguous. We have identified and functionally validated a crucial role for arginine-methylation of p53 as a mechanism for inhibition of p53-dependent apoptosis in response to oncogenic insults. Phosphorylation-dependent activation of PRMT5/MEP50 enforces catalytic targeting of p53 thereby reducing p53 occupancy on key target promoters and sustaining leukemia/lymphoma tumor cell proliferation and survival. The requisite role for PRMT5 in the context of multiple lymphoma/leukemia oncogenic drivers suggests a molecular rationale for therapeutic development.
Citation Format: J. Alan Diehl. Neomorphic functions of cyclin D1 during neoplastic development. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA02.
Abstract IA11: Transient CDK4/6 inhibition protects hematopoietic progenitors from chemotherapy-induced exhaustion
Authors: Sharpless Norman E. 
Published: November 2016

Abstract
Conventional cytotoxic chemotherapy is highly effective in certain cancers, but causes dose-limiting damage to normal proliferating cells, especially hematopoietic stem and progenitor cells (HSPCs). Serial exposure to cytotoxics causes a long-term hematopoietic compromise (“exhaustion”), which limits the use of chemotherapy and success of cancer therapy. I will discuss the use of small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) contemporaneously with DNA damaging stimuli such as cytotoxic chemotherapy to protect HSPC from chemotherapy-induced exhaustion. Specifically, CDK4/6 inhibitors will reduce HSPC proliferation, leading to decreased damage from cytotoxic agents, resulting in preserved HSPC function acutely after bone marrow injury as well as late time points well after hematopoietic recovery. In particular, I will show this approach leads to enhanced long-term HSC function resulting in enhanced serial transplantation and reduced myeloid skewing. I will discuss similarities between chemotherapy-induced HSC dysfunction and HSC aging. Moreover, these finding suggest that the combination of CDK4/6 inhibitors with DNA damaging chemotherapy provides a means to prevent therapy-induced bone marrow exhaustion.
Citation Format: Norman E. Sharpless. Transient CDK4/6 inhibition protects hematopoietic progenitors from chemotherapy-induced exhaustion. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA11.
Abstract PR04: Characterizing the sequence of cell-cycle events during proliferation and quiescence
Authors: Gookin Sara , Spencer Sabrina Leigh 
Published: November 2016

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR04) of the Conference Proceedings.
Although the cell-cycle field has identified most of the key biochemical events involved in cell-cycle progression, we do not have a clear picture of overall cell-cycle dynamics. The prevalence of cell-to-cell variability is increasingly appreciated, but this heterogeneity is blurred when bulk analysis approaches are used, potentially resulting in incorrect interpretations of biological data. Using a live-cell sensor for CDK2 activity, we recently discovered that unperturbed cycling cells bifurcate into two subpopulations as they exit mitosis: one subpopulation begins to immediately increase CDK2 activity (CDK2inc cells), whereas the other subpopulation turns off CDK2 activity and enters a period of quiescence (CDK2low cells). These cells can later re-enter the cell cycle by building up CDK2 activity (CDK2low-&gt;inc). Here we use single-cell time-lapse microscopy followed immediately by immunofluorescence to determine the dynamics of over 15 cell-cycle proteins in unperturbed cycling mammary epithelial cells. By sorting individual cells by their CDK2inc versus CDK2low trajectory, and aligning them as a function of time-since-anaphase, we identified several unexpected differences in protein levels (or modification states) in the two subpopulations. Moreover, we identified certain proteins whose concentrations steadily decrease the longer the cells are in quiescence, suggesting the existence of multiple levels of quiescence depth. Cells can also emerge from quiescence by engaging CDK2 activity. When we align these CDK2low-&gt;inc cells to the time of initial increase in CDK2 activity, we recapitulate the cell-cycle dynamics seen in the CDK2inc cells. These results argue that cell-cycle commitment is not a point in time, but rather a molecular event (CDK2 activation) that varies temporally across cells. In summary, our single-cell measurements provide a critical resource for the field by describing the dynamics and sequence of many key cell-cycle proteins in unperturbed proliferating and quiescent cells.
This abstract is also being presented as Poster A05.
Citation Format: Sara Gookin, Sabrina Leigh Spencer. Characterizing the sequence of cell-cycle events during proliferation and quiescence. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr PR04.
Abstract PR07: Recruitment of Pontin/Reptin by E2F1 amplifies E2F transcriptional response during cancer progression
Authors: Tarangelo Amy , Lo Nathanael , Teng Rebecca , Kim Eunsun , Raman Pichai , Viatour Patrick 
Published: November 2016

Abstract
Unrestricted E2F activity and increased E2F1 expression are hallmarks of liver cancer, but the consequences of aberrant E2F activity for liver cancer progression remain ill defined. Our data show that aberrant E2f activity, following inactivation of the Rb gene family in a mouse model of liver cancer, initially triggers a robust gene expression program associated with the cell cycle and predominantly driven by E2f2 and E2f3. During liver cancer progression, slowly accumulating E2f1 recruits a Pontin/Reptin complex to insert the H2a.z histone variant and open the chromatin conformation at E2f1-bound target genes. This epigenetic mechanism amplifies the E2f transcriptional response, leading to enhanced transactivation of cell cycle genes and de novo activation of low binding affinity E2f target genes that regulate non-cell cycle oncogenic features, such as the Warburg effect. In addition, extensive mouse genetic approaches indicate that E2f-driven liver cancer initiation and progression is cell type specific, suggesting that a permissive chromatin environment is necessary to enable E2f oncogenic functions. Collectively, these data indicate that sustained E2F activity expands E2F transcriptional response and connects the regulation of cell cycle with multiple non cell cycle functions that drive tumor progression.
This abstract is also being presented as Poster B13.
Citation Format: Amy Tarangelo, Nathanael Lo, Rebecca Teng, Eunsun Kim, Pichai Raman, Patrick Viatour. Recruitment of Pontin/Reptin by E2F1 amplifies E2F transcriptional response during cancer progression. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr PR07.
Abstract PR11: APC/CCdh1 maintains primordial follicles, germinal vesicle arrest and ensures balanced segregation of chromosomes by enabling removal of Shugoshin-2 from chromosomes arms
Authors: Rattani Ahmed , Mejia Randy Ballestros , Roberts Katherine , Roig Maurici B , Godwin Jonathan , Eguren Manuel , Ogushi Sugako , Okaz Elwy , Pendas Alberto , Marcos Malumbres , Herbert Mary , Nasmyth Kim 
Published: November 2016

Abstract
Germ cells in mammals, including humans, remain arrested at the primordial follicle stage from a few days to many years depending on the species. At each hormonal cycle, a few of these cells grow in size to become fully-grown oocytes but remain arrested in meiotic prophase. A resumption of meiosis is heralded by germinal vesicle breakdown (GVBD), a gradual rise in Cdk1 activity, condensation of bivalent chromosomes, and their eventual alignment on metaphase plates with maternal and paternal kinetochore pairs pulled in opposite directions (co-orientation). The first meiotic division is triggered by activation of a form of the Anaphase-promoting complex/cyclosome associated with Cdc20 (APC/CCdc20), which activates separase and thereby destroys sister chromatid cohesion along chromosome arms, resolving chiasmata. Because cohesion around centromeres is protected from separase by protein phosphatase 2A (PP2A) recruited by shugoshin (Sgol2), bivalents are converted at this division to dyad chromosomes in which sister chromatids are held together by peri-centric cohesin. We show here that an alternative version of the APC/C associated with the Cdc20-like Cdh1 protein (APC/CCdh1) has equally important roles. By promoting proteolysis of mitotic cyclins and Cdc25B, APC/CCdh1 delays the increase in Cdk1 activity leading to GVBD. More surprising, by moderating the rate at which Cdk1 is activated following GVBD, APC/CCdh1 creates conditions necessary for the removal of Sgol2 from chromosome arms by the Aurora B/C kinase, an event crucial for the efficient resolution of chiasmata. Lastly, by targeting proteins other than cyclins, APC/CCdh1 prevents apoptosis of primordial follicles during their extended prophase (G2) arrest.
This abstract is also being presented as Poster A24.
Citation Format: Ahmed Rattani, Randy Ballestros Mejia, Katherine Roberts, Maurici B Roig, Jonathan Godwin, Manuel Eguren, Sugako Ogushi, Elwy Okaz, Alberto Pendas, Malumbres Marcos, Mary Herbert, Kim Nasmyth. APC/CCdh1 maintains primordial follicles, germinal vesicle arrest and ensures balanced segregation of chromosomes by enabling removal of Shugoshin-2 from chromosomes arms. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr PR11.
Lifetime Risk and Risk Factors for Abdominal Aortic Aneurysm in a 24-Year Prospective Study
Authors: Tang Weihong , Yao Lu , Roetker Nicholas S. , Alonso Alvaro , Lutsey Pamela L. , Steenson Carol C. , Lederle Frank A. , Hunter David W. , Bengtson Lindsay G.S. , Guan Weihua , Missov Emil , Folsom Aaron R. 
Published: November 2016

Objective—
Abdominal aortic aneurysm (AAA) is an important vascular disease in older adults, but data on lifetime risk of AAA are sparse. We examined lifetime risk of AAA in a community-based cohort and prospectively assessed the association between midlife cardiovascular risk factors and AAAs.

Approach and Results—
In ARIC study (Atherosclerosis Risk in Communities), 15 792 participants were recruited at visit 1 in 1987 to 1989 and followed up through 2013. Longitudinal smoking status was defined using smoking behavior ascertained from visit 1 (1987–1989) to visit 4 (1996–1998). We followed up participants for incident, clinical AAAs using hospital discharge diagnoses, Medicare outpatient diagnoses, or death certificates through 2011 and identified 590 incident AAAs. An abdominal ultrasound was conducted in 2011 to 2013 in 5911 surviving participants, and 75 asymptomatic AAAs were identified. We estimated the lifetime risk of AAA from the index age 45 years through 85 years of age. At age 45, the lifetime risk for AAA was 5.6% (95% confidence interval, 4.8–6.1) and was higher in men (8.2%) and current smokers (10.5%). Smokers who quit smoking between visit 1 and visit 4 had a 29% lower AAA lifetime risk compared with continuous smokers but had a higher risk than pre-visit 1 quitters. The lifetime risk of rupture or medical intervention was 1.6% (95% confidence interval, 1.2–1.8). Smoking, white race, male sex, greater height, and greater low-density lipoprotein or total cholesterol were associated with an increased risk of clinical AAA and asymptomatic AAA.

Conclusions—
At least 1 in 9 middle-aged current smokers developed AAA in their lifetime. Smoking cessation reduced the lifetime risk of AAA.
Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1β Production
Authors: Ceneri Nicolle , Zhao Lina , Young Bryan D. , Healy Abigail , Coskun Suleyman , Vasavada Hema , Yarovinsky Timur O. , Ike Kenneth , Pardi Ruggero , Qin Lingfen , Qin Li , Tellides George , Hirschi Karen , Meadows Judith , Soufer Robert , Chun Hyung J. , Sadeghi Mehran M. , Bender Jeffrey R. , Morrison Alan R. 
Published: November 2016

Objective—
The calcium composition of atherosclerotic plaque is thought to be associated with increased risk for cardiovascular events, but whether plaque calcium itself is predictive of worsening clinical outcomes remains highly controversial. Inflammation is likely a key mediator of vascular calcification, but immune signaling mechanisms that promote this process are minimally understood.

Approach and Results—
Here, we identify Rac2 as a major inflammatory regulator of signaling that directs plaque osteogenesis. In experimental atherogenesis, Rac2 prevented progressive calcification through its suppression of Rac1-dependent macrophage interleukin-1β (IL-1β) expression, which in turn is a key driver of vascular smooth muscle cell calcium deposition by its ability to promote osteogenic transcriptional programs. Calcified coronary arteries from patients revealed decreased Rac2 expression but increased IL-1β expression, and high coronary calcium burden in patients with coronary artery disease was associated with significantly increased serum IL-1β levels. Moreover, we found that elevated IL-1β was an independent predictor of cardiovascular death in those subjects with high coronary calcium burden.

Conclusions—
Overall, these studies identify a novel Rac2-mediated regulation of macrophage IL-1β expression, which has the potential to serve as a powerful biomarker and therapeutic target for atherosclerosis.