tbuckley/cabot-search huggingface dataset:
Abstract 2816: The Jackson Laboratory Repository: Mouse models for cancer research
Authors: Deborah Boswell, Stephen Rockwood, Michael Sasner, The JAX Repository Team
Journal: Cancer Research (2017)

Abstract The mouse is a well-established model organism for research of the biology, prevention, diagnosis, and treatment of cancer. Among the advantages of this valuable biomedical research tool are a relatively short reproductive cycle, an accelerated lifespan, and the ease of genetic manipulation and modification. Serving as a resource to the scientific community, the JAX Repository collection encompasses over 10,000 mouse strains and acquires hundreds of new models each year. Some of these new models are highlighted in this poster. Many of these strains have applications for modeling human cancer, including genetically engineered mouse models for specific cancers and xenograft models. Research tool strains, such as cas9-expressing (CRISPR) lines, a suite of immunodeficient mice, and recombinase expressing strains, are available to investigators to generate customized mutant lines for specialized purposes. JAX offers supplementary research tools that include specialized strain platforms and other useful resources. The JAX patient-derived xenograft (PDX) cancer model resource leverages the immunodeficient NSG strain for tumor engraftment. The Repository maintains a searchable online resource to find mice (www.jaxmice.jax.org) and an Oncology Therapeutic Area page (www.jax.org/jax-mice-and-services/solutions-by-therapeutic-area/oncology) as a launch pad to featured JAX strains and resources related to oncology research. The Repository has a rigorous quality control program that inspects and confirms expected mutation identity and genetic background. JAX mouse lines are also screened for alleles (GFP, cre, lacZ, etc.) that may contaminate strains in mouse lines shared between labs—an underappreciated problem that may contribute to inconsistencies of reproducibility. In addition, the Reproductive Sciences group at JAX safeguards each strain by cryopreservation, and can create cohorts for studies rapidly using IVF technology. Researchers can submit their strains to be considered for inclusion in the Repository by using the on-line form available at The Jackson Laboratory website: www.jax.org/donate-a-mouse. The Jackson Laboratory Repository is supported by the NIH, The Howard Hughes Medical Institute, and other private charitable foundations. Citation Format: Deborah Boswell, Stephen Rockwood, Michael Sasner, The JAX Repository Team. The Jackson Laboratory Repository: Mouse models for cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2816. doi:10.1158/1538-7445.AM2017-2816
Abstract 3263: Is Latin America ready for the use of genomics in cancer care and control
Authors: Sandra Perdomo, Angela Torres, Javier Olivier, Cecilia Frecha, Rosalía Quezada-Urban, Clara Estela Díaz-Velasquez, Felipe Vaca
Journal: Cancer Research (2017)

Abstract In Latin American (LA) countries cancer is the second most frequent cause of death after cardiovascular disease. Disease patterns have changed from infectious to chronic, the population is increasing and becoming elderly, and countries lack planning to respond adequately to this epidemiological and socio-demographic transition. By 2025 and increment of nearly 30% of new cases and 35% of deaths from cancer are predicted. Genomic studies have profoundly changed cancer management from improved cancer diagnosis to reformulating cancer prognosis and treatment. However, all these key advances have been mainly concentrated in highly developed nations and little is known about the capacities and needs of cancer genomics in the LA context. In order to evaluate the capacity and development of cancer genomics in LA, we collected available information for all countries in Central, South America and Cuba. Data reviewed included: number of NGS platforms, number of cancer research institutions, research groups working in cancer genetics, publications on cancer genetics and genomics in the last 10 years, educational programs on genomics and related national cancer control policies. Currently, there are a total of 212 NGS platforms in LA. Mexico and Brazil are the countries with more users, and Peru and Ecuador have the fewest. 118 research groups in South America have been working in cancer genetics and started developing cancer genomics related projects. No data on research groups was available for countries in Central America. In the last 10 years, 231 articles in cancer genetic/genomic related topics were published by authors affiliated to LA institutions. Educational programs in genomics are scarce, almost exclusive of graduate programs and few applied to cancer. Twelve countries in LA have national cancer control plans (NCCP). All NCCPs reviewed consider secondary prevention strategies for early diagnosis, opportune treatment and decrease of mortality, areas where genomic analysis could be implemented. Only 5 NCCPs include cancer research as an action plan to increase cancer prevention strategies and reduce both incidence and mortality. Despite the recent advances in introducing cancer genomics knowledge and application in LA, the region lacks development of integrated genomic research projects, improved use of platforms, associated educational programs and health policies that might focus on the most frequent cancers and could impact cancer care. Citation Format: Sandra Perdomo, Angela Torres, Javier Olivier, Cecilia Frecha, Rosalía Quezada-Urban, Clara Estela Díaz-Velasquez, Felipe Vaca. Is Latin America ready for the use of genomics in cancer care and control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3263. doi:10.1158/1538-7445.AM2017-3263
Abstract 4131: ERRβ: Validating a novel target for triple negative breast cancer
Authors: Aileen I. Fernandez, Garrett Graham, Balázs Győrffy, Luciane Cavalli, Rebecca B. Riggins
Journal: Cancer Research (2017)

Abstract Triple negative breast cancer (TNBC) - defined as estrogen receptor- (ER), progesterone receptor- (PR), and human epidermal growth factor receptor 2- (HER2) negative - is a highly aggressive form of breast cancer prevalent in African-American (AA) women. Because ER- and HER2-targeted therapies are ineffective in TNBC, current treatment strategies rely on cytotoxic chemotherapy. There is a tremendous need for new approaches that can identify effective therapies with less toxicity for this devastating form of breast cancer. Nuclear receptors are highly druggable targets. Classical examples include ligand-regulated receptors like ER, but orphan nuclear receptors are also emerging as targets for cancer therapy. We recently published that increased mRNA expression of estrogen-related receptor beta (ERRβ, gene symbol ESRRB) correlates with better recurrence- and distant metastasis-free survival in women with TNBC, and that a small molecule agonist ligand for ERRβ (DY131, DY) has growth inhibitory and anti-mitotic activity in TNBC cell lines of multiple molecular subtypes. The goal of our current work is to validate ERRβ as a novel therapeutic target for TNBC in two distinct ways. First, we sought to determine whether ERRβ is correlated with survival outcome specifically in African-American (AA) women. Analysis of The Cancer Genome Atlas (TCGA) Breast Cancer RNAseq data shows that low ERRβ mRNA expression is specifically associated with poor overall survival in AA women with TNBC. This association is not observed in AA women with ER- or HER2-positive disease. We further find that while ERRβ mRNA expression is decreased in tumor vs. normal breast tissue regardless of race, this decrease is more pronounced in AA women. Ongoing studies in an independent cohort of AA and white women will determine whether this is due, in part, to copy number changes at the ERRβ locus (chromosome 14q24.3). Second, we sought to determine whether ERRβ expression could predict response to current treatment strategies commonly used in breast cancer, particularly TNBC. Using multiple combined datasets, we find that high ERRβ expression is associated with improved recurrence-free survival (RFS) in women with TNBC who received adjuvant or neoadjuvant therapy with anthracycline (e.g. doxorubicin, Adriamycin). No association between ERRβ and RFS is observed in patients treated with taxanes. Ongoing studies in TNBC cell lines seek to determine if activating ERRβ with its agonist ligand DY can enhance doxorubicin-mediated growth inhibition and cell death. Citation Format: Aileen I. Fernandez, Garrett Graham, Balázs Győrffy, Luciane Cavalli, Rebecca B. Riggins. ERRβ: Validating a novel target for triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4131. doi:10.1158/1538-7445.AM2017-4131
Abstract 706: Combination ionizing radiation and oncolytic Seneca Valley virus injection enhances tumor cell killing of pediatric gliomas
Authors: Yuchen Du
Journal: Cancer Research (2017)

Abstract Background and Purpose: Radiation therapy is the traditional and only therapy that offers benefits to patients with diffuse intrinsic pontine gliomas (DIPG) which are highly aggressive pediatric central nervous system tumors without known curative therapies. However, unfortunately, efficacy of radiation therapy is transient. Seneca Valley virus-001(SVV-001) is a novel non-pathogenic oncolytic piconavirus that can be systemically administered and pass through brain blood barrier (BBB). Phase I clinical trial of SVV has proven its efficacy in adults patients with cancers with neuroendocrine features and in pediatric patients with non-central nerve system (CNS) tumors. We sought to examine if combining ionizing radiation with an oncolytic virus SVV-001 would lead to synergistically enhanced tumor cell killing and significantly improve therapeutic efficacy in vivo in DIPG patient tumor-derived intra-brain stem orthotopic xenograft mouse models (PDOX). Methods: By infecting PDOX derived tumor cells with green fluorescent protein (GFP)-coupled SVV (SVV-GFP) or SVV-001, in vitro virus infection and anti-tumor activity of SVV were examined by cell viability assay, Western Blotting for apoptosis and autophagy-related protein and immunohistochemistry (IHC) staining or Flow cytometry for cell mitochondria content. In vivo therapeutic efficacy was evaluated by systemic administration of SVV into PDOX derived DIPG xenografts alone or in combination with irradiation. Results: We first had established a novel panel of nine PDOX derived orthotopic xenograft mouse models of DIPG. Our data confirmed that SVV can infect and efficiently kill DIPG tumor cells in vitro by inducing apoptosis and autophagy, leading to improved animal survival in a subset of DIPG xenograft models. We found that the lack of mitochondria in the xenograft tumor cells in vivo impaired the intracellular replication of SVV-001 and subsequently compromised its oncolytic cell killing of tumor cells in vivo. Radiation induced elevated mitochondria biogenesis in tumor cells therefore boosted SVV oncolysis of tumor cells. Moreover, combining fractionated radiation with single i.v.injection of SVV led to significant improvement of animal survival in a subset of DIPG models. Conclusion: SVV-001 killed DIPG xenograft cells in vitro. Radiation activated mitochondria content of tumor cells in vivo, which restored impaired SVV oncolytic function.Combining radiation with single systemic administration of SVV synergistically enhanced animal survival in a subset of DIPG xenograft models. Citation Format: Yuchen Du. Combination ionizing radiation and oncolytic Seneca Valley virus injection enhances tumor cell killing of pediatric gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 706. doi:10.1158/1538-7445.AM2017-706
Abstract 5338: Transcriptional elongation mediates human papillomavirus type 16 late promoter activation
Authors: William Songock, Jason Bodily
Journal: Cancer Research (2017)

Abstract Human papillomaviruses (HPVs) are small DNA viruses that infect keratinocytes of squamous epithelia and cause benign lesions that can progress to several malignancies, including cervical cancer. Upregulation of viral transcripts by the HPV16 late promoter is dependent on host cellular differentiation. We sought to investigate the main cellular transcription regulators that correlate with differentiation-dependent increase in the late viral transcripts. Here, we show evidence that the step in transcription cycle that is responsible for late promoter activation is transcriptional elongation. We began by establishing that the increase in viral transcripts originating from the late promoter is primarily regulated at the transcript synthesis level rather than post-transcription level. Based on this observation, we investigated whether there is a correlation between late promoter activation and activities that occur during the initiation, pausing or elongation steps of transcription cycle. Using chromatin immunoprecipitation (ChIP), we did not observed a differentiation-dependent increase of RNA Polymerase II (RNAP II) in the late promoter region. However, there was a significant increase of RNAP II at downstream sites of late promoter suggesting elongation is regulated by differentiation. We then sought to investigate the cyclin dependent kinases (CDKs) that are known to regulate transcription elongation. ChIP did not show a significant increase of the elongation factor CDK9 in the late promoter; however, the enrichment of CDK9 at downstream sites of the viral genome significantly increased upon differentiation, suggesting that differentiation induces recruitment of CDK9 to facilitate elongation. Additionally, CDK8, a component of the Mediator complex that recruits CDK9 to the RNAP II, was increased upon differentiation. Kinase inhibitors against CDK8 did not affect late viral transcripts; however, knocking down CDK8 resulted in significant reduction of viral transcripts, suggesting that CDK8 could be involved in protein-protein interactions that are required for the synthesis of late viral transcripts. These findings suggest that HPV has evolved to utilize cellular transcriptional elongation machinery as a way of regulating its late gene expression. This mechanism allows the virus to persistently infect host cells and cause HPV-associated malignancies. Citation Format: William Songock, Jason Bodily. Transcriptional elongation mediates human papillomavirus type 16 late promoter activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5338. doi:10.1158/1538-7445.AM2017-5338
Abstract 4596: Antibody-drug conjugates bearing pyrrolobenzodiazepine or tubulysin payloads alter the tumor immune microenvironment and synergize with multiple immunotherapies
Authors: Jonathan Rios-Doria, Jay Harper, Raymond Rothstein, Leslie Wetzel, Jon Chesebrough, Allison Marrero, Cui Chen, Patrick Strout, Kathy Mulgrew, Kelly McGlinchey, Ryan Fleming, Binyam Bezabeh, John Meekin, David Stewart, Maureen Kennedy, Philip Martin, Andrew Buchanan, Nazzareno Dimasi, Emil Michelotti, Robert Hollingsworth
Journal: Cancer Research (2017)

Abstract Immunogenic cell death (ICD) is the process by which certain cytotoxic drugs induce apoptosis of tumor cells in a manner that stimulates the immune system. In this study, we investigated whether ADCs conjugated with pyrrolobenzodiazepine dimer (PBD) or tubulysin payloads induced ICD, modulated the immune microenvironment, and could combine with IO drugs to enhance antitumor activity. We show that these payloads on their own induced an immune response that prevented the growth of tumors following subsequent tumor cell challenge. ADCs had greater antitumor activity in immunocompetent vs. immunodeficient mice, demonstrating a contribution of the immune system to the antitumor activity of these ADCs. These ADCs also induced immunological memory. In the CT26 model, depletion of CD8+ T cells abrogated the activity of these ADCs when used alone or in combination with a PD-L1 antibody, confirming a role for T cells in the antitumor activity. Combinations of ADCs in different tumor models with IO drugs including PD-1 or PD-L1 antibodies, or OX40 ligand or GITR ligand fusion proteins produced synergistic antitumor responses. Importantly, synergy was observed in some cases with suboptimal doses of ADCs, potentially providing an approach to achieve potent antitumor responses while minimizing ADC-induced toxicity. Immunophenotyping studies in different tumor models revealed broad immunomodulation of lymphoid and myeloid cells by ADCs and ADC/IO combinations. These results suggest that it may be possible to develop novel combinatorial therapies with PBD- and tubulysin-based ADCs and IO drugs that may increase clinical responses. Citation Format: Jonathan Rios-Doria, Jay Harper, Raymond Rothstein, Leslie Wetzel, Jon Chesebrough, Allison Marrero, Cui Chen, Patrick Strout, Kathy Mulgrew, Kelly McGlinchey, Ryan Fleming, Binyam Bezabeh, John Meekin, David Stewart, Maureen Kennedy, Philip Martin, Andrew Buchanan, Nazzareno Dimasi, Emil Michelotti, Robert Hollingsworth. Antibody-drug conjugates bearing pyrrolobenzodiazepine or tubulysin payloads alter the tumor immune microenvironment and synergize with multiple immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4596. doi:10.1158/1538-7445.AM2017-4596
Lasers and the treatment of periodontitis: the essence and the noise
Authors: Charles M. Cobb
Journal: Periodontology 2000 (2017)

Abstract The dental literature contains 25 years of accumulated reports and clinical studies addressing the utility of lasers in the treatment of periodontitis, both as a monotherapy or as an adjunct to surgical and nonsurgical therapy. Yet, the evidence from the 118 human clinical studies cited in this narrative review remains conflicted and insufficient to suggest that integration of a laser in a periodontal treatment protocol will provide antimicrobial and healing outcomes superior to those achieved by traditional therapy. When viewed as a collective body of evidence, it becomes apparent that a majority of the studies are underpowered and exhibit significant heterogeneity in design. Furthermore, the collected studies report a varied choice of parameters, even within the same wavelength of laser. There is little uniformity between studies in the reporting of measured clinical parameters. Most studies reported 3‐ and/or 6‐month post‐treatment results; however, the range of time intervals includes studies reporting results from 1 week to up to 1–12 months or longer. Lastly, many studies were considered at risk for bias as a result of a lack of examiner masking and/or calibration. There is great need for well‐designed, highly controlled multicenter clinical trials that are adequately powered in terms of subject enrollment, that use similar protocols in terms of laser parameters and that report measureable outcomes in a uniform manner. Without such studies, the questions surrounding the use of lasers in the treatment of periodontal disease will persist.
Abstract 4841: Suppression of metastasis by KP54 and non-KP54 kisspeptins
Authors: Kelsey Rebecca Hampton, Keke M. Pounds, Andrew P. Trembath, Danny R. Welch
Journal: Cancer Research (2017)

Abstract KISS1 is a secreted neuropeptide which can act as a metastasis suppressor protein. Expression of KISS1 inhibits metastatic colonization at secondary sites, rendering disseminated cells dormant. In order for KISS1 to suppress metastasis, it must be secreted outside of the cell, where furin cleaves KISS1 into kisspeptins. This cleavage liberates an internal kisspeptin, Kisspeptin-54 (KP54, K67 to F121), which is amidated and has the ability to bind a Gq/11-coupled protein receptor KISS1R. The mechanism of action for KISS1 metastasis suppression has long been assumed to be KP54 interacting with KISS1R. However, expression of KISS1R is not necessary for KISS1 metastasis suppression, and the extracellular processing of KISS1 hints at an alternative hypothesis: a different kisspeptin may be responsible for suppressing metastasis. To test this hypothesis, all possible kisspeptins were generated based on known dibasic cleavage sites (M1-Q145; M1-R56; M1-R67; M1-R124; R56-R66; R67-F121; R56-F121; R56-Q145; R67-Q145; R124-Q145) and were cloned to include the same secretion sequence as nascent KISS1. These kisspeptins (KISS1 Manufactured Peptides, or KMP) were independently expressed in B16-F10 murine melanoma cells. To test for experimental metastasis, B16-F10 cells expressing KMP were injected intravenously into the lateral tail vein of syngeneic mice and the lungs were examined for metastatic load. While KP54 suppressed metastasis, additional KMP lacking the KISS1R binding site (LRF-NH2) were able to completely suppress metastasis (p&amp;lt;0.05). When assessing metastasis-associated traits in vitro, suppressor KMP suppressed motility, increased mitochondrial biomass, and increased oxidative phosphorylation (phenotypes previously reported with KISS1 expression). In particular, one kisspeptin (KMP2, M1 - R56) suppressed metastatic traits in vitro as well as completely suppressing metastasis in vivo. As a whole, these data suggest that metastasis suppression by KISS1 is not necessarily contingent on KISS1R activation, and also supports investigation into additional receptors. Citation Format: Kelsey Rebecca Hampton, Keke M. Pounds, Andrew P. Trembath, Danny R. Welch. Suppression of metastasis by KP54 and non-KP54 kisspeptins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4841. doi:10.1158/1538-7445.AM2017-4841