bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA15: Multiple targetable pathways for epigenetic therapy
Authors: Issa Jean-Pierre 
Published: December 2017

Abstract
Epigenetic reprogramming erases the malignant potential of some transformed cells and the aim of epigenetic therapy is to achieve some degree of reprogramming in-vivo by targeting epigenetic writers/readers. The resultant gene expression response includes reactivation of tumor-suppressor genes and differentiation pathways as well as activation of an immune response program, all of which contribute to eventual clinical activity. The DNA methyltransferase inhibitors azacitidine, decitabine and guadecitabine induce clinically meaningful remissions or improvements in 30-60% of patients with myeloid leukemias and prolong survival compared to standard approaches including chemotherapy. This therapy is accompanied by (i) global and gene specific demethylation, (ii) reactivation of silenced gene expression, (iii) delayed responses that correlate with early epigenetic reactivation and result in clonal elimination and (iv) eventual relapses and resistance the mechanisms of which appear to involve genetic evolution in some cases. Multiple other classes of epigenetic modifiers have now been targeted therapeutically including histone acetylases and deacetylases, histone methylases and demethylases, and readers of the epigenetic marks such as the BET family of proteins. Clinical trials of these drugs are ongoing and have already shown impressive clinical activity in selected cases. Using a parallel approach, we have shown that gene expression directed unbiased phenotypic screens can also uncover new and repurposed drugs for epigenetic therapy (e.g. cardiac glycosides, arsenic trioxide, natural products), and unbiased genetic screens have suggested novel targets as well (SWI/SNF proteins, CHD4 etc.). An even greater promise of epigenetic therapy lies in sensitization to other treatment modalities such as chemotherapy and immunotherapy. Ultimately, epigenetic therapy will be integrated into comprehensive treatment plans aimed long term disease control in many human malignancies.
Citation Format: Jean-Pierre Issa. Multiple targetable pathways for epigenetic therapy [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA15.
Abstract IA19: Targeting the PRC2 complex through EED for anti-cancer therapy
Authors: Atadja Peter W. 
Published: December 2017

Abstract
The Polycomb Repressive Complex-2 (PRC2) plays important roles in regulating gene expression through its histone H3 lysine methyl transferase activity. Dysregulation of PRC2 is observed in multiple cancers. For example, gain of function mutations of the EZH2 catalytic subunit of PRC2 have been reported in B-cell lymphomas, melanoma and parathyroid carcinoma. Components of the complex are also overexpressed in a number of cancers. The PRC2-complex have therefore become a major target for anti-cancer drug discovery. We and others, have reported anti-tumor activity of small molecular weight agents targeting the SAM-binding pocket of EZH2 in preclinical models and a number of EZH2 inhibitors ore showing promising activity in clinical trials. EED and SUZ12 are two additional components of the PRC2 core complex required for regulation of its catalytic function. High resolution structures and other reports have showed that binding of EED to tri-methylated histone H3 Lysine 27 (H3K27Me3) further stimulates the catalytic effect of EZh2. This suggests that small molecular weight compounds binding to and interfering with the EED stimulatory effect on Ezh2 may be able to modulate PRC2 activity. Following this possibility, we launched a comprehensive effort to discover non-catalytic site PRC2 binders. The discovery and characterization of EED226, a highly potent and selective EED-binding inhibitor of PRC2 will be presented. Data will be presented to demonstrate that EED226 inhibits PRC2 function via a distinct allosteric mechanism by binding to the H3K27Me3 binding pocket of EED. Furthermore, EED226 potently inhibits cellular H3K27Me3 levels, modulates target gene expression similar to the SAM competitive Ezh2 inhibitors and inhibits the proliferation of cell lines carrying mutant Ezh2. Oral administration of EED226 to EZH2-mutant tumor bearing mice leads to profound tumor regression. Our data therefore demonstrates that the multi-subunit PRC2 complex can be targeted at non-catalytic binding pockets to achieve anti-tumor activity. Some unique features of the anti-tumor activity achieved through targeting PRC2 will be discussed.
Citation Format: Peter W. Atadja. Targeting the PRC2 complex through EED for anti-cancer therapy [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA19.
Abstract 49: Simultaneous quantification of HPV oncogene (E6, E7 mRNA) and PD-L1 protein expression in oral cancer samples using flow cytometry
Authors: Morgan Rian J. , Chargin Amanda N. , Mirghani Haitham , Patterson Bruce K. 
Published: December 2017

Abstract
Background: Human papillomaviruses are a family of DNA viruses that infect the epithelium leading to the formation of lesions with the ability to progress into carcinoma in many forms. Research into causality of head and neck cancers has found a link to HPV infections affiliated with better prognosis. In addition, advances in immuno-oncology have brought immunotherapy to the forefront of cancer treatment across cancer types. Here we present data that demonstrate a combined diagnostic approach to quantify two markers important in the management of head and neck cancer.
Methods: Swabs were collected from patients of Institut Gustave Roussy with lesions of the oral pharynx. Swabs were collected and placed into a collection vial with a proprietary fixation/permeabilization solution (IncellCollect, IncellDx, Inc.) and shipped overnight on cold packs for processing. Upon receipt, samples were passed through a 35 µM filter to remove aggregates. Cells were labeled with CD45 antibodies to separate epithelial from immune cells, RNA in situ hybridization with E6, E7 mRNA probes (HPV OncoTect) was performed, and these cells were labeled with PD-L1 Ab (clone 28-8) prior to analysis on the flow cytometer (CytoFlex, Beckman Coulter, Inc). Samples were also stained with DAPI to identify single nucleated cells, and to analyze cell cycle.
Results: We analyzed samples from 8 patients with oral cancer with the combined E6, E7 mRNA/PD-L1 protein assay by flow cytometry. The percentage of tumor cells expressing PD-L1 averaged 9.1% in all of the samples. Of the HPV DNA positive tumor samples, the percentage of cells overexpressing HPV E6, E7 mRNA was 4.8%. Interestingly, the percentage of cells overexpressing E6, E7 mRNA that also expressed PD-L1 was statistically lower (1.4%) than the percentage of all tumor cells that expressed PD-L1 (P=0.01).
Conclusions: We report a novel flow cytometric assay to quantify both HPV E6, E7 mRNA and PD-L1 simultaneously in single cells. Further, we found the expression of PD-L1 in tumor cells with HPV E6, E7 mRNA to be significantly lower than the expression of PD-L1 in tumor cells not expressing HPV E6, E7 mRNA. These findings may influence prognosis and treatment strategies.
Note: This abstract was not presented at the conference.
Citation Format: Rian J. Morgan, Amanda N. Chargin, Haitham Mirghani, Bruce K. Patterson. Simultaneous quantification of HPV oncogene (E6, E7 mRNA) and PD-L1 protein expression in oral cancer samples using flow cytometry [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 49.
Abstract IA08: Personalizing HNSCC treatment based on TP53 mutational status
Authors: Myers Jeffrey 
Published: December 2017

Abstract
Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer deaths worldwide, and resistance to standard treatments with radiation/chemotherapy accounts for the majority of HNSCC deaths. Mutation of TP53 occurs in 60-85% of non-HPV-associated HNSCC cases, and some mutant p53s display oncogenic properties, termed “gain-of-function (GOF),” which are independent of wild-type (WT) p53 functions. These GOF p53 mutant proteins can enhance cell transformation, increase tumor formation, and confer cellular resistance to chemo- and/or radio-therapy. Therefore, we are interested in the development of innovative therapeutic approaches to overcome this resistance. Pre-clinical studies both in vitro and in vivo have shown the promise of some novel targeted agents including Chk-1, Wee-1, and PARP inhibitors used alone or in combination with HDAC inhibition. In addition, COTI-2 is a novel drug with striking single-agent and radio-/chemo-sensitizing activity in pre-clinical models of HNSCC bearing TP53 mutations. Our preliminary data demonstrate that COTI-2 markedly decreases cell growth in vitro and induces p21, noxa, and puma expression in HNSCC cells. COTI-2 also negatively modulates the PI3K/AKT/mTOR survival pathway, which is constitutively activated in many types of cancer including HNSCC. In vitro studies in our laboratory have shown that COTI-2 has a nanomolar (IC50: 1.3-13.2 nm) activity in nine human HNSCC cell lines. Additionally, GOF mutant p53-bearing HNSCC cells are significantly delayed in outgrowth in an orthotopic nude mouse model of tongue cancer when treated with COTI-2. Current clinical studies are evaluating the safety and efficacy of the combination of COTI-2 alone and in combination with cisplatin in phase I/II studies of patients with refractory HNSCC and whether response is associated with TP53 mutational status of the tumor determined from sequencing of circulating cell free DNA. If this combination is found to safely provide sensitization of HNSCC to cisplatin-based chemotherapy in the majority of human patients who have TP 53 mutant tumors, this should make a major impact on the survival of individuals suffering from HNSCC, and potentially other p53 driven epithelial malignancies.
Citation Format: Jeffrey Myers. Personalizing HNSCC treatment based on TP53 mutational status [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr IA08.
Abstract IA09: Comprehensive genomic characterization of head and neck squamous cell carcinomas
Authors: Grandis Jennifer R. 
Published: December 2017

Abstract
Large and comprehensive genomic analyses of head and neck squamous cell carcinomas (HNSCC) are greatly increasing our understanding of the heterogeneity of this disease and identifying the key genomic changes that drive these tumors. HNSCC tumors associated with HPV are distinct from HNSCC disease linked to tobacco exposure (HPV-positive versus HPV-negative). HPV- tumors are characterized by: 1) amplification of receptor tyrosine kinases (RTK); 2) genomic loss of TP53 and loss of CKDN2A/RB1 by a variety of mechanisms including truncating mutation, deletion, and/or alternative splicing; 3) amplification of CCND1/CDK4/CDK6; 4) activation of NFE2L2/KEAP1/CUL3; and 5) loss of NOTCH1/FAT1/AJUBA. In contrast, HPV-positive HNSCCs harbor: 1) RTK amplification; 2) FGFR2/3 mutations and/or FGFR3-TACC3 fusions; 3) CDKN2A loss; and 4) E2F1 amplification. Interestingly, activating mutations in the PIK3CA oncogene are found in approximately one third of HPV-negative HNSCC and in over fifty percent of HPV-positive tumors. Mutually exclusive mutations in RAS family genes, specifically RHOA, KRAS, and HRAS, are present but infrequently found in HNSCC (6% of TCGA cases). Amplification of chromosome 3q, a region containing the TP63, SOX2, and PIK3CA genes, is seen in the majority of both HPV-negative and HPV-positive HNSCC. HPV-negative HNSCCs demonstrate clear evidence of molecular heterogeneity, as demonstrated by expression profiling studies indicating diverse biologic subclasses within HPV-negative disease, including a class of tumors without EGFR amplification and/or overexpression, previously termed “atypical” HNSCCs, which consist of approximately 20% of HPV-negative cases and the majority of HPV-positive HNSCCs. An intriguing mutational pattern identified by TCGA was a subset of HPV-negative HNSCC originating in the oral cavity with few to no copy-number alterations statistically enriched for HRAS, CASP8, and PIK3CA mutations and lack of TP53 mutation. With increasing genetic profiling of HNSCC cell lines and patient-derived xenografts, there is increasing opportunity to rationally select preclinical models to test specific precision medicine hypotheses.
Citation Format: Jennifer R. Grandis. Comprehensive genomic characterization of head and neck squamous cell carcinomas [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr IA09.
Abstract IA11: Interactions between the genome and immune microenvironment in head and neck cancer
Authors: Morris Luc G. T. 
Published: December 2017

Abstract
Precision oncology is a term used to describe the attempt to match every cancer patient's tumor to the right drug or treatment, generally based on molecular or genomic
features. At Memorial Sloan Kettering Cancer Center, the implementation of a targeted next-generation sequencing panel into routine clinical care for all patients with advanced tumors has allowed us to profile over 16,000 tumors in the past few years. The goal of such an approach has primarily been to match patients with recurrent and metastatic tumors to targeted therapies under the aegis of basket studies, and secondarily, to learn more about the unique biology of advanced cancers. This presentation will review the implementation of this precision oncology approach to patients with advanced head and neck cancer, particularly focused on squamous cell (HNSCC) and salivary carcinoma. The low number of targetable alterations in most head and neck tumor histologies has allowed for a modest degree of matching with targeted therapies. The program, however, has provided unprecedented insight into unique molecular features in recurrent/metastatic head and neck cancer. Some of the unique aspects discussed will be the genetic findings in aggressive HPV+ HNSCC and major subtypes of salivary cancer including adenoid cystic and salivary duct carcinoma.
We are now entering an exciting era where we now understand that immunotherapy is highly active in HNSCC. This is largely the result of decades of basic immunologic investigation into identifying and targeting specific T cell checkpoint molecules. Phenomenal responses have been observed in patients with HNSCC, with overall response rates for heavily pretreated patients with metastatic disease in the 15-25% range. Unfortunately, many patients currently do not experience tumor responses. There is therefore a critical need to understanding patient and tumor features that may be predictive of response to immunotherapies such as immune checkpoint inhibitors. Immunogenomic approaches can provide insight into some of the aspects of tumor cells (such as mutation or neoantigen burden), or the tumor immune microenvironment (such as immune cell infiltration, measures of T cell activation, and expression of immunoregulatory molecules). Implementation of such approaches for HNSCC and salivary cancers in the context of a precision oncology approach to cancer care, can provide important insights to guide the next steps of clinical research. Multidimensional immunogenomic analyses can provide new insights into how the tumor genome and immune system interact with and shape one another.
Citation Format: Luc G. T. Morris. Interactions between the genome and immune microenvironment in head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr IA11.
Abstract IA19: Clinical and imaging methods for grading and predicting dysphagia in patients with head and neck cancer
Authors: Hutcheson Katherine A. 
Published: December 2017

Abstract
Dysphagia is a priority issue in head and neck cancer care. Swallowing is a complex function tied both to psychosocial well-being and health in cancer survivorship. Much of our understanding of dysphagia relies on the method of measuring swallowing function along the continuum of care. Options to grade dysphagia are many and varied. Patient-reported outcome (PRO) questionnaires have been widely adopted both in research studies and increasingly in clinical practice with the goal of understanding the patients' perception of swallowing abilities. Yet, sensory aberrations and individual coping make it such that PROs are often found discordant with physical swallowing function on imaging studies, such as radiographic modified barium swallow (MBS) studies, particularly in long-term survivors. For these reasons, many groups advocate for multimodal or multidimensional swallowing outcome panels to comprehensively assess dysphagia in head and neck cancer survivorship. This session will review performance, psychometrics, and predictive yield of various dysphagia classification methods for the head and neck cancer population.
Citation Format: Katherine A. Hutcheson. Clinical and imaging methods for grading and predicting dysphagia in patients with head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr IA19.
Pml nuclear body disruption cooperates in APL pathogenesis and impairs DNA damage repair pathways in mice
Authors: Voisset Edwige , Moravcsik Eva , Stratford Eva W. , Jaye Amie , Palgrave Christopher J. , Hills Robert K. , Salomoni Paolo , Kogan Scott C. , Solomon Ellen , Grimwade David 
Published: December 2017

Key PointsA novel mouse model elucidates the impact of Pml NB disruption on APL pathogenesis and response to targeted therapy. The mode of action of this disruption appears to be via the perturbation of the NHEJ and HR pathways.
Predictors of sleepiness in obstructive sleep apnoea at baseline and after 6 months of continuous positive airway pressure therapy
Authors: Budhiraja Rohit , Kushida Clete A. , Nichols Deborah A. , Walsh James K. , Simon Richard D. , Gottlieb Daniel J. , Quan Stuart F. 
Published: December 2017

We evaluated factors associated with subjective and objective sleepiness at baseline and after 6 months of continuous positive airway pressure (CPAP) therapy in patients with obstructive sleep apnoea (OSA).We analysed data from the Apnoea Positive Pressure Long-term Efficacy Study (APPLES), a prospective 6-month multicentre randomised controlled trial with 1105 subjects with OSA, 558 of who were randomised to active CPAP. Epworth sleepiness scale (ESS) scores and the mean sleep latency (MSL) on the maintenance of wakefulness test at baseline and after 6 months of CPAP therapy were recorded.Excessive sleepiness (ESS score >10) was present in 543 (49.1%) participants. Younger age, presence of depression and higher apnoea–hypopnoea index were all associated with higher ESS scores and lower MSL. Randomisation to the CPAP group was associated with lower odds of sleepiness at 6 months. The prevalence of sleepiness was significantly lower in those using CPAP >4 h·night−1versususing CPAP ≤4 h·night−1. Among those with good CPAP adherence, those with ESS >10 at baseline had significantly higher odds (OR 8.2, p<0.001) of persistent subjective sleepiness.Lower average nightly CPAP use and presence of sleepiness at baseline were independently associated with excessive subjective and objective sleepiness after 6 months of CPAP therapy.
Outcome and recovery in first-episode psychosis
Authors: Power Paddy 
Published: December 2017

SummaryThere is now a good body of evidence about factors that determine outcome and recovery in a first episode of psychosis. However, so far, this is of limited benefit when making predictions at an individual level. Treatment protocols are one size fits all and the recommended duration of medication remains unclear. What is needed is a more sophisticated approach to predicting outcomes and tailoring treatment options to the individual. Removing predisposing factors is an important aspect of this.
Assessing the second-hand effects of a new no-smoking policy in an acute mental health trust
Authors: Perry Benjamin Ian , Meehan Katherine , Kumar Jainer Ashok 
Published: December 2017

Aims and methodTo examine whether a new no-smoking policy in an in-patient mental health setting had any effects outside of smoking cessation. Our hypothesis stated that a forced smoking ban for in-patients may result in an increased susceptibility for clinical incidents, aggression and lower admission rates. All patients admitted to adult in-patient mental health services in Coventry and Warwickshire Partnership NHS Trust were included in the analysis. Data 6 months post-implementation of the smoking policy (1 July 2015 to 1 January 2016) were compared with the same period 1 year prior (1 July 2014 to 1 January 2015). Patient demographics, admission rates, ward occupancy, average lengths of stay, numbers of reported incidents and use of the Mental Health Act 1983 (MHA) were compared.ResultsWe analysed 4223 admissions. We found a significantly increased number of admissions under the MHA (P= 0.007), a significantly greater number of reported smoking-related incidents (P< 0.001) and aggression-related incidents in the psychiatric intensive care unit (P< 0.001). However, we found no significant difference in capacity of in-patient wards (P= 0.39), admission length (P= 0.34) or total aggression-related incidents (P= 0.86).Clinical implicationsAlthough further comparisons over longer time periods are necessary, our results suggest that enforced smoking cessation on acutely unwell psychiatric patients admitted to the most restricted environments may have some negative effects. Nicotine replacement therapy should be offered to all patients to minimise the risk of clinical incident.