bluuebunny/crossref_metadata_2025 huggingface dataset:
Environmental Microbiota Drives Microbial Succession and Metabolic Profiles during Chinese Liquor Fermentation
Authors: Wang Xueshan , Du Hai , Zhang Yan , Xu Yan
Published: December 2017

Many microorganisms in the environment participate in the fermentation process of Chinese liquor. However, it is unknown to what extent the environmental microbiota influences fermentation. In this study, high-throughput sequencing combined with multiphasic metabolite target analysis was applied to study the microbial succession and metabolism changes during Chinese liquor fermentation from two environments (old and new workshops). SourceTracker was applied to evaluate the contribution of environmental microbiota to fermentation. Results showed that Daqu contributed 9.10 to 27.39% of bacterial communities and 61.06 to 80.00% of fungal communities to fermentation, whereas environments (outdoor ground, indoor ground, tools, and other unknown environments) contributed 62.61 to 90.90% of bacterial communities and 20.00 to 38.94% of fungal communities to fermentation. In the old workshop, six bacterial genera (Lactobacillus[11.73% average relative abundance],Bacillus[20.78%],Pseudomonas[6.13%],Kroppenstedtia[10.99%],Weissella[16.64%], andPantoea[3.40%]) and five fungal genera (Pichia[55.10%],Candida[1.47%],Aspergillus[10.66%],Saccharomycopsis[22.11%], andWickerhamomyces[3.35%]) were abundant at the beginning of fermentation. However, in the new workshop, the change of environmental microbiota decreased the abundances ofBacillus(5.74%),Weissella(6.64%),Pichia(33.91%),Aspergillus(7.08%), andWickerhamomyces(0.12%), and increased the abundances ofPseudomonas(17.04%),Kroppenstedtia(13.31%),Pantoea(11.41%),Acinetobacter(3.02%),Candida(16.47%), andKazachstania(1.31%). Meanwhile, in the new workshop, the changes of microbial community resulted in the increase of acetic acid, lactic acid, malic acid, and ethyl acetate, and the decrease of ethyl lactate during fermentation. This study showed that the environmental microbiota was an important source of fermentation microbiota and could drive both microbial succession and metabolic profiles during liquor fermentation.

IMPORTANCETraditional solid-state fermentation of foods and beverages is mainly carried out by complex microbial communities from raw materials, starters, and the processing environments. However, it is still unclear how the environmental microbiota influences the quality of fermented foods and beverages, especially for Chinese liquors. In this study, we utilized high-throughput sequencing, microbial source tracking, and multiphasic metabolite target analysis to analyze the origins of microbiota and the metabolic profiles during liquor fermentation. This study contributes to a deeper understanding of the role of environmental microbiota during fermentation.
Draft Genome Sequence of Heavy Metal-Resistant Soil Bacterium Serratia marcescens S2I7, Which Has the Ability To Degrade Polyaromatic Hydrocarbons
Authors: Kotoky Rhitu , Singha L. Paikhomba , Pandey Piyush
Published: December 2017

Serratia marcescens
S2I7 is a heavy metal-resistant, polyaromatic hydrocarbon-degrading bacterium isolated from petroleum-contaminated sites. The genome contains one circular chromosome (5,241,555 bp; GC content 60.1%) with 4,533 coding sequences. The draft genome sequence includes specific genetic elements for degradation of hydrocarbons and for heavy metal resistance.
The JavaScriptCore virtual machine (invited talk)
Authors: Pizlo Filip
Published: December 2017

JavaScriptCore (JSC) is an open-source high-performance implementation of JavaScript. JSC is used in the WebKit open source browser engine as well as a system framework on macOS and iOS. This talk will give a broad high-level overview of JSC’s performance-oriented architecture, including specific details about the object model, garbage collector, optimizing compilers, type inference, and deoptimization.
Challenges and progress toward efficient gradual typing (invited talk)
Authors: Siek Jeremy
Published: December 2017

Mixing static and dynamic type checking in the same language is catching on, with the TypeScript and Flow variants of JavaScript, the MyPy and Reticulated variants of Python, the Strongtalk and Gradualtalk variants of Smalltalk, as well as Typed Racket, Typed Clojure, and Perl 6. The gradual typing approach to such mixing seeks to protect the statically typed code from the dynamically typed code, allowing compilers to leverage type information when optimizing the static code. Unfortunately, ensuring soundness requires runtime checking at the boundaries of typed and untyped code, and the cost of this checking can drown out the performance benefits of optimization. For example, in Typed Racket, some partially typed programs are 1000X slower than the untyped or fully typed version of the same program. But all is not lost! In this talk I present the results of ongoing research to tame the runtime overheads of gradual typing in the context of a prototype compiler, named Grift, that we are developing at Indiana University.
Silverchain: a fluent API generator
Authors: Nakamaru Tomoki , Ichikawa Kazuhiro , Yamazaki Tetsuro , Chiba Shigeru
Published: December 2017

This paper presents a tool named Silverchain, which generates class definitions for a fluent API from the grammar of the API. A fluent API is an API that is used by method chaining and its grammar is a BNF-like set of rules that defines method chains accepted in type checking. Fluent APIs generated by Silverchain provide two styles of APIs: One is for building a chain by concatenating all method calls in series. The other is for building a chain from partial chains by passing child chains to method calls in the parent chain as their arguments. To generate such a fluent API, Silverchain first translates given grammar into a set of deterministic pushdown automata without ϵ-transitions, then encodes these automata into class definitions. Each constructed automata corresponds to a nonterminal in given grammar and recognizes symbol sequences produced from its corresponding nonterminal.
Analyzing the impact of natural language processing over feature location in models
Authors: Lapeña Raúl , Font Jaime , Pastor Óscar , Cetina Carlos
Published: December 2017

Feature Location (FL) is a common task in the Software Engineering field, specially in maintenance and evolution of software products. The results of FL depend in a great manner in the style in which Feature Descriptions and software artifacts are written. Therefore, Natural Language Processing (NLP) techniques are used to process them. Through this paper, we analyze the influence of the most common NLP techniques over FL in Conceptual Models through Latent Semantic Indexing, and the influence of human participation when embedding domain knowledge in the process. We evaluated the techniques in a real-world industrial case study in the rolling stocks domain.
Hormone-Targeted Therapy and Resistance
Authors: Metcalfe Ciara , Friedman Lori S. , Hager Jeffrey H.
Published: December 2017

It has been 40 years since the US Food and Drug Administration approved the estrogen receptor (ER) antagonist tamoxifen for the treatment of ER-positive breast cancer, ushering in the era of targeted therapy coupled with a companion diagnostic. The prostate cancer field quickly followed suit with the approval of the androgen receptor (AR) antagonist bicalutamide. In the years since, there has been sustained scientific interest in understanding these hormone-dependent signaling pathways and in drug discovery efforts to identify novel hormone-directed therapeutic agents. Recently, there have been breakthrough discoveries relating to mechanisms that enable reactivation of ER and AR signaling in the presence of antihormonal agents and that enable loss of hormone dependency, providing multiple routes of acquired resistance to hormone therapy. This review discusses parallels between breast and prostate cancer, including their pathobiologies, existing therapeutic modalities, acquired resistance to such therapeutics, and novel therapies being developed to target distinct states of resistance.
Abstract A21: Inhibition of Sonic Hedgehog Pathway by small molecule inhibitors: Targeting colon cancer stem cells
Authors: Omar Aadilah , Penny Clement , Ruff Paul
Published: December 2017

The existence of Cancer Stem Cells (CSCs) has been proven extensively in recent years. CSCs have been positively identified in, and isolated from colon cancer. They have been found to be resilient to therapy and are highly metastatic and it has been suggested that this could be attributed to the presence of CSCs expressing cell surface CD133. An active Hedgehog-Gli pathway has been detected in human colon carcinoma cells as well as their stem cells. Sonic Hedgehog (Shh) inhibitors such as cyclopamine have been successful in the treatment of other cancer types. CSCs were isolated from HT29 and DLD1 cells using the CD133 surface protein and these cells were further characterized via their expression of key stem cell markers using fluorescence microscopy. These markers included c-Myc, KLF4 and alkaline phosphatase, all of which showed elevated expression levels in the CSC fraction. The growth pattern of CSCs in comparison to non-CSCs was analyzed using cell-impedance (xCELLigence) assays, with clear differences noted in their growth rates. Adhesion assays revealed that although CSCs have a lower proliferation rate, their adhesive potential proved to be greater, possibly due to them being highly metastatic. The effects of the Shh inhibitors cyclopamine and SANT-2 on cellular adhesion of colon CSCs were compared to the Shh pathway control molecule tomatidine, and a marked decrease in adhesion potential was noted. With regard to cell invasion, this was significantly decreased when CSCs were treated with the small molecule inhibitors. In cell migration/scratch assays a similar trend was seen, wherein cell migration was retarded by Hh pathway inhibition. Using confocal microscopy, the cell surface expression of Shh and CD133 was observed following treatment with cyclopamine and while found to significantly reduce Shh expression, CD133 expression remained unaffected. Considering these in vitro results small molecule inhibitors targeting the Shh pathway appear to be promising therapeutic tools for the treatment of metastatic colon CSCs.

Citation Format: Aadilah Omar, Clement Penny, Paul Ruff. Inhibition of Sonic Hedgehog Pathway by small molecule inhibitors: Targeting colon cancer stem cells [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 A21.
Abstract A22: Identifying serum biomarkers for colorectal cancer using immunoproteomics
Authors: Smith Muneerah , Blackburn Jonathan M.
Published: December 2017

The Blackburn lab has developed a highly sensitive and selective native cancer-antigen (CT100+) microarray, which has been used to detect autoantibodies in the blood samples of cancer patients. Although technically advanced, the microarray has biological limitations as we observe a random antibody response in 10-20% of patients with various cancer-types. Our aim is therefore to use immunoproteomics to identify tumor specific antigens (TSAs) which can reproducibly be used for cancer diagnosis and prognosis. We have an archive of 67 cancer and paired normal tissues, with corresponding autologous blood plasma samples, from patients with colorectal cancer (CRC) (Groote Schuur Hospital, South Africa) for identifying novel TSAs. For each patient, we have a set of clinical information which can be used to identify cancer antigens associated with disease pathogenesis. To identify novel cancer antigens, we have developed an immuno-pulldown assay, in which Protein A and Protein G magnetic microbeads are used to selectively capture antibodies from the patient blood plasma. The Ig-bound microbeads were incubated with native cancer and control tissue lysates to capture antigens. After performing an on-bead tryptic digestion, the peptides were eluted and proteins were identified by mass spectrometry, using a Q-Exactive mass analyser. Using the MaxQuant proteomics software, we were able to identify a total of 1276 proteins, of which 360 were unique to the cancer samples. Eight of the 360 cancer-unique proteins were matched to the Tantigen database, a data source and analysis platform for cancer vaccine target discovery. Furthermore, 3 of the 8 proteins identified have been reported to induce antibody responses in cancer patients. In conclusion, we have developed an immuno-pulldown assay that captures and identifies proteins which are unique to cancer tissues, of which several have shown to induce a T- and B-cell response in cancer patients. Although we are able to identify protein candidates of interest, we observe several limitations with the assay, for which we are currently troubleshooting. Once the method is optimized, the newly identified TSAs will be fabricated on to the CT100+ microarray, and validated with patient sera to confirm the presence of cancer-specific antibody response.

Citation Format: Muneerah Smith, Jonathan M. Blackburn. Identifying serum biomarkers for colorectal cancer using immunoproteomics [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 A22.
Abstract B09: KPNB1-mediated nuclear import is required for inflammatory cytokine expression, invasion and survival of cancer cells
Authors: Stelma Tamara , Chi Alicia , Mall Anwar , Govender Dhiren , Leaner Virna D.
Published: December 2017

Karyopherin β1 (KPNB1) is a nuclear transport protein involved in the transport of transcription factors and other proteins containing a nuclear localization sequence (NLS) into the nucleus. Elevated KPNB1 expression has been reported in cancer and transformed cells and is suggested to sustain the increased metabolic and proliferative demands. Transcription factors such as NFκB and AP-1 contain a NLS which is required by KPNB1 for nuclear import. These transcription factors initiate the expression of multiple cytokines and factors associated with inflammation and cancer cell biology. An inflammatory microenvironment, a hallmark of cancer, contributes to factors such as sustained proliferation, invasion and neoangiogenesis. Our study aimed to investigate the effect of inhibiting nuclear import via KPNB1 on cell biology and inflammatory signaling associated with cancer using siRNA and the novel small molecule, Inhibitor of Nuclear Import- 43 (INI-43). Inhibition of KPNB1 lead to reduced migration and invasion of cervical cancer cells while extended inhibition caused decreased proliferation and apoptosis. KPNB1 is essential for the translocation of NFκB into the nucleus as inhibition of nuclear import resulted in its cytoplasmic retention and decreased transcriptional activity of both transcription factors; NFκB and AP-1. DNA-binding studies confirmed a reduced binding-ability or presence of NFκB in the nuclear extract of KPNB1-inhibited cells. Consequently reduced IL-6, IL-1β, TNF-α; and GM-CSF expression, target genes of NFκB and AP-1, was observed. INI-43 significantly inhibited tumor growth in an ectopic xenograft mouse model and histological analysis found the tumor tissue to be less invasive. Immunohistochemical analysis of mice tumors showed reduced overall expression of KPNB1 as well as a shift in cellular localization to be more cytoplasmic following INI-43 treatment. Our study provides evidence that inhibiting KPNB1 has anti-inflammatory and anti-cancer effects and shows promise as a chemotherapeutic target.

Citation Format: Tamara Stelma, Alicia Chi, Anwar Mall, Dhiren Govender, Virna D. Leaner. KPNB1-mediated nuclear import is required for inflammatory cytokine expression, invasion and survival of cancer cells [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 B09.
Abstract B42: An investigation into the synergistic action of chemotherapy and photodynamic therapy (PDT) in resistant human melanoma
Authors: Nsole-Biteghe Fleury Augustin , Ajuwon Olawale , Davids Lester M.
Published: December 2017

Cutaneous melanoma represents the most lethal form of skin cancer and remains refractory to current therapies. Failure of treatment has been attributed to the over-expression of ABC transporters. Alternative combinatorial approaches comprising chemotherapeutics and photodynamic therapy have been proposed to overcome resistance. The aim of this study was therefore to use the chemotherapeutic drug dacarbazine (DTIC), together with PDT on pigmented and unpigmented metastatic melanoma cell lines in vitro to assess efficacy and potentially identify mechanisms of resistance. We show a possible synergism of PDT+DTIC in reducing melanoma cell viability in vitro. At 24h post-treatment, only the unpigmented melanomas were sensitive to DTIC treatment (20-25% death at 1250µM). At 48h, a lethal dose of 50% was reached in these cells in contrast to the pigmented melanoma (20% at 48h). The same trend was observed with the combination therapy (PDT+DTIC) at both timepoints. Furthermore, PDT+DTIC suppressed the self-renewal capacity of both melanoma cell lines. No significant differences in ABCG2 protein expression was found at 24h post-treatment. Overall, these results suggest that ABCG2 transporters may not play a role in melanoma resistance to therapies and thus further work is required to elucidate the clinical efficacy of combination treatments in the fight against skin cancer.

Citation Format: Fleury Augustin Nsole-Biteghe, Olawale Ajuwon, Lester M. Davids. An investigation into the synergistic action of chemotherapy and photodynamic therapy (PDT) in resistant human melanoma [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 B42.
Abstract IA15: Multiple targetable pathways for epigenetic therapy
Authors: Issa Jean-Pierre
Published: December 2017

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

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

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

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

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

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

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.
John 4:23-24 in North African Preaching
Authors: Grabau Joseph L.
Published: December 2017

This paper explores the possibility of recovering a tradition of Donatist readings of John’s Gospel, by highlighting five of the so-called Donatist ‘anonymous’ homilies of the Vienna Collection (Sermones Escorial. 16, 19, 20, 22 and 23; cf. Leroy 1994/1999; Bass 2014/2016; Dossey 2010; and Shaw 2011). After pointing out their relatively limited, threefold Johaninne interest – chapters 4 and 8, and the ‘farewell discourse’ of chapters 14-17 (Tilley 1997) – I then focus on Sermo Escorial. 16, presenting its exegetical and theological strategies in the light of Donatist ecclesiology and its North African context. Here, I argue that a particular use of John 4:23, in conjunction with a modified form of a well-known concept of Cyprian (nulla salus extra ecclesiam), stands in sharp opposition to any of Augustine’s interpretations of the same verse. Thus, I suggest, Augustine seems both to correct Donatist views of salvation and the church, as well as a Donatist reading of the verse in question. This thesis is to be linked up with other Johannine citations in future research.
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 Points

A 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

There 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 method

To 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.

Results

We 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 implications

Although 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.
Πολιτική επικοινωνία, πολιτική συμμετοχή και κρίση της πολιτικής. Η συνεισφορά μιας εμπειρικής έρευνας δύο φάσεων
Authors: Καφετζής Παναγιώτης
Published: December 2017

[Δεν διατίθεται περίληψη / no abstract available]
Chromosome numbers, Sudanese wild forms, and classification of the watermelon genus Citrullus, with 50 names allocated to seven biological species
Authors: Renner Susanne S. , Sousa Aretuza , Chomicki Guillaume
Published: December 2017

Watermelons are among the most important vegetable crops worldwide, but targeted breeding is hindered by problems with Citrullus taxonomy. Here we clarify nomenclature and species relationships in Citrullus, its chromosome numbers, and the likely geographic region of watermelon domestication. We correct an erroneous chromosome count in recent literature, provide a count for an understudied species, and data on chromosome numbers for the entire genus. We also use a nuclear/plastid locus phylogeny to summarize data on Citrullus sexual systems, loss of tendrils, life history, and geographic ranges. Key insights from new sequences are that (i) material of C. vulgaris var. “colocynthoides”, collected by Schweinfurth in Egypt in 1882 represents the colocynth, C. colocynthis, and (ii) the citron or bitter watermelon, C. amarus, is indeed a separate species, not a subspecies of the dessert watermelon. Schweinfurth’s varietal name, a nomen nudum, has been widely used for seeds as old as 5400 BP, and it now needs to be investigated whether these seeds are colocynths, watermelon or a hybrid. To help improve Citrullus taxonomy and nomenclature, we allocate some 50 scientific names to seven biological species, tabulate chromosome counts, and provide notes on misidentified germplasms traceable by accession numbers. More wild‐collected herbarium‐verified material from northeast Africa is urgently needed, especially given the discovery of Russian breeders that populations of wild “cordophanus” from Sudan are closer to the cultivated watermelon than are any other wild populations so far known.
Amicable Dispute Resolution: a comparison of the Polish and Russian legal perspective
Authors: Зенкевич Адам , Zienkiewicz Adam Zygmunt
Published: December 2017

The article is devoted to Amicable Dispute Resolution (ADR). The essence of amicable means of dispute resolution and the basic forms of ADR (negotiation, mediation, arbitration) are considered. Author treats these forms as the first class justice. In his point of view mediation and the other basic forms of ADR are "the Complementary Forms of Justice". Then there is the detailed analysis focuses on the most important law acts concerning mediation in civil matters in Poland and the Russian Federation. The comparison presents the essential differences between the Polish and the Russian regulations. In conclusion, the five mainly motives of using ADR are noticed. The broader functions of ADR connected not only the classical regulatory, protective or harmonizing issues are shown.The article is devoted to Amicable Dispute Resolution (ADR). The essence of amicable means of dispute resolution and the basic forms of ADR (negotiation, mediation, arbitration) are considered. Author treats these forms as the first class justice. In his point of view mediation and the other basic forms of ADR are "the Complementary Forms of Justice". Then there is the detailed analysis focuses on the most important law acts concerning mediation in civil matters in Poland and the Russian Federation. The comparison presents the essential differences between the Polish and the Russian regulations. In conclusion, the five mainly motives of using ADR are noticed. The broader functions of ADR connected not only the classical regulatory, protective or harmonizing issues are shown.
Certification of the Leaders of the Capital’s Schools — an Open and Independent System
Authors: Рытов А. , Rytov A. , Мотуренко Н. , Moturenko N.
Published: December 2017

The procedure of qualifying examination of conformity of the post of head of the state educational organization as an open and independent system is considered. The structural systems are defi ned. The main content of each element of the qualifying examination system of the head of school is marked.
Fine Art Work As Metapractice of Cognitive Activity Activization of Pupils in Conditions of Profession-Oriented Training
Authors: Ротмирова Елена , Rotmirova Elena
Published: December 2017

The complex of what is happening in the society of the XXI century political, economic and cultural changes contribute to the intensifi cation of mechanisms of modernization of diff erent levels and facets of the education system. The modern paradigm of pedagogy of art, artistic-aesthetic development of personality implies the actualization of the understanding of artistic practices metarole activities. In conditions of competence-oriented requirements to the education fi gurative activity acquires a special artistic and creative, interdisciplinary status, showing the unique historical potential of cultural metapractice of the students’ knowledge expansion. Therefore, this article focuses on the actualization of this problem, suggesting further prognostic vision of a culture of fi ne processes and the development of artistic and educational situations of the development of productive, cultural and rational activities of the samples. The author examines the process of implementing cultural metapotential of fi ne arts in art-developing the system of profession-oriented education of contemporary students.