bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A32: Identifying actionable pathway malfunction scores with ML algorithm for omics data
Authors: Chebanov Dmitrii , Tatevosova Nadezhda , Mikhaylova Irina 
Published: December 2020

Abstract
Background: Driver mutations are traditionally considered as actionable biomarkers for targeted drugs, but the resistance and relapse effects often occur even when these events are precisely discovered. At the same time, primary DNA mutations can be only the triggers for cell malignancy and further development of the tumor occurs due to following pathways imbalance, which may be reflected in gene expression. The goal is to detect preaffected pathways that are most close to the oncogenic affected state, so during the treatment strategy planning we could consider these pathways as the next potential targets after nonresponse or relapse.
Methods: We took the data from TCGA Pan-Cancer Atlas on whole-exome sequencing and RNA expression for 33 cancers. Mutations were filtered based on their pathogenicity (1,2). The training set included data on mutations and corresponded RNA levels of 1821 cancer pathways-related genes (3). ML method-logistic regression, with 5-fold cross-validation with a test set, was realized on Python 3.7.
Results: Using gene expression data, 9 most common actionable events were predicted: oncogenic mutations affecting Ras, Raf, Ras/Raf/MEK, PI3K, CDK protein families, amplifications of EGFR, ERBB2, CDK4 genes, with an accuracy of 80% - 93%. Results were the probabilities of events: range 10-30% occurrence is shown.
Discussion: We considered the obtained molecular events probabilities as the scores of corresponding pathways’ malfunctions. For some molecular events, more than one-third of patients has &gt;10% affected (unbalanced) pathway state. This approach after validation can be used in clinical research practice for patient cohorts risk stratification, or as additional reinforcement for drug companion tests.
References: 1. COSMIC; 2. Chakravarty et al., 2017a; 3. KEGG.
Citation Format: Dmitrii Chebanov, Nadezhda Tatevosova, Irina Mikhaylova. Identifying actionable pathway malfunction scores with ML algorithm for omics data [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A32.
Abstract A35: Methanobrevibacter is associated with cervical dysplasia in Hispanics with HPV infections
Authors: Godoy-Vitorino Filipa , Romaguera Josefina 
Published: December 2020

Abstract
Bacteria have been extensively associated with several disease phenotypes. Archaea, a major neglected component of the microbiome, accounts for a relatively small percentage of the microbiota and has mostly been studied in the gastrointestinal tract. We hypothesized that dysbiosis in the genital tract included changes in both bacterial and archaeal organisms according to human papillomavirus infections and levels of dysplasia. We analyzed 62 patient samples from recruited patients coming for colposcopy clinics at the UPR and San Juan City clinics (Puerto Rico). From these, 52 were HPV positive and 10 were HPV negative and were stratified according to cytology results. From genomic DNA extracted from cervical swabs, we sequenced 16S rRNA genes and selected 10 patient samples for additional shotgun metagenomics. The patients were grouped in those without epithelial lesions, CIN 1 and CIN3. DNA data analyses were done with shotgun and QIIME. Analyses of the 16S rRNA reads revealed 16 archaeal OTUs, revealing an abundance of Methanobrevibacter associated with CIN3 lesions. Shotgun data revealed Methanosarcina to be dominant across all samples with higher dominance in patients without lesions and an increased dominance in Methanobrevibacter and Methanococcus in CIN3 lesions. No archaeal significant differences were found according to HPV risk (HPV infection); however, a significant decrease in Lactobacilli was associated with dysplasia. We found that archaea are commensals of the cervical mucosa and may contribute to dysbioses. Acetoclastic Methanosarcina are dominant across samples, and CIN3 lesions revealed a higher dominance of hydrogenotrophic methanogens such as Methanobrevibacter. The significance of these preliminary results may indicate that archaea cannot be taken out of the ecological context for future cervical cancer prevention strategies.
Grant support: Research reported in this abstract was partially supported by NIH National Institute on Minority Health and Health Disparities: RCMI Grant No. 2U54MD007600, an Institutional Development Award (IDeA) from the NIH National Institute of General Medical Sciences (Grant No. P20GM103475) and by the NIH/NIMHD Endowment program HiREC S21MD001830.
Citation Format: Filipa Godoy-Vitorino, Josefina Romaguera. Methanobrevibacter is associated with cervical dysplasia in Hispanics with HPV infections [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A35.
Abstract A38: RNA-seq analysis identified candidate pathogens for prostate cancer
Authors: Ashida Shingo , Kawada Chiaki , Daibata Masanori , Inoue Keiji , Nakagawa Hidewaki 
Published: December 2020

Abstract
There is an abundance of evidence that chronic inflammation is linked to prostate cancer (PC), and pathogen infection is considered to be one of the possible causes for PC. Prostate infections by bacteria or viruses have been widely investigated. However, most of these studies have showed conflicting and controversial results. Most studies have focused on the PCR-based targeted detection of bacteria or viruses, and pathogen for PC remains to be found. To identify pathogen for PC, we investigated the transcriptomes of human prostate samples using whole-genome next-generation sequencing. The prostate specimens obtained by radical prostatectomy from 20 PC patients were sliced and divided into four sections. High-quality RNAs were extracted from the sections including PC. RNA-seq libraries were constructed according to the Illumina protocol and next-generation sequenced on a HiSeq 2000 instrument. To explore the potential of other pathogens being associated with PC, we performed de novo assembly of unmapped reads from the RNA-seq data from 20 PC samples. RNA-seq analysis identified four bacteria as candidate pathogens, which included Cutibacterium acnes, uncultured Chroococcidiopsis, Micrococcus luteus, and Moraxella osloensis. Among these candidate pathogens, Cutibacterium acnes was detected in 19 of 20 PC tissue samples by immunohistochemistry. We also performed PCR to detect other candidate pathogens (uncultured Chroococcidiopsis, Micrococcus luteus, and Moraxella osloensis) in PC samples for validation. Our findings provide further evidence of Cutibacterium acnes infections in human PCs as a promising pathogen for PC, and suggest that uncultured Chroococcidiopsis, Micrococcus luteus, and Moraxella osloensis could be novel candidate pathogens for PC. Further research is required and ongoing to clarify the molecular mechanisms underlying bacterial pathogenesis of PC.
Citation Format: Shingo Ashida, Chiaki Kawada, Masanori Daibata, Keiji Inoue, Hidewaki Nakagawa. RNA-seq analysis identified candidate pathogens for prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A38.
Abstract A40: The SIAMCAT R package enables statistical and machine learning analyses for case-control microbiome datasets
Authors: Wirbel Jakob , Zych Konrad , Essex Morgan , Karcher Nicolai , Kartal Ece , Salazar Guillem , Bork Peer , Sunagawa Shinichi , Zeller Georg 
Published: December 2020

Abstract
Alterations in microbiome composition have been linked to many human diseases, including colorectal cancer or precancerous liver diseases. Findings from microbiome-association studies are increasingly explored as promising avenues for clinical applications due to their diagnostic or therapeutic potential. However, microbiome data complexity and the lack of integrated computational tools make it difficult to arrive at robust associations and predictive disease models. Here, we present the SIAMCAT R package as a modular and user-friendly toolbox for machine learning workflows, statistical analysis, and confounder detection for case-control microbiome datasets. Previously, we conducted a machine learning meta-analysis of colorectal cancer metagenomics studies (Wirbel, Pyl et al., Nat Med 2019) using the functionalities of SIAMCAT, which is now available to the wider community via Bioconductor. We showcase how SIAMCAT is a versatile tool by applying it to a large set of metagenomic datasets that have been processed with a wide variety of taxonomic and functional profiling tools. We furthermore demonstrate how SIAMCAT can help to detect confounding factors in microbiome association studies. By making stringent machine learning workflows and analysis pipelines available through a user-friendly and flexible interface, SIAMCAT will facilitate microbiome data analyses, biomarker discovery, and thus the translation of microbiome research to clinical applications, while simultaneously improving statistical rigor and safeguarding against common machine learning pitfalls.
Citation Format: Jakob Wirbel, Konrad Zych, Morgan Essex, Nicolai Karcher, Ece Kartal, Guillem Salazar, Peer Bork, Shinichi Sunagawa, Georg Zeller. The SIAMCAT R package enables statistical and machine learning analyses for case-control microbiome datasets [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A40.
Abstract B03: E-cigarette vapor exposure skews competition between colonizing oral Streptococci to allow biofilm formation of S. mutans and activation of stress and survival pathways in the oral cavity
Authors: Caldwell Matthew , Valentin Alma Catala , Bernard Joshua , Moore Sean , Andl Claudia D. 
Published: December 2020

Abstract
E-cigarette (e-cig) use is rising, but much is unknown about the effects of its vapor. This vapor contains chemicals such as propylene glycol, a known antimicrobial, and nicotine, whose derivatives are carcinogenic. Here, we study the effects of vaping on resident bacteria of the oral cavity and on oral cell inflammation, which is linked to tumorigenesis. Streptococcus mutans, Streptococcus sanguinis, and Streptococcus gordonii species are significant residents in the oral cavity, with S. mutans the primary cause of dental caries. Growth and biofilm formation is enhanced upon exposure to traditional cigarette smoke in vitro. We aim to analyze the interplay between e-cigarette vapor and oral streptococci colonizing of the oral epithelium. S. mutans, S. sanguinis, and S. gordonii were treated using nicotine-free and 3mg nicotine vapor, as well as double-shot menthol freeze flavored 3mg nicotine vapor in a vape chamber designed to phenocopy physiologically relevant exposure. Next, we analyzed the effects on growth and biofilm formation. Nicotine-independent inhibition of growth occurred upon exposure in all three species. Interestingly, biofilm formation was enhanced in S. mutans while decreased in S. sanguinis and S. gordonii. Upon exposure to the same conditions in the vape chamber, oral epithelial cells showed activation of survival pathways, such as ERK 1/2, by Western blot. Upon coculturing of bacterial and oral epithelial cells at a multiplicity of infection of one for five hours exposed to the same conditions, we observed activation of survival and inflammatory pathways, by Western blot. The pioneer colonizers S. gordonii and S. sanguinis generally antagonize caries-causing S. mutans, which can become a predominant member of the community under appropriate conditions, leading to dental caries formation. The observed decrease in the biofilm formation of the commensals S. sanguinis and S. gordonii upon e-cig vapor exposure indicates the opportunistic colonization of S. mutans, whose biofilm-forming abilities increased. Following e-cig usage, dental caries, periodontitis, and eventually cancer in the oral epithelium may result from this dysbiosis of the microbiome in the oral cavity.
Citation Format: Matthew Caldwell, Alma Catala Valentin, Joshua Bernard, Sean Moore, Claudia D. Andl. E-cigarette vapor exposure skews competition between colonizing oral Streptococci to allow biofilm formation of S. mutans and activation of stress and survival pathways in the oral cavity [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B03.
Abstract B25: Colorectal cancer-associated anaerobic bacteria proliferate in tumor spheroids and alter the microenvironment
Authors: Kasper Stephen H. , Morell-Perez Carolina , Wyche Thomas P. , Sana Theodore R. , Lieberman Linda A. , Hett Erik C. 
Published: December 2020

Abstract
Recent reports show that colorectal tumors contain microbiotas that are distinct from those that reside in a “normal” colon environment and that these microbiotas can contribute to cancer progression. Fusobacterium nucleatum is the most commonly observed species in the colorectal tumor microenvironment and reportedly influences disease progression through numerous mechanisms. However, a detailed understanding of the role of this organism in cancer progression is limited, in part due to challenges in maintaining F. nucleatum viability under standard aerobic cell culture conditions. Herein we describe the development of a 3-dimensional (3D) tumor spheroid model that can harbor and promote the growth of anaerobic bacteria. Bacteria-tumor cell interactions and metabolic crosstalk were extensively studied by measuring the kinetics of bacterial growth, cell morphology and lysis, cancer-related gene expression, and metabolomics. We observed that viable F. nucleatum assembles biofilm-like structures in the tumor spheroid microenvironment, whereas heat-killed F. nucleatum is internalized and sequestered in the cancer cells. Lastly, we use the model to coculture 28 Fusobacterium clinical isolates and demonstrate that the model successfully supports coculture with diverse fusobacterial species. This bacteria-spheroid coculture model enables mechanistic investigation of the role of anaerobic bacteria in the tumor microenvironment.
Citation Format: Stephen H. Kasper, Carolina Morell-Perez, Thomas P. Wyche, Theodore R. Sana, Linda A. Lieberman, Erik C. Hett. Colorectal cancer-associated anaerobic bacteria proliferate in tumor spheroids and alter the microenvironment [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B25.
Abstract B34: The ALPK1/TIFA/NF-kB axis links a bacterial carcinogen to replication stress and DNA damage
Authors: Bauer Michael , Nascakova Zuzana , Mihai Anca , Müller Anne 
Published: December 2020

Abstract
Exposure of gastric epithelial cells to the bacterial carcinogen Helicobacter pylori causes DNA double-strand breaks. Here, we show that H. pylori-induced DNA damage occurs co-transcriptionally in S-phase cells that activate NF-kB signaling upon innate immune recognition of LPS biosynthetic intermediates, such as ADP-heptose, by the ALPK1/TIFA pathway. DNA damage is accompanied by replication fork stalling as determined by DNA fiber assay and can be observed also in gastric organoids derived from bariatric surgery patients. We link H. pylori-induced DNA damage to the formation of RNA/DNA hybrids (R-loops), as overexpression of the R-loop-processing enzyme RNAse H1 prevents DNA damage and replication stress. R-loops form in infected cells as a consequence of ADP-heptose/ALPK1/TIFA/NF-kB signaling. Factors associated with R-loop processing and prevention are recurrently mutated in gastric cancer. In summary, our results link bacterial infection and NF-kB-driven innate immune responses to DNA damage, replication stress, and carcinogenesis.
Citation Format: Michael Bauer, Zuzana Nascakova, Anca Mihai, Anne Müller. The ALPK1/TIFA/NF-kB axis links a bacterial carcinogen to replication stress and DNA damage [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B34.
Abstract IA01: Molecular control of the gut microbiome to improve cancer chemotherapy
Authors: Redinbo Matthew 
Published: December 2020

Abstract
The diverse and complex communities of GI microbiota play important roles in human health, particularly with respect to cancer chemotherapy. We focused on systems where gut bacteria catalyze reactions that exert a profoundly negative impact on intestinal tissues and prove to be dose limiting for chemotherapy. The anticancer drug irinotecan is used to treat colon and pancreatic cancers and is eliminated as an inactivated drug-glucuronide by the phase II drug metabolism. Irinotecan’s dose-limiting toxicity is severe delayed diarrhea hypothesized to arise from the reactivation of the inactive irinotecan metabolite in the gut. We pinpointed the molecular basis of this reactivation to the beta-glucuronidase sugar-scavenging enzymes present in gut bacteria. We further developed potent, selective, and nonlethal inhibitors to bacterial beta-glucuronidase (GUS) enzymes and demonstrated that they prevented GI injury in mouse models of irinotecan-induced intestinal damage. Bacterial GUS inhibitors also prevent these sites of intestinal damage in mice treated with NSAIDs, which are glucuronidated and used to control cancer-related inflammation. We have since extended this work to the tyrosine kinase inhibitor regorafenib and to a probe-enabled activity-based proteomics pipeline to discover the enzymes driving the production of toxic metabolites. Together, our data demonstrate that enzyme targets in the GI microbiota can be inhibited to improve cancer care in a manner that can advance the promise of personalized medicine. Furthermore, our results shed significant light on the mammalian-microbial axes of chemical communication ongoing between two domains of life in the “higher-order” human superorganism.
Citation Format: Matthew Redinbo. Molecular control of the gut microbiome to improve cancer chemotherapy [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA01.
Abstract IA03: Control over colorectal tumor growth via bacteria-specific T-cell activation of the local immune response
Authors: Overacre-Delgoffe Abigail , Bumgarner Hannah , Hand Tim 
Published: December 2020

Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related death and its incidence is on the rise, particularly in young people. Therapy for late-stage CRC is often ineffective, and colorectal tumors are most often detected at stage 3 or 4. Immunotherapy is revolutionizing the treatment of many types of cancer but is only effective for a very small subset of CRC patients. Thus, there is a tremendous need for improved therapies for CRC. Colorectal tumors grow from the intestinal epithelium and are therefore subject to interaction with the dense and diverse colonic microbiota. Indeed, CRC has been associated with shifts in the composition of the microbiota that effect inflammation and tumor growth. How the microbiota shapes the CRC immune microenvironment is not fully understood. In general, the microbiota can directly shape T-cell responses, directing the differentiation of CD4 T cells to develop into either regulatory (Treg) or effector (Th1, Th17, etc.) T cells. This is particularly true of those T cells local to the intestine that are often specific to antigens derived from intestinal bacteria. We became interested in how colonization with different bacterial taxa might affect the T-cell immune response and control over colorectal cancer. Using a mouse model of CRC, we show that colonization with a single bacterial taxon, after tumors have already developed, leads to a reduction in tumor burden and size. Bacteria-dependent tumor reduction depended upon CD4 T cells but not CD8 T cells as antibody depletion of CD4 T cells completely abrogated the effect. Accordingly, de novo bacterial colonization was associated with a colorectal tumor environment that possessed fewer Tregs, increased CD4 IFNgamma-producing T cells, and increased CD103+ dendritic cells. We also observed that colonized mice develop increased numbers of organized tertiary lymphoid structures that were adjacent to colonic tumor. Importantly, bacteria-specific CD4 T cells were commonly found in these tertiary lymphoid structures, as were bacteria. Our hypothesis is that microbiota-driven and T cell-dependent development of TLS structures leads to enhanced tumor antigen presentation and augmented antitumor immune responses. This work has the potential to inform CRC therapies via the rational modification of the local microbiota to support TLS formation and antitumor immunity.
Citation Format: Abigail Overacre-Delgoffe, Hannah Bumgarner, Tim Hand. Control over colorectal tumor growth via bacteria-specific T-cell activation of the local immune response [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA03.
Abstract IA05: Microbiota, metabolites, and antitumor immunity
Authors: McCoy Kathy D. 
Published: December 2020

Abstract
The intestinal microbiome heavily influences development and regulation of the immune system. The microbiome, which includes bacteria, viruses, and fungi, can also influence the initiation, development, and progression of cancer, with modulation of the immune system as one of the key pathways involved. Gut bacteria have also been found to alter the efficacy of cancer therapies, including immune checkpoint blockade therapy. These immunotherapies utilize the therapeutic potential of the immune system and have revolutionized cancer treatment. Yet this promising new strategy is not effective in all individuals (or all cancers) and has shown poor efficacy in colorectal cancer. We therefore investigated whether the intestinal microbiota could play a role in modulating immunotherapy in mouse models of colorectal cancers. We have identified specific intestinal commensal bacteria and a bacterial metabolite that control the efficacy of immune checkpoint blockade in animal models of colorectal cancer. In this session I will discuss the cellular and molecular pathways involved in this novel microbiota-microbe-immune pathway and describe the potential of bacteria-checkpoint blockade cotherapies.
Citation Format: Kathy D. McCoy. Microbiota, metabolites, and antitumor immunity [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA05.