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 George Bebis · Takis Benos ·
Ken Chen · Katharina Jahn ·
Ernesto Lima (Eds.)
LNCS 11826

Mathematical and
Computational Oncology
First International Symposium, ISMCO 2019
Lake Tahoe, NV, USA, October 14–16, 2019
Proceedings
Lecture Notes in Computer Science 11826

Founding Editors
Gerhard Goos
Karlsruhe Institute of Technology, Karlsruhe, Germany
Juris Hartmanis
Cornell University, Ithaca, NY, USA

Editorial Board Members

Elisa Bertino
Purdue University, West Lafayette, IN, USA
Wen Gao
Peking University, Beijing, China
Bernhard Steffen
TU Dortmund University, Dortmund, Germany
Gerhard Woeginger
RWTH Aachen, Aachen, Germany
Moti Yung
Columbia University, New York, NY, USA
More information about this series at http://www.springer.com/series/7412
George Bebis Takis Benos Ken Chen
• • •

Katharina Jahn Ernesto Lima (Eds.)

•

Mathematical and
Computational Oncology
First International Symposium, ISMCO 2019
Lake Tahoe, NV, USA, October 14–16, 2019
Proceedings

123
Editors
George Bebis Takis Benos
University of Nevada University of Pittsburgh
Reno, NV, USA Pittsburgh, PA, USA
Ken Chen Katharina Jahn
The University of Texas ETH Zurich
MD Anderson Cancer Center Basel, Switzerland
Houston, TX, USA
Ernesto Lima
The University of Texas
Austin, TX, USA

ISSN 0302-9743 ISSN 1611-3349 (electronic)

Lecture Notes in Computer Science
ISBN 978-3-030-35209-7 ISBN 978-3-030-35210-3 (eBook)
https://doi.org/10.1007/978-3-030-35210-3
LNCS Sublibrary: SL6 – Image Processing, Computer Vision, Pattern Recognition, and Graphics

© Springer Nature Switzerland AG 2019

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the
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broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
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 Preface

It is with great pleasure that we welcome you to the proceedings of the First
International Symposium on Mathematical and Computational Oncology
(ISMCO 2019), which was held in Lake Tahoe, Nevada, USA (October 14–16, 2019).
The purpose of ISMCO is to provide a common interdisciplinary forum for
mathematicians, scientists, engineers, and clinical oncologists throughout the world to
present and discuss their latest research findings, ideas, developments, and applications
in mathematical and computational oncology. Despite significant advances in the
understanding of the principal mechanisms leading to various cancer types, less
progress has been made toward developing patient-specific treatments. Advanced
mathematical and computational models could play a significant role in examining the
most effective patient-specific therapies. ISMCO aspires to enable the forging of
stronger relationships among mathematics and physical sciences, computer science,
data science, engineering, and oncology with the goal of developing new insights into
the pathogenesis and treatment of malignancies.
The program included eight oral sessions, one special track, one tutorial, three
invited talks, and seven keynote presentations. We received 30 submissions from
which we accepted 19 submissions (7 papers and 12 abstracts) for oral presentation.
This LNCS volume includes only the papers accepted for presentation; all abstracts
accepted for presentation appeared in an online volume of Frontiers (link is provided on
the ISMCO website).
All submissions were reviewed with an emphasis on the potential to contribute to
the state of the art in the field. Selection criteria included accuracy and originality of
ideas, clarity and significance of results, and presentation quality. The review process
was quite rigorous, involving three independent blind reviews followed by several days
of discussion. During the discussion period we tried to correct anomalies and errors that
might have existed in the initial reviews. Despite our efforts, we recognize that some
papers worthy of inclusion may have not been included in the program. We offer our
sincere apologies to authors whose contributions might have been overlooked.
Organizing ISMCO for the first time was rewarding but also challenging due to the
diverse background and interests of the targeted audience. Although significant
advances have been made in various fields individually, it is evident now more than
ever that new challenges in oncology can only be addressed by truly transcending
disciplinary boundaries. Effectively bridging the gap among physical sciences,
computer science, engineering, data science, and oncology is an absolute necessity in
the hope of making significantly more progress in the fight against cancer.
Many contributed to the success of ISMCO 2019. First and foremost, we are grateful
to the Steering, Organizing, and Program Committees; they strongly welcomed,
supported, and promoted the organization of this new meeting. Second, we are deeply
indebted to the keynote speakers who warmly accepted our invitation to talk at
ISMCO 2019; their reputation in mathematical and computational oncology added
vi Preface

significant value to and excitement to the meeting. Next, we wish to thank the invited
speakers, the authors who submitted their work to ISMCO 2019 and the reviewers who
helped us to evaluate the quality of the submissions. It was because of their contri-
butions that we succeeded in putting together a technical program of high quality.
Finally, we would like to express our appreciation Springer-Verlag, Frontiers, and the
International Society for Computational Biology (ISCB) for sponsoring ISMCO 2019.
We sincerely hope that ISMCO 2019 offered participants opportunities for
professional growth. We look forward to many more successful meetings in
mathematical and computational oncology.

September 2019 George Bebis

Takis Benos
Ken Chen
Katharina Jahn
Ernesto Lima
 Organization

Steering Committee
Anastasiadis Panagiotis Mayo Clinic, USA
Bebis George (Chair) University of Nevada, Reno, USA
Levy Doron University of Maryland, College Park, USA
Rockne Russell City of Hope, USA
Schlesner Matthias German Cancer Research Center, Germany
Tafti Ahmad Mayo Clinic, USA
Vasmatzis George Mayo Clinic, USA

Program Chairs
Benos Takis University of Pittsburgh, USA
Chen Ken MD Anderson Cancer Center, USA
Jahn Katharina ETH Zurich, Switzerland
Ernesto Lima University of Texas, USA

Publicity Chairs
Loss Leandro QuantaVerse, ITU, ESSCA
Scalzo Fabien University of California at Los Angeles, USA
Erol Ali Eksperta Software, Turkey

Local Arrangements Chairs

Nguyen Tin University of Nevada, Reno, USA
Petereit Juli Nevada Center for Bioinformatics, USA

Special Tracks Chairs

Dadhania Seema Imperial College London
Marias Kostas Foundation for Research and Technology – Hellas

Tutorials Chairs
Bhattacharya Debswapna Auburn University
Shehu Armada George Mason University

Web Master
Isayas Berhe Adhanom University of Nevada, Reno
viii Organization

Program Committee
Pankaj Agarwal BioInfi, USA
Bissan Al-Lazikani The Institute of Cancer Research, UK
Max Alekseyev George Washington University, USA
Panos Anastasiadis Mayo Clinic, USA
Noemi Andor Moffitt Cancer Research Center, USA
Ioannis Androulakis Rutgers University, USA
Dinler Antunes Universidade Federal do Rio Grande do Sul, Brazil
Ferhat Ay La Jolla Institute, USA
Erman Ayday Case Western Reserve University, USA,
and Bilkent University, Turkey
Matteo Barberis University of Surrey, UK
Anastasia Baryshnikova Calico Life Sciences, USA
Ali Bashashati University of British Columbia, BC Cancer Agency,
Canada
George Bebis University of Nevada, Reno, USA
Takis Benos University of Pittsburgh, USA
Sebastien Benzekry Inria, France
Debswapna Bhattacharya Auburn University, USA
Jiang Bian University of Florida, USA
Valentina Boeva Institut Cochin, INSERM, CNRS, France
Mary Boland University of Pennsylvania, USA
Matthew Breitenstein University of Pennsylvania, USA
Amy Brock The University of Texas at Austin, USA
Anton Buzdin Omicsway Corp., USA
Raffaele Calogero University of Torino, Italy
Emidio Capriotti University of Bologna, Italy
Hannah Carter University of California San Diego, USA
Aristotelis Chatziioannou National Hellenic Research Foundation, Greece
Jake Chen University of Birmingham Alabama, USA
Ken Chen MD Anderson Cancer Center, USA
You Chen Vanderbilt University, USA
Juan Carlos Chimal Centro de Investigación en Computación del IPN,
Mexico
Heyrim Cho University of California, Riverside, USA
Giovanni Ciriello University of Lausanne, Switzerland
Colin Collins Vancouver Prostate Center, Canada
Francois Cornelis Sorbonne University, France
Paul-Henry Cournede Laboratory MICS, CentraleSupélec, France
Simona Cristea Harvard University, USA
Seema Dadhania Imperial College London, UK
Subhajyoti De Rutgers University, USA
Francesca Demichelis University of Trento, Italy
Mohammed El-Kebir University of Illinois at Urbana-Champaign, USA
Peter Elkin Ontolimatics, USA
 Organization ix

Sally Ellingson University of Kentucky, USA

Funda Ergun Indiana University Bloomington, USA
Xinzeng Feng The University of Texas at Austin, USA
Yusheng Feng The University of Texas at San Antonio, USA
Avner Friedman The Ohio State University, USA
Constantine Gatsonis Brown University, USA
Andrew Gentles Stanford University, USA
Philip Gerlee Chalmers University of Technology, Sweden
Jana Gevertz The College of New Jersey, USA
Preetam Ghosh Virginia Commonwealth University, USA
Jeremy Goecks Oregon Health and Science University, USA
Amy Gryshuk LLNL, USA
Wei Gu University of Luxembourg, Luxembourg
Michael Hallett Concordia University, Canada
Arif Harmanci University of Texas Health Sciences Center, USA
Leonard Harris Vanderbilt University, USA
Artemis Hatzigeorgiou BSRC Fleming, Greece
Zhe He Florida State University, USA
Carl Herrmann University of Heidelberg, Germany
Harry Hochheiser University of Pittsburgh, USA
David Hormuth The University of Texas at Austin, USA
Florence Hubert Aix-Marseille Université, France
Young Hwan Chang Oregon Health and Science University, USA
Rezarta Islamaj Dogan National Library of Medicine, USA
Trachette Jackson University of Michigan, USA
Katharina Jahn ETH Zurich, Switzerland
Harsh Jain Florida State University, USA
Anil Jegga Cincinnati Childrens Hospital Medical Center, USA
Xiaoqian Jiang UTHealth at Houston, USA
Ioannis Kavakiotis Hellenic Pasteur Institute, Greece
Saif Khairat The University of North Carolina at Chapel Hill, USA
Lenguyenquoc Khanh Nanyang Technological University, China
Samir Khleif Augusta University, USA
Marek Kimmel Rice University, USA
Maria Klapa Foundation for Research and Technology - Hellas,
Greece
Rachel Kolodny University of Haifa, Israel
Michael Krauthammer Yale University, USA
Smita Krishnaswamy Yale University, USA
Parvesh Kumar University of Nevada, Las Vegas, USA
Jens Lagergren KTH Royal Institute of Technology, Sweden
Hayan Lee Stanford University, USA
Kjong-Van Lehmann ETH Zurich, Switzerland
Mark Leiserson University of Maryland, USA
Thomas Lepoutre Inria, France
x Organization

Richard Levenson University of California, Davis, USA

Doron Levy University of Maryland, USA
Xiaotong Li Yale University, USA
Ernesto Lima The University of Texas, USA
Michal Linial Hebrew University of Jerusalem, Israel
Doron Lipson Foundation Medicine, USA
Hongfang Liu Mayo Clinic, USA
Leandro Loss QuantaVerse, ITU, ESSCA, France
Shaoke Lou Yale University, USA
Brad Malin Vanderbilt University, USA
Anna Marciniak-Czochra University of Heidelberg, Germany
Kostas Marias Foundation for Research and Technology - Hellas,
Greece
Scott Markel Dassault Systèmes BIOVIA, USA
Florian Markowetz University of Cambridge, UK
Schaefer Martin EMBL/CRG Systems Biology Research Unit,
Centre for Genomic Regulation, Germany
Bernard Moret Ecole Polytechnique Fédérale de Lausanne,
Switzerland
Abu Mosa University of Missouri, USA
Henning Müller HES-SO, Switzerland
Ulrike Münzner Kyoto University, Japan
Radhakrishnan Nagarajan University of Kentucky, USA
John Nagy Arizona State University, USA
Tin Nguyen University of Nevada, Reno, USA
Layla Oesper Carleton College, USA
Baldo Oliva University Pompeu Fabra, Spain
Laxmi Parida IBM, USA
Bahram Parvin University of Nevada, Reno, USA
Raphael Pelossof MSKCC, USA
Shirley Pepke Lyrid LLC, USA
Juli Petereit University of Nevada, Reno, USA
Evangelia Petsalaki EMBL-EBI, UK
Martin Pirkl ETH Zurich, Switzerland
Angela Pisco Chan Zuckerberg Biohub, USA
Clair Poignard Inria Bordeaux-Sud Ouest-Team MC2, France
David Posada University of Vigo, Spain
Gibin Powathil Swansea University, UK
Natasa Przulj University College London, UK
Teresa Przytycka NIH, USA
Víctor M. Pérez-García Universidad de Castilla-La Mancha, Spain
Ami Radunskaya Pomona College, USA
Luke Rasmussen Northwestern University, USA
Johannes Reiter Stanford University, USA
Katarzyna Rejniak H. Lee Moffitt Cancer Center & Research Institute,
USA
 Organization xi

Isidore Rigoutsos IBM Thomas J Watson Research Center, USA

Russell Rockne City of Hope National Medical Center, USA
Maria Rodriguez Martinez IBM, Zurich Research Laboratory, Switzerland
Venkata Pardhasaradhi University of Luxembourg and ELIXIR-Luxembourg,
Satagopam Luxembourg
Fabien Scalzo University of California, Los Angeles, USA
Grant Schissler University of Nevada, Reno, USA
Matthias Schlesner German Cancer Research Center, Germany
Alexander Schoenhuth Vrije Universiteit Amsterdam, The Netherlands
Russell Schwartz Carnegie Mellon University, USA
Jacob Scott Cleveland Clinic, USA
Amarda Shehu George Mason University, USA
Feichen Shen Mayo Clinic, USA
Yang Shen Texas A&M University, USA
Xinghua Shi The University of North Carolina at Charlotte, USA
Chi-Ren Shyu University of Missouri-Columbia, USA
Sunghwan Sohn Mayo Clinic, USA
Thomas Steinke Zuse Institute Berlin, Germany
Angelique Stephanou TIMC-IMAG, CNRS, France
Kyung Sung University of California, Los Angeles, USA
Ahmad Tafti Mayo Clinic, USA
Umit Topaloglu Wake Forest School of Medicine, USA
Tamir Tuller Tel Aviv University, Israel
Jack Tuszynski University of Alberta, Canada
Alexander V. Alekseyenko Medical University of South Carolina, USA
George Vasmatzis Mayo Clinic, USA
Volpert Vitaly Université Claude Bernard Lyon 1, France
Li-San Wang University of Pennsylvania, USA
Yanshan Wang Mayo Clinic, USA
Jeremy Warner Vanderbilt University, USA
Mark Wass University of Kent, UK
Lonnie Welch Ohio University, USA
Kenneth Wertheim University of Nebraska–Lincoln, USA
Matt Williams Imperial College, UK
Dominik Wodarz University of California, Irvine, USA
Yanji Xu Nevada University Reno, USA
Habil Zare University of Washington, USA
Meirav Zehavi Ben-Gurion University, Israel
Alex Zelikovsky Georgia State University, USA
Xuegong Zhang Tsinghua University, China
Xiaoming Zheng Central Michigan University, USA
Maryam Zolnoori Mayo Clinic, USA
xii Organization

Additional Reviewers

Bhattacharya, Sutanu
Chen, Ken
Gertz, Mike
Levy, Doron
Manandhar, Dinesh
Nguyen, Hung
Tran, Duc

Sponsors
Keynote Talks
Breast Cancer Genomics: Tackling Complexity
with Functional Genomics
and Patient-Derived Organoids

Ron Bose

Washington University School of Medicine, USA

Abstract. Breast cancer is a heterogeneous disease with multiple molecular

subtypes and three major clinical subtypes: hormone receptor positive, HER2
positive, and triple negative breast cancer. These three clinical subtypes are very
important because they determine the drugs used for patient treatment. Cellular,
molecular, and genomic understanding of breast cancer has resulted in new
treatments for breast cancer. In 2019, the FDA approved an oral PIK3CA
inhibitor for PIK3CA mutated, hormone receptor positive, Stage IV breast
cancer and immunotherapy for triple negative, Stage IV breast cancer. Major
challenges facing future research on breast cancer and other cancers are:
(1) Interpreting genome sequencing results to better understand the effects and
significance of new or under-characterized mutations, and (2) having platforms
for rapid biological testing of hypotheses. I will provide examples of how my
laboratory is trying to address both of these challenges.
 High Dimensional Unsupervised Approaches
for Dealing with Heterogeneity of Cell
Populations and Proliferation
of Algorithmic Tools

Yuval Kluger

Yale University School of Medicine, USA

Abstract. Revealing the clonal composition of a single tumor is essential for

identifying cell subpopulations with metastatic potential in primary tumors or
with resistance to therapies in metastatic tumors. Bulk sequencing technologies
provide only an overview of the aggregate of numerous cells. We propose an
evolutionary framework for deconvolving data from a bulk genome-wide
experiment to infer the composition, abundance and evolutionary paths of the
underlying cell subpopulations of a tumor. With advances in high throughput
single cell techniques, we can in principle resolve these issues. However, these
techniques introduce new challenges such as analyzing datasets of millions of
cells, batch effects, missing values etc. We provide several algorithmic solutions
for some of these challenges. Finally, a key challenge in bioinformatics is how
to rank and combine the possibly conflicting predictions of several algorithms,
of unknown reliability. We provide new mathematical insights of striking
conceptual simplicity that explain mutual relationships between independent
classifiers/algorithms. These insights enable the design of efficient, robust and
reliable methods to rank the classifiers performances and construct improved
predictions in the absence of ground truth.
 Career Development Opportunities:
The Government Can Help!

Susan Perkins

National Cancer Institute, USA

Abstract. The National Cancer Institute is committed to the training and support
of the next generation of cancer researchers. The NCI funds training at extra-
mural institutions across the nation, using funding mechanisms that include
fellowships, career development awards, and institutional training grants. This
session will provide a broad overview of this wide range of opportunities, with
an emphasis on some new NCI programs for early-stage investigators, as well as
some tips and tools for applicants.
 Bringing Math into the Clinic:
Mathematical Oncology at City of Hope

Russell Rockne

City of Hope, USA

Abstract. In this keynote lecture, I will provide vignettes of applications of

mathematical modeling aimed at use in the clinic within the Division of
Mathematical Oncology at City of Hope. I will focus on the use of non-invasive
imaging (MRI, PET) to calibrate and validate patient-specific mathematical
models of cancer growth and response to therapy. Applications include primary
brain tumors and breast cancer, with therapeutic applications including
cell-based therapies, radiation therapy, and combination therapies. I will provide
a forward-looking view of Mathematical Oncology at City of Hope and present
clinical challenges that may be addressed with mathematical modeling.
 Application of Functional Genomics
to Oncology Practice: Opportunities,
Successes, Failures and Barriers

Panos Anastasiadis and George Vasmatzis

Mayo Clinic, USA

Abstract. Radical improvement in cancer care can be accomplished by indi-

vidualizing patient management via the application of genomics and functional
model systems into clinical practice. Recent breakthroughs in immunotherapy
(i.e. checkpoint inhibitors) and targeted therapies (i.e. NTRK inhibitors) have
shown that therapy of advanced cancers might become agnostic to the organ of
origin, arguing for a more individualized approach to patient care. Emerging
genomics technologies, data integration and visualization platforms are powerful
tools to determine the state of the individual’s tumor and point to tailored
treatments. Furthermore, an efficient combination of comprehensive genomics
with 3D microcancer functional model systems can further refine treatment
decisions. However, applying such disruptive technologies in clinical practice is
not trivial. Regulatory, financial and clinical barriers will be discussed.
 Recognition of Non-synonymous Somatic
Mutations by Tumor Infiltrating Lymphocytes
(TIL) in Metastatic Breast Cancer

Nikos Zacharakis

National Cancer Institute, USA

Abstract. Adoptive transfer of tumor infiltrating lymphocytes (TIL) can mediate

long-term durable regression in patients with metastatic melanoma, a type of
cancer which is characterized by a high number of mutated genes and pro-
nounced lymphocytic infiltrate. Common epithelial cancers, including breast
cancer, express far fewer somatic mutations than melanoma and the level of
reactive TIL is limited. This pilot study investigated the ability to identify
personalized non-synonymous somatic mutations in metastatic breast cancer
lesions, to grow TIL that recognize the products of these mutations, and to
adoptively transfer these TIL into patients with metastatic breast cancer,
refractory to other treatments. Metastatic and primary tumor lesions from thirty
one patients with breast cancer were studied in the Surgery branch, NCI, NIH
and all of them were found to contain and express mutated genes (range: 4-1788
, median: 99). TIL recognized at least one (range: 1-10, median: 3) mutated
product in 21 of 32 the patients (66%). Five evaluable patients with metastatic
breast cancer, refractory to prior multiple lines of treatment, were treated with
enriched mutation-reactive TIL in our ongoing pilot clinical trial. The
immunogenicity of mutations in the majority of the patients with metastatic
breast cancer can be the platform for an adoptive T cell transfer therapeutic
approach targeting those mutated genes.
 Inferring Tumor Evolution from Bulk
and Single-cell Sequencing Data

Ben Raphael

Princeton University, USA

Abstract. Cancer is an evolutionary process driven by somatic mutations that

accumulate in a population of cells. These mutations provide markers to infer
the ancestral relationships between cells of a tumor, to describe populations of
cells that are sensitive/resistant to treatment, or to study migrations between a
primary tumor and distant metastases. However, such phylogenetic analyses are
complicated by specific features of cancer sequencing data such as heteroge-
neous mixtures of cells present in bulk tumor sequencing data, undersampling in
single-cell sequencing data, and large-scale genome rearrangements. In this talk,
I will describe algorithms to address several problems in tumor evolution
including: the inference of seeding patterns of metastases; the identification of
copy number aberrations and whole-genome duplications in multi-sample
sequencing data; and the integrated analysis of single-nucleotide mutations and
copy number aberrations in single-cell sequencing data.
 Contents

Special Track: Tumor Evolvability and Intra-tumor Heterogeneity

Phylogenies Derived from Matched Transcriptome Reveal

the Evolution of Cell Populations and Temporal Order
of Perturbed Pathways in Breast Cancer Brain Metastases . . . . . . . . . . . . . . 3
Yifeng Tao, Haoyun Lei, Adrian V. Lee, Jian Ma, and Russell Schwartz

Modeling the Evolution of Ploidy in a Resource Restricted Environment . . . . 29

Gregory Kimmel, Jill Barnholtz-Sloan, Hanlee Ji, Philipp Altrock,
and Noemi Andor

Imaging and Scientific Visualization for Cancer Research

cmIF: A Python Library for Scalable Multiplex Imaging Pipelines . . . . . . . . 37

Jennifer Eng, Elmar Bucher, Elliot Gray, Lydia Grace Campbell,
Guillaume Thibault, Laura Heiser, Summer Gibbs, Joe W. Gray,
Koei Chin, and Young Hwan Chang

Statistical Methods and Data Mining for Cancer Research (SMDM)

Accurate and Flexible Bayesian Mutation Call from Multi-regional

Tumor Samples. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Takuya Moriyama, Seiya Imoto, Satoru Miyano, and Rui Yamaguchi

Flexible Data Trimming for Different Machine Learning Methods

in Omics-Based Personalized Oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Victor Tkachev, Anton Buzdin, and Nicolas Borisov

Spatio-temporal Tumor Modeling and Simulation (STTMS)

Towards Model-Based Characterization of Biomechanical Tumor

Growth Phenotypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Daniel Abler, Philippe Büchler, and Russell C. Rockne

Population Modeling of Tumor Growth Curves, the Reduced Gompertz

Model and Prediction of the Age of a Tumor . . . . . . . . . . . . . . . . . . . . . . . 87
Cristina Vaghi, Anne Rodallec, Raphaelle Fanciullino, Joseph Ciccolini,
Jonathan Mochel, Michalis Mastri, John M. L. Ebos, Clair Poignard,
and Sebastien Benzekry

Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Special Track: Tumor Evolvability and
Intra-tumor Heterogeneity
 Phylogenies Derived from Matched
Transcriptome Reveal the Evolution
of Cell Populations and Temporal Order
of Perturbed Pathways in Breast Cancer
Brain Metastases

Yifeng Tao1,2 , Haoyun Lei1,2 , Adrian V. Lee3 , Jian Ma1 ,

and Russell Schwartz1,4(B)
1
Computational Biology Department, School of Computer Science,
Carnegie Mellon University, Pittsburgh, PA 15213, USA
2
Joint Carnegie Mellon–University of Pittsburgh Ph.D. Program in Computational
Biology, Pittsburgh, PA 15213, USA
3
Department of Pharmacology and Chemical Biology,
UPMC Hillman Cancer Center, Magee–Womens Research Institute,
University of Pittsburgh, Pittsburgh, PA 15213, USA
4
Department of Biological Sciences, Carnegie Mellon University,
Pittsburgh, PA 15213, USA
russells@andrew.cmu.edu

Abstract. Metastasis is the mechanism by which cancer results in mor-

tality and there are currently no reliable treatment options once it
occurs, making the metastatic process a critical target for new diagnos-
tics and therapeutics. Treating metastasis before it appears is challeng-
ing, however, in part because metastases may be quite distinct genom-
ically from the primary tumors from which they presumably emerged.
Phylogenetic studies of cancer development have suggested that changes
in tumor genomics over stages of progression often results from shifts
in the abundance of clonal cellular populations, as late stages of pro-
gression may derive from or select for clonal populations rare in the pri-
mary tumor. The present study develops computational methods to infer
clonal heterogeneity and temporal dynamics across progression stages
via deconvolution and clonal phylogeny reconstruction of pathway-level
expression signatures in order to reconstruct how these processes might
influence average changes in genomic signatures over progression. We
show, via application to a study of gene expression in a collection of
matched breast primary tumor and metastatic samples, that the method
can infer coarse-grained substructure and stromal infiltration across the
metastatic transition. The results suggest that genomic changes observed
in metastasis, such as gain of the ErbB signaling pathway, are likely
caused by early events in clonal evolution followed by expansion of minor
clonal populations in metastasis (Algorithmic details, parameter settings,
and proofs are provided in an Appendix with source code available at
https://github.com/CMUSchwartzLab/BrM-Phylo).

c Springer Nature Switzerland AG 2019

G. Bebis et al. (Eds.): ISMCO 2019, LNCS 11826, pp. 3–24, 2019.
https://doi.org/10.1007/978-3-030-35210-3_1
4 Y. Tao et al.

Keywords: Breast cancer · Brain metastases · Phylogenetics ·

Deconvolution · Pathways · Gene modules

1 Introduction

Metastatic disease is the primary mechanism by which cancer results in patient

mortality [6,7]. By the time metastases have appeared, there are generally no
viable treatment options [14]. Successful treatment thus depends on treating
not just the primary tumor but the seeds of metastasis that may linger after
a seemingly successful remission. Identifying successful treatment options for
metastasis is problematic, however, since the genomics of primary and metastatic
tumors may be quite different even in single patients and metastatic cell pop-
ulations may be poorly responsive to therapies effective on the primary tumor.
Studies of cell-to-cell variation in cancers have revealed often substantial clonal
heterogeneity in single tumors, with clonal populations sometimes dramatically
shifting across progression stages [13]. Phylogenetic studies of clonal populations
have been inconclusive on the typical evolutionary relationships between primary
and metastatic tumors [35] and it remains a matter of debate whether changes
in clonal composition occur primarily through ongoing clonal evolution, which
results in novel clones with metastatic potential and resistance to therapy, or
from selection on existing clonal heterogeneity already present at the time of
first treatment [5,10]. The degree to which either answer is true has impor-
tant implications for prospects for early detection or prophylactic treatment of
metastasis.

Fig. 1. The pipeline of BrM phylogenetics using matched bulk transcriptome.

 Phylogenies of Matched Transcriptome in Breast Cancer Brain Metastases 5

Brain metastases (BrMs) occur in around 10%–30% of metastatic breast

cancers cases [26]. Although recent advances in the treatment of metastatic
breast cancer have been able to achieve long-term overall survival, there are
limited treatment options for BrMs and clinical prognoses are still disappoint-
ing [41]. Recent work examining transcriptomic changes between paired primary
and BrM samples has demonstrated dramatic changes in expression programs
over metastasis, including changes in tumor subtype with important implications
for treatment options and prognosis [31,38]. Some past research has sought to
infer phylogenetic models to explain the development of brain metastases based
on somatic genomic alterations [4,21]. Such methods are challenged in draw-
ing robust conclusions about recurrent progression processes, though, by the
high heterogeneity both within single tumors and across progression stages and
patients. Changes in the activity of particular genetic pathways or modules may
provide a more robust measure of frequent genomic alterations across cancers.
In the present work, we develop a strategy for tumor phylogenetics to explore
how changes in clonal composition, via both novel molecular evolution and shifts
in population dynamics of tumor clones and associated stroma, influence changes
in expression programs across such progression stages. Our methods make use of
multi-site bulk transcriptomic data to profile changes evident in gene expression
programs between clones and progression stages. We break from past work in
this domain in that we seek to study not clones per se, as is typical in tumor
phylogenetics, but what we dub “cell communities”: collections of clones or other
stromal cell types that persist as a group with similar proportions across sam-
ples (Sect. 2.4). We accomplish this via a novel genomic deconvolution approach
designed to make use of multiple samples both within and between patients [36]
while improving robustness to inter- and intra-tumor heterogeneity by integrat-
ing deconvolution with pathway-based analyses of expression variation [30].

2 Methods
2.1 Overview
Cell populations evolve due to genomic perturbations that can result in changes
in the activity of various functional pathways between clones. Our overall method
for deriving coarse-grained portraits of cell community evolution at the path-
way level is illustrated by Fig. 1. After the preprocessing of transcriptome data
(Sect. 2.2), the overall workflow consists of three main steps: First, the bulk
expression profiles are mapped into the gene module and pathway space using
external knowledge bases to reduce redundancy, noise, sparsity, and to provide
markers of expression variation for the subsequent analysis (Sect. 2.3). Second,
a deconvolution step is implemented to resolve cell communities, i.e., coarse-
grained mixtures of cell types presumed to represent an associated population of
cancer clones and stromal cells, from the compressed pathway representation of
samples (Sect. 2.4). Third, phylogenies of these cell communities are built based
on the deconvolved communities as well as inferred ancestral (Steiner) commu-
nities to reconstruct likely trajectories of evolutionary progression by which cell
6 Y. Tao et al.

Fig. 2. Method details. (a) Neural network architecture of NND. (b) Test errors of
NND using 20-fold CV. Errors in unit of mean square error (MSE). (c) Illustration of
a phylogeny with five extant nodes and three Steiner nodes.

communities develop—through a combination of genetic mutations, expression

changes, and changes in population distributions—as a tumor progresses from
healthy tissue to primary and potentially metastatic tumor (Sect. 2.5).

2.2 Transcriptome Data Preprocessing

We applied a series of preprocessing methods, including quantile normaliza-
tion [1], to the raw bulk RNA-Sequencing data of 44 matched primary breast
and metastatic brain tumors from 22 patients [31,38]. See Appendix Sect. A1 for
detailed protocols of data preprocessing.

2.3 Mapping to Gene Modules and Cancer Pathways

The mapping step compresses the high dimensional data and provides markers
of cancer-related biological processes (Fig. 1 Step 1). Gene Modules: Genes in
the same “gene modules” [8,37] are usually affected by a common set of somatic
alterations [30], and therefore are co-expressed in cells. We mapped the protein-
coding gene expressions into gene modules using the DAVID tool and external
knowledge bases [17,18]. The z -scores of m1 = 109 gene modules in all the
n = 44 samples were represented as a matrix BM ∈ Rm1 ×n . Cancer Pathways:
We extracted the 23 cancer-related pathways from the KEGG database [19].
An additional recurrently gained RET pathway was added [38]. See y-axis of
Fig. 3d for the complete list of pathways. z -scores of m2 = 24 cancer pathways
were represented as BP ∈ Rm2 ×n . In summary, the raw gene expressions
 were

compressed into the gene module/pathway representation B = BM , BP ∈
Rm×n . The gene module serves for accurately deconvolving and unmixing the cell
communities, while the pathway serves as markers/probes and for interpretation
purpose. We will refer to the compressed representation containing both gene
modules and pathways as “pathway representation” for brevity if not specified.
See Appendix Sect. A2 for further details of the mapping.

2.4 Deconvolution of Bulk Data

We applied a type of matrix factorization (MF) with constraints on the pathway-
level expression signatures to deconvolve the communities/populations from
 Phylogenies of Matched Transcriptome in Breast Cancer Brain Metastases 7

primary and metastatic tumor samples (Fig. 1 Step 2) [22]. Note that com-
mon alternatives, such as principal components analysis (PCA) and non-negative
matrix factorization (NMF) [23] are not amenable to this case, since PCA does
not provide a feasible solution to the constrained problem, and the NMF does
not apply to our mixture data which can be either positive or negative.
Cell Communities. We define a cell community to be a set of clones/clonal
subpopulations and other cell types that propagate as a group during the evolu-
tion of a tumor. A community may be just a single subpopulation/clone, but is a
more general concept in the sense that it usually involves multiple related clones
and their associated stroma. For example, a set of immunogenic clones and the
immune cells infiltrating them might collectively form a community that has a
collective expression signature mixing signatures of the clones and associated
immune cells, even if the individual cell types are not distinguishable from bulk
expression data alone. While much work in this space has classically aimed to
separate individual clones, or perhaps individual cell types more broadly defined,
we note that deconvolution may be unable in principle to resolve distinct cell
types if they are always co-located in similar proportions. Particularly when
data is sparse and cell types are fit only approximately, as in the present work,
a model with large complexity to deconvolve the fine-grained populations is
prone to overfit. The community concept is intended in part to better describe
the results we expect to achieve from the kind of data examined here and in
part because identifying these communities is itself of interest in understanding
how tumor cells coevolve with their stroma during progression and metastasis.
Single-cell methods may provide an alternative, but are not amenable to pre-
served samples such as are needed when retrospectively studying primary tumors
and metastases that may have been biopsied years apart.
Formulation of Deconvolution. With a matrix of bulk pathway values
m×n
 ∈ R   , them×k
B deconvolution problem is to find a component matrix C =
CM , CP ∈ R that represents the inferred fundamental communities of
tumors, and the corresponding set of mixture fractions F ∈ Rk×n
+ :

2
min B − CFFr , (1)
C,F

s.t. Flj ≥ 0, l = 1, ..., k, j = 1, ..., n, (2)

k
Flj = 1, j = 1, ..., n, (3)
l=1

where ||X||Fr is the Frobenius norm. The column-wise normalization in Eq. (3)
aims for recovering the biologically meaningful cell communities. In addition,
they are equivalent to applying 1 regularizers and therefore enforce sparsity to
the fraction matrix F (Appendix Fig. 5).
Neural Network Deconvolution. Although it is possible to build new algo-
rithms for solving MF by adapting previous work [23], the additional but nec-
essary constraints of Eqs. (2–3) make the optimization much harder to solve.
For the problem Eqs. (1–3), one can prove that it does not generally guarantee
8 Y. Tao et al.

convexity (Appendix Sect. A3.1). A slightly modified version of the algorithm

to solve NMF with constraints may guarantee neither good fitting nor conver-
gence [25]. Therefore, instead of revising existing MF algorithms, such as ALS-
FunkSVD [3,12,22], we developed an algorithm which we call “neural network
deconvolution” (NND) to solve the optimization problem using gradient descent.
Specifically, the NND was implemented using backpropagation in the form of a
neural network (Fig. 2a) with PyTorch package (https://pytorch.org/) [20,34],
based on the revised constraints:
2
min B − CFFr , (4)
C,Fpar

s.t. F = cwn (|Fpar |) , (5)

where |X| applies element-wise absolute value, cwn (X) is column-wise normal-
ization, so that each column sums up to 1. The two operations of Eq. (5) naturally
rephrase and remove the two constraints in Eqs. (2–3), and meanwhile fit the
framework of neural networks. This implementation is easy to adapt to a wide
range of optimization scenarios with various constraints, and has the flexibility
of allowing for cross-validation to prevent overfitting.
Cross-Validation of NND. In order to find the best tradeoff between model
complexity and overfitting, we used cross-validation (CV) with the “masking”
method to choose the optimal number of components/communities k = 5 that
has the smallest test error (Fig. 2b). Note that the actual number of cell pop-
ulations is probably considerably larger than 5, and therefore each one of the
five communities may contain multiple cell populations. Furthermore, it is likely
that with sufficient numbers and precision of measurements, these communities
could be more finely resolved into their constituent cell types. However k = 5
represents the largest hypothesis space of NND model that can be applied to
the current dataset without severe overfitting.
See Appendix for details of NND, including architecture specifica-
tions (Sect. A3.2), hyperparameters (Sect. A3.3), evaluation of fitting ability
(Sect. A3.4), sparsity of results (Sect. A3.5), and cross-validation implementa-
tion (Sect. A3.6).

2.5 Phylogeny of Inferred Cell Subcommunities and Pathway

Inference of Steiner Nodes
We built “phylogenies” of cell subcommunities and estimated the pathway rep-
resentation of unobserved (Steiner) nodes [27] inferred to be ancestral to them,
with the goal of discovering critical communities that appear to be involved in
the transition to metastasis and identifying the important changes of functions
and expression pathways during this transition (Fig. 1 Step 3). Note that we are
using the term “phylogeny” loosely here, as these trees are intended to capture
evolution of populations of cells not just by accumulation of mutations from a
single ancestral clone but also changes in community structure, for example due
to generating or suppressing an immune response or migrating to a metastatic
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Virgin of Light, the, perhaps mentioned in Ophite address to
Astaphaeus, ii. 73 n. 2;
causes soul of Elijah to be planted in St John Baptist, ii. 137, 150;
her place and office, ii. 137 n. 3;
one of the two Leaders of the Middle, ii. 150;
working agent in salvation of souls, ii. 158;
her dealing with soul which has received lesser mysteries, ii. 165,
174;
the like with second mystery of First Mystery, ii. 167;
in Texts of Saviour gives the “Power,” ii. 184;
sends soul of slanderer into afflicted body, ii. 187;
reappears in Manichaeism, ii. 299 n. 1;
in Manichaeism retires into Moon at end of world, ii. 323 n. 4
Vohu Mano, the Amshaspand, reference to, in Apocalypse of
Salathiel, i. 167 n. 2;
first of Amshaspands in Avesta, i. 181 n. 1;
receives faithful soul at death, ii. 311
Vologeses or Valkash, King of Parthia, collects books of Avesta, ii.
278, 283;
his attempt at reformation of Zoroastrianism unsuccessful, ii. 284
Vonones, King of Parthia, his philhellenism offends his subjects, ii.
282
Vulcan, the god, on Mithraic monument, ii. 238 n. 3

Way, the Middle, in Texts of Saviour Jesus transfers himself and his
disciples to, ii. 182;
a place of torment, ii. 187
Wesley, John, founder of a “Free Church,” ii. 19
Wessely, Dr Karl, edits Magic Papyri, i. 101
Wheel of Salvation, in Manichaeism, ii. 297, 306, 308.
See Zodiac
Winckler, Dr Hugo, his astral theory of Oriental religion, i. 115 n. 1;
 his discovery of worship of Vedic gods in Asia Minor, ii. 45 n. 1,
231
Williams-Jackson, Prof. A. V., puts date of Zoroaster at 700 B.C., i. lxii
Woide, librarian of British Museum, first draws attention to Pistis
Sophia, ii. 134
Woman, the First, the Holy Spirit of the Ophites, ii. 40;
at first female form of Ophite Supreme Being, later proceeds from
Father and Son, ii. 41 n. 2;
story of superfluous Light which falls from, ii. 44;
Sophia springs from left side of, Christos from right, ii. 46;
not mentioned by Sophia when undeceiving Ialdabaoth, ii. 51 n. 5

Xenocrates of Chalcedon, his date, i. 47 n. 1;

speaks of a supernal and infernal Zeus, i. 47 n. 1; ii. 239 n. 6;
makes Zeus both male and female, i. 47 n. 4;
calls stars and planets, gods, i. 186 n. 2
Xenophanes of Colophon, says Demeter and Persephone the same
goddess, i. 46
Xenophon, authority for visits of the King’s Eye to satraps, i. 2 n. 1;
treats Socrates as polytheist, i. 11
Xisuthros, the Babylonian Noah, i. lx

Yahweh of Israel, a mountain god to Syrians, i. 10;

Hebrew Prophets’ and Psalmists’ monotheistic conception of, i. 11;
associated in magic with Zeus and Serapis, i. 107;
according to Jews, promises them exclusive temporal advantages,
i. 150;
on same authority, makes world for sake of Jews, i. 165;
stars the viceroys of (Philo), i. 187;
the “Father” of second or intermediate world of Simon, i. 188;
called Hypsistos in Asia Minor (Cumont), ii. 31, 85 n. 3;
Anat and Bethel assessors of, at Elephantine, ii. 32 n. 4, 43 n. 2;
name of, specially used in magic, ii. 33;
 name of, ineffable after Alexander, ii. 37 n. 1;
Sophia his delight and instrument, ii. 45 n. 1;
called Ialdabaoth by Ophites, ii. 47;
in Ophite system, power below the Supreme God, ii. 84;
called the Great Archon by Basilides, ii. 94;
probably the Jeû of Pistis Sophia, ii. 148
Yazatas, the. See Izeds
Yezdegerd II, the Shah, Zervanist sect dominant in Persia, temp., ii.
285
York, Mithraic monuments at, ii. 239
Yung, Dr Émile, his views on hypnotism and crystal-gazing, i. 110

Zacchaei, the, Gnostic sect mentioned by Epiphanius, ii. 27 n. 1

Zachariah, the Prophet, shows hatred of Gentiles, i. 167 n. 4
Zagreus, the god, secret worship of, in Greece in early times, i. 17;
Cretan legend of, i. 37;
the same as taught at Eleusis, i. 42;
and by Orphics, i. 124, 125;
Orphics connect Passion and Resurrection of, with history of man,
i. 126;
Orphics teach that man’s soul is part of, i. 127;
initiate becomes identified with Zagreus by eating raw flesh of
victim, i. 128;
identified with Iacchos at Eleusis, i. 130;
and with Sabazius, i. 137;
called “Highest of All” (Aeschylus), i. 137 n. 3;
rites of Sabazius explained by legend of, i. 138;
sewing of heart of, in thigh of Zeus and its result, i. 145
Zarazaz, cryptographic name of power in Texts of Saviour otherwise
Maskelli, ii. 75 n. 1, 148 n. 3;
perhaps Guardian of Veil of Treasure-house, ii. 148 n. 3
Zeesar, cryptographic name of heavenly river among Ophites, ii. 94
n. 3
Zeller, his view of Philo’s powers of God, i. 174
Zend Avesta. See Avesta
Zeno of Cyprus, why not quoted by Ophite writers, ii. 83
Zervan, said by Moses of Chorene to be the Patriarch Shem, i. lx;
Supreme God of Light in Tun-huang and Turfan texts, ii. 323, 342,
343
Zervan Akerene, supreme divinity of sect of Zoroastrian heretics, ii.
236;
head of Mithraic pantheon and father of Ormuzd and Ahriman
(Cumont), ii. 252;
Mihr Nerses’ proclamation concerning, ii. 285;
belief in, denounced in Khuastuanift, ii. 339
Zeus, Crete or Asia Minor birthplace of, i. 16;
identified with many gods of Asia and Europe, i. 17;
father of Zagreus by Persephone, i. 37, 42, 138;
union with Demeter shown in Mysteries, i. 40, 61 n. 1;
Hermes sent by, to Hades for deliverance of Persephone, i. 41;
father of Dionysos his destined successor, i. 46;
the Z. of Phidias model for Serapis, i. 49;
“Serapis is Z.”, i. 55;
Achilles’ flattery of, i. 95;
identified in magic spell with Serapis and Yahweh, i. 106, 107;
Orphic, swallows Phanes and becomes father of gods and men, i.
123;
his relations with Orphic Dionysos, i. 124;
blasts Titans after murder of Zagreus, i. 125;
Orphic “an initiate of Idaean Z.” (Euripides), i. 128;
man’s soul a descendant of, according to Orphics, i. 133;
relations of Orphic, with Demeter and Persephone, i. 142, 144,
145;
Titans enemies of, ii. 146;
identified by Orphics with Dionysos, ii. 147;
Samaritans offer Antiochus Epiphanes to dedicate Mt Gerizim
temple to, i. 177;
Orphics assign last age of world but one to, i. 186;
 called Metropator by Orphics, i. 190 n. 1;
Barnabas hailed as, in Phrygia, i. 191 n. 3; ii. 42;
legend of Z. and Persephone referred to Asia Minor, ii. 49;
Varuna perhaps prototype of, ii. 231;
“the whole circuit of the sky” to Persians (Herodotus), ii. 234;
identified with Ormuzd, ii. 237;
on Mithraic monuments, ii. 238, 254.
See Jupiter, Polycleitos
Zeus Chthonios, “the God” of Eleusis, i. 47;
mentioned by Hesiod, i. 126;
identified with Hades and Dionysos, i. 130;
and with Adonis, i. 137;
the serpent lover of Persephone, i. 145 n. 2
Zeus Labrandos, double axe symbol of, ii. 67 n. 3.
See Lairbenos
Zodiac, the, in Texts of Saviour salvation determined by entry of
benefic planet into certain signs of, i. 118;
in Pistis Sophia Twelve Aeons means, ii. 137 n. 1, 154;
Pythagoras’ division of, ii. 144 n. 8;
the Twelve “members of Light” in Manichaeism, ii. 293 n. 2;
the Wheel with twelve buckets in same, ii. 297 n. 2;
the twelve daughters of the Third Legate, ii. 328
Zoë or Life, member of second Valentinian syzygy, ii. 98
Zoroaster, Parsi belief in special inspiration of, i. liii;
religion of, once shared with Buddhism and Christianity belief of
civilized world, i. lviii;
Plutarch’s date for, i. lxii;
religion reformed by, may be pre-Homeric, i. lxiii;
date of, 700 B.C., i. 126 n. 3; ii. 232;
both Bardesanes and Marcion borrow from (Al-Bîrûnî), ii. 214 n. 2;
name and doctrine of, known in West long before Plutarch, ii. 234;
reform of, directed against worship of Ahriman (Rosenberg), ii. 253
n. 5;
Ardeshîr entrusts Magi with propagation of reformed religion of, ii.
280;
 divine origin of teaching of, acknowledged by Manes, ii. 316
Zoroastrianism, borrows from Babylonia, i. lxi;
our ignorance of origin and dates of, i. lxii;
adopts theory of seven planetary spheres surrounding earth, i.
117;
Orphic poems seem reminiscent of reformed, i. 122;
late form of, derives origin of man from death of Gayômort, i. 126
n. 3;
fire which burns wicked like warm milk to just, i, 134 n. 1;
doctrine of Essenes said to be derived from, i. 156;
doctrine of Amshaspands in, i. 181;
likeness between post-Exilic Judaism and (Cheyne), i. 181 n. 1;
Simon Magus’ ideas in part derived from (Franck), i. 197;
revolt of Gaumata perhaps directed against, ii. 233;
its restoration and reform by Ardeshîr, ii. 284;
Manes’ description of lot of justified taken from, ii. 310
Zwingli, founder of a “Free Church,” ii. 19
CAMBRIDGE: PRINTED BY JOHN CLAY, M.A. AT THE
UNIVERSITY PRESS

Footnotes
1. Col. ii. 18.

2. Lightfoot, St Paul’s Epistle to the Colossians, pp. 90 sqq.

3. So A. Jülicher in Encyc. Bibl. s.v. Gnosis.

4. Irenaeus, op. cit. Bk I. c. 23, p. 214, Harvey. Salmon in Dict. of

Christian Biog. s.v. Nicolaitans, thinks this an idea peculiar to
Irenaeus alone and not to be found in the older source from
which he drew his account of the other Gnostics.

5. The Canonical Apocalypse was probably written after the

siege of Jerusalem by Titus in 70 A.D., while the first
unmistakable mention we have of St John’s Gospel is by
Theophilus of Antioch a hundred years later. Earlier
quotations from it are anonymous, i.e. they give the words of
the Gospel as in the A.V. but without referring them to any
specified author. See Duchesne, Early Christian Church, Eng.
ed. pp. 102, 192.

6. Hegesippus, quoted by Eusebius, Hist. Eccl. Bk IV. c. 22, says

that the Church was untroubled by heresy until the reign of
Trajan.

7. Hegesippus (see last note) in his account of the martyrdom of

“James the Brother of the Lord,” op. cit. Bk II. c. 23.

8. See Schmiedel, Encyc. Bibl. s.v. Community of Goods. Cf.

Lucian, de Mort. Peregrini, c. XIII, and Mozley’s comments in
 Dict. Christian Biog. s.v. Lucianus.

9. Maran atha. See Epistle of Barnabas, c. XXI.

10. Winwood Reade, op. cit. pp. 237 sqq.

11. Eugène de Faye, “Formation d’un Doctrine de Dieu au IIme

Siècle,” R.H.R. t. LXIII. (1911), p. 9. He quotes Harnack in his
support.

12. Mark xi. 1.

13. On the ignorance of the first Christian writers, see de Faye,

op. cit. p. 4.

14. Origen, cont. Celsum, Bk III. c. 12. Cf. Krüger, La Grande

Encyclopédie, Paris, s.v. Gnosticisme.

15. “Those which say they are Jews, but are not”; Rev. ii. 9; ibid.
iii. 9. The Clementine Homilies, though of much later date,
never speak of the Christians otherwise than as Jews. Cf.
Duchesne, Early Christian Church, p. 12.

16. Acts viii. 1.

17. Renan (L’Antéchrist, p. 511, and note 1) gives a passage,

which he thinks is from Tacitus, showing that Titus aimed at
the suppression of the Christians as well as the Jews.
Doubtless many Christians perished in the punitive measures
taken in the Ist century against the Jews in Antioch and
elsewhere. Cf. Josephus, Wars of the Jews, Bk VII. c. 3;
Eusebius, H. E. Bk III. cc. 12, 17, 19, 20. It was the
persecution by the fanatical Jews that compelled the flight of
the Christians to Pella shortly before the siege. See Eusebius,
Bk III. c. 5; Epiph. Haer. XXIX. c. 7, p. 239, Oehler. The episode
of the “Woman clothed with the Sun” of the Canonical
Apocalypse is supposed by some to refer to this.
18. So that the members of the little Church of Pella who retained
the name of Jews gradually ceased to be regarded as
orthodox by the other Christian communities and were called
Ebionites. See Renan, L’Antéchrist, p. 548. Cf. Fuller in Dict.
Christian Biog. s.v. Ebionites for authorities. The connection
that Fuller would find between the Essenes and the Ebionites
seems to rest on little proof.

19. Thus Mgr Duchesne, op. cit. p. 14, says that “St Paul was a
Jew by birth, imbued with the exclusiveness and disdainful
spirit which inspired his race and influenced all their dealings
with other nations.”

20. Many of the Sicarii and other fanatics managed to escape

before the catastrophe of the First Jewish War to Egypt and
the Cyrenaica, where they continued to commit outrages and
make rebellion until they brought on themselves and their co-
religionists the wrath of the Romans. See Josephus, Wars, Bk
VII. cc. 10, 11. Cf. Renan, L’Antéchrist, p. 539; id., Les
Évangiles, p. 369.

21. Abel’s Orphica, Frgs. 243-248, especially the quotation from

Nigidius.

22. See Chapter II, supra.

23. So Renan, L’Antéchrist, p. 300, says that the Synoptic

Gospels probably first took shape in the Church at Pella. Thus
he explains the so-called “little Apocalypse” of Matthew xxiv.,
Mark xiii., and Luke xxi. Cf. ibid., p. 296 and note. For the
symbolic construction placed upon them by the Gnostics, see
Hatch, H. L., p. 75.

24. Hegesippus, who probably wrote about 150 A.D., speaks of

Thebuthis, Dositheus, and others as leaders of early sects.
Eusebius, Hist. Eccl. Bk IV. c. 22, and Origen (cont. Cels. Bk
VI. c. 11) make this last a contemporary of Simon Magus. The
Clementine Homilies (Bk II. c. 24), from whom both authors
 may have derived their information, have a long story about
Dositheus being with Simon a follower of John the Baptist,
and disputing with Simon the headship of the sect. From
presumably other sources, Hegesippus speaks of the
Essenes, the Masbothoeans and the Hemero-baptists, for
which last see Chapter XIII, infra, as pre-Christian sects.

25. Winwood Reade, op. cit. p. 244. Probably this is what is

meant by Gibbon when he says (Decline and Fall, Bury’s ed.
III. p. 153, n. 54) that no future bishop of Avila is likely to
imitate Priscillian by turning heretic, because the income of
the see is 20,000 ducats a year.

26. Apostolical Constitutions, Bk II. cc. 45, 46, 47. Harnack,

Expansion of Christianity, Eng. ed. II. p. 98 n. 1, gives the date
of this work as “middle of the 2nd century.” Duchesne, op. cit.
p. 109, thinks it is derived from the Didache which he puts not
later than Trajan.

27. Apost. Const. Bk II. c. 26: “He (i.e. the bishop) is your ruler
and governor; he is your king and potentate; he is next after
God, your earthly divinity, who has a right to be honoured by
you.”

28. Lucian, Proteus Peregrinus, passim; Acts of Paul and Thekla;

Acts of Peter of Alexandria.

29. Clement of Rome, First Epistle to the Corinthians, c. 44.

30. So Irenaeus, op. cit. Bk I. c. 26, pp. 219, 220, Harvey, says it
was the desire to become a διδάσκαλος or teacher that drove
Tatian, once a hearer of Justin Martyr’s, into heresy.
Hegesippus, ubi cit. supra, says that Thebuthis first corrupted
the Church, on account of his not being made a bishop. For
the same accusation in the cases of Valentinus and Marcion,
see Chapters IX and XI, infra.
31. Celsus apud Origen (op. cit. Bk III. cc. 10, 11) says: “Christians
at first were few in number, and all held like opinions, but
when they increased to a great multitude, they were divided
and separated, each wishing to have his own individual party;
for this was their object from the beginning”—a contention
which Origen rebuts.

32. Thus in Egypt it was almost exclusively the lower classes

which embraced Christianity at the outset. See Amélineau,
“Les Actes Coptes du martyre de St Polycarpe” in P.S.B.A.
vol. X. (1888), p. 392. Julian (Cyr. VI. p. 206) says that under
Tiberius and Claudius there were no converts of rank.

33. Thus Cerinthus, who is made by tradition the opponent of St

John, is said to have been a Jew and to have been trained in
the doctrines of Philo at Alexandria (Theodoret, Haer. Fab. Bk
II. § 3). Cf. Neander, Ch. Hist. (Eng. ed.) vol. II. pp. 42-47.
Neander says the same thing about Basilides (op. cit. p. 47
and note) and Valentinus (p. 71), although it is difficult to
discover any authority for the statement other than the Jewish
features in their doctrines. There is more evidence for the
statement regarding Marcus, the heresiarch and magician
whom Irenaeus (op. cit. Bk I. c. 7) accuses of the seduction of
Christian women, apparently in his own time, since the words
of Marcus’ ritual, which the Bishop of Lyons quotes, are in
much corrupted Hebrew, and the Jewish Cabala was used by
him. Renan’s view (Marc Aurèle, pp. 139 sqq.) that
Christianity in Egypt never passed through the Judaeo-
Christian stage may in part account for the desire of Jewish
converts there to set up schools of their own.

34. For Marcion, see Chapter XI, infra. Summary accounts of the
doctrines of other Gnostics mentioned are given by Irenaeus
and Hippolytus in the works quoted. See also the Dict. of
Christian Biog., under their respective names.

35. The lesser heresiologists, such as Philaster of Brescia, St

Augustine, the writer who is known as Praedestinatus, the
 author of the tract Adversus omnes Haereses wrongly
ascribed to Tertullian, and the other writers included in the first
volume of Oehler’s Corpus Haereseologici, Berlin, 1856, as
well as writers like Eusebius, all copy from one or other of
these sources. The Excerpta Theodoti appended to the works
of Clement of Alexandria are on a different footing, but their
effect at the time spoken of in the text was not appreciated.
Cf. Salmon in Dict. Christian Biog. s.v. Valentinus.

36. Bouché-Leclercq, L’Intolérance Religieuse et Politique, Paris,

1912, p. 140.

37. Ammianus Marcellinus, Bk XXII. c. 5, § 4.

38. An excellent and concise account of the discovery and the

subsequent controversy as to the authorship of the book is
given by Salmon in the Dict. Christian Biog. s.v. Hippolytus
Romanus. For Mgr Duchesne’s theory that Hippolytus was a
schismatic Pope, see his Hist. Christian Church, pp. 227-233.

39. Salmon’s position is set out by him in Hermathena, Dublin,

1885, pp. 389 sqq. For Stähelin’s, see his tractate Die
Gnostische Quellen Hippolyts, Leipzig, 1890, in Harnack’s
Texte und Untersuchungen. Both are skilfully summarized by
de Faye in his Introduction à l’Étude du Gnosticisme, Paris,
1903, pp. 25 sqq.

40. De Faye does not accept Stähelin’s contention as to the

forgery, but his conclusion as to the date is as stated in the
text. See Introduction, etc. pp. 68, 71.

41. Tertullian, Scorpiace, c. 1.

42. Neander, Ch. Hist. (Eng. ed.), I. p. 208, quotes a case from St
Augustine which I have not been able to verify.

43. Gibbon, Decline and Fall, II. p. 110 and note 144 (Bury’s ed.).
For the search which the Christian emperors directed to be
 made for the heretics’ books, see Eusebius, Vita Constantini,
Bk III. cc. 64, 65.

44. The actual transcription and translation were made by

Maurice Schwartze, a young German who was sent over here
to study the documents in the British Museum at the expense
of the King of Prussia. He died after the completion of his
task, and before the book could be printed.

45. Amélineau’s transcription and translation appeared in the

Notices et Extraits, etc. of the Académie des Inscriptions, t.
XXIX. pt 2 (Paris, 1891). He has also published a translation
into French without text of the Pistis Sophia (Paris, 1895). Dr
Carl Schmidt, of the University of Berlin, has published
translations into German of both works under the title
Koptisch-Gnostische Schriften, Bd I., Leipzig, 1905. None of
these versions are entirely satisfactory, and it is much to be
wished that an authoritative edition of the two works could be
put forward by English scholars. The present writer gave a
short history and analysis of them in the Scottish Review for
1893 under the title “Some Heretic Gospels.”

46. Clement was so far from being a heresiologist that he has not
escaped the reproach of being himself a heretic. He
repeatedly speaks in praise of the “true Gnostic,” meaning
thereby the perfect Christian, and although this is probably a
mere matter of words, it seems to have induced Photius in the
IXth century to examine his writings with a jealous eye. The
result was that, as M. Courdaveaux points out (R.H.R. 1892,
p. 293 and note), he found him guilty of teaching that matter
was eternal, the Son a simple creature of the Father, the
Incarnation only an appearance, that man’s soul entered
several bodies in succession, and that several worlds were
created before that of Adam. All these are Gnostic opinions,
and it may be that if we had all Clement’s books in our hands,
as had Photius, we might confirm M. Courdaveaux’s
 judgment, as does apparently Mgr Duchesne. Cf. his Hist. of
Christian Ch. pp. 244, 245.

47. Cf. A. C. McGiffert, Prolegomena to the Church History of

Eusebius (Schaff and Wace’s Nicene Library), Oxford, 1890,
vol. I. p. 179 and note.

48. Of the heresies mentioned in the Philosophumena only two,

viz. that of Simon Magus and that of those whom Hippolytus
calls the Sethiani, do not admit, either expressly or by
implication, the divinity of Jesus. This may be accounted for
by what has been said above as to both being pre-Christian in
origin.

49. E.g. Irenaeus, op. cit. Bk I. c. 1, I. p. 9, Harvey. Here he is

called ὅμοιος τε καὶ ἴσος τῷ προβαλόντι, “like and equal to
him who had sent him forth.” There is certainly here no
allusion to “begetting” in the ordinary sense of the word.

50. As in the epithet of Persephone in the Orphic Hymn quoted

above. See Chapter IV, supra. The unanimity with which all
post-Christian Gnostics accepted the superhuman nature of
Jesus seems to have struck Harnack. See his What is
Christianity? Eng. ed. 1904, pp. 209, 210.

51. Iliad I. ll. 560 sqq.; IV. ll. 57, 330; XIV. ll. 320 sqq.

52. Odyssey XI. ll. 600 sqq.; Plutarch, Life of Pelopidas, c. XVI.

53. Plutarch, de Is. et Os. c. LXXI.

54. Ibid. cc. XXV., XXVII., XXX.

55. Probably this was one of the reasons why the Mysteries which
showed the death of a god had in Greece to be celebrated in
secret. See Diodorus’ remark (Bk V. c. 77, § 3) that the things
which the Greeks only handed down in secret were by the
Cretans concealed from no one.
56. Hippolytus, op. cit. Bk VI. c. 19, p. 265, Cruice.

57. Irenaeus, op. cit. Bk I. c. 19, II. p. 200, Harvey.

58. ἀμορφία. Hippolytus, op. cit. Bk VII. c. 27, p. 366, Cruice.

59. Irenaeus, op. cit. Bk I. c. 18, p. 197, Harvey. Hippolytus, op.

cit. Bk VII. c. 28, p. 368, Cruice.

60. Hippolytus, op. cit. Bk VIII. c. 8.

61. Irenaeus, op. cit. Bk I. c. 1, § 13, pp. cxli and 61, Harvey.

62. Ibid. Bk I. c. 1, § 31, pp. cxli and 62, Harvey.

63. Irenaeus, op. cit. Bk I. c. 19, § 3, p. 202, Harvey; Hippolytus,

op. cit. Bk IV. c. 24, p. 225, Cruice; Tertullian, Scorpiace, c. I.

64. For the accusation against the Christians, see Athenagoras,

Apologia, cc. III., XXXI.; Justin Martyr, First Apol. c. XXVI. For
that against the Jews, Strack, Le Sang et la fausse
Accusation du Meurtre Rituel, Paris, 1893. For that against
the Freemasons, “Devil Worship and Freemasonry,”
Contemporary Review for 1896.

65. See n. 1, supra. So Eusebius speaks of the Simonians

receiving baptism and slipping into the Church without
revealing their secret tenets, Hist. Eccl. Bk II. c. 1.

66. Revillout, Vie et Sentences de Secundus, Paris, 1873, p. 3, n.

1.

67. Amélineau, Le Gnosticisme Égyptien, p. 75, thus enumerates

them: the doctrine of emanation, an unknown [i.e. an
inaccessible and incomprehensible] God, the resemblance of
the three worlds, the aeonology of Simon, and a common
cosmology. To this may be added the inherent malignity of
matter and the belief in salvation by knowledge. See Krüger,
La Grande Encyclopédie, s.v. Gnosticisme.
68. Renan, Mare Aurèle, p. 114.

69. Witness the confusion between Ennoia and Epinoia in

Chapter VI, vol. I. p. 180, n. 4, supra, and between Saturnilus
and Saturninus in this chapter, p. 9. So Irenaeus and others
record the opinions of an associate of Marcus whom they call
“Colarbasus,” a name which modern criticism has shown to
be a mistake for ‫ קול ארבע‬Kol-arba, “The Voice of the Four” or
the Supreme Tetrad. See Renan, Mare Aurèle, p. 129; Hort in
Dict. Christian Biog. s.h.v. So Clement of Alexandria, Protrept.
c. II. mistakes Evoe, the mystic cry of the Bacchantes, for the
Eve of Genesis.

70. Renan, L’Église Chrétienne, p. 140.

71. Hippolytus, op. cit. Bk V. c. 9, p. 177, Cruice.

72. As in the case of Clement of Alexandria, who seems to have

been initiated into most of the heathen mysteries then current.
It is to be noted, too, that Origen, although he speaks of the
Ophites as an insignificant sect (see Chapter VIII, infra), yet
professes to know all about their secret opinions.

73. Renan, Marc Aurèle, p. 139.

74. Thus Ambrose of Milan had been before his conversion a

Valentinian, Epiphanius a Nicolaitan. See Eusebius, H.E. Bk
VI. c. 18; Epiph. Haer. XXVI. c. 17, p. 198, Oehler.

75. It could be even self-administered, as in the Acts of Paul and

Thekla, where Thekla baptizes herself in the arena. See
Tischendorf’s text. The Clementine Homilies (Bk XIV. c. 1)
show that it could be immediately followed by the Eucharist
without any intermediate rite or preparation. Contrast with this
the elaborate ceremonies described by Cyril of Jerusalem,
where the white-robed band of converts after a long
catechumenate, including fasting and the communication of
secret doctrines and passwords, approach on Easter Eve the
 doors of the church where the lights turned darkness into day.
See Hatch, H. L. pp. 297, 299.

76. Duchesne, Hist. Christian Ch. p. 32; Harnack, What is

Christianity? Eng. ed. p. 210.

77. As Hatch, H. L. pp. 274-279, has pointed out, the term

όμοοὐσιος, which led to so much shedding of Christian blood,
first occurs among the post-Christian Gnostics, and led in turn
to most of the wranglings about “substance,” “person,” and
the other metaphysical distinctions and their result in “strife
and murder, the devastation of fair fields, the flame of fire and
sword” (ibid. p. 279). For the possibilities of Greek science,
had it not been opposed by the Church, see ibid. p. 26.

78. See the edict of Constantine, which Eusebius (Vit.

Constantini, cc. LXIV., LXV.) quotes with unholy glee, prohibiting
the Gnostics from presuming to assemble together either
publicly or privately, and commanding that their “houses of
prayer” should be confiscated and handed over to the
Catholic Church. Eusebius (ibid. c. LXVI.) says that the result of
this was that the “savage beasts crept secretly into the
Church,” and continued to disseminate their doctrines by
stealth. Perhaps such a result was to be expected.

79. “Eorum qui ante adventum Christi Haereseos arguuntur.”

Philastrius, Ep. Brixiensis, de Haeresibus Liber, c. I. vol. I. p. 5,
Oehler.

80. Augustinus, de Haeresibus (cf. ad Quod vult deum) Liber, c.

XVII. I. p. 200, Oehler.

81. Pseudo-Tertullianus, Adversus omnes Haereses, cc. V., VI. p.

273, Oehler. The writer was probably Victorinus of Pettau.

82. Pseudo-Hieronymus, Indiculus de Haeresibus, c. III., vol. I. p.

285, Oehler.
83. Acts vi. 5. It will be noted that Epiphanius, who himself
belonged to the sect in his youth, interposes only the
Basilidians between them and the followers of Saturninus, the
“heresy” of which last he derives directly from that of Simon
Magus.

84. Rev. ii. 6, 15.

85. Origen, cont. Celsum, Bk VI. c. 28. Possibly the Euphrates

called “the Peratic” or Mede by Hippolytus (op. cit. Bk IV. c. 2,
p. 54, Cruice).

86. Hippolytus, op. cit. Bk V. c. 7, p. 141, Cruice. This Mariamne is

doubtless the sister of Philip mentioned in the Apocryphal
Acta Philippi (c. XXXII., Tischendorf), which have, as is said
later, a strong Gnostic or Manichaean tinge. Celsus knew a
sect which took its name from her. See Origen, cont. Cels. Bk
V. c. 62.

87. The Canonical Apocalypse is not earlier than 70 A.D., and was
probably written soon after the fall of the Temple of
Jerusalem. Hippolytus and Origen wrote 130 years later.

88. Naassene is evidently derived from the Hebrew or Aramaean

‫“ נחש‬Serpent,” cf. Hipp. op. cit. Bk V. c. 6, p. 139, Cruice, and
exactly corresponds to the Greek ὀφίτης and the Latin
serpentinus (Low Latin serpentarius). “Worshipper of the
Serpent” seems to be the patristic gloss on the meaning of the
word.

89. Giraud, Ophitae, c. 4, § 65, p. 89. The question really

depends upon Hippolytus’ sources, as to which see last
chapter, pp. 11, 12. Cf. De Faye, Introduction, etc., p. 41.
Hippolytus’ Naassene author cannot be much earlier than 170
A.D. since he quotes from St John’s Gospel, and probably later
than the work of Irenaeus written in 180-185. Yet the Ophite
system described by Irenaeus is evidently not a primitive one
 and has been added to by his Latin translator. See n. 3, p. 47,
infra.

90. Irenaeus, Bk I. c. 27, § 1, p. 226, Harvey, says that the

Ophites are the same as the Sethians; Hippolytus, op. cit. Bk
V. c. 11, p. 184, Cruice, that they are connected with the
Peratae, the Sethians, and the system of Justinus.
Epiphanius, Haer. XXXVII. c. 1, p. 494, Oehler, while deriving
them from Nicolaus the Deacon, gives them a common origin
with those whom he calls Gnostics simply, and identifies these
last with the Borboriani, Coddiani, Stratiotici, Phibionitae,
Zacchaei, and Barbelitae (see Haer. XXVI. c. 3).

91. Hippolytus, op. cit. Bk V. c. 11, p. 184, Cruice.

92. ἑαυτοὺς γνωστικοὺς ὀνομάζοντες. Hippolytus, loc. cit.

Eusebius, H. E. Bk IV. c. 7, says that Carpocrates was the
father of the heresy of the Gnostics and contemporary with
Basilides.

93. Epiphanius, Haer. XXVI. c. 7, pp. 174, 176, Oehler.

94. Tertullian, de Praescript. Haer. c. XLII.

95. Josephus, Antiq. Bk XII. c. 3.

96. Ramsay, Cities and Bishoprics of Phrygia, II. pp. 667 sqq.; St
Paul, pp. 142 sqq.; Commentary on Galatians, pp. 189 sqq.
The fact that Timothy, the son of the Jewess Eunice by a
Greek father, was not circumcised (see Acts xvi. 1) is quoted
in support.

97. E.g. the Montanist, the most formidable of the heresies which
attacked the primitive Church, apart from Gnosticism. Cf. also
Galatians i. 6.

98. Mahaffy, Greek World under Roman Sway, p. 168. For the
tyranny of the Armenians, see Plutarch, Lucullus, cc. XIV., XXI.
 99. Mahaffy, Gk. World, p. 100.

100. Mahaffy, ibid. p. 225.

101. Ramsay, Cities, etc., I. p. 9.

102. Ramsay, Cities, etc., I. p. 87.

103. Ramsay, ibid. I. p. 92.

104. Ramsay, ibid. I. pp. 93, 94. The Galli or priests of Cybele, who
mutilated themselves in religious ecstasy, seem to have been
the feature of Anatolian religion which most struck the
Romans, when the statue of the Mother of the Gods first
appeared among them. Cf. next page. For the other side of
the religion, see Lucian, de Dea Syria, cc. VI., XLIII., and
Apuleius, Metamorph. Bk VIII. c. 29.

105. As in the hymn to Attis said to have been sung in the Great
Mysteries, given in the Philosophumena (see p. 54, infra). Cf.
Ramsay, Cities, etc., I. pp. 132, 263, 264, for other
identifications. The Anatolian name of the Dea Syria to whose
cult Nero was addicted, was Atargatis, which Prof. Garstang
would derive from the Babylonian Ishtar (Strong, Syrian
Goddess, 1913, p. vii); see Cumont, Les Religions Orientales
dans le Paganisme Romain, Paris, 1906, p. 126. The whole of
Cumont’s chapters on Syria and Asia Minor (op. cit. pp. 57-
89) can be consulted with advantage. The American edition,
1911, contains some additional notes. See, too, Decharme’s
article on Cybele in Daremberg and Saglio’s Dict. des Antiq.

106. Dill, Nero to Marcus Aurelius, pp. 548 sqq.

107. See n. 1, supra; Suetonius, Nero, c. LVI.

108. Dill, loc. cit., and authorities there quoted.