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Article ; Online: A brief primer on big data for surgeons.

Rubinstein, Jill C

2019 Volume 121, Issue 3, Page(s) 419–421

MeSH term(s)	Big Data ; Databases, Factual ; Humans ; Information Storage and Retrieval/standards ; Statistics as Topic ; Surgeons/standards
Language	English
Publishing date	2019-12-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	82063-5
ISSN	1096-9098 ; 0022-4790
ISSN (online)	1096-9098
ISSN	0022-4790
DOI	10.1002/jso.25818
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Article ; Online: Nextflow pipeline for Visium and H&E data from patient-derived xenograft samples.

Domanskyi, Sergii / Srivastava, Anuj / Kaster, Jessica / Li, Haiyin / Herlyn, Meenhard / Rubinstein, Jill C / Chuang, Jeffrey H

Cell reports methods

2024 , Page(s) 100759

Abstract: We designed a Nextflow DSL2-based pipeline, Spatial Transcriptomics Quantification (STQ), for simultaneous processing of 10x Genomics Visium spatial transcriptomics data and a matched hematoxylin and eosin (H&E)-stained whole-slide image (WSI), optimized ...

Abstract	We designed a Nextflow DSL2-based pipeline, Spatial Transcriptomics Quantification (STQ), for simultaneous processing of 10x Genomics Visium spatial transcriptomics data and a matched hematoxylin and eosin (H&E)-stained whole-slide image (WSI), optimized for patient-derived xenograft (PDX) cancer specimens. Our pipeline enables the classification of sequenced transcripts for deconvolving the mouse and human species and mapping the transcripts to reference transcriptomes. We align the H&E WSI with the spatial layout of the Visium slide and generate imaging and quantitative morphology features for each Visium spot. The pipeline design enables multiple analysis workflows, including single or dual reference genome input and stand-alone image analysis. We show the utility of our pipeline on a dataset from Visium profiling of four melanoma PDX samples. The clustering of Visium spots and clustering of H&E imaging features reveal similar patterns arising from the two data modalities.
Language	English
Publishing date	2024-04-10
Publishing country	United States
Document type	Journal Article
ISSN	2667-2375
ISSN (online)	2667-2375
DOI	10.1016/j.crmeth.2024.100759
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Article: Nextflow Pipeline for Visium and H&E Data from Patient-Derived Xenograft Samples.

Domanskyi, Sergii / Srivastava, Anuj / Kaster, Jessica / Li, Haiyin / Herlyn, Meenhard / Rubinstein, Jill C / Chuang, Jeffrey H

bioRxiv : the preprint server for biology

2023

Abstract: Highlights: We have developed an automated data processing pipeline to quantify mouse and human data from patient-derived xenograft samples assayed by Visium spatial transcriptomics with matched hematoxylin and eosin (H&E) stained image. We enable ... ...

Abstract	Highlights: We have developed an automated data processing pipeline to quantify mouse and human data from patient-derived xenograft samples assayed by Visium spatial transcriptomics with matched hematoxylin and eosin (H&E) stained image. We enable deconvolution of reads with Xenome, quantification of spatial gene expression from host and graft species with Space Ranger, extraction of B-allele frequencies, and splicing quantification with Velocyto. In the H&E image processing sub-workflow, we generate morphometric and deep learning-derived feature quantifications complementary to the Visium spots, enabling multi-modal H&E/expression comparisons. We have wrapped the pipeline into Nextflow DSL2 in a scalable, portable, and easy-to-use framework. Summary: We designed a Nextflow DSL2-based pipeline, Spatial Transcriptomics Quantification (STQ), for simultaneous processing of 10x Genomics Visium spatial transcriptomics data and a matched hematoxylin and eosin (H&E)-stained whole slide image (WSI), optimized for Patient-Derived Xenograft (PDX) cancer specimens. Our pipeline enables the classification of sequenced transcripts for deconvolving the mouse and human species and mapping the transcripts to reference transcriptomes. We align the H&E WSI with the spatial layout of the Visium slide and generate imaging and quantitative morphology features for each Visium spot. The pipeline design enables multiple analysis workflows, including single or dual reference genomes input and stand-alone image analysis. We showed the utility of our pipeline on a dataset from Visium profiling of four melanoma PDX samples. The clustering of Visium spots and clustering of imaging features of H&E data reveal similar patterns arising from the two data modalities.
Language	English
Publishing date	2023-07-30
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.07.27.550727
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Article: Spatiotemporal profiling defines persistence and resistance dynamics during targeted treatment of melanoma.

Rubinstein, Jill C / Domanskyi, Sergii / Sheridan, Todd B / Sanderson, Brian / Park, SungHee / Kaster, Jessica / Li, Haiyin / Anczukow, Olga / Herlyn, Meenhard / Chuang, Jeffrey H

bioRxiv : the preprint server for biology

2024

Abstract: Resistance of BRAF-mutant melanomas to targeted therapy arises from the ability of cells to enter a persister state, evade treatment with relative dormancy, and repopulate the tumor when reactivated. Using spatial transcriptomics in patient derived ... ...

Abstract	Resistance of BRAF-mutant melanomas to targeted therapy arises from the ability of cells to enter a persister state, evade treatment with relative dormancy, and repopulate the tumor when reactivated. Using spatial transcriptomics in patient derived xenograft models, we capture clonal lineage evolution during treatment, finding the persister state to show increased oxidative phosphorylation, decreased proliferation, and increased invasive capacity, with central-to-peripheral gradients. Phylogenetic tracing identifies intrinsic- and acquired-resistance mechanisms (e.g. dual specific phosphatases, Reticulon-4, CDK2) and suggests specific temporal windows of potential therapeutic efficacy. Using deep learning to analyze histopathological slides, we find morphological features of specific cell states, demonstrating that juxtaposition of transcriptomics and histology data enables identification of phenotypically-distinct populations using imaging data alone. In summary, we define state change and lineage selection during melanoma treatment with spatiotemporal resolution, elucidating how choice and timing of therapeutic agents will impact the ability to eradicate resistant clones. Statement of significance: Tumor evolution is accelerated by application of anti-cancer therapy, resulting in clonal expansions leading to dormancy and subsequently resistance, but the dynamics of this process are incompletely understood. Tracking clonal progression during treatment, we identify conserved, global transcriptional changes and local clone-clone and spatial patterns underlying the emergence of resistance.
Language	English
Publishing date	2024-02-05
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.02.577085
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Article ; Online: Next-generation Sequencing in the Management of Gastric and Esophageal Cancers.

Rubinstein, Jill C / Nicolson, Norman G / Ahuja, Nita

The Surgical clinics of North America

2019 Volume 99, Issue 3, Page(s) 511–527

Abstract: Next-generation sequencing has enabled genome-wide molecular profiling of gastric and esophageal malignancies at single-nucleotide resolution. The resultant genomic profiles provide information about the specific oncogenic pathways that are the likely ... ...

Abstract	Next-generation sequencing has enabled genome-wide molecular profiling of gastric and esophageal malignancies at single-nucleotide resolution. The resultant genomic profiles provide information about the specific oncogenic pathways that are the likely driving forces behind tumorigenesis and progression. The abundance of available genomic data has immense potential to redefine management paradigms for these difficult disease processes. The ability to capitalize on the information provided through high-throughput sequencing technologies will define cancer care in the coming decades and could shift the paradigm from current stage-based, organ-specific treatments toward tailored regimens that target the specific culprit pathways driving individual tumors.
MeSH term(s)	Adenocarcinoma/classification ; Adenocarcinoma/genetics ; Adenocarcinoma/therapy ; Esophageal Neoplasms/classification ; Esophageal Neoplasms/genetics ; Esophageal Neoplasms/therapy ; Genomics ; High-Throughput Nucleotide Sequencing/methods ; High-Throughput Nucleotide Sequencing/trends ; Humans ; Microsatellite Instability ; Molecular Targeted Therapy/methods ; Molecular Targeted Therapy/trends ; Stomach Neoplasms/classification ; Stomach Neoplasms/genetics ; Stomach Neoplasms/therapy ; Terminology as Topic
Language	English
Publishing date	2019-03-28
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	215713-5
ISSN	1558-3171 ; 0039-6109
ISSN (online)	1558-3171
ISSN	0039-6109
DOI	10.1016/j.suc.2019.02.005
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Article ; Online: Perspectives on an education in computational biology and medicine.

Rubinstein, Jill C

The Yale journal of biology and medicine

2012 Volume 85, Issue 3, Page(s) 331–337

Abstract: The mainstream application of massively parallel, high-throughput assays in biomedical research has created a demand for scientists educated in Computational Biology and Bioinformatics (CBB). In response, formalized graduate programs have rapidly evolved ...

Abstract	The mainstream application of massively parallel, high-throughput assays in biomedical research has created a demand for scientists educated in Computational Biology and Bioinformatics (CBB). In response, formalized graduate programs have rapidly evolved over the past decade. Concurrently, there is increasing need for clinicians trained to oversee the responsible translation of CBB research into clinical tools. Physician-scientists with dedicated CBB training can facilitate such translation, positioning themselves at the intersection between computational biomedical research and medicine. This perspective explores key elements of the educational path to such a position, specifically addressing: 1) evolving perceptions of the role of the computational biologist and the impact on training and career opportunities; 2) challenges in and strategies for obtaining the core skill set required of a biomedical researcher in a computational world; and 3) how the combination of CBB with medical training provides a logical foundation for a career in academic medicine and/or biomedical research.
MeSH term(s)	Biomedical Research/education ; Career Choice ; Clinical Medicine/education ; Computational Biology/education ; Curriculum ; Databases, Factual ; Education, Graduate/methods ; Humans ; Interdisciplinary Communication ; Medical Laboratory Personnel/education ; Students, Medical ; Workforce
Language	English
Publishing date	2012-09-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	200515-3
ISSN	1551-4056 ; 0044-0086
ISSN (online)	1551-4056
ISSN	0044-0086
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Article ; Online: Deep learning image analysis quantifies tumor heterogeneity and identifies microsatellite instability in colon cancer.

Rubinstein, Jill C / Foroughi Pour, Ali / Zhou, Jie / Sheridan, Todd B / White, Brian S / Chuang, Jeffrey H

Journal of surgical oncology

2022 Volume 127, Issue 3, Page(s) 426–433

Abstract: Background and objectives: Deep learning utilizing convolutional neural networks (CNNs) applied to hematoxylin & eosin (H&E)-stained slides numerically encodes histomorphological tumor features. Tumor heterogeneity is an emerging biomarker in colon ... ...

Abstract	Background and objectives: Deep learning utilizing convolutional neural networks (CNNs) applied to hematoxylin & eosin (H&E)-stained slides numerically encodes histomorphological tumor features. Tumor heterogeneity is an emerging biomarker in colon cancer that is, captured by these features, whereas microsatellite instability (MSI) is an established biomarker traditionally assessed by immunohistochemistry or polymerase chain reaction. Methods: H&E-stained slides from The Cancer Genome Atlas (TCGA) colon cohort are passed through the CNN. Resulting imaging features are used to cluster morphologically similar slide regions. Tile-level pairwise similarities are calculated and used to generate a tumor heterogeneity score (THS). Patient-level THS is then correlated with TCGA-reported biomarkers, including MSI-status. Results: H&E-stained images from 313 patients generated 534 771 tiles. Deep learning automatically identified and annotated cells by type and clustered morphologically similar slide regions. MSI-high tumors demonstrated significantly higher THS than MSS/MSI-low (p < 0.001). THS was higher in MLH1-silent versus non-silent tumors (p < 0.001). The sequencing derived MSIsensor score also correlated with THS (r = 0.51, p < 0.0001). Conclusions: Deep learning provides spatially resolved visualization of imaging-derived biomarkers and automated quantification of tumor heterogeneity. Our novel THS correlates with MSI-status, indicating that with expanded training sets, translational tools could be developed that predict MSI-status using H&E-stained images alone.
MeSH term(s)	Humans ; Microsatellite Instability ; Deep Learning ; Microsatellite Repeats ; Colonic Neoplasms/diagnostic imaging ; Colonic Neoplasms/genetics ; Colonic Neoplasms/pathology ; Colorectal Neoplasms/pathology
Language	English
Publishing date	2022-10-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	82063-5
ISSN	1096-9098 ; 0022-4790
ISSN (online)	1096-9098
ISSN	0022-4790
DOI	10.1002/jso.27118
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Article ; Online: APC mutational patterns in gastric adenocarcinoma are enriched for missense variants with associated decreased survival.

Rubinstein, Jill C / Khan, Sajid A / Christison-Lagay, Emily R / Cha, Charles

Genes, chromosomes & cancer

2019 Volume 59, Issue 1, Page(s) 64–68

Abstract: Adenomatous polyposis coli (APC) mutations are causally associated with familial adenomatous polyposis (FAP) and are recurrent somatic events across numerous tumor types, including gastric adenocarcinoma. Severity of disease in FAP correlates with ... ...

Abstract	Adenomatous polyposis coli (APC) mutations are causally associated with familial adenomatous polyposis (FAP) and are recurrent somatic events across numerous tumor types, including gastric adenocarcinoma. Severity of disease in FAP correlates with specific APC mutations, but the impact of given mutations on phenotype in gastric cancer is not well studied. Sequencing data from the Genomic Data Commons (GDC) demonstrate an APC mutational pattern in gastric cancer that differs dramatically from that seen in colon cancer. Exome sequencing data from APC-mutant colon and gastric adenocarcinomas in GDC was filtered for single nucleotide variants (SNVs) using MuTect2 Variant Aggregation and Masking pipeline, Somatic Aggregation Workflow. APC mutations were found in 57/441 gastric (12.9%) and 309/433 colon adenocarcinomas (71.4%). There was a significant difference in the proportion of stopgain, frameshift, and missense mutations between tumor types(P < .00001). Colon tumors were predominated by frameshift and stopgains, comprising 47.7% and 35.7%, respectively. In contrast, 47.1% of gastric mutations were missense. Gastric tumors harboring missense mutations showed decreased overall survival relative to other mutational subtypes(P = .008). In the gastric samples, 25.9% of frameshift and stopgain mutations are in the 3' portion of the gene, compared to 1.4% of colon samples. APC mutations demonstrate different distributions in gastric and colon adenocarcinoma, with a shift toward missense variants in gastric tumors and worse survival in gastric tumors harboring them. As different mutations confer variable degrees of protein dysfunction and resultant clinical manifestation, expanded investigation of specific mutational patterns will prove integral to future-risk stratification strategies.
Language	English
Publishing date	2019-08-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	1018988-9
ISSN	1098-2264 ; 1045-2257
ISSN (online)	1098-2264
ISSN	1045-2257
DOI	10.1002/gcc.22792
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Article ; Online: Recurrence and Complications in Pediatric and Adolescent Papillary Thyroid Cancer in a High-Volume Practice.

Rubinstein, Jill C / Herrick-Reynolds, Kayleigh / Dinauer, Catherine / Morotti, Raffaella / Solomon, Daniel / Callender, Glenda G / Christison-Lagay, Emily R

The Journal of surgical research

2020 Volume 249, Page(s) 58–66

Abstract: Background: Treatment approaches for pediatric papillary thyroid cancer (PTC) are historically extrapolated from adult experience. However, pediatric PTC demonstrates a greater propensity for lymph node involvement, early metastases, and recurrence, ... ...

Abstract	Background: Treatment approaches for pediatric papillary thyroid cancer (PTC) are historically extrapolated from adult experience. However, pediatric PTC demonstrates a greater propensity for lymph node involvement, early metastases, and recurrence, highlighting the need for pediatric-specific treatment paradigms. Materials and methods: A retrospective review included patients with PTC aged ≤21 y, with ≥18 mo of follow-up, treated between 2002 and 2015. Fisher's exact test and Cox proportional hazard were used to estimate the effect of risk factors on disease recurrence. Results: Seventy-two cases of PTC were identified with median age of 17.0 y and median follow-up of 64.1 mo. Disease recurred at a median of 24.6 mo (range 7.8-78.1) in 7 of 51 (13.7%) of patients with disease limited to the thyroid or central neck, 7 of 18 (39%) patients with lateral neck disease at presentation who underwent a compartment-based resection, and three of three patients (100%) with lateral neck disease who sought care after non-compartment-based resection. There were no deaths from disease. Univariate predictors of recurrence included tumor size >2 cm (P = 0.005), lateral neck disease (P = 0.004), lymphovascular invasion (P = 0.017), extracapsular invasion (P < 0.0001), multifocality (P = 0.03), and non-Caucasian race (P = 0.05). Multivariate analysis identified race (P = 0.05) as an independent predictor of recurrence. In patients without lateral neck disease, there was a trend toward lower recurrence in patients undergoing thyroidectomy with central neck dissection compared with thyroidectomy alone (P = 0.07). Conclusions: Pediatric PTC is associated with excellent survival, although recurrence is common in patients with lateral node involvement. Predictors of recurrence are multifactorial and may be influenced by extent of disease, patient or tumor biology, and aggressiveness of resection. Level of evidence: Prognosis study, level IV, retrospective case series.
MeSH term(s)	Adolescent ; Age Factors ; Child ; Female ; Follow-Up Studies ; Hospitals, High-Volume/statistics & numerical data ; Humans ; Lymph Nodes/pathology ; Lymphatic Metastasis/therapy ; Male ; Neoplasm Recurrence, Local/epidemiology ; Neoplasm Recurrence, Local/pathology ; Neoplasm Recurrence, Local/prevention & control ; Postoperative Complications/epidemiology ; Postoperative Complications/etiology ; Prognosis ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Survival Analysis ; Thyroid Cancer, Papillary/mortality ; Thyroid Cancer, Papillary/pathology ; Thyroid Cancer, Papillary/surgery ; Thyroid Gland/pathology ; Thyroid Gland/surgery ; Thyroid Neoplasms/mortality ; Thyroid Neoplasms/pathology ; Thyroid Neoplasms/surgery ; Thyroidectomy/adverse effects ; Thyroidectomy/methods ; Thyroidectomy/statistics & numerical data ; Treatment Outcome ; Young Adult
Language	English
Publishing date	2020-01-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	80170-7
ISSN	1095-8673 ; 0022-4804
ISSN (online)	1095-8673
ISSN	0022-4804
DOI	10.1016/j.jss.2019.12.002
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Article ; Online: SLC12A7 alters adrenocortical carcinoma cell adhesion properties to promote an aggressive invasive behavior.

Brown, Taylor C / Murtha, Timothy D / Rubinstein, Jill C / Korah, Reju / Carling, Tobias

Cell communication and signaling : CCS

2018 Volume 16, Issue 1, Page(s) 27

Abstract: Background: Altered expression of Solute Carrier Family 12 Member 7 (SLC12A7) is implicated to promote malignant behavior in multiple cancer types through an incompletely understood mechanism. Recent studies have shown recurrent gene amplifications and ... ...

Abstract	Background: Altered expression of Solute Carrier Family 12 Member 7 (SLC12A7) is implicated to promote malignant behavior in multiple cancer types through an incompletely understood mechanism. Recent studies have shown recurrent gene amplifications and overexpression of SLC12A7 in adrenocortical carcinoma (ACC). The potential mechanistic effect(s) of SLC12A7 amplifications in portending an aggressive behavior in ACC has not been previously studied and is investigated here using two established ACC cell lines, SW-13 and NCI-H295R. Methods: SW-13 cells, which express negligible amounts of SLC12A7, were enforced to express SLC12A7 constitutively, while RNAi gene silencing was performed in NCI-H295R cells, which have robust endogenous expression of SLC12A7. In vitro studies tested the outcomes of experimental alterations in SLC12A7 expression on malignant characteristics, including cell viability, growth, colony formation potential, motility, invasive capacity, adhesion and detachment kinetics, and cell membrane organization. Further, potential alterations in transcription regulation downstream to induced SLC12A7 overexpression was explored using targeted transcription factor expression arrays. Results: Enforced SLC12A7 overexpression in SW-13 cells robustly promoted motility and invasive characteristics (p < 0.05) without significantly altering cell viability, growth, or colony formation potential. SLC12A7 overexpression also significantly increased rates of cellular attachment and detachment turnover (p < 0.05), potentially propelled by increased filopodia formation and/or Ezrin interaction. In contrast, RNAi gene silencing of SLC12A7 stymied cell attachment strength as well as migration and invasion capacity in NCI-H295R cells. Transcription factor expression analysis identified multiple signally pathways potentially affected by SLC12A7 overexpression, including osmotic stress, bone morphogenetic protein, and Hippo signaling pathways. Conclusions: Amplification of SLC12A7 observed in ACCs is shown here, in vitro, to exacerbate the malignant behavior of ACC cells by promoting invasive capacities, possibly mediated by alterations in multiple signaling pathways, including the osmotic stress pathway.
MeSH term(s)	Adrenal Cortex Neoplasms/pathology ; Adrenocortical Carcinoma/pathology ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Cell Adhesion ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Humans ; Neoplasm Invasiveness ; Signal Transduction ; Symporters/genetics ; Symporters/metabolism
Chemical Substances	Biomarkers, Tumor ; SLC12A7 protein, human ; Symporters
Language	English
Publishing date	2018-06-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1478-811X
ISSN (online)	1478-811X
DOI	10.1186/s12964-018-0243-0
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