Publications

Journal Publications

September 17, 2015
S. Uttam, H. V. Pham, J. LaFace, B. Leibowitz, J. Yu , R. E. Brand, D. J. Hartman, and Y. Liu
Abstract

Early cancer detection currently relies on screening the entire at-risk population, as with colonoscopy and mammography. Therefore, frequent, invasive surveillance of patients at risk for developing cancer carries financial, physical, and emotional burdens because clinicians lack tools to accurately predict which patients will actually progress into malignancy. Here, we present a new method to predict cancer progression risk via nanoscale nuclear architecture mapping (nanoNAM) of unstained tissue sections based on the intrinsic density alteration of nuclear structure rather than the amount of stain uptake. We demonstrate that nanoNAM detects a gradual increase in the density alteration of nuclear architecture during malignant transformation in animal models of colon carcinogenesis and in human patients with ulcerative colitis, even in tissue that appears histologically normal according to pathologists. We evaluated the ability of nanoNAM to predict "future" cancer progression in patients with ulcerative colitis who did and did not develop colon cancer up to 13 years after their initial colonoscopy. NanoNAM of the initial biopsies correctly classified 12 of 15 patients who eventually developed colon cancer and 15 of 18 who did not, with an overall accuracy of 85%. Taken together, our findings demonstrate great potential for nanoNAM in predicting cancer progression risk and suggest that further validation in a multicenter study with larger cohorts may eventually advance this method to become a routine clinical test

February 10, 2014
Y. Liu, S. Uttam, S. Alexandrov, and R. K. Bista
Abstract

Background: The cell and tissue structural properties assessed with a conventional bright-field light microscope play a key role in cancer diagnosis, but they sometimes have limited accuracy in detecting early-stage cancers or predicting future risk of cancer progression for individual patients (i.e., prognosis) if no frank cancer is found. The recent development in optical microscopy techniques now permit the nanoscale structural imaging and quantitative structural analysis of tissue and cells, which offers a new opportunity to investigate the structural properties of cell and tissue below 200 – 250 nm as an early sign of carcinogenesis, prior to the presence of microscale morphological abnormalities. Identification of nanoscale structural signatures is significant for earlier and more accurate cancer detection and prognosis. Results: Our group has recently developed two simple spectral-domain optical microscopy techniques for assessing 3D nanoscale structural alterations – spectral-encoding of spatial frequency microscopy and spatial-domain low-coherence quantitative phase microscopy. These two techniques use the scattered light from biological cells and tissue and share a common experimental approach of assessing the Fourier space by various wavelengths to quantify the 3D structural information of the scattering object at the nanoscale sensitivity with a simple reflectance-mode light microscopy setup without the need for high-NA optics. This review paper discusses the physical principles and validation of these two techniques to interrogate nanoscale structural properties, as well as the use of these methods to probe nanoscale nuclear architectural alterations during carcinogenesis in cancer cell lines and well-annotated human tissue during carcinogenesis. Conclusions: The analysis of nanoscale structural characteristics has shown promise in detecting cancer before the microscopically visible changes become evident and proof-of-concept studies have shown its feasibility as an earlier or more sensitive marker for cancer detection or diagnosis. Further biophysical investigation of specific 3D nanoscale structural characteristics in carcinogenesis, especially with well-annotated human cells and tissue, is much needed in cancer research.

January 6, 2014
D. Hartman, A. Krasinskas, S. Uttam, K. Staton, R. K. Bista, S. Rizvi, A. Slivka, R. Brand, and Y. Liu
Abstract

Objectives:The accurate diagnosis of malignancy from small bile duct biopsy specimens is often challenging. This proof-of-concept study assessed the feasibility of a novel optical technology, spatial-domain low-coherence quantitative phase microscopy (SL-QPM), that assesses nanoscale structural alterations in epithelial nuclei for improving the diagnosis of malignancy in bile duct biopsy specimens. Methods: The SL-QPM analysis was performed on standard histology specimens of bile duct biopsy specimens from 45 patients. We analyzed normal cells with benign follow-up, histologically normal cells with pancreaticobiliary malignancy, and malignant epithelial cells. Results: The SL-QPM–derived nuclear nanomorphology marker can not only distinguish benign and malignant epithelial cells but can also detect features of malignancy in those cells normal by light microscopy with a discriminatory accuracy of 0.90. When combining pathology with SL-QPM, the sensitivity is improved to 88.5% from 65.4% of conventional pathology, while maintaining 100% specificity. Conclusions: SL-QPM–derived nuclear nanomorphology markers represent a novel approach for detecting malignancy from histologically normal-appearing epithelial cells, with potential as an adjunctive test in patients with negative or inconclusive pathologic diagnosis on bile duct biopsy specimens.

September 10, 2013
K. E. Fasanella, R. K. Bista, K. Staton, S. Rizvi, S. Uttam, C. Zhao, A. Sepulveda, R. E. Brand, K.McGrath, and Y. Liu
Abstract

Background: Barrett's esophagus (BE) affects up to 12 million Americans and confers an increased risk for development of esophageal adenocarcinoma (EAC). EAC is often fatal unless detected early. Given the high prevalence, high cost of surveillance and relatively low risk of most affected individuals, identification of high-risk patients for additional scrutiny, regular surveillance, or ablative therapy is crucial. The exploration of "field effect" by probing uninvolved esophageal mucosa to predict the risk of EAC has the potential as an improved surveillance and prevention strategy. In this study, we evaluate the ability of nuclear nano-architecture markers from normal squamous esophagus and gastric cardia to detect the "field effect" of esophageal dysplasia and EAC, and their response to endoscopic therapy. Methods: Patients with normal esophagus, gastroesophageal reflux, BE and EAC were eligible for enrollment. We performed endoscopic cytology brushings of the gastric cardia, ~1-2 cm below the gastroesophageal junction, and of the normal squamous esophageal mucosa at ~20 cm from the incisors and standard cytology slides were made using Thinprep method. Optical analysis was performed on the cell nuclei of cytologically normal-appearing epithelial cells. Results: The study cohort consisted of 128 patients. The nuclear nano-architecture markers detected the presence of esophageal dysplasia and EAC with statistical significance. The field effect does not exhibit a spatial dependence. These markers reverted toward normal in response to endoscopic therapy. Conclusions: Optical analysis of gastric cardia and upper squamous esophagus represents a potentially viable method to improve risk stratification and ease of surveillance of patients with Barrett's esophagus and to monitor the efficacy of ablative therapy.

March 22, 2013
S. Uttam, R. K. Bista, K. Staton, S. Alexandrov, S. Choi, C. Bakkenist, D. Hartman R. Brand, and Y. Liu
Abstract

We present depth-resolved spatial-domain low-coherence quantitative phase microscopy, a simple approach that utilizes coherence gating to construct a depth-resolved structural feature vector quantifying sub-resolution axial structural changes at different optical depths within the sample. We show that this feature vector is independent of sample thickness variation, and identifies nanoscale structural changes in clinically prepared samples. We present numerical simulations and experimental validation to demonstrate the feasibility of the approach. We also perform experiments using unstained cells to investigate the nanoscale structural changes in regulated cell proliferation through cell cycle and chromatin decondensation induced by histone acetylation.

Conference Presentations

K. Yadav, R. Pawar, A. Singhi, and S. Uttam
Characterizing the Three-Dimensional Nuclear Morphology of Normal Appearing, Immune, and Cancer Cells in Cancer Tumor Microenvironment
2022 Biomedical Engineering Society (BMES) Annual Meeting, Oct 12-15, 2022
October 1, 2022
P. N. Thota, J. Nasibli, P. Kumar, M.R. Sanaka, A. Chak, X. Zhang, X. Liu, S. Uttam, and Y. Liu
Nanoscale nuclear architecture mapping predicts neoplastic progression in Barrett’s esophagus: a proof-of-concept study
in Gastrointest. Endosc.; 95(6) Supplement, AB230-AB231
September 1, 2022
B. Kochetov, P.D. Bell, R. Raphael, B.J. Raymond, B.J. Leibowitz, J. Tong, B. Diergaarde , J. Yu, R.K. Pai, R.E. Schoen, L. Zhang, A. Singhi, and S. Uttam
Unsupervised sub-cellular segmentation of complex tissue and cell samples using highly multiplexed imaging-derived a priori knowledge
Abstract 1930. Cancer Res 15 June 2022; 82 (12_Supplement): 1930
June 1, 2022
B. Kochetov, R. Raphael, and S. Uttam
Unsupervised segmentation of complex tissue using multiplexed imaging-derived a priori knowledge
Biomedical Engineering Society (BMES) 2021 Annual Meeting; Oct 6 - 9, 2021; Orlando, Florida; Abstract 074 - 841 (2021)
October 6, 2021
S. Leng, J. Xu, Y. Liu, and S. Uttam
Demonstration of ability of nanoscale nuclear architecture mapping to study chromatin alteration
Biomedical Engineering Society (BMES) 2021 Annual Meeting; Oct 6 - 9, 2021; Orlando, Florida; Abstract reu-011-3129 (2021).
October 6, 2021
D. Pitlor, R. E. Brand, B. Dudley, E. Karlowski, A. Zyhowski, E. J. Metter, R. M. Brand, and S. Uttam
Coefficient of variation based multiplexed ELISA biomarker selection in HNPCC Syndrome Patients
Biomedical Engineering Society (BMES) 2021 Annual Meeting; Oct 6 - 9, 2021; Orlando, Florida; Abstract reu-007-3147 (2021)
October 6, 2021

Conference Presentations

S. Uttam
Nanoscale nuclear architecture mapping of early carcinogenesis
Paper 12389-32, Quantitative Phase Imaging IX, SPIE Photonics West, San Francisco (January 27 - Feb 1, 2023) [Invited]
February 1, 2023
S. Uttam
Label-free nanoscale nuclear architecture mapping of early carcinogenesis
2023 Biophysics and Quantitative Biology in the AI Era, NSF AI Planning Institute at Carnegie Mellon University (Jan 12-13, 2023)
January 25, 2023
S. Uttam
Overcoming the segmentation barrier in in multiplexed spatial proteomic images
UPMC Hillman Cancer Center, Spatial Omics and Computational Imaging in Human Diseases Symposium, Nov 14, 2022. [Invited]
December 1, 2022
S. Uttam
Cancer systems biology in space and scale
UPMC Hillman Cancer Center, Cancer Biology Program Retreat, Oct 24, 2022 [Invited]
November 20, 2022
B. Raymond, D. J. Hartman, and S. Uttam
Spatial Analysis of Cytotoxic T Lymphocyte Infiltration in Colorectal Tumors for Predicting Stage-independent Relapse and Death
2022 Biomedical Engineering Society (BMES) Annual Meeting, Oct 12-15, 2022
October 1, 2022
C. Newman, B. Kochetov, R. Raphael, L. Zhang, and S. Uttam
Understanding the Cellular Landscape of Preclinical Models of Colorectal Cancer
2022 Biomedical Engineering Society (BMES) Annual Meeting, Oct 12-15, 2022
October 1, 2022
K. Yadav, R. Pawar, A. Singhi, and S. Uttam
Characterizing the Three-Dimensional Nuclear Morphology of Normal Appearing, Immune, and Cancer Cells in Cancer Tumor Microenvironment
2022 Biomedical Engineering Society (BMES) Annual Meeting, Oct 12-15, 2022
October 1, 2022
P. N. Thota, J. Nasibli, P. Kumar, M.R. Sanaka, A. Chak, X. Zhang, X. Liu, S. Uttam, and Y. Liu
Nanoscale nuclear architecture mapping predicts neoplastic progression in Barrett’s esophagus: a proof-of-concept study
in Gastrointest. Endosc.; 95(6) Supplement, AB230-AB231
September 1, 2022
B. Kochetov, P.D. Bell, R. Raphael, B.J. Raymond, B.J. Leibowitz, J. Tong, B. Diergaarde , J. Yu, R.K. Pai, R.E. Schoen, L. Zhang, A. Singhi, and S. Uttam
Unsupervised sub-cellular segmentation of complex tissue and cell samples using highly multiplexed imaging-derived a priori knowledge
Abstract 1930. Cancer Res 15 June 2022; 82 (12_Supplement): 1930
June 1, 2022
B. Kochetov, R. Raphael, and S. Uttam
Unsupervised segmentation of complex tissue using multiplexed imaging-derived a priori knowledge
Biomedical Engineering Society (BMES) 2021 Annual Meeting; Oct 6 - 9, 2021; Orlando, Florida; Abstract 074 - 841 (2021)
October 6, 2021
S. Leng, J. Xu, Y. Liu, and S. Uttam
Demonstration of ability of nanoscale nuclear architecture mapping to study chromatin alteration
Biomedical Engineering Society (BMES) 2021 Annual Meeting; Oct 6 - 9, 2021; Orlando, Florida; Abstract reu-011-3129 (2021).
October 6, 2021
D. Pitlor, R. E. Brand, B. Dudley, E. Karlowski, A. Zyhowski, E. J. Metter, R. M. Brand, and S. Uttam
Coefficient of variation based multiplexed ELISA biomarker selection in HNPCC Syndrome Patients
Biomedical Engineering Society (BMES) 2021 Annual Meeting; Oct 6 - 9, 2021; Orlando, Florida; Abstract reu-007-3147 (2021)
October 6, 2021
S. Uttam
Sampling and scrambling in compressive sensing based spectral domain optical coherence tomography
CLEO Laser Science to Photonic Applications (Optical Society of America, 2020) JTu2F.7.
May 10, 2020
S. Uttam and Y. Liu
Three-dimensional nanoscale nuclear architecture mapping for improved cancer risk stratification
SPIE/OSA European Conferences on Biomedical Optics (ECBO) 2019, 23-27 June 2019, Munich, Germany; Paper 11076-38 (2019). [Invited paper]
June 23, 2019
S. Uttam, A.M. Stern, S. A. Furman, F. Pullara, F. Ginty, D. L. Taylor, S. C. Chennubhotla
Spatial proteomics with hyperplexed fluorescence imaging predicts risk of colorectal cancer recurrence and infers recurrence-specific protein-protein networks
Cancer Res; 79 (13 Supplement): 1642 (2019). [AACR Annual Meeting 2019, March 29-April 3 2019, Atlanta, Georgia.]
March 29, 2019
S. Uttam
Hyperplexed immunofluorescence imaging based on spatial proteomics predicts risk of colorectal cancer recurrence and infers recurrence-specific protein networks
Joint Immunology and Computational and Systems Biology Workshop, Jan 23, 2019, University of Pittsburgh, Pittsburgh, PA, USA (2019
January 23, 2019
R. C. Burgess and S. Uttam
Modeling the impact of chromatin modifications on the DNA damage response in yeast
Find Your Inner Modeler workshop, Aug 16-17, 2018, University of Illinois at Chicago, Chicago, Illinois, USA (2018). [Travel award]
August 16, 2018
F. Pullara, N. Bouhenni, S. Uttam, and S. C. Chennubhotla
Integrative strategies for probing energy landscapes and dynamics of IDPs
Workshop on Intrinsically Disordered Proteins, TSRC 2017, July 11--14, 2017; Telluride, Colorado, USA (2017)
July 11, 2017
S. Uttam, F. Pullara, and S. C. Chennubhotla
Comparative dynamics - An information theoretic perspective
Biomolecular Machines Conference - Protein Flexibility and Allostery, May 18-21, 2017, Banff, Alberta, Canada (2017)
May 17, 2017
S. Uttam
Nanoscale nuclear architecture mapping for cancer-risk stratification and prediction
Computational Pathology Lecture Series, April 14, 2017; Computational Pathology Interest Group and Lecture Series, University of Pittsburgh, Pittsburgh, Pennsylvania, USA (2017). [Invited talk]
April 17, 2017
Y. Liu, S. Uttam, H. V. Pham, and D. J. Hartman
Improved cancer risk stratification and diagnosis via quantitative phase microscopy
SPIE Photonics West (BIOS), Jan 28 -- Feb 2, 2017, San Francisco, USA; Conference: Quantitative Phase Imaging III, Paper 10074-40 (2017).[Invited paper]
February 2, 2017
R. Bista, S. Uttam, D. Hartman, W. Qiu, J. Yu, L. Zhang, R. Brand, and Y. Liu
Investigation of nuclear nano-morphology markers as a novel biomarker for cancer risk assessment using a mouse model
Gastroenterology - San Diego, 2012; 142(5):S-532.
May 1, 2012
S. Uttam, S. Alexandrov, R. Bista, and Y. Liu
Model-based demonstration of spectral tomographic imaging
in Biomedical Optics, OSA Technical Digest (Optical Society of America, 2012), paper BSu3A.61.
February 28, 2012
Y. Liu, S. Alexandrov, S. Uttam, and R. Bista
Probing Cell Nanoscale Structural Properties Using Intrinsic Contrast of Light Scattering
Biophysical Journal, Vol. 102, Issue 3, S1 (2012). [Invited talk ]
February 25, 2012
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