Background & aims: The assessment of therapeutic response after neoadjuvant treatment and pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) has been an ongoing challenge. Several limitations have been encountered when employing current grading systems for residual tumor. Considering endoscopic ultrasound (EUS) represents a sensitive imaging technique for PDAC, differences in tumor size between preoperative EUS and postoperative pathology after neoadjuvant therapy were hypothesized to represent an improved marker of treatment response. Methods: For 340 treatment-naive and 365 neoadjuvant-treated PDACs, EUS and pathologic findings were analyzed and correlated with patient overall survival (OS). A separate group of 200 neoadjuvant-treated PDACs served as a validation cohort for further analysis. Results: Among treatment-naive PDACs, there was a moderate concordance between EUS imaging and postoperative pathology for tumor size (r = 0.726, P < .001) and AJCC 8th edition T-stage (r = 0.586, P < .001). In the setting of neoadjuvant therapy, a decrease in T-stage correlated with improved 3-year OS rates (50% vs 31%, P < .001). Through recursive partitioning, a cutoff of ≥ 47% tumor size reduction was also found to be associated with improved OS (67% vs 32%, P < .001). Improved OS using ≥ 47% threshold was validated using a separate cohort of neoadjuvant-treated PDACs (72% vs 36%, P < .001). By multivariate analysis, a reduction in tumor size by ≥ 47% was an independent prognostic factor for improved OS (P = .007). Conclusions: The difference in tumor size between preoperative EUS imaging and postoperative pathology among neoadjuvant-treated PDAC patients is an important prognostic indicator and may guide subsequent chemotherapeutic management.

An unmet clinical need in solid tumor cancers is the ability to harness the intrinsic spatial information in primary tumors that can be exploited to optimize prognostics, diagnostics and therapeutic strategies for precision medicine. Here, we develop a transformational spatial analytics computational and systems biology platform (SpAn) that predicts clinical outcomes and captures emergent spatial biology that can potentially inform therapeutic strategies. We apply SpAn to primary tumor tissue samples from a cohort of 432 chemo-naïve colorectal cancer (CRC) patients iteratively labeled with a highly multiplexed (hyperplexed) panel of 55 fluorescently tagged antibodies. We show that SpAn predicts the 5-year risk of CRC recurrence with a mean AUROC of 88.5% (SE of 0.1%), significantly better than current state-of-the-art methods. Additionally, SpAn infers the emergent network biology of tumor microenvironment spatial domains revealing a spatially-mediated role of CRC consensus molecular subtype features with the potential to inform precision medicine

Patients with inflammatory bowel disease (IBD) colitis are at an increased risk of developing colorectal cancer and are currently recommended to undergo extensive annual or biennial colonoscopy, a costly and invasive procedure. Most surveillance colonoscopies are negative with no existing objective measures for assessing their risk of developing cancer. We have recently developed a less invasive, cost-effective and objective method to assess cancer risk by detecting the presence of colonic neoplasia via 3-dimensional (3D) nanoscale nuclear architecture mapping (nanoNAM) of normal-appearing rectal biopsies. To establish its translational relevance, we prospectively recruited 103 patients with IBD colitis undergoing surveillance colonoscopy and measured submicroscopic alterations in aberrant intrinsic nuclear architecture of epithelial cells from normal-appearing rectal biopsies with nanoNAM. The results were correlated with the histologic diagnoses from all random biopsies obtained during initial and follow-up colonoscopy within 3 years. Using nanoNAM-based structural characterization as input features into a soft margin-based ν-SVM risk classifier, we show that nanoNAM detects colonic neoplasia with AUC of 0.87 ± 0.04, sensitivity of 0.81 ± 0.09, and specificity of 0.82 ± 0.07 in the independent validation set. In addition, projecting nanoNAM features onto a 2-sphere reveals patients with low-risk and high-risk IBD colitis existing on separate hemispheres. Finally, we show that this ability to assess cancer risk translates to clinically-relevant estimation of individual-patient likelihood of being truly at risk. We demonstrate the potential of nanoNAM to identify patients with IBD at higher risk of developing cancer from normal-appearing rectum tissue, which may aid clinicians in patients with personalized IBD colitis surveillance

Telomeres are essential for genome stability. Oxidative stress caused by excess reactive oxygen species (ROS) accelerates telomere shortening. Although telomeres are hypersensitive to ROS-mediated 8-oxoguanine (8-oxoG) formation, the biological effect of this common lesion at telomeres is poorly understood because ROS have pleiotropic effects. Here we developed a chemoptogenetic tool that selectively produces 8-oxoG only at telomeres. Acute telomeric 8-oxoG formation increased telomere fragility in cells lacking OGG1, the enzyme that removes 8-oxoG, but did not compromise cell survival. However, chronic telomeric 8-oxoG induction over time shortens telomeres and impairs cell growth. Accumulation of telomeric 8-oxoG in chronically exposed OGG1-deficient cells triggers replication stress, as evidenced by mitotic DNA synthesis at telomeres, and significantly increases telomere losses. These losses generate chromosome fusions, leading to chromatin bridges and micronucleus formation upon cell division. By confining base damage to the telomeres, we show that telomeric 8-oxoG accumulation directly drives telomere crisis.

Histone modifications influence higher-order chromatin structures at individual epigenomic states and chromatin environments to regulate gene expression. However, genome-wide higher-order chromatin structures shaped by different histone modifications remain poorly characterized. With stochastic optical reconstruction microscopy (STORM), we characterized the higher-order chromatin structures at their epigenomic states, categorized into three major types in interphase: histone acetylation marks form spatially segregated nanoclusters, active histone methylation marks form spatially dispersed larger nanodomains, and repressive histone methylation marks form condensed large aggregates. These distinct structural characteristics are also observed in mitotic chromosomes. Furthermore, active histone marks coincide with less compact chromatin and exhibit a higher degree of co-localization with other active marks and RNA polymerase II (RNAP II), while repressive marks coincide with densely packed chromatin and spatially distant from repressive marks and active RNAP II. Taken together, super-resolution imaging reveals three distinct chromatin structures at various epigenomic states, which may be spatially coordinated to impact transcription.