Prostate cancer is heterogeneous and patients would benefit from methods that stratify those who are likely to respond to systemic therapy. Here, we employ single-cell assays for ...transposase-accessible chromatin (ATAC) and RNA sequencing in models of early treatment response and resistance to enzalutamide. In doing so, we identify pre-existing and treatment-persistent cell subpopulations that possess regenerative potential when subjected to treatment. We find distinct chromatin landscapes associated with enzalutamide treatment and resistance that are linked to alternative transcriptional programs. Transcriptional profiles characteristic of persistent cells are able to stratify the treatment response of patients. Ultimately, we show that defining changes in chromatin and gene expression in single-cell populations from pre-clinical models can reveal as yet unrecognized molecular predictors of treatment response. This suggests that the application of single-cell methods with high analytical resolution in pre-clinical models may powerfully inform clinical decision-making.
An understanding of signaling pathways has not been fully incorporated into prognostication and therapeutic options. We evaluated the hypothesis that information about cancer-related signaling ...pathways can improve prognostic stratification and explain some of the clinical heterogeneity in patients with metastatic colorectal cancer.
We analyzed prognostic relevance of signaling pathways in patients undergoing resection of colorectal liver metastases (CLM) from 2004–2017, and clinical actionability of gene alterations in 7 signaling pathways: p53, Wnt, RTK-RAS, PI3K, TGFβ, Notch, and cell cycle. To assess the wide applicability, the results were validated in an external retrospective cohort including patients with unresectable metastatic colorectal cancer.
Of 579 patients, the numbers of patients with pathway alterations were as follows: p53, n = 420 (72.5%); Wnt, 340 (58.7%); RTK-RAS, 333 (57.5%); PI3K, 110 (19.0%); TGFβ, 65 (11.2%); Notch, 41 (7.1%); and cell cycle, 15 (2.6%). More than 80% of alterations in each pathway occurred in a single predominant gene TP53, APC, KRAS, PIK3CA, FBXW7, and RB1 in p53, Wnt, RTK-RAS, PI3K, Notch, and cell cycle pathways, respectively. Alterations of 4 pathways (p53, RTK-RAS, TGFβ, and Notch) and corresponding predominant genes (TP53, RAS/BRAF, SMAD4, and FBXW7) were significantly associated with worse overall survival (OS), and alterations of Wnt pathway (APC) were associated with better OS in the median follow-up duration of 3.8 years. Similarly, in the external cohort, alterations of p53 (TP53) and RTK-RAS (RAS/BRAF) were significantly associated with worse OS, whereas alteration of Wnt (APC) was associated with better OS in the median follow-up duration of 2.6 years.
Genomic sequencing provides insights into clinical heterogeneity and permits finer prognostic stratification in patients with metastatic colorectal cancer.
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Liquid biopsies are increasingly tested in patients with colorectal cancer to assess tumor burden, response to therapy, and prognosis. The significance of liquid biopsy results after resection of ...colorectal liver metastases (CLMs) is not well-defined.
Sixty-three patients undergoing CLM resection between 2016 and 2018 had plasma drawn postoperatively for liquid biopsy evaluation. Next-generation sequencing analysis was performed to detect somatic mutations in 70 genes.
Liquid biopsy after CLM resection was positive in 42 of 63 patients (67%). Eleven patients (18%) had 1 gene mutation, 14 patients (22%) had 2 to 3 mutations, and 17 patients (27%) had 4 or more mutations. The most common mutation was APC, detected in 32 patients (76%), followed by TP53 (74%) and KRAS (38%). Two-year overall survival rate from date of liver resection was significantly worse among patients with a positive liquid biopsy (70% vs 100%; p = 0.005), particularly for those with 4 or more gene mutations detected, whose 2-year overall survival rate was 41%. Sixteen of the 63 patients underwent serial liquid biopsies, resulting in 100 liquid biopsies with matched serum CEA and CT scan results. Metastases were identified in 74 CT scans, which correlated with positive liquid biopsy in 77% of samples (p < 0.001) and CEA > 3 ng/mL in 45% of samples (p < 0.22).
Liquid biopsy results provide information about disease burden and prognosis that is complementary to serum CEA and CT imaging. A positive liquid biopsy after CLM resection is associated with worse overall survival, particularly when multiple gene mutations are detected.
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Damage to fracture transition has become a popular topic in the ductile fracture scientific community. Indeed, the transition from a damage continuous approach to a discontinuous fracture is not ...straightforward both from mechanical and numerical points of view. In the present study, a new improved Lode dependent phenomenological coupled damage model is used to investigate the ductile fracture in different mechanical tests. The remeshing and elements erosion techniques are employed to propagate the ductile cracks in 3D models using Forge® finite element code. This code is based on a mixed velocity–pressure formulation using the MINI element P1+/P1. In addition, the plasticity behavior is modeled by a Lode-dependent plasticity criterion. Applications to different mechanical tests at different loading configurations, using identified damage model parameters, show good agreement in terms of fracture prediction between experimental and numerical results.
•Six models in three approaches of ductile damage are implemented and identified.•Experiments are performed for models parameters identification.•Experiments are performed for wire drawing and wire ...flat rolling processes.•Fractures in experiments can be accurately predicted by the studied damage models.•Models accounting for Lode angle and triaxiality give accurate qualitative results.
Damage growth and ductile fracture prediction is still an open question for complex stress state applications. A lot of models, both phenomenological and micromechanical, have been extensively developed. There is a real need to compare them to choose the best suitable for complex loading applications. This is done here taking examples in cold metal forming, namely wire drawing and wire flat rolling. In the present study, the prediction of damage for the ultimate wire drawing and the wire flat rolling processes of a high carbon steel is investigated, using three different approaches of ductile damage: uncoupled phenomenological models (or fracture criteria), coupled phenomenological models (accounting for the softening effect of damage), and micromechanical models (accounting for damage associated microstructure evolution). These models were first implemented in a finite element code dedicated to forming process simulations, then calibrated via different mechanical tests exhibiting different stress states. Numerical results of the applications of these models to the two above-mentioned forming processes simulations were compared with experimental ones. These applications help comparing different approaches for fracture prediction in multi-stage forming processes and also in the process that involves important shear effect. The present study supplies important data for the characterization of ductile failure in forming processes, as well as an effective assessment of different phenomenological and micromechanical models, characterizing their performance for different stress states. It also suggests the use of “modular” models for complex loading cases, by combining different driving factors of damage accumulation at different stress states.
Barriers to multimodality therapy (MMT) completion among patients with resectable pancreatic adenocarcinoma include early cancer progression and postoperative major complications (PMC). We sought to ...evaluate the influence of these factors on MMT completion rates of patients treated with neoadjuvant therapy (NT) and surgery-first (SF) approaches. We evaluated all operable patients treated for clinically resectable pancreatic head adenocarcinoma at our institution from 2002 to 2007. Rates of MMT completion, 90-day PMC, and overall survival (OS) were evaluated. Ninety-five of 115 (83 %) NT and 29/50 (58 %) SF patients completed MMT. Patients who completed MMT lived longer than those who did not (36 vs. 11 months,
p
< 0.001). The most common reason that NT (11 %) and SF (26 %) patients failed to complete MMT was early disease progression. The rates of PMC among NT and SF patients were similar. Among SF patients, 69 % with no PMC completed MMT versus 29 % after PMC (
p
= 0.040). PMC were associated with decreased OS in SF patients but not in NT patients. The impact of early cancer progression and PMC upon completion of MMT is reduced by delivery of nonoperative therapies prior to pancreaticoduodenectomy. NT sequencing is a practical treatment strategy, particularly for patients at high biological or perioperative risk.
Using combined data from the Relativistic Heavy Ion and Large Hadron Colliders, we constrain the shear and bulk viscosities of quark-gluon plasma (QGP) at temperatures of ∼ 150 – 350 MeV . We use ...Bayesian inference to translate experimental and theoretical uncertainties into probabilistic constraints for the viscosities. With Bayesian model averaging we propagate an estimate of the model uncertainty generated by the transition from hydrodynamics to hadron transport in the plasma's final evolution stage, providing the most reliable phenomenological constraints to date on the QGP viscosities.
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