Initial clinical evaluation of stationary digital chest tomosynthesis in adult patients with cystic fibrosis

Objective: The imaging evaluation of cystic fibrosis currently relies on chest radiography or computed tomography. Recently, digital chest tomosynthesis has been proposed as an alternative. We have developed a stationary digital chest tomosynthesis (s-DCT) system based on a carbon nanotube (CNT) linear x-ray source array. This system enables tomographic imaging without movement of the x-ray tube and allows for physiological gating. The goal of this study was to evaluate the feasibility of clinical CF imaging with the s-DCT system. Materials and methods: CF patients undergoing clinically indicated chest radiography were recruited for the study and imaged on the s-DCT system. Three board-certified radiologists reviewed both the CXR and s-DCT images for image quality relevant to CF. CF disease severity was assessed by Brasfield score on CXR and chest tomosynthesis score on s-DCT. Disease severity measures were also evaluated against subject pulmonary function tests. Results: Fourteen patients underwent s-DCT imaging within 72 h of their chest radiograph imaging. Readers scored the visualization of proximal bronchi, small airways and vascular pattern higher on s-DCT than CXR. Correlation between the averaged Brasfield score and averaged tomosynthesis disease severity score for CF was -0.73, p = 0.0033. The CF disease severity score system for tomosynthesis had high correlation with FEV1 (r = -0.685) and FEF 25–75% (r = -0.719) as well as good correlation with FVC (r = -0.582). Conclusion: We demonstrate the potential of CNT x-ray-based s-DCT for use in the evaluation of cystic fibrosis disease status in the first clinical study of s-DCT. Key Points: • Carbon nanotube-based linear array x-ray tomosynthesis systems have the potential to provide diagnostically relevant information for patients with cystic fibrosis without the need for a moving gantry. • Despite the short angular span in this prototype system, lung features such as the proximal bronchi, small airways and pulmonary vasculature have improved visualization on s-DCT compared with CXR. Further improvements are anticipated with longer linear x-ray array tubes. • Evaluation of disease severity in CF patients is possible with s-DCT, yielding improved visualization of important lung features and high correlation with pulmonary function tests at a relatively low dose

eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with limited treatment options. Although metabolic reprogramming is a hallmark of many cancers, including PDA, previous attempts to target metabolic changes therapeutically have been stymied by drug toxicity and tumour cell plasticity. Here, we show that PDA cells engage an eIF4F-dependent translation program that supports redox and central carbon metabolism. Inhibition of the eIF4F subunit, eIF4A, using the synthetic rocaglate CR-1-31-B (CR-31) reduced the viability of PDA organoids relative to their normal counterparts. In vivo, CR-31 suppresses tumour growth and extends survival of genetically-engineered murine models of PDA. Surprisingly, inhibition of eIF4A also induces glutamine reductive carboxylation. As a consequence, combined targeting of eIF4A and glutaminase activity more effectively inhibits PDA cell growth both in vitro and in vivo. Overall, our work demonstrates the importance of eIF4A in translational control of pancreatic tumour metabolism and as a therapeutic target against PDA

Sex-specific aspects of left and right ventricular volume regulation in patients following tetralogy of Fallot repair

Ejection fraction (EF) is applied as a clinically relevant metric to assess both left (LV) and right ventricular (RV) function. EF depends on the interplay between end-systolic volume (ESV) and end-diastolic volume (EDV). The role of the two constitutive components is of particular interest for the follow-up study of Fallot patients at risk for RV volume overload. The volume regulation graph (VRG) relates ESV to EDV and has been advanced as a central tool to describe LV and RV function. The method permits additional analysis of the impact of clinically relevant determinants such as sex and age. Following Fallot repair and using MRI we evaluated LV and RV volumes in 124 patients (50 females), who were not taking any medication. Volumes were indexed for body surface area (BSA). The VRG regression lines are similar for both sexes, also when stratified for age (i.e. younger or older than 18 years), and different for LV and RV. However, RV ESV is larger (P=0.039) for adult males, as is RV EDV (P=0.026) in boys, relative to their female counterparts. For LV ESV we also found larger volumes, but only in boys (P=0.023) compared to girls. Average EF (only for RV) is lower in adult men compared to women (P=0.012), and to boys (P=0.007). These findings are partly in contrast with common observations made in individuals without a history of cardiac disease, where (with BSA indexation) LV and RV volumes are similar in children, but consistently larger in adult males. These results highlight the age- and sex-specific volumetric aspects of remodeling following surgery in Fallot patients, and emphasize the pivotal role of ESV size in both RV and LV

The injury response to DNA damage in live tumor cells promotes antitumor immunity

Inducing a DNA damage response in tumor cells ex vivo creates an immunogenic live-cell adjuvant.</jats:p

Transite: A Computational Motif-Based Analysis Platform That Identifies RNA-Binding Proteins Modulating Changes in Gene Expression

© 2020 The Author(s) Krismer et al. present a computational approach to identify RNA-binding proteins (RBPs) that modulate post-transcriptional control of gene expression using RNA expression data as inputs. By applying this approach to publicly available patient datasets, they identify and experimentally confirm that the RBP hnRNPC contributes to chemotherapy resistance in lung cancer

Organoid models of human and mouse ductal pancreatic cancer.

Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy