To evaluate the role of oncogenic RAS mutations in pancreatic tumorigenesis, we directed endogenous expression of KRAS(G12D) to progenitor cells of the mouse pancreas. We find that physiological levels of Kras(G12D) induce ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs), putative precursors to invasive pancreatic cancer. The PanINs are highly proliferative, show evidence of histological progression, and activate signaling pathways normally quiescent in ductal epithelium, suggesting potential therapeutic and chemopreventive targets for the cognate human condition. At low frequency, these lesions also progress spontaneously to invasive and metastatic adenocarcinomas, establishing PanINs as definitive precursors to the invasive disease. Finally, mice with PanINs have an identifiable serum proteomic signature, suggesting a means of detecting the preinvasive state in patients.

Erratum Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouseIn the article by Hingorani et al. (Cancer Cell 4,, there are several typographical errors in the text regarding the citation of the figures. On page 441, the sentence "In many of the older mice, the pancreata contained extensive ductal lesions, and the acinar parenchyma was largely replaced by an intense stromal, or desmoplastic, reaction comprised of inflammatory cells, fibroblasts, and collagen deposition (Figures 2I-2K)" should instead refer to Figures 2I-2L. Also on page 441, the sentence "Finally, we note that PanINs expressed only low levels of PDX-1, which can nevertheless be discerned when compared to the lack of expression in surrounding acini (Figures 2G and 2H) and to normal ducts in control animals (Figure 2I)" should refer instead to Figure 3, and thus should read "Finally, we note that PanINs expressed only low levels of PDX-1, which can nevertheless be discerned when compared to the lack of expression in surrounding acini (Figures 3G and 3H) and to normal ducts in control animals (Figure 3I)."

The biomass of marine “oligotri chous” ciliates has often been estimated by measuring the cell volume of preserved samples and converting to units of carbon based on theoretical carbon: volume (C: vol) ratios of 0.07–0.11 pg µm−3. Using laboratory cultures of several strains of Laboea strobila, Strombidium spp., and Strobilidium spiralis, we experimentally derived a C: vol conversion factor of 0.19 pg µm−3 for cells preserved with 2% vol : vol Lugol’s iodine. Cell volume estimates of Lugol’s‐preserved cells averaged 76% of cell volume estimates of Formalin‐preserved cells. Hence a C : vol ratio of 0.14 pg µm−3 applies to Formalin‐preserved cells. Our study indicates that the biomass of oligotrichous ciliates in marine systems has been significantly underestimated by the use of inappropriate C: vol ratios.

Objectives The aim of this study was to determine if individual or multiple biomarkers are associated with cardiotoxicity in patients with breast cancer undergoing cancer therapy. Background Current methods to identify patients at risk for cardiotoxicity from cancer therapy are inadequate. Methods We measured 8 biomarkers in a multicenter cohort of 78 patients with breast cancer undergoing doxorubicin and trastuzumab therapy: ultrasensitive troponin I (TnI), high-sensitivity C-reactive protein (CRP), N-terminal pro–B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor (sFlt)-1, and galectin (gal)-3. Cardiotoxicity, defined by the Cardiac Review and Evaluation Committee criteria, was assessed every 3 months for up to 15 months. Hazard ratios (HRs) of cardiotoxicity risk were assessed for each biomarker at baseline, at visit 2 (3 months), and as a function of the difference between visit 2 and baseline. Joint models were assessed for the most promising biomarkers. Results TnI, CRP, GDF-15, MPO, PlGF, and sFlt-1 levels increased from baseline to visit 2 (p < 0.05). A greater risk of cardiotoxicity was associated with interval changes in TnI (HR: 1.38 per SD; 95% confidence interval: 1.05 to 1.81; p = 0.02) and MPO (HR: 1.34 per SD; 95% confidence interval: 1.00 to 1.80; p = 0.048) and in models combining both markers (p = 0.007 and p = 0.03, respectively). The risk of cardiotoxicity was 46.5% in patients with the largest changes in both markers (ΔTnI >121.8 μg/l; ΔMPO >422.6 pmol/l). Conclusions Early increases in TnI and MPO levels offer additive information about the risk of cardiotoxicity in patients undergoing doxorubicin and trastuzumab therapy. Independent validation of these findings is necessary before application to clinical practice.

In this article, we describe a novel RT apparatus that delivers FLASH proton RT (PRT) using double scattered protons with CT guidance and provide the first report of proton FLASH RT-mediated normal tissue radioprotection. Purpose: Recent studies suggest that ultrahigh-dose-rate, "FLASH," electron radiation therapy (RT) decreases normal tissue damage while maintaining tumor response compared with conventional dose rate RT. Here, we describe a novel RT apparatus that delivers FLASH proton RT (PRT) using double scattered protons with computed tomography guidance and provide the first report of proton FLASH RT-mediated normal tissue radioprotection. Methods and Materials: Absolute dose was measured at multiple depths in solid water and validated against an absolute integral charge measurement using a Faraday cup. Real-time dose rate was obtained using a NaI detector to measure prompt gamma rays. The effect of FLASH versus standard dose rate PRT on tumors and normal tissues was measured using pancreatic flank tumors (MH641905) derived from the KPC autochthonous PanCa model in syngeneic C57BL/6J mice with analysis of fibrosis and stem cell repopulation in small intestine after abdominal irradiation.