Non-Standard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: Non-standard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for better reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants

Non-Invasive in vivo Molecular Imaging of Cancer Nanotherapy Uptake and Response with PET/MRI

Although researchers have made great strides toward understanding the biological processes underlying cancer pathology, this has not led to major improvements in the management of the disease. Development of new treatments to combat cancer remains imperative. Nanosized therapies show promise to improve tumor treatment response by localizing therapy while reducing treatment-related toxicity. Understanding how nanotherapies are taken up and cause their effects at the intact tumor level in vivo will complement ex vivo histological and in vitro biochemical studies and facilitate the translation of nanotherapy treatments to the clinic. Currently, few in vivo methods exist to study nanotherapy uptake and response at the intact tumor scale. Magnetic resonance imaging (MRI) and positron emission tomography (PET) are imaging methods that provide different but complementary information about the tumor microenvironment and nanotherapy uptake/response. Direct spatiotemporal correlation of PET and MRI data via their simultaneous acquisition has the potential to be powerfully synergistic, especially for the study of physiological processes that are time sensitive or where good spatial coregistration of the multimodal data is important. As the field of hybrid PET/MRI is still in its infancy, with only a handful of active systems worldwide, it is vital that continued PET/MRI technology development be pursued to realize its full potential. The objective of this thesis is to develop noninvasive, multimodal PET/MRI methods to study the uptake and response of cancer nanotherapies. Three studies were pursued toward this goal. First, we describe the development of a quantitative, small animal simultaneous PET/MRI system that is capable of dynamic, intratumoral imaging. The results show that the system provides quantitative images that are highly correlated with ex vivo autoradiography. The system was able to follow the uptake of a radiolabelled antibody inside the tumor over time, visualizing antibody movement from the vascular space to the tumor mass. Second, we adapted a functional MRI technique, diffusion MRI, to monitor treatment response of the cancer nanotherapy CRLX101. CRLX101-treated animals showed a significant diffusion MRI response within 2 days of treatment, before significant size changes were observed. Modeling of the diffusion MRI data was able to predict the potent antiproliferative effect of CRLX101, commensurate with histological data. Finally, we developed MRI and PET/MRI methods to study the tumor response to the tumor-penetrating peptide iRGD, which has shown good potential to improve cancer nanotherapy uptake. The results show that iRGD can have a variable tumor response, which may be dependent on the tumor microenvironment. The primary contributions of this thesis work is the development of small animal hybrid PET/MRI technology to enable multimodal intratumoral studies and the development of clinically-applicable imaging methods to monitor the uptake and response of cancer nanotherapies.</p

Oncofetal gene SALL4 in aggressive hepatocellular carcinoma

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Clinical utility of multimodality imaging with dynamic contrast-enhanced MRI, diffusion-weighted MRI, and 18F-FDG PET/CT for the prediction of neck control in oropharyngeal or hypopharyngeal squamous cell carcinoma treated with chemoradiation.

The clinical usefulness of pretreatment imaging techniques for predicting neck control in patients with oropharyngeal or hypopharyngeal squamous cell carcinoma (OHSCC) treated with chemoradiation remains unclear. In this prospective study, we investigated the role of pretreatment dynamic contrast-enhanced perfusion MR imaging (DCE-PWI), diffusion-weighted MR imaging (DWI), and [18F]fluorodeoxyglucose-positron emission tomography (18F-FDG PET)/CT derived imaging markers for the prediction of neck control in OHSCC patients treated with chemoradiation. Patients with untreated OHSCC scheduled for chemoradiation between August, 2010 and July, 2012 were eligible for the study. Clinical variables and the following imaging parameters of metastatic neck lymph nodes were examined in relation to neck control: transfer constant, volume of blood plasma, and volume of extracellular extravascular space (Ve) on DCE-PWI; apparent diffusion coefficient (ADC) on DWI; maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis on 18F-FDG PET/CT. There were 69 patients (37 with oropharynx SCC and 32 with hypopharynx SCC) with successful pretreatment DCE-PWI and DWI available for analysis. After a median follow-up of 31 months, 25 (36.2%) participants had neck failure. Multivariate analysis identified hemoglobin level 1.14×10-3 mm2/s (P = 0.003) as independent prognostic factors for 3-year neck control. A prognostic scoring system was formulated by summing up the three significant predictors of neck control. Patients with scores of 2-3 had significantly poorer neck control and overall survival rates than patients with scores of 0-1. We conclude that hemoglobin levels, Ve, and ADC are independent pretreatment prognostic factors for neck control in OHSCC treated with chemoradiation. Their combination may identify a subgroup of patients at high risk of developing neck failure

Atomic-Scale Mechanism on Nucleation and Growth of Mo₂C Nanoparticles Revealed by in Situ Transmission Electron Microscopy

With a similar electronic structure as that of platinum, molybdenum carbide (Mo₂C) holds significant potential as a high performance catalyst across many chemical reactions. Empirically, the precise control of particle size, shape, and surface nature during synthesis largely determines the catalytic performance of nanoparticles, giving rise to the need of clarifying the underlying growth characteristics in the nucleation and growth of Mo₂C. However, the high-temperature annealing involved during the growth of carbides makes it difficult to directly observe and understand the nucleation and growth processes. Here, we report on the use of advanced in situ transmission electron microscopy with atomic resolution to reveal a three-stage mechanism during the growth of Mo₂C nanoparticles over a wide temperature range: initial nucleation via a mechanism consistent with spinodal decomposition, subsequent particle coalescence and monomer attachment, and final surface faceting to well-defined particles with minimum surface energy. These microscopic observations made under a heating atmosphere offer new perspectives toward the design of carbide-based catalysts, as well as the tuning of their catalytic performances