Feasibility of free breathing Lung MRI for Radiotherapy using non-Cartesian k-space acquisition schemes

Objective: To test a free-breathing MRI protocol for anatomical and functional assessment during lung cancer radiotherapy by assessing two non-Cartesian acquisition schemes based on T1 weighted 3D gradient recall echo sequence: (i) stack-of stars (StarVIBE) and (ii) spiral (SpiralVIBE) trajectories. Methods: MR images on five healthy volunteers were acquired on a wide bore 3T scanner (MAGNETOM Skyra, Siemens Healthcare, Erlangen, Germany). Anatomical image quality was assessed on: (1) free breathing (StarVIBE), (2) the standard clinical sequence (volumetric interpolated breath-hold examination, VIBE) acquired in a 20 second (s) compliant breath-hold and (3) 20 s non-compliant breath-hold. For functional assessment, StarVIBE and the current standard breath-hold time-resolved angiography with stochastic trajectories (TWIST) sequence were run as multiphase acquisitions to replicate dynamic contrast enhancement (DCE) in one healthy volunteer. The potential application of the SpiralVIBE sequence for lung parenchymal imaging was assessed on one healthy volunteer. Ten patients with lung cancer were subsequently imaged with the StarVIBE and SpiralVIBE sequences for anatomical and structural assessment. For functional assessment, free-breathing StarVIBE DCE protocol was compared with breath-hold TWIST sequences on four prior lung cancer patients with similar tumour locations. Image quality was evaluated independently and blinded to sequence information by an experienced thoracic radiologist. Results: For anatomical assessment, the compliant breath-hold VIBE sequence was better than free-breathing StarVIBE. However, in the presence of a non-compliant breath-hold, StarVIBE was superior. For functional assessment, StarVIBE outperformed the standard sequence and was shown to provide robust DCE data in the presence of motion. The ultrashort echo of the SpiralVIBE sequence enabled visualisation of lung parenchyma. Conclusion: The two non-Cartesian acquisition sequences, StarVIBE and SpiralVIBE, provide a free-breathing imaging protocol of the lung with sufficient image quality to permit anatomical, structural and functional assessment during radiotherapy. Advances in knowledge: Novel application of non-Cartesian MRI sequences for lung cancer imaging for radiotherapy. Illustration of SpiralVIBE UTE sequence as a promising sequence for lung structural imaging during lung radiotherapy

MMTV-PyMT and derived Met-1 mouse mammary tumor cells as models for studying the role of the androgen receptor in triple-negative breast cancer progression

Triple-negative breast cancer (TNBC) has a faster rate of metastasis compared to other breast cancer subtypes and no effective targeted therapies are currently FDA-approved. Recent data indicate that the androgen receptor (AR) promotes tumor survival and may serve as a potential therapeutic target in TNBC. Studies of AR in disease progression and the systemic effects of anti-androgens have been hindered by the lack of an AR-positive (AR+) immunocompetent preclinical model. In this study we identified the transgenic MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor antigen) mouse mammary gland carcinoma model of breast cancer and Met-1 cells derived from this model as tools to study the role of AR in breast cancer progression. AR protein expression was examined in late-stage primary tumors and lung metastases from MMTV-PyMT mice as well as in Met-1 cells by immunohistochemistry (IHC). Sensitivity of Met-1 cells to the AR agonist dihydrotestosterone (DHT) and anti-androgen therapy was examined using cell viability, migration/invasion, and anchorage-independent growth assays. Late-stage primary tumors and lung metastases from MMTV-PyMT mice and Met-1 cells expressed abundant nuclear AR protein, while negative for estrogen and progesterone receptors. Met-1 sensitivity to DHT and AR antagonists demonstrated a reliance on AR for survival, and AR antagonists inhibited invasion and anchorage-independent growth. These data suggest that the MMTV-PyMT model and Met-1 cells may serve as valuable tools for mechanistic studies of the role of AR in disease progression and how anti-androgens affect the tumor microenvironment

Primordial Black Holes: sirens of the early Universe

Primordial Black Holes (PBHs) are, typically light, black holes which can form in the early Universe. There are a number of formation mechanisms, including the collapse of large density perturbations, cosmic string loops and bubble collisions. The number of PBHs formed is tightly constrained by the consequences of their evaporation and their lensing and dynamical effects. Therefore PBHs are a powerful probe of the physics of the early Universe, in particular models of inflation. They are also a potential cold dark matter candidate.Comment: 21 pages. To be published in "Quantum Aspects of Black Holes", ed. X. Calmet (Springer, 2014

Structural and Functional Characteristics of Color Vision Changes in Choroideremia

Color vision is considered a marker of cone function and its assessment in patients with retinal pathology is complementary to the assessments of spatial vision [best-corrected visual acuity (BCVA)] and contrast detection (perimetry). Rod-cone and chorioretinal dystrophies—such as choroideremia—typically cause alterations to color vision, making its assessment a potential outcome measure in clinical trials. However, clinical evaluation of color vision may be compromised by pathological changes to spatial vision and the visual field. The low vision Cambridge Color Test (lvCCT) was developed specifically to address these latter issues. We used the trivector version of the lvCCT to quantify color discrimination in a cohort of 53 patients with choroideremia. This test enables rapid and precise characterization of color discrimination along protan, deutan, and tritan axes more reliably than the historically preferred test for clinical trials, namely the Farnsworth Munsell 100 Hue test. The lvCCT demonstrates that color vision defects—particularly along the tritan axis—are seen early in choroideremia, and that this occurs independent of changes in visual acuity, pattern electroretinography and ellipsoid zone area on optical coherence tomography (OCT). We argue that the selective loss of tritan color discrimination can be explained by our current understanding of the machinery of color vision and the pathophysiology of choroideremia

Hunting for dark halo substructure using submilliarcsecond-scale observations of macrolensed radio jets

Dark halo substructure may reveal itself through secondary, small-scale gravitational lensing effects on light sources that are macrolensed by a foreground galaxy. Here, we explore the prospects of using Very Long Baseline Interferometry (VLBI) observations of multiply-imaged quasar jets to search for submilliarcsecond-scale image distortions produced by various forms of dark substructures in the 1e3-1e8 Msolar mass range. We present lensing simulations relevant for the angular resolutions attainable with the existing European VLBI Network (EVN), the global VLBI array, and an upcoming observing mode in which the Atacama Large Millimeter Array (ALMA) is connected to the global VLBI array. While observations of this type would not be sensitive to standard cold dark matter subhalos, they can be used to detect more compact forms of halo substructure predicted in alternative structure formation scenarios. By mapping ~5 strongly lensed systems, it should be possible to detect or robustly rule out primordial black holes in the 1e3-1e6 Msolar mass range if they constitute >1% percent of the dark matter in these lenses. Ultracompact minihalos are harder to detect using this technique, but 1e6-1e8 Msolar ultracompact minihalos could in principle be detected if they constitute >10% of the dark matter.Comment: 13 pages, 8 figures; v.2 accepted for publication in MNRA

Development of an Orthotopic Human Pancreatic Cancer Xenograft Model Using Ultrasound Guided Injection of Cells

Mice have been employed as models of cancer for over a century, providing significant advances in our understanding of this multifaceted family of diseases. In particular, orthotopic tumor xenograft mouse models are emerging as the preference for cancer research due to increased clinical relevance over subcutaneous mouse models. In the current study, we developed orthotopic pancreatic cancer xenograft models in mice by a minimally invasive method, ultrasound guided injection (USGI) comparable to highly invasive surgical orthotopic injection (SOI) methods. This optimized method prevented injection complications such as recoil of cells through the injection canal or leakage of cells out of the pancreas into the peritoneal cavity. Tumor growth was monitored in vivo and quantified by ultrasound imaging weekly, tumors were also detected by in vivo fluorescence imaging using a tumor targeted molecular probe. The mean tumor volumes for the USGI and SOI models after 2 weeks of tumor growth were 205 mm3 and 178 mm3 respectively. By USGI of human pancreatic cancer cell lines, human orthotopic pancreatic cancer xenografts were established. Based on ultrasound imaging, the orthotopic human pancreatic cancer xenograft take rate was 100% for both human pancreatic cancer cell lines used, MiaPaCa-2 and Su86.86, with mean tumor volumes of 28 mm3and 30 mm3. We demonstrated that this USGI method is feasible, reproducible, facile, minimally invasive and improved compared to the highly-invasive SOI method for establishing orthotopic pancreatic tumor xenograft models suitable for molecular imaging

Development of an Orthotopic Human Pancreatic Cancer Xenograft Model Using Ultrasound Guided Injection of Cells

Mice have been employed as models of cancer for over a century, providing significant advances in our understanding of this multifaceted family of diseases. In particular, orthotopic tumor xenograft mouse models are emerging as the preference for cancer research due to increased clinical relevance over subcutaneous mouse models. In the current study, we developed orthotopic pancreatic cancer xenograft models in mice by a minimally invasive method, ultrasound guided injection (USGI) comparable to highly invasive surgical orthotopic injection (SOI) methods. This optimized method prevented injection complications such as recoil of cells through the injection canal or leakage of cells out of the pancreas into the peritoneal cavity. Tumor growth was monitored in vivo and quantified by ultrasound imaging weekly, tumors were also detected by in vivo fluorescence imaging using a tumor targeted molecular probe. The mean tumor volumes for the USGI and SOI models after 2 weeks of tumor growth were 205 mm3 and 178 mm3 respectively. By USGI of human pancreatic cancer cell lines, human orthotopic pancreatic cancer xenografts were established. Based on ultrasound imaging, the orthotopic human pancreatic cancer xenograft take rate was 100% for both human pancreatic cancer cell lines used, MiaPaCa-2 and Su86.86, with mean tumor volumes of 28 mm3and 30 mm3. We demonstrated that this USGI method is feasible, reproducible, facile, minimally invasive and improved compared to the highly-invasive SOI method for establishing orthotopic pancreatic tumor xenograft models suitable for molecular imaging

Net Efficacy Adjusted for Risk (NEAR): A Simple Procedure for Measuring Risk:Benefit Balance

BACKGROUND: Although several mathematical models have been proposed to assess the risk:benefit of drugs in one measure, their use in practice has been rather limited. Our objective was to design a simple, easily applicable model. In this respect, measuring the proportion of patients who respond favorably to treatment without being affected by adverse drug reactions (ADR) could be a suitable endpoint. However, remarkably few published clinical trials report the data required to calculate this proportion. As an approach to the problem, we calculated the expected proportion of this type of patients. METHODOLOGY/PRINCIPAL FINDINGS: Theoretically, responders without ADR may be obtained by multiplying the total number of responders by the total number of subjects that did not suffer ADR, and dividing the product by the total number of subjects studied. When two drugs are studied, the same calculation may be repeated for the second drug. Then, by constructing a 2 x 2 table with the expected frequencies of responders with and without ADR, and non-responders with and without ADR, the odds ratio and relative risk with their confidence intervals may be easily calculated and graphically represented on a logarithmic scale. Such measures represent "net efficacy adjusted for risk" (NEAR). We assayed the model with results extracted from several published clinical trials or meta-analyses. On comparing our results with those originally reported by the authors, marked differences were found in some cases, with ADR arising as a relevant factor to balance the clinical benefit obtained. The particular features of the adverse reaction that must be weighed against benefit is discussed in the paper. CONCLUSION: NEAR representing overall risk-benefit may contribute to improving knowledge of drug clinical usefulness. As most published clinical trials tend to overestimate benefits and underestimate toxicity, our measure represents an effort to change this trend