Multiparametric MRI for assessment of early response to neoadjuvant sunitinib in renal cell carcinoma.

Funder: NIHR Cambridge Biomedical Research CentreFunder: Addenbrooke’s Charitable TrustFunder: National Institute for Health Research (NIHR)Funder: Mark Foundation For Cancer ResearchFunder: Cambridge Commonwealth, European and International TrustFunder: Cancer Research UKFunder: Cambridge Clinical Trials UnitFunder: Cancer Research UK Cambridge CentreFunder: Engineering and Physical Sciences Research Council Cancer Imaging Centre in Cambridge and ManchesterFunder: Cambridge Experimental Cancer Medicine CentrePURPOSE: To detect early response to sunitinib treatment in metastatic clear cell renal cancer (mRCC) using multiparametric MRI. METHOD: Participants with mRCC undergoing pre-surgical sunitinib therapy in the prospective NeoSun clinical trial (EudraCtNo: 2005-004502-82) were imaged before starting treatment, and after 12 days of sunitinib therapy using morphological MRI sequences, advanced diffusion-weighted imaging, measurements of R2* (related to hypoxia) and dynamic contrast-enhanced imaging. Following nephrectomy, participants continued treatment and were followed-up with contrast-enhanced CT. Changes in imaging parameters before and after sunitinib were assessed with the non-parametric Wilcoxon signed-rank test and the log-rank test was used to assess effects on survival. RESULTS: 12 participants fulfilled the inclusion criteria. After 12 days, the solid and necrotic tumor volumes decreased by 28% and 17%, respectively (p = 0.04). However, tumor-volume reduction did not correlate with progression-free or overall survival (PFS/OS). Sunitinib therapy resulted in a reduction in median solid tumor diffusivity D from 1298x10-6 to 1200x10-6mm2/s (p = 0.03); a larger decrease was associated with a better RECIST response (p = 0.02) and longer PFS (p = 0.03) on the log-rank test. An increase in R2* from 19 to 28s-1 (p = 0.001) was observed, paralleled by a decrease in Ktrans from 0.415 to 0.305min-1 (p = 0.01) and a decrease in perfusion fraction from 0.34 to 0.19 (p<0.001). CONCLUSIONS: Physiological imaging confirmed efficacy of the anti-angiogenic agent 12 days after initiating therapy and demonstrated response to treatment. The change in diffusivity shortly after starting pre-surgical sunitinib correlated to PFS in mRCC undergoing nephrectomy, however, no parameter predicted OS. TRIAL REGISTRATION: EudraCtNo: 2005-004502-82

Dynamic biomarker and imaging changes from a phase II study of pre- and post-surgical sunitinib.

Funder: Pfizer; Id: http://dx.doi.org/10.13039/100004319OBJECTIVE: To explore translational biological and imaging biomarkers for sunitinib treatment before and after debulking nephrectomy in the NeoSun (European Union Drug Regulating Authorities Clinical Trials Database [EudraCT] number: 2005-004502-82) single-centre, single-arm, single-agent, Phase II trial. PATIENTS AND METHODS: Treatment-naïve patients with metastatic renal cell carcinoma (mRCC) received 50 mg once daily sunitinib for 12 days pre-surgically, then post-surgery on 4 week-on, 2 week-off, repeating 6-week cycles until disease progression in a single arm phase II trial. Structural and dynamic contrast-enhanced magnet resonance imaging (DCE-MRI) and research blood sampling were performed at baseline and after 12 days. Computed tomography imaging was performed at baseline and post-surgery then every two cycles. The primary endpoint was objective response rate (Response Evaluation Criteria In Solid Tumors [RECIST]) excluding the resected kidney. Secondary endpoints included changes in DCE-MRI of the tumour following pre-surgery sunitinib, overall survival (OS), progression-free survival (PFS), response duration, surgical morbidity/mortality, and toxicity. Translational and imaging endpoints were exploratory. RESULTS: A total of 14 patients received pre-surgery sunitinib, 71% (10/14) took the planned 12 doses. All underwent nephrectomy, and 13 recommenced sunitinib postoperatively. In all, 58.3% (seven of 12) of patients achieved partial or complete response (PR or CR) (95% confidence interval 27.7-84.8%). The median OS was 33.7 months and median PFS was 15.7 months. Amongst those achieving a PR or CR, the median response duration was 8.7 months. No unexpected surgical complications, sunitinib-related toxicities, or surgical delays occurred. Within the translational endpoints, pre-surgical sunitinib significantly increased necrosis, and reduced cluster of differentiation-31 (CD31), Ki67, circulating vascular endothelial growth factor-C (VEGF-C), and transfer constant (KTrans , measured using DCE-MRI; all P < 0.05). There was a trend for improved OS in patients with high baseline plasma VEGF-C expression (P = 0.02). Reduction in radiological tumour volume after pre-surgical sunitinib correlated with high percentage of solid tumour components at baseline (Spearman's coefficient ρ = 0.69, P = 0.02). Conversely, the percentage tumour volume reduction correlated with lower baseline percentage necrosis (coefficient = -0.51, P = 0.03). CONCLUSION: Neoadjuvant studies such as the NeoSun can safely and effectively explore translational biological and imaging endpoints

A Multi-Element Detector System for Intelligent Imaging: I-ImaS

I-ImaS is a European project aiming to produce new, intelligent x-ray imaging systems using novel APS sensors to create optimal diagnostic images. Initial systems concentrate on mammography and encephalography. Later development will yield systems for other types of radiography such as industrial QA and homeland security. The I-ImaS system intelligence, due to APS technology and FPGAs, allows real-time analysis of data during image acquisition, giving the capability to build a truly adaptive imaging system with the potential to create images with maximum diagnostic information within given dose constraints. A companion paper deals with the DAQ system and preliminary characterization. This paper considers the laboratory x-ray characterization of the detector elements of the I-ImaS system. The characterization of the sensors when tiled to form a strip detector will be discussed, along with the appropriate correction techniques formulated to take into account the misalignments between individual sensors within the array. Preliminary results show that the detectors have sufficient performance to be used successfully in the initial mammographic and encephalographic I-ImaS systems under construction and this paper will further discuss the testing of these systems and the iterative processes used for intelligence upgrade in order to obtain the optimal algorithms and setting

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine

VIII Encuentro de Docentes e Investigadores en Historia del Diseño, la Arquitectura y la Ciudad

Acta de congresoLa conmemoración de los cien años de la Reforma Universitaria de 1918 se presentó como una ocasión propicia para debatir el rol de la historia, la teoría y la crítica en la formación y en la práctica profesional de diseñadores, arquitectos y urbanistas. En ese marco el VIII Encuentro de Docentes e Investigadores en Historia del Diseño, la Arquitectura y la Ciudad constituyó un espacio de intercambio y reflexión cuya realización ha sido posible gracias a la colaboración entre Facultades de Arquitectura, Urbanismo y Diseño de la Universidad Nacional y la Facultad de Arquitectura de la Universidad Católica de Córdoba, contando además con la activa participación de mayoría de las Facultades, Centros e Institutos de Historia de la Arquitectura del país y la región. Orientado en su convocatoria tanto a docentes como a estudiantes de Arquitectura y Diseño Industrial de todos los niveles de la FAUD-UNC promovió el debate de ideas a partir de experiencias concretas en instancias tales como mesas temáticas de carácter interdisciplinario, que adoptaron la modalidad de presentación de ponencias, entre otras actividades. En el ámbito de VIII Encuentro, desarrollado en la sede Ciudad Universitaria de Córdoba, se desplegaron numerosas posiciones sobre la enseñanza, la investigación y la formación en historia, teoría y crítica del diseño, la arquitectura y la ciudad; sumándose el aporte realizado a través de sus respectivas conferencias de Ana Clarisa Agüero, Bibiana Cicutti, Fernando Aliata y Alberto Petrina. El conjunto de ponencias que se publican en este Repositorio de la UNC son el resultado de dos intensas jornadas de exposiciones, cuyos contenidos han posibilitado actualizar viejos dilemas y promover nuevos debates. El evento recibió el apoyo de las autoridades de la FAUD-UNC, en especial de la Secretaría de Investigación y de la Biblioteca de nuestra casa, como así también de la Facultad de Arquitectura de la UCC; va para todos ellos un especial agradecimiento

T testing the immune system

Amid the flurry of grant writing and experimentation, statistical analysis sometimes gets less attention than it requires. Here, we describe fully the considerations that should go into the employment of the statistical two-sample t test

Stellar exotica in 47 tucanae

We present far-ultraviolet (FUV) spectroscopy obtained with HST for 48 blue objects in the core of 47 Tuc. Based on their position in a FUV-optical color-magnitude diagram, these were expected to include cataclysmic variables (CVs), blue stragglers (BSs), white dwarfs (WDs), and other exotic objects. For a subset of these sources, we also construct FUV-NIR spectral energy disributions. Based on our analysis of this extensive data set, we report the following main results. (1) We spectroscopically confirm 3 previously known or suspected CVs via the detection of emission lines and find new evidence for dwarf nova eruptions in two of these. (2) Only one other source in our spectroscopic sample exhibits marginal evidence for line emission, but predicted and observed CV numbers still agree to within a factor of about 2-3. (3) We have discovered a hot (Teff = 8700 K), low-mass (M = 0.05 M) secondary star in a previously known 0.8 day binary system. This exotic object is probably the remnant of a subgiant that has been stripped of its envelope and may represent the "smoking gun" of a recent dynamical encounter. (4) We have found a helium WD, the second to be optically detected in 47 Tuc, and the first outside a millisecond-pulsar system. (5) We have discovered a BS-WD binary system, the first known in any globular cluster. (6) We have found two additional candidate WD binary systems with putative main sequence and subgiant companions. (7) We estimate the WD binary fraction in the core of 47 Tuc to be 15%+ 17%?9% (stat) + 8%?7% (sys). (8) One BS in our sample may exceed twice the cluster turnoff mass, but the uncertainties are large. Taken as a whole, our study illustrates the wide range of stellar exotica that are lurking in the cores of GCs, most of which are likely to have undergone significant dynamical encounters

Chemical control of spin propagation between heterometallic rings

We present a synthetic, structural,theoretical, and spectroscopicstudy of a family of heterometallic ringdimers which have the formula[{Cr7NiF3ACHTUNGTRENUNG(Etglu)ACHTUNGTRENUNG(O2CtBu)15}2ACHTUNGTRENUNG(NLN)],in which Etglu is the pentadeprotonatedform of the sugar N-ethyl-d-glucamine,and NLN is an aromatic bridgingdiACHTUNGTRENUNGimine ligand. By varying NLN we areable to adjust the strength of the interactionbetween rings with the aim ofunderstanding how to tune our systemto achieve weak magnetic communicationbetween the spins, a prerequisitefor quantum entanglement. Micro-SQUID and EPR data reveal that themagnetic coupling between rings ispartly related to the through-bond distancebetween the spin centers, butalso depends on spin-polarizationmechanisms and torsion angles betweenaromatic rings. Density functionaltheory (DFT) calculations allow usto make predictions of how such chemicallyvariable parameters could beused to tune very precisely the interactionin such systems. For possible applicationsin quantum information processingand molecular spintronics, suchprecise control is essential