Development of the G3 Designed ankyrin repeat protein (DARPin) for HER2 imaging

Background: Human epidermal growth factor receptor-2 (HER2) expression predicts response to anti-HER2 therapy in breast and gastric cancer. HER2 status is assessed by tumour biopsy but this may not be representative of the larger tumour mass or other metastatic sites; risking misclassification and selection of suboptimal therapy. The G3 designed ankyrin repeat protein (DARPin) binds HER2 with high affinity at an epitope that does not overlap with trastuzumab and is biologically inert. This research aims to assess the pre-clinical efficacy and safety of G3 DARPin HER2 PET and SPECT imaging. Methods: Hexahistidine (His6), histidine-glutamate (HE)3 and untagged-G3 DARPins were manufactured using a GMP-compatible Pichia pastoris protocol and radiolabelled with 125I or site-specifically with 111In. BALB/c mice were injected with radiolabelled-G3 DARPins and biodistribution was evaluated. The lead construct, (HE)3-G3 was radiolabelled with 111In, 125I or 68Ga for assessment in mice bearing HER2-positive human breast tumour (BT474) xenografts. Mice received (HE)3-G3 at 50-100 times the human equivalent dose to assess acute toxicity. Results: (HE)3-G3 had significantly lower liver uptake than His6-G3 and untagged-G3 in non-tumour bearing mice when radiolabelled with 125I or 111In. In mice bearing HER2-positive tumour xenografts, 111In-(HE)3-G3 was better maintained in tumours and cleared faster from serum than 125I-(HE)3-G3, achieving superior tumour-to-blood ratios of 343.7±161.3 vs. 22.0±11.3 at 24 h, respectively. On microSPECT/CT 111In and 125I labelled (HE)3-G3, imaged HER2-positive tumours at 4 h post-administration but 111In-(HE)3-G3 had less non-specific uptake. 68Ga-(HE)3-G3 can image HER2-positive tumours at up to 2 h post-administration by PET scanning. (HE)3-G3 DARPin was well tolerated by mice treated at 50-100 times the human equivalent dose over 24 h. Conclusion: Radiolabelled (HE)3-G3 is a versatile radioligand with potential to acquire whole-body HER2 scans. (HE)3-G3 will be assessed in a regulatory standard pre-clinical toxicity study, prior to embarking on a first in human trial

Robust Multi-Image HDR Reconstruction for the Modulo Camera

Photographing scenes with high dynamic range (HDR) poses great challenges to consumer cameras with their limited sensor bit depth. To address this, Zhao et al. recently proposed a novel sensor concept - the modulo camera - which captures the least significant bits of the recorded scene instead of going into saturation. Similar to conventional pipelines, HDR images can be reconstructed from multiple exposures, but significantly fewer images are needed than with a typical saturating sensor. While the concept is appealing, we show that the original reconstruction approach assumes noise-free measurements and quickly breaks down otherwise. To address this, we propose a novel reconstruction algorithm that is robust to image noise and produces significantly fewer artifacts. We theoretically analyze correctness as well as limitations, and show that our approach significantly outperforms the baseline on real data.Comment: to appear at the 39th German Conference on Pattern Recognition (GCPR) 201

Maladaptation and the paradox of robustness in evolution

Background. Organisms use a variety of mechanisms to protect themselves against perturbations. For example, repair mechanisms fix damage, feedback loops keep homeostatic systems at their setpoints, and biochemical filters distinguish signal from noise. Such buffering mechanisms are often discussed in terms of robustness, which may be measured by reduced sensitivity of performance to perturbations. Methodology/Principal Findings. I use a mathematical model to analyze the evolutionary dynamics of robustness in order to understand aspects of organismal design by natural selection. I focus on two characters: one character performs an adaptive task; the other character buffers the performance of the first character against perturbations. Increased perturbations favor enhanced buffering and robustness, which in turn decreases sensitivity and reduces the intensity of natural selection on the adaptive character. Reduced selective pressure on the adaptive character often leads to a less costly, lower performance trait. Conclusions/Significance. The paradox of robustness arises from evolutionary dynamics: enhanced robustness causes an evolutionary reduction in the adaptive performance of the target character, leading to a degree of maladaptation compared to what could be achieved by natural selection in the absence of robustness mechanisms. Over evolutionary time, buffering traits may become layered on top of each other, while the underlying adaptive traits become replaced by cheaper, lower performance components. The paradox of robustness has widespread implications for understanding organismal design

Chloroplast microsatellites: measures of genetic diversity and the effect of homoplasy

Chloroplast microsatellites have been widely used in population genetic studies of conifers in recent years. However, their haplotype configurations suggest that they could have high levels of homoplasy, thus limiting the power of these molecular markers. A coalescent-based computer simulation was used to explore the influence of homoplasy on measures of genetic diversity based on chloroplast microsatellites. The conditions of the simulation were defined to fit isolated populations originating from the colonization of one single haplotype into an area left available after a glacial retreat. Simulated data were compared with empirical data available from the literature for a species of Pinus that has expanded north after the Last Glacial Maximum. In the evaluation of genetic diversity, homoplasy was found to have little influence on Nei's unbiased haplotype diversity (H(E)) while Goldstein's genetic distance estimates (D2sh) were much more affected. The effect of the number of chloroplast microsatellite loci for evaluation of genetic diversity is also discussed

Generalized Bayesian Record Linkage and Regression with Exact Error Propagation

Record linkage (de-duplication or entity resolution) is the process of merging noisy databases to remove duplicate entities. While record linkage removes duplicate entities from such databases, the downstream task is any inferential, predictive, or post-linkage task on the linked data. One goal of the downstream task is obtaining a larger reference data set, allowing one to perform more accurate statistical analyses. In addition, there is inherent record linkage uncertainty passed to the downstream task. Motivated by the above, we propose a generalized Bayesian record linkage method and consider multiple regression analysis as the downstream task. Records are linked via a random partition model, which allows for a wide class to be considered. In addition, we jointly model the record linkage and downstream task, which allows one to account for the record linkage uncertainty exactly. Moreover, one is able to generate a feedback propagation mechanism of the information from the proposed Bayesian record linkage model into the downstream task. This feedback effect is essential to eliminate potential biases that can jeopardize resulting downstream task. We apply our methodology to multiple linear regression, and illustrate empirically that the "feedback effect" is able to improve the performance of record linkage.Comment: 18 pages, 5 figure

Flow through a circular tube with a permeable Navier slip boundary

For Newtonian fluid flow in a right circular tube, with a linear Navier slip boundary, we show that a second flow field arises which is different to conventional Poiseuille flow in the sense that the corresponding pressure is quadratic in its dependence on the length along the tube, rather than a linear dependence which applies for conventional Poiseuille flow. However, assuming that the quadratic pressure is determined, say from known experimental data, then the new solution only exists for a precisely prescribed permeability along the boundary. While this cannot occur for conventional pipe flow, for fluid flow through carbon nanotubes embedded in a porous matrix, it may well be an entirely realistic possibility, and could well explain some of the high flow rates which have been reported in the literature. Alternatively, if the radial boundary flow is prescribed, then the new flow field exists only for a given quadratic pressure. Our primary purpose here is to demonstrate the existence of a new pipe flow field for a permeable Navier slip boundary and to present a numerical solution and two approximate analytical solutions. The maximum flow rate possible for the new solution is precisely twice that for the conventional Poiseuille flow, which occurs for constant inward directed flow across the boundary

a M. T. Akadémia által az 1886-ik évi pályázaton a Teleky-díjjal jutalmazott eredeti társadalmi tragoedia 3 felvonásban - irta Csiky Gergely

Debreczeni Városi Szinház. Kedden, 1897. évi október hó 19-én.Debreceni Egyetem Egyetemi és Nemzeti Könyvtá

Charged Dilatonic AdS Black Branes in Arbitrary Dimensions

We study electromagnetically charged dilatonic black brane solutions in arbitrary dimensions with flat transverse spaces, that are asymptotically AdS. This class of solutions includes spacetimes which possess a bulk region where the metric is approximately invariant under Lifshitz scalings. Given fixed asymptotic boundary conditions, we analyze how the behavior of the bulk up to the horizon varies with the charges and derive the extremality conditions for these spacetimes.Comment: References update

Bilateral testicular self-castration due to cannabis abuse: a case report

<p>Abstract</p> <p>Introduction</p> <p>The self-mutilating patient is an unusual psychiatric presentation in the emergency room. Nonetheless, serious underlying psychiatric pathology and drug abuse are important background risk factors. A careful stepwise approach in the emergency room is essential, although the prognosis, follow-up, and eventual rehabilitation can be problematic.</p> <p>We present a unique and original case of bilateral self-castration caused by cannabis abuse.</p> <p>Case Presentation</p> <p>We report a case of a 40-year-old Berber man, who was presented to our emergency room with externalization of both testes using his long fingernails, associated with hemodynamic shock. After stabilization of his state, our patient was admitted to the operating room where hemostasis was achieved.</p> <p>Conclusion</p> <p>The clinical characteristics of self-mutilation are manifold and there is a lack of agreement about its etiology. The complex behavior associated with drug abuse may be one cause of self-mutilation. Dysfunction of the inhibitory brain circuitry caused by substance abuse could explain why this cannabis-addicted patient lost control and self-mutilated. To the best of our knowledge, this is the first case report which presents an association between self-castration and cannabis abuse.</p

Ready or not? Expectations of faculty and medical students for clinical skills preparation for clerkships

Background: Preclerkship clinical-skills training has received increasing attention as a foundational preparation for clerkships. Expectations among medical students and faculty regarding the clinical skills and level of skill mastery needed for starting clerkships are unknown. Medical students, faculty teaching in the preclinical setting, and clinical clerkship faculty may have differing expectations of students entering clerkships. If students&#x0027; expectations differ from faculty expectations, students may experience anxiety. Alternately, congruent expectations among students and faculty may facilitate integrated and seamless student transitions to clerkships. Aims: To assess the congruence of expectations among preclerkship faculty, clerkship faculty, and medical students for the clinical skills and appropriate level of clinical-skills preparation needed to begin clerkships. Methods: Investigators surveyed preclinical faculty, clerkship faculty, and medical students early in their basic clerkships at a North American medical school that focuses on preclerkship clinical-skills development. Survey questions assessed expectations for the appropriate level of preparation in basic and advanced clinical skills for students entering clerkships. Results: Preclinical faculty and students had higher expectations than clerkship faculty for degree of preparation in most basic skills. Students had higher expectations than both faculty groups for advanced skills preparation. Conclusions: Preclinical faculty, clerkship faculty, and medical students appear to have different expectations of clinical-skills training needed for clerkships. As American medical schools increasingly introduce clinical-skills training prior to clerkships, more attention to alignment, communication, and integration between preclinical and clerkship faculty will be important to establish common curricular agendas and increase integration of student learning. Clarification of skills expectations may also alleviate student anxiety about clerkships and enhance their learning