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Multispecific drugs herald a new era of biopharmaceutical innovation 期刊论文
NATURE, 2020, 580 (7803) : 329-338
作者:  Gallego, Laura D.;  Schneider, Maren;  Mittal, Chitvan;  Romanauska, Anete;  Carrillo, Ricardo M. Gudino;  Schubert, Tobias;  Pugh, B. Franklin;  Koehler, Alwin
收藏  |  浏览/下载:32/0  |  提交时间:2020/07/03

The modern biopharmaceutical industry traces its roots to the dawn of the twentieth century, coincident with marketing of aspirin-a signature event in the history of modern drug development. Although the archetypal discovery process did not change markedly in the first seven decades of the industry, the past fifty years have seen two successive waves of transformative innovation in the development of drug molecules: the rise of '  rational drug discovery'  methodology in the 1970s, followed by the invention of recombinant protein-based therapeutic agents in the 1980s. An incipient fourth wave is the advent of multispecific drugs. The successful development of prospectively designed multispecific drugs has the potential to reconfigure our ideas of how target-based therapeutic molecules can work, and what it is possible to achieve with them. Here I review the two major classes of multispecific drugs: those that enrich a therapeutic agent at a particular site of action and those that link a therapeutic target to a biological effector. The latter class-being freed from the constraint of having to directly modulate the target upon binding-may enable access to components of the proteome that currently cannot be targeted by drugs.


  
Video-based AI for beat-to-beat assessment of cardiac function 期刊论文
NATURE, 2020, 580 (7802) : 252-+
作者:  Pleguezuelos-Manzano, Cayetano;  Puschhof, Jens;  Huber, Axel Rosendahl;  van Hoeck, Arne;  Wood, Henry M.;  Nomburg, Jason;  Gurjao, Carino;  Manders, Freek;  Dalmasso, Guillaume;  Stege, Paul B.;  Paganelli, Fernanda L.;  Geurts, Maarten H.;  Beumer, Joep;  Mizutani, Tomohiro;  Miao, Yi;  van der Linden, Reinier;  van der Elst, Stefan;  Garcia, K. Christopher;  Top, Janetta;  Willems, Rob J. L.;  Giannakis, Marios;  Bonnet, Richard;  Quirke, Phil;  Meyerson, Matthew;  Cuppen, Edwin;  van Boxtel, Ruben;  Clevers, Hans
收藏  |  浏览/下载:117/0  |  提交时间:2020/07/03

A video-based deep learning algorithm-EchoNet-Dynamic-accurately identifies subtle changes in ejection fraction and classifies heart failure with reduced ejection fraction using information from multiple cardiac cycles.


Accurate assessment of cardiac function is crucial for the diagnosis of cardiovascular disease(1), screening for cardiotoxicity(2) and decisions regarding the clinical management of patients with a critical illness(3). However, human assessment of cardiac function focuses on a limited sampling of cardiac cycles and has considerable inter-observer variability despite years of training(4,5). Here, to overcome this challenge, we present a video-based deep learning algorithm-EchoNet-Dynamic-that surpasses the performance of human experts in the critical tasks of segmenting the left ventricle, estimating ejection fraction and assessing cardiomyopathy. Trained on echocardiogram videos, our model accurately segments the left ventricle with a Dice similarity coefficient of 0.92, predicts ejection fraction with a mean absolute error of 4.1% and reliably classifies heart failure with reduced ejection fraction (area under the curve of 0.97). In an external dataset from another healthcare system, EchoNet-Dynamic predicts the ejection fraction with a mean absolute error of 6.0% and classifies heart failure with reduced ejection fraction with an area under the curve of 0.96. Prospective evaluation with repeated human measurements confirms that the model has variance that is comparable to or less than that of human experts. By leveraging information across multiple cardiac cycles, our model can rapidly identify subtle changes in ejection fraction, is more reproducible than human evaluation and lays the foundation for precise diagnosis of cardiovascular disease in real time. As a resource to promote further innovation, we also make publicly available a large dataset of 10,030 annotated echocardiogram videos.