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Pancreatic Adenocarcinoma
Cancer of the pancreas is predominantly adenocarcinoma and involves activating
KRAS
mutations in the large majority of cases. Surgical resection can be effective in localized disease; combination chemotherapy offers some palliation in advanced disease.
Pancreatic ductal adenocarcinoma is the most lethal common cancer because it is usually diagnosed at an advanced stage and is resistant to therapy. In this article, we review current understanding of the biology and treatment of pancreatic adenocarcinoma.
Epidemiology and Risk Factors
Pancreatic adenocarcinoma is rarely diagnosed in persons younger than 40 years of age, and the median age at diagnosis is 71 years. Worldwide, the incidence of all types of pancreatic cancer (85% of which are adenocarcinomas) ranges from 1 to 10 cases per 100,000 people, is generally higher in developed countries and among men, and has remained stable . . .
Journal Article
The dispatcher
Ian Hunt is the police dispatcher for the small town of Bulls Mouth, East Texas. Just as his shift is ending he gets a call from his fourteen-year-old daughter, Maggie. Maggie, who has just been declared dead, having been snatched from her bedroom seven years ago. Her call ends in a scream. The trail leads to a local couple, but this is just the start of his battle to get his daughter back. What follows is a bullet-strewn cross-country chase along Interstate 10, from Texas to California.
Book
GNINA 1.0: molecular docking with deep learning
Molecular docking computationally predicts the conformation of a small molecule when binding to a receptor. Scoring functions are a vital piece of any molecular docking pipeline as they determine the fitness of sampled poses. Here we describe and evaluate the 1.0 release of the Gnina docking software, which utilizes an ensemble of convolutional neural networks (CNNs) as a scoring function. We also explore an array of parameter values for Gnina 1.0 to optimize docking performance and computational cost. Docking performance, as evaluated by the percentage of targets where the top pose is better than 2Å root mean square deviation (Top1), is compared to AutoDock Vina scoring when utilizing explicitly defined binding pockets or whole protein docking.
Gnina
, utilizing a CNN scoring function to rescore the output poses, outperforms AutoDock Vina scoring on redocking and cross-docking tasks when the binding pocket is defined (Top1 increases from 58% to 73% and from 27% to 37%, respectively) and when the whole protein defines the binding pocket (Top1 increases from 31% to 38% and from 12% to 16%, respectively). The derived ensemble of CNNs generalizes to unseen proteins and ligands and produces scores that correlate well with the root mean square deviation to the known binding pose. We provide the 1.0 version of
Gnina
under an open source license for use as a molecular docking tool at
https://github.com/gnina/gnina
.
Journal Article
Gilbert Simondon's Psychic and collective individuation : a critical introduction and guide
A critical commentary on Simondon's Psychic and collective individuation. This book clarifies Simondon's complex terminology and structure through chapter by chapter commentary. It also invites a dialogue with other thinkers/philosophers and places the work in its historical context. It includes a discussion about Simondon's relevance to current ideas about biopolitics and post-Nietzschean ethics.
Book
Virtual Screening with Gnina 1.0
Virtual screening—predicting which compounds within a specified compound library bind to a target molecule, typically a protein—is a fundamental task in the field of drug discovery. Doing virtual screening well provides tangible practical benefits, including reduced drug development costs, faster time to therapeutic viability, and fewer unforeseen side effects. As with most applied computational tasks, the algorithms currently used to perform virtual screening feature inherent tradeoffs between speed and accuracy. Furthermore, even theoretically rigorous, computationally intensive methods may fail to account for important effects relevant to whether a given compound will ultimately be usable as a drug. Here we investigate the virtual screening performance of the recently released Gnina molecular docking software, which uses deep convolutional networks to score protein-ligand structures. We find, on average, that Gnina outperforms conventional empirical scoring. The default scoring in Gnina outperforms the empirical AutoDock Vina scoring function on 89 of the 117 targets of the DUD-E and LIT-PCBA virtual screening benchmarks with a median 1% early enrichment factor that is more than twice that of Vina. However, we also find that issues of bias linger in these sets, even when not used directly to train models, and this bias obfuscates to what extent machine learning models are achieving their performance through a sophisticated interpretation of molecular interactions versus fitting to non-informative simplistic property distributions.
Journal Article
The President Will See Whom Now? Presidential Engagement with Organized Interests
Though presidents often criticize organized interests, presidents also expend considerable effort engaging them. Using original elite interviews, a survey of lobbyists, and administrative data, I consider how this engagement manifests, why presidents engage interests, and with which interests presidents engage. Unlike in other institutions, presidents exercise substantial control over engagement with interests, and they engage to mobilize interests’ institutional resources in service of their goals. To optimize mobilization, presidents focus engagement on well-resourced interests and interests who share presidents’ preferences. Pairing over seven million White House visitor log entries from two administrations with lobbying and campaign finance records, I demonstrate that presidential engagement is informed by interests’ electoral and policy resources and partisan alignment, though these characteristics’ substantive effects are modest. My findings highlight coalition building with interests as an underappreciated source of presidential power and elucidate the degree to which presidents amplify the political voice of well-resourced and copartisan interests.
Journal Article
Cytoreductive surgery plus hyperthermic perioperative chemotherapy to treat peritoneal metastases from colorectal cancer: standard of care or an experimental approach?
Peritoneal carcinomatosis is a common presentation in patients with metastatic colorectal cancer and the overall survival is poor. In most patients, the disease remains limited to the peritoneal cavity. Therefore, investigators have applied cytoreductive surgery and hyperthermic perioperative chemotherapy as the standard approach for selected patients with peritoneal metastases from colorectal cancer. Overall, very promising long-term survival has been shown in a subset of patients with a limited extent of peritoneal disease before treatment. Whether randomised, controlled trials are needed to definitively show the magnitude of benefit, if any, of this approach is an important question. This Debate outlines the arguments on each side of this issue.
Journal Article