Caught between a ROCK and a hard place: current challenges in structure-based drug design.

The discipline of structure-based drug design (SBDD) is several decades old and it is tempting to think that the proliferation of experimental structures for many drug targets might make computer-aided drug design (CADD) straightforward. However, this is far from true. In this review, we illustrate some of the challenges that CADD scientists face every day in their work, even now.

Preoperative downstaging of pancreatic cancer is associated with improved survival after multi-agent chemotherapy, but not after radiation.

Background: Downstaging has been associated with improved survival for many cancers. However, the implications of downstaging are unclear for pancreatic cancer in an era of effective neoadjuvant systemic chemotherapy.

Methods: NCDB retrospective cohort study of resected pancreatic carcinoma treated with neoadjuvant therapy.

Paul Clairmont and his connections to American surgery.

Purpose: To examine the life and influences of Paul Clairmont (1875-1942).

Method: Review and analysis of published and archival information.

Results: The Clairmont family was associated with famous individuals in English literary history.

Sebetralstat (KVD900): A Potent and Selective Small Molecule Plasma Kallikrein Inhibitor Featuring a Novel P1 Group as a Potential Oral On-Demand Treatment for Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare genetic disorder in which patients experience sudden onset of swelling in various locations of the body. HAE is associated with uncontrolled plasma kallikrein (PKa) enzyme activity and generation of the potent inflammatory mediator, bradykinin, resulting in episodic attacks of angioedema. Herein, we disclose the discovery and optimization of novel small molecule PKa inhibitors.

Upfront resection versus neoadjuvant therapy for T1/T2 pancreatic cancer.

Background: The role of neoadjuvant therapy remains controversial for resectable pancreatic neoplasms. We evaluated treatment outcomes for T1/T2 tumors.

Methods: Retrospective study of patients with T1/T2 (Stage I-II) pancreatic cancer within the NCDB.

Virtual Screening: Is Bigger Always Better? Or Can Small Be Beautiful?

This viewpoint is intended to counterbalance some recent publications describing large-scale virtual screening by illustrating how success in launching drug discovery projects has been achieved with much more modest resources. Two examples of small-scale virtual screening that led to the discovery of clinical candidates are cited in favor of this argument.

Moose-Motor Vehicle Collision: A Continuing Hazard in Northern New England.

Background: Moose-motor vehicle collisions (MMVC) are especially dangerous to vehicle occupants because of the height and mass of the animal, which often collapses the roof and has a direct impact into the passenger compartment.

Study Design: Public data on MMVC were obtained from the states of New England (NE), and trauma registry data from centers in NH and ME.

Results: For all of NE, the annual incidence of reported MMVC has declined from a peak of >1,200 in 1998, but has still averaged >500 over the last 5 years, predominantly in ME, NH, and VT.

Automated De Novo Drug Design: Are We Nearly There Yet?

Medicinal chemistry and, in particular, drug design have often been perceived as more of an art than a science. The many unknowns of human disease and the sheer complexity of chemical space render decision making in medicinal chemistry exceptionally demanding. Computational models can assist the medicinal chemist in this endeavour.

Racial disparities exist among burn patients despite insurance coverage.

Background: Age, total burn surface area (TBSA), and inhalation injury are proven predictors of mortality and morbidity following burn injury. Most previous studies have also found that African Americans and females with burns also fare worse. We sought to determine whether these disparities were reduced when burn victims were analyzed separately by categories of insurance coverage.

Open-access programs for injury categorization using ICD-9 or ICD-10.

Background: The article introduces Programs for Injury Categorization, using the International Classification of Diseases (ICD) and R statistical software (ICDPIC-R). Starting with ICD-8, methods have been described to map injury diagnosis codes to severity scores, especially the Abbreviated Injury Scale (AIS) and Injury Severity Score (ISS). ICDPIC was originally developed for this purpose using Stata, and ICDPIC-R is an open-access update that accepts both ICD-9 and ICD-10 codes.

R A Cowley, the "Golden Hour," the "Momentary Pause," and the "Third Space".

R Adams Cowley (1917-1991), the Baltimore thoracic and trauma surgeon, was an outstanding politician and promoter of emergency medical services. His skills included the effective use of language, for example, identifying the critical time immediately after injury as a "golden hour," and describing shock as a "momentary pause in the act of death." Conversely, Cowley avoided the tendency of some contemporaries to justify massive crystalloid infusion by invoking a "third space.

Procedure-based postoperative risk prediction using NSQIP data.

Background: The National Surgical Quality Improvement Program (NSQIP) has proposed using procedure-based hierarchical models to predict adverse outcomes, but it is not clear whether this approach was used to develop the NSQIP "Surgical Risk Calculator". We therefore wished to demonstrate how procedure-based hierarchical models can be constructed and to describe their results.

Methods: NSQIP data from 2015 were used to construct statistical models predicting 30-day postoperative mortality and morbidity, using two-level logistic regression with preoperative patient-level variables as fixed effects and procedure-specific codes as a random intercept.

Discovery of LRRK2 inhibitors by using an ensemble of virtual screening methods.

In this paper, we present the results of a ligand- and structure-based virtual screen targeting LRRK2, a kinase that has been implicated in Parkinson's disease. For the ligand-based virtual screen, the structures of 12 competitor compounds were used as queries for a variety of 2D and 3D searches. The structure-based virtual screen relied on homology models of LRRK2, as no X-ray structure is currently available in the public domain.

Application of virtual screening to the discovery of novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with potential for the treatment of cancer and axonopathies.

NAMPT may represent a novel target for drug discovery in various therapeutic areas, including oncology and inflammation. Additionally, recent work has suggested that targeting NAMPT has potential in treating axon degeneration. In this work, publicly available X-ray co-crystal structures of NAMPT and the structures of two known NAMPT inhibitors were used as the basis for a structure- and ligand-based virtual screening campaign.

Colorectal carcinoma in pediatric patients: A comparison with adult tumors, treatment and outcomes from the National Cancer Database.

Background: Pediatric colorectal cancer (CRC) is rare. Comparison with adult CRC tumors, management, and outcomes may identify opportunities for improvement in pediatric CRC care.

Study Design: CRC patients in the National Cancer Data Base from 1998 to 2011, were grouped into Pediatric (≤21years), early onset adult (22-50) and older adult (>50) patients.

Comparison of the ability of veterinary medical students to perform laparoscopic versus conventional open ovariectomy on live dogs.

Objective: To compare the feasibility of training veterinary medicine students to perform laparoscopic versus conventional open ovariectomy in live dogs.

Design: Randomized prospective parallel-group experiment.

Population: 25 students completing the second year of their veterinary curriculum.

Ethanolamine Signaling Promotes Salmonella Niche Recognition and Adaptation during Infection.

Chemical and nutrient signaling are fundamental for all cellular processes, including interactions between the mammalian host and the microbiota, which have a significant impact on health and disease. Ethanolamine is an essential component of cell membranes and has profound signaling activity within mammalian cells by modulating inflammatory responses and intestinal physiology. Here, we describe a virulence-regulating pathway in which the foodborne pathogen Salmonella enterica serovar Typhimurium (S.

A Multistate Model Predicting Mortality, Length of Stay, and Readmission for Surgical Patients.

Objective: Simultaneously evaluate postoperative mortality, length of stay (LOS), and readmission.

Data Source: National Surgical Quality Improvement Program (NSQIP).

Design: Retrospective cohort.

Evaluating adverse rural crash outcomes using the NHTSA State Data System.

Introduction: The population-based rate of motor vehicle crash mortality is consistently higher in rural locations, but it is unclear how much of this disparity might be due to geographic barriers or deficiencies in emergency medical services (EMS). We sought to analyze separately factors associated with the occurrence of a severe injury and those associated with death after injury had occurred.

Methods: Data from all police-reported crashes in 11 states from 2005-2007 were obtained through the National Highway Traffic Safety Administration (NHTSA) State Data System (SDS).