Targeting Ras-, Rho-, and Rab-family GTPases via a conserved cryptic pocket.

The family of Ras-like GTPases consists of over 150 different members, regulated by an even larger number of guanine exchange factors (GEFs) and GTPase-activating proteins (GAPs) that comprise cellular switch networks that govern cell motility, growth, polarity, protein trafficking, and gene expression. Efforts to develop selective small molecule probes and drugs for these proteins have been hampered by the high affinity of guanosine triphosphate (GTP) and lack of allosteric regulatory sites. This paradigm was recently challenged by the discovery of a cryptic allosteric pocket in the switch II region of K-Ras.

Probing the KRas Switch II Groove by Fluorine NMR Spectroscopy.

While there has been recent success in the development of KRas inhibitors, unmet needs for selective inhibitors of KRas and the remaining oncogenic KRas proteins remain. Here, we applied trifluoromethyl-containing ligands of KRas proteins as competitive probe ligands to assay the occupancy of the switch II pocket by F NMR spectroscopy. Structure-activity-relationship studies of probe ligands increased the sensitivity of the assay and identified structures that differentially detected each nucleotide state of KRas.

KRAS is vulnerable to reversible switch-II pocket engagement in cells.

Current small-molecule inhibitors of KRAS(G12C) bind irreversibly in the switch-II pocket (SII-P), exploiting the strong nucleophilicity of the acquired cysteine as well as the preponderance of the GDP-bound form of this mutant. Nevertheless, many oncogenic KRAS mutants lack these two features, and it remains unknown whether targeting the SII-P is a practical therapeutic approach for KRAS mutants beyond G12C. Here we use NMR spectroscopy and a cellular KRAS engagement assay to address this question by examining a collection of SII-P ligands from the literature and from our own laboratory.

Drugging the Next Undruggable KRAS Allele-Gly12Asp.

Since its discovery as the first human oncogene in 1983, the small GTPase KRAS has been a major target of cancer drug discovery. The paper reported in this issue describes a long-awaited small molecule drug candidate of the oncogenic KRAS (G12D) mutant for the treatment of currently incurable pancreatic cancer.

GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf.

We report the identification of three cyclic peptide ligands of K-Ras(G12D) using an integrated translation-mRNA display selection platform. These cyclic peptides show preferential binding to the GTP-bound state of K-Ras(G12D) over the GDP-bound state and block Ras-Raf interaction. A co-crystal structure of peptide KD2 with K-Ras(G12D)·GppNHp reveals that this peptide binds in the Switch II groove region with concomitant opening of the Switch II loop and a 40° rotation of the α2 helix, and that a threonine residue (Thr10) on KD2 has direct access to the mutant aspartate (Asp12) on K-Ras.

Findings from a mixed-methods pragmatic cluster trial evaluating the impact of ethics education interventions on residential care-givers.

There has been little previous research regarding the effectiveness of ethics education interventions for residential care-givers. The Researching Interventions to Promote Ethics in social care project responded to the question: Which is the most effective ethics education intervention for care-givers in residential social care? A pragmatic cluster trial explored the impact of three ethics education interventions for: (a) interactive face-to-face ethics teaching; (b) reflective ethics discussion groups; and (c) an immersive simulation experience. There was also a control arm (d).

Exploring the experiences of domiciliary caregivers simulating the role of care recipients.

Aim: To find out if an immersive simulation intervention would be feasible in a domiciliary care context, and to explore what effect, if any, the intervention would have on the domiciliary caregivers who participated.

Method: This was an immersive simulation pilot project in which six domiciliary caregivers (simulants) assumed the profile of people receiving domiciliary care. Second-year and third-year nursing students provided domiciliary care to the simulants, with support from a registered nurse.

Is obesity a contraindication for kidney donation?

Introduction: To enlarge the donor pool, kidney donors with obesity have been considered. We hypothesized that it is safe for patients with obesity to serve as living kidney donors.

Methods: In this single-center retrospective analysis, we examined the effect of obesity (body mass index (BMI) of 30-35 kg/m) on glomerular filtration rate (GFR) and creatinine in patients undergoing laparoscopic donor nephrectomy.

Herbal supplements in the print media: communicating benefits and risks.

Background: The rise in use of food supplements based on botanical ingredients (herbal supplements) is depicted as part of a trend empowering consumers to manage their day-to-day health needs, which presupposes access to clear and accurate information to make effective choices. Evidence regarding herbal supplement efficacy is extremely variable so recent regulations eliminating unsubstantiated claims about potential effects leave producers able to provide very little information about their products. Medical practitioners are rarely educated about herbal supplements and most users learn about them via word-of-mouth, allowing dangerous misconceptions to thrive, chief among them the assumption that natural products are inherently safe.

Understanding How Consumers Categorise Health Related Claims on Foods: A Consumer-Derived Typology of Health-Related Claims.

The Nutrition and Health Claims Regulation (NHCR) EC No 1924/2006 aims to provide an appropriate level of consumer protection whilst supporting future innovation and fair competition within the EU food industry. However, consumers' interpretation of health claims is less well understood. There is a lack of evidence on the extent to which consumers are able to understand claims defined by this regulatory framework.

The role of causal models and beliefs in interpreting health claims.

Objective: Health claims on food packaging are regulated to inform and protect consumers; however, many consumers do not accurately interpret the meaning of the claims. Whilst research has shown different types of misinterpretation, it is not clear how those interpretations are formed. The aim of this study was to elicit the causal beliefs and causal models about food and health held by consumers, that is their understanding of the causal relationships between nutrients, health outcomes, and the causal pathways connecting them, and investigate how well this knowledge explains the variation in inferences they draw about health benefits from health claims.

Reductive Elimination from Phosphine-Ligated Alkylpalladium(II) Amido Complexes To Form sp Carbon-Nitrogen Bonds.

We report the formation of phosphine-ligated alkylpalladium(II) amido complexes that undergo reductive elimination to form alkyl-nitrogen bonds and a combined experimental and computational investigation of the factors controlling the rates of these reactions. The free-energy barriers to reductive elimination from t-BuP-ligated complexes were significantly lower (ca. 3 kcal/mol) than those previously reported from NHC-ligated complexes.

Perioperative Infections after Open Abdominal Aortic Aneurysm Repair Lead to Increased Risk of Subsequent Complications.

Background: Patients undergoing open abdominal aortic aneurysm (AAA) repair are at risk of perioperative infections that can lead to subsequent complications. Our goal was to understand how an initial infectious complication influences the risk of subsequent complications in this cohort of patients.

Methods: Using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database (2005-2012), we evaluated the relationship between 3 index infectious complications after open elective AAA repair (pneumonia, deep/organ surgical site infection [SSI], and urinary tract infection [UTI]) and subsequent complications.

Hypoalbuminemia Predicts Perioperative Morbidity and Mortality after Infrainguinal Lower Extremity Bypass for Critical Limb Ischemia.

Background: Poor nutritional status has been associated with a higher risk of morbidity and mortality in general surgery patients; however, outcomes in vascular surgery patients are unclear. Our goal was to determine the effect of poor nutritional status on perioperative morbidity and mortality after lower extremity bypass (LEB).

Methods: The 2005-2012 National Surgical Quality Improvement Program was analyzed to determine associated complications, mortality, length of stay (LOS), and readmissions for patients with hypoalbuminemia (serum albumin <3.

Thirty-day and 90-day hospital readmission after outpatient upper extremity hemodialysis access creation.

Objective: Patients with end-stage renal disease have multiple comorbidities and are at increased risk for postoperative complications and resource utilization. Our goal was to determine the rate and causes of 30-day and 90-day hospital readmissions after the creation of outpatient hemodialysis access.

Methods: We retrospectively reviewed all outpatient upper extremity hemodialysis access creations performed at our medical center from 2008 to 2015.

Index complications predict secondary complications after infrainguinal lower extremity bypass for critical limb ischemia.

Objective: Patients undergoing lower extremity bypass (LEB) are at high risk of perioperative complications that can lead to a cascade of secondary complications. Our goal was to understand the association of index complications with secondary complications after LEB.

Methods: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database from 2005 to 2012 was used to analyze secondary complications after five index complications after LEB: deep/organ space surgical site infection, urinary tract infection (UTI), myocardial infarction (MI), pneumonia, and acute renal failure (ARF).

Preoperative hypoalbuminemia is associated with poor clinical outcomes after open and endovascular abdominal aortic aneurysm repair.

Objective: The effect of preoperative malnutrition on outcomes in patients undergoing major vascular surgery is unclear. We investigated the effects of preoperative hypoalbuminemia, a marker for malnutrition, on outcomes after open abdominal aortic aneurysm repair (OAR) and endovascular abdominal aortic aneurysm repair (EVAR).

Methods: Patients undergoing OAR or EVAR were identified in the 2005 to 2012 American College of Surgeons National Surgical Quality Improvement Program database and stratified into three groups: normal albumin (serum albumin >3.

Characterization of Planned and Unplanned 30-Day Readmissions Following Vascular Surgical Procedures.

Objective: Thirty-day readmission is increasingly used as a quality of care indicator. Patients undergoing vascular surgery have historically been at high risk for readmission. We analyzed hospital readmission details to identify patients at high risk for readmission in order to better understand these readmissions and improve resource utilization in this patient population.

Care-givers' reflections on an ethics education immersive simulation care experience: A series of epiphanous events.

There has been little previous scholarship regarding the aims, options and impact of ethics education on residential care-givers. This manuscript details findings from a pragmatic cluster trial evaluating the impact of three different approaches to ethics education. The focus of the article is on one of the interventions, an immersive simulation experience.

Palladium-Catalyzed Cross Coupling of Secondary and Tertiary Alkyl Bromides with a Nitrogen Nucleophile.

We report a new class of catalytic reaction: the thermal substitution of a secondary and or tertiary alkyl halide with a nitrogen nucleophile. The alkylation of a nitrogen nucleophile with an alkyl halide is a classical method for the construction of C-N bonds, but traditional substitution reactions are challenging to achieve with a secondary and or tertiary alkyl electrophile due to competing elimination reactions. A catalytic process could address this limitation, but thermal, catalytic coupling of alkyl halides with a nitrogen nucleophile and any type of catalytic coupling of an unactivated tertiary alkyl halide with a nitrogen nucleophile are unknown.

Assessment of open operative vascular surgical experience among general surgery residents.

Background: General surgeons have traditionally performed open vascular operations. However, endovascular interventions, vascular residencies, and work-hour limitations may have had an impact on open vascular surgery training among general surgery residents. We evaluated the temporal trend of open vascular operations performed by general surgery residents to assess any changes that have occurred.

Oxidative Damage to RPA Limits the Nucleotide Excision Repair Capacity of Human Cells.

Nucleotide excision repair (NER) protects against sunlight-induced skin cancer. Defective NER is associated with photosensitivity and a high skin cancer incidence. Some clinical treatments that cause photosensitivity can also increase skin cancer risk.

Guiding healthier food choice: systematic comparison of four front-of-pack labelling systems and their effect on judgements of product healthiness.

Different front-of-pack (FOP) labelling systems have been developed in Europe by industry and organisations concerned with health promotion. A study (n 2068) was performed to establish the extent to which inclusion of the most prevalent FOP systems--guideline daily amounts (GDA), traffic lights (TL), GDA+TL hybrid (HYB) and health logos (HL)--impact consumer perceptions of healthiness over and above the provision of a FOP basic label (BL) containing numerical nutritional information alone. The design included within- and between-subjects factors.