A paradigm shift: analytical ultracentrifugation as a multi-attribute platform method in targeted protein degradation.

Targeted protein degradation (TPD) has garnered appreciable interest in drug discovery due to its unique mechanism of action - degradation of a target in an event-driven manner, instead of traditional occupancy-driven inhibitor-based therapies. This is achieved by employing mono- or hetero-bifunctional small molecules known as degraders to induce the proximity of two proteins: a target protein and an E3 ubiquitin ligase, ultimately resulting in clearance of the target protein by the cell's inherent degradation machinery. A critical step in this pathway is ternary complex formation (TCF) between the ligase, degrader molecule, and the target protein.

Original Research: Can a Palliative Care Lay Health Advisor-Nurse Partnership Improve Health Equity for Latinos with Cancer?

Purpose: A palliative care infrastructure is lacking for Latinos with life-threatening illness, especially in rural regions of the United States. The purpose of this study was to develop and evaluate a community-based palliative care lay health advisor (LHA) intervention for rural-dwelling Latino adults with cancer.

Methods: An exploratory mixed-methods participatory action research design was carried out by an interprofessional research team that included community and academic members.

Enantioselective Bioreduction of Medicinally Relevant Nitrogen-Heteroaromatic Ketones.

We herein report an enantioselective bioreduction of ketones that bear the most frequently used nitrogen-heteroaromatics in FDA-approved drugs. Ten varieties of these nitrogen-containing heterocycles were systematically investigated. Eight categories were studied for the first time and seven types were tolerated, significantly expanding the substrate scope of plant-mediated reduction.

Is the use of nonsteroidal anti-inflammatories after bowel anastomosis in trauma safe?

Background: With an increasing interest in multimodal and opioid-reducing pain strategies, nonsteroidal anti-inflammatory drugs (NSAIDs) have become common place in the care of injured patients. Long-standing concerns of increased anastomotic leak (AL) rate with the use of NSAIDs, however, have persisted. We hypothesized that there would be no significant risk associated with NSAID use after bowel anastomosis in trauma patients.

Patient Outcomes in Laparoscopic Appendectomy With Acute Surgical Care Model Compared to Traditional Call.

Introduction: Shift-based models for acute surgical care (ACS), where surgical emergencies are treated by a dedicated team of surgeons working shifts, without a concurrent elective practice, are becoming more common nationwide. We compared the outcomes for appendectomy, one of the most common emergency surgical procedures, between the traditional (TRAD) call and ACS model at the same institution during the same time frame.

Methods: A retrospective review of patients who underwent laparoscopic appendectomy for acute appendicitis during 2017-2018.

Impaired Redox and Protein Homeostasis as Risk Factors and Therapeutic Targets in Toxin-Induced Biliary Atresia.

Background & Aims: Extrahepatic biliary atresia (BA) is a pediatric liver disease with no approved medical therapy. Recent studies using human samples and experimental modeling suggest that glutathione redox metabolism and heterogeneity play a role in disease pathogenesis. We sought to dissect the mechanistic basis of liver redox variation and explore how other stress responses affect cholangiocyte injury in BA.

A Case Series of Successful Abdominal Closure Utilizing a Novel Technique Combining a Mechanical Closure System with a Biologic Xenograft that Accelerates Wound Healing.

In the acute setting, once intra-abdominal injuries have been addressed, the next great hurdle is restoring a functional and intact abdominal compartment. The short and long-term consequences of living with a chronically open abdominal compartment include pulmonary, musculoskeletal, gastrointestinal, and emotional disability. The closure of catastrophic open abdomens presents a challenge to the surgeon.

A 3-(4-nitronaphthen-1-yl) amino-benzoate analog as a bifunctional AKR1C3 inhibitor and AR antagonist: Head to head comparison with other advanced AKR1C3 targeted therapeutics.

Drugs used for the treatment of castration resistant prostate cancer (CRPC) include Abiraterone acetate (Zytiga®) and Enzalutamide (XTANDI®). However, these drugs provide clinical benefit in metastatic disease for only a brief period before drug resistance emerges. One mechanism of drug resistance involves the overexpression of type 5 17-β-hydroxysteroid dehydrogenase (aldo-keto reductase 1C3 or AKR1C3), a major enzyme responsible for the formation of intratumoral androgens that activate the androgen receptor (AR).

N-(7-Cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (TAK632) Promotes Inhibition of BRAF through the Induction of Inhibited Dimers.

BRAF is the most common activating mutation in melanoma and patients treated with BRAF inhibitors all develop resistance within one year. A significant resistance pathway is paradoxical activation (transactivation) involving BRAF dimers, whereby an inhibitor bound protein subunit allosterically activates the other subunit. We recently reported on dimeric BRAF -selective vemurafenib inhibitors that stabilize an inactive αC-out/αC-out homodimeric conformation with improved inhibitor potency and selectivity in vitro.

Synthesis and Structure-Activity Relationship Study of Biliatresone, a Plant Isoflavonoid That Causes Biliary Atresia.

We report the first synthesis of the plant isoflavonoid biliatresone. The convergent synthesis has been applied to the synthesis of several analogs, which have facilitated the first structure-activity relationship study for this environmental toxin that, on ingestion, recapitulates the phenotype of biliary atresia.

Chemically Linked Vemurafenib Inhibitors Promote an Inactive BRAF Conformation.

The BRAF kinase, within the mitogen activated protein kinase (MAPK) signaling pathway, harbors activating mutations in about half of melanomas and to a significant extent in many other cancers. A single valine to glutamic acid substitution at residue 600 (BRAF) accounts for about 90% of these activating mutations. While BRAF-selective small molecule inhibitors, such as debrafenib and vemurafenib, have shown therapeutic benefit, almost all patients develop resistance.