Identification and biophysical characterization of a novel domain-swapped camelid antibody specific for fentanyl.

Opioid use disorders (OUD) and overdoses are ever-evolving public health threats that continue to grow in incidence and prevalence in the United States and abroad. Current treatments consist of opioid receptor agonists and antagonists, which are safe and effective but still suffer from some limitations. Murine and humanized monoclonal antibodies (mAb) have emerged as an alternative and complementary strategy to reverse and prevent opioid-induced respiratory depression.

Development of an Engineered Single-Domain Antibody for Targeting MET in Non-Small Cell Lung Cancer.

The Mesenchymal Epithelial Transition (MET) receptor tyrosine kinase is upregulated or mutated in 5% of non-small-cell lung cancer (NSCLC) patients and overexpressed in multiple other cancers. We sought to develop a novel single-domain camelid antibody with high affinity for MET that could be used to deliver conjugated payloads to MET expressing cancers. From a naïve camelid variable-heavy-heavy (VHH) domain phage display library, we identified a VHH clone termed 1E7 that displayed high affinity for human MET and was cross-reactive with MET across multiple species.

Childhood Adversity Among Adults With Chronic Pain: Prevalence and Association With Pain-related Outcomes.

Objectives: Adverse childhood experiences (ACEs) have been linked to the development and impact of chronic pain in adulthood. The goal of this study was to investigate the prevalence of ACEs in a treatment-seeking sample of adults with chronic pain and the relationship between number and type(s) of ACEs and pain-related outcomes.

Methods: Adults (N=1794) presenting for treatment at a multidisciplinary pain management center completed self-report measures of childhood adversity, pain, functioning, emotional distress, and adjustment to pain.

Mediators of change in depressed mood following pain rehabilitation among participants with mild, moderate, or severe depressive symptoms.

Background: Prior research indicates that depression and chronic pain commonly co-exist and impact each other. Interdisciplinary pain rehabilitation programs (IPRPs) have been shown to lead to statistically and clinically significant improvements for patients who report both depressed mood and chronic pain, however there is a gap in the literature regarding the mechanisms by which these improvements occur.

Methods: This two-site, distinct sample study (Study 1: N = 303, 10-week, individual format, ACT-based program; Study 2: N = 406, 3-week, group format, CBT-based program) evaluated mediators of treatment improvement in depressive symptoms among adult IPRP participants who reported elevated depressive symptoms at program admission and examined treatment mechanisms for depressive symptoms.

Sex differences in interdisciplinary pain rehabilitation outcomes: a systematic review.

Objectives: Interdisciplinary pain rehabilitation programs (IPRPs) are evidence-based treatments for chronic pain. Previous research has demonstrated that initial presentations of adult men and women admitted to IPRPs differ, but less is known about sex differences in IPRP treatment outcomes. To summarize and synthesize the current literature base on this topic, a systematic literature review was conducted that asked: are sex differences present in participant outcomes upon completion of interdisciplinary pain rehabilitation programs for cisgender patients? Four core domains of outcome measures were assessed: depression, pain catastrophizing, pain interference, and pain intensity/severity.

Mechanisms of SARS-CoV-2 neutralization by shark variable new antigen receptors elucidated through X-ray crystallography.

Single-domain Variable New Antigen Receptors (VNARs) from the immune system of sharks are the smallest naturally occurring binding domains found in nature. Possessing flexible paratopes that can recognize protein motifs inaccessible to classical antibodies, VNARs have yet to be exploited for the development of SARS-CoV-2 therapeutics. Here, we detail the identification of a series of VNARs from a VNAR phage display library screened against the SARS-CoV-2 receptor binding domain (RBD).

Patients with Clinically Elevated Depressive Symptoms Report Improvements in Mood, Pain, and Functioning Following Participation in Interdisciplinary Pain Rehabilitation.

Objective: Chronic pain and depression frequently co-occur and exacerbate one another; therefore, it is important to treat both conditions to improve patient outcomes. The current study evaluates an interdisciplinary pain rehabilitation program (IPRP) with respect to the following questions: 1) How do clinically elevated depressive symptoms impact pain-related treatment outcomes? and 2) To what extent does IPRP participation yield reliable and clinically significant change in depressed mood?

Methods: Participants in this study included 425 adults who engaged in a 10-week IPRP and completed self-report measures of pain, mood, and functioning at intake and discharge. Participants were categorized into 4 groups based on self-reported depressive symptoms (PROMIS Depression): within normal limits (WNL; n = 121), Mild (n = 115), Moderate (n = 153), and Severe (n = 36).

Adverse Childhood Experiences and Chronic Pain Rehabilitation Treatment Outcomes in Adults.

Objectives: Adverse childhood experiences (ACEs) are commonly reported by individuals with chronic pain. However, little is known about how ACE exposure influences treatment outcomes. The goal of the current study was to evaluate group and treatment-related differences among adults with varying levels of ACE exposure participating in a pain rehabilitation treatment program.

Partner Abuse Among Treatment-Seeking Individuals with Chronic Pain: Prevalence, Characteristics, and Association with Pain-Related Outcomes.

Objective: This study assessed the prevalence of abusive partner relationships among individuals presenting for chronic pain treatment. In addition, this study examined the association between partner abuse histories and pain-relevant outcome variables.

Design: Cross-sectional.

Treatment Outcomes and Mechanisms for an ACT-Based 10-Week Interdisciplinary Chronic Pain Rehabilitation Program.

Background: Interdisciplinary pain rehabilitation programs are an evidence-based biopsychosocial treatment approach for chronic pain. The purpose of the current study is to assess outcomes for a 10-week interdisciplinary, acceptance and commitment therapy (ACT)-based, outpatient treatment model and to evaluate the relationship between psychological process variables (ie, pain catastrophizing, pain acceptance, pain self-efficacy) and treatment outcomes.

Methods: 137 adults with chronic pain completed an interdisciplinary pain rehabilitation program.

Quantitative conformational profiling of kinase inhibitors reveals origins of selectivity for Aurora kinase activation states.

Protein kinases undergo large-scale structural changes that tightly regulate function and control recognition by small-molecule inhibitors. Methods for quantifying the conformational effects of inhibitors and linking them to an understanding of selectivity patterns have long been elusive. We have developed an ultrafast time-resolved fluorescence methodology that tracks structural movements of the kinase activation loop in solution with angstrom-level precision, and can resolve multiple structural states and quantify conformational shifts between states.

A dynamic mechanism for allosteric activation of Aurora kinase A by activation loop phosphorylation.

Many eukaryotic protein kinases are activated by phosphorylation on a specific conserved residue in the regulatory activation loop, a post-translational modification thought to stabilize the active DFG-In state of the catalytic domain. Here we use a battery of spectroscopic methods that track different catalytic elements of the kinase domain to show that the ~100 fold activation of the mitotic kinase Aurora A (AurA) by phosphorylation occurs without a population shift from the DFG-Out to the DFG-In state, and that the activation loop of the activated kinase remains highly dynamic. Instead, molecular dynamics simulations and electron paramagnetic resonance experiments show that phosphorylation triggers a switch within the DFG-In subpopulation from an autoinhibited DFG-In substate to an active DFG-In substate, leading to catalytic activation.