Glycosylation Improves the Proteolytic Stability of Exenatide.

Exenatide was the first marketed GLP-1 receptor agonist for the treatment of type 2 diabetes. Modification to the chemical structure or the formulation has the potential to increase the stability of exenatide. We introduced human complex-type sialyloligosaccharide to exenatide at the native Asn28 position. The synthesis was achieved using both solid phase peptide synthesis (SPPS) and Omniligase-1-mediated chemoenzymatic ligation. The results demonstrate that glycosylation increases the proteolytic stability of exenatide while retaining its full biological activity.

A randomised, double-blind, placebo-controlled phase 3 study of lenabasum in diffuse cutaneous systemic sclerosis: RESOLVE-1 design and rationale.

OBJECTIVES: The multi-systemic, heterogenous nature of diffuse cutaneous systemic sclerosis (dcSSc) presents challenges in designing clinical studies that can demonstrate a treatment effect on overall disease burden. We describe the design of the first Phase 3 study in dcSSc patients where the American College of Rheumatology (ACR) Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score was chosen prospectively as the primary outcome. The CRISS measures key clinical disease parameters and patient-reported outcomes (PROs). METHODS: RESOLVE-1 is a Phase 3, randomised, double-blind, placebo-controlled trial of dcSSc patients evaluating the efficacy and safety of lenabasum. Patients ≥18 years of age with dc-SSc and disease duration ≤6 years were eligible. Patients could continue stable background therapy for dcSSc, including stable immunosuppressive therapies. They were randomised to lenabasum 5 or 20 mg twice daily or placebo. The primary efficacy outcome was the mean change from baseline to 52 weeks in the ACR CRISS score. RESULTS: The study enrolled 365 patients over 1.5 years at 77 sites in 13 countries in North America, Europe, Israel, and Asia-Pacific, with the last patient first visit on May 1, 2019. CONCLUSIONS: RESOLVE-1 is the first Phase 3 interventional study to date in dcSSc to prospectively use the ACR CRISS as the primary efficacy outcome. Eligibility criteria allowed background therapy as might occur in clinical practice. This approach also facilitated timely patient enrolment. RESOLVE-1 provides a novel study design that may be used for future Phase 3 dcSSc studies to assess the holistic efficacy of therapy.

African American Nurses Describe Experiences of Mistrust and Trust While in Nursing School.

AIM: This qualitative descriptive study is a secondary analysis of previously collected data to describe the consequences of the racial experiences of nursing school for African American students. BACKGROUND: African Americans' health outcomes are negatively influenced by racism and historic oppression. A racially integrated health care workforce can improve health outcomes, yet nursing does not attract or retain an adequate number of African American students. METHOD: The sample for this qualitative descriptive study included 14 African American nurses who reflected on their nursing school experiences. RESULTS: Two key paradoxical themes across the transcripts were mistrust and trust of European American faculty members. CONCLUSION: While working to build trusting relationships with African American students, forge relationships over time, and serve as mentors, faculty members need to understand the impact of societal stereotypes and mistrustful behaviors (e.g., stereotyping, saying one thing and doing another, using a double standard).

Teenage Childbearing, Reproductive Justice, and Infant Mental Health.

Reproductive justice advocates emphasize the rights of women to choose to have children, to decide the conditions under which they give birth, and to parent their children with support, safety, and dignity. This article examines what a reproductive justice perspective contributes to infant mental health work with teenage mothers and their families. It explores the historical framing of teenage pregnancy in which young mothers are the cause of a variety of social problems and in which the primary policy and practice approach is pregnancy prevention. The article offers alternative framings of teenage childbearing, based on reproductive justice principles, which focus on social conditions surrounding teenage parenthood and the meaning of motherhood in the lives of young women. These alternative frames shift the practice agenda to eradicating unjust social conditions and providing supports for young women in their roles as parents. The article then describes ways in which two infant mental health programs have incorporated reproductive justice principles into their work with young families: Chicago's community doula model and Florida's Young Parents Project for court-involved teenage parents. Finally, the article extracts a set of principles deriving from a reproductive justice perspective that are relevant to infant mental health work with young families.

Los defensores de la justicia reproductiva enfatizan los derechos de la mujer de escoger tener niños, decidir las condiciones bajo las cuales dan a luz, y criar sus niños con apoyo, seguridad y dignidad. Este ensayo examina lo que una perspectiva de justicia reproductiva contribuye al trabajo de salud mental infantil con madres adolescentes y sus familias. El ensayo explora el marco histórico del embarazo adolescente en el que las jóvenes mamás son la causa de una variedad de problemas sociales y para el que el principal acercamiento de la política y práctica es la prevención del embarazo. El estudio ofrece alternativas para enmarcar la maternidad adolescente, con base en los principios de la justicia reproductiva, la cual se enfoca en las condiciones sociales que rodean la maternidad adolescente y el significado de maternidad en la vida de las mujeres jóvenes. Estos marcos alternativos cambian la agenda práctica a erradicar las condiciones sociales injustas y proveer apoyo a las mujeres jóvenes en su papel de madres. El estudio describe a continuación maneras por medio de las cuales dos programas de salud mental infantil han incorporado principios de justicia reproductiva en su trabajo con familias jóvenes: el modelo comunitario de Chicago de mujeres que acompañan y ayudan durante el embarazo (Doulas) y el Proyecto de Madres Jóvenes de Florida para progenitores adolescentes involucrados en asuntos legales. Finalmente, el ensayo extrae una serie de principios que se derivan de una perspectiva de justicia reproductiva que son relevantes para el trabajo de salud mental infantil con familias jóvenes.

Les avocats de la justice reproductive mettent l'accent sur les droits des femmes à choisir d'avoir des enfants, à décider des conditions dans lesquelles elles vont donner naissance, et à parenter leurs enfants avec soutien, sécurité et dignité. Cet article examine qu'une perspective de justice reproductive contribue au travail de santé mentale du nourrisson avec des mères adolescentes et leurs familles. Nous explorons le contexte historique de la grossesse adolescente qui veut que les jeunes mères soient la cause d'une variété de problèmes sociaux et au sein duquel la politique primaire et la pratique d'approche consistent en prévention de grossesse. Cet article offre des contextes ou des encadrements alternatifs de la grossesse adolescente, basée sur les principes de justice reproductive, mettant l'accent sur les conditions sociales qui entourent le parentage adolescent et la signification de la maternité dans les vies des jeunes femmes. Ces perspectives alternatives déplacent le but de la pratique vers l'éradication de conditions sociales injustes et l'offre de soutien à ces jeunes femmes dans leurs rôles de parents. Nous décrivons ensuite des manières dont deux programmes de santé mentale du nourrisson ont incorporé des principes de justice reproductive dans leur travail avec des jeunes familles: le modèle de doula communautaire de la ville de Chicago aux Etats-Unis et le Projet de Jeunes Parents pour les parents se trouvant dans un tribunal, programme de l'état de Floride aux Etats-Unis. Enfin, nous présentons un ensemble de principles dérivés d'une perspective de justice reproductive qui sont pertinent pour le travail de santé mentale du nourrisson avec les jeunes familles.

Reestablishing a host-affiliate relationship: migratory fish reintroduction increases native mussel recruitment.

Co-extirpation among host-affiliate species is thought to be a leading cause of biodiversity loss worldwide. Freshwater mussels (Unionida) are at risk globally and face many threats to survival, including limited access to viable host fish required to complete their life history. We examine the relationship between the common eastern elliptio mussel (Elliptio complanata) and its migratory host fish the American eel (Anguilla rostrata), whose distribution in the Chesapeake Bay watershed is limited, in part, by dams. We examined population demographics of E. complanata across locations in the Chesapeake Bay watershed, primarily in the Susquehanna River in the absence of American eels, and conducted experimental restocking of eels to assess potential impacts on mussel recruitment. Compared to surveys completed ~20 yr prior, E. complanata could be experiencing declines at several historically abundant sites. These sites also had extremely limited evidence of recruitment. Restoration of host fish improved recruitment, but results were not equivalent between stocking sites, indicating that host reintroduction alone may not be fully effective in reestablishing mussel populations. One site where eels were introduced (Pine Creek, Tioga County, Pennsylvania, USA) experienced an increase from 0 juveniles found during quantitative surveys prior to eel stocking to 151 (21% of individuals collected during quantitative surveys) E. complanata juveniles found four years after stocking. A second site (Buffalo Creek, Union County, Pennsylvania) experienced a more moderate increase from 2 to 7 juveniles found during 2010 and 2014 quantitative surveys, respectively. Continued examination of other potential interacting factors affecting recruitment, including water quality or habitat conditions, is necessary to target favorable sites for successful restoration.

The effects of a multicomponent intervention program on clinical outcomes associated with falls in healthy older adults.

BACKGROUND: Multicomponent intervention programs have been shown to be effective in reducing risk factors associated with falls, but the primary target population of these interventions is often low-functioning older adults. AIMS: The purpose of this study was to investigate the effectiveness of a multicomponent intervention program focusing on balance and muscle strength for independently functioning community-dwelling older adults. METHODS: Fifty-three independently functioning older adults, aged 80.09 ± 6.62 years, participated in a group exercise class (conducted 2 times/week for 8 weeks) emphasizing balance. Outcome measures were balance performance using the Fullerton Advanced Balance (FAB) scale and muscle strength using the Senior Fitness Test (SFT). RESULTS: The intervention improved balance (P < 0.001), and older adults who were classified as having high fall risks based on the FAB scores at pre-testing improved more than older adults who were classified as having low fall risks (P = 0.017). As a result, 22 participants transitioned from a high fall risk group at pre-testing to a low fall risk group at post-testing (P < 0.001). The intervention also enhanced both upper and lower muscle extremity strength based on SFT results (P < 0.001) regardless of participants' classification of fall risk status. CONCLUSIONS AND DISCUSSION: The multicomponent intervention conducted two times per week for 8 weeks was effective in improving balance and enhancing muscle strength of independently functioning older adults. The results underscore the importance of providing fall prevention interventions to healthy older adults, a population often not a target of balance interventions.

An examination of occupation-based, client-centered, evidence-based occupational therapy practices in New Hampshire.

This study surveyed occupational therapy practitioners to gain a better understanding of the nature of occupational therapy practices in the State of New Hampshire. A questionnaire was developed and distributed to a sample of practitioners working in New Hampshire to gather information regarding the extent to which occupation-based, client-centered, evidence-based services were being provided. Results suggested that practitioners highly value these service delivery attributes. However, day-to-day practice decisions regarding evaluation methods, where to conduct intervention sessions, goal writing, and choices of intervention activities suggest a stronger emphasis on the evaluation and remediation of specific performance skill and body function deficits, rather than on client performance of desired occupations. In light of the findings, the discrepancy between practitioner values and daily clinical practices is discussed, along with the challenges inherent in providing authentic, evidence-based occupational therapy.

Engineering of a Biologically Active Glycosylated Glucagon-Like Peptide-1 Analogue.

Glucagon-like peptide receptor (GLP-1R) agonists (e.g., semaglutide, liraglutide, etc.) are efficient treatment options for people with type 2 diabetes and obesity. The manufacturing method to produce semaglutide, a blockbuster GLP-1 drug on the market, involves multistep synthesis. The large peptide has a hydrophobic fatty acid side chain that makes it sparingly soluble, and its handling, purification, and large-scale production difficult. The growing demand for semaglutide that the manufacturer is not capable of addressing immediately triggered a worldwide shortage. Thus, we have developed a potential alternative analogue to semaglutide by replacing the hydrophobic fatty acid with a hydrophilic human complex-type biantennary oligosaccharide. Our novel glycoGLP-1 analogue was isolated in an ∼10-fold higher yield compared with semaglutide. Importantly, our glycoGLP-1 analogue possessed a similar GLP-1R activation potency to semaglutide and was biologically active in vivo in reducing glucose levels to a similar degree as semaglutide.

Nurses Christian Fellowship International: Partners in Care.

The Nurses Christian Fellowship International Quadrennial Conference was held November 5-10, 2012, in Santiago, Chile. The theme, "Partners in Care: Unity in diversity through Christ" brought together nurses from all over the world for Bible teaching, education, networking, and fellowship. Plenary and session abstracts are available as supplemental digital content through the HTML and PDF versions of this article at journalofchristiannursing.com.

Validation of Cutaneous Dermatomyositis Disease Area and Severity Index Activity Score and Other Efficacy Outcomes as Measures of Skin Disease in Dermatomyositis in the Lenabasum Phase 3 Trial.

In the past decade, there have been six industry-sponsored phase 3 trials in adult patients with dermatomyositis (DM), primarily focusing on improving muscle weakness. However, skin disease is a cardinal manifestation of DM. This study evaluated the sensitivity of Cutaneous Dermatomyositis Disease Area and Severity Index Activity score, Cutaneous Dermatomyositis Activity Investigator Global Assessment, Total Improvement Score, and other outcome measures used in DM clinical trials to detect improvement in DM skin disease activity. Data analyzed from the lenabasum phase 3 trial in DM showed that improvement in Cutaneous Dermatomyositis Disease Area and Severity Index Activity score increased proportionately with the degree of patient- or physician-reported improvement in skin disease, consistently measuring improvement when clinically meaningful improvement was reported at weeks 16-52. In contrast, Cutaneous Dermatomyositis Activity Investigator Global Assessment measured little change from baseline with reported no improvement in skin disease but also a similar change from baseline with slight improvement. No Skindex-29+3 subscale performed well at reflecting increasing degrees of improvement in skin disease. Extramuscular Global Assessment and Total Improvement Score generally showed increasing levels of improvement as the degree of patient- and physician-reported improvement in skin disease increased, but these are composite measures and are not specific to improvement in DM skin disease. To measure clinically meaningful improvement in skin disease in a DM trial, Cutaneous Dermatomyositis Disease Area and Severity Index Activity score is the more sensitive outcome measure across time points.

Total Chemical Synthesis of Palmitoyl-Conjugated Insulin.

Commercially available insulins are manufactured by recombinant methods for the treatment of diabetes. Long-acting insulin drugs (e.g., detemir and degludec) are obtained by fatty acid conjugation at LysB29 ε-amine of insulin via acid-amide coupling. There are three amine groups in insulin, and they all react with fatty acids in alkaline conditions. Due to the lack of selectivity, such conjugation reactions produce non-desired byproducts. We designed and chemically synthesized a novel thiol-insulin scaffold (CysB29-insulin II), by replacing the LysB29 residue in insulin with the CysB29 residue. Then, we conjugated a fatty acid moiety (palmitic acid, C16) to CysB29-insulin II by a highly efficient and selective thiol-maleimide conjugation reaction. We obtained the target peptide (palmitoyl-insulin) rapidly within 5 min without significant byproducts. The palmitoyl-insulin is shown to be structurally similar to insulin and biologically active both in vitro and in vivo. Importantly, unlike native insulin, palmitoyl-insulin is slow and long-acting.

Efficacy and Safety of Lenabasum, a Cannabinoid Type 2 Receptor Agonist, in a Phase 3 Randomized Trial in Diffuse Cutaneous Systemic Sclerosis.

OBJECTIVE: This phase 3 study was undertaken to investigate the efficacy and safety of lenabasum, a cannabinoid type 2 receptor agonist, in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: A multinational double-blind study was conducted in 365 dcSSc patients who were randomized and dosed 1:1:1 with lenabasum 20 mg, lenabasum 5 mg, or placebo, each twice daily and added to background treatments, including immunosuppressive therapies (IST). RESULTS: The primary end point, the American College of Rheumatology combined response index in dcSSc (CRISS) at week 52 for lenabasum 20 mg twice a day versus placebo, was not met, with CRISS score of 0.888 versus 0.887 (P = 0.4972, using mixed models repeated measures [MMRM]). The change in the modified Rodnan skin thickness score (MRSS) at week 52 for lenabasum 20 mg twice a day versus placebo was -6.7 versus -8.1 (P = 0.1183, using MMRM). Prespecified analyses showed higher CRISS scores, greater improvement in MRSS, and lower decline in forced vital capacity in patients on background mycophenolate and those who were taking IST for ≤1 year. No deaths or excess in serious or severe adverse events related to lenabasum were observed. CONCLUSION: A benefit of lenabasum in dcSSc was not demonstrated. Most patients were treated with background IST, and treatment with mycophenolate mofetil in particular was associated with better outcomes. These findings support the use of IST in the treatment of dcSSc and highlight the challenge of demonstrating a treatment effect when investigational treatment is added to standard of care IST. These findings have relevance to trial design in SSc, as well as to clinical care.

American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials.

OBJECTIVE: Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a definition. METHODS: A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecified analyses from RA clinical trials. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to define remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate definitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analyzed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes. RESULTS: Survey results for the definition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (e.g., tender and swollen joint counts, C-reactive protein [CRP] level, and global assessments on a 0-10 scale). Analyses suggested the need to include a patient-reported measure. Examination of 2-year followup data suggested that many candidate definitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score-based measures of remission did not predict good radiographic outcomes as well as the other candidate definitions did. Given these and other considerations, we propose that a patient's RA can be defined as being in remission based on one of two definitions: (a) when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0-10 scale) are all ≤ 1, or (b) when the score on the Simplified Disease Activity Index is ≤ 3.3. CONCLUSION: We propose two new definitions of remission, both of which can be uniformly applied and widely used in RA clinical trials. We recommend that one of these be selected as an outcome measure in each trial and that the results on both be reported for each trial.

Fine-needle aspiration biopsy of thyroid bed lesions in post-thyroidectomy patients: what is the importance of nondiagnostic biopsy results?

OBJECTIVES: The purpose of this study was to determine the importance of nondiagnostic fine-needle aspiration biopsy results for post-thyroidectomy bed lesions in patients with thyroid cancer. METHODS: The Institutional Review Board approved this retrospective Health Insurance Portability and Accountability Act-compliant study with a waiver for informed consent. Twenty-one patients with nondiagnostic fine-needle aspiration biopsy of a thyroid bed lesion after thyroidectomy with at least 1 year of follow-up with neck imaging were retrospectively enrolled in our study. The tumor type, local staging, radiotherapy, serum thyroglobulin levels, and imaging characteristics of the thyroid bed lesions were recorded. All patients underwent sonographically guided fine-needle aspiration biopsy of the thyroid bed lesion. RESULTS: The mean imaging follow-up ± SD was 46.3 ± 28.7 months. Lesions in 20 patients (95.2%) were stable on imaging. Most thyroid bed lesions were hypoechoic (80.9%), and none showed calcifications. The mean thyroid bed mass maximum diameter was 1.17 ± 0.6 cm (range, 0.3-2.9 cm). CONCLUSIONS: Thyroid bed lesions with nondiagnostic fine-needle aspiration biopsy results after thyroidectomy can be managed with imaging follow-up; 1-year imaging is a reasonable interval after biopsy.

Lenabasum Reduces Porphyromonas gingivalis-Driven Inflammation.

The aim of this study was to evaluate the potential anti-inflammatory and anti-resorptive effects of lenabasum in the context of Porphyromonas gingivalis (Pg)-induced inflammation. Lenabasum or ajulemic acid (1',1'-dimethylheptyl-THC-11-oic-acid), a synthetic analog of THC-11-oic acid, has already demonstrated anti-inflammatory properties for the treatment of several inflammatory diseases. In vitro, the cytocompatibility of lenabasum was evaluated in human oral epithelial cells (EC), oral fibroblasts and osteoblasts by metabolic activity assay. The effect of lenabasum (5 µM) treatment of Pg-LPS- and P. gingivalis-infected EC on the pro- and anti-inflammatory markers was studied through RTqPCR. In vivo, lenabasum was injected subcutaneously in a P. gingivalis-induced calvarial abscess mouse model to assess its pro-healing effect. Concentrations of lenabasum up to 5 µM were cytocompatible in all cell types. Treatment of Pg-LPS and Pg-infected EC with lenabasum (5 µM; 6 h) reduced the gene expression of TNF-α, COX-2, NF-κB, and RANKL, whereas it increased the expression of IL-10 and resolvin E1 receptor respectively (p < 0.05). In vivo, the Pg-elicited inflammatory lesions' clinical size was significantly reduced by lenabasum injection (30 µM) vs untreated controls (45%) (p < 0.05). Histomorphometric analysis exhibited improved quantity and quality of bone (with reduced lacunae) and significantly reduced calvarial soft tissue inflammatory score in mice treated with lenabasum (p < 0.05). Tartrate-resistant acid phosphatase activity assay (TRAP) also demonstrated decreased osteoclastic activity in the treatment group compared to that in the controls. Lenabasum showed promising anti-inflammatory and pro-resolutive properties in the management of Pg-elicited inflammation, and thus, its potential as adjuvant periodontal treatment should be further investigated.

Safety and Efficacy of Lenabasum, a Cannabinoid Receptor Type 2 Agonist, in Patients with Dermatomyositis with Refractory Skin Disease: A Randomized Clinical Trial.

BACKGROUND: Treatment options are limited for skin disease in dermatomyositis. Lenabasum is a cannabinoid receptor type 2 agonist that triggers the resolution of inflammation. OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of lenabasum in patients with refractory cutaneous dermatomyositis. DESIGN: This study was a single-center, double-blind, randomized, placebo-controlled phase 2 study conducted from July 2015 to August 2017. POPULATION: The population included subjects aged ≥18 years with at least moderately active dermatomyositis skin activity by Cutaneous Dermatomyositis Disease Area and Severity Index activity ≥ 14 and failure or intolerance to hydroxychloroquine. INTERVENTION: Participants received 20 mg lenabasum daily for 28 days and then 20 mg twice per day for 56 days or placebo. MAIN OUTCOMES AND MEASURES: The primary outcome was a change in Cutaneous Dermatomyositis Disease Area and Severity Index activity. Safety and other secondary efficacy assessments were performed till day 113. RESULTS: A total of 22 subjects were randomized to lenabasum (n = 11) or placebo (n = 11). No serious or severe adverse events were related to lenabasum, and no participants discontinued the study. The adjusted least-squares mean for Cutaneous Dermatomyositis Disease Area and Severity Index activity decreased more for lenabasum, and the difference was significant on day 113 (least-squares mean [standard error] difference = ‒6.5 [3.1], P = 0.038). Numerically greater improvements were seen in multiple secondary efficacy outcomes and biomarkers with lenabasum. CONCLUSION: Lenabasum treatment was well tolerated and was associated with greater improvement in Cutaneous Dermatomyositis Disease Area and Severity Index activity and multiple efficacy outcomes. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov, NCT02466243.

The AR in bone marrow progenitor cells protects against short-term high-caloric diet-induced weight gain in male mice.

We previously identified a novel pathway of testosterone action via the androgen receptor (AR) in bone marrow mesenchymal precursor cells (BM-PCs) to negatively regulate fat mass and improve metabolic function in male mice. This was achieved using our PC-AR Gene Replacement mouse model in which the AR is only expressed in BM-PCs and deleted in all other tissues. We hypothesise that the markedly reduced fat mass and increased insulin sensitivity of PC-AR Gene Replacements will confer protection from diet-induced overweight and obesity. To test this, 6-week-old male PC-AR Gene Replacements and controls (WT, global-AR knockouts (KOs)) were fed a chow or high-caloric diet (HCD) for 8 or 18 weeks. Following 8 weeks (short-term) of HCD, WT and Global-ARKOs had markedly increased subcutaneous white adipose tissue (WAT) and retroperitoneal visceral adipose tissue (VAT) mass compared to chow-fed controls. In contrast, PC-AR Gene Replacements were resistant to WAT and VAT accumulation following short-term HCD feeding accompanied by fewer large adipocytes and upregulation of expression of the metabolic genes Acaca and Pnlpa2. Following long-term HCD feeding for 18 weeks, the PC-AR Gene Replacements were no longer resistant to increased WAT and VAT adiposity, however, maintained their improved whole-body insulin sensitivity with an increased rate of glucose disappearance and increased glucose uptake into subcutaneous WAT. In conclusion, the action of testosterone via the AR in BM-PCs to negatively regulate fat mass and improve metabolism confers resistance from short-term diet-induced weight gain and partial protection from long-term diet-induced obesity in male mice.

Cannabinoid type 2 receptor (CB2R) distribution in dermatomyositis skin and peripheral blood mononuclear cells (PBMCs) and in vivo effects of LenabasumTM.

BACKGROUND: Lenabasum is a cannabinoid type 2 receptor (CB2R) reverse agonist that demonstrates anti-inflammatory effects in vivo and in vitro in dermatomyositis (DM) and is currently being investigated for therapeutic potential. The purpose of our study is to investigate CB2R distribution as well as the effects of lenabasum in DM. METHODS: Immunohistochemistry staining (IHC) was utilized to examine immune cell and cytokine production changes in lesional DM skin biopsies from lenabasum and placebo-treated patients. CB2R expression in various immune cell populations within DM skin was investigated with image mass cytometry (IMC), whereas flow cytometry elucidated CB2R expression in DM peripheral blood mononuclear cells (PBMCs) as well as cytokine production by CB2R-expressing cell populations. RESULTS: After 12 weeks of lenabasum treatment, IHC staining showed that CD4+ T cells, CB2R, IL-31, IFN-γ, and IFN-ß cytokines were downregulated. IFN-γ and IFN-ß mRNA decreased in lesional DM skin but not in PBMCs. IMC findings revealed that CB2R was upregulated in DM lesional skin compared to HC skin and DM PBMCs (p<0.05). In DM skin, CB2R was upregulated on dendritic cells, B cells, T cells, and macrophages while dendritic cells had the greatest expression in both DM skin and PBMCs (p<0.05). These CB2R+ cells in the skin produce IL-31, IL-4, IFN-γ, and IFN-ß. CONCLUSION: Our findings of differential CB2R expression based on location and cell type suggest modes by which lenabasum may exert anti-inflammatory effects in DM and highlights dendritic cells as potential therapeutic targets.

Bentracimab for Ticagrelor Reversal in Patients Undergoing Urgent Surgery.

BACKGROUND: Ticagrelor is a reversible oral P2Y12 platelet inhibitor used to treat patients with acute coronary syndromes, prior myocardial infarction, high-risk coronary artery disease, transient ischemic attack, or ischemic stroke. A healthy volunteer study showed that the intravenous monoclonal antibody bentracimab rapidly reverses ticagrelor, but the effect in patients was unknown. METHODS: In a prespecified interim analysis of a single-arm, prospective study, bentracimab was evaluated in ticagrelor-treated patients who required urgent surgery or had major hemorrhage. The extent of reversal was determined using the VerifyNow P2Y12 assay. Clinical hemostasis was assessed by central adjudication using validated criteria. Treatment-emergent safety events were evaluated. The trial is ongoing and will enroll approximately 200 patients with evaluable data. RESULTS: Of 150 enrolled patients, 142 required urgent surgery and 8 had major hemorrhage. For the end-point analysis, 129 patients had analyzable platelet data; 122 had data on adjudicated hemostasis. Bentracimab provided a rapid reversal of ticagrelor's antiplatelet effects within 5 to 10 minutes. The reversal was sustained for more than 24 hours, as measured with the VerifyNow P2Y12 and vasodilator-stimulated phosphoprotein phosphorylation assays (P<0.001, with both assays and in all subgroups). Adjudicated hemostasis was achieved for more than 90% of patients (P<0.001); approximately 5% of patients had thrombotic events. No allergic or infusion-related reactions were reported. CONCLUSIONS: Bentracimab provided immediate and sustained reversal of the antiplatelet effects of ticagrelor in patients undergoing surgical procedures. (Funded by PhaseBio Pharmaceuticals, Inc.; ClinicalTrials.gov number, NCT04286438.)

Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I, first-in-human study.

OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profiles of mavrilimumab, a human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor-α, in subjects with rheumatoid arthritis (RA). METHODS: A randomised, double-blind, placebo-controlled, dose-escalating phase I study in subjects with RA who received stable methotrexate treatment for ≥3 months before enrolment. SUBJECTS: received single intravenous escalating doses of mavrilimumab (0.01-10.0 mg/kg) or placebo. RESULTS: 32 subjects were enrolled in this study (1 unblinded subject at 0.01 mg/kg and another at 0.03 mg/kg were followed by five sequential double-blinded cohorts, n=6 each, treated with 0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg, respectively). Adverse events were mild or moderate and were reported with similar frequency across all treatment cohorts. One subject (10.0 mg/kg) experienced moderate face and neck urticaria during infusion that resolved with symptomatic treatment. Systemic clearance of mavrilimumab approached that of endogenous IgG at doses >1.0 mg/kg; pharmacodynamic activity was confirmed in the 1.0 and 3.0 mg/kg cohorts by suppression of suppressor of cytokine signalling 3 mRNA transcripts. In exploratory analyses, reductions of acute phase reactants were observed in subjects with elevated C-reactive protein (>5 mg/l) and erythrocyte sedimentation rate (≥20.0 mm/h) at baseline. No significant change in Disease Activity Score 28-joint assessment (DAS28) was seen in any of the cohorts. In mavrilimumab-treated subjects (n=15) with baseline DAS28 >3.2, mean disease activity (DAS28) was significantly reduced at 4 weeks. CONCLUSION: In this first-in-human study, mavrilimumab showed preliminary evidence of pharmacodynamic activity. Importantly, the safety and pharmacokinetic profiles of mavrilimumab support further clinical studies in RA. TRIAL REGISTRATION NUMBER: NCT00771420.