183 A phase 1B/2A trial of tofacitinib, an oral janus kinase inhibitor, in systemic lupus erythematosus

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Real-time predictors and consequences of binge eating among adults with type 1 diabetes

Abstract Background Objective binge eating (OBE) is common among individuals with type 1 diabetes (T1D) and may have negative consequences for glycemic control. Recent studies have suggested that diabetes distress (i.e., emotional distress specific to diabetes and living with the burden of management) is a distinct emotional experience among individuals with diabetes. Preliminary studies have found diabetes distress is associated with eating disorder symptoms and poor glycemic control. The aim of the current study was to examine real-time emotional precursors and consequences of OBE in adults with T1D (i.e., general negative affect, specific emotional states and diabetes distress) using ecological momentary assessment methods. We also explore the impact of OBE on 2-h postprandial glycemic control relative to non-OBE eating episodes. Methods Adults with T1D (N = 83) completed 3-days of ecological momentary assessment assessing mood and eating behavior using a telephone-based survey system. Participants were prompted to rate momentary affect, including level diabetes distress, at random intervals and reported on eating episodes. Participants also wore continuous glucose monitors allowing for ongoing assessment of glycemic control. Multi-level modeling was used to examine between- and within-person effects of momentary increases in emotions prior to eating on the likelihood of OBE and the impact of OBE on postprandial blood glucose. Generalized linear mixed models examined whether change in post-meal affect differed between OBE and non-OBE episodes. Results Participants were predominately middle-aged (Mean = 42; SD = 12.43) Caucasian (87%) females (88%) reporting clinically significant eating disorder symptoms (76%). Nearly half of the sample (43%) reported OBE during the 3-day study period. The between-person effect for negative affect was significant (OR = 1.93, p < .05), indicating a 93% increased risk of OBE among individuals with higher negative affect compared to individuals with average negative affect. Between-person effects were also significant for guilt, frustration and diabetes distress (OR = 1.48–1.77, ps < .05). Analyses indicated that mean change in post-meal negative affect was significantly greater for OBE relative to non-OBE episodes (B = 0.44, p < .001). Blood glucose at 120 min postprandial was also higher for OBE than for non-OBE episodes (p = .03). Conclusions Findings indicate that individuals who tend to experience negative affect and diabetes distress before eating are at increased risk of OBE at the upcoming meal. Results also suggest that engaging in binge eating may result in greater subsequent negative affect, including diabetes distress, and lead to elevated postprandial blood glucose levels. These findings add to a growing literature suggesting diabetes distress is related to eating disordered behaviors among individuals with T1D

Small-Molecule Natural Product Physachenolide C Potentiates Immunotherapy Efficacy by Targeting BET Proteins

Screening for sensitizers of cancer cells to TRAIL-mediated apoptosis identified a natural product of the 17β-hydroxywithanolide (17-BHW) class, physachenolide C (PCC), as a promising hit. In this study, we show that PCC was also able to sensitize melanoma and renal carcinoma cells to apoptosis in response not only to TRAIL, but also to the synthetic polynucleotide poly I:C, a viral mimetic and immune activator, by reducing levels of antiapoptotic proteins cFLIP and Livin. Both death receptor and TLR3 signaling elicited subsequent increased assembly of a proapoptotic ripoptosome signaling complex. Administration of a combination of PCC and poly I:C in human M14 melanoma xenograft and a syngeneic B16 melanoma model provided significant therapeutic benefit as compared with individual agents. In addition, PCC enhanced melanoma cell death in response to activated human T cells in vitro and in vivo in a death ligand-dependent manner. Biochemical mechanism-of-action studies established bromo and extraterminal domain (BET) proteins as major cellular targets of PCC. Thus, by targeting of BET proteins to reduce antiapoptotic proteins and enhance caspase-8-dependent apoptosis of cancer cells, PCC represents a unique agent that can potentially be used in combination with various immunotherapeutic approaches to promote tumor regression and improve outcome. SIGNIFICANCE: These findings demonstrate that PCC selectively sensitizes cancer cells to immune-mediated cell death, potentially improving the efficacy of cancer immunotherapies.12 month embargo; published first 09 April 2021This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus

Increased risk of premature cardiovascular disease in systemic lupus erythematosus (SLE) is not well understood, but in animal models, the Janus kinase inhibitor tofacitinib improves related phenotypes. Here the authors report a Phase 1 double-blind randomized trial that shows tofacitinib is safe and well tolerated in in patients with SLE

Safety and immunogenicity of a variant-adapted SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant as a booster in adults primed with authorized vaccines: a phase 3, parallel-group studyResearch in context

Summary: Background: In a parallel-group, international, phase 3 study (ClinicalTrials.gov NCT04762680), we evaluated prototype (D614) and Beta (B.1.351) variant recombinant spike protein booster vaccines with AS03-adjuvant (CoV2 preS dTM-AS03). Methods: Adults, previously primed with mRNA (BNT162b2, mRNA-1273), adenovirus-vectored (Ad26.CoV2.S, ChAdOx1nCoV-19) or protein (CoV2 preS dTM-AS03 [monovalent D614; MV(D614)]) vaccines were enrolled between 29 July 2021 and 22 February 2022. Participants were stratified by age (18–55 and ≥ 56 years) and received one of the following CoV2 preS dTM-AS03 booster formulations: MV(D614) (n = 1285), MV(B.1.351) (n = 707) or bivalent D614 + B.1.351 (BiV; n = 625). Unvaccinated adults who tested negative on a SARS-CoV-2 rapid diagnostic test (control group, n = 479) received two primary doses, 21 days apart, of MV(D614). Anti-D614G and anti-B.1.351 antibodies were evaluated using validated pseudovirus (lentivirus) neutralization (PsVN) assay 14 days post-booster (day [D]15) in 18–55-year-old BNT162b2-primed participants and compared with those pre-booster (D1) and on D36 in 18–55-year-old controls (primary immunogenicity endpoints). PsVN titers to Omicron BA.1, BA.2 and BA.4/5 subvariants were also evaluated. Safety was evaluated over a 12-month follow-up period. Planned interim analyses are presented up to 14 days post-last vaccination for immunogenicity and over a median duration of 5 months for safety. Findings: All three boosters elicited robust anti-D614G or -B.1.351 PsVN responses for mRNA, adenovirus-vectored and protein vaccine-primed groups. Among BNT162b2-primed adults (18–55 years), geometric means of the individual post-booster versus pre-booster titer ratio (95% confidence interval [CI]) were: for MV (D614), 23.37 (18.58–29.38) (anti-D614G); for MV(B.1.351), 35.41 (26.71–46.95) (anti-B.1.351); and for BiV, 14.39 (11.39–18.28) (anti-D614G) and 34.18 (25.84–45.22 (anti-B.1.351). GMT ratios (98.3% CI) versus post-primary vaccination GMTs in controls, were: for MV(D614) booster, 2.16 (1.69; 2.75) [anti-D614G]; for MV(B.1.351), 1.96 (1.54; 2.50) [anti-B.1.351]; and for BiV, 2.34 (1.84; 2.96) [anti-D614G] and 1.39 (1.09; 1.77) [anti-B.1.351]. All booster formulations elicited cross-neutralizing antibodies against Omicron BA.2 (across priming vaccine subgroups), Omicron BA.1 (BNT162b2-primed participants) and Omicron BA.4/5 (BNT162b2-primed participants and MV D614-primed participants). Similar patterns in antibody responses were observed for participants aged ≥56 years. Reactogenicity tended to be transient and mild-to-moderate severity in all booster groups. No safety concerns were identified. Interpretation: CoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine. Funding: Sanofi and Biomedical Advanced Research and Development Authority (BARDA)