Abstract
BACKGROUND Alcohol use disorder has a detrimental impact on global health and new treatment targets are needed. Preclinical studies show attenuating effects of glucagon-like peptide-1 (GLP-1) agonists on addiction-related behaviors in rodents and nonhuman primates. Some trials have shown an effect of GLP-1 agonism on reward processes in humans; however, results from clinical studies remain inconclusive.METHODS This is a predefined secondary analysis of a double-blind, randomized, placebo-controlled trial evaluating the GLP-1 agonist dulaglutide as a therapy for smoking cessation. The main objective was to assess differences in alcohol consumption after 12 weeks of treatment with dulaglutide compared to placebo. The effect of dulaglutide on alcohol consumption was analyzed using a multivariable generalized linear model.RESULTS In the primary analysis, participants out of the cohort (n = 255) who reported drinking alcohol at baseline and who completed 12 weeks of treatment (n = 151; placebo n = 75, dulaglutide n = 76) were included. The median age was 42 (IQR 33–53) with 61% (n = 92) females. At week 12, participants receiving dulaglutide drank 29% less (relative effect = 0.71, 95% CI 0.52–0.97, P = 0.04) than participants receiving placebo. Changes in alcohol consumption were not correlated with smoking status at week 12.CONCLUSION These results provide evidence that dulaglutide reduces alcohol intake in humans and contribute to the growing body of literature promoting the use of GLP-1 agonists in treatment of substance use disorders.TRIAL REGISTRATION ClinicalTrials.gov NCT03204396.FUNDING Swiss National Foundation, Gottfried Julia Bangerter-Rhyner Foundation, Goldschmidt-Jacobson Foundation, Hemmi Foundation, University of Basel, University Hospital Basel, Swiss Academy of Medical Science.
Authors
Leila Probst, Sophie Monnerat, Deborah R. Vogt, Sophia Lengsfeld, Thilo Burkard, Andrea Meienberg, Cemile Bathelt, Mirjam Christ-Crain, Bettina Winzeler
Abstract
BACKGROUND Kaposi sarcoma (KS) is among the most common childhood cancers in Eastern and Central Africa. Pediatric KS has a distinctive clinical presentation compared with adult KS, which includes a tendency for primary lymph node involvement, a considerable proportion of patients lacking cutaneous lesions, and a potential for fulminant disease. The molecular mechanisms or correlates for these disease features are unknown.METHODS This was a cross-sectional study. All cases were confirmed by IHC for KS-associated herpesvirus (KSHV) LANA protein. Baseline blood samples were profiled for HIV and KSHV genome copy numbers by qPCR and secreted cytokines by ELISA. Biopsies were characterized for viral and human transcription, and KSHV genomes were determined when possible.RESULTS Seventy participants with pediatric KS were enrolled between June 2013 and August 2019 in Malawi and compared with adult patients with KS. They exhibited high KSHV genome copy numbers and IL-6/IL-10 levels. Four biopsies (16%) had a viral transcription pattern consistent with lytic viral replication.CONCLUSION The unique features of pediatric KS may contribute to the specific clinical manifestations and may direct future treatment options.FUNDING US National Institutes of Health U54-CA-254569, PO1-CA019014, U54-CA254564, RO1-CA23958.
Authors
Carolina Caro-Vegas, Alice Peng, Angelica Juarez, Allison Silverstein, William Kamiyango, Jimmy Villiera, Casey L. McAtee, Rizine Mzikamanda, Tamiwe Tomoka, Erin C. Peckham-Gregory, Razia Moorad, Carrie L. Kovarik, Liane R. Campbell, Parth S. Mehta, Peter N. Kazembe, Carl E. Allen, Michael E. Scheurer, Nmazuo W. Ozuah, Dirk P. Dittmer, Nader Kim El-Mallawany
Abstract
BACKGROUND Slow-flow vascular malformations frequently harbor activating mutations in the PI3K/AKT/mTOR cascade. Phase II trials pinpointed sirolimus effectiveness as a drug therapy. Efficacy and safety of sirolimus thus need to be evaluated in large prospective phase III trials.METHODS The Vascular Anomaly-Sirolimus-Europe (VASE) trial, initiated in 2016, is a large multicentric prospective phase III trial (EudraCT 2015-001703-32), which evaluates efficacy and safety of sirolimus for 2 years in pediatric and adult patients with symptomatic slow-flow vascular malformations. In this interim analysis, we studied all patients enrolled up to October 2021 who received sirolimus for 12 or more months or who prematurely stopped the treatment.RESULTS Thirty-one pediatric and 101 adult patients were included in this analysis; 107 completed 12 or more months of sirolimus, including 61 who were treated for the whole 2-year period. Sirolimus resulted in a clinical improvement in 85% of patients. The efficacy appeared within the first month for the majority of them. Grade 3–4 adverse events were observed in 24 (18%) patients; all resolved after treatment interruption/arrest. Sirolimus increased feasibility of surgery or sclerotherapy in 20 (15%) patients initially deemed unsuitable for intervention. Among the 61 patients who completed the 2-year treatment, 33 (54%) reported a recurrence of symptoms after a median follow-up of 13 months after sirolimus arrest. While there was no difference in efficacy, clinical improvement was faster but subsided more rapidly in PIK3CA-mutated (n = 24) compared with TIE2-mutated (n = 19) patients.CONCLUSION Sirolimus has a high efficacy and good tolerance in treatment of slow-flow vascular malformations in children and adults.TRIAL REGISTRATION ClinicalTrials.gov NCT02638389 and EudraCT 2015-001703-32.FUNDING The Fonds de la Recherche Scientifique (FNRS grants T.0247.19, P.C005.22, T.0146.16, and P.C013.20), the Fund Generet managed by the King Baudouin Foundation (grant 2018-J1810250-211305), the Walloon Region through the FRFS-WELBIO strategic research programme (WELBIO-CR-2019C-06), the MSCA-ITN network V.A. Cure no. 814316, the Leducq Foundation Networks of Excellence Program grant “ReVAMP” (LFCR grant 21CVD03), the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 874708 (Theralymph), the Swiss National Science Foundation under the Sinergia project no. CRSII5_193694, and a Pierre M. fellowship.
Authors
Emmanuel Seront, An Van Damme, Catherine Legrand, Annouk Bisdorff-Bresson, Philippe Orcel, Thomas Funck-Brentano, Marie-Antoinette Sevestre, Anne Dompmartin, Isabelle Quere, Pascal Brouillard, Nicole Revencu, Martina De Bortoli, Frank Hammer, Philippe Clapuyt, Dana Dumitriu, Miikka Vikkula, Laurence M. Boon
Abstract
BACKGROUND. Although 25-hydroxyvitamin D (25(OH)D) concentrations ≥30ng/mL are known to reduce injury risk and boost strength, the influence on anterior cruciate ligament reconstruction (ACLR) outcomes remains unexamined. This study aimed to define the vitamin D signaling response to ACLR, assess the relationship between vitamin D status and muscle fiber cross-sectional area (CSA) and bone density outcomes, and discover vitamin D receptor (VDR) targets post-ACLR. METHODS. 21 young, healthy, physically active participants with recent ACL tears were enrolled (17.8 ± 3.2 yr, BMI: 26.0 ± 3.5 kg/m2). Data were collected through blood samples, vastus lateralis biopsies, DXA bone density measurements, and isokinetic dynamometer measures at baseline, 1 week, 4 months, and 6 months post-ACLR. The biopsies facilitated CSA, western blot, RNA-seq, and VDR ChIP-seq analyses. RESULTS. ACLR surgery led to decreased circulating bioactive vitamin D and increased VDR and activating enzyme expression in skeletal muscle one week post-operation. Participants with < 30 ng/mL 25(OH)D levels (n = 13) displayed more significant quadriceps fiber CSA loss one week and 4 months post-ACLR than those with ≥30 ng/mL (n = 8; P < 0.01 for post-hoc comparisons; P = 0.041 for time x vitamin D status interaction). RNA-seq and ChIP-seq data integration revealed genes associated with energy metabolism and skeletal muscle recovery, potentially mediating the impact of vitamin D status on ACLR recovery. No difference in bone mineral density (BMD) losses between groups was observed. CONCLUSION. Correcting vitamin D status prior to ACLR may aid in preserving skeletal muscle during recovery.
Authors
Yuan Wen, Christine M. Latham, Angelique N. Moore, Nicholas T. Thomas, Brooke D. Lancaster, Kelsey A. Reeves, Alexander R. Keeble, Christopher S. Fry, Darren L. Johnson, Katherine L. Thompson, Brian Noehren, Jean L. Fry
Abstract
Background: Cardiorenal syndrome (CRS)—renal injury during heart failure (HF)—is linked to higher morbidity. Whether circulating extracellular vesicles (EVs) and their RNA cargo directly impact its pathogenesis remains unclear. Methods: We investigated the role of circulating EVs from patients with CRS on renal epithelial/endothelial cells using a microfluidic kidney-on-chip model (KOC). The small RNA cargo of circulating EVs was regressed against serum creatinine to prioritize subsets of functionally relevant EV miRNAs and their mRNA targets investigated using in silico pathway analysis, human genetics, and interrogation of expression in the KOC model and in renal tissue. The functional effects of EV-RNAs on kidney epithelial cells were experimentally validated.Results: Renal epithelial and endothelial cells in the KOC model exhibited uptake of EVs from HF patients. HF-CRS EVs led to higher expression of renal injury markers (IL18, LCN2, HAVCR1) relative to non-CRS EVs. 15 EV-miRNAs were associated with creatinine, targeting 1143 gene targets specifying pathways relevant to renal injury, including TGF beta and AMPK signaling. We observed directionally consistent changes in the expression of TGF beta pathway members (BMP6, FST, TIMP3) in the KOC model exposed to CRS EVs, which were validated in epithelial cells treated with corresponding inhibitors and mimics of miRNAs. A similar trend was observed in renal tissue with kidney injury. Mendelian randomization suggested a role for FST in renal function. Conclusion: Plasma EVs in CRS patients elicit adverse transcriptional and phenotypic responses in a KOC model by regulating biologically relevant pathways, suggesting a role for EVs in CRS.
Authors
Emeli Chatterjee, Rodosthenis S. Rodosthenous, Ville J. Kujala, Priyanka Gokulnath, Michail Spanos, H. Immo Lehmann, Getulio P de Oliveira-Jr, Mingjian Shi, Tyne W. Miller-Fleming, Guoping Li, Ionita Ghiran, Katia Karalis, JoAnn Lindenfeld, Jonathan D. Mosley, Emily S. Lau, Jennifer E. Ho, Quanhu Sheng, Ravi Shah, Saumya Das
Abstract
BACKGROUND. Oxidized ApoB (oxLDL) and other oxidation-modified lipoproteins (OMLs), such as oxidized ApoA-I (oxHDL), are known pro-atherogenic factors. However, OMLs prognostic value for assessing high-risk coronary plaques by coronary computed tomography angiography (CCTA) has not been fully evaluated. METHODS. In a prospective, observational study, 306 participants with known cardiovascular disease (CVD) had extensive lipoprotein profiling, including plasma OMLs and HDL function measured. Proteomics analysis was performed on oxHDL isolated by anti-oxApoA-I antibody. Atherosclerotic plaque assessment was accomplished by quantitative CCTA (QAngio, Medis). RESULTS. Patients were predominantly white, overweight males (58.5%) on statin therapy (43.5%). Significant increases in LDL-C, ApoB, LDL-TG, sdLDL-C (P<0.001 for all), and TGs (P=0.03) were observed in high oxLDL group, accompanied by less efficient HDL function. High oxLDL was associated with necrotic (NB) (β=0.20; P<0.0001) and fibro-fatty (FFB) burdens (β=0.15; P=0.001) after multivariate adjustment. Low oxHDL had a significant reverse association with these plaque characteristics. Plasma oxHDL levels better predicted NB and FFB after adjustment (2.22, 1.27-3.88 and 2.80, 1.71-4.58) (ORs, 95% CIs) compared to oxLDL and HDL-C. Interestingly, oxHDL was associated with fibrous burden (FB) change over 3.3 years of follow-up (rho=0.535; P=0.033), when compared to oxLDL. Finally, combined Met(136) monooxidation and Trp(132) dioxidation of HDL showed the most evident association with CAC score (r=0.786; P<0.001) and FB (r=0.539; P=0.012) in high oxHDL, whereas Met(136) monooxidation significantly associated with high-risk plaque in low oxHDL. CONCLUSION. Our findings suggest that the investigated OMLs are associated with high-risk coronary plaque features and progression over time in CVD patients. TRIAL REGISTRATION. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01621594. FUNDING. This work was supported by the National Heart, Lung and Blood Institute (NHLBI) at the National Institutes of Health Intramural Research Program. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Authors
Alexander V. Sorokin, Christin G. Hong, Angel M. Aponte, Elizabeth M. Florida, Jingrong Tang, Nidhi Patel, Irina N. Baranova, Haiou Li, Philip M. Parel, Vicky Chen, Sierra R. Wilson, Emily L. Ongstad, Anna Collén, Martin P. Playford, Thomas L. Eggerman, Marcus Y. Chen, Kazuhiko Kotani, Alexander V. Bocharov, Alan T. Remaley
Abstract
BACKGROUND. The locus coeruleus (LC) is the primary source of norepinephrine in the brain and regulates arousal and sleep. Animal research shows that it plays important roles in the transition between sleep and wakefulness, and between slow wave sleep and rapid eye movement sleep (REMS). It is unclear, however, whether the activity of the LC predicts sleep variability in humans. METHODS. We used 7 Tesla functional Magnetic Resonance Imaging, sleep electroencephalography (EEG) and a sleep questionnaire to test whether the LC activity during wakefulness was associated with sleep quality in 33 healthy younger (~22y; 28 women) and 19 older (~61y; 14 women) individuals. RESULTS. We found that, in older, but not in younger participants, higher LC activity, as probed during an auditory attentional task, was associated with worse subjective sleep quality and with lower power over the EEG theta band during REMS. The results remained robust even when accounting for the age-related changes in the integrity of the LC. CONCLUSION. These findings suggest that LC activity correlates with the perception of the sleep quality and an essential oscillatory mode of REMS, and that the LC may be an important target in the treatment of sleep and age-related diseases. FUNDING. This work was supported by Fonds National de la Recherche Scientifique (FRS-FNRS, T.0242.19 & J. 0222.20). Action de Recherche Concertée – Fédération Wallonie-Bruxelles (ARC SLEEPDEM 17/27-09), Fondation Recherche Alzheimer (SAO-FRA 2019/0025), University of Liège, European Regional Development Fund (Radiomed & Biomed-Hub).
Authors
Ekaterina Koshmanova, Alexandre Berger, Elise Beckers, Islay Campbell, Nasrin Mortazavi, Roya Sharifpour, Ilenia Paparella, Fermin Balda, Christian Berthomier, Christian Degueldre, Eric Salmon, Laurent Lamalle, Christine Bastin, Maxime Van Egroo, Christophe Phillips, Pierre Maquet, Fabienne Collette, Vincenzo Muto, Daphne Chylinski, Heidi I.L. Jacobs, Puneet Talwar, Siya Sherif, Gilles Vandewalle
Abstract
BACKGROUND While B cell depletion is associated with attenuated antibody responses to SARS-CoV-2 mRNA vaccination, responses vary among individuals. Thus, elucidating the factors that affect immune responses after repeated vaccination is an important clinical need.METHODS We evaluated the quality and magnitude of the T cell, B cell, antibody, and cytokine responses to a third dose of BNT162b2 or mRNA-1273 mRNA vaccine in patients with B cell depletion.RESULTS In contrast with control individuals (n = 10), most patients on anti-CD20 therapy (n = 48) did not demonstrate an increase in spike-specific B cells or antibodies after a third dose of vaccine. A third vaccine elicited significantly increased frequencies of spike-specific non-naive T cells. A small subset of B cell–depleted individuals effectively produced spike-specific antibodies, and logistic regression models identified time since last anti-CD20 treatment and lower cumulative exposure to anti-CD20 mAbs as predictors of those having a serologic response. B cell–depleted patients who mounted an antibody response to 3 vaccine doses had persistent humoral immunity 6 months later.CONCLUSION These results demonstrate that serial vaccination strategies can be effective for a subset of B cell–depleted patients.FUNDING The NIH (R25 NS079193, P01 AI073748, U24 AI11867, R01 AI22220, UM 1HG009390, P01 AI039671, P50 CA121974, R01 CA227473, U01CA260507, 75N93019C00065, K24 AG042489), NIH HIPC Consortium (U19 AI089992), the National Multiple Sclerosis Society (CA 1061-A-18, RG-1802-30153), the Nancy Taylor Foundation for Chronic Diseases, Erase MS, and the Claude D. Pepper Older Americans Independence Center at Yale (P30 AG21342).
Authors
Hiromitsu Asashima, Dongjoo Kim, Kaicheng Wang, Nikhil Lele, Nicholas C. Buitrago-Pocasangre, Rachel Lutz, Isabella Cruz, Khadir Raddassi, William E. Ruff, Michael K. Racke, JoDell E. Wilson, Tara S. Givens, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Steven H. Kleinstein, Ruth R. Montgomery, Albert C. Shaw, Fangyong Li, Rong Fan, David A. Hafler, Mary M. Tomayko, Erin E. Longbrake
Abstract
BACKGROUND. Severe forms of idiopathic nephrotic syndrome require prolonged immune-suppressive therapies and repeated courses of high-dose glucocorticoids. Mesenchymal stromal cells (MSCs) have promising immunomodulatory properties that may be employed therapeutically to reduce patient exposure to medications and their side effects. METHODS. We performed a phase 1 open-label trial assessing safety and feasibility of autologous bone marrow-derived (BM) MESenchymal stromal cells in children and young adults with severe forms of steroid-dependent NEPHrotic syndrome, (MESNEPH). Following autologous BM-MSC preparation and infusion, oral immunosuppression was tapered. Safety, efficacy and immunomodulatory effects in vivo were monitored for 12 months. RESULTS. Sixteen patients (10 children, 6 adults) were treated. Adverse events were limited and not related to BM-MSC infusions. All patients relapsed during follow-up, but in the 10 treated children, time to first relapse was delayed (p=0.02) and number of relapses was reduced (p=0.002) after BM-MSC infusion, compared to the previous 12 months. Cumulative prednisone dose was also reduced at 12 months compared to baseline (p<0.05). No treatment benefit was observed in adults. In children, despite tapering of immunosuppression, clinical benefit was mirrored by a significant reduction of total CD19+, mature and memory B cells and an increase of regulatory T cells in vivo up to 3-6 months following BM-MSC infusion. CONCLUSION. Treatment with autologous BM-MSC is feasible and safely reduces relapses and immunosuppression at 12 months in children with severe steroid-dependent INS. Immunomodulatory studies suggest that repeating MSC infusions at 3-6 months may sustain benefit. TRIAL REGISTRATION. EudraCT 2016-004804-77 FUNDING. AIFA Ricerca Indipendente 2016-02364623
Authors
Marina Vivarelli, Manuela Colucci, Mattia Algeri, Federica Zotta, Francesco Emma, Ines L'Erario, Marco Busutti, Stefano Rota, Chiara Capelli, Martino Introna, Marta Todeschini, Federica Casiraghi, Annalisa Perna, Tobia Peracchi, Andrea De Salvo, Nadia Rubis, Franco Locatelli, Giuseppe Remuzzi, Piero Ruggenenti
Abstract
Low-dose anti-thymocyte globulin (ATG) transiently preserves C-peptide and lowers HbA1c in individuals with recent-onset type 1 diabetes (T1D); however, the mechanisms of action and features of response remain unclear. Here, we characterized the post-hoc immunological outcomes of ATG administration and their potential use as biomarkers of metabolic response to therapy (i.e., improved preservation of endogenous insulin production). We assessed gene and protein expression, targeted gene methylation, and cytokine concentrations in peripheral blood following treatment with ATG (n=29), ATG plus granulocyte-colony stimulating factor (ATG/G-CSF, n=28), or placebo (n=31). Treatment with low-dose ATG preserved regulatory T cells (Tregs), as measured by stable methylation of FOXP3 Treg-specific demethylation region (TSDR) and increased proportions of CD4+FOXP3+ Tregs (p<0.001) identified by flow cytometry. While treatment effects were consistent across participants, not all maintained C-peptide. Responders exhibited a transient rise in IL-6, IP-10, and TNFα (p<0.05 for all) 2 weeks post-treatment and a durable CD4 exhaustion phenotype (increased PD-1+KLRG1+CD57- on CD4+ T cells [p=0.011] and PD1+CD4 TEMRA MFI [p<0.001] at 12 weeks, following ATG and ATG/G-CSF, respectively). ATG non-responders displayed higher proportions of senescent T cells (at baseline and post-treatment) and increased methylation of EOMES (i.e., less expression of this exhaustion marker). Altogether in these exploratory analyses, Th1 inflammation-associated serum, CD4 exhaustion transcript and cellular phenotyping profiles may be useful for identifying signatures of clinical response to ATG in T1D.
Authors
Laura M. Jacobsen, Kirsten Diggins, Lori Blanchfield, James A. McNichols, Daniel J. Perry, Jason Brant, Xiaoru Dong, Rhonda Bacher, Vivian H. Gersuk, Desmond A. Schatz, Mark A. Atkinson, Clayton E. Mathews, Michael J. Haller, S. Alice Long, Peter S. Linsley, Todd M. Brusko
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