BACKGROUND. The induction of beige adipocytes in s.c. white adipose tissue (WAT) depots of humans is postulated to improve glucose and lipid metabolism in obesity. The ability of obese, insulin-resistant humans to induce beige adipose tissue is unknown. METHODS. We exposed lean and obese research participants to cold (30-minute ice pack application each day for 10 days of the upper thigh) or treated them with the β3 agonist mirabegron. We determined beige adipose marker expression by IHC and quantitative PCR, and we analyzed mitochondrial bioenergetics and UCP activity with an Oxytherm system. RESULTS. Cold significantly induced UCP1 and TMEM26 protein in both lean and obese subjects, and this response was not associated with age. Interestingly, these proteins increased to the same extent in s.c. WAT of the noniced contralateral leg, indicating a crossover effect. We further analyzed the bioenergetics of purified mitochondria from the abdominal s.c. WAT of cold-treated subjects and determined that repeat ice application significantly increased uncoupled respiration, consistent with the UCP1 protein induction and subsequent activation. Cold also increased State 3 and maximal respiration, and this effect on mitochondrial bioenergetics was stronger in summer than winter. Chronic treatment (10 weeks; 50 mg/day) with the β3 receptor agonist mirabegron induces UCP1, TMEM26, CIDEA, and phosphorylation of HSL on serine660 in obese subjects. CONCLUSION. Cold or β3 agonists cause the induction of beige adipose tissue in human s.c. WAT; this phenomenon may be exploited to increase beige adipose in older, insulin-resistant, obese individuals. TRIAL REGISTRATION. Clinicaltrials.gov NCT02596776, NCT02919176. FUNDING. NIH (DK107646, DK112282, P20GM103527, and by CTSA grant UL1TR001998).
Brian S. Finlin, Hasiyet Memetimin, Amy L. Confides, Ildiko Kasza, Beibei Zhu, Hemendra J. Vekaria, Brianna Harfmann, Kelly A. Jones, Zachary R. Johnson, Philip M. Westgate, Caroline M. Alexander, Patrick G. Sullivan, Esther E. Dupont-Versteegden, Philip A. Kern
To what extent does the subarachnoid cerebrospinal fluid (CSF) compartment communicate directly with the extravascular compartment of human brain tissue? Interconnection between the subarachnoid CSF compartment and brain perivascular spaces is reported in some animal studies, but with controversy, and in vivo CSF tracer studies in humans are lacking. In the present work, we examined the distribution of a CSF tracer in the human brain by MRI over a prolonged time span. For this, we included a reference cohort, representing close to healthy individuals, and a cohort of patients with dementia and anticipated compromise of CSF circulation (idiopathic normal pressure hydrocephalus). The MRI contrast agent gadobutrol, which is confined to the extravascular brain compartment by the intact blood-brain barrier, was used as a CSF tracer. Standardized T1-weighted MRI scans were performed before and after intrathecal gadobutrol at defined time points, including at 24 hours, 48 hours, and 4 weeks. All MRI scans were aligned and brain regions were segmented using FreeSurfer, and changes in normalized T1 signals over time were quantified as percentage change from baseline. The study provides in vivo evidence of access to all human brain subregions of a substance administered intrathecally. Clearance of the tracer substance was delayed in the dementia cohort. These observations translate previous findings in animal studies into humans and open new prospects concerning intrathecal treatment regimens, extravascular contrast-enhanced MRI, and assessment of brain clearance function.
Geir Ringstad, Lars M. Valnes, Anders M. Dale, Are H. Pripp, Svein-Are S. Vatnehol, Kyrre E. Emblem, Kent-Andre Mardal, Per K. Eide
BACKGROUND. The red cell distribution width (RDW) is associated with health outcomes. Whether non-RDW risk information is contained in RBC sizes is unknown. This study evaluated the association of the percentage of extreme macrocytic RBCs (%Macro, RBC volume > 120 fl) and microcytic RBCs (%Micro, RBC volume < 60 fl) and the RDW–size distribution (RDW-sd) with mortality and morbidity. METHODS. Patients (females, n = 165,770; males, n = 100,210) at Intermountain Healthcare were studied if they had a hematology panel between May 2014 and September 2016. Adjusted sex-specific associations of %Macro/%Micro and RDW-sd with mortality and 33 morbidities were evaluated. RESULTS. Among females with fourth-quartile values of %Macro quartile and %Micro (referred to throughout as 4/4), there was an average of 7.2 morbidities versus 2.9 in the lowest risk (LR1) categories, 1/1, 1/2, 2/1, and 2/2 (P < 0.001). Among males, those in the 4/4 category had 8.0 morbidities, while those in the LR1 had 3.4 (P < 0.001). Cox regressions found %Macro/%Micro (4/4 vs. LR1, females: hazard ratio [HR] = 1.97 [95% CI = 1.53, 2.54]; males: HR = 2.17 [CI = 1.72, 2.73]), RDW-sd (quartile 4 vs. 1, females: HR = 1.33 [CI = 1.04, 1.69]; males: HR = 1.41 [CI = 1.10, 1.80]), and RDW (quartile 4 vs. 1, females: HR = 1.59 [CI = 1.26, 2.00]; males: HR = 1.23 [CI = 0.99, 1.52]) independently predicted mortality. Limitations include that the observational design did not reveal causality and unknown confounders may be unmeasured. CONCLUSIONS. Concomitantly elevated %Macro and %Micro predicted the highest mortality risk and the greatest number of morbidities, revealing predictive ability of RBC volume beyond what is measured clinically. Mechanistic investigations are needed to explain the biological basis of these observations. FUNDING. This study was supported by internal Intermountain Heart Institute funds and in-kind support from Sysmex America Inc.
Benjamin D. Horne, Joseph B. Muhlestein, Sterling T. Bennett, Joseph Boone Muhlestein, Kurt R. Jensen, Diane Marshall, Tami L. Bair, Heidi T. May, John F. Carlquist, Matthew Hegewald, Stacey Knight, Viet T. Le, T. Jared Bunch, Donald L. Lappé, Jeffrey L. Anderson, Kirk U. Knowlton
BACKGROUND. Human papillomavirus–related (HPV-related) oropharyngeal squamous cell carcinomas (OPSCCs) have an excellent response rate to platinum-based chemoradiotherapy. Genomic differences between primary HPV-related OPSCCs that do or do not recur are unknown. Furthermore, it is unclear if HPV-related OPSCCs that recur share a genomic landscape with HPV-negative head and neck cancers (HNCs). METHODS. We utilized whole exome sequencing to analyze somatic nucleotide (SNVs) and copy number variants (CNVs) among a unique set of 51 primary HPV-related OPSCCs, including 35 that did not recur and 16 that recurred. We evaluated 12 metachronous recurrent OPSCCs (7 with paired primary OPSCCs) and 33 primary HPV-unrelated oral cavity and OPSCCs. RESULTS.KMT2D was the most frequently mutated gene among primary HPV-related OPSCCs (n = 51; 14%) and among metachronous recurrent OPSCCs (n = 12; 42%). Primary HPV-related OPSCCs that recurred shared a genomic landscape with primary HPV-related OPSCCs that did not recur. However, TSC2, BRIP1, NBN, and NFE2L2 mutations occurred in primary OPSCCs that recurred but not in those that did not recur. Moreover, primary HPV-related OPSCCs that recur harbor features of HPV-unrelated HNCs, notably including MAPK, JAK/STAT, and differentiation signaling pathway aberrations. Metachronous recurrent OPSCCs shared a genomic landscape with HPV-unrelated HNCs, including a high frequency of TP53, CASP8, FAT1, HLA-A, AJUBA, and NSD1 genomic alterations. CONCLUSION. Overall, primary HPV-related OPSCCs that recur share a genomic landscape with nonrecurrent OPSCCs. Metachronous recurrent OPSCCs share genomic features with HPV-negative HNCs. These data aim to guide future deescalation endeavors and functional experiments. FUNDING. This study is supported by the American Cancer Society (RSG TBG-123653), funding support for RAH (T32DC00018, Research Training in Otolaryngology, University of Washington), funds to EM from Seattle Translational Tumor Research (Fred Hutchinson Cancer Research Center), and center funds from the Fred Hutchinson Cancer Research Center to EM. UD is supported by the Department of Veterans Affairs, Biomedical Laboratory Research and Development (BLR&D), grant IO1-oo23456, and funds from the Pittsburgh Foundation and PNC Foundation.
R. Alex Harbison, Mark Kubik, Eric Q. Konnick, Qing Zhang, Seok-Geun Lee, Heuijoon Park, Jianan Zhang, Christopher S. Carlson, Chu Chen, Stephen M. Schwartz, Cristina P. Rodriguez, Umamaheswar Duvvuri, Eduardo Méndez
BACKGROUND. Immune checkpoint inhibitors provide significant clinical benefit to a subset of patients, but novel prognostic markers are needed to predict which patients will respond. This study was initiated to determine if features of patient T cell repertoires could provide insights into the mechanisms of immunotherapy, while also predicting outcomes. METHODS. We examined T cell receptor (TCR) repertoires in peripheral blood of 25 metastatic pancreatic cancer patients treated with ipilimumab with or without GVAX (a pancreatic cancer vaccine), as well as peripheral blood and tumor biopsies from 32 patients treated with GVAX and mesothelin-expressing Listeria monocytogenes with or without nivolumab. Statistics from these repertoires were then tested for their association with clinical response and treatment group. RESULTS. We demonstrate that, first, the majority of patients receiving these treatments experience a net diversification of their peripheral TCR repertoires. Second, patients receiving ipilimumab experienced larger changes in their repertoires, especially in combination with GVAX. Finally, both a low baseline clonality and a high number of expanded clones following treatment were associated with significantly longer survival in patients who received ipilimumab but not in patients receiving nivolumab. CONCLUSIONS. We show that these therapies have measurably different effects on the peripheral repertoire, consistent with their mechanisms of action, and demonstrate the potential for TCR repertoire profiling to serve as a biomarker of clinical response in pancreatic cancer patients receiving immunotherapy. In addition, our results suggest testing sequential administration of anti–CTLA-4 and anti–PD-1 antibodies to achieve optimal therapeutic benefit. TRIAL REGISTRATION. Samples used in this study were collected from the NCT00836407 and NCT02243371 clinical trials. FUNDING. Research supported by a Stand Up To Cancer Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research grant (SU2C-AACR-DT14-14). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research (AACR). Additional clinical trial funding was provided by AACR-Pancreatic Cancer Action Network Research Acceleration Network grant (14-90-25-LE), NCI SPORE in GI Cancer (CA062924), Quick-Trials for Novel Cancer Therapies: Exploratory Grants (R21CA126058-01A2), and the US Food and Drug Administration (R01FD004819). Research collaboration and financial support were provided by Adaptive Biotechnologies.
Alexander C. Hopkins, Mark Yarchoan, Jennifer N. Durham, Erik C. Yusko, Julie A. Rytlewski, Harlan S. Robins, Daniel A. Laheru, Dung T. Le, Eric R. Lutz, Elizabeth M. Jaffee
BACKGROUND. The prevalence of chronic kidney disease (CKD) is increasing worldwide. The identification of factors contributing to its progression is important for designing preventive measures. Previous studies have suggested that chronically high vasopressin is deleterious to renal function. Here, we evaluated the association of plasma copeptin, a surrogate of vasopressin, with the incidence of CKD in the general population. METHODS. We studied 3 European cohorts: DESIR (n = 5,047; France), MDCS-CC (n = 3,643; Sweden), and PREVEND (n = 7,684; the Netherlands). Median follow-up was 8.5, 16.5, and 11.3 years, respectively. Pooled data were analyzed at an individual level for 4 endpoints during follow-up: incidence of stage 3 CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m2); the KDIGO criterion “certain drop in eGFR”; rapid kidney function decline (eGFR slope steeper than –3 ml/min/1.73 m2/yr); and incidence of microalbuminuria. RESULTS. The upper tertile of plasma copeptin was significantly and independently associated with a 49% higher risk for stage 3 CKD (P < 0.0001); a 64% higher risk for kidney function decline, as defined by the KDIGO criterion (P < 0.0001); a 79% higher risk for rapid kidney function decline (P < 0.0001); and a 24% higher risk for microalbuminuria (P = 0.008). CONCLUSIONS. High copeptin levels are associated with the development and the progression of CKD in the general population. Intervention studies are needed to assess the potential beneficial effect on kidney health in the general population of reducing vasopressin secretion or action. FUNDING. INSERM and Danone Research Centre for Specialized Nutrition.
Ray El Boustany, Irina Tasevska, Esther Meijer, Lyanne M. Kieneker, Sofia Enhörning, Guillaume Lefèvre, Kamel Mohammedi, Michel Marre, Frédéric Fumeron, Beverley Balkau, Nadine Bouby, Lise Bankir, Stephan J.L. Bakker, Ronan Roussel, Olle Melander, Ron T. Gansevoort, Gilberto Velho
BACKGROUND. Noroviruses are the leading cause of epidemic acute gastroenteritis and foodborne diarrheal disease in humans. However, there are no approved vaccines for noroviruses. Potential correlates of protection identified through human challenge studies include mucosal IgA, memory B cells, and serum-blocking antibody titers (BT50). METHODS. We conducted a single-site, randomized, double-blind, placebo-controlled clinical trial of an oral norovirus vaccine to determine safety and immunogenicity. This tablet vaccine is comprised of a nonreplicating adenovirus-based vector expressing the VP1 gene from the GI.1 norovirus strain and a double-stranded RNA adjuvant. Sixty-six adult subjects meeting inclusion/exclusion criteria were randomized 2:1 to receive a single vaccine dose or placebo, respectively. Immunogenicity was primarily assessed by serum BT50. Additional outcomes included serum ELISA titers, fecal and saliva antibody titers, memory and antibody-secreting cell (ASC) frequency, and B cell phenotyping. RESULTS. The vaccine was well-tolerated, with no dose-limiting toxicities. Adverse events were mild or moderate. The primary immunological endpoint (increase in BT50 titers) was met in the high-dose group (P = 0.0003), with 78% showing a ≥2-fold rise in titers after a single immunization. Vaccine recipients also developed mucosally primed VP1-specific circulating ASCs, IgA+ memory B cells expressing gut-homing receptor (α4β7), and fecal IgA, indicating substantial and local responses potentially relevant to prevent norovirus infection. CONCLUSION. This oral norovirus vaccine was well-tolerated and generated substantial immune responses, including systemic and mucosal antibodies as well as memory IgA/IgG. These results are a major step forward for the development of a safe and immunogenic oral norovirus vaccine. TRIAL REGISTRATION. ClinicalTrials.gov NCT02868073. FUNDING. Vaxart.
Leesun Kim, David Liebowitz, Karen Lin, Kassandra Kasparek, Marcela F. Pasetti, Shaily J. Garg, Keith Gottlieb, George Trager, Sean N. Tucker
BACKGROUND. Necroptosis is a form of programmed necrotic cell death that is rapidly emerging as an important pathophysiological pathway in numerous disease states. Necroptosis is dependent on receptor-interacting protein kinase 3 (RIPK3), a protein shown to play an important role in experimental models of critical illness. However, there is limited clinical evidence regarding the role of extracellular RIPK3 in human critical illness. METHODS. Plasma RIPK3 levels were measured in 953 patients prospectively enrolled in 5 ongoing intensive care unit (ICU) cohorts in both the USA and Korea. RIPK3 concentrations among groups were compared using prospectively collected phenotypic and outcomes data. RESULTS. In all 5 cohorts, extracellular RIPK3 levels in the plasma were higher in patients who died in the hospital compared with those who survived to discharge. In a combined analysis, increasing RIPK3 levels were associated with elevated odds of in-hospital mortality (odds ratio [OR] 1.7 for each log10-unit increase in RIPK3 level, P < 0.0001). When adjusted for baseline severity of illness, the OR for in-hospital mortality remained statistically significant (OR 1.33, P = 0.007). Higher RIPK3 levels were also associated with more severe organ failure. CONCLUSIONS. Our findings suggest that elevated levels of RIPK3 in the plasma of patients admitted to the ICU are associated with in-hospital mortality and organ failure. FUNDING. Supported by NIH grants P01 HL108801, R01 HL079904, R01 HL055330, R01 HL060234, K99 HL125899, and KL2TR000458-10. Supported by Samsung Medical Center grant SMX1161431.
Kevin C. Ma, Edward J. Schenck, Ilias I. Siempos, Suzanne M. Cloonan, Eli J. Finkelzstein, Maria A. Pabon, Clara Oromendia, Karla V. Ballman, Rebecca M. Baron, Laura E. Fredenburgh, Angelica Higuera, Jin Young Lee, Chi Ryang Chung, Kyeongman Jeon, Jeong Hoon Yang, Judie A. Howrylak, Jin-Won Huh, Gee Young Suh, Augustine M.K. Choi
BACKGROUND. Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder of life-threatening hyperphagia, obesity, intellectual deficits, compulsivity, and other behavioral problems. The efficacy and safety of i.n. carbetocin, an oxytocin analog, was evaluated in a prospective, randomized, double-blinded trial in adolescents with PWS. METHODS. Eligible patients aged 10–18 years with genetically confirmed PWS were randomized (1:1) to i.n. carbetocin or placebo 3 times daily for 14 days. The primary efficacy endpoint was change in parent/caregiver-rated Hyperphagia in PWS Questionnaire–Responsiveness (HPWSQ-R) total score. Secondary efficacy endpoints included HPWSQ-R behavior, drive, and severity domains; clinician-rated HPWSQ; Children’s Yale-Brown Obsessive-Compulsive Severity Scale; food domain of the Reiss Profile; and Clinical Global Impression–Improvement scale. Endpoints were assessed using analysis of covariance. Relationship between primary and secondary endpoints was assessed using Pearson correlation coefficients. Safety was assessed throughout the study. RESULTS. Demographics and clinical characteristics were similar between treatment groups (carbetocin, n = 17; placebo, n = 20). Patients receiving carbetocin had statistically significant reductions in HPWSQ-R total score at study end (–15.6) versus patients receiving placebo (–8.9; P = 0.029); several secondary efficacy endpoints also demonstrated significant differences (P < 0.05). Treatment effects for the primary and secondary endpoints were highly correlated (P ≤ 0.0001). Incidence of adverse events (AEs) was similar between treatment groups. CONCLUSION. I.n. carbetocin was well tolerated and improved hyperphagia and behavioral symptoms of PWS. TRIAL REGISTRATION. ClinicalTrials.gov: NCT01968187 FUNDING. The study was funded by Ferring Pharmaceuticals. Recruitment was aided by ongoing work in PWS performed through Eunice Kennedy Shriver National Institute of Child Health and Human Development grant U54 HD083211.
Elisabeth M. Dykens, Jennifer Miller, Moris Angulo, Elizabeth Roof, Michael Reidy, Hind T. Hatoum, Richard Willey, Guy Bolton, Paul Korner
BACKGROUND. Heat shock protein peptide complex-96 (HSPPC-96) triggers adaptive and innate antitumor immune responses. The safety and efficacy of HSPPC-96 vaccination was examined in patients with newly diagnosed glioblastoma multiforme (GBM). METHODS. In this open-label, single-arm, phase I study, adult patients were vaccinated with HSPPC-96 in combination with the standard treatment for newly diagnosed GBM after surgical resection. Primary endpoints were frequency of adverse events and progression-free survival (PFS) at 6 months. Secondary endpoints included overall survival (OS), PFS, and tumor-specific immune response (TSIR). RESULTS. A total of 20 patients with newly diagnosed GBM were enrolled from September 2013 to February 2015. No grade 3 or 4 vaccine-related adverse events were noted. After a median follow-up of 42.3 months, PFS was 89.5% (95% CI, 66.9%–98.7%) at 6 months, median PFS was 11.0 months (95% CI, 8.2–13.8), and median OS was 31.4 months (95% CI, 14.9–47.9). TSIR was significantly increased by 2.3-fold (95% CI, 1.7–3.2) after vaccination. Median OS for patients with high TSIR after vaccination was >40.5 months (95% CI, incalculable) as compared with 14.6 months (95% CI, 7.0–22.2) for patients with low TSIR after vaccination (hazard ratio, 0.25; 95% CI, 0.071–0.90; P = 0.034). A multivariate Cox regression model revealed TSIR after vaccination as a primary independent predicator for survival. CONCLUSION. The HSPPC-96 vaccination, combined with the standard therapy, is a safe and effective strategy for treatment of newly diagnosed GBM patients. TSIR after vaccination would be a good indicator predicting the vaccine efficacy. TRIAL REGISTRATION. ClinicalTrials.gov NCT02122822. FUNDING. National Key Technology Research and Development Program of the Ministry of Science and Technology of China (2014BAI04B01, 2014BAI04B02), Beijing Natural Science Foundation (7164253), Beijing Talents Fund (2014000021469G257), and Shenzhen Science and Technology Innovation Committee (JSGG20170413151359491).
Nan Ji, Yang Zhang, Yunpeng Liu, Jian Xie, Yi Wang, Shuyu Hao, Zhixian Gao
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