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BACKGROUND. Excessive insulin secretion may lead to glucose dysregulation. Our aim was to identify primary (independent of insulin resistance) insulin hypersecretion in subjects with normal glucose tolerance and its role in the progression of dysglycemia. METHODS. In 1,168 adults, insulin secretion rate (ISR) and β cell function were estimated by C-peptide modeling during an oral glucose tolerance test (OGTT) and an i.v. glucose tolerance test. Whole-body insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp. After regressing ISR on insulin sensitivity, subjects in the upper tertile of the distribution of residuals were defined as primary hypersecretors. This approach was applied to a biethnic cohort of 182 obese adolescents, who received an OGTT, a hyperglycemic, and a euglycemic clamp. RESULTS. Adult hypersecretors showed older age, more familial diabetes, sedentary lifestyle, increased fat mass, and worse lipid profile compared with the rest of the cohort, despite virtually identical BMI and insulin sensitivity. Insulin secretion was increased by 53% due to enhanced (+23%) β cell glucose sensitivity. Despite the resulting hyperinsulinemia, glucose tolerance was worse in hypersecretors among both adults and adolescents, coupled with higher indices of liver insulin resistance and increased availability of gluconeogenic substrates. At the 3-year follow-up, adult hypersecretors had increased incidence of impaired glucose tolerance/type 2 diabetes. CONCLUSION. Primary insulin hypersecretion, independent of insulin resistance, is associated with a worse clinical and metabolic phenotype in adults and adolescents and predicts deterioration of glucose control over time. FUNDING. The relationship between insulin sensitivity and cardiovascular disease (RISC) Study was partly supported by EU grant QLG1-CT-2001-01252.
Domenico Tricò, Andrea Natali, Silva Arslanian, Andrea Mari, Ele Ferrannini
Total views: 2649
Visceral fat is considered the genuine and harmful white adipose tissue (WAT) that is associated to development of metabolic disorders, cardiovascular disease, and cancer. Here, we present a new concept to turn the harmful visceral fat into a beneficial energy consumption depot, which is beneficial for improvement of metabolic dysfunctions in obese mice. We show that low temperature–dependent browning of visceral fat caused decreased adipose weight, total body weight, and body mass index, despite increased food intake. In high-fat diet–fed mice, low temperature exposure improved browning of visceral fat, global metabolism via nonshivering thermogenesis, insulin sensitivity, and hepatic steatosis. Genome-wide expression profiling showed upregulation of WAT browning–related genes including
Xiaoyan Yang, Wenhai Sui, Meng Zhang, Mei Dong, Sharon Lim, Takahiro Seki, Ziheng Guo, Carina Fischer, Huixia Lu, Cheng Zhang, Jianmin Yang, Meng Zhang, Yangang Wang, Caixia Cao, Yanyan Gao, Xingguo Zhao, Meili Sun, Yuping Sun, Rujie Zhuang, Nilesh J. Samani, Yun Zhang, Yihai Cao
Total views: 1488
Immunotherapies targeting the PD-1 pathway produce durable responses in many cancers, but the tumor-intrinsic factors governing response and resistance are largely unknown. MHC-II expression on tumor cells can predict response to anti–PD-1 therapy. We therefore sought to determine how MHC-II expression by tumor cells promotes PD-1 dependency. Using transcriptional profiling of anti-PD-1–treated patients, we identified unique patterns of immune activation in MHC-II+ tumors. In patients and preclinical models, MHC-II+ tumors recruited CD4+ T cells and developed dependency on PD-1 as well as Lag-3 (an MHC-II inhibitory receptor), which was upregulated in MHC-II+ tumors at acquired resistance to anti–PD-1. Finally, we identify enhanced expression of FCRL6, another MHC-II receptor expressed on NK and T cells, in the microenvironment of MHC-II+ tumors. We ascribe this to what we believe to be a novel inhibitory function of FCRL6 engagement, identifying it as an immunotherapy target. These data suggest a MHC-II–mediated context-dependent mechanism of adaptive resistance to PD-1-targeting immunotherapy.
Douglas B. Johnson, Mellissa J. Nixon, Yu Wang, Daniel Y. Wang, Emily Castellanos, Monica V. Estrada, Paula I. Ericsson-Gonzalez, Candace H. Cote, Roberto Salgado, Violeta Sanchez, Phillip T. Dean, Susan R. Opalenik, Daniel M. Schreeder, David L. Rimm, Ju Young Kim, Jennifer Bordeaux, Sherene Loi, Leora Horn, Melinda E. Sanders, P. Brent Ferrell Jr., Yaomin Xu, Jeffrey A. Sosman, Randall S. Davis, Justin M. Balko
Total views: 1204
Incidence of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) has been increasing dramatically. Although long-term survival rates for these patients are high, they often suffer from permanent radiotherapy-related morbidity. This has prompted the development of de-escalation clinical protocols to reduce morbidity. However, a subset of patients do not respond even to standard therapy and have poor outcomes. It is unclear how to properly identify and treat the high- and low-risk HPV+ OPSCC patients. Since HPV positivity drives radiotherapy sensitivity, we hypothesized that variations in HPV biology may cause differences in treatment response and outcome. By analyzing gene expression data, we identified variations in HPV-related molecules among HPV+ OPSCC. A subset of tumors presented a molecular profile distinct from that of typical HPV+ tumors and exhibited poor treatment response, indicating molecular and clinical similarities with HPV– tumors. These molecular changes were also observed in vitro and correlated with radiation sensitivity. Finally, we developed a prognostic biomarker signature for identification of this subgroup of HPV+ OPSCC and validated it in independent cohorts of oropharyngeal and cervical carcinomas. These findings could translate to improved patient stratification for treatment deintensification and new therapeutic approaches for treatment-resistant HPV-related cancer.
Frederico O. Gleber-Netto, Xiayu Rao, Theresa Guo, Yuanxin Xi, Meng Gao, Li Shen, Kelly Erikson, Nene N. Kalu, Shuling Ren, Guorong Xu, Kathleen M. Fisch, Keiko Akagi, Tanguy Seiwert, Maura Gillison, Mitchell J. Frederick, Faye M. Johnson, Jing Wang, Jeffrey N. Myers, Joseph Califano, Heath D. Skinner, Curtis R. Pickering
Total views: 1104
In heart failure and type 2 diabetes mellitus (DM), the majority of patients have hypomagnesemia, and magnesium (Mg) supplementation has improved cardiac function and insulin resistance. Recently, we have shown that DM can cause cardiac diastolic dysfunction (DD). Therefore, we hypothesized that Mg supplementation would improve diastolic function in DM. High-fat diet–induced diabetic mouse hearts showed increased cardiac DD and hypertrophy. Mice with DM showed a significantly increased E/e’ ratio (the ratio of transmitral Doppler early filling velocity [E] to tissue Doppler early diastolic mitral annular velocity [e’]) in the echocardiogram, left ventricular end diastolic volume (LVEDV), incidence of DD, left ventricular posterior wall thickness in diastole (PWTd), and ratio of heart weight to tibia length (HW/TL) when compared with controls. DM mice also had hypomagnesemia. Ventricular cardiomyocytes isolated from DM mice exhibited decreased mitochondrial ATP production, a 1.7- ± 0.2-fold increase of mitochondrial ROS, depolarization of the mitochondrial membrane potential, and mitochondrial Ca2+ overload. Dietary Mg administration (50 mg/ml in the drinking water) for 6 weeks increased plasma Mg concentration and improved cardiac function. At the cellular level, Mg improved mitochondrial function with increased ATP, decreased mitochondrial ROS and Ca2+ overload, and repolarized mitochondrial membrane potential. In conclusion, Mg supplementation improved mitochondrial function, reduced oxidative stress, and prevented DD in DM.
Man Liu, Euy-Myoung Jeong, Hong Liu, An Xie, Eui Young So, Guangbin Shi, Go Eun Jeong, Anyu Zhou, Samuel C. Dudley Jr.
Total views: 1031
Adeno-associated virus–mediated (AAV-mediated) CRISPR editing is a revolutionary approach for treating inherited diseases. Sustained, often life-long mutation correction is required for treating these diseases. Unfortunately, this has never been demonstrated with AAV CRISPR therapy. We addressed this question in the mdx model of Duchenne muscular dystrophy (DMD). DMD is caused by dystrophin gene mutation. Dystrophin deficiency leads to ambulation loss and cardiomyopathy. We treated 6-week-old mice intravenously and evaluated disease rescue at 18 months. Surprisingly, nominal dystrophin was restored in skeletal muscle. Cardiac dystrophin was restored, but histology and hemodynamics were not improved. To determine the underlying mechanism, we evaluated components of the CRISPR-editing machinery. Intriguingly, we found disproportional guide RNA (gRNA) vector depletion. To test whether this is responsible for the poor outcome, we increased the gRNA vector dose and repeated the study. This strategy significantly increased dystrophin restoration and reduced fibrosis in all striated muscles at 18 months. Importantly, skeletal muscle function and cardiac hemodynamics were significantly enhanced. Interestingly, we did not see selective depletion of the gRNA vector after intramuscular injection. Our results suggest that gRNA vector loss is a unique barrier for systemic AAV CRISPR therapy. This can be circumvented by vector dose optimization.
Chady H. Hakim, Nalinda B. Wasala, Christopher E. Nelson, Lakmini P. Wasala, Yongping Yue, Jacqueline A. Louderman, Thais B. Lessa, Aihua Dai, Keqing Zhang, Gregory J. Jenkins, Michael E. Nance, Xiufang Pan, Kasun Kodippili, N. Nora Yang, Shi-jie Chen, Charles A. Gersbach, Dongsheng Duan
Total views: 971
BACKGROUND. Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid used in multiple sclerosis and intractable epilepsies. Preclinical studies show CBD has numerous cardiovascular benefits, including a reduced blood pressure (BP) response to stress. The aim of this study was to investigate if CBD reduces BP in humans. METHODS. Nine healthy male volunteers were given 600 mg of CBD or placebo in a randomized, placebo-controlled, double-blind, crossover study. Cardiovascular parameters were monitored using a finometer and laser Doppler. RESULTS. CBD reduced resting systolic BP (–6 mmHg; P < 0.05) and stroke volume (–8 ml; P < 0.05), with increased heart rate (HR) and maintained cardiac output. Subjects who had taken CBD had lower BP (–5 mmHg; P < 0.05, especially before and after stress), increased HR (+10 bpm; P < 0.01), decreased stroke volume (–13 ml; P < 0.01), and a blunted forearm skin blood flow response to isometric exercise. In response to cold stress, subjects who had taken CBD had blunted BP (–6 mmHg; P < 0.01) and increased HR (+7 bpm; P < 0.05), with lower total peripheral resistance. CONCLUSIONS. This data shows that acute administration of CBD reduces resting BP and the BP increase to stress in humans, associated with increased HR. These hemodynamic changes should be considered for people taking CBD. Further research is required to establish whether CBD has a role in the treatment of cardiovascular disorders.
Khalid A. Jadoon, Garry D. Tan, Saoirse E. O’Sullivan
Total views: 887
BACKGROUND. Increasing evidence indicates a role for EBV in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T cell immunity. We sought to determine the feasibility and safety of treating progressive MS patients with autologous EBV-specific T cell therapy. METHODS. An open-label phase I trial was designed to treat 5 patients with secondary progressive MS and 5 patients with primary progressive MS with 4 escalating doses of in vitro–expanded autologous EBV-specific T cells targeting EBV nuclear antigen 1, latent membrane protein 1 (LMP1), and LMP2A. Following adoptive immunotherapy, we monitored the patients for safety and clinical responses. RESULTS. Of the 13 recruited participants, 10 received the full course of T cell therapy. There were no serious adverse events. Seven patients showed improvement, with 6 experiencing both symptomatic and objective neurological improvement, together with a reduction in fatigue, improved quality of life, and, in 3 patients, reduced intrathecal IgG production. All 6 patients receiving T cells with strong EBV reactivity showed clinical improvement, whereas only 1 of the 4 patients receiving T cells with weak EBV reactivity showed improvement (P = 0.033, Fisher’s exact test). CONCLUSION. EBV-specific adoptive T cell therapy was well tolerated. Clinical improvement following treatment was associated with the potency of EBV-specific reactivity of the administered T cells. Further clinical trials are warranted to determine the efficacy of EBV-specific T cell therapy in MS. TRIAL REGISTRATION. Australian New Zealand Clinical Trials Registry, ACTRN12615000422527. FUNDING. MS Queensland, MS Research Australia, Perpetual Trustee Company Ltd., and donations from private individuals who wish to remain anonymous.
Michael P. Pender, Peter A. Csurhes, Corey Smith, Nanette L. Douglas, Michelle A. Neller, Katherine K. Matthews, Leone Beagley, Sweera Rehan, Pauline Crooks, Tracey J. Hopkins, Stefan Blum, Kerryn A. Green, Zara A. Ioannides, Andrew Swayne, Blake T. Aftab, Kaye D. Hooper, Scott R. Burrows, Kate M. Thompson, Alan Coulthard, Rajiv Khanna
Total views: 862
Drug-induced kidney injury, largely caused by proximal tubular intoxicants, limits development and clinical use of new and approved drugs. Assessing preclinical nephrotoxicity relies on animal models that are frequently insensitive; thus, potentially novel techniques — including human microphysiological systems, or “organs on chips” — are proposed to accelerate drug development and predict safety. Polymyxins are potent antibiotics against multidrug-resistant microorganisms; however, clinical use remains restricted because of high risk of nephrotoxicity and limited understanding of toxicological mechanisms. To mitigate risks, structural analogs of polymyxins (NAB739 and NAB741) are currently in clinical development. Using a microphysiological system to model human kidney proximal tubule, we exposed cells to polymyxin B (PMB) and observed significant increases of injury signals, including kidney injury molecule-1 KIM-1and a panel of injury-associated miRNAs (each P < 0.001). Surprisingly, transcriptional profiling identified cholesterol biosynthesis as the primary cellular pathway induced by PMB (P = 1.22 ×10–16), and effluent cholesterol concentrations were significantly increased after exposure (P < 0.01). Additionally, we observed no upregulation of the nuclear factor (erythroid derived-2)–like 2 pathway, despite this being a common pathway upregulated in response to proximal tubule toxicants. In contrast with PMB exposure, minimal changes in gene expression, injury biomarkers, and cholesterol concentrations were observed in response to NAB739 and NAB741. Our findings demonstrate the preclinical safety of NAB739 and NAB741 and reveal cholesterol biosynthesis as a potentially novel pathway for PMB-induced injury. To our knowledge, this is the first demonstration of a human-on-chip platform used for simultaneous safety testing of new chemical entities and defining unique toxicological pathway responses of an FDA-approved molecule.
Elijah J. Weber, Kevin A. Lidberg, Lu Wang, Theo K. Bammler, James W. MacDonald, Mavis J. Li, Michelle Redhair, William M. Atkins, Cecilia Tran, Kelly M. Hines, Josi Herron, Libin Xu, Maria Beatriz Monteiro, Susanne Ramm, Vishal Vaidya, Martti Vaara, Timo Vaara, Jonathan Himmelfarb, Edward J. Kelly
Total views: 729
Tregs are impaired in human systemic lupus erythematosus (SLE) and contribute to effector T cell activation. However, the mechanisms responsible for the Treg deficiency in SLE remain unclear. We hypothesized that the OX40L/OX40 axis is implicated in Treg and regulatory follicular helper T (Tfr) cell dysfunction in human SLE. OX40L/OX40 axis engagement on Tregs and Tfr cells not only specifically impaired their ability to regulate effector T cell proliferation, but also their ability to suppress T follicular helper (Tfh) cell–dependent B cell activation and immunoglobulin secretion. Antigen-presenting cells from patients with active SLE mediated Treg dysfunction in an OX40L-dependent manner, and OX40L-expressing cells colocalized with Foxp3+ cells in active SLE skin lesions. Engagement of the OX40L/OX40 axis resulted in Foxp3 downregulation in Tregs, and expression in SLE Tregs correlated with the proportion of circulating OX40L-expressing myeloid DCs. These data support that OX40L/OX40 signals are implicated in Treg dysfunction in human SLE. Thus, blocking the OX40L/OX40 axis appears to be a promising therapeutic strategy.
Clément Jacquemin, Jean-François Augusto, Marc Scherlinger, Noémie Gensous, Edouard Forcade, Isabelle Douchet, Emeline Levionnois, Christophe Richez, Estibaliz Lazaro, Pierre Duffau, Marie-Elise Truchetet, Julien Seneschal, Lionel Couzi, Jean-Luc Pellegrin, Jean-François Viallard, Thierry Schaeverbeke, Virginia Pascual, Cécile Contin-Bordes, Patrick Blanco
Total views: 547