We recently showed that activation of G protein-coupled receptor 119 (GPR119) (also termed glucose dependent insulinotropic receptor) improves glucose homeostasis via direct cAMP-mediated enhancement ...of glucose-dependent insulin release in pancreatic β-cells. Here we show that GPR119 also stimulates incretin hormone release and thus may regulate glucose homeostasis by this additional mechanism. GPR119 mRNA was found to be expressed at significant levels in intestinal subregions that produce glucose-dependent insulinotropic peptide and glucagon-like peptide (GLP)-1. Furthermore, in situ hybridization studies indicated that most GLP-1-producing cells coexpress GPR119 mRNA. In GLUTag cells, a well-established model of intestinal L-cell function, the potent GPR119 agonist AR231453 stimulated cAMP accumulation and GLP-1 release. When administered in mice, AR231453 increased active GLP-1 levels within 2 min after oral glucose delivery and substantially enhanced total glucose-dependent insulinotropic peptide levels. Blockade of GLP-1 receptor signaling with exendin(9–39) reduced the ability of AR231453 to improve glucose tolerance in mice. Conversely, combined administration of AR231453 and the DPP-4 inhibitor sitagliptin to wild-type mice significantly amplified both plasma GLP-1 levels and oral glucose tolerance, relative to either agent alone. In mice lacking GPR119, no such enhancement was seen. Thus, GPR119 regulates glucose tolerance by acting on intestinal endocrine cells as well as pancreatic β-cells. These data also suggest that combined stimulation of incretin hormone release and protection against incretin hormone degradation may be an effective antidiabetic strategy.
G protein-coupled receptor 119 (GPR119) is largely restricted to pancreatic insulin-producing β-cells and intestinal glucagon-like peptide-1-producing L-cells. Synthetic agonists of this receptor ...elicit glucose-dependent release of these endocrine factors, thereby enhancing glycemic control. Oleoylethanolamide also activates GPR119, but it remains unclear whether endogenous production of this lipid modulates GPR119 activity under normal or dysglycemic conditions. We show here that a relatively diverse set of lipid amides activate GPR119. Among these, the endovallinoid N-oleoyldopamine (OLDA) stimulated cAMP accumulation in GPR119-transfected cells as effectively as oleoylethanolamide and the previously described synthetic agonist AR231453. None of these lipid amides increased cAMP in control-transfected cells or in cells transfected with a number of other G protein-coupled receptors. OLDA stimulated both cAMP accumulation and insulin release in HIT-T15 cells, which express GPR119 endogenously, and in GPR119-transfected RIN-5F cells. Oral administration of OLDA to C57bl/6 mice elicited significant improvement in glucose tolerance, whereas GPR119-deficient mice were essentially unresponsive. OLDA also acutely elevated plasma gastric inhibitory peptide levels, a known hallmark of GPR119 activation. OLDA represents a possible paracrine modulator of GPR119 in pancreatic islets, where markers of dopamine synthesis correlated well with GPR119 expression. However, no such correlation was seen in the colon. Collectively, these studies indicate that multiple, distinct classes of lipid amides, acting via GPR119, may be important modulators of glucose homeostasis.
Structurally novel endogenous activators of GPR119 are identified, suggesting that diverse lipid amides may contribute to receptor activation in vivo.
Cytotoxic T lymphocyte (CTL) activity and CD4+ helper T cell responses to the hepatitis B virus (HBV) core antigen (HBcAg) have been implicated in clearance of acute and chronic HBV infections. We ...showed that intramuscular injections of a novel recombinant retroviral vector expressing an HBcAg-neomycin phosphotransferase II (HBc-NEO) fusion protein induces HBc/eAg-specific antibodies and CD4+ and CD8+ T cell responses in mice and rhesus monkeys. We have now immunized three chronically infected chimpanzees, each with 10(10) CFU of nonreplicating retroviral vector particles expressing the HBc-NEO fusion protein. Of two immunized chimpanzees examined for CTL responses, one developed HBcAg-specific CTLs and showed marginal, transient elevations of alanine aminotransferase (ALT) levels following injection. However, both chimpanzees remained positive for serum HBeAg, negative for anti-HBe antibody by conventional assays, and displayed no change in HBV viral load throughout the study. In contrast, the third chimpanzee exhibited a traditional seroconversion evidenced by a loss of serum HBeAg and the subsequent emergence of anti-HBe antibodies within 24 weeks after the first injection. Simultaneously, two transient ALT flares and a significant decrease in the serum HBV DNA levels were noted. Despite its limitations, the present study demonstrates (1) the safety of treatment with high titers of retroviral vector in chimpanzees, (2) the capability of a retroviral vector expressing HBcAg to stimulate immune responses in HBV chronic carrier chimpanzees, and (3) that retroviral vector immunization may be therapeutically beneficial in the treatment of chronic HBV infection.
This book compiles the basic science and technologies used to convert terrestrial and aquatic biomass into essential molecular compounds and polymeric materials. The book provides in depth insights ...into this fairly recent concept of industrial chemistry that aims to achieve optimal economic profits while minimizing the environmental impact. Chapters written by renowned experts cover, amongst others, the application of catalysis, downstream processing, biomass sourced olefins, lignin biorefinery techniques and biogas. The authors thoroughly examine and explain the value chain for biomass conversion into platform molecules and their transformation into final products. A comprehensive thematic overview on the topic giving beginners access to fundamental concepts is presented. Supplemented by numerous full color figures and tables, the contents impart knowledge about the involved techniques. Advanced students and experts in the field will find the summary of state-of-the-art research and current literature of valuable interest.
Mathematical control theory has evolved from the study of practical problems in engineering and sciences to the elaboration of deep, important concepts in mathematics and applied sciences. This ...volume concerns contemporary trends in nonlinear geometric control theory and its applications. It is a fine collection of papers presenting new results, relevant open problems, and important applications regarding academic and real-world problems.The book is dedicated to Velimir Jurdjevic whose scientific activity has been influential in the research of many of the authors. It contains a number of articles specially written by colleagues and friends of Vel Jurdjevic, all of them leading applied mathematicians and control theorists. There is also place for surveys on topics of current research which present the state of the art of modern geometric control theory. Finally, the volume contains several new mathematical ideas generated by geometric control theory techniques, which may initiate new directions of research beyond control theory.
Nivolumab received US Food and Drug Administration approval as a single agent or in combination with ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) ...metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on CheckMate 142. Presented are results of nivolumab plus low-dose ipilimumab in the first-line therapy cohort from the phase II CheckMate 142 study.
Patients with no prior treatment in the metastatic setting for MSI-H/dMMR CRC were treated with nivolumab every 2 weeks plus low-dose ipilimumab every 6 weeks until disease progression. The primary end point was objective response rate (investigator assessment; RECIST v1.1).
Median age of treated patients was 66 years (N = 45). Median follow-up was 29.0 months. Objective response rate and disease control rate were 69% (95% CI, 53 to 82) and 84% (95% CI, 70.5 to 93.5), respectively, with 13% complete response rate. Median duration of response was not reached; 74% of responders had ongoing responses at data cutoff. Median progression-free survival and median overall survival were not reached with minimum follow-up of 24.2 months (24-month rates, 74% and 79%, respectively). Clinical benefit was observed regardless of baseline demographic and tumor characteristics, including
or
mutation status. In a post hoc analysis, of 14 patients who discontinued treatment and did not receive subsequent therapy, 10 remained progression-free. Patient-reported outcomes were stable over the treatment period. Grade 3-4 treatment-related adverse events occurred in 22% of patients; 13% discontinued because of any-grade treatment-related adverse events.
Nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated as a first-line treatment for MSI-H/dMMR mCRC. Based on these promising data, randomized studies are warranted.
The decrease of physical abilities and functional decline that can be caused by musculoskeletal conditions such as sarcopenia, can lead to higher levels of dependency and disability. Therefore, it ...may influence patient reported outcome measures (PROM), such as the health‐related quality of life (HRQoL). The purpose of this systematic review and meta‐analysis is to provide a comprehensive overview of the relationship between sarcopenia and HRQoL. Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) were followed throughout the whole process of this work. A protocol was previously published on PROSPERO. The electronic databases MEDLINE, Scopus, Allied and Complementary Medicine (AMED), EMB Review – ACP Journal Club, EBM Review ‐ Cochrane Central of Register of Controlled Trials and APA PsychInfo were searched until October 2022 for observational studies reporting a HRQoL assessment in both sarcopenic and non‐sarcopenic individuals. Study selection and data extraction were carried out by two independent researchers. Meta‐analysis was performed using a random effect model, reporting an overall standardized mean difference (SMD) and its 95% confidence interval (CI) between sarcopenic and non‐sarcopenic individuals. Study quality was measured using the Newcastle‐Ottawa Scale and the strength of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool. The search strategy identified 3725 references from which 43 observational studies were eligible and included in this meta‐synthesis study. A significantly lower HRQoL was observed for sarcopenic individuals compared with non‐sarcopenic ones (SMD −0.76; 95% CI −0.95; −0.57). Significant heterogeneity was associated with the model (I2 = 93%, Q test P‐value <0.01). Subgroup analysis showed a higher effect size when using the specific questionnaire SarQoL compared with generic questionnaires (SMD −1.09; 95% CI −1.44; −0.74 with the SarQoL versus −0.49; 95% CI −0.63; −0.36 with generic tools; P‐value for interaction <0.01). A greater difference of HRQoL between sarcopenic and non‐sarcopenic was found for individuals residing in care homes compared with community‐dwelling individuals (P‐value for interaction <0.001). No differences were found between age groups, diagnostic techniques, and continents/regions. The level of evidence was rated as moderate using the GRADE assessment. This systematic review and meta‐analysis combining 43 observational studies shows that HRQoL is significantly reduced in sarcopenic patients. The use of disease‐specific HRQoL instruments may better discriminate sarcopenic patients with respect to their quality of life.
Abstract
Background
in 2010, the European Working Group on Sarcopenia in Older People (EWGSOP) published a sarcopenia definition that aimed to foster advances in identifying and caring for people ...with sarcopenia. In early 2018, the Working Group met again (EWGSOP2) to update the original definition in order to reflect scientific and clinical evidence that has built over the last decade. This paper presents our updated findings.
Objectives
to increase consistency of research design, clinical diagnoses and ultimately, care for people with sarcopenia.
Recommendations
sarcopenia is a muscle disease (muscle failure) rooted in adverse muscle changes that accrue across a lifetime; sarcopenia is common among adults of older age but can also occur earlier in life. In this updated consensus paper on sarcopenia, EWGSOP2: (1) focuses on low muscle strength as a key characteristic of sarcopenia, uses detection of low muscle quantity and quality to confirm the sarcopenia diagnosis, and identifies poor physical performance as indicative of severe sarcopenia; (2) updates the clinical algorithm that can be used for sarcopenia case-finding, diagnosis and confirmation, and severity determination and (3) provides clear cut-off points for measurements of variables that identify and characterise sarcopenia.
Conclusions
EWGSOP2's updated recommendations aim to increase awareness of sarcopenia and its risk. With these new recommendations, EWGSOP2 calls for healthcare professionals who treat patients at risk for sarcopenia to take actions that will promote early detection and treatment. We also encourage more research in the field of sarcopenia in order to prevent or delay adverse health outcomes that incur a heavy burden for patients and healthcare systems.
The European Working Group on Sarcopenia in Older People (EWGSOP) developed a practical clinical definition and consensus diagnostic criteria for age-related sarcopenia. EWGSOP included ...representatives from four participant organisations, i.e. the European Geriatric Medicine Society, the European Society for Clinical Nutrition and Metabolism, the International Association of Gerontology and Geriatrics—European Region and the International Association of Nutrition and Aging. These organisations endorsed the findings in the final document. The group met and addressed the following questions, using the medical literature to build evidence-based answers: (i) What is sarcopenia? (ii) What parameters define sarcopenia? (iii) What variables reflect these parameters, and what measurement tools and cut-off points can be used? (iv) How does sarcopenia relate to cachexia, frailty and sarcopenic obesity? For the diagnosis of sarcopenia, EWGSOP recommends using the presence of both low muscle mass + low muscle function (strength or performance). EWGSOP variously applies these characteristics to further define conceptual stages as ‘presarcopenia’, ‘sarcopenia’ and ‘severe sarcopenia’. EWGSOP reviewed a wide range of tools that can be used to measure the specific variables of muscle mass, muscle strength and physical performance. Our paper summarises currently available data defining sarcopenia cut-off points by age and gender; suggests an algorithm for sarcopenia case finding in older individuals based on measurements of gait speed, grip strength and muscle mass; and presents a list of suggested primary and secondary outcome domains for research. Once an operational definition of sarcopenia is adopted and included in the mainstream of comprehensive geriatric assessment, the next steps are to define the natural course of sarcopenia and to develop and define effective treatment.
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