A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings.

Obesity is a major public health crisis. Multi-specific peptides have emerged as promising therapeutic strategies for clinical weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are endogenous incretins that regulate weight through their receptors (R). AMG 133 (maridebart cafraglutide) is a bispecific molecule engineered by conjugating a fully human monoclonal anti-human GIPR antagonist antibody to two GLP-1 analogue agonist peptides using amino acid linkers. Here, we confirm the GIPR antagonist and GLP-1R agonist activities in cell-based systems and report the ability of AMG 133 to reduce body weight and improve metabolic markers in male obese mice and cynomolgus monkeys. In a phase 1, randomized, double-blind, placebo-controlled clinical study in participants with obesity ( NCT04478708 ), AMG 133 had an acceptable safety and tolerability profile along with pronounced dose-dependent weight loss. In the multiple ascending dose cohorts, weight loss was maintained for up to 150 days after the last dose. These findings support continued clinical evaluation of AMG 133.

An apoA-I mimetic peptibody generates HDL-like particles and increases alpha-1 HDL subfraction in mice.

The aim of this study is to investigate the capability of an apoA-I mimetic with multiple amphipathic helices to form HDL-like particles in vitro and in vivo. To generate multivalent helices and to track the peptide mimetic, we have constructed a peptibody by fusing two tandem repeats of 4F peptide to the C terminus of a murine IgG Fc fragment. The resultant peptidbody, mFc-2X4F, dose-dependently promoted cholesterol efflux in vitro, and the efflux potency was superior to monomeric 4F peptide. Like apoA-I, mFc-2X4F stabilized ABCA1 in J774A.1 and THP1 cells. The peptibody formed larger HDL particles when incubated with cultured cells compared with those by apoA-I. Interestingly, when administered to mice, mFc-2X4F increased both pre-ß and α-1 HDL subfractions. The lipid-bound mFc-2X4F was mostly in the α-1 migrating subfraction. Most importantly, mFc-2X4F and apoA-I were found to coexist in the same HDL particles formed in vivo. These data suggest that the apoA-I mimetic peptibody is capable of mimicking apoA-I to generate HDL particles. The peptibody and apoA-I may work cooperatively to generate larger HDL particles in vivo, either at the cholesterol efflux stage and/or via fusion of HDL particles that were generated by the peptibody and apoA-I individually.

Value of surveillance computed tomography in the follow-up of diffuse large B-cell and follicular lymphomas.

Computed tomography (CT) as a routine follow-up has been a standard practice for patients with non-Hodgkin lymphoma although it is not recommended in most guidelines. We aimed to describe the value of surveillance CT in detection of disease relapse in patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma grade 3 (FL3) and to evaluate whether relapse detected by different methods influenced outcome. In this retrospective review of consecutive 341 patients with DLBCL or FL3 diagnosed between 2003 and 2009 in complete response (CR) or unconfirmed CR, 113 patients experienced relapses. We found that routine surveillance CT detected asymptomatic relapse in 25 patients (22.1%; group 1), including 22 of 100 patients with DLBCL and three of 13 with FL3. The first presentation of relapse of the other 88 patients (group 2) included patient-reported symptoms (60.2%), physical examination (13.3%), or abnormal laboratory data (4.4%). For 72 patients received chemotherapy after relapse, the overall survival after relapse was not different between groups 1 and 2 (p = 0.569). The results of our study suggested that routine surveillance CT only has a limited role in the early detection of relapse and the relapse detected by surveillance CT or not has no impact on survival after relapse for patients with DLBCL or FL3.

[The experiences of caregivers caring for children with cord blood transplantation].

BACKGROUND: Advancing technology has greatly increased cord blood transplantation (CBT) success rates. However, transplant patient caregivers may encounter a great deal of stress related to knowledge deficits with regard to post-transplant care and lack of relevant care experience. Existing studies for CBT primarily focus on investigating the transplant process and survival rate. Studies on the experience of caregivers caring for CBT children are extremely scarce. It is important for future studies to explore the care experiences of CBT caregivers. PURPOSE: This study explored the experiences of primary caregivers responsible to care for pediatric patients after CBT. METHODS: Researchers conducted a phenomenological study of lived experiences using qualitative interviews that were in-depth, face-to-face, and semi-structured. RESULTS: Colaizzi analysis identified three themes, as follows: (1) emotional transition; (2) bearing indescribable of stress; (3) searching for management in meaningful resolutions. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Study results can provide valuable insights and information to healthcare providers developing preparatory educational programs for caregivers of discharged CBT patients. Findings can help alleviate care stress and anxiety in caregivers and nurses.

GIPR antagonist antibodies conjugated to GLP-1 peptide are bispecific molecules that decrease weight in obese mice and monkeys.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) regulate glucose and energy homeostasis. Targeting both pathways with GIP receptor (GIPR) antagonist antibody (GIPR-Ab) and GLP-1 receptor (GLP-1R) agonist, by generating GIPR-Ab/GLP-1 bispecific molecules, is an approach for treating obesity and its comorbidities. In mice and monkeys, these molecules reduce body weight (BW) and improve many metabolic parameters. BW loss is greater with GIPR-Ab/GLP-1 than with GIPR-Ab or a control antibody conjugate, suggesting synergistic effects. GIPR-Ab/GLP-1 also reduces the respiratory exchange ratio in DIO mice. Simultaneous receptor binding and rapid receptor internalization by GIPR-Ab/GLP-1 amplify endosomal cAMP production in recombinant cells expressing both receptors. This may explain the efficacy of the bispecific molecules. Overall, our GIPR-Ab/GLP-1 molecules promote BW loss, and they may be used for treating obesity.

[The enhancement of 1.5 microm near infrared luminescence in Er3+ and Yb3+ codoped Y2O3 nanocrystalline].

Y0.96 Er0.02 Yb0.02)O3 nanocrystals of 10 and 40 nm average particle size were prepared by combustion method. And bulk materials of the same components were obtained by annealing at 1 200 degrees C. X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectra, transmission electron microscope (TEM), and scanning electron microscopy (SEM) were used to characterize the crystal structure and morphology of the samples. The upconversion emission spectra and NIR (near-infrared) emission spectra were measured, under 980 nm excitation. The research result indicates that as the particle size decreases, the upconversion red emission and NIR emission components increase in the emission spectra. This phenomenon is attributed to the large ratio of surface area to volume in nanocrystals. This characteristic makes the nanocrystals absorb more OH-, whose vibrational energy is 3 200-3 800 cm(-1). The increase in the OH- number enhances the rate of nonradiative relaxation from Er3+ 4I11/2 to 4I13/2 energy level (energy gap is 3 600 cm(-1)). This nonradiative relaxation process depopulates the 4I11/2 level and makes the green emission weaker. Meanwhile, this process populates the 4I3/2 level and makes the red and NIR emissions stronger. The intensity of 1.5 microm main peak is 1.6 times that of bulk materials. This result has great significance in actual applications of nanophosphors.

Glucose-Dependent Insulinotropic Polypeptide Receptor Therapies for the Treatment of Obesity, Do Agonists = Antagonists?

Glucose-dependent insulinotropic polypeptide receptor (GIPR) is associated with obesity in human genome-wide association studies. Similarly, mouse genetic studies indicate that loss of function alleles and glucose-dependent insulinotropic polypeptide overexpression both protect from high-fat diet-induced weight gain. Together, these data provide compelling evidence to develop therapies targeting GIPR for the treatment of obesity. Further, both antagonists and agonists alone prevent weight gain, but result in remarkable weight loss when codosed or molecularly combined with glucagon-like peptide-1 analogs preclinically. Here, we review the current literature on GIPR, including biology, human and mouse genetics, and pharmacology of both agonists and antagonists, discussing the similarities and differences between the 2 approaches. Despite opposite approaches being investigated preclinically and clinically, there may be viability of both agonists and antagonists for the treatment of obesity, and we expect this area to continue to evolve with new clinical data and molecular and pharmacological analyses of GIPR function.

An acyl-ghrelin-specific neutralizing antibody inhibits the acute ghrelin-mediated orexigenic effects in mice.

Ghrelin is a 28-amino acid peptide secreted mainly by the stomach. Acyl-ghrelin, which binds to and activates the growth hormone secretagogue receptor type 1a (GHS-R1a), is considered to be the active form for its orexigenic effects. It has been demonstrated that peripheral administration of ghrelin stimulates food intake and adiposity in rodents and humans. Accordingly, different approaches to antagonize ghrelin/GHS-R1a signaling have been pursued for the treatment of obesity. In the present study, we generated and characterized high-affinity anti-acyl ghrelin-specific monoclonal antibodies (mAbs). In vitro, the lead mAb (33A) displayed specific binding to acyl-ghrelin, with an estimated K(d) value < 100 pM. In recombinant receptor cell-based assays, 33A dose-dependently inhibited the ghrelin-mediated calcium signal, with an IC(50) of approximately 3.5 nM. In vivo, ghrelin dose-dependently stimulated food intake in mice, and this effect was fully blocked by a single injection of 33A. In a 4-week chronic study, 33A was shown to effectively bind to endogenous acyl-ghrelin; however, long-term administration of 33A did not affect food intake or body weight gain in a mouse model of diet-induced obesity. Our results indicate that peripheral neutralization of ghrelin can suppress appetite stimulated by a transient surge in ghrelin levels. The lack of long-term effects on body weight control by 33A suggests that compensatory mechanisms may contribute to the regulation of energy balance.

Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models--association with liver and adipose tissue effects.

Recombinant fibroblast growth factor (FGF)21 has antihyperglycemic, antihyperlipidemic, and antiobesity effects in diabetic rodent and monkey models. Previous studies were confined to measuring steady-state effects of FGF21 following subchronic or chronic administration. The present study focuses on the kinetics of biological actions of FGF21 following a single injection and on the associated physiological and cellular mechanisms underlying FGF21 actions. We show that FGF21 resulted in rapid decline of blood glucose levels and immediate improvement of glucose tolerance and insulin sensitivity in two animal models of insulin resistance (ob/ob and DIO mice). In ob/ob mice, FGF21 led to a 40-60% decrease in blood glucose, insulin, and amylin levels within 1 h after injection, and the maximal effects were sustained for more than 6 h despite the 1- to 2-h half-life of FGF21. In DIO mice, FGF21 reduced fasting blood glucose and insulin levels and improved glucose tolerance and insulin sensitivity within 3 h of treatment. The acute improvement of glucose metabolism was associated with a 30% reduction of hepatic glucose production and an increase in peripheral glucose turnover. FGF21 appeared to have no direct effect on ex vivo pancreatic islet insulin or glucagon secretion. However, it rapidly induced typical FGF signaling in liver and adipose tissues and in several hepatoma-derived cell lines and differentiated adipocytes. FGF21 was able to inhibit glucose release from H4IIE hepatoma cells and stimulate glucose uptake in 3T3-L1 adipocytes. We conclude that the acute glucose-lowering and insulin-sensitizing effects of FGF21 are potentially associated with its metabolic actions in liver and adipose tissues.

Au@CdSe heteroepitaxial nanorods: An example of metal nanorods fully covered by a semiconductor shell with strong photo-induced interfacial charge transfer effects.

Synthesis of metal@semiconductor heteroepitaxial nanorods fully covered by a semiconductor shell remains challenging due to the large lattice mismatch between the two components. Here, we prepared Au@CdSe heteroepitaxial nanorods by employing pre-growth of Ag2Se as an intermediate layer that favored the formation of a complete CdSe shell via a cation-exchange process. The optical properties of these hybrid nanostructures can be tailored by changing the shell thickness with thicker shells resulting in a redshift of the longitudinal surface plasmon resonance. The resonance energy, intensity, and linewidth of the longitudinal surface plasmon resonance were measured by single-particle dark-field scattering spectroscopy, confirming significant electron transfer from the Au nanorod to the CdSe shell. In addition, we also studied the dependence of the catalytic reactivity on shell thickness in photocatalysis of methylene blue under UV illumination. These studies revealed that a thinner shell thickness resulted in higher photocatalytic activity.

Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models.

Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) has been identified in multiple genome-wide association studies (GWAS) as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). On the basis of this genetic evidence, we developed anti-GIPR antagonistic antibodies as a potential therapeutic strategy for the treatment of obesity and observed that a mouse anti-murine GIPR antibody (muGIPR-Ab) protected against body weight gain, improved multiple metabolic parameters, and was associated with reduced food intake and resting respiratory exchange ratio (RER) in DIO mice. We replicated these results in obese nonhuman primates (NHPs) using an anti-human GIPR antibody (hGIPR-Ab) and found that weight loss was more pronounced than in mice. In addition, we observed enhanced weight loss in DIO mice and NHPs when anti-GIPR antibodies were codosed with glucagon-like peptide-1 receptor (GLP-1R) agonists. Mechanistic and crystallographic studies demonstrated that hGIPR-Ab displaced GIP and bound to GIPR using the same conserved hydrophobic residues as GIP. Further, using a conditional knockout mouse model, we excluded the role of GIPR in pancreatic ß-cells in the regulation of body weight and response to GIPR antagonism. In conclusion, these data provide preclinical validation of a therapeutic approach to treat obesity with anti-GIPR antibodies.

[Preparation and luminescence of nanocrystalline ZrO2 : Pr3+ and ZrO2 : Pr3+, Sm3+].

The nanocrystalline ZrO2 : Pr3+ and ZrO2 : Pr3+, Sm3+ powders with room temperature sharp characteristic emissions were prepared by coprecipitation method. Luminescence properties of nanocrystalline ZrO2 : Pr3+ with different sintering temperatures and doping concentrations were studied. The energy transfer between the nanocrystalline ZrO2 host and the dopants was observed. The different Pr3+ concentration dependence of emission intensities of levels 3P0 and 1D2 was discussed. The dependence on Pr3+ concentration in nanocrystalline ZrO2 : Pr3+, Sm3+ of the emission intensity of 4G(5/2)-6H(7/2) transitions of Sm3+ ions and the energy transfer between Pr3+ and Sm3+ ions were investigated and discussed.

[Preparation and room temperature emission of nanocrystalline ZnO: Er3+].

The nanocrystalline ZnO:RE powders with room temperature sharp photoluminescence were prepared successfully by chemical precipitation method in the present work. This is a great progress in the study of rare earth doped ZnO. For the ZnO:Er3+ obtained in the present paper, the room temperature sharp characteristic emissions from the trivalent rare earth Er3+, including upconversion and near infrared emission, and the energy transfer between the nanocrystalline ZnO host and the dopants were observed.

Strategy for the identification of GPR23/LPA4 receptor agonists and inverse agonists.

Lysophosphatidic acid (LPA) is a bioactive phospholipid that signals through G-protein-coupled receptors to produce a range of biological responses. A recently reported LPA receptor GPR23 (LPA4 receptor) has a low homology to the LPA(1-3) receptors identified previously. In Chinese hamster ovary cells expressing the human GPR23, LPA induced an increase in cellular cyclic adenosine monophosphate (cAMP) and calcium levels. GPR23-selective agonists or antagonists have not been reported previously. Such ligands, if available, would be valuable tools for studying the functions of this receptor. Here we report the identification of novel GPR23 agonists, inverse agonists, and a negative modulator from 2 high-throughput screens, a beta-lactamase reporter screen, and a [3H]LPA-binding screen. Several screening hits were selected for mechanism of action studies using the beta-lactamase reporter assay and a cAMP assay. An evaluation of their selectivity at the other LPA receptors was also conducted. This study demonstrates a strategy for the identification of GPR23 agonists and inverse agonists. We believe the strategy employed here is applicable to other constitutively active GPCRs.

Resveratrol is not a direct activator of SIRT1 enzyme activity.

Resveratrol is a plant polyphenol capable of exerting beneficial metabolic effects which are thought to be mediated in large by the activation of the NAD(+)-dependent protein deacetylase SIRT1. Although resveratrol has been claimed to be a bona fide SIRT1 activator using a peptide substrate (Fluor de Lys-SIRT1 peptide substrate), recent reports indicate that this finding might be an experimental artifact and need to be clarified. Here, we show that: (i) the Fluor de Lys-SIRT1 peptide is an artificial SIRT1 substrate because in the absence of the covalently linked fluorophore the peptide itself is not a substrate of the enzyme, (ii) resveratrol does not activate SIRT1 in vitro in the presence of either a p53-derived peptide substrate or acetylated PGC-1alpha isolated from cells, and (iii) although SIRT1 deacetylates PGC-1alpha in both in vitro and cell-based assays, resveratrol did not activate SIRT1 under these conditions. Based on these observations, we conclude that the pharmacological effects of resveratrol in various models are unlikely to be mediated by a direct enhancement of the catalytic activity of the SIRT1 enzyme. In consequence, our data challenge the overall utility of resveratrol as a pharmacological tool to directly activate SIRT1.