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Growth hormone-releasing hormone (GHRH) agonist, a 29-amino acid peptide, shows significant potential in treating myocardial infarction (MI) by aiding the repair of injured heart tissue. The challenge lies in the effective on-site delivery of GHRH agonist. This study explores the use of a targetable delivery system employing ROS-responsive PEG-PPS-PEG polymers to encapsulate and deliver GHRH agonist MR409 for enhanced therapeutic efficacy. We synthesized a self-assembling poly (ethylene glycol)-poly (propylene sulfide)-poly (ethylene glycol) polymer (PEG-PPS-PEG) amphiphilic polymer responsive to reactive oxygen species (ROS). The hydrophilic peptide GHRH agonist MR409 was encapsulated within these polymers to form nano PEG-PPS-PEG@MR409 vesicles (NPs). Cardiomyocyte apoptosis was induced under hypoxia and serum-free culture condition for 24 hours, and their production of ROS was detected by fluorescence dye staining. The cellular uptake of PEG-PPS-PEG@MR409 NPs was observed using fluorescence-labeled MR409. Targeting ability and therapeutic efficacy were evaluated using a mouse MI model. PEG-PPS-PEG@MR409 NPs were efficiently internalized by cardiomyocytes, reducing ROS levels and apoptosis. These NPs exhibited superior targeting to the infarcted heart compared to naked MR409 peptide. With a reduced injection frequency (once every three days), PEG-PPS-PEG@MR409 NPs significantly promoted cardiac function recovery post-MI, matching the efficacy of daily MR409 injections. ROS-responsive PEG-PPS-PEG polymers provide a novel and effective platform for the targeted delivery of GHRH agonist peptides, improving cardiac function and offering a new approach for peptide therapy in MI treatment.

The deposition of hydroxyapatite (HAp) crystals plays an important role in the development of vascular calcification (VC). This study aimed to demonstrate the effects of nanosized HAp (nHAp) on vascular smooth muscle cells (VSMCs) and VC progression. Transmission electron microscopy (TEM) was used to examine cellular uptake of nHAp. Cell viability was determined using CCK-8 assay kit. Mitochondrial impairment and reactive oxygen species were detected by TEM and fluorescence dye staining, respectively. Cell apoptosis was detected by Western blot analysis and Annexin V staining. Mouse model of VC was built via applying nHAp on the surface of abdominal aorta. Calcification was visualized by Alizarin red and von Kossa staining. We found that nHAp could promote osteogenic transformation of VSMCs by elevating expression of runt-related factor 2 (Runx2), osteopontin (OPN) and alkaline phosphatase (ALP), impairing function and morphology of mitochondria and inducing apoptosis of VSMCs. More phosphorylation of c-Jun N-terminal protein kinase/c-JUN (JNK/c-JUN) in VSMCs was detected after mixing nHAp with VSMCs. HAp-induced osteogenic transformation of VSMCs was blocked by JNK inhibitor SP600125, resulted in decreased ALP activity, less Runx2 and OPN expressions. SP600125 also inhibited apoptosis of VSMCs. Application of nHAp to outside of aorta induced osteogenic transformation and apoptosis of VSMCs, and significant deposition of calcium on the vessel walls of mice, which can be effectively attenuated by SP600125. JNK/c-JUN signaling pathway is critical for nHAp-induced calcification, which could be a potential therapeutic target for controlling the progression of VC.

Background Studies reporting the effects of metabolic surgery, lifestyle intervention, and intensive insulin therapy for the remission of type 2 diabetes (T2DM) has been increasing, with fruitful results better conducted and yielded. However, there are only a few studies on the remission of T2DM using oral hypoglycemic drugs. Therefore, this study aims to investigate the remission effect of canagliflozin and metformin on participants with newly diagnosed T2DM and its possible underlying mechanism(s) through which these two medications elicit diabetes remission. Method To this end, we performed a multicenter, parallel-group, randomized, controlled, and open-label trial. A total of 184 participants with a ≤ 3-year course of T2DM will be enrolled and randomly assigned to the canagliflozin or metformin treatment group in a ratio of 1:1. Participants in each group will maintain their medication for 3 months after achieving the target blood glucose level and then stop it. These participants will be followed up for one year to determine remission rates in both groups. Discussion In this study, we will establish that whether canagliflozin is superior to metformin in terms of remission rate in participants with newly diagnosed T2DM. The results of this trial may provide robust evidence regarding the efficacy and mechanisms of the action of sodium-glucose cotransporter-2 inhibitors (SGLT2is) in T2DM remission. Trial registration ChiCTR2100043770(February 28, 2021).

Abstract Disclosure: P. xiang: None. R. Latif: None. T.F. Davies: None. The relative role of the different TSH receptor antibodies generated in patients with Graves’ disease remains unclear. Several animal models of Graves' disease (GD) and thyroid eye disease (TED) have been reported in response to immunization with different forms of TSH receptor (TSHR) antigen and should have helped clarify this immunopathology. However, these animal models remain insufficiently robust and continue to fall short in fully replicating the complexities of the human disease with its mixture of stimulating, blocking and neutral TSH receptor antibodies. In this study, we further evaluated a mouse model of GD and the role of TSHR antibodies of differing bioactivity. Balb/c mice were immunized with an IM injection of an adenovirus expressing residues 1-289 of the human TSHR (Ad-TSHR 289) (absent the hinge region) or control vector (Ad-Lacz) with 10 injections at 3-week intervals. Thyroid function was assessed by total thyroxine (T4) and TSH levels. The presence of TSHR binding antibodies as well as stimulating TSHR antibodies (TSAb), and TSH-blocking TSHR antibodies (TBAb) were evaluated using flow cytometry and a luciferase based cell bioassay. To further assess the induced changes we also carried out thyroid gland ultrasound and histology, and for eye changes we performed MRI scans along with histological examination of the eyes at 30 weeks. Out of 16 mice, 9 became hyperthyroid - characterized by decreased TSH levels, increased T4 levels, and diffuse enlargement of the thyroid glands. All mice developed TSHR antibodies when assessed by flow cytometry. 8/9 of the hyperthyroid mice had detectable TSAb of low levels when compared to that obtained with TSH ligand and control TSAb. Seven additional mice showed detectable TBAb only and only 2 mice had detectable linear antibodies to the TSHR. Five hyperthyroid mice showed eye signs, including conjunctival redness and eyelid thickening. MRI scans and histological staining revealed mild enlargement of retrobulbar adipose tissue and retro-orbital muscle accompanied by a macrophage infiltration. Hyperthyroidism was only found in 9/16 (56%) of mice despite all mice expressing TSHR antibodies. The TSAbs detected were of a low level and in their presence we could not detect TBAb in these mice although such blocking antibodies may have developed simultaneously explaining the low stimulating bioactivity. In support of this interpretation, additional mice developed detectable TBAb only - highly suggestive of their dampening any TSAb response and preventing the onset of hyperthyroidism. These multiple antibodies to TSHR antigen (the reactome) have to be considered in all immunization mouse models of GD since they are the ultimate determination of the thyroid response. Presentation: Monday, July 14, 2025

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor‐β super family. It has multiple effects on development, physiology and diseases. However, the role of GDF11 in the development of mesenchymal stem cells (MSCs) is not clear. To explore the effects of GDF11 on the differentiation and pro‐angiogenic activities of MSCs, mouse bone marrow–derived MSCs were engineered to overexpress GDF11 (MSCGDF11) and their capacity for differentiation and paracrine actions were examined both in vitro and in vivo. Expression of endothelial markers CD31 and VEGFR2 at the levels of both mRNA and protein was significantly higher in MSCGDF11 than control MSCs (MSCVector) during differentiation. More tube formation was observed in MSCGDF11 as compared with controls. In an in vivo angiogenesis assay with Matrigel plug, MSCGDF11 showed more differentiation into CD31+ endothelial‐like cells and better pro‐angiogenic activity as compared with MSCVector. Mechanistically, the enhanced differentiation by GDF11 involved activation of extracellular‐signal‐related kinase (ERK) and eukaryotic translation initiation factor 4E (EIF4E). Inhibition of either TGF‐β receptor or ERK diminished the effect of GDF11 on MSC differentiation. In summary, our study unveils the function of GDF11 in the pro‐angiogenic activities of MSCs by enhancing endothelial differentiation via the TGFβ‐R/ERK/EIF4E pathway.

Abstract Context The natural history of benign thyroid nodules is typically characterized by slow growth and minimal risk of malignant transformation. Available data have, to date, been unable to elucidate the diversity of benign nodule growth patterns over time nor predictive of which patients follow which pattern. Objective We aimed to better define the diverse patterns of benign nodule behavior and their predictors. Methods We prospectively studied 389 consecutive patients with solitary, solid, cytologically benign thyroid nodules ≥1 cm and follow-up ultrasound for at least 4 years. Demographic, sonographic, biochemical data were collected at initial evaluation, and subsequent growth patterns were identified over the follow-up. Predictors of growth at initial evaluation and 3 years of follow-up were defined. Results The mean (±SD) follow-up was 7.7 (±2.7) years. Three distinct growth patterns were identified: A) stagnant nodules with average growth rate < 0.2 mm/year; B) slow-growing nodules with a rate 0.2 to 1.0 mm/year; and C) fast-growing nodules increasing > 1.0 mm/year. Fast-growing nodules represented 17.2% of the cohort, and were more frequent in patients younger than 50 years (OR 2.2 [1.2-4.1], P = 0.016), and in larger nodules (2.0-2.9 cm, OR 3.5 [1.7-7.1], P = 0.001; >3.0 cm, OR 4.4 [1.8-10.4], P = 0.001 vs reference 1-1.9 cm). In a multiple regression model, nodule growth at 3 years at an average growth rate over 0.2 mm/year over 3 years since initial evaluation was an independent predictor of longer-term fast nodule growth, even after adjusting for age, biological sex, TSH level, and nodule size (P < 0.001). Conclusion The natural history of benign nodule growth is diverse, with over 80% of nodules demonstrating minimal to no growth long-term. Nearly 20% of cytologically benign nodules may exhibit a fast, continued growth pattern, which can be predicted by the 3-year growth rate pattern. These findings can help inform decision making for tailored benign nodule follow-up and monitoring.

Abstract Context Molecular testing can refine the risk of malignancy in thyroid nodules with indeterminate cytology to decrease unnecessary diagnostic surgery. Objective This study was performed to evaluate the outcomes of cytologically indeterminate thyroid nodules managed with Afirma genomic sequencing classifier (GSC) testing. Methods Adult patients who underwent a biopsy at 3 major academic centers between July 2017 and June 2021 with Bethesda III or IV cytology were included. All patients had surgery or minimum follow-up of 1 year ultrasound surveillance. The primary outcomes were the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of GSC in Bethesda III and IV nodules. Results The median nodule size of the 834 indeterminate nodules was 2.1 cm and the median follow-up was 23 months. GSC sensitivity, specificity, PPV, and NPV across all institutions were 95%, 81%, 50%, and 99% for Bethesda III nodules and 94%, 82%, 65%, and 98% for Bethesda IV nodules, respectively. The overall false-negative rate was 2%. The NPV of GSC in thyroid nodules with oncocytic predominance was 100% in Bethesda III nodules and 98% in Bethesda IV nodules. However, the PPV of oncocytic nodules was low (17% in Bethesda III nodules and 45% in Bethesda IV nodules). Only 22% of thyroid nodules with benign GSC results grew during surveillance. Conclusion GSC is a key tool for managing patients with indeterminate cytology, including the higher-risk Bethesda IV category. GSC-benign thyroid nodules can be observed similarly to thyroid nodules with benign cytology.

Immune thrombocytopenia (ITP) is a common hematological manifestation of systemic lupus erythematosus (SLE). The diversity of its clinical features and treatment responses may reveal the complex pathophysiological mechanisms of the disease. To enhance the therapeutic response rate and improve the prognosis for SLE patients with concurrent ITP, while reducing adverse events during the treatment process, it is crucial to accurately identify and apply clinical parameters to predict patients’ responses to treatment. In addition to conventional therapeutic approaches such as glucocorticoids, immunosuppressants, and intravenous immunoglobulin (IVIG), a range of emerging therapies are gradually becoming the focus of research. These innovative therapeutic strategies include thrombopoietin receptor agonists (TPO-RAs), targeted therapies against B-cells, and plasma cell–targeted treatments. With a deepening understanding of the role of platelets in immune and inflammatory responses, novel platelet–targeted therapeutic agents in the field of SLE-ITP treatment may demonstrate significant potential. Despite this, to ensure the clinical efficacy and safety of these therapeutic approaches, we must rely on rigorously designed randomized controlled trials (RCTs) for further validation. This article provides a systematic review of the pathogenesis of systemic lupus erythematosus (SLE) complicated by immune thrombocytopenia (ITP) and conducts a comprehensive overview of current treatment strategies. The article also provides an in-depth exploration of the key biomarkers that may influence the therapeutic response in SLE-ITP patients. This comprehensive analysis aims to elucidate the factors that potentially affect the efficacy of treatments and contribute to a more personalized approach to patient care.

Abstract Disclosure: P. xiang: None. R. Latif: None. S.A. Morshed: None. T.F. Davies: None. The “Neutral” thyrotropin receptor autoantibodies (N-TSHR-Ab) directed at the TSHR ectodomain's hinge region have been shown to induce thyroid cell damage in vitro and also when administered in vivo. For example, during these earlier studies we developed a mouse monoclonal antibody (MC1) specific for a peptide (aa 322-340) in the hinge region (MC1 - Mab) which was able to induce thyroid cell stress and apoptosis. In order to examine the effect of in vivo generated N-TSHR-Abs we immunized Balb/c mice with the same hinge region peptide and examined their thyroid function over the subsequent 18 weeks. We found that TSHR-peptide immunized mice developed N-TSHR-Abs against the peptide which resulted in thyroid damage shown by thyroid follicular cell apoptosis, thyroglobulin release, induction of thyroglobulin antibodies and hypothyroidism with increased TSH levels. These data add further evidence to the complexity of the immune response to the TSHR and indicate that the simple presence of stimulating type TSHR antibodies is not the entire story of Graves’ disease. Presentation: 6/3/2024

Dysregulated expression of microRNAs （miRNAs） in various tissues has been associated with a variety of diseases, including cancers. Here we demonstrate that miRNAs are present in the serum and plasma of humans and other animals such as mice, rats, bovine fetuses, calves, and horses. The levels of miRNAs in serum are stable, reproducible, and consistent among individuals of the same species. Employing Solexa, we sequenced all serum miRNAs of healthy Chinese subjects and found over 100 and 91 serum miRNAs in male and female subjects, respectively. We also identified specific expression patterns of serum miRNAs for lung cancer, colorectal cancer, and diabetes, providing evidence that serum miRNAs contain fingerprints for various diseases. Two non-small cell lung cancer-specific serum miRNAs obtained by Solexa were further validated in an independent trial of 75 healthy donors and 152 cancer patients, using quantitative reverse transcription polymerase chain reaction assays. Through these analyses, we conclude that serum miRNAs can serve as potential biomarkers for the detection of various cancers and other diseases.