Therapeutic efficacy of an alpha-particle emitter labeled anti-GD2 humanized antibody against osteosarcoma-a proof of concept study.

PURPOSE: Current treatments for osteosarcoma (OS) have a poor prognosis, particularly for patients with metastasis and recurrence, underscoring an urgent need for new targeted therapies to improve survival. Targeted alpha-particle therapy selectively delivers cytotoxic payloads to tumors with radiolabeled molecules that recognize tumor-associated antigens. We have recently demonstrated the potential of an FDA approved, humanized anti-GD2 antibody, hu3F8, as a targeted delivery vector for radiopharmaceutical imaging of OS. The current study aims to advance this system for alpha-particle therapy of OS. METHODS: The hu3F8 antibody was radiolabeled with actinium-225, and the safety and therapeutic efficacy of the [225Ac]Ac-DOTA-hu3F8 were evaluated in both orthotopic murine xenografts of OS and spontaneously occurring OS in canines. RESULTS: Significant antitumor activity was proven in both cases, leading to improved overall survival. In the murine xenograft's case, tumor growth was delayed by 16-18 days compared to the untreated cohort as demonstrated by bioluminescence imaging. The results were further validated with magnetic resonance imaging at 33 days after treatment, and microcomputed tomography and planar microradiography post-mortem. Histological evaluations revealed radiation-induced renal toxicity, manifested as epithelial cell karyomegaly and suggestive polyploidy in the kidneys, suggesting rapid recovery of renal function after radiation damage. Treatment of the two canine patients delayed the progression of metastatic spread, with an overall survival time of 211 and 437 days and survival beyond documented metastasis of 111 and 84 days, respectively. CONCLUSION: This study highlights the potential of hu3F8-based alpha-particle therapy as a promising treatment strategy for OS.

Genome-wide 5-hydroxymethylcytosines in circulating cell-free DNA as noninvasive diagnostic markers for gastric cancer.

BACKGROUND: 5-Hydroxymethylcytosine-enriched gene profiles and regions show tissue-specific and tumor specific. There is a potential value to explore cell-free DNA 5-hydroxymethylcytosine feature biomarkers for early gastric cancer detection. METHODS: A matched case‒control study design with 50 gastric cancer patients and 50 controls was performed to sequence the different 5-hydroxymethylcytosine modification features of cell free DNA. Significantly differential 5-hydroxymethylcytosine modification genes were identified to construct a gastric cancer diagnostic model. Data set from GEO was used as an external testing set to test the robustness of the diagnostic model. RESULTS: Accounting for more than 90% of 5-hydroxymethylcytosine peaks were distributed in the gene body in both the gastric cancer and control groups. The diagnostic model was developed based on five different 5-hydroxymethylcytosine modification genes, FBXL7, PDE3A, TPO, SNTG2 and STXBP5. The model could effectively distinguish gastric cancer patients from controls in the training (AUC = 0.95, sensitivity = 88.6%, specificity = 94.3%), validation (AUC = 0.87, sensitivity = 73.3%, specificity = 93.3%) and testing (AUC = 0.90, sensitivity = 81.9%, specificity = 90.2%) sets. The risk scores of the controls from the model were significantly lower than those of gastric cancer patients in both our own data (P < 0.001) and GEO external testing data (P < 0.001), and no significant difference between different TNM stage patients (P = 0.09 and 0.66). Furthermore, there was no significant difference between the healthy control and benign gastric disease patients in the testing set from GEO (P = 0.10). CONCLUSIONS: The characteristics of 5-hydroxymethylcytosine in cell free DNA are specific to gastric cancer patients, and the diagnostic model constructed by five genes' 5-hydroxymethylcytosine features could effectively identify gastric cancer patients.

Modified peroral endoscopic myotomy technique with retrograde on-demand myotomy for achalasia: a retrospective cohort study (with video).

BACKGROUND: Although myotomy is crucial in peroral endoscopic myotomy (POEM) surgeries, its optimum length remains controversial. Herein, we propose a modified POEM with new method of tailoring myotomy length aim to evaluate the safety, efficacy, and clinical outcomes of this modified POEM compared with standard POEM in type I or II achalasia. METHODS: Seventy-five patients with type I or II achalasia who underwent POEM at the First Hospital of Jilin University between January 2018 and December 2022 were retrospectively analyzed. According to the myotomy approach, these patients were divided into the retrograde on-demand myotomy (RDM, n = 34), with myotomy beginning on gastric side and length tailored by determining the degree of lower esophageal sphincter (LES) distention, and standard myotomy (SM, n = 41) groups. The baseline data, myotomy length, operation time, clinical success rate, adverse event rate, and reflux-related adverse events were compared and analyzed. RESULTS: The median myotomy length in the RDM group was significantly shorter than that in the SM group (6 vs. 8 cm, respectively; p < 0.001). Moreover, the median myotomy time in the RDM group was significantly shorter than that in the SM group (10 vs. 16 min, respectively; p < 0.001). POEM was successfully performed in all the patients. At the 2-year follow-up, high clinical success rates were observed in both the RDM and SM groups (92.0% vs. 93.3%, respectively; p = 1.000). The incidence of intraoperative adverse events and postoperative reflux-related adverse events was low and comparable in both groups. CONCLUSIONS: RDM POEM is a safe and effective method for patients with type I or II achalasia. Furthermore, it has a shorter myotomy length and operation time than standard POEM technique.

Balancing Safety and Efficacy to Determine the Most Suitable Size of Imaging-Visible Embolic Microspheres for Bariatric Arterial Embolization in a Preclinical Model.

OBJECTIVES: To identify the most suitable size of imaging-visible embolic agents with balanced safety and efficacy for bariatric arterial embolization (BAE) in a preclinical model. MATERIALS AND METHODS: Twenty-seven pigs were divided into 3 cohorts. In Cohort I, 16 pigs were randomized to receive (n = 4 each) 40-100-µm microspheres in 1 or 2 fundal arteries, 70-340-µm radiopaque microspheres in 2 fundal arteries, or saline. In Cohort II, 3 pigs underwent renal arterial embolization with either custom-made 100-200-µm, 200-250-µm, 200-300-µm, or 300-400-µm radiopaque microspheres or Bead Block 300-500 µm with microsphere distribution assessed histologically. In Cohort III, 8 pigs underwent BAE in 2 fundal arteries with tailored 100-200-µm radiopaque microspheres (n = 5) or saline (n = 3). RESULTS: In Cohort I, no significant differences in weight or ghrelin expression were observed between BAE and control animals. Moderate-to-severe gastric ulcerations were noted in all BAE animals. In Cohort II, renal embolization with 100-200-µm microspheres occluded vessels with a mean diameter of 139 µm ± 31, which is within the lower range of actual diameters of Bead Block 300-500 µm. In Cohort III, BAE with 100-200-µm microspheres resulted in significantly lower weight gain (42.3% ± 5.7% vs 51.6% ± 2.9% at 8 weeks; P = .04), fundal ghrelin cell density (16.1 ± 6.7 vs 23.6 ± 12.6; P = .045), and plasma ghrelin levels (1,709 pg/mL ± 172 vs 4,343 pg/mL ± 1,555; P < .01) compared with controls and superficial gastric ulcers (5/5). CONCLUSIONS: In this preclinical model, tailored 100-200-µm microspheres were shown to be most suitable for BAE in terms of safety and efficacy.

Anti-GD2 antibody for radiopharmaceutical imaging of osteosarcoma.

PURPOSE: Osteosarcoma (OS) is the most frequently diagnosed bone cancer in children with little improvement in overall survival in the past decades. The high surface expression of disialoganglioside GD2 on OS tumors and restricted expression in normal tissues makes it an ideal target for anti-OS radiopharmaceuticals. Since human and canine OS share many biological and molecular features, spontaneously occurring OS in canines has been an ideal model for testing new imaging and treatment modalities for human translation. In this study, we evaluated a humanized anti-GD2 antibody, hu3F8, as a potential delivery vector for targeted radiopharmaceutical imaging of human and canine OS. METHODS: The cross-reactivity of hu3F8 with human and canine OS cells and tumors was examined by immunohistochemistry and flow cytometry. The hu3F8 was radiolabeled with indium-111, and the biodistribution of [111In]In-hu3F8 was assessed in tumor xenograft-bearing mice. The targeting ability of [111In]In-hu3F8 to metastatic OS was tested in spontaneous OS canines. RESULTS: The hu3F8 cross reacts with human and canine OS cells and canine OS tumors with high binding affinity. Biodistribution studies revealed selective uptake of [111In]In-hu3F8 in tumor tissue. SPECT/CT imaging of spontaneous OS canines demonstrated avid uptake of [111In]In-hu3F8 in all metastatic lesions. Immunohistochemistry confirmed the extensive binding of radiolabeled hu3F8 within both osseous and soft lesions. CONCLUSION: This study demonstrates the feasibility of targeting GD2 on OS cells and spontaneous OS canine tumors using hu3F8-based radiopharmaceutical imaging. Its ability to deliver an imaging payload in a targeted manner supports the utility of hu3F8 for precision imaging of OS and potential future use in radiopharmaceutical therapy.

Positive H. pylori status predicts better prognosis of non-cardiac gastric cancer patients: results from cohort study and meta-analysis.

BACKGROUND: Previous researches have associated Helicobacter pylori (H. pylori) with a prognosis of gastric cancer (GC), however, without a concert conclusion. This study aimed to study this issue further by a prospective cohort study and a meta-analysis. METHODS: Histologically diagnosed gastric cancer (GC) patients were recruited into the primary prospective cohort study between January 2009 to December 2013. All the patients were followed-up periodically to record information on post-surgery therapy and overall survival status. The pre-surgery status of H. pylori was measured by enzyme-linked immunosorbent assay. A meta-analysis was conducted after retrieving related researches in the databases of PubMed and Embase up to April 2020. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were summarized to validate the relationship between H. pylori infection and the survival time of GC patients. I2 statistics and Q test were used to assess the heterogeneity. Sensitivity analyses were performed using Galbraith's plot, leave-one-out analysis, subgroup analyses and meta-regression to explore the sources of heterogeneity and the stability of the summary results. RESULTS: A total of 743 GC patients with radical tumorectomy were included prospectively and 516 (69.4%) were positive on H. pylori. H. pylori-positive patients tended to survive longer than -negative ones (HR 0.92, 95%CI: 0.74-1.15), though the tendency was not statistically significant. Cohort studies on the prognosis of GC were retrieved comprehensively by assessing the full-text and 59 published studies, together with the result of our study, were included in the further meta-analysis. The summarized results related the positive status of H. pylori to better overall survival (HR 0.81, 95%CI: 0.72-0.90) and disease-free survival (HR 0.83, 95%CI: 0.67-0.99). Results from subgroup analyses indicated that the pooled magnitude of this association was relatively lower in studies not referring to H. pylori in title and abstract. CONCLUSIONS: In conclusion, gastric cancer patients with H. pylori have a better prognosis than patients of H. pylori negative. More stringent surveillance strategies may be necessary for patients with H. pylori negative at cancer diagnosis.

Angiographic Revascularization after Bariatric Embolization in a Swine Model.

This study evaluated fundal arteriole angiographic revascularization after embolization with embolic microspheres of 3 different diameters in a swine model (16 swine, 31 arterioles). In the 50-µm group, 7 of 11 (64%) arterioles recanalized completely, 3 of 11 (27%) arterioles recanalized partially, and 1 of 11 (9%) arterioles had collateralization (no recanalization). In the 100- to 300-µm group, 7 of 10 (70%) arterioles recanalized completely and 3 of 10 (30%) arterioles) recanalized partially. In the 300- to 500-µm group, 7 of 10 (70%) arterioles recanalized completely, 1 of 10 (10%) arterioles recanalized partially, and 2 of 10 (20%) arterioles had collateralization. No difference was found between the groups in the degree of recanalization (P = .64). All embolized arterioles exhibited some degree of angiographic revascularization, irrespective of the microsphere size.

Profiling of schizophrenia-associated serum peptides by MALDI-TOF-MS.

Schizophrenia is a psychiatric condition characterized by poor prognosis and severe symptoms that decrease the quality of life of patients. It is therefore important to develop rapid and reliable methods for early diagnosis. To achieve this aim, identification of accurate biomarkers will promote research into the mechanisms of schizophrenia and the design of effective diagnosis tools. Discriminative peptides in the serum of participants (277 schizophrenia patients and 294 healthy controls) were detected using the matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF-MS). The diagnostic model for schizophrenia was validated using the ClinProTool software. Discrimination models were tested in the training set (200 schizophrenia patients and 200 healthy controls), and the robustness of the models was evaluated using the independent test set (77 cases and 94 controls). A total of 77 peaks were significantly different between schizophrenia patients and healthy controls with a signal-to-noise ratio of over 5. Among them, 35 peptides were down-regulated and 42 peptides were up-regulated in schizophrenia patients. With a cross-validation rate of 92.7% and a recognition capability rate of 96.5%, the supervised neural network comprising 25 discriminative peaks was found to be the most efficient model for schizophrenia diagnosis (sensitivity = 96.10%, specificity = 94.68%). Peptides at m/z = 2022.18 corresponded to complement C3f, and peptides at m/z = 1020.89, 1351.02, 1466.1 were identified as fragments of fibrinopeptide A. These two peptides may be potential biomarkers for schizophrenia in the Chinese population. The serum peptide levels present a potential clinical diagnostic tool for schizophrenia.

Bariatric Arterial Embolization with Calibrated Radiopaque Microspheres and an Antireflux Catheter Suppresses Weight Gain and Appetite-Stimulating Hormones in Swine.

PURPOSE: To examine safety and efficacy of bariatric arterial embolization (BAE) with x-ray-visible embolic microspheres (XEMs) and an antireflux catheter in swine. MATERIAL AND METHODS: BAE with selective infusion of XEMs (n = 6) or saline (n = 4, control) into gastric fundal arteries was performed under x-ray guidance. Weight and plasma hormone levels were measured at baseline and weekly for 4 weeks after embolization. Cone-beam CT images were acquired immediately after embolization and weekly for 4 weeks. Hormone-expressing cells in the stomach were assessed by immunohistochemical staining. RESULTS: BAE pigs lost weight 1 week after embolization followed by significantly impaired weight gain relative to control animals (14.3% vs 20.9% at 4 weeks, P = .03). Plasma ghrelin levels were significantly lower in BAE pigs than in control animals (1,221.6 pg/mL vs 1,706.2 pg/mL at 4 weeks, P < .01). XEMs were visible on x-ray and cone-beam CT during embolization, and radiopacity persisted over 4 weeks (165.5 HU at week 1 vs 158.5 HU at week 4, P = .9). Superficial mucosal ulcerations were noted in 1 of 6 BAE animals. Ghrelin-expressing cell counts were significantly lower in the gastric fundus (17.7 vs 36.8, P < .00001) and antrum (24.2 vs 46.3, P < .0001) of BAE pigs compared with control animals. Gastrin-expressing cell counts were markedly reduced in BAE pigs relative to control animals (98.5 vs 127.0, P < .02). Trichrome staining demonstrated significantly more fibrosis in BAE animals compared with control animals (13.8% vs 8.7%, P < .0001). CONCLUSIONS: XEMs enabled direct visualization of embolic material during and after embolization. BAE with XEMs and antireflux microcatheters was safe and effective.

Quantitative CT and 19F-MRI tracking of perfluorinated encapsulated mesenchymal stem cells to assess graft immunorejection.

OBJECTIVES: Peripheral artery disease (PAD) affects 12-14% of the world population, and many are not eligible for conventional treatment. For these patients, microencapsulated stem cells (SCs) offer a novel means to transplant mismatched therapeutic SCs to prevent graft immunorejection. Using c-arm CT and 19F-MRI for serial evaluation of dual X-ray/MR-visible SC microcapsules (XMRCaps) in a non-immunosuppressed rabbit PAD model, we explore quantitative evaluation of capsule integrity as a surrogate of transplanted cell fate. MATERIALS AND METHODS: XMRCaps were produced by impregnating 12% perfluorooctylbromine (PFOB) with rabbit or human SCs (AlloSC and XenoSC, respectively). Volume and 19F concentration measurements of XMRCaps were assessed both in phantoms and in vivo, at days 1, 8 and 15 after intramuscular administration in rabbits (n = 10), by 3D segmenting the injection sites and referencing to standards with known concentrations. RESULTS: XMRCap volumes and concentrations showed good agreement between CT and MRI both in vitro and in vivo in XenoSC rabbits. Injected capsules showed small variations over time and were similar between AlloSC and XenoSC rabbits. Histological staining revealed high cell viability and intact capsules 2 weeks after administration. CONCLUSIONS: Quantitative and non-invasive tracking XMRCaps using CT and 19F-MRI may be useful to assess graft immunorejection after SC transplantation.

Bariatric Arterial Embolization: Effect of Microsphere Size on the Suppression of Fundal Ghrelin Expression and Weight Change in a Swine Model.

Purpose To determine whether microsphere size effects ghrelin expression and weight gain after selective bariatric arterial embolization (BAE) in swine. Materials and Methods BAE was performed in 10 swine by using smaller (100-300 µm; n = 5) or larger (300-500 µm; n = 5) calibrated microspheres into gastric arteries. Nine control pigs underwent a sham procedure. Weight and fasting plasma ghrelin levels were measured at baseline and weekly for 16 weeks. Ghrelin-expressing cells (GECs) in the stomach were assessed by using immunohistochemical staining and analyzed by using the Wilcoxon rank-sum test. Results In pigs treated with smaller microspheres, mean weight gain at 16 weeks (106.9% ± 15.0) was less than in control pigs (131.9% ± 11.6) (P < .001). Mean GEC density was lower in the gastric fundus (14.8 ± 6.3 vs 25.0 ± 6.9, P < .001) and body (27.5 ± 12.3 vs 37.9 ± 11.8, P = .004) but was not significantly different in the gastric antrum (28.2 ± 16.3 vs 24.3 ± 11.6, P = .84) and duodenum (9.2 ± 3.8 vs 8.7 ± 2.9, P = .66) versus in control pigs. BAE with larger microspheres failed to suppress weight gain or GECs in any stomach part compared with results in control swine. Plasma ghrelin levels were similar between BAE pigs and control pigs, regardless of microsphere size. Week 1 endoscopic evaluation for gastric ulcers revealed none in control pigs, five ulcers in five pigs embolized by using smaller microspheres, and three ulcers in five pigs embolized by using larger microspheres. Conclusion In bariatric arterial embolization, smaller microspheres rather than larger microspheres showed greater weight gain suppression and fundal ghrelin expression with more gastric ulceration in a swine model. © RSNA, 2018.

Association Study between Ghrelin Gene Polymorphism and Metabolic Syndrome in a Han Chinese Population.

BACKGROUND: Ghrelin, in humans, is a hormone secreted from the stomach with an orexigenic effect, which is good for digestion and absorption, as well as regulating physical growth, metabolism, and energy balance. It is also involved in the development of metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM). This study assessed the association between single nucleotide variants of the GHRL gene and the risk of metabolic syndrome in a Han Chinese population. METHODS: A case-control study was performed on 3780 Han Chinese comprising 1813 MetS cases and 1967 controls. Three missense polymorphisms in GHRL (rs26802, rs10490816, and rs696217) were selected, and the association between these polymorphisms and the risk of MetS was investigated. Metabolic syndrome was defined according to the criteria of the International Diabetes Federation (IDF). RESULTS: Using Pearson's 2 test, we found that there were no significant differences in genotype distributions and allele frequencies between cases and controls (all p > 0.05). There were also no significant differences in haplotype distributions between MetS cases and healthy controls. Furthermore, we confirmed that rs26802 of the GHRL gene is associated with body mass index (BMI), waist circumference, systolic blood pressure (SBP), and fasting glucose; rs10490816 is associated with triglycerides (TG) and total cholesterol (TC); while rs696217 is associated with hip circumference and fasting glucose. CONCLUSIONS: We concluded that mutations in the GHRL gene did not confer risk for MetS in our study population. Therefore, functional analysis and replication studies in other populations are needed to further investigate the exact role of the GHRL gene in MetS.

Bariatric Radioembolization: A Pilot Study on Technical Feasibility and Safety in a Porcine Model.

PURPOSE: To evaluate feasibility of left gastric artery (LGA) yttrium-90 ((90)Y) radioembolization as potential treatment for obesity in a porcine model. MATERIALS AND METHODS: This study included 8 young female pigs (12-13 weeks, 21.8-28.1 kg). Six animals received infusions of (90)Y resin microspheres (46.3-105.1 MBq) into the main LGA and the gastric artery arising from the splenic artery. Animal weight and serum ghrelin were measured before treatment and weekly thereafter. Animals were euthanized 69-74 days after treatment, and histologic analyses of mucosal integrity and ghrelin immunoreactive cell density were performed. RESULTS: Superficial mucosal ulcerations < 3.0 cm(2) were noted in 5 of 6 treated animals. Ghrelin immunoreactive cell density was significantly lower in treated versus untreated animals in the stomach fundus (13.5 vs 34.8, P < .05) and stomach body (11.2 vs 19.8, P < .05). Treated animals gained less weight than untreated animals over the study duration (40.2 kg ± 5.4 vs 54.7 kg ± 6.5, P = .053). Average fundic parietal area (165 cm(2) vs 282 cm(2), P = .067) and average stomach weight (297.2 g vs 397.0 g, P = .067) were decreased in treated versus untreated animals. Trichrome staining revealed significantly more fibrosis in treatment animals compared with control animals (13.0 vs 8.6, P < .05). No significant differences were identified in plasma ghrelin concentrations (P = .24). CONCLUSIONS: LGA (90)Y radioembolization is promising as a potential treatment for obesity. A larger preclinical study is needed to evaluate the safety and efficacy of this procedure further.

Poor mental health status and its associations with demographic characteristics and chronic diseases in Chinese elderly.

OBJECTIVE: Although poor mental health is associated with significant personal and societal burden, it is rarely reported in older Chinese populations. This study examined the mental health status of a large representative sample of Chinese elderly in relation to socio-demographic characteristics, lifestyle, and chronic diseases. METHODS: Multistage stratified cluster sampling was used in this cross-sectional study. A total of 4115 people aged between 60 and 79 years were selected and interviewed with standardized assessment tools. The 12-item General Health Questionnaire (GHQ-12) was used to measure general mental health with the total score of ≥4 as the threshold for poor mental health status. RESULTS: The adjusted percentage of poor mental health status in the whole sample was 23.8 %; 18.5 % in men and 28.9 % in women. Multivariate logistic regression analysis revealed that female gender, widowed/separated marital status, rural abode, low income, poor diet, lack of physical exercise, and multi-morbidity were independently associated with poor mental health. The percentage of poor mental health status was significantly higher in patients with anemia, diabetes, hyperlipidemia, cataract/glaucoma, ischemic heart disease, cerebrovascular diseases, nasopharyngitis, chronic gastroenteritis/peptic ulcer, liver diseases, cholecystitis/gallstone, arthritis, or chronic low back pain. CONCLUSION: Given the high rate of poor mental health status among older Chinese population, policy makers and health professionals in China should address the mental health burden of its aging population.

Zinc Finger Protein 259 (ZNF259) Polymorphisms are Associated with the Risk of Metabolic Syndrome in a Han Chinese Population.

BACKGROUND: Zinc finger protein 259 (ZNF259) binds to the cytoplasmic domain of epidermal growth factor receptor (EGFR) in quiescent cells and contributes tolipid metabolism. This case and control study investigated the association between ZNF259 single nucleotide polymorphisms (SNPs) and metabolic syndrome (MetS). METHODS: This study included 1,812 MetS patients and 2,036 controls from the Jilin province of Northeastern China. MetS was diagnosed using the International Diabetes Federation (IDF) criteria. Three ZNF259 SNPs (rs964184, rs2075290 and rs2075294) were genotyped using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS). RESULTS: There were significant differences between metabolic syndrome and healthy control subjects for the ZNF259 rs964184 and rs2075290 genotypes. The minor alleles of both SNPs were associated with an increased risk of MetS and associated conditions (elevated triglycerides, elevated blood pressure, increased abdominal obesity, fasting hyperglycemia, and low HDL-C; p < 0.05). The distribution of haplotype G-G-G (rs964184, rs2075290 and rs2075294) was significantly different between MetS patients and controls (OR = 1.39; 95% CI, 1.24 - 1.56; p < 0.01). CONCLUSIONS: This study demonstrated that ZNF259 variants were associated with elevated MetS risk in a Han Chinese population from the Jilin province of Northeastern China.

Fused X-ray and MR imaging guidance of intrapericardial delivery of microencapsulated human mesenchymal stem cells in immunocompetent swine.

PURPOSE: To assess intrapericardial delivery of microencapsulated, xenogeneic human mesenchymal stem cells (hMSCs) by using x-ray fused with magnetic resonance (MR) imaging (x-ray/MR imaging) guidance as a potential treatment for ischemic cardiovascular disease in an immunocompetent swine model. MATERIALS AND METHODS: All animal experiments were approved by the institutional animal care and use committee. Stem cell microencapsulation was performed by using a modified alginate-poly-l-lysine-alginate encapsulation method to include 10% (wt/vol) barium sulfate to create barium-alginate microcapsules (BaCaps) that contained hMSCs. With x-ray/MR imaging guidance, eight female pigs (approximately 25 kg) were randomized to receive either BaCaps with hMSCs, empty BaCaps, naked hMSCs, or saline by using a percutaneous subxiphoid approach and were compared with animals that received empty BaCaps (n = 1) or BaCaps with hMSCs (n = 2) by using standard fluoroscopic delivery only. MR images and C-arm computed tomographic (CT) images were acquired before injection and 1 week after delivery. Animals were sacrificed immediately or at 1 week for histopathologic validation. Cardiac function between baseline and 1 week after delivery was evaluated by using a paired Student t test. RESULTS: hMSCs remained highly viable (94.8% ± 6) 2 days after encapsulation in vitro. With x-ray/MR imaging, successful intrapericardial access and delivery were achieved in all animals. BaCaps were visible fluoroscopically and at C-arm CT immediately and 1 week after delivery. Whereas BaCaps were free floating immediately after delivery, they consolidated into a pseudoepicardial tissue patch at 1 week, with hMSCs remaining highly viable within BaCaps; naked hMSCs were poorly retained. Follow-up imaging 1 week after x-ray/MR imaging-guided intrapericardial delivery showed no evidence of pericardial adhesion and/or effusion or adverse effect on cardiac function. In contradistinction, BaCaps delivery with x-ray fluoroscopy without x-ray/MR imaging (n = 3) resulted in pericardial adhesions and poor hMSC viability after 1 week. CONCLUSION: Intrapericardial delivery of BaCaps with hMSCs leads to high cell retention and survival. With x-ray/MR imaging guidance, intrapericardial delivery can be performed safely in the absence of preexisting pericardial effusion to provide a novel route for cardiac cellular regenerative therapy.

Tracking of stem cells in vivo for cardiovascular applications.

In the past ten years, the concept of injecting stem and progenitor cells to assist with rebuilding damaged blood vessels and myocardial tissue after injury in the heart and peripheral vasculature has moved from bench to bedside. Non-invasive imaging can not only provide a means to assess cardiac repair and, thereby, cellular therapy efficacy but also a means to confirm cell delivery and engraftment after administration. In this first of a two-part review, we will review the different types of cellular labeling techniques and the application of these techniques in cardiovascular magnetic resonance and ultrasound. In addition, we provide a synopsis of the cardiac cellular clinical trials that have been performed to-date.

Microencapsulated cell tracking.

Microencapsulation of therapeutic cells has been widely pursued to achieve cellular immunoprotection following transplantation. Initial clinical studies have shown the potential of microencapsulation using semi-permeable alginate layers, but much needs to be learned about the optimal delivery route, in vivo pattern of engraftment, and microcapsule stability over time. In parallel with noninvasive imaging techniques for 'naked' (i.e. unencapsulated) cell tracking, microcapsules have now been endowed with contrast agents that can be visualized by (1) H MRI, (19) F MRI, X-ray/computed tomography and ultrasound imaging. By placing the contrast agent formulation in the extracellular space of the hydrogel, large amounts of contrast agents can be incorporated with negligible toxicity. This has led to a new generation of imaging biomaterials that can render cells visible with multiple imaging modalities.

X-ray-visible microcapsules containing mesenchymal stem cells improve hind limb perfusion in a rabbit model of peripheral arterial disease.

The therapeutic goal in peripheral arterial disease (PAD) patients is to restore blood flow to ischemic tissue. Stem cell transplantation offers a new avenue to enhance arteriogenesis and angiogenesis. Two major problems with cell therapies are poor cell survival and the lack of visualization of cell delivery and distribution. To address these therapeutic barriers, allogeneic bone marrow-derived mesenchymal stem cells (MSCs) were encapsulated in alginate impregnated with a radiopaque contrast agent (MSC-Xcaps). In vitro MSC-Xcap viability by a fluorometric assay was high (96.9% ± 2.7% at 30 days postencapsulation) and as few as 10 Xcaps were visible on clinical x-ray fluoroscopic systems. Using an endovascular PAD model, rabbits (n = 21) were randomized to receive MSC-Xcaps (n = 6), empty Xcaps (n = 5), unencapsulated MSCs (n = 5), or sham intramuscular injections (n = 5) in the ischemic thigh 24 hours postocclusion. Immediately after MSC transplantation and 14 days later, digital radiographs acquired on a clinical angiographic system demonstrated persistent visualization of the Xcap injection sites with retained contrast-to-noise. Using a modified TIMI frame count, quantitative angiography demonstrated a 65% improvement in hind limb perfusion or arteriogenesis in MSC-Xcap-treated animals versus empty Xcaps. Post-mortem immunohistopathology of vessel density by anti-CD31 staining demonstrated an 87% enhancement in angiogenesis in Xcap-MSC-treated animals versus empty Xcaps. MSC-Xcaps represent the first x-ray-visible cellular therapeutic with enhanced efficacy for PAD treatment.

Novel insights into modifiable risk factors for arteriovenous fistula failure and the importance of CKD lipid profile: A meta-analysis.

BACKGROUND: Arteriovenous fistula (AVF) failure can occur in patients undergoing hemodialysis (HD). In this study, we explored the correlation between hyperlipidemia and AVF failure in patients undergoing HD. Moreover, we compared the lipid profiles of patients with chronic kidney disease (CKD) with those of healthy people to provide a basis for lipid-lowering in patients undergoing HD. METHOD AND ANALYSIS: We searched PubMed, Web of Science, Embase, the Cochrane library, CNKI, CBM, the China Science Periodical Database, and the China Science and Technology Journal Database. The final search was conducted on August 31, 2021, and the search period was restricted between 2000 and August 31, 2021, without publication restrictions. All studies met the inclusion criteria, and the influences of sex, age, geographical location, diagnosis method, and publication year were excluded. The data were analyzed using the random-effects model and the fixed-effects model. RESULTS: Twenty-eight studies were included in the meta-analysis with 121,666 patients in the CKD group and 1714 patients in the AVF failure group. Triglyceride concentration in patients with CKD was higher than in healthy subjects (MD: -31.56, 95% CI: -41.23 to -21.90, p < 0.00001). A high total cholesterol (TC) concentration (MD: 6.97, 95% CI: 2.19-11.74, p = 0.004) and a high low-density lipoprotein cholesterol (LDL-C) concentration (MD: 23.83, 95% CI: 18.48-29.18, p < 0.00001) were associated with AVF failure. Furthermore, HDL-C was lower in the AVF failure group than in the AVF patency group (MD: -2.68, 95% CI: -4.60 to -0.76, p = 0.006). CONCLUSION: Our analysis indicates that the AVF failure may be related to the increase of TC/LDL-C and the decrease of HDL-C. Although current guidelines do not consider intensive lipid-lowering therapy as necessary in patients undergoing HD, our research indicates that patients with AVF undergoing HD may need regular TC/LDL-C-lowering therapy to prevent AVF failure. However, this issue still needs well designed prospective trials.