scholarly journals Bioenergetics of Islet Preparations in a Pilot Clinical Trial of Peri-Transplant Hydroxychloroquine for Autologous Islet Transplantation

2021 ◽  
Vol 30 ◽  
pp. 096368972110574
Author(s):  
Ruth E. McDowell ◽  
Khawla F. Ali ◽  
Saloni Lad ◽  
Vicente T. San Martin ◽  
Rita Bottino ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Islet Transplantation ◽  
Graft Function ◽  
Flux Analysis ◽  
Islet Function ◽  
Clinical Endpoints ◽  
Extracellular Flux ◽  
Autologous Islet Transplantation

The inflammatory response is an obstacle to success in both allogeneic and autologous islet transplantation. In autologous islet transplantation (AIT), however, the recipient is also the donor, permitting pretreatment of donor/recipient for a controlled duration prior to transplantation. We sought to exploit this feature of (AIT) by pretreating donor/recipients with chronic pancreatitis undergoing total pancreatectomy and autologous islet transplantation (TPAIT) to test the hypothesis that peri-transplant treatment with the FDA-approved anti-inflammatory hydroxychloroquine (HCQ) improves graft function. In this randomized placebo-controlled pilot clinical study, patients ( n = 6) were treated with oral HCQ for 30 days prior to and 90 days after TPAIT. In vivo islet function was assessed via Mixed Meal Tolerance Testing before HCQ treatment, 6- and 12-months after surgery. In vitro islet bioenergetics were assessed at the time of transplantation via extracellular flux analysis of islet preparation samples from the clinical trial cohort and six additional patients ( n = 12). Our study shows that HCQ did not alter clinical endpoints, but HCQ-treated patients showed greater spare respiratory capacity (SRC) compared to samples from control patients ( P=0.028). Glycolytic metabolism of islet preparations directly correlated with stimulated C-peptide secretion both before and after TPAIT ( P=0.01, R 2=0.489 and P=0.03, R 2=0.674, respectively), and predicted in vivo islet function better than mitochondrial metabolism of islet preps or islet equivalents infused. Overnight culture of islet preparations altered bioenergetic function, significantly decreasing SRC and maximal respiration ( P<0.001). In conclusion, while HCQ did not alter clinical outcomes, it was associated with significantly increased SRC in islet preparations. Bioenergetic analyses of islet preparations suggests that culture should be avoided and that glycolysis may be a more sensitive indicator of in vivo islet function than current metrics, including islet oxygen consumption and islet equivalents infused.

scholarly journals Role of Exosomes in Islet Transplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Jordan Mattke ◽  
Srividya Vasu ◽  
Carly M. Darden ◽  
Kenjiro Kumano ◽  
Michael C. Lawrence ◽  
...  
Keyword(s):  
Islet Transplantation ◽  
Graft Function ◽  
Pancreatic Islet Transplantation ◽  
Complex Molecules ◽  
Wide Range ◽  
And Function ◽  
Antigen Presenting

Exosomes are known for their ability to transport nucleic acid, lipid, and protein molecules, which allows for communication between cells and tissues. The cargo of the exosomes can have a variety of effects on a wide range of targets to mediate biological function. Pancreatic islet transplantation is a minimally invasive cell replacement therapy to prevent or reverse diabetes mellitus and is currently performed in patients with uncontrolled type 1 diabetes or chronic pancreatitis. Exosomes have become a focus in the field of islet transplantation for the study of diagnostic markers of islet cell viability and function. A growing list of miRNAs identified from exosomes collected during the process of isolating islets can be used as diagnostic biomarkers of islet stress and damage, leading to a better understanding of critical steps of the isolation procedure that can be improved to increase islet yield and quality. Exosomes have also been implicated as a possible contributor to islet graft rejection following transplantation, as they carry donor major histocompatibility complex molecules, which are then processed by recipient antigen-presenting cells and sensed by the recipient immune cells. Exosomes may find their way into the therapeutic realm of islet transplantation, as exosomes isolated from mesenchymal stem cells have shown promising results in early studies that have seen increased viability and functionality of isolated and grafted islets in vitro as well as in vivo. With the study of exosomes still in its infancy, continued research on the role of exosomes in islet transplantation will be paramount to understanding beta cell regeneration and improving long-term graft function.

scholarly journals Creatine Supplementation for Patients with Inflammatory Bowl Diseases: A Scientific Rationale for a Clinical Trial

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1429
Author(s):  
Theo Wallimann ◽  
Caroline H. T. Hall ◽  
Sean P. Colgan ◽  
Louise E. Glover
Keyword(s):  
Ulcerative Colitis ◽  
Clinical Trial ◽  
Crohn’S Disease ◽  
Pilot Study ◽  
Crohn's Disease ◽  
Single Case ◽  
Initial Period ◽  
Creatine Supplementation

Based on theoretical considerations, experimental data with cells in vitro, animal studies in vivo, as well as a single case pilot study with one colitis patient, a consolidated hypothesis can be put forward, stating that “oral supplementation with creatine monohydrate (Cr), a pleiotropic cellular energy precursor, is likely to be effective in inducing a favorable response and/or remission in patients with inflammatory bowel diseases (IBD), like ulcerative colitis and/or Crohn’s disease”. A current pilot clinical trial that incorporates the use of oral Cr at a dose of 2 × 7 g per day, over an initial period of 2 months in conjunction with ongoing therapies (NCT02463305) will be informative for the proposed larger, more long-term Cr supplementation study of 2 × 3–5 g of Cr per day for a time of 3–6 months. This strategy should be insightful to the potential for Cr in reducing or alleviating the symptoms of IBD. Supplementation with chemically pure Cr, a natural nutritional supplement, is well tolerated not only by healthy subjects, but also by patients with diverse neuromuscular diseases. If the outcome of such a clinical pilot study with Cr as monotherapy or in conjunction with metformin were positive, oral Cr supplementation could then be used in the future as potentially useful adjuvant therapeutic intervention for patients with IBD, preferably together with standard medication used for treating patients with chronic ulcerative colitis and/or Crohn’s disease.

Cardiac-specific VEGFB overexpression reduces lipoprotein lipase activity and improves insulin action in rat heart

2021 ◽  
Author(s):  
Rui Shang ◽  
Nathaniel Lal ◽  
ChaeSyng Lee ◽  
Yajie Zhai ◽  
Karanjit Puri ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Lipoprotein Lipase ◽  
Insulin Action ◽  
Insulin Signalling ◽  
Isolated Heart ◽  
Cardiac Metabolism ◽  
Metabolic Reprogramming ◽  
Flux Analysis

Cardiac muscle utilizes multiple sources of energy including glucose and fatty acid (FA). The heart cannot synthesize FA and relies on obtaining it from other sources, with lipoprotein lipase (LPL) breakdown of lipoproteins suggested to be a key source of FA for cardiac use. Recent work has indicated that cardiac vascular endothelial growth factor B (VEGFB) overexpression expands the coronary vasculature and facilitates metabolic reprogramming that favours glucose utilization. We wanted to explore whether this influence of VEGFB on cardiac metabolism involves regulation of LPL activity with consequent effects on lipotoxicity and insulin signalling. The transcriptomes of rats with and without cardiomyocyte-specific overexpression of human VEGFB were compared by using RNA-sequencing. Isolated perfused hearts or cardiomyocytes incubated with heparin were used to enable measurement of LPL activity. Untargeted metabolomic analysis was performed for quantification of cardiac lipid metabolites. Cardiac insulin sensitivity was evaluated using fast-acting insulin. Isolated heart and cardiomyocytes were used to determine transgene-encoded VEGFB isoform secretion patterns and mitochondrial oxidative capacity using high-resolution respirometry and extracellular flux analysis. In vitro, primary transgenic cardiomyocytes incubated overnight and thus exposed to abundantly secreted VEGFB isoforms in the absence of any in vivo confounding regulators of cardiac metabolism demonstrated higher basal oxygen consumption. In the whole heart, VEGFB overexpression induced an angiogenic response that was accompanied by limited cardiac LPL activity through multiple mechanisms. This was associated with a lowered accumulation of lipid intermediates, diacylglycerols and lysophosphatidylcholine, that are known to influence insulin action. In response to exogenous insulin, transgenic hearts demonstrated increased insulin sensitivity. In conclusion, the interrogation of VEGFB function on cardiac metabolism uncovered an intriguing and previously unappreciated effect to lower LPL activity and prevent lipid metabolite accumulation to improve insulin action. VEGFB could be a potential cardioprotective therapy to treat metabolic disorders, for example diabetes.

Pharmacological Properties of Curcumin

2020 ◽  
pp. 235-248
Author(s):  
Anuradha Singh
Keyword(s):  
Clinical Trial ◽  
Natural Product ◽  
Mechanisms Of Action ◽  
Clinical Settings ◽  
Pharmacological Properties ◽  
Pharmacological Effects ◽  
The Poor ◽  
Cellular Factors

Curcumin, the polyphenol natural product, is a constituent of the traditional medicine known as turmeric. Extensive research over the last 50 years has indicated that this polyphenol displays potent pharmacological effects by targeting many critical cellular factors through a diverse array of mechanisms of action. However, there are some obstacles that prevent this wonder molecule to be effective in clinical settings and limit its use to topical applications only. Curcumin has recently been classified as both PAINS (panassay interference compounds) and an IMPS (invalid metabolic panaceas) candidate. Due to likely false activity of curcumin in vitro and in vivo has resulted unsuccessful clinical trial of curcumin against several disease. The chapter will review the essential medicinal chemistry of curcumin as well as envisage a compilation and discussion on the poor bioavailability of curcumin.

Failure of Demonstrated Clinical Efficacy of Antibiotic-Bonded Continuous Ambulatory Peritoneal Dialysis (CAPD) Catheters

1990 ◽  
Vol 10 (1) ◽  
pp. 57-59 ◽  
Author(s):  
Stanley Z. Trooskin ◽  
Richard A. Harvey ◽  
T. w. J. Lennard ◽  
Ralph S. Greco
Keyword(s):  
Clinical Trial ◽  
Peritoneal Dialysis ◽  
Continuous Ambulatory Peritoneal Dialysis ◽  
Infectious Complications ◽  
Clinical Report ◽  
Age And Gender ◽  
And Gender ◽  
To Receive

Previous in vitro, in vivo, and a preliminary clinical report have demonstrated efficacy of noncovalently bonding antibiotics to the surface of continuous ambulatory peritoneal dialysis (CAPO) catheters in decreasing infectious complications. A larger prospective randomized clinical trial was completed. Eighty-six patients with chronic renal failure were enrolled in the study and randomized to receive either a surfactant treated or untreated control catheter. All catheters were soaked in cefoxitin at the time of insertion. Groups were comparable in terms of pre-existing illnesses, age, and gender. No differences were shown in the incidence of cathetertract infections, peritonitis or mechanical complications. There was also no differences in microbiologic culture results. Therefore, it is concluded that this clinical trial did not demonstrate a reduction in catheter-related infectious complications by antibiotic bonding.

scholarly journals In vivo and in vitro hepatic phosphorus-31 magnetic resonance spectroscopy and electron microscopy in chronic ductopenic rejection of human liver allografts

Gut ◽  
1998 ◽  
Vol 42 (5) ◽  
pp. 735-743 ◽  
Author(s):  
S D Taylor-Robinson ◽  
J Sargentoni ◽  
J D Bell ◽  
E L Thomas ◽  
C D Marcus ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Graft Function ◽  
Phospholipid Metabolism ◽  
Biliary Duct ◽  
Resonance Spectroscopy ◽  
Liver Transplant Recipients

Background—In vivo hepatic phosphorus-31 magnetic resonance spectroscopy (MRS) provides non-invasive information about phospholipid metabolism.Aims—To delineate MRS abnormalities in patients with chronic ductopenic rejection (CDR) and to characterise spectral changes by in vitro MRS and electron microscopy.Patients and methods—Sixteen liver transplant recipients (four with CDR; 12 with good graft function) and 29 controls (23 healthy volunteers; six patients with biliary duct strictures) were studied with in vivo 31P MRS. Peak area ratios of phosphomonoesters (PME) and phosphodiesters (PDE), relative to nucleotide triphosphates (NTP) were measured. In vitro MRS and electron microscopy were performed on biopsy specimens from five patients with CDR, freeze clamped at retransplantation. Phosphoethanolamine (PE), phosphocholine (PC), glycerophosphorylethanolamine (GPE), and glycerophosphorylcholine (GPC) concentrations were measured.Results—The 12 patients with good graft function displayed no spectral abnormalities in vivo; the four patients with CDR showed significantly elevated PME:NTP (p<0.01) and PDE:NTP ratios (p<0.005). Patients with biliary strictures had significant differences in PME:NTP (p<0.01) from patients with CDR, but not in mean PDE:NTP. In vitro spectra from CDR patients showed elevated PE and PC, mirroring the in vivo changes in PME, but reduced GPE and GPC concentrations were observed, at variance with the in vivo PDE findings. On electron microscopy, there was no proliferation in hepatocyte endoplasmic reticulum.Conclusions—The increase in PME:NTP reflects altered phospholipid metabolism in patients with CDR, while the increase in PDE:NTP may represent a significant contribution from bile phospholipid.

scholarly journals Extra-Hepatic Islet Transplantation

2018 ◽  
Vol 27 (8) ◽  
pp. 1289-1293 ◽  
Author(s):  
Anaïs Schaschkow ◽  
Séverine Sigrist ◽  
Carole Mura ◽  
Caroline Dissaux ◽  
Karim Bouzakri ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Cell Therapy ◽  
Islet Transplantation ◽  
Graft Function ◽  
Surgical Techniques ◽  
Diabetic Rats ◽  
C Peptide ◽  
And Function ◽  
Islet Survival

Following the tremendous development of hydrogels for cell therapy, there is now a growing need for surgical techniques to validate in vivo scaffold benefits for islet transplantation. Therefore, we propose a newly designed surgical procedure involving the injection of hydrogel-embedded pancreatic islets in the omentum, which is considered a favorable environment for cell survival and function. Our technique, called h-Omental Matrix Islet filliNG (hOMING) was designed to test the benefits of hydrogel on islet survival and function in vivo. Islets were implanted in the omentum of diabetic rats using the hOMING technique and alginate as an islet carrier. Blood glucose and C-peptide levels were recorded to assess graft function. After 2 months, grafts were explanted and studied using insulin and vessel staining. All rats that underwent hOMING exhibited graft function characterized by a glycemia decrease and a C-peptidemia increase ( P < 0.001 compared with preoperative levels). Furthermore, hOMING appeared to preserve islet morphology and insulin content and allowed the proper revascularization of grafted islets. The results suggest that hOMING is a viable and promising approach to test in vivo the benefits of hydrogel administration for islet transplantation into the omental tissue.

scholarly journals Loss-of-Function Mutation of the Galanin Gene Is Associated with Perturbed Islet Function in Mice

Endocrinology ◽  
2004 ◽  
Vol 145 (7) ◽  
pp. 3190-3196 ◽  
Author(s):  
Bo Ahrén ◽  
Giovanni Pacini ◽  
David Wynick ◽  
Nils Wierup ◽  
Frank Sundler
Keyword(s):  
Insulin Secretion ◽  
Islet Cells ◽  
Insulin Response ◽  
Tolerance Test ◽  
Glucose Disposal ◽  
Islet Function ◽  
Loss Of Function ◽  
Euglycemic Hyperinsulinemic Clamp

Abstract The neuropeptide galanin is expressed in sympathetic nerve terminals that surround islet cells and inhibits insulin secretion. To explore its role for islet function, we studied mice with a loss-of-function mutation in the galanin gene [galanin knockout (KO) mice]. Intravenous 2-deoxy-glucose, which activates both the sympathetic and parasympathetic branches of the autonomic nervous system, caused an initial (1–5 min) inhibition of insulin secretion that was impaired in galanin KO mice (P = 0.027), followed by a subsequent stimulation of insulin secretion that was augmented in galanin KO mice (P &lt; 0.01). Similar effects were seen after chemical sympathectomy by 6-hydroxydopamine. In contrast, galanin KO mice had a reduced insulin response to glucose, both in vivo (P &lt; 0.001) and in isolated islets (P &lt; 0.001), and to arginine, both in vivo (P = 0.012) and in vitro (P = 0.018). During an iv glucose tolerance test, galanin KO mice had impaired glucose disposal (P = 0.005) due to a reduced insulin response (P &lt; 0.001) and a reduced insulin-independent glucose elimination (glucose effectiveness; P = 0.040). Insulin sensitivity, as judged by a euglycemic, hyperinsulinemic clamp technique, was slightly increased in galanin KO mice (P = 0.032). We conclude that 1) galanin may contribute to sympathetic influences inhibiting insulin secretion in mice, and 2) galanin KO mice have a reduced glucose-induced insulin secretion.

In Vivo Evaluation of Immunomodulating Effects of Lenalidomide (L) on Tumor Cell Microenvironment as a Possible Underlying Mechanism of the Antitumor Effects Observed in Patients (pts) with Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2975-2975 ◽  
Author(s):  
Asher Alban Chanan-Khan ◽  
Swaminathan Padmanabhan ◽  
Kena C. Miller ◽  
Paula Pera ◽  
Laurie DiMiceli ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Study ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Immune Cell ◽  
Underlying Mechanism ◽  
Antitumor Effects ◽  
Absolute Increase

Abstract Introduction: L is a more potent analogue of thalidomide with antitumor activity reported in MDS and multiple myeloma. Clinical anti-leukemic activity of L is reported for the first time by our group in pts with CLL. The underlying mechanism of its antitumor activity remains undetermined. We investigated the effect of L on the tumor microenvironment and studied the modulation of soluble cytokines and immune cells (T and NK cells) in pts receiving L. Patients and Methods: CLL pts enrolled on the clinical study with L were eligible. Pre and post (day 7) samples were obtained for evaluation of changes in serum cytokine and immune cell environment. Malignant cells were also obtained to investigate the in vitro antitumor activity of L prior to initiating treatment on clinical trial. Results: With Anexin V staining for evaluation of apoptosis induction, in vitro testing of pts samples (n=10) showed only a modest increase in apoptosis at 200mg of L - levels clinically not achievable. Yet same pts treated with L on clinical study showed significant antitumor response, suggesting the mechanism to be possibly related to modulation of the tumor microenvironment. In evaluation of the tumor cytokine microenvironment (n= 10) we noted significant L induced increase in IL-10 (n=6), IL-8 (n=8), IP-10 (n=10), IL-8 (n=8), TNF-alpha (n=4) and decrease in PDGF (n=5) and RANTES (n=5). While evaluation of the immune cell repertoire we observed an absolute increase in T-cell as well as NK-cell after treatment with L. Conclusion: Our in vitro evaluation does not suggest a direct apoptotic effect of L on the malignant CLL cells and thus support the hypothesis that the anti-leukemic effect noted in the clinical trial (reported separately) is most likely from in vivo modulation of the tumor microenvironment as is demonstrated from changes in the cytokine milieu and the cellular immune response. Collectively these changes may be responsible for the immune modulating properties of L and the resultant anti-CLL activity in pts.

Enhanced In Vivo activation of Adoptively Transferred Genetically Targeted T Cells Following Cyclophosphamide Chemotherapy: Initial Results From a Phase I Clinical Trial Treating CLL Patients with Autologous CD19-Targeted T Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3436-3436
Author(s):  
Renier J. Brentjens ◽  
Daniel Hollyman ◽  
Jae Park ◽  
Elmer Santos ◽  
Raymond Yeh ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
High Efficiency ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Autologous Tumor

Abstract Abstract 3436 Poster Board III-324 Patient T cells may be genetically modified to express chimeric antigen receptors (CARs) targeted to antigens expressed on tumor cells. We have initiated a clinical trial treating chemotherapy-refractory chronic lymphocytic leukemia (CLL) patients with autologous T cells modified to express the 19-28z CAR targeted to the CD19 antigen expressed on most B cell malignancies. In the first cohort of this trial, patients were infused with the lowest planned dose of modified T cells alone. All patients treated in this cohort experienced low-grade fevers following modified T cell infusion, and 2 of 3 treated patients exhibited subjective and laboratory evidence of transient reductions in tumor burden. The first patient treated on the second cohort of this study received prior cyclophophamide chemotherapy followed by the same dose of modified T cells administered to the first cohort of patients. This patient experienced persistent fevers, dyspnea, hypotension, renal failure, and died 44 hours following modified T cell infusion, likely secondary to sepsis. Modified T cells were not detectable in the peripheral blood of treated patients at 1 hour following completion of T cell infusion. However, post mortem analyses revealed a rapid infiltration of targeted T cells into anatomical sites of tumor involvement. Serum levels of the inflammatory cytokines IL-5, IL-8, and GM-CSF, but not TNFα, markedly and rapidly increased following infusion of genetically targeted T cells in this patient, mirroring the in vitro cytokine secretion profile of this patient's T cells, and consistent with marked in vivo activation of the modified T cells. Similar cytokine signatures were not found in patients from the first cohort. Significantly, serum cytokine analyses from the second cohort patient revealed a marked increase in the pro-proliferative cytokines IL-2, IL-7, IL-12, and IL-15 following cyclophosphamide therapy, in contrast to the baseline levels found in the first cohort. This report demonstrates the high efficiency trafficking of CD19-targeted T cells and in vivo activation of T cells encoding a second generation CD28/zeta chain-based chimeric antigen receptor. Furthermore, these data highlight mechanisms whereby cyclophosphamide may generate an in vivo milieu that enhances the anti-tumor efficacy of autologous tumor targeted T cells. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document