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The role of ultrasound in enhancing mesenchymal stromal cell-based therapies. Stem cells translational medicine Liu, D. D., Ullah, M., Concepcion, W., Dahl, J. J., Thakor, A. S. 2020
Abstract

Mesenchymal stromal cells (MSCs) have been a popular platform for cell-based therapy in regenerative medicine due to their propensity to home to damaged tissue and act as a repository of regenerative molecules that can promote tissue repair and exert immunomodulatory effects. Accordingly, a great deal of research has gone into optimizing MSC homing and increasing their secretion of therapeutic molecules. A variety of methods have been used to these ends, but one emerging technique gaining significant interest is the use of ultrasound. Sound waves exert mechanical pressure on cells, activating mechano-transduction pathways and altering gene expression. Ultrasound has been applied both to cultured MSCs to modulate self-renewal and differentiation, and to tissues-of-interest to make them a more attractive target for MSC homing. Here, we review the various applications of ultrasound to MSC-based therapies, including low-intensity pulsed ultrasound, pulsed focused ultrasound, and extracorporeal shockwave therapy, as well as the use of adjunctive therapies such as microbubbles. At a molecular level, it seems that ultrasound transiently generates a local gradient of cytokines, growth factors, and adhesion molecules that facilitate MSC homing. However, the molecular mechanisms underlying these methods are far from fully elucidated and may differ depending on the ultrasound parameters. We thus put forth minimal criteria for ultrasound parameter reporting, in order to ensure reproducibility of studies in the field. A deeper understanding of these mechanisms will enhance our ability to optimize this promising therapy to assist MSC-based approaches in regenerative medicine.

View details for DOI 10.1002/sctm.19-0391

View details for PubMedID 32157802
Controlled Nutrient Delivery to Pancreatic Islets Using Polydopamine-Coated Mesoporous Silica Nanoparticles. Nano letters Razavi, M., Primavera, R., Kevadiya, B. D., Wang, J., Ullah, M., Buchwald, P., Thakor, A. S. 2020
Abstract

In the present study, we created a nanoscale platform that can deliver nutrients to pancreatic islets in a controlled manner. Our platform consists of a mesoporous silica nanoparticle (MSNP), which can be loaded with glutamine (G: an essential amino acid required for islet survival and function). To control the release of G, MSNPs were coated with a polydopamine (PD) layer. With the optimal parameters (0.5 mg/mL and 0.5 h), MSNPs were coated with a layer of PD, which resulted in a delay of G release from MSNPs over 14 d (57.4 � 4.7% release). Following syngeneic renal subcapsule islet transplantation in diabetic mice, PDG-MSNPs improved the engraftment of islets (i.e., enhanced revascularization and reduced inflammation) as well as their function, resulting in re-establishment of glycemic control. Collectively, our data show that PDG-MSNPs can support transplanted islets by providing them with a controlled and sustained supply of nutrients.

View details for DOI 10.1021/acs.nanolett.0c02576

View details for PubMedID 32909757
Facilitating islet transplantation using a three-step approach with mesenchymal stem cells, encapsulation, and pulsed focused ultrasound. Stem cell research & therapy Razavi, M., Ren, T., Zheng, F., Telichko, A., Wang, J., Dahl, J. J., Demirci, U., Thakor, A. S. 2020; 11 (1): 405
Abstract

The aim of this study was to examine the effect of a three-step approach that utilizes the application of adipose tissue-derived mesenchymal stem cells (AD-MSCs), encapsulation, and pulsed focused ultrasound (pFUS) to help the engraftment and function of transplanted islets.In step 1, islets were co-cultured with AD-MSCs to form a coating of AD-MSCs on islets: here, AD-MSCs had a cytoprotective effect on islets; in step 2, islets coated with AD-MSCs were conformally encapsulated in a thin layer of alginate using a co-axial air-flow method: here, the capsule enabled AD-MSCs to be in close proximity to islets; in step 3, encapsulated islets coated with AD-MSCs were treated with pFUS: here, pFUS enhanced the secretion of insulin from islets as well as stimulated the cytoprotective effect of AD-MSCs.Our approach was shown to prevent islet death and preserve islet functionality in vitro. When 175 syngeneic encapsulated islets coated with AD-MSCs were transplanted beneath the kidney capsule of diabetic mice, and then followed every 3�days with pFUS treatment until day 12 post-transplantation, we saw a significant improvement in islet function with diabetic animals re-establishing glycemic control over the course of our study (i.e., 30?days). In addition, our approach was able to enhance islet engraftment by facilitating their revascularization and reducing inflammation.This study demonstrates that our clinically translatable three-step approach is able to improve the function and viability of transplanted islets.

View details for DOI 10.1186/s13287-020-01897-z

View details for PubMedID 32948247
Locoregional delivery of stem cell-based therapies. Science translational medicine Ng, N. N., Thakor, A. S. 2020; 12 (547)
Abstract

Interventional regenerative medicine (IRM) uses image-guided, minimally invasive procedures for the targeted delivery of stem cell-based therapies to regenerate, replace, or repair damaged organs. Although many cellular therapies have shown promise in the preclinical setting, clinical results have been suboptimal. Most intravenously delivered cells become trapped in the lungs and reticuloendothelial system, resulting in little therapy reaching target tissues. IRM aims to increase the efficacy of cell-based therapies by locoregional stem cell delivery via endovascular, endoluminal, or direct injection into tissues. This review highlights routes of delivery, disease states, and mechanisms of action involved in the targeted delivery of stem cells.

View details for DOI 10.1126/scitranslmed.aba4564

View details for PubMedID 32522806
A Collagen Based Cryogel Bioscaffold that Generates Oxygen for Islet Transplantation. Advanced functional materials Razavi, M., Primavera, R., Kevadiya, B. D., Wang, J., Buchwald, P., Thakor, A. S. 2020; 30 (15)
Abstract

The aim of this work was to develop, characterize and test a novel 3D bioscaffold matrix which can accommodate pancreatic islets and provide them with a continuous, controlled and steady source of oxygen to prevent hypoxia-induced damage following transplantation. Hence, we made a collagen based cryogel bioscaffold which incorporated calcium peroxide (CPO) into its matrix. The optimal concentration of CPO integrated into bioscaffolds was 0.25wt.% and this generated oxygen at 0.21�0.02mM/day (day 1), 0.19�0.01mM/day (day 6), 0.13�0.03mM/day (day 14), and 0.14�0.02mM/day (day 21). Accordingly, islets seeded into cryogel-CPO bioscaffolds had a significantly higher viability and function compared to islets seeded into cryogel alone bioscaffolds or islets cultured alone on traditional cell culture plates; these findings were supported by data from quantitative computational modelling. When syngeneic islets were transplanted into the epididymal fat pad (EFP) of diabetic mice, our cryogel-0.25wt.%CPO bioscaffold improved islet function with diabetic animals re-establishing glycemic control. Mice transplanted with cryogel-0.25wt.%CPO bioscaffolds showed faster responses to intraperitoneal glucose injections and had a higher level of insulin content in their EFP compared to those transplanted with islets alone (P<0.05). Biodegradability studies predicted that our cryogel-CPO bioscaffolds will have long-lasting biostability for approximately 5 years (biodegradation rate: 16.00�0.65%/year). Long term implantation studies (i.e. 6 months) showed that our cryogel-CPO bioscaffold is biocompatible and integrated into the surrounding fat tissue with minimal adverse tissue reaction; this was further supported by no change in blood parameters (i.e. electrolyte, metabolic, chemistry and liver panels). Our novel oxygen-generating bioscaffold (i.e. cryogel-0.25wt.%CPO) therefore provides a biostable and biocompatible 3D microenvironment for islets which can facilitate islet survival and function at extra-hepatic sites of transplantation.

View details for DOI 10.1002/adfm.201902463

View details for PubMedID 33071709

View details for PubMedCentralID PMC7567341
Nanooncology: The Future of Cancer Diagnosis and Therapy CA-A CANCER JOURNAL FOR CLINICIANS Thakor, A. S., Gambhir, S. S. 2013; 63 (6): 395-418
Abstract

In recent years, there has been an unprecedented expansion in the field of nanomedicine with the development of new nanoparticles for the diagnosis and treatment of cancer. Nanoparticles have unique biological properties given their small size and large surface area-to-volume ratio, which allows them to bind, absorb, and carry compounds such as small molecule drugs, DNA, RNA, proteins, and probes with high efficiency. Their tunable size, shape, and surface characteristics also enable them to have high stability, high carrier capacity, the ability to incorporate both hydrophilic and hydrophobic substances and compatibility with different administration routes, thereby making them highly attractive in many aspects of oncology. This review article will discuss how nanoparticles are able to function as carriers for chemotherapeutic drugs to increase their therapeutic index; how they can function as therapeutic agents in photodynamic, gene, and thermal therapy; and how nanoparticles can be used as molecular imaging agents to detect and monitor cancer progression.

View details for DOI 10.3322/caac.21199

View details for PubMedID 24114523
The Fate and Toxicity of Raman-Active Silica-Gold Nanoparticles in Mice SCIENCE TRANSLATIONAL MEDICINE Thakor, A. S., Luong, R., Paulmurugan, R., Lin, F. I., Kempen, P., Zavaleta, C., Chu, P., Massoud, T. F., Sinclair, R., Gambhir, S. S. 2011; 3 (79)
Abstract

Raman spectroscopy is an optical imaging method that is based on the Raman effect, the inelastic scattering of a photon when energy is absorbed from light by a surface. Although Raman spectroscopy is widely used for chemical and molecular analysis, its clinical application has been hindered by the inherently weak nature of the Raman effect. Raman-silica-gold-nanoparticles (R-Si-Au-NPs) overcome this limitation by producing larger Raman signals through surface-enhanced Raman scattering. Because we are developing these particles for use as targeted molecular imaging agents, we examined the acute toxicity and biodistribution of core polyethylene glycol (PEG)-ylated R-Si-Au-NPs after different routes of administration in mice. After intravenous administration, PEG-R-Si-Au-NPs were removed from the circulation by macrophages in the liver and spleen (that is, the reticuloendothelial system). At 24 hours, PEG-R-Si-Au-NPs elicited a mild inflammatory response and an increase in oxidative stress in the liver, which subsided by 2 weeks after administration. No evidence of significant toxicity was observed by measuring clinical, histological, biochemical, or cardiovascular parameters for 2 weeks. Because we are designing targeted PEG-R-Si-Au-NPs (for example, PEG-R-Si-Au-NPs labeled with an affibody that binds specifically to the epidermal growth factor receptor) to detect colorectal cancer after administration into the bowel lumen, we tested the toxicity of the core nanoparticle after administration per rectum. We observed no significant bowel or systemic toxicity, and no PEG-R-Si-Au-NPs were detected systemically. Although additional studies are required to investigate the long-term effects of PEG-R-Si-Au-NPs and their toxicity when carrying the targeting moiety, the results presented here support the idea that PEG-R-Si-Au-NPs can be safely used in living subjects, especially when administered rectally.

View details for DOI 10.1126/scitranslmed.3001963

View details for PubMedID 21508310
Oxidative Stress Mediates the Effects of Raman-Active Gold Nanoparticles in Human Cells SMALL Thakor, A. S., Paulmurugan, R., Kempen, P., Zavaleta, C., Sinclair, R., Massoud, T. F., Gambhir, S. S. 2011; 7 (1): 126-136
Abstract

Polyethylene glycol (PEG)ylated Raman-active gold nanoparticles (PEG-R-AuNPs) consist of an interchangeable Raman organic molecule layer held onto a gold nanocore by a silica shell. PEG-R-AuNPs have been shown preclinically to increase the sensitivity and specificity of Raman spectroscopy, with picomolar sensitivity and multiplexing capabilities. Although clinical trials are being designed to use functionalized PEG-R-AuNPs in various applications (e.g., to target dysplastic bowel lesions during colonoscopy), the effects of these nanoparticles on human cells remain unknown. The occurrence and mechanisms underlying any potential cytotoxicity induced by these nanoparticles (0-1000 PEG-R-AuNPs/cell) are investigated in immortalized human HeLa and HepG2 cell lines at several time points (0-48 h) after exposure. Using fluorometric assays, cell viability (MTT), reactive oxygen species (ROS) generation (dichlorofluorescein diacetate), protein oxidation (protein carbonyl content), and total cellular antioxidant concentrations the concentrations (metmyoblobin-induced oxidation of ABTS) are assessed. Analysis of lipid oxidation using an enzyme immunoassay (8-isoprostane concentrations), gene expression of antioxidant enzymes using quantitative reverse transcription polymerase chain reactions, and the intracellular location of PEG-R-AuNPs using transmission electron microscopy is also undertaken. PEG-R-AuNPs cause no cytotoxicity in either HeLa or HepG2 cells in the acute setting as ROS generation is balanced by antioxidant enzyme upregulation. Following prolonged exposures (48 h) at relatively high concentrations (1000 PEG-R-AuNPs/cell), nanoparticles are found within vesicles inside cells. Under these conditions, a minimal amount of cytotoxicity is seen in both cell lines owing to increases in cellular oxidative stress, most likely due to ROS overwhelming the antioxidant defenses. Evidence of oxidative stress-induced damage includes increased lipid and protein oxidation. Although further in vivo toxicity studies are necessary, these initial encouraging results show that PEG-R-AuNPs cause minimal toxicity in human cells in the acute setting, which bodes well for potential future applications of these nanoparticles in living subjects.

View details for DOI 10.1002/smll.201001466

View details for PubMedID 21104804
Altered Cardiovascular Defense to Hypotensive Stress in the Chronically Hypoxic Fetus HYPERTENSION Allison, B. J., Brain, K. L., Niu, Y., Kane, A. D., Herrera, E. A., Thakor, A. S., Botting, K. J., Cross, C. M., Itani, N., Shaw, C. J., Skeffington, K. L., Beck, C., Giussani, D. A. 2020; 76 (4): 1195?1207
Abstract

The hypoxic fetus is at greater risk of cardiovascular demise during a challenge, but the reasons behind this are unknown. Clinically, progress has been hampered by the inability to study the human fetus non-invasively for long period of gestation. Using experimental animals, there has also been an inability to induce gestational hypoxia while recording fetal cardiovascular function as the hypoxic pregnancy is occurring. We use novel technology in sheep pregnancy that combines induction of controlled chronic hypoxia with simultaneous, wireless recording of blood pressure and blood flow signals from the fetus. Here, we investigated the cardiovascular defense of the hypoxic fetus to superimposed acute hypotension. Pregnant ewes carrying singleton fetuses surgically prepared with catheters and flow probes were randomly exposed to normoxia or chronic hypoxia from 121�1 days of gestation (term ?145 days). After 10 days of exposure, fetuses were subjected to acute hypotension via fetal nitroprusside intravenous infusion. Underlying in vivo mechanisms were explored by (1) analyzing fetal cardiac and peripheral vasomotor baroreflex function; (2) measuring the fetal plasma catecholamines; and (3) establishing fetal femoral vasoconstrictor responses to the ?1-adrenergic agonist phenylephrine. Relative to controls, chronically hypoxic fetal sheep had reversed cardiac and impaired vasomotor baroreflex function, despite similar noradrenaline and greater adrenaline increments in plasma during hypotension. Chronic hypoxia markedly diminished the fetal vasopressor responses to phenylephrine. Therefore, we show that the chronically hypoxic fetus displays markedly different cardiovascular responses to acute hypotension, providing in vivo evidence of mechanisms linking its greater susceptibility to superimposed stress.

View details for DOI 10.1161/HYPERTENSIONAHA.120.15384

View details for Web of Science ID 000571818100024

View details for PubMedID 32862711

View details for PubMedCentralID PMC7480941
Pulsed focused ultrasound enhances the therapeutic effect of mesenchymal stromal cell-derived extracellular vesicles in acute kidney injury. Stem cell research & therapy Ullah, M., Liu, D. D., Rai, S., Razavi, M., Concepcion, W., Thakor, A. S. 2020; 11 (1): 398
Abstract

BACKGROUND: Acute kidney injury (AKI) is characterized by rapid failure of renal function and has no curative therapies. Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) are known to carry therapeutic factors, which have shown promise in regenerative medicine applications, including AKI. However, there remains an unmet need to optimize their therapeutic effect. One potential avenue of optimization lies in pulsed focused ultrasound (pFUS), where tissues-of-interest are treated with sound waves. pFUS has been shown to enhance MSC therapy via increased cell homing, but its effects on cell-free EV therapy remain largely unexplored.METHODS: We combine pFUS pretreatment of the kidney with MSC-derived EV therapy in a mouse model of cisplatin-induced AKI.RESULTS: EVs significantly improved kidney function, reduced injury markers, mediated increased proliferation, and reduced inflammation and apoptosis. While pFUS did not enhance EV homing to the kidney, the combined treatment resulted in a superior therapeutic effect compared to either treatment alone. We identified several molecular mechanisms underlying this synergistic therapeutic effect, including upregulation of proliferative signaling (MAPK/ERK, PI3K/Akt) and regenerative pathways (eNOS, SIRT3), as well as suppression of inflammation.CONCLUSION: Taken together, pFUS may be a strategy for enhancing the therapeutic efficacy of MSC-derived EV treatment for the treatment of AKI.

View details for DOI 10.1186/s13287-020-01922-1

View details for PubMedID 32928310
Loop-Mediated Isothermal Amplification (LAMP): A Rapid, Sensitive, Specific, and Cost-Effective Point-of-Care Test for Coronaviruses in the Context of COVID-19 Pandemic. Biology Augustine, R., Hasan, A., Das, S., Ahmed, R., Mori, Y., Notomi, T., Kevadiya, B. D., S Thakor, A. 2020; 9 (8)
Abstract

The rampant spread of COVID-19 and the worldwide prevalence of infected cases demand a rapid, simple, and cost-effective Point of Care Test (PoCT) for the accurate diagnosis of this pandemic. The most common molecular tests approved by regulatory bodies across the world for COVID-19 diagnosis are based on Polymerase Chain Reaction (PCR). While PCR-based tests are highly sensitive, specific, and remarkably reliable, they have many limitations ranging from the requirement of sophisticated laboratories, need of skilled personnel, use of complex protocol, long wait times for results, and an overall high cost per test. These limitations have inspired researchers to search for alternative diagnostic methods that are fast, economical, and executable in low-resource laboratory settings. The discovery of Loop-mediated isothermal Amplification (LAMP) has provided a reliable substitute platform for the accurate detection of low copy number nucleic acids in the diagnosis of several viral diseases, including epidemics like Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). At present, a cocktail of LAMP assay reagents along with reverse transcriptase enzyme (Reverse Transcription LAMP, RT-LAMP) can be a robust solution for the rapid and cost-effective diagnosis for COVID-19, particularly in developing, and low-income countries. In summary, the development of RT-LAMP based diagnostic tools in a paper/strip format or the integration of this method into a microfluidic platform such as a Lab-on-a-chip may revolutionize the concept of PoCT for COVID-19 diagnosis. This review discusses the principle, technology and past research underpinning the success for using this method for diagnosing MERS and SARS, in addition to ongoing research, and the prominent prospect of RT-LAMP in the context of COVID-19 diagnosis.

View details for DOI 10.3390/biology9080182

View details for PubMedID 32707972
HSP70-Mediated NLRP3 Inflammasome Suppression Underlies Reversal of Acute Kidney Injury Following Extracellular Vesicle and Focused Ultrasound Combination Therapy. International journal of molecular sciences Ullah, M., Liu, D. D., Rai, S., Concepcion, W., Thakor, A. S. 2020; 21 (11)
Abstract

Acute kidney injury (AKI) is the abrupt loss of renal function, for which only supportive therapies exist. Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) have been shown to be therapeutically effective in treating AKI by spurring endogenous cell proliferation and survival while suppressing inflammation. Pre-treating kidneys with pulsed focused ultrasound (pFUS) has also been shown to enhance MSC therapy for AKI, but its role in MSC-derived EV therapy remains unexplored. Using a mouse model of cisplatin-induced AKI, we show that combination therapy with pFUS and EVs restores physiological and molecular markers of kidney function, more so than either alone. Both pFUS and EVs downregulate heat shock protein 70 (HSP70), the NLRP3 inflammasome, and its downstream pro-inflammatory cytokines IL-1beta and IL-18, all of which are highly upregulated in AKI. In vitro knockdown studies suggest that HSP70 is a positive regulator of the NLRP3 inflammasome. Our study therefore demonstrates the ability of pFUS to enhance EV therapy for AKI and provides further mechanistic understanding of their anti-inflammatory and regenerative effects.

View details for DOI 10.3390/ijms21114085

View details for PubMedID 32521623
Liposomal nanotheranostics for multimode targeted in vivo bioimaging and near-infrared light mediated cancer therapy. Communications biology Prasad, R., Jain, N. K., Yadav, A. S., Chauhan, D. S., Devrukhkar, J., Kumawat, M. K., Shinde, S., Gorain, M., Thakor, A. S., Kundu, G. C., Conde, J., Srivastava, R. 2020; 3 (1): 284
Abstract

Developing a nanotheranostic agent with better image resolution and high accumulation into solid tumor microenvironment is a challenging task. Herein, we established a light mediated phototriggered strategy for enhanced tumor accumulation of nanohybrids. A multifunctional liposome based nanotheranostics loaded with gold nanoparticles (AuNPs) and emissive graphene quantum dots (GQDs) were engineered named as NFGL. Further, doxorubicin hydrochloride was encapsulated in NFGL to exhibit phototriggered chemotherapy and functionalized with folic acid targeting ligands. Encapsulated agents showed imaging bimodality for in vivo tumor diagnosis due to their high contrast and emissive nature. Targeted NFGL nanohybrids demonstrated near infrared light (NIR, 750nm) mediated tumor reduction because of generated heat and Reactive Oxygen Species (ROS). Moreover, NFGL nanohybrids exhibited remarkable ROS scavenging ability as compared to GQDs loaded liposomes validated by antitumor study. Hence, this approach and engineered system could open new direction for targeted imaging and cancer therapy.

View details for DOI 10.1038/s42003-020-1016-z

View details for PubMedID 32504032
Dynamic Hydrodissection for Skin Protection during Cryoablation of Superficial Lesions. Journal of vascular and interventional radiology : JVIR Sandberg, J. K., Shoaf, K. R., Lungren, M. P., Young, V. A., Josephs, S., Thakor, A. S. 2020
View details for DOI 10.1016/j.jvir.2020.01.025

View details for PubMedID 32418774
A Collagen Based Cryogel Bioscaffold that Generates Oxygen for Islet Transplantation ADVANCED FUNCTIONAL MATERIALS Razavi, M., Primavera, R., Kevadiya, B. D., Wang, J., Buchwald, P., Thakor, A. S. 2020
View details for DOI 10.1002/adfm.201902463

View details for Web of Science ID 000518155100001
Rapid Antibody-Based COVID-19 Mass Surveillance: Relevance, Challenges, and Prospects in a Pandemic and Post-Pandemic World. Journal of clinical medicine Augustine, R., Das, S., Hasan, A., S, A., Abdul Salam, S., Augustine, P., Dalvi, Y. B., Varghese, R., Primavera, R., Yassine, H. M., Thakor, A. S., Kevadiya, B. D. 2020; 9 (10)
Abstract

The aggressive outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) as COVID-19 (coronavirus disease-2019) pandemic demands rapid and simplified testing tools for its effective management. Increased mass testing and surveillance are crucial for controlling the disease spread, obtaining better pandemic statistics, and developing realistic epidemiological models. Despite the advantages of nucleic acid- and antigen-based tests such as accuracy, specificity, and non-invasive approaches of sample collection, they can only detect active infections. Antibodies (immunoglobulins) are produced by the host immune system within a few days after infection and persist in the blood for at least several weeks after infection resolution. Antibody-based tests have provided a substitute and effective method of ultra-rapid detection for multiple contagious disease outbreaks in the past, including viral diseases such as SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome). Thus, although not highly suitable for early diagnosis, antibody-based methods can be utilized to detect past infections hidden in the population, including asymptomatic ones. In an active community spread scenario of a disease that can provide a bigger window for mass detections and a practical approach for continuous surveillance. These factors encouraged researchers to investigate means of improving antibody-based rapid tests and employ them as reliable, reproducible, sensitive, specific, and economic tools for COVID-19 mass testing and surveillance. The development and integration of such immunoglobulin-based tests can transform the pandemic diagnosis by moving the same out of the clinics and laboratories into community testing sites and homes. This review discusses the principle, technology, and strategies being used in antibody-based testing at present. It also underlines the immense prospect of immunoglobulin-based testing and the efficacy of repeated planned deployment in pandemic management and post-pandemic sustainable screenings globally.

View details for DOI 10.3390/jcm9103372

View details for PubMedID 33096742
Reversal of Hyperglycemia and Suppression of Type 1 Diabetes in the NOD Mouse with Apoptotic DNA Immunotherapy? (ADi?), ADi-100. Biomedicines Alleva, D. G., Rezaee, M., Yip, L., Ren, G., Rosenberg, J., Concepcion, W., Escher, A., Shabahang, S., Thakor, A. S. 2020; 8 (3)
Abstract

The antigen-specific apoptotic DNA immunotherapeutic, ADi-100, is designed to suppress type 1 diabetes and consists of two DNA plasmids encoding genetic sequences of the apoptosis-inducing molecule, BAX, and the secreted form of the autoantigen, glutamic acid decarboxylase 65, that is CpG hyper-methylated to avoid inflammatory signaling (msGAD55). Upon a four-day treatment with ADi-100 of young female non-obese diabetic (NOD) mice, the frequency of various tolerogenic dendritic cell populations increased in draining lymph nodes; these cells lost the capacity to stimulate glutamic acid decarboxylase (GAD)-specific CD4+ T lymphocytes and were associated with the previously demonstrated enhancement of GAD-specific regulatory T cells. The efficacy of two ADi-100 formulations containing different proportions of BAX and msGAD55, 1:4 (10/40 �g) and 1:2 (17/33 �g), was evaluated in mildly hyperglycemic pre-diabetic NOD female mice. Both formulations suppressed the incidence of diabetes by 80% in an antigen-specific manner, while all untreated mice developed diabetes. However, treatment of pre-diabetic mice with significantly higher hyperglycemia, denoting progressive disease, showed that ADi-100 1:2 strongly suppressed diabetes incidence by 80% whereas the ADi-100 1:4 was less effective (50%). As an antigen-specific monotherapy, ADi-100 is highly efficacious in reversing elevated hyperglycemia to prevent diabetes, in which increasing apoptosis-inducing BAX content is a promising immune tolerance feature.

View details for DOI 10.3390/biomedicines8030053

View details for PubMedID 32143316
Reversing Acute Kidney Injury Using Pulsed Focused Ultrasound and MSC Therapy: A Role for HSP-Mediated PI3K/AKT Signaling. Molecular therapy. Methods & clinical development Ullah, M., Liu, D. D., Rai, S., Dadhania, A., Jonnakuti, S., Concepcion, W., Thakor, A. S. 2020; 17: 683?94
Abstract

Acute kidney injury (AKI) is characterized by a sudden failure of renal function, but despite increasing worldwide prevalence, current treatments are largely supportive, with no curative therapies. Mesenchymal stromal cell (MSC) therapy has been shown to have a promising regenerative effect in AKI but is limited by the ability of cells to home to damaged tissue. Pulsed focused ultrasound (pFUS), wherein target tissues are sonicated by short bursts of sound waves, has been reported to enhance MSC homing by upregulating local homing signals. However, the exact mechanism by which pFUS enhances MSC therapy remains insufficiently explored. In this study, we studied the effect of bone marrow-derived MSCs (BM-MSCs), in conjunction with pFUS, in a mouse model of cisplatin-induced AKI. Here, BM-MSCs improved kidney function, reduced histological markers of kidney injury, decreased inflammation and apoptosis, and promoted cellular proliferation. Surprisingly, whereas pFUS did not upregulate local cytokine expression or improve BM-MSC homing, it did potentiate the effect of MSC treatment in AKI. Further analysis linked this effect to the upregulation of heat shock protein (HSP)20/HSP40 and subsequent phosphatidylinositol 3-kinase (PI3K)/Akt signaling. In summary, our results suggest that pFUS and BM-MSCs have independent as well as synergistic therapeutic effects in the context of AKI.

View details for DOI 10.1016/j.omtm.2020.03.023

View details for PubMedID 32346546

View details for PubMedCentralID PMC7177168
Emerging role of stem cell-derived extravesicular microRNAs in age-associated human diseases and in different therapies of longevity. Ageing Research Reviews Ullah, M., Ng, N. N., Concepcion, W., Thakor, A. S. 2020
View details for DOI 10.1016/j.arr.2019.100979
A Novel Approach to Deliver Therapeutic Extracellular Vesicles Directly into the Mouse Kidney Cells Ullah, M., Liu, D. D., Rai, S., Razavi, M., Choi, J., Wang, J., Concepcion, W., Thakor, A. S. 2020; 9 (4): 937
View details for DOI 10.3390/cells9040937
Emerging role of stem cell-derived extravesicular microRNAs in age-associated human diseases and in different therapies of longevity. Ageing Research Reviews Ullah, M., Ng, N. N., Concepcion, W., Thakor, A. S. 2020; 57: 100979
Abstract

Organismal aging involves the progressive decline in organ function and increased susceptibility to age-associated diseases. This has been associated with the aging of stem cell populations within the body that decreases the capacity of stem cells to self-renew, differentiate, and regenerate damaged tissues and organs. This review aims to explore how aging is associated with the dysregulation of stem cell-derived extracellular vesicles (SCEVs) and their corresponding miRNA cargo (SCEV-miRNAs), which are short non-coding RNAs involved in post-transcriptional regulation of target genes. Recent evidence has suggested that in aging stem cells, SCEV-miRNAs may play a vital role regulating various processes that contribute to aging: cellular senescence, stem cell exhaustion, telomere length, and circadian rhythm. Hence, further clarifying the age-dependent molecular mechanisms through which SCEV-miRNAs exert their downstream effects may inform a greater understanding of the biology of aging, elucidate their role in stem cell function, and identify important targets for future regenerative therapies. Additionally, current studies evaluating therapeutic role of SCEVs and SCEV-miRNAs in treating several age-associated diseases are also discussed.

View details for DOI 10.1016/j.arr.2019.100979
Emerging Nano- and Micro-Technologies Used in the Treatment of Type-1 Diabetes. Nanomaterials (Basel, Switzerland) Primavera, R., Kevadiya, B. D., Swaminathan, G., Wilson, R. J., De Pascale, A., Decuzzi, P., Thakor, A. S. 2020; 10 (4)
Abstract

Type-1 diabetes is characterized by high blood glucose levels due to a failure of insulin secretion from beta cells within pancreatic islets. Current treatment strategies consist of multiple, daily injections of insulin or transplantation of either the whole pancreas or isolated pancreatic islets. While there are different forms of insulin with tunable pharmacokinetics (fast, intermediate, and long-acting), improper dosing continues to be a major limitation often leading to complications resulting from hyper- or hypo-glycemia. Glucose-responsive insulin delivery systems, consisting of a glucose sensor connected to an insulin infusion pump, have improved dosing but they still suffer from inaccurate feedback, biofouling and poor patient compliance. Islet transplantation is a promising strategy but requires multiple donors per patient and post-transplantation islet survival is impaired by inflammation and suboptimal revascularization. This review discusses how nano- and micro-technologies, as well as tissue engineering approaches, can overcome many of these challenges and help contribute to an artificial pancreas-like system.

View details for DOI 10.3390/nano10040789

View details for PubMedID 32325974
Stem cell-derived extracellular vesicles: role in oncogenic processes, bioengineering potential, and technical challenges. Stem cell research & therapy Ullah, M., Qiao, Y., Concepcion, W., Thakor, A. S. 2019; 10 (1): 347
Abstract

Extracellular vesicles (EVs) are cellular-derived versatile transporters with a specialized property for trafficking a variety of cargo, including metabolites, growth factors, cytokines, proteins, lipids, and nucleic acids, throughout the microenvironment. EVs can act in a paracrine manner to facilitate communication between cells as well as modulate immune, inflammatory, regenerative, and remodeling processes. Of particular interest is the emerging association between EVs and stem cells, given their ability to integrate complex inputs for facilitating cellular migration to the sites of tissue injury. Additionally, stem cell-derived EVs can also act in an autocrine manner to influence stem cell proliferation, mobilization, differentiation, and self-renewal. Hence, it has been postulated that stem cells and EVs may work synergistically in the process of tissue repair and that dysregulation of EVs may cause a loss of homeostasis in the microenvironment leading to disease. By harnessing the property of EVs for delivery of small molecules, stem cell-derived EVs possess significant potential as a platform for developing bioengineering approaches for next-generation cancer therapies and targeted drug delivery methods. Although one of the main challenges of clinical cancer treatment remains a lack of specificity for the delivery of effective treatment options, EVs can be modified via genetic, biochemical, or synthetic methods for enhanced targeting ability of chemotherapeutic agents in promoting tumor regression. Here, we summarize recent research on the bioengineering potential of EV-based cancer therapies. A comprehensive understanding of EV modification may provide a novel strategy for cancer therapy and for the utilization of EVs in the targeting of oncogenic processes. Furthermore, innovative and emerging new technologies are shifting the paradigm and playing pivotal roles by continually expanding novel methods and materials for synthetic processes involved in the bioengineering of EVs for enhanced precision therapeutics.

View details for DOI 10.1186/s13287-019-1468-6

View details for PubMedID 31771657
A Study Comparing the Effects of Targeted Intra-Arterial and Systemic Chemotherapy in an Orthotopic Mouse Model of Pancreatic Cancer. Scientific reports Rezaee, M., Wang, J., Razavi, M., Ren, G., Zheng, F., Hussein, A., Ullah, M., Thakor, A. S. 2019; 9 (1): 15929
Abstract

Systemic chemotherapy is the first line treatment for patients with unresectable pancreatic cancer, however, insufficient drug delivery to the pancreas is a major problem resulting in poor outcomes. We evaluated the therapeutic effects of targeted intra-arterial (IA) delivery of gemcitabine directly into the pancreas in an orthotopic mouse model of pancreatic cancer. Nude mice with orthotopic pancreatic tumors were randomly assigned into 3 groups receiving gemcitabine: systemic intravenous (IV) injection (low: 0.3mg/kg and high: 100mg/kg) and direct IA injection (0.3mg/kg). Treatments were administered weekly for 2 weeks. IA treatment resulted in a significantly greater reduction in tumor growth compared to low IV treatment. To achieve a comparable reduction in tumor growth as seen with IA treatment, gemcitabine had to be given IV at over 300x the dose (high IV treatment) which was associated with some toxicity. After 2 weeks, tumor samples from animals treated with IA gemcitabine had significantly lower residual cancer cells, higher cellular necrosis and evidence of increased apoptosis when compared to animals treated with low IV gemcitabine. Our study shows targeted IA injection of gemcitabine directly into the pancreas, via its arterial blood supply, has a superior therapeutic effect in reducing tumor growth compared to the same concentration administered by conventional systemic injection.

View details for DOI 10.1038/s41598-019-52490-1

View details for PubMedID 31685925
Imaging Tumor Oxidative Stress with Surface Enhanced Raman Scattering Gold Nanoparticles JOURNAL OF BIOMEDICAL NANOTECHNOLOGY Razavi, M., Ren, G., Wang, J., Kimura, R., Thakor, A. S. 2019; 15 (10): 2130?41
Abstract

We synthesized a new surface enhanced Raman scattering nanoparticle (SERS NP) which can detect reactive oxygen species (ROS) and thus changes in oxidative stress (OS). Our SERS NP was synthesized using a gold nanoparticle (AuNP) core which was then coated with a dihydrorhodamine (DHR123) Raman layer. In the presence of ROS, DHR123 is converted to rhodamine123 (Rd123) which has a distinct Raman fingerprint. Next, AuNP-DHR123 were encapsulated in a mesoporous-SiO? shell to help appose DHR123 to the AuNP core. Finally, the AuNP-DHR123-mesoporous-SiO? was functionalized with cystine knot peptides that target integrin ?v?6. Our SERS NP was initially optimized in vitro using solutions containing reactive oxygen species as well as human cancer cell lines. Finally, in a xenograft animal model, we demonstrated the in vivo ability of our SERS NP to target a tumor, as well as provide a reading of the amount of OS within the tumor.

View details for DOI 10.1166/jbn.2019.2819

View details for Web of Science ID 000483950600010

View details for PubMedID 31462377
Improving the Function and Engraftment of Transplanted Pancreatic Islets Using Pulsed Focused Ultrasound Therapy. Scientific reports Razavi, M., Zheng, F., Telichko, A., Wang, J., Ren, G., Dahl, J., Thakor, A. S. 2019; 9 (1): 13416
Abstract

This study demonstrates that pulsed focused ultrasound (pFUS) therapy can non-invasively enhance the function and engraftment of pancreatic islets following transplantation. In vitro, we show that islets treated with pFUS at low (peak negative pressure (PNP): 106kPa, spatial peak temporal peak intensity (Isptp): 0.71W/cm2), medium (PNP: 150kPa, Isptp: 1.43W/cm2) or high (PNP: 212kPa, Isptp: 2.86W/cm2) acoustic intensities were stimulated resulting in an increase in their function (i.e. insulin secretion at low-intensity: 1.15�0.17, medium-intensity: 2.02�0.25, and high-intensity: 2.54�0.38 fold increase when compared to control untreated islets; P<0.05). Furthermore, we have shown that this improvement in islet function is a result of pFUS increasing the intracellular concentration of calcium (Ca2+) within islets which was also linked to pFUS increasing the resting membrane potential (Vm) of islets. Following syngeneic renal sub-capsule islet transplantation in C57/B6 mice, pFUS (PNP: 2.9MPa, Isptp: 895W/cm2) improved the function of transplanted islets with diabetic animals rapidly re-establishing glycemic control. In addition, pFUS was able to enhance the engraftment by facilitating islet revascularization and reducing inflammation. Given a significant number of islets are lost immediately following transplantation, pFUS has the potential to be used in humans as a novel non-invasive therapy to facilitate islet function and engraftment, thereby improving the outcome of diabetic patients undergoing islet transplantation.

View details for DOI 10.1038/s41598-019-49933-0

View details for PubMedID 31527773
Three-dimensional cryogels for biomedical applications. Journal of biomedical materials research. Part A Razavi, M., Qiao, Y., Thakor, A. S. 2019
Abstract

Cryogels are a subset of hydrogels synthesized under sub-zero temperatures: initially solvents undergo active freezing, which causes crystal formation, which is then followed by active melting to create interconnected supermacropores. Cryogels possess several attributes suited for their use as bioscaffolds, including physical resilience, bio-adaptability, and a macroporous architecture. Furthermore, their structure facilitates cellular migration, tissue-ingrowth, and diffusion of solutes, including nano- and micro-particle trafficking, into its supermacropores. Currently, subsets of cryogels made from both natural biopolymers such as gelatin, collagen, laminin, chitosan, silk fibroin, and agarose and/or synthetic biopolymers such as hydroxyethyl methacrylate, poly-vinyl alcohol, and poly(ethylene glycol) have been employed as 3D bioscaffolds. These cryogels have been used for different applications such as cartilage, bone, muscle, nerve, cardiovascular, and lung regeneration. Cryogels have also been used in wound healing, stem cell therapy and diabetes cellular therapy. In this review, we summarize the synthesis protocol and properties of cryogels, evaluation techniques as well as current in vitro and in vivo cryogel applications. A discussion of the potential benefit of cryogels for future research and their application are also presented. This article is protected by copyright. All rights reserved.

View details for DOI 10.1002/jbm.a.36777

View details for PubMedID 31408265
An emerging role of CD9 in stemness and chemoresistance. Oncotarget Ullah, M., Akbar, A., Thakor, A. S. 2019; 10 (40): 4000?4001
View details for DOI 10.18632/oncotarget.27021

View details for PubMedID 31258843
Adipose tissue-derived mesenchymal stem cells rescue the function of islets transplanted in sub-therapeutic numbers via their angiogenic properties CELL AND TISSUE RESEARCH Ren, G., Rezaee, M., Razavi, M., Taysir, A., Wang, J., Thakor, A. S. 2019; 376 (3): 353?64
View details for DOI 10.1007/s00441-019-02997-w

View details for Web of Science ID 000468934500004
Adipose tissue-derived mesenchymal stem cells rescue the function of islets transplanted in sub-therapeutic numbers via their angiogenic properties. Cell and tissue research Ren, G., Rezaee, M., Razavi, M., Taysir, A., Wang, J., Thakor, A. S. 2019
Abstract

A significant proportion of islets are lost following transplantation due to hypoxia and inflammation. We hypothesize that adipose tissue-derived mesenchymal stem cells (AD-MSCs) can rescue a sub-therapeutic number of transplanted islets by helping them establish a new blood supply and reducing inflammation. Diabetic mice received syngeneic transplantation with 75 (minimal), 150 (sub-therapeutic), or 225 (therapeutic) islets, with or without 1*106 mouse AD-MSCs. Fasting blood glucose (FBG) values were measured over 6weeks with tissue samples collected for islet structure and morphology (H&E, insulin/glucagon staining). Histological and immunohistochemical analyses of islets were also performed at 2weeks in animals transplanted with a sub-therapeutic number of islets, with and without AD-MSCs, to determine new blood vessel formation, the presence of pro-angiogenic factors facilitating revascularization, and the degree of inflammation. AD-MSCs had no beneficial effect on FBG values when co-transplanted with a minimal or therapeutic number of islets. However, AD-MSCs significantly reduced FBG values and restored glycemic control in diabetic animals transplanted with a sub-therapeutic number of islets. Islets co-transplanted with AD-MSCs preserved their native morphology and organization and exhibited less aggregation when compared to islets transplanted alone. In the sub-therapeutic group, AD-MSCs significantly increased islet revascularization and the expression of angiogenic factors including hepatocyte growth factor (HGF) and angiopoietin-1 (Ang-1) while also reducing inflammation. AD-MSCs can rescue the function of islets when transplanted in a sub-therapeutic number, for at least 6weeks, via their ability to maintain islet architecture while concurrently facilitating islet revascularization and reducing inflammation.

View details for PubMedID 30707291
Ferumoxytol Does Not Impact Standardized Uptake Values on PET/MR Scans. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Muehe, A. M., Yerneni, K., Theruvath, A. J., Thakor, A. S., Pribnow, A., Avedian, R., Steffner, R., Rosenberg, J., Hawk, K. E., Daldrup-Link, H. E. 2019
Abstract

Tumor response assessments on positron emission tomography (PET)/magnetic resonance imaging (MRI) scans require correct quantification of radiotracer uptake in tumors and normal organs. Historically, MRI scans have been enhanced with gadolinium (Gd)-based contrast agents, which are now controversial due to brain deposition. Recently, ferumoxytol nanoparticles have been identified as an alternative to Gd-based contrast agents because they provide strong tissue enhancement on MR images but are not deposited in the brain. However, it is not known if the strong T1- and T2-contrast obtained with iron oxide nanoparticles such as ferumoxytol could affect MR-based attenuation correction of PET data. The purpose of our study was to investigate if ferumoxytol administration prior to a 2-deoxy-2-[18F]fluoro-D-glucose [18F]FDG PET/MR scan would change standardized uptake values (SUV) of normal organs.Thirty pediatric patients (6-18�years) with malignant tumors underwent [18F]FDG-PET/MR scans (dose 3�MBq/kg). Fifteen patients received an intravenous ferumoxytol injection (5�mg�Fe/kg) prior to the [18F]FDG-PET/MR scans (group 1). Fifteen additional age- and sex-matched patients received unenhanced [18F]FDG-PET/MR scans (group 2). For attenuation correction of PET data, we used a Dixon-based gradient echo sequence (TR 4.2�ms, TE 1.1, 2.3�ms, FA 5), which accounted for soft tissue, lung, fat, and background air. We used a mixed linear effects model to compare the tissue MRI enhancement, quantified as the signal-to-noise ratio (SNR), as well as tissue radiotracer signal, quantified as SUVmean and SUVmax, between group 1 and group 2. Alpha was assumed at 0.05.The MRI enhancement of the blood and solid extra-cerebral organs, quantified as SNR, was significantly higher on ferumoxytol-enhanced MRI scans compared to unenhanced scans (p??0.05).Ferumoxytol administration prior to a [18F]FDG PET/MR scan did not change standardized uptake values (SUV) of solid extra-cerebral organs. This is important, because it allows injection of ferumoxytol contrast prior to a PET/MRI procedure and, thereby, significantly accelerates image acquisition times.

View details for DOI 10.1007/s11307-019-01409-3

View details for PubMedID 31325083
Mesenchymal Stromal Cell Homing: Mechanisms and Strategies for Improvement. iScience Ullah, M., Liu, D. D., Thakor, A. S. 2019; 15: 421?38
Abstract

Mesenchymal stromal cells (MSCs) have been widely investigated for their therapeutic potential in regenerative medicine, owing to their ability to home damaged tissue and serve as a reservoir of growth factors and regenerative molecules. As such, clinical applications of MSCs are reliant on these cells successfully migrating to the desired tissue following their administration. Unfortunately, MSC homing is inefficient, with only a small percentage of cells reaching the target tissue following systemic administration. This attrition represents a major bottleneck in realizing the full therapeutic potential of MSC-based therapies. Accordingly, a variety of strategies have been employed in the hope of improving this process. Here, we review the molecular mechanisms underlying MSC homing, based on a multistep model involving (1) initial tethering by selectins, (2) activation by cytokines, (3) arrest by integrins, (4) diapedesis or transmigration using matrix remodelers, and (5) extravascular migration toward chemokine gradients. We then review the various strategies that have been investigated for improving MSC homing, including genetic modification, cell surface engineering, in�vitro priming of MSCs, and in particular, ultrasound techniques, which have recently gained significant interest. Contextualizing these strategies within the multistep homing model emphasizes that our ability to optimize this process hinges on our understanding of its molecular mechanisms. Moving forward, it is only with a combined effort of basic biology and translational work that the potential of MSC-based therapies can be realized.

View details for DOI 10.1016/j.isci.2019.05.004

View details for PubMedID 31121468
Mesenchymal stem cells confer chemoresistance in breast cancer via a CD9 dependent mechanism Oncotarget Ullah, M., Akbar, A., Ng, N. N., Concepcion, W., Thakor, A. S. 2019; 10 (37): 3435-3450
View details for DOI 10.18632/oncotarget.26952
Mesenchymal stem cells confer chemoresistance in breast cancer via a CD9 dependent mechanism. Oncotarget Ullah, M., Akbar, A., Ng, N. N., Concepcion, W., Thakor, A. S. 2019; 10 (37): 3435?50
Abstract

The development of chemotherapy drug resistance remains a significant barrier for effective therapy in several cancers including breast cancer. Bone marrow-derived mesenchymal stem cells (BMMSCs) have previously been shown to influence tumor progression and the development of chemoresistance. In the present study, we showed that when GFP labelled BMMSCs and RFP labelled HCC1806 cells are injected together in vivo, they create tumors which contain a new hybrid cell that has characteristics of both BMMSCs and HCC1806 cells. By labelling these cells prior to their injection, we were then able to isolate new hybrid cell from harvested tumors using FACS (DP-HCC1806:BMMSCs). Interestingly, when DP-HCC1806:BMMSCs were then injected into the mammary fat pad of NOD/SCID mice, they produced xenograft tumors which were smaller in size, and exhibited resistance to chemotherapy drugs (i.e. doxorubicin and 5-fluorouracil), when compared tumors from HCC1806 cells alone. This chemoresistance was shown to associated with an increased expression of tetraspanins (CD9, CD81) and drug resistance proteins (BCRP, MDR1). Subsequent siRNA-mediated knockdown of BMMSC-CD9 in DP-HCC1806:BMMSCs resulted in an attenuation of doxorubicin and 5-fluorouracil chemoresistance associated with decreased BCRP and serum cytokine expression (CCL5, CCR5, CXCR12). Our findings suggest that within the tumor microenvironment, CD9 is responsible for the crosstalk between BMMSCs and HCC1806 breast cancer cells (via CCL5, CCR5, and CXCR12) which contributes to chemoresistance. Hence, BMMSC-CD9 may serve as an important therapeutic target for the treatment of breast cancer.

View details for DOI 10.18632/oncotarget.26952

View details for PubMedID 31191817

View details for PubMedCentralID PMC6544397
Effect of Pulsed Focused Ultrasound on the Native Pancreas. Ultrasound in medicine & biology Razavi, M., Zheng, F., Telichko, A., Ullah, M., Dahl, J., Thakor, A. S. 2019
Abstract

Pulsed focused ultrasound (pFUS) utilizes short cycles of sound waves to mechanically shake cells within tissues which, in turn, causes transient local increases in cytokines, growth factors and cell adhesion molecules. Although the effect of pFUS has been investigated in several different organs including the kidney, muscle and heart, its effect on the pancreas has not been investigated. In the present work, we applied pFUS to the rodent pancreas with the following parameters: 1.1-MHz frequency, 5-Hz pulse repetition frequency, 5% duty cycle, 10-ms pulse length, 160-s duration. Low-intensity pFUS had a spatial average temporal average intensity of 11.5 W/cm2 and a negative peak pressure of 3 MPa; high-intensity pFUS had a spatial average temporal average intensity of 18.5 W/cm2 and negative peak pressure of 4 MPa. Here we found that pFUS changed the expression of several cytokines while having no effect on the underlying tissue histology or health of pancreatic cells (as reflected by no significant change in plasma levels of amylase and lipase). Furthermore, we found that this effect on cytokine expression in the pancreas was acoustic intensity dependent; while pFUS at low intensities turned off the expression of several cytokines, at high intensities it had the opposite effect and turned on the expression of these cytokines. The ability to non-invasively manipulate the microenvironment of the pancreas using sound waves could have profound implications for priming and modulating this organ for the application of cellular therapies in the context of both regenerative medicine (i.e., diabetes and pancreatitis) and oncology (i.e., pancreatic cancer).

View details for DOI 10.1016/j.ultrasmedbio.2019.11.016

View details for PubMedID 31882169
Advances in Precision Health and Emerging Diagnostics for Women. Journal of clinical medicine Fitzpatrick, M. B., Thakor, A. S. 2019; 8 (10)
Abstract

During the Dutch winter famine of 1944-1945, an interesting observation was made about the offspring born during this time-They had an increased risk of developing metabolic syndrome and other chronic diseases. Subsequent research has confirmed this finding as well as noting that health outcomes for many diseases are different, and often worse, for women. These findings, combined with the lack of enrollment of women in clinical trials and/or analysis of sex-specific differences are important factors which need to be addressed. In fact, Women's health research and sex differences have historically been overlooked or lumped together and assumed equivalent to those of men. Hence, a focus on women's health and disease prevention is critical to improve the lives of women in the 21st Century. In this review, we point out the critical differences biologically and socially that present both challenges and opportunities for development of novel platforms for precision health. The technologic and scientific advances specific to women's precision health have the potential to improve the health and wellbeing for all females across the world.

View details for DOI 10.3390/jcm8101525

View details for PubMedID 31547515
Adult and Pediatric Antibiotic Prophylaxis during Vascular and IR Procedures: A Society of Interventional Radiology Practice Parameter Update Endorsed by the Cardiovascular and Interventional Radiological Society of Europe and the Canadian Association for Interventional Radiology JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Chehab, M. A., Thakor, A. S., Tulin-Silver, S., Connolly, B. L., Cahill, A., Ward, T. J., Padia, S. A., Kohi, M. P., Midia, M., Chaudry, G., Gemmete, J. J., Mitchell, J. W., Brody, L., Crowley, J. J., Heran, M. S., Weinstein, J. L., Nikolic, B., Dariushnia, S. R., Tam, A. L., Venkatesan, A. M. 2018; 29 (11): 1483?1501
View details for DOI 10.1016/j.jvir.2018.06.007

View details for Web of Science ID 000450542400001
Orthotopic Liver Transplantation After Stereotactic Body Radiotherapy for Pediatric Hepatocellular Carcinoma with Central Biliary Obstruction and Nodal Involvement. Cureus Chen, E., Rangaswami, A., Esquivel, C. O., Concepcion, W., Lungren, M., Thakor, A. S., Yoo, C. H., Donaldson, S. S., Hiniker, S. M. 2018; 10 (10): e3499
Abstract

Here we describe the case of a 10-year-old boy with a history of chronic hepatitis B who was diagnosed with hepatocellular carcinoma (HCC) with a large central hepatic mass and metastatic disease in a celiac lymph node. His tumor wasunresectable, due to location and lack of clear margins, and he could not receive chemotherapy due to elevated bilirubin. He was treated with stereotactic body radiotherapy (SBRT) to the primary site and involved nodal region. After completing radiotherapy, his total bilirubin level fell below 1.0 mg/dL, allowing him to begin systemic therapy with cisplatinand doxorubicin.At threemonths after SBRT, his bilirubin was 0.1 mg/dL, alpha-fetoprotein (AFP) was 88 ng/mL, and imaging demonstrated a decrease in tumor size (total volume 28.7 cc), with no evidence of local or distant disease progression.He then developed distant disease within the liver, but his disease remained controlled at the primary site and nodes that had been treated with SBRT.He underwent orthotopic liver transplantation (OLT) with an uneventful operative course and remains with no evidence of disease at sevenmonths after OLT. This is one of the first reported cases of successful downstaging of pediatric HCC with nodal involvement to allow for OLT, and it argues for consideration of similar patients for OLT.

View details for PubMedID 30648040
Orthotopic Liver Transplantation After Stereotactic Body Radiotherapy for Pediatric Hepatocellular Carcinoma with Central Biliary obstruction and Nodal Involvement CUREUS Chen, E., Rangaswami, A., Esquivel, C., Concepcion, W., Lungren, M., Thakor, A. S., Yoo, C. H., Donaldson, S. S., Hiniker, S. M. 2018; 10 (10)
View details for DOI 10.7759/cureus.3499

View details for Web of Science ID 000458694700038
Adult and Pediatric Antibiotic Prophylaxis during Vascular and IR Procedures: A Society of Interventional Radiology Practice Parameter Update Endorsed by the Cardiovascular and Interventional Radiological Society of Europe and the Canadian Association for Interventional Radiology. Journal of vascular and interventional radiology : JVIR Chehab, M. A., Thakor, A., Tulin-Silver, S., Connolly, B. L., Cahill, A. M., Ward, T. J., Padia, S. A., Kohi, M. P., Midia, M., Chaudry, G., Gemmete, J. J., Mitchell, J. W., Brody, L., Crowley, J. J., Heran, M. K., Weinstein, J. L., Nikolic, B., Dariushnia, S. R., Tam, A. L., Venkatesan, A. M. 2018
View details for PubMedID 30274857
A collagen based cryogel bioscaffold coated with nanostructured polydopamine as a platform for mesenchymal stem cell therapy JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Razavi, M., Hu, S., Thakor, A. S. 2018; 106 (8): 2213?28
View details for DOI 10.1002/jbm.a.36428

View details for Web of Science ID 000437119800012
An oxygen plasma treated poly(dimethylsiloxane) bioscaffold coated with polydopamine for stem cell therapy JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE Razavi, M., Thakor, A. S. 2018; 29 (5): 54
Abstract

In this study, 3D macroporous bioscaffolds were developed from poly(dimethylsiloxane) (PDMS) which is inert, biocompatible, non-biodegradable, retrievable and easily manufactured at low cost. PDMS bioscaffolds were synthesized using a solvent casting and particulate leaching (SCPL) technique and exhibited a macroporous interconnected architecture with 86?�?3% porosity and 300?�?100?�m pore size. As PDMS intrinsically has a hydrophobic surface, mainly due to the existence of methyl groups, its surface was modified by oxygen plasma treatment which, in turn, enabled us to apply a novel polydopamine coating onto the surface of the bioscaffold. The addition of a polydopamine coating to bioscaffolds was confirmed using composition analysis. Characterization of oxygen plasma treated-PDMS bioscaffolds coated with polydopamine (polydopamine coated-PDMS bioscaffolds) showed the presence of hydroxyl and secondary amines on their surface which resulted in a significant decrease in water contact angle when compared to uncoated-PDMS bioscaffolds (35?�?3%, P?
View details for PubMedID 29725867
A collagen based cryogel bioscaffold coated with nanostructured polydopamine as a platform for mesenchymal stem cell therapy. Journal of biomedical materials research. Part A Razavi, M., Hu, S., Thakor, A. S. 2018
Abstract

Cryo-hydrogels (cryogels) are polymer hydrogels formed at sub-zero temperatures. Bioscaffolds created from cryogels have interconnected macropores which allow for cell migration, tissue-ingrowth, unhindered diffusion of solutes and mass transport of therapeutics. In this study, we developed collagen based cryogel bioscaffolds and coated them with polydopamine using a simple two-step technique. Cryogel bioscaffolds were synthesized by collagen crosslinking at -20�C and exhibited a macroporous interconnected architecture with 75%�3% porosity. Two groups of pore sizes were observed: 300�50 m and 30�10 m in diameter. The addition of a polydopamine coating to cryogel bioscaffolds was confirmed using composition analysis. This resulted in a 41%�5% decrease in water uptake, 81%�10% decrease in swelling rate and 12%�3% decrease in their degree of dissolution (p<0.05), with a 48%�2% increase in stiffness and 57%�5% increase in compressive strength (p<0.05). Seeding adipose tissue-derived mesenchymal stem cells (AD-MSCs) into polydopamine coated-cryogel bioscaffolds resulted in cells demonstrating a 52%�4% increase in viability and 33%�3% increase in proliferation when compared to AD-MSCs seeded into uncoated-cryogel bioscaffolds (p<0.05). In summary, our novel polydopamine coated-cryogel bioscaffold represents an efficient and low-cost bioscaffold platform to support MSC therapies. � 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2018.

View details for PubMedID 29637738
Role of interventional radiology in managing pediatric liver tumors PEDIATRIC RADIOLOGY Lungren, M. P., Towbin, A. J., Roebuck, D. J., Monroe, E. J., Gill, A. E., Thakor, A., Towbin, R. B., Cahill, A., Hawkins, C. 2018; 48 (4): 555?64
Abstract

Primary liver malignancies are rare in children. Hepatoblastoma and hepatocellular carcinoma (HCC) together represent the overwhelming majority of cases. Overall survival of hepatoblastoma approaches 80% with multimodal treatment approaches that include chemotherapy, surgery and transplantation. However, there remains a subset of children with hepatoblastoma in whom resection or transplantation is not possible. The 5-year survival for children diagnosed with HCC is less than 30% and remains a significant therapeutic challenge. The poor outcomes for children with primary liver tumors motivate investigation of new therapeutic alternatives. Interventional oncology offers a broad scope of percutaneous and transcatheter endovascular cancer therapies that might provide clinical benefits. Minimally invasive approaches are distinct from medical, surgical and radiation oncologic treatments, and in adults these approaches have been established as the fourth pillar of cancer care. Transarterial chemoembolization is a minimally invasive locoregional treatment option performed by interventional radiologists with level-I evidence as standard of care in adults with advanced liver malignancy; transarterial chemoembolization in adults has served to prolong disease-free progression, downstage and bridge patients for surgical and transplant interventions, and improve overall survival. However, while several groups have reported that transarterial chemoembolization is feasible in children, the published experience is limited primarily to small retrospective case series. The lack of prospective trial evidence has in part limited the utilization of transarterial chemoembolization in the pediatric patient population. The purpose of this article is to provide an overview of the role of interventional radiology in the diagnosis and endovascular management of hepatic malignancies in children.

View details for PubMedID 29362840
Role of interventional radiology in managing pediatric liver tumors PEDIATRIC RADIOLOGY Hawkins, C., Towbin, A. J., Roebuck, D. J., Monroe, E. J., Gill, A. E., Thakor, A. S., Towbin, R. B., Cahill, A., Lungren, M. P. 2018; 48 (4): 565?80
View details for DOI 10.1007/s00247-018-4072-5

View details for Web of Science ID 000427800100012
A Novel Approach for Therapeutic Delivery to the Rodent Pancreas Via Its Arterial Blood Supply. Pancreas Choi, J., Wang, J., Ren, G., Thakor, A. S. 2018; 47 (7): 910?15
Abstract

Endovascular techniques can now access the arterial blood supply of the pancreas in humans to enable therapeutics to reach the gland in high concentrations while concurrently avoiding issues related to non-targeted delivery. However, there is no way to replicate this in small animals. In a rat model, we therefore developed a novel non-terminal technique to deliver therapeutics to different regions of the pancreas, via its arterial blood supply.In female Wistar rats, selective branches of the celiac artery were temporarily ligated, depending on the region of the pancreas being targeted. Trypan blue dye was then administered as a surrogate marker for a therapeutic agent, via the celiac artery, and its staining/distribution throughout the pancreas determined. Postoperatively, animals were monitored daily, and serum was evaluated for markers of pancreatitis, liver, and metabolic function.Using this technique, we could selectively target the head, body/tail, or entire gland of the pancreas, via its arterial blood supply, with minimal nontarget staining. Following the procedure, all animals recovered with no evidence of pancreatitis or liver/metabolic dysfunction.Our study demonstrates a novel technique that can be used to selectively deliver therapeutics directly to the rat pancreas in a safe manner with full recovery of the animal.

View details for PubMedID 29975350
Role of interventional radiology in managing pediatric liver tumors : Part 2: percutaneous interventions. Pediatric radiology Matthew Hawkins, C., Towbin, A. J., Roebuck, D. J., Monroe, E. J., Gill, A. E., Thakor, A. S., Towbin, R. B., Cahill, A. M., Lungren, M. P. 2018; 48 (4): 565?80
Abstract

Hepatoblastoma and hepatocellular carcinoma (HCC) are the most common pediatric liver malignancies, with hepatoblastoma occurring more commonly in younger children and HCC occurring more commonly in older children and adolescents. Although surgical resection (including transplant when necessary) and systemic chemotherapy have improved overall survival rate for hepatoblastoma to approximately 80% from 30%, a number of children with this tumor type are not eligible for operative treatment. In contradistinction, pediatric HCC continues to carry a dismal prognosis with an overall 5-year survival rate of 30%. The Paediatric Hepatic International Tumour Trial (PHITT) is an international trial aimed at evaluating both existing and emerging oncologic therapies for primary pediatric liver tumors. Interventional radiology offers a number of minimally invasive procedures that aid in diagnosis and therapy of pediatric liver tumors. For diagnosis, the PHITT biopsy guidelines emphasize and recommend percutaneous image-guided tumor biopsy. Additionally, both percutaneous and endovascular procedures provide therapeutic alternatives that have been, to this point, only minimally utilized in the pediatric population. Specifically, percutaneous ablation offers a number of cytotoxic technologies that can potentially eradicate disease or downstage children with unresectable disease. Percutaneous portal vein embolization is an additional minimally invasive procedure that might be useful to induce remnant liver hypertrophy prior to extended liver resection in the setting of a primary liver tumor. PHITT offers an opportunity to collect data from children treated with these emerging therapeutic options across the world. The purpose of this manuscript is to describe the potential role of minimally invasive percutaneous transhepatic procedures, as well as review the existing data largely stemming from the adult HCC experience.

View details for PubMedID 29396792
Use of Blood Pool Agents With Steady-State MRI to Assess the Vascular System JOURNAL OF MAGNETIC RESONANCE IMAGING Thakor, A. S., Chung, J., Patel, P., Chan, A., Ahmed, A., McNeil, G., Liu, D. M., Forster, B., Klass, D. 2017; 45 (6): 1559-1572
Abstract

Over the past two decades there have been significant advances in the use of magnetic resonance imaging (MRI) to assess the vascular system. New imaging sequences and improvements in magnet design have enabled the creation of higher spatial resolution images. MRI is now a viable alternative imaging modality when compared to both invasive angiography and computed tomographic angiography. The use of blood pool agents has further facilitated the use of MR angiography (MRA); their high molecular weight allows for lower doses of contrast medium administration while their prolonged presence in the blood stream allows for repeated high-quality volumetric imaging of both the arterial and venous circulation. As such, MRA is now no longer constrained by the tight windows for first-pass arterial and venous enhancement, which has resulted in the ability to assess and diagnose a large range of vascular pathologies in both arterial and venous systems. The intent of this review is to highlight MRI findings in common vascular pathologies including peripheral arterial disease (PAD), abnormalities of the abdominal aortic branches, postendovascular aortic aneurysm repair (EVAR) endoleak assessment, popliteal artery entrapment syndrome (PAES), deep venous thrombosis (DVT), vascular thoracic outlet syndrome (TOS), and vascular malformations. In addition, the latest MRI techniques currently used to optimally assess each of these pathologies will be discussed.5 Technical Efficacy: Stage 3 J. MAGN. RESON. IMAGING 2017;45:1559-1572.

View details for DOI 10.1002/jmri.25636

View details for PubMedID 28422344
Stereotactic body radiotherapy for pediatric hepatocellular carcinoma with central biliary obstruction PEDIATRIC BLOOD & CANCER Hiniker, S. M., Rangaswami, A., Lungren, M. P., Thakor, A. S., Concepcion, W., Balazy, K. E., Kovalchuk, N., Donaldson, S. S. 2017; 64 (6)
Abstract

Here, we present the case of a pediatric patient with newly diagnosed hepatocellular carcinoma causing central biliary obstruction and persistently elevated bilirubin of 3.0-4.3�mg/dl despite placement of bilateral internal-external biliary drains. The tumor was not resectable, and the patient was not a candidate for liver transplant due to nodal disease, for chemotherapy due to hyperbilirubinemia, or for local therapies aside from stereotactic body radiotherapy (SBRT). In this report, we discuss the successful use of SBRT in the management of this patient, and its role in allowing the patient to become a candidate for additional therapies.

View details for DOI 10.1002/pbc.26330

View details for PubMedID 28436210
Stereotactic body radiotherapy for pediatric hepatocellular carcinoma with central biliary obstruction PEDIATRIC BLOOD & CANCER Hiniker, S. M., Rangaswami, A., Lungren, M. P., Thakor, A. S., Concepcion, W., Balazy, K. E., Kovalchuk, N., Donaldson, S. S. 2017; 64 (6)
View details for DOI 10.1002/pbc.26330

View details for Web of Science ID 000400616500005
Transradial Access for Interventional Radiology: Single-Centre Procedural�and Clinical Outcome Analysis. Canadian Association of Radiologists journal = Journal l'Association canadienne des radiologistes Thakor, A. S., Alshammari, M. T., Liu, D. M., Chung, J., Ho, S. G., Legiehn, G. M., Machan, L., Fischman, A. M., Patel, R. S., Klass, D. 2017
Abstract

The study sought to describe a single centre's technical approach to transradial intervention and report on clinical outcomes and safety.A total of 749 transradial access (TRA) procedures were performed at a single hospital in 562 patients (174 women and 388 men). Procedures included 445 bland embolizations or chemoembolizations of the liver, 88 uterine artery embolizations, and 148 procedures for Selective Internal Radiation Therapy (Y90), which included mapping and administration. The mean age of the patients was 62�years (range 27-96�years).Four cases (0.5%) required crossover to transfemoral (tortuous anatomy, inability to secure a stable position for embolization, vessel spasm and base catheter not being of a sufficient length). A single asymptomatic, short-segment radial artery occlusion occurred (0.3%), 3 patients (0.4%) developed small hematomas postprocedurally, and 2 patients (0.7%) had transient neurological pain, which was resolved within a week without treatment. It was found that 98% of patients who had a previous femoral access procedure would choose radial access for subsequent procedures.Transradial access is a safe, effective technique, with a learning curve; however, this procedure has the potential to significantly improve departmental workflow and cost savings for the department and patient experience.

View details for DOI 10.1016/j.carj.2016.09.003

View details for PubMedID 28396005
Clinically Approved Nanoparticle Imaging Agents JOURNAL OF NUCLEAR MEDICINE Thakor, A. S., Jokerst, J. V., Ghanouni, P., Campbell, J. L., Mittra, E., Gambhir, S. S. 2016; 57 (12): 1833?37
View details for DOI 10.2967/jnumed.116.181362

View details for Web of Science ID 000389106800005
Clinically Approved Nanoparticle Imaging Agents. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Thakor, A. S., Jokerst, J. V., Ghanouni, P., Campbell, J., Mittra, E., Gambhir, S. S. 2016
Abstract

Nanoparticles are a new class of imaging agent used for both anatomic and molecular imaging. Nanoparticle-based imaging exploits the signal intensity, stability, and biodistribution behavior of submicron-diameter molecular imaging agents. This review focuses on nanoparticles used in human medical imaging, with an emphasis on radionuclide imaging and MRI. Newer nanoparticle platforms are also discussed in relation to theranostic and multimodal uses.

View details for PubMedID 27738007
MR cone-beam CT fusion image overlay for fluoroscopically guided percutaneous biopsies in pediatric patients PEDIATRIC RADIOLOGY Thakor, A. S., Patel, P. A., Gu, R., Rea, V., Amaral, J., Connolly, B. L. 2016; 46 (3): 407-412
Abstract

Lesions only visible on magnetic resonance (MR) imaging cannot easily be targeted for image-guided biopsy using ultrasound or X-rays but instead require MR guidance with MR-compatible needles and long procedure times (acquisition of multiple MR sequences). We developed an alternative method for performing these difficult biopsies in a standard interventional suite, by fusing MR with cone-beam CT images. The MR cone-beam CT fusion image is then used as an overlay to guide a biopsy needle to the target area under live fluoroscopic guidance. Advantages of this technique include (i) the ability for it to be performed in a conventional interventional suite, (ii) three-dimensional planning of the needle trajectory using cross-sectional imaging, (iii) real-time fluoroscopic guidance for needle trajectory correction and (iv) targeting within heterogeneous lesions based on MR signal characteristics to maximize the potential biopsy yield.

View details for DOI 10.1007/s00247-015-3479-5

View details for PubMedID 26563298
Fetal in vivo continuous cardiovascular function during chronic hypoxia. journal of physiology Allison, B. J., Brain, K. L., Niu, Y., Kane, A. D., Herrera, E. A., Thakor, A. S., Botting, K. J., Cross, C. M., Itani, N., Skeffington, K. L., Beck, C., Giussani, D. A. 2016; 594 (5): 1247-1264
Abstract

The in vivo fetal cardiovascular defence to chronic hypoxia has remained by and large an enigma because no technology has been available to induce significant and prolonged fetal hypoxia whilst recording longitudinal changes in fetal regional blood flow as the hypoxic pregnancy is developing. We introduce a new technique able to maintain chronically instrumented maternal and fetal sheep preparations under isobaric chronic hypoxia for most of gestation, beyond levels that can be achieved by high altitude and of relevance in magnitude to the human intrauterine growth-restricted fetus. This technology permits wireless recording in free-moving animals of longitudinal maternal and fetal cardiovascular function, including beat-to-beat alterations in pressure and blood flow signals in regional circulations. The relevance and utility of the technique is presented by testing the hypotheses that the fetal circulatory brain sparing response persists during chronic fetal hypoxia and that an increase in reactive oxygen species in the fetal circulation is an involved mechanism.Although the fetal cardiovascular defence to acute hypoxia and the physiology underlying it have been established for decades, how the fetal cardiovascular system responds to chronic hypoxia has been comparatively understudied. We designed and created isobaric hypoxic chambers able to maintain pregnant sheep for prolonged periods of gestation under controlled significant (10% O2 ) hypoxia, yielding fetal mean PaO2 levels (11.5��0.6�mmHg) similar to those measured in human fetuses of hypoxic pregnancy. We also created a wireless data acquisition system able to record fetal blood flow signals in addition to fetal blood pressure and heart rate from free moving ewes as the hypoxic pregnancy is developing. We determined in vivo longitudinal changes in fetal cardiovascular function including parallel measurement of fetal carotid and femoral blood flow and oxygen and glucose delivery during the last third of gestation. The ratio of oxygen (from 2.7��0.2 to 3.8��0.8; P�<�0.05) and of glucose (from 2.3��0.1 to 3.3��0.6; P�<�0.05) delivery to the fetal carotid, relative to the fetal femoral circulation, increased during and shortly after the period of chronic hypoxia. In contrast, oxygen and glucose delivery remained unchanged from baseline in normoxic fetuses. Fetal plasma urate concentration increased significantly during chronic hypoxia but not during normoxia (?: 4.8��1.6�vs. 0.5��1.4 ?mol�l(-1) , P<0.05). The data support the hypotheses tested and show persisting redistribution of substrate delivery away from peripheral and towards essential circulations in the chronically hypoxic fetus, associated with increases in xanthine oxidase-derived reactive oxygen species.

View details for DOI 10.1113/JP271091

View details for PubMedID 26926316

View details for PubMedCentralID PMC4771786
The Other Path-Think Radial. Canadian Association of Radiologists journal = Journal l'Association canadienne des radiologistes Thakor, A. S., Munk, P. L., Klass, D. 2015; 66 (3): 191-?
View details for DOI 10.1016/j.carj.2015.06.001

View details for PubMedID 26209289
Melatonin modulates the fetal cardiovascular defense response to acute hypoxia JOURNAL OF PINEAL RESEARCH Thakor, A. S., Allison, B. J., Niu, Y., Botting, K. J., Seron-Ferre, M., Herrera, E. A., Giussani, D. A. 2015; 59 (1): 80-90
Abstract

Experimental studies in animal models supporting protective effects on the fetus of melatonin in adverse pregnancy have prompted clinical trials in human pregnancy complicated by fetal growth restriction. However, the effects of melatonin on the fetal defense to acute hypoxia, such as that which may occur during labor, remain unknown. This translational study tested the hypothesis, in�vivo, that melatonin modulates the fetal cardiometabolic defense responses to acute hypoxia in chronically instrumented late gestation fetal sheep via alterations in fetal nitric oxide (NO) bioavailability. Under anesthesia, 6 fetal sheep at 0.85 gestation were instrumented with vascular catheters and a Transonic flow probe around a femoral artery. Five days later, fetuses were exposed to acute hypoxia with or without melatonin treatment. Fetal blood was taken to determine blood gas and metabolic status and plasma catecholamine concentrations. Hypoxia during melatonin treatment was repeated during in�vivo NO blockade with the NO clamp. This technique permits blockade of de novo synthesis of NO while compensating for the tonic production of the gas, thereby maintaining basal cardiovascular function. Melatonin suppressed the redistribution of blood flow away from peripheral circulations and the glycemic and plasma catecholamine responses to acute hypoxia. These are important components of the fetal brain sparing response to acute hypoxia. The effects of melatonin involved NO-dependent mechanisms as the responses were reverted by fetal treatment with the NO clamp. Melatonin modulates the in vivo fetal cardiometabolic responses to acute hypoxia by increasing NO bioavailability.

View details for DOI 10.1111/jpi.12242

View details for PubMedID 25908097
Radiological Evaluation of Abdominal Endovascular Aortic Aneurysm Repair. Canadian Association of Radiologists journal = Journal l'Association canadienne des radiologistes Thakor, A. S., Tanner, J., Ong, S. J., Hughes-Roberts, Y., Ilyas, S., Cousins, C., See, T. C., Klass, D., Winterbottom, A. P. 2015; 66 (3): 277-290
Abstract

Endovascular aortic aneurysm repair (EVAR) is an alternative to open surgical repair of aortic aneurysms offering lower perioperative mortality and morbidity. As experience increases, clinicians are undertaking complex repairs with hostile aortic anatomy using branched or fenestrated devices or extra components such as chimneys to ensure perfusion to visceral branch vessels whilst excluding the aneurysm. Defining the success of EVAR depends on both clinical and radiographic criteria, but ultimately depends on complete exclusion of the aneurysm from the circulation. Aortic stent grafts are monitored using a combination of imaging modalities including computed tomography angiography (CTA), ultrasonography, magnetic resonance imaging, plain films, and nuclear medicine studies. This article describes when and how to evaluate aortic stent grafts using each of these modalities along with the characteristic features of several of the main stent grafts currently used in clinical practice. The commonly encountered complications from EVAR are also discussed and how they can be detected using each imaging modality. As the radiation burden from serial follow up CTA imaging is now becoming a concern, different follow-up imaging strategies are proposed depending on the complexity of the repair and based on the relative merits and disadvantages of each imaging modality.

View details for DOI 10.1016/j.carj.2014.12.003

View details for PubMedID 25978867
Percutaneous autologous pancreatic islet cell transplantation for traumatic pancreatic injury. journal of clinical endocrinology & metabolism Thakor, A. S., Sangha, B. S., Ho, S. G., Warnock, G. L., Meloche, M., Liu, D. M. 2015; 100 (4): 1230-1233
Abstract

Traumatic pancreatic injury with pancreatic duct disruption is surgically managed with at least a partial pancreatectomy, often leading to poor blood glucose control and the subsequent development of diabetes mellitus. Autologous ?-islet cell transplantation may therefore help to preserve pancreatic endocrine function.We describe 3 patients with pancreatic duct disruption from traumatic pancreatic injury who were treated with a partial pancreatectomy followed by autologous ?-islet cell transplantation via a percutaneous transhepatic approach. Immediately after trauma, 2 of the 3 patients had difficulty with glucose control that resolved after autologous ?-islet cell transplantation. At follow-up, all patients remained normoglycemic.In patients requiring partial pancreatectomy after pancreatic trauma, percutaneous transhepatic autologous ?-islet cell transplantation should be considered to minimize the risk of development of diabetes mellitus.

View details for DOI 10.1210/jc.2014-4165

View details for PubMedID 25590216
Endovascular aneurysm repair (EVAR) follow-up imaging: the assessment and treatment of common postoperative complications. Clinical radiology Ilyas, S., Shaida, N., Thakor, A. S., Winterbottom, A., Cousins, C. 2015; 70 (2): 183-196
Abstract

Endovascular abdominal aortic aneurysm repair (EVAR) is a well-established procedure, which has long-term mortality rates similar to that of open repair. It has the additional benefit of being less invasive, making it the favoured method of treating abdominal aortic aneurysms in elderly and high-risk patients with multiple co-morbidities. The main disadvantage of EVAR is the higher rate of re-intervention, due to device-related complications, including endoleaks, limb occlusion, stent migration, kinking, and infection. As a result lifelong surveillance is required. In order to avoid missing these complications, intricate knowledge of stent graft design, good-quality diagnostic ultrasound skills, multiplanar reformatting of CT images, and reproducible investigations are important. Most of these complications can be treated via an endovascular approach using cuff extensions, uncovered stents, coils, and liquid embolic agents. Open surgery is reserved for complex complications, where an endovascular approach is not feasible.

View details for DOI 10.1016/j.crad.2014.09.010

View details for PubMedID 25443774
The use of cone-beam CT in assisting percutaneous translumbar catheter placement into the inferior vena cava. Clinical radiology Thakor, A. S., Chung, J., Patel, R., Cormack, R., Legiehn, G., Klass, D. 2015; 70 (1): 21-24
View details for DOI 10.1016/j.crad.2014.09.009

View details for PubMedID 25443775
Y90 selective internal radiation therapy. Surgical oncology clinics of North America Lee, E. W., Thakor, A. S., Tafti, B. A., Liu, D. M. 2015; 24 (1): 167-185
Abstract

Primary liver malignancies and liver metastases are affecting millions of individuals worldwide. Because of their late and advanced stage presentation, only 10% of patients can receive curative surgical treatment, including transplant or resection. Alternative treatments, such as systemic chemotherapy, ablative therapy, and chemoembolization, have been used with marginal survival benefits. Selective internal radiation therapy (SIRT), also known as radioembolization, is a compelling alternative treatment option for primary and metastatic liver malignancies with a growing body of evidence. In this article, an introduction to SIRT including background, techniques, clinical outcomes, and complications is reviewed.

View details for DOI 10.1016/j.soc.2014.09.011

View details for PubMedID 25444474
A review of conventional and drug-eluting chemoembolization in the treatment of colorectal liver metastases: principles and proof. Future oncology Liu, D. M., Thakor, A. S., Baerlocher, M., Alshammari, M. T., Lim, H., Kos, S., Kennedy, A. S., Wasan, H. 2015; 11 (9): 1421-1428
Abstract

The management of colorectal liver metastasis has undergone a significant change since the development of novel ablation and embolization. Drug-eluting microsphere platforms, designed to deliver targeted concentrations of systemic therapy directly into the tumor via its arterial vasculature, have garnered interest and gained in popularity in recent years. Based on in vitro and in vivo data, multiple factors contribute to locoregional exposure including carrier base, smaller particle size (larger surface area), chemotherapeutic and chemotherapeutic intensity. Based on the current published clinical data, therapy appears well tolerated but the questions remain as to the ideal technique, patient population and overall efficacy. The purpose of this article is to provide a perspective on the scientific basis, and clinical review of the current data supporting the use of this platform in the setting of metastatic colorectal carcinoma.

View details for DOI 10.2217/fon.15.3

View details for PubMedID 25602287
Heart disease link to fetal hypoxia and oxidative stress. Advances in experimental medicine and biology Giussani, D. A., Niu, Y., Herrera, E. A., Richter, H. G., Camm, E. J., Thakor, A. S., Kane, A. D., Hansell, J. A., Brain, K. L., Skeffington, K. L., Itani, N., Wooding, F. B., Cross, C. M., Allison, B. J. 2014; 814: 77-87
Abstract

The quality of the intrauterine environment interacts with our genetic makeup to shape the risk of developing disease in later life. Fetal chronic hypoxia is a common complication of pregnancy. This chapter reviews how fetal chronic hypoxia programmes cardiac and endothelial dysfunction in the offspring in adult life and discusses the mechanisms via which this may occur. Using an integrative approach in large and small animal models at the in vivo, isolated organ, cellular and molecular levels, our programmes of work have raised the hypothesis that oxidative stress in the fetal heart and vasculature underlies the mechanism via which prenatal hypoxia programmes cardiovascular dysfunction in later life. Developmental hypoxia independent of changes in maternal nutrition promotes fetal growth restriction and induces changes in the cardiovascular, metabolic and endocrine systems of the adult offspring, which are normally associated with disease states during ageing. Treatment with antioxidants of animal pregnancies complicated with reduced oxygen delivery to the fetus prevents the alterations in fetal growth, and the cardiovascular, metabolic and endocrine dysfunction in the fetal and adult offspring. The work reviewed offers both insight into mechanisms and possible therapeutic targets for clinical intervention against the early origin of cardiometabolic disease in pregnancy complicated by fetal chronic hypoxia.

View details for DOI 10.1007/978-1-4939-1031-1_7

View details for PubMedID 25015802
A scanning transmission electron microscopy approach to analyzing large volumes of tissue to detect nanoparticles. Microscopy and microanalysis Kempen, P. J., Thakor, A. S., Zavaleta, C., Gambhir, S. S., Sinclair, R. 2013; 19 (5): 1290-1297
Abstract

The use of nanoparticles for the diagnosis and treatment of cancer requires the complete characterization of their toxicity, including accurately locating them within biological tissues. Owing to their size, traditional light microscopy techniques are unable to resolve them. Transmission electron microscopy provides the necessary spatial resolution to image individual nanoparticles in tissue, but is severely limited by the very small analysis volume, usually on the order of tens of cubic microns. In this work, we developed a scanning transmission electron microscopy (STEM) approach to analyze large volumes of tissue for the presence of polyethylene glycol-coated Raman-active-silica-gold-nanoparticles (PEG-R-Si-Au-NPs). This approach utilizes the simultaneous bright and dark field imaging capabilities of STEM along with careful control of the image contrast settings to readily identify PEG-R-Si-Au-NPs in mouse liver tissue without the need for additional time-consuming analytical characterization. We utilized this technique to analyze 243,000 ?m3 of mouse liver tissue for the presence of PEG-R-Si-Au-NPs. Nanoparticles injected into the mice intravenously via the tail vein accumulated in the liver, whereas those injected intrarectally did not, indicating that they remain in the colon and do not pass through the colon wall into the systemic circulation.

View details for DOI 10.1017/S143192761300192X

View details for PubMedID 23803218
A role for xanthine oxidase in the control of fetal cardiovascular function in late gestation sheep JOURNAL OF PHYSIOLOGY-LONDON Herrera, E. A., Kane, A. D., Hansell, J. A., Thakor, A. S., Allison, B. J., Niu, Y., Giussani, D. A. 2012; 590 (8): 1825-1837
Abstract

Virtually nothing is known about the effects on fetal physiology of xanthine oxidase inhibition. This is despite maternal treatment with the xanthine oxidase inhibitor allopurinol being considered in human complicated pregnancy to protect the infant?s brain from excessive generation of ROS.We investigated the in vivo effects of maternal treatment with allopurinol on fetal cardiovascular function in ovine pregnancy in late gestation. Under anaesthesia, pregnant ewes and their singleton fetus were instrumented with vascular catheters and flow probes around an umbilical and a fetal femoral artery at 118�1 dGA (days of gestational age; termca. 145 days). Five days later, mothers were infused I.V. with either vehicle (n =11) or allopurinol (n =10). Fetal cardiovascular function was stimulated with increasing bolus doses of phenylephrine (PE) following maternal vehicle or allopurinol. The effects of maternal allopurinol on maternal and fetal cardiovascular function were also investigated following fetal NO blockade (n =6) or fetal ?1-adrenergic antagonism (n =7). Maternal allopurinol led to significant increases in fetal heart rate, umbilical blood flow and umbilical vascular conductance, effects abolished by fetal ?1-adrenergic antagonism but not by fetal NO blockade. Maternal allopurinol impaired fetal ?1-adrenergic pressor and femoral vasopressor responses and enhanced the gain of the fetal cardiac baroreflex. These effects of maternal allopurinol were restored to control levels during fetal NO blockade. Maternal treatment with allopurinol induced maternal hypotension, tachycardia and acid?base disturbance. We conclude that maternal treatment with allopurinol alters in vivo maternal, umbilical and fetal vascular function via mechanisms involving NO and ?1-adrenergic stimulation. The evidence suggests that the use of allopurinol in clinical practice should be approached with caution.

View details for DOI 10.1113/jphysiol.2011.224576

View details for Web of Science ID 000302799300012

View details for PubMedID 22331413
Developmental Programming of Cardiovascular Dysfunction by Prenatal Hypoxia and Oxidative Stress PLOS ONE Giussani, D. A., Camm, E. J., Niu, Y., Richter, H. G., Blanco, C. E., Gottschalk, R., Blake, E. Z., Horder, K. A., Thakor, A. S., Hansell, J. A., Kane, A. D., Wooding, F. B., Cross, C. M., Herrera, E. A. 2012; 7 (2)
Abstract

Fetal hypoxia is a common complication of pregnancy. It has been shown to programme cardiac and endothelial dysfunction in the offspring in adult life. However, the mechanisms via which this occurs remain elusive, precluding the identification of potential therapy. Using an integrative approach at the isolated organ, cellular and molecular levels, we tested the hypothesis that oxidative stress in the fetal heart and vasculature underlies the molecular basis via which prenatal hypoxia programmes cardiovascular dysfunction in later life. In a longitudinal study, the effects of maternal treatment of hypoxic (13% O(2)) pregnancy with an antioxidant on the cardiovascular system of the offspring at the end of gestation and at adulthood were studied. On day 6 of pregnancy, rats (n = 20 per group) were exposed to normoxia or hypoxia � vitamin C. At gestational day 20, tissues were collected from 1 male fetus per litter per group (n = 10). The remaining 10 litters per group were allowed to deliver. At 4 months, tissues from 1 male adult offspring per litter per group were either perfusion fixed, frozen, or dissected for isolated organ preparations. In the fetus, hypoxic pregnancy promoted aortic thickening with enhanced nitrotyrosine staining and an increase in cardiac HSP70 expression. By adulthood, offspring of hypoxic pregnancy had markedly impaired NO-dependent relaxation in femoral resistance arteries, and increased myocardial contractility with sympathetic dominance. Maternal vitamin C prevented these effects in fetal and adult offspring of hypoxic pregnancy. The data offer insight to mechanism and thereby possible targets for intervention against developmental origins of cardiac and peripheral vascular dysfunction in offspring of risky pregnancy.

View details for DOI 10.1371/journal.pone.0031017

View details for Web of Science ID 000302733900020

View details for PubMedID 22348036
Gold Nanoparticles: A Revival in Precious Metal Administration to Patients NANO LETTERS Thakor, A. S., Jokerst, J., Zavaleta, C., Massoud, T. F., Gambhir, S. S. 2011; 11 (10): 4029-4036
Abstract

Gold has been used as a therapeutic agent to treat a wide variety of rheumatic diseases including psoriatic arthritis, juvenile arthritis, and discoid lupus erythematosus. Although the use of gold has been largely superseded by newer drugs, gold nanoparticles are being used effectively in laboratory based clinical diagnostic methods while concurrently showing great promise in vivo either as a diagnostic imaging agent or a therapeutic agent. For these reasons, gold nanoparticles are therefore well placed to enter mainstream clinical practice in the near future. Hence, the present review summarizes the chemistry, pharmacokinetics, biodistribution, metabolism, and toxicity of bulk gold in humans based on decades of clinical observation and experiments in which gold was used to treat patients with rheumatoid arthritis. The beneficial attributes of gold nanoparticles, such as their ease of synthesis, functionalization, and shape control are also highlighted demonstrating why gold nanoparticles are an attractive target for further development and optimization. The importance of controlling the size and shape of gold nanoparticles to minimize any potential toxic side effects is also discussed.

View details for DOI 10.1021/nl202559p

View details for PubMedID 21846107
Preclinical Evaluation of Raman Nanoparticle Biodistribution for their Potential Use in Clinical Endoscopy Imaging SMALL Zavaleta, C. L., Hartman, K. B., Miao, Z., James, M. L., Kempen, P., Thakor, A. S., Nielsen, C. H., Sinclair, R., Cheng, Z., Gambhir, S. S. 2011; 7 (15): 2232-2240
Abstract

Raman imaging offers unsurpassed sensitivity and multiplexing capabilities. However, its limited depth of light penetration makes direct clinical translation challenging. Therefore, a more suitable way to harness its attributes in a clinical setting would be to couple Raman spectroscopy with endoscopy. The use of an accessory Raman endoscope in conjunction with topically administered tumor-targeting Raman nanoparticles during a routine colonoscopy could offer a new way to sensitively detect dysplastic lesions while circumventing Raman's limited depth of penetration and avoiding systemic toxicity. In this study, the natural biodistribution of gold surface-enhanced Raman scattering (SERS) nanoparticles is evaluated by radiolabeling them with (64) Cu and imaging their localization over time using micropositron emission tomography (PET). Mice are injected either intravenously (IV) or intrarectally (IR) with approximately 100 microcuries (?Ci) (3.7 megabecquerel (MBq)) of (64) Cu-SERS nanoparticles and imaged with microPET at various time points post injection. Quantitative biodistribution data are obtained as % injected dose per gram (%ID g(-1)) from each organ, and the results correlate well with the corresponding microPET images, revealing that IV-injected mice have significantly higher uptake (p < 0.05) in the liver (5 h = 8.96% ID g(-1); 24 h = 8.27% ID g(-1)) than IR-injected mice (5 h = 0.09% ID g(-1); 24 h = 0.08% ID g(-1)). IR-injected mice show localized uptake in the large intestine (5 h = 10.37% ID g(-1); 24 h = 0.42% ID g(-1)) with minimal uptake in other organs. Raman imaging of excised tissues correlate well with biodistribution data. These results suggest that the topical application of SERS nanoparticles in the mouse colon appears to minimize their systemic distribution, thus avoiding potential toxicity and supporting the clinical translation of Raman spectroscopy as an endoscopic imaging tool.

View details for DOI 10.1002/smll.201002317

View details for Web of Science ID 000294361200015

View details for PubMedID 21608124
Molecular imaging of the Epidermal Growth Factor Receptor in rodent colon via Affibody-functionalized surface enhanced Raman scattering (SERS) nanoparticles 241st National Meeting and Exposition of the American-Chemical-Society (ACS) Jokerst, J. V., Miao, Z., Thakor, A. S., Cheng, Z., Gambhir, S. S. AMER CHEMICAL SOC. 2011
View details for Web of Science ID 000291982802272
The radiation burden from increasingly complex endovascular aortic aneurysm repair. Insights into imaging Thakor, A. S., Winterbottom, A., Mercuri, M., Cousins, C., Gaunt, M. E. 2011; 2 (6): 699?704
Abstract

OBJECTIVES: With increasing experience, endovascular aortic aneurysm repair (EVAR) has been extended to patients with less suitable aorto-iliac anatomy in an attempt to reduce peri-operative mortality. However, more complex EVAR procedures may take longer and can result in higher rates of complications, additional interventional procedures and more frequent radiological imaging, which may offset some of the benefit. This study determined the radiation burden for standard EVAR, as determined by the EVAR-1 trial criteria, and more complex EVAR. METHODS: A total of 123 elective patients aged >60, with aneurysms >5.5�cm who received a bifurcated stent-graft were allocated into a group based on whether or not they fulfilled strict EVAR-1 trial criteria. The mean radiation dose was calculated for each group, together with the additional radiation burden from routine pre- and post-EVAR CT examinations and pre-EVAR iliac artery embolisation. RESULTS: Patients not meeting the EVAR-1 trial criteria had significantly longer fluoroscopic screening times and higher radiation doses. The radiation burden in all patients was higher following exposure from routine CT examinations and following pre-EVAR iliac artery embolisation. CONCLUSION: Whilst the radiation from standard EVAR is acceptable, more complicated and challenging EVARs, accompanied with additional radiological investigations and procedures, can significantly increase the radiation burden.

View details for DOI 10.1007/s13244-011-0120-5

View details for PubMedID 22347987

View details for PubMedCentralID PMC3259354
Allopurinol Reduces Oxidative Stress in the Ovine Fetal Cardiovascular System After Repeated Episodes of Ischemia-Reperfusion PEDIATRIC RESEARCH Derks, J. B., Oudijk, M. A., Torrance, H. L., Rademaker, C. M., Benders, M. J., Rosen, K. G., Cindrova-Davies, T., Thakor, A. S., Visser, G. H., Burton, G. J., van Bel, F., Giussani, D. A. 2010; 68 (5): 374-380
Abstract

In complicated labor, neonatal outcome may depend not only on the extent of fetal asphyxia and acidosis but also on the effects on the fetal cardiovascular system of reactive oxygen species (ROS) generated during the ischemia-reperfusion (I/R) associated with repeated compressions of the umbilical cord. This study tested the hypothesis that maternal treatment with clinical doses of the antioxidant allopurinol in the setting of fetal asphyxia would reduce oxidative stress in the fetal cardiovascular system. The hypothesis was tested in chronically instrumented fetal sheep in late gestation by investigating the effects of maternal treatment with therapeutic doses of allopurinol or vehicle on the fetal cardiovascular system during and after episodes of I/R. The latter were produced by repeated, measured compressions of the umbilical cord. The data show that maternal treatment with allopurinol helped maintain umbilical blood flow and it reduced fetal cardiac oxidative stress after I/R of the type associated with clinically relevant acidemia and repetitive fetal heart rate decelerations. The data support the hypothesis tested and suggest that maternal treatment with allopurinol may offer plausible clinical intervention in the management of perinatal asphyxia in complicated labor.

View details for Web of Science ID 000283409700002

View details for PubMedID 20613682
Redox modulation of the fetal cardiovascular defence to hypoxaemia JOURNAL OF PHYSIOLOGY-LONDON Thakor, A. S., Richter, H. G., Kane, A. D., Dunster, C., Kelly, F. J., Poston, L., Giussani, D. A. 2010; 588 (21): 4235-4247
Abstract

Episodes of hypoxia in utero present a potentially serious challenge to the fetus, but are counteracted by defence responses including marked redistribution of blood flow from peripheral circulations to the brain. Here, we report the novel observation that the oxidant tone is an important modulator of this cardiovascular defence. Using pregnant Welsh Mountain sheep surgically prepared for long-term recording, we investigated in vivo the effects on the fetal cardiovascular defence to acute hypoxaemia of fetal treatment with the antioxidant vitamin C. The mechanisms via which vitamin C may affect the vascular oxidant tone were investigated by monitoring fetal plasma concentrations of nitrates and nitrites, by determining changes in the activity of superoxide dismutase (SOD) in fetal plasma, and by investigating the effect of vitamin C treatment on the fetal cardiovascular defence to hypoxaemia following nitric oxide (NO) synthase blockade. Fetal treatment with vitamin C markedly depressed the normal femoral constrictor response to acute hypoxaemia in the fetus (5.2 � 1.0 vs. 1.1 � 0.3 mmHg (ml min(-1))(-1), mean � s.e.m.; P < 0.05) an effect which was completely restored following NO synthase blockade (6.2 � 1.3 mmHg (ml min(-1))(-1)). Compared to saline infusion, fetal treatment with vitamin C during acute hypoxaemia also significantly increased fetal plasma SOD activity from normoxic baseline (-8.9 � 6.5 vs. 15.0 � 6.6% inhibition, P < 0.05) and decreased the plasma concentration ratio of nitrate:nitrite from normoxic baseline (?NO3(-):NO2(-); 0.15 � 0.30 vs. -0.29 � 0.11, P < 0.05). The data provide in vivo evidence of redox modulation of redistribution of blood flow in the fetus, part of the fetal brain sparing during acute hypoxaemic stress.

View details for DOI 10.1113/jphysiol.2010.196402

View details for Web of Science ID 000283718800021

View details for PubMedID 20807788

View details for PubMedCentralID PMC3002453
Melatonin and vitamin C increase umbilical blood flow via nitric oxide-dependent mechanisms JOURNAL OF PINEAL RESEARCH Thakor, A. S., Herrera, E. A., Seron-Ferre, M., Giussani, D. A. 2010; 49 (4): 399-406
Abstract

Inadequate umbilical blood flow leads to intrauterine growth restriction, a major killer in perinatal medicine today. Nitric oxide (NO) is important in the maintenance of umbilical blood flow, and antioxidants increase NO bioavailability. What remains unknown is whether antioxidants can increase umbilical blood flow. Melatonin participates in circadian, seasonal, and reproductive physiology, but has also been reported to act as a potent endogenous antioxidant. We tested the hypothesis that treatment during pregnancy with melatonin increases umbilical blood flow via NO-dependent mechanisms. This was tested in pregnant sheep by investigating in vivo the effects on continuous measurement of umbilical blood flow of melatonin before and after NO blockade with a NO clamp. These effects of melatonin were compared with those of the traditional antioxidant, vitamin C. Under anesthesia, 12 pregnant sheep and their fetuses (0.8 of gestation) were fitted with catheters and a Transonic probe around an umbilical artery, inside the fetal abdomen. Following 5 days of recovery, cardiovascular variables were recorded during fetal i.v. treatment with either melatonin (n=6, 0.5�0.1 ?g/kg/min) or vitamin C (n=6, 8.9�0.4 mg/kg/min) before and after fetal NO blockade with the NO clamp. Fetal treatment with melatonin or vitamin C increased umbilical blood flow, independent of changes in fetal arterial blood pressure. Fetal NO blockade prevented the increase in umbilical blood flow induced by melatonin or vitamin C. Antioxidant treatment could be a useful clinical tool to increase or maintain umbilical blood flow in complicated pregnancy.

View details for DOI 10.1111/j.1600-079X.2010.00813.x

View details for Web of Science ID 000283169300010

View details for PubMedID 20958954
The relation of S100beta and metabolic and endocrine responses to acute fetal hypoxemia. Frontiers in bioscience (Elite edition) Thakor, A. S., Gazzolo, D., Frulio, R., Giussani, D. A. 2010; 2: 59-67
Abstract

Elevations in S100beta protein in umbilical cord blood have been proposed as a reproducible marker of fetal stress, leading to cell damage within the central nervous system. However, it remains unknown whether fetal S100beta concentrations correlate with established endocrine and metabolic indices of fetal distress. Hence, in the late gestation ovine fetus, plasma concentrations of S100beta, adrenocorticotropic hormone (ACTH), cortisol, neuropeptide Y (NPY), and catecholamines and blood concentrations of glucose and lactate were measured during acute hypoxemia. Under general anesthesia, 5 sheep fetuses were chronically instrumented with catheters and subjected 5 days later to 1h normoxia, 0.5h hypoxemia and 1h recovery. Plasma samples were taken during each experimental period. Hypoxemia induced significant falls in PaO2 with increases in fetal plasma concentrations of ACTH, cortisol, catecholamines and NPY, and elevations in blood glucose and lactate, all of which showed significant positive relationships with fetal plasma S100beta concentrations. Hence, evaluation of S100beta may provide a valuable clinical tool in the assessment of fetal well-being in suspected complicated pregnancies.

View details for PubMedID 20036854
Factor V Leiden Mutation and Antiphospholipid Syndrome: Risk Factors for Atherosclerotic and Arterial Thromboembolic Disease JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Thakor, A. S., Shah, D., Miller, F., Gaunt, M. E. 2009; 20 (8): 1097-1098
View details for DOI 10.1016/j.jvir.2009.04.073

View details for Web of Science ID 000269337200016

View details for PubMedID 19574060
Toxic epidermal necrolysis and neutropaenia: Complications of omeprazole AUSTRALASIAN JOURNAL OF DERMATOLOGY Thakor, A. S., Burke, A., Handfield-Jones, S., Sinha, A., Palmer, M., Burns, A. 2009; 50 (3): 207-210
Abstract

Worldwide, proton pump inhibitors (PPI) are one of the most frequently prescribed drugs; however, up to 70% of patients taking these drugs have no appropriate indication. Although PPI are relatively well tolerated, they are not free from side-effects and several life-threatening complications are associated with them. In the present report, a 43-year-old woman presented to her general practitioner with an erythematous rash over her face and chest, having been started on omeprazole for chronic abdominal bloating. Over the next 24 h she became increasingly unwell and was admitted to hospital with shortness of breath, pyrexia and the rash spreading over her back, arms and legs. Vesicles had now started to appear within the erythematous regions over her upper body and within 24 h the rash became confluent and desquamative, spreading to involve her entire body. A diagnosis of toxic epidermal necrolysis (TEN) was made. Despite supportive treatment within a critical care setting, she became neutropaenic and her skin loss became more extensive, resulting in 95% epidermal detachment. This case highlights that TEN is a life-threatening condition associated with a high incidence of morbidity and mortality. Optimal management requires early diagnosis and transfer to a specialized unit. Clinicians need to be aware that PPI are not free from side-effects and that their routine prescription should be strongly discouraged.

View details for DOI 10.1111/j.1440-0960.2009.00540.x

View details for Web of Science ID 000268260500010

View details for PubMedID 19659985
Nitric Oxide Reduces Vagal Baroreflex Sensitivity in the Late Gestation Fetus PEDIATRIC RESEARCH Thakor, A. S., Giussani, D. A. 2009; 65 (3): 269-273
Abstract

Goals to understand the etiology of essential hypertension have proposed that this problem arises, in part, because of changes within brainstem circuits involved in arterial blood pressure (ABP) control. It has been suggested that nitric oxide (NO) exerts inhibitory influences on the integration of afferent discharge from the arterial baroreceptors. This study tested the hypothesis that the inhibitory influence of NO on the arterial baroreflex is present in fetal life. Fetal baroreflex sensitivity was calculated in fetal sheep, before and during the NO-clamp; a technique that permits NO synthase (NOS) blockade with l-NAME while maintaining basal cardiovascular function with sodium nitroprusside. Under halothane anesthesia, five fetal sheep at 0.8 gestation were instrumented with vascular catheters. Five days later, fetuses received a range of bolus doses of phenylephrine (5-75 microg I.A.) in randomized order either during saline or treatment with the NO clamp. Basal fetal ABP and heart rate before (50 +/- 4 mm Hg, 170 +/- 3 bpm) or during (51 +/- 4 mm Hg, 173 +/- 3 bpm) the NO-clamp were similar. The gradient of the pulse interval-ABP relationship was nearly doubled during NOS blockade (14.2 =/- 2.5 versus 7.8 +/- 1.6 ms/mm Hg). The data provide in vivo evidence that NO attenuates the sensitivity of the cardiac baroreflex during fetal life.

View details for Web of Science ID 000263543000003

View details for PubMedID 19391249
Infective endocarditis from injecting heroin into a leg ulcer. BMJ case reports Thakor, A. S., Wijenaike, N. 2009; 2009
View details for DOI 10.1136/bcr.07.2008.0493

View details for PubMedID 21686779
Postpartum rupture of a splenic artery aneurysm presenting as disseminated intravascular coagulation INTERNATIONAL JOURNAL OF OBSTETRIC ANESTHESIA Sinha, A., Meldrum, D., Sinha, B., Thakor, A. S. 2009; 18 (1): 95-96
View details for DOI 10.1016/j.ijoa.2008.08.002

View details for Web of Science ID 000262736700027

View details for PubMedID 19046872
Multiple inflammatory aneurysms: A rare complication of idiopathic inflammatory aortitis European Journal of Radiology Thakor, A. S., Hiemstra, T. F., Cousins, C., See, T. C. 2009; 70: e141-e144
Double superior vena cavae. BMJ case reports Thakor, A. S., Massoud, T. 2009; 2009
View details for DOI 10.1136/bcr.10.2008.1098

View details for PubMedID 21686460
Effects of acute acidemia on the fetal cardiovascular defense to acute hypoxemia AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Thakor, A. S., Giussani, D. A. 2009; 296 (1): R90-R99
Abstract

In complicated pregnancy, fetal hypoxemia rarely occurs in isolation but is often accompanied by fetal acidemia. There is growing clinical concern about the combined effects of fetal hypoxemia and fetal acidemia on neonatal outcome. However, the effects on the fetal defense responses to acute hypoxemia during fetal acidemia are not well understood. This study tested the hypothesis that fetal acidemia affects the fetal defense responses to acute hypoxemia. The hypothesis was tested by investigating, in the late-gestation sheep fetus surgically prepared for long-term recording, the in vivo effects of acute fetal acidemia on 1) the fetal cardiovascular responses to acute hypoxemia and 2) the neural and endocrine mechanisms mediating these responses. Under general anesthesia, five sheep fetuses at 0.8 gestation were instrumented with catheters and Transonic flow probes around the femoral and umbilical arteries. After 5 days, animals were subjected to an acute hypoxemia protocol during intravenous infusion of saline or treatment with acidified saline. Treatment with acidified saline reduced fetal basal pH from 7.35 +/- 0.01 to 7.29 +/- 0.01 but did not alter basal cardiovascular variables, blood glucose, or plasma concentrations of catecholamines, ACTH, and cortisol. During hypoxemia, treatment with acidified saline increased the magnitude of the fetal bradycardia and femoral vasoconstriction and concomitantly increased chemoreflex function and enhanced the increments in plasma concentrations of catecholamines, ACTH, and cortisol. Acidemia also reversed the increase in umbilical vascular conductance during hypoxemia to vasoconstriction. In conclusion, the data support our hypothesis and show that acute acidemia markedly alters fetal hemodynamic, metabolic, and endocrine responses to acute hypoxemia.

View details for DOI 10.1152/ajpregu.90689.2008

View details for Web of Science ID 000262056300013

View details for PubMedID 18922958
A new effective non-invasive method of cooling patients with malignant hyperthermia ANAESTHESIA Thakor, A. S., Levy, N. 2008; 63 (11): 1266-1267
View details for Web of Science ID 000259937300038

View details for PubMedID 19032278
Anaemia, weight loss, and round shadows in the lungs LANCET Thakor, A. S., Hiemstra, T. F., Jayne, D. R. 2008; 371 (9606): 88-88
View details for Web of Science ID 000252192600035

View details for PubMedID 18177780
A rare life-threatening complication of an indwelling hemodialysis catheter KIDNEY INTERNATIONAL Thakor, A. S., Hiemstra, T. F., Bradley, J. R. 2008; 73 (2): 244-244
View details for DOI 10.1038/sj.ki.5002582

View details for Web of Science ID 000252115200020

View details for PubMedID 18165817
Acute small bowel obstruction as a result of a Meckel's diverticulum encircling the terminal ileum: A case report. Journal of medical case reports Thakor, A. S., Liau, S. S., O'riordan, D. C. 2007; 1: 8-?
Abstract

In the developed world, small bowel obstruction accounts for 20% of all acute surgical admissions. The aetiology for majority of these cases includes postoperative adhesions and herniae. However, a relatively uncommon cause is a Meckel's diverticulum. Although this diagnosis is primarily reported in the adolescent population, it should also be considered in adults.In the present report, we present a rare case where a fit and healthy 74-year-old gentleman, with no previous history of abdominal surgery, presented with the cardinal symptoms and signs of small bowel obstruction as the result of a Meckel's diverticulum encircling his terminal ileum. Initial investigations included a supine abdominal x-ray showing dilated loops of small bowel and computerised tomographic imaging of the abdomen, which revealed a stricture in the terminal ileum of unknown aetiology. At laparotomy, multiple loops of distended small bowel were seen from the duodeno-jeujenal junction to the terminal ileum, which was encircled by a Meckel's diverticulum. The Meckel's diverticulum was then divided to release the obstruction, mobilised and subsequently removed. Finally, the small bowel contents were decompressed into the stomach and the nasogastric tube aspirated, before returning the loops of bowel into the abdomen in sequence. The patient made a good postoperative recovery and was discharged home 5 days later.This report highlights the importance of considering a Meckel's diverticulum as a cause of small bowel obstruction in individuals from all age groups and especially in a person with no previous abdominal pathology or surgery.

View details for PubMedID 17411459
Comments on Point-Counterpoint "Positive effects of intermittent hypoxia (live high:train low) on exercise performance are/are not mediated primarily by augmented red cell volume". Journal of applied physiology Giussani, D. A., Thakor, A. S. 2006; 100 (1): 363-364
View details for PubMedID 16402423
The role of calcitonin gene-related peptide in the in vivo pituitary-adrenocortical response to acute hypoxemia in the late-gestation sheep fetus ENDOCRINOLOGY Thakor, A. S., Giussani, D. A. 2005; 146 (11): 4871-4877
Abstract

This study tested the hypothesis that calcitonin gene-related peptide (CGRP) has a role in mediating the in vivo fetal adrenal glucocorticoid response to acute stress. The hypothesis was tested by investigating the effects of fetal treatment with a selective CGRP antagonist on plasma ACTH and cortisol responses to acute hypoxemia in the late-gestation sheep fetus. Under anesthesia, six fetuses at 0.8 of gestation were surgically instrumented with vascular catheters. Five days later, fetuses were subjected to 0.5-h hypoxemia during treatment with either iv saline or a CGRP antagonist, in randomized order, on different days. Treatment started 30 min before hypoxemia and ran continuously until the end of the challenge. Arterial blood samples were collected for plasma ACTH and cortisol measurements (RIA) and blood gas monitoring. CGRP antagonism did not alter basal arterial blood gas or endocrine status. During hypoxemia, similar falls in arterial partial pressure of oxygen occurred in all fetuses. During saline infusion, acute hypoxemia induced significant increases in fetal ACTH and cortisol concentrations. During CGRP antagonism, the pituitary-adrenal responses were markedly attenuated. Correlation of paired plasma ACTH and cortisol values from all individual fetuses during normoxia and hypoxemia showed positive linear relationships; however, neither the slope nor the intercept of the peptide-steroid relationship was affected by CGRP antagonism. These data support the hypothesis that CGRP is involved in the in vivo regulation of fetal adrenocortical steroidogenesis during acute hypoxemia. In addition, the data reveal that CGRP may have a role in the control of other components of the hypothalamo-pituitary-adrenal axis during stimulated conditions in fetal life.

View details for DOI 10.1210/en.2005-0444

View details for Web of Science ID 000232585200034

View details for PubMedID 16055428
Role of nitric oxide in mediating in vivo vascular responses to calcitonin gene-related peptide in essential and peripheral circulations in the fetus CIRCULATION Thakor, A. S., Giussani, D. A. 2005; 112 (16): 2510-2516
Abstract

The role of calcitonin gene-related peptide (CGRP) in cardiovascular regulation is gaining clinical and scientific interest. In the adult, in vivo studies have shown that CGRP-stimulated vasodilation in several vascular beds depends, at least in part, on nitric oxide (NO). However, whether CGRP acts as a vasodilator in the fetus in vivo and whether this effect is mediated via NO have been addressed only minimally. This study tested the hypothesis that CGRP has potent NO-dependent vasodilator actions in essential and peripheral vascular beds in the fetus in late gestation.Under anesthesia, 5 fetal sheep at 0.8 gestation were instrumented with vascular catheters and Transonic flow probes around an umbilical artery and a femoral artery. Five days later, fetuses received 2- and 5-microg doses of exogenous CGRP intra-arterially in randomized order. Doses were repeated during NO blockade with the NO clamp. This technique permits blockade of de novo synthesis of NO while compensating for tonic production of the gas, thereby maintaining basal cardiovascular function. CGRP resulted in potent and long-lasting NO-dependent dilation in the umbilical and femoral circulations, hypotension, and a positive cardiac chronotropic effect. During NO blockade, the femoral vasodilator response to CGRP was diminished. In contrast, in the umbilical vascular bed, the dilator response was not only prevented but reversed to vasoconstriction.CGRP has potent NO-dependent vasodilator actions in fetal essential and peripheral vascular beds. CGRP-induced NO-dependent effects in the umbilical vascular bed may provide an important mechanism in the control and maintenance of umbilical blood flow during pregnancy.

View details for DOI 10.1161/CIRCULATIONAHA.105.562546

View details for Web of Science ID 000232607000019

View details for PubMedID 16216959
Acute hypoxia increases S100 beta protein in association with blood flow redistribution away from peripheral circulations in fetal sheep PEDIATRIC RESEARCH Giussani, D. A., Thakor, A. S., Frulio, R., Gazzolo, D. 2005; 58 (2): 179-184
Abstract

We investigated in fetal sheep during late gestation the effects of acute hypoxemia on fetal plasma S100beta protein concentrations and how these relate to fetal redistribution of blood flow and acid-base status. Under general anesthesia, five Welsh Mountain sheep fetuses were instrumented with vascular catheters, and transit-time flow transducers were implanted around a femoral artery and an umbilical artery. At least 5 d after surgery, fetuses were subjected to 1 h of normoxia, 0.5 h of hypoxemia, and 1 h of recovery. Hypoxemia induced significant falls in fetal pH(a), arterial oxygen pressure, acid-base excess, and [HCO(3)(-)], without alteration to arterial partial pressure of carbon dioxide. An increase in arterial blood pressure, a fall in heart rate, an increase in femoral vascular resistance, and a decrease in umbilical vascular resistance occurred in all fetuses. During hypoxemia, plasma S100beta increased significantly and remained elevated until the end of the protocol. Within individual fetuses, plasma S100beta correlated with femoral vascular resistance and pH. In contrast, no relationship was found between S100beta and umbilical vascular resistance. This study reports for the first time that a controlled period of fetal hypoxemia with associated acidemia leads to persistent elevations in plasma S100beta concentrations that strongly correlate with hemodynamic changes that are known to occur during fetal blood flow redistribution. These findings open up a new role for changes in fetal S100beta concentrations as a possible early marker of fetal hypoxia with associated acidemia in perinatal medicine.

View details for DOI 10.1203/01.PDR.0000169999.66157.C0

View details for Web of Science ID 000230995500002

View details for PubMedID 16006424
Calcitonin gene-related peptide antagonism attenuates the haemodynamic and glycaemic responses to acute hypoxaemia in the late gestation sheep fetus JOURNAL OF PHYSIOLOGY-LONDON Thakor, A. S., Bloomfield, M. R., Patterson, M., Giussani, D. A. 2005; 566 (2): 587-597
Abstract

The fetal defence to acute hypoxaemia involves cardiovascular and metabolic responses, which include peripheral vasoconstriction and hyperglycaemia. Both these responses are mediated via neuroendocrine mechanisms, which require the stimulation of the sympathetic nervous system. In the adult, accumulating evidence supports a role for calcitonin gene-related peptide (CGRP) in the activation of sympathetic outflow. However, the role of CGRP in stimulated cardiovascular and metabolic functions before birth is completely unknown. This study tested the hypothesis that CGRP plays a role in the fetal cardiovascular and metabolic defence responses to acute hypoxaemia by affecting sympathetic outflow. Under anaesthesia, five sheep fetuses at 0.8 of gestation were surgically instrumented with catheters and a femoral arterial Transonic flow-probe. Five days later, fetuses were subjected to 0.5 h hypoxaemia during either i.v. saline or a selective CGRP antagonist in randomised order. Treatment started 30 min before hypoxaemia and ran continuously until the end of the challenge. Arterial samples were taken for blood gases, metabolic status and hormone analyses. CGRP antagonism did not alter basal arterial blood gas, metabolic, cardiovascular or endocrine status. During hypoxaemia, similar falls in Pa,O2 occurred in all fetuses. During saline infusion, hypoxaemia induced hypertension, bradycardia, femoral vasoconstriction, hyperglycaemia and an increase in haemoglobin, catecholamines and neuropeptide Y (NPY). In contrast, CGRP antagonism markedly diminished the femoral vasoconstrictor and glycaemic responses to hypoxaemia, and attenuated the increases in haemoglobin, catecholamines and NPY. Combined, these results strongly support the hypothesis that CGRP plays a role in the fetal cardiovascular and metabolic defence to hypoxaemia by affecting sympathetic outflow.

View details for DOI 10.1113/jphysiol.2005.085431

View details for Web of Science ID 000230909200023

View details for PubMedID 15860534
Calcitonin gene-related peptide contributes to the umbilical haemodynamic defence response to acute hypoxaemia JOURNAL OF PHYSIOLOGY-LONDON Thakor, A. S., Giussani, D. A. 2005; 563 (1): 309-317
Abstract

Despite clinical advances in obstetric practice, undiagnosed fetal hypoxaemia still contributes to a high incidence of perinatal morbidity. The fetal defence to hypoxaemia involves a redistribution of blood flow away from peripheral circulations towards essential vascular beds, such as the umbilical, cerebral, myocardial and adrenal circulations. In marked contrast to other essential vascular beds, the mechanisms mediating maintained perfusion of the umbilical circulation during hypoxaemia remain unknown. This study determined the role of calcitonin gene-related peptide (CGRP) in the maintenance of umbilical blood flow during basal and hypoxaemic conditions. Under anaesthesia, five sheep fetuses were instrumented with catheters and a Transonic probe around an umbilical artery, inside the fetal abdomen, at 0.8 of gestation. Five days later, fetuses were subjected to 0.5 h hypoxaemia during either i.v. saline or a selective CGRP antagonist in randomised order. Treatment started 30 min before hypoxaemia and ran continuously until the end of the challenge. The CGRP antagonist did not alter basal blood gas or cardiovascular status in the fetus. A similar fall in Pa,O2 occurred in fetuses during either saline (21 +/- 0.8 to 9 +/- 0.9 mmHg) or antagonist treatment (20 +/- 0.9 to 9 +/- 1.2 mmHg). Hypoxaemia during saline led to significant increases in arterial blood pressure, umbilical blood flow and umbilical vascular conductance. In marked contrast, hypoxaemia during CGRP antagonist treatment led to pronounced falls in both umbilical blood flow and umbilical vascular conductance without affecting the magnitude of the hypertensive response. In conclusion, CGRP plays an important role in the umbilical haemodynamic defence response to hypoxaemia in the late gestation fetus.

View details for DOI 10.1113/jphysiol.2004.077024

View details for Web of Science ID 000227224900023

View details for PubMedID 15611032
Effects of prolonged reduction in blood flow on submandibular secretory function in anesthetized sheep JOURNAL OF APPLIED PHYSIOLOGY Thakor, A. S., Brown, C. N., Edwards, A. V. 2003; 95 (2): 751-757
Abstract

Submandibular vascular and secretory responses to parasympathetic chorda-lingual (C-L) stimulation were investigated in anesthetized sheep before, during, and after an intracarotid (ic) infusion of endothelin-1 (ET-1). Stimulation of the peripheral end of the C-L nerve at 4 and 8 Hz produced a frequency-dependent reduction in submandibular vascular resistance (SVR) associated with a frequency-dependent increase in submandibular blood flow, salivary flow, and Na+, K+, and protein output from the gland. During stimulation at 4 Hz, ic ET-1 significantly increased SVR (P < 0.01), without significantly affecting either the aortic blood pressure or heart rate. Submandibular blood flow (SBF) was reduced by 48 +/- 4% and the flow of saliva by 50 +/- 1%. The effect on blood and salivary flow persisted for at least 30 min after the infusion of ET-1. The reduction in SBF was associated with a diminution in the output of Na+,K+, and protein in the saliva (P < 0.01). These effects persisted for 30 min after the infusion of ET-1 had been discontinued and were linearly related to the flow of plasma throughout.

View details for DOI 10.1152/japplphysiol.00992.2002

View details for Web of Science ID 000184016000039

View details for PubMedID 12730153
Effects of prolonged reduction in blood flow on submandibular secretory function in anaesthetized sheep Journal of Applied Physiology Thakor, A. S., Brown, C. N., Edwards, A. V. 2003; 95: 751-757

Avnesh Thakor

Assistant Professor of Radiology (Pediatric Radiology) at the Stanford University Medical Center

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