Safety evaluation of allogeneic umbilical cord blood mononuclear cell therapy for degenerative conditions

<p>Abstract</p> <p>Background</p> <p>The current paradigm for cord blood transplantation is that HLA matching and immune suppression are strictly required to prevent graft versus host disease (GVHD). Immunological arguments and historical examples have been made that the use of cord blood for non-hematopoietic activities such as growth factor production, stimulation of angiogenesis, and immune modulation may not require matching or immune suppression.</p> <p>Methods</p> <p>114 patients suffering from non-hematopoietic degenerative conditions were treated with non-matched, allogeneic cord blood. Doses of 1-3 × 10⁷cord blood mononuclear cells per treatment, with 4-5 treatments both intrathecal and intravenously were performed. Adverse events and hematological, immunological, and biochemical parameters were analyzed for safety evaluation.</p> <p>Results</p> <p>No serious adverse effects were reported. Hematological, immunological, and biochemical parameters did not deviate from normal ranges as a result of therapy.</p> <p>Conclusion</p> <p>The current hematology-based paradigm of need for matching and immune suppression needs to be revisited when cord blood is used for non-hematopoietic regenerative purposes in immune competent recipients.</p

Combination stem cell therapy for heart failure

Patients with congestive heart failure (CHF) that are not eligible for transplantation have limited therapeutic options. Stem cell therapy such as autologous bone marrow, mobilized peripheral blood, or purified cells thereof has been used clinically since 2001. To date over 1000 patients have received cellular therapy as part of randomized trials, with the general consensus being that a moderate but statistically significant benefit occurs. Therefore, one of the important next steps in the field is optimization. In this paper we discuss three ways to approach this issue: a) increasing stem cell migration to the heart; b) augmenting stem cell activity; and c) combining existing stem cell therapies to recapitulate a "therapeutic niche". We conclude by describing a case report of a heart failure patient treated with a combination stem cell protocol in an attempt to augment beneficial aspects of cord blood CD34 cells and mesenchymal-like stem cells

Exosomes as a tumor immune escape mechanism: possible therapeutic implications

Advances in cancer therapy have been substantial in terms of molecular understanding of disease mechanisms, however these advances have not translated into increased survival in the majority of cancer types. One unsolved problem in current cancer therapeutics is the substantial immune suppression seen in patients. Conventionally, investigations in this area have focused on antigen-nonspecific immune suppressive molecules such as cytokines and T cell apoptosis inducing molecules such as Fas ligand. More recently, studies have demonstrated nanovesicle particles termed exosomes are involved not only in stimulation but also inhibition of immunity in physiological conditions. Interestingly, exosomes secreted by cancer cells have been demonstrated to express tumor antigens, as well as immune suppressive molecules such as PD-1L and FasL. Concentrations of exosomes from plasma of cancer patients have been associated with spontaneous T cell apoptosis, which is associated in some situations with shortened survival. In this paper we place the "exosome-immune suppression" concept in perspective of other tumor immune evasion mechanisms. We conclude by discussing a novel therapeutic approach to cancer immune suppression by extracorporeal removal of exosomes using hollow fiber filtration technolog

Feasibility of combination allogeneic stem cell therapy for spinal cord injury: a case report

Cellular therapy for spinal cord injury (SCI) is overviewed focusing on bone marrow mononuclear cells, olfactory ensheathing cells, and mesenchymal stem cells. A case is made for the possibility of combining cell types, as well as for allogeneic use. We report the case of 29 year old male who suffered a crush fracture of the L1 vertebral body, lacking lower sensorimotor function, being a score A on the ASIA scale. Stem cell therapy comprised of intrathecal administration of allogeneic umbilical cord blood ex-vivo expanded CD34 and umbilical cord matrix MSC was performed 5 months, 8 months, and 14 months after injury. Cell administration was well tolerated with no adverse effects observed. Neuropathic pain subsided from intermittent 10/10 to once a week 3/10 VAS. Recovery of muscle, bowel and sexual function was noted, along with a decrease in ASIA score to "D". This case supports further investigation into allogeneic-based stem cell therapies for SCI

Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis

The stromal vascular fraction (SVF) of adipose tissue is known to contain mesenchymal stem cells (MSC), T regulatory cells, endothelial precursor cells, preadipocytes, as well as anti-inflammatory M2 macrophages. Safety of autologous adipose tissue implantation is supported by extensive use of this procedure in cosmetic surgery, as well as by ongoing studies using in vitro expanded adipose derived MSC. Equine and canine studies demonstrating anti-inflammatory and regenerative effects of non-expanded SVF cells have yielded promising results. Although non-expanded SVF cells have been used successfully in accelerating healing of Crohn's fistulas, to our knowledge clinical use of these cells for systemic immune modulation has not been reported. In this communication we discuss the rationale for use of autologous SVF in treatment of multiple sclerosis and describe our experiences with three patients. Based on this rationale and initial experiences, we propose controlled trials of autologous SVF in various inflammatory conditions

Nutraceutical augmentation of circulating endothelial progenitor cells and hematopoietic stem cells in human subjects

The medical significance of circulating endothelial or hematopoietic progenitors is becoming increasing recognized. While therapeutic augmentation of circulating progenitor cells using G-CSF has resulted in promising preclinical and early clinical data for several degenerative conditions, this approach is limited by cost and inability to perform chronic administration. Stem-Kine is a food supplement that was previously reported to augment circulating EPC in a pilot study. Here we report a trial in 18 healthy volunteers administered Stem-Kine twice daily for a 2 week period. Significant increases in circulating CD133 and CD34 cells were observed at days 1, 2, 7, and 14 subsequent to initiation of administration, which correlated with increased hematopoietic progenitors as detected by the HALO assay. Augmentation of EPC numbers in circulation was detected by KDR-1/CD34 staining and colony forming assays. These data suggest Stem-Kine supplementation may be useful as a stimulator of reparative processes associated with mobilization of hematopoietic and endothelial progenitors

Feasibility investigation of allogeneic endometrial regenerative cells

Endometrial Regenerative Cells (ERC) are a population of mesenchymal-like stem cells having pluripotent differentiation activity and ability to induce neoangiogenesis. In vitro and animal studies suggest ERC are immune privileged and in certain situations actively suppress ongoing immune responses. In this paper we describe the production of clinical grade ERC and initial safety experiences in 4 patients with multiple sclerosis treated intravenously and intrathecally. The case with the longest follow up, of more than one year, revealed no immunological reactions or treatment associated adverse effects. These preliminary data suggest feasibility of clinical ERC administration and support further studies with this novel stem cell type

Intravenous ascorbic acid to prevent and treat cancer-associated sepsis?

The history of ascorbic acid (AA) and cancer has been marked with controversy. Clinical studies evaluating AA in cancer outcome continue to the present day. However, the wealth of data suggesting that AA may be highly beneficial in addressing cancer-associated inflammation, particularly progression to systemic inflammatory response syndrome (SIRS) and multi organ failure (MOF), has been largely overlooked. Patients with advanced cancer are generally deficient in AA. Once these patients develop septic symptoms, a further decrease in ascorbic acid levels occurs. Given the known role of ascorbate in: a) maintaining endothelial and suppression of inflammatory markers; b) protection from sepsis in animal models; and c) direct antineoplastic effects, we propose the use of ascorbate as an adjuvant to existing modalities in the treatment and prevention of cancer-associated sepsis

Approximation of the two-fluid flow problem for viscoelastic fluids using the level set method and pressure enriched finite element shape functions

The numerical simulation of complex flows has been a subject of intense research in the last years with important industrial applications in many fields. In this paper we present a finite element method to solve the two immiscible fluid flow problems using the level set method. When the interface between both fluids cuts an element, the discontinuity in the material properties leads to discontinuities in the gradients of the unknowns which cannot be captured using a standard finite element interpolation. The method presented in this work features a local enrichment for the pressure unknowns which allows one to capture pressure gradient discontinuities in fluids presenting different density values. The method is tested on two problems: the first example consists of a sloshing case that involves the interaction of a Giesekus and a Newtonian fluid. This example shows that the enriched pressure functions permit the exact resolution of the hydrostatic rest state. The second example is the classical jet buckling problem used to validate our method. To permit the use of equal interpolation between the variables, we use a variational multiscale formulation proposed recently by Castillo and Codina (2014) [21], that has shown very good stability properties, permitting also the resolution of the jet buckling flow problem in the the range of Weissenberg number 0 < We < 100, using the Oldroyd-B model without any sign of numerical instability. Additional features of the work are the inclusion of a discontinuity capturing technique for the constitutive equation and some comparisons between a monolithic resolution and a fractional step approach to solve the viscoelastic fluid flow problem from the point of view of computational requirements. (C) 2015 Elsevier B.V. All rights reserved.Postprint (author's final draft

Multi-Wavelength Variability of BL Lacertae Measured with High Time Resolution

In an effort to locate the sites of emission at different frequencies and physical processes causing variability in blazar jets, we have obtained high time-resolution observations of BL Lacertae over a wide wavelength range: with the \emph{Transiting Exoplanet Survey Satellite} (TESS) at 6,000-10,000 \AA\ with 2-minute cadence; with the Neil Gehrels \emph{Swift} satellite at optical, UV, and X-ray bands; with the Nuclear Spectroscopic Telescope Array at hard X-ray bands; with the \emph{Fermi} Large Area Telescope at $\gamma$-ray energies; and with the Whole Earth Blazar Telescope for measurement of the optical flux density and polarization. All light curves are correlated, with similar structure on timescales from hours to days. The shortest timescale of variability at optical frequencies observed with TESS is $\sim 0.5$ hr. The most common timescale is $13\pm1$~hr, comparable with the minimum timescale of X-ray variability, 14.5 hr. The multi-wavelength variability properties cannot be explained by a change solely in the Doppler factor of the emitting plasma. The polarization behavior implies that there are both ordered and turbulent components to the magnetic field in the jet. Correlation analysis indicates that the X-ray variations lag behind the $\gamma$-ray and optical light curves by up to $\sim 0.4$ days. The timescales of variability, cross-frequency lags, and polarization properties can be explained by turbulent plasma that is energized by a shock in the jet and subsequently loses energy to synchrotron and inverse Compton radiation in a magnetic field of strength $\sim3$ GComment: 33 pages, 25 figures, 14 tables. Accepted to Ap