Optimization of Unrelated Donor Cord Blood Transplantation for Thalassemia: Implications for Other Non‐Malignant Indications such as HIV Infection or Autoimmune Diseases

Since the first cord blood transplantation (CBT), many indications have been proven for this stem cell therapy. Besides the standard hematological indications, such as leukemia, lymphomas, and aplastic anemia, CBT has also been a proven curative therapy for non-hematological indications such as Krabbe’s disease, and osteopetrosis. As transplant-related mortality (TRM), overall survival (OS) and disease-free survival (DFS) for CBT continue to improve with larger inventories, double CBT, higher cell dose CB products, optimal conditioning, GvHD, HLA matching, and infection prophylaxis and treatment, the utility of this stem cell source will expand to certain indications which in the past, rarely used CBT. For patients and physicians to accept CBT for indications such as thalassemia, autoimmune diseases or HIV, the benefit-risk ratio has to be significantly improved so that patients will take a chance on a risky procedure in order to improve their lifespan or quality of life. We review here some of the efforts to improve clinical outcome of CBT for thalassemia through increasing cell dosage using a combination strategy – (1) Chow’s MaxCell second and third generation technologies that maximize CB cell dosage, (2) double CBT, (3) no-wash thaw direct infusion advocated by Chow et al., and (4) optimal product selection

Cord Blood Stem Cell Processing, Banking and Thawing

Unrelated donor cord blood (CB) is one of the three sources of hematopoietic stem cell transplantation (HSCT) that are capable of curing ~80–160 standard hematologic and certain non-hematologic indications. Despite its many advantages, the principal drawback for CB in HSCT is its limited cell dose. Our group has focused on developing minimally manipulated technologies and strategies to maximize stem, progenitor, and nucleated cell doses to overcome this limitation. The term “MaxCell” is used in this chapter to denote two proprietary CB volume reduction processing technologies that yield virtually 100% recovery of all cell lineages in the manufactured CB products, including what the authors designate as “second generation” (2nd Gen) or plasma depletion/reduction (PDR) and “third generation” (3rd Gen) MaxCB or MaxCord CB processing technologies. In our proposed nomenclature system, the traditional red cell reduction (RCR) processing techniques are designated as “first generation” methods. The properties of various popular 1st Gen techniques are compared to the MaxCell CB processing technologies. Parallel processing with the traditional hetastarch (HES) RCR technique and the patented MaxCell CB processing technology were used to compare recovery of the various stem, progenitor, nucleated, and red cell lineages. MaxCell processing technology achieved virtually 100% recovery of all stem, progenitor, and nucleated cells tested after processing, with high cell viability upon thawing. The higher cell recovery produced MaxCell inventory with higher average stem, progenitor and nucleated cell doses, allowing patients to receive CB products with higher cell doses. Clinical outcome of HSCT using MaxCell CB products was compared to the outcome of HSCT with RCR CB products published in the literature from transplant data registries or CB banks. To allow for more rigorous comparisons, two matched-pair analysis (MP) were performed using a logistic regression model to find pairs of pediatric patients with hematologic malignancies and thalassemia transplanted with RCR CB or MaxCell CB, and patients receiving MaxCell CB showed superior engraftment, survival, and transplant-related mortality, confirming pre-match observations

Antitumor activity of the tea polyphenol epigallocatechin-3-gallate encapsulated in targeted vesicles after intravenous administration

The therapeutic potential of epigallocatechin gallate, a green tea polyphenol with anti-cancer properties, is limited by its inability to specifically reach tumors following intravenous administration. The purpose of this study is to determine whether a tumor-targeted vesicular formulation of epigallocatechin gallate would suppress the growth of A431 epidermoid carcinoma and B16-F10 melanoma in vitro and in vivo. Transferrin-bearing vesicles encapsulating epigallocatechin gallate were intravenously administered to mice bearing subcutaneous A431 and B16-F10 tumors. The intravenous administration of epigallocatechin gallate encapsulated in transferrin-bearing vesicles resulted in tumor suppression for 40% of A431 and B16-F10 tumors. Animal survival was improved by more than 20 days compared to controls. Encapsulation of epigallocatechin gallate in transferrin-bearing vesicles is a promising therapeutic strategy

Stabilization and Localization of Xist RNA are Controlled by Separate Mechanisms and are Not Sufficient for X Inactivation

These studies address whether XIST RNA is properly localized to the X chromosome in somatic cells where human XIST expression is reactivated, but fails to result in X inactivation (Tinker, A.V., and C.J. Brown. 1998. Nucl. Acids Res. 26:2935–2940). Despite a nuclear RNA accumulation of normal abundance and stability, XIST RNA does not localize in reactivants or in naturally inactive human X chromosomes in mouse/ human hybrid cells. The XIST transcripts are fully stabilized despite their inability to localize, and hence XIST RNA localization can be uncoupled from stabilization, indicating that these are separate steps controlled by distinct mechanisms. Mouse Xist RNA tightly localized to an active X chromosome, demonstrating for the first time that the active X chromosome in somatic cells is competent to associate with Xist RNA. These results imply that species-specific factors, present even in mature, somatic cells that do not normally express Xist, are necessary for localization. When Xist RNA is properly localized to an active mouse X chromosome, X inactivation does not result. Therefore, there is not a strict correlation between Xist localization and chromatin inactivation. Moreover, expression, stabilization, and localization of Xist RNA are not sufficient for X inactivation. We hypothesize that chromosomal association of XIST RNA may initiate subsequent developmental events required to enact transcriptional silencing

Development of a porcine skeletal muscle cDNA microarray: analysis of differential transcript expression in phenotypically distinct muscles

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Background Microarray profiling has the potential to illuminate the molecular processes that govern the phenotypic characteristics of porcine skeletal muscles, such as hypertrophy or atrophy, and the expression of specific fibre types. This information is not only important for understanding basic muscle biology but also provides underpinning knowledge for enhancing the efficiency of livestock production. Results We report on the de novo development of a composite skeletal muscle cDNA microarray, comprising 5500 clones from two developmentally distinct cDNA libraries (longissimus dorsi of a 50-day porcine foetus and the gastrocnemius of a 3-day-old pig). Clones selected for the microarray assembly were of low to moderate abundance, as indicated by colony hybridisation. We profiled the differential expression of genes between the psoas (red muscle) and the longissimus dorsi (white muscle), by co-hybridisation of Cy3 and Cy5 labelled cDNA derived from these two muscles. Results from seven microarray slides (replicates) correctly identified genes that were expected to be differentially expressed, as well as a number of novel candidate regulatory genes. Quantitative real-time RT-PCR on selected genes was used to confirm the results from the microarray. Conclusion We have developed a porcine skeletal muscle cDNA microarray and have identified a number of candidate genes that could be involved in muscle phenotype determination, including several members of the casein kinase 2 signalling pathway.Peer Reviewe

Domestic Violence Service Providers’ Technology Readiness and Information Needs

Technology-based applications hold promise as effective, efficient means of disseminating research- and practice-based information to professionals whose work relates to domestic violence. Other related uses of technology in the field have grown, including safety planning to address technology-related risks to victims and software programs being integrated into domestic violence agencies. However, to date, the levels of technology readiness and technology-related information needs of these professionals have received minimal research attention. This study involved a national survey of 471 professionals whose work addresses domestic violence. The findings demonstrate differences in professionals’ technology readiness based on key demographic and professional characteristics. They also reveal the most frequently noted information needs within this professional field. Implications for future research and practice are provided

Biodegradable electroactive polymers for electrochemically-triggered drug delivery

We report biodegradable electroactive polymer (EAP)-based materials and their application as drug delivery devices. Copolymers composed of oligoaniline-based electroactive blocks linked to either polyethylene glycol or polycaprolactone blocks via ester bonds were synthesized in three steps from commercially available starting materials and isolated without the need for column chromatography. The physicochemical and electrochemical properties of the polymers were characterized with a variety of techniques. The ability of the polymers to deliver the anti-inflammatory drug dexamethasone phosphate on the application of electrochemical stimuli was studied spectroscopically. Films of the polymers were shown to be degradable and cell adhesive in vitro. Such EAP-based materials have prospects for integration in implantable fully biodegradable/bioerodible EAP-based drug delivery devices that are capable of controlling the chronopharmacology of drugs for future clinical application

Conducting polymer-based multilayer films for instructive biomaterial coatings

Aim: To demonstrate the design, fabrication and testing of conformable conducting biomaterials that encourage cell alignment. Materials & methods: Thin conducting composite biomaterials based on multilayer films of poly (3,4-ethylenedioxythiophene) derivatives, chitosan and gelatin were prepared in a layer-by-layer fashion. Fibroblasts were observed with fluorescence microscopy and their alignment (relative to the dipping direction and direction of electrical current passed through the films) was determined using ImageJ. Results: Fibroblasts adhered to and proliferated on the films. Fibroblasts aligned with the dipping direction used during film preparation and this was enhanced by a DC current. Conclusion: We report the preparation of conducting polymer-based films that enhance the alignment of fibroblasts on their surface which is an important feature of a variety of tissues. Lay abstract: Cells inhabit environments known as the extracellular matrix (ECM) which consists of a mixture of different biomolecules, and the precise composition and topographical properties are different in different tissues (e.g., bone, brain, muscle, skin). Cells interact intimately with the ECM, not only constructing the biomolecules, but assist its organization in 3D space, and its degradation (which is important for tissue remodeling); reciprocally, cells respond to the ECM (e.g., by modifying their size, shape, etc). Cellular alignment is observed in organs and tissues such as bones, muscles and skin, and this alignment is important for the healthy functioning of the organ/tissue. Here, we present a novel method of aligning cells on biomaterials, simply by applying an electrical current through the biomaterial