Therapeutic utility of the newly discovered properties of interleukin-21.

Since its discovery in 2000, interleukin-21 (IL-21) has been shown to display a broad spectrum of pleiotropic actions including the regulation of development, differentiation and function of lymphoid-myeloid cells. More specifically, IL-21 modulates the effector functions of T, B and NK cells, which not only have key roles in antitumoral and antiviral immunity but also in exerting major effects on inflammatory responses promoting the development of autoimmune diseases. Recent studies have unveiled an unexpected role for IL-21 in immune regulation and de novo T-cell development. While highlighting its critical role in immunity, this review will mainly focus on recent advances in IL-21 biology and how such newly discovered properties could potentially be exploited therapeutically in the establishment of future clinical trials.

Interleukin-21 administration to aged mice rejuvenates their peripheral T-cell pool by triggering de novo thymopoiesis.

The vaccination efficacy in the elderly is significantly reduced compared to younger populations due to thymic involution and age-related intrinsic changes affecting their naïve T-cell compartment. Interleukin (IL)-21 was recently shown to display thymostimulatory properties. Therefore, we hypothesized that its administration to ageing hosts may improve T-cell output and thus restore a competent peripheral T-cell compartment. Indeed, an increase in the production of recent thymic emigrants (RTEs) attributable to intrathymic expansion of early thymic progenitors (ETPs), double-negative (DN), and double-positive (DP) thymocytes as well as thymic epithelial cell (TEC) was observed in recombinant (r)IL-21-treated aged mice. In sharp contrast, no alterations in the frequency of bone marrow (BM)-derived progenitors were detected following rIL-21 administration. Enhanced production of naïve T cells improved the T-cell receptor (TCR) repertoire diversity and re-established a pool of T cells exhibiting higher levels of miR-181a and diminished amounts of the TCR-inhibiting phosphatases SHP-2 and DUSP5/6. As a result, stimulation of T cells derived from rIL-21-treated aged mice displayed enhanced activation of Lck, ZAP-70, and ERK, which ultimately boosted their IL-2 production, CD25 expression, and proliferation capabilities in comparison with T cells derived from control aged mice. Consequently, aged rIL-21-treated mice vaccinated using a tyrosinase-related protein 2 (Trp2)-derived peptide exhibited a substantial delay in B16 tumor growth and improved survival. The results of this study highlight the immunorestorative function of rIL-21 paving its use as a strategy for the re-establishment of effective immunity in the elderly.

Clinical, angiographic, and intravascular ultrasound results of the VestSaync II Trial

We sought to assess the long term efficacy of the novel VESTAsyncTM ElutingStent (VES) combining a Cro-Co platform with a nanothin-microporous hydroxyapatitesurface coating impregnated with a polymer-free low-dose of Sirolimus (55 lg). Methods:The Vestasync II trial was a randomized (2:1), double-blinded, multicenter comparisonof the VES to its platform, the Gen X stent, with microporous hydroxyapatitesurface coating without sirolimus. Patients were eligible if they presented de novolesions in native coronary arteries with 3.0–3.5 mm diameter and 14 mm in length.Primary endpoint was 8-month in-stent late loss and % of stent obstruction. Lifelongaspirin and 6-month clopidogrel were prescribed to all patients. Results: Seventy-fivepatients were enrolled (VES550 pts). Baseline characteristics included mean age of 58years and 29% of diabetics. Reference vessel diameter and lesion length were 2.860.4mm and 13.062.0 mm, respectively. In-stent late loss (0.3960.20 vs. 0.7460.52,P50.03) and % of neointima hyperplasia (9.366.6% vs. 17.669.4%, P50.0016) weresignificantly reduced in the VES cohort. Up to 1 year, there was a single case ofmyocardial infarction and one target lesion revascularization (TLR) (2%) in the VESgroup while in the control cohort there were one TLR (4%) and one cardiac death (4%).Conclusion: The VestSync II trial is a proof-of-concept study and demonstrates thesustained efficacy of this novel polymer-free sirolimus drug-eluting stents. A largertrial, with more complex lesions, clinical endpoints and longer FU period is warranted.

Gene banking of the neotropical fish Leporinus obtusidens (Valenciennes, 1836): a protocol to freeze its sperm in the field.

A practical sperm cryopreservation protocol using a dry-shipper and a diluent of simple composition is described for the neotropical fish Leporinus obtusidens (Valenciennes, 1836). The cooling rate of the dry-shipper and its period of useful time, established under laboratory conditions, were respectively 25.7-30.8 degrees C/min (between 0 and -60 degrees C) and 9 days after charging. Sperm donors were selected on the basis of their hyperemic genital papilla and the ability to ooze milt under gentle manual pressure, during the reproductive months of November to January. Milt volume (1.3+/-0.3 mL; n=9 fish), fresh sperm motility rate (93.3+/-2.5%; n=6 fish), and sperm concentration (10.9+/-3.0 x 10(9)spermatozoa/mL of milt) were obtained. The sperm cryopreservation experiments were conducted with the following cryoprotectants (all at 10%, before mixing with milt): dimethyl sulphoxide (DMSO; n=10 fish), methanol (n=6 fish), propanediol (n=6 fish) and ethylene glycol (n=5 fish). Glucose (5%) and hen's egg yolk (10%) made up the diluents containing DMSO, ethylene glycol or propanediol. Milk powder (10%) replaced hen's egg yolk in the diluent containing methanol. Distilled water (up to 100%) completed the diluent solutions. Milt freezing (in 0.5-mL straws) was performed in the dry-shipper after 1:5 (milt:diluent) dilution. Thawed sperm cryopreserved in DMSO-containing diluent and activated by 119 mM NaHCO(3) gave the highest motility rate (62+/-14%). The fertilizing capacity of L. obtusidens sperm was tested using the combination of DMSO-containing diluent as the cryoprotectant and 119 mM NaHCO(3) as the activating solution. Oocytes were obtained from artificial spawning and fertilized with different proportions of spermatozoa. The greatest rate of fertilization (74%) occurred when the ratio of about 112,000 motile spermatozoa:oocyte was used. Thus, a protocol to freeze L. obtusidens sperm can be elaborated as follows. Milt (<1.5 mL fish(-1)) was readily available only in November to January; a simple solution, composed of 10% DMSO (concentration before adding milt), 5% glucose, and 10% hen yolk egg, in distilled water, was used as sperm diluent; cooling rate of 25-30 degrees C/min, yielded in a portable dry-shipper, was adequate to freeze diluted milt (1:5; milt:diluent), in 5-mL straws; about 112,000 thawed motile spermatozoa:oocyte activated by 119 mM NaHCO(3) assured a fertilization rate of 74%.