Role of chitosan nanoparticles in the oral absorption of Gemcitabine

Gemcitabine is a known cytotoxic agent with a wide spectrum of antitumor activity. It has been employed in therapeutic regimens for various malignancies such as the lung, ovary, breast, and bladder cancers. It also has been used in the treatment of pancreatic cancer, in combination chemotherapy of non-small cell lung cancer (NSCLC) and in leukemia. Its effect results from incorporation into DNA with subsequent inhibition of cell proliferation. Unfortunately, Gemcitabine is rapidly metabolized by the so-called cytidine-deaminase which limits its efficacy. Because of extensive deamination by intestinal cells, its oral administration results in very low bioavailability. The aim of this study was to introduce an oral formulation of the drug for the first time and improve its physicochemical properties. Chitosan nanoparticles containing were produced based on ionic gelation method and tripolyphosphate (TPP). Physicochemical properties such as particle size and shape, loading efficiency and release rate were evaluated. Oral absorption of both free and nanoparticle-loaded drugs was measured using the rat intestinal sac model. The Gemcitabine-loaded chitosan nanoparticles were spherical with a mean size of 95±8nm and high drug loading (63%). The nanoparticles showed controlled release pattern characterized by a fast initial release (61%) during the first 8h, followed by slower and continuous release (74.66%). The absorption study showed that Gemcitabine intestinal transport increased 3-5 folds by loading in chitosan nanocarrier.     

Response functions for computing absorbed dose to skeletal tissues from photon irradiation--an update

A comprehensive set of photon fluence-to-dose response functions (DRFs) is presented for two radiosensitive skeletal tissues-active and total shallow marrow-within 15 and 32 bone sites, respectively, of the ICRP reference adult male. The functions were developed using fractional skeletal masses and associated electron-absorbed fractions as reported for the UF hybrid adult male phantom, which in turn is based upon micro-CT images of trabecular spongiosa taken from a 40 year male cadaver. The new DRFs expand upon both the original set of seven functions produced in 1985, and a 2007 update calculated under the assumption of secondary electron escape from spongiosa. In this study, it is assumed that photon irradiation of the skeleton will yield charged particle equilibrium across all spongiosa regions at energies exceeding 200 keV. Kerma coefficients for active marrow, inactive marrow, trabecular bone and spongiosa at higher energies are calculated using the DRF algorithm setting the electron-absorbed fraction for self-irradiation to unity. By comparing kerma coefficients and DRF functions, dose enhancement factors and mass energy-absorption coefficient (MEAC) ratios for active marrow to spongiosa were derived. These MEAC ratios compared well with those provided by the NIST Physical Reference Data Library (mean difference of 0.8%), and the dose enhancement factors for active marrow compared favorably with values calculated in the well-known study published by King and Spiers (1985 Br. J. Radiol. 58 345-56) (mean absolute difference of 1.9 percentage points). Additionally, dose enhancement factors for active marrow were shown to correlate well with the shallow marrow volume fraction (R(2) = 0.91). Dose enhancement factors for the total shallow marrow were also calculated for 32 bone sites representing the first such derivation for this target tissue.     

An image-based skeletal model for the ICRP reference adult male-specific absorbed fractions for neutron-generated recoil protons

Recoiling hydrogen nuclei are a principle mechanism for energy deposition from incident neutrons. For neutrons incident on the human skeleton, the small sizes of two contrasting media (trabecular bone and marrow) present unique problems due to a lack of charged-particle (protons) equilibrium. Specific absorbed fractions have been computed for protons originating in the human skeletal tissues for use in computing neutron dose response functions. The proton specific absorbed fractions were computed using a pathlength-based range-energy calculation in trabecular skeletal samples of a 40 year old male cadaver.     

Research collaboration in Tehran University of Medical Sciences: two decades after integration

Background  

In 1985 medical schools were integrated into the Ministry of Health, and the Ministry of Health and Medical Education was created in Iran. Under this infrastructure education, research and service provision are unified, and it is expected that collaboration between researchers and decision makers become easier in such an integrated context.     

High PR3 or ELA2 expression by CD34+ cells in advanced-phase chronic myeloid leukemia is associated with improved outcome following allogeneic stem cell transplantation and may improve PR1 peptide-driven graft-versus-leukemia effects

The primary granule proteins elastase (ELA2) and proteinase 3 (PR3) both contain the nonapeptide PR1, which can induce cytotoxic T lymphocyte (CTL) responses against chronic myeloid leukemia (CML) cells. To investigate whether eradication of CML after allogeneic stem cell transplantation (SCT) was influenced by PR3 and ELA2 gene expression or PR1-specific CTL responses, we studied cells from 87 CML patients and 27 HLA-A*0201(+) donors collected prior to T-cell-depleted HLA-identical sibling SCT. For patients in advanced phase (AdP), a higher expression of both PR3 and ELA2 in CD34(+) progenitors before SCT was associated with a lower incidence of relapse-related death, improved leukemia-free survival (LFS), and overall survival (OS); in chronic phase patients, no differences were observed. PR1-CTL responses were detected in 7 of 27 HLA-identical sibling donors, and associated with improved LFS and OS after SCT on follow-up. PR1-CTL responses detected in 7 of 28 CML patients before transplantation were not predictive of outcome and correlated inversely with PR3 and ELA2 expression. These findings suggest that assessment of PR3 and ELA2 expression in leukemic progenitors is useful for predicting posttransplantation outcome in AdP patients undergoing SCT. The presence of a donor immune response against PR1 may be advantageous and could be exploited therapeutically.