Translational Research RSS feed: Current Issue. Translational Research delivers original investigations in the broad fields of laboratory, clinical, and public health research. Interdisciplinary and cross-disciplinary in scope, it keeps readers up-to-date on significant biomedical research from all subspecialties of medicine. Aiming to expedite the translation of scientific discovery into new or improved standards of care, it promotes a wide-ranging exchange between basic, preclinical, clinical, epidemiologic, and health outcomes research. It encourages submission of studies describing preclinical research with potential for application to human disease, and studies describing research obtained from preliminary human experimentation with potential to refine the understanding of biological principles underpinning human disease. Also encouraged are studies describing public health research with potential for application to the clinic, disease prevention, or healthcare policy.http://www.translationalres.com/?rss=yesElsevier Inc.en © 2010 Published by Elsevier Inc. All rights reserved. Translational Research1931-52441562August 2010 © 2010 Published by Elsevier Inc. All rights reserved. healthpermissions@elsevier.comhttp://www.translationalres.com/article/PIIS193152441000126X/abstract?rss=yesContents10.1016/S1931-5244(10)00126-XTranslational Research 156, 2 (2010)2010-08-01Translational Research2010-08-011562S1931-5244(10)X0007-XIFCIFChttp://www.translationalres.com/article/PIIS1931524410001210/abstract?rss=yesRegular blood transfusions are a life-saving treatment for patients with severe anemias, including those with beta thalassemia, sickle cell disease, myelodysplastic syndromes, and other conditions. But the treatment is a double-edged sword; each unit of transfused blood contains 200 mg of iron, and because the body has no mechanism to excrete excess iron, chronic iron overload often results, causing damage to the liver, heart, endocrine organs, and other tissues. Iron chelation therapy, thus, has played a vital role in the management of these patients since the introduction of the parenterally administered chelator deferoxamine (DFO) more than 40 years ago.More pieces to the iron chelation puzzleJill Waalen10.1016/j.trsl.2010.06.006Translational Research 156, 2 (2010)2010-07-05Translational Research2010-07-051562S1931-5244(10)X0007-XCommentary5354http://www.translationalres.com/article/PIIS1931524410000927/abstract?rss=yesIn iron overload conditions, plasma contains non-transferrin bound iron species, collectively referred to as plasma NTBI. These include iron citrate species, some of which are protein bound. Because NTBI is taken into tissues susceptible to iron loading, its removal by chelation is desirable but only partial using standard deferoxamine (DFO) therapy. Speciation plots suggest that, at clinically achievable concentrations, deferiprone (DFP) will shuttle iron onto DFO to form feroxamine (FO), but whether NTBI chelation by DFO is enhanced to therapeutically relevant rates by DFP is unknown. As FO is highly stable, kinetic measurements of FO formation by high-performance liquid chromatography or by stopped-flow spectrometry are achievable. In serum from thalassemia major patients supplemented with 10 μM DFO, FO formation paralleled NTBI removal but never exceeded 50% of potentially available NTBI; approximately one third of NTBI was chelated rapidly but only 15% of the remainder at 20 h. Addition of DFP increased the magnitude of the slower component, with increments in FO formation equivalent to complete NTBI removal by 8 h. This shuttling effect was absent in serum from healthy control subjects, indicating no transferrin iron removal. Studies with iron citrate solutions also showed biphasic chelation by DFO, the slow component being accelerated by the addition of DFP, with optimal enhancement at 30 μM. Physiological concentrations of albumin also enhanced DFO chelation from iron citrate, and the co-addition of DFP further accelerated this effect. We conclude that at clinically relevant concentrations, DFP enhances plasma NTBI chelation with DFO by rapidly accessing and shuttling NTBI fractions that are otherwise only slowly available to DFO.Mechanisms for the shuttling of plasma non-transferrin-bound iron (NTBI) onto deferoxamine by deferipronePatricia Evans, Reem Kayyali, Robert C. Hider, John Eccleston, John B. Porter10.1016/j.trsl.2010.05.002Translational Research 156, 2 (2010)2010-05-31Translational Research2010-05-311562S1931-5244(10)X0007-XOriginal Articles5567http://www.translationalres.com/article/PIIS1931524410001179/abstract?rss=yesThe post-transplant immune responses, viremia, and allograft histology after living donor liver transplantation were studied in 39 hepatitis C virus (HCV)-infected recipients. The recipients were classified into the following groups according to a hierarchical clustering of their preoperative CD8CD45 T-cell isoforms: group I, naive-dominant; group II, effector memory-dominant; and group III, effector-dominant. Plasma HCV-RNA rapidly increased and then peaked as an initial burst around postoperative day (POD) 25 in group I, on POD 40 in group II, and on POD 55 in group III. The initial burst of viremia was suppressed by the high expression of CD8+CD28-CD27- subsets. The progression of fibrosis ≥F2 was significantly more frequent for those patients with the highest viremia levels. Moreover, the initial T-cell immune response became less important throughout time, and new immune responses emerged after 2 months that modified the host–virus interaction. It is suggested that the interferon (IFN)-alpha/ribavirin therapy starting 2 months may be an effective option and now is undertaken.Initial burst of viremia related to CD8 effector memory T cells after living donor liver transplantation in hepatitis C virus-infected recipientsYasutsugu Takada, Kazue Ozawa, Hiroto Egawa, Satoshi Teramukai, Akira Mori, Toshimi Kaido, Mureo Kasahara, Kohei Ogawa, Masako Ono, Hiroshi Sato, Koichi Tanaka, Shinji Uemoto10.1016/j.trsl.2010.06.002Translational Research 156, 2 (2010)2010-06-23Translational Research2010-06-231562S1931-5244(10)X0007-XOriginal Articles6879http://www.translationalres.com/article/PIIS193152441000099X/abstract?rss=yesGlomerular hyperfiltration is associated with mesangial cell hypocontractility. How 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) influence mesangial cell contraction is unclear. We investigated the effect of statins on mesangial cell hypocontractility and identified candidate proteins and filamentous/globular (F/G)-actin involved in this process. A high-glucose-induced mouse mesangial cell hypocontractility model was treated with fungal statins, simvastatin (Sim), lovastatin (Lov), and pravastatin (Pra). The optimum statin dose was determined by an 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay and then applied to a cell model. A 2-dimensional gel/matrix-assisted laser desorption/ionization time-of-flight mass spectrometer analysis was used to evaluate protein expression cells incubated in the presence of a normal level of glucose (N), a high level of glucose (H), and a high level of glucose plus Sim (H + S). Candidate proteins were analyzed. Finally, the ratio of F/G actin in groups N, H, and H+S was evaluated. The MTT assay showed that Sim and Lov exerted dose- and time-related inhibition of proliferation of mesangial cells at N, but Pra had no effect. The optimum doses selected for Sim was 1 μM and for Lov was 3 μM, which were 1 increment before significant proliferation inhibition. Both doses reversed cell hypocontractility significantly, but Sim was chosen for further proteomic and F/G actin analyses. Proteomic analysis of groups N, H, and H + S showed that 18 proteins were involved in hypocontractility. These proteins were grouped and analyzed based on their known functions. Two selected proteins, TCP-1β and GRP78, that were upregulated and downregulated, respectively, were confirmed by Western blot and immunohistochemistry. In regard to the F/G actin, group H had a significantly lower ratio than that of group N, and group H + S returned to a level similar to that of group N. In conclusion, Sim and Lov both seem to reverse mesangial cell hypocontractility. The process of Sim reversal of mesangial cell hypocontractility may involve F-actin, TCP-1β, and GRP78.Effects of fungal statins on high-glucose-induced mouse mesangial cell hypocontractility may involve filamentous actin, t-complex polypeptide 1 subunit beta, and glucose regulated protein 78Jyh-Chang Hwang, Li-Chien Chang, Yuh-Feng Lin, Hao-Ai Shui, Jin-Shuen Chen10.1016/j.trsl.2010.05.006Translational Research 156, 2 (2010)2010-06-21Translational Research2010-06-211562S1931-5244(10)X0007-XOriginal Articles8090http://www.translationalres.com/article/PIIS1931524410001155/abstract?rss=yesTo assess complete remission before subjecting nongermline metastatic retinoblastoma patients to an autologous peripheral stem cell transplant, we tested for patient-specific retinoblastoma tumor suppressor gene (RB1) mutant alleles in cerebrospinal fluid (CSF) and bone marrow. In 1 child with CSF and 1 with bone marrow metastases, allele-specific polymerase chain reaction (AS-PCR) detected the biallelic RB1 mutations specific to their tumors. The tumor of Child A was homozygous for R251X, and in Child B, it was homozygous for R358X. In Child A, the R251X mutation was detected in mutant controls diluted to 1:12,800 but not in CSF samples, corroborating clinical remission after chemotherapy. In Child B's bone marrow, AS-PCR for R358X was strongly positive at the detection of relapse, and subsequent bone marrow samples corroborated clinical remission after chemotherapy. No mutant tumor RB1 alleles were detected in their harvested peripheral blood stem cells. Both children were deemed suitable candidates for supralethal-dosage consolidation chemotherapy followed by autologous peripheral stem cell rescue of the bone marrow aimed at curing their metastatic retinoblastoma. When Child A recurred, the mutant tumor RB1 allele was detected 3.5 months before conventional pathology detected retinoblastoma tumor cells in the CSF. Assaying tumor-specific RB1 mutations complements cytological and immunohistochemical assessment of retinoblastoma involvement of CSF and bone marrow. Tumor cells can be detected in numbers lower than possible by conventional methods. An early diagnosis of relapse may allow an early institution of new therapy. A prospective international multicenter trial of the rare patients with metastatic retinoblastoma would assess the role of molecular monitoring in surveillance for minimal residual disease and recurrence.Using RB1 mutations to assess minimal residual disease in metastatic retinoblastomaHelen Dimaras, Diane Rushlow, William Halliday, John J. Doyle, Paul Babyn, Esteban M. Abella, James Williams, Elise Héon, Brenda L. Gallie, Helen S.L. Chan10.1016/j.trsl.2010.05.009Translational Research 156, 2 (2010)2010-06-28Translational Research2010-06-281562S1931-5244(10)X0007-XOriginal Articles9197http://www.translationalres.com/article/PIIS1931524410001003/abstract?rss=yesActivating V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and V-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene mutations are important predictive markers for antiepidermal growth factor receptor chemotherapy in colorectal cancer (CRC). However, a rapid and accurate assay for KRAS/BRAF mutation detection from routine pathological specimens is lacking in clinical practice. We applied the cycleave polymerase chain reaction (PCR) method to routine KRAS/BRAF genotyping of CRC patients at our institution from 2001 to 2009. The accuracy of cycleave PCR genotyping was shown by the high concordance with reverse transcriptase-PCR-coupled direct sequencing. KRAS gene mutations were analyzed successfully from small biopsy or cytology specimens. Although some surgical specimens could not be evaluated by cycleave PCR, corresponding biopsy specimens could be used instead. This PCR failure observed for some biopsy specimens may have been a result of the use of formalin fixation, as overfixation of surgical specimens by formalin impaired PCR amplification. In conclusion, cycleave PCR is practically applicable to KRAS/BRAF genotyping using small amounts of biopsied tumor cells. Care must be taken in the selection of pathological specimens for KRAS/BRAF testing.Cycleave polymerase chain reaction method is practically applicable for V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)/V-raf murine sarcoma viral oncogene homolog B1 (BRAF) genotyping in colorectal cancerTomoya Yokota, Noriko Shibata, Takashi Ura, Daisuke Takahari, Kohei Shitara, Kei Muro, Yasushi Yatabe10.1016/j.trsl.2010.05.007Translational Research 156, 2 (2010)2010-06-21Translational Research2010-06-211562S1931-5244(10)X0007-XOriginal Articles98105http://www.translationalres.com/article/PIIS1931524410001271/abstract?rss=yesMasthead10.1016/S1931-5244(10)00127-1Translational Research 156, 2 (2010)2010-08-01Translational Research2010-08-011562S1931-5244(10)X0007-XFrontmatterA1A1http://www.translationalres.com/article/PIIS1931524410001283/abstract?rss=yesEditorial Advisory Board10.1016/S1931-5244(10)00128-3Translational Research 156, 2 (2010)2010-08-01Translational Research2010-08-011562S1931-5244(10)X0007-XFrontmatterA2A2http://www.translationalres.com/article/PIIS1931524410001295/abstract?rss=yesAuthor Guidelines10.1016/S1931-5244(10)00129-5Translational Research 156, 2 (2010)2010-08-01Translational Research2010-08-011562S1931-5244(10)X0007-XFrontmatterA3A4