Differential TAM receptor regulation of hepatic physiology and injury

AbstractThe TAM receptor tyrosine kinases (RTK) Mer and Axl have been implicated in liver disease, yet our understanding of their roles in liver homeostasis and injury is limited. We therefore examined the performance of Mer and Axl mutant mice during aging, and in four models of liver injury. We find that Mer and Axl are most prominently expressed in Kupffer and hepatic endothelial cells, and that asAxl-/-Mertk-/-mice normally age, they develop profound liver disease. We further find that Mer signaling is critical to the phagocytosis of apoptotic hepatocytes that are generated during acute hepatic injury, and that Mer and Axl act in concert to inhibit injury-triggered cytokine production. TAM expression in Kupffer cells is crucial for these effects. In contrast, we show that Axl is uniquely important in mitigating liver damage during acute acetaminophen intoxication. Finally, we demonstrate that Axl exacerbates the fibrosis that develops in a model of chronic hepatic injury. These divergent effects have important implications for the design and implementation of TAM-directed therapeutics that target these RTKs in the liver.</jats:p

The amniotic membrane as a source of stem cells

Cellular therapy has emerged as a new potential tool for curing a wide range of degenerative diseases and tissue necrosis. Embryonic stem cells possess potential for differentiation into a wide range of cell lineages, but the ethical issues associated with establishment of this human cell line have to be resolved prior to any use. The bone marrow (BM) is the usual source of adult stem cells for hematopoietic stem cell transplants and cellular therapy, but the BM harvest is a surgical procedure that requires general anesthesia or sedation, and there seems to be a reduction of the proliferative potential and differentiation capacity of the marrow mesenchymal stem cells in older donors. For these reasons there is an increasing interest in other sources of stem cells from adult and fetal tissues. The amniotic membrane (AM) or amnion is a tissue of particular interest because its cells possess characteristics of stem cells with multipotent differentiation ability, and because of low immunogenicity and easy procurement from the placenta, which is a discarded tissue after parturition, thus avoiding the current controversies associated with the use of human embryonic stem cells. Therefore, amniotic membrane has been proposed as a good candidate to be used in cellular therapy and regenerative medicine

Differential regulation of hepatic physiology and injury by the TAM receptors Axl and Mer

Genome-wide association studies have implicated the TAM receptor tyrosine kinase (RTK) Mer in liver disease, yet our understanding of the role that Mer and its related RTKs Tyro3 and Axl play in liver homeostasis and the response to acute injury is limited. We find that Mer and Axl are most prominently expressed in hepatic Kupffer and endothelial cells and that as mice lacking these RTKs age, they develop profound liver disease characterized by apoptotic cell accumulation and immune activation. We further find that Mer is critical to the phagocytosis of apoptotic hepatocytes generated in settings of acute hepatic injury, and that Mer and Axl act in concert to inhibit cytokine production in these settings. In contrast, we find that Axl is uniquely important in mitigating liver damage during acetaminophen intoxication. Although Mer and Axl are protective in acute injury models, we find that Axl exacerbates fibrosis in a model of chronic injury. These divergent effects have important implications for the design and implementation of TAM-directed therapeutics that might target these RTKs in the liver.</jats:p

Spectroscopical and Molecular Studies of Four Manganese(I) PhotoCORMs with Bioinspired Ligands Containing Non-Coordinated Phenol Groups

Carbonyl compounds are widely explored in medicinal inorganic chemistry and have drawn attention due to their signaling functions in homeostasis. Carbon-monoxide-releasing molecules (CORMs) were developed with the purpose of keeping the CO inactive until its release in the intracellular environment, considering its biological relevance. However, for therapeutic applications, the mechanisms of photorelease and which electronic and structural variations influence its rates must be fully understood. In this work, four ligands containing a pyridine, a secondary amine, and a phenolic group with different substituents were used to prepare new Mn(I) carbonyl compounds. Structural and physicochemical characterization of these complexes was carried out and confirmed the proposed structures. X-ray diffractometry structures obtained for the four organometallic compounds revealed that the substituents in the phenolic ring promote only negligible distortions in their geometry. Furthermore, UV-Vis and IR kinetics showed the direct dependence of the electron-withdrawing or donating ability of the substituent group, indicating an influence of the phenol ring on the CO release mechanism. These differences in properties were also supported by theoretical studies at the DFT, TD-DFT, and bonding situation analyses (EDA-NOCV). Two methods were used to determine the CO release constants (kCO,old and kCO,new), where Mn-HbpaBr (1) had the greatest kCO by both methods (Kco,old = 2.36 × 10−3 s−1 and kCO,new = 2.37 × 10−3 s−1). Carbon monoxide release was also evaluated using the myoglobin assay, indicating the release of 1.248 to 1.827 carbon monoxides upon light irradiation

Fludarabine and Busuphan (Flu-Bu) as Reduced Intensity-Conditioning (RIC) Regimen in HLA-Identical Sibling Allogeneic Hematopoietic Stem Transplantation (Allo-SCT) for Myeloid Malignancies. Results of a Prospective Multicenter Study.

Abstract Allo-SCT is the only curative treatment in many myeloid malignancies. The reduction of non-relapse mortality (NRM) achieved with RIC regimens has allowed high risk patients to undergo an Allo-SCT. In this study we show the results achieved with Flu-Bu conditioning as RIC Allo-SCT. In this prospective, multicenter study we included all 107 consecutive patients who underwent an RIC HLA-identical sibling Allo-SCT in 6 Spanish hospitals between November 1997 and April 2006. Conditioning consisted of fludarabine 30 mg/m2 since day -9 to -5 and busulphan 1 mg/kg/6 hours since day -4 to -2 (total dose 8–10 mg/kg). Graft versus host disease (GVHD) prophylaxis consisted of cyclosporine A (CyA) (from day -1 until at least day +90) and methotrexate (MTX) (days +1, +3 and +6) or mycophenolate mofetil (MMF) (since day +1 until at least day +28). MTX and MMF were used in combination with CyA in two consecutive cohorts (1997–2003 and 2004–2006, respectively) There were 38 (35%) women, median age 58 years (range 21–70 years). There were 58 (54%) acute myeloid leukemia, 35 (33%) myelodisplastic syndrome, 8 (7%) chronic myeloid leukemia and 6 (6%) other chronic myeloprolipherative syndrome. Twenty six (23%) patients were in advanced phase (Refractory disease, partial remission or more than 2nd complete remission). Median time to achieve more than 0.5×109/l neutrophils and more than 20×109/l platelets was 16 (7–29) and 12 (0–59) days respectively. Median follow up for survivors was 43.3 (3–69) months. Four year overall (OS) and disease free survival (DFS) were 47% (95% C.I 42–52%) and 46% (95% C.I 41–51%) respectively. Thirty-seven patients relapsed at median of 4.5 (0.7–45) months. The risk of relapse at 4 years was 45% (95% C.I 39–51%). The development of chronic GVHD was associated with lower relapse rate and higher DFS (29% vs 69%, P&lt;0.001) and (70% vs 23%; P&lt;0.001) respectively. Twenty-five patients died as consequence of NRM at median of 5.4 (0.3–21.4) months, the cumulative incidence (Cum Inc) of NRM at 100 days and 1 year was 7% (95% C.I 4–15%) and 19% (95% C.I 13–28%). Forty-three (39%) patients developed acute GVHD at a median of 58 (13–173), 30 (27%) patients grade 2–4, for a Cum Inc of acute GVHD of 50% (95% CI 40–62%). Fifty nine (71%) of 83 evaluable patients developed chronic GVHD (41 extensive) at a median of 128 (61–831) days. The Cum Inc of chronic GVHD was 66% (95% CI 56–77%). In conclusion Flu-Bu RIC conditioning offers a curative option for myeloid neoplasias with an acceptable TRM. The development of chronic GVHD was associated with lower relapse rate and better DFS. Relapse is still the most important cause of treatment failure and new strategies are needed to improve the relapse rate.</jats:p

Polypyridyl iron(<scp>iii</scp>) complexes containing long alkyl chains: synthesis, characterization, DFT calculations and biological activity

A bis(picolyl)amine ligand was functionalized with a long alkyl chain, and two iron(iii) complexes were prepared and their biological activity was presented.</p