Chitohexaose Activates Macrophages by Alternate Pathway through TLR4 and Blocks Endotoxemia

Sepsis is a consequence of systemic bacterial infections leading to hyper activation of immune cells by bacterial products resulting in enhanced release of mediators of inflammation. Endotoxin (LPS) is a major component of the outer membrane of Gram negative bacteria and a critical factor in pathogenesis of sepsis. Development of antagonists that inhibit the storm of inflammatory molecules by blocking Toll like receptors (TLR) has been the main stay of research efforts. We report here that a filarial glycoprotein binds to murine macrophages and human monocytes through TLR4 and activates them through alternate pathway and in the process inhibits LPS mediated classical activation which leads to inflammation associated with endotoxemia. The active component of the nematode glycoprotein mediating alternate activation of macrophages was found to be a carbohydrate residue, Chitohexaose. Murine macrophages and human monocytes up regulated Arginase-1 and released high levels of IL-10 when incubated with chitohexaose. Macrophages of C3H/HeJ mice (non-responsive to LPS) failed to get activated by chitohexaose suggesting that a functional TLR4 is critical for alternate activation of macrophages also. Chitohexaose inhibited LPS induced production of inflammatory molecules TNF-α, IL-1β and IL-6 by macropahges in vitro and in vivo in mice. Intraperitoneal injection of chitohexaose completely protected mice against endotoxemia when challenged with a lethal dose of LPS. Furthermore, Chitohexaose was found to reverse LPS induced endotoxemia in mice even 6/24/48 hrs after its onset. Monocytes of subjects with active filarial infection displayed characteristic alternate activation markers and were refractory to LPS mediated inflammatory activation suggesting an interesting possibility of subjects with filarial infections being less prone to develop of endotoxemia. These observations that innate activation of alternate pathway of macrophages by chtx through TLR4 has offered novel opportunities to cell biologists to study two mutually exclusive activation pathways of macrophages being mediated through a single receptor

Predicting survival of de novo metastatic breast cancer in Asian women: Systematic review and validation study

10.1371/journal.pone.0093755PLoS ONE94-POLN

Milk fat globule epidermal growth factor-factor 8-derived peptide attenuates organ injury and improves survival in sepsis

INTRODUCTION: Sepsis involves overwhelming inflammatory responses with subsequent immune-suppression that can lead to multiple organ dysfunction and ultimately death. Milk fat globule epidermal growth factor-factor 8 (MFG-E8) is a secretory protein found to have multiple biological activities against autoimmune and inflammatory diseases. MFG-E8 contains an Arg-Gly-Asp (RGD) motif involved in cell-cell and cell-matrix interactions. In sepsis, excessive neutrophils migration through endothelial cells and matrix to sites of inflammation results in organ damage. We hypothesized that MFG-E8-derived short peptides (MSP) flanking its RGD motif could provide protection against organ injury in sepsis. METHODS: The differentiated human neutrophil-like HL-60 cells (dHL60) were incubated with a series of peptides flanking the RGD motif of human MFG-E8 for a cell adhesion assay to fibronectin or human pulmonary artery endothelial cells (PAECs). For the induction of sepsis, male C57BL/6 mice (20–25 g) were subjected to cecal ligation and puncture (CLP). Peptide MSP68 (1 mg/kg body weight) or normal saline (vehicle) was injected intravenously at 2 h after CLP. Blood and tissue samples were collected at 20 h after CLP for various measurements. RESULTS: After screening, peptide MSP68 (VRGDV) had the highest inhibition of dHL-60 cell adhesion to fibronectin by 55.8 % and to PAEC by 67.7 %. MSP68 treatment significantly decreased plasma levels of organ injury marker AST by 37.1 % and the proinflammatory cytokines IL-6 and TNF-α by 61.9 % and 22.1 %, respectively after CLP. MSP68 improved the integrity of microscopic architectures, decreased IL-6 levels in the lungs by 85.1 %, and reduced apoptosis. MSP68 treatment also significantly reduced the total number of neutrophil infiltration by 61.9 % and 48.3 % as well as MPO activity by 40.8 % and 47.3 % in the lungs and liver, respectively, after CLP. Moreover, the number of bacteria translocated to mesenteric lymph nodes was decreased by 57 % with MSP68 treatment. Finally, the 10-day survival rate was increased from 26 % in the vehicle group to 58 % in the MSP68-treated group. CONCLUSIONS: MSP68 effectively inhibits excessive neutrophils infiltrating to organs, leading to moderate attenuation of organ injury and significantly improved survival in septic mice. Thus, MSP68 may be a potential therapeutic agent for treating sepsis

Cisplatin-based chemotherapy: Add high-frequency audiometry in the regimen

Background : Cisplatin-induced ototoxicity shows high interindividual variability and is often accompanied by transient or permanent tinnitus. It is not possible to identify the susceptible individuals before commencement of the treatment. We conducted a prospective, randomized and observational study in a tertiary care centre and evaluated the effects of different doses of cisplatin on hearing. Materials and Methods : Fifty-seven patients scheduled for cisplatin-based chemotherapy were included in the study. All patients were divided into three groups depending on the dose of cisplatin infused in 3 weeks. Results : The subjective hearing loss was found in seven patients, while six patients had tinnitus during the chemotherapy. The hearing loss was sensorineural, dose dependent, symmetrical, bilateral and irreversible. Higher frequencies were first to be affected in cisplatin chemotherapy. Conclusion : As use of high-frequency audiometry is still limited in research work only, we need a strict protocol of adding high-frequency audiometry in the cisplatin-based chemotherapy regimen

Cisplatin-based chemotherapy: Add high-frequency audiometry in the regimen

Background : Cisplatin-induced ototoxicity shows high interindividual variability and is often accompanied by transient or permanent tinnitus. It is not possible to identify the susceptible individuals before commencement of the treatment. We conducted a prospective, randomized and observational study in a tertiary care centre and evaluated the effects of different doses of cisplatin on hearing. Materials and Methods : Fifty-seven patients scheduled for cisplatin-based chemotherapy were included in the study. All patients were divided into three groups depending on the dose of cisplatin infused in 3 weeks. Results : The subjective hearing loss was found in seven patients, while six patients had tinnitus during the chemotherapy. The hearing loss was sensorineural, dose dependent, symmetrical, bilateral and irreversible. Higher frequencies were first to be affected in cisplatin chemotherapy. Conclusion : As use of high-frequency audiometry is still limited in research work only, we need a strict protocol of adding high-frequency audiometry in the cisplatin-based chemotherapy regimen

The Predictive Accuracy of PREDICT : A Personalized Decision-Making Tool for Southeast Asian Women With Breast Cancer

Web-based prognostication tools may provide a simple and economically feasible option to aid prognostication and selection of chemotherapy in early breast cancers. We validated PREDICT, a free online breast cancer prognostication and treatment benefit tool, in a resource-limited setting. All 1480 patients who underwent complete surgical treatment for stages I to III breast cancer from 1998 to 2006 were identified from the prospective breast cancer registry of University Malaya Medical Centre, Kuala Lumpur, Malaysia. Calibration was evaluated by comparing the model-predicted overall survival (OS) with patients' actual OS. Model discrimination was tested using receiver-operating characteristic (ROC) analysis. Median age at diagnosis was 50 years. The median tumor size at presentation was 3 cm and 54% of patients had lymph node-negative disease. About 55% of women had estrogen receptor-positive breast cancer. Overall, the model-predicted 5 and 10-year OS was 86.3% and 77.5%, respectively, whereas the observed 5 and 10-year OS was 87.6% (difference: - 1.3%) and 74.2%(difference: 3.3%), respectively; P values for goodness-of-fit testwere 0.18 and 0.12, respectively. The programwas accurate in most subgroups of patients, but significantly overestimated survival in patients aged Based on its accurate performance in this study, PREDICT may be clinically useful in prognosticating women with breast cancer and personalizing breast cancer treatment in resource-limited settings

Neues Musik-Institut

Wiener Musiklehranstalt, gegründet von E. Pirkhert