DC-SIGN, C1q, and gC1qR form a trimolecular receptor complex on the surface of monocyte-derived immature dendritic cells

C1q modulates the differentiation and function of cells committed to the monocyte-derived dendritic cell (DC) lineage. Because the 2 C1q receptors found on the DC surface-gC1qR and cC1qR-lack a direct conduit into intracellular elements, we postulated that the receptors must form complexes with transmembrane partners. In the present study, we show that DC-SIGN, a C-type lectin expressed on DCs, binds directly to C1q, as assessed by ELISA, flow cytometry, and immunoprecipitation experiments. Surface plasmon resonance analysis revealed that the interaction was specific, and both intact C1q and the globular portion of C1q bound to DC-SIGN. Whereas IgG reduced this binding significantly, the Arg residues (162-163) of the C1q-A chain, which are thought to contribute to the C1q-IgG interaction, were not required for C1q binding to DC-SIGN. Binding was reduced significantly in the absence of Ca(2+) and by preincubation of DC-SIGN with mannan, suggesting that C1q binds to DC-SIGN at its principal Ca(2+)-binding pocket, which has increased affinity for mannose residues. Antigen-capture ELISA and immunofluorescence microscopy revealed that C1q and gC1qR associate with DC-SIGN on blood DC precursors and immature DCs. The results of the present study suggest that C1q/gC1qR may regulate DC differentiation and function through the DC-SIGN-mediated induction of cell-signaling pathways.     

A Simple Method of Electroelution of Individual Protein Bands from SDS Polyacrylamide Gels for Direct Study in Cellular Assays

A very simple and effective procedure which allows simultaneous electroelution of separated proteins from SDS polyacrylamide gel into small quantity of elution buffer is described. Elution parameters have been optimized for maximum possible recovery (50-60%). Protein fractions were collected in physiological buffer and an efficient removal of SDS have been obtained, thus fractions collected were suited for direct testing in cell cultures. Method was used to investigate human T-cell responses to purified secreted M. tuberculosis H37Rv proteins. Eight low molecular weight (M.w. range 10 kD to 25 kD) culture filtrate proteins were purified in quantities, sufficient for immunological characterization. Lymphocyte proliferative responses and cytokine release pattern from tuberculosis patients, healthy contacts and healthy controls were studied on stimulation with purified culture filtrate proteins. Immunologically important M. tuberculosis proteins were identified by using this method. This approach should be applicable to the rapid identification and characterization of any interesting T cell antigen.     

Efficacy of HIV/STI Behavioral Interventions for Heterosexual African American Men in the United States: A Meta-Analysis

This meta-analysis estimates the overall efficacy of HIV prevention interventions to reduce HIV sexual risk behaviors and sexually transmitted infections (STIs) among heterosexual African American men. A comprehensive search of the literature published during 1988-2008 yielded 44 relevant studies. Interventions significantly reduced HIV sexual risk behaviors and STIs. The stratified analysis for HIV sexual risk behaviors indicated that interventions were efficacious for studies specifically targeting African American men and men with incarceration history. In addition, interventions that had provision/referral of medical services, male facilitators, shorter follow-up periods, or emphasized the importance of protecting family and significant others were associated with reductions in HIV sexual risk behaviors. Meta-regression analyses indicated that the most robust intervention component is the provision/referral of medical services. Findings indicate that HIV interventions for heterosexual African American men might be more efficacious if they incorporated a range of health care services rather than HIV/STI-related services alone.     

“Plasma Cell Hepatitis” in Liver Allografts: Identification and Characterization of an IgG4‐Rich Cohort

Plasma cell hepatitis (PCH), also known as “de novo autoimmune” hepatitis, is an increasingly recognized, but suboptimally named and poorly understood, category of late allograft dysfunction strongly resembling autoimmune hepatitis (AIH): They share plasma‐cell‐rich necro‐inflammatory activity on biopsy, autoantibodies and steroid responsiveness, but overlap with rejection is problematic. A retrospective study of clinical, serological, histopathological and IgG4 immunohistological features of PCH (n = 20) in liver allograft recipients, native liver AIH (n = 19) and plasma‐cell‐rich renal allograft rejection (n = 20) showed: (1) high frequency (44%) of HLA‐DR15; (2) less female predominance (p = 0.03) and (3) n = 9/20 PCH recipients showed >25 IgG4+ plasma cells/high‐power field (IgG4+ PCH) versus AIH (n = 1/19, p = 0.008) or plasma‐cell‐rich kidney rejection (n = 2/20, p = 0.03). The IgG4+ PCH (n = 9) subgroup showed lower alanine transaminase (ALT) (p < 0.01) and aspartate transaminase (AST) (p < 0.05) at index biopsy but (a) higher plasma cell number/percentage, (b) more aggressive‐appearing portal/periportal and perivenular necro‐inflammatory activity and (c) more severe portal/periportal fibrosis than IgG4? PCH (n = 11). Significant demographic, histopathologic and plasma cell phenotype differences between PCH and AIH suggest distinct pathogenic mechanisms for at least the IgG4+ PCH subgroup likely representing an overlap between allo‐ and auto‐immunity. IgG4+ PCH was associated with fibrosis, but also highly responsive to increased immunosuppression.

     

A novel semi-mechanistic tumor growth fraction model for translation of preclinical efficacy of anti-glypican 3 antibody drug conjugate to human

The growing fraction (GF) of tumor has been reported as one of the predictive markers of the efficacy of chemotherapeutics. Therefore, a semi-mechanistic model has been developed that describes tumor growth on the basis of cell cycle, allowing the incorporation of the GF of a tumor in pharmacokinetic/pharmacodynamic (PK/PD) modeling. Efficacy data of anti-glypican 3 (GPC3) antibody drug conjugate (ADC) in a hepatocellular carcinoma (HCC) patient derived xenograft (PDX) model was used for evaluation of this proposed model. Our model was able to describe the kinetics of growth inhibition of HCC PDX models following treatment with anti-GPC3 ADC remarkably well. The estimated tumurostatic concentrations were used in tandem with human PKs translated from cynomolgus monkey for prediction of the efficacious dose. The projected efficacious human dose of anti-GPC3 ADC was in the range 0.20–0.63 mg/kg for the Q3W dosing regimen, with a median dose of 0.50 mg/kg. This publication is the first step in evaluating the applicability of GF in PK/PD modeling of ADCs. The authors are hopeful that incorporation of GF will result in an improved translation of the preclinical efficacy of ADCs to clinical settings and thereby better prediction of the efficacious human dose.     

Information and communication technology developments in asthma management: a systematic review

This review aims to explain the progress of information and communication technology (ICT) applications in asthma management. Appropriate literature was printed out from the bibliographic databases and library source using relevant key phrases of ICT and asthma. The ICT developments from simple to complex modules to augment the conventional methods of asthma care with a caution of excessive reliance upon technology were discussed. However, it should be noted ICTs are for maximizing the human clinician's own ability to receive and process information as well as providing unique opportunities for patients, physicians, pharmacists and researchers.