Integrin expression in malignant melanoma and their role in cell attachment and migration on extracellular matrix proteins.

The interaction between melanoma cells and extracellular matrix (ECM) components may be important for invasion and metastasis. The integrins belong to a family of protein heterodimers composed of alpha and beta subunits and the beta 1-integrins are especially important as ECM receptors. We investigated the expression of beta 1-integrins on four human melanoma cell lines (two primary, one from the radial growth phase (RGP) and another from the vertical growth phase (VGP), and two metastatic) and examined their attachment and migration on laminin (LN), type IV collagen (CN) and fibronectin (FN). Among LN and/or CN integrin receptors, only alpha 2 beta 1 (VLA2) was expressed at significantly higher levels in the VGP and metastatic cell lines in comparison to the RGP cell line. In addition, enhanced attachment and migration on LN and CN were significantly inhibited by anti-VLA2 monoclonal antibody (mAb). As to FN receptors, alpha 4 beta 1 and alpha 5 beta 1 expression was heterogeneous among the cell lines, however, it was directly related to enhanced attachment and migration on FN, which also could be inhibited by anti-VLA4 and anti-VLA5 mAbs. Our findings provide evidence for a role in beta 1-integrins, in particular alpha 2 beta 1, in melanoma progression and metastasis.     

In vitro pharmacodynamics of ceftazidime against Pseudomonas aeruginosa isolates from cystic fibrosis patients.

The concentration/MIC (C/MIC) ratio maximizing the bactericidal activity of ceftazidime against 10 Pseudomonas aeruginosa isolates from cystic fibrosis patients was identified. Bactericidal activity was assessed by determining the percent difference in the area under the killing curve at each C/MIC ratio for all of the isolates from that of their growth control. The percent effect at each C/MIC ratio was fitted to a sigmoidal Emax model with maximum bactericidal activity defined as the C/MIC ratio that produced an effect that was 90% of the Emax. Our results suggest that at least some isolates may require higher C/MIC ratios than previously reported for maximal activity.     

Pigmented lesions of the conjunctiva

A careful examination of the conjunctiva and ocular adnexa should be performed as part of a complete dermatologic examination. This article reviews the clinical presentation and classification of pigmented lesions of the conjunctiva. The histologic features of these conjunctival lesions are compared with those of pigmented lesions of the skin. (J Am Acad Dermatol 1998;38:971-8.)     

Recurrent biliary calculi: duodenal diverticula as a predisposing factor

Several studies indicate a causal relationship between duodenal diverticula and gallstone disease. The diverticula persist after biliary tract surgery, and it is therefore presumed that patients with diverticula have an increased disposition to develop new calculi in the bile ducts after cholecystectomy. To test this hypothesis, the occurrence of recurrent biliary calculi was studied in 101 patients who had cholecystectomy, all with an asymptomatic period of two years or more following the primary biliary surgery. All patients had symptoms, that indicated biliary tract or pancreatic diseases. The incidence of recurrent calculi in patients with diverticula was 87.5% (95% confidence interval, 66.9-95.8). In patients without diverticula, the incidence was 31.9% (95% confidence interval, 21.5-44.3). The difference is highly significant, and the results support the assumption tht diverticula in the area of the papilla of Vater dispose to gallstone disease.     

Markers and tissue resources for melanoma: meeting report

The Markers and Tissue Resources for Melanoma meeting convened by the Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, Specialized Programs of Research Excellence at the Organ Systems Branch of the National Cancer Institute (NCI), and the Melanoma Research Foundation was held in Gaithersburg, MD on October 2005. The meeting reviewed the current status of biomarkers for early- and advanced-stage melanoma and addressed some of the challenges scientists and clinicians face as they unravel the biology of melanoma and try to apply these findings to patient care. Specifically, the participants focused on molecular changes associated with melanoma progression, potential diagnostic and prognostic markers emerging from molecular profiling studies, and new treatment targets for current and future clinical trials. They also highlighted the ongoing challenges about translational research in melanoma, including availability of tissue resources, and summarized the status of nevus and melanoma tissue microarrays, recently developed as a collaborative project between the melanoma research community and the NCI. The meeting report is intended to provide a perspective on emerging scientific approaches in translational research that can enhance the progress in discovery and validation of markers for melanoma. (Cancer Res 2006; 66(22): 10652-7).     

Molecular mechanisms of metastasis

A major topic covered at the First International Symposium on Cancer Metastasis and the Lymphovascular System was the molecular mechanisms of metastasis. This has become of major interest in recent years as we have discovered new metastasis-related genes and gained understanding of the molecular events of lymphatic metastasis. The symposium covered new aspects and important questions related to the events of metastasis in both humans and animals. The basic and clinical related research covered in this topic represented many disciplines. The presentations showed novel findings and at the same time, raised many new unanswered questions, indicating the limited knowledge we still have regarding the molecular events of metastasis. The hope is that further unraveling of the direct and indirect molecular events of lymphatic metastasis will lead to new approaches in developing effective therapeutics. Presented as Session III of the First International Symposium on Cancer Metastasis and the Lymphovascular System. April 28–30, 2005, San Francisco, CA; Chaired by Dave S.B. Hoon.     

Dysplastic melanocytic nevi in histologic association with 234 primary cutaneous melanomas

Dysplastic melanocytic nevi (DMN) are irregularly pigmented lesions characterized by (1) atypical melanocytic hyperplasia in a lentiginous epidermal pattern (AMHL), (2) one or more dermal mesenchymal changes, and (3) frequently a dermal nevocellular nevus. In order to determine an association between DMN and cutaneous melanoma, the dominant histologic feature of DMN (namely, AMHL) was sought in histologic contiguity with 234 primary melanomas. Of these 234 cases, 9 were lentigo maligna melanomas. Of the remaining 225 cases, 49 (21.8%) were associated with AMHL in the same histologic section as (but beyond the most lateral margin of) intraepidermal and invasive melanoma. AMHL was directly associated with the presence of dermal nevocellular nevi in histologic contiguity with melanoma, and a greater number of histologic slides with melanoma available for review. AMHL was inversely associated with nodular melanoma. Most of the AMHL cases were not associated with familial melanoma, but the total number of familial cases was low. The histologic association between AMHL and melanoma in one fifth of cases in this series supports the hypothesis that at least some cutaneous melanomas may have an origin in DMN.     

Amino acid variations in hepatitis C virus p7 and sensitivity to antiviral combination therapy with amantadine in chronic hepatitis C

BACKGROUND: Formation of transmembrane ion channels by hepatitis C virus (HCV) p7 and abrogation of channel function by amantadine was demonstrated in vitro. The relevance of HCV p7 amino acid (aa) variations for response to antiviral therapy with amantadine is unknown. METHODS: HCV p7 was sequenced in 86 individuals who were infected with HCV genotype 1. Thirty-six of 86 patients received amantadine within an interferon-alpha (IFN-alpha)-based antiviral therapy. Helical wheel modelling for HCV p7 was performed. RESULTS: No significant correlation of overall aa variations within HCV p7 was observed with response to IFN-alpha-based therapy with amantadine in HCV genotype 1alpha/b infected patients. When analysis was restricted to non-conservative aa variations, a higher number of aa substitutions within complete HCV p7 and transmembrane helix 2 was associated with non-response in HCV-1b-infected patients receiving therapy with amantadine (P=0.015 and P=0.037, respectively), without amantadine (P=0.106 and P=0.118, respectively), and in the total cohort of HCV-1b-infected patients (P=0.00007 and P=0.011, respectively). Furthermore, substitution L20F was observed more often in non-responders than responders with HCV-1b infection and therapy with amantadine (P=0.099). By in silico modelling, aa 20 was located toward the p7 channel lumen. Substitution L20F may impair amantadine action by altering the shape of the ion channel pore. CONCLUSION: Substitution L20F within HCV p7 may be associated with non-response to combination therapy specifically with amantadine in HCV-1b-infected patients. Non-responders with HCV-1b infection showed higher numbers of non-conservative aa variations within HCV p7 than responders, irrespective of the application of amantadine.