No abstract

Purpose: The precise molecular targets of IFN-a therapy in the context of malignant melanoma are unknown but seem to involve signal transducers and activators of transcription 1signal transduction within host immune effector cells. We hypothesized that the in vitro transcriptional response of patient peripheral blood mononuclear cells (PBMC) to IFN-a would be similar to the in vivo response to treatment with high-dose IFN-a. Experimental Design: The gene expression profiles of PBMCs and immune cell subsets treated in vitro with IFN-a were evaluated, as were PBMCs obtained from melanoma patients receiving adjuvant IFN-a. Results: Twenty-seven genes were up-regulated in PBMCs from normal donors after treatment with IFN-a in vitro for18 hours (>2-fold, P < 0.001). A subset of these genes (in addition to others) was significantly expressed in IFN-a^treated Tcells, natural killer cells, and monocytes. Analysis of gene expression within PBMCs from melanoma patients (n = 13) receiving high-dose IFN-a2b (20 MU/m 2 i.v.) revealed significant up-regulation (>2-fold) of 21genes (P < 0.001). Also, the gene expression profile of in vitro IFN-a^stimulated patient PBMCs was similar to that of PBMCs obtained from the same patient after IFN-a therapy. Conclusions: This report is the first to describe the transcriptional response of T cells, natural killer cells, and monocytes to IFN-a and characterize the transcriptional profiles of PBMCs from melanoma patients undergoing IFN-a immunotherapy. In addition, it was determined that microarray analysis of patient PBMCs after in vitro stimulation with IFN-a may be a useful predictor of the in vivo response of immune cells to IFN-a immunotherapy.Surgical treatment of early-stage malignant melanoma is frequently curative. However, the therapeutic options for patients with metastatic disease are limited. IFN-a has been used, both as an adjuvant after the surgical resection of high-risk lesions (lymph node metastases or primary tumor thickness, >4 mm) and in advanced disease setting. The IFN-a receptor is expressed on melanoma tumor cells, as well as on immune effectors, and mediates many of its effects via activation of the Janus kinase -signal transducers and activators of transcription (STAT) pathway. IFN-a exerts direct antiproliferative, proapoptotic, and antiangiogenic effects on melanoma cells in culture and has distinct immunostimulatory effects that vary according to the immune subset under study (1-4). Unfortunately, the precise molecular targets of exogenously given IFN-a are unknown. As a result, it is not currently possible to identify patients who would have a high likelihood of responding to this treatment.We have examined the role of the Janus kinase -STAT signaling pathway in a murine model of malignant melanoma using STAT1-deficient mice and STAT1-deficient melanoma cell lines. It was found that loss of STAT1 signal transduction within the host abrogated the antitumor effects of IFN-a (5). In contrast, the survival benefits associated with IFN-a administration w...

Conclusion:These results suggest that lower doses of IFN-a-2b are as effective as higher doses with respect to the induction of Janus-activated kinase-STAT signal transduction and the transcription of ISGs within immune effector cells.

This case report was performed to display the visually significant damage to the retina that can occur with brief exposure to a handheld laser pointer. Laser use in the military is ever increasing in form of target designators, rangefinders, or radar warning systems with powers far greater than used in this case. There is great potential for future cases of retinal damage among active duty members, and the importance of prevention through laser safety programs and recognition through trained medical personnel is paramount.

This retrospective, comparative case series assesses the 10-year outcomes of intravitreal anti-VEGF injections with and without verteporfin photodynamic therapy for the treatment of choroidal neovascularization secondary to presumed ocular histoplasmosis syndrome.

Supplementary Table S1 from Gene Expression Profiling Reveals Similarities between the <i>In vitro</i> and <i>In vivo</i> Responses of Immune Effector Cells to IFN-α

<div>Abstract<p><b>Purpose:</b> The precise molecular targets of IFN-α therapy in the context of malignant melanoma are unknown but seem to involve signal transducers and activators of transcription 1 signal transduction within host immune effector cells. We hypothesized that the <i>in vitro</i> transcriptional response of patient peripheral blood mononuclear cells (PBMC) to IFN-α would be similar to the <i>in vivo</i> response to treatment with high-dose IFN-α.</p><p><b>Experimental Design:</b> The gene expression profiles of PBMCs and immune cell subsets treated <i>in vitro</i> with IFN-α were evaluated, as were PBMCs obtained from melanoma patients receiving adjuvant IFN-α.</p><p><b>Results:</b> Twenty-seven genes were up-regulated in PBMCs from normal donors after treatment with IFN-α <i>in vitro</i> for 18 hours (>2-fold, <i>P</i> < 0.001). A subset of these genes (in addition to others) was significantly expressed in IFN-α–treated T cells, natural killer cells, and monocytes. Analysis of gene expression within PBMCs from melanoma patients (<i>n</i> = 13) receiving high-dose IFN-α-2b (20 MU/m² i.v.) revealed significant up-regulation (>2-fold) of 21 genes (<i>P</i> < 0.001). Also, the gene expression profile of <i>in vitro</i> IFN-α–stimulated patient PBMCs was similar to that of PBMCs obtained from the same patient after IFN-α therapy.</p><p><b>Conclusions:</b> This report is the first to describe the transcriptional response of T cells, natural killer cells, and monocytes to IFN-α and characterize the transcriptional profiles of PBMCs from melanoma patients undergoing IFN-α immunotherapy. In addition, it was determined that microarray analysis of patient PBMCs after <i>in vitro</i> stimulation with IFN-α may be a useful predictor of the <i>in vivo</i> response of immune cells to IFN-α immunotherapy.</p></div>

<div>Abstract<p><b>Purpose:</b> The precise molecular targets of IFN-α therapy in the context of malignant melanoma are unknown but seem to involve signal transducers and activators of transcription 1 signal transduction within host immune effector cells. We hypothesized that the <i>in vitro</i> transcriptional response of patient peripheral blood mononuclear cells (PBMC) to IFN-α would be similar to the <i>in vivo</i> response to treatment with high-dose IFN-α.</p><p><b>Experimental Design:</b> The gene expression profiles of PBMCs and immune cell subsets treated <i>in vitro</i> with IFN-α were evaluated, as were PBMCs obtained from melanoma patients receiving adjuvant IFN-α.</p><p><b>Results:</b> Twenty-seven genes were up-regulated in PBMCs from normal donors after treatment with IFN-α <i>in vitro</i> for 18 hours (>2-fold, <i>P</i> < 0.001). A subset of these genes (in addition to others) was significantly expressed in IFN-α–treated T cells, natural killer cells, and monocytes. Analysis of gene expression within PBMCs from melanoma patients (<i>n</i> = 13) receiving high-dose IFN-α-2b (20 MU/m² i.v.) revealed significant up-regulation (>2-fold) of 21 genes (<i>P</i> < 0.001). Also, the gene expression profile of <i>in vitro</i> IFN-α–stimulated patient PBMCs was similar to that of PBMCs obtained from the same patient after IFN-α therapy.</p><p><b>Conclusions:</b> This report is the first to describe the transcriptional response of T cells, natural killer cells, and monocytes to IFN-α and characterize the transcriptional profiles of PBMCs from melanoma patients undergoing IFN-α immunotherapy. In addition, it was determined that microarray analysis of patient PBMCs after <i>in vitro</i> stimulation with IFN-α may be a useful predictor of the <i>in vivo</i> response of immune cells to IFN-α immunotherapy.</p></div>