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1.  The Natural Product Phyllanthusmin C Enhances IFN-γ Production by Human Natural Killer Cells through Upregulation of TLR-Mediated NF-κB Signaling 
Natural products are a major source for cancer drug development. NK cells are a critical component of innate immunity with the capacity to destroy cancer cells, cancer initiating cells, and clear viral infections. However, few reports describe a natural product that selectively stimulates NK cell IFN-γ production and unravel a mechanism of action. In this study, through screening, we found that a natural product, phyllanthusmin C (PL-C), alone enhanced IFN-γ production by human NK cells. PL-C also synergized with IL-12, even at the low cytokine concentration of 0.1 mg/ml, and stimulated IFN-γ production in both human CD56bright and CD56dim NK cell subsets. Mechanistically, TLR1 and/or TLR6 mediated PL-C’s activation of the NF-κB p65 subunit that in turn bound to the proximal promoter of IFNG and subsequently resulted in increased IFN-γ production in NK cells. However, IL-12/IL-15 receptors and their related STAT signaling pathways were not significantly modulated by PL-C. PL-C induced little or no T cell IFN-γ production or NK cell cytotoxicity. Collectively, we identify a natural product with the capacity to selectively activate human NK cell IFN-γ. Given the role of IFN-γ in immune surveillance, additional studies to understand the role of this natural product in prevention of cancer or infection in select populations are warranted.
PMCID: PMC4162489  PMID: 25122922
Phyllanthusmin C; NK cells; IFN-γ; NF-κB; p65; TLR
2.  Biobehavioral, immune, and health benefits following recurrence for psychological intervention participants 
A clinical trial was designed to test the hypothesis that a psychological intervention could reduce the risk for cancer recurrence. Newly diagnosed regional breast cancer patients (n=227) were randomized to Intervention with assessment or Assessment only arms. The intervention had positive psychological, social, immune, and health benefits, and after a median of 11 years the Intervention arm was found to have reduced risk of recurrence [hazard ratio (HR), 0.55; P=0.034]. In follow-up, we hypothesized that the Intervention arm might also show longer survival after recurrence. If observed, we then would examine potential biobehavioral mechanisms.
Experimental Design
All patients were followed; 62 recurred. Survival analyses included all 62. Upon recurrence diagnosis, those available for further biobehavioral study were accrued (n=41, 23 Intervention and 18 Assessment). For those 41, psychological, social, adherence, health, and immune (natural killer cell cytotoxicity; T-cell proliferation) data were collected at recurrence diagnosis and 4, 8, and 12 months later.
Intent-to-treat analysis revealed reduced risk of death following recurrence for the Intervention arm (HR, 0.41; P=0.014). Mixed-effects follow-up analyses with biobehavioral data showed that all patients responded with significant psychological distress at recurrence diagnosis, but thereafter only the Intervention arm improved (P values<0.023). Immune indices were significantly higher for the Intervention arm at 12 months (P values<0.017).
Hazards analyses augment previous findings in showing improved survival for the Intervention arm after recurrence. Follow-up analyses showing biobehavioral advantages for the Intervention arm contribute to our understanding of how improved survival was achieved.
PMCID: PMC2910547  PMID: 20530702
psychological; intervention; survival; cancer; biobehavioral
Interlukin-29 (IL-29) is a member of the type III interferon (IFN) family that has been shown to have antiviral activity and inhibit cell growth. Melanoma cell lines were tested for the expression of the IL-29R and their response to IL-29.
Expression of IL-28R1 and IL-10R2, components of the IL-29R, was evaluated using RT-PCR. A combination of immunoblot analysis and flow cytometry was used to evaluate IL-29-induced signal transduction. U133 Plus 2.0 Arrays and real-time PCR were used to evaluate gene expression. Apoptosis was measured using Annexin V/Propridium Iodide staining. In situ PCR for the IL-29R was performed on paraffin-embedded melanoma tumors.
Both IL-28R1 and IL-10R2 were expressed on the A375, 1106 MEL, Hs294T, 18105 MEL, MEL 39, SK MEL 5 and F01 cell lines. Incubation of melanoma cell lines with IL-29 (10–1000 ng/mL) led to phosphorylation of STAT1 and STAT2. Microarray analysis and qRT-PCR showed a marked increase in transcripts of IFN-regulated genes after treatment with IL-29. In the F01 cell line, bortezomib-induced and temozolomide-induced apoptosis was synergistically enhanced following the addition of IL-29. In situ PCR revealed that IL-10R2 and IL-28R1 were present in six of eight primary human melanoma tumors but were not present in benign nevi specimens.
IL-29 receptors are expressed on the surface of human melanoma cell lines and patient samples and treatment of these cell lines with IL-29 leads to signaling via the Jak-STAT pathway, the transcription of a unique set of genes, and apoptosis.
PMCID: PMC2820597  PMID: 20103601
IL-29; Interferon-lambda; malignant melanoma; Jak-STAT
4.  Prognostic significance of interleukin-6 single nucleotide polymorphism genotypes in neuroblastoma: rs1800795 (promoter) and rs8192284 (receptor) 
Neuroblastoma is a childhood cancer of the sympathetic nervous system and many patients present with high risk disease. Risk stratification, based on pathology and tumor-derived biomarkers, has improved prediction of clinical outcomes, but overall survival rates remain unfavorable and new therapeutic targets are needed. Some studies suggest a link between interleukin-6 and more aggressive behavior in neuroblastoma tumor cells. Therefore, we examined the impact of two IL-6 single nucleotide polymorphisms (SNP) on neuroblastoma disease progression.
Experimental design
DNA samples from 96 high risk neuroblastoma patients were screened for two SNP that are known to regulate the serum levels of IL-6 and the soluble IL-6 receptor (IL-6R), rs1800795 and rs8192284 respectively. The genotype for each SNP was determined in a blinded fashion and independent statistical analysis was performed to determine SNP-related event free survival (EFS) and overall survival (OS) rates.
The rs1800795 IL-6 promoter SNP is an independent prognostic factor for EFS and OS in -high risk neuroblastoma patients. In contrast, the rs8192284 IL-6 receptor SNP revealed no prognostic value.
The rs1800795 SNP (-174 IL-6 (G>C) represents a novel and independent prognostic marker for both EFS and OS in high risk neuroblastoma. Since the rs1800795 SNP (-174 IL-6 (G>C) has been shown to correlate with production of IL-6, this cytokine may represent a target for development of new therapies in neuroblastoma.
PMCID: PMC2740837  PMID: 19671870

Results 1-4 (4)