THE ASSOCIATION BETWEEN THE IL-1 PATHWAY

Cutaneous malignant melanoma (CMM) is a potentially lethal malignancy that warrants attention and further research, as it is known to that there is an increasing rate of incidence in theUnited States, and it is also known that exposure to UV light is its most crucial risk factor, and family history of melanoma is also an important risk factor. Melanoma is an aggressive and lethal cancer in humans. There are an estimated new 132,000 melanoma cases annually worldwide, and the trend has doubled in the past 20 years. However, attempts to treat melanoma have encountered considerable resistance and remained ineffective. The 5-year survival rate for metastatic melanoma remains less than 5%. CMM patients may develop an immune response to their tumors, but innate anti-tumor immune responses are insufficient for controlling the development of the tumor. Melanoma is a very immunogenic tumor, sometimes exhibiting spontaneous remissions, making it one of the foremost targets for immunotherapy. Unfortunately, despite the attempts at making tumor-infiltrating lymphocyte treatments, the clinical response has been borderline. The immunosuppressive microenvironment of tumor cells becomes significant and intertwines with the resistance of tumor treatment. Furthermore, IL-1 can hinder the immune response to melanoma. The pathway of MAPK activation leads to the production interleukin(IL)-1α/β. IL-1 conducts immunomodulatory activity through tumor-associated fibroblasts and locks in the turnkey position of the immunosuppression pathway to resist the cytotoxic T lymphocyte function. Hence, IL-1 is a key target of interest in treating melanoma, along with the entire pathway flowing from it. Polymorphisms in genes regulating the immune response could result in increased susceptibility to and/or poorer prognosis in certain individuals. For this study, one of the objectives was to examine if single nucleotide polymorphisms (SNPs) of certain pro- and anti-inflammatory cytokines and growth factors, namely IL-1, IL-6, IL-8, IFN-γ, and TNF-α are associated with melanoma outcome of death, recurrence, or composite, and thus susceptibility. Those genes are the upstream and downstream targets for the greater IL-1 pathway. The greater IL-1 pathway has multiple genes in between those upstream and downstream targets. Those genes are IL-1RI, IL-1RAcP, IL-1RA, MYD88, TOLLIP, IRAKs, MEKK1, MEK3, MEK6, JNK, P38, c-JUN, ECSIT, TRAF6, TAB1, TAK1, RKIP, NIK, IKKα, IKKβ, IκBα, and NF-κB. The individual SNP analysis proved to be interesting though inconclusive. There were some borderline significant results, such as associations of the SNPs rs16944, rs1143627, rs1071676, and rs3136558 with the endpoint of death. The French validation verified a significant association of rs3136558 with death but none of the others. The next objective was to perform a full pathway analysis, incorporating all available SNPs for each gene in the overall IL-1 pathway to determine if any components were significant and if so, to attempt further verification at the protein level if the data were available. By using the SKAT program for pathway analysis, several genes in the IL-1 pathway were found to be significant. They were IL-1, c-JUN, and ECSIT, with borderline significance for TAK1. With the observation of associations of these four genes with melanoma outcomes at the DNA level, the next step was to determine if they were also significantly associated with melanoma outcomes at the expression level. The data for the DNA level studies did not include protein expression studies, so we used data provided by The Cancer Genome Atlas (TCGA). TAK1 data was not available, but RNA expression data were gathered for IL-1, c-JUN, and ECSIT. At the protein level, only c-JUN data was available. At the RNA level, IL1 showed that survival was proportional to IL-1 level, ECSIT showed lower survival for higher level, while c-JUN showed higher survival for higher levels. At the protein level, c-JUN was significant at the protein level, both adjusted and unadjusted via logistic regression. It seems that for developing further therapy against melanoma, c-JUN may be be a crucial target in the IL-1 pathway. IL-1 and ECSIT could also play important roles related to melanoma outcomes but require future studies where protein expression data is available to confirm the DNA- and RNA-based results

Investigation of Bioterrorism-Related Anthrax, United States, 2001: Epidemiologic Findings

In October 2001, the first inhalational anthrax case in the United States since 1976 was identified in a media company worker in Florida. A national investigation was initiated to identify additional cases and determine possible exposures to Bacillus anthracis. Surveillance was enhanced through health-care facilities, laboratories, and other means to identify cases, which were defined as clinically compatible illness with laboratory-confirmed B. anthracis infection. From October 4 to November 20, 2001, 22 cases of anthrax (11 inhalational, 11 cutaneous) were identified; 5 of the inhalational cases were fatal. Twenty (91%) case-patients were either mail handlers or were exposed to worksites where contaminated mail was processed or received. B. anthracis isolates from four powder-containing envelopes, 17 specimens from patients, and 106 environmental samples were indistinguishable by molecular subtyping. Illness and death occurred not only at targeted worksites, but also along the path of mail and in other settings. Continued vigilance for cases is needed among health-care providers and members of the public health and law enforcement communities

A Four-Gene Signature Predicts Disease Progression in Muscle Invasive Bladder Cancer

There are no reliable criteria to handle disease progression of muscle invasive bladder cancer (MIBC), which strongly influences patient survival. Therefore, an accurate predicting method to identify progressive MIBC patients is greatly needed. The aim of this study was to identify a genetic signature associated with disease progression in MIBC. To address this issue, we analyzed three independent cohorts (a training set, test set 1 and test set 2) comprising a total of 128 MIBC patients. Microarray gene expression profiling, including gene network analysis, was performed in the training set to identify a gene expression signature associated with disease progression. The prognostic value of the signature was validated in test set 1 and test set 2 by microarray and real-time reverse transcriptase polymerase chain reaction (RT-PCR), respectively. The determination of gene expression patterns by microarray data analysis identified 1,320 genes associated with disease progression. Gene network analysis of the 1,320 genes suggested that IL1B, S100A8, S100A9 and EGFR were important mediators of MIBC progression. We validated this putative four-gene signature in two independent cohorts (log-rank test, P < 0.05 each, respectively) and estimated the predictive value of the signature by multivariate Cox regression analysis (hazard ratio [HR], 6.24; 95% confidence interval [CI], 1.58–24.61; P = 0.009). Finally, signature-based stratification demonstrated that the four-gene signature was an independent predictor of MIBC progression. In conclusion, a molecular signature defined by four genes represents a promising diagnostic tool for the identification of MIBC patients at high risk of progression