BACKGROUND: Pulmonary Langerhans cell histiocytosis (PLCH) is a rare cystic lung disease usually affecting young adults. It is predicted that PLCH is a lung tumor precursor associated with dysfunction of the myeloid dendritic cells in the lung.
METHODS: A 70-year-old male patient presented with chronic cough and sputum. He had symptoms for 5 years and described shortness of breath on exertion for the previous 3 years. He had a 60 packs/year smoking history. Computerized tomography of the thorax revealed an 11-mm nodule in the right lung lower lobe superior segment and a 7-mm nodule in the right lung lower lobe poster basal segment. Those two nodules were resected by means of right thoracoscopic surgery. Pathological evaluation revealed a squamous cell carcinoma and PLCH.
CONCLUSIONS: Coexistent squamous cell carcinoma and PLCH suggest possible association between PLCH and lung cancer.

Protein kinase inhibitors have been widely used as therapeutic agents to treat a variety of diseases, but many of them may cause off-target effects by unexpectedly targeting other noncognate kinases due to high conversion across the protein kinase family. The mitogen-activated protein kinase (MAPK) signaling pathway plays an essential role in tumorigenesis, which has been recognized as a high priority in the druggable target candidates of anticancer therapy. Here, we attempt to investigate the untargeted kinase-inhibitor interactions (UKIIs) of kinase-targeted therapies for the cancer MAPK signaling cascade via an integration of biomolecular modeling, cell viability assay and kinase inhibition analysis. A systematic kinase-inhibitor interaction profile is created for 28 FDA-approved kinase inhibitor drugs across 9 caner-related MAPK kinases. The created profile is analyzed at structural, energetic and dynamic levels and, consequently, totally 18 promising UKII pairs with high theoretical affinity are derived, from which the noncognate inhibitors Cabozantinib, Regorafenib and Crizotinib are selected to test their cytotoxic effects on human epithelial colorectal adenocarcinoma Caco-2 cell line and inhibition activity against the recombinant protein of human p38α kinase domain. The obtained results are compared with two cognate MAPK inhibitors JNK-IN-8 and BIRB796. As might be expected, the Regorafenib, Crizotinib and Cabozantinib exhibit high, moderate and low cytotoxicities, respectively. In addition, the Regorafenib is determined to have a potent p38α-inhibitory activity. This is basically in line with the test results of positive controls JNK-IN-8 and BIRB796 and can be well confirmed by computational modeling.

Furan is a chemical hepatocarcinogen in mice and rats. Its previously postulated cancer mode of action (MOA) is chronic cytotoxicity followed by sustained regenerative proliferation; however, its molecular basis is unknown. To this end, we conducted toxicogenomic analysis of B3C6F1 mouse livers following three week exposures to non-carcinogenic (0, 1, 2mg/kgbw) or carcinogenic (4 and 8mg/kgbw) doses of furan. We saw enrichment for pathways responsible for cytotoxicity: stress-activated protein kinase (SAPK) and death receptor (DR5 and TNF-alpha) signaling, and proliferation: extracellular signal-regulated kinases (ERKs) and TNF-alpha. We also noted the involvement of NF-kappaB and c-Jun in response to furan, which are genes that are known to be required for liver regeneration. Furan metabolism by CYP2E1 produces cis-2-butene-1,4-dial (BDA), which is required for ensuing cytotoxicity and oxidative stress. NRF2 is a master regulator of gene expression during oxidative stress and we suggest that chronic NFR2 activity and chronic inflammation may represent critical transition events between the adaptive (regeneration) and adverse (cancer) outcomes. Another objective of this study was to demonstrate the applicability of toxicogenomics data in quantitative risk assessment. We modeled benchmark doses for our transcriptional data and previously published cancer data, and observed consistency between the two. Margin of exposure values for both transcriptional and cancer endpoints were also similar. In conclusion, using furan as a case study we have demonstrated the value of toxicogenomics data in elucidating dose-dependent MOA transitions and in quantitative risk assessment.

Prostate cancer (PCa) is a malignant disease influencing numerous men worldwide every year. However, the exact pathogenesis and the genes, environment, and other factors involved have not been explained clearly. Some studies have proposed that cell signaling pathways might play a key role in the development and progression of PCa. According to our previous study, the RTK/ERK pathway containing nearly 40 genes was associated with PCa risk. On the basis of these genes, we conducted a meta-analysis with our own Chinese Consortium for Prostate Cancer Genetics (ChinaPCa) study and available studies in the databases to describe the association between the pathway and PCa on the SNP level. The results suggested that rs4764695/IGF1 (recessive model: pooled OR=0.92, 95%CI=0.852-0.994, P=0.034; I(2)=0%, P=0.042; allele analysis: pooled OR=0.915, 95%CI=0.874-0.958, P=0; I(2)=0%, P=0.424; codominant model: OR=0.835, 95%CI=0.762-0.916, P=0; I(2)=0%, P=0.684) and rs1570360/VEGF (recessive model: OR=0.596, 95%CI=0.421-0.843, P=0.003; I(2)=23.9%, P=0.269; codominant model: OR=0.576, 95%CI=0.404-0.820, P=0.002; I(2)=49.1%, P=0.140) were significantly associated with PCa. In subgroup analysis, the relationship was also found in Caucasians for IGF1 (dominant model: OR=0.834, 95%CI=0.769-0.904, P=0; allele analysis: OR=0.908, 95%CI=0.863-0.955, P=0; AA vs CC: OR=0.829, 95%CI=0.750-0.916, P=0; AC vs CC: OR=0.837, 95%CI=0.768-0.912, P=0). In addition, in Asians (allele analysis: OR=0.21, 95%CI=0.168-0.262, P=0) and Caucasians (recessive model: OR=0.453, 95%CI: 0.240-0.855, P=0.015; codominant model: OR=0.464, 95%CI=0.240-0.898, P=0.023) for VEGF, the association was significant. The results indicated that rs4764695/IGF1 and rs1570360/VEGF might play a key role in the development and progression of PCa. On the SNP level, we suggest that the study gives us a new view of gene-pathway analysis and targeted therapy for PCa.