Anti-IL1R2 monoclonal antibody, clone 45252

Squamous cell carcinoma (SCC) is the second most common human skin cancer and the second leading cause of skin cancer-related death. Recently, a new compound, ingenol mebutate, was approved for treatment of actinic keratosis, a precursor of SCC. As the mechanism of action is poorly understood, we have further investigated the mechanism of ingenol mebutate-induced cell death. We elucidate direct effects of ingenol mebutate on primary keratinocytes, patient-derived SCC cells, and a SCC cell line. Transcriptional profiling followed by pathway analysis was performed on ingenol mebutate-treated primary keratinocytes and patient-derived SCC cells to find key mediators and identify the mechanism of action. Activation of the resulting pathways was confirmed in cells and human skin explants and supported by a phosphorylation screen of treated primary cells. The necessity of these pathways was demonstrated by inhibition of certain pathway components. Ingenolmebutate inhibited viability and proliferation of all keratinocyte-derived cells in a biphasic manner. Transcriptional profiling identified the involvement of PKC/MEK/ERK signaling in the mechanism of action and inhibition of this signaling pathway rescued ingenol mebutate-induced cell death after treatment with 100 nmol/L ingenol mebutate, the optimal concentration for the first peak of response. We found the interleukin decoy receptors IL1R2 and IL13RA2 induced by ingenol mebutate in a PKC/MEK/ERK-dependent manner. Furthermore, siRNA knockdown of IL1R2 and IL13RA2 partially rescued ingenol mebutate-treated cells. In conclusion, we have shown that ingenol mebutate-induced cell death is mediated through the PKCd/MEK/ERK pathway, and we have functionally linked the downstream induction of IL1R2 and IL13RA2 expression to the reduced viability of ingenol mebutate-treated cells. (C) 2015 AACR.

Aims: Insulin resistance (IR) detection is challenging and no test is currently used in clinical practice. We developed salivary biomarkers that could be used for IR detection. Methods: We collected saliva from 186 healthy and 276 pre-diabetic participants, divided them into high and low IR groups based on a HOMA cutoff of 2.5. We profiled extracellular transcriptome by microarray in saliva supernatant from 23 high IR and 15 low IR participants, and pre-validated the top ten extracellular mRNA (exRNA) markers in a new cohort of 40 high and 40 low IR participants. A prediction panel was then built and validated in an independent cohort of 149 high and 195 low IR participants. Results: Transcriptomic analyses identified 42 exRNA candidates differentially present in saliva of high and low IR participants. From the top ten candidates, six were individually validated (PRKCB, S100A12, IL1R2, CAMP, VPS4B, CAP1) (p < 0.01) and yielded AUC values ranging from 0.66 to 0.76. Body mass index (BMI) was significant higher in high compared to low IR group with AUC of 0.66, and showed no correlation with any of candidate biomarkers. The combination of four exRNA markers (IL1R2, VPS4B, CAP1, LUZP6) with BMI achieved excellent results in the prediction panel building dataset (AUC = 0.79, sensitivity = 79%, specificity = 64%). The prediction model was validated in an independent cohort (AUC = 0.82, sensitivity = 63%, specificity = 92%). Conclusions: A panel of four salivary exRNA biomarkers (IL1R2, VPS4B, CAP1, LUZP6) and BMI was validated that can distinguish high and low IR participants, overall and in subgroups of healthy and pre-diabetic participants. (C) 2017 Elsevier B.V. All rights reserved.