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Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening., Competing Interests: Declaration of interests M.G. Best, R.J.A.N., and T.W. are inventors on relevant patent applications (PCT/NL2011/050518 and PCT/NL2018/050110). R.J.A.N. and T.W. are shareholders of Illumina, Inc. M.H. is chief formulation officer at Nurish.Me, Inc., and Camelina Sun LLC and has equity in those companies (whose business activities are unrelated to the present work). D.M.P. and D.K.L. are shareholders of ExBiome BV., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Increasing evidence indicates calcium-binding S100 protein involvement in inflammation and tumor progression. In this prospective study, we evaluated the mRNA levels of two members of this family, S100A9 and S100A12 , in peripheral blood mononuclear cells (PBMCs) in a cohort of 121 prostate cancer patients using RT-PCR. Furthermore, monocyte count was determined by flow cytometry. By stratifying patients into different risk groups, according to TNM stage, Gleason score and PSA concentration at diagnosis, expression of S100A9 and S100A12 was found to be significantly higher in patients with metastases compared to patients without clinically detectable metastases. In line with this, we observed that the protein levels of S100A9 and S100A12 in plasma were higher in patients with advanced disease. Importantly, in patients with metastases at diagnosis, high monocyte count and high levels of S100A9 and S100A12 were significantly associated with short progression free survival (PFS) after androgen deprivation therapy (ADT). High monocyte count and S100A9 levels were also associated with short cancer-specific survival, with monocyte count providing independent prognostic information. These findings indicate that circulating levels of monocytes, as well as S100A9 and S100A12 , could be biomarkers for metastatic prostate cancer associated with particularly poor prognosis.

Blood-based liquid biopsies, including tumor-educated blood platelets (TEPs), have emerged as promising biomarker sources for non-invasive detection of cancer. Here we demonstrate that particle-swarm optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA-sequencing libraries (n = 779). This resulted in accurate TEP-based detection of early- and late-stage non-small-cell lung cancer (n = 518 late-stage validation cohort, accuracy, 88%; AUC, 0.94; 95% CI, 0.92-0.96; p < 0.001; n = 106 early-stage validation cohort, accuracy, 81%; AUC, 0.89; 95% CI, 0.83-0.95; p < 0.001), independent of age of the individuals, smoking habits, whole-blood storage time, and various inflammatory conditions. PSO enabled selection of gene panels to diagnose cancer from TEPs, suggesting that swarm intelligence may also benefit the optimization of diagnostics readout of other liquid biopsy biosources., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Tumor cells present high levels of oxidative stress. Cancer therapeutics exploiting such biochemical changes by increasing reactive oxygen species (ROS) production or decreasing intracellular ROS scavengers could provide a powerful treatment strategy., Methods: To test the effect of our compound, obtusaquinone (OBT), we used several cell viability assays on seven different glioblastoma (GBM) cell lines and primary cells and on 12 different cell lines representing various cancer types in culture as well as on subcutaneous (n = 7 mice per group) and two intracranial GBM (n = 6-8 mice per group) and breast cancer (n = 6 mice per group) tumor models in vivo. Immunoblotting, immunostaining, flow cytometry, and biochemical assays were used to investigate the OBT mechanism of action. Histopathological analysis (n = 2 mice per group) and blood chemistry (n = 2 mice per group) were used to test for any compound-related toxicity. Statistical tests were two-sided., Results: OBT induced rapid increase in intracellular ROS levels, downregulation of cellular glutathione levels and increase in its oxidized form, and activation of cellular stress pathways and DNA damage, subsequently leading to apoptosis. Oxidative stress is believed to be the main mechanism through which this compounds targets cancer cells. OBT was well tolerated in mice, slowed tumor growth, and statistically prolonged survival in GBM tumor models. The ratio of median survival in U251 intracranial model in OBT vs control was 1.367 (95% confidence interval [CI] of ratio = 1.031 to 1.367, P = .008). Tumor growth inhibition was also observed in a mouse breast cancer model (average tumor volume per mouse, OBT vs control: 36.3 vs 200.4mm(3), difference = 164.1mm(3), 95% CI =72.6 to 255.6mm(3), P = .005)., Conclusions: Given its properties and efficacy in cancer killing, our results suggest that OBT is a promising cancer therapeutic.

Nuclear factor kappaB (NF-kappaB) is a transcription factor that plays a major role in many human disorders, including immune diseases and cancer. We designed a reporter system based on NF-kappaB responsive promoter elements driving expression of the secreted Gaussia princeps luciferase (Gluc). We show that this bioluminescent reporter is a highly sensitive tool for noninvasive monitoring of the kinetics of NF-kappaB activation and inhibition over time, both in conditioned medium of cultured cells and in the blood and urine of animals. NF-kappaB activation was successfully monitored in real time in endothelial cells in response to tumor angiogenic signaling, as well as in monocytes in response to inflammation. Further, we demonstrated dual blood monitoring of both NF-kappaB activation during tumor development as correlated to tumor formation using the NF-kappaB Gluc reporter, as well as the secreted alkaline phosphatase reporter. This NF-kappaB reporter system provides a powerful tool for monitoring NF-kappaB activity in real time in vitro and in vivo.