Dhir, R. | bioRxiv Science

bioRxiv2021

Pathway centered analysis to guide clinical decision-making in precision medicine

Changes in the human proteome caused by disease before, during and after medical care is phenotype-dependent, so the proteome of each individual at any time point is a snapshot of the bodys response to disease and to disease treatment. Here, we introduce a new concept named differential Personal Pathway index (dPPi). This tool extracts and summates comprehensive disease-specific information contained within an individuals proteome as a holistic way to follow the response to disease and medical care over time. We demonstrate the principle of the dPPi algorithm on proteins found in urine from patients suffering from neoplasia of the bladder. The relevance of the dPPi results to the individual clinical cases is described. The dPPi concept can be extended to other malignant and non-malignant diseases, and to other types of biopsies, such as plasma, serum or saliva. We envision the dPPi as a tool for clinical decision-making in precision medicine.

biochemistry↗

bioRxiv2021

6mer Seed Toxicity and Platinum Resistance in Ovarian Cancer

Numerous micro(mi)RNAs (short noncoding RNAs that negatively regulate gene expression) have been linked to platinum (Pt) sensitivity and resistance in ovarian cancer (OC). miRNA activity occurs when the guide strand of the miRNA, with its seed sequence (pos. 2-7/8), is loaded into the RNA induced silencing complex (RISC) and targets complementary short seed matches in the 3 untranslated region of mRNAs. Toxic seeds, targeting genes critical for cancer cell survival, have been found in tumor suppressive miRNAs. Many si- and shRNAs can also kill cancer cells via toxic seeds, the most toxic carrying G-rich 6mer seed sequences. We now show that treatment of OC cells with Pt leads to an increase in RISC-bound miRNAs carrying toxic 6mer seeds and a decrease in miRNAs with nontoxic seeds. Pt-resistant cells did not exhibit this toxicity shift but retained sensitivity to cell death mediated by siRNAs carrying toxic 6mer seeds. Analysis of RISC-bound miRNAs in OC patients revealed that the ratio between miRNAs with toxic versus miRNAs with nontoxic seeds was predictive of treatment outcome. Application of the 6mer seed toxicity concept to cancer relevant miRNAs provides a new framework for understanding and predicting cancer therapy responses.

cancer biology↗