Epistemological risk aspects

The paper considers risk in the context of the main characteristics of non-classical epistemology. It states that non-classical epistemology is characterized by transformation, according to which the major priority of cognitive activity shifts the focus from the present to the past. In this situation a subject is keen not on what he or she has learnt but on what can be learnt. Truth being a crucial criterion of scientific knowledge is becoming of less priority, while risk is becoming more and more significant and acts as one of the major epistemology measurements. Risk is gaining the status of epistemological phenomenon, which shows a growing degree of uncertainty as a cognitive process background and the necessity for a subject to learn the world (make decisions) under the conditions of uncertainty degree strengthening. The author states that risk is a comprehensive notion and it obtains a base value for all other aspects of its application, specifically, in the role of epistemological phenomenon

Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma

The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-kappaB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of 500 mice and 1,000 patients revealed a common MAPK-MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8+ T cells with reduced immunosuppressive regulatory T (Treg) cells, while late MYC acquisition in slow progressors was associated with lower CD8+ T cell infiltration and more abundant Treg cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8+ T cells versus Treg cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8+ T/Treg cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8+ T cell cytotoxicity or depleting Treg cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials