Shifting the paradigm: engaging multicellular networks for cancer therapy.

Most anti-cancer modalities are designed to directly kill cancer cells deploying mechanisms of action (MOAs) centered on the presence of a precise target on cancer cells. The efficacy of these approaches is limited because the rapidly evolving genetics of neoplasia swiftly circumvents the MOA generating therapy-resistant cancer cell clones. Other modalities engage endogenous anti-cancer mechanisms by activating the multi-cellular network (MCN) surrounding neoplastic cells in the tumor microenvironment (TME). These modalities hold a better chance of success because they activate numerous types of immune effector cells that deploy distinct cytotoxic MOAs. This in turn decreases the chance of developing treatment-resistance. Engagement of the MCN can be attained through activation of immune effector cells that in turn kill cancer cells or when direct cancer killing is complemented by the production of proinflammatory factors that secondarily recruit and activate immune effector cells. For instance, adoptive cell therapy (ACT) supplements cancer cell killing with the release of homeostatic and pro-inflammatory cytokines by the immune cells and damage associated molecular patterns (DAMPs) by dying cancer cells. The latter phenomenon, referred to as immunogenic cell death (ICD), results in an exponential escalation of anti-cancer MOAs at the tumor site. Other approaches can also induce exponential cancer killing by engaging the MCN of the TME through the release of DAMPs and additional pro-inflammatory factors by dying cancer cells. In this commentary, we will review the basic principles that support emerging paradigms likely to significantly improve the efficacy of anti-cancer therapy.

Sprint Start Kinetics of Amputee and Non-Amputee Sprinters.

The purpose of this study was to explore the relationship between the forces applied to the starting blocks and the start performances (SPs) of amputee sprinters (ASs) and non-amputee sprinters (NASs). SPs of 154 male and female NASs (100-m personal records [PRs], 9.58-14.00 s) and 7 male ASs (3 unilateral above knee, 3 unilateral below knee, 1 bilateral below knee; 100 m PRs, 11.70-12.70 s) with running specific prostheses (RSPs) were analysed during full-effort sprint starts using instrumented starting blocks that measured the applied forces in 3D. Using the NAS dataset and a combination of factor analysis and multiple regression techniques, we explored the relationship between force characteristics and SP (quantified by normalized average horizontal block power). Start kinetics were subsequently compared between ASs and NASs who were matched based on their absolute 100 m PR and their 100 m PR relative to the world record in their starting class. In NASs, 86% of the variance in SP was shared with five latent factors on which measured parameters related to force application to the rear and front blocks and the respective push-off directions in the sagittal plane of motion were loaded. Mediolateral force application had little influence on SP. The SP of ASs was significantly reduced compared to that of NASs matched on the basis of relative 100-m PR (-33.8%; d = 2.11, p < 0.001), while a non-significant performance reduction was observed when absolute 100-m PRs were used (-17.7%; d = 0.79, p = 0.09). These results are at least partially explained by the fact that force application to the rear block was clearly impaired in the affected legs of ASs.

Genome-wide association study of prostate cancer-specific survival.

BACKGROUND: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical. METHODS: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR). RESULTS: We observed no significant association between genetic variants and prostate cancer survival. CONCLUSIONS: Common genetic variants with large impact on prostate cancer survival were not observed in this study. IMPACT: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes.