Prostate-specific markers to identify rare prostate cancer cells in liquid biopsies

WOS: 000455051200006PubMed ID: 30479377Despite improvements in early detection and advances in treatment, patients with prostate cancer continue to die from their disease. Minimal residual disease after primary definitive treatment can lead to relapse and distant metastases, and increasing evidence suggests that circulating tumour cells (CTCs) and bone marrow-derived disseminated tumour cells (BM-DTCs) can offer clinically relevant biological insights into prostate cancer dissemination and metastasis. Using epithelial markers to accurately detect CTCs and BM-DTCs is associated with difficulties, and prostate-specific markers are needed for the detection of these cells using rare cell assays. Putative prostate-specific markers have been identified, and an optimized strategy for staining rare cancer cells from liquid biopsies using these markers is required. The ideal prostate-specific marker will be expressed on every CTC or BM-DTC throughout disease progression (giving high sensitivity) and will not be expressed on non-prostate-cancer cells in the sample (giving high specificity). Some markers might not be specific enough to the prostate to be used as individual markers of prostate cancer cells, whereas others could be truly prostate-specific and would make ideal markers for use in rare cell assays. The goal of future studies is to use sensitive and specific prostate markers to consistently and reliably identify rare cancer cells.NCI [F32CA206394, U54CA143803, CA163124, CA093900, CA143055]; Prostate Cancer Foundation; Patrick C. Walsh Fund; Cure for Cancer FoundationThis work is supported by NCI grants U54CA143803, CA163124, CA093900, and CA143055 as well as the Prostate Cancer Foundation, the Patrick C. Walsh Fund and a gift from the Stutt family. E.E.v.d.T. is supported by the Cure for Cancer Foundation. K.C.V. is supported by NCI grant F32CA206394

A novel Bcr-Abl-mTOR-eIF4A axis regulates IRES-mediated translation of LEF-1.

Internal ribosome entry sites (IRESs) in cellular mRNAs direct expression of growth-promoting factors through an alternative translation mechanism that has yet to be fully defined. Lymphoid enhancer factor-1 (LEF-1), a Wnt-mediating transcription factor important for cell survival and metastasis in cancer, is produced via IRES-directed translation, and its mRNA is frequently upregulated in malignancies, including chronic myeloid leukaemia (CML). In this study, we determined that LEF1 expression is regulated by Bcr-Abl, the oncogenic protein that drives haematopoietic cell transformation to CML. We have previously shown that the LEF1 5' untranslated region recruits a complex of proteins to its IRES, including the translation initiation factor eIF4A. In this report, we use two small molecule inhibitors, PP242 (dual mTOR (mammalian target of rapamycin) kinase inhibitor) and hippuristanol (eIF4A inhibitor), to define IRES regulation via a Bcr-Abl-mTOR-eIF4A axis in CML cell lines and primary patient leukaemias. We found that LEF1 and other IRESs are uniquely sensitive to the activities of Bcr-Abl/mTOR. Most notably, we discovered that eIF4A, an RNA helicase, elicits potent non-canonical effects on the LEF1 IRES. Hippuristanol inhibition of eIF4A stalls translation of IRES mRNA and triggers dissociation from polyribosomes. We propose that a combination drug strategy which targets mTOR and IRES-driven translation disrupts key factors that contribute to growth and proliferation in CML

The 3-phase-model of dyadic adaptation to dementia: why it might sometimes be better to be worse

In the next years and decades, the number of old spousal dyads having to deal with the onset and progression of dementia in one partner will increase significantly. Existing research indicates that caregiving for an ill spouse is related to decreased caregiver well-being and high levels of caregiver stress. In this theoretical paper, we argue that three aspects deserve additional theoretical and empirical attention: (a) Some spousal caregivers seem to exhibit stable pattern of individual well-being, (b) dyads may be able to adapt their ways of supporting each other to maintain a maximum of dyadic autonomy, and (c) the progression of the dementia increasingly compromising the individual autonomy is likely to require different behaviors and skills of the dyad to achieve high levels of dyadic wellbeing. We suggest a 3-phase-model of dyadic adaptation to dementia-related losses of patients’ individual autonomy and discuss adaptive processes in three phases of dementia that may allow stable levels of well-being in caregivers over time. Thereby, our model can integrate existing findings and theories and allows deriving areas of future research

Evolution of indirect reciprocity

Natural selection is conventionally assumed to favour the strong and selfish who maximize their own resources at the expense of others. But many biological systems, and especially human societies, are organized around altruistic, cooperative interactions. How can natural selection promote unselfish behaviour? Various mechanisms have been proposed, and a rich analysis of indirect reciprocity has recently emerged: I help you and somebody else helps me. The evolution of cooperation by indirect reciprocity leads to reputation building, morality judgement and complex social interactions with ever-increasing cognitive demands