Metastatic Conditioning of Myeloid Cells at a Subcutaneous Synthetic Niche Reflects Disease Progression and Predicts Therapeutic Outcomes.

Monitoring metastatic events in distal tissues is challenged by their sporadic occurrence in obscure and inaccessible locations within these vital organs. A synthetic biomaterial scaffold can function as a synthetic metastatic niche to reveal the nature of these distal sites. These implanted scaffolds promote tissue ingrowth, which upon cancer initiation is transformed into a metastatic niche that captures aggressive circulating tumor cells. We hypothesized that immune cell phenotypes at synthetic niches reflect the immunosuppressive conditioning within a host that contributes to metastatic cell recruitment and can identify disease progression and response to therapy. We analyzed the expression of 632 immune-centric genes in tissue biopsied from implants at weekly intervals following inoculation. Specific immune populations within implants were then analyzed by single-cell RNA-seq. Dynamic gene expression profiles in innate cells, such as myeloid-derived suppressor cells, macrophages, and dendritic cells, suggest the development of an immunosuppressive microenvironment. These dynamics in immune phenotypes at implants was analogous to that in the diseased lung and had distinct dynamics compared with blood leukocytes. Following a therapeutic excision of the primary tumor, longitudinal tracking of immune phenotypes at the implant in individual mice showed an initial response to therapy, which over time differentiated recurrence versus survival. Collectively, the microenvironment at the synthetic niche acts as a sentinel by reflecting both progression and regression of disease. SIGNIFICANCE: Immune dynamics at biomaterial implants, functioning as a synthetic metastatic niche, provides unique information that correlates with disease progression. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/3/602/F1.large.jpg.See related commentary by Wolf and Elisseeff, p. 377.

Distorting temporal fine structure by phase shifting and its effects on speech intelligibility and neural phase locking.

Envelope (E) and temporal fine structure (TFS) are important features of acoustic signals and their corresponding perceptual function has been investigated with various listening tasks. To further understand the underlying neural processing of TFS, experiments in humans and animals were conducted to demonstrate the effects of modifying the TFS in natural speech sentences on both speech recognition and neural coding. The TFS of natural speech sentences was modified by distorting the phase and maintaining the magnitude. Speech intelligibility was then tested for normal-hearing listeners using the intact and reconstructed sentences presented in quiet and against background noise. Sentences with modified TFS were then used to evoke neural activity in auditory neurons of the inferior colliculus in guinea pigs. Our study demonstrated that speech intelligibility in humans relied on the periodic cues of speech TFS in both quiet and noisy listening conditions. Furthermore, recordings of neural activity from the guinea pig inferior colliculus have shown that individual auditory neurons exhibit phase locking patterns to the periodic cues of speech TFS that disappear when reconstructed sounds do not show periodic patterns anymore. Thus, the periodic cues of TFS are essential for speech intelligibility and are encoded in auditory neurons by phase locking.