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Long-range alignment ordering of fibroblasts have been observed in the vicinity of cancerous tumors and can be recapitulated with in vitro experiments. However, the mechanisms driving their ordering are not understood. Here, we show that local collisiondriven nematic alignment interactions among fibroblasts are insufficient to explain observed long-range alignment. One possibility is that there exists another orientation field coevolving with the cells and reinforcing their alignment. We propose that this field reflects the mechanical cross-talk between the fibroblasts and the underlying fibrous material on which they move. We show that this long-range interaction can give rise to high nematic order and to the observed patterning of the cancer microenvironment.alignment | fibroblasts | long-range order | extracellular matrix | collagen fibers F ibroblasts are spindle-shaped cells that are highly motile and are involved in many critical biological processes, such as wound healing (1, 2). Recently, their major role in shaping the local microenvironment around a growing tumor was shown in numerous studies (3-5). As a result, fibroblasts can affect the ability of cancer cells to metastasize (6-8) and conversely, the ability of the immune system to find and attack those cells (9).An isolated fibroblast moves back and forth on coverslips for over 60 h without significant change of the direction of its major axis (10). Typically, those fibroblasts are in a spindle shape with an aspect ratio from two to five. Apart from steric constraints, fibroblasts barely interact with each other (10). Curiously, imaging of tumor microenvironments often indicates longrange ordering of fibroblasts. This order often takes the form of circumferential alignment of the cells in a region surrounding the cancer cells (11,12). The mechanisms that lead to this ordering are not well-understood.Notably, a similar ordering can be observed for underlying collagen fibers (6, 13). Collagen fibers are the main structural component in the extracellular space of various normal connective tissues and play a significant role in local cancer cell invasion and in metastasis (14). Aligned fibers perpendicular to the boundary cancer cell clusters facilitate local invasions of cancer cells, and conversely, aligned fibers parallel to the tumor boundary may restrict the migration of cancer cells. Furthermore, the circumferential collagen fiber structure has been hypothesized to be responsible for the observed separation between immune and cancer cells (13). Specifically, ex vivo assays indicate that the migration of tumor-killing CD8 + T cells is reduced where dense collagen fibers form conduit-like structures (15). Therefore, understanding the mechanism of the pattern formation of fibroblasts and collagen fibers in the cancer microenvironment is important to strike a balance between constraining cancer cell from invasion and enabling the infiltration of cancer-killing immune cells.In vivo experimental observation of this pattern formation dynamically is techn...

Short-range electron transfer (ET) in proteins is an ultrafast process on the similar time scales as local protein-solvent fluctuation, and thus the two dynamics are coupled. Here we use semiquinone flavodoxin and systematically characterized the photoinduced redox cycle with 11 mutations of different aromatic electron donors (tryptophan and tyrosine) and local residues to change redox properties. We observed the forward and backward ET dynamics in a few picoseconds, strongly following a stretched behavior resulting from a coupling between local environment relaxations and these ET processes. We further observed the hot vibrational-state formation through charge recombination and the subsequent cooling dynamics also in a few picoseconds. Combined with the ET studies in oxidized flavodoxin, these results coherently reveal the evolution of the ET dynamics from single to stretched exponential behaviors and thus elucidate critical time scales for the coupling. The observed hot vibration-state formation is robust and should be considered in all photoinduced back ET processes in flavoproteins.

A heavily pretreated patient with triple negative breast cancer distinguished by cutaneous metastases received p53MVA vaccine in combination with pembrolizumab. Her cutaneous metastases regressed and after 2 cycles of therapy, a skin biopsy showed a complete pathological response. Systemic response was confirmed with restaging CT and bone scans. Activation of p53-specific T cell responses and elevation of multiple immune response genes in peripheral blood correlated with the rapid clinical response which lasted for 6 months after the initiation of combined therapy.