Heterogeneous cancer-associated fibroblast population potentiates neuroendocrine differentiation and castrate resistance in a CD105-dependent manner.

Heterogeneous prostatic carcinoma-associated fibroblasts (CAF) contribute to tumor progression and resistance to androgen signaling deprivation therapy (ADT). CAF subjected to extended passaging, compared to low passage CAF, were found to lose tumor expansion potential and heterogeneity. Cell surface endoglin (CD105), known to be expressed on proliferative endothelia and mesenchymal stem cells, was diminished in high passage CAF. RNA-sequencing revealed SFRP1 to be distinctly expressed by tumor-inductive CAF, which was further demonstrated to occur in a CD105-dependent manner. Moreover, ADT resulted in further expansion of the CD105+ fibroblastic population and downstream SFRP1 in 3-dimensional cultures and patient-derived xenograft tissues. In patients, CD105+ fibroblasts were found to circumscribe epithelia with neuroendocrine differentiation. CAF-derived SFRP1, driven by CD105 signaling, was necessary and sufficient to induce prostate cancer neuroendocrine differentiation in a paracrine manner. A partially humanized CD105 neutralizing antibody, TRC105, inhibited fibroblastic SFRP1 expression and epithelial neuroendocrine differentiation. In a novel synthetic lethality paradigm, we found that simultaneously targeting the epithelia and its microenvironment with ADT and TRC105, respectively, reduced castrate-resistant tumor progression, in a model where either ADT or TRC105 alone had little effect

The competitiveness of U.S. manufactured goods: recent changes and prospects

Competition ; Manufactures ; Prices ; International trade

Serpentinization and Synthesis: Searching for Abiotic and Biotic Non-Volatile Organic Molecules in the Subsurface of the Atlantis Massif

High concentrations of hydrogen created during serpentinization can promote the formation of abiotic organic carbon molecules such as methane, formate, and short chain hydrocarbons and, in laboratory experiments, larger molecules containing up to 32 carbon atoms. Subsurface archaeal and bacterial communities can use these reduced compounds for metabolic energy. International Ocean Discovery Project Expedition 357 drilled 17 boreholes into the Atlantis Massif with the goals of investigating carbon cycling and the presence of life in a zone of active serpentinization. The expedition recovered multiple lithologies including gabbros, basalts, carbonate sands, and serpentinites. A subset of contrasting lithologies were analyzed for n-alkane and fatty acid content to determine if non-volatile organic molecules are produced abiotically in serpentinizing environments and to identify ‘hot spots’ of microbial life in the subsurface. Given the high potential for contamination during drilling, a suite of materials used in sample collection and processing were also analyzed to characterize their signatures. Biologically-derived lipid biomarkers could not be identified in any of the samples, indicating any biological communities present in the subsurface of the Massif were in abundances below our ability to detect them. An n-alkane series ranging from C18 to C30 with δ13C isotopic values of -30.9‰ to -28.8‰ were present in various lithologically diverse samples. The distribution of these compounds was similar to those observed in previous grab samples from the same region, and to compounds formed abiotically in laboratory experiments. For the current set of samples, multiple lines of evidence point to the rock saw used to remove core exteriors during sample processing as the source of the n-alkanes. This result highlights the importance of careful prevention and characterization of contamination to allow for more accurate interpretations of complex and dynamic subsurface processes. Many of the other sample-handling procedures designed to reduce surface contamination were determined to be effective and should be implemented in future projects. The definitive detection and identification of abiotic and biological lipids in the subsurface of an actively serpentinizing system would be a significant step towards understanding the evolution of pre-biotic chemistry and life in extreme environments, but future reports of these compounds must occur in conjunction with thorough contamination assessments

Twin-Rainbow Metrology. I. Measurement of the Thickness of a Thin Liquid Film Draining Under Gravity

We describe twin-rainbow metrology, a new optical technique used to measure the thickness of thin films in a cylindrical geometry. We also present an application of the technique: measurement of the thickness of a Newtonian fluid draining under gravity. We compare these measurements with fluid mechanics models. (C) 2003 Optical Society of America

Cancer epithelia-derived mitochondrial DNA is a targetable initiator of a paracrine signaling loop that confers taxane resistance.

Stromal-epithelial interactions dictate cancer progression and therapeutic response. Prostate cancer (PCa) cells were identified to secrete greater concentration of mitochondrial DNA (mtDNA) compared to noncancer epithelia. Based on the recognized coevolution of cancer-associated fibroblasts (CAF) with tumor progression, we tested the role of cancer-derived mtDNA in a mechanism of paracrine signaling. We found that prostatic CAF expressed DEC205, which was not expressed by normal tissue-associated fibroblasts. DEC205 is a transmembrane protein that bound mtDNA and contributed to pattern recognition by Toll-like receptor 9 (TLR9). Complement C3 was the dominant gene targeted by TLR9-induced NF-κB signaling in CAF. The subsequent maturation complement C3 maturation to anaphylatoxin C3a was dependent on PCa epithelial inhibition of catalase in CAF. In a syngeneic tissue recombination model of PCa and associated fibroblast, the antagonism of the C3a receptor and the fibroblastic knockout of TLR9 similarly resulted in immune suppression with a significant reduction in tumor progression, compared to saline-treated tumors associated with wild-type prostatic fibroblasts. Interestingly, docetaxel, a common therapy for advanced PCa, further promoted mtDNA secretion in cultured epithelia, mice, and PCa patients. The antiapoptotic signaling downstream of anaphylatoxin C3a signaling in tumor cells contributed to docetaxel resistance. The inhibition of C3a receptor sensitized PCa epithelia to docetaxel in a synergistic manner. Tumor models of human PCa epithelia with CAF expanded similarly in mice in the presence or absence of docetaxel. The combination therapy of docetaxel and C3 receptor antagonist disrupted the mtDNA/C3a paracrine loop and restored docetaxel sensitivity

Biomolecules as Model Indicators of In Vitro and In Vivo Cold Plasma Safety

The potential applications for cold plasma in medicine are extensive, from microbial inactivation and induction of apoptosis in cancer cells to stimulating wound healing and enhancing the blood coagulation cascade. The safe bio-medical application of cold plasma and subsequent effect on complex biological pathways requires precision and a distinct understanding of how physiological redox chemistry is manipulated. Chemical modification of biomolecules such as carbohydrates, proteins, and lipids treated with cold plasma have been characterized, however, the context of how alterations of these molecules affect cell behavior or in vivo functionality has not been determined. Thus, this study examines the cytotoxic and mutagenic effects of plasmatreated molecules in vitro using CHO-K1 cells and in vivo in Galleria mellonella larvae. Specifically, albumin, glucose, cholesterol, and arachidonic acid were chosen as representative biomolecules, with established involvement in diverse bioprocesses including; cellular respiration, intracellular transport, cell signaling or membrane structure. Long- and short-term effects depended strongly on the molecule type and the treatment milieu indicating the impact of chemical and physical modifications on downstream biological pathways. Importantly, absence of short-term toxicity did not always correlate with absence of longer-term effects, indicating the need to comprehensively assess ongoing effects for diverse biological applications