Cancer stem cells (CSCs) or tumor progenitor cells are involved in tumor progression and metastasis1. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs2–5 and miRNA dysregulation has been implicated in tumorigenesis6. CSCs in many tumors, including cancers of the breast7, pancreas8, head and neck9, colon10,11, small intestine12, liver13, stomach14, bladder15, and ovary16 have been identified using adhesion molecule CD44, either individually or in combination with other marker(s). Prostate cancer (PCa) stem/progenitor cells with enhanced clonogenic17 and tumor-initiating and metastatic18,19 capacities are also enriched in the CD44+ cell population, but whether miRNAs regulate the CD44+ PCa cells and PCa metastasis remains unclear. Here we show, through expression analysis, that miR-34a, a p53 target20–24, was under-expressed in CD44+ PCa cells purified from xenograft and primary tumors. Enforced expression of miR-34a in bulk PCa cells inhibited clonogenic expansion and tumor development. miR-34a re-expression in CD44+ PCa cells blocked whereas miR-34a antagomirs in CD44− PCa cells promoted tumor regeneration and metastasis. Systemically delivered miR-34a inhibited PCa metastasis and extended animal survival. Of significance, CD44 was identified and validated as a direct and functional target of miR-34a and CD44 knockdown phenocopied miR-34a over-expression in inhibiting PCa regeneration and metastasis. Our study reveals miR-34a as a critical negative regulator of CD44+ PCa cells and establishes a strong rationale for developing miR-34a as a novel therapeutic against prostate CSCs.

Tumor development has long been known to resemble abnormal embryogenesis. The embryonic stem cell (ESC) self-renewal gene NANOG is purportedly expressed by some epithelial cancer cells but a causal role in tumor development has remained unclear. Here, we provide compelling evidence that cultured cancer cells, as well as xenograft- and human primary prostate cancer cells (HPCa) express a functional variant of Nanog. NANOG mRNA in cancer cells is derived predominantly from a retrogene locus termed NANOGP8. NANOG protein is detectable in the nucleus of cancer cells and is expressed higher in patient prostate tumors than matched benign tissues. NANOGP8 mRNA and/or NANOG protein levels are enriched in putative cancer stem/progenitor cell populations. Importantly, extensive loss-of-function analysis reveals that RNAi-mediated Nanog knockdown inhibits tumor development, establishing a functional significance for Nanog expression in cancer cells. Nanog-shRNA transduced cancer cells exhibit decreased long-term clonal and clonogenic growth, reduced proliferation and, in some cases, altered differentiation. Thus, our results demonstrate that Nanog, a cell-fate regulatory molecule known to be important for ESC self-renewal, also plays a novel role in tumor development.

Cancer cell molecular mimicry of stem cells (SC) imbues neoplastic cells with enhanced proliferative and renewal capacities. In support, numerous mediators of SC self-renewal have been evinced to exhibit oncogenic potential. We have recently reported that shRNA-mediated knockdown of the embryonic stem cell (ESC) self-renewal gene NANOG significantly reduced the clonogenic and tumorigenic capabilities of various cancer cells. In this study, we sought to test the potential pro-tumorigenic functions of NANOG, particularly, in prostate cancer (PCa). Using quantitative RT-PCR, we first confirmed that PCa cells expressed NANOG mRNA primarily from the NANOGP8 locus on chromosome 15q14. We then constructed a lentiviral promoter reporter in which the -3.8 kb NANOGP8 genomic fragment was used to drive the expression of green fluorescence protein (GFP). We observed that NANOGP8-GFP+ PCa cells exhibited cancer stem cell (CSC) characteristics such as enhanced clonal growth and tumor regenerative capacity. To further investigate the functions and mechanisms of NANOG in tumorigenesis, we established tetracycline-inducible NANOG overexpressing cancer cell lines, including both prostate (Du145 and LNCaP) and breast (MCF-7) cancer cells. NANOG induction promoted drug-resistance in MCF-7 cells, tumor regeneration in Du145 cells, and, most importantly, castration-resistant tumor development in LNCaP cells. These pro-tumorigenic effects of NANOG were associated with key molecular changes, including an upregulation of molecules such as CXCR4, IGFBP5, CD133 and ALDH1. The present gain-of-function studies, coupled with our recent loss-of-function work, establish the integral role for NANOG in neoplastic processes and shed light on its mechanisms of action.

Rational design of selective CO2-to-fuels electrocatalysts requires direct knowledge of the electrode surface structure during turnover. Metallic Cu is the most versatile CO2-to-fuels catalyst, capable of generating a wide array of value-added products, including methane, ethylene, and ethanol. All of these products are postulated to form via a common surface-bound CO intermediate. Therefore, the kinetics and thermodynamics of CO adsorption to Cu play a central role in determining fuel-formation selectivity and efficiency, highlighting the need for direct observation of CO surface binding equilibria under catalytic conditions. Here, we synthesize nanostructured Cu films adhered to IR-transparent Si prisms, and we find that these Cu surfaces enhance IR absorption of bound molecules. Using these films as electrodes, we examine Cu-catalyzed CO2 reduction in situ via IR spectroelectrochemistry. We observe that Cu surfaces bind electrogenerated CO, derived from CO2, beginning at −0.60 V vs RHE with increasing surface population at more negative potentials. Adsorbed CO is in dynamic equilibrium with dissolved 13CO and exchanges rapidly under catalytic conditions. The CO adsorption profiles are pH independent, but adsorbed CO species undergo a reversible transformation on the surface in modestly alkaline electrolytes. These studies establish the potential, concentration, and pH dependencies of the CO surface population on Cu, which serve to maintain a pool of this vital intermediate primed for further reduction to higher order fuel products.

Mimicking soft tissue mechanical properties and the high conductivity required for electrical transmission in the native spinal cord is critical in nerve tissue regeneration scaffold designs. However, fabricating scaffolds of high conductivity, tissue-like mechanical properties, and excellent biocompatibility simultaneously remains a great challenge. Here, a soft, highly conductive, biocompatible conducting polymer hydrogel (CPH) based on a plant-derived polyphenol, tannic acid (TA), cross-linking and doping conducting polypyrrole (PPy) chains is developed to explore its therapeutic efficacy after a spinal cord injury (SCI). The developed hydrogels exhibit an excellent electronic conductivity (0.05–0.18 S/cm) and appropriate mechanical properties (0.3–2.2 kPa), which can be achieved by controlling TA concentration. In vitro, a CPH with a higher conductivity accelerated the differentiation of neural stem cells (NSCs) into neurons while suppressing the development of astrocytes. In vivo, with relatively high conductivity, the CPH can activate endogenous NSC neurogenesis in the lesion area, resulting in significant recovery of locomotor function. Overall, our findings evidence that the CPHs without being combined with any other therapeutic agents have stimulated tissue repair following an SCI and thus have important implications for future biomaterial designs for SCI therapy.

COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T-cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56 dim CD16 hi NK cells linked positively to circulating IL-15. CD8 + T cell activation was apparent without signs of exhaustion. While cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery-fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.

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