Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a critical role in cancer progression, metastasis, stem cell maintenance, and therapy resistance. Here, we describe a rationally designed first-in-class inhibitor of LIFR, EC359, which directly interacts with LIFR to effectively block LIF/LIFR interactions. EC359 treatment exhibits antiproliferative effects, reduces invasiveness and stemness, and promotes apoptosis in triple-negative breast cancer (TNBC) cell lines. The activity of EC359 is dependent on LIF and LIFR expression, and treatment with EC359 attenuated the activation of LIF/LIFR-driven pathways, including STAT3, mTOR, and AKT. Concomitantly, EC359 was also effective in blocking signaling by other LIFR ligands (CTF1, CNTF, and OSM) that interact at LIF/LIFR interface. EC359 significantly reduced tumor progression in TNBC xenografts and patient-derived xenografts (PDX), and reduced proliferation in patientderived primary TNBC explants. EC359 exhibits distinct pharmacologic advantages, including oral bioavailability, and in vivo stability. Collectively, these data support EC359 as a novel targeted therapeutic that inhibits LIFR oncogenic signaling. See related commentary by Shi et al., p.

Glioblastoma (GBM) is the most commonly diagnosed brain tumor that exhibit high mortality rate and chemotherapy resistance is a major clinical problem. Recent studies suggest that estrogen receptor beta (ERβ), may function as a tumor suppressor in GBM. However, the mechanism(s) by which ERβ contributes to GBM suppression and chemotherapy response remains unknown. We examined the role of ERβ in the DNA damage response of GBM cells, and tested whether ERβ sensitizes GBM cells to chemotherapy. Cell viability and survival assays using multiple epitope tagged ERβ expressing established and primary GBM cells demonstrated that ERβ sensitizes GBM cells to DNA damaging agents including temozolomide (TMZ). RNA-seq studies using ERβ overexpression models revealed downregulation of number of genes involved in DNA recombination and repair, ATM signaling and cell cycle check point control. Gene set enrichment analysis (GSEA) suggested that ERβ–modulated genes were correlated negatively with homologous recombination, mismatch repair and G2M checkpoint genes. Further, RT-qPCR analysis revealed that chemotherapy induced activation of cell cycle arrest and apoptosis genes were attenuated in ERβKO cells. Additionally, ERβ overexpressing cells had a higher number of γH2AX foci following TMZ treatment. Mechanistic studies showed that ERβ plays an important role in homologous recombination (HR) mediated repair and ERβ reduced expression and activation of ATM upon DNA damage. More importantly, GBM cells expressing ERβ had increased survival when compared to control GBM cells in orthotopic GBM models. ERβ overexpression further enhanced the survival of mice to TMZ therapy in both TMZ sensitive and TMZ resistant GBM models. Additionally, IHC analysis revealed that ERβ tumors had increased expression of γH2AX and cleaved caspase-3. Using ERβ-overexpression and ERβ-KO GBM model cells, we have provided the evidence that ERβ is required for optimal chemotherapy induced DNA damage response and apoptosis in GBM cells.

We investigate theoretically the transport properties of surface plasmon in a metal nanowire with linear and nonlinear dispersion relations coupled to a quantum dot with three levels in cascaded configuration by full quantum-mechanical approach. The transmission and reflection amplitudes are obtained. The reflection spectrum shows two peaks for the surface plasmon with linear dispersion relation while it can exhibit four peaks when the plasmon has quadratic dispersion relation. The calculations reveal that one can control the plasmon transport properties by adjusting Rabi frequency and circular frequency of a classic optical field.

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We investigate theoretically entanglement generation between two distant quantum dot molecules (QDMs) mediated by quantum bus of metal nanoring with surface plasmon polaritons. We show that the two QDMs can be in an entangled state by adjusting the external gate voltage and the coupling strength between the QDMs and the surface plasmon polaritons. The quantum state transfer between the two QDMs is also discussed. Our scheme may find applications in on-chip quantum networks and integrated optoelectronics devices.

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The pathogenesis of COVID-19 is still elusive, which impedes disease progression prediction, differential diagnosis, and targeted therapy. Plasma cell-free RNAs (cfRNAs) carry unique information from human tissue and thus could point to resourceful solutions for pathogenesis and host-pathogen interactions. Here, we performed a comparative analysis of cfRNA profiles between COVID-19 patients and healthy donors using serial plasma. Analyses of the cfRNA landscape, potential gene regulatory mechanisms, dynamic changes in tRNA pools upon infection, and microbial communities were performed. A total of 380 cfRNA molecules were up-regulated in all COVID-19 patients, of which seven could serve as potential biomarkers (AUC > 0.85) with great sensitivity and specificity. Antiviral (NFKB1A, IFITM3, and IFI27) and neutrophil activation (S100A8, CD68, and CD63)–related genes exhibited decreased expression levels during treatment in COVID-19 patients, which is in accordance with the dynamically enhanced inflammatory response in COVID-19 patients. Noncoding RNAs, including some microRNAs (let 7 family) and long noncoding RNAs (GJA9-MYCBP) targeting interleukin (IL6/IL6R), were differentially expressed between COVID-19 patients and healthy donors, which accounts for the potential core mechanism of cytokine storm syndromes; the tRNA pools change significantly between the COVID-19 and healthy group, leading to the accumulation of SARS-CoV-2 biased codons, which facilitate SARS-CoV-2 replication. Finally, several pneumonia-related microorganisms were detected in the plasma of COVID-19 patients, raising the possibility of simultaneously monitoring immune response regulation and microbial communities using cfRNA analysis. This study fills the knowledge gap in the plasma cfRNA landscape of COVID-19 patients and offers insight into the potential mechanisms of cfRNAs to explain COVID-19 pathogenesis.