The emerging new VOC B.1.1.529 (Omicron) variant has raised serious concerns due to multiple mutations, reported significant immune escape, and unprecedented rapid spreading speed. Currently, studies describing the neutralization ability of different homologous and heterologous booster vaccination against Omicron are still lacking. In this study, we explored the immunogenicity of COVID-19 breakthrough patients, BBIBP-CorV homologous booster group and BBIBP-CorV/ZF2001 heterologous booster group against SARS-CoV-2 pseudotypes corresponding to the prototype, Beta, Delta, and the emergent Omicron variant. Notably, at 14 days post two-dose inactivated vaccines, pVNT titre increased to 67.4 GMTs against prototype, 8.85 against Beta and 35.07 against Delta, while neutralization activity against Omicron was below the lower limit of quantitation in 80% of the samples. At day 14 post BBIBP-CorV homologous booster vaccination, GMTs of pVNT significantly increased to 285.6, 215.7, 250.8, 48.73 against prototype, Beta, Delta, and Omicron, while at day 14 post ZF2001 heterologous booster vaccination, GMTs of pVNT significantly increased to 1436.00, 789.6, 1501.00, 95.86, respectively. Post booster vaccination, 100% samples showed positive neutralization activity against Omicron, albeit illustrated a significant reduction (5.86- to 14.98-fold) of pVNT against Omicron compared to prototype at 14 days after the homologous or heterologous vaccine boosters. Overall, our study demonstrates that vaccine-induced immune protection might more likely be escaped by Omicron compared to prototypes and other VOCs. After two doses of inactivated whole-virion vaccines as the “priming” shot, a third heterologous protein subunit vaccine and a homologous inactivated vaccine booster could improve neutralization against Omicron.

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Estrogen (E2) signaling is conveyed by the transcription factors estrogen receptor (ER) ␣ and ␤. ERs modulate the expression of genes involved in cellular proliferation, motility, and death. The regulation of transcription by E2-ER␣ through binding to estrogen-responsive elements (EREs) in DNA constitutes the ERE-dependent signaling pathway. E2-ER␣ also modulates gene expression by interacting with transregulators bound to cognate DNA-regulatory elements, and this regulation is referred to as the ERE-independent signaling pathway. The relative importance of the ERE-independent pathway in E2-ER␣ signaling is unclear. To address this issue, we engineered an ERE-binding defective ER␣ mutant (ER␣ EBD ) by changing residues in an ␣-helix of the protein involved in DNA binding to render the receptor functional only through the ERE-independent signaling pathway. Using recombinant adenovirus-infected ER-negative MDA-MB-231 cells derived from a breast adenocarcinoma, we found that E2-ER␣ EBD modulated the expression of a subset of ER␣-responsive genes identified by microarrays and verified by quantitative PCR. However, E2-ER␣ EBD did not affect cell cycle progression, cellular growth, death, or motility in contrast to E2-ER␣. ER␣ EBD in the presence of E2 was also ineffective in inducing phenotypic alterations in ER-negative U-2OS cells derived from an osteosarcoma. E2-ER␣, on the other hand, effectively repressed growth in this cell line. Our findings suggest that genomic responses from the ERE-dependent signaling pathway are required for E2-ER␣ to induce alterations in cellular responses. 17␤-Estradiol (E2),5 as the main circulating estrogen hormone, plays critical roles in the physiology and pathophysiology of many tissues (1, 2). The effects of E2 are primarily mediated by estrogen receptor (ER) ␣ and ␤ (1, 2). ERs display functionally distinct structural features. The amino terminus of ER␣ contains a ligand-independent transactivation function. The central region is the DNA binding domain (DBD). The flexible hinge domain contains a nuclear localization signal and links the DBD domain to the multifunctional carboxyl-terminal ligand binding (LBD) domain. The LBD is involved in ligand binding, dimerization, and ligand-dependent transactivation function.Following synthesis, ER␣ dimerizes and translocates to the nucleus independent of E2 (3). Fractions of the ER␣ population also partition to the perimembrane, cytoplasm, and mitochondria (4). The binding of E2 to ER␣ leads to a major structural reorganization of the LBD that converts the inactive ER␣ to the functionally active form by generating surfaces that support protein-protein interactions (5). The integration of E2-ER␣ signaling generated from various cellular locations is thought to be critical for the regulation of responsive gene expression involved in cellular proliferation, differentiation, motility, and death (4, 6).One of the primary nuclear E2-ER␣ signaling events involves the interaction of E2-ER␣ with specific DNA sequences, known as estrogen-responsive e...

Estrogen hormone 17b-estradiol (E 2 ) is involved in the physiology and pathology of many tissues. E 2 information is conveyed by the transcription factors estrogen receptors (ER) a and b that mediate a complex array of nuclear and non-nuclear events. The interaction of ER with specific DNA sequences, estrogen-responsive elements (EREs), constitutes a critical nuclear signaling pathway. In addition, E 2 -ER regulates transcription through interactions with transfactors bound to their cognate regulatory elements on DNA, hence the ERE-independent signaling pathway. However, the relative importance of the EREindependent pathway in E 2 -ERb signaling is unclear. To address this issue, we engineered an ERE-binding defective ERb mutant (ERb EBD ) by changing critical residues in the DNA-binding domain required for ERE binding. Biochemical and functional studies revealed that ERb EBD signaled exclusively through the ERE-independent pathway. Using the adenovirus infected ER-negative cancer cell models, we found that although E 2 -ERb EBD regulated the expression of a number of genes identified by microarrays, it was ineffective in altering cellular proliferation, motility, and death in contrast to E 2 -ERb. Our results indicate that genomic responses from the ERE-independent pathway to E 2 -ERb are not sufficient to alter the cellular phenotype. These findings suggest that the ERE-dependent pathway is a required signaling route for E 2 -ERb to induce cellular responses.

Gastrointestinal diseases affect many people in the world and significantly impair life quality and burden the healthcare system. The functional parameters of the gastrointestinal tract such as motility and pH can effectively reflect the changes of gastrointestinal activity in physiological and pathological conditions. Thus, a noninvasive method for real-time and quantitative measurement of gastrointestinal functional parameters in vivo is highly desired. At present, there are many strategies widely used for the diagnosis of gastrointestinal diseases in clinic, including X-ray barium meal examination, ultrasound imaging, radionuclide examination, endoscopy, etc. However, these methods are limited in determining the gastrointestinal status and cannot provide comprehensive quantitative information. Photoacoustic imaging (PAI) is a rapid noninvasive real-time imaging technique in which multiple types of functional and quantitative information can be simultaneously obtained. Unfortunately, very few ratiometric PAI contrast agents have been reported for quantification of gastrointestinal functional parameters in vivo. In this work, a broad, pH-responsive ratiometric sensor based on polyaniline and Au triangular nanoplates was developed. Utilizing the sensor as a contrast agent, PAI served as an all-in-one technique, accurately measuring the gastrointestinal functional parameters in a single test. Notably, this sensor was examined to be ultrasensitive with pH responses as fast as 0.6 s and durability as long as 24 h, and was repeatable and reversible for longitudinal monitoring. The quantitative results demonstrated a significant disorder in motility and decrease in pH for gastric and duodenal ulcers. Collectively, the combination of PAI and this broad pH-responsive sensor might be a promising candidate for quantitative diagnosis of gastrointestinal diseases.

Introduction Pemetrexed is an S-phase targeted drug in front-line or maintenance therapy of advanced non-squamous non-small cell lung cancer (NSCLC) but methods are needed for predicting the drug response. Dexamethasone is typically administered the day before, the day of and the day after pemetrexed. As dexamethasone strongly regulates many genes including p53 through the glucocorticoid receptor (GR), we hypothesized that dexamethasone influences tumor response to pemetrexed. Methods Eight non-squamous NSCLC cell line models with varied p53 and GRα/GRβ status were used for gene expression and cell cycle analyses and for loss/gain-of-function experiments. Results In three cell lines dexamethasone profoundly, but reversibly, suppressed the fraction of S-phase cells. Dexamethasone also reversibly repressed expression of thymidylate synthase and dihydrofolate reductase which are primary targets of pemetrexed but are also quintessential S-phase enzymes as well as the S-phase dependent expression of thymidine kinase 1. Dexamethasone also decreased expression of the major pemetrexed transporters, the reduced folate carrier and the proton coupled folate transporter. Only cells expressing relatively high GRα showed these dexamethasone effects, regardless of p53 status. In cells expressing low GRα, the dexamethasone response was rescued by ectopic GRα. Further, depletion of p53 did not attenuate the dexamethasone effects. The presence of dexamethasone during pemetrexed treatment protected against pemetrexed cytotoxicity, in only the dexamethasone responsive cells. Conclusions The results predict that in non-squamous NSCLC tumors, reversible S-phase suppression by dexamethasone, possibly combined with a reduction in the drug transporters, attenuates responsiveness to pemetrexed and that GR status is a principal determinant of tumor variability of this response.

Distal metastasis of luminal breast cancer is frequent and incurable, yet the metastasis mechanisms are poorly understood. Estrogen, even at postmenopausal concentrations, suppresses invasiveness of luminal breast cancer cells through the estrogen receptor (ER). Invasive tumors overexpress the short progesterone receptor A (PR-A) isoform. Even at postmenopausal concentrations, progesterone activates PR-A, inducing invasiveness by counteracting estrogen's effects, particularly when cells are hypersensitized to progesterone by PR-A overexpression. To interrogate the role of this cross-talk in metastasis, we investigated selective cross-talk mechanisms of PR-A with ER. We developed a quantitative PCR-based lymph node infiltration assay to address the slowness of metastasis of tumor xenografts. We found that 15 microRNAs (miRNAs) are regulated by progesterone via PR-A, but not the longer PR-B isoform, with increased progesterone sensitivity when PR-A was overexpressed. Two of these miRNAs whose induction (miR-92a-3p) or repression (miR-26b-5p) by estrogen was suppressed by progesterone plus PR-A were critical for the PR-A-ER cross-talk causing a gene-regulatory pattern of invasiveness and metastasis and complete rescue of invasiveness Constitutive expression of miR-92a-3p or inhibition of miR-26b-5p profoundly suppressed metastasis. Finally, in primary breast tumors, PR-A expression was correlated negatively with miR-92a-3p expression and positively with miR-26b-5p expression. Therefore, hormonal cross-talk of PR-A with ER is probably a fundamental mechanism that enables metastasis of luminal breast cancer. Moreover, miRNA biomarkers of hyperactive PR-A may help predict metastatic potential of luminal breast tumors. Further, miR-92a-3p and miR-26b-5p may reveal target pathways for selective intervention to suppress hormone-regulated metastasis, both pre- and postmenopause.

Although photoacoustic imaging (PAI) in the second near-infrared (NIR-II) region (1.0–1.7 μm) is admired for deeper penetration and higher contrast, few organic NIR-II absorbers are available as exogenous contrast agents in vivo. A1094 belongs to the very few ∼1.1 μm absorbing croconaine dyes that have superior extinction coefficient and tend to form irregular aggregation. In this study, shape-controlled A1094@DSPE-PEG2000 micelles with a J-aggregate core with remarkable 1.2–1.3 μm absorption are fabricated as biocompatible organic agents. Excellent capabilities in photothermal conversion, photostability, and PAI are found in in vitro studies. In vivo PAI of inguinal lymph nodes and in situ glioma pre- and post-resection, all demonstrate high lymph/tumor-targeting efficiency. An ∼4.54 mm deep brain lesion is imaged at 1200 nm with minimized background and increased contrast compared to 970 nm. Overall, we achieved significant bathochromic shift of organic absorbers and expanded their PAI application to the long-wavelength end of the NIR-IIa region.