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Background: Chemotherapy plus immunotherapy has become the standard first-line treatment of advanced or metastatic esophageal squamous cell carcinoma (ESCC), but median duration of response is only 7.0-8.3 months and progression-free survival (PFS, ∼6 months) is still far from satisfactory. We aim to evaluate whether early involvement of radiotherapy might improve the treatment outcome if objective response to first-line chemo-immunotherapy was observed in locally advanced or metastatic ESCC. Methods: Patients were retrospectively collected from 3 institutions in China. Patients with histopathologically confirmed diagnoses of locally advanced or metastatic ESCC were identified, who objectively responded to first-line chemo-immunotherapy (complete or partial response, or stable disease) and also received radiotherapy of primary lesions with radiation dose of over 40 Gy, with or without radiotherapy of metastatic lesions before the first disease progression. Results: A total of 72 eligible patients were identified. With median follow-up duration of 14.6 (range, 7.1-34.8) months, median progression-free survival (PFS) and overall survival (OS) were 13.5 (95 % CI,10.4-NA) months and 31.8 (95 % CI, 23.0-NA) months, respectively. Median duration from initiation of chemo-immunotherapy to radiotherapy was 2.9 (range, 0-15.1) months. Besides lower tumor burden as a significant factor of better treatment outcome, radiation dose ≥ 50 Gy was associated with superior PFS, while OS might be mainly related to tumor response to the induction chemo-immunotherapy. A low incidence of Grade 3 or above treatment-related adverse events were observed (19 %), and no treatment-related death occurred. Conclusion: Our multi-center retrospective study showed survival benefit brought by early involvement of radiotherapy after first-line chemo-immunotherapy for patients with locally advanced or metastatic ESCC. However, further investigation is warranted in future prospective, controlled trials to assess the value of radio-immunotherapy in advanced or metastatic ESCC.

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This randomized phase II trial (NCT05978193) combines low-dose radiotherapy (LDRT) and conventionally fractionated radiotherapy (CFRT) with immunochemotherapy for metastatic esophageal squamous cell carcinoma, aiming to assess the potential enhanced effect of radiotherapy on immunotherapy. Patients are administered a PD-1 inhibitor along with paclitaxel and platinum-based chemotherapy (arm B), or combined with LDRT and CFRT (arm A). Immunotherapy is given every 3 weeks with chemotherapy for 4 cycles, followed by immunotherapy maintenance therapy for up to 24 months. In arm A, LDRT (2 Gy, 2 fractions; delivered to the primary and all metastatic tumors) precedes each immunochemotherapy cycle for 4 cycles, followed by CFRT (40-50 Gy, 20-25 fractions; delivered to the primary tumor) starting from the fifth immunotherapy cycle. The primary end point is median progression-free survival. Clinical Trial Registration: NCT05978193 (clinicaltrials.gov).

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To develop accurate and accessible prediction methods for assessing pathologic response following NICT prior to surgery, we conducted a retrospective study including 137 patients with esophageal squamous cell carcinoma (ESCC) who underwent surgery after two cycles of NICT between January 2019 and March 2022 at our center. We collected clinical parameters to evaluate the dynamic changes in the primary tumor. Univariate and multivariate analyses were performed to determine the correlations between these parameters and the pathologic response of the primary tumor. Subsequently, we constructed prediction models for pCR and MPR using multivariate logistic regression. The MPR prediction Model 2 was internally validated using bootstrapping and externally validated using an independent cohort from our center. The univariate logistic analysis revealed significant differences in clinical parameters reflecting tumor regression among patients with varying pathologic responses. The clinical models based on these assessments demonstrated excellent predictive performance, with the training cohort achieving a C-index of 0.879 for pCR and 0.912 for MPR, while the testing cohort also achieved a C-index of 0.912 for MPR. Notably, the MPR prediction Model 2, with a threshold cut-off of 0.74, exhibited 92.7% specificity and greater than 70% sensitivity, indicating a low rate of underestimating residual tumors. In conclusion, our study demonstrated the high accuracy of clinical assessment-based models in pathologic response prediction, aiding in decision-making regarding organ preservation and radiotherapy adjustments after induction immunochemotherapy.

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Active metasurfaces with dynamically switchable functionalities are highly in demands in various practical applications. In this paper, we experimentally present an active metasurface based on PIN diodes which can realize nearly perfect reflection, transmission and absorption in a single design. Such switchable functionalities are accomplished by controlling the PIN diodes integrated in both layers of the metasurface. A transmission line model is employed to further investigate the underlying mechanism of the metasurface. This proposal is confirmed by numerical simulations and experiments. As a novel metasurface with multiple switchable functionalities, our design may find some practical applications such as smart radomes.

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In eukaryotes, N6-methyladenosine (m6A) is one of the most abundant modifications on RNAs, and it plays important roles in many biological processes and diseases such as cancer. While most m6A researches focus on message RNAs and long non-coding RNAs, recent studies have reported the presence of m6A in small RNAs. Nevertheless, current knowledge about m6A prevalence in mature microRNAs (miRNA) is extremely limited and the functional significance of m6A methylation in miRNAs remains to be elucidated. Here, we demonstrated cell-specific m6A profiles of miRNAs in A549 human non-small cell lung cancer (NSCLC) cells and HEK293A cells by using miRNA m6A immunoprecipitation sequencing and constructed the consensus motif in m6A-enriched miRNAs de novo. We found that miR-21-5p, an oncogenic miRNA, showed the highest m6A enrichment in NSCLC cells. Depletion of the demethylase ALKBH5 did not change the expression level of miR-21-5p, but altered the m6A abundance of miR-21-5p, thereby changing the expression levels of its target gene. We further synthesized m6A modified miR-21-5p mimics in vitro and demonstrated that in NSCLC cells, m6A marks in mature miR-21-5p could directly affect its silencing potency towards target genes, which finally impaired its promotion to proliferation and motility. Together, our findings reveal the landscape of m6A modification in mature miRNAs, and provide the first evidence that it may contribute to the mRNA responses to cancer-related miRNAs.

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Rapid progress has been made toward small interfering RNA (siRNA)-based therapy for human disorders, but rationally optimizing siRNAs for high specificity and potent silencing remains a challenge. In this study, we explored the effect of chemical modification at the cleavage site of siRNAs. We found that modifications at positions 9 and 10 markedly reduced the silencing potency of the unmodified strand of siRNAs but were well tolerated by the modified strand. Intriguingly, addition of the 2'-methoxyethyl (MOE) group at the cleavage site improved both the specificity and silencing activity of siRNAs by facilitating the oriented RNA-induced silencing complex (RISC) loading of the modified strand. Furthermore, we combined MOE modifications at positions 9 and 10 of one strand together with 2'-O-methylation (OMe) at position 14 of the other strand and found a synergistic effect that improved the specificity of siRNAs. The surprisingly beneficial effect of the combined modification was validated using siRNA-targeting endogenous gene intercellular adhesion molecule 1 (ICAM1). We found that the combined modifications eliminated its off-target effects. In conclusion, we established effective strategies to optimize siRNAs using site-specific MOE modifications. The findings may allow the creation of superior siRNAs for therapy in terms of activity and specificity.

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Polycations are generally used to work as delivery vector to develop siRNA-based therapy for gene-related diseases. The contradiction between inevitable toxicity, internalization, and pharmacokinetics of polycations/siRNA is a critical challenge for polycations and impedes their further application. Herein, we synthesized the ECMD polycations and constructed ECMD/siRNA/HA complexes with slight negative charge to address the above mentioned issue. We found that equipping with HA could effectively shield the positive charge and dramatically improve cell viability. Moreover, the ternary complexes with slight negative charge exhibited similar cellular uptake efficiency and knockdown efficiency compared with ECMD/siRNA binary complexes because of CD44 protein-mediated endocytosis. Pharmacokinetics experiment and in vivo distribution elucidated that the ternary complexes with negative charge could help to prolong the circulation time of siRNA in blood and affect the organs distribution after i.v. injection. In addition, with time going by, the accumulation amount of siRNA loaded by the ternary complexes was much more in tumor compared with the binary complexes. Therefore, we believed that building the complexes was a feasible method to further develop polycationic vectors for siRNA delivery.

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Synergistic effects of anticancer drug and siRNA have displayed superior advantages for cancer therapy. Herein, we deeply analyzed the feasibility that whether doxorubicin (DOX) and siRNA could be co-delivered by mPEG-PCL-graft-PDMAEMA (PECD) micelles, which mediated excellent DNA/siRNA delivery in vitro and in vivo reported in our previous work. DOX-loaded NPs (PECD-D) were developed by nanoprecipitation technology and exhibited high drug loading content (DLC, 9.5%). In vitro cytotoxicity study in MDA-MB-231 cells, PECD-D treated groups had lower IC50 compared to free DOX groups (F-DOX) at different transfection time (24, 48, and 72h), which maybe attribute to its high cellular uptake and endosomal escape properties. The speculation was confirmed with the results of drug release profile in acidic media, flow cytometry analysis and confocal images. Futhermore, Cy5 labeled siRNA was introduced in PECD-D micelles (PECD-D/siRNA) to track the behavior of dual-loaded nanodrug in vitro and in vivo. Flow cytometry analysis presented that DOX and siRNA were successfully co-delivered into cells, the positive cells ratio were 94.6 and 99.5%, respectively. Confocal images showed that not only DOX and siRNA existed in cytoplasm, but DOX traversed endosome/lysosome and entered into cell nucleus. For in vivo tumor-targeting evaluation in BALB/c nude mice, both DOX and Cy5-siRNA could be detected in tumor sites after intravenous injection with PECD-D/siRNA formulation. Therefore, we believed that PECD micelles have a potential ability as DOX and siRNA co-delivery carrier for cancer therapy.

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Long non-coding HOX transcript antisense intergenic RNA (HOTAIR) plays an important role in breast cancer. The purpose of this study was to determine whether circulating HOTAIR can be used for breast cancer diagnosis. HOTAIR in serum was measured by PCR-based direct detection. Reverse transcriptase and DNase I treatment were used to distinguish the DNA and RNA forms of HOTAIR. To determine whether circulating HOTAIR is a biomarker for breast cancer, the DNA of HOTAIR from breast cancer patients and healthy controls was measured at both the discovery stage (48 individuals) and an independent validation stage (156 individuals). The diagnostic accuracy was assessed by the receiver operating characteristic curve (ROC) and the area under the curve (AUC). We showed that the major form of HOTAIR-derived fragment in serum is DNA rather than RNA in our study, the same as for MALAT-1, another well-described lincRNA. A higher circulating DNA level of HOTAIR was found in patients at the discovery stage (P = 0.0008). ROC analysis revealed that the circulating HOTAIR DNA distinguished breast cancer patients from healthy individuals (AUC = 0.799). This finding was confirmed at the validation stage. Though circulating MALAT-1 DNA was altered in the discovery stage, it showed no significant difference in the validation stage. In the entire set of 204 samples, the circulating HOTAIR DNA showed a 2.15-fold change in patients compared with healthy controls (P < 0.0001, AUC = 0.786). The optimal cutoff value for diagnosis was 0.30 with sensitivity of 80.0 % and specificity of 68.3 %. Moreover, a correlation between the DNA level of circulating HOTAIR and the progress of breast cancer was established. We have demonstrated that the circulating DNA of HOTAIR is a potential biomarker for breast cancer.

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Aggregation changes of whey protein induced by high-pressure microfluidization (HPM) treatment have been investigated in relation with their functional properties. Whey protein was treated with HPM under pressure from 40 to 160 MPa. Functional properties (solubility, foaming, and emulsifying properties) of whey protein concentrate (WPC) ultrafiltered from fluid whey were evaluated. The results showed significant modifications in the solubility (30% to 59%) and foaming properties (20% to 65%) of WPC with increasing pressure. However, emulsifying property of WPC treated at different pressures was significantly worse than untreated sample. To better understand the mechanism of the modification by HPM, the HPM-induced aggregation changes were examined using particle size distribution, scanning electron microscopy, and hydrophobicity. It was indicated that HPM induced 2 kinds of aggregation changes on WPC: deaggregation and reaggregation of WPC, which resulted in the changes of functional properties of WPC modified by HPM.

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