Ti3C2Tx MXene- and Sulfuric Acid-Treated Double-Network Hydrogel with Ultralow Conductive Filler Content for Stretchable Electromagnetic Interference Shielding.

Hydrogels are emerging as stretchable electromagnetic interference (EMI) shielding materials because of their tissue-like mechanical properties and water-rich porous cellular structures. However, achieving high-performance hydrogel shields remains a challenge because enhancing conductivity often results in a compromise in deformation adoptability. This work proposes a treatment strategy involving sulfuric acid/titanium carbide MXene, which can simultaneously enhance the conductivity and stretchability of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS)/poly(vinyl alcohol) (PVA) double-network hydrogels. Multiple spectroscopic characterizations reveal that sulfuric acid promotes the linear conformation transition of the PEDOT molecular chain, while MXene increases charge delocalization and hydrogen bond cross-linking sites. The hydrogels, synthesized with a combined content of 0.6 wt % of MXene and PEDOT:PSS, exhibit an average X-band EMI SE of 41 dB. This performance is sustained at 94.5%, even following stretching and release at a strain of 200%. Interestingly, the EMI SE is found to linearly increase, reaching a value of 99 dB as the frequency is increased to 26.5 GHz. This increase is attributed to the enhanced water molecular polarization process, as supported by theoretical calculations of the impedance and attenuation constant. This work introduces a post-treatment technique that optimizes double-network hydrogels, providing deep insights into their EMI shielding mechanism and enabling high-performance EMI shielding with an ultralow conductive filler content.

High-performance transient SBS-based microwave measurement using high-chirp-rate modulation and advanced algorithms.

The transient stimulated Brillouin scattering (SBS) effect, enabled by optical chirp chain (OCC) technology, has already been proposed and demonstrated for microwave frequency identification with high temporal resolution. Through increasing the OCC chirp rate, the instantaneous bandwidth can be effectively extended without loss of the temporal resolution. However, the higher chirp rate results in more asymmetric transient Brillouin spectra, which worsens the demodulation accuracy when using the traditional fitting method. In this Letter, advanced algorithms, including image processing and artificial neural network, are employed to improve the measurement accuracy and demodulation efficiency. A microwave frequency measurement scheme is implemented with 4 GHz instantaneous bandwidth and 100 ns temporal resolution. Through the proposed algorithms, the demodulation accuracy of transient Brillouin spectra under 50 MHz/ns high chirp rate is improved from 9.85 MHz to 1.17 MHz. Moreover, owing to the matrix computations of the proposed algorithm, the time consumption is reduced by two orders of magnitude compared with the fitting method. The proposed method allows a high-performance OCC transient SBS-based microwave measurement, which provides new possibilities to realize real-time microwave tracking for diverse application fields.

Development of a Universal Multi-Epitope Vaccine Candidate against Streptococcus suis Infections Using Immunoinformatics Approaches.

Streptococcus suis is a significant zoonotic pathogen that is a great threat not only to the swine industry but also to human health, causing arthritis, meningitis, and even streptococcal toxic shock-like syndrome. Owing to its many serotypes and high geographic variability, an efficacious cross-protective S. suis vaccine is not readily available. Therefore, this study aimed to design a universal multi-epitope vaccine (MVHP6) that involved three highly immunogenic proteins of S. suis, namely, the surface antigen containing a glycosaminoglycan binding domain (HP0197), endopeptidase (PepO), and 6-phosphogluconate dehydrogenase (6PGD). Forecasted T-cell and B-cell epitopes with high antigenic properties and a suitable adjuvant were linked to construct a multi-epitope vaccine. In silico analysis showed that the selected epitopes were conserved in highly susceptible serotypes for humans. Thereafter, we evaluated the different parameters of MVHP6 and showed that MVHP6 was highly antigenic, non-toxic, and non-allergenic. To verify whether the vaccine could display appropriate epitopes and maintain high stability, the MVHP6 tertiary structure was modeled, refined, and validated. Molecular docking studies revealed a strong binding interaction between the vaccine and the toll-like receptor (TLR4), whereas molecular dynamics simulations demonstrated the vaccine's compatibility, binding stability, and structural compactness. Moreover, the in silico analysis showed that MVHP6 could evoke strong immune responses and enable worldwide population coverage. Moreover, MVHP6 was cloned into the pET28a (+) vector in silico to ensure the credibility, validation, and proper expression of the vaccine construct. The findings suggested that the proposed multi-epitope vaccine can provide cross-protection against S. suis infections.

Dose-adjusted EPOCH-R vs. R-CHOP in frontline management of Waldeyer's ring diffuse large B-cell lymphoma: a retrospective study from a single institution.

BACKGROUND: To compare the efficacy and safety of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in Waldeyer's ring diffuse large B-cell lymphoma (WR-DLBCL) at a single institution. METHODS: This retrospective study included 115 newly diagnosed patients with WR-DLBCL, of whom 68 patients received R-CHOP, and 47 patients received DA-EPOCH-R as their first-line treatment. The baseline features of the two groups were well balanced using a 1:1 propensity score matching method, and a total of 84 cases were obtained, including respective 42 cases in the R-CHOP and DA-EPOCH-R groups, for further survival and prognosis analysis. The primary objectives included progression-free survival (PFS) and overall survival (OS). RESULTS: During a median follow-up of 45 months, there were nine (21.4%) deaths in the R-CHOP group and two (4.8%) in the DA-EPOCH-R group. Kaplan-Meier analysis showed statistically significant improvements in PFS and OS in patients with DA-EPOCH-R compared with those treated with R-CHOP (log-rank test, P  = 0.025 and P  = 0.035, respectively). The 2-year PFS and OS rates in the DA-EPOCH-R group were 90.1% (95% confidence interval [CI]: 81.4-99.8%) and 95.2% (95% CI: 89.0-100.0%), respectively, and 80.5% (95% CI: 69.3-93.6%) and 90.5% (95% CI: 52.8-99.8%) in the R-CHOP group. Patients without B symptoms and elevated lactate dehydrogenase levels had a higher PFS in the DA-EPOCH-R group, with P values of 0.038 (hazard ratio [HR]: 0.11; 95% CI: 0.01-0.88) and 0.042 (HR: 0.19; 95% CI: 0.04-0.94), respectively. There were no statistically significant differences in clinical responses and treatment-related toxicities between the two groups. CONCLUSION: Compared with patients received R-CHOP, those treated by DA-EPOCH-R had superior PFS, OS, and controlled toxicity in patients with WR-DLBCL.

High expression of AP2M1 correlates with worse prognosis by regulating immune microenvironment and drug resistance to R-CHOP in diffuse large B cell lymphoma.

BACKGROUND: First-line treatment with R-CHOP has cured 50%-60% patients of diffuse large B cell lymphoma (DLBCL), and more than one-third patients will eventually progressed to relapsed/refractory disease with dismal outcomes. Adaptor Related Protein Complex 2 Subunit Mu 1 (AP2M1) is required for the activity of a vacuolar ATPase and may also play an important role in regulating the intracellular trafficking and function of CTLA-4 protein. Herein, using both public databases and our own tumor samples, we aimed to demonstrate the prognostic role of AP2M1 and the potential tumor-promoting mechanisms in DLBCL. METHOD: Using public datasets of DLBCL from both GEO and TCGA databases, we analyzed the role of AP2M1 in mediating chemoresistance to R-CHOP and its correlation with various clinical parameters and prognosis. By using various R packages, we evaluated the role of AP2M1 on regulating tumor immune microenvironment. Moreover, tumor samples of DLBCL from Beijing TongRen Hospital were used to validate our findings by immunohistochemistry staining. RESULT: Expression of AP2M1 was significantly increased in DLBCL, which was correlated with poor prognosis and a variety of clinical indicators. On the basis of enrichment analysis, it was found that AP2M1 may be related to intracellular receptor signaling pathway. Through immune analysis and drug prediction, we found that the expression of AP2M1 affected the immune environment and drug response of DLBCL, which further revealed the important role of AP2M1 in DLBCL. By analyzing 61 patients treated uniformly with R-CHOP regimen in our center, we validated the above findings that high expression of AP2M1 correlated with inferior survival outcomes and affected sensitivity to R-CHOP treatment. CONCLUSION: Expression of AP2M1 may affect the prognosis of DLBCL patients probably by affecting the immune environment and the responses to many drugs in treating DLBCL, indicating AP2M1 as a potential therapy target in DLBCL.

Chicken miR-126-5p negatively regulates antiviral innate immunity by targeting TRAF3.

Innate immunity plays an essential role in preventing the invasion of pathogenic microorganisms. However, innate immunity is a double-edged sword, whose excessive activation is detrimental to immune homeostasis and even leads to a "cytokine storm" of the infected host. The host develops a series of negative regulatory mechanisms to balance the immune response. Here, we report a negative regulatory mechanism of chicken innate immunity mediated by miRNA. In the GEO database, we found that miR-126-5p was markedly up-regulated in chickens infected by RNA viruses. Upregulation of miR-126-5p by RNA virus was then further shown via both a cell model and in vivo tests. Overexpression of miR-126-5p significantly inhibited the expression of interferon and inflammatory cytokine-related genes induced by RNA viruses. The opposite result was achieved after the knockdown of miR-126-5p expression. Bioinformatics analysis identified TRAF3 as candidate target gene of miR-126-5p. Experimentally, miR-126-5p can target TRAF3, as shown by the effects of miR-126-5p on the endogenous expression of TRAF3, and by the TRAF3 3'UTR driven luciferase reporter assay. Furthermore, we demonstrated that miR-126-5p negatively regulated innate immunity by blocking the MAVS-TRAF3-TBK1 axis, with a co-expression assay. Overall, our results suggest that miR-126-5p is involved in the negative regulation of chicken innate immunity, which might contribute to maintaining immune balance.

Malignant clonal evolution drives multiple myeloma cellular ecological diversity and microenvironment reprogramming.

BACKGROUND: Multiple myeloma (MM) is a heterogeneous disease with different patterns of clonal evolution and a complex tumor microenvironment, representing a challenge for clinicians and pathologists to understand and dissect the contribution and impact of polyclonality on tumor progression. METHODS: In this study, we established a global cell ecological landscape of the bone marrow (BM) from MM patients, combining single-cell RNA sequencing and single-molecule long-read genome sequencing data. RESULTS: The malignant mutation event was localized to the tumor cell clusters with shared mutation of ANK1 and IFITM2 in all malignant subpopulations of all MM patients. Therefore, these two variants occur in the early stage of malignant clonal origin to mediate the malignant transformation of proplasmacytes or plasmacytes to MM cells. Tumor cell stemness index score and pseudo-sequential clonal evolution analysis can be used to divide the evolution model of MM into two clonal origins: types I and IX. Notably, clonal evolution and the tumor microenvironment showed an interactive relationship, in which the evolution process is not only selected by but also reacts to the microenvironment; thus, vesicle secretion enriches immune cells with malignant-labeled mRNA for depletion. Interestingly, microenvironmental modification exhibited significant heterogeneity among patients. CONCLUSIONS: This characterization of the malignant clonal evolution pattern of MM at the single-cell level provides a theoretical basis and scientific evidence for a personalized precision therapy strategy and further development of a potential new adjuvant strategy combining epigenetic agent and immune checkpoint blockade.

Biomarkers for predicting the efficacy of immune checkpoint inhibitors.

Immune checkpoint blockade has vastly changed the landscape of cancer treatment and showed a promising prognosis for cancer patients. However, there is still a large portion of patients who have no response to this therapy. Therefore, it's essential to investigate biomarkers to predict the efficacy of immune checkpoint inhibitors. This article summarizes the predictive value of established biomarkers, including programmed cell death ligand 1(PD-L1) expression level, tumor mutational burden, tumor-infiltrating lymphocytes, and mismatch repair deficiency. It also addresses the predictive value of tumorous mutations, circulation factors, immune-related factors, and gut microbiome with immunotherapy treatment. Furthermore, some of the emerging novel biomarkers, and potential markers for hyper progressive disease are discussed, which should be validated in clinical trials in the future.

An Immune-Related Prognostic Classifier Is Associated with Diffuse Large B Cell Lymphoma Microenvironment.

BACKGROUND: Diffuse large B cell lymphoma (DLBCL) is a life-threatening malignant tumor characterized by heterogeneous clinical, phenotypic, and molecular manifestations. Given the association between immunity and tumors, identifying a suitable immune biomarker could improve DLBCL diagnosis. METHODS: We systematically searched for DLBCL gene expression microarray datasets from the GEO database. Immune-related genes (IRGs) were obtained from the ImmPort database, and 318 transcription factor (TF) targets in cancer were retrieved from the Cistrome Cancer database. An immune-related classifier for DLBCL prognosis was constructed using Cox regression and LASSO analysis. To assess differences in overall survival between the low- and high-risk groups, we analyzed the tumor microenvironment (TME) and immune infiltration in DLBCL using the ESTIMATE and CIBERSORT algorithms. WGCNA was applied to study the molecular mechanisms explaining the clinical significance of our immune-related classifier and TFs. RESULTS: Eighteen IRGs were selected to construct the classifier. The multi-IRG classifier showed powerful predictive ability. Patients with a high-risk score had poor survival. Based on the AUC for three- and five-year survival, the classifier exhibited better predictive power than clinical data. Discrepancies in overall survival between the low- and high-risk score groups might be explained by differences in immune infiltration, TME, and transcriptional regulation. CONCLUSIONS: Our study describes a novel prognostic IRG classifier with strong predictive power in DLBCL. Our findings provide valuable guidance for further analysis of DLBCL pathogenesis and clinical treatment.

TLR4 Agonist Combined with Trivalent Protein JointS of Streptococcus suis Provides Immunological Protection in Animals.

Streptococcus suis (S. suis) serotype 2 (SS2) is the causative agent of swine streptococcosis and can cause severe diseases in both pigs and humans. Although the traditional inactive vaccine can protect pigs from SS2 infection, novel vaccine candidates are needed to overcome its shortcomings. Three infection-associated proteins in S. suis-muramidase-released protein (MRP), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and DLD, a novel putative dihydrolipoamide dehydrogenase-have been previously identified by immunoproteomic assays. In this study, the effective immune protection of the recombinant trivalent protein GAPDH-MRP-DLD (JointS) against SS2, SS7, and SS9 was determined in zebrafish. To improve the immune efficacy of JointS, monophosphoryl lipid A (MPLA) as a TLR4 agonist adjuvant, which induces a strong innate immune response in the immune cells of mice and pigs, was combined with JointS to immunize the mice. The results showed that immunized mice could induce the production of a high titer of anti-S. suis antibodies; as a result, 100% of mice survived after SS2 infection. Furthermore, JointS provides good protection against virulent SS2 strain infections in piglets. Given the above, there is potential to develop JointS as a novel subunit vaccine for piglets to prevent infection by SS2 and other S. suis serotypes.

LncRNA BCYRN1-induced autophagy enhances asparaginase resistance in extranodal NK/T-cell lymphoma.

Background: Asparaginase (ASP) is the cornerstone drug in the treatment of extranodal NK/T-cell lymphoma (ENKTCL), and the mechanisms of resistance to ASP remain largely unknown. Long non-coding RNAs play important roles in chemotherapy resistance in various cancers. However, the expression of BCYRN1 and its role in ENKTCL still remain unidentified. Methods: Lentivirus-mediated BCYRN1 overexpression and knockdown were performed in SNK-6 cells. Cell autophagy was analyzed by adenovirus expressing GFP-LC3B fusion protein. RNA pull-down and RNA Binding Protein Immunoprecipitation Assay were performed to investigate the relationship between BCYRN1 and p53. Western blot analysis was performed to assess the effect of BCYRN1 on different autophagy pathways. Finally, in vivo xenograft tumor model was constructed to analyze the effect of BCYRN1 on tumor growth and ASP resistance. Results: BCYRN1 was overexpressed in ENKTCL than normal NK cells, and patients with higher expression had significantly inferior progression-free survival (PFS). The IC50 value of ASP was significantly increased in BCYRN1-overexpressed SNK-6 cells and BCYRN1 overexpression could resist the inhibitory effect of ASP on proliferation. ASP could induce concurrent apoptosis and autophagy in ENKTCL, and the latter process was enhanced by overexpression of BCYRN1, mainly through affecting both PI3K/AKT/mTOR and p53/mTOR pathways. BCYRN1 could induce the degradation of p53 via ubiquitination, thus resulting in enhancement of autophagy and ASP resistance, which could be reversed by drug-induced autophagy inhibition. The effect of BCYRN1 on tumor growth and autophagy were confirmed in vivo xenograft model. Conclusions: It was found that BCYRN1 was a valuable prognostic biomarker in ENKTCL. BCYRN1 could promote resistance to ASP by inducing autophagy, which could be reversed by inhibition of autophagy. Our findings highlight the feasibility of combining autophagy inhibition and ASP in the treatment of ENKTCL.

MiR-624-3p Promotes Esophageal Squamous Cell Carcinoma Progression via Targeting Phosphatase and Tensin Homologue.

The emerging role of miRNA as regulators in esophageal squamous cell carcinoma (ESCC) progression has aroused great attention recently. In this study, the effects of miR-624-3p in ESCC progression were explored through cell proliferation, colony formation, cell cycle, and apoptosis analyses. Results showed that increased expression of miR-624-3p enhanced cancer cell viability, proliferation, migration, and invasion but inhibited apoptosis in ESCC. Moreover, luciferase reporter assay demonstrated that miR-624-3p bound to the 3'-untranslated region of phosphatase and tensin homologue (PTEN). Further study showed that miR-624-3p exerted its tumor promoting role through targeting PTEN. Taken together, these results elucidate the regulatory role of miR-624-3p in ESCC progression, shedding light on its possible clinical application in ESCC treatment.

N-doped carbon dots modified with the epithelial cell adhesion molecule antibody as an imaging agent for HepG2 cells using their ultra-sensitive response to Al3.

Carbon dots (CDs) are emerging as an ideal multifunctional materials due to their ease of preparation and excellent properties in medical imaging technology, environmental monitoring, chemical analysis and other fields. N-doped CDs modified with the epithelial cell adhesion molecule antibody (anti-EpCAM-NCDs) were synthesized in an ingenious and high-output approach. Due to the fluorescence enhancement effect of the introduced N atoms, the obtained anti-EpCAM-NCDs exhibited a strong green emission with an absolute quantum yield of up to 32.5%. Anti-EpCAM-NCDs have immunofluorescent properties and an active targeting function. The fluorescence effect and fluorescence quenching of anti-EpCAM-NCDs are used to image cells and detect Al3+, respectively. Experimental results show that this probe exhibited a wide linear response to Al3+over a concentration range of 0-100µM with a detection limit and quantification limit of 3 nM and 6 nM, respectively. Significantly, anti-EpCAM-NCDs, which have negligible cytotoxicity, excellent biocompatibility and high photostability, could be used for the intracellular imaging of HepG2 cells and the detection of Al3+in environmental and biological samples. As an efficient multifunctional material, anti-EpCAM-NCDs hold great promise for a number of applications in biological systems.

Combinatorial discovery of Mo-based polyoxometalate clusters for tumor photothermal therapy and normal cell protection.

Nanomaterials with multiple functions such as precision diagnosis, therapeutic efficacy and biosafety are attractive for tumor treatment but remain a technical challenge. In this study, molybdenum (Mo)-based polyoxometalate clusters (Mo-POM) with considerable photothermal conversion efficiency (∼56.6%) and high stability (>30 days) were prepared through a modification of the Folin-Ciocalteu method. These synthetic particles accumulated at the target site, and induced thermal ablation of the tumor following near infrared (NIR) absorption. Furthermore, the Mo-POM effectively scavenged reactive oxygen species (ROS) through charge transfer between Mo(vi) and Mo(v) states, thereby avoiding off-target effects on normal cells and improving the therapeutic efficiency both in vitro and in vivo. Therefore, for the first time, we prepared Mo-POM having two key functions, i.e., photothermal therapy (PTT) for cancer cells and protection of normal cells. These exceptional features may open up the exploration of Mo-POM as new tools for PTT against tumors in clinical applications.

Fast Brillouin optical time-domain analysis using frequency-agile and compressed sensing.

A fast Brillouin optical time-domain analysis (BOTDA) sensor has been proposed and experimentally demonstrated based on the frequency-agile and compressed-sensing technique. The proposed scheme employs a data-adaptive sparse base obtained by the principle component analysis algorithm, enabling the sparse representation of Brillouin spectrum. Then, it can be reconstructed successfully with random frequency sampling and orthogonal matching-pursuit algorithms. In the experiment, the Brillouin gain spectrum (BGS) is mapped by the conventional fast BOTDA, where the frequency step and span are 4 MHz and 500 MHz, respectively. By using compressed-sensing technology, the BGS is successfully recovered with 37 random frequency samples, the number of which is only 30% of the full data. With fewer sampling frequencies, the compressed-sensing technology is able to improve the sensing performance of the conventional fast BOTDA, including a 3.3-time increase in sampling rate and 70% reduction in data storage.

Synthesis of Gelatin-Based Dual-Targeted Nanoparticles of Betulinic Acid for Antitumor Therapy.

Betulinic acid (BA) is a natural antitumor agent and has biological activity against multiple human tumor cell lines with low cytotoxicity to normal cells, while the high hydrophobicity and the short half-life of this compound limit its clinical application. Here, gelatin-based dual-targeted nanoparticles of BA are promising to solve this problem. Hydrophobic BA is loaded in cyclodextrin to increase its solubility and prolong the circulation time in vivo. The nanoscale drug delivery systems can further enhance the bioavailability and the antitumor effect of BA and are passively targeted to the tumor tissue sites by enhanced permeability and retention effect. The RGD sequence of gelatin specifically recognizes tumor cells and brings agents into tumor cells. The nanoparticles were characterized by transmission electron microscopy, Fourier transform infrared, nuclear magnetic resonance, etc. In addition, we observed antitumor activity of the nanoparticles using both cell-based assays and mouse xenograft tumors, which proved that betulinic acid/gelatin-γ-cyclodextrin nanoparticles had a better tumor inhibition effect than betulinic acid/γ-cyclodextrin inclusion compound.

Synthesis of dual functional gallic-acid-based carbon dots for bioimaging and antitumor therapy.

Carbon quantum dots are excellent photoluminescent materials because of their unique fluorescence properties. They are widely used in biomedical imaging due to their good biocompatibility. However, carbon quantum dots with antitumor activity have rarely been reported. Gallic acid (GA) is an anticancer agent and effective against many types of tumor cells. In this study, GA based carbon dots (GACDs) with fluorescence and antitumor activity were synthesized by a simple microwave-assisted method and characterized by transmission electron microscopy (TEM), and Fourier transformed infrared (FTIR) and X-ray photoelectron spectroscopy (XPS). Studies of optical properties indicated that the GACDs exhibited significant photoluminescence. In addition, we observed the antitumor activity of the GACDs using both cell-based assays and mouse xenograft tumors. Our results demonstrated that the GACDs can be used as both a bioimaging material and an antitumor agent, suggesting their great potential in future clinical applications.

Dichloroacetate induces protective autophagy in esophageal squamous carcinoma cells.

Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase, which promotes the flux of carbohydrates into mitochondria and enhances the aerobic oxidation of glucose. DCA has previously been demonstrated to exhibit antitumor properties. The present study revealed that treatment with DCA induced increased levels of autophagy-associated proteins in esophageal squamous carcinoma cells while minimally affecting apoptosis. The present study examined the localization of light chain (LC)-3 by adenovirus infection with a green fluorescent protein (FP)-red FP-LC3 reporter construction and confirmed that DCA treatment induced significant autophagy. Furthermore, the inhibition of DCA-induced autophagy facilitated cell apoptosis and improved the drug sensitivity of esophageal squamous carcinoma cells to DCA and 5-FU (5-fluorouracil). The proliferation of TE-1 cells was markedly inhibited at low concentrations of DCA and 5-FU treatment when subjected to Atg5 mRNA interference, indicating that autophagy performed a protective role in cell survival upon DCA treatment. To determine the underlying mechanism of DCA-induced autophagy, the present study measured alterations in autophagy-associated signaling pathways. Notably, the protein kinase B (Akt)-mechanistic target of rapamycin (mTOR) signaling pathway, an important negative regulator of autophagy, was demonstrated to be suppressed by DCA treatment. These results may direct the development of novel strategies for the treatment of esophageal squamous carcinoma based on the combined use of DCA and autophagy inhibitors.