Multi-MXene assisted large-scale manufacturing of electrochemical biosensors based on enzyme-nanoflower enhanced electrodes for the detection of H2O2 secreted from live cancer cells.

In situ monitoring of H2O2 in cellular microenvironments plays a critical role in the early diagnosis and pretreatment of cancer, but is limited by the lack of efficient and low-cost strategies for the large-scale preparation of real-time biosensors. Herein, a universal strategy for MXene-based composite inks combined with a scalable screen-printing process is validated in large-scale manufacturing of electrochemical biosensors for in situ detection of H2O2 secreted from live cells. Compositing biocompatible carboxymethyl cellulose (CMCS) with excellent conductive MXene, a water-based ink electrode (MXene/CMCS) with tunable viscosity is efficiently printed with desirable printing accuracy. Subsequently, the MXene/CMCS@HRP electrochemical biosensor exhibits stable electrochemical performance through HRP nanoflower modification, showing rapid electron transport and high electrocatalytic capacity, and demonstrating a low limit of detection (0.29 µM) with a wide linear detection range (0.5 µM-3 mM), superior sensitivity (56.45 µA mM-1 cm-2), long-term stability and high anti-interference ability. Moreover, this electrochemical biosensor is effectively employed for in situ detection of H2O2 secreted from HeLa cells, revealing good biocompatibility and outstanding biosensing capability. This proposed strategy not only extends the possibility of low-cost biomedical devices, but also provides a promising approach for early diagnosis and treatment of cancer.

Non-Invasive Multi-Gas Detection Enabled by Cu-CuO/PEDOT Microneedle Sensor.

Metal-oxide-based gas sensors are extensively utilized across various domains due to their cost-effectiveness, facile fabrication, and compatibility with microelectronic technologies. The copper (Cu)-based multifunctional polymer-enhanced sensor (CuMPES) represents a notably tailored design for non-invasive environmental monitoring, particularly for detecting diverse gases with a low concentration. In this investigation, the Cu-CuO/PEDOT nanocomposite was synthesized via a straightforward chemical oxidation and vapor-phase polymerization. Comprehensive characterizations employing X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), X-ray diffraction (XRD), and micro Raman elucidated the composition, morphology, and crystal structure of this nanocomposite. Gas-sensing assessments of this CuMPES based on Cu-CuO/PEDOT revealed that the response current of the microneedle-type CuMPES surpassed that of the pure Cu microsensor by nearly threefold. The electrical conductivity and surface reactivity are enhanced by poly (3,4-ethylenedioxythiophene) (PEDOT) polymerized on the CuO-coated surface, resulting in an enhanced sensor performance with an ultra-fast response/recovery of 0.3/0.5 s.

Nuclear autoantigenic sperm protein facilitates glioblastoma progression and radioresistance by regulating the ANXA2/STAT3 axis.

AIMS: Although radiotherapy is a core treatment modality for various human cancers, including glioblastoma multiforme (GBM), its clinical effects are often limited by radioresistance. The specific molecular mechanisms underlying radioresistance are largely unknown, and the reduction of radioresistance is an unresolved challenge in GBM research. METHODS: We analyzed and verified the expression of nuclear autoantigenic sperm protein (NASP) in gliomas and its relationship with patient prognosis. We also explored the function of NASP in GBM cell lines. We performed further mechanistic experiments to investigate the mechanisms by which NASP facilitates GBM progression and radioresistance. An intracranial mouse model was used to verify the effectiveness of combination therapy. RESULTS: NASP was highly expressed in gliomas, and its expression was negatively correlated with the prognosis of glioma. Functionally, NASP facilitated GBM cell proliferation, migration, invasion, and radioresistance. Mechanistically, NASP interacted directly with annexin A2 (ANXA2) and promoted its nuclear localization, which may have been mediated by phospho-annexin A2 (Tyr23). The NASP/ANXA2 axis was involved in DNA damage repair after radiotherapy, which explains the radioresistance of GBM cells that highly express NASP. NASP overexpression significantly activated the signal transducer and activator of transcription 3 (STAT3) signaling pathway. The combination of WP1066 (a STAT3 pathway inhibitor) and radiotherapy significantly inhibited GBM growth in vitro and in vivo. CONCLUSION: Our findings indicate that NASP may serve as a potential biomarker of GBM radioresistance and has important implications for improving clinical radiotherapy.

Radiomic profiling for insular diffuse glioma stratification with distinct biologic pathway activities.

Current literature emphasizes surgical complexities and customized resection for managing insular gliomas; however, radiogenomic investigations into prognostic radiomic traits remain limited. We aimed to develop and validate a radiomic model using multiparametric magnetic resonance imaging (MRI) for prognostic prediction and to reveal the underlying biological mechanisms. Radiomic features from preoperative MRI were utilized to develop and validate a radiomic risk signature (RRS) for insular gliomas, validated through paired MRI and RNA-seq data (N = 39), to identify core pathways underlying the RRS and individual prognostic radiomic features. An 18-feature-based RRS was established for overall survival (OS) prediction. Gene set enrichment analysis (GSEA) and weighted gene coexpression network analysis (WGCNA) were used to identify intersectional pathways. In total, 364 patients with insular gliomas (training set, N = 295; validation set, N = 69) were enrolled. RRS was significantly associated with insular glioma OS (log-rank p = 0.00058; HR = 3.595, 95% CI:1.636-7.898) in the validation set. The radiomic-pathological-clinical model (R-P-CM) displayed enhanced reliability and accuracy in prognostic prediction. The radiogenomic analysis revealed 322 intersectional pathways through GSEA and WGCNA fusion; 13 prognostic radiomic features were significantly correlated with these intersectional pathways. The RRS demonstrated independent predictive value for insular glioma prognosis compared with established clinical and pathological profiles. The biological basis for prognostic radiomic indicators includes immune, proliferative, migratory, metabolic, and cellular biological function-related pathways.

Study on articular surface morphology of atlantoaxial lateral mass based on differential manifold.

OBJECTIVES: To propose a surface reconstruction algorithm based on a differential manifold (a space with local Euclidean space properties), which can be used for processing of clinical images and for modeling of the atlantoaxial joint. To describe the ideal anatomy of the lateral atlantoaxial articular surface by measuring the anatomical data. METHODS: Computed tomography data of 80 healthy subjects who underwent cervical spine examinations at our institution were collected between October 2019 and June 2022, including 46 males and 34 females, aged 37.8 ± 5.1 years (28-59 years). A differential manifold surface reconstruction algorithm was used to generate the model based on DICOM data derived by Vision PACS system. The lateral mass articular surface was measured and compared in terms of its sagittal diameter, transverse diameter, articular surface area, articular curvature and joint space height. RESULTS: There was no statistically significant difference between left and right sides of the measured data in normal adults (P > 0.05). The atlantoaxial articular surface sagittal diameter length was (15.83 ± 1.85) and (16.22 ± 1.57) mm on average, respectively. The transverse diameter length of the articular surface was (16.29 ± 2.16) and (16.49 ± 1.84) mm. The lateral articular surface area was (166.53 ± 7.69) and (174.48 ± 6.73) mm2 and the curvature was (164.03 ± 5.27) and (153.23 ± 9.03)°, respectively. The joint space height was 3.05 ± 0.11mm, respectively. There is an irregular articular space in the lateral mass of atlantoaxial, and both upper and lower surfaces of the articular space are concave. A sagittal plane view shows that the inferior articular surface of the atlas is mainly concave above; however, the superior articular surface of the axis is mainly convex above. In the coronal plane, the inferior articular surface of the atlas is mostly concave above, with most concave vertices located in the medial region, and the superior articular surface of the axis is mainly concave below, with most convex vertices located centrally and laterally. CONCLUSION: A differential manifold algorithm can effectively process atlantoaxial imaging data, fit and control mesh topology, and reconstruct curved surfaces to meet clinical measurement applications with high accuracy and efficiency; the articular surface of the lateral mass of atlantoaxial mass in normal adults has relatively constant sagittal diameter, transverse diameter and area. The distance difference between joint spaces is small, but the shape difference of articular surfaces differs greatly.

Radiomic features from multiparametric magnetic resonance imaging predict molecular subgroups of pediatric low-grade gliomas.

BACKGROUND: We aimed to develop machine learning models for prediction of molecular subgroups (low-risk group and intermediate/high-risk group) and molecular marker (KIAA1549-BRAF fusion) of pediatric low-grade gliomas (PLGGs) based on radiomic features extracted from multiparametric MRI. METHODS: 61 patients with PLGGs were included in this retrospective study, which were divided into a training set and an internal validation set at a ratio of 2:1 based on the molecular subgroups or the molecular marker. The patients were classified into low-risk and intermediate/high-risk groups, BRAF fusion positive and negative groups, respectively. We extracted 5929 radiomic features from multiparametric MRI. Thereafter, we removed redundant features, trained random forest models on the training set for predicting the molecular subgroups or the molecular marker, and validated their performance on the internal validation set. The performance of the prediction model was verified by 3-fold cross-validation. RESULTS: We constructed the classification model differentiating low-risk PLGGs from intermediate/high-risk PLGGs using 4 relevant features, with an AUC of 0.833 and an accuracy of 76.2% in the internal validation set. In the prediction model for predicting KIAA1549-BRAF fusion using 4 relevant features, an AUC of 0.818 and an accuracy of 81.0% were achieved in the internal validation set. CONCLUSIONS: The current study demonstrates that MRI radiomics is able to predict molecular subgroups of PLGGs and KIAA1549-BRAF fusion with satisfying sensitivity. TRIAL REGISTRATION: This study was retrospectively registered at clinicaltrials.gov (NCT04217018).

Improving Noninvasive Classification of Molecular Subtypes of Adult Gliomas With Diffusion-Weighted MR Imaging: An Externally Validated Machine Learning Algorithm.

BACKGROUND: Genetic testing for molecular markers of gliomas sometimes is unavailable because of time-consuming and expensive, even limited tumor specimens or nonsurgery cases. PURPOSE: To train a three-class radiomic model classifying three molecular subtypes including isocitrate dehydrogenase (IDH) mutations and 1p/19q-noncodeleted (IDHmut-noncodel), IDH wild-type (IDHwt), IDH-mutant and 1p/19q-codeleted (IDHmut-codel) of adult gliomas and investigate whether radiomic features from diffusion-weighted imaging (DWI) could bring additive value. STUDY TYPE: Retrospective. POPULATION: A total of 755 patients including 111 IDHmut-noncodel, 571 IDHwt, and 73 IDHmut-codel cases were divided into training (n = 480) and internal validation set (n = 275); 139 patients including 21 IDHmut-noncodel, 104 IDHwt, and 14 IDHmut-codel cases were utilized as external validation set. FIELD STRENGTH/SEQUENCE: A 1.5 T or 3.0 T/multiparametric MRI, including T1-weighted (T1), T1-weighted gadolinium contrast-enhanced (T1c), T2-weighted (T2), fluid attenuated inversion recovery (FLAIR), and DWI. ASSESSMENT: The performance of multiparametric radiomic model (random-forest model) using 22 selected features from T1, T2, FLAIR, T1c images and apparent diffusion coefficient (ADC) maps, and conventional radiomic model using 20 selected features from T1, T2, FLAIR, and T1c images was assessed in internal and external validation sets by comparing probability values and actual incidence. STATISTICAL TESTS: Mann-Whitney U test, Chi-Squared test, Wilcoxon test, receiver operating curve (ROC), and area under the curve (AUC); DeLong analysis. P < 0.05 was statistically significant. RESULTS: The multiparametric radiomic model achieved AUC values for IDHmut-noncodel, IDHwt, and IDHmut-codel of 0.8181, 0.8524, and 0.8502 in internal validation set and 0.7571, 0.7779, and 0.7491 in external validation set, respectively. Multiparametric radiomic model showed significantly better diagnostic performance after DeLong analysis, especially in classifying IDHwt and IDHmut-noncodel subtypes. DATA CONCLUSION: Radiomic features from DWI could bring additive value and improve the performance of conventional MRI-based radiomic model for classifying the molecular subtypes especially IDHmut-noncodel and IDHwt of adult gliomas. TECHNICAL EFFICACY: Stage 2.

Pushing the Electrochemical Performance Limits of Polypyrrole Toward Stable Microelectronic Devices.

Conducting polymers have achieved remarkable attentions owing to their exclusive characteristics, for instance, electrical conductivity, high ionic conductivity, visual transparency, and mechanical tractability. Surface and nanostructure engineering of conjugated conducting polymers offers an exceptional pathway to facilitate their implementation in a variety of scientific claims, comprising energy storage and production devices, flexible and wearable optoelectronic devices. A two-step tactic to assemble high-performance polypyrrole (PPy)-based microsupercapacitor (MSC) is utilized by transforming the current collectors to suppress structural pulverization and increase the adhesion of PPy, and then electrochemical co-deposition of PPy-CNT nanostructures on rGO@Au current collectors is performed. The resulting fine patterned MSC conveyed a high areal capacitance of 65.9 mF cm-2 (at a current density of 0.1 mA cm-2), an exceptional cycling performance of retaining 79% capacitance after 10,000 charge/discharge cycles at 5 mA cm-2. Benefiting from the intermediate graphene, current collector free PPy-CNT@rGO flexible MSC is produced by a facile transfer method on a flexible substrate, which delivered an areal capacitance of 70.25 mF cm-2 at 0.1 mA cm-2 and retained 46% of the initial capacitance at a current density of 1.0 mA cm-2. The flexible MSC is utilized as a skin compatible capacitive micro-strain sensor with excellent electromechanochemical characteristics.

Stepping Further from Coupling Tools: Development of Functional Polymers via the Biginelli Reaction.

Multicomponent reactions (MCRs) have been used to prepare polymers with appealing functions. The Biginelli reaction, one of the oldest and most famous MCRs, has sparked new scientific discoveries in polymer chemistry since 2013. Recent years have seen the Biginelli reaction stepping further from simple coupling tools; for example, the functions of the Biginelli product 3,4-dihydropyrimidin-2(1H)-(thi)ones (DHPM(T)) have been gradually exploited to develop new functional polymers. In this mini-review, we mainly summarize the recent progress of using the Biginelli reaction to identify polymers for biomedical applications. These polymers have been documented as antioxidants, anticancer agents, and bio-imaging probes. Moreover, we also provide a brief introduction to some emerging applications of the Biginelli reaction in materials and polymer science. Finally, we present our perspectives for the further development of the Biginelli reaction in polymer chemistry.

Ursodeoxycholic acid reduces antitumor immunosuppression by inducing CHIP-mediated TGF-ß degradation.

TGF-ß is essential for inducing systemic tumor immunosuppression; thus, blocking TGF-ß can greatly enhance antitumor immunity. However, there are still no effective TGF-ß inhibitors in clinical use. Here, we show that the clinically approved compound ursodeoxycholic acid (UDCA), by degrading TGF-ß, enhances antitumor immunity through restraining Treg cell differentiation and activation in tumor-bearing mice. Furthermore, UDCA synergizes with anti-PD-1 to enhance antitumor immunity and tumor-specific immune memory in tumor-bearing mice. UDCA phosphorylates TGF-ß at T282 site via TGR5-cAMP-PKA axis, causing increased binding of TGF-ß to carboxyl terminus of Hsc70-interacting protein (CHIP). Then, CHIP ubiquitinates TGF-ß at the K315 site, initiating p62-dependent autophagic sorting and subsequent degradation of TGF-ß. Notably, results of retrospective analysis shows that combination therapy with anti-PD-1 or anti-PD-L1 and UDCA has better efficacy in tumor patients than anti-PD-1 or anti-PD-L1 alone. Thus, our results show a mechanism for TGF-ß regulation and implicate UDCA as a potential TGF-ß inhibitor to enhance antitumor immunity.

Circ_LPAR3 promotes the progression of oral squamous cell carcinoma (OSCC).

BACKGROUND: circ_LPAR3 is an oncogene in esophageal squamous cell carcinoma. However, its role in oral squamous cell carcinoma (OSCC) is unknown. PURPOSE: To reveal the functions of circ_LPAR3 in OSCC. METHODS: Online bioinformatic analysis was performed to disclose the differential expression of circ_LPAR3, VEGFC, AKT1 in OSCC and also the target predictions of miR-513b-5p. Transfection was applied in OSCC cells. RT-qPCR was used to detect the RNA expression and western blot to measure the proteins, VEGFC and phosphor-AKT1 (ser473, p-AKT1). CCK8 kit was used for viability detection and Flow cytometry for apoptosis evaluation. RNA pull-down and luciferase reporter methods were used to validate the binding sites to miR-513b-5p on circ_LPAR3, VEGFC and AKT1. OSCC mice models were established to further unveil the functions of circ_LPAR3 in OSCC in vivo. H&E staining and immunohistochemistry (CD34, VEGFC and p-AKT1) were further applied to analyze the pathological changes in association with circ_LPAR3 downregulation. RESULTS: circ_LPAR3 was upregulated in OSCC. Its knockdown in cells could decrease cell survival and mobility and in mice model, could inhibit the tumor growth and angiogenesis. Circ_LPAR3 promoted VEGFC and AKT1 activity by sponging miR-513b-5p in OSCC cells. CONCLUSION: Knockdown of circ_LPAR3 could inhibit the OSCC progression by sponging miR-513b-5p and activating VEGFC and AKT1.

Multi-Slice Dense-Sparse Learning for Efficient Liver and Tumor Segmentation.

Accurate automatic liver and tumor segmentation plays a vital role in treatment planning and disease monitoring. Recently, deep convolutional neural network (DCNNs) has obtained tremendous success in 2D and 3D medical image segmentation. However, 2D DCNNs cannot fully leverage the inter-slice information, while 3D DCNNs are computationally expensive and memory intensive. To address these issues, we first propose a novel dense-sparse training flow from a data perspective, in which, densely adjacent slices and sparsely adjacent slices are extracted as inputs for regularizing DCNNs, thereby improving the model performance. Moreover, we design a 2.5D light-weight nnU-Net from a network perspective, in which, depthwise separable convolutions are adopted to improve the efficiency. Extensive experiments on the LiTS dataset have demonstrated the superiority of the proposed method.Clinical relevance- The proposed method can effectively segment livers and tumors from CT scans with low complexity, which can be easily implemented into clinical practice.

Oridonin inhibits 4T1 tumor growth by suppressing Treg differentiation via TGF-ß receptor.

The Chinese herbal medicine oridonin has potent anti-inflammatory and antitumor activities. In addition, oridonin treatment effectively suppresses breast cancer growth. However, the underlying mechanisms are poorly defined. Here, we reported that oridonin decreased Treg differentiation in vitro and in vivo. Oridonin inhibition of Treg differentiation was dependent on decreasing TGF-ß receptor expression. Oridonin attenuated Tregs' immunosuppressive ability; thus, oridonin did not inhibit CD8+ T cell proliferation very well in vitro. Oridonin greatly delayed the progression of 4T1 tumors in vivo. In addition, oridonin combined with anti-PD-1 activated a robust antitumor immune response and suppressed 4T1 tumor growth. Therefore, our results indicate that oridonin inhibits TNBC growth by modulating Treg differentiation, which provides new directions for the clinical treatment of TNBC.

Fas signaling-mediated TH9 cell differentiation favors bowel inflammation and antitumor functions.

Fas induces apoptosis in activated T cell to maintain immune homeostasis, but the effects of non-apoptotic Fas signaling on T cells remain unclear. Here we show that Fas promotes TH9 cell differentiation by activating NF-κB via Ca2+-dependent PKC-ß activation. In addition, PKC-ß also phosphorylates p38 to inactivate NFAT1 and reduce NFAT1-NF-κB synergy to promote the Fas-induced TH9 transcription program. Fas ligation exacerbates inflammatory bowel disease by increasing TH9 cell differentiation, and promotes antitumor activity in p38 inhibitor-treated TH9 cells. Furthermore, low-dose p38 inhibitor suppresses tumor growth without inducing systemic adverse effects. In patients with tumor, relatively high TH9 cell numbers are associated with good prognosis. Our study thus implicates Fas in CD4+ T cells as a target for inflammatory bowel disease therapy. Furthermore, simultaneous Fas ligation and low-dose p38 inhibition may be an effective approach for TH9 cell induction and cancer therapy.

Study on internal stress damage detection in long-distance oil and gas pipelines via weak magnetic method.

Weak magnetic stress detection is an important issue in oil-gas pipeline internal detection area. In order to verify the characteristics of weak magnetic stress internal detection signals, we built herein a magneto-mechanics equivalent model having a balanced magnetic field. First, we calculated the relationship between the stress and the weak magnetic signals; consequently, the analysis propagation laws of the weak magnetic signals with non-magnetic saturation were pointed out. Finally, the theoretical model was validated by a systematic experimental research. The analytical results show that a one-to-one linear link between the weak magnetic signals and the stress concentration is clear. Instead, the change of the weak magnetic signals with the liftoff is nonlinear, therefore we are proposing the Boltzmann liftoff correction factor whose degree of adaptability of the equivalent model can reach the value of 94%. It is possible to note that when the liftoff is in the approximate linear stage, the relevance ratio and the recognition rate of the magneto-mechanics curve show a high-quality. This conclusion is important in the engineering field for the set of the liftoff.

Tumor-derived exosomes educate dendritic cells to promote tumor metastasis via HSP72/HSP105-TLR2/TLR4 pathway.

How the tumor microenvironment educates dendritic cells (DCs) to promote tumorigenesis remains largely unknown, and the role of tumor-derived exosomes (TEXs) in tumorigenesis is controversial. Here, we report that in addition to the activation of DCs, TEXs induce DCs to produce increased interleukin-6 (IL-6), which dramatically promotes tumor invasion by increasing signal transducer and activator of transcription 3 (STAT3)-dependent matrix metalloproteinases 9 transcription activity in tumor cells. HSP72 and HSP105 on the TEX surface induce IL-6 secretion of DCs in a TLR2- and TLR4-dependent manner. In addition, HSP72 and HSP105 are predominantly present on exosomes from sera of tumor patients but not healthy people, indicating their value in tumor prediction. Furthermore, TEXs are powerful activators of DCs, and the depletion of IL-6 converts TEXs from tumor promoters to tumor inhibitors in vivo. Therefore, our results reveal a novel mechanism for the TEX-mediated education of DCs and shed light on the conundrum that TEXs present by playing dual roles in tumorigenesis.