Ordered assembly of the cytosolic RNA-sensing MDA5-MAVS signaling complex via binding to unanchored K63-linked poly-ubiquitin chains.

The RNA sensor MDA5 recruits the signaling adaptor MAVS to initiate type I interferon signaling and downstream antiviral responses, a process that requires K63-linked polyubiquitin chains. Here, we examined the mechanisms whereby K63-polyUb chain regulate MDA5 activation. Only long unanchored K63-polyUbn (n ≥ 8) could mediate tetramerization of the caspase activation and recruitment domains of MDA5 (MDA5CARDs). Cryoelectron microscopy structures of a polyUb13-bound MDA5CARDs tetramer and a polyUb11-bound MDA5CARDs-MAVSCARD assembly revealed a tower-like formation, wherein eight Ubs tethered along the outer rim of the helical shell, bridging MDA5CARDs and MAVSCARD tetramers into proximity. ATP binding and hydrolysis promoted the stabilization of RNA-bound MDA5 prior to MAVS activation via allosteric effects on CARDs-polyUb complex. Abundant ATP prevented basal activation of apo MDA5. Our findings reveal the ordered assembly of a MDA5 signaling complex competent to recruit and activate MAVS and highlight differences with RIG-I in terms of CARD orientation and Ub sensing that suggest different abilities to induce antiviral responses.

B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity.

The antibody gene mutator activation-induced cytidine deaminase (AID) promiscuously damages oncogenes, leading to chromosomal translocations and tumorigenesis. Why nonimmunoglobulin loci are susceptible to AID activity is unknown. Here, we study AID-mediated lesions in the context of nuclear architecture and the B cell regulome. We show that AID targets are not randomly distributed across the genome but are predominantly grouped within super-enhancers and regulatory clusters. Unexpectedly, in these domains, AID deaminates active promoters and eRNA(+) enhancers interconnected in some instances over megabases of linear chromatin. Using genome editing, we demonstrate that 3D-linked targets cooperate to recruit AID-mediated breaks. Furthermore, a comparison of hypermutation in mouse B cells, AID-induced kataegis in human lymphomas, and translocations in MEFs reveals that AID damages different genes in different cell types. Yet, in all cases, the targets are predominantly associated with topological complex, highly transcribed super-enhancers, demonstrating that these compartments are key mediators of AID recruitment.

Co-transplantation of autologous Treg cells in a cell therapy for Parkinson's disease.

The specific loss of midbrain dopamine neurons (mDANs) causes major motor dysfunction in Parkinson's disease, which makes cell replacement a promising therapeutic approach1-4. However, poor survival of grafted mDANs remains an obstacle to successful clinical outcomes5-8. Here we show that the surgical procedure itself (referred to here as 'needle trauma') triggers a profound host response that is characterized by acute neuroinflammation, robust infiltration of peripheral immune cells and brain cell death. When midbrain dopamine (mDA) cells derived from human induced pluripotent stem (iPS) cells were transplanted into the rodent striatum, less than 10% of implanted tyrosine hydroxylase (TH)+ mDANs survived at two weeks after transplantation. By contrast, TH- grafted cells mostly survived. Notably, transplantation of autologous regulatory T (Treg) cells greatly modified the response to needle trauma, suppressing acute neuroinflammation and immune cell infiltration. Furthermore, intra-striatal co-transplantation of Treg cells and human-iPS-cell-derived mDA cells significantly protected grafted mDANs from needle-trauma-associated death and improved therapeutic outcomes in rodent models of Parkinson's disease with 6-hydroxydopamine lesions. Co-transplantation with Treg cells also suppressed the undesirable proliferation of TH- grafted cells, resulting in more compact grafts with a higher proportion and higher absolute numbers of TH+ neurons. Together, these data emphasize the importance of the initial inflammatory response to surgical injury in the differential survival of cellular components of the graft, and suggest that co-transplanting autologous Treg cells effectively reduces the needle-trauma-induced death of mDANs, providing a potential strategy to achieve better clinical outcomes for cell therapy in Parkinson's disease.

Author Correction: The Apostasia genome and the evolution of orchids.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PARP1 recruits DNA translocases to restrain DNA replication and facilitate DNA repair.

Replication fork reversal which restrains DNA replication progression is an important protective mechanism in response to replication stress. PARP1 is recruited to stalled forks to restrain DNA replication. However, PARP1 has no helicase activity, and the mechanism through which PARP1 participates in DNA replication restraint remains unclear. Here, we found novel protein-protein interactions between PARP1 and DNA translocases, including HLTF, SHPRH, ZRANB3, and SMARCAL1, with HLTF showing the strongest interaction among these DNA translocases. Although HLTF and SHPRH share structural and functional similarity, it remains unclear whether SHPRH contains DNA translocase activity. We further identified the ability of SHPRH to restrain DNA replication upon replication stress, indicating that SHPRH itself could be a DNA translocase or a helper to facilitate DNA translocation. Although hydroxyurea (HU) and MMS induce different types of replication stress, they both induce common DNA replication restraint mechanisms independent of intra-S phase activation. Our results suggest that the PARP1 facilitates DNA translocase recruitment to damaged forks, preventing fork collapse and facilitating DNA repair.

Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance.

BACKGROUND: Although DHFR gene amplification has long been known as a major mechanism for methotrexate (MTX) resistance in cancer, the early changes and detailed development of the resistance are not yet fully understood. METHODS: We performed genomic, transcriptional and proteomic analyses of human colon cancer cells with sequentially increasing levels of MTX-resistance. RESULTS: The genomic amplification evolved in three phases (pre-amplification, homogenously staining region (HSR) and extrachromosomal DNA (ecDNA)). We confirm that genomic amplification and increased expression of DHFR, with formation of HSRs and especially ecDNAs, is the major driver of resistance. However, DHFR did not play a detectable role in the early phase. In the late phase (ecDNA), increase in FAM151B protein level may also have an important role by decreasing sensitivity to MTX. In addition, although MSH3 and ZFYVE16 may be subject to different posttranscriptional regulations and therefore protein expressions are decreased in ecDNA stages compared to HSR stages, they still play important roles in MTX resistance. CONCLUSION: The study provides a detailed evolutionary trajectory of MTX-resistance and identifies new targets, especially ecDNAs, which could help to prevent drug resistance. It also presents a proof-of-principal approach which could be applied to other cancer drug resistance studies.

Supermolecular Confined Silicon Phosphorescence Nanoprobes for Time-Resolved Hypoxic Imaging Analysis.

Room temperature phosphorescence (RTP) nanoprobes play crucial roles in hypoxia imaging due to their high signal-to-background ratio (SBR) in the time domain. However, synthesizing RTP probes in aqueous media with a small size and high quantum yield remains challenging for intracellular hypoxic imaging up to present. Herein, aqueous RTP nanoprobes consisting of naphthalene anhydride derivatives, cucurbit[7]uril (CB[7]), and organosilicon are reported via supermolecular confined methods. Benefiting from the noncovalent confinement of CB[7] and hydrolysis reactions of organosilicon, such small-sized RTP nanoprobes (5-10 nm) exhibit inherent tunable phosphorescence (from 400 to 680 nm) with microsecond second lifetimes (up to ∼158.7 µs) and high quantum yield (up to ∼30%). The as-prepared RTP nanoprobes illustrate excellent intracellular hypoxia responsibility in a broad range from ∼0.1 to 21% oxygen concentrations. Compared to traditional fluorescence mode, the SBR value (∼108.69) of microsecond-range time-resolved in vitro imaging is up to 2.26 times greater in severe hypoxia (<0.1% O2), offering opportunities for precision imaging analysis in a hypoxic environment.

DNA Origami Plasmonic Nanoantenna for Programmable Biosensing of Multiple Cytokines in Cancer Immunotherapy.

Herein, we report a DNA origami plasmonic nanoantenna for the programmable surface-enhanced Raman scattering (SERS) detection of cytokine release syndrome (CRS)-associated cytokines (e.g., tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)) in cancer immunotherapy. Typically, the nanoantenna was made of self-assembled DNA origami nanotubes (diameter: ∼19 nm; length: ∼90 nm) attached to a silver nanoparticle-modified silicon wafer (AgNP/Si). Each DNA origami nanotube contains one miniature gold nanorod (AuNR) inside (e.g., length: ∼35 nm; width: ∼7 nm). Intriguingly, TNF-α and IFN-γ logically regulate the opening of the nanotubes and the dissociation of the AuNRs from the origami structure upon binding to their corresponding aptamers. On this basis, we constructed a complete set of Boolean logic gates that read cytokine molecules as inputs and return changes in Raman signals as outputs. Significantly, we demonstrated that the presented system enables the quantification of TNF-α and IFN-γ in the serum of tumor-bearing mice receiving different types of immunotherapies (e.g., PD1/PD-L1 complex inhibitors and STING agonists). The sensing results are consistent with those of the ELISA. This strategy fills a gap in the use of DNA origami for the detection of multiple cytokines in real systems.

LI-RADS CT and MRI Ancillary Feature Association with Hepatocellular Carcinoma and Malignancy: An Individual Participant Data Meta-Analysis.

Background The independent contribution of each Liver Imaging Reporting and Data System (LI-RADS) CT or MRI ancillary feature (AF) has not been established. Purpose To evaluate the association of LI-RADS AFs with hepatocellular carcinoma (HCC) and malignancy while adjusting for LI-RADS major features through an individual participant data (IPD) meta-analysis. Materials and Methods Medline, Embase, Cochrane Central Register of Controlled Trials, and Scopus were searched from January 2014 to January 2022 for studies evaluating the diagnostic accuracy of CT and MRI for HCC using LI-RADS version 2014, 2017, or 2018. Using a one-step approach, IPD across studies were pooled. Adjusted odds ratios (ORs) and 95% CIs were derived from multivariable logistic regression models of each AF combined with major features except threshold growth (excluded because of infrequent reporting). Liver observation clustering was addressed at the study and participant levels through random intercepts. Risk of bias was assessed using a composite reference standard and Quality Assessment of Diagnostic Accuracy Studies 2. Results Twenty studies comprising 3091 observations (2456 adult participants; mean age, 59 years ± 11 [SD]; 1849 [75.3%] men) were included. In total, 89% (eight of nine) of AFs favoring malignancy were associated with malignancy and/or HCC, 80% (four of five) of AFs favoring HCC were associated with HCC, and 57% (four of seven) of AFs favoring benignity were negatively associated with HCC and/or malignancy. Nonenhancing capsule (OR = 3.50 [95% CI: 1.53, 8.01]) had the strongest association with HCC. Diffusion restriction (OR = 14.45 [95% CI: 9.82, 21.27]) and mild-moderate T2 hyperintensity (OR = 10.18 [95% CI: 7.17, 14.44]) had the strongest association with malignancy. The strongest negative associations with HCC were parallels blood pool enhancement (OR = 0.07 [95% CI: 0.01, 0.49]) and marked T2 hyperintensity (OR = 0.18 [95% CI: 0.07, 0.45]). Seventeen studies (85%) had a high risk of bias. Conclusion Most LI-RADS AFs were independently associated with HCC, malignancy, or benignity as intended when adjusting for major features. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Crivellaro in this issue.

Defect-Rich Metastable MoS2 Promotes Macrophage Reprogramming in Breast Cancer: A Clinical Perspective.

Tumor-associated macrophages (TAMs) play a crucial function in solid tumor antigen clearance and immune suppression. Notably, 2D transitional metal dichalcogenides (i.e., molybdenum disulfide (MoS2) nanozymes) with enzyme-like activity are demonstrated in animal models for cancer immunotherapy. However, in situ engineering of TAMs polarization through sufficient accumulation of free radical reactive oxygen species for immunotherapy in clinical samples remains a significant challenge. In this study, defect-rich metastable MoS2 nanozymes, i.e., 1T2H-MoS2, are designed via reduction and phase transformation in molten sodium as a guided treatment for human breast cancer. The as-prepared 1T2H-MoS2 exhibited enhanced peroxidase-like activity (≈12-fold enhancement) than that of commercial MoS2, which is attributed to the charge redistribution and electronic state induced by the abundance of S vacancies. The 1T2H-MoS2 nanozyme can function as an extracellular hydroxyl radical generator, efficiently repolarizing TAMs into the M1-like phenotype and directly killing cancer cells. Moreover, the clinical feasibility of 1T2H-MoS2 is demonstrated via ex vivo therapeutic responses in human breast cancer samples. The apoptosis rate of cancer cells is 3.4 times greater than that of cells treated with chemotherapeutic drugs (i.e., doxorubicin).

Atomic Imaging of Multi-Dimensional Ruddlesden-Popper Interfaces in Lead-Halide Perovskites.

Ruddlesden-Popper (RP) interface with defined stacking structure will fundamentally influence the optoelectronic performances of lead-halide perovskite (LHP) materials and devices. However, it remains challenging to observe the atomic local structures in LHPs, especially for multi-dimensional RP interface hidden inside the nanocrystal. In this work, the advantages of two imaging modes in scanning transmission electron microscopy (STEM), including high-angle annular dark field (HAADF) and integrated differential phase contrast (iDPC) STEM, are successfully combined to study the bulk and local structures of inorganic and organic/inorganic hybrid LHP nanocrystals. Then, the multi-dimensional RP interfaces in these LHPs are atomically resolved with clear gap and blurred transition region, respectively. In particular, the complex interface by the RP stacking in 3D directions can be analyzed in 2D projected image. Finally, the phase transition, ion missing, and electronic structures related to this interface are investigated. These results provide real-space evidence for observing and analyzing atomic multi-dimensional RP interfaces, which may help to better understand the structure-property relation of LHPs, especially their complex local structures.

Allosteric Regulation and Inhibition of Coronavirus 3CLpro Revealed by HDX-MS.

Coronavirus (CoV) infections have caused contagious and fatal respiratory diseases in humans worldwide. CoV 3-chymotrypsin-like proteases (3CLpro or Mpro) play an important role in viral maturation, and maintenance of their dimeric conformation is crucial for viral activity. Therefore, allosterically regulated dimerization of 3CLpro can be employed as a drug development target. Here, we investigated the allosteric regulatory mechanism of 3CLpro dimerization by using hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) technology. We found that the FLAG tag directly coupled to the N-finger of 3CLpro significantly increased HDX kinetics at the dimer interface, and 3CLpro transformed from a dimer to a monomer. The 3CLpro mutants of SARS-CoV-2, which are monomeric, also exhibited increased deuterium exchange. Binding of the allosteric inhibitor Gastrodenol to most betacoronavirus 3CLpros led to increased allosteric deuterium exchange, resulting in the monomeric conformation of the CoV 3CLpro upon binding. Molecular dynamics (MD) simulation analysis further indicated the molecular mechanism of action of Gastrodenol on CoV 3CLpro: binding of Gastrodenol to SARS-CoV-2 3CLpro destroyed the hydrogen bond in the dimer interface. These results suggest that Gastrodenol may be a potential broad-spectrum anti-betacoronavirus drug.

Gongronella sp. w5 hydrolyzes plant sucrose and releases fructose to recruit phosphate-solubilizing bacteria to provide plants with phosphorus.

The mechanisms of how plant-beneficial rhizospheric fungi interact with the soil microbial community to promote plant growth by facilitating their phosphorus acquisition are poorly understood. This work supported that a Mucoromycotina fungus, Gongronella sp. w5 (w5), could promote phosphorus uptake of Medicago truncatula by increasing the available phosphorus (P) in the soil. The abundance of phosphate-solubilizing bacteria (PSB) and the activity of alkaline phosphatase (ALP) in alfalfa rhizosphere soil increased after w5 inoculation. Further analysis showed that w5 donated a portion of ALP activity and also stimulated the PSB to secrete ALP during plant-w5-PSB interaction to help release more available P in the rhizosphere of M. truncatula. Unlike most plant-beneficial rhizospheric fungi that mainly acquire hexoses from plants, w5 gained sucrose directly from the host plant and then recruited PSB to aid P acquisition by hydrolyzing sucrose and releasing mainly fructose to induce PSB to secrete ALP. IMPORTANCE: This work supported that after absorbing plant sucrose, Gongronella sp. w5 mainly releases sucrose hydrolysis product fructose into the environment. Fructose was used as a carbon source and signaling molecules to induce PSB to co-produce higher alkaline phosphatase activity, releasing soil-available phosphorus and promoting M. truncatula growth. This is the first report that plant-beneficial fungi could directly metabolize sucrose from plants and then recruit PSB to aid P acquisition by providing fructose. Our findings revealed the diversity in pathways of plant-fungi-PSB interactions on soil P acquisition and deepened our understanding of the cooperation of growth-promoting microorganisms in plant rhizosphere.

Fully automated hybrid approach on conventional MRI for triaging clinically significant liver fibrosis: A multi-center cohort study.

Establishing reliable noninvasive tools to precisely diagnose clinically significant liver fibrosis (SF, ≥F2) remains an unmet need. We aimed to build a combined radiomics-clinic (CoRC) model for triaging SF and explore the additive value of the CoRC model to transient elastography-based liver stiffness measurement (FibroScan, TE-LSM). This retrospective study recruited 595 patients with biopsy-proven liver fibrosis at two centers between January 2015 and December 2021. At Center 1, the patients before December 2018 were randomly split into training (276) and internal test (118) sets, the remaining were time-independent as a temporal test set (96). Another data set (105) from Center 2 was collected for external testing. Radiomics scores were built with selected features from Deep learning-based (ResUNet) automated whole liver segmentations on MRI (T2FS and delayed enhanced-T1WI). The CoRC model incorporated radiomics scores and relevant clinical variables with logistic regression, comparing routine approaches. Diagnostic performance was evaluated by the area under the receiver operating characteristic curve (AUC). The additive value of the CoRC model to TE-LSM was investigated, considering necroinflammation. The CoRC model achieved AUCs of 0.79 (0.70, 0.86), 0.82 (0.73, 0.89), and 0.81 (0.72-0.91), outperformed FIB-4, APRI (all p < 0.05) in the internal, temporal, and external test sets and maintained the discriminatory power in G0-1 subgroups (AUCs range, 0.85-0.86; all p < 0.05). The AUCs of joint CoRC-LSM model were 0.86 (0.79-0.94), and 0.81 (0.72-0.90) in the internal and temporal sets (p = 0.01). The CoRC model was useful for triaging SF, and may add value to TE-LSM.

Facile Synthesis of Rigid Binuclear Manganese Complexes for Magnetic Resonance Angiography and SLC39A14-Mediated Hepatic Imaging.

Manganese(II)-based contrast agents (MBCAs) are potential candidates for gadolinium-free enhanced magnetic resonance imaging (MRI). In this work, a rigid binuclear MBCA (Mn2-PhDTA2) with a zero-length linker was developed via facile synthetic routes, while the other dimer (Mn2-TPA-PhDTA2) with a longer rigid linker was also synthesized via more complex steps. Although the molecular weight of Mn2-PhDTA2 is lower than that of Mn2-TPA-PhDTA2, their T1 relaxivities are similar, being increased by over 71% compared to the mononuclear Mn-PhDTA. In the presence of serum albumin, the relaxivity of Mn2-PhDTA2 was slightly lower than that of Mn2-TPA-PhDTA2, possibly due to the lower affinity constant. The transmetalation reaction with copper(II) ions confirmed that Mn2-PhDTA2 has an ideal kinetic inertness with a dissociation half-life of approximately 10.4 h under physiological conditions. In the variable-temperature 17O NMR study, both Mn-PhDTA and Mn2-PhDTA2 demonstrated a similar estimated q close to 1, indicating the formation of monohydrated complexes with each manganese(II) ion. In addition, Mn2-PhDTA2 demonstrated a superior contrast enhancement to Mn-PhDTA in in vivo vascular and hepatic MRI and can be rapidly cleared through a dual hepatic and renal excretion pattern. The hepatic uptake mechanism of Mn2-PhDTA2 mediated by SLC39A14 was validated in cellular uptake studies.

Prediction model based on MRI morphological features for distinguishing benign and malignant thyroid nodules.

BACKGROUND: The low specificity of Thyroid Imaging Reporting and Data System (TI-RADS) for preoperative benign-malignant diagnosis leads to a large number of unnecessary biopsies. This study developed and validated a predictive model based on MRI morphological features to improve the specificity. METHODS: A retrospective analysis was conducted on 825 thyroid nodules pathologically confirmed postoperatively. Univariate and multivariate logistic regression were used to obtain ß coefficients, construct predictive models and nomogram incorporating MRI morphological features in the training cohort, and validated in the validation cohort. The discrimination, calibration, and decision curve analysis of the nomogram were performed. The diagnosis efficacy, area under the curve (AUC) and net reclassification index (NRI) were calculated and compared with TI-RADS. RESULTS: 572 thyroid nodules were included (training cohort: n = 397, validation cohort: n = 175). Age, low signal intensity on T2WI, restricted diffusion, reversed halo sign in delay phase, cystic degeneration and wash-out pattern were independent predictors of malignancy. The nomogram demonstrated good discrimination and calibration both in the training cohort (AUC = 0.972) and the validation cohort (AUC = 0.968). The accuracy, sensitivity, specificity, PPV, NPV and AUC of MRI-based prediction were 94.4%, 96.0%, 93.4%, 89.9%, 96.5% and 0.947, respectively. The MRI-based prediction model exhibited enhanced accuracy (NRI>0) in comparison to TI-RADSs. CONCLUSIONS: The prediction model for diagnosis of benign and malignant thyroid nodules demonstrated a more notable diagnostic efficacy than TI-RADS. Compared with the TI-RADSs, predictive model had better specificity along with a high sensitivity and can reduce overdiagnosis and unnecessary biopsies.

Abdominal Diffusion-Weighted MRI With Simultaneous Multi-Slice Acquisition: Agreement and Reproducibility of Apparent Diffusion Coefficients Measurements.

BACKGROUND: Simultaneous multi-slice diffusion-weighted imaging (SMS-DWI) can shorten acquisition time in abdominal imaging. PURPOSE: To investigate the agreement and reproducibility of apparent diffusion coefficient (ADC) from abdominal SMS-DWI acquired with different vendors and different breathing schemes. STUDY TYPE: Prospective. SUBJECTS: Twenty volunteers and 10 patients. FIELD STRENGTH/SEQUENCE: 3.0 T, SMS-DWI with a diffusion-weighted echo-planar imaging sequence. ASSESSMENT: SMS-DWI was acquired using breath-hold and free-breathing techniques in scanners from two vendors, yielding four scans in each participant. Average ADC values were measured in the liver, pancreas, spleen, and both kidneys. Non-normalized ADC and ADCs normalized to the spleen were compared between vendors and breathing schemes. STATISTICAL TESTS: Paired t-test or Wilcoxon signed rank test; intraclass correlation coefficient (ICC); Bland-Altman method; coefficient of variation (CV) analysis; significance level: P < 0.05. RESULTS: Non-normalized ADCs from the four SMS-DWI scans did not differ significantly in the spleen (P = 0.262, 0.330, 0.166, 0.122), right kidney (P = 0.167, 0.538, 0.957, 0.086), and left kidney (P = 0.182, 0.281, 0.504, 0.405), but there were significant differences in the liver and pancreas. For normalized ADCs, there were no significant differences in the liver (P = 0.315, 0.915, 0.198, 0.799), spleen (P = 0.815, 0.689, 0.347, 0.423), pancreas (P = 0.165, 0.336, 0.304, 0.584), right kidney (P = 0.165, 0.336, 0.304, 0.584), and left kidney (P = 0.496, 0.304, 0.443, 0.371). Inter-reader agreements of non-normalized ADCs were good to excellent (ICCs ranged from 0.861 to 0.983), and agreement and reproducibility were good to excellent depending on anatomic location (CVs ranged from 3.55% to 13.98%). Overall CVs for abdominal ADCs from the four scans were 6.25%, 7.62%, 7.08, and 7.60%. DATA CONCLUSION: The normalized ADCs from abdominal SMS-DWI may be comparable between different vendors and breathing schemes, showing good agreement and reproducibility. ADC changes above approximately 8% may potentially be considered as a reliable quantitative biomarker to assess disease or treatment-related changes. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

The Chemo-Immunotherapeutic Roles of Tumor-Derived Extracellular Vesicle-Based Paclitaxel Delivery System in Hepatocarcinoma.

As a first-line chemotherapeutic agent, albumin-bound paclitaxel (PA) has a considerable effect on the treatment of various cancers. However, in chemotherapy for hepatocarcinoma, the sensitivity to PA is low owing to the innate resistance of hepatocarcinoma cells; the toxicity and side effects are severe, and the clinical treatment impact is poor. In this study, we present a unique nanodrug delivery system. The ultraviolet (UV)-induced tumor-cell-derived extracellular vesicles (EVs) were isolated and purified by differential centrifugation. Then, PA was loaded by coextrusion to create a vesicle drug delivery system (EVPA). By employing the EV-dependent enhanced retention effect and specific homing effect, EVPA would passively and actively target tumor tissues, activate the immune response to release PA, and achieve the combination therapeutic effect of chemo-immunotherapy on hepatocarcinoma. We demonstrated that the tumor-killing effect of EVPA is superior to that of PA, both in vivo and in vitro and that EVPA can be effectively taken up by hepatocarcinoma and dendritic cells, activate the body's specific immune response, promote the infiltration of CD4+ and CD8+ T cells in tumor tissues, and exert a precise killing effect on hepatocarcinoma cells via chemo-immunotherapy.

Multifunctional, High-Strength Electronic Skin Based on the Natural Sheepskin Fiber Network for Multifaceted Human Health Monitoring and Management.

Inspired by the animal skin fiber network, we developed an electronic skin (e-skin) utilizing natural sheepskin as the primary substrate. This innovative design addresses the limitations of conventional e-skins, including inadequate mechanical strength, overly complex artificial network construction, and limited health monitoring capabilities. This e-skin successfully retains the structure and properties of natural sheepskin while exhibiting exceptional mechanical strength (with a breaking strength of 4.01 MPa) and high elongation (with an elongation at a break of 304.8%). Moreover, it possesses various desirable attributes such as electrical conductivity, antibacterial properties, biocompatibility, and environmental stability. In addition, this e-skin has the advantage of diverse data collection (joint movement, bioelectricity, foot health detection, and speech disorder communication systems). Therefore, this e-skin breaks the traditional construction strategy and single-mode application and is expected to become an ideal material for building smart sensor devices.

Development and validation of a clinical-radiomics model for prediction of prostate cancer: a multicenter study.

PURPOSE: To develop an early diagnosis model of prostate cancer based on clinical-radiomics to improve the accuracy of imaging diagnosis of prostate cancer. METHODS: The multicenter study enrolled a total of 449 patients with prostate cancer from December 2017 to January 2022. We retrospectively collected information from 342 patients who underwent prostate biopsy at Minhang Hospital. We extracted T2WI images through 3D-Slice, and used mask tools to mark the prostate area manually. The radiomics features were extracted by Python using the "Pyradiomics" module. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used for data dimensionality reduction and feature selection, and the radiomics score was calculated according to the correlation coefficients. Multivariate logistic regression analysis was used to develop predictive models. We incorporated the radiomics score, PI-RADS, and clinical features, and this was presented as a nomogram. The model was validated using a cohort of 107 patients from the Xuhui Hospital. RESULTS: In total, 110 effective radiomics features were extracted. Finally, 9 features were significantly associated with the diagnosis of prostate cancer, from which we calculated the radiomics score. The predictors contained in the individualized prediction nomogram included age, fPSA/tPSA, PI-RADS, and radiomics score. The clinical-radiomics model showed good discrimination in the validation cohort (C-index = 0.88). CONCLUSION: This study presents a clinical-radiomics model that incorporates age, fPSA/PSA, PI-RADS, and radiomics score, which can be conveniently used to facilitate individualized prediction of prostate cancer before prostate biopsy.