A mitochondrion-targeted cyanine agent for NIR-II fluorescence-guided surgery combined with intraoperative photothermal therapy to reduce prostate cancer recurrence.

Poorly identified tumor boundaries and nontargeted therapies lead to the high recurrence rates and poor quality of life of prostate cancer patients. Near-infrared-II (NIR-II) fluorescence imaging provides certain advantages, including high resolution and the sensitive detection of tumor boundaries. Herein, a cyanine agent (CY7-4) with significantly greater tumor affinity and blood circulation time than indocyanine green was screened. By binding albumin, the absorbance of CY7-4 in an aqueous solution showed no effects from aggregation, with a peak absorbance at 830 nm and a strong fluorescence emission tail beyond 1000 nm. Due to its extended circulation time (half-life of 2.5 h) and high affinity for tumor cells, this fluorophore was used for primary and metastatic tumor diagnosis and continuous monitoring. Moreover, a high tumor signal-to-noise ratio (up to ~ 10) and excellent preferential mitochondrial accumulation ensured the efficacy of this molecule for photothermal therapy. Therefore, we integrated NIR-II fluorescence-guided surgery and intraoperative photothermal therapy to overcome the shortcomings of a single treatment modality. A significant reduction in recurrence and an improved survival rate were observed, indicating that the concept of intraoperative combination therapy has potential for the precise clinical treatment of prostate cancer.

Flexible Point-of-Care Electrodes for Ultrasensitive Detection of Bladder Tumor-Relevant miRNA in Urine.

Portable point-of-care testing (POCT) is currently drawing enormous attention owing to its great potential for disease diagnosis and personal health management. Electrochemical biosensors, with the intrinsic advantages of cost-effectiveness, fast response, ease of miniaturization, and integration, are considered as one of the most promising candidates for POCT application. However, the clinical application of electrochemical biosensors-based POCT is hindered by the decreased detection sensitivity due to the low abundance of disease-relevant biomolecules in extremely complex biological samples. Herein, we construct a flexible electrochemical biosensor based on single-stranded DNA functionalized single-walled carbon nanotubes (ssDNA-SWNTs) for high sensitivity and stability detection of miRNA-21 in human urine to achieve bladder cancer (BCa) diagnosis and classification. The ssDNA-SWNT electrodes with a 2D interconnected network structure exhibit a high electrical conductivity, thus enabling the ultrasensitive detection of miRNA-21 with a detection limit of 3.0 fM. Additionally, the intrinsic flexibility of ssDNA-SWNT electrodes endows the biosensors with the capability to achieve high stability detection of miRNA-21 even under large bending deformations. In a cohort of 40 BCa patients at stages I-III and 44 negative control samples, the constructed ssDNA-SWNT biosensors could detect BCa with a 92.5% sensitivity, an 88.6% specificity, and classify the cancer stages with an overall accuracy of 81.0%. Additionally, the flexible ssDNA-SWNT biosensors could also be utilized for treatment efficiency assessment and cancer recurrence monitoring. Owing to their excellent sensitivity and stability, the designed flexible ssDNA-SWNT biosensors in this work propose a strategy to realize point-of-care detection of complex clinical samples to achieve personalized healthcare.

Hot Spot Engineering in Hierarchical Plasmonic Nanostructures.

The controllable nanogap structures offer an effective way to obtain strong and tunable localized surface plasmon resonance (LSPR). A novel hierarchical plasmonic nanostructure (HPN) is created by incorporating a rotating coordinate system into colloidal lithography. In this nanostructure, the hot spot density is increased drastically by the long-range ordered morphology with discrete metal islands filled in the structural units. Based on the Volmer-Weber growth theory, the precise HPN growth model is established, which guides the hot spot engineering for improved LSPR tunability and strong field enhancement. The hot spot engineering strategy is examined by the application of HPNs as the surface-enhanced Raman spectroscopy (SERS) substrate. It is universally suitable for various SERS characterization excited at different wavelengths. Based on the HPN and hot spot engineering strategy, single-molecule level detection and long-range mapping can be realized simultaneously. In that sense, it offers a great platform and guides the future design for various LSPR applications like surface-enhanced spectra, biosensing, and photocatalysis.

Polydopamine-Induced Modification on the Highly Charged Surface of Asymmetric Nanofluidics: A Strategy for Adjustable Ion Current Rectification Properties.

Surface charge effects in nanoconfines is one of the fundamentals in the ion current rectification (ICR) of nanofluidics, which provides entropic driving force by asymmetric surface charges and causes ion enrichment/depletion by the electrostatic interaction of fixed surface charges. However, the surface charge effect causes a significant electrostatic repulsion in nanoconfines, restricting additional like charge or elaborate chemistry on the highly charged confined surface, which limits ICR manipulation. Here, we use polydopamine (PDA), a nearly universal adhesive, that adheres to the highly positive-charged poly(ethyleneimine) (PEI) gel network in a nanochannel array. PDA enhances the ICR effect from a low rectification ratio of 9.5 to 92.6 by increasing the surface charge and hydrophobicity of the PEI gel network and, meanwhile, shrinking its gap spacing. Theoretical and experimental results demonstrate the determinants of the fixed surface charge in the enrichment/depletion region on ICR properties, which is adjustable by PDA-induced change in a nanoconfined environment. Chemically active PDA brings Au nanoparticles by chloroauric reduction for further hydrophobization and the modification of negative-charged DNA complexes in nanochannels, whereby ICR effects can be manipulated in versatile means. The results describe an adjustable and versatile strategy for adjusting the ICR behaviors of nanofluidics by manipulating local surface charge effects using PDA.

Development of a four-gene prognostic model for clear cell renal cell carcinoma based on transcriptome analysis.

This study aimed to develop a prognostic model for clear cell renal cell carcinoma (ccRCC) based on transcriptome analysis. We screened Gene Expression Omnibus (GEO) database and the Cancer Genome Atlas (TCGA) database for gene expression data and clinical characteristics of ccRCC. After differentially expression analysis, we identified 533 key genes of the development of ccRCC. Next, a weighted gene co-expression network analysis (WGCNA) was executed to investigate the association between differentially expressed genes and clinical characteristics. Then, based on protein-protein interaction (PPI) network, least absolute shrinkage and selection operator (LASSO) regression and Cox regression, a four-gene (COL4A5, ABCB1, NR3C2 and PLG) prognostic model has been constructed in TCGA training cohort. Finally, we examined the predictive power of this model with survival analysis and receiver operating characteristic (ROC) curve both in training cohort and in validation cohorts. And we found this model was significantly correlated with infiltrating immune cells. The four-gene prognosis model could be a potential prediction tool with high accuracy and reliability for ccRCC patients.

Biologically Safe, Versatile, and Smart Bismuthene Functionalized with a Drug Delivery System Based on Red Phosphorus Quantum Dots for Cancer Theranostics.

Two-dimensional nanomaterials are attracting attention for cancer therapy. However, high toxicity, insensitivity to external stimuli and single therapeutic modality are still key issues hindering their clinical application. Therefore, the construction of a safe, intelligent and versatile nanocomposite is needed to meet clinical expectations. Herein, we developed a nanocomposite of Bi@RP-PEG-DOX with 2D bismuthene loaded with 0D red phosphorus quantum dots and DOX. The nanocomposite with DOX loading capacity (ca. 250 %) and photothermal conversion efficiency (ca. 54 %) showed both photothermal and photodynamic effects and a sensitive response of drug release to the acidic tumor microenvironment or NIR II laser irradiation. The nanocomposite exhibits good biosafety. Through the X-ray attenuation properties of bismuth, the nanocomposite serves as an excellent CT contrast agent, providing potential to perform CT-guided therapy.

Ionic Signal Enhancement by the Space Charge Effect through the DNA Rolling Circle Amplification on the Outer Surface of Nanochannels.

DNA species are recognized as a powerful probe for nanochannel analyses to address the issues of specific target recognition and highly efficient signal conversion due to their programmable and predictable Watson-Crick bases. However, in the conventional view, abundant sophisticated DNA structures synthesized by DNA amplification strategies are unsuitable for use in nanochannel analyses owing to their low probability to enter a nanochannel restricted by the smaller opening of the nanochannel, as well as the faint ion signal produced by the steric effect. Here, we present an integrated strategy of nanochannel analyses that combines the target recognitions by encoded rolling circle amplification (RCA) in solution and the ionic signal enhancement by the space charge effect through the immobilization of highly negative-charged RCA amplicons on the outer surface of the nanochannels. Owing to the highly negative-charged RCA amplicons with 100 nm sizes, a sharp increase of ionic current up to 7454% has been achieved. The RCA amplicon triggered by mRNA-21 on the outer surface of the poly(ethylene terephthalate) membrane with a single nanochannel realized the single-base mismatch detection of mRNA-21 with a sensitivity of 6 fM. The DNA amplicon endows the nanochannel with high sensitivity and selectivity that could extend to other applications, such as DNA sequencing, desalination, sieving, and water-energy nexus.

CENPA promotes clear cell renal cell carcinoma progression and metastasis via Wnt/ß-catenin signaling pathway.

Clear cell renal cell carcinoma (ccRCC) is the most common malignant tumor of the kidney. New and reliable biomarkers are in urgent need for ccRCC diagnosis and prognosis. The CENP family is overexpressed in many types of cancers, but its functions in ccRCC have not been fully clarified. In this paper, we found that several CENP family members were highly expressed in ccRCC tissues. Also, CENPA expression level was related to clinicopathological grade and prognosis by weighted gene co-expression network analysis (WGCNA). CENPA served as a representative CENP family member as a ccRCC biomarker. Further in vitro experiments verified that overexpression of CENPA promoted ccRCC proliferation and metastasis by accelerating the cell cycle and activating the Wnt/ß-catenin signaling pathway. The elevated ß-catenin led by CENPA overexpression translocated to nucleus for downstream effect. Functional recovery experiment confirmed that Wnt/ß-catenin pathway was essential for ccRCC progression and metastasis. Developing selective drugs targeting CENPA may be a promising direction for cancer treatment.

IMPDH1/YB-1 Positive Feedback Loop Assembles Cytoophidia and Represents a Therapeutic Target in Metastatic Tumors.

Recently, cytoophidium, a nonmembrane-bound intracellular polymeric structure, has been shown to exist in various organisms, including tumor tissues, but its function and mechanism have not yet been examined. Examination of cytoophidia-assembled gene inosine monophosphate dehydrogenase (IMPDH) and cytidine triphosphate synthetase (CTPS) mRNA levels showed that only IMPDH1 levels were significantly higher in the clear cell renal cell carcinoma (ccRCC). IMPDH1 was positively correlated with the metastasis-related gene Y-box binding protein 1 (YB-1) and served as an independent prognostic factor in ccRCC. Kaplan-Meier analysis indicated that patients with tumors that expressed high IMPDH1 levels had a shorter overall survival (OS) and disease-free survival (DFS). Furthermore, detection of cytoophidia by immunofluorescence staining in ccRCC tissues showed that IMPDH1-assembled cytoophidia are positively associated with tumor metastasis. Mechanistically, IMPDH1 and YB-1 formed an autoregulatory positive feedback loop: IMPDH1 maintained YB-1 protein stabilization; YB-1 induced IMPDH1 expression by binding to the IMPDH1 promoter motif. Functionally, IMPDH1-assembled cytoophidia physically interacted with YB-1 and translocated YB-1 into the cell nucleus, thus correlating with ccRCC metastasis. Our findings provide the first solid theoretical rationale for targeting the IMPDH1/YB-1 axis to improve metastatic renal cancer treatment.

Miniature Hollow Gold Nanorods with Enhanced Effect for In Vivo Photoacoustic Imaging in the NIR-II Window.

The miniaturization of gold nanorods exhibits a bright prospect for intravital photoacoustic imaging (PAI) and the hollow structure possesses a better plasmonic property. Herein, miniature hollow gold nanorods (M-AuHNRs) (≈46 nm in length) possessing strong plasmonic absorbance in the second near-infrared (NIR-II) window (1000-1350 nm) are developed, which are considered as the most suitable range for the intravital PAI. The as-prepared M-AuHNRs exhibit 3.5 times stronger photoacoustic signal intensity than the large hollow Au nanorods (≈105 nm in length) at 0.2 optical density under 1064 nm laser irradiation. The in vivo biodistribution measurement shows that the accumulation in tumor of miniature nanorods is twofold as high as that of the large counterpart. After modifying with a tumor-targeting molecule and fluorochrome, in living tumor-bearing mice, the M-AuHNRs group gives a high fluorescence intensity in tumors, which is 3.6-fold that of the large ones with the same functionalization. Moreover, in the intravital PAI of living tumor-bearing mice, the M-AuHNRs generate longer-lasting and stronger photoacoustic signal than the large counterpart in the NIR-II window. Overall, this study presents the fabrication of M-AuHNRs as a promising contrast agent for intravital PAI.

ELL Protein-associated Factor 2 (EAF2) Inhibits Transforming Growth Factor ß Signaling through a Direct Interaction with Smad3.

A series of in vitro and in vivo studies has shown that EAF2 can affect multiple signaling pathways involved in cellular processes. However, the molecular mechanisms underlying its effects have remained elusive. Here we report the discovery of a new functional link between EAF2 and TGF-ß signaling. Promoter reporter assays indicated that EAF2 suppresses Smad3 transcriptional activity, resulting in inhibition of TGF-ß signaling. Coimmunoprecipitation assays showed that EAF2 specifically interacts with Smad3 in vitro and in vivo but not with other Smad proteins. In addition, we observed that EAF2 binding does not alter Smad3 phosphorylation but causes Smad3 cytoplasmic retention, competes with Smad4 for binding to Smad3, and prevents p300-Smad3 complex formation. Furthermore, we demonstrated that EAF2 suppresses both TGF-ß-induced G1 cell cycle arrest and TGF-ß-induced cell migration. This study identifies and characterizes a novel repressor of TGF-ß signaling.

Quencher group induced high specificity detection of telomerase in clear and bloody urines by AIEgens.

Telomerase is a widely used tumor biomarker for early cancer diagnosis. On the basis of the combined use of aggregation-induced emission (AIE) fluorogens and quencher, a quencher group induced high specificity strategy for detection of telomerase activity from cell extracts and cancer patients' urine specimens was creatively developed. In the absence of telomerase, fluorescence background is extremely low due to the short distance between quencher and AIE dye. In the addition of telomerase, fluorescence enhances significantly. The telomerase activity in the E-J, MCF-7, and HeLa extracts equivalent to 5-10 000 cells can be detected by this method in ∼1 h. Furthermore, the distinguishing of telomerase extracted from 38 cancer and 15 normal urine specimens confirms the reliability and practicality of this protocol. In contrast to our previous results (Anal. Chem. 2015, 87, 6822-6827), these advanced experiments obtain more remarkable specificity.

Finite-time adaptive super-twisting sliding mode control for autonomous robotic manipulators with actuator faults.

This paper proposes a new adaptive super-twisting global integral terminal sliding mode control algorithm for the trajectory tracking of autonomous robotic manipulators with uncertain parameters, unknown disturbances, and actuator faults. Firstly, a novel global integral terminal sliding mode surface is designed to ensure that the tracking errors of autonomous robotic manipulators converge to zero in finite time and the global robustness of the system is also enhanced. Then a new adaptive method is devised to deal with the adverse effect of nonlinear uncertainty. To suppress the chattering phenomenon, the adaptive super-twisting algorithm is used in this paper, which can ensure that the control torque is a continuous input signal. Based on the adaptive mechanism, the adaptive super-twisting global integral terminal sliding mode controller is developed to provide superior control performance. The stability analysis of the system is demonstrated by using the Lyapunov method. Ultimately, the effectiveness of the control scheme is confirmed by a simulation study.

In Situ Mitochondrial Biomineralization for Drug-Free Cancer Therapy.

The common clinical chemotherapy often brings serious side effects to patients, mainly due to the off-target and leakage of toxic drugs. However, this is fatal for some specific clinical tumors, such as brain tumors and neuroma. This study performs a drug-free approach by encapsulating black phosphorus (BP) and calcium peroxide (CaO2) in liposomes with surface-modified triphenylphosphonium (BCLT) to develop mitochondria targeting calcification for cancer therapy without damaging normal cells. BCLT preferentially accumulates inside tumor mitochondria and then is activated by near-infrared (NIR) laser irradiation to produce abundant PO4 3- and Ca2+ to accelerate in situ mitochondrial mineralization, leading to mitochondrial dysfunction and cancer cell death. More importantly, both PO4 3- and Ca2+ are essential components of metabolism in the body, and random gradient diffusion or premature leakage does not cause damage to adjacent normal cells. This achievement promises to be an alternative to conventional chemotherapy in clinical practice for many specific tumor types.

TransVFS: A spatio-temporal local-global transformer for vision-based force sensing during ultrasound-guided prostate biopsy.

Robot-assisted prostate biopsy is a new technology to diagnose prostate cancer, but its safety is influenced by the inability of robots to sense the tool-tissue interaction force accurately during biopsy. Recently, vision based force sensing (VFS) provides a potential solution to this issue by utilizing image sequences to infer the interaction force. However, the existing mainstream VFS methods cannot realize the accurate force sensing due to the adoption of convolutional or recurrent neural network to learn deformation from the optical images and some of these methods are not efficient especially when the recurrent convolutional operations are involved. This paper has presented a Transformer based VFS (TransVFS) method by leveraging ultrasound volume sequences acquired during prostate biopsy. The TransVFS method uses a spatio-temporal local-global Transformer to capture the local image details and the global dependency simultaneously to learn prostate deformations for force estimation. Distinctively, our method explores both the spatial and temporal attention mechanisms for image feature learning, thereby addressing the influence of the low ultrasound image resolution and the unclear prostate boundary on the accurate force estimation. Meanwhile, the two efficient local-global attention modules are introduced to reduce 4D spatio-temporal computation burden by utilizing the factorized spatio-temporal processing strategy, thereby facilitating the fast force estimation. Experiments on prostate phantom and beagle dogs show that our method significantly outperforms existing VFS methods and other spatio-temporal Transformer models. The TransVFS method surpasses the most competitive compared method ResNet3dGRU by providing the mean absolute errors of force estimation, i.e., 70.4 ± 60.0 millinewton (mN) vs 123.7 ± 95.6 mN, on the transabdominal ultrasound dataset of dogs.

Circularly polarized light emission and detection by chiral inorganic semiconductors.

Chiral inorganic semiconductors with high dissymmetric factor are highly desirable, but it is generally difficult to induce chiral structure in inorganic semiconductors because of their structure rigidity and symmetry. In this study, we introduced chiral ZnO film as hard template to transfer chirality to CsPbBr3 film and PbS quantum dots (QDs) for circularly polarized light (CPL) emission and detection, respectively. The prepared CsPbBr3/ZnO thin film exhibited CPL emission at 520 nm and the PbS QDs/ZnO film realized CPL detection at 780 nm, featuring high dissymmetric factor up to around 0.4. The electron transition based mechanism is responsible for chirality transfer.

Stimuli-Responsive Ion Transport Regulation in Nanochannels by Adhesion-Induced Functionalization of Macroscopic Outer Surface.

Responsive regulation of ion transport through nanochannels is crucial in the design of smart nanofluidic devices for sequencing, sensing, and water-energy nexus. Functionalization of the inner wall of the nanochannel enhances interaction with ions and fluid but restricts versatile chemical approaches and accurate characterizations of fluidic interfaces. Herein, we reveal a responsive regulating mechanism of ion transport through nanochannels by polydopamine (PDA)-induced functionalization on the macroscopic outer surface of nanochannels. Responsive molecules were codeposited with PDA on the outer surface of nanochannels and formed a valve of nanometer thickness to manually manipulate ion transport by changing its gap spacing, surface charge, and wettability under external stimulus. The response ratio can be up to 100-fold by maximizing the proportion of responsive molecules on the outer surface. Laminating the codepositions of different responsive molecules with PDA on the channel's outer surface produces multiple responses. A nearly universal adhesion of PDA with responsive molecules on the open outer surface induces nanochannels responsive to different external stimuli with variable response ratios and arbitrary combinations. The results challenge the primary role of functionalization on the nanoconfined interface of nanofluidics and open opportunities for developing new-style nanofluidic devices through the functionalization of macroscopic interface.

Natural bioactive lysosomes extracted from multiple cells for tumor therapy.

Nanoparticles of biological origin exhibit many unique properties in biological applications due to their exquisite structure, specific composition, and natural biological functionality. In this study, we obtained lysosomes from three distinct cell types (one normal cell and two activated immune cells) and demonstrated their potential as natural therapeutic nanoparticles for tumor therapy. In vitro experiments revealed that these lysosomes maintained their structural integrity, were well-distributed, and exhibited significant biological activity, which effectively induced cancer cell death by generating ROS and disrupting biological substrates. Additionally, in vivo investigations showed that these lysosomes could accumulate in tumor tissues after intravenous administration and exhibited exceptional therapeutic effects through the destruction of tumor blood vessels and the degradation of immunosuppressive proteins, with complete tumor disappearance in a single treatment. This research on the utilization of bioactive lysosomes for tumor treatment provides valuable insights into drug development and tumor treatment, particularly when conventional approaches have proven ineffective.

A temporal enhanced semi-supervised training framework for needle segmentation in 3D ultrasound images.

Objective.Automated biopsy needle segmentation in 3D ultrasound images can be used for biopsy navigation, but it is quite challenging due to the low ultrasound image resolution and interference similar to the needle appearance. For 3D medical image segmentation, such deep learning networks as convolutional neural network and transformer have been investigated. However, these segmentation methods require numerous labeled data for training, have difficulty in meeting the real-time segmentation requirement and involve high memory consumption.Approach.In this paper, we have proposed the temporal information-based semi-supervised training framework for fast and accurate needle segmentation. Firstly, a novel circle transformer module based on the static and dynamic features has been designed after the encoders for extracting and fusing the temporal information. Then, the consistency constraints of the outputs before and after combining temporal information are proposed to provide the semi-supervision for the unlabeled volume. Finally, the model is trained using the loss function which combines the cross-entropy and Dice similarity coefficient (DSC) based segmentation loss with mean square error based consistency loss. The trained model with the single ultrasound volume input is applied to realize the needle segmentation in ultrasound volume.Main results.Experimental results on three needle ultrasound datasets acquired during the beagle biopsy show that our approach is superior to the most competitive mainstream temporal segmentation model and semi-supervised method by providing higher DSC (77.1% versus 76.5%), smaller needle tip position (1.28 mm versus 1.87 mm) and length (1.78 mm versus 2.19 mm) errors on the kidney dataset as well as DSC (78.5% versus 76.9%), needle tip position (0.86 mm versus 1.12 mm) and length (1.01 mm versus 1.26 mm) errors on the prostate dataset.Significance.The proposed method can significantly enhance needle segmentation accuracy by training with sequential images at no additional cost. This enhancement may further improve the effectiveness of biopsy navigation systems.

Amorphous Albumin Gadolinium-Based Nanoparticles for Ultrahigh-Resolution Magnetic Resonance Angiography.

Magnetic resonance angiography (MRA) contrast agents are extensively utilized in clinical practice due to their capability of improving the image resolution and sensitivity. However, the clinically approved MRA contrast agents have the disadvantages of a limited acquisition time window and high dose administration for effective imaging. Herein, albumin-coated gadolinium-based nanoparticles (BSA-Gd) were meticulously developed for in vivo ultrahigh-resolution MRA. Compared to Gd-DTPA, BSA-Gd exhibits a significantly higher longitudinal relaxivity (r1 = 76.7 mM-1 s-1), nearly 16-fold greater than that of Gd-DTPA, and an extended blood circulation time (t1/2 = 40 min), enabling a dramatically enhanced high-resolution imaging of microvessels (sub-200 µm) and low dose imaging (about 1/16 that of Gd-DTPA). Furthermore, the clinically significant fine vessels were successfully mapped in large mammals, including a circle of Willis, kidney and liver vascular branches, tumor vessels, and differentiated arteries from veins using dynamic contrast-enhanced MRA BSA-Gd, and have superior imaging capability and biocompatibility, and their clinical applications hold substantial promise.