H2S-driven chemotherapy and mild photothermal therapy induced mitochondrial reprogramming to promote cuproptosis.

The elevated level of hydrogen sulfide (H2S) in colon cancer hinders complete cure with a single therapy. However, excessive H2S also offers a treatment target. A multifunctional cascade bioreactor based on the H2S-responsive mesoporous Cu2Cl(OH)3-loaded hypoxic prodrug tirapazamine (TPZ), in which the outer layer was coated with hyaluronic acid (HA) to form TPZ@Cu2Cl(OH)3-HA (TCuH) nanoparticles (NPs), demonstrated a synergistic antitumor effect through combining the H2S-driven cuproptosis and mild photothermal therapy. The HA coating endowed the NPs with targeting delivery to enhance drug accumulation in the tumor tissue. The presence of both the high level of H2S and the near-infrared II (NIR II) irradiation achieved the in situ generation of photothermic agent copper sulfide (Cu9S8) from the TCuH, followed with the release of TPZ. The depletion of H2S stimulated consumption of oxygen, resulting in hypoxic state and mitochondrial reprogramming. The hypoxic state activated prodrug TPZ to activated TPZ (TPZ-ed) for chemotherapy in turn. Furthermore, the exacerbated hypoxia inhibited the synthesis of adenosine triphosphate, decreasing expression of heat shock proteins and subsequently improving the photothermal therapy. The enriched Cu2+ induced not only cuproptosis by promoting lipoacylated dihydrolipoamide S-acetyltransferase (DLAT) heteromerization but also performed chemodynamic therapy though catalyzing H2O2 to produce highly toxic hydroxyl radicals ·OH. Therefore, the nanoparticles TCuH offer a versatile platform to exert copper-related synergistic antitumor therapy.

A chemodynamic nanoenzyme with highly efficient Fenton reaction for cancer therapy.

Chemodynamic therapy (CDT) is a rising technology for cancer therapy by converting intracellular hydrogen peroxide (H2O2) into hydroxyl radical (•OH) via transition-metal-containing nanoparticles (NPs) catalysis reaction (i.e. Fenton reaction) to kill tumor cells. Highly efficient Fenton reaction and favorable delivery of the catalytic NPs 'nanoenzyme' are the key for successful treatment of cancer. In this work, we developed a novel nanoenzyme MnFe2O4@GFP forin vitroandin vivoantitumor therapy. A new MnFe2O4nanoparticle containing two transition-metal-element Fe and Mn was synthesized for enhanced Fenton reaction and used to co-deliver protein with high biocompatibility through post-modification with dopamine polymerization, green fluorescent protein adsorption, and PEG coating. The enrichment of H2O2and glutathione (GSH) in tumor tissue provided a favorable microenvironment forin situgeneration of toxic free radicals. Fe3+and GSH triggered a redox reaction to produce Fe2+, which in turn catalyzed H2O2into •OH, with the consumption of antioxidant GSH. By combining Fe3+with another catalyzer, the catalytic efficiency of the nanoenzyme were greatly improved. Consequently, the nanoenzyme showed efficient antitumor ability bothin vitroandin vivo. Thus, the multifunctional CDT nanoenzyme platform shows great promising for antitumor therapy through the combination of catalyzers Fe3+and Mn2+and codelivery of protein cargo.

A component-optimized chemo-dynamic nanoagent for enhanced tumour cell-selective chemo-dynamic therapy with minimal side effects in a glioma mouse model.

Although CuO-deposited bovine serum albumin (CuO-BSA) and glucose oxidase (GOx) were combined to achieve H2O2 self-supplied chemo-dynamic therapy (CDT) and glucose consumption-based starvation therapy, the uses of copper and GOx have not been optimized to enhance tumour-selective reactive oxygen species (ROS) generation and minimize toxicity to normal cells as well. Here, chemo-dynamic nanoparticles (CBGP NPs) were prepared through a facile biomineralization process and subsequent coatings with GOx and the cationic polymer PEG2k-PEI1.8k. Through optimizing the use of copper, GOx, and PEG2k-PEI1.8k, the CBGP NPs showed high cellular uptake efficiency, enhanced tumour-selective ROS generation, and minimal side effects toward normal cells. The CBGP NP-mediated glucose consumption, GSH-depletion, and ˙OH generation synergistically induced tumour cell apoptosis both in vitro and in vivo. It is believed that the optimized CBGP NPs can be a promising nanoplatform for effective tumour therapy with minimal side effects.

HS-Vectors: Heart Sound Embeddings for Abnormal Heart Sound Detection Based on Time-Compressed and Frequency-Expanded TDNN With Dynamic Mask Encoder.

In recent years, auxiliary diagnosis technology for cardiovascular disease based on abnormal heart sound detection has become a research hotspot. Heart sound signals are promising in the preliminary diagnosis of cardiovascular diseases. Previous studies have focused on capturing the local characteristics of heart sounds. In this paper, we investigate a method for mapping heart sound signals with complex patterns to fixed-length feature embedding called HS-Vectors for abnormal heart sound detection. To get the full embedding of the complex heart sound, HS-Vectors are obtained through the Time-Compressed and Frequency-Expanded Time-Delay Neural Network(TCFE-TDNN) and the Dynamic Masked-Attention (DMA) module. HS-Vectors extract and utilize the global and critical heart sound characteristics by masking out irreverent information. Based on the TCFE-TDNN module, the heart sound signal within a certain time is projected into fixed-length embedding. Then, with a learnable mask attention matrix, DMA stats pooling aggregates multi-scale hidden features from different TCFE-TDNN layers and masks out irrelevant frame-level features. Experimental evaluations are performed on a 10-fold cross-validation task using the 2016 PhysioNet/CinC Challenge dataset and the new publicly available pediatric heart sound dataset we collected. Experimental results demonstrate that the proposed method excels the state-of-the-art models in abnormality detection.

Prognostic Significance of Gene Signature of Tertiary Lymphoid Structures in Patients With Lung Adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is a highly mortal cancer. Tertiary lymphoid structures (TLS) are ectopic lymphoid organs with similar morphological and molecular characters to secondary lymphoid organ. The aim of this study is to investigate the prognostic effect of a gene signature associated with TLSs, including B-cell-specific genes. METHODS: Clinical data of 515 LUAD patients in the TGCA cohort were used to examine the relationship of TLS signature with immune microenvironment, tumor mutational burden (TMB), and driver gene mutations. Patients were divided into the TLS signature high group and TLS signature low group, and comparative analysis of survival and its influencing factors between the two groups was performed. The resulting data were then validated in the GSE37745 cohort. RESULTS: TLS signature high group had significantly better overall survival (OS) and progression-free interval (PFI) as well as significantly higher infiltration of immune cell subsets, cancer immune cycle (CIC) signature except for immunogram score2 (IGS2), and expression of major checkpoint genes than the TLS signature low group. Notably, while TLS signature was not markedly associated with TMB and mutation frequencies of driver genes, there were significant differences in overall survival of patients with given mutation status of EGFR, KRAS, BRAF and TP53 genes between the TLS signature high and low groups. CONCLUSION: This study provided evidence that LUAD patients with high TLS signature had a favorable immune microenvironment and better prognosis, suggesting that TLS signature is an independent positive prognostic factor for LUAD patients.

Adaptive Separation of Respiratory and Heartbeat Signals among Multiple People Based on Empirical Wavelet Transform Using UWB Radar.

The non-contact monitoring of vital signs by radar has great prospects in clinical monitoring. However, the accuracy of separated respiratory and heartbeat signals has not satisfied the clinical limits of agreement. This paper presents a study for automated separation of respiratory and heartbeat signals based on empirical wavelet transform (EWT) for multiple people. The initial boundary of the EWT was set according to the limited prior information of vital signs. Using the initial boundary, empirical wavelets with a tight frame were constructed to adaptively separate the respiratory signal, the heartbeat signal and interference due to unconscious body movement. To verify the validity of the proposed method, the vital signs of three volunteers were simultaneously measured by a stepped-frequency continuous wave ultra-wideband (UWB) radar and contact physiological sensors. Compared with the vital signs from contact sensors, the proposed method can separate the respiratory and heartbeat signals among multiple people and obtain the precise rate that satisfies clinical monitoring requirements using a UWB radar. The detection errors of respiratory and heartbeat rates by the proposed method were within ±0.3 bpm and ±2 bpm, respectively, which are much smaller than those obtained by the bandpass filtering, empirical mode decomposition (EMD) and wavelet transform (WT) methods. The proposed method is unsupervised and does not require reference signals. Moreover, the proposed method can obtain accurate respiratory and heartbeat signal rates even when the persons unconsciously move their bodies.

Exploring the optimal ratio of d-glucose/l-aspartic acid for targeting carbon dots toward brain tumor cells.

Targeting imaging to the desired site of action can increase the accuracy and effectiveness of diagnostic and treatment. In this work, a series of fluorescent carbon dots (CDs) were prepared by varying molar ratios of d-glucose (Glu) to l-aspartic acid (Asp). Their photophysical properties, morphologies and structures were investigated in detail. More important, the targeting ability was screened by confocal laser scanning microscopy and flow cytometry. The results indicate that CDs prepared from the optimal molar ratio of Glu/Asp (7:3) exhibit the highest targeting ability on C6 glioma cells. This work highlights the interplay of molecular design and corresponding functions, and open new possibility of developing state-of-art nanoparticles for biomedical applications.

[Clinical significance of fractional exhaled nitric oxide combined with in vitro allergen test in identifying children at a high risk of asthma among those with recurrent wheezing].

OBJECTIVE: To investigate the clinical value of combined determination of in vitro allergens and fractional exhaled nitric oxide (FeNO) in indentifying children at a high risk of asthma among those with recurrent wheezing. METHODS: A total of 148 children with recurrent wheezing (0.5-6 years old) were enrolled as study subjects, and 80 healthy children who underwent physical examination were enrolled as the control group. Pharmacia UniCAP immunoassay analyzer was used to measure specific immunoglobulin E (sIgE). Nano Coulomb Nitric Oxide Analyzer was used to measure FeNO. The asthma predictive index (API) was evaluated. RESULTS: The recurrent wheezing group had a significantly higher proportion of children with positive sIgE than the control group [68.9% (102/148) vs 11.3% (9/80); P<0.05]. The recurrent wheezing group also had significantly higher levels and positive rate of FeNO than the control group (P<0.05). The overall positive rate of API in children with wheezing was 32.4%, and the API-positive children had a significantly higher FeNO value than the API-negative children (51±6 ppb vs 13±5 ppb; P<0.05). The detection rate of API was 40.2% (41/102) in positive-sIgE children and 50.1% (38/73) in FeNO-positive children, and there was no significant difference between these two groups. The children with positive sIgE and FeNO had a significantly higher detection rate of API (81.4%) than those with positive sIgE or FeNO (P<0.05). CONCLUSIONS: Combined determination of FeNO and in vitro allergens is more sensitive in detecting children at a high risk of asthma than FeNO or in vitro allergens determination alone and provides a good method for early identification, diagnosis, and intervention of asthma in children.

Identification of Buried Objects in GPR Using Amplitude Modulated Signals Extracted from Multiresolution Monogenic Signal Analysis.

It is necessary to detect the target reflections in ground penetrating radar (GPR) images, so that surface metal targets can be identified successfully. In order to accurately locate buried metal objects, a novel method called the Multiresolution Monogenic Signal Analysis (MMSA) system is applied in ground penetrating radar (GPR) images. This process includes four steps. First the image is decomposed by the MMSA to extract the amplitude component of the B-scan image. The amplitude component enhances the target reflection and suppresses the direct wave and reflective wave to a large extent. Then we use the region of interest extraction method to locate the genuine target reflections from spurious reflections by calculating the normalized variance of the amplitude component. To find the apexes of the targets, a Hough transform is used in the restricted area. Finally, we estimate the horizontal and vertical position of the target. In terms of buried object detection, the proposed system exhibits promising performance, as shown in the experimental results.