PESSA: A web tool for pathway enrichment score-based survival analysis in cancer.

The activation levels of biologically significant gene sets are emerging tumor molecular markers and play an irreplaceable role in the tumor research field; however, web-based tools for prognostic analyses using it as a tumor molecular marker remain scarce. We developed a web-based tool PESSA for survival analysis using gene set activation levels. All data analyses were implemented via R. Activation levels of The Molecular Signatures Database (MSigDB) gene sets were assessed using the single sample gene set enrichment analysis (ssGSEA) method based on data from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), The European Genome-phenome Archive (EGA) and supplementary tables of articles. PESSA was used to perform median and optimal cut-off dichotomous grouping of ssGSEA scores for each dataset, relying on the survival and survminer packages for survival analysis and visualisation. PESSA is an open-access web tool for visualizing the results of tumor prognostic analyses using gene set activation levels. A total of 238 datasets from the GEO, TCGA, EGA, and supplementary tables of articles; covering 51 cancer types and 13 survival outcome types; and 13,434 tumor-related gene sets are obtained from MSigDB for pre-grouping. Users can obtain the results, including Kaplan-Meier analyses based on the median and optimal cut-off values and accompanying visualization plots and the Cox regression analyses of dichotomous and continuous variables, by selecting the gene set markers of interest. PESSA (https://smuonco.shinyapps.io/PESSA/ OR http://robinl-lab.com/PESSA) is a large-scale web-based tumor survival analysis tool covering a large amount of data that creatively uses predefined gene set activation levels as molecular markers of tumors.

Design, synthesis and biological evaluation of new RNF126-based p300/CBP degraders.

Histone acetyltransferase CREB-binding protein (CBP) and its homologous protein p300 are key transcriptional activators that can activate oncogene transcription, which present promising targets for cancer therapy. Here, we designed and synthesized a series of p300/CBP targeted low molecular weight PROTACs by assembling the covalent ligand of RNF126 E3 ubiquitin ligase and the bromodomain ligand of the p300/CBP. The optimal molecule A8 could effectively degrade p300 and CBP through the ubiquitin-proteasome system in time- and concentration-dependent manners, with half-maximal degradation (DC50) concentrations of 208.35/454.35 nM and 82.24/79.45 nM for p300/CBP in MV4-11 and Molm13 cell lines after 72 h of treatment. And the degradation of p300/CBP by A8 is dependent on the ubiquitin-proteasome pathway and its simultaneous interactions with the target proteins and RNF126. A8 exhibits good antiproliferative activity in a series of p300/CBP-dependent cancer cells. It could transcriptionally inhibit the expression of c-Myc, induce cell cycle arrest in the G0/G1 phase and apoptosis in MV4-11 cells. This study thus provided us a new chemotype for the development of drug-like PROTACs targeting p300/CBP, which is expected to be applied in cancer therapy.

Enhanced pyroptosis induction with pore-forming gene delivery for osteosarcoma microenvironment reshaping.

Osteosarcoma is the most common malignant bone tumor without efficient management for improving 5-year event-free survival. Immunotherapy is also limited due to its highly immunosuppressive tumor microenvironment (TME). Pore-forming gasdermins (GSDMs)-mediated pyroptosis has gained increasing concern in reshaping TME, however, the expressions and relationships of GSDMs with osteosarcoma remain unclear. Herein, gasdermin E (GSDME) expression is found to be positively correlated with the prognosis and immune infiltration of osteosarcoma patients, and low GSDME expression was observed. A vector termed as LPAD contains abundant hydroxyl groups for hydrating layer formation was then prepared to deliver the GSDME gene to upregulate protein expression in osteosarcoma for efficient TME reshaping via enhanced pyroptosis induction. Atomistic molecular dynamics simulations analysis proved that the hydroxyl groups increased LPAD hydration abilities by enhancing coulombic interaction. The upregulated GSDME expression together with cleaved caspase-3 provided impressive pyroptosis induction. The pyroptosis further initiated proinflammatory cytokines release, increased immune cell infiltration, activated adaptive immune responses and create a favorable immunogenic hot TME. The study not only confirms the role of GSDME in the immune infiltration and prognosis of osteosarcoma, but also provides a promising strategy for the inhibition of osteosarcoma by pore-forming GSDME gene delivery induced enhanced pyroptosis to reshape the TME of osteosarcoma.

Multimodal ChatGPT-4V for ECG Interpretation: Promise and Limitations.

UNSTRUCTURED: Electrocardiogram (ECG) interpretation is an essential skill in cardiovascular medicine. This study evaluated the capabilities of newly released ChatGPT-4V, a large language model with visual recognition abilities, in interpreting ECG waveforms and answering related multiple-choice questions. A total of 62 ECG-related multiple-choice questions were collected from reputable medical exams. ChatGPT was prompted to answer the questions by analyzing the accompanying ECG images. Requiring at least 1 of 3 responses to be correct, ChatGPT achieved an overall accuracy of 83.87% across all question types. ChatGPT demonstrated significantly lower performance on counting-based questions like calculating QT intervals compared to diagnostic and treatment recommendation questions. The findings indicate that while ChatGPT shows promising potential in ECG interpretation and decision-making, its diagnostic reliability and quantitative analysis abilities need improvement before real clinical use. Further large-scale studies are warranted to fully evaluate ChatGPT's capabilities and track its progress as the model accumulates more medical knowledge through ongoing training. With technological advancements, multimodal AI like ChatGPT may one day play an important role in assisting clinicians with ECG interpretation and cardiovascular care.

CPADS: a web tool for comprehensive pancancer analysis of drug sensitivity.

Drug therapy is vital in cancer treatment. Accurate analysis of drug sensitivity for specific cancers can guide healthcare professionals in prescribing drugs, leading to improved patient survival and quality of life. However, there is a lack of web-based tools that offer comprehensive visualization and analysis of pancancer drug sensitivity. We gathered cancer drug sensitivity data from publicly available databases (GEO, TCGA and GDSC) and developed a web tool called Comprehensive Pancancer Analysis of Drug Sensitivity (CPADS) using Shiny. CPADS currently includes transcriptomic data from over 29 000 samples, encompassing 44 types of cancer, 288 drugs and more than 9000 gene perturbations. It allows easy execution of various analyses related to cancer drug sensitivity. With its large sample size and diverse drug range, CPADS offers a range of analysis methods, such as differential gene expression, gene correlation, pathway analysis, drug analysis and gene perturbation analysis. Additionally, it provides several visualization approaches. CPADS significantly aids physicians and researchers in exploring primary and secondary drug resistance at both gene and pathway levels. The integration of drug resistance and gene perturbation data also presents novel perspectives for identifying pivotal genes influencing drug resistance. Access CPADS at https://smuonco.shinyapps.io/CPADS/ or https://robinl-lab.com/CPADS.

Gaining Insight into Updated MR Imaging for Quantitative Assessment of Cartilage Injury in Knee Osteoarthritis.

PURPOSE OF THE REVIEW: Knee Osteoarthritis (KOA) entails progressive cartilage degradation, reviewed via MRI for morphology, biochemical composition, and microtissue alterations, discussing clinical advantages, limitations, and research applicability. RECENT FINDINGS: Compositional MRI, like T2/T2* mapping, T1rho mapping, gagCEST, dGEMRIC, sodium imaging, diffusion-weighted imaging, and diffusion-tensor imaging, provide insights into cartilage injury in KOA. These methods quantitatively measure collagen, glycosaminoglycans, and water content, revealing important information about biochemical compositional and microstructural alterations. Innovative techniques like hybrid multi-dimensional MRI and diffusion-relaxation correlation spectrum imaging show potential in depicting initial cartilage changes at a sub-voxel level. Integration of automated image analysis tools addressed limitations in manual cartilage segmentation, ensuring robust and reproducible assessments of KOA cartilage. Compositional MRI techniques reveal microstructural changes in cartilage. Multi-dimensional MR imaging assesses biochemical alterations in KOA-afflicted cartilage, aiding early degeneration identification. Integrating artificial intelligence enhances cartilage analysis, optimal diagnostic accuracy for early KOA detection and monitoring.

PC4 promotes bladder cancer progression and stemness by directly interacting with Sp1 to transcriptionally activate the Wnt5a/ß-catenin pathway.

Bladder cancer is a common malignancy with a poor prognosis worldwide. Positive cofactor 4 (PC4) is widely reported to promote malignant phenotypes in various tumors. Nonetheless, the biological function and mechanism of PC4 in bladder cancer remain unclear. Here, for the first time, we report that PC4 is elevated in bladder cancer and is associated with patient survival. Moreover, PC4 deficiency obviously inhibited bladder cancer cell proliferation and metastasis by reducing the expression of genes related to cancer stemness (CD44, CD47, KLF4 and c-Myc). Through RNA-seq and experimental verification, we found that activation of the Wnt5a/ß-catenin pathway is involved in the malignant function of PC4. Mechanistically, PC4 directly interacts with Sp1 to promote Wnt5a transcription. Thus, our study furthers our understanding of the role of PC4 in cancer stemness regulation and provides a promising strategy for bladder cancer therapy.

The role of ZC3H12D-regulated TLR4-NF-κB pathway in LPS-induced pro-inflammatory microglial activation.

Lipopolysaccharide (LPS) is an important neurotoxin that can cause inflammatory activation of microglia. ZC3H12D is a novel immunomodulator, which plays a remarkable role in neurological pathologies. It has not been characterized whether ZC3H12D is involved in the regulation of microglial activation. The aim of this study was to investigate the role of ZC3H12D in LPS-induced pro-inflammatory microglial activation and its potential mechanism. To elucidate this, we established animal models of inflammatory injury by intraperitoneal injection of LPS (10 mg/kg). The results of the open-field test showed that LPS caused impaired motor function in mice. Meanwhile, LPS caused pro-inflammatory activation of microglia in the mice cerebral cortex and inhibited the expression of ZC3H12D. We also constructed in vitro inflammatory injury models by treating BV-2 microglia with LPS (0.5 µg/mL). The results showed that down-regulated ZC3H12D expression was associated with LPS-induced pro-inflammatory microglial activation, and further intervention of ZC3H12D expression could inhibited LPS-induced pro-inflammatory activation of microglia. In addition, LPS activated the TLR4-NF-κB signaling pathway, and this process can also be reversed by promoting ZC3H12D expression. At the same time, the addition of resveratrol, a nutrient previously proven to inhibit pro-inflammatory microglial activation, can also reverse this process by increasing the expression of ZC3H12D. Summarized, our data elucidated that ZC3H12D in LPS-induced pro-inflammatory activation of brain microglia via restraining the TLR4-NF-κB pathway. This study may provide a valuable clue for potential therapeutic targets for neuroinflammation-related injuries.

Ventricular Netrin-1 deficiency leads to defective pyramidal decussation and mirror movement in mice.

The corticospinal tract (CST) is the principal neural pathway responsible for conducting voluntary movement in the vertebrate nervous system. Netrin-1 is a well-known guidance molecule for midline crossing of commissural axons during embryonic development. Families with inherited Netrin-1 mutations display congenital mirror movements (CMM), which are associated with malformations of pyramidal decussation in most cases. Here, we investigated the role of Netrin-1 in CST formation by generating conditional knockout (CKO) mice using a Gfap-driven Cre line. A large proportion of CST axons spread laterally in the ventral medulla oblongata, failed to decussate and descended in the ipsilateral spinal white matter of Ntn1Gfap CKO mice. Netrin-1 mRNA was expressed in the ventral ventricular zone (VZ) and midline, while Netrin-1 protein was transported by radial glial cells to the ventral medulla, through which CST axons pass. The level of transported Netrin-1 protein was significantly reduced in Ntn1Gfap CKO mice. In addition, Ntn1Gfap CKO mice displayed increased symmetric movements. Our findings indicate that VZ-derived Netrin-1 deletion leads to an abnormal trajectory of the CST in the spinal cord due to the failure of CST midline crossing and provides novel evidence supporting the idea that the Netrin-1 signalling pathway is involved in the pathogenesis of CMM.

Liquid biopsy for human cancer: cancer screening, monitoring, and treatment.

Currently, tumor treatment modalities such as immunotherapy and targeted therapy have more stringent requirements for obtaining tumor growth information and require more accurate and easy-to-operate tumor information detection methods. Compared with traditional tissue biopsy, liquid biopsy is a novel, minimally invasive, real-time detection tool for detecting information directly or indirectly released by tumors in human body fluids, which is more suitable for the requirements of new tumor treatment modalities. Liquid biopsy has not been widely used in clinical practice, and there are fewer reviews of related clinical applications. This review summarizes the clinical applications of liquid biopsy components (e.g., circulating tumor cells, circulating tumor DNA, extracellular vesicles, etc.) in tumorigenesis and progression. This includes the development process and detection techniques of liquid biopsies, early screening of tumors, tumor growth detection, and guiding therapeutic strategies (liquid biopsy-based personalized medicine and prediction of treatment response). Finally, the current challenges and future directions for clinical applications of liquid biopsy are proposed. In sum, this review will inspire more researchers to use liquid biopsy technology to promote the realization of individualized therapy, improve the efficacy of tumor therapy, and provide better therapeutic options for tumor patients.

Enhancing Surface Hydroxyl Group Modulation on Carbon Nitride Boosts the Effectiveness of Photodynamic Treatment for Brain Glioma.

The effectiveness of photodynamic therapy (PDT) in treating brain gliomas is limited by the solubility of photosensitizers and the production of reactive oxygen species (ROS), both of which are influenced by the concentration of photosensitizers and catalyst active sites. In this study, we developed a controllable surface hydroxyl concentration for the photosensitizer CN11 to address its poor water solubility issue and enhance PDT efficacy in tumor treatment. Compared to pure g-C3N4 (CN), CN11 exhibited 4.6 times higher hydrogen peroxide production under visible light, increased incidence of the n → π* electron transition, and provided more available reaction sites for cytotoxic ROS generation. These findings resulted in a 2.43-fold increase in photodynamic treatment efficacy against brain glioma cells. Furthermore, in vivo experiments conducted on mice demonstrated that CN11 could be excreted through normal cell metabolism with low cytotoxicity and high biosafety, effectively achieving complete eradication of tumor cells.

AAV-mediated gene therapy restores natural fertility and improves physical function in the Lhcgr-deficient mouse model of Leydig cell failure.

Leydig cell failure (LCF) caused by gene mutations leads to testosterone deficiency, infertility and reduced physical function. Adeno-associated virus serotype 8 (AAV8)-mediated gene therapy shows potential in treating LCF in the Lhcgr-deficient (Lhcgr-/-) mouse model. However, the gene-treated mice still cannot naturally sire offspring, indicating the modestly restored testosterone and spermatogenesis in AAV8-treated mice remain insufficient to support natural fertility. Recognizing this, we propose that enhancing gene delivery could yield superior results. Here, we screened a panel of AAV serotypes through in vivo transduction of mouse testes and identified AAVDJ as an impressively potent vector for testicular cells. Intratesticular injection of AAVDJ achieved markedly efficient transduction of Leydig cell progenitors, marking a considerable advance over conventional AAV8 vectors. AAVDJ-Lhcgr gene therapy was well tolerated and resulted in significant recovery of testosterone production, substantial improvement in sexual development, and remarkable restoration of spermatogenesis in Lhcgr-/- mice. Notably, this therapy restored fertility in Lhcgr-/- mice through natural mating, enabling the birth of second-generation. Additionally, this treatment led to remarkable improvements in adipose, muscle, and bone function in Lhcgr-/- mice. Collectively, our findings underscore AAVDJ-mediated gene therapy as a promising strategy for LCF and suggest its broader potential in addressing various reproductive disorders.

ChatGPT's ability to generate realistic experimental images poses a new challenge to academic integrity.

The rapid advancements in large language models (LLMs) such as ChatGPT have raised concerns about their potential impact on academic integrity. While initial concerns focused on ChatGPT's writing capabilities, recent updates have integrated DALL-E 3's image generation features, extending the risks to visual evidence in biomedical research. Our tests revealed ChatGPT's nearly barrier-free image generation feature can be used to generate experimental result images, such as blood smears, Western Blot, immunofluorescence and so on. Although the current ability of ChatGPT to generate experimental images is limited, the risk of misuse is evident. This development underscores the need for immediate action. We suggest that AI providers restrict the generation of experimental image, develop tools to detect AI-generated images, and consider adding "invisible watermarks" to the generated images. By implementing these measures, we can better ensure the responsible use of AI technology in academic research and maintain the integrity of scientific evidence.

Atomically Precise Chiral Metal Nanoclusters for Circularly Polarized Light Detection.

Circularly polarized light (CPL) detection is of great significance in various applications such as drug identification, sensing and imaging. Atomically precise chiral metal nanoclusters with intense circular dichroism (CD) signals are promising candidates for CPL detection, which can further facilitate device miniaturization and integration. Herein, we report the preparation of a pair of optically active chiral silver nanoclusters [Ag7(R/S-DMA)2(dpppy)3] (BF4)3 (R/S-Ag7) for direct CPL detection. The crystal structure and molecular formula of R/S-Ag7 clusters are confirmed by single-crystal x-ray diffraction and high-resolution mass spectrometry. R/S-Ag7 clusters exhibit strong CD spectra and CPL luminescence both in solution and solid states. When used as the photoactive materials in photodetectors, R/S-Ag7 enables effective discrimination between left-handed circularly polarized and right-handed circularly polarized light at 520 nm with short response time, high responsivity and considerable discrimination ratio. This study is the first report on using atomically precise chiral metal nanoclusters for CPL detection.

Burden of Stroke Attributable to Nonoptimal Temperature in 204 Countries and Territories: A Population-Based Study, 1990-2019.

BACKGROUND AND OBJECTIVES: Stroke attributable to nonoptimal temperature needs more attention with dramatic climate change. The aim of this study was to estimate the global burden and distribution characteristics of the burden. METHODS: In this ecological study, we collected data from the Climate Research Unit Gridded Time Series, the World Bank databases, and the Global Burden of Diseases study to estimate the distribution of burden. We used the joinpoint model, decomposition analysis, age-period-cohort model, panel data analysis, and health inequality analysis to assess the different types of stroke burden attributable to different climatic conditions. RESULTS: The burden of stroke attributable to nonoptimal temperature continued to grow, and aging was a key factor in this increase. In 2019, 521,031 (95% uncertainty interval [UI] 402,433-663,996) deaths and 9,423,649 (95% UI 7,207,660-12,055,172) disability-adjusted life years [DALYs] attributable to stroke due to nonoptimal temperature were recorded globally. Globally, men (age-standardized mortality rate [ASMR] 7.70, 95% UI 5.80-9.73; age-standardized DALY rate [ASDR] 139.69, 95% UI 102.96-178.54 in 2019) had a heavier burden than women (ASMR 5.89, 95% UI 4.50-7.60; ASDR 96.02, 95% UI 72.62-123.85 in 2019). Central Asia (ASMR 18.12, 95% UI 13.40-24.53; ASDR 327.35, 95% UI 240.24-440.61 in 2019) had the heaviest burden at the regional level. In the national level, North Macedonia (ASMR 32.97, 95% UI 20.57-47.44 in 2019) and Mongolia (ASDR 568.54, 95% UI 242.03-1,031.14 in 2019) had the highest ASMR/ASDR, respectively. Low temperature currently contributes to the main burden (deaths 474,002, 95% UI 355,077-606,537; DALYs 8,357,198, 95% UI 6,186,217-10,801,911 attributable to low temperature vs deaths 48,030, 95% UI 5,630-104,370; DALYs 1,089,329, 95% UI 112,690-2,375,345 attributable to high temperature in 2019). However, the burden due to high temperature has increased rapidly, especially among people aged older than 10 years, and was disproportionately concentrated in low sociodemographic index (SDI) regions such as Africa. In addition, the rapid increase in the stroke burden due to high temperature in Central Asia also requires special attention. DISCUSSION: This is the first study to assess the global stroke burden attributed to nonoptimal temperature. The dramatic increase in the burden due to high temperature requires special attention, especially in low-SDI countries.