EGCG-vanadium nanomedicine with neutral pH Fenton reaction activity inhibits heat shock proteins for enhanced photothermal/chemodynamic therapy.

A burgeoning interest has recently focused on the development of nanomedicine to integrate noninvasive photothermal therapy (PTT) and chemodynamic therapy (CDT) for synergistic tumor treatments, owing to PTT's amplification effect on CDT. However, challenges emerge as hyperthermia often induces an unwarranted overexpression of cytoprotective heat shock proteins (HSPs), thereby curtailing PTT efficacy. Additionally, the nearly neutral tumor intracellular pH (pHi ≈ 7.2) that handicaps the Fenton reaction poses a leading limitation to CDT. Addressing these hurdles, we introduce EVP, a nanomedicine developed through the straightforward assembly of epigallocatechin gallate (EGCG), vanadium sulfate (VOSO4), and Pluronic F-127 (PF127). EVP comprehensively downregulates overexpressed HSPs (HSP 60, 70, 90) through the collaborative action of EGCG and vanadyl (VO2+). Moreover, the tumor intracellular pH-processed Fenton-like reaction by VO2+ ensures highly efficient hydroxyl radicals (OH) production in cytosols, overcoming the stringent acidity requirement for CDT. Additionally, the hyperthermia induced by PTT augments OH production, further enhancing CDT efficacy. In vitro and in vivo experiments validate EVP's excellent biocompatibility and potent tumor inhibition, highlighting its substantial potential in tumor therapy.

miR-200b-3p accelerates progression of pituitary adenomas by negatively regulating expression of RECK.

MicroRNA (miR)-200b-3p has been associated with many tumors, but its involvement in pituitary adenoma is unclear. This study investigated the molecular mechanism underlying miR-200b-3p regulation in pituitary adenomas to provide a theoretical basis for treatment. Bioinformatics was used to analyze pituitary adenoma-related genes and screen new targets related to RECK and miRNA. As well, the relationship between miR-200b-3p and RECK protein was verified using a double-luciferase reporter gene assay. The expression of miR-200b-3p in clinical samples was analyzed by in situ hybridization. Transfection of the miR-200b-3p inhibitor and small interfering-RECK (si-RECK) was verified by qPCR. GH3 cell viability and proliferation were detected using CCK8 and EdU assays. Apoptosis was detected by flow cytometry and western blotting. Wound healing and Transwell assays were used to detect cell migration and invasion. The effects of miR-200b-3p and RECK on GH3 cells were verified using salvage experiments. miR-200b-3p was highly expressed in pituitary tumor tissue. Inhibitors of miR-200b-3p inhibited cell proliferation promoted cell apoptosis, inhibited invasion and migration, and inhibited the expression of matrix metalloproteinases. Interestingly, miR-200b-3p negatively regulated RECK. The expression of RECK in pituitary adenoma tissues was lower than that in neighboring tissues. Si-RECK rescued the function of miR-200b-3p inhibitors in the above cellular behaviors, and miR-200b-3p accelerated the development of pituitary adenoma by negatively regulating RECK expression. In summary, this study investigated the molecular mechanism by which miR-200b-3p regulates the progression of pituitary adenoma through the negative regulation of RECK. The findings provide a new target for the treatment of pituitary adenoma.

DrugMGR: a deep bioactive molecule binding method to identify compounds targeting proteins.

MOTIVATION: Understanding the intermolecular interactions of ligand-target pairs is key to guiding the optimization of drug research on cancers, which can greatly mitigate overburden workloads for wet labs. Several improved computational methods have been introduced and exhibit promising performance for these identification tasks, but some pitfalls restrict their practical applications: (i) first, existing methods do not sufficiently consider how multigranular molecule representations influence interaction patterns between proteins and compounds; and (ii) second, existing methods seldom explicitly model the binding sites when an interaction occurs to enable better prediction and interpretation, which may lead to unexpected obstacles to biological researchers. RESULTS: To address these issues, we here present DrugMGR, a deep multigranular drug representation model capable of predicting binding affinities and regions for each ligand-target pair. We conduct consistent experiments on three benchmark datasets using existing methods and introduce a new specific dataset to better validate the prediction of binding sites. For practical application, target-specific compound identification tasks are also carried out to validate the capability of real-world compound screen. Moreover, the visualization of some practical interaction scenarios provides interpretable insights from the results of the predictions. The proposed DrugMGR achieves excellent overall performance in these datasets, exhibiting its advantages and merits against state-of-the-art methods. Thus, the downstream task of DrugMGR can be fine-tuned for identifying the potential compounds that target proteins for clinical treatment. AVAILABILITY AND IMPLEMENTATION: https://github.com/lixiaokun2020/DrugMGR.

Nanobiotechnology augmented cancer stem cell guided management of cancer: liquid-biopsy, imaging, and treatment.

Cancer stem cells (CSCs) represent both a key driving force and therapeutic target of tumoral carcinogenesis, tumor evolution, progression, and recurrence. CSC-guided tumor diagnosis, treatment, and surveillance are strategically significant in improving cancer patients' overall survival. Due to the heterogeneity and plasticity of CSCs, high sensitivity, specificity, and outstanding targeting are demanded for CSC detection and targeting. Nanobiotechnologies, including biosensors, nano-probes, contrast enhancers, and drug delivery systems, share identical features required. Implementing these techniques may facilitate the overall performance of CSC detection and targeting. In this review, we focus on some of the most recent advances in how nanobiotechnologies leverage the characteristics of CSC to optimize cancer diagnosis and treatment in liquid biopsy, clinical imaging, and CSC-guided nano-treatment. Specifically, how nanobiotechnologies leverage the attributes of CSC to maximize the detection of circulating tumor DNA, circulating tumor cells, and exosomes, to improve positron emission computed tomography and magnetic resonance imaging, and to enhance the therapeutic effects of cytotoxic therapy, photodynamic therapy, immunotherapy therapy, and radioimmunotherapy are reviewed.

Fluorescence Lifetime Imaging of Human Retinal Pigment Epithelium in Pentosan Polysulfate Toxicity Using Adaptive Optics Scanning Light Ophthalmoscopy.

Purpose: Fluorescence lifetime ophthalmoscopy (FLIO) is an emerging clinical modality that could provide biomarkers of retinal health beyond fluorescence intensity. Adaptive optics (AO) ophthalmoscopy provides the confocality to measure fluorescence lifetime (FL) primarily from the retinal pigment epithelium (RPE) whereas clinical FLIO has greater influence from fluorophores in the inner retina and lens. Adaptive optics fluorescence lifetime ophthalmoscopy (AOFLIO) measures of FL in vivo could provide insight into RPE health at different stages of disease. In this study, we assess changes in pentosan polysulfate sodium (PPS) toxicity, a recently described toxicity that has clinical findings similar to advanced age-related macular degeneration. Methods: AOFLIO was performed on three subjects with PPS toxicity (57-67 years old) and six age-matched controls (50-64 years old). FL was analyzed with a double exponential decay curve fit and with phasor analysis. Regions of interest (ROIs) were subcategorized based on retinal features on optical coherence tomography (OCT) and compared to age-matched controls. Results: Twelve ROIs from PPS toxicity subjects met the threshold for analysis by curve fitting and 15 ROIs met the threshold for phasor analysis. Subjects with PPS toxicity had prolonged FL compared to age-matched controls. ROIs of RPE degeneration had the longest FLs, with individual pixels extending longer than 900 ps. Conclusions: Our study shows evidence that AOFLIO can provide meaningful information in outer retinal disease beyond what is obtainable from fluorescence intensity alone. More studies are needed to determine the prognostic value of AOFLIO.

Gra-CRC-miRTar: The pre-trained nucleotide-to-graph neural networks to identify potential miRNA targets in colorectal cancer.

Colorectal cancer (CRC) is the third most diagnosed cancer and the second deadliest cancer worldwide representing a major public health problem. In recent years, increasing evidence has shown that microRNA (miRNA) can control the expression of targeted human messenger RNA (mRNA) by reducing their abundance or translation, acting as oncogenes or tumor suppressors in various cancers, including CRC. Due to the significant up-regulation of oncogenic miRNAs in CRC, elucidating the underlying mechanism and identifying dysregulated miRNA targets may provide a basis for improving current therapeutic interventions. In this paper, we proposed Gra-CRC-miRTar, a pre-trained nucleotide-to-graph neural network framework, for identifying potential miRNA targets in CRC. Different from previous studies, we constructed two pre-trained models to encode RNA sequences and transformed them into de Bruijn graphs. We employed different graph neural networks to learn the latent representations. The embeddings generated from de Bruijn graphs were then fed into a Multilayer Perceptron (MLP) to perform the prediction tasks. Our extensive experiments show that Gra-CRC-miRTar achieves better performance than other deep learning algorithms and existing predictors. In addition, our analyses also successfully revealed 172 out of 201 functional interactions through experimentally validated miRNA-mRNA pairs in CRC. Collectively, our effort provides an accurate and efficient framework to identify potential miRNA targets in CRC, which can also be used to reveal miRNA target interactions in other malignancies, facilitating the development of novel therapeutics.

Proton Sponge Nanocomposites for Synergistic Tumor Elimination via Autophagy Inhibition-Promoted Cell Apoptosis and Macrophage Repolarization-Enhanced Immune Response.

Cytoprotective autophagy and an immunosuppressive tumor microenvironment (TME) are two positive promoters for tumor proliferation and metastasis that severely hinder therapeutic efficacy. Inhibiting autophagy and reconstructing TME toward macrophage activation simultaneously are of great promise for effective tumor elimination, yet are still a huge challenge. Herein, a kind of dendrimer-based proton sponge nanocomposites was designed and constructed for tumor chemo/chemodynamic/immunotherapy through autophagy inhibition-promoted cell apoptosis and macrophage repolarization-enhanced immune response. These obtained nanocomposites contain a proton sponge G5AcP dendrimer, a Fenton-like agent Cu(II), and chemical drug doxorubicin (DOX). When accumulated in tumor regions, G5AcP can act as an immunomodulator to realize deacidification-promoted macrophage repolarization toward antitumoral type, which then secretes inflammatory cytokines to activate T cells. They also regulate intracellular lysosomal pH to inhibit cytoprotective autophagy. The released Cu(II) and DOX can induce aggravated damage through a Fenton-like reaction and chemotherapeutic effect in this autophagy-inhibition condition. Tumor-associated antigens are released from these dying tumor cells to promote the maturity of dendritic cells, further activating T cells. Effective tumor elimination can be achieved by this dendrimer-based therapeutic strategy, providing significant guidance for the design of a promising antitumor nanomedicine.

Piezo1 channel exaggerates ferroptosis of nucleus pulposus cells by mediating mechanical stress-induced iron influx.

To date, several molecules have been found to facilitate iron influx, while the types of iron influx channels remain to be elucidated. Here, Piezo1 channel was identified as a key iron transporter in response to mechanical stress. Piezo1-mediated iron overload disturbed iron metabolism and exaggerated ferroptosis in nucleus pulposus cells (NPCs). Importantly, Piezo1-induced iron influx was independent of the transferrin receptor (TFRC), a well-recognized iron gatekeeper. Furthermore, pharmacological inactivation of Piezo1 profoundly reduced iron accumulation, alleviated mitochondrial ROS, and suppressed ferroptotic alterations in stimulation of mechanical stress. Moreover, conditional knockout of Piezo1 (Col2a1-CreERT Piezo1flox/flox) attenuated the mechanical injury-induced intervertebral disc degeneration (IVDD). Notably, the protective effect of Piezo1 deficiency in IVDD was dampened in Piezo1/Gpx4 conditional double knockout (cDKO) mice (Col2a1-CreERT Piezo1flox/flox/Gpx4flox/flox). These findings suggest that Piezo1 is a potential determinant of iron influx, indicating that the Piezo1-iron-ferroptosis axis might shed light on the treatment of mechanical stress-induced diseases.

Robot-assisted Percutaneous Radiofrequency Ablation for the Treatment of Osteoid Osteomas.

OBJECTIVE: Percutaneous CT-guided radiofrequency ablation (CT-RFA) is a widely accepted procedure for treatment of osteoid osteomas. However, the application of CT-RFA was restricted as a result of some drawbacks, such as radiation exposure, and inconvenience in general anesthesia. The primary aim of this study is to evaluate the safety and efficacy of intra-operative TiRobot-assisted percutaneous RFA of osteoid osteomas. METHODS: We retrospectively reviewed 21 medical files of patients who were treated with percutaneous RFA of osteoid osteomas guided by the TiRobot system in our institution between March 2021 and April 2022. The three-dimensional images obtained by a 3D C-arm intra-operatively were sent to the TiRobot system. The puncture point and trajectory were designed. Then the guide pin was positioned to the lesion with the assistance of TiRobot and the biopsy sheath was inserted into the lesion through the guide pin. The tumor was biopsied for pathological examination. Then the RFA needle was inserted into the nidus through the biopsy sheath for thermal ablation. Data were extracted on the associated complications, the reduction in pain at 1 month and 1 year postoperatively assessed by the visual analogue scale (VAS). A paired t-test was used to compare the pre-operative and post-operative VAS scores. RESULTS: The patients included 17 males and four females with a mean age of 19.5 ± 10.4 years (range 3-45 years). Lesions were located on the femur in nine cases, on the tibia in nine cases, on the humerus in one case, on the calcaneus in one case, and on the acetabulum in one case. TiRobot-assisted percutaneous RFA was successfully performed on all 21 patients. There was no intra-operative or post-operative complications observed. Pathological diagnosis of osteoid osteoma was obtained in 11 patients, but the other 10 cases were not pathologically diagnosed. The mean follow-up time was 18.8 months (range: 12-26 months).Post-operative VAS scores were reduced significantly in all cases. The mean VAS score decreased from 6.5 pre-operatively to 0.5 at 1 month post-operatively and to 0.1 at 1 year post-operatively. CONCLUSION: As a reliable technique for localizing and resection of nidus, TiRobot-assisted percutaneous RFA is a safe and effective option for the treatment of osteoid osteomas.

An experimental and theoretical study on cell swelling for osmotic imbalance induced by electroporation.

The cellular membrane serves as a pivotal barrier in regulating intra- and extracellular matter exchange. Disruption of this barrier through pulsed electric fields (PEFs) induces the transmembrane transport of ions and molecules, creating a concentration gradient that subsequently results in the imbalance of cellular osmolality. In this study, a multiphysics model was developed to simulate the electromechanical response of cells exposed to microsecond pulsed electric fields (µsPEFs). Within the proposed model, the diffusion coefficient of the cellular membrane for various ions was adjusted based on electropore density. Cellular osmolality was governed and described using Van't Hoff theory, subsequently converted to loop stress to dynamically represent the cell swelling process. Validation of the model was conducted through a hypotonic experiment and simulation at 200 mOsm/kg, revealing a 14.2% increase in the cell's equivalent radius, thereby confirming the feasibility of the cell mechanical model. With the transmembrane transport of ions induced by the applied µsPEF, the hoop stress acting on the cellular membrane reached 179.95 Pa, and the cell equivalent radius increased by 11.0% when the extra-cellular medium was supplied with normal saline. The multiphysics model established in this study accurately predicts the dynamic changes in cell volume resulting from osmotic imbalance induced by PEF action. This model holds theoretical significance, offering valuable references for research on drug delivery and tumor microenvironment modulation.

JCAD deficiency attenuates activation of hepatic stellate cells and cholestatic fibrosis.

BACKGROUND/AIMS: Cholestatic liver diseases including primary biliary cholangitis (PBC) are associated with active hepatic fibrogenesis, which ultimately progresses to cirrhosis. Activated hepatic stellate cells (HSCs) are the main fibrogenic effectors in response to cholangiocyte damage. JCAD regulates cell proliferation and malignant transformation in nonalcoholic steatoheaptitis-associated hepatocellular carcinoma (NASH-HCC). However, its participation in cholestatic fibrosis has not been explored yet. METHODS: Serial sections of liver tissue of PBC patients were stained with immunofluorescence. Hepatic fibrosis was induced by bile duct ligation (BDL) in wild-type (WT), global JCAD knockout mice (JCAD-KO) and HSC-specific JCAD knockout mice (HSC-JCAD-KO), and evaluated by histopathology and biochemical tests. In situ-activated HSCs isolated from BDL mice were used to determine effects of JCAD on HSC activation. RESULTS: In consistence with staining of liver sections from PBC patients, immunofluorescent staining revealed that JCAD expression was identified in smooth muscle α-actin (α-SMA)-positive fibroblast-like cells and was significantly up-regulated in WT mice with BDL. JCAD deficiency remarkably ameliorated BDL-induced hepatic injury and fibrosis, as documented by liver hydroxyproline content, when compared to WT mice with BDL. Histopathologically, collagen deposition was dramatically reduced in both JCAD-KO and HSC-JCAD-KO mice compared to WT mice, as visualized by Trichrome staining and semi-quantitative scores. Moreover, JCAD deprivation significantly attenuated in situ HSC activation and reduced expression of fibrotic genes after BDL. CONCLUSION: JCAD deficiency effectively suppressed hepatic fibrosis induced by BDL in mice, and the underlying mechanisms are largely through suppressed Hippo-YAP signaling activity in HSCs.

Multiple strategies, including 6mA methylation, affecting plant alternative splicing in allopolyploid peanut.

Alternative splicing (AS), an important post-transcriptional regulation mechanism in eukaryotes, can significantly increase transcript diversity and contribute to gene expression regulation and many other complicated developmental processes. While plant gene AS events are well described, few studies have investigated the comprehensive regulation machinery of plant AS. Here, we use multi-omics to analyse peanut AS events. Using long-read isoform sequencing, 146 464 full-length non-chimeric transcripts were obtained, resulting in annotation corrections for 1782 genes and the identification of 4653 new loci. Using Iso-Seq RNA sequences, 271 776 unique splice junctions were identified, 82.49% of which were supported by transcriptome data. We characterized 50 977 polyadenylation sites for 23 262 genes, 12 369 of which had alternative polyadenylation sites. AS allows differential regulation of the same gene by miRNAs at the isoform level coupled with polyadenylation. In addition, we identified many long non-coding RNAs and fusion transcripts. There is a suppressed effect of 6mA on AS and gene expression. By analysis of chromatin structures, the genes located in the boundaries of topologically associated domains, proximal chromosomal telomere regions, inter- or intra-chromosomal loops were found to have more unique splice isoforms, higher expression, lower 6mA and more transposable elements (TEs) in their gene bodies than the other genes, indicating that chromatin interaction, 6mA and TEs play important roles in AS and gene expression. These results greatly refine the peanut genome annotation and contribute to the study of gene expression and regulation in peanuts. This work also showed AS is associated with multiple strategies for gene regulation.

Spinal gout with intervertebral foramen infiltration: A rare case perfectly mimicking degenerative lumbar disc disease.

Spinal gout is a relatively rare disease characterized by significant clinical symptoms. In the current study, the first case of spinal gout with tophus in the intervertebral foramen, which perfectly mimicked degenerative lumbar disc disorders, was presented. The patient was a 57-year-old man with a medical history of gout who had suffered from progressive neurological deterioration for the last 12 months. Imaging examination revealed bilateral stenosis in the L5/S1 intervertebral foramen, mimicking degenerative lumbar disc disease. Nerve root radiculography and blocking were performed and the neurological symptoms were completely relieved. Open surgery was further performed and unexpectedly, the intra-operative findings were amorphous chalky white lesions. Histopathology confirmed the diagnosis of spinal gout. After surgery, the patient was prescribed a medication and achieved complete remission of clinical symptoms. No deterioration was found at the 1-year follow-up. To the best of our knowledge, this is the first report of spinal gout tophus in intervertebral foramen in the literature. It was concluded that, although intraspinal tophaceous gout is relatively rare, orthopedic surgeons should take it into consideration as a differential diagnosis, particularly if the patient has a medical history of gout. Early diagnosis and timely medical management may possibly be able to avoid neurological compromise and the need for surgery.

Automatic Detection and Classification of Modic Changes in MRI Images Using Deep Learning: Intelligent Assisted Diagnosis System.

OBJECTIVE: Modic changes (MCs) are the most prevalent classification system for describing intravertebral MRI signal intensity changes. However, interpreting these intricate MRI images is a complex and time-consuming process. This study investigates the performance of single shot multibox detector (SSD) and ResNet18 network-based automatic detection and classification of MCs. Additionally, it compares the inter-observer agreement and observer-classifier agreement in MCs diagnosis to validate the feasibility of deep learning network-assisted detection of classified MCs. METHOD: A retrospective analysis of 140 patients with MCs who underwent MRI diagnosis and met the inclusion and exclusion criteria in Tianjin Hospital from June 2020 to June 2021 was used as the internal dataset. This group consisted of 55 males and 85 females, aged 25 to 89 years, with a mean age of (59.0 ± 13.7) years. An external test dataset of 28 patients, who met the same criteria and were assessed using different MRI equipment at Tianjin Hospital, was also gathered, including 11 males and 17 females, aged 31 to 84 years, with a mean age of 62.7 ± 10.9 years. After Physician 1 (with 15 years of experience) annotated all MRI images, the internal dataset was imported into the deep learning model for training. The model comprises an SSD network for lesion localization and a ResNet18 network for lesion classification. Performance metrics, including accuracy, recall, precision, F1 score, confusion matrix, and inter-observer agreement parameter Kappa value, were used to evaluate the model's performance on the internal and external datasets. Physician 2 (with 1 year of experience) re-labeled the internal and external test datasets to compare the inter-observer agreement and observer-classifier agreement. RESULTS: In the internal dataset, when models were utilized for the detection and classification of MCs, the accuracy, recall, precision and F1 score reached 86.25%, 87.77%, 84.92% and 85.60%, respectively. The Kappa value of the inter-observer agreement was 0.768 (95% CI: 0.656, 0.847),while observer-classifier agreement was 0.717 (95% CI: 0.589, 0.809).In the external test dataset, the model's the accuracy, recall, precision and F1 scores for diagnosing MCs reached 75%, 77.08%, 77.80% and 74.97%, respectively. The inter-observer agreement was 0.681 (95% CI: 0.512, 0.677), and observer-classifier agreement was 0.519 (95% CI: 0.290, 0.690). CONCLUSION: The model demonstrated strong performance in detecting and classifying MCs, achieving high agreement with physicians in MCs diagnosis. These results suggest that deep learning models have the potential to facilitate the application of intelligent assisted diagnosis techniques in the field of spine research.

Rational therapeutic targets with biomolecular liquid-liquid phase separation regulating synergy: A pan-cancer analysis.

Liquid-liquid phase separation (LLPS) is characterized as an ubiquitous framework for diverse biological processes including carcinogenesis and cancer progression. While targeting cancer from perspective of LLPS offers an opportunity to drug the conventionally undruggables with cancer-driving potential, the therapeutic value of cancer associated LLPS (CAL) proteins remains elusive. Here, we report the genomic landscape, prognostic relevance, immune-infiltration association, down-stream pathway alteration and small molecular responsiveness of CAL protein-coding gene signatures based on protein-coding associated mutations and transcriptional abundance in pan-cancer. Correlations of CAL protein-coding associated mutations and transcriptional abundances to overall survival and progression-free survival were observed in an array of cancers and further characterized by differential survival outcomes between patients with intrinsic disordered region (IDR) enriched and non-IDR enriched mutations in endometrial cancer. Altered signaling pathways and universal pattern of immune infiltrates on account of CAL protein-coding associated gene-set mutations involved key components of oncogenesis in various cancer types and well established therapeutic targets including MAPK signaling pathway and implied an inflamed tumor immunity that might be highly responsive to immunotherapy. LLPS inhibitor enhanced cytotoxicity of cisplatin/paclitaxel in selective cancer cell lines. These findings provide preliminary evidences for rational chemo-, targeted- and immuno-therapeutic innovation with LLPS regulating synergy.

Evaluation of Two Chemoenzymatic Glycan Remodeling Approaches to Generate Site-Specific Antibody-Drug Conjugates.

Fc-glycosite-specific antibody-drug conjugation represents a promising direction for the preparation of site-specific antibody-drug conjugates (ADCs). In the present research, we conducted a systemic evaluation of two endoglycosidase-catalyzed chemoenzymatic glycoengineering technologies to prepare glycosite-specific ADCs. In the first two-step approach, the antibody was deglycosylated and then reglycosylated with a modified intact N-glycan oxazoline. In the second one-pot approach, antibodies were deglycosylated and simultaneously glycosylated with a functionalized disaccharide oxazoline. For the comprehensive evaluation, we first optimized and scaled-up the preparation of azido glycan oxazolines. Afterwards, we proved that the one-pot glycan-remodeling approach was efficient for all IgG subclasses. Subsequently, we assembled respective ADCS using two technology routes, with two different linker-payloads combinations, and performed systemic in vitro and in vivo evaluations. All the prepared ADCs achieved high homogeneity and illustrated excellent stability in buffers with minimum aggregates, and exceptional stability in rat serum. All ADCs displayed a potent killing of BT-474 breast cancer cells. Moving to the mouse study, the ADCs prepared from two technology routes displayed potent and similar efficacy in a BT-474 xenograft model, which was comparable to an FDA-approved ADC generated from random conjugation. These ADCs also demonstrated excellent safety and did not cause body weight loss at the tested dosages.

Mitochondrial subtype MB-G3 contains potential novel biomarkers and therapeutic targets associated with prognosis of medulloblastoma.

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. There are four groups, each with different causal mutations, affected pathways and prognosis. Here, we investigated the role of mitochondria in medulloblastoma and whether there are differences between the different groups. METHODS: We compared the gene expression levels in the four different medulloblastoma groups (MB-WNT, MB-SHH, MB-G3 and MB-G4), with the focus on genes associated with mitochondria. We used several tools including Salmon, Tximeta, DESeq2, BiomaRt, STRING, Ggplot2, EnhancedVolcano, Venny 2.1 and Metscape. RESULTS: A total of 668 genes were differentially expressed and the most abundant genes were associated with cell division pathway followed by modulation of chemical synaptic transmission. We also identified several genes (ABAT, SOX9, ALDH5A, FOXM1, ABL1, NHLH1, NEUROD1 and NEUROD2) known to play vital role in medulloblastoma. Comparative expression analysis revealed OXPHOS complex-associated proteins of mitochondria. The most significantly expressed genes in the MB-SHH and MB-G4 groups were AHCYL1 and SFXN5 while PAICS was significantly upregulated in MB-WNT group. Notably, MB-G3 contained the most downregulated genes from the OXPHOS complexes, except COX6B2 which was strongly upregulated. CONCLUSIONS: We show the importance of mitochondria and compare their role in the four different medulloblastoma groups.

Cortical Endplate Bone Density Measured by Novel Phantomless Quantitative Computed Tomography May Predict Cage Subsidence more Conveniently and Accurately.

OBJECTIVE: Previous studies have shown that bone mineral density (BMD) is a predictor of cage subsidence. Phantom-less quantitative computed tomography (PL-QCT) can measure volumetric bone mineral density (vBMD) of lumbar trabecular and cortical bone. The study of endplate vBMD (EP-vBMD) is important in predicting cage settlement after extreme lateral interbody fusion (XLIF). This study aimed to determine the risk factors for postoperative cage subsidence after XLIF, particularly focusing on the relationship between vBMD measured by automatic PL-QCT and cage subsidence. METHODS: Patients who underwent XLIF surgery from January 2018 to October 2020 with a minimum of 6 months of follow-up were retrospectively included. Cage subsidence was defined as >2 mm cage sinking on the adjacent endplate in follow-up imaging evaluation. Outcome measures were localized vBMDs included EP-vBMDs with different region of interest (ROI) heights measured by PL-QCT based on a customized muscle-fat algorithm. Shapiro-Wilk test, one-way ANOVA, Mann-Whitney test, Fisher exact test, univariable and multivariable logistic regression and receiver operating characteristic (ROC) curve analysis were executed in this study. RESULTS: One hundred and thirteen levels of 78 patients were included in the analysis. The mean age was 65 ± 7.9 years for 11 males and 67 females. Cage subsidence occurred on 45 (39.8%) surgical levels. There was no significant difference in demographics, fused levels, or preoperative radiographic parameters. 1.25-mm EP-vBMD (0.991 [0.985,0.997], p = 0.004) and P-TB-vBMD (cage-positioned trabecular volumetric bone mineral density) (0.988 [0.977-0.999], p = 0.026) were cage-subsidence relevant according to univariate analysis. Low 1.25-mm EP-vBMD (0.992 [0.985, 0.999], p = 0.029) was an independent risk factor according to multifactorial analysis. CONCLUSION: Preoperative low EP-vBMD was an independent risk factor for postoperative cage subsidence after XLIF. EP-vBMD measured by most cortex-occupied ROI may be the optimal vBMD parameter for cage subsidence prediction.

A Small Object Detection Method for Oil Leakage Defects in Substations Based on Improved Faster-RCNN.

Since substations are key parts of power transmission, ensuring the safety of substations involves monitoring whether the substation equipment is in a normal state. Oil leakage detection is one of the necessary daily tasks of substation inspection robots, which can immediately find out whether there is oil leakage in the equipment in operation so as to ensure the service life of the equipment and maintain the safe and stable operation of the system. At present, there are still some challenges in oil leakage detection in substation equipment: there is a lack of a more accurate method of detecting oil leakage in small objects, and there is no combination of intelligent inspection robots to assist substation inspection workers in judging oil leakage accidents. To address these issues, this paper proposes a small object detection method for oil leakage defects in substations. This paper proposes a small object detection method for oil leakage defects in substations, which is based on the feature extraction network Resnet-101 of the Faster-RCNN model for improvement. In order to decrease the loss of information in the original image, especially for small objects, this method is developed by canceling the downsampling operation and replacing the large convolutional kernel with a small convolutional kernel. In addition, the method proposed in this paper is combined with an intelligent inspection robot, and an oil leakage decision-making scheme is designed, which can provide substation equipment oil leakage maintenance recommendations for substation workers to deal with oil leakage accidents. Finally, the experimental validation of real substation oil leakage image collection is carried out by the intelligent inspection robot equipped with a camera. The experimental results show that the proposed FRRNet101-c model in this paper has the best performance for oil leakage detection in substation equipment compared with several baseline models, improving the Mean Average Precision (mAP) by 6.3%, especially in detecting small objects, which has improved by 12%.

Detection, mechanisms, and therapeutic implications of oncometabolites.

Metabolic abnormalities are a hallmark of cancer cells and are essential to tumor progression. Oncometabolites have pleiotropic effects on cancer biology and affect a plethora of processes, from oncogenesis and metabolism to therapeutic resistance. Targeting oncometabolites, therefore, could offer promising therapeutic avenues against tumor growth and resistance to treatments. Recent advances in characterizing the metabolic profiles of cancer cells are shedding light on the underlying mechanisms and associated metabolic networks. This review summarizes the diverse detection methods, molecular mechanisms, and therapeutic targets of oncometabolites, which may lead to targeting oncometabolism for cancer therapy.