SIRT7 promotes Hippo/YAP activation and cancer cell proliferation in hepatocellular carcinoma via suppressing MST1.

Abnormal activation of the oncogene YAP in the Hippo pathway is a major feature in liver cancer and inactivation of MST1/2 has been shown to be responsible for the overactivation of YAP that led to tumorigenesis. However, mechanisms underlying MST1/2 dysregulation remain poorly understood. RNA-seq analysis and genome (KEGG) pathway enrichment analysis were used to identify genes and pathways that were regulated by SIRT7. qRT-PCR, ChIP, and luciferase assay were used to investigate transcriptional regulation. Mass spectrometry, co-immunoprecipitation and immunoprecipitation were used to exam protein-protein interaction and post-transcriptional modification. A xenograft mouse model was used to confirm the effect of SIRT7 and SIRT7 inhibitors on hepatocellular carcinoma (HCC) proliferation in vivo. We found that SIRT7 suppresses MST1 by both transcriptional regulation and post-transcriptional modification, which in turn promotes YAP nuclear localization and transcriptional activation in liver cancer. Mechanistically, we revealed that SIRT7 suppresses MST1 transcription by binding to the MST1 promoter and inducing H3K18 deacetylation in its promoter region. In addition, SIRT7 directly binds to and deacetylates MST1, which primes acetylation-dependent MST1 ubiquitination and protein degradation. In clinical samples, we confirmed a negative correlation between SIRT7 and MST1 protein levels, and high SIRT7 expression correlated with elevated YAP expression and nuclear localization. In addition, SIRT7 specific inhibitor 2800Z sufficiently inhibited HCC growth by disrupting the SIRT7/MST1/YAP axis. Our data thus revealed the previously undescribed function of SIRT7 in regulating the Hippo pathway in HCC and further proved that targeting SIRT7 might provide novel therapeutic options for the treatment of liver cancer.

Comprehensive analysis of m6A modification in lipopolysaccharide-induced acute lung injury in mice.

BACKGROUND: N6-Methyladenosine (m6A) methylation is the most prevalent post-transcriptional modification in mRNA, and plays significant roles in various diseases. Nevertheless, the precise functions of m6A modification in the formation of ALI remain unclear. In this study we explore the transcriptome distribution of m6A methylation and its probable roles of in ALI. METHODS: Lipopolysaccharide (LPS) was utilized to establish an ALI mouse model. Real-time qPCR, Western blotting and m6A dot blot were utilized to assess m6A methylation level and the expression of m6A methylation enzymes. MeRIP-Seq and RNA-seq were utilized to explore differential m6A modifications and differentially expressed genes in ALI mice. The hub genes and enriched pathways were assessed by Real-time qPCR and Western blotting. RESULTS: Our findings showed that overall m6A methylation level was increased in ALI mice lung tissues, accompanied by lower levels of METTL3 and FTO. Notably, the protein expression of these methylases were different in various cells. There were 772 differently expressed m6A peaks in ALI as compared to the control group, with 316 being hypermethylated and 456 being hypomethylated. GO and KEGG analyses demonstrated these differentially methylated genes were associated with the calcium signaling pathway and cAMP signaling pathway. Furthermore, we identified 50 genes with distinct m6A peaks and mRNA expressions by combined analysis of MeRIP-Seq and RNA-Seq. KEGG analysis also demonstrated that these overlapped genes were closely associated with the calcium signaling pathway, cGMP-PKG signaling pathway, etc. Besides, Western blotting results demonstrated that the protein expression of Fibronectin leucine-rich transmembrane protein 3 (Flrt3) as well as the calcium signaling pathway and cGMP-PKG signaling pathway, increased significantly after ALI. CONCLUSIONS: m6A modification was paramount in the pathogenesis of ALI, and provided a foundation for the further investigation in the prevention and treatment of ALI.

pH-Modulated 1D Hierarchical Self-Assembly of a Brush-Like Poly-Para-Phenylene Homopolymer.

The controllable self-assembly of conjugated homopolymers, especially homopolymers without other segments (a prerequisite for phase separation), which can afford chances to achieve tunable optical/electronic properties, remains a great challenge due to their poor solubility and has remained rarely documented. Herein, a conjugated homopolymer (DPPP-COOH) is synthesized, which has a unique brush-like structure with a conjugated dendritic poly-para-phenylene (DPPP) backbone and alkyl-carboxyl side chains at both edges of the backbone. The introduction of carboxyl makes the brush-like homopolymer exhibit pH-modulated 1D hierarchical self-assembly behavior in dilute solution, and allows for flexible morphological regulation of the assemblies, forming some uncommon superstructures including ultralong nanowires (at pH 7), superhelices (at pH 10) and "single-wall" nanotubes (at pH 13), respectively. Furthermore, the good aqueous dispersibility and 1D feature endow the superstructures formed in a high-concentration neutral solution with high broad-spectrum antibacterial performance superior to that of many conventional 1D materials.

Mangiferin alleviates diabetic pulmonary fibrosis in mice via inhibiting endothelial-mesenchymal transition through AMPK/FoxO3/SIRT3 axis.

Diabetes mellitus results in numerous complications. Diabetic pulmonary fibrosis (DPF), a late pulmonary complication of diabetes, has not attracted as much attention as diabetic nephropathy and cardiomyopathy. Mangiferin (MF) is a natural small molecular compound that exhibits a variety of pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetes, and anti-fibrosis effects. In this study, we investigated whether long-term diabetes shock induces DPF, and explored whether MF had a protective effect against DPF. We first examined the lung tissues and sections of 20 diabetic patients obtained from discarded lung surgical resection specimens and found that pulmonary fibrosis mainly accumulated around the pulmonary vessels, accompanied by significantly enhanced endothelial-mesenchymal transition (EndMT). We established a mouse model of DPF by STZ injections. Ten days after the final STZ injection, the mice were administered MF (20, 60 mg/kg, i.g.) every 3 days for 4 weeks, and kept feeding until 16 weeks and euthanized. We showed that pulmonary fibrotic lesions were developed in the diabetic mice, which began around the pulmonary vessels, while MF administration did not affect long-term blood glucose levels, but dose-dependently alleviated diabetes-induced pulmonary fibrosis. In human umbilical vein endothelial cells (HUVECs), exposure to high glucose (33.3 mM) induced EndMT, which was dose-dependently inhibited by treatment with MF (10, 50 µM). Furthermore, MF treatment promoted SIRT3 expression in high glucose-exposed HUVECs by directly binding to AMPK to enhance the activity of FoxO3, which finally reversed diabetes-induced EndMT. We conclude that MF attenuates DPF by inhibiting EndMT through the AMPK/FoxO3/SIRT3 axis. MF could be a potential candidate for the early prevention and treatment of DPF.

Artificial intelligence-based model for lymph node metastases detection on whole slide images in bladder cancer: a retrospective, multicentre, diagnostic study.

BACKGROUND: Accurate lymph node staging is important for the diagnosis and treatment of patients with bladder cancer. We aimed to develop a lymph node metastases diagnostic model (LNMDM) on whole slide images and to assess the clinical effect of an artificial intelligence-assisted (AI) workflow. METHODS: In this retrospective, multicentre, diagnostic study in China, we included consecutive patients with bladder cancer who had radical cystectomy and pelvic lymph node dissection, and from whom whole slide images of lymph node sections were available, for model development. We excluded patients with non-bladder cancer and concurrent surgery, or low-quality images. Patients from two hospitals (Sun Yat-sen Memorial Hospital of Sun Yat-sen University and Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China) were assigned before a cutoff date to a training set and after the date to internal validation sets for each hospital. Patients from three other hospitals (the Third Affiliated Hospital of Sun Yat-sen University, Nanfang Hospital of Southern Medical University, and the Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China) were included as external validation sets. A validation subset of challenging cases from the five validation sets was used to compare performance between the LNMDM and pathologists, and two other datasets (breast cancer from the CAMELYON16 dataset and prostate cancer from the Sun Yat-sen Memorial Hospital of Sun Yat-sen University) were collected for a multi-cancer test. The primary endpoint was diagnostic sensitivity in the four prespecified groups (ie, the five validation sets, a single-lymph-node test set, the multi-cancer test set, and the subset for a performance comparison between the LNMDM and pathologists). FINDINGS: Between Jan 1, 2013 and Dec 31, 2021, 1012 patients with bladder cancer had radical cystectomy and pelvic lymph node dissection and were included (8177 images and 20 954 lymph nodes). We excluded 14 patients (165 images) with concurrent non-bladder cancer and also excluded 21 low-quality images. We included 998 patients and 7991 images (881 [88%] men; 117 [12%] women; median age 64 years [IQR 56-72]; ethnicity data not available; 268 [27%] with lymph node metastases) to develop the LNMDM. The area under the curve (AUC) for accurate diagnosis of the LNMDM ranged from 0·978 (95% CI 0·960-0·996) to 0·998 (0·996-1·000) in the five validation sets. Performance comparisons between the LNMDM and pathologists showed that the diagnostic sensitivity of the model (0·983 [95% CI 0·941-0·998]) substantially exceeded that of both junior pathologists (0·906 [0·871-0·934]) and senior pathologists (0·947 [0·919-0·968]), and that AI assistance improved sensitivity for both junior (from 0·906 without AI to 0·953 with AI) and senior (from 0·947 to 0·986) pathologists. In the multi-cancer test, the LNMDM maintained an AUC of 0·943 (95% CI 0·918-0·969) in breast cancer images and 0·922 (0·884-0·960) in prostate cancer images. In 13 patients, the LNMDM detected tumour micrometastases that had been missed by pathologists who had previously classified these patients' results as negative. Receiver operating characteristic curves showed that the LNMDM would enable pathologists to exclude 80-92% of negative slides while maintaining 100% sensitivity in clinical application. INTERPRETATION: We developed an AI-based diagnostic model that did well in detecting lymph node metastases, particularly micrometastases. The LNMDM showed substantial potential for clinical applications in improving the accuracy and efficiency of pathologists' work. FUNDING: National Natural Science Foundation of China, the Science and Technology Planning Project of Guangdong Province, the National Key Research and Development Programme of China, and the Guangdong Provincial Clinical Research Centre for Urological Diseases.

The Circ_35953 induced by the NF-κB mediated the septic AKI via targeting miR-7219-5p/HOOK3 and IGFBP7 axis.

A few studies suggested that CircRNAs were involved in the development of septic AKI. However，the role and regulation mechanism of CircRNA_35953 in septic AKI remains unclear. Here, we found that Circ_35953 was induced by LPS via activation of NF-κB signal in BUMPT cells. Functionally, Circ_35953 mediated the LPS induced the apoptosis in BUMPT cells. Moreover, we demonstrated that Circ_35953 sponged miR-7219-5p to upregulate the expression of HOOK3 and IGFBP7. Finally, we verified that knock down of Circ_35953 alleviated the progression of CLP-induced AKI via targeting the miR-7219-5p/HOOK3 and IGFBP7 signal. Collectively, the data suggested that Circ_35953 /miR-7219-5p/HOOK3 and IGFBP7 axis mediated the septic AKI, which also revealed a potential mechanism of septic AKI.

Synergistic Effect of Electron Scattering and Space Charge Transfer Enabled Unprecedented Room Temperature NO2 Sensing Response of SnO2.

Metal oxide gas sensors have long faced the challenge of low response and poor selectivity, especially at room temperature (RT). Herein, a synergistic effect of electron scattering and space charge transfer is proposed to comprehensively improve gas sensing performance of n-type metal oxides toward oxidizing NO2 (electron acceptor) at RT. To this end, the porous SnO2 nanoparticles (NPs) assembled from grains of about 4 nm with rich oxygen vacancies are developed through an acetylacetone-assisted solvent evaporation approach combined with precise N2 and air calcinations. The results show that the as-fabricated porous SnO2 NPs sensor exhibits an unprecedented NO2 -sensing performance, including outstanding response (Rg /Ra  = 772.33 @ 5 ppm), fast recovery (<2 s), an extremely low detection limit (10 ppb), and exceptional selectivity (response ratio >30) at RT. Theoretical calculation and experimental tests confirm that the excellent NO2 sensing performance is mainly attributed to the unique synergistic effect of electron scattering and space charge transfer. This work proposes a useful strategy for developing high-performance RT NO2 sensors using metal oxides, and provides an in-depth understanding for the basic characteristics of the synergistic effect on gas sensing, paving the way for efficient and low power consumption gas detection at RT.

The Role of Histone Deacetylases in Acute Lung Injury-Friend or Foe.

Acute lung injury (ALI), caused by intrapulmonary or extrapulmonary factors such as pneumonia, shock, and sepsis, eventually disrupts the alveolar-capillary barrier, resulting in diffuse pulmonary oedema and microatasis, manifested by refractory hypoxemia, and respiratory distress. Not only is ALI highly lethal, but even if a patient survives, there are also multiple sequelae. Currently, there is no better treatment than supportive care, and we urgently need to find new targets to improve ALI. Histone deacetylases (HDACs) are epigenetically important enzymes that, together with histone acetylases (HATs), regulate the acetylation levels of histones and non-histones. While HDAC inhibitors (HDACis) play a therapeutic role in cancer, inflammatory, and neurodegenerative diseases, there is also a large body of evidence suggesting the potential of HDACs as therapeutic targets in ALI. This review explores the unique mechanisms of HDACs in different cell types of ALI, including macrophages, pulmonary vascular endothelial cells (VECs), alveolar epithelial cells (AECs), and neutrophils.

Buformin alleviates sepsis-induced acute lung injury via inhibiting NLRP3-mediated pyroptosis through an AMPK-dependent pathway.

BACKGROUND: NOD-like receptor family pyrin domain containing 3 (NLRP3)-mediated macrophage pyroptosis plays an important role in sepsis-induced acute lung injury (ALI). Inhibition of pyroptosis may be a way to alleviate inflammation as well as tissue damage triggered after lipopolysaccharide (LPS) stimulation. The aim of the present study was to explore whether buformin (BF), a hypoglycemic agent, could alleviate sepsis-induced ALI by inhibiting pyroptosis. METHODS: Wildtype C57BL/6 mice were randomly divided into control group, BF group, LPS group and LPS+BF group. BF group and LPS+BF group were pretreated with BF at a dose of 25 mg/kg, and the changes were observed. In addition, BF was used to interfere with THP-1 cells. The therapeutic effect of BF has been verified by intraperitoneal injection of BF in vivo after LPS stimulation. RESULTS: Inflammation and injury was significantly reduced in BF pretreated mice, and the indexes related to pyroptosis were suppressed. The phosphorylation of AMP-activated protein kinase (AMPK) in lung tissues of mice in the BF and LPS+BF groups was significantly higher. In THP-1 cells, the AMPK inhibitor, Compound C was added to demonstrate that BF worked via AMPK to inhibit NLRP3 inflammasome. It was further demonstrated that BF up-regulated autophagy, which in turn promoted NLRP3 inflammasome degradation. On the other hand, BF decreased NLRP3 mRNA level by increasing nuclear factor-erythroid 2 related factor 2 (Nrf2). And BF showed a therapeutic effect after LPS challenge. CONCLUSION: Our study confirmed that BF inhibited NLRP3-mediated pyroptosis in sepsis-induced ALI by up-regulating autophagy and Nrf2 protein level through an AMPK-dependent pathway. This provides a new strategy for clinical mitigation of sepsis-induced ALI.

PM2.5-induced lung injury is attenuated in macrophage-specific NLRP3 deficient mice.

Fine particulate matter (PM2.5) is one of the most important components of environmental pollutants and is associated with lung injury. Pyroptosis, a form of programmed cell death mainly mediated by the NLRP3 inflammasome, has been reported to be involved in sepsis-induced or ischemia/reperfusion-induced lung injury. However, the specific mechanisms of pyroptosis in PM2.5-induced lung injury are not yet clear. We constructed macrophage-specific NLRP3 knockout mice to explore the mechanism of PM2.5-induced lung injury in terms of inflammatory response, oxidative stress, and apoptosis levels, including the relationship between these effects and pyroptosis. The results disclosed that PM2.5 exposure increased the infiltration of macrophages and leukocytes and the secretion of inflammatory cytokines, including TNF-α and IL-6, in lung tissue. The activity of antioxidant enzymes, including SOD, GSH-PX, and CAT, significantly decreased, while MDA, the end product of lipid oxidation, remarkably increased. The level of apoptosis in lung tissue, measured by the TUNEL assay and apoptosis-related proteins (BAX and BCL-2), was significantly increased. Macrophage-specific NLRP3 knockout could offset these effects. We further observed that PM2.5 treatment activated the NLRP3 inflammasome and subsequently induced pyroptosis, as evidenced by the increased production of IL-1ß and IL-18 and the increase of the protein levels of NLRP3, ASC, caspase-1, and GSDMD, which were inhibited when NLRP3 was knocked out in macrophages. Taken together, these results revealed that NLRP3-mediated macrophage pyroptosis promoted PM2.5-induced lung injury through aggravating inflammation, oxidative stress, and apoptosis. Targeting the inhibition of NLRP3-mediated macrophage pyroptosis provides a new way to study lung injury induced by the exposure to PM2.5.

Facile and low-cost fabrication of a humidity sensor using naturally available sepiolite nanofibers.

Much effort has focussed on enhancing the humidity-sensing performances of humidity sensors, but their fabrication using facile and low-cost methods is also desirable. In this work, a humidity sensor based on a naturally available nanomaterial, sepiolite nanofibers (SNFs), was facilely fabricated without any expensive raw materials or complex processes. Characterization results show that SNFs have a natural slender nanofiber structure (diameter 20-50 nm) and abundant hydrophilic functional groups (-OH). The results of humidity-sensing tests show that the SNF humidity sensor has outstanding humidity-sensing properties (i.e. large response, good linearity and repeatability) within the relative humidity range from 10.9% to 91.5% at room temperature (25 °C). This work presents a moderate and cost-effective strategy for the fabrication of high-performance humidity sensors using the natural SNF nanomaterial.

Characterizing pump line phase offset of a single-soliton Kerr comb by dual comb interferometry.

We report phase retrieval of a single-soliton Kerr comb using electric field cross-correlation implemented via dual-comb interferometry. The phase profile of the Kerr comb is acquired through the heterodyne beat between the Kerr comb and an electro-optic comb with a pre-characterized phase profile. The soliton Kerr comb has a nearly flat phase profile, and the pump line is observed to show a phase offset which depends on the pumping parameters. The experimental results are in agreement with numerical simulations.

Retraction: Differential expression of exosomal miRNAs in osteoblasts in osteoarthritis [Journal of Central South University. Medical Science, 2018, 43(12):1294-1300. DOI: 10.11817/j.issn.1672-7347.2018.12.003].

The article entitled "Differential expression of exosomal miRNAs in osteoblasts in osteoarthritis" published on Journal of Central South University (Medical Science), in Volume 43, Issue 12, 2018 (DOI: 10.11817/j.issn.1672-7347.2018.12.003) may have an unclear risk of bias due to insufficient understanding for some results. Further experimental studies are needed. We all agree to retract this article, and apologize to the Journal and readers for the possible negative impact.

Space-time focusing in a highly multimode fiber via optical pulse shaping.

Fields propagating through a highly scattering material will be distorted in both space (intensity speckles) and time (spectral and temporal speckles), inhibiting tasks such as imaging and communication in both the optical and radio frequency regions. In optics, research thus far has demonstrated spatial focusing, image transmission, and short pulse delivery through bulk scattering materials and multimode fibers by taking advantage of spatial wavefront-shaping techniques. Here, we exploit spectral phase shaping for reference-free characterization of spectral and temporal speckle, and space-time focusing of broadband ultrafast pulses distorted by modal dispersion in a multimode fiber. We show that temporal speckle fields at different multimode fiber output locations are uncorrelated and demonstrate the ability to focus a short pulse at a specific output spatial location, while keeping the field at other output locations noise-like, offering opportunities to expand multimode fiber imaging and communication capacity.

[Differential expression of exosomal miRNAs in osteoblasts in osteoarthritis].

OBJECTIVE: To analyze the differentially expressed exosomal miRNAs in subchondral osteoblasts in patients with osteoarthritis (OA) and to investigate the key miRNAs potentially involved in the occurrence and progression of OA.
 Methods: Subchondral bones were harvested from 6 patients with OA. All subjects were divided into two groups which was based on the severity of joint wear: An OA group, severely worn side of subchondral bone, and a control group, less worn side of subchondral bone. The exosomes were extracted from osteoblast cells and their characteristics were identified. Then exosomal miRNAs were extracted and sequencing analysis was conducted to compare the expression in the two groups. The most differentially expressed ones (log2Ratio≥2) were subject to miRNA target prediction and quantitative reverse transcription PCR (RT-qPCR) to further quantify the difference.
 Results: Osteoblast extractions were confirmed to be exosomes, which were small double-membranous vesicles with 30-200 nm in diameter and 50-150 nm in peak value of particle size under the scanning microscope. High-throughput sequencing revealed 124 miRNAs whose expression significantly increased in the OA group. The most differentially expressed one with maximum fold change was hsa-miR-4717-5p and its target gene was RGS2. RT-qPCR demonstrated hsa-miR-4717-5p expression in the OA group was relatively higher than that in the control group (2.243 vs 0.480, P<0.01).
 Conclusion: There is distinct difference in expression profiles of exosomal miRNAs in subchondral osteoblasts between patients with OA and normal subjects. Up-regulated expression of miRANs might participate in OA occurrance and progression.

Comparative efficacy of commercial oral poly-herbal traditional Chinese medicine formulations combined with western medicine in benign prostatic hyperplasia management: a systematic review and network meta-analysis.

Background: Benign prostatic hyperplasia (BPH) is prevalent among the aging male population and often presents with distressing lower urinary tract symptoms. There is emerging evidence that commercial oral poly-herbal traditional Chinese medicine (TCM) formulation combined with Western medicine (WM) may offer enhanced therapeutic effects compared to WM alone in BPH treatment. Nevertheless, determining the optimal formulations for BPH remains controversial. We aimed to employ a network meta-analysis to compare and assess differences among commonly used and recommended poly-herbal TCM formulations outlined in the Chinese guidelines for BPH treatment, providing clinical medication recommendations and guidance. Methods: We extensively searched for RCTs of BPH patients that had oral poly-herbal TCM formulations and WM treatment, covering both English and Chinese databases up to 31 October 2023. The quality of the included studies was evaluated using the Cochrane risk-of-bias tool Version 2 (ROB2). A Bayesian network meta-analysis was performed to assess the effectiveness of various formulations, followed by sensitivity and subgroup analyses. Results: Our meta-analysis included 107 RCTs involving 11,037 patients across 16 oral poly-herbal TCM formulations. The quality of the selected studies was assessed as "Some concerns". Most formulations combined with WM demonstrated superior therapeutic efficacy compared to WM alone. For clinical effective rate, Jingui Shenqi pill (JGSQ) + WM had the highest-ranking probability (87.38%). Concerning International Prostate Symptom Score (IPSS) and maximum flow rate of urine, Guizhi Fuling capsule (GZFL) + WM was most effective (91.10% and 98.55%). Regarding the quality of life score and postvoid residual urine, Pulean tablet (PLA) + WM ranked first (86.71% and 91.81%). In controlling prostate volume, Huange capsule (HE) + WM demonstrated the highest efficacy (95.65%). Additionally, among the interventions, Lingze (LZ) + WM capsule exhibited the lowest incidence of adverse drug reactions (2.32%). Conclusion: Combining oral poly-herbal TCM formulations with WM may provide greater therapeutic benefits in BPH treatment compared to WM alone. JGSQ, GZFL, PLA, and HE emerged as promising treatment options. However, further rigorous empirical studies are essential to substantiate these findings. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=459651, CRD 42023459651.

Shigella induces stress granule formation by ADP-riboxanation of the eIF3 complex.

Under stress conditions, translationally stalled mRNA and associated proteins undergo liquid-liquid phase separation and condense into cytoplasmic foci called stress granules (SGs). Many viruses hijack SGs for their pathogenesis; however, whether pathogenic bacteria also exploit this pathway remains unknown. Here, we report that members of the OspC family of Shigella flexneri induce SG formation in infected cells. Mechanistically, the OspC effectors target multiple subunits of the host translation initiation factor 3 complex by ADP-riboxanation. The modification of eIF3 leads to translational arrest and thus the formation of SGs. Furthermore, OspC-mediated SGs are beneficial for S. flexneri replication within infected host cells, and bacterial strains unable to induce SGs are attenuated for virulence in a murine model of infection. Our findings reveal a mechanism by which bacterial pathogens induce SG assembly by inactivating host translational machinery and promote bacterial proliferation in host cells.

Measurements of peri-prostatic adipose tissue by MRI predict bone metastasis in patients with newly diagnosed prostate cancer.

Objectives: To investigate the role of MRI measurements of peri-prostatic adipose tissue (PPAT) in predicting bone metastasis (BM) in patients with newly diagnosed prostate cancer (PCa). Methods: We performed a retrospective study on 156 patients newly diagnosed with PCa by prostate biopsy between October 2010 and November 2022. Clinicopathologic characteristics were collected. Measurements including PPAT volume and prostate volume were calculated by MRI, and the normalized PPAT (PPAT volume/prostate volume) was computed. Independent predictors of BM were determined by univariate and multivariate logistic regression analysis, and a new nomogram was developed based on the predictors. Receiver operating characteristic (ROC) curves were used to estimate predictive performance. Results: PPAT and normalized PPAT were associated with BM (P<0.001). Normalized PPAT positively correlated with clinical T stage(cT), clinical N stage(cN), and Grading Groups(P<0.05). The results of ROC curves indicated that PPAT and normalized PPAT had promising predictive value for BM with the AUC of 0.684 and 0.775 respectively. Univariate and multivariate analysis revealed that high normalized PPAT, cN, and alkaline phosphatase(ALP) were independently predictors of BM. The nomogram was developed and the concordance index(C-index) was 0.856. Conclusions: Normalized PPAT is an independent predictor for BM among with cN, and ALP. Normalized PPAT may help predict BM in patients with newly diagnosed prostate cancer, thus providing adjunctive information for BM risk stratification and bone scan selection.

Mitochondrial quality control in human health and disease.

Mitochondria, the most crucial energy-generating organelles in eukaryotic cells, play a pivotal role in regulating energy metabolism. However, their significance extends beyond this, as they are also indispensable in vital life processes such as cell proliferation, differentiation, immune responses, and redox balance. In response to various physiological signals or external stimuli, a sophisticated mitochondrial quality control (MQC) mechanism has evolved, encompassing key processes like mitochondrial biogenesis, mitochondrial dynamics, and mitophagy, which have garnered increasing attention from researchers to unveil their specific molecular mechanisms. In this review, we present a comprehensive summary of the primary mechanisms and functions of key regulators involved in major components of MQC. Furthermore, the critical physiological functions regulated by MQC and its diverse roles in the progression of various systemic diseases have been described in detail. We also discuss agonists or antagonists targeting MQC, aiming to explore potential therapeutic and research prospects by enhancing MQC to stabilize mitochondrial function.

Development and validation of an artificial intelligence-based model for detecting urothelial carcinoma using urine cytology images: a multicentre, diagnostic study with prospective validation.

Background: Urine cytology is an important non-invasive examination for urothelial carcinoma (UC) diagnosis and follow-up. We aimed to explore whether artificial intelligence (AI) can enhance the sensitivity of urine cytology and help avoid unnecessary endoscopy. Methods: In this multicentre diagnostic study, consecutive patients who underwent liquid-based urine cytology examinations at four hospitals in China were included for model development and validation. Patients who declined surgery and lacked associated histopathology results, those diagnosed with rare subtype tumours of the urinary tract, or had low-quality images were excluded from the study. All liquid-based cytology slides were scanned into whole-slide images (WSIs) at 40 × magnification and the WSI-labels were derived from the corresponding histopathology results. The Precision Urine Cytology AI Solution (PUCAS) was composed of three distinct stages (patch extraction, features extraction, and classification diagnosis) and was trained to identify important WSI features associated with UC diagnosis. The diagnostic sensitivity was mainly used to validate the performance of PUCAS in retrospective and prospective validation cohorts. This study is registered with the ChiCTR, ChiCTR2300073192. Findings: Between January 1, 2018 and October 31, 2022, 2641 patients were retrospectively recruited in the training cohort, and 2335 in retrospective validation cohorts; 400 eligible patients were enrolled in the prospective validation cohort between July 7, 2023 and September 15, 2023. The sensitivity of PUCAS ranged from 0.922 (95% CI: 0.811-0.978) to 1.000 (0.782-1.000) in retrospective validation cohorts, and was 0.896 (0.837-0.939) in prospective validation cohort. The PUCAS model also exhibited a good performance in detecting malignancy within atypical urothelial cells cases, with a sensitivity of over 0.84. In the recurrence detection scenario, PUCAS could reduce 57.5% of endoscopy use with a negative predictive value of 96.4%. Interpretation: PUCAS may help to improve the sensitivity of urine cytology, reduce misdiagnoses of UC, avoid unnecessary endoscopy, and reduce the clinical burden in resource-limited areas. The further validation in other countries is needed. Funding: National Natural Science Foundation of China; Key Program of the National Natural Science Foundation of China; the National Science Foundation for Distinguished Young Scholars; the Science and Technology Planning Project of Guangdong Province; the National Key Research and Development Programme of China; Guangdong Provincial Clinical Research Centre for Urological Diseases.