A review of functions and mechanisms of clay soil conditioners and catalysts in thermal remediation compared to emerging photo-thermal catalysis.

High temperatures and providing sufficient time for the thermal desorption of persistent organic pollutants (POPs) from contaminated clay soils can lead to intensive energy consumption. Therefore, this article provides a critical review of the potential additives which can improve soil texture and increase the volatility of POPs, and then discusses their enhanced mechanisms for contributing to a green economy. Ca-based additives have been used to reduce plasticity of bentonite clay, absorb water and replenish system heat. In contrast, non-Ca-based additives have been used to decrease the plasticity of kaolin clay. The soil structure and soil plasticity can be changed through cation exchange and flocculation processes. The transition metal oxides and alkali metal oxides can be applied to catalyze and oxidize polycyclic aromatic hydrocarbons, petroleum and emerging contaminants. In this system, reactive oxygen species (•O2- and •OH) are generated from thermal excitation without strong chemical oxidants. Moreover, multiple active ingredients in recycled solid wastes can be controlled to reduce soil plasticity and enhance thermal catalysis. Alternatively, the alkali, nano zero-valent iron and nano-TiN can catalyze hydrodechlorination of POPs under reductive conditions. Especially, photo and photo-thermal catalysis are discussed to accelerate replacement of fossil fuels by renewable energy in thermal remediation.

Phenotyping Refractory Cardiogenic Shock Patients Receiving Venous-Arterial Extracorporeal Membrane Oxygenation Using Machine Learning Algorithms.

Background: This study used machine learning to categorize cardiogenic shock (CS) patients treated with venous-arterial extracorporeal membrane oxygenation (VA-ECMO) into distinct phenotypes. Subsequently, it aimed to clarify the wide mortality variance observed in refractory CS, attributing it to the condition's inherent heterogeneity. Methods: This study enrolled a cohort of CS patients who received VA-ECMO support. By employing rigorous machine learning (ML) techniques, we generated and validated clusters based on determinants identified through algorithmic analysis. These clusters, characterized by distinct clinical outcomes, facilitated the examination of clinical and laboratory profiles to enhance the understanding of patient responses to VA-ECMO treatment. Results: In a study of 210 CS patients undergoing VA-ECMO treatment, 70.5% were male with a median age of 62, ranging from 53 to 67 years. Survival rates were 67.6% during VA-ECMO and 49.5% post-discharge. Patients were classified into three phenotypes based on the clinical and laboratory findings: "platelet preserved (I)", those with stable platelet counts, "hyperinflammatory (II)", those indicating significant inflammation, and "hepatic-renal (III)", those showing compromised liver and kidney functions. Mortality rates (25.0%, 52.8%, and 55.9% for phenotypes I, Ⅱ, and Ⅲ, respectively (p = 0.005)) varied significantly among these groups, highlighting the importance of phenotype identification in patient management. Conclusions: This study identified three distinct phenotypes among refractory CS patients treated using VA-ECMO, each with unique clinical characteristics and mortality risks. Thus, highlighting the importance of early detection and targeted intervention, these findings suggest that proactive management could improve outcomes for those showing critical signs.

Bacterial specialists playing crucial roles in maintaining system stability and governing microbial diversity in bioremediation of oil-polluted sediments under typical deep-sea condition.

Ecologically, interactions and contributions of microbiota generalists and specialists remain largely unexplored in remediation of deep-sea oil pollution. Herein, ecological and evolutionary characteristics of the two taxa were comprehensively investigated in restoration of oil-polluted sediment at deep-sea microcosm. Niche-specialized taxa exhibited rapid speciation rate, more complex network structure and highly interspecific mutualism. In contrast, generalists possessed higher richness but with poor local performance, as evidenced by higher extinction rate, lower stability, and more interspecific antagonism. Generalists were the primary oil degraders, while specialists acted as auxiliaries promoting degradation via production of biofilm and biosurfactant. Evolutionarily, the continuous transition from specialists to generalists insured the exclusion of generalist at a relatively constant level for ecological trade-offs. Collectively, the findings emphasize the importance of specialists in facilitating oil degradation by elucidating their vital roles in maintaining system stability and regulating microbial diversity during process, and offer valuable guidance for designing remediation plans.

Oncolytic herpes simplex virus propagates tertiary lymphoid structure formation via CXCL10/CXCR3 to boost antitumor immunity.

Inducing tertiary lymphoid structure (TLS) formation can fuel antitumor immunity. It is necessary to create mouse models containing TLS to explore strategies of TLS formation. Oncolytic herpes simplex virus-1 (oHSV) exhibited intense effects in preclinical and clinical trials. However, the role of oHSV in TLS formation remains to be elucidated. Here, we observed the presence of TLS in 4MOSC1 and MC38 subcutaneous tumour models. Interestingly, oHSV evoked TLS formation, and increased infiltration of B cells and stem-like TCF1+CD8+ T cells proliferation. Mechanistically, oHSV increased the expression of TLS-related chemokines, along with upregulated CXCL10/CXCR3 to facilitate TLS formation. Notably, CXCL10 and CXCR3 were favourable prognostic factors for cancer patients, and closely related with immune cells infiltration. Inhibiting CXCL10/CXCR3 reduced TCF1+CD8+ T cells and granzyme B expression, and impaired oHSV-mediated TLS formation. Furthermore, oHSV-mediated TLS formation revealed superior response and survival rate when combined with αPD-1 treatment. Collectively, these findings indicate that oHSV recruits stem-like TCF1+CD8+ T cells through CXCL10/CXCR3 pathway to propagate TLS formation, and warrants future antitumor immunity development.

PAFE: A lightweight visualization-based fast malware classification method.

With the development of automated malware toolkits, cybersecurity faces evolving threats. Although visualization-based malware analysis has proven to be an effective method, existing approaches struggle with challenging malware samples due to alterations in the texture features of binary images during the visualization preprocessing stage, resulting in poor performance. Furthermore, to enhance classification accuracy, existing methods sacrifice prediction time by designing deeper neural network architectures. This paper proposes PAFE, a lightweight and visualization-based rapid malware classification method. It addresses the issue of texture feature variations in preprocessing through pixel-filling techniques and applies data augmentation to overcome the challenges of class imbalance in small sample datasets. PAFE combines multi-scale feature fusion and a channel attention mechanism, enhancing feature expression through modular design. Extensive experimental results demonstrate that PAFE outperforms the current state-of-the-art methods in both efficiency and effectiveness for malware variant classification, achieving an accuracy rate of 99.25 % with a prediction time of 10.04 ms.

Rational design of Au-Bi bimetallic nanozyme for NIR-II laser mediated multifunctional combined tumor therapy.

To maximize the therapeutic effects and minimize the adverse effects of synergistic tumor therapies, a multifunctional nanozyme Au-Bi/ZIF-8@DOX@HA (ABZ@DOX@HA) was designed and synthesized through the Au and Bi bimetallic doping of ZIF-8, loading of the DOX, and modifying with hyaluronic acid (HA). The ABZ@DOX@HA nanoparticles (NPs) could simulate the enzymatic activities of glucose oxidase (GOx) and peroxidase (POD). Upon irradiated by near-infrared region (NIR-II) laser, the strong synergism of the photothermal abilities of the loaded Au and Bi nanodots accelerated the collapse of the ABZ structure at the tumor site considerably and released Au, Bi nanodots and DOX. The results in vitro and in vivo proved that ABZ@DOX@HA nanozyme could effectively exert the combined tumor therapy of starvation treatment, photothermal therapy (PTT), chemodynamic therapy (CDT) and chemotherapy. The current research provides a new strategy to address the inherent challenges of easy clearance and short blood circulation of small-sized NPs during the treatment of tumors with nanomedicine, as well as the aggregation and oxidation of inorganic nanodots.

Crocin-1 laden thermosensitive chitosan-based hydrogel with smart anti-inflammatory performance for severe full-thickness burn wound therapeutics.

Burns are the fourth most common type of civilian trauma worldwide, and the management of severe irregular scald wounds remains a significant challenge. Herein, crocin-1 laden hydroxybutyl chitosan (CRO-HBC) thermosensitive hydrogel with smart anti-inflammatory performance was developed for accelerating full-thickness burn healing. The injectable and shape adaptability of the CRO-HBC gel make it a promising candidate for effectively filling scald wounds with irregular shapes, while simultaneously providing protection against external pathogens. The CRO-HBC gel network formed by hydrophobic interactions exhibited an initial burst release of crocin-1, followed by a gradual and sustained release over time. The excessive release of ROS and pro-inflammatory cytokines should be effectively regulated in the early stage of wound healing. The controlled release of crocin-1 from the CRO-HBC gel adequately addresses this requirement for wound healing. The CRO-HBC hydrogel also exhibited an excellent biocompatibility, an appropriate biodegradability, keratinocyte migration facilitation properties, and a reactive oxygen species scavenging capability. The composite CRO-HBC hydrogel intelligently mitigated inflammatory responses, promoted angiogenesis, and exhibited a commendable efficacy for tissue regeneration in a full-thickness scalding model. Overall, this innovative temperature-sensitive CRO-HBC injectable hydrogel dressing with smart anti-inflammatory performance has enormous potential for managing severe scald wounds.

Comparative analysis of 12 water lily plastid genomes reveals genomic divergence and evolutionary relationships in early flowering plants.

The aquatic plant Nymphaea, a model genus of the early flowering plant lineage Nymphaeales and family Nymphaeaceae, has been extensively studied. However, the availability of chloroplast genome data for this genus is incomplete, and phylogenetic relationships within the order Nymphaeales remain controversial. In this study, 12 chloroplast genomes of Nymphaea were assembled and analyzed for the first time. These genomes were 158,290-160,042 bp in size and contained 113 non-repeat genes, including 79 protein-coding genes, 30 tRNA genes, and four rRNA genes. We also report on codon usage, RNA editing sites, microsatellite structures, and new repetitive sequences in this genus. Comparative genomics revealed that expansion and contraction of IR regions can lead to changes in the gene numbers. Additionally, it was observed that the highly variable regions of the chloroplast genome were mainly located in intergenic regions. Furthermore, the phylogenetic tree showed the order Nymphaeales was divided into three families, and the genus Nymphaea can be divided into five (or three) subgenera, with the subgenus Nymphaea being the oldest. The divergence times of nymphaealean taxa were analyzed, with origins of the order Nymphaeales and family Nymphaeaceae being about 194 and 131 million years, respectively. The results of the phylogenetic analysis and estimated divergence times will be useful for future evolutionary studies of basal angiosperm lineages. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-024-00242-0.

Spatially fractionated radiotherapy (Lattice SFRT) in the palliative treatment of locally advanced bulky unresectable head and neck cancer.

Objectives: Locally advanced bulky unresectable head neck cancer causes significant tumor mass effects, leading to severe symptoms. This study aims to report the safety and outcomes in patients undergoing Lattice spatially fractionated radiotherapy (Lattice SFRT) for locally advanced bulky unresectable head and neck cancer. Methods: Patients with bulky head and neck cancer received Lattice SFRT between June 2022 and June 2023. Lattice SFRT was administered in 2-3 fractions of 12 Gy (Gy) using 6-megavolt (MV) photon beams through a multileaf collimator (MLC) based on VMAT technology. The primary endpoints were symptomatic and tumor response rates. Secondary endpoints were overall survival, local control, and acute and late toxicity rates. Results: 19 consecutive patients meeting the study criteria were identified, predominantly with squamous cell carcinoma histology. The median patient age was 62 years (range 39-79 years), and the median tumor volume was 208 cc (cc) (range 48-701 cc). All patients completed radiotherapy. Among all investigated patients, 16 of 19 (84.2 %) patients achieved an objective response, including 10 individuals achieved a partial response (PR), with 3 of them exhibiting regression exceeding 75 %. 17 patients showed symptom improvement to varying degrees. Acute toxicity of Radiation Therapy Oncology Group (RTOG) grade 1 or higher occurred in 5 patients, while no grade 3 adverse events was observed. Conclusions: Lattice SFRT proves to be a viable treatment option for the palliative management of bulky head and neck cancer. In the palliative setting, Lattice SFRT offers timely symptom relief, enhancing patient quality of life. Treatment toxicity remains within an acceptable range. Continued optimization of Lattice SFRT delivery and patient selection can benefit from further data on the feasibility and efficacy of this radiation modality.

Causal role of immune cells in bipolar disorder: a Mendelian randomization study.

Background: The understanding of the immunological mechanisms underlying bipolar disorder (BD) has enhanced in recent years due to the extensive use of high-density genetic markers for genotyping and advancements in genome-wide association studies (GWAS). However, studies on the relationship between immune cells and the risk of BD remain limited, necessitating further investigation. Methods: Bidirectional two-sample Mendelian Randomization (MR) analysis was employed to investigate the causal association between immune cell morphologies and bipolar disorder. Immune cell traits were collected from a research cohort in Sardinia, whereas the GWAS summary statistics for BD were obtained from the Psychiatric Genomics Consortium. Sensitivity analyses were conducted, and the combination of MR-Egger and MR-Presso was used to assess horizontal pleiotropy. Cochran's Q test was employed to evaluate heterogeneity, and the results were adjusted for false discovery rate (FDR). Results: The study identified six immune cell phenotypes significantly associated with BD incidence (P< 0.01). These phenotypes include IgD- CD27- %lymphocyte, CD33br HLA DR+ CD14- AC, CD8 on CD28+ CD45RA+ CD8br, CD33br HLA DR+ AC, CD14 on CD14+ CD16+ monocyte, and HVEM on CD45RA- CD4+. After adjusting the FDR to 0.2, two immune cell phenotypes remained statistically significant: IgD-CD27-% lymphocyte (OR=1.099, 95% CI: 1.051-1.149, P = 3.51E-05, FDR=0.026) and CD33br HLA DR+ CD14-AC (OR=0.981, 95% CI: 0.971-0.991, P = 2.17E-04, FDR=0.079). In the reverse MR analysis, BD significantly impacted the phenotypes of four monocytes (P< 0.01), including CD64 on CD14+ CD16+ monocyte, CD64 on monocyte, CX3CR1 on CD14- CD16-, CD64 on CD14+ CD16- monocyte. However, after applying the FDR correction (FDR < 0.2), no statistically significant results were observed. Conclusions: This MR investigation reveals associations between immune cell phenotypes, bipolar disorder, and genetics, providing novel perspectives on prospective therapeutic targets for bipolar disorder.

Ulnar lengthening for children with forearm deformity from hereditary multiple exostoses: a retrospective study from a tertiary medical center.

BACKGROUND: Patients with hereditary multiple exostosis (HME) usually present with forearm deformity with or without radial head dislocation. Ulna lengthening has been proposed to address this condition. Exostosis resection plus ulna lengthening has been adopted in our hospital since 2008, and patients with this condition were retrospectively reviewed. Herein, we aimed to investigate the optimal timing and clinical outcomes of this surgical approach. METHODS: In all, thirty-five patients (40 forearms), including 22 boys and 13 girls, were enrolled in our study from July 2014 to September 2020. We divided the patients into 4 groups based on the age when they received surgery and the status of the radial head. Pronation and supination of the forearm, flexion and extension of the elbow, wrist ulnar deviation and wrist radial deviation, and radiological parameters including ulnar length (UL), ulnar variance (UV), the percentage of radial bowing (RB/RL), radio articular angle (RAA) and carpal slip (CS), were assessed and recorded. RESULTS: The mean UL was significantly improved after surgery in four Groups (P<0.05). In patients with radial head dislocation, we found significant improvement in forearm, wrist function and elbow flexion (p < 0.05). For the patients with radial head dislocation, the juniors demonstrated better improvement in % RB and RAA (p<0.05, p = 0.003 and 0.031). CONCLUSION: Exostosis resection and ulna lengthening with unilateral external fixation can effectively improve the function and radiological parameters of forearm deformity in HME children. For patients with radial head dislocation, early surgery can achieve better results. For patients not associated with radial head dislocation, we recommend regular follow-up and surgical treatment after 10 years of age.

Preparation of tenofovir amibufenamide fumarate spherical particles to improve tableting performance and sticking propensity by designing a spherical crystallization process.

Tenofovir amibufenamide fumarate (TMF) is the first oral drug developed in Asia for the treatment of adult patients with chronic viral hepatitis B, however, further applications are limited by poor tableting performance and high sticking propensity. In this work, the spherulitic growth process of TMF has been designed and explored with the help of molecular dynamics simulation and process analysis technologies (ATR-FTIR, FBRM and EasyViewer). The spherical particles with high bulk density, good flowability and uniform particle size distribution are prepared by a simple quenching process. More importantly, experimental results show that spherical particles have higher average tensile strength (100.8% increase), higher plastic deformability and lower amount of punch sticking (87.4% decrease in 30 tablets) compared to the commercial powder products. These contributions not only shed light on the design principle of drug spherulitic growth processes, but also provide guidance for the manufacture of high-quality tablet products.

How atmospheric deposition contribute to watershed heavy metals contamination in coastal watersheds in China: A case study of Laizhou Bay.

Atmospheric deposition is a significant source of heavy metal (HM) pollution. In order to understand the migration and transformation process of atmospheric HMs within the watershed and quantify the amount transported offshore by rivers, the Soil and Water Assessment Tool (SWAT) was developed to trace the migration of HMs from atmospheric deposition. The model simulates HMs in three forms: dissolved, adsorbed, and granular. It quantifies the movements of Cd, Cr, Cu, Hg, Pb, and Zn from atmospheric deposition into the sea via rivers in five coastal watersheds in East China and analyzes the effects of meteorological factors, vegetation cover, and slope on non-point pollution of these metals by Spearman correlation analysis. The results showed that the annual flux of HMs from atmospheric deposition to the sea through rivers accounted for 5 %-69 % of the total rivers flux. Among meteorological factors, precipitation demonstrated the strongest correlation with the monthly loads of HMs entering rivers from atmospheric deposition. Additionally, HMs loads entering rivers from atmospheric deposition were more closely related to vegetation cover than topographic slope. This model provides a new approach to distinguishing the flux of atmospheric HMs entering offshore waters through rivers. The findings will deepen our understanding of the migration and transformation of HMs from atmospheric deposition, enhance the ability to control offshore HMs pollution, and reduce the ecological risks associated by HMs.

Non-targeted metabolomics reveals the characteristics of the unique bitterness substances in quinoa.

Bitterness is a key factor that affects the consumption of quinoa products, even if they are nutritious. In this study, a non-targeted metabolomics approach based on UHPLC-Orbitrap-MS was applied to comprehensively profile the characteristic metabolites of twenty-two quinoas. A total of twenty key metabolites were identified correlated with bitterness, among which, fifteen were triterpenoid saponins. In addition, these metabolites bind to the active site of the human bitter taste receptor and are the main compounds that produce the bitter taste of quinoa. Our results contribute to a deeper understanding of the origin of quinoa bitterness and provide directions for optimizing its flavor to improve market acceptance.

Global trends and hotspots of exercise interventions for mild cognitive impairment: A global bibliometric analysis.

BACKGROUND: Exercise interventions for mild cognitive impairment (MCI) have been extensively studied. However, there is no bibliometric study on exercise interventions for MCI. This study aimed to identify the collaborative networks, research hotspots, evolution trends, and future directions. METHODS: Relevant documents were retrieved from the Web of Science Core Collection database. VOSviewer was used to analyze the co-authorship of the author, countries and institutions, and the keywords co-occurrence. CiteSpace was used to detect burst keywords' research trends. RESULTS: A total of 569 articles were included and showed an overall increasing trend in annual publications. The most influential subject categories, authors, journals, country, and institutions were "geriatrics gerontology," "Doi, Takehiko and Shimada, Hiroyuki," "Journal of Alzheimer's Disease," USA, and "Veterans Health Administration," respectively. The research hotspots are "effectiveness," "neural mechanism" and "correlation" of exercise interventions, and the emerging trend is "intervention quality." CONCLUSION: This area is in a rapid development phase, whereby research hotpots are focused and the research trend is clear. The highly productive authors and institutions have made outstanding contributions and the subject categories present an interdisciplinary trend. However, there is weak cooperation between countries and institutions, and a substantial research gap exists between developed and developing countries. Future research may highlight the intervention quality, emphasizing the combination with virtual reality technology.

Evolved cytidine and adenine base editors with high precision and minimized off-target activity by a continuous directed evolution system in mammalian cells.

Continuous directed evolution of base editors (BEs) has been successful in bacteria cells, but not yet in mammalian cells. Here, we report the development of a Continuous Directed Evolution system in Mammalian cells (CDEM). CDEM enables the BE evolution in a full-length manner with Cas9 nickase. We harness CDEM to evolve the deaminases of cytosine base editor BE3 and adenine base editors, ABEmax and ABE8e. The evolved cytidine deaminase variants on BE4 architecture show not only narrowed editing windows, but also higher editing purity and low off-target activity without a trade-off in on-targeting activity. The evolved ABEmax and ABE8e variants exhibit narrowed or shifted editing windows to different extents, and lower off-target effects. The results illustrate that CDEM is a simple but powerful approach to continuously evolve BEs without size restriction in the mammalian environment, which is advantageous over continuous directed evolution system in bacteria cells.

Construct prognostic models of multiple myeloma with pathway information incorporated.

Multiple myeloma (MM) is a hematological disease exhibiting aberrant clonal expansion of cancerous plasma cells in the bone marrow. The effects of treatments for MM vary between patients, highlighting the importance of developing prognostic models for informed therapeutic decision-making. Most previous models were constructed at the gene level, ignoring the fact that the dysfunction of the pathway is closely associated with disease development and progression. The present study considered two strategies that construct predictive models by taking pathway information into consideration: pathway score method and group lasso using pathway information. The former simply converted gene expression to sample-wise pathway scores for model fitting. We considered three methods for pathway score calculation (ssGSEA, GSVA, and z-scores) and 14 data sources providing pathway information. We implemented these methods in microarray data for MM (GSE136324) and obtained a candidate model with the best prediction performance in interval validation. The candidate model is further compared with the gene-based model and previously published models in two external data. We also investigated the effects of missing values on prediction. The results showed that group lasso incorporating Vax pathway information (Vax(grp)) was more competitive in prediction than the gene model in both internal and external validation. Immune information, including VAX pathways, seemed to be more predictive for MM. Vax(grp) also outperformed the previously published models. Moreover, the new model was more resistant to missing values, and the presence of missing values (<5%) would not evidently deteriorate its prediction accuracy using our missing data imputation method. In a nutshell, pathway-based models (using group lasso) were competitive alternatives to gene-based models for MM. These models were documented in an R package (https://github.com/ShuoStat/MMMs), where a missing data imputation method was also integrated to facilitate future validation.

Using a Dual-Disease Target Mapping Network Pharmacology Approach, Verbascoside Ameliorates Osteoporosis by Activating Estrogen Signaling to Alleviate Oxidative Stress.

BACKGROUND: Verbascoside, a compound classified as a phenylethanol glycoside in Dihuang, has been the subject of modern pharmacological investigations. These studies have revealed its noteworthy antioxidant, anti-inflammatory, memory-enhancing, neuroprotective, antitumor, and various other pharmacological properties. While verbascoside exhibits favorable antioxidant effects, its precise mechanism of action in ameliorating osteoporosis through the treatment of oxidative stress remains unclear. METHODS: This study employed CCK8, ALP, ELISA, and ROS staining techniques to examine the osteoporotic effects of verbascoside on zebrafish and MC3T3-E1 cells. Additionally, this study aimed to investigate the molecular mechanism by which verbascoside improves osteoporosis by mitigating oxidative stress. To identify the common targets of verbascoside in relation to oxidative stress and osteoporosis, network pharmacology and molecular dynamics simulation were employed. The construction of the verbascoside - oxidative stress - osteoporosis - potential target gene network aimed to identify the core targets, while the mechanism of action was elucidated through KEGG analysis, and the accuracy was confirmed by assessing the mRNA expression of the targets. RESULTS: In vivo experiments demonstrated that verbascoside exhibited therapeutic effects on osteoporosis and reduced ROS production in zebrafish. In vitro experiments further revealed that verbascoside enhanced the proliferation and differentiation of MC3T3-E1 cells, thereby improving the oxidative stress status of osteoblasts. Thirteen core targets and estrogen signaling pathways were identified through the application of network pharmacology. The pivotal role of the estrogen signaling pathway in facilitating the ability of verbascoside to mitigate oxidative stressinduced osteoporosis was substantiated by the modulation of target protein mRNA expression. CONCLUSION: The findings underscore the considerable therapeutic potential of verbascoside in ameliorating osteoporosis through the alleviation of oxidative stress, thus establishing it as a promising compound for the treatment of this condition.

Tumor contour irregularity on preoperative CT predicts prognosis in renal cell carcinoma: a multi-institutional study.

Background: Radiology-based prognostic biomarkers play a crucial role in patient counseling, enhancing surveillance, and designing clinical trials effectively. This study aims to assess the predictive significance of preoperative CT-based tumor contour irregularity in determining clinical outcomes among patients with renal cell carcinoma (RCC). Methods: We conducted a retrospective multi-institutional review involving 2218 patients pathologically diagnosed with RCC. The training and internal validation sets included patients at Zhongshan Hospital between January 2009 and August 2019. The external test set comprised patients from the First Affiliated Hospital, Zhejiang University School of Medicine (January 2016 to January 2018), the Xiamen Branch of Zhongshan Hospital (November 2017 to June 2023), and the Cancer Imaging Archive. The contour irregularity degree (CID), quantified as the ratio of irregular cross-sections to the total tumor cross-sections, was analyzed for its prognostic relevance across different subgroups of RCC patients. A novel CID-based scoring system was developed, and its predictive efficacy was evaluated and compared with existing prognostic models. Findings: The CID exhibited significant discriminatory power in predicting overall survival (OS), recurrence-free survival (RFS), and disease-specific survival (DSS) among patients with RCC tumors measuring 3 cm or larger (all p < 0.001). Multivariate analyses confirmed the CID as an independent prognostic indicator. Notably, the CID augmented prognostic stratification among RCC patients within distinct risk subgroups delineated by SSIGN models and ISUP grades. The CID-based nomogram (C-Model) demonstrated robust predictive performance, with C-index values of 0.88 (95%CI: 0.84-0.92) in the training set, 0.92 (95%CI: 0.88-0.98) in the internal validation set, and 0.86 (95%CI: 0.81-0.90) in the external test set, surpassing existing prognostic models. Interpretation: Routine imaging-based assessment of the CID serves as an independent prognostic factor, offering incremental prognostic value to existing models in RCC patients with tumors measuring 3 cm or larger. Funding: This study was funded by grants from National Natural Science Foundation of China; Shanghai Municipal Health Commission; China National Key R&D Program and Science and Technology Commission of Shanghai Municipality.

Synthesis of a celastrol derivative as a cancer stem cell inhibitor through regulation of the STAT3 pathway for treatment of ovarian cancer.

Accumulating evidence suggests that the root of drug chemoresistance in ovarian cancer is tightly associated with subpopulations of cancer stem cells (CSCs), whose activation is largely associated with signal transducer and activator of transcription 3 (STAT3) signaling. Recently, celastrol has shown a significant anti-cancer effect on ovarian cancer, but its clinical translation is very challenging due to its oral bioavailability and high organ toxicity. In this study, a celastrol derivative (Cel-N) was synthesized to augment the overall efficacy, and its underlying mechanisms were also explored. Different ovarian cancer cells, SKOV3 and A2780, were used to evaluate and compare the anticancer effects. Cel-N displayed potent activities against all the tested ovarian cancer cells, with the lowest IC50 value of 0.14-0.25 µM. Further studies showed that Cel-N effectively suppressed the colony formation and sphere formation ability, decreased the percentage of CD44+CD24- and ALDH+ cells, and induced ROS production. Furthermore, western blot analysis indicated that Cel-N significantly inhibited both Tyr705 and Ser727 phosphorylation and reduced the protein expression of STAT3. In addition, Cel-N could dramatically induce apoptosis and cell cycle arrest, and inhibit migration and invasion. Importantly, Cel-N showed a potent antitumor efficacy with no or limited systemic toxicity in mice xenograft models. The anticancer effect of Cel-N is stronger than celastrol. Cel-N attenuates cancer cell stemness, inhibits the STAT3 pathway, and exerts anti-ovarian cancer effects in cell and mouse models. Our data support that Cel-N is a potent drug candidate for ovarian cancer.