Development and validation of a circulating tumor DNA-based optimization-prediction model for short-term postoperative recurrence of endometrial cancer.

BACKGROUND: Endometrial cancer (EC) is a common gynecological malignancy that typically requires prompt surgical intervention; however, the advantage of surgical management is limited by the high postoperative recurrence rates and adverse outcomes. Previous studies have highlighted the prognostic potential of circulating tumor DNA (ctDNA) monitoring for minimal residual disease in patients with EC. AIM: To develop and validate an optimized ctDNA-based model for predicting short-term postoperative EC recurrence. METHODS: We retrospectively analyzed 294 EC patients treated surgically from 2015-2019 to devise a short-term recurrence prediction model, which was validated on 143 EC patients operated between 2020 and 2021. Prognostic factors were identified using univariate Cox, Lasso, and multivariate Cox regressions. A nomogram was created to predict the 1, 1.5, and 2-year recurrence-free survival (RFS). Model performance was assessed via receiver operating characteristic (ROC), calibration, and decision curve analyses (DCA), leading to a recurrence risk stratification system. RESULTS: Based on the regression analysis and the nomogram created, patients with postoperative ctDNA-negativity, postoperative carcinoembryonic antigen 125 (CA125) levels of < 19 U/mL, and grade G1 tumors had improved RFS after surgery. The nomogram's efficacy for recurrence prediction was confirmed through ROC analysis, calibration curves, and DCA methods, highlighting its high accuracy and clinical utility. Furthermore, using the nomogram, the patients were successfully classified into three risk subgroups. CONCLUSION: The nomogram accurately predicted RFS after EC surgery at 1, 1.5, and 2 years. This model will help clinicians personalize treatments, stratify risks, and enhance clinical outcomes for patients with EC.

3D-QSAR, Scaffold Hopping, Virtual Screening, and Molecular Dynamics Simulations of Pyridin-2-one as mIDH1 Inhibitors.

Isocitrate dehydrogenase 1 (IDH1) is a necessary enzyme for cellular respiration in the tricarboxylic acid cycle. Mutant isocitrate dehydrogenase 1 (mIDH1) has been detected overexpressed in a variety of cancers. mIDH1 inhibitor ivosidenib (AG-120) was only approved by the Food and Drug Administration (FDA) for marketing, nevertheless, a range of resistance has been frequently reported. In this study, several mIDH1 inhibitors with the common backbone pyridin-2-one were explored using the three-dimensional structure-activity relationship (3D-QSAR), scaffold hopping, absorption, distribution, metabolism, excretion (ADME) prediction, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, R2 = 0.980, Q2 = 0.765) and comparative molecular similarity index analysis (CoMSIA, R2 = 0.997, Q2 = 0.770) were used to build 3D-QSAR models, which yielded notably decent predictive ability. A series of novel structures was designed through scaffold hopping. The predicted pIC50 values of C3, C6, and C9 were higher in the model of 3D-QSAR. Additionally, MD simulations culminated in the identification of potent mIDH1 inhibitors, exhibiting strong binding interactions, while the analyzed parameters were free energy landscape (FEL), radius of gyration (Rg), solvent accessible surface area (SASA), and polar surface area (PSA). Binding free energy demonstrated that C2 exhibited the highest binding free energy with IDH1, which was -93.25 ± 5.20 kcal/mol. This research offers theoretical guidance for the rational design of novel mIDH1 inhibitors.

REEP3 is a potential diagnostic and prognostic biomarker correlated with immune infiltration in pancreatic cancer.

Receptor Expression-Enhancing Protein 3 (REEP3) serves as a pivotal enzyme crucial for endoplasmic reticulum (ER) clearance during mitosis and is implicated in the advancement of diverse malignancies. Nonetheless, the biological role and mechanisms of REEP3 in pancreatic cancer patients, along with its interplay with immune infiltration, remain inadequately elucidated. In this study, we initially analyzed the differential expression of REEP3 between pancreatic cancer tissues and normal pancreas tissues using the Cancer Genome Atlas (TCGA), GTEx and Gene Expression Omnibus (GEO) databases. Subsequently, we utilized Kaplan-Meier analysis, Cox regression and ROC curve to determine the predictive value of REEP3 for the clinical outcomes of pancreatic cancer patients. Functional enrichment analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA), were conducted to explore the potential signaling pathways and biological functions associated with pancreatic cancer. Furthermore, we investigated the PPI network, miRNA, RBP and transcription factor interactions of REEP3 using databases such as GeneMania, STRING, StarBase, KnockTK, ENCODE, Jaspar and hTFtarget. Lastly, the "ssGSEA" algorithm and TIMER database were employed to investigate the correlation between REEP3 expression and immune infiltration as well as immune checkpoints. The expression of REEP3 in pancreatic cancer showed a significantly higher level compared to that in normal tissues. ROC curve analysis indicated that REEP3 holds substantial diagnostic potential for pancreatic cancer patients. Elevated REEP3 expression correlated with unfavorable outcomes in terms of both overall survival and relapse-free survival, establishing it as a notable adverse prognostic marker in pancreatic cancer. Moreover, both univariate and multivariate Cox regression analyses demonstrated that REEP3 maintained an independent association with overall survival. Functional enrichment analyses revealed pathways significantly linked to REEP3, including cytoplasmic translation, wound healing, viral processes, regulation of cellular component size and actin filament organization. Additionally, REEP3 expression displayed a significant positive correlation with CD8+ T cells, B cells, natural killer cells, dendritic cells and macrophages. REEP3 is a potential diagnostic, prognostic marker and immunotherapeutic target for pancreatic cancer.

Targeting SUMOylation with an injectable nanocomposite hydrogel to optimize radiofrequency ablation therapy for hepatocellular carcinoma.

BACKGROUND: Incomplete radiofrequency ablation (iRFA) in hepatocellular carcinoma (HCC) often leads to local recurrence and distant metastasis of the residual tumor. This is closely linked to the development of a tumor immunosuppressive environment (TIME). In this study, underlying mechanisms and potential therapeutic targets involved in the formation of TIME in residual tumors following iRFA were explored. Then, TAK-981-loaded nanocomposite hydrogel was constructed, and its therapeutic effects on residual tumors were investigated. RESULTS: This study reveals that the upregulation of small ubiquitin-like modifier 2 (Sumo2) and activated SUMOylation is intricately tied to immunosuppression in residual tumors post-iRFA. Both knockdown of Sumo2 and inhibiting SUMOylation with TAK-981 activate IFN-1 signaling in HCC cells, thereby promoting dendritic cell maturation. Herein, we propose an injectable PDLLA-PEG-PDLLA (PLEL) nanocomposite hydrogel which incorporates self-assembled TAK-981 and BSA nanoparticles for complementary localized treatment of residual tumor after iRFA. The sustained release of TAK-981 from this hydrogel curbs the expansion of residual tumors and notably stimulates the dendritic cell and cytotoxic lymphocyte-mediated antitumor immune response in residual tumors while maintaining biosafety. Furthermore, the treatment with TAK-981 nanocomposite hydrogel resulted in a widespread elevation in PD-L1 levels. Combining TAK-981 nanocomposite hydrogel with PD-L1 blockade therapy synergistically eradicates residual tumors and suppresses distant tumors. CONCLUSIONS: These findings underscore the potential of the TAK-981-based strategy as an effective therapy to enhance RFA therapy for HCC.

Magnetic resonance imaging features and classification of intraspinal echinococcosis.

Objective: This study aimed to investigate the magnetic resonance imaging (MRI) features and classification of echinococcosis of the spinal canal. Methods: The clinical manifestations and MRI findings and classification of 19 patients diagnosed with intraspinal echinococcosis over 10 years (2011-2020) were retrospectively analyzed. Results: The mean age of the nine males and 10 females was 39 years (range 28-65 years). Among these, the number of cases with thoracic, lumbar, sacral, thoracolumbar, and lumbosacral, cervical, and lumbar segments was nine (47 %), five (26 %), one (5 %), one (5 %), two (11 %), and one (5 %) cases, respectively. Furthermore, 13 cases (69 %) involved adjacent vertebral bodies, accessories, and surrounding soft tissues. The lesion was confined to the intramedullary, extramedullary subdural, extramedullary epidural, and multiple spaces in one (Type I) (5 %), four (Type II) (21 %), one (Type III) (5 %), and thirteen (69 %) cases, respectively. Moreover, nine cases (47 %) had a history of hydatid disease in the spine or other tissues. The clinical manifestations were chest and lumbosacral pain in 18 cases (95 %) and chest and lumbosacral pain accompanied by lower limb dysfunction in four cases (21 %). The MRI revealed different sizes of T1WI low-signal and T2WI high-signal vesicles with a "grape-like" appearance, with 16 cases (84 %) showing low signals on the edge of the cyst wall. Conclusion: Intraspinal echinococcosis is rare, even in endemic areas. However, intraspinal echinococcosis should be considered when there is a history of echinococcosis in other sites or when there are clear MRI characteristics for the disease.

Diagnostic Value of Clear Cell Likelihood Score v1.0 and v2.0 for Common Subtypes of Small Renal Masses: A Multicenter Comparative Study.

BACKGROUND: Clear cell likelihood score (ccLS) is reliable for diagnosing small renal masses (SRMs). However, the diagnostic value of Clear cell likelihood score version 1.0 (ccLS v1.0) and v2.0 for common subtypes of SRMs might be a potential score extension. PURPOSE: To compare the diagnostic performance and interobserver agreement of ccLS v1.0 and v2.0 for characterizing five common subtypes of SRMs. STUDY TYPE: Retrospective. POPULATION: 797 patients (563 males, 234 females; mean age, 53 ± 12 years) with 867 histologically proven renal masses. FIELD STRENGTH/SEQUENCES: 3.0 and 1.5 T/T2 weighted imaging, T1 weighted imaging, diffusion-weighted imaging, a dual-echo chemical shift (in- and opposed-phase) T1 weighted imaging, multiphase dynamic contrast-enhanced imaging. ASSESSMENT: Six abdominal radiologists were trained in the ccLS algorithm and independently scored each SRM using ccLS v1.0 and v2.0, respectively. All SRMs had definite pathological results. The pooled area under curve (AUC), accuracy, sensitivity, and specificity were calculated to evaluate the diagnostic performance of ccLS v1.0 and v2.0 for characterizing common subtypes of SRMs. The average κ values were calculated to evaluate the interobserver agreement of the two scoring versions. STATISTICAL TESTS: Random-effects logistic regression; Receiver operating characteristic analysis; DeLong test; Weighted Kappa test; Z test. The statistical significance level was P < 0.05. RESULTS: The pooled AUCs of clear cell likelihood score version 2.0 (ccLS v2.0) were statistically superior to those of ccLS v1.0 for diagnosing clear cell renal cell carcinoma (ccRCC) (0.907 vs. 0.851), papillary renal cell carcinoma (pRCC) (0.926 vs. 0.888), renal oncocytoma (RO) (0.745 vs. 0.679), and angiomyolipoma without visible fat (AMLwvf) (0.826 vs. 0.766). Interobserver agreement for SRMs between ccLS v1.0 and v2.0 is comparable and was not statistically significant (P = 0.993). CONCLUSION: The diagnostic performance of ccLS v2.0 surpasses that of ccLS v1.0 for characterizing ccRCC, pRCC, RO, and AMLwvf. Especially, the standardized algorithm has optimal performance for ccRCC and pRCC. ccLS has potential as a supportive clinical tool. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 2.

Cerium-Doped Nickel Sulfide Nanospheres as Efficient Catalysts for Overall Water Splitting.

The development of non-precious metal electrocatalysts with excellent activity and durability for electrochemical water splitting has always been a goal. Transition metal sulfides are attractive electrocatalysts for both hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). In this article, we designed and constructed efficient catalysts with multiple synergistic interactions and synthesized Ce-NiS2@NF nanosphere using a solvothermal method. Ce-NiS2@NF exhibits excellent HER performance, OER performance, and overall water splitting capability in alkaline electrolytes, demonstrating good stability. The addition of Ce influences the activity of the catalysts, attributed to the synergistic interactions creating more active sites and higher intrinsic activity through the introduction of Ce heteroatoms. Additionally, the self-supported conductive substrate promotes electron transfer, enhancing the intrinsic activity and active site density of the catalyst. This study provides an in-depth investigation into structural design and performance enhancement, offering ideas for designing efficient catalysts for overall water electrolysis. This work provides an in-depth study in terms of structural design performance enhancement and provides ideas for designing efficient alkaline bifunctional catalysts. Valuable insights have been provided in elucidating the intrinsic mechanism of the catalytic activity of cerium-doped nickel sulfide nanospheres, thus providing new guidance in the field of energy conversion technology.

[Retracted] Tripartite motif 16 suppresses breast cancer stem cell properties through regulation of Gli­1 degradation via the ubiquitin­proteasome pathway.

Following the publication of the above paper, it was drawn to the Editors' attention by a concerned reader that the data obtained from sphere­forming assay experiments shown in Figs. 4C­F and 8B and C, and western blotting data in Figs. 4A and 8A, were strikingly similar to data appearing in different form in other articles by different authors from different research institutes that had already been published, one of which has been retracted. Moreover, a pair of data panels comparing between Fig. 4E and 8C were partly overlapping, such that these data appear to have been derived from the same original source. Owing to the fact that the contentious data in the above article had already been published elsewhere prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 35: 1204­1212, 2016; DOI: 10.3892/or.2015.4437].

Experimental and computational study on anti-gastric cancer activity and mechanism of evodiamine derivatives.

Introduction: Human topoisomerase 1 (TOP1) is an important target of various anticancer compounds. The design and discovery of inhibitors targeting TOP1 are of great significance for the development of anticancer drugs. Evodiamine and thieno [2,3-d] pyridine hybrids show potential antitumor activity. Herein, the anti-gastric cancer activities of these hybrids were investigated. Methods: The inhibitory effects of different concentrations of ten evodiamine derivatives on the gastric cancer cell line SGC-7901 were assessed using a methyl thiazolyl tetrazolium assay. Compounds EVO-1 and EVO-6 strongly inhibited gastric cancer cell proliferation, with inhibition rates of 81.17% ± 5.08% and 80.92% ± 2.75%, respectively. To discover the relationship between the structure and activity of these two derivatives, density functional theory was used to investigate their optimized geometries, natural population charges, frontier molecular orbitals, and molecular electrostatic potentials. To clarify their anti-gastric cancer mechanisms, molecular docking, molecular dynamics simulations, and binding free energy calculations were performed against TOP1. Results: The results demonstrated that these compounds could intercalate into the cleaved DNA-binding site to form a TOP1-DNA-ligand ternary complex, and the ligand remained secure at the cleaved DNA-binding site to form a stable ternary complex. As the binding free energy of compound EVO-1 with TOP1 (-38.33 kcal·mol-1) was lower than that of compound EVO-6 (-33.25 kcal·mol-1), compound EVO-1 could be a more potent anti-gastric cancer agent than compound EVO-6. Discussion: Thus, compound EVO-1 could be a promising anti-gastric cancer drug candidate. This study may facilitate the design and development of novel TOP1 inhibitors.

Prediction of Visual Outcome After Rhegmatogenous Retinal Detachment Surgery Using Artificial Intelligence Techniques.

Purpose: This study aimed to develop artificial intelligence models for predicting postoperative functional outcomes in patients with rhegmatogenous retinal detachment (RRD). Methods: A retrospective review and data extraction were conducted on 184 patients diagnosed with RRD who underwent pars plana vitrectomy (PPV) and gas tamponade. The primary outcome was the best-corrected visual acuity (BCVA) at three months after the surgery. Those with a BCVA of less than 6/18 Snellen acuity were classified into a vision impairment group. A deep learning model was developed using presurgical predictors, including ultra-widefield fundus images, structural optical coherence tomography (OCT) images of the macular region, age, gender, and preoperative BCVA. A fusion method was used to capture the interaction between different modalities during model construction. Results: Among the participants, 74 (40%) still had vision impairment after the treatment. There were significant differences in age, gender, presurgical BCVA, intraocular pressure, macular detachment, and extension of retinal detachment between the vision impairment and vision non-impairment groups. The multimodal fusion model achieved a mean area under the curve (AUC) of 0.91, with a mean accuracy of 0.86, sensitivity of 0.94, and specificity of 0.80. Heatmaps revealed that the macular involvement was the most active area, as observed in both the OCT and ultra-widefield images. Conclusions: This pilot study demonstrates that artificial intelligence techniques can achieve a high AUC for predicting functional outcomes after RRD surgery, even with a small sample size. Machine learning methods identified The macular region as the most active region. Translational Relevance: Multimodal fusion models have the potential to assist clinicians in predicting postoperative visual outcomes prior to undergoing PPV.

Differentiating mixed epithelial and stromal tumor family from predominantly cystic renal cell carcinoma using magnetic resonance imaging-based Bosniak classification system version 2019.

PURPOSE: To differentiate mixed epithelial and stromal tumor family (MESTF) of the kidney from predominantly cystic renal cell carcinoma (RCC) using the magnetic resonance imaging (MRI)-based Bosniak classification system version 2019 (v2019). MATERIALS AND METHODS: The study included 36 consecutive patients with MESTF and 77 with predominantly cystic RCC who underwent preoperative renal MRI. One radiologist evaluated and documented the clinical and MRI characteristics (age, sex, laterality, R.E.N.A.L. Nephrometry Score [RNS], surgical approach, the signal intensity on T2-weighted imaging, restricted diffusion and enhancement features in corticomedullary phase). Blinded to clinical and pathological information, another two radiologists independently evaluated Bosniak category of all masses. Interobserver agreement based on Bosniak classification system v2019 was measured by the weighted Cohen/Conger's Kappa coefficient. Furthermore, predominantly cystic RCCs and MESTFs were divided into low (categories I, II, and IIF) and high-class (categories III, and IV) tumors. The independent sample t test (Mann-Whitney U test) or Pearson Chi-square test (Fisher's exact probability test) was utilized to compare clinical and imaging characteristics between MESTFs and predominantly cystic RCCs. The performance of the Bosniak classification system v2019 in distinguishing MESTF from predominantly cystic RCC was investigated via receiver operating characteristic curve analysis. RESULTS: MESTF and predominantly cystic RCC groups significantly differed in terms of age, lesion size, RNS, restricted diffusion, and obvious enhancement in corticomedullary phase, but not sex, laterality, surgical approach, and the signal intensity on T2WI. Interobserver agreement was substantially based on the Bosniak classification system v2019. There were 24 low-class tumors and 12 high-class tumors in the MESTF group. Meanwhile, 13 low-class tumors and 64 high-class tumors were observed in the predominantly cystic RCC group. The distribution of low- or high-class tumors significantly differed between the MESTF and predominantly cystic RCC groups. Bosniak classification system v2019 had excellent discrimination (cutoff value = category III), and an area under curve value was 0.81; accuracy, 80.5%; sensitivity, 87.0%; and specificity, 66.7%. CONCLUSION: The MRI-based Bosniak classification system v2019 can effectively distinguish MESTF from predominantly cystic RCC if category III was used as a cutoff reference.

Meta-Analysis of Efficacy of Platelet-Rich Plasma Combined with Minoxidil for Androgenetic Alopecia.

BACKGROUND: Androgenetic alopecia (AGA) is a prevalent type of hair loss that impacts individuals of both genders. Platelet-rich plasma (PRP) and minoxidil have been employed as therapeutic interventions for AGA, yet the efficacy of their concurrent use remains ambiguous. OBJECTIVE: To perform a comprehensive review and meta-analysis aimed at evaluating the effectiveness of platelet-rich plasma (PRP) in combination with minoxidil for the treatment of androgenetic alopecia (AGA). METHODS: We conducted a comprehensive search of the databases PubMed, Embase, Web of Science, and Cochrane Library, encompassing their complete records up until December 2023. Eligible studies were randomized controlled trials that compared the combination of PRP and minoxidil with minoxidil or PRP alone in patients with AGA. The primary outcome measure was the change in hair growth as assessed by the hair density or hair thickness. Secondary outcome measures included patient satisfaction, and global photographic assessment. RESULTS: A total of 6 studies involving 343 participants were included in this meta-analysis. The results showed that PRP combined with minoxidil significantly improved hair growth compared to minoxidil or PRP alone. The pooled analysis demonstrated a significant increase in hair density (weighted mean difference [WMD] = 9.14; 95% confidence interval [CI]: 6.57-11.70) and hair diameter (WMD = 4.72; 95% CI 3.21-6.23) in the PRP combined with minoxidil group. Moreover, patients receiving PRP combined with minoxidil reported higher satisfaction rates compared to those using minoxidil or PRP alone. CONCLUSIONS: This meta-analysis suggests that PRP combined with minoxidil is an effective treatment for AGA, providing significant improvement in hair growth and patient satisfaction. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

An analysis of health-related quality of life in children and adolescents after parotidectomy based on patient-reported outcomes.

PURPOSE: To assess health-related quality of life (HRQoL) and its influencing factors in these pediatric patients undergoing parotidectomy. METHODS: This was a cross-sectional study that included 37 children and adolescents (≤ 19 years) with parotid gland tumors who were treated in Sichuan Cancer Hospital between January 2006 and November 2021. HRQoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30). The Wilcoxon rank sum test was used to analyze the factors influencing patients' HRQoL. RESULTS: 37 children and adolescents were included in the study, including 22 cases of benign tumors and 15 cases of malignant tumors. All patients underwent surgery, and some patients with malignant tumors received radiotherapy or chemotherapy. Malignancy, permanent facial palsy, and Frey syndrome were associated with worse HRQoL in children and adolescents with parotid gland tumors. Radiotherapy and no cervical lymph node dissection were associated with worse HRQoL in pediatric patients with malignancy. The surgical approach of parotid is not a factor influencing HRQoL. CONCLUSION: Factors associated with HRQoL in children and adolescents with parotid gland tumors include pathological types, permanent facial palsy, and Frey syndrome. In addition, factors affecting patients with malignancy include lateral lymph node dissection and radiotherapy.

Stimuli-Responsive Aptamer-Drug Conjugates for Targeted Drug Delivery and Controlled Drug Release.

Chemotherapy is widely used for cancer therapy but with unsatisfied efficacy, mainly due to the inefficient delivery of anticancer agents. Among the critical "five steps" drug delivery process, internalization into tumor cells and intracellular drug release are two important steps for the overall therapeutic efficiency. Strategy based on active targeting or TME-responsive is developed individually to improve therapeutic efficiency, but with limited improvement. However, the combination of these two strategies could potentially augment the drug delivery efficiency and therapeutic efficiency, consequently. Therefore, this work constructs a library of stimuli-responsive aptamer-drug conjugates (srApDCs), as "dual-targeted" strategy for cancer treatment that enables targeted drug delivery and controlled drug release. Specifically, this work uses different stimuli-responsive linkers to conjugate a tumor-targeting aptamer (i.e., AS1411) with drugs, forming the library of srApDCs for targeted cancer treatment. This design hypothesis is validated by the experimental data, which indicated that the aptamer could selectively enhance uptake of the srApDCs and the linkers could be cleaved by pathological cues in the TME to release the drug payload, leading to a significant enhancement of therapeutic efficacy. These results underscore the potential of the approach, providing a promising methodology for cancer therapy.

On the Relationship between MMA Levels in Blood Products and Donor Sex, Age, and Donation Frequency.

As the aging process accelerates, the age structure of blood donors turns to older and even aged groups. Methylmalonic acid (MMA), a byproduct of propionate metabolism, may be upregulated in the serum of older adults. As a mediator of chronic disease and tumor progression, the MMA content in blood products has become the focus of research. Absolute concentrations of MMA in blood products were determined based on the liquid chromatography-tandem mass spectrometry, so as to analyze how they were affected by donors' age, sex, and frequency of blood donation. The MMA content in leukocyte-depleted suspended red blood cell (lds-RBC) was significantly higher than that in fresh plasma (p<0.0001). The MMA content among five age groups showed no difference in either fresh plasma or lds-RBCs. The MMA content in fresh plasma was similar in the parameters of the sex, whereas that in lds-RBCs was higher in males than that in females (p=0.035). There were no significant differences in MMA content when it comes to different frequencies of blood donors in either fresh plasma or lds-RBCs. Additionally, there was no significant difference or clear trend in the rate of elevated plasma MMA levels among different sexes, age groups, and blood donation frequency groups. MMA in the blood products from donors in China does not compromise the safety of blood transfusions for cancer patients. Nevertheless, there is a need to focus on MMA levels in Chinese and to develop race-specific and age-specific normal reference ranges.

Edaravone dexborneol attenuates cognitive impairment in a rat model of vascular dementia by inhibiting hippocampal oxidative stress and inflammatory responses and modulating the NMDA receptor signaling pathway.

Exploring the intricate pathogenesis of Vascular Dementia (VD), there is a noted absence of potent treatments available in the current medical landscape. A new brain-protective medication developed in China, Edaravone dexboeol (EDB), has shown promise due to its antioxidant and anti-inflammatory properties, albeit with a need for additional research to elucidate its role and mechanisms in VD contexts. In a research setup, a VD model was established utilizing Sprague-Dawley (SD) rats, subjected to permanent bilateral typical carotid artery occlusion (2VO). Behavioral assessment of the rats was conducted using the Bederson test and pole climbing test, while cognitive abilities, particularly learning and memory, were evaluated via the novel object recognition test and the Morris water maze test. Ensuing, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), IL-1ß, IL-6, IL-4, and tumor necrosis factor-α (TNF-α) were determined through Enzyme-Linked Immunosorbent Assay (ELISA). Synaptic plasticity-related proteins, synaptophysin (SYP), post-synaptic density protein 95 (PSD-95), and N-methyl-D-aspartate (NMDA) receptor proteins (NR1, NR2A, NR2B) were investigated via Western blotting technique. The findings imply that EDB has the potential to ameliorate cognitive deficiencies, attributed to VD, by mitigating oxidative stress, dampening inflammatory responses, and modulating the NMDA receptor signaling pathway, furnishing new perspectives into EDB's mechanism and proposing potential avenues for therapeutic strategies in managing VD.

Squalene-epoxidase-catalyzed 24(S),25-epoxycholesterol synthesis promotes trained-immunity-mediated antitumor activity.

The importance of trained immunity in antitumor immunity has been increasingly recognized, but the underlying metabolic regulation mechanisms remain incompletely understood. In this study, we find that squalene epoxidase (SQLE), a key enzyme in cholesterol synthesis, is required for ß-glucan-induced trained immunity in macrophages and ensuing antitumor activity. Unexpectedly, the shunt pathway, but not the classical cholesterol synthesis pathway, catalyzed by SQLE, is required for trained immunity induction. Specifically, 24(S),25-epoxycholesterol (24(S),25-EC), the shunt pathway metabolite, activates liver X receptor and increases chromatin accessibility to evoke innate immune memory. Meanwhile, SQLE-induced reactive oxygen species accumulation stabilizes hypoxia-inducible factor 1α protein for metabolic switching into glycolysis. Hence, our findings identify 24(S),25-EC as a key metabolite for trained immunity and provide important insights into how SQLE regulates trained-immunity-mediated antitumor activity.

Comprehensive characterization of ß-alanine metabolism-related genes in HCC identified a novel prognostic signature related to clinical outcomes.

Hepatocellular carcinoma (HCC) stands out as the most prevalent type of liver cancer and a significant contributor to cancer-related fatalities globally. Metabolic reprogramming, particularly in glucose, lipid, and amino acid metabolism, plays a crucial role in HCC progression. However, the functions of ß-alanine metabolism-related genes (ßAMRGs) in HCC remain understudied. Therefore, a comprehensive evaluation of ßAMRGs is required, specifically in HCC. Initially, we explored the pan-cancer landscape of ßAMRGs, integrating expression profiles, prognostic values, mutations, and methylation levels. Subsequently, scRNA sequencing results indicated that hepatocytes had the highest scores of ß-alanine metabolism. In the process of hepatocyte carcinogenesis, metabolic pathways were further activated. Using ßAMRGs scores and expression profiles, we classified HCC patients into three subtypes and examined their prognosis and immune microenvironments. Cluster 3, characterized by the highest ßAMRGs scores, displayed the best prognosis, reinforcing ß-alanine's significant contribution to HCC pathophysiology. Notably, immune microenvironment, metabolism, and cell death modes significantly varied among the ß-alanine subtypes. We developed and validated a novel prognostic panel based on ßAMRGs and constructed a nomogram incorporating risk degree and clinicopathological characteristics. Among the model genes, EHHADH has been identified as a protective protein in HCC. Its expression was notably downregulated in tumors and exhibited a close correlation with factors such as tumor staging, grading, and prognosis. Immunohistochemical experiments, conducted using HCC tissue microarrays, substantiated the validation of its expression levels. In conclusion, this study uncovers ß-alanine's significant role in HCC for the first time, suggesting new research targets and directions for diagnosis and treatment.

Ethanolic extract of Arctium lappa leaves alleviates cerebral ischemia reperfusion-induced inflammatory injury via HDAC9-mediated NF-κB pathway.

BACKGROUND: Ischemic stroke (IS) is a major cause of mortality and disability worldwide. Inflammatory response is crucial in the pathogenesis of tissue injury in cerebral infarction. Arctium lappa leaves are traditionally used to treat IS. PURPOSES: To investigate the neuroprotective effects and molecular mechanisms of the ethanolic extract of A. lappa leaves (ALLEE) on cerebral ischemia-reperfusion (CIR). METHODS: Middle cerebral artery obstruction reperfusion (MCAO/R) rats and an oxygen-glucose deprivation/reoxygenation (OGD/R) cell model were used to evaluate ALLEE pharmacodynamics. Various methods, including neurological function, 2,3,5-triphenyltetrazolium chloride, hematoxylin and eosin, and Nissl, enzyme-linked immunosorbent, and TdT-mediated dUTP nick-end labeling assays, were used to analyze the neuroprotective effects of ALLEE in vitro and in vivo. The major chemical components and potential target genes of ALLEE were screened using network pharmacology. Molecular docking, western blotting, and immunofluorescence analyses were performed to confirm the effectiveness of the targets in related pathways. RESULTS: ALLEE exerted potent effects on the MCAO/R model by decreasing the neurological scores, infarct volumes, and pathological features (p < 0.01). Furthermore, network pharmacology results revealed that the treatment of IS with ALLEE involved the regulation of various inflammatory pathways, such as the tumor necrosis factor (TNF) and chemokine signaling pathways. ALLEE also played key roles in targeting key molecules, including nuclear factor (NF)-κBIA, NF-κB1, interleukin (IL)-6, TNF-α and IL1ß, and regulating the histone deacetylase (HDAC)-9-mediated signaling pathway. In vivo and in vitro analyses revealed that ALLEE significantly regulated the NF-κB pathway, promoted the phosphorylation activation of NF-κB P65, IκB and IKK (p < 0.01 or p < 0.05), and decreased the expression levels of the inflammatory factors, IL-1ß, IL-6 and TNF-α (p < 0.01). Moreover, ALLEE significantly decreased the expression of HDAC9 (p < 0.01) that is associated with inflammatory responses. However, HDAC9 overexpression partially reversed the neuroprotective effects of ALLEE and its suppressive effects on inflammation and phosphorylation of NF-κB (p < 0.01). CONCLUSIONS: In conclusion, our results revealed that ALLEE ameliorates MCAO/R-induced experimental CIR by modulating inflammatory responses via the inhibition of HDAC9-mediated NF-κB pathway.