Ferroptosis plays a critical role in tumor development and treatment response, but its regulatory mechanisms in endometrial cancer (EC) are not well understood. This study aimed to identify ferroptosis-related genes in EC and explore their roles and mechanisms. Differentially expressed genes from EC datasets were intersected with ferroptosis-related gene sets to identify key candidates. The functional role of GOT1 was studied using in vitro assays, while transcriptomic and proteomic profiling were integrated to explore downstream pathways. Immunohistochemistry (IHC) was performed on 35 EC samples and 11 adjacent normal tissues. GOT1's contribution to medroxyprogesterone acetate (MPA) resistance was evaluated both in vitro and in vivo. GOT1 expression was significantly elevated in EC tissues and correlated with poor prognosis. Silencing GOT1 impaired EC cell proliferation and migration, increasing intracellular Fe²⁺, lipid ROS, and 4-HNE levels. IHC confirmed elevated GOT1, STAT3, GPX4, TFRC, TFAP4, and PAX8 in EC tissues. Transcriptome data showed that GOT1 knockdown reduced GPX4 and altered metabolism pathways. Overexpression of GPX4 reversed the ferroptosis and growth inhibition caused by GOT1 depletion. Proteomic analysis revealed that GOT1 physically interacts with STAT3 and functionally enhances STAT3-dependent transcription, thereby indirectly promoting GPX4 expression. GOT1 overexpression reduced EC cell sensitivity to MPA in vitro and in vivo, whereas GOT1 inhibition partially restored MPA responsiveness. It contributes to EC progression and ferroptosis resistance via the STAT3-GPX4 axis, diminishing MPA efficacy. GOT1 may serve as potential biomarker and therapeutic target to enhance ferroptosis-based strategies in EC.

Objectives. Temporal bone squamous cell carcinoma (TBSCC) is the most common subtype of temporal bone malignancy. However, its low incidence, high misdiagnosis rate, and the difficulty of conducting large-scale studies and clinical trials have limited researchers' understanding of its occurrence and progression, and diagnostic and therapeutic biomarkers remain lacking. Addressing these gaps requires a clearer understanding of TBSCC tumor heterogeneity and microenvironment. This study aimed to characterize the tumor heterogeneity and microenvironment ofTBSCC. Methods. Single-cell RNA sequencing (scRNA-seq) is an effective approach for interrogating tumor heterogeneity. Here, we report scRNA-seq data for TBSCC. We collected and sequenced 113,344 cells from nine samples (five cancer tissues and four histologically verified adjacent normal temporal bone tissues) obtained from six patients withTBSCC. Results. The proportion of S-phase cancer cells was higher in samples with tumor invasion, and the pseudotime trajectory of cancer cells closely corresponded with the TBSCC differentiation level. We also detected higher communication intensity between certain immune cell pairs in cancer tissues than in histologically verified adjacent normal temporal bone tissues. In addition, we identified several cancer-related genes as potential diagnostic markers of TBSCC. Conclusion. This study is the first to characterize the complex heterogeneity and tumor microenvironment of TBSCC using scRNA-seq, providing new avenues for diagnosing, classifying, and treating this rare carcinoma.

Background: Digestive system cancers remain a major public-health challenge in Asia, where rapid population ageing and heterogeneous socioeconomic transitions could reshape future cancer burden. We quantified long-term trends, drivers, inequalities, and future trajectories of digestive system cancers across Asia. Methods: Using Global Burden of Disease Study 2023 estimates, we analysed incidence, deaths, and disability-adjusted life-years for six digestive system cancers in 51 Asian countries and territories from 1990 to 2023. We assessed age-standardised rates, estimated annual percentage changes, socioeconomic inequalities, decomposition of burden change, and projections to 2050 using Bayesian age–period–cohort models. Findings: In 2023, Asia had 3·33 million incident cases and 2·37 million deaths from digestive system cancers. The age-standardised incidence rate was 61·55 per 100 000 population and the age-standardised mortality rate was 44·36 per 100 000 population. From 1990 to 2023, both rates declined, with estimated annual percentage changes of –1·15% for incidence and –1·82% for mortality. East Asia had the highest age-standardised burden, whereas South Asia showed increasing trends. Population ageing was the dominant contributor to increases in absolute burden. Colon and rectum cancer had the highest age-standardised incidence rate in 2023, whereas stomach cancer remained the leading cause of deaths. By 2050, incident cases and deaths are projected to increase to 13·50 million and 9·37 million, respectively. Interpretation: Despite declining age-standardised rates, digestive system cancers will impose an increasing absolute burden in Asia, mainly because of population ageing. Prevention, screening, early diagnosis, and guideline-concordant cancer care should be strengthened, particularly in settings with rising trends and limited health-system capacity.

Background:Current unidimensional cancer evaluation systems limit precise cancer control. This study establishes a novel burden-quality framework that integrates disease burden and quality-of-care index (QCI) to better assess cancer management effectiveness globally. Methods:The QCI was derived by principal component analysis of six standardized indicators using the Global Burden of Disease data (1990-2021). A four-quadrant framework integrated QCI with disease burden to classify 34 cancers across 204 countries/regions. The sociodemographic index (SDI) and gender disparity ratios (GDR) were used to assess inequalities. Results:Substantial heterogeneity exists in the burden and QCI across 34 cancers. Highly fatal cancers such as TBL cancers (tracheal, bronchus, and lung cancers) and pancreatic cancers are persistently trapped in a "high burden-low quality" dilemma. In contrast, high-burden breast cancer and low-burden thyroid cancer demonstrate superior QCI, though the latter may carry overtreatment risks. Socioeconomic factors have a profound influence on intervention equity, with SDI exhibiting a strong positive correlation with QCI (r = 0.90, P < 0.001) but a significant negative correlation with GDR (r = -0.71, P < 0.001). Notably, the trend of QCI improvement and overall reduction in cancer burden is asynchronous: high-survival cancers and high-SDI regions showed slow QCI gains, middle-SDI regions exhibited substantial increases, while low-SDI areas remained persistently disadvantaged. Demographic disparities further exacerbated these inequities - older populations bore a disproportionate disease burden yet achieved the fastest QCI improvements, whereas adolescent groups maintained high baseline quality but stagnated in progress. Additionally, gender disparities were pervasive, with females receiving better-quality care for most cancers and across most regions. Conclusion:This multidimensional burden-quality framework shifts cancer evaluation from singular evaluation to precision intervention. It emphasizes: (1) optimizing resources for high-burden-low-quality cancers, (2) avoiding overtreatment in low-burden cancers, and (3) reducing inequities linked to socioeconomic disparities and vulnerable groups (especially elderly and male patients). This research provides a foundation for precise and equitable global cancer control.

BACKGROUND:Cisplatin is an effective chemotherapeutic agent, but its clinical use is limited by dose-dependent ototoxicity that leads to irreversible sensorineural hearing loss. Accumulating evidence implicates impaired autophagy-lysosomal homeostasis in cisplatin-induced ototoxicity. Transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, represents a promising therapeutic target. Clotrimazole, an FDA-approved antifungal drug with emerging cytoprotective properties, has not been investigated for its potential to mitigate cisplatin-induced ototoxicity. METHODS:We evaluated the protective effects of clotrimazole using House Ear Institute-Organ of Corti 1 cells, cochlear explants, and an adult C57BL/6J mouse model of transtympanic cisplatin ototoxicity. Apoptosis, reactive oxygen species (ROS), and autophagy flux were assessed using biochemical assays and imaging. RNA-sequencing was performed to identify transcriptional pathways regulated by clotrimazole. TFEB dependence was verified using small interfering RNA knockdown and pharmacological inhibition of AMP-activated protein kinase (AMPK). Cochlear function was assessed using auditory brainstem responses (ABRs), and hair-cell and synapse survival were quantified by immunofluorescence. RESULTS:Clotrimazole significantly reduced cisplatin-induced apoptosis, ROS generation, and calcium overload. Transcriptomic profiling and functional assays revealed robust activation of autophagy. Clotrimazole promoted AMPK activation, suppressed mTORC1 signaling, and enhanced TFEB nuclear translocation. TFEB or AMPK inhibition abrogated these protective effects. In vivo, intratympanic clotrimazole preserved hair cell survival, maintained ribbon synapses, and significantly reduced ABR threshold shifts. CONCLUSIONS:Clotrimazole protects against cisplatin-induced ototoxicity by activating the AMPK-mTOR-TFEB axis and restoring autophagy lysosomal homeostasis. These findings support TFEB-targeted autophagy activation as a promising therapeutic strategy for preventing cisplatin-induced hearing loss. Antioxid. Redox Signal. 44, 928-950.

The prognosis of metastatic endometrial carcinoma (EC), one of the most common gynecological malignancies worldwide, remains poor, and the underlying driver of metastases is poorly understood. Dysregulation in estrogen-related signaling and inactivation of tumor suppressor PTEN are two essential risk factors of EC. However, whether and how they are interconnected during EC development remains unclear. Here, we demonstrate that the deacetylase SIRT7 is upregulated in EC patients and mouse models, facilitating EC progression in vitro and in vivo. Mechanistically, in an estrogen-dependent fashion, SIRT7 mediates PTEN deacetylation at K260, promoting PTEN ubiquitination by the E3 ligase NEDD4L, accelerating PTEN degradation and, consequently, expediting EC metastasis. Additionally, SIRT7 expression strongly correlates with poor survival in EC patients with wild-type PTEN, though no significant correlation is observed in PTEN mutation patients. These results lay the foundation for the study of targeting estrogen-SIRT7-PTEN axis, to restore PTEN abundance, offering potential avenues for EC therapy.

BACKGROUND: Oral squamous cell carcinogenesis is a complex biological process, although some progress has been made in predicting the risk of malignant transformation of oral squamous cell carcinoma (OSCC). We aimed to visualise the dynamic metabolic characteristics of the progression of OSCC using desorption electrospray ionisation mass spectrometry imaging (DESI-MSI). METHODS: Eight matched OSCC samples were analysed using DESI-MSI. MetaboAnalyst database was used to screen for differential metabolism, and perform metabolic pathway analysis. Key pathways and enzymes were validated using immunohistochemical (IHC) techniques in an additional 60 patients with OSCC. Knockdown OSCC cell lines were constructed and functional experiments were carried out to elucidate the effect of key enzyme on the proliferation and migration of OSCC. RESULTS: Spatial metabolomics revealed 55 differential metabolites between cancer and normal mucosal tissues, 59 between cancer and precancerous tissues, and 52 between precancerous and normal mucosal tissues. We further identified 30 metabolites that were either increased or decreased from normal tissues to precancerous lesions and then to cancer tissues. Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathway analysis confirmed that sphingolipid metabolism and biosynthesis of unsaturated fatty acids are the main metabolic pathways involved in OSCC. Dihydroceramide desaturase (DEGS1) is the key enzyme in sphingolipid metabolism and is involved in ceramide synthesis, which is closely related to tumour carcinogenesis. We further confirmed that high expression of DEGS1 predicts poor overall survival and disease-free survival, and is closely related to the pathological grade of the tumour. In multivariate COX regression analysis, high expression of DEGS1 in tumor cells was an independent risk factor for OS in OSCC patients. Moreover, we demonstrated that DEGS1 knockdown inhibited the proliferation and migration of OSCC cells in vitro. CONCLUSION: Our study used DESI-MSI to uncover the progression of OSCC at the spatial metabolomics level, and discovered key metabolic molecules involved in the carcinogenesis of OSCC. Sphingolipid metabolism plays an important role in OSCC carcinogenesis, and its key metabolic enzyme, DEGS1, is expected to become a new therapeutic target for OSCC in the future.

Noise-induced hearing loss (NIHL), a common sensory disorder, is traditionally thought to stem primarily from direct damage to sound-sensing hair cells (HCs). Here, we demonstrate that supporting cells (SCs), neighboring cells not previously implicated in NIHL pathogenesis, orchestrate hearing loss and HC degeneration through Gasdermin D (GSDMD) activation. Mechanistically, noise-induced oxidative stress in HCs triggers activation of epidermal growth factor receptor in SCs, leading to extracellular-regulated kinase phosphorylation and caspase-11-dependent cleavage of GSDMD, thereby establishing an HC-to-SC signaling cascade. Furthermore, GSDMD activation in SCs reciprocally exacerbates oxidative injury in HCs, creating a pathogenic positive feedback loop between the two cell types. Our findings uncover a central role for SCs in noise-induced hearing loss and identify GSDMD-mediated intercellular communication as a potential therapeutic target.

Precisely regulated spermatocyte growth, differentiation, and apoptosis are crucial for sustainable male fertility. miR-143 has been demonstrated to regulate gene expression and cell apoptosis in various human cancers. However, the function of mmu-mir-143 (miR-143) in mammalian testes and its underlying mechanism remains unexplored. In this study, the expression of miR-143 was detected in C57BL/6 mice spermatocytes by in situ hybridization (ISH) and immunofluorescence (IF) co-staining and transfecting miR-143 inhibitor into GC-2 cells (mouse spermatogenic cells) shows that miR-143 inhibits cleaved Caspase 3 (CC3)-induced male germ cell death. The current study used IF co-staining of KI67 and gamma-H2A.X in the testes of C57BL/6 mice at different developmental stages, revealing that active proliferation and apoptosis of spermatocytes occurred simultaneously in the testes at 14 day post-partum (dpp). Kras was predicted as a potential target of miR-143 in mice using of the online database TargetScan, verified by quantitative real-time PCR (qPCR), western blotting (WB), and Dualluciferase reporter gene assay. Co-transfection of miR-143 inhibitor and Kras siRNA into GC-2 cells revealed an antagonistic correlation between miR-143 and Kras in regulating male germ cell death. Finally, miR-143 inhibitor and mimics were administered into the seminiferous tubule of 3-week-old C57BL/6 mice. The histomorphology, IF co-staining, and WB data indicated that the testes treated with the miR-143 inhibitor showed significantly aberrant phenotypes, including damaged seminiferous tubules, reduced spermatocyte quantity, and elevated levels of apoptosis. This study uncovered the mechanism by which miR-143 inhibits male germ cell apoptosis through the repression of Kras/KRAS levels and the inhibition of Caspase 3 activation, providing insight into the role of miRNA in spermatogenesis and the maintenance of male fertility.

BACKGROUND:Current ultrasound-based screening for endometrial cancer (EC) primarily relies on endometrial thickness (ET) and morphological evaluation, which suffer from low specificity and high interobserver variability. This study aimed to develop and validate an artificial intelligence (AI)-driven diagnostic model to improve diagnostic accuracy and reduce variability. METHODS:A total of 1,861 consecutive postmenopausal women were enrolled from two centers between April 2021 and April 2024. Super-resolution (SR) technique was applied to enhance image quality before feature extraction. Radiomics features were extracted using Pyradiomics, and deep learning features were derived from convolutional neural network (CNN). Three models were developed: (1) R model: radiomics-based machine learning (ML) algorithms; (2) CNN model: image-based CNN algorithms; (3) DLR model: a hybrid model combining radiomics and deep learning features with ML algorithms. RESULTS:Using endometrium-level regions of interest (ROI), the DLR model achieved the best diagnostic performance, with an area under the receiver operating characteristic curve (AUROC) of 0.893 (95% CI: 0.847-0.932), sensitivity of 0.847 (95% CI: 0.692-0.944), and specificity of 0.810 (95% CI: 0.717-0.910) in the internal testing dataset. Consistent performance was observed in the external testing dataset (AUROC 0.871, sensitivity 0.792, specificity 0.829). The DLR model consistently outperformed both the R and CNN models. Moreover, endometrium-level ROIs yielded better results than uterine-corpus-level ROIs. CONCLUSIONS:This study demonstrates the feasibility and clinical value of AI-enhanced ultrasound analysis for EC detection. By integrating radiomics and deep learning features with SR-based image preprocessing, our model improves diagnostic specificity, reduces false positives, and mitigates operator-dependent variability. This non-invasive approach offers a more accurate and reliable tool for EC screening in postmenopausal women. CLINICAL TRIAL NUMBER:Not applicable.

Hearing loss in children has become a pressing public health issue, with otitis media (OM) being a leading cause. This study aims to comprehensively assess the prevalence and burden of OM-induced hearing loss in children. Data from the Global Burden of Disease (GBD) database were used. We evaluated the Age-standardized Prevalence Rates (ASPR), Age-standardized Years Lived with Disability rates (ASYR), and Estimated Annual Percentage Changes (EAPC) over the past 32 years. The analysis included stratification, correlation analysis, and projections. From 1990 to 2021, the global prevalence of OM-induced hearing loss in children under 15 years increased from 31.18 million cases to 34.71 million cases, representing an 11.32

Saliva, which is a critical component of the oral ecosystem, undergoes dynamic changes, particularly during the onset and progression of periodontitis. This study used Gas Chromatography-Mass Spectrometry (GC-MS), a reliable and high-throughput tool for metabolomic analysis, to detect salivary metabolic shifts across various stages of periodontitis (T1-T4). We compared differential changes in metabolites between the HC and T1 groups, the T1 and T2 groups, the T2 and T3 groups, and the T3 and T4 groups. By analysing saliva samples from 116 individuals-10 healthy controls (HC) and 106 patients with periodontitis across stages T1 (22 individuals) to T4 (28 individuals), we identified differential metabolites including Glucose, 3-Aminobutanoic Acid, N-(1-Cyclopropylethyl) Aniline, and Methylmalonic Acid. Compared to HC, the metabolites in patients with periodontitis exhibited progressive concentration changes correlating with the severity of the disease. Furthermore, KEGG pathway analysis was used to elucidate the metabolic pathways involved in the development of periodontitis. Our findings demonstrate the potential of salivary metabolites as biomarkers for monitoring periodontitis progression and offer valuable insights into its pathogenesis and potential therapeutic targets.

Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer. It is of great significance to search for biomarkers associated with OSCC progression through minimally invasive methods. Conductive polymer spray ionization mass spectrometry (CPSI-MS) was used to perform a rapid metabolic analysis of trace volume serum from OSCC and healthy controls. Key metabolites were identified by receiver operating characteristic (ROC) curves and further validated by desorption electrospray ionization mass spectrometry (DESI-MSI) and ultra–high performance liquid chromatography-tandem mass spectrometer (UHPLC-MS/MS). The study identified 125 metabolites that significantly differentiated early-stage OSCC from healthy controls. 47 metabolites showed an upward or downward trend in the OSCC staging (I-IV). Through ROC curve analysis and trend assessment of metabolite levels, 10 key metabolites associated with OSCC staging were pinpointed. KEGG pathway enrichment analysis showed that glycerophospholipid metabolism is closely related to OSCC staging. Representative serum metabolites were validated by DESI-MS and UHPLC-MS/MS at tissue level. Kaplan-Meier (KM) survival analysis showed that PC (40:6) was an independent prognostic factor for OSCC. We identified 10 metabolites associated with OSCC staging, and found that glycerophospholipid metabolism may promote the progression of OSCC. Moreover, the key metabolite PC(40:6) is closely related to the prognosis of OSCC.

Background:Cervical cancer is preceded by low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL). Human papillomavirus (HPV) test is a sensitive method for cervical cancer screening, but it is less specific compared with cytological examination, leading to overtreatment and reduced patient compliance. Therefore, new detection methods that can improve the accuracy of cervical cancer screening are needed. Methods:In the present study, cervical exfoliated cell samples were collected from 228 Chinese individuals, including 114 healthy control individuals, 46 patients with LSIL, 21 patients with HSIL and 47 patients with cervical cancer. The DNA methylation levels of 12 cervical cancer-related genes were detected using quantitative multiplex methylation-specific PCR. All individuals were divided into high- or low-risk groups. Patients with HSIL and cervical cancer were assigned to the high-risk group, whereas healthy controls and patients with LSIL were assigned to the low-risk group. The ability to predict cancer risks was evaluated using ROC curves and a predictive model for cancer risk was constructed by linear regression analysis. Results:The methylation levels were significantly higher for all 12 genes in individuals with cervical cancer or HSIL, compared with those in LSIL or normal group. Family with sequence similarity 19 member A4 (FAM19A4), phosphatase and actin regulator 3 (PHACTR3), somatostatin (SST), Zic family member 1 (ZIC1), paired box 1 (PAX1) and zinc finger protein 671 (ZNF671) were used to construct a predictive model for cancer risk prediction, with a specificity of 89.6% and a sensitivity of 95.0%. Conclusion:The present study demonstrated the methylation levels of 12 cervical cancer-related genes were higher in Chinese patients with HSIL or cervical cancer. Also, a predictive model was constructed to distinguish cervical cancer or HSCL from individuals with low risk.

Cisplatin-based chemotherapy improves the control of distant metastases in patients with nasopharyngeal carcinoma (NPC); however, around 30% of patients fail treatment due to acquired drug resistance. Epigenetic regulation is known to contribute to cisplatin resistance; nevertheless, the underlying mechanisms remain poorly understood. Here, we showed that lysine-specific demethylase 5B (KDM5B) was overexpressed and correlates with tumor progression and cisplatin resistance in patients with NPC. We also showed that specific inhibition of KDM5B impaired the progression of NPC and reverses cisplatin resistance, both in vitro and in vivo. Moreover, we found that KDM5B inhibited the expression of ZBTB16 by directly reducing H3K4me3 at the ZBTB16 promoter, which subsequently increased the expression of Topoisomerase II- α (TOP2A) to confer cisplatin resistance in NPC. In addition, we showed that the deubiquitinase USP7 was critical for deubiquitinating and stabilizing KDM5B. More importantly, the deletion of USP7 increased sensitivity to cisplatin by disrupting the stability of KDM5B in NPC cells. Therefore, our findings demonstrated that USP7 stabilized KDM5B and promoted cisplatin resistance through the ZBTB16/TOP2A axis, suggesting that targeting KDM5B may be a promising cisplatin-sensitization strategy in the treatment of NPC.

BACKGROUND:Oral squamous cell carcinoma (OSCC) is a prevalent malignancy affecting the head and neck region. The prognosis for OSCC patients remains unfavorable due to the absence of precise and efficient early diagnostic techniques. Metabolomics offers a promising approach for identifying distinct metabolites, thereby facilitating early detection and treatment of OSCC. OBJECTIVE:This review aims to provide a comprehensive overview of recent advancements in metabolic marker identification for early OSCC diagnosis. Additionally, the clinical significance and potential applications of metabolic markers for the management of OSCC are discussed. RESULTS:This review summarizes metabolic changes during the occurrence and development of oral squamous cell carcinoma and reviews prospects for the clinical application of characteristic, differential metabolites in saliva, serum, and OSCC tissue. In this review, the application of metabolomic technology in OSCC research was summarized, and future research directions were proposed. CONCLUSION:Metabolomics, detection technology that is the closest to phenotype, can efficiently identify differential metabolites. Combined with statistical data analyses and artificial intelligence technology, it can rapidly screen characteristic biomarkers for early diagnosis, treatment, and prognosis evaluations.

The emerging tumor microenvironment (TME) is a complex and constantly evolving entity. Cancer-associated fibroblasts (CAFs) are a vital component of the TME with diverse functions. They interact closely with cancer cells through reciprocal signaling and play a crucial role in tumor progression. Exosomes, which contain diverse biological information, are identified as an important mediator of cell–cell communication. This study aimed to investigate how CAF-derived exosomes promote metastasis of endometrial cancer (EC). Our findings revealed that CAF-derived exosomes significantly enhanced EC cell proliferation and migration compared to normal fibroblast-derived exosomes. Quantitative proteomics analysis of CAF/NF-derived exosomes demonstrated differential expression of CTHRC1, a protein overexpressed in multiple tumors, promoting cancer progression through enhanced cell migration and invasion. Exosomal overload of CTHRC1 significantly contributes to EC cell migration. Mechanically, we determined that ITGB3 was immunoprecipitated by CTHRC1 and phosphorylated FAK on Tyr397, which was important for exosomal CTHRC1 mediated migratory ability of EC cells. Overexpression of CTHRC1 in secreted exosomes promotes the metastatic ability of EC cells in mouse models and may be eliminated by Defactinib, an inhibitor of FAK Tyr397 phosphorylation. Moreover, overexpression of CTHRC1 was increased in EC patients, elevating with cancer progression, and correlated with negative tumor prognosis. Our results revealed that CAF mediated endometrial cancer progression is related to high levels of CTHRC1 and exosomal CTHRC1 derived from CAF may be a promising therapeutic strategy for metastatic endometrial cancer.

OBJECTIVES:Neoadjuvant chemoimmunotherapy has shown promising results for resectable, locoregionally advanced (LA) head and neck squamous cell carcinoma (L/A HNSCC). We published the first phase II trial of neoadjuvant camrelizumab combined with chemotherapy in resectable, L/A HNSCC, demonstrating it was safe and feasible with favorable pathological complete response (pCR). Here, we report the final analysis results for neoadjuvant chemoimmunotherapy in L/A HNSCC (minimum 2.0 years of follow-up). MATERIALS AND METHODS:Three cycles of chemoimmunotherapy were administered before surgery to patients with L/A HNSCC. Two-year disease-free survival (DFS), overall survival (OS) and quality of life (QOL) were reported. RESULTS:The overall two-year DFS and OS rates were 90 % and 100 %, respectively. With a median follow-up of 33.7 months, 9 of 10 (90 %) patients with pCR were alive and disease free. Patients with TNM stage (II/III) or < 20 % of residual viable tumor trended toward improved DFS; hazard ratio (HR), 0.44 [95 % confidence interval (CI), 0.04-5.28] and HR, 0.26 (95 % CI, 0.03-2.36), respectively. All QLQ-C30 functioning and symptom scales other than nausea and vomiting were resolved at 2 years after the completion of radiotherapy. CONCLUSION:Neoadjuvant camrelizumab in combination with chemotherapy provided encouraging clinical outcomes for patients with L/A HNSCC. Further studies with longer follow-up and larger samples are warranted. TRIAL REGISTRATION:Chictr.org.cn, ChiCTR1900025303. Registered Aug 22, 2019. https://www.chictr.org.cn/showproj.html?proj=41380.

Endometrial cancer (EC) stands as one of the most prevalent malignancies affecting the female genital tract, witnessing a rapid surge in incidence globally. Despite the well-established association of histone methyltransferase SMYD3 with the development and progression of various cancers, its specific oncogenic role in endometrial cancer remains unexplored. In the present study, we report that the expression level of SMYD3 is significantly upregulated in EC samples and associated with EC progression. Through meticulous in vivo and in vitro experiments, we reveal that depletion of SMYD3 curtails cell proliferation, migration, and invasion capabilities, leading to compromised non-homologous end joining repair (NHEJ) and heightened sensitivity of EC cells to radiation. Furthermore, our pathway enrichment analysis underscores the pivotal involvement of the DNA damage repair pathway in regulating EC progression. Mechanistically, in response to DNA damage, SMYD3 is recruited to these sites in a PARP1-dependent manner, specifically methylating LIG4. This methylation sets off a sequential assembly of the LIG4/XRCC4/XLF complex, actively participating in the NHEJ pathway and thereby fostering EC progression. Notably, our findings highlight the promise of SMYD3 as a crucial player in NHEJ repair and its direct correlation with EC progression. Intriguingly, pharmacological intervention targeting SMYD3 with its specific inhibitor, BCI-121, emerges as a potent strategy, markedly suppressing the tumorigenicity of EC cells and significantly enhancing the efficacy of radiotherapy. Collectively, our comprehensive data position SMYD3 as a central factor in NHEJ repair and underscore its potential as a promising pharmacological target for endometrial cancer therapy, validated through both in vitro and in vivo systems.

OBJECTIVE:To evaluate changes in the neutrophil-to-lymphocyte ratio (NLR) between day 4 and day 0 in ectopic pregnancy (EP) patients treated with single-dose methotrexate (MTX) and investigate its predictive value for treatment outcome.METHODS:A total of 406 EP patients receiving single-dose MTX therapy at Shanghai First Maternity and Infant Hospital from January 10, 2013 to September 30, 2019 were studied. A multivariate model was constructed to predict treatment outcome.RESULTS:Among the 406 patients, 281 were treated successfully. Treatment success declined significantly when NLR decreased by less than 23% (74.8% vs 58.5%, P = 0.004). Multivariate regression analysis identified NLR reduction of less than 23% on day 4 (odds ratio [OR] 2.09, 95% confidence interval [CI] 1.27-3.44), a human chorionic gonadotropin (hCG) decrease of 15% or less (OR 3.17, 95% CI 1.62-6.34), and an hCG increase of more than 15% on day 4 (OR 5.47, 95% CI 3.05-10.22) as independent risk factors for single-dose MTX treatment failure. The final predictive model had a sensitivity of 0.768 and a specificity of 0.569, using a cut-off value of 3. The area under the receiver operating characteristic curve was 0.712. Patients with a predictive score of ≥3 were more likely to fail single-dose MTX therapy.CONCLUSION:The present study concluded that an NLR decrease of less than 23% on day 4, a plateau or increase in serum hCG on day 4, and an hCG value greater than 1000 mIU/mL on day 0 were predictors of single-dose MTX treatment failure in EP patients.