This study aimed to develop and internally validate a nomogram prediction model based on preoperative clinical indicators, designed to identify patients with papillary thyroid carcinoma (PTC) who fall into the intermediate- and high-risk categories of the 2015 American Thyroid Association (ATA) initial recurrence risk stratification system following surgery, thereby providing a reference for preoperative risk assessment. Relevant clinical data were collected from 404 patients with PTC who underwent surgical treatment at the institution between June 2021 and October 2024. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with the postoperative ATA intermediate-to-high risk category, and a combined model was established along with a nomogram. The performance of the combined model was evaluated by the receiver operating characteristic (ROC) curve, the Hosmer-Lemeshow goodness-of-fit test, calibration curve, and decision curve analysis (DCA). Additionally, a baseline model was constructed to compare its effectiveness with that of the combined model using the DeLong test. This study comprised 404 PTC patients, and the cohort was randomly partitioned into a training set (n = 284) and a validation set (n = 120). Results from univariate and multivariate logistic regression analysis in the training set showed that age, ipsilateral nodular goiter (NG), multifocality, maximum diameter, and thyroglobulin (Tg) were identified as predictive factors for the postoperative ATA intermediate-to-high risk category in PTC. Good fitting and calibration were demonstrated by the combined model, with area under the curve (AUC) values of 0.795 and 0.777 observed in the training and validation sets, respectively. DCA revealed a net positive benefit of the combined model within a broad range of risk thresholds. Although the combined model had numerically higher AUC values than the baseline model in both the training and validation sets, the differences were not statistically significant. The nomogram based on preoperative clinical indicators shows good predictive performance for the postoperative ATA intermediate-to-high risk category, with the potential to preoperatively identify patients at this risk level and assist in clinical decision-making. Nevertheless, its clinical utility warrants further confirmation through multicenter external validation with large sample sizes.

Patients with impaired tumour-specific major histocompatibility complex class I (tsMHC-Iimpaired) often fail to respond to immune checkpoint blockade (ICB), presenting a major clinical challenge. However, through our multicentre investigation, we observed that a subset of patients with tsMHC-Iimpaired remains responsive to ICB, a phenomenon that has not been fully explained. Here we identify a COTL1high natural killer (NK) subset that mediates ICB responsiveness in these patients. Mechanistically, PD-L1+ macrophages coexpress GITRL and engage GITR on COTL1high NK cells, whereas PD-L1 blockade relieves the PD-1-mediated inhibition of GITR signalling and promotes NK cell activation. Activated COTL1high NK cells enhance immunological synapse stability and IFN-γ production via a metabolic-H3K27ac-RBPJ axis, thereby upregulating tsMHC-I expression and reinforcing adaptive anti-tumour immunity. Notably, GITR activation significantly enhances the sensitivity to anti-PD-L1 therapy in tsMHC-Iimpaired models. Our findings identify COTL1high NK cells as key determinants of ICB responsiveness and highlight the GITRL-GITR axis as a promising therapeutic target for tsMHC-Iimpaired tumours.

Dysregulation of RNA m6A modification has been implicated in Alzheimer's disease (AD), but the molecular mechanisms remain largely unclear. Here, we identified the presence of m6A on mitochondria-encoded messenger RNAs (mt-mRNAs) in the brain, with elevated levels correlated with amyloid-β (Aβ) deposition. Under physiological conditions, cytosolic m6A-modified mt-Nd4 is recognized and degraded by the m6A reader protein YTHDF2, thereby preventing aberrant activation of the RIG-I-MAVS innate immune pathway in neurons. Under Aβ-associated pathological conditions, YTHDF2 expression is markedly down-regulated in neurons, leading to the accumulation of m6A-modified mt-Nd4 in the cytosol. This accumulation triggers RIG-I-MAVS activation and type I interferon (IFN) responses. Neuron-derived IFN-β then amplifies neuroinflammation by activating surrounding microglia through a paracrine mechanism. Furthermore, neuronal Ythdf2 deficiency exacerbates Aβ-associated neuroinflammation and cognitive decline. Together, these findings reveal a previously unrecognized m6A/YTHDF2-dependent regulatory axis that links mitochondrial RNA metabolism to innate immune activation and neuroinflammation in Aβ pathology.

The acclimation at mild low temperature can improve the ability of cold tolerance and protect tissues from stress-induced injury in many species, but mechanisms triggering the signal transduction of cold acclimation remain largely unknown. Here, we deciphered the early signaling events associated with immediate temperature drops in zebrafish larvae. Early alternations in the phosphoproteome of larval zebrafish were captured during cold exposure by using an optimized sampling protocol of denaturing with trichloroacetic acid and a tandem mass tagging-based quantitative phosphoproteomic approach. A total of 12,916 phosphosites on 4931 proteins were identified in the phosphoproteome and 7329 phosphosites on 3391 proteins were quantified with 1490 phosphosites on 1098 proteins differentially regulated by cold exposure. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of upregulated phosphosites identified immediate early phosphorylation events on transmembrane proteins, MAPK and transcription factors, and signal pathways that are essential for cold acclimation in larval zebrafish. Moreover, key kinases activated during cold acclimation of larval zebrafish including Ca2+/calmodulin-dependent protein kinase-II, protein kinase C, and protein kinase A were experimentally confirmed. Furthermore, a scaffolding protein AHNAK and many other proteins in AHNAK-mediated signaling pathways were robustly phosphorylated, suggesting their key roles in coordinating cold signal perception and transduction. Together, these findings provide a solid foundation for systematically understanding the signaling events of cold acclimation and a valuable phosphoproteome resource for functional studies of stress responses.

Background:Studies on the treatment-related adverse events have mostly overlooked sleep quality and psychological distress in patients with cancer. The aim of this study was to analyze the relationship between sleep disturbance, treatment-related adverse events, and psychological distress in Chinese patients with breast cancer. Methods:This was a prospective cohort study of 300 female patients diagnosed with breast cancer, who were recruited from two medical centers in China. Sleep disturbances and psychological distress were assessed before and after every treatment cycle using the Pittsburgh Sleep Quality Index and the Symptom Checklist-90 questionnaire. Treatment-related adverse events were assessed using a validated 26‑item scale after each of 6 chemotherapy cycles. Spearman's rank correlation was used for bivariate analyses and multivariable linear regression was used to test independent associations. False Discovery Rate correction was applied for multiple comparisons. Results:The incidence of most treatment-related adverse events was significantly higher in the baseline sleep disorder group than in the normal sleep group (all P values <0.05). Psychological distress at baseline was correlated with the total treatment-related adverse events score (rs=0.54, P<0.001). Multivariate analysis showed that psychological distress was independently associated with the occurrence of treatment-related adverse events (β=0.19, P<0.001). In addition, the pre-treatment total psychological distress score in the baseline sleep disorder group was significantly higher than that in the normal sleep group (P=0.001). Furthermore, the severity of treatment-related adverse events and baseline sleep quality were associated with psychological distress (all P values <0.05). Conclusion:Poor baseline sleep quality is correlated with increased occurrence and severity of treatment-related adverse events. In addition, baseline psychological distress is correlated with the occurrence of treatment-related adverse events. Both baseline sleep quality and the severity of treatment-related adverse events were associated with the psychological distress of patients after treatment for breast cancer.

During primordial germ cell (PGC) specification, repression of somatic programs is essential for the establishment of germline identity. However, mechanisms that safeguard PGC fate thereafter remain unknown. Here, we identify the E3 ubiquitin ligase TRIM37 as a critical safeguard of PGC fate during migration. Trim37 deficiency causes severe PGC defects beginning at embryonic day 9.5 (E9.5) with complete PGC depletion by E12.5, and leads to an aberrant transition toward somatic cell states. Mechanistically, TRIM37 binds TRIM28 through its MATH domain and ubiquitinates TRIM28 via its RING domain, enhancing the TRIM37-TRIM28 interaction and promoting the nuclear retention of TRIM37. Forced nuclear export of TRIM37 results in PGC loss. Moreover, disruption of TRIM37 ligase activity or mutation of TRIM28 ubiquitination sites compromises PGC maintenance. We further show that the TRIM37-TRIM28 complex, likely acting in cooperation with AP2γ, restricts chromatin accessibility and H3K27ac levels at somatic gene loci, thereby repressing somatic transcriptional programs in PGCs. Together, our findings uncover a TRIM37-TRIM28-AP2γ regulatory complex that safeguards germ cell fate by preventing the activation of somatic transcriptional programs during PGC migration.

High‑throughput transcriptome projects have revealed thousands of mammalian genes with little or no functional annotation. Among these are hundreds of loci assigned provisional “Rik” identifiers following discovery in the RIKEN cDNA annotation effort. Although often dismissed as genomic dark matter, such genes may encode tissue‑restricted proteins that modulate physiologic functions and influence disease. The retina is a highly specialised neural tissue and a common site of inherited disorders; understanding its molecular repertoire could illuminate novel therapeutic avenues. We integrated bulk RNA‑seq from ten adult mouse tissues, evolutionary and domain analysis, single‑cell RNA‑seq, and CRISPR/Cas9 gene disruption to systematically catalogue protein‑coding Rik genes enriched in the retina and test the function of a representative gene. A rigorous differential expression analysis identified 44 Rik genes with robust retina‑specific expression compared with nine non‑retinal tissues. Many of these genes lack orthologues beyond rodents, while others show broad conservation, illustrating a continuum from lineage‑restricted to conserved retinopathy candidates. Single‑cell transcriptomics revealed that these genes are expressed across retinal cell types, with the highest aggregate expression in cone photoreceptors and inner interneurons. To evaluate physiological significance, we generated a 1190005I06Rik knockout mouse. Although retinal architecture appeared normal, loss of 1190005I06Rik enhanced electroretinogram b‑wave amplitudes and altered light‑avoidance behaviour, indicating that this previously uncharacterised gene acts as a negative modulator of visual signalling. We present a curated atlas of retina‑enriched Rik genes and demonstrate that 1190005I06RIK modulates retinal circuit function. This resource expands the molecular landscape of the retina and provides new candidates for the genetic basis of inherited retinal disease. Our findings underscore that unannotated genes may exert measurable effects on sensory processing and warrant systematic exploration in the context of human ocular disorders.

Dear Editor, Large-scale phenotyping efforts have shown that placental defects correlate strongly with embryonic lethal mouse mutants(Perez-Garcia et al.,2018).To rescue normal development of these mutant embryos,tetraploid complemen-tation can be a reliable strategy,in which,tetraploid cells form extraembryonic lineages thus providing the embryo with a wild-type placenta(Nagy et al.,1990).

Background: This study aimed to explore the relationship between sleep disturbance, treatment-related adverse events, and psychological distress in Chinese patients with breast cancer. Methods: This prospective cohort study reported on 300 female patients with breast cancer recruited from two medical centers across China between January 1, 2023, and October 31, 2023. Sleep disturbance and psychological health were assessed before and after every cycle of treatment using the Pittsburgh Sleep Quality Index (PSQI) and the Symptom Checklist-90 questionnaire (SCL-90). Statistical tests including t-test, Mann–Whitney U test, Spearman’s rank correlation analysis and multivariate linear regression analysis were used. The study was approved by the ethics committee of the National Cancer Center and written informed consent was obtained from each participant (22/272-3474). Findings: Patients were dichotomized into two groups: those with normal sleep (control; N=168) vs. those with sleep disorder (N=132). The incidence of most treatment-related adverse events such as nausea and vomiting (P=0.04), fatigue (P<0.001), numbness in the hands or feet (P=0.004), alopecia (P=0.02), memory deterioration (P=0.02), and photophobia (P=0.02) were significantly higher in the sleep disorder group at baseline compared to the normal sleep group. The baseline sleep quality of the patients was significantly correlated with the severity of adverse events (rs=0.16, P=0.007). Psychological health at baseline was also correlated with the adverse events score (rs=0.57, P<0.001). Multivariate analysis showed that psychological health was independently associated with the occurrence of adverse events (β=0.19, P <0.001). Besides, the pre-treatment total psychological health score in the baseline sleep disorder group was significantly higher than that in the normal sleep group (Z=-3.42, P=0.001). Furthermore, the severity of treatment-related adverse events (rs=0.32, P<0.001) and baseline sleep quality (rs=0.20, P=0.001) were respectively associated with psychological health. Interpretation: Poor baseline sleep quality is correlated with increased occurrence and severity of treatment-related adverse events in breast cancer patients. Besides, baseline psychological health is correlated with the occurrence of adverse events in breast cancer patients. Both baseline sleep quality and the severity of treatment-related adverse events significantly affect the psychological health of patients after treatment for breast cancer. We fill the knowledge gap and provide new insights for the factors affecting adverse events in breast cancer patients, which could reduce the incidence and severity of treatment-related adverse events and improve quality of life in patients with breast cancer. Our limitations are that we recorded only recent treatment-related adverse events instead of long-term effects and prognoses. Funding: This study was supported by the Nursing Cultivation Fund Project of the Key Discipline Fund of Internal Medicine from the Cancer Hospital of the Chinese Academy of Medical Sciences (grant no.: CICAMS-MONP2022001).

Background: The survival outcomes of carboplatin plus taxane neoadjuvant chemotherapy(NAC) in triple negative breast cancer(TNBC) was lack of a large-sample study. The predictive biomarker of efficacy based on cell-free DNA (cfDNA) whole-methylome sequencing (WMS) has not been reported yet. Methods: The prospective multi-center cohort study was conducted in four hospitals of China between 2016 and 2023. Stage II-III TNBC patients were enrolled to receive NAC of carboplatin (AUC 5) every 3 weeks or carboplatin (AUC 4) every 2 weeks plus taxane(standard dose) for 4-6 cycles. Plasma samples were prospectively collected at baseline(T1) and end of NAC (T2). Chromosomal aneuploidy of featured fragments (CAFF), fragment size index (FSI) and methylation density score (MD) of cfDNA were detected with WMS. The primary endpoint were relapse-free survival (RFS) and exploratory biomarker analysis. Result: A total of 267 patients were included in the study. The median age was 49 years, 156 patients (58.4%) were stage III disease. cT3-T4 were 28.1% (75/267), cN3 were 17.2% (46/267). 40.3% patients (106/263) achieved pathologic complete response (pCR). The 3-year RFS and overall survival (OS) were 77.9%, 87.6%, respectively. Patients who achieved pCR had a significant better RFS(95.5%) and OS(97.7%) than those non-pCR (68.5%, 81.2%, all P<0.001). Survival of patients with minimal residual disease (ypT1mi/1a/1b N0) are comparable to those pCR, 3-year RFS and OS were 80.2% vs 92.3%(Log-rank P=0.060), 90.5% vs 97.4% (Log-rank P=0.247), respectively, after excluding cN3 patients. Patients with residual node number >2 had a poor 3-year RFS and OS compared to number≤2( All Log-rank P<0.0001). A total of 66 patients with 120 plasma samples (64 samples at T1, 56 samples at T2) were included in WMS analysis. Patients with CAFF, FSI or MD positive at T1 had a higher tumor burden (stage III or cN2-3, all P values <0.05). The proportion of patients with FSI negative at T2 was significantly higher in pCR group compared to non-pCR(86.2% vs 59.3%,P=0.034). Similar tendency were observed in patients with CAFF negative. A linear SVM model was developed to predict pCR with an AUC of 0.90 in the training datase and an AUC of 0.86 in the testing dataset. Moreover, patients with MD positive at T1 was significantly associated with poor RFS compared to MD negative (HR = 7.36, Log-rank P=0.028). Conclusion: Our large-sample study further confirmed that carboplatin plus taxanes as NAC in TNBC was a preferred regimen with the comparable survival outcome, especially for patients who cannot tolerate anthracyclines or immunotherapy. Biomarkers based on cfDNA WMS may provide predictive and prognostic information, warranting further investigation. Citation Format: Xi Chen, Meng Xiu, Hua Kang, Yan Zhang, Hua Yang, Qiao Li, Qing Li, Xueyan Cheng, Jiayu Wang, Ying Fan, Bo Lan, Bin Hua, Min Xiao, Xiaoyan Qian, Xiang Wang, Binghe Xu, Pin Zhang. Survival outcomes of carboplatin plus taxanes neoadjuvant chemotherapy in triple negative breast cancer and cell-free DNA whole methylome based biomarker analysis: A prospective multi-center cohort study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-09-19.

Background: Comprehensive Geriatric Assessment (CGA) contains multiple dimensions and involves complex scales, thereby limiting its clinical application. This study aims to develop a clinically applicable geriatric assessment method (Geriatric Vulnerability Score, GVS) tailored to older patients with metastatic breast cancer (MBC) and to analyze its association with survival. Methods: This study included MBC patients aged over 65 years. They underwent geriatric assessment(GA) including Charlson Comorbidity Index (CCI), Activities of Daily Living (ADL);Peripheral blood lymphocyte absolute count and albumin were recorded for assessment of immune system reserve and nutritional reserve. Data analysis included descriptive statistics, Cox multivariate regression, student’s t-tests, one-way ANOVA, Kaplan-Meier curves and Harrell's concordance statistic. Results: A total of 233 patients were included with the median age of 69 years. The median CCI was 0 (0-4). 33 (14.2%) patients had an ADL score<90; 25 (10.7%) patients had a lymphopenia ≤1×109/L, and 17 (7.3%) patients had an albumemia ≤35g/L. 159 (66.8%) patients were treatment-naive in metastatic setting. Multivariate analysis showed that ADL score<90, lymphopenia ≤1×109/L, and albumemia ≤35 g/L were independent adverse factors for OS in patients (all P <0.05), whereas CCI was not an independent prognostic factor (P>0.05).When the significant GA items (ADL <90, lymphopenia ≤1×109/L, albumemia ≤35 g/L, each assigned a value of one) were scored to develop GVS, it showed that the higher GVS, the worse OS of patients (HR: 2.228, 95% CI: 1.640-3.027, P <0.001). Furthermore, this score was validated in the treatment-naive group (HR: 3.215, 95% CI: 1.975-5.232, P <0.001). Adding GVS to tumor characteristics improved the accuracy of prognostic prediction (C-index, all patients: from 0.670 to 0.709; treatment-naive group: from 0.694 to 0.742). Conclusion: GVS is an objective, simple, and feasible method that can serve as one of the dimensions for predicting the prognosis of old MBC. It is worth verifying its clinical application value in a larger sample. Citation Format: Min Xiao, Lei Ji, Xi Chen, Song Ge, Qing Li, Qiao Li, Pin Zhang. Prognostic Value of the Geriatric Vulnerability Score in Older Patients with Metastatic Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-08-24.

Tumor mutational burden (TMB) is a recognized biomarker for predicting immunotherapy efficacy in non-small cell lung cancer (NSCLC). Its assessment requires whole-exome sequencing (WES), but the high cost and stringent sample requirements of WES limit its clinical application. This study aims to assess the predictive value of accessible systemic inflammation markers for identifying high TMB lung cancer populations. WES was performed on tumor samples and paired peripheral blood from 72 lung adenocarcinoma patients. Genomic analysis identified mutation patterns across different TMB groups. Systemic inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), lymphocyte-to-monocyte ratio (LMR), and platelet to lymphocyte ratio (PLR), were collected. Generalized linear models and restricted cubic spline (RCS) plots were used to explore the predictive value of these markers for TMB. The Xgboost model assessed the importance of each variable for TMB prediction. Among the 72 lung adenocarcinoma patients, missense mutations were the most common, with single nucleotide variants being the predominant mutation type. The most frequently mutated genes were EGFR (35

Genome sequencing (GS) refers to a technology that comprehensively and systematically detects the DNA sequences of an individual's nuclear and mitochondrial genomes. It aims to identify genetic variants and investigate their roles in human health and disease progression. As an emerging diagnostic tool, GS offers significant support for clinical diagnosis due to its high throughput, accuracy, and comprehensiveness. However, the complexity of data analysis and interpretation requires substantial professional expertise and experience, posing considerable challenges. When applying GS technology for molecular diagnosis of genetic diseases, ethical and technical issues related to clinical application arise, including informed consent, diagnostic data interpretation, and defining the scope and content of clinical reports. This expert consensus outlines the core workflow of clinical genome sequencing (cGS), clarifies its testing scope and technical limitations, and provides key steps for data quality control, analysis, annotation, and variant interpretation. It also addresses controversial issues related to report content and informed consent. This consensus aims to assist professionals in accurately understanding and appropriately utilizing clinical genome sequencing, thereby improving diagnostic accuracy for genetic diseases, enhancing the clinical utility of the technology, and advancing medical scientific research.

Due to the lack of an in-depth evaluation of urothelial carcinoma (UC) HER2 expression in both primary and recurrent UC, we examined possible clinical and pathological variables associated with altered UC HER2 expression. The HER2 status and clinicopathological features of primary UCs and matched recurrences from 2015 to 2023 (n = 1352) were compared by evolution category (stable or altered). In 1352 UC patients, HER2 protein expression was linked with age, histological grade, and recurrence. HER2 was expressed in 794 UC patients (58.7

e12518 Background: The clinicopathological and prognostic features of HER2-low female breast cancer (BC) have been widely studied. Current knowledge suggests that HER2-low could be identified as a special entity for treatment. However, limited research has focused on the HER2-low subtype in early-stage male breast cancer. Methods: This retrospective study screened male BC cases from all breast cancer patients at a single institution between January 2010 and September 2023. Early-stage cases with non-HER2-positive tumors were included and categorized into HER2-low and HER2-zero groups. Clinicopathological features were collected and compared between the two groups. The primary endpoints were disease-free survival (DFS) and overall survival (OS). Statistical analysis was conducted using descriptive statistics, the Kaplan-Meier method with the Log-rank test, and the Cox proportional hazards model to evaluate differences in DFS and OS between the groups. Results: A total of 99 early-stage non-HER2-positive male BC cases were identified, with 41 classified as HER2-low and 58 as HER2-zero, and these cases were included in the final analysis. Regarding the clinicopathological features, the HER2-low subgroup exhibited higher androgen receptor (AR) expression (P = 0.003). Regarding survival outcomes, no significant difference was observed in DFS (P = 0.1), but the HER2-low subgroup had a significantly longer OS compared to the HER2-zero subgroup (P = 0.01). Multivariate analysis identified age and TNM stage as independent prognostic factors for DFS, while age and HER2-low were independent prognostic factors for OS. Conclusions: HER2-low population in early-stage male BC had a different clinicopathological feature and prognostic role compared to HER2-zero counterparts. The HER2-low subgroup had a better OS compared to the HER2-zero subgroup, and HER2-low was determined as an independent prognostic factor for OS, but not for DFS.

Background: Pathological complete response (pCR) has been proven to be related to prognosis. pCR can be further classified as pCR of the breast (bpCR), pCR of axillary lymph nodes (apCR) or pCR of both tumors. The aim of this study was to elucidate the outcomes and clinicopathological characteristics associated with different patterns of pCR. Methods: Patients with node-positive disease who received neoadjuvant chemotherapy between August 2009 and July 2016 and who achieved pCR in axillary lymph nodes, breast or both were included. Multivariate logistic regression was used to identify factors related to different patterns of pCR. Results: Among the 271 patients who were included in the study, 42.1% achieved total pCR, 46.1% achieved ApCR, and 11.8% achieved BpCR. Disease-free survival (DFS) was significantly better in the total pCR group than in the limited pCR groups throughout the entire cohort (p=0.042). Univariate and multivariate analyses indicated that patients with HR-negative disease and a high Ki-67 proliferation index were more likely to achieve total pCR. Patients with earlier T stage disease were more likely to achieve pCR only in the breast. Among patients who achieved limited pCR, there was no significant difference in terms of whether these patients received intensified adjuvant chemotherapy. Conclusions: Total pCR is still the best marker for predicting survival benefit in patients receiving neoadjuvant chemotherapy, and total pCR is more likely to be achieved in patients with HR-negative disease and a high Ki-67 proliferation index. T stage and N stage may predict apCR and bpCR, respectively.

AIMS:This study compared pathologic complete response (pCR) rates to neoadjuvant chemotherapy (NAC) in HER2-negative early breast cancer patients with versus without homologous recombination repair (HRR) mutation, focusing on BRCA1/2. METHODS:This retrospective cohort study included HER-2-negative breast cancer patients who completed HRR genetic testing and received NAC. The primary endpoint was the pCR rate among HRR mutation carriers and noncarriers. RESULT:Among 211 HER2-negative breast cancer patients analyzed, 64 (30.3%) harbored pathogenic/likely pathogenic HRR mutations, predominantly in BRCA1 (42.2%), BRCA2 (31.3%), and other HRR genes (26.6%). Hormone receptor positive patients accounted for 55.9% (118/211). Half of the patients (51.2%) treated with platinum-containing regimens. pCR rates were comparable between HRR mutation carriers and noncarriers (26.6% vs. 24.5%, p = 0.750), regardless of hormone receptor status. However, BRCA1 carriers achieved significantly higher pCR rates than BRCA2 carriers (40.7% vs. 10.0%, p = 0.001). Platinum-containing regimens (51.2% of patients) yielded greater benefit in BRCA1 carriers (pCR 61.1% vs. 12.5% in BRCA2; p = 0.022). CONCLUSION:These data indicated that HRR mutations had no effect on pCR in HER-2 negative patients receiving NAC regardless of hormone receptor status. BRCA1 mutation carriers have a higher rate of pCR and are more benefit from platinum-containing regimen than BRCA2 mutation carriers.

Previous studies often combined double hormone receptor-positive (dHR +) and single HR-positive (sHR +) tumors, thus not accounting for the distinct characteristics of sHR + , particularly in the neoadjuvant setting. Moreover, adding immunotherapy to cytotoxic chemotherapy has shown encouraging efficacy in certain HR-positive early breast cancers. This study sought to assess pathological complete response (pCR) and survival outcomes in sHR + /HER2- breast cancer after neoadjuvant chemotherapy, while also investigating its specific biological traits and immune profile. Clinical data were sourced from the Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS, n = 1049), and the Surveillance, Epidemiology, and End Results (SEER, n = 21,092) database to examine neoadjuvant chemosensitivity and survival outcomes. Additionally, clinicopathological and subtype data from CHCAMS, SEER, the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1052), and Fudan University Shanghai Cancer Center (FUSCC, n = 570) were analyzed to identify biological features that correlate with pCR rates and prognosis in sHR + /HER2- breast cancer. Further genomic and transcriptomic data from METABRIC, The Cancer Genome Atlas (TCGA, n = 741), and MSK-IMPCAT (n = 1535) were reviewed to uncover their potential links with endocrine and immunotherapy responses. In comparison to dHR + (ER + and PR +)/HER2- breast cancer, sHR + (ER + /PR- or ER-/PR +)/HER2- breast cancer displayed a higher pCR rate (20.2

BACKGROUND & AIMS:Etomidate, a prevalent intravenous anesthetic agent, has been implicated in the attenuation of tumorigenesis. Our recent investigations elucidated its capacity to impede the malignant progression of hepatocellular carcinoma (HCC). This study aims to elucidate how etomidate modulates the immunosuppressive tumor microenvironment in HCC. METHODS:To investigate the multifaceted effects and underlying molecular mechanisms of etomidate, we employed an integrative approach encompassing in vitro and in vivo systems, including patient-derived HCC organoids, 3-dimensional co-culture platforms, patient-derived xenografts, and orthotopic HCC models. A suite of advanced methodologies such as single-cell cytometry by time-of-flight (CyTOF), multiplex immunohistochemistry, and flow cytometric analyses were applied. RESULTS:Our data reveal that etomidate suppresses programmed death-ligand 1 (PD-L1) expression in HCC cells, thereby potentiating antitumor immunity. Mechanistically, etomidate inhibits the Janus kinase 2/signal transducer and activator of transcription 3 axis in tumor cells, leading to reduced PD-L1 transcription and increased infiltration and activation of cytotoxic CD8+ T lymphocytes. CONCLUSIONS:These findings support the hypothesis that etomidate enhances antitumor immunity and boosts the therapeutic efficacy of immune checkpoint blockade, thereby laying a theoretical foundation for precision immunotherapy in HCC.