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Programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) interaction plays a crucial role in tumor-associated immune escape. Here, we verify that triple-negative breast cancer (TNBC) has higher PD-L1 expression than other subtypes. We then discover that nucleophosmin (NPM1) binds to PD-L1 promoter specifically in TNBC cells and activates PD-L1 transcription, thus inhibiting T cell activity in vitro and in vivo. Furthermore, we demonstrate that PARP1 suppresses PD-L1 transcription through its interaction with the nucleic acid binding domain of NPM1, which is required for the binding of NPM1 at PD-L1 promoter. Consistently, the PARP1 inhibitor olaparib elevates PD-L1 expression in TNBC and exerts a better effect with anti-PD-L1 therapy. Together, our research has revealed NPM1 as a transcription regulator of PD-L1 in TNBC, which could lead to potential therapeutic strategies to enhance the efficacy of cancer immunotherapy. PD-L1 is highly expressed in triple-negative breast cancers (TNBC). Here, the authors show that nucleophosmin 1 (NPM1) transcriptionally activates PD-L1 expression and inhibits T cell activity in TNBC.

Development of active and durable electrocatalyst for oxygen reduction reaction (ORR) remains one challenge for the polymer electrolyte membrane fuel cell (PEMFC) technology. Pt-based nanomaterials show the greatest promise as electrocatalyst for this reaction among all current catalytic structures. This review focuses on Pt-based ORR catalyst material development and covers the past achievements, current research status and perspectives in this research field. In particular, several important categories of Pt-based catalytic structures and the research advances are summarized. Key factors affecting the catalyst activity and durability are discussed. An outlook of future research direction of ORR catalyst research is provided.

The growing interest in two-dimensional imine-based covalent organic frameworks (COFs) is inspired by their crystalline porous structures and the potential for extensive π-electron delocalization. The intrinsic reversibility and strong polarization of imine linkages, however, leads to insufficient chemical stability and optoelectronic properties. Developing COFs with improved robustness and π-delocalization is highly desirable but remains an unsettled challenge. Here we report a facile strategy that transforms imine-linked COFs into ultrastable porous aromatic frameworks by kinetically fixing the reversible imine linkage via an aza-Diels-Alder cycloaddition reaction. The as-formed, quinoline-linked COFs not only retain crystallinity and porosity, but also display dramatically enhanced chemical stability over their imine-based COF precursors, rendering them among the most robust COFs up-to-date that can withstand strong acidic, basic and redox environment. Owing to the chemical diversity of the cycloaddition reaction and structural tunability of COFs, the pores of COFs can be readily engineered to realize pre-designed surface functionality. Despite recent success in developing new covalent organic frameworks (COFs) materials, synthesis of chemically stable COFs still remains challenging. Here the authors demonstrate a facile strategy that transforms imine-linked COFs into robust porous aromatic frameworks by kinetically fixing the reversible imine linkage via an aza-Diels-Alder cycloaddition reaction.

Ding Ma, Hui Wang, Xun Xu and colleagues report a genome-wide map of HPV integration sites in cervical cancer samples and cell lines. In addition to discovering new integration hot spots, the authors identify microhomology-mediated DNA repair as a likely mechanism by which HPV integrates into the human genome. Human papillomavirus (HPV) integration is a key genetic event in cervical carcinogenesis 1 . By conducting whole-genome sequencing and high-throughput viral integration detection, we identified 3,667 HPV integration breakpoints in 26 cervical intraepithelial neoplasias, 104 cervical carcinomas and five cell lines. Beyond recalculating frequencies for the previously reported frequent integration sites POU5F1B (9.7%), FHIT (8.7%), KLF12 (7.8%), KLF5 (6.8%), LRP1B (5.8%) and LEPREL1 (4.9%), we discovered new hot spots HMGA2 (7.8%), DLG2 (4.9%) and SEMA3D (4.9%). Protein expression from FHIT and LRP1B was downregulated when HPV integrated in their introns. Protein expression from MYC and HMGA2 was elevated when HPV integrated into flanking regions. Moreover, microhomologous sequence between the human and HPV genomes was significantly enriched near integration breakpoints, indicating that fusion between viral and human DNA may have occurred by microhomology-mediated DNA repair pathways 2 . Our data provide insights into HPV integration-driven cervical carcinogenesis.

Cervical cancer (CC) seriously affects women’s health. Therefore, elucidation of the exact mechanisms and identification of novel therapeutic targets are urgently needed. In this study, we identified FAM83F, which was highly expressed in CC cells and tissues, as a potential target. Our clinical data revealed that FAM83F protein expression was markedly elevated in CC tissues and was positively correlated with poor prognosis. Moreover, we observed that FAM83F knockdown significantly inhibited cell proliferation, induced apoptosis, and suppressed glycolysis in CC cells, while its overexpression displayed opposite effects. Mechanistically, FAM83F regulated CC cell growth and glycolysis by the modulation of Wnt/β-catenin pathway. The enhancing effects of FAM83F overexpression on CC cell proliferation and glycolysis could be impaired by the Wnt/β-catenin inhibitor XAV939. Moreover, we found that c-Myc bound to the FAM83F promoter and activated the transcription of FAM83F. Notably, knockdown of FAM83F impaired the enhancement of cell proliferation and glycolysis induced by ectopic c-Myc. Consistent with in vitro findings, results from a xenograft mouse model confirmed the promoting role of FAM83F. In summary, our study demonstrated that FAM83F promoted CC growth and glycolysis through regulating the Wnt/β-catenin pathway, suggesting that FAM83F may be a potential molecular target for CC treatment. Schematic summary of c-Myc-activated FAM83F transcription to promote cervical cancer growth and glycolysis by targeting the Wnt/β-catenin signal pathway.

Metastasis is the main cause of laryngeal cancer-related death; its molecular mechanism remains unknown. Here we identify protein arginine methyltransferase 5 (PRMT5) as a new metastasis-promoting factor in laryngeal carcinoma, and explore its underlying mechanism of action in regulating laryngeal cancer progression. We illustrated that PRMT5 expression was positively correlated with tumor stages, lymphatic metastasis, and unfavorable outcome. Functional assays revealed that PRMT5 promoted laryngeal carcinoma cell proliferation, migration, and invasive capacity in vitro, as well as lymph-node metastasis in vivo. The ectopic expression of PRMT5 induced EMT with downregulation of E-cadherin and upregulation of N-cadherin, snail, and MMP9. Mechanistic results revealed that the metastatic effects could be attributed to PRMT5-mediated activation of Wnt signaling, and Wnt4 is an important driver of Wnt/β-catenin signaling pathway. Wnt4 silencing could reverse PRMT5-induced cell proliferation, migration, and invasion capacities. Furthermore, inhibition of the Wnt/β-catenin signaling pathway abolished the effect of PRMT5-induced proliferation, whereas activation of the pathway enhanced the effect of PRMT5 overexpression on cell proliferation. These results demonstrated that the oncogenic role of PRMT5 could be attributed to PRMT5/Wnt4 axis-mediated activation of the Wnt/β-catenin signaling pathway. PRMT5 may serve as a novel prognostic marker and a therapeutic target for lymphatic metastasis of laryngeal carcinoma.

Background The oncological outcomes of fertility-sparing surgery (FSS) compared to radical surgery (RS) in patients with stage I epithelial ovarian cancer (EOC) remain a subject of debate. We evaluated the risk ratios (RRs) for outcomes in patients with stage I EOC who underwent FSS versus RS. Methods We conducted a systematic search of PubMed, Web of Science, and Embase for articles published up to November 29, 2023. Studies that did not involve surgical procedures or included pregnant patients were excluded. We calculated the RRs for disease-free survival, overall survival, and recurrence rate. The quality of the included studies was assessed using the Cochrane Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool. The meta-analysis was registered on PROSPERO (CRD42024546460). Results From the 5,529 potentially relevant articles, we identified 83 articles for initial screening and included 12 articles in the final meta-analysis, encompassing 2,906 patients with epithelial ovarian cancer. There were no significant differences between the two groups in disease-free survival (RR [95% confidence interval {CI}], 0.90 [0.51, 1.58]; P  = 0.71), overall survival (RR [95% CI], 0.74 [0.53, 1.03]; P  = 0.07), and recurrence rate (RR [95% CI], 1.10 [0.69, 1.76]; P  = 0.68). In sensitivity analyses, the significant difference was observed only for overall survival (before exclusion: RR [95% CI], 0.74 [0.53–1.03], P  = 0.07; after exclusion: RR [95% CI], 0.70 [0.50–0.99]; P  = 0.04). Conclusions This is the first and only individual patient data meta-analysis comparing disease-free survival, overall survival, and recurrence rate of patients with early-stage epithelial ovarian cancer undergoing FSS and RS. FSS was associated with similar disease-free survival and risk of recurrence as RS. We hypothesized that the decreased overall survival in the FSS group could not be attributed to distant metastases from epithelial ovarian cancer.

High-risk human papillomavirus (HR-HPV) has been recognized as a major causative agent for cervical cancer. Upon HPV infection, early genes E6 and E7 play important roles in maintaining malignant phenotype of cervical cancer cells. By using clustered regularly interspaced short palindromic repeats- (CRISPR-) associated protein system (CRISPR/Cas system), a widely used genome editing tool in many organisms, to target HPV16-E7 DNA in HPV positive cell lines, we showed for the first time that the HPV16-E7 single-guide RNA (sgRNA) guided CRISPR/Cas system could disrupt HPV16-E7 DNA at specific sites, inducing apoptosis and growth inhibition in HPV positive SiHa and Caski cells, but not in HPV negative C33A and HEK293 cells. Moreover, disruption of E7 DNA directly leads to downregulation of E7 protein and upregulation of tumor suppressor protein pRb. Therefore, our results suggest that HPV16-E7 gRNA guided CRISPR/Cas system might be used as a therapeutic strategy for the treatment of cervical cancer.

Background Suicide thoughts and behaviors (STB), including suicidal ideation (SI) and suicide attempts (SA), are significant concerns in major depressive disorder (MDD), yet their neurobiological mechanisms remain poorly understood. This study aims to identify key regional brain activity and connectivity abnormalities associated with STB in MDD by combining a meta-analysis of regional brain activity comparing MDD patients with STB to non-STB controls (both MDD without STB and healthy controls) and an exploratory functional connectivity (FC) analysis in an independent sample of MDD patients. Methods A meta-analysis employing Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) software identified regional brain abnormalities. Studies included were those comparing MDD patients with STB to non-STB controls, employing resting-state fMRI with whole-brain analyses, using ALFF, fALFF, and ReHo metrics. The identified abnormal brain regions were used as regions of interest (ROIs) for FC analyses in 57 first-episode, drug-naive MDD patients. Results The meta-analysis included 12 studies (13 datasets) comprising 555 MDD patients with STB and 430 non-STB controls. Compared to non-STB controls, MDD-STB patients showed increased activity in the right middle occipital gyrus (MOG) and right inferior frontal gyrus, triangular part (IFGtriang), while decreased activity in right precuneus. Subgroup analysis of SA revealed increased activity in the left angular gyrus in MDD patients with SA, compared to non-SA controls. SI subgroup analysis and two medication status subgroup analyses showed no significant results. In independent sample, FC analysis yielded two significant FCs after Bonferroni correction. Correlation analysis showed a negative association between right MOG-IFGtriang FC and most severe SI scores measured by the Beck Scale for Suicidal Ideation ( P  = 0.04), though it was non-significant after correction. Conclusions These findings provide novel insights into the neural mechanisms of STB in MDD, identifying specific brain regions and FC patterns associated with STB. These results align with prior studies, highlighting the role of visual processing and cognitive control regions in STB. By combining a meta-analysis of regional abnormalities with an exploratory FC analysis, this study offers a comprehensive understanding of the brain networks implicated in STB and suggests potential targets for future interventions.

Understanding the growth pathway of faceted alloy nanoparticles at the atomic level is crucial to morphology control and property tuning. Yet, it remains a challenge due to complexity of the growth process and technical limits of modern characterization tools. We report a combinational use of multiple cutting-edge in situ techniques to study the growth process of octahedral Pt 3 Ni nanoparticles, which reveal the particle growth and facet formation mechanisms. Our studies confirm the formation of octahedral Pt 3 Ni initiates from Pt nuclei generation, which is followed by continuous Pt reduction that simultaneously catalyzes Ni reduction, resulting in mixed alloy formation with moderate elemental segregation. Carbon monoxide molecules serve as a facet formation modulator and induce Ni segregation to the surface, which inhibits the (111) facet growth and causes the particle shape to evolve from a spherical cluster to an octahedron as the (001) facet continues to grow. Understanding the growth pathway of faceted alloy nanoparticles at the atomic level is crucial to morphology control and property tuning, but remains a challenge. Here, the authors reveal the particle growth and facet formation mechanisms of octahedral Pt 3 Ni nanoparticles using multiple cutting-edge in situ techniques.