Growing evidence shows tumor-infiltrating neutrophils (TINs) involvement in tumorigenesis. The objective of this study is to assess the prognostic effect of TINs and its impact on adjuvant chemotherapy benefits in muscle invasive bladder cancer (MIBC). A total of 142 MIBC patients from Zhongshan Hospital, 119 MIBC patients from FUSCC, and 405 MIBC patients from TCGA cohort were enrolled in the study. TINs were evaluated by immunohistochemical staining of CD66b or the CIBERSORT method. Patients with high TINs had a significantly poorer overall survival (p = 0.001, p < 0.001, and p = 0.002, respectively) in the three sets. In the multivariate analysis, the presence of high TINs (HR = 2.122, p = 0.007; HR = 3.807, p < 0.001; HR = 2.104, p = 0.001; respectively) was identified as an independent prognostic factor for overall survival in the three sets. More importantly, Low TINs patients had significantly longer overall survival in patients without ACT in the three sets. Gene set enrichment analysis showed that lymphocyte activation (p < 0.001) and T cell activation (p = 0.008) were significantly enriched in the low TINs group. In addition, TINs were negatively correlated with CD8+ T cells, suggesting that the status of high-TINs was linked to the status of immunosuppression in MIBC. TINs could be used as independent prognostic factor. Low TINs identified a subgroup of MIBC patients who appeared to benefit from adjuvant chemotherapy. Incorporation of TINs into TNM system could further stratify patients with different prognosis.
The E3 ubiquitin ligase murine double minute 2 (MDM2) binds the p53 transcriptional activation domain and acts as a potent inhibitor of TP53 pathway, one of the three most crucial oncogenic pathways in urothelial carcinoma (UC). However, the clinical significance and impact on tumor immune contexture of MDM2 amplification in UC remain unclear. This study analyzed 240 patients with UC with matched clinical annotations from two local cohorts (ZSHS cohort and FUSCC cohort). We assessed the correlation between MDM2 status and clinical outcomes, therapeutic efficacy, and immunological characteristics by immunohistochemical analysis and targeted sequencing. Additionally, 2264 UC samples from five independent external cohorts, with genomic, transcriptomic, and clinical data, were used for validation. MDM2 amplification (MDM2 Amp) or protein overexpression (MDM2OE) was associated with inferior overall survival (ZSHS cohort, Log-rank p<0.001; FUSCC cohort, Log-rank p=0.030) and reduced response to platinum-based chemotherapy (ZSHS cohort, Log-rank p<0.001) as well as anti-PD-1/PD-L1 immunotherapy (FUSCC cohort, Log-rank p=0.016) in patients with UC, irrespective of TP53/p53 status. MDM2 amplification or overexpression was further linked to high-grade UC tumors with dedifferentiated morphology. In addition, UC with MDM2 amplification or overexpression was associated with an immuno-evasive contexture characterized by lower proportion of tertiary lymphoid structure infiltration, lower abundance of CD8+ T cells, IFN-γ+ cells, GZMB+ cells, and decreased expression of immune checkpoint molecules including programmed death-ligand 1 (PD-L1), programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). MDM2 amplification or overexpression defines a lethal subset of patients with UC with inferior prognosis and resistance to both platinum-based chemotherapy and immunotherapy irrespective of TP53/p53 status. These tumors are characterized by dedifferentiated morphology and an immunosuppressive microenvironment. Accurate assessment of MDM2 status can improve risk stratification and enable personalized genomics-guided treatment for patients with UC.
Rationale: Magnetic resonance imaging (MRI) is a powerful diagnostic technology by providing high-resolution imaging.Although MRI is sufficiently valued in its resolving morphology, it has poor sensitivity for tracking biomarkers.Therefore, contrast agents are often used to improve MRI diagnostic sensitivity.However, the clinically used Gd chelates are limited in improving MRI sensitivity owing to their low relaxivity.The objective of this study is to develop a novel contrast agent to achieve a highly sensitive tracking of biomarkers in vivo.Methods: A Gd-based nanoprobe composed of a gadolinium nanoparticle encapsulated within a human H-ferritin nanocage (Gd-HFn) has been developed.The specificity and sensitivity of Gd-HFn were evaluated in vivo in tumor-bearing mice and apolipoprotein E-deficient mice (Apoe -/ -) by MRI.Results: The Gd-HFn probe shows extremely high relaxivity values (r1 = 549 s -1 mM -1 , r2 = 1555 s -1 mM -1 under a 1.5-T magnetic field; and r1 = 428 s -1 mM -1 and r2 = 1286 s -1 mM -1 under a 3.0-T magnetic field), which is 175-fold higher than that of the clinically standard Dotarem (Gd-DOTA, r1 =3.13 s -1 mM -1 ) under a 1.5-T magnetic field, and 150-fold higher under a 3.0-T magnetic field.Owing to the substantially enhanced relaxivity values, Gd-HFn achieved a highly sensitive tracking for the tumor targeting receptor of TfR1 and enabled the in vivo MRI visualization of tumors approaching the angiogenic switch.Conclusions: The developed Gd-HFn contrast agent makes MRI a more powerful tool by simultaneously providing functional and morphological imaging information, which paves the way for a new perspective in molecular imaging.
Programmed cell death ligand-1 (PD-L1) expression as a single biomarker for immune checkpoint blockade (ICB) was controversial. NKG2A was a PD1/PD-L1 axis-related immunity-dependent factor. NKG2A and PD-L1 expression as a combinatorial biomarker might improve the prediction of PD-L1 in patients with muscle-invasive bladder cancer (MIBC).Three independent cohorts were enrolled in our study. 195 patients with bladder-derived metastatic urothelial carcinoma on PD-L1 inhibitor treatment from the IMvigor210 trial were enrolled. 124 MIBC patients from Zhongshan Hospital and 391 patients with MIBC from The Cancer Genome Atlas database were included in this study.The PD-L1/NKG2A-based risk stratification was validated in three independent cohorts, and its association with response to ICB and adjuvant chemotherapy (ACT), immune contexture and molecular features was evaluated. Histologic staining and genomic algorithm were performed to detect characteristics of NKG2A and PD-L1 expression and infiltration of immune cells.We identified NKG2AhiPD-L1hi patients could benefit more from cisplatin-based ACT and PD-L1 inhibitor. Further analyses revealed NKG2A and PD-L1 expression panel was linked to an immune-active tumor microenvironment with highly immune effector cells and effector molecules. In addition, NKG2A and PD-L1 expression panel was intrinsically correlated with genomic alterations related to therapeutic response in MIBC.NKG2A and PD-L1 expression panel was associated with an immune inflamed microenvironment and acted as a combinatorial biomarker to predict the therapeutic response to ACT and PD-L1 blockade in MIBC.
RAD51, a key recombinase that catalyzes homologous recombination (HR), is commonly overexpressed in multiple cancers. It is curial for DNA damage repair (DDR) to maintain genomic integrity which could further determine the therapeutic response. Herein, we attempt to explore the clinical value of RAD51 in therapeutic guidance in muscle-invasive bladder cancer (MIBC). In this retrospective study, a total of 823 patients with MIBC were included. Zhongshan hospital (ZSHS) cohort (n=134) and The Cancer Genome Atlas-Bladder Cancer (TCGA-BLCA) cohort (n=391) were included for the investigation of chemotherapeutic response. The IMvigor210 cohort (n=298) was utilized to interrogate the predictive efficacy of RAD51 status to programmed cell death ligand-1 (PD-L1) blockade. In addition, the association of RAD51 with genomic instability and tumor immune contexture was investigated. Patients with RAD51 overexpression were more likely to benefit from both platinum-based chemotherapy and immunotherapy rather than RAD51-low patients. The TMB high PD-L1 high RAD51 high subgroup possessed the best clinical benefits from PD-L1 blockade. RAD51-high tumors featured by genomic instability were correlated to highly inflamed and immunogenic contexture with activated immunotherapeutic pathway in MIBC. RAD51 could serve as a prognosticator for treatment response to platinum-based chemotherapy and PD-L1 inhibitor in MIBC patients. Besides, it could also improve the predictive efficacy of TMB and PD-L1.
Some of the fucosylation catalyzed by fucosyltransferase-III mediates the epithelial-mesenchymal transition and enhances tumor cell-macrophage signaling, which promotes malignant transforming and immune evasion. The aim of the study was to investigate the association between the expression of fucosyltransferase-III and clinical outcomes of patients with clear-cell renal cell carcinoma after surgery.High fucosyltransferase-III expression was associated with a greater risk of recurrence (p = 0.002) and shortened overall survival (p < 0.001). We then established a prognostic nomogram including tumor size, pathologic T, N, M stage, coagulative necrosis, lymphovascular invasion and fucosyltransferase-III expression. Furthermore, the predictive accuracy of the Leibovich prognostic score was improved when fucosyltransferase-III expression was added (p = 0.009 for overall survival and p = 0.002 for recurrence-free survival).We conducted a retrospective cohort study of 406 patients who underwent partial or radical nephrectomy between January 2008 and December 2009 in a single institute. Fucosyltransferase-III expression levels were evaluated by immunohistochemical staining in tumor tissues. Kaplan-Meier method was applied to compare survival curves. Cox regression models were fitted to analyze the effect of prognostic factors on recurrence-free and overall survival. Harrell's concordance index and Akaike's Information Criteria were calculated to assess predictive accuracy.Fucosyltransferase-III is a predictive factor for poor overall survival and recurrence free survival in patients with ccRCC. The inhibitor of fucosyltransferase-III might be a potential therapeutic method for the disease.
Automatic speaker naming is the problem of localizing as well as identifying each speaking character in a TV/movie/live show video. This is a challenging problem mainly attributes to its multimodal nature, namely face cue alone is insufficient to achieve good performance. Previous multimodal approaches to this problem usually process the data of different modalities individually and merge them using handcrafted heuristics. Such approaches work well for simple scenes, but fail to achieve high performance for speakers with large appearance variations. In this paper, we propose a novel convolutional neural networks (CNN) based learning framework to automatically learn the fusion function of both face and audio cues. We show that without using face tracking, facial landmark localization or subtitle/transcript, our system with robust multimodal feature extraction is able to achieve state-of-the-art speaker naming performance evaluated on two diverse TV series. The dataset and implementation of our algorithm are publicly available online.
Microwave-induced thermoacoustic imaging (TAI) is a noninvasive modality based on the differences in microwave absorption of various biological tissues. TAI has been extensively researched in recent years, and several studies have revealed that TAI possesses advantages such as high resolution, high contrast, high imaging depth and fast imaging speed. In this paper, we reviewed the development of the TAI technique, its excitation source, data acquisition system and biomedical applications. It is believed that TAI has great potential applications in biomedical research and clinical study.
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