Downregulation of HNRNPA1 induced neoantigen generation via regulating alternative splicing.

BACKGROUND: Immunotherapies effectively treat human malignancies, but the low response and resistance are major obstacles. Neoantigen is an emerging target for tumor immunotherapy that can enhance anti-tumor immunity and improve immunotherapy. Aberrant alternative splicing is an important source of neoantigens. HNRNPA1, an RNA splicing factor, was found to be upregulated in the majority of tumors and play an important role in the tumor immunosuppressive microenvironment. METHODS: Whole transcriptome sequencing was performed on shHNRNPA1 SKOV3 cells and transcriptomic data of shHNRNPA1 HepG2, MCF-7M, K562, and B-LL cells were downloaded from the GEO database. Enrichment analysis was performed to elucidate the mechanisms underlying the activation of anti-tumor immunity induced by HNRNPA1 knockdown. mRNA alternative splicing was analyzed and neoantigens were predicted by JCAST v.0.3.5 and Immune epitope database. The immunogenicity of candidate neoantigens was calculated by Class I pMHC Immunogenicity and validated by the IFN-γ ELISpot assay. The effect of shHNRNPA1 on tumor growth and immune cells in vivo was evaluated by xenograft model combined with immunohistochemistry. RESULTS: HNRNPA1 was upregulated in a majority of malignancies and correlated with immunosuppressive status of the tumor immune microenvironment. Downregulation of HNRNPA1 could induce the activation of immune-related pathways and biological processes. Disruption of HNRNPA1 resulted in aberrant alternative splicing events and generation of immunogenic neoantigens. Downregulation of HNRNPA1 inhibited tumor growth and increased CD8+ T cell infiltration in vivo. CONCLUSION: Our study demonstrated that targeting HNRNPA1 could produce immunogenic neoantigens that elicit anti-tumor immunity by inducing abnormal mRNA splicing. It suggests that HNRNPA1 may be a potential target for immunotherapy.

AutoDeconJ: a GPU-accelerated ImageJ plugin for 3D light-field deconvolution with optimal iteration numbers predicting.

MOTIVATION: Light-field microscopy (LFM) is a compact solution to high-speed 3D fluorescence imaging. Usually, we need to do 3D deconvolution to the captured raw data. Although there are deep neural network methods that can accelerate the reconstruction process, the model is not universally applicable for all system parameters. Here, we develop AutoDeconJ, a GPU-accelerated ImageJ plugin for 4.4× faster and more accurate deconvolution of LFM data. We further propose an image quality metric for the deconvolution process, aiding in automatically determining the optimal number of iterations with higher reconstruction accuracy and fewer artifacts. RESULTS: Our proposed method outperforms state-of-the-art light-field deconvolution methods in reconstruction time and optimal iteration numbers prediction capability. It shows better universality of different light-field point spread function (PSF) parameters than the deep learning method. The fast, accurate and general reconstruction performance for different PSF parameters suggests its potential for mass 3D reconstruction of LFM data. AVAILABILITY AND IMPLEMENTATION: The codes, the documentation and example data are available on an open source at: https://github.com/Onetism/AutoDeconJ.git. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Segmentation of Low-Light Optical Coherence Tomography Angiography Images under the Constraints of Vascular Network Topology.

Optical coherence tomography angiography (OCTA) offers critical insights into the retinal vascular system, yet its full potential is hindered by challenges in precise image segmentation. Current methodologies struggle with imaging artifacts and clarity issues, particularly under low-light conditions and when using various high-speed CMOS sensors. These challenges are particularly pronounced when diagnosing and classifying diseases such as branch vein occlusion (BVO). To address these issues, we have developed a novel network based on topological structure generation, which transitions from superficial to deep retinal layers to enhance OCTA segmentation accuracy. Our approach not only demonstrates improved performance through qualitative visual comparisons and quantitative metric analyses but also effectively mitigates artifacts caused by low-light OCTA, resulting in reduced noise and enhanced clarity of the images. Furthermore, our system introduces a structured methodology for classifying BVO diseases, bridging a critical gap in this field. The primary aim of these advancements is to elevate the quality of OCTA images and bolster the reliability of their segmentation. Initial evaluations suggest that our method holds promise for establishing robust, fine-grained standards in OCTA vascular segmentation and analysis.

Lightweight Cross-Modal Information Mutual Reinforcement Network for RGB-T Salient Object Detection.

RGB-T salient object detection (SOD) has made significant progress in recent years. However, most existing works are based on heavy models, which are not applicable to mobile devices. Additionally, there is still room for improvement in the design of cross-modal feature fusion and cross-level feature fusion. To address these issues, we propose a lightweight cross-modal information mutual reinforcement network for RGB-T SOD. Our network consists of a lightweight encoder, the cross-modal information mutual reinforcement (CMIMR) module, and the semantic-information-guided fusion (SIGF) module. To reduce the computational cost and the number of parameters, we employ the lightweight module in both the encoder and decoder. Furthermore, to fuse the complementary information between two-modal features, we design the CMIMR module to enhance the two-modal features. This module effectively refines the two-modal features by absorbing previous-level semantic information and inter-modal complementary information. In addition, to fuse the cross-level feature and detect multiscale salient objects, we design the SIGF module, which effectively suppresses the background noisy information in low-level features and extracts multiscale information. We conduct extensive experiments on three RGB-T datasets, and our method achieves competitive performance compared to the other 15 state-of-the-art methods.

MCM2 in human cancer: functions, mechanisms, and clinical significance.

BACKGROUND: Aberrant DNA replication is the main source of genomic instability that leads to tumorigenesis and progression. MCM2, a core subunit of eukaryotic helicase, plays a vital role in DNA replication. The dysfunction of MCM2 results in the occurrence and progression of multiple cancers through impairing DNA replication and cell proliferation. CONCLUSIONS: MCM2 is a vital regulator in DNA replication. The overexpression of MCM2 was detected in multiple types of cancers, and the dysfunction of MCM2 was correlated with the progression and poor prognoses of malignant tumors. According to the altered expression of MCM2 and its correlation with clinicopathological features of cancer patients, MCM2 was thought to be a sensitive biomarker for cancer diagnosis, prognosis, and chemotherapy response. The anti-tumor effect induced by MCM2 inhibition implies the potential of MCM2 to be a novel therapeutic target for cancer treatment. Since DNA replication stress, which may stimulate anti-tumor immunity, frequently occurs in MCM2 deficient cells, it also proposes the possibility that MCM2 targeting improves the effect of tumor immunotherapy.

miR-133a targets YES1 to reduce cisplatin resistance in ovarian cancer by regulating cell autophagy.

BACKGROUND: Accumulating evidence has revealed that aberrant microRNA (miRNA) expression can affect the development of chemotherapy drug resistance by modulating the expression of relevant target proteins. Emerging evidence has demonstrated that miR-133a participates in the tumorigenesis of various cancers. However, whether miR-133a is associated with cisplatin resistance in ovarian cancer remains unclear. OBJECTIVE: To investigate the role of miR-133a in the development of cisplatin resistance in ovarian cancer. METHODS: MiR-133a expression in cisplatin-resistant ovarian cancer cell lines was assessed by reverse-transcription quantitative PCR (RT-qPCR). A cell counting kit-8 (CCK-8) assay was used to evaluate the viability of tumour cells treated with cisplatin in the presence or absence of miR-133a. A luciferase reporter assay was used to analyse the binding of miR-133a with the 3' untranslated region (3'UTR) of YES proto-oncogene 1 (YES1). The YES1 expression level was analysed using a dataset from the International Cancer Genome Consortium (ICGC) and assessed by RT-qPCR and western blotting in vitro. The roles and mechanisms of YES1 in cell functions were further probed via gain- and loss-of-function analysis. RESULTS: The expression of miR-133a was significantly decreased in cisplatin-resistant ovarian cancer cell lines (A2780-DDP and SKOV3-DDP), and the overexpression of the miR-133a mimic reduced cisplatin resistance in A2780-DDP and SKOV3-DDP cells. Treatment with the miR-133a inhibitor increased cisplatin sensitivity in normal A2780 and SKOV3 cells. MiR-133a binds the 3'UTR of YES1 and downregulates its expression. Bioinformatics analysis revealed that YES1 expression was upregulated in recurrent cisplatin-resistant ovarian cancer tissue, and in vitro experiments also verified its upregulation in cisplatin-resistant cell lines. Furthermore, we discovered that miR-133a downregulated the expression of YES1 and thus inhibited cell autophagy to reduce cisplatin resistance. Yes1 knockdown significantly suppressed the cisplatin resistance of ovarian cancer cells by inhibiting autophagy in vitro. Xenograft tumour implantation further demonstrated that Yes1 overexpression promoted ovarian tumour development and cisplatin resistance. CONCLUSIONS: Our results suggest that the miR-133a/YES1 axis plays a critical role in cisplatin resistance in human ovarian cancer by regulating cell autophagy, which might serve as a promising therapeutic target for ovarian cancer chemotherapy treatment in the future.

Quality-Aware Selective Fusion Network for V-D-T Salient Object Detection.

Depth images and thermal images contain the spatial geometry information and surface temperature information, which can act as complementary information for the RGB modality. However, the quality of the depth and thermal images is often unreliable in some challenging scenarios, which will result in the performance degradation of the two-modal based salient object detection (SOD). Meanwhile, some researchers pay attention to the triple-modal SOD task, namely the visible-depth-thermal (VDT) SOD, where they attempt to explore the complementarity of the RGB image, the depth image, and the thermal image. However, existing triple-modal SOD methods fail to perceive the quality of depth maps and thermal images, which leads to performance degradation when dealing with scenes with low-quality depth and thermal images. Therefore, in this paper, we propose a quality-aware selective fusion network (QSF-Net) to conduct VDT salient object detection, which contains three subnets including the initial feature extraction subnet, the quality-aware region selection subnet, and the region-guided selective fusion subnet. Firstly, except for extracting features, the initial feature extraction subnet can generate a preliminary prediction map from each modality via a shrinkage pyramid architecture, which is equipped with the multi-scale fusion (MSF) module. Then, we design the weakly-supervised quality-aware region selection subnet to generate the quality-aware maps. Concretely, we first find the high-quality and low-quality regions by using the preliminary predictions, which further constitute the pseudo label that can be used to train this subnet. Finally, the region-guided selective fusion subnet purifies the initial features under the guidance of the quality-aware maps, and then fuses the triple-modal features and refines the edge details of prediction maps through the intra-modality and inter-modality attention (IIA) module and the edge refinement (ER) module, respectively. Extensive experiments are performed on VDT-2048 dataset, and the results show that our saliency model consistently outperforms 13 state-of-the-art methods with a large margin. Our code and results are available at https://github.com/Lx-Bao/QSFNet.

Tyrosine hydroxylase inhibits HCC progression by downregulating TGFß/Smad signaling.

The alteration of metabolic processes has been found to have significant impacts on the development of hepatocellular carcinoma (HCC). Nevertheless, the effects of dysfunction of tyrosine metabolism on the development of HCC remains to be discovered. This research demonstrated that tyrosine hydroxylase (TH), which responsible for the initial and limiting step in the bio-generation of the neuro-transmitters dopamine and adrenaline, et al. was shown to be reduced in HCC. Increased expression of TH was found facilitates the survival of HCC patients. In addition, decreased TH indicated larger tumor size, much more numbers of tumor, higher level of AFP, and the presence of cirrhosis. TH effectively impairs the growth and metastasis of HCC cells, a process dependent on the phosphorylation of serine residues (S19/S40). TH directly binds to Smad2 and hinders the cascade activation of TGFß/Smad signaling with the treatment of TGFß1. In summary, our study uncovered the non-metabolic functions of TH in the development of HCC and proposes that TH might be a promising biomarker for diagnosis as well as an innovative target for metastatic HCC.

Identification of an Autophagy-Related Signature for Prognosis and Immunotherapy Response Prediction in Ovarian Cancer.

BACKGROUND: Ovarian cancer (OC) is one of the most malignant tumors in the female reproductive system, with a poor prognosis. Various responses to treatments including chemotherapy and immunotherapy are observed among patients due to their individual characteristics. Applicable prognostic markers could make it easier to refine risk stratification for OC patients. Autophagy is closely implicated in the occurrence and development of tumors, including OC. Whether autophagy -related genes can be used as prognostic markers for OC patients remains unclear. METHODS: The gene transcriptome data of 374 OC patients were downloaded from The Cancer Genome Atlas (TCGA) database. The correlation between the autophagy levels and outcomes of OC patients was identified through the single sample gene set enrichment analysis (ssGSEA). Recognized molecular markers of autophagy in different clinical specimens were detected by immunohistochemistry (IHC) assay. The gene set enrichment analysis (GSEA), ESTIMATE, and CIBERSORT analysis were applied to explore the correlation of autophagy with the tumor immune microenvironment (TIME). Single-cell RNA-sequencing (scRNA-seq) data from seven OC patients were included for characterizing cell-cell interaction patterns of autophagy-high or low tumor cells. Machine learning, Stepwise Cox regression and LASSO-Cox analysis were used to screen autophagy hub genes, which were used to establish an autophagy-related signature for prognosis evaluation. Four tumor immunotherapy cohorts were obtained from the GEO (Gene Expression Omnibus) database and the literature for autophagy risk score validation. RESULTS: The autophagy levels were closely related to the prognosis of the OC patients. Additionally, the autophagy levels were correlated with TIME status including immune score, and immune-cell infiltration. The scRNA-seq analysis found that tumor cells with high or low autophagy levels had different interactions with immune cells, especially macrophages. Eight autophagy-hub genes (ZFYVE1, AMBRA1, LAMP2, TRAF6, PDPK1, ATG2B, DAPK1 and TP53INP2) were screened for an autophagy-related signature. According to this signature, higher risk score was correlated with poor prognosis and better immunotherapy response in the OC patients. CONCLUSIONS: The autophagy-related signature is applicable to predict the prognosis and immune checkpoint inhibitors (ICIs) therapy efficiency in OC patients. It is possible to identify OC patients who will respond to ICIs therapy and have a favorable prognosis, although more verification is needed.

Comprehensive Analysis Reveals Distinct Immunological and Prognostic Characteristics of CD276/B7-H3 in Pan-Cancer.

Background: CD276 (also known as B7-H3), a newly discovered immunoregulatory protein that belongs to the B7 family, is a significant and attractive target for cancer immunotherapy. Existing evidence demonstrates its pivotal role in the tumorigenesis of some cancers. However, there still lacks a systematic and comprehensive pan-cancer analysis of the role of CD276 in tumor immunology and prognosis. Methods: We explored and validated the mRNA and protein expression levels of CD276 in multiple tumors through public databases and clinical tissues specimens. The Univariate Cox regression analysis and Kaplan-Meier analysis were applied to assess the prognostic value of CD276. The correlation between CD276 expression and clinical characteristics and immunological features in diverse tumors was also explored. GSEA was performed to illuminate the biological function and involved pathways of CD276. Moreover, the CellMiner database was used to interpret the relationship between CD276 and multiple chemotherapeutic agents. CCK-8 assay was performed to validate the biological function of CD276 in vitro. Results: In general, CD276 was differentially expressed between most tumor tissues and their corresponding normal tissues. Higher expression levels of CD276 were associated with poorer survival outcomes in most tumor cohorts from TCGA. There was a close correlation between CD276 expression and clinical features, the infiltration levels of specific immune cells, immune subtypes, TMB, MSI, MMR, recognized immunoregulatory genes and drug sensitivity across diverse human cancers. The scRNA-seq data analysis further revealed that CD276 was mainly expressed on the tumor infiltrating macrophages. Additionally, in vitro experiments showed that knockdown of CD276 inhibited the proliferation of ovarian cancer (OV) and cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) cell lines. Conclusion: CD276 is a potent biomarker for predicting the prognosis and immunological features in some tumors, and it may play a critical role in the tumor immune microenvironment (TIME) through macrophage-associated signaling.

Predicting Protein-Protein Interactions Based on Ensemble Learning-Based Model from Protein Sequence.

Protein-protein interactions (PPIs) play an essential role in many biological cellular functions. However, it is still tedious and time-consuming to identify protein-protein interactions through traditional experimental methods. For this reason, it is imperative and necessary to develop a computational method for predicting PPIs efficiently. This paper explores a novel computational method for detecting PPIs from protein sequence, the approach which mainly adopts the feature extraction method: Locality Preserving Projections (LPP) and classifier: Rotation Forest (RF). Specifically, we first employ the Position Specific Scoring Matrix (PSSM), which can remain evolutionary information of biological for representing protein sequence efficiently. Then, the LPP descriptor is applied to extract feature vectors from PSSM. The feature vectors are fed into the RF to obtain the final results. The proposed method is applied to two datasets: Yeast and H. pylori, and obtained an average accuracy of 92.81% and 92.56%, respectively. We also compare it with K nearest neighbors (KNN) and support vector machine (SVM) to better evaluate the performance of the proposed method. In summary, all experimental results indicate that the proposed approach is stable and robust for predicting PPIs and promising to be a useful tool for proteomics research.

Identification of Biomarkers for Predicting Ovarian Reserve of Primordial Follicle via Transcriptomic Analysis.

Ovarian reserve (OR) is mainly determined by the number of primordial follicles in the ovary and continuously depleted until ovarian senescence. With the development of assisted reproductive technology such as ovarian tissue cryopreservation and autotransplantation, growing demand has arisen for objective assessment of OR at the histological level. However, no specific biomarkers of OR can be used effectively in clinic nowadays. Herein, bulk RNA-seq datasets of the murine ovary with the biological ovarian age (BOA) dynamic changes and single-cell RNA-seq datasets of follicles at different stages of folliculogenesis were obtained from the GEO database to identify gene signature correlated to the primordial follicle pool. The correlations between gene signature expression and OR were also validated in several comparative OR models. The results showed that genes including Lhx8, Nobox, Sohlh1, Tbpl2, Stk31, and Padi6 were highly correlated to the OR of the primordial follicle pool, suggesting that these genes might be used as biomarkers for predicting OR at the histological level.

Learning Frequency Domain Priors for Image Demoireing.

Image demoireing is a multi-faceted image restoration task involving both moire pattern removal and color restoration. In this paper, we raise a general degradation model to describe an image contaminated by moire patterns, and propose a novel multi-scale bandpass convolutional neural network (MBCNN) for single image demoireing. For moire pattern removal, we propose a multi-block-size learnable bandpass filters (M-LBFs), based on a block-wise frequency domain transform, to learn the frequency domain priors of moire patterns. We also introduce a new loss function named Dilated Advanced Sobel loss (D-ASL) to better sense the frequency information. For color restoration, we propose a two-step tone mapping strategy, which first applies a global tone mapping to correct for a global color shift, and then performs local fine tuning of the color per pixel. To determine the most appropriate frequency domain transform, we investigate several transforms including DCT, DFT, DWT, learnable non-linear transform and learnable orthogonal transform. We finally adopt the DCT. Our basic model won the AIM2019 demoireing challenge. Experimental results on three public datasets show that our method outperforms state-of-the-art methods by a large margin.

Involvement of Cancer Stem Cells in Chemoresistant Relapse of Epithelial Ovarian Cancer Identified by Transcriptome Analysis.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. Despite the initial resection and chemotherapeutic treatment, relapse is common, which leads to poor survival rates in patients. A primary cause of recurrence is the persistence of ovarian cancer stem cells (OCSCs) with high tumorigenicity and chemoresistance. To achieve a better therapeutic response in EOC relapse, the mechanisms underlying acquired chemoresistance associated with relapse-initiating OCSCs need to be studied. Transcriptomes of both chemosensitive primary and chemoresistant relapse EOC samples were obtained from ICGC OV-AU dataset for differential expression analysis. The upregulated genes were further studied using KEGG and GO analysis. Significantly increased expression of eighteen CSC-related genes was found in chemoresistant relapse EOC groups. Upregulation of the expression in four hub genes including WNT3A, SMAD3, KLF4, and PAX6 was verified in chemoresistant relapse samples via immunohistochemistry staining, which confirmed the existence and enrichment of OCSCs in chemoresistant relapse EOC. KEGG and GO enrichment analysis in microarray expression datasets of isolated OCSCs indicated that quiescent state, increased ability of drug efflux, and enhanced response to DNA damage may have caused the chemoresistance in relapse EOC patients. These findings demonstrated a correlation between OCSCs and acquired chemoresistance and illustrated potential underlying mechanisms of OCSC-initiated relapse in EOC patients. Meanwhile, the differentially expressed genes in OCSCs may serve as novel preventive or therapeutic targets against EOC recurrence in the future.

Dynamic Selective Network for RGB-D Salient Object Detection.

RGB-D saliency detection is receiving more and more attention in recent years. There are many efforts have been devoted to this area, where most of them try to integrate the multi-modal information, i.e. RGB images and depth maps, via various fusion strategies. However, some of them ignore the inherent difference between the two modalities, which leads to the performance degradation when handling some challenging scenes. Therefore, in this paper, we propose a novel RGB-D saliency model, namely Dynamic Selective Network (DSNet), to perform salient object detection (SOD) in RGB-D images by taking full advantage of the complementarity between the two modalities. Specifically, we first deploy a cross-modal global context module (CGCM) to acquire the high-level semantic information, which can be used to roughly locate salient objects. Then, we design a dynamic selective module (DSM) to dynamically mine the cross-modal complementary information between RGB images and depth maps, and to further optimize the multi-level and multi-scale information by executing the gated and pooling based selection, respectively. Moreover, we conduct the boundary refinement to obtain high-quality saliency maps with clear boundary details. Extensive experiments on eight public RGB-D datasets show that the proposed DSNet achieves a competitive and excellent performance against the current 17 state-of-the-art RGB-D SOD models.