Dark horse target Claudin18.2 opens new battlefield for pancreatic cancer.

Pancreatic cancer is one of the deadliest malignant tumors, which is a serious threat to human health and life, and it is expected that pancreatic cancer may be the second leading cause of cancer death in developed countries by 2030. Claudin18.2 is a tight junction protein expressed in normal gastric mucosal tissues, which is involved in the formation of tight junctions between cells and affects the permeability of paracellular cells. Claudin18.2 is highly expressed in pancreatic cancer and is associated with the initiation, progression, metastasis and prognosis of cancer, so it is considered a potential therapeutic target. Up to now, a number of clinical trials for Claudin18.2 are underway, including solid tumors such as pancreatic cancers and gastric cancers, and the results of these trials have not yet been officially announced. This manuscript briefly describes the Claudia protein, the dual roles of Cluadin18 in cancers, and summarizes the ongoing clinical trials targeting Claudin18.2 with a view to integrating the research progress of Claudin18.2 targeted therapy. In addition, this manuscript introduces the clinical research progress of Claudin18.2 positive pancreatic cancer, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, CAR-T cell therapy, and hope to provide feasible ideas for the clinical treatment of Claudin18.2 positive pancreatic cancer.

Therapeutic role of EGFR - Tyrosine kinase inhibitors in non-small cell lung cancer with leptomeningeal metastasis.

Leptomeningeal metastasis (LM) is a significant complication that advances fast and has a poor prognosis for patients with advanced non-small cell lung cancer (NSCLC) who have epidermal growth factor receptor (EGFR) mutations. Current therapies for LM are inconsistent and ineffective, and established techniques such as radiation, chemotherapy, and surgery continue to fall short of potential outcomes. Nonetheless, EGFR tyrosine kinase inhibitors (TKIs) exhibit potent anti-tumor activity and hold considerable promise for NSCLC patients with EGFR mutations. Thus, assessing EGFR-TKIs effectiveness in treating these central nervous system (CNS) problems is crucial. This review integrates current literature on the intracranial efficacy of EGFR-TKIs to explore the varying impacts of approved EGFR-TKIs in LM patients and the therapeutic possibilities presented by other EGFR-TKIs in development. To delineate the optimal clinical treatment strategy, further exploration is needed regarding the optimal sequencing of EGFR-TKIs and the selection of alternative therapy options following initial treatment failure with EGFR-TKIs.

A super-resolution network using channel attention retention for pathology images.

Image super-resolution (SR) significantly improves the quality of low-resolution images, and is widely used for image reconstruction in various fields. Although the existing SR methods have achieved distinguished results in objective metrics, most methods focus on real-world images and employ large and complex network structures, which are inefficient for medical diagnosis scenarios. To address the aforementioned issues, the distinction between pathology images and real-world images was investigated, and an SR Network with a wider and deeper attention module called Channel Attention Retention is proposed to obtain SR images with enhanced high-frequency features. This network captures contextual information within and across blocks via residual skips and balances the performance and efficiency by controlling the number of blocks. Meanwhile, a new linear loss was introduced to optimize the network. To evaluate the work and compare multiple SR works, a benchmark dataset bcSR was created, which forces a model training on wider and more critical regions. The results show that the proposed model outperforms state-of-the-art methods in both performance and efficiency, and the newly created dataset significantly improves the reconstruction quality of all compared models. Moreover, image classification experiments demonstrate that the suggested network improves the performance of downstream tasks in medical diagnosis scenarios. The proposed network and dataset provide effective priors for the SR task of pathology images, which significantly improves the diagnosis of relevant medical staff. The source code and the dataset are available on https://github.com/MoyangSensei/CARN-Pytorch.

A Rumor Detection Model Incorporating Propagation Path Contextual Semantics and User Information.

Currently, social media is full of rumors. To stop rumors from spreading further, rumor detection has received increasing attention. Recent rumor detection methods treat all propagation paths and all nodes on the paths as equally important, resulting in models that fail to extract the key features. In addition, most methods ignore user features, leading to limitations in the performance improvement of rumor detection. To address these problems, we propose a Dual-Attention Network model on propagation Tree structures named DAN-Tree, where a node-and-path dual-attention mechanism is designed to organically fuse deep structure and semantic information on the propagation structures of rumors, and path oversampling and structural embedding are employed to enhance the learning of deep structures. Finally, we deeply integrate user profiles into the propagation trees in DAN-Tree, thus proposing the DAN-Tree++ model to further improve performance. Empirical studies on four rumor datasets have shown that DAN-Tree outperforms the state-of-the-art rumor detection models learning on propagation structures, and the results on two datasets with user information validate the superior performance of DAN-Tree++ over other models using both user profiles and propagation structures. What's more, DAN-Tree, especially DAN-Tree++, has achieved the best performance on early detection tasks.

Self-supervised global context graph neural network for session-based recommendation.

Session-based recommendation (SBR) aims to recommend the next items based on anonymous behavior sequences over a short period of time. Compared with other recommendation paradigms, the information available in SBR is very limited. Therefore, capturing the item relations across sessions is crucial for SBR. Recently, many methods have been proposed to learn article transformation relationships over all sessions. Despite their success, these methods may enlarge the impact of noisy interactions and ignore the complex high-order relationship between non-adjacent items. In this study, we propose a self-supervised global context graph neural network (SGC-GNN) to model high-order transition relations between items over all sessions by using virtual context vectors, each of which connects to all items in a given session and enables to collect and propagation information beyond adjacent items. Moreover, to improve the robustness of the proposed model, we devise a contrastive self-supervised learning (SSL) module as an auxiliary task to jointly learn more robust representations of the items in sessions and train the model to fulfill the SBR task. Experimental results on three benchmark datasets demonstrate the superiority of our model over the state-of-the-art (SOTA) methods and validate the effectiveness of context vectors and the self-supervised module.

CRDet: Improving Signet Ring Cell Detection by Reinforcing the Classification Branch.

Detecting signet ring cells on histopathologic images is a critical computer-aided diagnostic task that is highly relevant to cancer grading and patients' survival rates. However, the cells are densely distributed and exhibit diverse and complex visual patterns in the image, together with the commonly observed incomplete annotation issue, posing a significant barrier to accurate detection. In this article, we propose to mitigate the detection difficulty from a model reinforcement point of view. Specifically, we devise a Classification Reinforcement Detection Network (CRDet). It is featured by adding a dedicated Classification Reinforcement Branch (CRB) on top of the architecture of Cascade RCNN. The proposed CRB consists of a context pooling module to perform a more robust feature representation by fully making use of context information, and a feature enhancement classifier to generate a superior feature by leveraging the deconvolution and attention mechanism. With the enhanced feature, the small-sized cell can be better characterized and CRDet enjoys a more accurate signet ring cell identification. We validate our proposal on a large-scale real clinical signet ring cell data set. It is shown that CRDet outperforms several popular convolutional neural network-based object detection models on this particular task.

Integrated network analysis of symptom clusters across disease conditions.

Identifying the symptom clusters (two or more related symptoms) with shared underlying molecular mechanisms has been a vital analysis task to promote the symptom science and precision health. Related studies have applied the clustering algorithms (e.g. k-means, latent class model) to detect the symptom clusters mostly from various kinds of clinical data. In addition, they focused on identifying the symptom clusters (SCs) for a specific disease, which also mainly concerned with the clinical regularities for symptom management. Here, we utilized a network-based clustering algorithm (i.e., BigCLAM) to obtain 208 typical SCs across disease conditions on a large-scale symptom network derived from integrated high-quality disease-symptom associations. Furthermore, we evaluated the underlying shared molecular mechanisms for SCs, i.e., shared genes, protein-protein interaction (PPI) and gene functional annotations using integrated networks and similarity measures. We found that the symptoms in the same SCs tend to share a higher degree of genes, PPIs and have higher functional homogeneities. In addition, we found that most SCs have related symptoms with shared underlying molecular mechanisms (e.g. enriched pathways) across different disease conditions. Our work demonstrated that the integrated network analysis method could be used for identifying robust SCs and investigate the molecular mechanisms of these SCs, which would be valuable for symptom science and precision health.

Network Patterns of Herbal Combinations in Traditional Chinese Clinical Prescriptions.

As a well-established multidrug combinations schema, traditional Chinese medicine (herbal prescription) has been used for thousands of years in real-world clinical settings. This paper uses a complex network approach to investigate the regularities underlying multidrug combinations in herbal prescriptions. Using five collected large-scale real-world clinical herbal prescription datasets, we construct five weighted herbal combination networks with herb as nodes and herbal combinational use in herbal prescription as links. We found that the weight distribution of herbal combinations displays a clear power law, which means that most herb pairs were used in low frequency and some herb pairs were used in very high frequency. Furthermore, we found that it displays a clear linear negative correlation between the clustering coefficients and the degree of nodes in the herbal combination network (HCNet). This indicates that hierarchical properties exist in the HCNet. Finally, we investigate the molecular network interaction patterns between herb related target modules (i.e., subnetworks) in herbal prescriptions using a network-based approach and further explore the correlation between the distribution of herb combinations and prescriptions. We found that the more the hierarchical prescription, the better the corresponding effect. The results also reflected a well-recognized principle called "Jun-Chen-Zuo-Shi" in TCM formula theories. This also gives references for multidrug combination development in the field of network pharmacology and provides the guideline for the clinical use of combination therapy for chronic diseases.

Locally Weighted Fusion of Structural and Attribute Information in Graph Clustering.

Attributed graphs have attracted much attention in recent years. Different from conventional graphs, attributed graphs involve two different types of heterogeneous information, i.e., structural information, which represents the links between the nodes, and attribute information on each of the nodes. Clustering on attributed graphs usually requires the fusion of both types of information in order to identify meaningful clusters. However, most of existing works implement the combination of these two types of information in a "global" manner by treating all nodes equally and learning a global weight for the information fusion. To address this issue, this paper proposed a novel weighted K -means algorithm with "local" learning for attributed graph clustering, called adaptive fusion of structural and attribute information (Adapt-SA) and analyzed the convergence property of the algorithm. The key advantage of this model is to automatically balance the structural connections and attribute information of each node to learn a fusion weight, and get densely connected clusters with high attribute semantic similarity. Experimental study of weights on both synthetic and real-world data sets showed that the weights learned by Adapt-SA were reasonable, and they reflected which one of these two types of information was more important to decide the membership of a node. We also compared Adapt-SA with the state-of-the-art algorithms on the real-world networks with varieties of characteristics. The experimental results demonstrated that our method outperformed the other algorithms in partitioning an attributed graph into a community structure or other general structures.

Node Attribute-enhanced Community Detection in Complex Networks.

Community detection involves grouping the nodes of a network such that nodes in the same community are more densely connected to each other than to the rest of the network. Previous studies have focused mainly on identifying communities in networks using node connectivity. However, each node in a network may be associated with many attributes. Identifying communities in networks combining node attributes has become increasingly popular in recent years. Most existing methods operate on networks with attributes of binary, categorical, or numerical type only. In this study, we introduce kNN-enhance, a simple and flexible community detection approach that uses node attribute enhancement. This approach adds the k Nearest Neighbor (kNN) graph of node attributes to alleviate the sparsity and the noise effect of an original network, thereby strengthening the community structure in the network. We use two testing algorithms, kNN-nearest and kNN-Kmeans, to partition the newly generated, attribute-enhanced graph. Our analyses of synthetic and real world networks have shown that the proposed algorithms achieve better performance compared to existing state-of-the-art algorithms. Further, the algorithms are able to deal with networks containing different combinations of binary, categorical, or numerical attributes and could be easily extended to the analysis of massive networks.

A disease similarity matrix based on the uniqueness of shared genes.

BACKGROUND: Complex diseases involve many genes, and these genes are often associated with several different illnesses. Disease similarity measurement can be based on shared genotype or phenotype. Quantifying relationships between genes can reveal previously unknown connections and form a reference base for therapy development and drug repurposing. METHODS: Here we introduce a method to measure disease similarity that incorporates the uniqueness of shared genes. For each disease pair, we calculated the uniqueness score and constructed disease similarity matrices using OMIM and Disease Ontology annotation. RESULTS: Using the Disease Ontology-based matrix, we identified several interesting connections between cancer and other disease and conditions such as malaria, along with studies to support our findings. We also found several high scoring pairwise relationships for which there was little or no literature support, highlighting potentially interesting connections warranting additional study. CONCLUSIONS: We developed a co-occurrence matrix based on gene uniqueness to examine the relationships between diseases from OMIM and DORIF data. Our similarity matrix can be used to identify potential disease relationships and to motivate further studies investigating the causal mechanisms in diseases.

Knowledge-based three-body potential for transcription factor binding site prediction.

A structure-based statistical potential is developed for transcription factor binding site (TFBS) prediction. Besides the direct contact between amino acids from TFs and DNA bases, the authors also considered the influence of the neighbouring base. This three-body potential showed better discriminate powers than the two-body potential. They validate the performance of the potential in TFBS identification, binding energy prediction and binding mutation prediction.

Network based integrated analysis of phenotype-genotype data for prioritization of candidate symptom genes.

BACKGROUND: Symptoms and signs (symptoms in brief) are the essential clinical manifestations for individualized diagnosis and treatment in traditional Chinese medicine (TCM). To gain insights into the molecular mechanism of symptoms, we develop a computational approach to identify the candidate genes of symptoms. METHODS: This paper presents a network-based approach for the integrated analysis of multiple phenotype-genotype data sources and the prediction of the prioritizing genes for the associated symptoms. The method first calculates the similarities between symptoms and diseases based on the symptom-disease relationships retrieved from the PubMed bibliographic database. Then the disease-gene associations and protein-protein interactions are utilized to construct a phenotype-genotype network. The PRINCE algorithm is finally used to rank the potential genes for the associated symptoms. RESULTS: The proposed method gets reliable gene rank list with AUC (area under curve) 0.616 in classification. Some novel genes like CALCA, ESR1, and MTHFR were predicted to be associated with headache symptoms, which are not recorded in the benchmark data set, but have been reported in recent published literatures. CONCLUSIONS: Our study demonstrated that by integrating phenotype-genotype relationships into a complex network framework it provides an effective approach to identify candidate genes of symptoms.

A new exhaustive method and strategy for finding motifs in ChIP-enriched regions.

ChIP-seq, which combines chromatin immunoprecipitation (ChIP) with next-generation parallel sequencing, allows for the genome-wide identification of protein-DNA interactions. This technology poses new challenges for the development of novel motif-finding algorithms and methods for determining exact protein-DNA binding sites from ChIP-enriched sequencing data. State-of-the-art heuristic, exhaustive search algorithms have limited application for the identification of short (l, d) motifs (l ≤ 10, d ≤ 2) contained in ChIP-enriched regions. In this work we have developed a more powerful exhaustive method (FMotif) for finding long (l, d) motifs in DNA sequences. In conjunction with our method, we have adopted a simple ChIP-enriched sampling strategy for finding these motifs in large-scale ChIP-enriched regions. Empirical studies on synthetic samples and applications using several ChIP data sets including 16 TF (transcription factor) ChIP-seq data sets and five TF ChIP-exo data sets have demonstrated that our proposed method is capable of finding these motifs with high efficiency and accuracy. The source code for FMotif is available at http://211.71.76.45/FMotif/.

Combining a popularity-productivity stochastic block model with a discriminative-content model for general structure detection.

Latent community discovery that combines links and contents of a text-associated network has drawn more attention with the advance of social media. Most of the previous studies aim at detecting densely connected communities and are not able to identify general structures, e.g., bipartite structure. Several variants based on the stochastic block model are more flexible for exploring general structures by introducing link probabilities between communities. However, these variants cannot identify the degree distributions of real networks due to a lack of modeling of the differences among nodes, and they are not suitable for discovering communities in text-associated networks because they ignore the contents of nodes. In this paper, we propose a popularity-productivity stochastic block (PPSB) model by introducing two random variables, popularity and productivity, to model the differences among nodes in receiving links and producing links, respectively. This model has the flexibility of existing stochastic block models in discovering general community structures and inherits the richness of previous models that also exploit popularity and productivity in modeling the real scale-free networks with power law degree distributions. To incorporate the contents in text-associated networks, we propose a combined model which combines the PPSB model with a discriminative model that models the community memberships of nodes by their contents. We then develop expectation-maximization (EM) algorithms to infer the parameters in the two models. Experiments on synthetic and real networks have demonstrated that the proposed models can yield better performances than previous models, especially on networks with general structures.

A fast weak motif-finding algorithm based on community detection in graphs.

BACKGROUND: Identification of transcription factor binding sites (also called 'motif discovery') in DNA sequences is a basic step in understanding genetic regulation. Although many successful programs have been developed, the problem is far from being solved on account of diversity in gene expression/regulation and the low specificity of binding sites. State-of-the-art algorithms have their own constraints (e.g., high time or space complexity for finding long motifs, low precision in identification of weak motifs, or the OOPS constraint: one occurrence of the motif instance per sequence) which limit their scope of application. RESULTS: In this paper, we present a novel and fast algorithm we call TFBSGroup. It is based on community detection from a graph and is used to discover long and weak (l,d) motifs under the ZOMOPS constraint (zero, one or multiple occurrence(s) of the motif instance(s) per sequence), where l is the length of a motif and d is the maximum number of mutations between a motif instance and the motif itself. Firstly, TFBSGroup transforms the (l, d) motif search in sequences to focus on the discovery of dense subgraphs within a graph. It identifies these subgraphs using a fast community detection method for obtaining coarse-grained candidate motifs. Next, it greedily refines these candidate motifs towards the true motif within their own communities. Empirical studies on synthetic (l, d) samples have shown that TFBSGroup is very efficient (e.g., it can find true (18, 6), (24, 8) motifs within 30 seconds). More importantly, the algorithm has succeeded in rapidly identifying motifs in a large data set of prokaryotic promoters generated from the Escherichia coli database RegulonDB. The algorithm has also accurately identified motifs in ChIP-seq data sets for 12 mouse transcription factors involved in ES cell pluripotency and self-renewal. CONCLUSIONS: Our novel heuristic algorithm, TFBSGroup, is able to quickly identify nearly exact matches for long and weak (l, d) motifs in DNA sequences under the ZOMOPS constraint. It is also capable of finding motifs in real applications. The source code for TFBSGroup can be obtained from http://bioinformatics.bioengr.uic.edu/TFBSGroup/.

Screening of potential pseudo att sites of Streptomyces phage ΦC31 integrase in the human genome.

AIM: ΦC31 integrase mediates site-specific recombination between two short sequences, attP and attB, in phage and bacterial genomes, which is a promising tool in gene regulation-based therapy since the zinc finger structure is probably the DNA recognizing domain that can further be engineered. The aim of this study was to screen potential pseudo att sites of ΦC31 integrase in the human genome, and evaluate the risks of its application in human gene therapy. METHODS: TFBS (transcription factor binding sites) were found on the basis of reported pseudo att sites using multiple motif-finding tools, including AlignACE, BioProspector, Consensus, MEME, and Weeder. The human genome with the proposed motif was scanned to find the potential pseudo att sites of ΦC31 integrase. RESULTS: The possible recognition motif of ΦC31 integrase was identified, which was composed of two co-occurrence conserved elements that were reverse complement to each other flanking the core sequence TTG. In the human genome, a total of 27924 potential pseudo att sites of ΦC31 integrase were found, which were distributed in each human chromosome with high-risk specificity values in the chromosomes 16, 17, and 19. When the risks of the sites were evaluate more rigorously, 53 hits were discovered, and some of them were just the vital functional genes or regulatory regions, such as ACYP2, AKR1B1, DUSP4, etc. CONCLUSION: The results provide clues for more comprehensive evaluation of the risks of using ΦC31 integrase in human gene therapy and for drug discovery.

KemaDom: a web server for domain prediction using kernel machine with local context.

Predicting domains of proteins is an important and challenging problem in computational biology because of its significant role in understanding the complexity of proteomes. Although many template-based prediction servers have been developed, ab initio methods should be designed and further improved to be the complementarity of the template-based methods. In this paper, we present a novel domain prediction system KemaDom by ensembling three kernel machines with the local context information among neighboring amino acids. KemaDom, an alternative ab initio predictor, can achieve high performance in predicting the number of domains in proteins. It is freely accessible at http://www.iipl.fudan.edu.cn/lschen/kemadom.htm and http://www.iipl.fudan.edu.cn/~lschen/kemadom.htm.