HLAIImaster: a deep learning method with adaptive domain knowledge predicts HLA II neoepitope immunogenic responses.

While significant strides have been made in predicting neoepitopes that trigger autologous CD4+ T cell responses, accurately identifying the antigen presentation by human leukocyte antigen (HLA) class II molecules remains a challenge. This identification is critical for developing vaccines and cancer immunotherapies. Current prediction methods are limited, primarily due to a lack of high-quality training epitope datasets and algorithmic constraints. To predict the exogenous HLA class II-restricted peptides across most of the human population, we utilized the mass spectrometry data to profile >223 000 eluted ligands over HLA-DR, -DQ, and -DP alleles. Here, by integrating these data with peptide processing and gene expression, we introduce HLAIImaster, an attention-based deep learning framework with adaptive domain knowledge for predicting neoepitope immunogenicity. Leveraging diverse biological characteristics and our enhanced deep learning framework, HLAIImaster is significantly improved against existing tools in terms of positive predictive value across various neoantigen studies. Robust domain knowledge learning accurately identifies neoepitope immunogenicity, bridging the gap between neoantigen biology and the clinical setting and paving the way for future neoantigen-based therapies to provide greater clinical benefit. In summary, we present a comprehensive exploitation of the immunogenic neoepitope repertoire of cancers, facilitating the effective development of "just-in-time" personalized vaccines.

DrugMGR: a deep bioactive molecule binding method to identify compounds targeting proteins.

MOTIVATION: Understanding the intermolecular interactions of ligand-target pairs is key to guiding the optimization of drug research on cancers, which can greatly mitigate overburden workloads for wet labs. Several improved computational methods have been introduced and exhibit promising performance for these identification tasks, but some pitfalls restrict their practical applications: (i) first, existing methods do not sufficiently consider how multigranular molecule representations influence interaction patterns between proteins and compounds; and (ii) second, existing methods seldom explicitly model the binding sites when an interaction occurs to enable better prediction and interpretation, which may lead to unexpected obstacles to biological researchers. RESULTS: To address these issues, we here present DrugMGR, a deep multigranular drug representation model capable of predicting binding affinities and regions for each ligand-target pair. We conduct consistent experiments on three benchmark datasets using existing methods and introduce a new specific dataset to better validate the prediction of binding sites. For practical application, target-specific compound identification tasks are also carried out to validate the capability of real-world compound screen. Moreover, the visualization of some practical interaction scenarios provides interpretable insights from the results of the predictions. The proposed DrugMGR achieves excellent overall performance in these datasets, exhibiting its advantages and merits against state-of-the-art methods. Thus, the downstream task of DrugMGR can be fine-tuned for identifying the potential compounds that target proteins for clinical treatment. AVAILABILITY AND IMPLEMENTATION: https://github.com/lixiaokun2020/DrugMGR.

ColonNet: A novel polyp segmentation framework based on LK-RFB and GPPD.

Colorectal cancer (CRC) holds the distinction of being the most prevalent malignant tumor affecting the digestive system. It is a formidable global health challenge, as it ranks as the fourth leading cause of cancer-related fatalities around the world. Despite considerable advancements in comprehending and addressing colorectal cancer (CRC), the likelihood of recurring tumors and metastasis remains a major cause of high morbidity and mortality rates during treatment. Currently, colonoscopy is the predominant method for CRC screening. Artificial intelligence has emerged as a promising tool in aiding the diagnosis of polyps, which have demonstrated significant potential. Unfortunately, most segmentation methods face challenges in terms of limited accuracy and generalization to different datasets, especially the slow processing and analysis speed has become a major obstacle. In this study, we propose a fast and efficient polyp segmentation framework based on the Large-Kernel Receptive Field Block (LK-RFB) and Global Parallel Partial Decoder(GPPD). Our proposed ColonNet has been extensively tested and proven effective, achieving a DICE coefficient of over 0.910 and an FPS of over 102 on the CVC-300 dataset. In comparison to the state-of-the-art (SOTA) methods, ColonNet outperforms or achieves comparable performance on five publicly available datasets, establishing a new SOTA. Compared to state-of-the-art methods, ColonNet achieves the highest FPS (over 102 FPS) while maintaining excellent segmentation results, achieving the best or comparable performance on the five public datasets. The code will be released at: https://github.com/SPECTRELWF/ColonNet.

Ambiguity-aware breast tumor cellularity estimation via self-ensemble label distribution learning.

In this work, we address the task of tumor cellularity (TC) estimation with a novel framework based on the label distribution learning (LDL) paradigm. We propose a self-ensemble label distribution learning framework (SLDL) to resolve the challenges of existing LDL-based methods, including difficulties for inter-rater ambiguity exploitation, proper and flexible label distribution generation, and accurate TC value recovery. The proposed SLDL makes four main contributions which have been demonstrated to be quite effective in numerous experiments. First, we propose an expertness-aware conditional VAE for diversified single-rater modeling and an attention-based multi-rater fusion strategy that enables effective inter-rater ambiguity exploitation. Second, we propose a template-based label distribution generation method that is tailored for the TC estimation task and constructs label distributions based on the annotation priors. Third, we propose a novel restricted distribution loss, significantly improving the TC value estimation by effectively regularizing the learning with unimodal loss and regression loss. Fourth, to the best of our knowledge, we are the first to simultaneously leverage inter-rater and intra-rater variability to address the label ambiguity issue in the breast tumor cellularity estimation tasks. The experimental results on the public BreastPathQ dataset demonstrate that the SLDL outperforms the existing methods by a large margin and achieves new state-of-the-art results in the TC estimation task. The code will be available from https://github.com/PerceptionComputingLab/ULTRA.

Pan-Cancer Methylated Dysregulation of Long Non-coding RNAs Reveals Epigenetic Biomarkers.

Different cancer types not only have common characteristics but also have their own characteristics respectively. The mechanism of these specific and common characteristics is still unclear. Pan-cancer analysis can help understand the similarities and differences among cancer types by systematically describing different patterns in cancers and identifying cancer-specific and cancer-common molecular biomarkers. While long non-coding RNAs (lncRNAs) are key cancer modulators, there is still a lack of pan-cancer analysis for lncRNA methylation dysregulation. In this study, we integrated lncRNA methylation, lncRNA expression and mRNA expression data to illuminate specific and common lncRNA methylation patterns in 23 cancer types. Then, we screened aberrantly methylated lncRNAs that negatively regulated lncRNA expression and mapped them to the ceRNA relationship for further validation. 29 lncRNAs were identified as diagnostic biomarkers for their corresponding cancer types, with lncRNA AC027601 was identified as a new KIRC-associated biomarker, and lncRNA ACTA2-AS1 was regarded as a carcinogenic factor of KIRP. Two lncRNAs HOXA-AS2 and AC007228 were identified as pan-cancer biomarkers. In general, the cancer-specific and cancer-common lncRNA biomarkers identified in this study may aid in cancer diagnosis and treatment.

Performance of novel deep learning network with the incorporation of the automatic segmentation network for diagnosis of breast cancer in automated breast ultrasound.

OBJECTIVE: To develop novel deep learning network (DLN) with the incorporation of the automatic segmentation network (ASN) for morphological analysis and determined the performance for diagnosis breast cancer in automated breast ultrasound (ABUS). METHODS: A total of 769 breast tumors were enrolled in this study and were randomly divided into training set and test set at 600 vs. 169. The novel DLNs (Resent v2, ResNet50 v2, ResNet101 v2) added a new ASN to the traditional ResNet networks and extracted morphological information of breast tumors. The accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under the receiver operating characteristic (ROC) curve (AUC), and average precision (AP) were calculated. The diagnostic performances of novel DLNs were compared with those of two radiologists with different experience. RESULTS: The ResNet34 v2 model had higher specificity (76.81%) and PPV (82.22%) than the other two, the ResNet50 v2 model had higher accuracy (78.11%) and NPV (72.86%), and the ResNet101 v2 model had higher sensitivity (85.00%). According to the AUCs and APs, the novel ResNet101 v2 model produced the best result (AUC 0.85 and AP 0.90) compared with the remaining five DLNs. Compared with the novice radiologist, the novel DLNs performed better. The F1 score was increased from 0.77 to 0.78, 0.81, and 0.82 by three novel DLNs. However, their diagnostic performance was worse than that of the experienced radiologist. CONCLUSIONS: The novel DLNs performed better than traditional DLNs and may be helpful for novice radiologists to improve their diagnostic performance of breast cancer in ABUS. KEY POINTS: • A novel automatic segmentation network to extract morphological information was successfully developed and implemented with ResNet deep learning networks. • The novel deep learning networks in our research performed better than the traditional deep learning networks in the diagnosis of breast cancer using ABUS images. • The novel deep learning networks in our research may be useful for novice radiologists to improve diagnostic performance.

Reciprocal interaction between IK1 and If in biological pacemakers: A simulation study.

Pacemaking dysfunction (PD) may result in heart rhythm disorders, syncope or even death. Current treatment of PD using implanted electronic pacemakers has some limitations, such as finite battery life and the risk of repeated surgery. As such, the biological pacemaker has been proposed as a potential alternative to the electronic pacemaker for PD treatment. Experimentally and computationally, it has been shown that bio-engineered pacemaker cells can be generated from non-rhythmic ventricular myocytes (VMs) by knocking out genes related to the inward rectifier potassium channel current (IK1) or by overexpressing hyperpolarization-activated cyclic nucleotide gated channel genes responsible for the "funny" current (If). However, it is unclear if a bio-engineered pacemaker based on the modification of IK1- and If-related channels simultaneously would enhance the ability and stability of bio-engineered pacemaking action potentials. In this study, the possible mechanism(s) responsible for VMs to generate spontaneous pacemaking activity by regulating IK1 and If density were investigated by a computational approach. Our results showed that there was a reciprocal interaction between IK1 and If in ventricular pacemaker model. The effect of IK1 depression on generating ventricular pacemaker was mono-phasic while that of If augmentation was bi-phasic. A moderate increase of If promoted pacemaking activity but excessive increase of If resulted in a slowdown in the pacemaking rate and even an unstable pacemaking state. The dedicated interplay between IK1 and If in generating stable pacemaking and dysrhythmias was evaluated. Finally, a theoretical analysis in the IK1/If parameter space for generating pacemaking action potentials in different states was provided. In conclusion, to the best of our knowledge, this study provides a wide theoretical insight into understandings for generating stable and robust pacemaker cells from non-pacemaking VMs by the interplay of IK1 and If, which may be helpful in designing engineered biological pacemakers for application purposes.

Identification of Pan-Cancer Prognostic Biomarkers Through Integration of Multi-Omics Data.

Prognostic biomarkers dedicating to treat cancer are very difficult to identify. Although high-throughput sequencing technology allows us to mine prognostic biomarkers much deeper by analyzing omics data, there is lack of effective methods to comprehensively utilize multi-omics data. In this work, we integrated multi-omics data [DNA methylation (DM), gene expression (GE), somatic copy number alternation, and microRNA expression (ME)] and proposed a method to rank genes by desiring a "Score." Applying the method, cancer-specific prognostic biomarkers for 13 cancers were obtained. The prognostic powers of the biomarkers were further assessed by C-indexes (ranged from 0.76 to 0.96). Moreover, by comparing the 13 survival-related gene lists, seven genes (SLK, API5, BTBD2, PTAR1, VPS37A, EIF2B1, and ZRANB1) were found to be associated with prognosis in a variety of cancers. In particular, SLK was more likely to be cancer-related due to its high missense mutation rate and associated with cell adhesion. Furthermore, after network analysis, EPRS, HNRNPA2B1, BPTF, LRRK1, and PUM1 were demonstrated to have a broad correlation with cancers. In summary, our method has a better integration of multi-omics data that can be extended to the researches of other diseases. And the prognostic biomarkers had a better prognostic power than previous methods. Our results could provide a reference for translational medicine researchers and clinicians.

Computational Analysis of the Action of Chloroquine on Short QT Syndrome Variant 1 and Variant 3 in Human Ventricles.

AIMS: The short QT syndrome (SQTS) is a rare genetic disorder associated with arrhythmias and sudden cardiac death (SCD). The SQTI and SQT3, SQTS variants, result from gain-of-function mutations (N588K and D172N, respectively) in the KCNH2-encoded and KCNJ2-encoded potassium channels, in which treatment with potassium channel blocking agents has demonstrated some efficacy. This study used in silico modelling to gain mechanistic insights into the actions of anti-malarial drug chloroquine (CQ) in the setting of SQTI and SQT3. METHODS AND RESULTS: The ten Tusscher et al. human ventricle model was modified to a Markov chain formulation of $I_{J}$

Concatenated and Connected Random Forests With Multiscale Patch Driven Active Contour Model for Automated Brain Tumor Segmentation of MR Images.

Segmentation of brain tumors from magnetic resonance imaging (MRI) data sets is of great importance for improved diagnosis, growth rate prediction, and treatment planning. However, automating this process is challenging due to the presence of severe partial volume effect and considerable variability in tumor structures, as well as imaging conditions, especially for the gliomas. In this paper, we introduce a new methodology that combines random forests and active contour model for the automated segmentation of the gliomas from multimodal volumetric MR images. Specifically, we employ a feature representations learning strategy to effectively explore both local and contextual information from multimodal images for tissue segmentation by using modality specific random forests as the feature learning kernels. Different levels of the structural information is subsequently integrated into concatenated and connected random forests for gliomas structure inferring. Finally, a novel multiscale patch driven active contour model is exploited to refine the inferred structure by taking advantage of sparse representation techniques. Results reported on public benchmarks reveal that our architecture achieves competitive accuracy compared to the state-of-the-art brain tumor segmentation methods while being computationally efficient.

A robust statistics driven volume-scalable active contour for segmenting anatomical structures in volumetric medical images with complex conditions.

BACKGROUND: Accurate segmentation of anatomical structures in medical images is a critical step in the development of computer assisted intervention systems. However, complex image conditions, such as intensity inhomogeneity, noise and weak object boundary, often cause considerable difficulties in medical image segmentation. To cope with these difficulties, we propose a novel robust statistics driven volume-scalable active contour framework, to extract desired object boundary from magnetic resonance (MR) and computed tomography (CT) imagery in 3D. METHODS: We define an energy functional in terms of the initial seeded labels and two fitting functions that are derived from object local robust statistics features. This energy is then incorporated into a level set scheme which drives the active contour evolving and converging at the desired position of the object boundary. Due to the local robust statistics and the volume scaling function in the energy fitting term, the object features in local volumes are learned adaptively to guide the motion of the contours, which thereby guarantees the capability of our method to cope with intensity inhomogeneity, noise and weak boundary. In addition, the initialization of active contour is simplified by select several seeds in the object and/or background to eliminate the sensitivity to initialization. RESULTS: The proposed method was applied to extensive public available volumetric medical images with challenging image conditions. The segmentation results of various anatomical structures, such as white matter (WM), atrium, caudate nucleus and brain tumor, were evaluated quantitatively by comparing with the corresponding ground truths. It was found that the proposed method achieves consistent and coherent segmentation accuracy of 0.9246 ± 0.0068 for WM, 0.9043 ± 0.0131 for liver tumors, 0.8725 ± 0.0374 for caudate nucleus, 0.8802 ± 0.0595 for brain tumors, etc., measured by Dice similarity coefficients value for the overlap between the algorithm one and the ground truth. Further comparative experimental results showed desirable performances of the proposed method over several well-known segmentation methods in terms of accuracy and robustness. CONCLUSION: We proposed an approach to accurate segment volumetric medical images with complex conditions. The accuracy of segmentation, robustness to noise and contour initialization were validated on the basis of extensive MR and CT volumes.

Effects of maximal sodium and potassium conductance on the stability of Hodgkin-Huxley model.

Hodgkin-Huxley (HH) equation is the first cell computing model in the world and pioneered the use of model to study electrophysiological problems. The model consists of four differential equations which are based on the experimental data of ion channels. Maximal conductance is an important characteristic of different channels. In this study, mathematical method is used to investigate the importance of maximal sodium conductance gNA and maximal potassium conductance gK. Applying stability theory, and taking gNA and gK as variables, we analyze the stability and bifurcations of the model. Bifurcations are found when the variables change, and bifurcation points and boundary are also calculated. There is only one bifurcation point when gNA is the variable, while there are two points when gK is variable. The (gNA, gK) plane is partitioned into two regions and the upper bifurcation boundary is similar to a line when both gNA and gK are variables. Numerical simulations illustrate the validity of the analysis. The results obtained could be helpful in studying relevant diseases caused by maximal conductance anomaly.