Improving diagnosis and outcome prediction of gastric cancer via multimodal learning using whole slide pathological images and gene expression.

For the diagnosis and outcome prediction of gastric cancer (GC), machine learning methods based on whole slide pathological images (WSIs) have shown promising performance and reduced the cost of manual analysis. Nevertheless, accurate prediction of GC outcome may rely on multiple modalities with complementary information, particularly gene expression data. Thus, there is a need to develop multimodal learning methods to enhance prediction performance. In this paper, we collect a dataset from Ruijin Hospital and propose a multimodal learning method for GC diagnosis and outcome prediction, called GaCaMML, which is featured by a cross-modal attention mechanism and Per-Slide training scheme. Additionally, we perform feature attribution analysis via integrated gradient (IG) to identify important input features. The proposed method improves prediction accuracy over the single-modal learning method on three tasks, i.e., survival prediction (by 4.9% on C-index), pathological stage classification (by 11.6% on accuracy), and lymph node classification (by 12.0% on accuracy). Especially, the Per-Slide strategy addresses the issue of a high WSI-to-patient ratio and leads to much better results compared with the Per-Person training scheme. For the interpretable analysis, we find that although WSIs dominate the prediction for most samples, there is still a substantial portion of samples whose prediction highly relies on gene expression information. This study demonstrates the great potential of multimodal learning in GC-related prediction tasks and investigates the contribution of WSIs and gene expression, respectively, which not only shows how the model makes a decision but also provides insights into the association between macroscopic pathological phenotypes and microscopic molecular features.

The role of host traits and geography in shaping the gut microbiome of insectivorous bats.

The gut microbiome is a symbiotic microbial community associated with the host and plays multiple important roles in host physiology, nutrition, and health. A number of factors have been shown to influence the gut microbiome, among which diet is considered to be one of the most important; however, the relationship between diet composition and gut microbiota in wild mammals is still not well recognized. Herein, we characterized the gut microbiota of bats and examined the effects of diet, host taxa, body size, gender, elevation, and latitude on the gut microbiota. The cytochrome C oxidase subunit I (COI) gene and 16S rRNA gene amplicons were sequenced from the feces of eight insectivorous bat species in southern China, including Miniopterus fuliginosus, Aselliscus stoliczkanus, Myotis laniger, Rhinolophus episcopus, Rhinolophus osgoodi, Rhinolophus ferrumequinum, Rhinolophus affinis, and Rhinolophus pusillus. The results showed that the composition of gut microbiome and diet exhibited significant differences among bat species. Diet composition and gut microbiota were significantly correlated at the order, family, genus, and operational taxonomic unit levels, while certain insects had a marked effect on the gut microbiome at specific taxonomic levels. In addition, elevation, latitude, body weight of bats, and host species had significant effects on the gut microbiome, but phylosymbiosis between host phylogeny and gut microbiome was lacking. These findings clarify the relationship between gut microbiome and diet and contribute to improving our understanding of host ecology and the evolution of the gut microbiome in wild mammals. IMPORTANCE: The gut microbiome is critical for the adaptation of wildlife to the dynamic environment. Bats are the second-largest group of mammals with short intestinal tract, yet their gut microbiome is still poorly studied. Herein, we explored the relationships between gut microbiome and food composition, host taxa, body size, gender, elevation, and latitude. We found a significant association between diet composition and gut microbiome in insectivorous bats, with certain insect species having major impacts on gut microbiome. Factors like species taxa, body weight, elevation, and latitude also affected the gut microbiome, but we failed to detect phylosymbiosis between the host phylogeny and the gut microbiome. Overall, our study presents novel insights into how multiple factors shape the bat's gut microbiome together and provides a study case on host-microbe interactions in wildlife.

Molecular adaptations underlying high-frequency hearing in the brain of CF bats species.

BACKGROUND: The majority of bat species have developed remarkable echolocation ability, especially for the laryngeally echolocating bats along with high-frequency hearing. Adaptive evolution has been widely detected for the cochleae in the laryngeally echolocating bats, however, limited understanding for the brain which is the central to echolocation signal processing in the auditory perception system, the laryngeally echolocating bats brain may also undergo adaptive changes. RESULT: In order to uncover the molecular adaptations related with high-frequency hearing in the brain of laryngeally echolocating bats, the genes expressed in the brain of Rhinolophus ferrumequinum (CF bat) and Myotis pilosus (FM bat) were both detected and also compared. A total of 346,891 genes were detected and the signal transduction mechanisms were annotated by the most abundant genes, followed by the transcription. In hence, there were 3,088 DEGs were found between the two bat brains, with 1,426 highly expressed in the brain of R. ferrumequinum, which were significantly enriched in the neuron and neurodevelopmental processes. Moreover, we found a key candidate hearing gene, ADCY1, playing an important role in the R. ferrumequinum brain and undergoing adaptive evolution in CF bats. CONCLUSIONS: Our study provides a new insight to the molecular bases of high-frequency hearing in two laryngeally echolocating bats brain and revealed different nervous system activities during auditory perception in the brain of CF bats.

The Tao Hong Si Wu Decoction ameliorates diabetes-associated cognitive dysfunction by inhibiting the formation of amyloid plaques.

OBJECTIVES: The herbs in Tao Hong Si Wu Decoction (THSWD) are beneficial in the treatment of cognitive impairment. However, the underlying mechanisms of THSWD in treating diabetes-associated cognitive dysfunction (DACD) are not entirely explored. This study is aimed to investigate the therapeutic effects of THSWD in DACD model rats and the underlying mechanism. METHODS: Ultra-high-phase liquid chromatography was employed to identify the main compounds contained in the THSWD extract. DACD rat model was induced by feeding with a high-sugar and high-fat diet and injecting streptozotocin (35 mg/kg). DACD rats were gavaged with THSWD for 1 week. The learning and memory abilities of the rats were measured by using the Morris water maze. Western blotting was used to detect the changes in DACD rat targets. Statistical methods were used to evaluate the correlation between proteins. RESULTS: The results show that THSWD effectively reduced the escape latency, hippocampal neuron damage, glycosylated hemoglobin, type A1C, and blood lipid levels in DACD rats. Furthermore, DACD rats showed significantly increased amyloid precursor protein, ß-secretase, Aß1-40 , Aß1-42 , Tau phosphorylation, and advanced glycation end products (AGEs) expression. However, THSWD treatment can reverse this phenomenon. CONCLUSIONS: THSWD can improve the learning and memory abilities of DACD rats by inhibiting the expression of AEGs-AGE receptors pathway, which provides an experimental basis for the clinical application of THSWD. In addition, the experiment combines pharmacological and statistical methods, which offers a new perspective for the study of Chinese herbal medicine.

DBLiPro: A Database for Lipids and Proteins in Human Lipid Metabolism.

To help researchers in the field of biology, medicine, chemistry, and materials science to use lipidomic data conveniently, there is an urgent need to develop a platform that provides a systematic knowledgebase of human lipid metabolism and lipidome-centric omics analysis tools. DBLiPro is a user-friendly webserver allowing for access to human metabolism-related lipids and proteins knowledge database and an interactive bioinformatics integrative analysis workflow for lipidomics, transcriptomics, and proteomics data. In DBLiPro, there are 3109 lipid-associated proteins (LAPs) and 2098 lipid metabolites in the knowledge base section, which were obtained from Uniprot, Kyoto Encyclopedia of Genes and Genomes (KEGG) and were further annotated by information from other public resources in the knowledge base section, such as RaftProt and PubChem. DBLiPro offers a step-by-step interactive analysis workflow for lipidomics, transcriptomics, proteomics, and their integrating multi-omics analysis focusing on the human lipid metabolism. In summary, DBLiPro is capable of helping users discover key molecules (lipids and proteins) in human lipid metabolism and investigate lipid-protein functions underlying mechanisms based on their own omics data. The DBLiPro is freely available at http://lipid.cloudna.cn/home.

Spatially resolved multi-omics highlights cell-specific metabolic remodeling and interactions in gastric cancer.

Mapping tumor metabolic remodeling and their spatial crosstalk with surrounding non-tumor cells can fundamentally improve our understanding of tumor biology, facilitates the designing of advanced therapeutic strategies. Here, we present an integration of mass spectrometry imaging-based spatial metabolomics and lipidomics with microarray-based spatial transcriptomics to hierarchically visualize the intratumor metabolic heterogeneity and cell metabolic interactions in same gastric cancer sample. Tumor-associated metabolic reprogramming is imaged at metabolic-transcriptional levels, and maker metabolites, lipids, genes are connected in metabolic pathways and colocalized in the heterogeneous cancer tissues. Integrated data from spatial multi-omics approaches coherently identify cell types and distributions within the complex tumor microenvironment, and an immune cell-dominated "tumor-normal interface" region where tumor cells contact adjacent tissues are characterized with distinct transcriptional signatures and significant immunometabolic alterations. Our approach for mapping tissue molecular architecture provides highly integrated picture of intratumor heterogeneity, and transform the understanding of cancer metabolism at systemic level.

Abalign: a comprehensive multiple sequence alignment platform for B-cell receptor immune repertoires.

The utilization of high-throughput sequencing (HTS) for B-cell receptor (BCR) immune repertoire analysis has become widespread in the fields of adaptive immunity and antibody drug development. However, the sheer volume of sequences generated by these experiments presents a challenge in data processing. Specifically, multiple sequence alignment (MSA), a critical aspect of BCR analysis, remains inadequate for handling massive BCR sequencing data and lacks the ability to provide immunoglobulin-specific information. To address this gap, we introduce Abalign, a standalone program specifically designed for ultrafast MSA of BCR/antibody sequences. Benchmark tests demonstrate that Abalign achieves comparable or even better accuracy than state-of-the-art MSA tools, and shows remarkable advantages in terms of speed and memory consumption, reducing the time required for high-throughput analysis from weeks to hours. In addition to its alignment capabilities, Abalign offers a broad range of BCR analysis features, including extracting BCRs, constructing lineage trees, assigning VJ genes, analyzing clonotypes, profiling mutations, and comparing BCR immune repertoires. With its user-friendly graphic interface, Abalign can be easily run on personal computers instead of computing clusters. Overall, Abalign is an easy-to-use and effective tool that enables researchers to analyze massive BCR/antibody sequences, leading to new discoveries in the field of immunoinformatics. The software is freely available at http://cao.labshare.cn/abalign/.

Research on Comprehensive Evaluation and Early Warning of Transmission Lines' Operation Status Based on Dynamic Cloud Computing.

The current methods for evaluating the operating condition of electricity transmission lines (ETLs) and providing early warning have several problems, such as the low correlation of data, ignoring the influence of seasonal factors, and strong subjectivity. This paper analyses the sensitive factors that influence dynamic key evaluation indices such as grounding resistance, sag, and wire corrosion, establishes the evaluation criteria of the ETL operation state, and proposes five ETL status levels and seven principles for selecting evaluation indices. Nine grade I evaluation indices and twenty-nine grade II evaluation indices, including passageway and meteorological environments, are determined. The cloud model theory is embedded and used to propose a warning technology for the operation state of ETLs based on inspection defect parameters and the cloud model. Combined with the inspection defect parameters of a line in the Baicheng district of Jilin Province and the critical evaluation index data such as grounding resistance, sag, and wire corrosion, which are used to calculate the timeliness of the data, the solid line is evaluated. The research shows that the dynamic evaluation model is correct and that the ETL status evaluation and early warning method have reasonable practicability.

Associations between maternal urinary isoflavone concentrations and anogenital distance of offspring throughout infancy: a prospective cohort study.

STUDY QUESTION: Are maternal urinary isoflavone (ISO) concentrations during pregnancy associated with anogenital distance (AGD) in infants at birth, and at 6 and 12 months of age? SUMMARY ANSWER: Higher maternal urinary ISO concentrations during pregnancy were associated with longer AGD in infants of both sexes, and equol (EQU) and daidzein (DAD) were identified as the important ISO mixture components in the observed associations. WHAT IS KNOWN ALREADY: Evidence of the association of prenatal exposure to ISO with offspring's AGD is mainly derived from animal studies, which used different study designs and had inconsistent results. Only one human study has been reported and it found null associations between maternal ISO exposure during pregnancy and AGD among boys at birth, with a small sample size and a wide range of exposure windows. No human study on girls was found. STUDY DESIGN, SIZE, DURATION: Prospective cohort study (Shanghai-Minhang Birth Cohort Study), with pregnant women recruited at 12-16 weeks of gestation in Shanghai, China between April and December 2012. One thousand two hundred and twenty-five live singletons were left in the cohort at delivery of which 480 mother-infant pairs had data on both maternal urinary ISO concentrations and at least one AGD measurement and were included in the present study. Anopenile distance (AGDAP) and anoscrotal distance (AGDAS) of boys and anoclitoral distance (AGDAC) and anofourchette distance (AGDAF) of girls were measured at birth and at 6 and 12 months of age. PARTICIPANTS/MATERIALS, SETTING, METHODS: Multiple linear regression models were used to examine the associations between maternal ISO concentrations and AGD. Bayesian kernel machine regression (BKMR) was implemented to examine both the overall effects of ISO mixture and the single effect of each ISO and identify important components of ISO mixture. MAIN RESULTS AND THE ROLE OF CHANCE: A general profile of higher concentrations of maternal ISO associated with longer AGD in infants of both sexes was observed, when maternal education, parity, BMI before pregnancy (BMI, categorical variable), passive smoking during early pregnancy, age at delivery, gestational weeks and infant body size were adjusted for. Among boys, EQU was associated with increased AGDAS at birth and at 6 and 12 months, and DAD was associated with increased AGDAP at birth. Among girls, the associations of EQU and DAD with increased AGDAC and AGDAF at birth were found. When gestational weight gain and feeding patterns of infants in the first 6 months were additionally adjusted for, and maternal BMI was adjusted for as a continuous variable, more pronounced associations were observed, especially for associations of genistein (GEN), DAD and glycitein (GLY) with increased AGDAP and AGDAS at 6 months in boys. However, these associations were not always observed in the highest tertile group, and no consistent dose-response relationships were found. Similar results were observed in BKMR models, showing positive correlations of concentration of ISO mixture with increased AGDAS at both 6 and 12 months among boys, and increased AGDAC and AGDAF at birth among girls. Statistically significant increments of 4.96 mm (95% credible interval (CrI): 1.40, 8.52) and 1.07 mm (95% CrI: 0.02, 2.13) in AGDAS at 6 months among boys and AGDAC at birth among girls, respectively, were observed at the 75th percentile of ISO mixture, compared with 25th percentile. EQU and DAD were identified as the important components among ISO-AGD associations. LIMITATIONS, REASONS FOR CAUTION: First, due to the short half-lives of ISO, the accuracy of a single spot urine sample reflecting ISO exposure during pregnancy may be limited, and thus may cause non-differential misclassification. Second, despite the adjustments for several important covariates in the study, unmeasured and residual confounding factors may remain a concern. Third, false discovery due to multiple testing may remain. Finally, the reduced sample sizes attributed to the loss of follow-up and missing data of confounders may limit our ability to detect an association, if any existed. WIDER IMPLICATIONS OF THE FINDINGS: Prenatal ISO exposure may affect the reproductive development of offspring. As ISO can be widely detected in pregnant women, especially in Eastern countries, more studies are warranted to provide evidence of the effects of prenatal ISO exposure on long-term reproductive outcomes. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the National Key Research and Development Program of China (2021YFC2701003), the National Natural Science Foundation of China (22076123), the Science and Technology Commission of Shanghai Municipality (21ZR1454700 and 20ZR1448000), the Shanghai Municipal Health Commission (20194Y0160) and Innovation-oriented Science and Technology Grant from NHC Key Laboratory of Reproduction Regulation (CX2022-04). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

DrugRep: an automatic virtual screening server for drug repurposing.

Computationally identifying new targets for existing drugs has drawn much attention in drug repurposing due to its advantages over de novo drugs, including low risk, low costs, and rapid pace. To facilitate the drug repurposing computation, we constructed an automated and parameter-free virtual screening server, namely DrugRep, which performed molecular 3D structure construction, binding pocket prediction, docking, similarity comparison and binding affinity screening in a fully automatic manner. DrugRep repurposed drugs not only by receptor-based screening but also by ligand-based screening. The former automatically detected possible binding pockets of the receptor with our cavity detection approach, and then performed batch docking over drugs with a widespread docking program, AutoDock Vina. The latter explored drugs using seven well-established similarity measuring tools, including our recently developed ligand-similarity-based methods LigMate and FitDock. DrugRep utilized easy-to-use graphic interfaces for the user operation, and offered interactive predictions with state-of-the-art accuracy. We expect that this freely available online drug repurposing tool could be beneficial to the drug discovery community. The web site is http://cao.labshare.cn/drugrep/ .

Controlled Construction of Heteroleptic [Pd2 (LA )2 (LB )(LC )]4+ Cages: A Facile Approach for Site-Selective endo-Functionalization of Supramolecular Cavities.

Construction of supramolecular structures with internal functionalities is a promising approach to build enzyme-like cavities. The endo-functionalized [Pd12 L24 ] and [Pd2 L4 ] coordination cages represent the most successful systems in this regard. However, these systems mainly contain one type of endo-moiety. We herein provide a solution for the controlled endo-functionalization of [Pd2 L4 ] cages. Site-selective introduction of the endo-functional group was achieved through the formation of heteroleptic [Pd2 (LA )2 (LB )(LC )] cages. Using two orthogonal steric control elements is the key for the selective formation of the hetero-assemblies. We demonstrated the construction of two hetero-cages with a single internal functional group as well as a hetero-cage with two distinct endohedral functionalities. The endo-functionalized hetero-cages bound sulfonate guests with fast-exchange dynamics. This strategy provides a new solution for the controlled endo-functionalization of supramolecular cavities.

Extensive Adaptive Variation in Gene Expression within and between Closely Related Horseshoe Bats (Chiroptera, Rhinolophus) Revealed by Three Organs.

In the process of species differentiation and adaption, the relative influence of natural selection on gene expression variation often remains unclear (especially its impact on phenotypic divergence). In this study, we used differentially expressed genes from brain, cochlea, and liver samples collected from two species of bats to determine the gene expression variation forced by natural selection when comparing at the interspecific (Rhinolophus siamensis and R. episcopus episcopus) and the intraspecific (R. e. episcopus and R. episcopus spp.) levels. In both cases, gene expression variation was extensively adaptive (>66.0%) and mainly governed by directional selection, followed by stabilizing selection, and finally balancing selection. The expression variation related to acoustic signals (resting frequency, RF) and body size (forearm length, FA) was also widely governed by natural selection (>69.1%). Different functional patterns of RF- or FA-related adaptive expression variation were found between the two comparisons, which manifested as abundant immune-related regulations between subspecies (indicating a relationship between immune response and phenotypic adaption). Our study verifies the extensive adaptive expression variation between both species and subspecies and provides insight into the effects of natural selection on species differentiation and adaptation as well as phenotypic divergence at the expression level.

Paraquat is an agonist of STIM1 and increases intracellular calcium levels.

Paraquat (PQ) is an efficient herbicide but leads to high mortality with no antidote in mammals. PQ produces reactive oxygen species (ROS), leading to epithelial-mesenchymal transition (EMT) for pulmonary fibrosis in type II alveolar (AT II) cells. Intriguingly, strategies reducing ROS exhibit limited therapeutic effects, indicating other targets existing for PQ toxicity. Herein we report that PQ is also an agonist for STIM1 that increases intracellular calcium levels. Particularly, PQ promotes STIM1 puncta formation and association with TRPC1 or ORAI for extracellular calcium entry and thus intracellular calcium influx. Further studies reveal the importance of P584&Y586 residues in STIM1 for PQ association that facilitates STIM1 binding to TRPC1. Consequently, the STIM1-TRPC1 route facilitates PQ-induced EMT for pulmonary fibrosis as well as cell death. Our results demonstrate that PQ is an agonist of STIM1 that induces extracellular calcium entry, increases intracellular calcium levels, and thus promotes EMT in AT II cells.

Identification of prognostic gene expression signatures based on the tumor microenvironment characterization of gastric cancer.

Increasing evidence has elucidated that the tumor microenvironment (TME) shows a strong association with tumor progression and therapeutic outcome. We comprehensively estimated the TME infiltration patterns of 111 gastric cancer (GC) and 21 normal stomach mucosa samples based on bulk transcriptomic profiles based on which GC could be clustered as three subtypes, TME-Stromal, TME-Mix, and TME-Immune. The expression data of TME-relevant genes were utilized to build a GC prognostic model-GC_Score. Among the three GC TME subtypes, TME-Stomal displayed the worst prognosis and the highest GC_Score, while TME-Immune had the best prognosis and the lowest GC_Score. Connective tissue growth factor (CTGF), the highest weighted gene in the GC_Score, was found to be overexpressed in GC. In addition, CTGF exhibited a significant correlation with the abundance of fibroblasts. CTGF has the potential to induce transdifferentiation of peritumoral fibroblasts (PTFs) to cancer-associated fibroblasts (CAFs). Beyond characterizing TME subtypes associated with clinical outcomes, we correlated TME infiltration to molecular features and explored their functional relevance, which helps to get a better understanding of carcinogenesis and therapeutic response and provide novel strategies for tumor treatments.

Exploring Tumor Immune Microenvironment and Its Associations With Molecular Characteristics in Melanoma.

Background: The tumor microenvironment (TME), which involves infiltration of multiple immune cells into the tumor tissues, plays an essential role in clinical benefit to therapy. The chemokines and their receptors influence migration and functions of both tumor and immune cells. Also, molecular characteristics are associated with the efficacy of melanoma therapy. However, there lacked exploration of immune characteristics and the association with molecular characteristics. Methods: We collected the currently available 569 melanoma samples that had both the genomic and transcriptional data from TCGA and SRA databases. We first identified TME subtypes based on the developed immune signatures, and then divided the samples into two immune cohorts based on the immune score. Next, we estimated the compositions of the immune cells of the two cohorts, and performed differential expression genes (DEGs) and functional enrichments. In addition, we investigated the interactions of chemokines and their receptors under immune cells. Finally, we explored the genomic characteristics under different immune subtypes. Results: TME type D had a better prognosis among the four subtypes. The high-immunity cohort had significantly high 16 immune cells. The 63 upregulated and 384 downregulated genes in the high-immunity cohort were enriched in immune-related biological processes, and keratin, pigmentation and epithelial cells, respectively. The correlations of chemokines and their receptors with immune cell infiltration, such as CCR5-CCL4/CCL5 and CXCR3-CXCL9/CXCL10/CXCL11/CXCL13 axis, showed that the recruitments of 11 immune cells, such as CD4T cells and CD8T cells, were modulated by chemokines and their receptors. The proportions of the four TME subtypes in each molecular subtype were comparable. The two driver genes, CDKN2A and PRB2, had significantly different MAFs between the high-immunity and low-immunity. Conclusion: We dissected the characteristics of immune infiltration, the interactions of chemokines and their receptors under immune cells, and the correlation of molecular and immune characteristics. Our work will enable the reasonable selection of anti-melanoma treatments and accelerate the development of new therapeutic strategies for melanoma.

Skin Microbiota Variation Among Bat Species in China and Their Potential Defense Against Pathogens.

Host-associated skin bacteria are essential for resisting pathogen infections and maintaining health. However, we have little understanding of how chiropteran skin microbiota are distributed among bat species and their habitats, or of their putative roles in defending against Pseudogymnoascus destructans in China. In this study, we characterized the skin microbiomes of four bat species at five localities using 16S rRNA gene amplicon sequencing to understand their skin microbial composition, structure, and putative relationship with disease. The alpha- and beta-diversities of skin microbiota differed significantly among the bat species, and the differences were affected by environmental temperature, sampling sites, and host body condition. The chiropteran skin microbial communities were enriched in bacterial taxa that had low relative abundances in the environment. Most of the potential functions of skin microbiota in bat species were associated with metabolism. Focusing on their functions of defense against pathogens, we found that skin microbiota could metabolize a variety of active substances that could be potentially used to fight P. destructans. The skin microbial communities of bats in China are related to the environment and the bat host, and may be involved in the host's defense against pathogens.

Performance characterization of PCR-free whole genome sequencing for clinical diagnosis.

ABSTRACT: To evaluate the performance of polymerase chain reaction (PCR)-free whole genome sequencing (WGS) for clinical diagnosis, and thereby revealing how experimental parameters affect variant detection.Five NA12878 samples were sequenced using MGISEQ-2000. NA12878 samples underwent WGS with differing deoxyribonucleic acid (DNA) input and library preparation protocol (PCR-based vs PCR-free protocols for library preparation). The depth of coverage and genotype quality of each sample were compared. The performance of each sample was measured for sensitivity, coverage of depth and breadth of coverage of disease-related genes, and copy number variants. We also developed a systematic WGS pipeline (PCR-free) for the analysis of 11 clinical cases.In general, NA12878-2 (PCR-free WGS) showed better depth of coverage and genotype quality distribution than NA12878-1 (PCR-based WGS). With a mean depth of ∼40×, the sensitivity of homozygous and heterozygous single nucleotide polymorphisms (SNPs) of NA12878-2 showed higher sensitivity (>99.77% and >99.82%) than NA12878-1, and positive predictive value exceeded 99.98% and 99.07%. The sensitivity and positive predictive value of homozygous and heterozygous indels for NA12878-2 (PCR-free WGS) showed great improvement than NA128878-1. The breadths of coverage for disease-related genes and copy number variants are slightly better for samples with PCR-free library preparation protocol than the sample with PCR-based library preparation protocol. DNA input also influences the performance of variant detection in samples with PCR-free WGS. All the 19 previously confirmed variants in 11 clinical cases were successfully detected by our WGS pipeline (PCR free).Different experimental parameters may affect variant detection for clinical WGS. Clinical scientists should know the range of sensitivity of variants for different methods of WGS, which would be useful when interpreting and delivering clinical reports.

AADAC promotes therapeutic activity of cisplatin and imatinib against ovarian cancer cells.

OBJECTIVE: To explore how AADAC functions in the malignant progression of ovarian cancer, and the effect of AADAC on drug therapeutic activity against ovarian cancer cells. METHODS: AADAC level in tumor and normal samples from TCGA-OV dataset and its survival significance were analyzed by bioinformatics methods. Signaling pathway enrichment analysis for the high- and low-AADAC patients was achieved by using GSEA software. AADAC expression in the cell lines with different treatments was evaluated via qRT-PCR. Cell proliferative ability was assessed via MTT assay Cell migratory and invasive abilities were evaluated via transwell assay. Angiogenesis assay was performed to examine the angiogenetic ability. RESULTS: AADAC was upregulated in ovarian cancer tissues, and patients with high expression of AADAC had favorable survival conditions compared to the low AADAC expression ones. Overexpression of AADAC inhibited the malignant progression of ovarian cancer cells. Both cisplatin and imatinib suppressed cancer cell malignant progression, while overexpressed AADAC synergistically enhanced such inhibition. CONCLUSIONS: The study demonstrated that AADAC could somehow suppress the malignant progression of ovarian cancer, especially at the cellular level. In addition, synergic tumor-inhibitory effects between AADAC and the anti-cancer drugs were identified. All the above results proposed a novel idea and candidate biomarker for ovarian cancer therapy.

The dynamic alteration of transcriptional regulation by crucial TFs during tumorigenesis of gastric cancer.

BACKGROUND: The mechanisms of Gastric cancer (GC) initiation and progression are complicated, at least partly owing to the dynamic changes of gene regulation during carcinogenesis. Thus, investigations on the changes in regulatory networks can improve the understanding of cancer development and provide novel insights into the molecular mechanisms of cancer. METHODS: Differential co-expression analysis (DCEA), differential gene regulation network (GRN) modeling and differential regulation analysis (DRA) were integrated to detect differential transcriptional regulation events between gastric normal mucosa and cancer samples based on GSE54129 dataset. Cytological experiments and IHC staining assays were used to validate the dynamic changes of CREB1 regulated targets in different stages. RESULTS: A total of 1955 differentially regulated genes (DRGs) were identified and prioritized in a quantitative way. Among the top 1% DRGs, 14 out of 19 genes have been reported to be GC relevant. The four transcription factors (TFs) among the top 1% DRGs, including CREB1, BPTF, GATA6 and CEBPA, were regarded as crucial TFs relevant to GC progression. The differentially regulated links (DRLs) around the four crucial TFs were then prioritized to generate testable hypotheses on the differential regulation mechanisms of gastric carcinogenesis. To validate the dynamic alterations of gene regulation patterns of crucial TFs during GC progression, we took CREB1 as an example to screen its differentially regulated targets by using cytological and IHC staining assays. Eventually, TCEAL2 and MBNL1 were proved to be differentially regulated by CREB1 during tumorigenesis of gastric cancer. CONCLUSIONS: By combining differential networking information and molecular cell experiments verification, testable hypotheses on the regulation mechanisms of GC around the core TFs and their top ranked DRLs were generated. Since TCEAL2 and MBNL1 have been reported to be potential therapeutic targets in SCLC and breast cancer respectively, their translation values in GC are worthy of further investigation.