Blood molecular markers associated with COVID-19 immunopathology and multi-organ damage.

COVID-19 is characterized by dysregulated immune responses, metabolic dysfunction and adverse effects on the function of multiple organs. To understand host responses to COVID-19 pathophysiology, we combined transcriptomics, proteomics, and metabolomics to identify molecular markers in peripheral blood and plasma samples of 66 COVID-19-infected patients experiencing a range of disease severities and 17 healthy controls. A large number of expressed genes, proteins, metabolites, and extracellular RNAs (exRNAs) exhibit strong associations with various clinical parameters. Multiple sets of tissue-specific proteins and exRNAs varied significantly in both mild and severe patients suggesting a potential impact on tissue function. Chronic activation of neutrophils, IFN-I signaling, and a high level of inflammatory cytokines were observed in patients with severe disease progression. In contrast, COVID-19-infected patients experiencing milder disease symptoms showed robust T-cell responses. Finally, we identified genes, proteins, and exRNAs as potential biomarkers that might assist in predicting the prognosis of SARS-CoV-2 infection. These data refine our understanding of the pathophysiology and clinical progress of COVID-19.

Molecular Profiling Provides Clinical Insights Into Targeted and Immunotherapies as Well as Colorectal Cancer Prognosis.

BACKGROUND & AIMS: Tumor genetic testing is indispensable in the management of primary and metastatic colorectal cancer (CRC), yet the indications for genomics-guided precision medicine and immunotherapy must be better understood and defined. METHODS: We prospectively sequenced tumors from 869 Chinese patients with CRC by a large panel and evaluated the clinical significance of single-gene somatic mutations and co-occurring events in metastatic CRC, as well as their functional effects and tumorigenic mechanisms. We systematically assessed the heterogeneity of the tumor immune microenvironment in different genomic contexts through the combined analysis of Immunoscore, multiplex immunostaining, whole-exome sequencing, transcriptome, and single-cell sequencing. RESULTS: Single-gene somatic mutations in BRAF or RBM10 were associated with shorter progression-free survival in patients with metastatic CRC. Functional studies suggested RBM10 acts as a tumor suppressor in CRC development. Co-mutations of KRAS/AMER1 or KRAS/APC were enriched in the metastatic cohort, which had poor progression-free survival and did not benefit from bevacizumab due to accelerated drug metabolism. Forty patients (4.6%) carried pathogenic or likely pathogenic germline alterations in the DNA damage repair pathway and 37.5% of these tumors had secondary-hit events with loss of heterozygosity or biallelic alterations. A high tumor insertion or deletion burden with high microsatellite instability suggested immunogenicity with numerous activated tumor-infiltrating lymphocytes, whereas polymerase epsilon exonuclease mutation with ultrahigh tumor mutation burden indicated a relatively quiescent immunophenotype. The heterogeneous genomic-immunologic interactions were reflected in the divergent neoantigen presentation and depletion, immune checkpoint expression, PD-1/PD-L1 interaction, and T-cell responsiveness to pembrolizumab. CONCLUSIONS: Our integrated analysis provides insights into CRC prognostic stratification, drug response, and personalized genomics-guided targeted and immunotherapies.

Chronic PM2.5 exposure disrupts intestinal barrier integrity via microbial dysbiosis-triggered TLR2/5-MyD88-NLRP3 inflammasome activation.

BACKGROUND: PM2.5, a known public health risk, is increasingly linked to intestinal disorders, however, the mechanisms of its impact are not fully understood. PURPOSE: This study aimed to explore the impact of chronic PM2.5 exposure on intestinal barrier integrity and to uncover the underlying molecular mechanisms. METHODS: C57BL/6 J mice were exposed to either concentrated ambient PM2.5 (CPM) or filtered air (FA) for six months to simulate urban pollution conditions. We evaluated intestinal barrier damage, microbial shifts, and metabolic changes through histopathology, metagenomics, and metabolomics. Analysis of the TLR signaling pathway was also conducted. RESULTS: The mean concentration of PM2.5 in the CPM exposure chamber was consistently measured at 70.9 ± 26.8 µg/m³ throughout the study period. Our findings show that chronic CPM exposure significantly compromises intestinal barrier integrity, as indicated by reduced expression of the key tight junction proteins Occludin and Tjp1/Zo-1. Metagenomic sequencing revealed significant shifts in the microbial landscape, identifying 35 differentially abundant species. Notably, there was an increase in pro-inflammatory nongastric Helicobacter species and a decrease in beneficial bacteria, such as Lactobacillus intestinalis, Lactobacillus sp. ASF360, and Eubacterium rectale. Metabolomic analysis further identified 26 significantly altered metabolites commonly associated with intestinal diseases. A strong correlation between altered bacterial species and metabolites was also observed. For example, 4 Helicobacter species all showed positive correlations with 13 metabolites, including Lactate, Bile acids, Pyruvate and Glutamate. Additionally, increased expression levels of TLR2, TLR5, Myd88, and NLRP3 proteins were noted, and their expression patterns showed a strong correlation, suggesting a possible involvement of the TLR2/5-MyD88-NLRP3 signaling pathway. CONCLUSIONS: Chronic CPM exposure induces intestinal barrier dysfunction, microbial dysbiosis, metabolic imbalance, and activation of the TLR2/5-MyD88-NLRP3 inflammasome. These findings highlight the urgent need for intervention strategies to mitigate the detrimental effects of air pollution on intestinal health and identify potential therapeutic targets.

Functional consequences of a rare missense BARD1 c.403G>A germline mutation identified in a triple-negative breast cancer patient.

We identified a rare missense germline mutation in BARD1 (c.403G>A or p.Asp135Asn) as pathogenic using integrated genomics and transcriptomics profiling of germline and tumor samples from an early-onset triple-negative breast cancer patient who later was administrated with a PARP inhibitor for 2 months. We demonstrated in cell and mouse models that, compared to the wild-type, (1) c.403G>A mutant cell lines were more sensitive to irradiation, a DNA damage agent, and a PARP inhibitor; (2) c.403G>A mutation inhibited interaction between BARD1 and RAD51 (but not BRCA1); and (3) c.403G>A mutant mice were hypersensitive to ionizing radiation. Our study shed lights on the clinical interpretation of rare germline mutations of BARD1.

PreMedKB: an integrated precision medicine knowledgebase for interpreting relationships between diseases, genes, variants and drugs.

One important aspect of precision medicine aims to deliver the right medicine to the right patient at the right dose at the right time based on the unique 'omics' features of each individual patient, thus maximizing drug efficacy and minimizing adverse drug reactions. However, fragmentation and heterogeneity of available data makes it challenging to readily obtain first-hand information regarding some particular diseases, drugs, genes and variants of interest. Therefore, we developed the Precision Medicine Knowledgebase (PreMedKB) by seamlessly integrating the four fundamental components of precision medicine: diseases, genes, variants and drugs. PreMedKB allows for search of comprehensive information within each of the four components, the relationships between any two or more components, and importantly, the interpretation of the clinical meanings of a patient's genetic variants. PreMedKB is an efficient and user-friendly tool to assist researchers, clinicians or patients in interpreting a patient's genetic profile in terms of discovering potential pathogenic variants, recommending therapeutic regimens, designing panels for genetic testing kits, and matching patients for clinical trials. PreMedKB is freely accessible and available at http://www.fudan-pgx.org/premedkb/index.html#/home.

ECCDIA: an interactive web tool for the comprehensive analysis of clinical and survival data of esophageal cancer patients.

BACKGROUND: Esophageal cancer (EC) is considered as one of the deadliest malignancies with respect to incidence and mortality rate, and numerous risk factors may affect the prognosis of EC patients. For better understanding of the risk factors associated with the onset and prognosis of this malignancy, we develop an interactive web-based tool for the convenient analysis of clinical and survival characteristics of EC patients. METHODS: The clinical data were obtained from The Surveillance, Epidemiology, and End Results (SEER) database. Seven analysis and visualization modules were built with Shiny. RESULTS: The Esophageal Cancer Clinical Data Interactive Analysis (ECCDIA, http://webapps.3steps.cn/ECCDIA/ ) was developed to provide basic data analysis, visualization, survival analysis, and nomogram of the overall group and subgroups of 77,273 EC patients recorded in SEER. The basic data analysis modules contained distribution analysis of clinical factor ratios, Sankey plot analysis for relationships between clinical factors, and a map for visualizing the distribution of clinical factors. The survival analysis included Kaplan-Meier (K-M) analysis and Cox analysis for different subgroups of EC patients. The nomogram module enabled clinicians to precisely predict the survival probability of different subgroups of EC patients. CONCLUSION: ECCDIA provides clinicians with an interactive prediction and visualization tool for visualizing invaluable clinical and prognostic information of individual EC patients, further providing useful information for better understanding of esophageal cancer.

Surgical treatment for basilar invagination with irreducible atlantoaxial dislocation: transoral atlantoaxial reduction plate fixation vs occipitocervical fixation.

BACKGROUND: Transoral atlantoaxial reduction plate (TARP) fixation or occipitocervical fixation (OF) is an effective treatment for basilar invagination (BI) with irreducible atlantoaxial dislocation (IAAD). But, all current clinical studies involved a single surgical procedure. The clinical effects of TARP and OF operation for BI with IAAD have yet to be compared. We therefore present this report to compare the treatment of TARP and OF procedure for BI with IAAD. METHODS: Fifty-six patients with BI with IAAD who underwent TARP or OF operation from June 2011 to June 2017 were retrospectively analyzed. Among these, 35 patients underwent TARP operation (TARP group), and 21 patients underwent OF operation (OF group). We compared the difference of clinical, radiological, and surgical outcomes between the TARP and OF groups postoperatively. RESULTS: Compared with OF group, the operative time and blood loss in TARP group were lower. There was no statistical difference in the atlantodental interval (ADI), clivus canal angle (CCA), cervicomedullary angle (CMA), distance between the top of the odontoid process and the Chamberlain line (CL) and Japanese Orthopaedic Association (JOA) score between the TARP and OF groups preoperatively, but the improvements of these parameters in the TARP group were superior to those in the OF group postoperatively. The fusion rates were higher in the TARP group than those in the OF group at the early stage postoperatively. CONCLUSIONS: TARP and OF operations are effective surgical treatment for BI with IAAD, but the performance of reduction and decompression and earlier bone fusion rates of TARP procedure are superior to those of OF.

Commensal Microbes Affect Host Humoral Immunity to Bordetella pertussis Infection.

As important players in the host defense system, commensal microbes and the microbiota influence multiple aspects of host physiology. Bordetella pertussis infection is highly contagious among humans. However, the roles of the microbiota in B. pertussis pathogenesis are poorly understood. Here, we show that antibiotic-mediated depletion of the microbiota results in increased susceptibility to B. pertussis infection during the early stage. The increased susceptibility was associated with a marked impairment of the systemic IgG, IgG2a, and IgG1 antibody responses to B. pertussis infection after antibiotic treatment. Furthermore, the microbiota impacted the short-lived plasma cell responses as well as the recall responses of memory B cells to B. pertussis infection. Finally, we found that the dysbiosis caused by antibiotic treatment affects CD4+ T cell generation and PD-1 expression on CD4+ T cells and thereby perturbs plasma cell differentiation. Our results have revealed the importance of commensal microbes in modulating host immune responses to B. pertussis infection and support the possibility of controlling the severity of B. pertussis infection in humans by manipulating the microbiota.

MicroRNA-302d promotes the proliferation of human pluripotent stem cell-derived cardiomyocytes by inhibiting LATS2 in the Hippo pathway.

Recent evidence has shown that cardiomyocytes (CMs) can proliferate at a low level after myocardial infarction (MI), but it is insufficient to reestablish heart function. Several microRNAs (miRNAs) have been proven to sufficiently induce rodent CM proliferation. However, whether miRNAs identified in rodents can promote human CM proliferation is unknown due to the poorly conserved functions of miRNAs among species. In the present study, we demonstrate that i) expression of microRNA-302d (miR-302d) decreased significantly during CM differentiation from human pluripotent stem cells (hPSCs) from day 4 to day 18; ii) miR-302d efficiently promoted proliferation of hPSC-derived CMs; iii) miR-302d promoted CM proliferation by targeting LATS2 in the Hippo pathway; and iv) RNA-sequencing analysis revealed that overexpression of miR-302d induced changes in gene expression, which mainly converged on the cell cycle. Our study provides further evidence for the therapeutic potential of miR-302d.

Analysis of PD-1 related immune transcriptional profile in different cancer types.

BACKGROUND: Programmed cell death 1 (PD-1) functions as an immune checkpoint in the process of anti-tumor immune response. The PD-1 blockade is now becoming a fundamental part in cancer immunotherapy. So it's essential to elicit the PD-1 related immune process in different types of cancer. METHODS: The Cancer Genome Atlas was used to collect the RNA-seq data of 33 cancer types. The microenvironment cell populations-counter was used to analyze the immune cell infiltrates. KEGG and GO analysis were performed to investigate PD-1 associated biological process. Kaplan-Meier survival curves and Cox's proportional hazards model were performed for prognostic value analysis. RESULTS: We demonstrated that PD-1 expression varied in different cancer types. The uveal melanoma had a low PD-1 expression and poor infiltrated with immune cells. But it showed the strong correlation of PD-1 with the most types of immune cells. The PD-1 demonstrated a robust relationship with other immunomodulators and showed its involvement in critical functions correlated with anti-tumor immune pathways. Survival analysis indicated the PD-1 expression suggested different prognosis in different cancer types. CONCLUSIONS: Our investigations promote a better understanding of the PD-1 blockade and provide PD-1 related personized combined immunotherapy for different types of cancer patients.

rNMPID: a database for riboNucleoside MonoPhosphates in DNA.

Motivation: Ribonucleoside monophosphates (rNMPs) are the most abundant non-standard nucleotides embedded in genomic DNA. If the presence of rNMP in DNA cannot be controlled, it can lead to genome instability. The actual regulatory functions of rNMPs in DNA remain mainly unknown. Considering the association between rNMP embedment and various diseases and cancer, the phenomenon of rNMP embedment in DNA has become a prominent area of research in recent years. Results: We introduce the rNMPID database, which is the first database revealing rNMP-embedment characteristics, strand bias, and preferred incorporation patterns in the genomic DNA of samples from bacterial to human cells of different genetic backgrounds. The rNMPID database uses datasets generated by different rNMP-mapping techniques. It provides the researchers with a solid foundation to explore the features of rNMP embedded in the genomic DNA of multiple sources, and their association with cellular functions, and, in future, disease. It also significantly benefits researchers in the fields of genetics and genomics who aim to integrate their studies with the rNMP-embedment data. Availability and implementation: rNMPID is freely accessible on the web at https://www.rnmpid.org.

miR-29a-5p rescues depressive-like behaviors in a CUMS-induced mouse model by facilitating microglia M2-polarization in the prefrontal cortex via TMEM33 suppression.

BACKGROUND: Depression accounts for a high proportion of neuropsychiatric disorders and is associated with abnormal states of neurons in specific brain regions. Microglia play a pivotal role in the inflammatory state during depression development; however, the exact mechanism underlying chronic mood states remains unknown. Thus, the present study aimed to determine whether microRNAs (miRNAs) alleviate stress-induced depression-like behavior in mice by regulating the expression levels of their target genes, explore the role of neuroinflammation induced by microglial activation in the pathogenesis and progression of depression, and determine whether the role of the miR-29a-5p/transmembrane protein 33 (TMEM33) axis. METHODS: In this study, chronic unpredictable mild stress (CUMS) mouse depression model, various behavioral tests, western blotting, dual-luciferase reporter assay, enzyme-linked immunosorbent assay, real-time quantitative reverse transcription PCR, immunofluorescence and lentivirus-mediated gene transfer were used. RESULTS: After exposure to the CUMS paradigm, miR-29a-5p was significantly down-regulated. This downregulation subsequently promoted the polarization of microglia M1 by upregulating the expression of TMEM33, resulting in enhanced inflammatory chemokines affecting neurons. Conversely, the upregulation of miR-29a-5p within the prefrontal cortex (PFC) suppressed TMEM33 expression, facilitated microglia M2-polarization, and ameliorated depressive-like behavior. LIMITATIONS: Only rodent models of depression were used, and human samples were not included. CONCLUSIONS: The results of this study suggest that miR-29a-5p deficits within the PFC mediate microglial anomalies and contribute to depressive-like behaviors. miR-29a-5p and TMEM33 may, therefore, serve as potential therapeutic targets for the treatment of depression.

Mechanism of miR-98-5p in gastric cancer cell proliferation, migration, and invasion through the USP44/CTCFL axis.

Objectives: Gastric cancer (GC) is the leading digestive malignancy with high incidence and mortality rate. microRNAs (miRs) play an important role in GC progresssion. This study aimed to investigate the effect of miR-98-5p on proliferation, migration, and invasion of GC cells. Methods: The expression levels of miR-98-5p, ubiquitin specific peptidase 44 (USP44), and CCCTCbinding factor-like (CTCFL) in GC tissues and cells were identified using reversetranscription quantitative polymerase chain reaction and Western blot assay. The relationship between miR-98-5p expression/USP44 and the clinicopathological features in GC patients was analyzed. GC cell proliferation, invasion, and migration were evaluated by cell counting kit-8 and clone formation assays and Transwell assays. The bindings of miR-98-5p to USP44 and USP44 to CTCFL were examined using dualluciferase assay and co-immunoprecipitation. GC cells were treated with MG132 and the ubiquitination level of CTCFL was examined using ubiquitination assay. Rescue experiments were performed to verify the roles of USP44 and CTCFL in GC cells. Results: miR-98-5p was downregulated in GC. miR-98-5p overexpression inhibited the proliferation, migration, and invasion of GC cells. miR-98-5p inhibited USP44 expression. USP44 bound to CTCFL and limited ubiquitination degradation of CTCFL. Overexpression of USP44 and CTCFL attenuated the inhibitory effects of miR-98-5p overexpression on GC cell progression. Conclusion: miR-98-5p overexpression limited USP44-mediated CTCFL deubiquitination, and suppressed CTCFL expression, mitigating GC cell proliferation, migration, and invasion.

Deep learning framework for comprehensive molecular and prognostic stratifications of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype. Molecular stratification and target therapy bring clinical benefit for TNBC patients, but it is difficult to implement comprehensive molecular testing in clinical practice. Here, using our multi-omics TNBC cohort (N = 425), a deep learning-based framework was devised and validated for comprehensive predictions of molecular features, subtypes and prognosis from pathological whole slide images. The framework first incorporated a neural network to decompose the tissue on WSIs, followed by a second one which was trained based on certain tissue types for predicting different targets. Multi-omics molecular features were analyzed including somatic mutations, copy number alterations, germline mutations, biological pathway activities, metabolomics features and immunotherapy biomarkers. It was shown that the molecular features with therapeutic implications can be predicted including the somatic PIK3CA mutation, germline BRCA2 mutation and PD-L1 protein expression (area under the curve [AUC]: 0.78, 0.79 and 0.74 respectively). The molecular subtypes of TNBC can be identified (AUC: 0.84, 0.85, 0.93 and 0.73 for the basal-like immune-suppressed, immunomodulatory, luminal androgen receptor, and mesenchymal-like subtypes respectively) and their distinctive morphological patterns were revealed, which provided novel insights into the heterogeneity of TNBC. A neural network integrating image features and clinical covariates stratified patients into groups with different survival outcomes (log-rank P < 0.001). Our prediction framework and neural network models were externally validated on the TNBC cases from TCGA (N = 143) and appeared robust to the changes in patient population. For potential clinical translation, we built a novel online platform, where we modularized and deployed our framework along with the validated models. It can realize real-time one-stop prediction for new cases. In summary, using only pathological WSIs, our proposed framework can enable comprehensive stratifications of TNBC patients and provide valuable information for therapeutic decision-making. It had the potential to be clinically implemented and promote the personalized management of TNBC.

Quartet metabolite reference materials for inter-laboratory proficiency test and data integration of metabolomics profiling.

BACKGROUND: Various laboratory-developed metabolomic methods lead to big challenges in inter-laboratory comparability and effective integration of diverse datasets. RESULTS: As part of the Quartet Project, we establish a publicly available suite of four metabolite reference materials derived from B lymphoblastoid cell lines from a family of parents and monozygotic twin daughters. We generate comprehensive LC-MS-based metabolomic data from the Quartet reference materials using targeted and untargeted strategies in different laboratories. The Quartet multi-sample-based signal-to-noise ratio enables objective assessment of the reliability of intra-batch and cross-batch metabolomics profiling in detecting intrinsic biological differences among the four groups of samples. Significant variations in the reliability of the metabolomics profiling are identified across laboratories. Importantly, ratio-based metabolomics profiling, by scaling the absolute values of a study sample relative to those of a common reference sample, enables cross-laboratory quantitative data integration. Thus, we construct the ratio-based high-confidence reference datasets between two reference samples, providing "ground truth" for inter-laboratory accuracy assessment, which enables objective evaluation of quantitative metabolomics profiling using various instruments and protocols. CONCLUSIONS: Our study provides the community with rich resources and best practices for inter-laboratory proficiency tests and data integration, ensuring reliability of large-scale and longitudinal metabolomic studies.

Integrated multiomic profiling of breast cancer in the Chinese population reveals patient stratification and therapeutic vulnerabilities.

Molecular profiling guides precision treatment of breast cancer; however, Asian patients are underrepresented in publicly available large-scale studies. We established a comprehensive multiomics cohort of 773 Chinese patients with breast cancer and systematically analyzed their genomic, transcriptomic, proteomic, metabolomic, radiomic and digital pathology characteristics. Here we show that compared to breast cancers in white individuals, Asian individuals had more targetable AKT1 mutations. Integrated analysis revealed a higher proportion of HER2-enriched subtype and correspondingly more frequent ERBB2 amplification and higher HER2 protein abundance in the Chinese HR+HER2+ cohort, stressing anti-HER2 therapy for these individuals. Furthermore, comprehensive metabolomic and proteomic analyses revealed ferroptosis as a potential therapeutic target for basal-like tumors. The integration of clinical, transcriptomic, metabolomic, radiomic and pathological features allowed for efficient stratification of patients into groups with varying recurrence risks. Our study provides a public resource and new insights into the biology and ancestry specificity of breast cancer in the Asian population, offering potential for further precision treatment approaches.

Extend the benchmarking indel set by manual review using the individual cell line sequencing data from the Sequencing Quality Control 2 (SEQC2) project.

Accurate indel calling plays an important role in precision medicine. A benchmarking indel set is essential for thoroughly evaluating the indel calling performance of bioinformatics pipelines. A reference sample with a set of known-positive variants was developed in the FDA-led Sequencing Quality Control Phase 2 (SEQC2) project, but the known indels in the known-positive set were limited. This project sought to provide an enriched set of known indels that would be more translationally relevant by focusing on additional cancer related regions. A thorough manual review process completed by 42 reviewers, two advisors, and a judging panel of three researchers significantly enriched the known indel set by an additional 516 indels. The extended benchmarking indel set has a large range of variant allele frequencies (VAFs), with 87% of them having a VAF below 20% in reference Sample A. The reference Sample A and the indel set can be used for comprehensive benchmarking of indel calling across a wider range of VAF values in the lower range. Indel length was also variable, but the majority were under 10 base pairs (bps). Most of the indels were within coding regions, with the remainder in the gene regulatory regions. Although high confidence can be derived from the robust study design and meticulous human review, this extensive indel set has not undergone orthogonal validation. The extended benchmarking indel set, along with the indels in the previously published known-positive set, was the truth set used to benchmark indel calling pipelines in a community challenge hosted on the precisionFDA platform. This benchmarking indel set and reference samples can be utilized for a comprehensive evaluation of indel calling pipelines. Additionally, the insights and solutions obtained during the manual review process can aid in improving the performance of these pipelines.

Optimization of SSVEP-BCI Virtual Reality Stereo Stimulation Parameters Based on Knowledge Graph.

The steady-state visually evoked potential (SSVEP) is an important type of BCI that has various potential applications, including in virtual environments using virtual reality (VR). However, compared to VR research, the majority of visual stimuli used in the SSVEP-BCI are plane stimulation targets (PSTs), with only a few studies using stereo stimulation targets (SSTs). To explore the parameter optimization of the SSVEP-BCI virtual SSTs, this paper presents a parameter knowledge graph. First, an online VR stereoscopic stimulation SSVEP-BCI system is built, and a parameter dictionary for VR stereoscopic stimulation parameters (shape, color, and frequency) is established. The online experimental results of 10 subjects under different parameter combinations were collected, and a knowledge graph was constructed to optimize the SST parameters. The best classification performances of the shape, color, and frequency parameters were sphere (91.85%), blue (94.26%), and 13Hz (95.93%). With various combinations of virtual reality stereo stimulation parameters, the performance of the SSVEP-BCI varies. Using the knowledge graph of the stimulus parameters can help intuitively and effectively select appropriate SST parameters. The knowledge graph of the stereo target stimulation parameters presented in this work is expected to offer a way to convert the application of the SSVEP-BCI and VR.

Differences of molecular events driving pathological and radiological progression of lung adenocarcinoma.

BACKGROUND: Ground-glass opacity (GGO)-like lung adenocarcinoma (LUAD) has been detected increasingly in the clinic and its inert property and superior survival indicate unique biological characteristics. However, we do not know much about them, which hampers identification of key reasons for the inert property of GGO-like LUAD. METHODS: Using whole-exome sequencing and RNA sequencing, taking into account both radiological and pathological classifications of the same 197 patients concomitantly, we systematically interrogate genes driving the progression from GGO to solid nodule and potential reasons for the inertia of GGO. Using flow cytometry and IHC, we validated the abundance of immune cells and activity of cell proliferation. FINDINGS: Identifying the differences between GGO and solid nodule, we found adenocarcinoma in situ/minimally invasive adenocarcinoma (AIS/MIA) and GGO-like LUAD exhibited lower TP53 mutation frequency and less active cell proliferation-related pathways than solid nodule in LUAD. Identifying the differences in GGO between AIS/MIA and LUAD, we noticed that EGFR mutation frequency and CNV load were significantly higher in LUAD than in AIS/MIA. Regulatory T cell was also higher in LUAD, while CD8+ T cell decreased from AIS/MIA to LUAD. Finally, we constructed a transcriptomic signature to quantify the development from GGO to solid nodule, which was an independent predictor of patients' prognosis in 11 external LUAD datasets. INTERPRETATION: Our results provide deeper insights into the indolent nature of GGO and provide a molecular basis for the treatment of GGO-like LUAD. FUNDING: This study was supported in part by the National Natural Science Foundation of China (32170657), the National Natural Science Foundation of China (82203037), and Shanghai Sailing Program (22YF1408900).

Short- and Long-Term Outcomes of the Minimal Proximal Resection Margin in Total Gastrectomy for Siewert II Adenocarcinoma of the Esophagogastric Junction.

OBJECTIVE: This study aimed to investigate the feasibility of the minimal proximal resection margin (PRM) in total gastrectomy (TG) for Siewert II adenocarcinoma of the esophagogastric junction (AEG). METHODS: This study finally included 178 Siewert II advanced AEG patients who underwent TG from January 2017 to September 2020. According to the PRM length, patients were divided into 20-25 mm group and 30-35 mm group. Intraoperative, short-, and long-term postoperative outcomes were compared between two groups. RESULTS: The PRM of the 20-25 mm group had significantly less operation time compared with the PRM of the 30-35 mm group (P < .001), but the amount of blood loss, management of the diaphragmatic crura, and the incidence of positive resection margin were not significantly different between two groups (P > .05). In short-term postoperative outcomes, first gas-passing time, gastric-tube removal time, start time of diet, hospitalization, postoperative complications, and body weight loss were similar between two groups (P > .05). During the follow-up, the 3-year overall survival rates and the recurrence rates were not significantly different between the PRM of 20-25 mm and 30-35 mm groups (81.2% vs 83.5%, P = .695; 18.8% vs 15.5%, P = .812, respectively). CONCLUSION: With less operation time and more preserved esophagus, the minimal PRM length of 20-25 mm could be an appropriate option in TG for patients with Siewert II advanced AEG.