Molecular and immune characterization of Chinese early-stage non-squamous non-small cell lung cancer: a multi-omics cohort study.

Background: Albeit considered with superior survival, around 30% of the early-stage non-squamous non-small cell lung cancer (Ns-NSCLC) patients relapse within 5 years, suggesting unique biology. However, the biological characteristics of early-stage Ns-NSCLC, especially in the Chinese population, are still unclear. Methods: Multi-omics interrogation of early-stage Ns-NSCLC (stage I-III), paired blood samples and normal lung tissues (n=76) by whole-exome sequencing (WES), RNA sequencing, and T-cell receptor (TCR) sequencing were conducted. Results: An average of 128 exonic mutations were identified, and the most frequently mutant gene was EGFR (55%), followed by TP53 (37%) and TTN (26%). Mutations in MUC17, ABCA2, PDE4DIP, and MYO18B predicted significantly unfavorable disease-free survival (DFS). Moreover, cytobands amplifications in 8q24.3, 14q13.1, 14q11.2, and deletion in 3p21.1 were highlighted in recurrent cases. Higher incidence of human leukocyte antigen loss of heterozygosity (HLA-LOH), higher tumor mutational burden (TMB) and tumor neoantigen burden (TNB) were identified in ever-smokers than never-smokers. HLA-LOH also correlated with higher TMB, TNB, intratumoral heterogeneity (ITH), and whole chromosomal instability (wCIN) scores. Interestingly, higher ITH was an independent predictor of better DFS in early-stage Ns-NSCLC. Up-regulation of immune-related genes, including CRABP2, ULBP2, IL31RA, and IL1A, independently portended a dismal prognosis. Enhanced TCR diversity of peripheral blood mononuclear cells (PBMCs) predicted better prognosis, indicative of a noninvasive method for relapse surveillance. Eventually, seven machine-learning (ML) algorithms were employed to evaluate the predictive accuracy of clinical, genomic, transcriptomic, and TCR repertoire data on DFS, showing that clinical and RNA features combination in the random forest (RF) algorithm, with area under the curve (AUC) of 97.5% and 83.3% in the training and testing cohort, respectively, significantly outperformed other methods. Conclusions: This study comprehensively profiled the genomic, transcriptomic, and TCR repertoire spectrums of Chinese early-stage Ns-NSCLC, shedding light on biological underpinnings and candidate biomarkers for prognosis development.

Total Neoadjuvant Therapy With PD-1 Blockade for High-Risk Proficient Mismatch Repair Rectal Cancer.

Importance: Total neoadjuvant therapy (TNT) is the standard treatment for locally advanced rectal cancer, especially for patients with high-risk factors. However, the efficacy of TNT combined with immunotherapy for patients with proficient mismatch repair (pMMR) rectal cancer is unknown. Objectives: To evaluate the safety and efficacy of TNT with induction chemoimmunotherapy followed by long-course chemoradiation in patients with high-risk, pMMR rectal cancer and to identify potential molecular biomarkers associated with treatment efficacy. Design, Setting, and Participants: This cohort study was a single-arm phase 2 trial conducted at Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, from June 2020 to October 2021. Biopsies and plasma were collected before treatment for whole-exome sequencing and cell-free DNA sequencing, respectively. Data were analyzed from May 2022 to September 2022. Interventions: Participants received 3 cycles of induction oxaliplatin and capecitabine combined with camrelizumab and radiotherapy (50.6 Gy in 22 fractions) with concurrent capecitabine. Patients without disease progression received 2 cycles of consolidation oxaliplatin/capecitabine. Main Outcomes and Measures: The primary end point was pathologic complete response rate. Results: Of 25 patients enrolled (19 men [76%]; 6 women [24%]; median [IQR] age, 58 [48-64] years), 22 patients (88%) completed the TNT schedule. The pathologic complete response rate was 33.3% (7/21). Twelve patients (48%) achieved clinical complete response, and 4 patients (16%) chose to watch and wait. R0 resection was achieved in 21 of 21 patients, and the major pathologic response rate was 38.1% (8/21). The most common adverse event was nausea (80%, 20/25); grade 3 toxic effects occurred in 9 of 25 patients (36%). Patients with tumor shrinkage of 50% or greater after induction oxaliplatin/capecitabine and camrelizumab or clinical complete response had higher percentages of LRP1B mutation. Mutation of LRP1B was associated with high tumor mutation burden and tumor neoantigen burden. Patients with high tumor mutation burden all benefited from therapy. Conclusions and Relevance: This study found that TNT with induction chemoimmunotherapy followed by long-course chemoradiation was safe and effective for patients with high-risk rectal cancer with pMMR status. Longer follow-up and larger clinical studies are needed to validate this innovative regimen. There is also an urgent need to further validate the predictive value of LRP1B and discover other novel biomarkers with potential predictive value for rectal cancer.

Integrative analysis of rs717620 polymorphism in therapeutic response to anti-seizure medications.

Background: Previous studies have shown that the rs717620 polymorphism in ABCC2, the gene encoding multidrug resistance protein 2, influences the therapeutic response to anti-seizure medications (ASMs). However, this result is not consistent, and the mechanism by which rs717620 influences ASM responses is unclear. Aims: The present study evaluated the association between rs717620 genotype and ASM efficacy, and examined the potential mechanisms. Main: methods: We conducted a literature search of five electronic databases, Embase, Medline, Web of Science, China National Knowledge Infrastructure, and Wanfang, to identify relevant studies on response to ASM therapy among rs717620 genotypes. Expression quantitative trait loci analysis and drug-gene interaction analysis were also performed to assess the underlying mechanisms. Key findings: The pooled results for 18 studies revealed a significant association between rs717620 genotype and ASM resistance under the recessive model (TT vs. CT + CC: OR = 1.68, 95 % CI = 1.27-2.21, I2 = 3.1 %). A significant association was also found in the Asian population under the recessive model (TT vs. CT + CC: OR = 1.70, 95 % CI = 1.26-2.29, I2 = 29.3 %). Further analysis revealed that rs717620 regulates the expression of ABCC2 in human brain, while drug-gene interaction analysis suggested that ABCC2 interacts with oxcarbazepine and carbamazepine. Significance: The rs717620 polymorphism influences ASM therapeutic responses by altering brain expression levels of ABCC2.

Spatiotemporal changes in summer days (SU25) in China from 1961 to 2017 and associated circulation factors.

Understanding the spatiotemporal variations in climate extremes indices, as well as the influencing factors, is critical to the scientific response to climate change. The temporal and spatial variations of SU25 (annual count of days when daily maximum temperature > 25 °C) were discussed in this study, based on daily maximum temperature data from 2398 meteorological stations in China from 1961 to 2017. The contributions of associated large-scale circulation factors to SU25 were quantitatively assessed by using the geographical detector method (GMD). The overall spatial distribution of SU25 was marked by a considerable increase from north to south. The SU25 increased significantly over time, with the national SU25 increasing at a rate of 2.5 days/decade. The Tibet Plateau (TP) had the slowest growth rate, with an average increase rate of 1.4 days/decade. The Hurst values of SU25 in all the subregions were generally high, indicating that most stations of SU25 would continue to increase in the future. Except for TP, the tipping years of other subregions were concentrated in the 1990s, and SU25 increased after the years. Among the large-scale circulation factors affecting SU25 in each subregion, Atlantic Multidecadal Oscillation (AMO) played a major role in SU25 variability. As a whole, the result of the pairwise interaction of each circulation factor was mainly nonlinear enhancement. The joint contributions of multiple factors to SU25 were larger than the contribution of each individual factor.

A Novel Computational Framework for Predicting the Survival of Cancer Patients With PD-1/PD-L1 Checkpoint Blockade Therapy.

Background: Immune checkpoint inhibitors (ICIs) induce durable responses, but only a minority of patients achieve clinical benefits. The development of gene expression profiling of tumor transcriptomes has enabled identifying prognostic gene expression signatures and patient selection with targeted therapies. Methods: Immune exclusion score (IES) was built by elastic net-penalized Cox proportional hazards (PHs) model in the discovery cohort and validated via four independent cohorts. The survival differences between the two groups were compared using Kaplan-Meier analysis. Both GO and KEGG analyses were performed for functional annotation. CIBERSORTx was also performed to estimate the relative proportion of immune-cell types. Results: A fifteen-genes immune exclusion score (IES) was developed in the discovery cohort of 65 patients treated with anti-PD-(L)1 therapy. The ROC efficiencies of 1- and 3- year prognosis were 0.842 and 0.82, respectively. Patients with low IES showed a longer PFS (p=0.003) and better response rate (ORR: 43.8% vs 18.2%, p=0.03). We found that patients with low IES enriched with high expression of immune eliminated cell genes, such as CD8+ T cells, CD4+ T cells, NK cells and B cells. IES was positively correlated with other immune exclusion signatures. Furthermore, IES was successfully validated in four independent cohorts (Riaz's SKCM, Liu's SKCM, Nathanson's SKCM and Braun's ccRCC, n = 367). IES was also negatively correlated with T cell-inflamed signature and independent of TMB. Conclusions: This novel IES model encompassing immune-related biomarkers might serve as a promising tool for the prognostic prediction of immunotherapy.

Predicting Durable Responses to Immune Checkpoint Inhibitors in Non-Small-Cell Lung Cancer Using a Multi-Feature Model.

Due to the complex mechanisms affecting anti-tumor immune response, a single biomarker is insufficient to identify patients who will benefit from immune checkpoint inhibitors (ICIs) treatment. Therefore, a comprehensive predictive model is urgently required to predict the response to ICIs. A total of 162 non-small-cell lung cancer (NSCLC) patients undergoing ICIs treatment from three independent cohorts were enrolled and used as training and test cohorts (training cohort = 69, test cohort1 = 72, test cohort2 = 21). Eight genomic markers were extracted or calculated for each patient. Ten machine learning classifiers, such as the gaussian process classifier, random forest, and support vector machine (SVM), were evaluated. Three genomic biomarkers, namely tumor mutation burden, intratumoral heterogeneity, and loss of heterozygosity in human leukocyte antigen were screened out, and the SVM_poly method was adopted to construct a durable clinical benefit (DCB) prediction model. Compared with a single biomarker, the DCB multi-feature model exhibits better predictive value with the area under the curve values equal to 0.77 and 0.78 for test cohort1 and cohort2, respectively. The patients predicted to have DCB showed improved median progression-free survival (mPFS) and median overall survival (mOS) than those predicted to have non-durable clinical benefit.

Construction and validation of an immunoediting-based optimized neoantigen load (ioTNL) model to predict the response and prognosis of immune checkpoint therapy in various cancers.

BACKGROUND: Only a minority of patients clinically benefit from immune checkpoint therapy. Tumor clones with neoantigens have immunogenicity; therefore, they are eliminated by T-cell-mediated immune editing. Identifying neoantigen clones with the ability to induce immune elimination may better predict the clinical outcome of immunotherapy. METHODS: We developed ioTNL model, which indicates the immunoediting-based optimized tumor neoantigen load, by identifying tumor clones that could induce immune elimination. Data of more than two hundred patients from our patient pool and previously reported studies who underwent anti-PD-(L)1 therapy were collected to validate the prediction performance of ioTNL model. Clonal architectures, immune editing scores and ioTNL scores were identified. The association between the response as well as prognosis and the ioTNL were evaluated. Panel sequencing of genes from 2,469 patients within 20 cancer types was performed to profile the landscape of immunoediting. RESULTS: As expected, the ioTNL score could predict the response in patients who underwent immune checkpoint inhibitor (ICI) immunotherapy for various cancers, including non-small cell lung cancer (NSCLC; p = 0.0066), skin cutaneous melanoma (SKCM; p = 0.026) and nasopharyngeal carcinoma (NPC; p = 0.0025). Patients with a high ioTNL score demonstrated longer survival than those with a low score. We verified the ioTNL on our cohort through panel sequencing and found that the ioTNL was associated with the response (p = 0.025) and prognosis (p = 0.00082) in anti-PD-(L)1 monotherapy. In addition, we found that the immune editing score correlated with the tumor mutation burden (TMB) and the objective response rate of immunotherapy. CONCLUSIONS: Identifying neoantigen clones with the ability to induce immune elimination would better predict the efficacy of immunotherapy. We have proved that the reliable method of ioTNL can be applied to whole-exome sequencing (WES) and panel data and would have a broad application in precision diagnosis in immunotherapy.

[Tongdu Tiaoshen acupuncture combined with carotid endarterectomy for carotid artery stenosis: a randomized controlled trial].

OBJECTIVE: To observe the clinical therapeutic effect of Tongdu Tiaoshen acupuncture combined with carotid endarterectomy (CEA) and simple CEA on carotid artery stenosis (CAS). METHODS: A total of 60 patients with CAS were randomized into an observation group (30 cases, 2 cases dropped off) and a control group (30 cases, 3 cases dropped off). Both groups were treated with eversion CEA (eCEA). The conventional treatment of internal medicine and antiplatelet drugs i.e. aspirin enteric-coated tablet and clopidogrel hydrogen sulfate tablet were given in the control group for 4 weeks. On the basis of the treatment in the control group, Tongdu Tiaoshen acupuncture was applied at Baihui (GV 20), Fengfu (GV 16), Yamen (GV 15), cervical Jiaji (EX-B 2), Dazhui (GV 14), etc. in the observation group, once a day, 1-day rest was taken after 6-day treatment, 2 weeks were as one course and totally 2 courses were required. The carotid intima-media thickness (IMT) before and after treatment was detected by ultrasonic diagnostic apparatus, the TCM symptom score was compared before and after treatment and in the follow-up of 6 months after treatment, the clinical efficacy was evaluated in the two groups. The occurrence of endpoints within 1 year was recorded. RESULTS: After treatment, the carotid IMT and TCM symptom scores were decreased compared before treatment in the both groups (P<0.05), and the changes in the observation group were greater than the control group (P<0.05). In the follow-up, the TCM symptom scores were decreased compared before treatment in the both groups (P<0.05). The total effective rate was 96.4% (27/28) in the observation group, which was superior to 88.9% (24/27) in the control group (P<0.05). There were 1 case of stoke in the observation group and 2 cases of stroke in the control group within 1-year follow-up, and there was no significant difference in the number of endpoints between the two groups within 1 year (P>0.05). CONCLUSION: Tongdu Tiaoshen acupuncture combined with CEA can effectively reduce the IMT in patients with CAS, improve the TCM symptom score, the efficacy is superior to simple CEA treatment.

Fault Diagnosis of Rolling Bearings Based on WPE by Wavelet Decomposition and ELM.

The fault diagnosis classification method based on wavelet decomposition and weighted permutation entropy (WPE) by the extreme learning machine (ELM) is proposed to address the complexity and non-smoothness of rolling bearing vibration signals. The wavelet decomposition based on 'db3' is used to decompose the signal into four layers and extract the approximate and detailed components, respectively. Then, the WPE values of the approximate (CA) and detailed (CD) components of each layer are calculated and composed to be the feature vectors, which are finally fed into the extreme learning machine with optimal parameters for classification. The comparative study of the simulations based on WPE and permutation entropy (PE) shows that the classification method of seven kinds of signals of normal bearing signals and six types of fault states (7 mils and 14 mils) based on WPE (CA, CD) with the number of nodes in the hidden layers of ELM determined by the five-fold cross-validation has the best performances, the training accuracy can reach 100%, and the testing accuracy can reach 98.57% with 37 nodes of the hidden layer by ELM. The proposed method using WPE (CA, CD) by ELM provides guidance for the multi-classification of normal bearing signals.

Personalized neoantigen pulsed dendritic cell vaccine for advanced lung cancer.

Neoantigens are considered to be ultimate target of tumor immunotherapy due to their high tumor specificity and immunogenicity. Dendritic cell (DCs) vaccines based on neoantigens have exciting effects in treatment of some malignant tumors and are a promising therapeutic modality. Lung cancer is a lethal disease with the highest morbidity and mortality rate in the world. Despite the rapid development of targeted therapy and immune checkpoint inhibitors for lung cancer in recent years, their efficacy is still unsatisfactory overall. Therefore, there is an urgent unmet clinical need for lung cancer treatment. Here, we attempted to treat lung cancer using a personalized neoantigen peptide-pulsed autologous DC vaccine and conducted a single-arm, 2 medical centers, pilot study initiated by the investigator (ChiCTR-ONC-16009100, NCT02956551). The patients enrolled were patients with heavily treated metastatic lung cancer. Candidate neoantigens were derived from whole-exome sequencing and RNA sequencing of fresh biopsy tissues as well as bioinformatics analysis. A total of 12 patients were enrolled in this study. A total of 85 vaccine treatments were administered with a median value of 5 doses/person (range: 3-14 doses/person). In total, 12-30 peptide-based neoantigens were selected for each patient. All treatment-related adverse events were grade 1-2 and there were no delays in dosing due to toxic effects. The objective effectiveness rate was 25%; the disease control rate was 75%; the median progression-free survival was 5.5 months and the median overall survival was 7.9 months. This study provides new evidence for neoantigen vaccine therapy and new therapeutic opportunities for lung cancer treatment.

TruNeo: an integrated pipeline improves personalized true tumor neoantigen identification.

BACKGROUND: Neoantigen-based personal vaccines and adoptive T cell immunotherapy have shown high efficacy as a cancer treatment in clinical trials. Algorithms for the accurate prediction of neoantigens have played a pivotal role in such studies. Some existing bioinformatics methods, such as MHCflurry and NetMHCpan, identify neoantigens mainly through the prediction of peptide-MHC binding affinity. However, the predictive accuracy of immunogenicity of these methods has been shown to be low. Thus, a ranking algorithm to select highly immunogenic neoantigens of patients is needed urgently in research and clinical practice. RESULTS: We develop TruNeo, an integrated computational pipeline to identify and select highly immunogenic neoantigens based on multiple biological processes. The performance of TruNeo and other algorithms were compared based on data from published literature as well as raw data from a lung cancer patient. Recall rate of immunogenic ones among the top 10-ranked neoantigens were compared based on the published combined data set. Recall rate of TruNeo was 52.63%, which was 2.5 times higher than that predicted by MHCflurry (21.05%), and 2 times higher than NetMHCpan 4 (26.32%). Furthermore, the positive rate of top 10-ranked neoantigens for the lung cancer patient were compared, showing a 50% positive rate identified by TruNeo, which was 2.5 times higher than that predicted by MHCflurry (20%). CONCLUSIONS: TruNeo, which considers multiple biological processes rather than peptide-MHC binding affinity prediction only, provides prioritization of candidate neoantigens with high immunogenicity for neoantigen-targeting personalized immunotherapies.

Metagenomic Analysis Identified Stenotrophomonas maltophilia Pneumonia in an Infant Suffering From Unexplained Very Severe Pneumonia.

Pneumonia poses a significant global morbidity and mortality burden on children. Etiological diagnosis and matched anti-microbial therapy are particularly important for very severe pneumonia. Although great advances have been achieved in diagnostic approaches, it remains challenging to identify pathogens in unexplained pneumonia (UP) cases. In this study, we applied next-generation sequencing (NGS) technology and a metagenomic approach to detect and characterize respiratory bactiera in an UP case in infant. Stenotrophomonas maltophilia was the only bacterial pathogen detected in blood. Metagenomic sequencing also provided bacteria genomic sequences, which could be used to evaluate the role of this pathogen in the disease. This NGS method has the potential to improve the identification of causative organisms in patients with pneumonia and the delivery of appropriate, pathogen-directed antibiotic therapy.

Genomic analysis-integrated whole-exome sequencing of neuroblastomas identifies genetic mutations in axon guidance pathway.

Neuroblastoma (NB) is a childhood solid malignant tumor originating from precursor cells of the peripheral nervous system. We have previously established a risk classification system based on DNA copy number profiles. To further explore the pathogenesis of NBs in distinct risk groups, we performed whole-exome sequencing analysis of 57 primary and 7 recurrent/metastatic tumors with unique chromosomal aberration profiles as categorized by our genomic sub-grouping system. Overall, a low frequency of somatic mutations was found. Besides ALK (4/64, 6.3%), SEMA6C, SLIT1 and NRAS, genes involved in the axon guidance pathway, were identified as recurrently mutated in 6 of 64 tumors (9.4%). Pathway enrichment analysis revealed enrichment of 25 mutated genes in the mitogen-activated protein kinase (MAPK) pathway, 13 genes in the Wnt pathway, and 12 genes in the axon guidance pathway. Genomic analyses demonstrated that primary and matched recurrent or metastatic tumors obtained from sporadic and monozygotic twin NBs were clonally related with variable extents of genetic heterogeneity. Monozygotic twin NBs displayed different evolutionary trajectories. These results indicate the involvement of the axon guidance, MAPK and Wnt pathways in NB and demonstrate genomic diversity with NB progression.

Evacuating Hypertensive Intracerebral Hematoma with a Cortical Sulcus Approach.

OBJECTIVE: To study the curative effect and prognosis of patients with basal ganglia cerebral hemorrhages treated using a transcortical-sulcus approach and compare with results obtained using the traditional cerebral cortex approach. METHODS: Clinical data were collected from 106 patients with hypertensive hemorrhage in the basal ganglia who were treated using either a transcortical-sulcus approach or traditional cerebral cortex approach. The rate of rehemorrhage, incidence of epilepsy, and 3-month efficacy (defined by an activities of daily living score) rate between the 2 groups were compared. RESULTS: The 3-month efficacy rates of patients treated using the transcortical-sulcus and traditional cerebral cortex surgical approaches were 78.4% and 60%, respectively (P < 0.05). The incidence of epilepsy was lower in the transcortical-sulcus approach group compared with the traditional approach group, and significant differences were detected between the 2 groups (P < 0.05). CONCLUSIONS: The transcortical-sulcus approach can significantly improve the prognosis of patients with intracerebral hemorrhages in the basal ganglia and reduce the incidence of postoperative seizures.

Genome-wide association study identifies 8p21.3 associated with persistent hepatitis B virus infection among Chinese.

Hepatitis B virus (HBV) infection is a common infectious disease. Here we perform a genome-wide association study (GWAS) among Chinese populations to identify novel genetic loci involved in persistent HBV infection. GWAS scan is performed in 1,251 persistently HBV infected subjects (PIs, cases) and 1,057 spontaneously recovered subjects (SRs, controls), followed by replications in four independent populations totally consisting of 3,905 PIs and 3,356 SRs. We identify a novel locus at 8p21.3 (index rs7000921, odds ratio=0.78, P=3.2 × 10(-12)). Furthermore, we identify significant expression quantitative trait locus associations for INTS10 gene at 8p21.3. We demonstrate that INST10 suppresses HBV replication via IRF3 in liver cells. In clinical plasma samples, we confirm that INST10 levels are significantly decreased in PIs compared with SRs, and negatively correlated with the HBV load. These findings highlight a novel antiviral gene INTS10 at 8p21.3 in the clearance of HBV infection.

Whole Exome Sequencing Identifies Frequent Somatic Mutations in Cell-Cell Adhesion Genes in Chinese Patients with Lung Squamous Cell Carcinoma.

Lung squamous cell carcinoma (SQCC) accounts for about 30% of all lung cancer cases. Understanding of mutational landscape for this subtype of lung cancer in Chinese patients is currently limited. We performed whole exome sequencing in samples from 100 patients with lung SQCCs to search for somatic mutations and the subsequent target capture sequencing in another 98 samples for validation. We identified 20 significantly mutated genes, including TP53, CDH10, NFE2L2 and PTEN. Pathways with frequently mutated genes included those of cell-cell adhesion/Wnt/Hippo in 76%, oxidative stress response in 21%, and phosphatidylinositol-3-OH kinase in 36% of the tested tumor samples. Mutations of Chromatin regulatory factor genes were identified at a lower frequency. In functional assays, we observed that knockdown of CDH10 promoted cell proliferation, soft-agar colony formation, cell migration and cell invasion, and overexpression of CDH10 inhibited cell proliferation. This mutational landscape of lung SQCC in Chinese patients improves our current understanding of lung carcinogenesis, early diagnosis and personalized therapy.