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During the exploration and development of deep coalbed methane (CBM), delineating the thickness of coal seam and lithofacies of the roof and floor is one of the major challenging tasks. In past attempts, the prediction methods of these parameters have been limited to the conventional inversion. However, the effect of coal shielding on adjacent reflecting layers restricts the identification of underlying sand effectively by conventional inversion. Also, the depth at which the deep CBM zone is located (1,500–2000 m) produces a significant overlap of P-wave impedance and Vp/Vs of sands and shale which increases classification uncertainty between these two lithofacies. We proposed a new workflow for high-precision quantitative seismic interpretation of deep CBM reservoir. Not only P-wave impedance but also GR is selected as the optimized attributes for lithofacies classification. To reduce the effect of strong reflection of coal seam and identifying thin coal layers, the seismic waveform indication inversion method is used to obtain high-resolution results of P-wave impedance and GR. It uses horizontal changes in seismic waveforms to reflect lithological assemblage characteristics for facies-controlled constraints. Then, Bayesian classification theory is used to achieve three-dimensional lithofacies classification with multi-source data. To improve the continuity and accuracy of the interpreted results, a Markov chain is applied in the Bayesian rule as the spatial prior constraint. A well-associated synthetic test and field data application in Ordos Basin demonstrates the accuracy of the proposed workflow. Compared with conventional inversion, the results of proposed workflow showed higher resolution and accuracy. By providing a new solution for the identification of roof and floor lithofacies of deep CBM reservoir, this workflow aims to contribute to the better exploration and development of deep CBM.

Crayfish (Procambarus clarkii) are economically important freshwater crustaceans. With the growth of the crayfish industry, the associated food-safety risks should be seriously considered. Although Vibrio parahaemolyticus is commonly recognized as a halophilic foodborne pathogen associated with seafood, it has been found to be a major pathogen in crayfish-associated food poisoning cases. In this study, the V. parahaemolyticus contamination level in crayfish production-sale chain was investigated using crayfish and environmental samples collected from crayfish farms and markets. Serious V. parahaemolyticus contamination (detection rate of 66%) was found in the entire crayfish production-sale chain, while the V. parahaemolyticus contamination level of the market samples was extremely high (detection rate of 92%). The V. parahaemolyticus detection rate of crayfish surface was similar to that of whole crayfish, indicating that crayfish surface was important for V. parahaemolyticus contamination. The simulation experiments of crayfish for sale being contaminated by different V. parahaemolyticus sources were performed. All the contamination sources, containing V. parahaemolyticus-positive tank, water, and crayfish, were found to be efficient to contaminate crayfish. The crayfish tank displayed the most significant contaminating role, while the water seemed to inhibit the V. parahaemolyticus contamination. The contamination extent of the crayfish increased with the number of V. parahaemolyticus cells the tank carried and the contact time of the crayfish and the tank, but decreased with the time that the crayfish were maintained in the water. It was also confirmed that the crayfish surface was more susceptible to V. parahaemolyticus contamination than the crayfish intestine. Furthermore, the adsorption of V. parahaemolyticus onto the crayfish shell was analyzed. Over 90% of the V. parahaemolyticus cells were adsorbed onto the crayfish shell in 6 h, indicating a significant adsorption effect between V. parahaemolyticus and the crayfish shell. In conclusion, within a water-free sale style, the fresh crayfish for sale in aquatic products markets uses its shell to capture V. parahaemolyticus cells from the V. parahaemolyticus-abundant environments. The V. parahaemolyticus contamination in crayfish for sale exacerbates the crayfish-associated food-safety risk. This study sheds light on V. parahaemolyticus control and prevention in crayfish industry.

Abstract Human-machine interfaces for capturing, conveying, and sharing tactile information across time and space hold immense potential for healthcare, augmented and virtual reality, human-robot collaboration, and skill development. To realize this potential, such interfaces should be wearable, unobtrusive, and scalable regarding both resolution and body coverage. Taking a step towards this vision, we present a textile-based wearable human-machine interface with integrated tactile sensors and vibrotactile haptic actuators that are digitally designed and rapidly fabricated. We leverage a digital embroidery machine to seamlessly embed piezoresistive force sensors and arrays of vibrotactile actuators into textiles in a customizable, scalable, and modular manner. We use this process to create gloves that can record, reproduce, and transfer tactile interactions. User studies investigate how people perceive the sensations reproduced by our gloves with integrated vibrotactile haptic actuators. To improve the effectiveness of tactile interaction transfer, we develop a machine-learning pipeline that adaptively models how each individual user reacts to haptic sensations and then optimizes haptic feedback parameters. Our interface showcases adaptive tactile interaction transfer through the implementation of three end-to-end systems: alleviating tactile occlusion, guiding people to perform physical skills, and enabling responsive robot teleoperation.

Abstract Background ARHGAP10 is a tumor‐suppressor gene related to ovarian cancer (OC) progression; however, its specific mechanism is unclear. Aims To investigate the effect of ARHGAP10 on OC cell migration, invasion, and glycolysis. Methods and Results Quantitative real‐time PCR (qRT‐PCR) quantified mRNA and protein expressions of AKT, p‐AKT, HK2, and SMAD4 were tested by Western blot. EdU, Wound healing, and Transwell assay were utilized to evaluate OC cell proliferation, migration, and invasion. We used a Seahorse XF24 Extracellular Flux Analyzer to monitor cellular oxygen consumption rates (OCR) and extracellular acidification rates (ECAR). Chromatin immunoprecipitation (ChIP) was used to analyze the transcriptional regulation of ARHGAP10 by SMAD4. ARHGAP10 expression in OC tissues was detected by immunohistochemistry. Our results showed that ARHGAP10 expression was negatively related to lactate levels in human OC tissues. ARHGAP10 overexpression can inhibit the migration, proliferation, and invasion of OC cells, and this function can be blocked by 2‐Deoxy‐D‐glucose. Moreover, we found that ARHGAP10 expression can be rescued with the AKT inhibitor LY294002. Conclusions This study revealed that the antitumor effects of ARHGAP10 in vivo and in vitro possibly suppress oncogenic glycolysis through the PI3K/AKT/HK2‐regulated glycolysis metabolism pathway.

Background. An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic occurred throughout China from December 2022 to January 2023, and the vast majority of those infected individuals were mild. The symptom characteristics of mildly infected individuals in this epidemic wave of the Omicron variant have not been well described. Methods. We conducted a nationwide survey of symptomatic characteristics of nonhospitalized individuals with mild Omicron infection through a WeChat app. Results. Respondents (68.6% female) were aged 18–87 years (42.6 ± 13.1 years), of whom 79.8% were diagnosed by SARS-CoV-2 PCR or antigen test. Of the 19 symptoms predefined in the questionnaire, an average of 7.8 symptoms was reported. The most common symptoms included cough (81.2%), fever (79.9%), fatigue (73.8%), muscle soreness (62.2%), headache (59.2%), and phlegm (55.1%). Painful swallowing was present in 38.3% of the participants and was one of the most severe symptoms perceived by the participants. Also, we found that young people were more likely to have symptoms such as fever, painful swallowing, and headache compared to the elderly population. 36.9% of respondents graded their symptoms as severe, and the severity of symptoms was higher in young people than in older adults, with fever, cough, painful swallowing, fatigue, and headache being the most severe. In addition, women experienced a significantly higher prevalence of symptoms than men, but there was no significant difference in the severity of most symptoms. The presence of comorbidities did not increase the incidence or severity of symptoms in those with mildly infected individuals. Conclusions. The symptom profile of mild COVID-19 cases in the nationwide Omicron wave in China was markedly different from previous reports, featuring a high incidence of symptoms, multiple symptoms, and heavy symptoms. The symptoms of mild Omicron infection cases are not mild and are more pronounced in young people.

To evaluate the detection performance of ozone lidars, the first comprehensive vertical ozone observation experiment in China was conducted at the Xilinhot National Climate Observatory in Inner Mongolia from August to December 2023. The ozone profiles and concentrations of four ozone lidars were systematically compared and assessed with ozone radiosonde measurements and ozone analyzer observations both at ground-based stations and on an Unmanned Aerial Vehicle. The results show that the relative deviations of four ozone lidars are less than 20% compared with ozone radiosonde measurements at a height between 150 and 400 m. Ozone lidars have better behavior between 400 m and 2000 m than the lower altitude, with the deviation within 10% and the correlation coefficient around 0.8. However, relative deviations of lidars increased with altitude above 2000 m. The surface ozone concentrations observed using ozone lidars agreed well with the ground-based ozone analyzer, especially during periods with ozone concentrations higher than 40 µg·m−3. The correlation coefficients for most models of ozone lidar are higher than 0.53. A further investigation of the influence of precipitation events on ozone lidar measurement has been conducted, which revealed that thick cloud layers, low cloud base, and an intensive precipitation event with large raindrop particles can result in high anomalies and reduce the inversion accuracy of the ozone lidar. During the experiment, four ozone lidars were assessed quantitatively according to the comprehensive performance, which could help to improve inversion algorithms and the system design of this promising technique.

Idiopathic pulmonary aneurysm is a clinically rare condition characterized by an unknown etiology and episodic occurrence. Despite its rarity, idiopathic pulmonary artery aneurysm poses potential risks to patients. Currently, there is a lack of established clinical guidelines and consensus regarding its management, leading to ongoing controversies in treatment strategies. Particularly, the optimal approach for addressing the main pulmonary artery, its branches, and the pulmonary artery valve remains uncertain. A 57-year-old female patient presented with chest pain and tightness, leading to the diagnosis of idiopathic pulmonary artery aneurysm after excluding other potential causes. Subsequently, she underwent surgical treatment. However, during the surgery, the pulmonary artery wall was found to be extremely weak, prompting us to employ a surgical approach involving the utilization of autologous vessel wrapping with artificial grafts. By summarizing almost all surgical treatment strategies reported in recent years, including the management of pulmonary artery vessels and the pulmonary valve, we have developed a treatment flow chart. This flowchart serves as a valuable guide for the management of future cases presenting similar challenges, offering clinicians valuable insights and evidence-based recommendations.

Background: Whole-genome bisulfite sequencing (WGBS) technology can provide comprehensive DNA methylation at a single-base resolution on a genome-wide scale, and is considered to be the gold standard for the detection of 5-methylcytosine (5 mC). However, the International Human Epigenome Consortium propose a full DNA methylome should have at least 30 fold redundant coverage of the reference genome from a single biological replicate. Therefore, it remains cost prohibitive for large-scale studies. To find a solution, the DNBSEQ-Tx sequencing was developed that can generate up to 6 Tb data in a single run for projects involving large-scale sequencing. Results: In this study, we provided two WGBS library construction methods DNB_PREBSseq and DNB_SPLATseq optimized for the DNBSEQ-Tx sequencer, and demonstrated the performance of these two methods on the DNBSEQ-Tx platform, using the DNA extracted from four different cell lines. We also compared the sequencing data from these two WGBS library construction methods with HeLa cell line data from ENCODE sequenced on Illumina HiSeq X Ten and WGBS data of two other cell lines sequenced on HiSeq2500. Various quality control (QC) analyses such as the base quality scores, methylation-bias (m-bias), and conversion efficiency indicated that the data sequenced on the DNBSEQ-Tx platform met the WGBS-required quality controls. Meanwhile, our data closely resembled the coverage shown by the data generated by the Illumina platform. Conclusions: Our study showed that with our optimized methods, DNBSEQ-Tx could generate high-quality WGBS data with relatively good stability for large-scale WGBS sequencing applications. Thus, we conclude that DNBSEQ-Tx can be used for a wide range of WGBS research.

Summary: Diffuse large B cell lymphoma (DLBCL) is one of the most common types of aggressive lymphoid malignancies. Here, we explore the contribution of RNA editing to DLBCL pathogenesis. We observed that DNA mutations and RNA editing events are often mutually exclusive, suggesting that tumors can modulate pathway outcomes by altering sequences at either the genomic or the transcriptomic level. RNA editing targets transcripts within known disease-driving pathways such as apoptosis, p53 and NF-κB signaling, as well as the RIG-I-like pathway. In this context, we show that ADAR1-mediated editing within MAVS transcript positively correlates with MAVS protein expression levels, associating with increased interferon/NF-κB signaling and T cell exhaustion. Finally, using targeted RNA base editing tools to restore editing within MAVS 3′UTR in ADAR1-deficient cells, we demonstrate that editing is likely to be causal to an increase in downstream signaling in the absence of activation by canonical nucleic acid receptor sensing.

The great challenge in the aldol condensation of tailored fermentation products (acetone–butanol–ethanol, ABE) into energy intensive fuels is to develop a suitable catalyst with high activity and low–cost. In this study, Co, Ni, and Co–Ni supported on Mg–Al oxide catalysts were prepared and their pore diameters were enlarged via adding active carbon as a hard template into Mg–Al hydrotalcite. During the aldol condensation reaction, the catalyst activity was enhanced after enlarging the pore diameter and Co–Ni bimetal supported catalyst presented the highest activity, which was resulted from that the electron transfer between Co and Ni in Co–Ni alloy enhanced the dehydrogenation activity and large pore lowered the mass transfer resistance. After optimizing the reaction conditions, acetone conversion and the total selectivity of C5–C11 desired products in the aldol condensation of ABE reached up to 76% and 90%, respectively. The stability study showed that the activity was decreased with the increase of reaction number because of the oxidation of metallic Co and Ni, but this could be solved via a simple hydrogen reduction method.

Circumferential yielding lining is able to tolerate controlled displacements without failure, which has been proven to be an effective solution to large deformation problem in squeezing tunnels. However, up to now, there has not been a well-established design method for it. This paper aims to present a detailed analytical computation of support characteristic curve (SCC) for circumferential yielding lining, which is a significant aspect of the implementation of convergence-confinement method (CCM) in tunnel support design. Circumferential yielding lining consists of segmental shotcrete linings and highly deformable elements, and its superior performance mainly depends on the mechanical characteristic of highly deformable element. The deformation behavior of highly deformable element is firstly investigated. Its whole deforming process can be divided into three stages including elastic, yielding and compaction stages. Especially in the compaction stage of highly deformable element, a nonlinear stress–strain relationship can be observed. For mathematical convenience, the stress–strain curve in this period is processed as several linear sub-curves. Then, the reasons for closure of circumferential yielding lining in different stages are explained, and the corresponding accurate equations required for constructing the SCC are provided. Furthermore, this paper carries out two case studies illustrating the application of all equations needed to construct the SCC for circumferential yielding lining, where the reliability and feasibility of theoretical derivation are also well verified. Finally, this paper discusses the sensitivity of sub-division in element compaction stage and the influence of element length on SCC. The outcome of this paper could be used in the design of proper circumferential yielding lining.

Abstract Background With the identification of new targetable drivers and the recent emergence of novel targeted drugs, using comprehensive genomic profiling in lieu of the routine testing for classic drivers in the clinical care for advanced NSCLC has been increasingly advocated. However, the key assumption justifying this practice, that comprehensive genomic profiling could lead to effective anticancer therapies and improve patient outcomes, remains unproved. Methods Comprehensive genomic profiling was prospectively applied in 1564 advanced NSCLC patients to identify potentially actionable genomic alterations. Patients were assigned to genotype-matched targeted therapies or nonmatched therapies based on the profiling results. Its utility in directing treatments was determined by the proportion of patients receiving genotype-matched targeted therapies and the proportion of patients being enrolled into genotype-matched clinical trials. Its impacts on patient outcomes were assessed by comparing progression-free survival (PFS) and overall survival (OS) between patients who received a genotype-matched and nonmatched therapy. Results From October 2016 to October 2019, tumor genomic profiles were established in 1166 patients, leading to a matched targeted therapy in 37.7% (n = 440) and a genotype-matched trial enrollment in 20.9% of patients (n = 244). Potentially actionable alterations were detected in 781 patients (67.0%). For these patients, a genomic profiling-directed matched therapy significantly improved PFS (9.0 months vs 4.9 months, P

Abstract Background CD70 is a costimulatory molecule that is transiently expressed on a small set of activated lymphocytes and is involved in T‐cell‐mediated immunity. However, the role of CD70 in B‐cell malignancies remains controversial. Methods We investigated the clinical relevance of CD70 genetic alterations and its protein expression in two diffuse large B‐cell lymphoma (DLBCL) cohorts with different ethnic backgrounds. We also performed transcriptomic analysis to explore the role of CD70 alterations in tumour microenvironment. We further tested the blockade of CD70 in combination with PD‐L1 inhibitor in a murine lymphoma model. Results We showed that CD70 genetic aberrations occurred more frequently in the Chinese DLBCL cohort (56/233, 24.0%) than in the Swedish cohort (9/84, 10.8%), especially in those with concomitant hepatitis B virus (HBV) infection. The CD70 genetic changes in DLBCL resulted in a reduction/loss of protein expression and/or CD27 binding, which might impair T cell priming and were independently associated with poor overall survival. Paradoxically, we observed that over‐expression of CD70 protein was also associated with a poor treatment response, as well as an advanced disease stage and EBV infection. More exhausted CD8+ T cells were furthermore identified in CD70 high‐expression DLBCLs. Finally, in a murine lymphoma model, we demonstrated that blocking the CD70/CD27 and/or PD1/PD‐L1 interactions could reduce CD70+ lymphoma growth in vivo, by directly impairing the tumour cell proliferation and rescuing the exhausted T cells. Conclusions Our findings suggest that CD70 can play a role in either tumour suppression or oncogenesis in DLBCL, likely via distinct immune evasion mechanisms, that is, impairing T cell priming or inducing T cell exhaustion. Characterisation of specific dysfunction of CD70 in DLBCL may thus provide opportunities for the development of novel targeted immuno‐therapeutic strategies.

Objective: Increased white blood cell count (WBC) is known to be associated with preeclampsia (PE). This study aimed to determine whether WBC count >10×109/L had significant impact on late-onset PE (LOPE) during the first and second trimesters. Methods: This prospective study was conducted in 600 pregnant women from Shanghai Pudong Hospital in China from July 2019 to August 2020. They were classified into four groups: Group 1: WBC count ≤10×109/L at 10th–12th week and 24th–26th week; Group 2, WBC count ≤10×109/L at 10th–12th week but WBC count >10×109/L at 24th–26th week; Group 3, WBC count >10×109/L at 10th–12th week but WBC count≤10×109/L at 24th–26th week; Group 4, WBC count >10×109/L at 10th–12th week and 24th–26th week. Complete blood count results from 10th–12th week and 24th–26th week were obtained for each patient. Maternal laboratory values including white blood cell (WBC) count were compared between the four groups. Results: 34 women were diagnosed with LOPE at predelivery. The estimated incidence rate of LOPE during pregnancy was 3.6% in Group 1, 5.8% in Group 2, 7.2% in Group 3, and 11% in Group 4 for the respective WBC level of Group 1, 2, 3 and 4. After adjusting for potential influencing factors of PE, the respective relative risks for LOPE was 1.0 (reference), 1.76 (95% CI 0.37, 8.30), 2.23 (0.85, 5.89), and 3.07 (1.34, 7.02) (P for trend = 0.048). Conclusions: Our results demonstrated that WBC count >10×109/L during the first and second trimesters is a risk of LOPE.

Abstract Background Green tea has been one of the most popular beverages in China since ancient times. Mixed results concerning the effect of green tea consumption on the incidence of hypertension have been published over the past decades. However, no previous studies have focused on longevous individuals in China and the sex differences in the association between habitual green tea intake and hypertension. Methods The data extracted from the database of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) in 2018 were used for a secondary analysis. Logistic regression models were employed to examine the odds ratio (OR) of daily green tea consumption on the incidence of hypertension by sex. Results A total of 9277 individuals were included in the analysis (39.8% were men). The included individuals had a mean age of 80.9 and 84.8 years for those who drank green tea daily and those who had never, respectively (p

Given the practical limitations of solid matrix-based protocols in organoid culture, Yumiko Hirokawa et al. assess the ability of low-concentration Matrigel conditions to promote intestinal organoid growth. Their results suggest that a low-viscosity culture system can improve live cell yield compared to the existing dome method, while maintaining similar morphology, and represents a useful approach for high-throughput applications of organoids.

Current methods for the diagnosis and monitoring of bladder cancer are invasive and have suboptimal sensitivity. Liquid biopsy as a non-invasive approach has been capturing attentions recently. To explore the ability of urine-based liquid biopsy in detecting and monitoring genitourinary tumors, we developed a method based on promoter-targeted DNA methylation of urine sediment DNA. We used samples from a primary bladder cancer cohort (n=40) and a healthy cohort (n=40) to train a model and obtained an integrated area under the curve (AUC) > 0.96 in the 10-fold cross-validation, which demonstrated the ability of our method for detecting bladder cancer from the healthy. We next validated the model with samples from a recurrent cohort (n=21) and a non-recurrent cohort (n=19) and obtained an AUC > 0.91, which demonstrated the ability of our model in monitoring the progress of bladder cancer. Moreover, 80% (4/5) of samples from patients with benign urothelial diseases had been considered to be healthy sample rather than cancer sample, preliminarily demonstrating the potential of distinguishing benign urothelial diseases from cancer. Further analysis basing on multiple-time point sampling revealed that the cancer signal in 80% (4/5) patients had decreased as expected when they achieved the recurrent-free state. All the results suggested that our method is a promising approach for noninvasive detection and prognostic monitoring of bladder cancer.

BackgroundDifferentiating multiple pulmonary lesions as multiple primary lung cancer (MLC) or intra-pulmonary metastasis (IPM) is critical. Lung cancer also has a high genetic heterogeneity, which influenced the treatment strategy. Genetic information may aid in tracing lineage information on multiple lung lesions. This study applied comprehensive genomic profiling to decipher the intrinsic genetics of multiple lung lesions.MethodsSixty-six lung adenocarcinomas (LUAD) tumor lesions (FFEP) archived from 30 patients were included in this study. The 508 cancer-related genes were evaluated by targeted next-generation sequencing (MGI-seq 2000).ResultsThe study included a total of 30 LUADs (66 samples). The majority of tumors demonstrated intra-tumoral heterogeneity. Two hundred twenty-four mutations were detected by sequencing the 66 samples. We investigated the driver gene mutations of NSCLC patients with multiple lesions. EGFR was the most frequently (48/198) mutated driver gene. The codons in EGFR mainly affected by mutations were p.L858R (18/66 [27.3%]) and exon 19del (8/66 [12.1%]). In addition, additional driver genes were found, including TP53, BRAF, ERBB2, MET, and PIK3CA. We also found that the inter-component heterogeneity of different lesions and more than two different mutation types of EGFR were detected in seven patients with two lesions (P3, P10, P24, P25, P28, P29, and P30). The TMB values of different lesions in each patient were different in 26 patients (except P4, P5, P14, and P30).ConclusionsComprehensive genomic profiling should be applied to distinguishing the nature of multiple lung lesions irrespective of radiologic and histologic diagnoses.

Immunotherapy has greatly improved the clinical benefits of cancer treatment, especially in melanoma. Ferroptosis is a novel mechanism of cell death which relates to immunity. This study aimed at understanding the potential link between ferroptosis and cancer immunocompetent in melanoma using multiple bioinformatics analyses. By the WGCNA assay, we first constructed a key module–gene of ferroptosis, which was strongly correlated with the diagnosis, prognosis, and infiltration of immune cells in melanoma. The elevated module–gene could effectively distinguish melanoma from normal tissues and acted as a good prognostic marker. The module–gene of ferroptosis was positively correlated with the infiltration of immune cells. In particular, the module was positively correlated with the expression of PD-L1 and sensitively increased after effective anti-PD-1 treatment. Furthermore, the differential expression of the module–gene between normal and tumor tissues was observed in pan-cancer. The similarity correlations of the module–gene with infiltration of immune cells and the expressions of PD-L1 were confirmed in the pan-cancer level. Our study demonstrated that the key module–gene of ferroptosis was closely related with diagnosis, prognosis, and anti-immune response in melanoma, as well as in pan-cancer.

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoid malignancy and a highly heterogeneous disease. In this study, we performed whole-genome and transcriptome sequencing, and a genome-wide CRISPR-Cas9-knockout screen to study an activated B-cell-like DLBCL cell line (RC-K8). We identified a distinct pattern of genetic essentialities in RC-K8, including a dependency on CREBBP and MDM2. The dependency on CREBBP is associated with a balanced translocation involving EP300, which results in a truncated form of the protein that lacks the critical histone acetyltransferase (HAT) domain. The synthetic lethal interaction between CREBBP and EP300 genes, two frequently mutated epigenetic modulators in B-cell lymphoma, was further validated in the previously published CRISPR-Cas9 screens and inhibitor assays. Our study suggests that integration of the unbiased functional screen results with genomic and transcriptomic data can identify both common and unique druggable vulnerabilities in DLBCL and histone acetyltransferases inhibition could be a therapeutic option for CREBBP or EP300 mutated cases.

Rong Xiang et al. analyze the expression of non-coding genes encoded peptides in publicly-available proteomics data from five cancer types and matched controls. They identify peptides from non-coding genes including DGCR9 and RHOXF1P3 that are upregulated in tumors compared to controls, suggesting that non-coding gene-encoded peptides may be a source of neoantigens in some cancers.

Photoactivatable Pt(IV) anticancer prodrugs with the structure of [PtIV(N1)(N2)(L1)(L2)(A1)(A2)], where N1 and N2 are non-leaving nitrogen donor ligands, L1 and L2 are leaving ligands, and A1 and A2 are axial ligands, have attracted increasing attention due to their promising photo-cytotoxicity even to cisplatin-resistant cancer cells. These photochemotherapeutic prodrugs have high dark-stability under physiological conditions, while they can be activated by visible light restrained at the disease areas, as a consequence showing higher spatial and temporal controllability and much more safety than conventional chemotherapy. The coordinated ligands to the Pt center have been proved to be pivotal in determining the function and activity of the photoactivatable Pt(IV) prodrugs. In this review, we will focus on the development of the coordinated ligands in such Pt(IV) prodrugs and discuss the effects of diverse ligands on their photochemistry and photoactivity as well as the future evolution directions of the ligands. We hope this review can help to facilitate the design and development of novel photoactivatable Pt(IV) anticancer prodrugs.

Age of information (AoI) captures the freshness of information and has been used broadly as an important performance metric in big data analytics in the Internet of Things (IoT). We consider a general scenario where a meaningful piece of information consists of multiple packets and the information is not complete until all related packets have been correctly received. Minimizing AoI in this general scenario is challenging in both scheduling algorithm design and theoretical analysis, because we need to track the history of received packets before a complete piece of information can be updated. We first analyse the necessary condition for optimal scheduling, based on which we present an optimal scheduling method. The optimal solution, however, has high time complexity. To address the problem, we investigate the problem with a special type of learning, i.e., learning in restless multi-armed bandits (RMAB), and propose a Whittle index-based scheduling method. We also propose a new transmission strategy based on erasure codes to improve the performance of scheduling policies in lossy networks. Performance evaluation results demonstrate that our solution outperforms other baseline policies such as greedy policy and naïve Whittle index policy in both lossless and lossy networks.

MicroRNA-92a (miR-92a) may serve as a novel promising biomarker in multiple cancers, including colorectal cancer (CRC); however, the diagnostic accuracy and the underlying molecular mechanism of miR-92a in CRC is poorly understood. We first carried out meta-analysis and found that serum/plasma miR-92a yield better diagnostic efficacy when compared to stool samples and CRC tissues, and this finding was validated by our independent study through stool sample. Multiple bioinformatics assay indicated that miR-92a expression was positively correlated with heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1) expression and closely related with the clinical characteristics of CRC. Experimental evidence showed that knockdown of HNRNPA2B1 could significantly decrease miR-92a expression and secretion in RKO cells. HNRNPA2B1 mediated miR-92a via m6A RNA modification. These findings indicate that HNRNPA2B1-m6A RNA modification-derived MicroRNA-92a upregulation and section from the local CRC acts a candidate noninvasive serum biomarker in colorectal cancer. Our study provides a novel insight into miR-92a mechanisms in relation to both expression and secretion for CRC diagnosis.

Background. Vaspin is an important adipokine that is involved in cardiovascular diseases. This study is aimed at investigating whether vaspin participates in sepsis-induced cardiac injury and explored the possible mechanism. Methods. First, cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) were used to establish a mouse model of sepsis, and cardiac vaspin expression was examined. In addition, after pretreatment with vaspin or phosphate-buffered saline (PBS), wild-type (WT) mice underwent CLP to establish a septic model and received sham as a control. Finally, WT mice and kallikrein 7 (KLK7-/-) mice were underwent CLP with or without vaspin pretreatment. Results. Mice that underwent CLP and were administered LPS exhibited increased vaspin expression in both the heart and serum compared with sham- or saline-treated mice. In CLP mice, pretreatment with vaspin reduced mortality and alleviated the expression of cardiac injury markers and cardiac dysfunction. In addition, vaspin reduced the cardiac levels of CD45+ cells and CD68+ cells, alleviated the cardiac inflammatory response, and reduced cardiomyocyte apoptosis. The protective effects of vaspin on CLP mice were masked by the deletion of KLK7, which was demonstrated to be a downstream signal of vaspin. Conclusions. Vaspin alleviates cardiac inflammation and plays a protective role in sepsis-induced cardiac injury by reducing KLK7 expression.

Background. There exist sex differences in the clinical profile, management, and outcome of atrial fibrillation (AF). Catheter ablation of AF has become a first-line therapy and has markedly made headway over the recent decades. Little is known about sex differences and temporal trends in hospitalization for catheter ablation of AF in the real-world setting. Methods. We retrospectively retrieved medical records of patients at Beijing Anzhen Hospital between January 2005 and December 2019. The patients undergoing catheter ablation of AF were enrolled. Demographical and clinical data were compared between sexes. The temporal trends of sex differences were evaluated. Results. We identified 13502 male patients (66.8%) and 6713 female patients (33.2%). The number of patients undergoing AF ablation had remarkably increased over time, but no sex differences were observed (p=0.17). The median age of women was five years older than that of men (p

Abstract Background To investigate the occurrence frequency, changing trends, and epidemiological distribution of unintentional suffocation in children under 5 years old. Methods The data were collected from the Maternal and Child Health Surveillance system from 2009 to 2018. The cause of death was classified by ICD-10. Data on unintentional suffocation death were calculated according to the characteristics of the population, time, space, cause of death and medical treatment, and constituent ratio were calculated. Results The mortality rate of children under 5 years old showed a downward trend, but the mortality of unintentional suffocation initially decreased and then increased. The death rate of unintentional suffocation in children less than 1-year-old was much higher than that in children aged 1 to 4 years old. The death rate of unintentional suffocation was higher in boys than in girls, and the rate was higher for rural children than for urban children. The number of low-weight and pre-term infants in the group under 1-year-old was significantly higher than that in the group of 1–4 years old. Children under 1-year-old are more likely to die at home than children aged 1 to 4 years old, and a higher proportion of younger children did not receive treatment. More than 80% of children under the age of 5 go untreated because it was too late to go to the hospital. Conclusion For areas and populations with a high incidence of unintentional suffocation, we suggest that priorities should include prevention, the development of a safe environment, strengthened prevention, the development of safety habits, and the popularization of first aid knowledge.

This article analyzes the performance of pinned photodiode (PPD) for Time-of-Flight(ToF) applications on high resistivity epitaxial wafers. Due to its wide depletion region, high epitaxial resistivity PPDs feature some key advantages in collecting photogenerated charges. This article compares the demodulation contrast of the same pixel design on epitaxial wafers with different resistivity at near-infrared wavelength to analyze their performance. By comparing the simulated profile of pixels with different epitaxial resistivity, the characteristics of the PPD pixel on high resistivity epitaxial wafer when collecting photogenerated charges are concluded. This article also discusses the effects of using high resistivity epitaxial wafer with various design parameters. It is found that the use of high resistivity epitaxial wafer can greatly improve crosstalk performance, allow pixels to work at higher modulation frequencies, and enable large-sized pixels to have good demodulation capabilities.

Abstract Background To explore the patterns of failures and areas at highest risk of recurrence for postoperative intrahepatic cholangiocarcinoma (IHCC), with the aim to guide IHCC adjuvant radiotherapy. Methods Patients with IHCC who had undergone radical surgery at our institution from July 2010 to August 2017 were retrospectively analyzed. The survival and prognostic factors were analyzed by univariate and multivariate analysis. All sites of recurrence were found out and classified as the surgical margin, regional lymph nodes, liver remnant and distant metastasis. According to the recurring area at highest risk, the target volume of adjuvant radiotherapy was proposed. Results The median follow-up time was 23.5 months (2–85 months). The median recurrence free survival (RFS) and overall survival (OS) were 12.1 months and 24.8 months, respectively. Seventy-three (73/127, 57.5%) IHCC patients developed tumor recurrence. Initial recurrences occurred in the potential postoperative radiotherapy (PORT) volume, remnant liver and distant sits were 46 (46/73, 63.0%), 36 (36/73, 49.3%) and 22 (22/73, 30.1%) cases, respectively. Of the 46 patients whose initial recurrence inside the potential PORT volume, 29 (29/73, 39.7%) developed recurrence only inside the potential PORT volume, including 13 tumor bed recurrences, 7 lymph node metastases, and 9 with both tumor bed recurrences and lymph node metastases. The most common lymph node metastases sites were nodes around the abdominal aorta, followed by lymph nodes along the celiac artery, the common hepatic artery, and in the hepatoduodenal ligament. Conclusions High proportion of the recurrences occurred only inside the potential PORT volume, implying adjuvant radiotherapy might improve the local-regional control. Surgical margins and lymph node stations No.16a2, 9, 8, 12, 13, and 14 are suggested to be included in the radiation volume.

The study aimed to investigate the economic costs in families of children with autism spectrum disorder (ASD) and explored how the time interval from diagnosis to treatment time interval from the date children first diagnosed with ASD to the date of first speech/behavior treatment influenced the economic costs. It was a cross-sectional study that recruited families with autistic children in Changsha, Hunan Province of China during March to November 2018. A self-designed questionnaire was applied to collect ASD-related economic costs in the two vital periods including the 12-month period after diagnosis and the most recent 12 months during the course of ASD. In total, 136 families with autistic children completed the interview. The results showed that 46.3% of children started intervention within 1 month. The median of total economic costs of these families in the 12-month period after diagnosis and the most recent 12 months was 26,502.26 RMB and 29,411.91 RMB, respectively. Compared with the time interval shorter than 1 month, time interval over 6 months was significantly associated with high direct economic costs (βSD = 0.308, 95% CI = 0.177, 1.254), inpatient/outpatient and drugs costs (βSD = 0.276, 95% CI = 0.104, 1.181), direct non-medical costs (βSD = 0.287, 95% CI = 0.140, 1.206), and total economic burden (βSD = 0.311, 95% CI = 0.186, 1.262); besides, time interval between 4 and 6 months was significantly related to large indirect costs (βSD = 0.230, 95% CI = 0.098, 1.363) in the 12-month period after diagnosis. Similarly, time interval between 1 and 3 months was significantly associated with high direct non-medical costs (βSD = 0.198, 95% CI = 0.004, 1.013) in the 12-month period after diagnosis. However, time interval from diagnosis to treatment was not correlated to economic costs in the recent 12 months. In the long term, shortening the time interval from diagnosis to treatment would reduce the economic burden on families, especially in the 12-month period after diagnosis.

Escherichia albertii is an emerging zoonotic foodborne enteropathogen leading to human gastroenteritis outbreaks. Although E. albertii has been isolated from birds which have been considered as the potential reservoirs of this bacterium, its prevalence in migratory birds has rarely been described. In this study, E. albertii in migratory birds from Poyang Lake was investigated and characterized using whole genome sequencing. Eighty-one fecal samples from nine species of migratory birds were collected and 24/81 (29.6%) tested PCR-positive for E. albertii-specific genes. A total of 47 isolates was recovered from 18 out of 24 PCR-positive samples. All isolates carried eae and cdtB genes. These isolates were classified into eight E. albertii O-genotypes (EAOgs) (including three novel EAOgs) and three E. albertii H-genotypes (EAHgs). Whole genome phylogeny separated migratory bird-derived isolates into different lineages, some isolates in this study were phylogenetically closely grouped with poultry-derived or patient-derived strains. Our findings showed that migratory birds may serve as an important reservoir for heterogeneous E. albertii, thereby acting as potential transmission vehicles of E. albertii to humans.

Summary: Tumor multiregion sequencing reveals intratumor heterogeneity (ITH) and clonal evolution playing a key role in tumor progression and metastases. Large-scale high-depth multiregional sequencing of colorectal cancer, comparative analysis among patients with right-sided colon cancer (RCC), left-sided colon cancer (LCC), and rectal cancer (RC), as well as the study of lymph node metastasis (LN) with extranodal tumor deposits (ENTDs) from evolutionary perspective remain weakly explored. Here, we recruited 68 patients with RCC (18), LCC (20), and RC (30). We performed high-depth whole-exome sequencing of 206 tumor regions including 176 primary tumors, 19 LN, and 11 ENTD samples. Our results showed ITH with a Darwinian pattern of evolution and the evolution pattern of LCC and RC was more complex and divergent than RCC. Genetic and evolutionary evidences found that both LN and ENTD originated from different clones. Moreover, ENTD was a distinct entity from LN and evolved later.

It is common to find that some of the lactose in dairy powders and pharmaceutical tablets is present in the unstable amorphous state. Therefore, their crystallization thermodynamics in different solvents are particularly important. In this paper, the solubility of α-lactose monohydrate (α-LM) in 15 mono-solvents such as ethanol, isopropanol, methanol, 1-propanol, 1-butanol, 2-butanol, isobutanol, 1-pentanol, isoamylol, 1-hexanol, 1-heptanol, 1-octanol, propanoic acid, acetonitrile, and cyclohexanone was evaluated by using the gravimetric method in the temperature ranges from 274.05 K to 323.05 K at constant pressure (1 atm). In the given temperature range, the solubility of α-LM in these solvents increased with the rising of temperature, the highest solubility of α-LM was found in methanol (2.37 × 104), and the lowest was found in 1-hexanol (0.80 × 105). In addition, the increase of α-LM solubility in isopropanol was the largest. The sequence at 298.15 K was: methanol > 1-butanol > isopropanol > ethanol > 1-propanol > 1-heptanol > isobutanol > propionic acid > 1-pentanol > 1-octanol > acetonitrile > isoamylol > 2-butanol > cyclohexanone > 1-hexanol. Solvent effect analysis shows that the properties of α-LM are more important than those of solvents. The Apelblat equation, λh equation, Wilson model, and NRTL model were used to correlate the experimental values. The root-mean-square deviation (RMSD) and relative average deviation (RAD) of all models were less than 2.68 × 10−2 and 1.41 × 10−6, respectively, implying that the fitted values of four thermodynamic models all agreed well with the experimental values. Moreover, the thermodynamic properties of the dissolution process (i.e., dissolution Gibbs free energy (ΔdisG), molar enthalpy (ΔdisH), and molar entropy (ΔdisS)) for α-LM in selected solvents were determined. The results indicate that ΔdisH/(J/mol) (from 0.2551 to 6.0575) and ΔdisS/(J/mol/K) (from 0.0010 to 0.0207) of α-LM in these solvents are all positive, and the values of ΔdisH and ΔdisS. ΔdisG/(J/mol) (from −0.0184 to −0.6380) are all negative. The values were observed to decrease with rising temperatures, implying that α-LM dissolution is an endothermic, entropy-driven, and spontaneous process. The solid–liquid equilibrium data and dissolution thermodynamics of α-LM were obtained, which provide a basis for industrial production.

Tumor mutation burden (TMB) serves as an effective biomarker predicting efficacy of mono-immunotherapy for non-small cell lung cancer (NSCLC). Establishing a precise TMB predicting model is essential to select which populations are likely to respond to immunotherapy or prognosis and to maximize the benefits of treatment. In this study, available Formalin-fixed paraffin embedded tumor tissues were collected from 499 patients with NSCLC. Targeted sequencing of 636 cancer related genes was performed, and TMB was calculated. Distribution of TMB was significantly (p < 0.001) correlated with sex, clinical features (pathological/histological subtype, pathological stage, lymph node metastasis, and lympho-vascular invasion). It was also significantly (p < 0.001) associated with mutations in genes like TP53, EGFR, PIK3CA, KRAS, EPHA3, TSHZ3, FAT3, NAV3, KEAP1, NFE2L2, PTPRD, LRRK2, STK11, NF1, KMT2D, and GRIN2A. No significant correlations were found between TMB and age, neuro-invasion (p = 0.125), and tumor location (p = 0.696). Patients with KRAS p.G12 mutations and FAT3 missense mutations were associated (p < 0.001) with TMB. TP53 mutations also influence TMB distribution (P < 0.001). TMB was reversely related to EGFR mutations (P < 0.001) but did not differ by mutation types. According to multivariate logistic regression model, genomic parameters could effectively construct model predicting TMB, which may be improved by introducing clinical information. Our study demonstrates that genomic together with clinical features yielded a better reliable model predicting TMB-high status. A simplified model consisting of less than 20 genes and couples of clinical parameters were sought to be useful to provide TMB status with less cost and waiting time.

The rare lung cancer subtype pulmonary lymphoepithelioma-like carcinoma is linked to Epstein-Barr virus infection. Here, the authors provide a mutational landscape for this cancer, showing a low burden of somatic mutations and high prevalence of copy number variations.

Abstract Background & Aims Although the prognosis of patients with occult hepatitis B virus (HBV) infection (OBI) is usually benign, a small portion may undergo cirrhosis and subsequently hepatocellular carcinoma (HCC). We studied the mechanism of life-long Integration of virus DNA into OBI host’s genome, of which may induce hepatocyte transformation. Methods We applied HBV capture sequencing on single cells from an OBI patient who, developed multiple HCC tumors and underwent liver resection in May 2013 at Tongji Hospital in China. Despite with the undetectable virus DNA in serum, we determined the pattern of viral integration in tumor cells and adjacent non-tumor cells and obtained the details of the viral arrangement in host genome, and furthermore the HBV integrated region in cancer genome. Results HBV captured sequencing of tissues and individual cells revealed that samples from multiple tumors shared two viral integration sites that could affect three host genes, including CSMD2 on chr1 and MED30/EXT1 on chr8. Whole genome sequencing further indicated one hybrid chromosome formed by HBV integrations between chr1 and chr8 that was shared by multiple tumors. Additional 50 poorly differentiated liver tumors and the paired adjacent non-tumors were evaluated and functional studies suggested up-regulated EXT1 expression promoted HCC growth. We further observed that the most somatic mutations within the tumor cell genome were common among the multiple tumors, suggesting that HBV associated, multifocal HCC is monoclonal in origin. Conclusion Through analyzing the HBV integration sites in multifocal HCC, our data suggested that the tumor cells were monoclonal in origin and formed in the absence of active viral replication, whereas the affected host genes may subsequently contribute to carcinogenesis.

Although the National Comprehensive Cancer Network and the Chinese Society of Clinical Oncology guidelines recommend comprehensive genomic profiling of lung adenocarcinoma, it has not been widely applied in Chinese hospitals. This observational study aimed to determine real-world evidence of whether comprehensive genomic profiling can benefit the survival of patients with lung cancer. We investigated the frequency of genomic alterations, treatment strategies, and clinical outcomes in 233 patients with advanced non-small cell lung carcinoma who were routinely screened using a 508-gene panel. The most prevalent drivers were mutations of EGFR (51%), KRAS (9%), PIK3CA (7%), ALK (7%), MET (6%), and BRAF (5%). Mutations in tumor suppressor genes included TP53, KEAP1, RB1, PTEN, and APC. Median overall survival (OS) was significantly shorter among patients harboring KRAS (mutant, n = 17; WT, n = 154) and TP53 (mutant, n = 103; WT n =68) mutations (11.3 vs. 24.0 months; P = 0.16 and 18.7 vs. 28.7 months; P = 0.018, respectively). The OS was longer among patients with tumors harboring EGFR (P = 0.069) and ALK (P = 0.51) mutations. Most patients (65.4%) with the driver gene-positive (EGFR, ALK, and ROS1) tumors were received TKI treatment, whereas those with driver gene wild tumors (53.1%) chose platinum-based therapy. Univariate and multivariate analyses associated a shorter OS among patients with tumors harboring concomitant TP53 and EGFR mutations. These findings provide additional evidence from real-world on the potential importance of targeted therapies as a treatment option in NSCLC patients harboring clinically actionable mutation.

Introduction: This study aimed to develop and validate the combination of radiomic features and clinical characteristics that can predict patient survival in hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) treated with stereotactic body radiotherapy (SBRT).Materials and Methods: The prediction model was developed in a primary cohort of 70 patients with HCC and PVTT treated with SBRT, using data acquired between December 2015 and June 2017. The radiomic features were extracted from computed tomography (CT) scans. A least absolute shrinkage and selection operator regression model was used to build the model. Multivariate Cox-regression hazard models were created for analyzing survival outcomes and the radiomic features and clinical characteristics were presented with a nomogram. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the model. Participants were divided into a high-risk group and a low-risk group based on the radiomic features.Results: A total of four radiomic features and six clinical characteristics were extracted for survival analysis. A combination of the radiomic features and clinical characteristics resulted in better performance for the estimation of overall survival (OS) [area under the curve (AUC) = 0.859 (CI: 0.770–0.948)] than that with clinical characteristics alone [AUC = 0.761 (CI: 0.641–0.881)]. These patients were divided into high-risk and low-risk groups according to the radiomic features.Conclusion: This study demonstrated that a nomogram of combined radiomic features and clinical characteristics can be conveniently used to assess individualized preoperative prediction of OS in patients with HCC with PVTT before SBRT.

The application of tunnel-slag-improved high liquid limit soil as filling materials in subgrade is a green environmental technology. This study explored the influence of tunnel slag mixing on the physical and mechanical properties of improved soils, based on the engineering background of Liyu highway, Guangxi Province, China. Firstly, the optimal moisture content, maximum dry density, shear strength parameters, California bearing ratio (CBR) and resilience modulus of plain and tunnel-slag-improved high liquid limit soils were experimentally determined. Results showed that the direct utilization of untreated soil was unacceptable in subgrade practice. A significant enhancement of integrity of high liquid limit soils could be obtained by tunnel slag mixing, and the value of 15% was determined as the optimal tunnel slag content in soils, leading to improved soil performance meeting the specification requirements. Then, numerical simulation on the stability of subgrade slope of tunnel-slag-improved soils at the content of 15% was conducted. It also reported the long-term subgrade settlements. The feasibility of utilization of tunnel slag in improving properties of high liquid limit soils was further validated. Finally, a good application of tunnel-slag-improved high liquid limit soil as subgrade filling materials in Liyu highway was achieved. The findings in this study could provide useful guidance for similar engineering.

In this study, multilayer graphene oxide (GO) was used to prepare the functional layer of polyimide/GO composite membrane with polyimide (P84) used as the supporting layer. Chitosan added in the functional layer was utilized to adjust the selectivity of the composite membrane. The effects of GO and chitosan contents on membrane morphology and separation performance were investigated in detail. The composite membrane showed high rejection to Congo red and Methyl orange with high flux but low rejection to Na2SO4 and MgCl2 at 0.2 MPa and ambient temperature. The membrane exhibited excellent solvent resistance in N,N-dimethylacetamide (DMAc) after being crosslinked with 0.5 wt.% triethylene tetramine. The result means that a highly selective and solvent-resistant P84/GO composite membrane was prepared with the facile filtration preparation method.

Shotcrete lining shows high resistance but extremely low deformability. The utilization of yielding elements in shotcrete lining, which leads to the so-called ductile lining, provides a good solution to cope with tunnel squeezing deformations. Although ductile lining exhibits great advantages regarding tunnel squeezing deformation control, little information has been comprehensively and systematically available for its mechanism and design. This is a review paper for the purpose of summarizing the development history and discussing the state of the art of ductile lining. It begins by providing a brief introduction of ductile lining and an explanation of the importance of studying this issue. A following summary of supporting mechanism and benefits of ductile lining used in tunnels excavated in squeezing ground conditions is provided. Then, it summarizes the four main types of yielding elements applied in shotcrete lining and introduces their basic structures and mechanical performances. The influences of parameters of yielding elements on the supporting effect are discussed and the design methods for ductile lining are reviewed as well. Furthermore, recommendations for further research in ductile lining are proposed. Finally, a brief summary is presented.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel class of glucose-lowering agents that significantly improve the prognosis of patients with type 2 diabetes (T2D) and heart failure. SGLT2i has recently been implicated in the treatment of atrial fibrillation (AF) with clinical data demonstrating that these agents decrease the incidence of AF events in patients with T2D. Fundamental findings have suggested that SGLT2i may alleviate atrial electrical and structural remodeling. The underlying mechanisms of SGLT2i are likely associated with balancing the sodium and calcium handling disorders and mitigating the mitochondrial dysfunction in atrial myocytes. This review illustrates the advances in understanding the underlying mechanisms of SGLT2i as an evolving treatment modality for AF.

Modeling of genomic profiles from the Cancer Genome Atlas (TCGA) by using recently developed mathematical frameworks has associated a genome-wide pattern of DNA copy-number alterations with a shorter, roughly one-year, median survival time in glioblastoma (GBM) patients. Here, to experimentally test this relationship, we whole-genome sequenced DNA from tumor samples of patients. We show that the patients represent the U.S. adult GBM population in terms of most normal and disease phenotypes. Intratumor heterogeneity affects ≈ 11 % and profiling technology and reference human genome specifics affect 30%. With a 2.25-year Kaplan–Meier median survival difference, a 3.5 univariate Cox hazard ratio, and a 0.78 concordance index, i.e., accuracy, the pattern predicts survival better than and independent of age at diagnosis, which has been the best indicator since 1950. The prognostic classification by the pattern may, therefore, help to manage GBM pseudoprogression. The diagnostic classification may help drugs progress to regulatory approval. The therapeutic predictions, of previously unrecognized targets that are correlated with survival, may lead to new drugs. Other methods missed this relationship in the roughly 3B-nucleotide genomes of the small, order of magnitude of 100, patient cohorts, e.g., from TCGA. Previous attempts to associate GBM genotypes with patient phenotypes were unsuccessful. This is a proof of principle that the frameworks are uniquely suitable for discovering clinically actionable genotype–phenotype relationships.

Platinum(II) terpyridine complexes has attracted increasing attention as they have displayed great potential as antitumor agents due to their high intercalation affinity with nucleic acids. Epidermal growth factor receptor (EGFR) is often overexpressed in various tumor cells, leading to uncontrolled growth of tumor, and is regarded as an important target for developing novel antitumor drugs. Herein, we report four platinum(II) terpyridine complexes bearing EGFR inhibiting 4-anilinoquinazoline derivatives as potent multi-targeting antiproliferation agents against a series of cancer cells. EGFR inhibition assay revealed that these complexes are highly potent EGFR inhibitors. But competitive DNA binding assay and docking simulations also suggested that these complexes exhibited multiple modes of DNA interaction, especially great affinity toward DNA minor groove. Finally, cellular uptake and distribution measurements by inductively coupled plasma mass spectrometry (ICP-MS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) demonstrated that both nucleus DNA and membrane proteins are important targets for their anticancer mechanisms. The complexes herein can therefore be regarded as promising multi-targeting anticancer agents.