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Beethoven is renowned for his masterful compositions, but his personal life was rife with challenges that deeply affected his work. This paper examines the ups and downs of Beethoven's life, including his struggles with family, friendship, love, career, political demands, and general life challenges. The study analyzes the four major misfortunes that impacted Beethoven's life, leading to a sense of hopelessness before he created his most notable works. The paper explores how these misfortunes impacted Beethoven's world view and creative output. The study concludes that the artist's personal challenges, particularly negative experiences such as sorrows and pains, had a significant impact on his creativity. It is through these struggles that Beethoven created masterpieces that conveyed the humanity and reality of the world. This paper provides insights into Beethoven's life and offers a reference for future studies on the artist's personal experiences, particularly in his formative years.

Although 1-hydroxy-4-quinolone derivatives, such as 2-heptyl-4-hydroxyquinoline-N-oxide (HQNO), aurachin C, and floxacrine, have been reported as effective cytochrome bc1 complex inhibitors, the bioactivity of these products is not ideal, presumably due to their low bioavailability in tissues, particularly their poor solubility and low mitochondrial accumulation. In order to overcome the drawbacks of these compounds and develop their use as agricultural fungicides acting by cytochrome bc1 inhibition, in this study, three novel mitochondria-targeting quinolone analogs (mitoQNOs) were designed and synthesized by conjugating triphenylphosphonium (TPP) with quinolone. They exhibited greatly enhanced fungicidal activity compared to the parent molecule, especially mitoQNO11, which showed high antifungal activity against Phytophthora capsici and Sclerotinia sclerotiorum with EC50 values of 7.42 and 4.43 μmol/L, respectively. In addition, mitoQNO11 could inhibit the activity of the cytochrome bc1 complex of P. capsici in a dose-dependent manner and effectively depress its respiration and ATP production. The greatly decreased mitochondrial membrane potential and massively generated reactive oxygen species (ROS) strongly suggested that the inhibition of complex III led to the leakage of free electrons, which resulted in the damage of the pathogen cell structure. The results of this study indicated that TPP-conjugated QNOs might be used as agricultural fungicides by conjugating them with TPP.

Chemokines and immunomodulatory factors involve in tumor development. Papillary thyroid carcinoma (PTC) is considered to start from dendritic cell infiltration and then produce immunomodulatory factors. In this study, CXCR4 and PD-L1 biomarkers were used to explore their prognostic role in PTC survival. Confocal microscopy detected the transfection efficiency in tumor cells. 42 PTC patients and thyroiditis patients (control) were enrolled to measure the expressions of CXCR4 and PD-L1. Multi-factor analysis analyzed the effect of combined CXCR4 and PD-L1 expression on ROC. The two groups had no differences in the baseline characteristics. CTXCR4 and PD-L1 level in PTC patients was significantly higher than control. CXCR4 was lowly expressed in thyroid cancer tissue and PD-L1 was highly expressed in serological samples. Compared with single measurement, the combined detection of CXCR4 and PD-L1 showed more ROC area. In conclusion, reduced CXCR4 and increased PD-L1 level is found in thyroid cancer and their level might be used as predictive markers for PTC to improve the curative effect.

Phallus rubrovolvatus is a unique mushroom used for medicinal and dietary purposes in China. In recent years, however, the rot disease of P. rubrovolvatus has seriously affected its yield and quality, becoming an economically important threat. In this study, samples of symptomatic tissues were collected, isolated, and identified from five major P. rubrovolvatus production regions in Guizhou Province, China. Based on combined analyses of phylogenies (ITS and EF1-α), morphological characteristics and Koch’s postulates, Trichoderma koningiopsis and Trichoderma koningii were identified as the pathogenic fungal species. Among these, T. koningii exhibited stronger pathogenicity than the other strains; thus, T. koningii was used as the test strain in the follow-up experiments. Upon co-culturing T. koningii with P. rubrovolvatus, the hyphae of the two species were intertwined, and the color of the P. rubrovolvatus hyphae changed from white to red. Moreover, T. koningii hyphae were wrapped around P. rubrovolvatus hyphae, leading to their shortening and convolution and ultimately inhibiting their growth due to wrinkling; T. koningii penetrated the entire basidiocarp tissue of P. rubrovolvatus, causing serious damage to the host basidiocarp cells. Further analyses revealed that T. koningii infection resulted in the swelling of basidiocarps and significantly enhanced the activity of defense-related enzymes, such as malondialdehyde, manganese peroxidase, and polyphenol oxidase. These findings offer theoretical support for further research on the infection mechanisms of pathogenic fungi and the prevention of diseases caused by them.

Supple Fig 1, Supple Table 1-8, and Supple Ref. Supplementary Figure S1. 2100 Bioanalyzer spectra of total DNA extracted from CSF samples. Supplementary Table S1. Sample collection information. Supplementary Table S2. Genes/regions included in the LungPlasma panel. Supplementary Table S3. Genes included in the customized SeqCap EZ Choice Library. Supplementary Table S4. List of hotspot mutations and structural rearrangements. Supplementary Table S5. Co-existence of EGFR and PIK3CA mutations as reported in NSCLC patient datasets Supplementary Table S6. Occurrence of somatic protein-changing variants in primary tumor and CSF. Supplementary Table S7. Genes and biological pathways with recurrent somatic protein-changing variants in primary tumor or CSF. Supplementary Table S8. Comparison of EGFR mutation type(s) in CSF cfDNA and pellet DNA as detected by droplet digital PCR (ddPCR).

Purpose: Leptomeningeal metastasis (LM) is a detrimental complication of non–small cell lung cancer (NSCLC) and associated with poor prognosis. However, the underlying mechanisms of the metastasis process are still poorly understood.Experimental Design: We performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF), and matched normal controls from epidermal growth factor receptor (EGFR) mutation-positive NSCLC patients with LM.Results: The status of EGFR-activating mutations was highly concordant between primary tumor and CSF. PIK3CA aberrations were high in these patients, implicating an association with LM risk. Intriguingly, low overlapping of somatic protein-changing variants was observed between paired CSF and primary lesions, exhibiting tumor heterogeneity and genetic divergence. Moreover, genes with CSF-recurrent genomic alterations were predominantly involved in cell-cycle regulation and DNA-damage response (DDR), suggesting a role of the pathway in LM development.Conclusions: Our study has shed light on the genomic variations of NSCLC-LM, demonstrated genetic heterogeneity and divergence, uncovered involvement of cell-cycle and DDR pathway, and paved the way for potential therapeutic approaches to this unmet medical need. Clin Cancer Res; 24(1); 209–16. ©2017 AACR.

Cancer is a highly heterogeneous disease, and different individuals of the same cancer type can display different therapeutic effects and prognosis. Genetic variation of long non-coding RNA is the key factor driving tumor development, and plays an important role in genetic and biological heterogeneity. Therefore, it is of great significance to identify lncRNA as a driving factor in the non-coding region and explain its function in tumors for revealing the pathogenesis of cancer. In this study, we developed an integrated method to identify Personalized Functional Driver lncRNAs (PFD-lncRNAs) by integrating the DNA copy number data, gene expression data, and the biological subpathways information. Then, we applied the method to identify 2695 PFD-lncRNAs in 5334 samples across 19 cancer types. We performed an analysis of the association between PFD-lncRNAs and drug sensitivity, which provides medication guidance in disease therapy and drug discovery in the individual. Our research is of great significance for elucidating the biological roles of lncRNA genetic variation in cancer, revealing the related mechanism of cancer, and providing novel insights for individualized medicine.

Introduction: The Medium Energy X-ray telescope (ME) is a collimated X-ray telescope onboard the Insight hard X-ray modulation telescope (Insight-HXMT) satellite. It has 1728 Si-PIN pixels readout using 54 low noise application-specific integrated circuits (ASICs). ME covers the energy range of 5-30 keV and has a total detection area of 952 cm2. The typical energy resolution of ME at the beginning of the mission is 3 keV at 17.8 keV (Full Width at Half Maximum, FWHM) and the time resolution is 255 us. In this study, we present the in-orbit performance of ME in its first 5 years of operation. Methods: The performance of ME was monitored using onboard radioactive sources and astronomical X-ray objects. ME carries six 241Am radioactive sources for onboard calibration, which can continuously illuminate the calibration pixels. The long-term performance evolution of ME can be quantified using the properties of the accumulated spectra of the calibration pixels. In addition, observations of the Crab Nebula and the pulsar were used to check the long-term evolution of the detection efficiency as a function of energy. Conclusion: After 5 years of operation, 742 cm2 of the Si-PIN pixels were still working normally. The peak positions of 241Am emission lines gradually shifted to the high energy region, implying a slow increase in ME gain of 1.43%. A comparison of the ME spectra of the Crab Nebula and the pulsar shows that the E-C relations and the redistribution matrix file are still acceptable for most data analysis works, and there is no detectable variation in the detection efficiency.

Elastography ultrasound (EUS) imaging is a vital ultrasound imaging modality. The current use of EUS faces many challenges, such as vulnerability to subjective manipulation, echo signal attenuation, and unknown risks of elastic pressure in certain delicate tissues. The hardware requirement of EUS also hinders the trend of miniaturization of ultrasound equipment. Here we show a cost-efficient solution by designing a deep neural network to synthesize virtual EUS (V-EUS) from conventional B-mode images. A total of 4580 breast tumor cases were collected from 15 medical centers, including a main cohort with 2501 cases for model establishment, an external dataset with 1730 cases and a portable dataset with 349 cases for testing. In the task of differentiating benign and malignant breast tumors, there is no significant difference between V-EUS and real EUS on high-end ultrasound, while the diagnostic performance of pocket-sized ultrasound can be improved by about 5% after V-EUS is equipped.

BACKGROUND: Transperineal percutaneous laser ablation (TPLA) has been proved a feasible and minimally invasive treatment for lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). However, the comparison with other therapeutic options, in particular transurethral resection of the prostate (TURP), the most widely used and gold standard surgical method for BPH patients, remained absent. METHODS: Totally 51 BPH patients treated between 6/2019 and 12/2021 who had maximum urinary flow rate (Qmax) ≤15 mL/s and international prostate symptom score (IPSS) ≥8 were enrolled and randomly assigned to TURP or TPLA group at the ratio 1:1. TPLA was conducted with Esaote MyLab Twice equipped with flexible optical fiber, and TURP was performed by Olympus UES-40 SurgMaster System under standard procedure. The results were compared at 1, 3, 6 and 12 months after the operation. The efficacy endpoints included IPSS, Qmax, quality of life (QoL), European questionnaire-five dimensions (EQ-5D), residual urine volume (RUV), international index of erectile function-5 (IIEF-5) and ejaculatory dysfunction score. The safety endpoints included the incidence of complications, blood loss, visual analogue score (VAS) of pain, and catheter indwelling time. RESULTS: The IPSS decreased by 14.17±6.13 at 3 months after TPLA, and by 13.19±5.86 after TURP (P=0.706). The complication rate of TPLA and TURP was 16% and 19.23% respectively (P=0.811).TPLA proved less Intraoperative blood loss (6.84±3.1mL,P＜0.001) and better ejaculatory protection within 6 months (P＜0.05). TURP has advantages in catheter indwelling time(P=0.012) and Qmax within 6 months(P＜0.05). CONCLUSIONS: TPLA is comparable to TURP in the symptom relief of BPH patients, and with shorter operation time, less invasiveness and better protection, which may be more suitable for patients intolerant to TURP, or with underlying diseases such as anemia.

Until menopause, women have a lower propensity to develop metabolic diseases than men, suggestive of a protective role for sex hormones. Although a functional synergy between central actions of estrogens and leptin has been demonstrated to protect against metabolic disturbances, the underlying cellular and molecular mechanisms mediating this crosstalk have remained elusive. By using a series of embryonic, adult-onset, and tissue/cell-specific loss-of-function mouse models, we document an unprecedented role of hypothalamic Cbp/P300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 1 (Cited1) in mediating estradiol (E2)-dependent leptin actions that control feeding specifically in pro-opiomelanocortin (Pomc) neurons. We reveal that within arcuate Pomc neurons, Cited1 drives leptin's anorectic effects by acting as a co-factor converging E2 and leptin signaling via direct Cited1-ERα-Stat3 interactions. Together, these results provide new insights on how melanocortin neurons integrate endocrine inputs from gonadal and adipose axes via Cited1, thereby contributing to the sexual dimorphism in diet-induced obesity.

With the development of precision medicine, therapies of targeting driver genes have significantly prolonged survival in advanced non-small cell lung cancer (NSCLC) patients. Among them, BRAF gene mutation is relatively rare, and the traditional regimen follows the treatment plan of NSCLC without driver gene mutation, which is far from meeting the clinical needs. In recent years, targeted therapy for NSCLC patients with BRAF V600E mutations has shown good efficacy when we are still exploring the better targeted therapies for other BRAF-mutated subtypes. Immunotherapy also showed positive antitumor activity in V600E and non-V600E subtypes of BRAF-mutated NSCLC. This article reviewed the progress of immunological and targeted therapy for patients with BRAF-mutated NSCLC.

Methoxyfenozide and metaflumizone are insecticides used on Chinese broccoli to prevent insects and increase yield. However, the residues are potentially harmful to the environment and consumers. In this study, the quick, easy, cheap, effective, rugged, safe method with high-performance liquid chromatography with tandem mass spectrometry was modified and validated for determination of methoxyfenozide and metaflumizone in Chinese broccoli. The clean-up efficiency of different sorbents including C18 , primary secondary amine, graphitized carbon black, and carbon nanofiber was compared. Recoveries of the validated method were 71.8-94.6% with relative standard deviations of 1.5-3.2% and the limits of quantification were 0.01 and 0.005 mg/kg for methoxyfenozide and metaflumizone, respectively. A storage stability test showed almost no degradation of methoxyfenozide in Chinese broccoli, however, the degradation rate of metaflumizone was 22.9% after 10-wk storage at -20°C. In field trials in four producing regions, the dissipation of both methoxyfenozide and metaflumizone in Chinese broccoli was fast, with half-lives of only 1.0-5.1 and 0.7-2.5 days, respectively. Terminal residues after application of the two pesticides were all below 1.0 mg/kg after 5 days.

Background There existed evidence that type 2 diabetes mellitus (T2DM) prevalence and control rate have seasonal variation. Our study aimed to examine the ambient temperature and fasting plasma glucose (FPG) association and estimate temperature-adjusted T2DM prevalence and control rate. Methods Four cross-sectional health surveys with 26,350 respondents were conducted in Guangdong Province from 2007 to 2015. Multistage cluster sampling was used to recruit study participants. The data of demographic characteristics, lifestyle factors, diet and use of hypoglycemic medicine, height, weight, FPG and meteorological information were collected. And an inverse distance-weighted method was employed to estimate daily temperature exposures at the individual’ s residential district/county. Base on World Health Organization 2006 criteria, participants were divided into normal fasting glucose (NFG) participants (n = 23,877), known T2DM patients (n = 916) and newly detected T2DM patients (n = 1557). Generalized additive mixed model was employed to evaluate the nonlinear associations between temperature and FPG among different T2DM subgroups. The T2DM prevalence and control rate were estimated based on temperature-FPG association. Results The curves of temperature and FPG were downward parabola for total, NFG and known T2DM groups, while it was “U”-shaped for newly detected T2DM patients. When temperature decreased from 30 °C to 4 °C, the FPG significantly increased 0.24 (95%CI: 0.15, 0.33) mmol/L, 0.10 (95%CI: 0.06, 0.14) mmol/L and 1.34 (95%CI: 0.56, 2.12) mmol/L in total, NFG and known T2DM groups, respectively. Compared to 19 °C, newly detected T2DM patients’ FPGs were increased 0.73 (95%CI: 0.13, 1.30) mmol/L at 4 °C and 0.53 (0.00, 1.07) mmol/L at 30 °C. The model-estimated temperature-adjusted T2DM prevalence had a down and up trend, with 9.7% at 5 °C, 8.9% at 20 °C and 9.4% at 30 °C, respectively. At 5, 10, 15, 20, 25 and 30 °C, the model-estimated temperature-adjusted T2DM control rates were 33.2, 35.4, 38.2, 43.6, 49.1 and 55.2%. Conclusion Temperature was negatively associated with FPG for NFG and known T2DM subgroups, while their association was U-shape for newly detected T2DM patients. Hence, the temperature-adjusted T2DM prevalence show a dip/peak pattern and T2DM control rate display a rising trend when temperature increase. Our findings suggest temperature should be considered in T2DM clinic management and epidemiological survey.

Combination of the strong light-absorbing power of plasmonic metals with the superior charge carrier dynamics of halide perovskites is appealing for bio-inspired solar-energy conversion due to the potential to acquire long-lived plasmon-induced hot electrons. However, the direct coupling of these two materials, with Au/CsPbBr

Previous small-size studies reported BRAF-mutated NSCLC patients have comparable sensitivity to immune checkpoint inhibitors (ICIs). However, how BRAF mutation affects the tumor immune microenvironment (TIME) is unknown. We performed Nanostring-panel RNA sequencing to evaluate TIME in 57 BRAF mutated and wild-type (WT) NSCLC specimens (cohort A). The efficacy of ICI monotherapy or combined therapies was determined in 417 patients with WT and BRAF mutated NSCLC (cohort B). We found that BRAF-mutant tumors had similar ratios of CD8+ T cells to Tregs, the balance of cytotoxicity gene expression signatures and immune suppressive features, and similar ICI-response-related biomarkers to WT NSCLC. A similar TIME pattern was observed between the BRAF V600E and Non-V600E subgroups of NSCLC. The further retrospective study confirmed that treatment with ICI monotherapy or combined therapies resulted in similar overall survival (OS) (HR: 0.85; 95% CI, 0.56 to 1.30; p = 0.47) and progress-free survival (PFS) (HR: 1.02; 95% CI, 0.72 to 1.44; p = 0.91) of patients with WT (n = 358) and BRAF mutant (n = 59) NSCLC. Similarly, both patients with BRAF V600E or Non-V600E NSCLC had similar responses to immunotherapy. Our findings support that BRAF mutation did not modulate TIME in NSCLC and therapeutic responses to ICIs. Patients with NSCLC harboring BRAF mutation should not be denied treatment with ICIs.

Recently, many studies have shown that lncRNA can mediate the regulation of TF-gene in drug sensitivity. However, there is still a lack of systematic identification of lncRNA-TF-gene regulatory triplets for drug sensitivity. In this study, we propose a novel analytic approach to systematically identify the lncRNA-TF-gene regulatory triplets related to the drug sensitivity by integrating transcriptome data and drug sensitivity data. Totally, 1570 drug sensitivity-related lncRNA-TF-gene triplets were identified, and 16 307 relationships were formed between drugs and triplets. Then, a comprehensive characterization was performed. Drug sensitivity-related triplets affect a variety of biological functions including drug response-related pathways. Phenotypic similarity analysis showed that the drugs with many shared triplets had high similarity in their two-dimensional structures and indications. In addition, Network analysis revealed the diverse regulation mechanism of lncRNAs in different drugs. Also, survival analysis indicated that lncRNA-TF-gene triplets related to the drug sensitivity could be candidate prognostic biomarkers for clinical applications. Next, using the random walk algorithm, the results of which we screen therapeutic drugs for patients across three cancer types showed high accuracy in the drug-cell line heterogeneity network based on the identified triplets. Besides, we developed a user-friendly web interface-DrugSETs (http://bio-bigdata.hrbmu.edu.cn/DrugSETs/) available to explore 1570 lncRNA-TF-gene triplets relevant with 282 drugs. It can also submit a patient’s expression profile to predict therapeutic drugs conveniently. In summary, our research may promote the study of lncRNAs in the drug resistance mechanism and improve the effectiveness of treatment.

Background Genomic studies of colorectal cancer have revealed the complex genomic heterogeneity of the tumor. The acquisition and selection of genomic alterations may be critical to understanding the initiation and progression of this disease. Methods In this study, we have systematically characterized the clonal architecture of 97 driver genes in 536 colorectal cancer patients from TCGA. Results A high proportion of clonal mutations in 93 driver genes were observed. 40 genes showed significant associations between their clonality and multiple clinicopathologic factors. Kaplan–Meier analysis suggested that the mutation clonality of ANK1, CASP8, SMAD2, and ARID1A had a significant impact on the CRC patients' outcomes. Multivariable analysis revealed that subclonal ANK1 mutations, clonal CASP8 mutations, and clonal SMAD2 mutations independently predicted for shorter overall survival after adjusting for clinicopathological factors. The poor outcome of the subclonal ANK1 mutation may be caused by upregulation of IL4I1, IDO1, IFNG and MAPK12 which showed potential roles in tumor immune evasion through accumulation of immunosuppressive cells such as regulatory T cells and myeloid derived suppressor cells. Conclusion These results suggested that the clonality of driver genes could act as prognostic markers and potential therapeutic targets in human colorectal cancer.

Nitrate is an important raw material for chemical fertilizers, but it is industrially manufactured in multiple steps at high temperature and pressure, urgently motivating the design of a green and sustainable strategy for nitrate production. We report the photosynthesis of nitrate from N

The growing demand for safer energy storage devices leads to wide research on solid-state lithium-ion batteries. However, as an important component in the solid-state battery, the solid-state electrolyte often encounters problems, especially the low conductivity at room temperature, inhibiting the development of solid-state batteries. Here, improved electrochemical performances of lithium-ion batteries are obtained by designing a composite gel polymer electrolyte with a sponge-like structure. The porous composite gel polymer electrolyte (PCGPE) is developed by a facile phase inversion process of poly(vinylidiene fluoride-hexafluoropropylene) (PVdF-HFP) and Li6.4La3Zr1.4Ta0.6O12 (LLZTO). The solid-state nuclear magnetic resonance test proves the continuous porous structure constructs fast Li-ion transport pathways on internal interfaces. As a result, the ionic conductivity of PCGPE is up to 5.45 × 10-4 S cm-1 at room temperature. Moreover, an initial capacity of 142.2 mAh g-1 and 82.6% capacity retention at 1 C after 350 cycles are successfully achieved in flexible LiFPO4//PCGPE//Li batteries.

Objectives To analyse the patterns of transition of health burden for 110 causes of death by stratification of age, sex and geographic regions in Guangdong between 2005 and 2015. Methods We analysed the age-specific, sex-specific, region-specific mortality in Guangdong based on assembled databases. County-level surveillance data were calculated to inform city-level changes. Results The age-standardised mortality of all causes, non-communicable diseases (NCDs), communicable diseases, maternal diseases, neonatal diseases, malnutrition and injury declined progressively. Despite declining mortality of NCDs, the overall burden of disease was dominated by NCDs (ie, cerebrovascular disease, chronic obstructive pulmonary disease) that still accounted for 86.93% and 88.12% of death in 2005 and 2015, respectively. Considerable variations across geographic regions were observed (lowest in Pearl River Delta and highest in west Guangdong). There was a modest shift to transport injuries at younger ages and unintentional injuries in the elderly. Conclusions We have documented a dramatic change in the overall mortality and age-specific, sex-specific and cause-specific mortality in Guangdong province between 2005 and 2015. The significant burden of NCDs remains a major healthcare issue despite the notable progress in reducing mortality in Guangdong, China. Our findings highlight important unmet needs to refine healthcare services by taking into account the inequity of age, sex and geographic regions. Identification of the ‘treatable’ risk factors and improved disease surveillance should be continuously improved to minimised the overall and cause-specific mortality.

Elastography ultrasound (EUS) imaging is a vital ultrasound imaging modality. The current use of EUS faces many challenges, such as vulnerability to subjective manipulation, echo signal attenuation, and unknown risks of elastic pressure in certain delicate tissues. The hardware requirement of EUS also hinders the trend of miniaturization of ultrasound equipment. We therefore present a cost-efficient solution by designing a deep neural network to synthesize augmented reality EUS (AR-EUS) from conventional B-mode images. By using 4580 cases from 15 medical centers, we evaluate the performance of AR-EUS on breast cancer diagnosis. The quantitative metric and blind evaluation results show no significant difference between AR-EUS and real EUS in image authenticity and in clinical diagnosis. The performance of pocket-sized ultrasound in breast tumor diagnosis is also significantly improved after AR-EUS is equipped. These results highlight the potential of AR-EUS in clinical application.

BACKGROUND: Second-line treatment options for small cell lung cancer (SCLC) are limited. Preclinical research shows that inhibition of poly (ADP-ribose) polymerase (PARP) could upregulate programmed death-ligand 1 (PD-L1), and thus render cancer cells more sensitive to immune checkpoint inhibitors. This study investigated the tolerability, safety, and preliminary antitumor activity of fuzuloparib (a PARP inhibitor) plus SHR-1316 (a PD-L1 inhibitor) for relapsed SCLC. METHODS: Patients with SCLC who failed previous first-line platinum-based therapy were enrolled in this two-stage phase Ib trial. In stage 1, 2 dose levels were designed: fuzuloparib 100 mg or 150 mg twice daily plus SHR-1316 600 mg every 2 weeks, with 6 patients in each dose level. Based on the tolerability during the first 28-day cycle and the preliminary antitumor activity in stage 1, a recommended phase II dose (RP2D) was determined and introduced in the stage 2 expansion phase. The primary endpoints were safety and RP2D in stage 1 and objective response rate (ORR) in stage 2. RESULTS: A total of 23 patients were enrolled, with 16 receiving fuzuloparib 100 mg plus SHR-1316 and 7 receiving fuzuloparib 150 mg plus SHR-1316. At data cutoff on April 23, 2021, the median follow-up duration was 6.4 months (IQR, 3.0–9.7 months). All patients discontinued study treatment. One patient receiving fuzuloparib 150 mg plus SHR-1316 had clinically significant toxicities, and fuzuloparib 100 mg plus SHR-1316 was considered as the RP2D. In the RP2D cohort, the confirmed ORR was 6.3% (95% CI: 0.2–30.2%), and the disease control rate was 37.5% (95% CI: 15.2–64.6%). The median progression-free survival was 1.4 months (95% CI: 1.3–2.8 months), and the median overall survival was 5.6 months (95% CI: 3.0–16.7 months). Grade ≥3 treatment-related adverse events (TRAE) occurred in 8 patients (34.8%). No treatment-related death occurred, and no patients discontinued treatment due to TRAEs. CONCLUSIONS: Fuzuloparib combined with SHR-1316 failed to improve the outcomes in unselected patients with relapsed SCLC. Future studies with biomarker analysis are warranted to select patients most likely to benefit from this combination treatment. Fuzuloparib 100 and 150 mg plus SHR-1316 were both tolerable with no new signals observed.

Glioma is the most common malignant tumor of the central nervous system. Tumor purity is a source of important prognostic factor for glioma patients, showing the key roles of the microenvironment in glioma prognosis. In this study, we systematically screened functional characterization related to the tumor immune microenvironment and constructed a risk model named Glioma MicroEnvironment Functional Signature (GMEFS) based on eight cohorts. The prognostic value of the GMEFS model was also verified in another two glioma cohorts, glioblastoma (GBM) and low-grade glioma (LGG) cohorts, from The Cancer Genome Atlas (TCGA). Nomograms were established in the training and testing cohorts to validate the clinical use of this model. Furthermore, the relationships between the risk score, intrinsic molecular subtypes, tumor purity, and tumor-infiltrating immune cell abundance were also evaluated. Meanwhile, the performance of the GMEFS model in glioma formation and glioma recurrence was systematically analyzed based on 16 glioma cohorts from the Gene Expression Omnibus (GEO) database. Based on multiple-cohort integrated analysis, risk subpathway signatures were identified, and a drug–subpathway association network was further constructed to explore candidate therapy target regions. Three subpathways derived from Focal adhesion (path: 04510) were identified and contained known targets including platelet derived growth factor receptor alpha (PDGFRA), epidermal growth factor receptor (EGFR), and erb-b2 receptor tyrosine kinase 2 (ERBB2). In conclusion, the novel functional signatures identified in this study could serve as a robust prognostic biomarker, and this study provided a framework to identify candidate therapeutic target regions, which further guide glioma patients’ clinical decision.

The growing demand for safer lithium-ion batteries draws researchers' attention to solid-state electrolytes. In general, a desired electrolyte should be flexible, mechanically strong, and with high ionic conductivity. A solid-state electrolyte with a polymer as a matrix seems to be able to meet these demands. However, a pure polymer electrolyte lacks sufficient strength to suppress Li dendrites, and hybrids with ceramic components often lead to poor flexibility, both far from satisfactory. Herein, a solid-state electrolyte is designed by employing a mass-produced porous polyamide (PA) film infiltrated with polyethylene oxide (PEO)/lithium bis(trifluoromethanesulfonyl)imide (LiTFSI). The PA/PEO/LiTFSI electrolyte is flexible but robust with a Young's modulus of up to 1030 MPa, ensuring steady Li//Li cycling without short circuit for more than 400 h. Also, the porous structure of the PA film decreases the crystalline regions and effectively enhances the ionic conductivity (2.05 × 10-4 S cm-1 at 30 °C). When cycled at 1C, solid-state LiFePO4//Li batteries assembled with the PA/PEO/LiTFSI electrolyte retain 82% capacity after 300 cycles (60 °C). In addition, a flexible LiFePO4//PA/PEO/LiTFSI//Li pouch cell can also work well in harsh operating environments, such as being folded, crimped, and pierced.

BACKGROUND Fluazinam is an effective fungicide in controlling gray mold, but has short duration of efficacy. Increasing application dosage may cause phytotoxicity. To overcome this shortage, a controlled-release technology was studied by encapsulating fluazinam. Ethyl cellulose polymer microcapsules were loaded with fluazinam to formulate a fluazinam capsule suspension (FCS). The efficacy for inhibition of B. cinerea and persistency of the FCS were examined by comparing with fluazinam technical concentrate (FTC) and aqueous fluazinam suspension concentrate (FSC) using microscopic observation and high-performance liquid chromatography analysis. RESULTS FCS formed capsules, with median size of 3.17 μm in diameter, had 82.3% encapsulation efficiency. It had a stronger inhibitory activity against B. cinerea than FTC and FSC measured 7 days after the treatments. The half-life of FCS on cucumber leaves was 3.4 days, longer than the 2.3 days of FSC. CONCLUSION FCS formulation significantly improved the inhibition of B. cinerea and resulted in prolonged and sustained release. Moreover, microencapsulation increased the duration of the efficacy of fluazinam on target crops. This formulation could help to sustain pesticides and protect the environment. © 2021 Society of Chemical Industry.

Microglia is a major class of brain-resident myeloid cells and non-coding RNAs (ncRNAs) serves as key regulators in microglia homeostasis and inflammatory process. Here, we constructed the systematical association between microglia and ncRNAs including miRNAs, lncRNAs and circRNAs from two aspects, manual retrieval and computational detection. A total of 648 experimental verified ncRNA-microglia associations were obtained from published studies, including ncRNA regulatory patterns within different experimental models. Furthermore, we extracted 9 miRNA and 1 lncRNA expression profiles from the GEO database. Also, we obtained 31 sample-match miRNA and mRNA expression profiles, containing a total of 2335 normal or disordered brain samples. Finally, we developed a platform named MG-ncRexplorer (http://bio-bigdata.hrbmu.edu.cn/MG-ncRexplorer/), exploring the associations between ncRNAs and microglia among experimental validated and computational detection. To demonstrate the usage of MG-ncRexplorer, we constructed regulatory target networks based on manual retrieval associations and identified risk glioma miRNAs among multiple high-throughput expression profiles.

Objectives: We sought to investigate the effects of occupational exposure to vapors, gases, dust and fumes (VGDF) on chronic bronchitis and lung function impairment. Methods: We conducted chronic obstructive pulmonary disease surveillance in six cities of south China between 2014 and 2019. We recorded the diagnosis of chronic bronchitis, respiratory symptoms, occupational exposure to VGDF and other covariates by using a structured questionnaire. Logistic regression and multivariate linear regression model were adopted for analysis. Results: A total of 7418 and 5249 participants were included. Cough (OR: 1.60, 95%CI: 1.22 to 2.08) and phlegm (OR: 1.49, 95%CI: 1.19 to 1.85) correlated significantly with the exposure to dust. There was an increased risk of cough (OR: 1.53, 95%CI: 1.11 to 2.07) for occupational exposure to gas/vapor/fume. Dual exposure to dust and gas/vapor/fume was associated with a significantly increased risk of chronic bronchitis (OR: 1.74, 95%CI: 1.20 to 2.52), as well as cough (OR: 1.43, 95%CI: 1.15 to 1.79) and phlegm (OR: 1.49, 95%CI: 1.24 to 1.79). Gas/vapor/fume was associated with the reduced ratio of forced expiratory volume in one second and forced vital capacity (FEV1/FVC) (β: -1.05, 95%CI: -1.85 to -0.26) and maximal mid-expiratory flow(MMEF) (β: -0.15, 95%CI: -0.23 to -0.07). Dual exposure to dust and gas/vapor/fume was significantly associated with decreased FEV1/FVC (β: -0.74, 95%CI: -1.28 to -0.20) and MMEF (β: -0.06, 95%CI: -0.12 to -0.01) . Results of sensitivity analysis did not materially change. Conclusions: VGDF exposure was associated with chronic bronchitis, respiratory symptoms and impaired lung function, suggesting that VGDF contribute to the pathogenesis and progression of COPD.

Objective: Patient-derived xenograft (PDX) models have shown great promise in preclinical and translational applications, but their consistency with primary tumors in phenotypic, genetic, and pharmacodynamic heterogeneity has not been well-studied. This study aimed to establish a PDX repository for non-small cell lung cancer (NSCLC) and to further elucidate whether it could preserve the heterogeneity within and between tumors in patients. Methods: A total of 75 surgically resected NSCLC specimens were implanted into immunodeficient NOD/SCID mice. Based on the successful establishment of the NSCLC PDX model, we compared the expressions of vimentin, Ki67, EGFR, and PD-L1 proteins between cancer tissues and PDX models using hematoxylin and eosin staining and immunohistochemical staining. In addition, we detected whole gene expression profiling between primary tumors and PDX generations. We also performed whole exome sequencing (WES) analysis in 17 first generation xenografts to further assess whether PDXs retained the patient heterogeneities. Finally, paclitaxel, cisplatin, doxorubicin, atezolizumab, afatininb, and AZD4547 were used to evaluate the responses of PDX models to the standard-of-care agents. Results: A large collection of serially transplantable PDX models for NSCLC were successfully developed. The histology and pathological immunohistochemistry of PDX xenografts were consistent with the patients’ tumor samples. WES and RNA-seq further confirmed that PDX accurately replicated the molecular heterogeneities of primary tumors. Similar to clinical patients, PDX models responded differentially to the standard-of-care treatment, including chemo-, targeted- and immuno-therapeutics. Conclusions: Our established PDX models of NSCLC faithfully reproduced the molecular, histopathological, and therapeutic characteristics, as well as the corresponding tumor heterogeneities, which provides a clinically relevant platform for drug screening, biomarker discovery, and translational research.

Background: Because the halo around the tumor in shear wave elastography (SWE) is defined as the “stiff rim” sign, the diagnosis of breast lesions with the stiff rim sign is popular. However, only a few studies have described the stiff rim sign quantitatively. Objective: This study aimed to investigate the usefulness of the stiff rim sign in the diagnosis and tumor, node, metastasis stage of breast cancer. Methods: Two hundred and ten breast lesions were analyzed retrospectively. The maximum, mean, minimum Young's modulus (YM), and the YM standard deviation in the lesion, the peritumoral stiffness (shell), and the region containing lesion and shell were obtained. The suspicious SWE feature with the best diagnostic performance was chosen to downgrade or upgrade the Breast Imaging Reporting and Data System (BI-RADS) classification. The coincidence rates of SWE and B-mode ultrasound in T staging and their positive predictive value (PPV) for T staging were compared. Results: The presence of “stiff rim” sign was selected to upgrade or downgrade the BI-RADS classification because of its best performance. In pathological benign lesions, 18.9% (25 of 132) of lesions should undergo biopsy if BI-RADS combined with the stiff rim sign were referred while it was 57.6% (76 of 132) if BI-RADS alone was referred. The coincidence rate of T2 staging evaluated by SWE was significantly higher than B-mode ultrasound (about 30% increase, P < 0.001). The PPVs of SWE for T1 and T2 staging were higher than B-mode ultrasound (P < 0.05). Conclusions: BI-RADS combined with “stiff rim” sign is expected to improve the diagnostic performance of breast lesions to avoid unnecessary biopsy. The maximum diameter of the lesion measured in SWE is more accurate than B-mode ultrasound in the estimation of T staging, which is beneficial to the treatment and prognosis of breast cancer.