Proto-oncogene c-Myb potentiates cisplatin resistance of ovarian cancer cells by downregulating lncRNA NKILA and modulating cancer stemness and LIN28A-let7 axis.

Ovarian cancer is a major gynecological cancer that has poor prognosis associated mainly to its late diagnosis. Cisplatin is an FDA approved ovarian cancer therapy and even though the therapy is initially promising, the patients mostly progress to resistance against cisplatin. The underlying mechanisms are complex and not very clearly understood. Using two different paired cell lines representing cisplatin-sensitive and the cisplatin-resistant ovarian cancer cells, the ES2 and the A2780 parental and cisplatin-resistant cells, we show an elevated proto-oncogene c-Myb in resistant cells. We further show down-regulated lncRNA NKILA in resistant cells with its de-repression in resistant cells when c-Myb is silenced. NKILA negatively correlates with cancer cell and invasion but has no effect on cellular proliferation or cell cycle. C-Myb activates NF-κB signaling which is inhibited by NKILA. The cisplatin resistant cells are also marked by upregulated stem cell markers, particularly LIN28A and OCT4, and downregulated LIN28A-targeted let-7 family miRNAs. Whereas LIN28A and downregulated let-7s individually de-repress c-Myb-mediated cisplatin resistance, the ectopic expression of let-7s attenuates LIN28A effects, thus underlying a c-Myb-NKILA-LIN28A-let-7 axis in cisplatin resistance of ovarian cancer cells that needs to be further explored for therapeutic intervention.

Effects of the Host Plants of the Maize-Based Intercropping Systems on the Growth, Development and Preference of Fall Armyworm, Spodoptera frugiperda (Lepidoptera: Noctuidae).

In this paper, the effects of maize and its three intercropping plants, sweet potato, soybean and peanut, on the growth and development of FAW, feeding preference of larvae, olfactory response and oviposition preference of adults were studied in the laboratory. The results showed that maize and peanut were suitable for the survival and development of FAW, while sweet potato and soybean were not suitable for multigenerational reproduction. The larvae significantly preferred to feed on maize compared to the other three plants. The olfactory response test indicated that soybean showed a strong deterrent effect against FAW adults. Furthermore, the intercropping plants reduced the host selection rate of adults compared to maize alone. In two-choice tests of the maize vs. the intercropping plants, the female adult preferred to oviposit and lay more eggs on maize rather than on the intercropping plants. The intercropping plants significantly reduced the oviposition selection of FAW adults when the combination (maize + intercropping plant), especially soybean and sweet potato, was compared to maize alone. These may be the reasons for why the maize-soybean intercropping system reduced FAW damage in the field. We also speculated that the maize-sweet potato system may also reduce the FAW damage. This study provided a theoretical basis for the comprehensive management of FAW by utilizing an intercropping system.

Socioeconomic Status Impacts the Prognosis of Chronic Rhinosinusitis Treated by Endoscopic Sinus Surgery: An Observational Cohort Study in Northeast China.

Objective: To explore the association between socioeconomic status (SES) and postoperative outcomes in patients with chronic sinusitis (CRS) after functional endoscopic sinus surgery (ESS). Methods: We conducted an observational cohort study of 1,047 patients with CRS undergoing ESS. Discharged patients were followed up to 72 weeks for all-cause recurrence events. Baseline SES was established based on occupation, education level, and family income of the patients 1 year before the operation. Kaplan-Meier method was used to calculate the recovery rate after ESS, and Cox proportional hazards regression analysis was used to evaluate the relationship between SES and prognosis. Results: Patients of middle SES had lower unadjusted all-cause recurrence than those of low or high SES; 24-week overall recovery rate was 90.4% [95 % confidence interval ( CI): 89.6%-91.2%] in patients of middle SES, 13.5% (95 % CI: 12.8%-14.2%) in patients of low SES, and 31.7% (95 % CI: 30.7%-32.7%) in patients of high SES (both log-rank P < 0.001). After adjustment for covariates, hazard ratios ( HRs) were 7.69 (95 % CI: 6.17-9.71, P trend < 0.001) for all-cause recurrence for low SES versus middle SES, and 6.19 (95 % CI: 4.78-7.93, P trend < 0.001) for middle SES versus high SES. Conclusion: Low SES and high SES were more associated with the worse prognosis of CRS patients after ESS than middle SES.

Cellular senescence of renal tubular epithelial cells in renal fibrosis.

Renal fibrosis (RF) is the common pathological manifestation of virtually all chronic kidney diseases (CKD) and one of the major causes of end-stage renal disease (ESRD), but the pathogenesis of which is still unclear. Renal tubulointerstitial lesions have been identified as a key pathological hallmark of RF pathology. Renal tubular epithelial cells are the resident cells of the tubulointerstitium and play an important role in kidney recovery versus renal fibrosis following injury. Studies in recent years have shown that senescence of renal tubular epithelial cells can accelerate the progression of renal fibrosis. Oxidative stress(OS), telomere attrition and DNA damage are the major causes of renal tubular epithelial cell senescence. Current interventions and therapeutic strategies for cellular senescence include calorie restriction and routine exercise, Klotho, senolytics, senostatics, and other related drugs. This paper provides an overview of the mechanisms and the key signaling pathways including Wnt/ß-catenin/RAS, Nrf2/ARE and STAT-3/NF-κB pathway involved in renal tubular epithelial cell senescence in RF and therapies targeting renal tubular epithelial cell senescence future therapeutic potential for RF patients. These findings may offer promise for the further treatment of RF and CKD.

Migration Dynamics of Fall Armyworm Spodoptera frugiperda (Smith) in the Yangtze River Delta.

The Yangtze River Delta, located in East China, is an important passage on the eastern pathway of the northward migration of fall armyworm Spodoptera frugiperda (Smith) in China, connecting China's year-round breeding area and the Huang-Huai-Hai summer maize area. Clarifying the migration dynamics of S. frugiperda in the Yangtze River Delta is of great significance for the scientific control and prevention of S. frugiperda in the Yangtze River Delta, even in the Huang-Huai-Hai region and Northeast China. This study is based on the pest investigation data of S. frugiperda in the Yangtze River Delta from 2019 to 2021, combining it with the migration trajectory simulation approach and the synoptic weather analysis. The result showed that S. frugiperda migrated to the Yangtze River Delta in March or April at the earliest, and mainly migrated to the south of the Yangtze River in May, which can be migrated from Guangdong, Guangxi, Fujian, Jiangxi, Hunan and other places. In May and June, S. frugiperda migrated further into the Jiang-Huai region, and its source areas were mainly distributed in Jiangxi, Hunan, Zhejiang, Jiangsu, Anhui and Hubei provinces. In July, it mainly migrated to the north of Huai River, and the source areas of the insects were mainly distributed in Jiangsu, Anhui, Hunan, Hubei and Henan. From the south of the Yangtze River to the north of the Huai River, the source areas of S. frugiperda were constantly moving north. After breeding locally, S. frugiperda can not only migrate to other regions of the Yangtze River Delta, but also to its surrounding provinces of Jiangxi, Hunan, Hubei, Henan, Shandong and Hebei, and even cross the Shandong Peninsula into Northeast China such as Liaoning and Jilin provinces. Trajectory simulation showed that the emigrants of S. frugiperda from the Yangtze River Delta moved northward, westward and eastward as wind direction was quite diverse in June-August. This paper analyzes the migration dynamics of S. frugiperda in the Yangtze River Delta, which has important guiding significance for the monitoring, early warning and the development of scientific prevention and control strategies for whole country.

Expression dynamics of periodic transcripts during cancer cell cycle progression and their correlation with anticancer drug sensitivity.

BACKGROUND: The cell cycle is at the center of cellular activities and is orchestrated by complex regulatory mechanisms, among which transcriptional regulation is one of the most important components. Alternative splicing dramatically expands the regulatory network by producing transcript isoforms of genes to exquisitely control the cell cycle. However, the patterns of transcript isoform expression in the cell cycle are unclear. Therapies targeting cell cycle checkpoints are commonly used as anticancer therapies, but none of them have been designed or evaluated at the alternative splicing transcript level. The utility of these transcripts as markers of cell cycle-related drug sensitivity is still unknown, and studies on the expression patterns of cell cycle-targeting drug-related transcripts are also rare. METHODS: To explore alternative splicing patterns during cell cycle progression, we performed sequential transcriptomic assays following cell cycle synchronization in colon cancer HCT116 and breast cancer MDA-MB-231 cell lines, using flow cytometry and reference cell cycle transcripts to confirm the cell cycle phases of samples, and we developed a new algorithm to describe the periodic patterns of transcripts fluctuating during the cell cycle. Genomics of Drug Sensitivity in Cancer (GDSC) drug sensitivity datasets and Cancer Cell Line Encyclopedia (CCLE) transcript datasets were used to assess the correlation of genes and their transcript isoforms with drug sensitivity. We identified transcripts associated with typical drugs targeting cell cycle by determining correlation coefficients. Cytotoxicity assays were used to confirm the effect of ENST00000257904 against cyclin dependent kinase 4/6 (CDK4/6) inhibitors. Finally, alternative splicing transcripts associated with mitotic (M) phase arrest were analyzed using an RNA synthesis inhibition assay and transcriptome analysis. RESULTS: We established high-resolution transcriptome datasets of synchronized cell cycle samples from colon cancer HCT116 and breast cancer MDA-MB-231 cells. The results of the cell cycle assessment showed that 43,326, 41,578 and 29,244 transcripts were found to be periodically expressed in HeLa, HCT116 and MDA-MB-231 cells, respectively, among which 1280 transcripts showed this expression pattern in all three cancer cell lines. Drug sensitivity assessments showed that a large number of these transcripts displayed a higher correlation with drug sensitivity than their corresponding genes. Cell cycle-related drug screening showed that the level of the CDK4 transcript ENST00000547281 was more significantly associated with the resistance of cells to CDK4/6 inhibitors than the level of the CDK4 reference transcript ENST00000257904. The transcriptional inhibition assay following M phase arrest further confirmed the M-phase-specific expression of the splicing transcripts. Combined with the cell cycle-related drug screening, the results also showed that a set of periodic transcripts, for example, ENST00000314392 (a dolichyl-phosphate mannosyltransferase polypeptide 2 isoform transcript), was more associated with drug sensitivity than the levels of their corresponding gene transcripts. CONCLUSIONS: In summary, we identified a panel of cell cycle-related periodic transcripts and found that the levels of transcripts of drug target genes showed different values for predicting drug sensitivity, providing novel insights into alternative splicing-related drug development and evaluation.

[Research progress on Astragali Radix and prediction of its quality markers (Q-markers)].

Astragali Radix, a medicinal herb for invigorating Qi, has anti-aging, anti-tumor, immunoregulatory, blood sugar-and lipid-lowering, anti-fibrosis, anti-radiation and other pharmacological effects. This article reviewed the studies about the chemical components and pharmacological effects of Astragali Radix. According to the theory of quality markers(Q-markers) of Chinese medicinal materials, we predicted the Q-markers of Astragali Radix from traditional efficacy, chemical component validity, measurability, plant phylogeny, and pharmacokinetis. The results showed that total polysaccharides, flavonoids(e.g., calycosin-7-O-ß-D-glucoside, formononetin, calycosin, quercetin, and ononin), and saponins(e.g., astragalosides Ⅱ, Ⅲ, and Ⅳ) can be taken as the main Q-markers. This review lays a foundation for regulating the quality research and standard establishment of Astragali Radix, and benefits the control and quality supervision of the production process of Astragali Radix and its related products.

ctDNA-adjusted bTMB as a predictive biomarker for patients with NSCLC treated with PD-(L)1 inhibitors.

BACKGROUND: In non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs), higher blood tumor mutational burden (bTMB) was usually associated with better progression-free survival (PFS) and objective response rate (ORR). However, the association between bTMB and overall survival (OS) benefit remains undefined. It has been reported that patients harboring a high level of circulating tumor DNA (ctDNA) had poor survival. We hypothesized that ctDNA-adjusted bTMB might predict OS benefit in NSCLC patients receiving ICIs. METHODS: Our study was retrospectively performed in three cohorts, including OAK and POPLAR cohort (n = 853), Shanghai and Wuhan (SH&WH) cohort (n = 44), and National Cancer Center (NCC) cohort (n = 47). Durable clinical benefit (DCB) was defined as PFS lasting ≥ 6 months. The cutoff value of ctDNA-adjusted bTMB for DCB prediction was calculated based on a receiver operating characteristic curve. Interaction between treatments and ctDNA-adjusted bTMB was assessed. RESULTS: The bTMB score was significantly associated with tumor burden, while no association was observed between ctDNA-adjusted bTMB with tumor burden. In the OAK and POPLAR cohort, significantly higher ORR (P = 0.020) and DCB (P < 0.001) were observed in patients with high ctDNA-adjusted bTMB than those with low ctDNA-adjusted bTMB. Importantly, the interactions between ctDNA-adjusted bTMB and treatments were significant for OS (interaction P = 0.019) and PFS (interaction P = 0.002). In the SH&WH cohort, the interactions between ctDNA-adjusted bTMB and treatment were marginally significant for OS (interaction P = 0.081) and PFS (interaction P = 0.062). Similar result was demonstrated in the NCC cohort. CONCLUSIONS: Our study indicated that ctDNA-adjusted bTMB might predict OS benefit in NSCLC patients receiving ICIs. The potential of ctDNA-adjusted bTMB as a noninvasive predictor for immunotherapy should be confirmed in future studies.

[Distribution Characteristics and Health Risk Assessment of Metal Elements for Groundwater in the Ningxia Region of China].

To explore the distribution characteristics of metal elements in groundwater and evaluate the health risks they pose to the population in the Ningxia region of China, a total of 210 groundwater samples were collected, and eight metal elements (As, Cr, Al, Cu, Pb, Mn, Fe, and Sr) in the water samples were analyzed. The pollution characteristics, distribution, and health risks of the metals in the groundwater were revealed by a comprehensive pollution assessment, multivariate statistical analysis, and health risk assessment model, respectively. The results revealed that the mean mass concentrations of metal elements in groundwater from the study area were in the following order:ρ(Sr) > ρ(Al) > ρ(Mn) > ρ(Cu) > ρ(Pb) > ρ(Cr) > ρ(As) > ρ(Fe). The ρ(Sr) content of 75.24% of the samples exceeded that from drinking natural mineral water[0.2 mg·L-1of ρ(Sr)] as per China's standard. The maximum ρ(As) 76.60 µg·L-1, ρ(Cr) 145.01 µg·L-1, ρ(Pb) 59.93 µg·L-1, and ρ(Mn) 734.67 µg·L-1 exceeded the corresponding standard limits. Compared with the natural control, the As and Pb pollution in the study area was more serious, showing a planar distribution. Mn and Cr pollution were relatively concentrated, mainly distributed in the northern Yellow River and southeast, respectively. Other metals were lightly polluted. The results of the multivariate statistical analysis showed that the concentrations of As and Pb pollution may be caused by natural factors, industrial activities, and the use of pesticides. Mn pollution may be caused by irrigation with the Yellow River. Cr pollution may be caused by mining for oil. The health risk assessment showed that the health risk to children was higher than that to adults, and the risk of drinking water exposure was higher than that of skin infiltration exposure. The non-carcinogenic health risk (HI) was mainly caused by As through the drinking water pathway. Due to the pollution of As and Cr, the carcinogenic risk through the drinking water and skin penetration pathways to children and adults in the study area was higher than the safety level (5.0×10-5). The contribution rate of Cr to the carcinogenic risk through the two pathways was greater than 80%. For drinking water safety, the concentrations of As and Cr should be controlled before drinking.

DUBR suppresses migration and invasion of human lung adenocarcinoma cells via ZBTB11-mediated inhibition of oxidative phosphorylation.

Long noncoding RNAs (lncRNAs) are involved in a variety of cancers, but the role of LncRNA DUBR in lung adenocarcinoma (LUAD), the most prevalent form of lung cancer, remains unclear. In this study we investigated the expression of DUBR in LUAD to ascertain its association with the clinical pathology and prognosis of LUAD. Analysis of mRNA expression in The Cancer Genome Atlas (TCGA) LUAD database and in-house LUAD cohort (n = 94) showed that DUBR was significantly downregulated in LUAD, and was associated with poor prognosis. In LUAD cell lines (H1975, A549), overexpression of DUBR significantly suppressed the migration and invasion of the LUAD cells. We demonstrated that c-Myc could bind to the promoter of DUBR, and transcriptionally suppressed its expression. Knockdown of c-Myc almost completely blocked the invasion and migration of LUAD cells, whereas knockdown of DUBR partially rescued c-Myc-knockdown suppressed cell migration and invasion. Furthermore, DUBR overexpression significantly increased the expression of a downstream protein of DUBR, zinc finger, and BTB domain containing 11 (ZBTB11), in H1975 and A549 cells; knockdown of ZBTB11 partially rescued the DUBR-overexpression suppressed cell migration and invasion; knockdown of c-Myc significantly upregulated the expression of ZBTB11 in LUAD cells. Finally, we revealed that DUBR/ZBTB11 axis suppressed oxidative phosphorylation in LUAD cells. In short, we demonstrate that c-Myc/DUBR/ZBTB11 axis suppresses migration and invasion of LUAD by attenuating cell oxidative phosphorylation, which provides new insights into the regulatory mechanism of DUBR.

The effect of lead exposure on copper transporter protein in mouse cerebral cortex / 中国职业医学

@#Abstract: Objective ， To explore the effects of lead exposure on copper level copper transporter protein expression and Methods oxidative stress in mouse cerebral cortex. The specific pathogen free adult male C57BL/6 mice were randomly ， - - - divided into control group low lead exposure group and high lead exposure group with 10 mice in each group. The mice in low - ， and high lead exposure groups were respectively given 250 and 500 mg/L lead acetate in drinking water every day and the mice - ， in the control group were given double distilled water for 12 weeks. Twenty four hours after exposure Morris water maze and ， elevated cross maze were used to test the neurobehavioral function of mice. The cerebral cortex of mice was isolated and the levels of lead and copper were detected by inductively coupled plasma mass spectrometry. The activities of glutathione （ - ）， （ ） （ ） peroxidase GSH Px catalase CAT and malondialdehyde MDA were detected by histochemical method. The relative （ ） ， ， expression levels of copper transporter such as synthesis of cytochrome C oxidase SCO 1 SCO 2 and cytochrome C oxidase （ ） Results - - assembly protein 11 COX11 were detected by western blot. The escape latencies of mice in the low and high lead （ P ）， ， - exposure groups were prolonged all <0.05 while the number of crossing the platform the percentage of open arm entry - （ P ） times and the percentage of open arm retention time decreased all <0.05 compared with the control group. Mice in both the - - （ P ）， - low and high lead exposure groups increased levels of lead and copper in the cerebral cortex all <0.05 decreased GSH Px （ P ）， （ P ） and CAT activity all <0.05 and increased SCO1 relative expression all <0.05 compared with the control group. Mice in - （P ）， - the high lead exposure group showed prolonged escape latency <0.05 reduced GSH Px and CAT activities in the cerebral （ P ）， （ P ） - cortex all <0.05 increased MDA level and relative expression of SCO1 and SCO2 all <0.05 compared to mice in the low Conclusion - lead exposure group. Lead exposure increased the expression of copper and copper transport related proteins in mouse cerebral cortex and induced oxidative stress leading to central nervous system damage resulting in neurobehavioral abnormalities in mice.

Assessment of Benchmark Dose in BEAS-2B Cells by Evaluating the Cell Relative Viability with Particulates in Motorcycle Exhaust via the Air-liquid Interface Exposure.

OBJECTIVE: This study aimed to use an air-liquid interface (ALI) exposure system to simulate the inhalation exposure of motorcycle exhaust particulates (MEPs) and then investigate the benchmark dose (BMD) of MEPs by evaluating cell relative viability (CRV) in lung epithelial BEAS-2B cells. METHODS: The MEPs dose was characterized by measuring the number concentration (NC), surface area concentration (SAC), and mass concentration (MC). BEAS-2B cells were exposed to MEPs at different concentrations via ALI and CRV was determined using Cell Counting Kit (CCK-8) assay. BMD software was applied to calculate BMD and the lower limit of benchmark dose (BMDL) according to Akaike Information Coefficient (AIC), with P-value based on Hill, Linear, Polynomial, and Power model. RESULTS: Our results reveal that BMD of NC and SAC were estimated by the best-fitting Hill model, while MC was estimated by Polynomial model. The BMDL for CRV following ALI exposure to MEPs were as follows: 364.2#/cm 3 for NC; 0.662 × 10 7 nm 2/cm 3 for SAC; and 0.278 µg/m 3 for MC. CONCLUSION: These results indicate that MEPs exposure via ALI system induces a dose-dependent decrease of CRV and provides the potential exposure threshold of MEPs in a lung cell model.

Differential development and electrophysiological activity in cultured cortical neurons from the mouse and cynomolgus monkey.

In vitro cultures of primary cortical neurons are widely used to investigate neuronal function. However, it has yet to be fully investigated whether there are significant differences in development and function between cultured rodent and primate cortical neurons, and whether these differences influence the utilization of cultured cortical neurons to model pathological conditions. Using in vitro culture techniques combined with immunofluorescence and electrophysiological methods, our study found that the development and maturation of primary cerebral cortical neurons from cynomolgus monkeys were slower than those from mice. We used a microelectrode array technique to compare the electrophysiological differences in cortical neurons, and found that primary cortical neurons from the mouse brain began to show electrical activity earlier than those from the cynomolgus monkey. Although cultured monkey cortical neurons developed slowly in vitro, they exhibited typical pathological features-revealed by immunofluorescent staining-when infected with adeno-associated viral vectors expressing mutant huntingtin (HTT), the Huntington's disease protein. A quantitative analysis of the cultured monkey cortical neurons also confirmed that mutant HTT significantly reduced the length of neurites. Therefore, compared with the primary cortical neurons of mice, cultured monkey cortical neurons have longer developmental and survival times and greater sustained physiological activity, such as electrophysiological activity. Our findings also suggest that primary cynomolgus monkey neurons cultured in vitro can simulate a cell model of human neurodegenerative disease, and may be useful for investigating time-dependent neuronal death as well as treatment via neuronal regeneration. All mouse experiments and protocols were approved by the Animal Care and Use Committee of Jinan University of China (IACUC Approval No. 20200512-04) on May 12, 2020. All monkey experiments were approved by the IACUC protocol (IACUC Approval No. LDACU 20190820-01) on August 23, 2019 for animal management and use.

Atezolizumab prolongs overall survival over docetaxel in advanced non-small-cell lung cancer patients harboring STK11 or KEAP1 mutation.

Somatic mutations of STK11 or KEAP1 are associated with poor clinical outcomes for advanced non-small-cell lung cancer (aNSCLC) patients receiving immune checkpoint inhibitors (ICIs), chemotherapy, or targeted therapy. Which treatment regimens work better for STK11 or KEAP1 mutated (SKmut) aNSCLC patients is unknown. In this study, the efficacy of atezolizumab versus docetaxel in SKmut aNSCLC was compared. A total of 157 SKmut aNSCLC patients were identified from POPLAR and OAK trials, who were tested by blood-based FoundationOne next-generation sequencing assay. Detailed clinical data and genetic alterations were collected. Two independent cohorts were used for biomarker validation (n = 30 and 20, respectively). Median overall survival was 7.3 months (95% confidence interval [CI], 4.8 to 9.9) in the atezolizumab group versus 5.8 months (95% CI, 4.4 to 7.2) in the docetaxel group (adjusted hazard ratio [HR] for death, 0.70; 95% CI, 0.49 to 0.99; P = .042). Among atezolizumab-treated patients, objective response rate, disease control rate, and durable clinical benefit were higher when blood tumor mutation burden (bTMB) and PD-L1 being higher (biomarker 1, n = 61) or with FAT3 mutation-positive tumors (biomarker 2, n = 83) than otherwise. The interactions for survival between these two biomarkers and treatments were significant, which were further validated in two independent cohorts. In SKmut patients with aNSCLC, atezolizumab was associated with significantly longer overall survival in comparison to docetaxel. Having FAT3 mutation or high TMB and PD-L1 expression potentially predict favorable response in SKmut patients receiving atezolizumab.

Synthesis and in vitro and in vivo biological evaluation of novel derivatives of flexicaulin A as antiproliferative agents.

As our research focuses on anticancer drugs, a series of novel derivatives of flexicaulin A (FA), an ent-kaurene diterpene, condensed with an aromatic ring were synthesized, and their antiproliferative activities against four human cancer cell lines (TE-1, EC109, MCF-7, and MGC-803) were evaluated. The activities of most of the new compounds were better than those of FA. Compound 2y exhibited the best activity with an IC50 value reaching 0.13 µM against oesophageal cancer cells (EC109 cells). The IC50 values for 2y in normal cells (GES-1 cells and HUVECs) were 0.52 µM and 0.49 µM, respectively. Subsequent mechanistic investigations found that compound 2y can inhibit the proliferation of cancer cells and cell cloning. In addition, 2y could reduce the mitochondrial membrane potential, increase the apoptosis rate, and increase the ROS level in EC109 cells. Moreover, 2y can upregulate the expression of ROS/JNK pathway-related proteins (p-ASK1, p-MKK4, p-JNK, and p-Cjun (ser63)) and pro-apoptotic proteins (Bax, Bad, and Bim). In vivo experiments showed that 2y can inhibit tumour growth in nude mice. The mechanism involves an increase in protein expression in the ROS pathway, leading to changes in apoptosis-related proteins. In addition, compound 2y shows low toxicity. These results indicate that compound 2y holds promising potential as an antiproliferative agent.

Biological, clinical and epidemiological features of COVID-19, SARS and MERS and AutoDock simulation of ACE2.

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) has caused a public catastrophe and global concern. The main symptoms of COVID-19 are fever, cough, myalgia, fatigue and lower respiratory tract infection signs. Almost all populations are susceptible to the virus, and the basic reproduction number (R0) is 2.8-3.9. The fight against COVID-19 should have two aspects: one is the treatment of infected patients, and the other is the mobilization of the society to avoid the spread of the virus. The treatment of patients includes supportive treatment, antiviral treatment, and oxygen therapy. For patients with severe acute respiratory distress syndrome (ARDS), extracorporeal membrane oxygenation (ECMO) and circulatory support are recommended. Plasma therapy and traditional Chinese medicine have also achieved good outcomes. This review is intended to summarize the research on this new coronavirus, to analyze the similarities and differences between COVID-19 and previous outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) and to provide guidance regarding new methods of prevention, diagnosis and clinical treatment based on autodock simulations. METHODS: This review compares the multifaceted characteristics of the three coronaviruses including COVID-19, SARS and MERS. Our researchers take the COVID-19, SARS, and MERS as key words and search literatures in the Pubmed database. We compare them horizontally and vertically which respectively means concluding the individual characteristics of each coronavirus and comparing the similarities and differences between the three coronaviruses. RESULTS: We searched for studies on each outbreak and their solutions and found that the main biological differences among SARS-CoV-2, SARS-CoV and MERS-CoV are in ORF1a and the sequence of gene spike coding protein-S. We also found that the types and severity of clinical symptoms vary, which means that the diagnosis and nursing measures also require differentiation. In addition to the common route of transmission including airborne transmission, these three viruses have their own unique routes of transmission such as fecal-oral route of transmission COVID-19. CONCLUSIONS: In evolutionary history, these three coronaviruses have some similar biological features as well as some different mutational characteristics. Their receptors and routes of transmission are not all the same, which makes them different in clinical features and treatments. We discovered through the autodock simulations that Met124 plays a key role in the efficiency of drugs targeting ACE2, such as remdesivir, chloroquine, ciclesonide and niclosamide, and may be a potential target in COVID-19.

Grade 3 Pancreatic Neuroendocrine Tumors on MDCT: Establishing a Diagnostic Model and Comparing Survival Against Pancreatic Ductal Adenocarcinoma.

OBJECTIVE. The purpose of this study is to establish a diagnostic model for differentiating grade 3 (G3) pancreatic neuroendocrine tumors (PNETs) from pancreatic ductal adenocarcinomas (PDACs) and to analyze survival outcomes. MATERIALS AND METHODS. Twenty patients with G3 PNETs and 58 patients with PDACs confirmed by surgery or biopsy were retrospectively included. Demographic and radiologic information was collected. Univariate analyses and binary logistic regression analyses were performed to identify independent factors and establish a diagnostic model. An ROC curve was created to determine diagnostic ability. Kaplan-Meier survival analysis was performed. RESULTS. Patients with G3 PNETs were more likely to present with normal carbohydrate antigen (CA) 19-9 levels, normal pancreatic ducts, and round tumors with well-defined margins and higher portal enhancement ratios than were patients with PDAC (p < 0.05). After multivariate analysis, a normal CA 19-9 level (odds ratio, 0.0125; 95% CI, 0.0008-0.2036), round tumor shape (odds ratio, 0.0143; 95% CI, 0.0004-0.5461), and pancreatic duct dilation of 4 mm or less (odds ratio, 17.9804; 95% CI, 1.0098-320.1711) were independent predictors of G3 PNETs. The AUC of the ROC curve was 0.916, and sensitivity and specificity were 90.0% and 81.0%, respectively. Furthermore, patients with G3 PNETs had better overall survival than patients with PDACs. Among patients in the G3 PNET subgroup, patients with liver or lymph node metastases had worse overall survival than patients without metastases. CONCLUSION. A diagnostic model was established to differentiate G3 PNETs from PDACs. A normal CA 19-9 level, round tumor shape, and pancreatic duct dilation of 4 mm or less were factors that were strongly predictive of G3 PNET.

Prognostic and Predictive Value of Blood Tumor Mutational Burden in Patients With Lung Cancer Treated With Docetaxel.

BACKGROUND: Biomarkers for chemotherapy efficacy in non-small cell lung cancer (NSCLC) are lacking. This retrospective study assesses the association between blood-based tumor mutational burden (bTMB) and clinical benefit of chemotherapy. METHODS: Clinical and targeted next-generation sequencing data from the OAK trial (training set; n=318) and POPLAR trial (validation set; n=106) in the docetaxel arm were analyzed. The cutoff value of bTMB for outcome prediction was determined based on a time-dependent receiver operating characteristic curve in the training set, and propensity score matching (PSM) was conducted. The primary outcome was overall survival (OS). Durable clinical benefit (DCB) was defined as OS lasting >12 months. Interaction between treatment and bTMB was assessed in the combined set. RESULTS: A lower bTMB was observed in patients with DCB compared with no durable benefit, and in those with a partial response and stable disease compared with progressive disease. The optimized cutoff value of bTMB for predicting OS was 7 single-nucleotide variants per megabase. In the training set, a low bTMB was significantly associated with longer OS and progression-free survival (PFS). The prognostic value of bTMB was confirmed in the validation set and PSM set. The interaction between bTMB and treatment was significant for PFS (interaction P=.043) in the combined set. Mutations in KEAP1 were associated with high bTMB and a lack of benefit from chemotherapy. CONCLUSIONS: Low bTMB is associated with a survival advantage in patients with NSCLC treated with docetaxel, suggesting the prognostic and predictive potential of bTMB for determining chemotherapy efficacy.

Regulation of MYB mediated cisplatin resistance of ovarian cancer cells involves miR-21-wnt signaling axis.

c-MYB has been reported to be elevated in few cancers, including in ovarian cancer. It influences resistance to cisplatin but the details are not very well understood. The objective of this study was to further evaluate role of c-MYB in ovarian cancer's cisplatin resistance. To elucidate the underlying mechanism of cisplatin resistance in ovarian cancer, we focused on the epigenetic regulation by miRNAs. Two cell lines, ES2 and OVCAR3, were used as the model systems. C-MYB expression was either up-regulated or silenced and the resulting effect on cisplatin resistance evaluated, along with the mechanistic role of miR-21, through transfections with pre/anti-miRNAs. An in vivo cisplatin resistance model was also employed to verify findings. High c-MYB correlated with increased miR-21. High c-MYB also resulted in induction of EMT and increased resistance against cisplatin which was attenuated by anti-miR-200s. c-MYB decreased ß-catenin phosphorylation and thus activated wnt signaling. Silencing of c-MYB resulted in reduced miR-21 levels, reduced EMT, reduced cisplatin IC-50s and increased ß-catenin phosphorylation. In an in vivo mice model of cisplatin resistance, c-MYB overexpressing ES2 xenografts were more aggressive than their control counterparts. These c-MYB overexpressing ES xenografts were significantly more resistant to cisplatin but could be sensitized to cisplatin by anti-miR-21. Our results provide a novel mechanism of cisplatin resistance by c-MYB which involves an essential role of miR-21.

Advanced Non-Small Cell Lung Cancer Patients With Low Tumor Mutation Burden Might Derive Benefit From Immunotherapy.

The aim of this study is to investigate the association between tumor mutation burden (TMB) and survival in non-small cell lung cancer (NSCLC) patients with anti-programmed cell death protein 1 and anti-programmed death-ligand 1 blockade. Two retrospective cohorts and The Cancer Genome Atlas NSCLC data set were included in this study. The restricted cubic spline analysis was used to explore the association between TMB and survival. The cutoff values for TMB were determined by X-tile software. Primary outcomes were overall survival (OS). The associations between TMB and intratumor heterogeneity, number of segments, fraction of genome alterations, aneuploidy score, and T-cell populations were also investigated. In the restricted cubic spline plots, TMB showed an inverted U-shaped curve with OS. The median OS in the low TMB group was significantly longer than those in the medium TMB group. In The Cancer Genome Atlas NSCLC data set, low TMB was also associated with longer OS in comparison with medium TMB. Furthermore, NSCLC patients with low TMB had significantly lower intratumor heterogeneity, number of segments, fraction of genome alterations, aneuploidy score, T-helper type 2 (Th2) cells, and CD8 T cells, but higher levels of Th1 and Th17 cells. Low TMB might be a prognostic factor for NSCLC patients receiving anti-programmed cell death protein 1/programmed death-ligand 1 immunotherapy.