Search

TRAF2 (Tumor necrosis factor receptor-associated factor 2) is a dual function protein, acting as an adaptor protein and a ubiquitin E3 ligase, which plays an essential role in mediating the TNFα-NFκB signal pathway. Dysregulated expression of TRAF2 has been reported in a variety of human cancers. Whether and how TRAF2 regulates the growth of liver cancer cells remains elusive. The goal of this study is to investigate potential dysregulation of TRAF2 and its biological function in liver cancer, and to elucidate the underlying mechanism, leading to validation of TRAF2 as an attractive liver cancer target. Here, we reported TRAF2 is up-regulated in human liver cancer cell lines and tissues, and high TRAF2 expression is associated with a poor prognosis of HCC patients. Proteomics profiling along with Co-immunoprecipitation analysis revealed that p62 is a new substrate of TRAF2, which is subjected to TRAF2-induced polyubiquitination via the K63 linkage at the K420 residue. A strong negative correlation was found between the protein levels of p62 and TRAF2 in human HCC samples. TRAF2 depletion inhibited growth and survival of liver cancer cells both in vitro and in vivo by causing p62 accumulation, which is partially rescued by simultaneous p62 knockdown. Mechanistically, TRAF2-mediated p62 polyubiquitylation activates the mTORC1 by forming the p62-mTORC1-Rag complex, which facilitates the lysosome localization of mTORC1. TRAF2 depletion inhibited mTORC1 activity through the disruption of interaction between p62 and the mTORC1 complex. In conclusion, our study provides the proof-of-concept evidence that TRAF2 is a valid target for liver cancer.

Hepatitis B virus (HBV) infection is a major public health problem. The high levels of HBV DNA and HBsAg are positively associated with the development of secondary liver diseases, including hepatocellular carcinoma (HCC). Current treatment with nucleos(t)ide analogues mainly reduces viral DNA, but has minimal, if any, inhibitory effect on the viral antigen. Although IFN reduces both HBV DNA and HBsAg, the serious associated side effects limit its use in clinic. Thus, there is an urgent demanding for novel anti‐HBV therapy. In our study, viral parameters were determined in the supernatant of HepG2.2.15 cells, HBV‐expressing Huh7 and HepG2 cells which transfected with HBV plasmids and in the serum of HBV mouse models with hydrodynamic injection of pAAV‐HBV1.2 plasmid. RT‐qPCR and Southern blot were performed to detect 35kb mRNA and cccDNA. RT‐qPCR, Luciferase assay and Western blot were used to determine anti‐HBV effects of MLN4924 and the underlying mechanisms. We found that treatment with MLN4924, the first‐in‐class neddylation inhibitor currently in several phase II clinical trials for anti‐cancer application, effectively suppressed production of HBV DNA, HBsAg, 3.5kb HBV RNA as well as cccDNA. Mechanistically, MLN4924 blocks cullin neddylation and activates ERK to suppress the expression of several transcription factors required for HBV replication, including HNF1α, C/EBPα and HNF4α, leading to an effective blockage in the production of cccDNA and HBV antigen. Our study revealed that neddylation inhibitor MLN4924 has impressive anti‐HBV activity by inhibiting HBV replication, thus providing sound rationale for future MLN4924 clinical trial as a novel anti‐HBV therapy.

Acetaminophen (APAP) overdose can cause severe liver injury and APAP-induced liver injury (AILI) is one of the leading causes of acute liver failure (ALF). Bruton's tyrosine kinase (BTK) is a key tyrosine kinase in immune responses, which plays an important role in many inflammatory diseases. However, its effect on AILI is still not clear. Here, we aimed to assess the effect of BTK on AILI and explore its underlying mechanism.In our study, western blot and immunohistochemistry were used to detect the expression of BTK in AILI. The C57BL/6 mice were used to check the protective effect of BTK inhibition on AILI and the activation of BTK was confirmed in mice macrophages treated with APAP. Immunofluorescence, immunohistochemistry, oxygen consumption rate (OCR) detection, polymerase chain reaction (PCR), flow cytometry and western blot were used to determine the role of BTK in mitochondrial dynamics and function of macrophages and the underlying mechanisms in AILI.Our results showed that BTK upregulated in AILI. BTK inhibition protected mice from AILI and BTK was activated in mice macrophages in response to APAP. Mechanically, BTK inhibition promoted mitochondrial fusion and restored mitochondrial function through phospholipase C gamma 2 (PLCγ2)-reactive oxygen species (ROS)-Optic Atrophy 1(OPA1) pathway in macrophages and finally suppressed the release of proinflammatory cytokines.In conclusion, we found that BTK inhibition protected mice from AILI by restoring the mitochondrial function of macrophages through the improvement of the mitochondrial dynamic imbalance via PLCγ2-ROS-OPA1 signaling pathway, which indicated that BTK might be a potential therapeutic target of AILI.

Traditional research on lake eutrophication has failed to consider the effect of the South-to-North Water Transfer Project (SNWTP) policy; thus, the difference-in-differences (DID) model, which is usually applied to economic factors, was innovatively introduced to evaluate the effect of such policies on lake eutrophication. Nansi Lake and Dongping Lake in the Shandong Peninsula were selected as the experimental group, and Daming Lake and Mata Lake were selected as the control group. The eutrophication indices of the experimental group and the control group were calculated by the measured chlorophyll-a, total phosphorus, total nitrogen, water transparency and chemical oxygen demand data and used as the explanatory variables of the DID model. Nine environmental and socio-economic factors, such as dissolved oxygen and rural population, were selected as the control variables of the DID model to analyze the impact of the SNWTP policy on lake eutrophication. A joint consideration of environmental and socio-economic factors showed that the eutrophication degree of the experimental lakes deteriorated by 7.10% compared with the control under the influence of the implemented policy. Dissolved oxygen is the main factor affecting the eutrophication of the Shandong Peninsula. This study verifies that the DID model has the potential for use in quantitative analyses of the effect of the SNWTP policy on lake eutrophication. HIGHLIGHTS Using DID model to estimate the impact of policy on lake eutrophication is reasonable.; Eutrophication deteriorated by 7.10% under the effect of policy and control variables.; DO is the key control variables influencing the eutrophication of the Shandong Peninsula.

In order to solve regional water security issues, such as shortage of water resources, the aggravation of water pollution, the destruction of the ecological environment, etc., this study proposed the flood control security index, resource security index and ecological security index, respectively, according to the construction principle of human development index. Based on the above security indexes, a novel water security comprehensive evaluation model is established by combining the coupling coordination degree model and the state space model. The proposed model has the advantage of simple operation and fast data speed, which is convenient for water security evaluation in different periods and regions. Taking China as an example, the water security conditions were evaluated from 2007 to 2016 for 31 provincial-level administrative regions in China, including flood control security index, resource security index, ecological security index and water security level of each region, and the specific problems of water security in each region were obtained. The evaluation results are consistent with the actual situation in each region, which provides the scientific basis for the local government authorities to formulate the corresponding regional water security policy.

Rainwater harvesting potential provides a basis for alleviating regional drought and water shortages. The resilience of rainwater harvesting potential is directly related to the sustainable level of actual available rainwater. Thus, SWAT model was combined with the proposed rainwater harvesting potential evaluation model to quantify rainwater harvesting potential, its resilience and actual available rainwater in the study area. The results showed that: (1) restoration of forest and grass increased the rainwater resource potential in the study area by 12.41 %, especially in the northeast, central and southwest of the study area. Although the surface runoff increased slightly in the past 20 years, it remained stable at 28.62 % of rainwater harvesting potential, which was benefited from the rainwater harvesting potential resilience to maintain the component stability; (2) rainwater harvesting potential resilience in the study area increased from class II to class III, which was closely related to the 17.93 % increase in the resilience intensity of the study area to resist external interference; and (3) surface runoff and net soil moisture content were the main components affecting the spatiotemporal variation of actual available rainwater, and lateral flow was also the main component affecting the spatial variation of actual available rainwater. In the past 20 years, the actual available rainwater has been increasing, and its conversion rate exceeded 89 %. The high level of actual available rainwater has been expanding to the western region with dense grassland coverage. This study provides a scientific basis for clarifying the sustainable utilization level of rainwater.

ND-L02-s0201 is a lipid nanoparticle encapsulating an siRNA which inhibits expression of heat shock protein 47 (HSP47), a collagen-specific chaperone. Accumulated evidence demonstrates a close association between increased level of HSP47 and excessive accumulation of collagen in fibrotic diseases. Our objective was to test ND-L02-s0201 efficacy in preclinical lung fibrosis models and characterise the downstream histological and functional consequences of inhibiting the expression of HSP47. Comprehensive optimisation and characterisation of bleomycin (BLM) and silica-induced rat lung fibrosis models were conducted, which ensured progressive pathological changes were sustained throughout the study during evaluation of the anti-fibrotic potential of ND-L02-s0201. In the BLM model, we demonstrated dose-dependent and statistically significant reduction in the relative lung weight, collagen deposition and histology, and fibrosis scores following ND-L02-s0201 treatment. Lung tissue mRNA profiling demonstrated that 11 out of 84 fibrosis-relevant genes were upregulated following BLM induction and were downregulated by approximately 4.5-fold following ND-L02-s0201 treatment. Epithelial–mesenchymal transition was characterised in the BLM model following ND-L02-s0201 treatment. Cell enrichment demonstrated that myofibroblasts contained the highest HSP47 mRNA expression. BLM led to more than a five-fold increase in myofibroblasts and ND-L02-s0201 treatment reduced the myofibroblasts to sham levels. Statistically significant improvement in lung function was noted in the BLM model which was determined by running endurance capacity using a 7-minute treadmill test. Comparable anti-fibrotic efficacy was also observed in the silica model. Results from two robust chronic rodent models of pulmonary fibrosis demonstrated significant anti-fibrotic effects and improved lung function which support the evaluation of ND-L02-s0201 in subjects with idiopathic pulmonary fibrosis., By targeting HSP47 and facilitating normalisation of EMT, siRNA lipid nanoparticle ND-L02-s0201 reverses interstitial pulmonary fibrosis, restores structural integrity of the lung, and improves pulmonary function in preclinical rat models. https://bit.ly/3a2lo1B

Neddylation is a ubiquitin-like posttranslational modification that conjugates neural precursor cell expressed developmentally downregulated-8 (Nedd8) to specific substrates for regulation of protein activity. In light of current researches, the neddylation pathway is aberrant in the pathogenesis of many diseases. In our review, we summarize the versatile roles of neddylation in chronic liver diseases (CLDs). CLDs are one of the leading causes of chronic disease-associated deaths worldwide. There are diverse etiologic agents causing CLDs, mainly including hepatitis B virus (HBV) infection, nonalcoholic fatty liver disease (NAFLD), chronic exposure to alcohol or drugs, and autoimmune causes. So far, however, there remains a paucity of effective therapeutic approach to CLDs. In this review, we summarized the role of the neddylation pathway which runs through the chronic hepatitis B/NAFLD-liver fibrosis-cirrhosis-hepatocellular carcinoma (HCC) axis, a canonical pattern in the process of CLD development and progression. The dysregulation of neddylation may provide a better understanding of CLD pathology and even a novel therapeutic strategy. Correspondingly, inhibiting neddylation via MLN4924, a small molecule compound targeting NEDD8-activating enzyme (NAE), can potently alleviate CLD progression and improve the outcome. On this basis, profiling and characterization of the neddylation pathway can provide new insights into the CLD pathology as well as novel therapeutic strategies, independently of the etiology of CLD.

Studying the complex adaptability of regional water resources systems (WRS) plays an important role in promoting the sustainable utilization of water resources and improving the adaptation of WRS to environmental change. This study proposed a comprehensive co-evolution model, based on the conditions of the elements and on the mechanism of their interaction, to study the adaptive development of WRS. Using the model, the survival fitness of each subsystem, the coordination degree between each subsystem, and the survival fitness of the WRS were obtained, and the main factors that affect the adaptation of the WRS were analyzed. Shandong Province in China was used as an example. The results showed that during 2006–2015, the average annual survival fitness of the resource, social, economic, and ecological subsystems was 0.257, 0.282, 0.257, and 0.251, respectively, which indicated a low adaptability for each subsystem. The coordination degree between each subsystem (resource–society, resource–economy, resource–ecology, social–economic, social–ecological, and economic–ecological) was 0.319, 0.355, 0.334, 0.364, 0.333, and 0.351, respectively, which indicated minimal coordination between each subsystem. The average annual survival fitness of the WRS was 0.551, and the adaptability of the WRS was classified as basic. Further analysis revealed that the coordination problem caused by the interaction of the elements in each subsystem was responsible for the low adaptability. The coordination problem, therefore, places severe constraints on the adaptive development of WRS. Therefore, solving the problem of coordination between elements is fundamental to improving the adaptability of WRS and promoting its sustainable development.

Coupling and coordination analyses of regional water resource systems (WRS) play an important role in promoting the sustainable and coordinated development of those systems. In this paper, a dynamic coupling coordination model is introduced to study the coordinated development of WRS. The weight of each index is obtained using an improved entropy weight method. The coupling and coordination degrees between resource subsystems and other subsystems and an entire system of water resources can be obtained using this model. Taking Heilongjiang, China, as an example, the results show that in 2005–2014, the WRS exhibited low coupling and low coordination characteristics due to a substantial contradiction between the resource subsystem and the social and economic and ecological subsystems. Therefore, strengthening the overall development of water resources, society, economy and ecology and improving the coupling abilities between resource subsystems and each of the other subsystems are effective strategies for promoting the coordinated development of WRS.

Hepatocellular carcinoma remains the sixth most lethal malignancy in the world. While HCC is often diagnosed via current biomarkers at a late stage, early detection of HCC has proven to be very difficult. Recent studies have focused on using exosomal miRNAs in clinical diagnostics and therapeutics, because they have improved stability in exosomes than as free miRNAs themselves. Exosomal miRNAs act through novel mechanisms for inducing cellular responses in a variety of biological circumstances. Dysregulated expression of miRNAs in exosomes can also accelerate HCC progression, including cell proliferation and metastasis, via alteration of a network of genes. Growing evidence demonstrates that exosomal miRNAs can affect many aspects of physiological and pathological conditions in HCC and indicates that miRNAs in exosomes can not only serve as sensitive biomarkers for cancer diagnostics and recurrence but can also potentially be used as therapeutics to target HCC progression. In this review, we summarize the latest findings between exosomal miRNAs and HCC, in order to better comprehend the functions and applications in HCC. Moreover, we discuss critical issues to consider when developing anti-tumor exosomal miRNAs as a novel therapeutic strategy for treating HCC in the clinic.

Cloud model theory provides a reliable method to effectively solve the problem of uncertainty associated with lake water quality assessments. To accurately match water quality parameters obtained from water samples and water quality standards, water quality parameters from water samples and water quality class levels were used as inputs to a reverse cloud generator algorithm to derive corresponding sample and level clouds. A multidimensional shape-position similarity cloud model (MSPSCM) was then developed to accurately evaluate lake water quality by considering shape and position similarities between the sample and level clouds. Using monthly water quality monitoring data from 2017 to 2019, spatiotemporal variability of water quality parameters of Nansi Lake in Shandong Province was analyzed, and the MSPSCM was used to further study the spatiotemporal variability of water pollution in Nansi Lake. Results showed that total nitrogen and total phosphorus were the main sources of pollution in Nansi Lake. Except for the severe pollution of the upper lake and its inflow waters (Class V water quality standard) in November 2017 and September 2019, Nansi Lake waters meet Class III water quality standard, and are suitable for drinking after being treated by a sewage treatment plant. Concentration of residential areas and industries around the upper lake is relatively high; large quantities of pollutants are discharged into the upper lake, resulting in considerably severe pollution of the upper lake (Class IV). Difference between water quality of Nansi Lake and that of its inflow water indicates that the purification ability of Nansi Lake should not be underestimated. In addition, compared with the existing cloud model used to evaluate lake water quality, the MSPSCM can more accurately reflect lake water quality, and provides a more flexible and effective method for lake water quality evaluation.

A unified co-evolutionary model was developed to study the adaptability conditions of regional water security systems, which is important for the coordinated development of these systems. In this work, the main factors that affect the adaptability of regional water security systems, the contribution of each sub-problem domain to the development of the problem domain, and the fitness values of regional water security systems were analyzed based on the model. Taking Jiansanjiang as an example, the results showed that in 2002–2011, the water resources system had strong adaptability and contributed greatly to improve the adaptability of the water security system; the socioeconomic system had poor adaptability to environmental changes and contributed little to the adaptability of the water security system; and the eco-environmental system was barely able to adapt to the changing environment and contributed less to the adaptability of the water security system. Due to the influence of the socioeconomic and eco-environmental systems, the adaptability of the water security system was relatively weak. Therefore, strengthening the sustainable utilization of water resources, promoting the coordinated development of the social economy, and improving the quality of the ecological environment are effective strategies to improve the adaptability of water security systems.

Point sources are important routes through which pollutants enter rivers. It is important to identify the characteristics of and trace the origins of water pollutants. In this study, an artificial intelligence system called the integrated long short-term memory network (LSTM), using cross-correlation and association rules (Apriori), was used to identify the characteristics of water pollutants and trace industrial point sources of pollutants. Water quality monitoring data from Shandong Province, China, were used to verify the applicability of the artificial intelligence system using a cross-correlation method to develop a water quality cross-correlation map. The map was used to identify highly correlated pollutants affecting water quality, then the association rules (Apriori) were used to track the pollutants to industries common in the study area. The highly correlated water pollutants and relevant industries were used as inputs for the LSTM to determine how well the LSTM traced sources of water pollutants. The results showed that (1) changes in water quality were affected in different ways by different industries and different distributions and production cycles of the pollutant point sources; (2) water quality correlation maps can be used to identify regular and abnormal fluctuations in point source pollutant emissions by identifying changes in water quality characteristics and frequent itemsets in water quality indices can be used to trace the industries that most strongly affect water quality; and (3) the LSTM accurately traced point sources of future changes in water quality. In conclusion, the artificial intelligence scheme described here can be applied to aquatic systems.

Lake eutrophication is characterized by a variety of indicators, including nitrogen and phosphorus concentrations, chemical oxygen demand, chlorophyll levels, and water transparency. In this study, a multidimensional similarity cloud model (MSCM) is combined with a random weighting method to reduce the impacts of random errors in eutrophication monitoring data and the fuzziness of lake eutrophication definitions on the consistency and reliability of lake eutrophication evaluations. Measured samples are assigned to lake eutrophication levels based on the cosine of the angle between the cloud digital characteristics vectors of each sample and those of each eutrophication grade. To field test this method, the eutrophication level of Nansi Lake in Shandong Province was evaluated based on monitoring data collected in 2009–2016. Results demonstrate that, in 2009 and in 2011–2015, the upper lake of Nansi Lake exhibited moderate eutrophication while the lower lake exhibited mild eutrophication. In 2010, 2016, elevated concentrations of total nitrogen and total phosphorus led to an increase in the eutrophication level of the lower lake, matching that of the upper lake. Based on the results of these field tests, we conclude that the MSCM presented in this study provides a more flexible and effective method for evaluating lake eutrophication data than the existing multidimensional normal cloud model.

This paper addresses the problem of missing latent time series information caused by the differences in the analysis of time series data and non-time series data. A time series trend structure model (TSTM) was established using the analysis of time series patterns and rules, the trends of patterns and rules, and trends in confidence and support. Shandong Province was selected as the study area. Rainfall and evaporation time series data from this area were input into the TSTM. The results show that: (1) the structure of multi-year precipitation and evaporation trends of the meteorological stations in the study area have continuously increasing or decreasing characteristics. The TSTM can excavate the different trend structure characteristics of different meteorological elements and enables diversity in time series data analysis; (2) the evaporation trend structure tends to change synchronously with increases and decreases in precipitation and evaporation. The synchronous change frequency is essentially the same as that of the rainfall trend structure. This indicates that the TSTM has spatial and temporal characteristics for time series data analysis; and (3) from the maximal non-descending and non-ascending subsequence in the TSTM, it can be concluded that there exists continuity in the years when the trend structure of precipitation and evaporation increases and decreases synchronously. In addition, the degree of similarity in the model is well reflected in the spatial distribution characteristics of time series data, and the model provides clustering characteristics for time series data analysis. The TSTM proposed in this paper can effectively obtain the potential hydrological information contained in time series data, and provides a scientific and reliable basis for rules for the spatial optimization of watershed data and for the calibration of hydrological models.

Background: ND-L02-s0201/BMS-986263 is a lipid nanoparticle encapsulating a siRNA which inhibits expression of heat shock protein 47 (HSP47), a collagen-specific chaperone. ND-L02-s0201 is being evaluated for the treatment of hepatic fibrosis. IPF patient data show elevated HSP47 lung expression and linkage to poor prognosis. Our objective was to test ND-L02-s0201 efficacy in preclinical lung fibrosis models. Methods: We developed aggressive and sustained bleomycin (BLM) and silica induced rat lung fibrosis models. These therapeutic models ensure treatment of established disease that is maintained through-out the study. Key endpoints included lung weights, hydroxyproline (measure of collagen formation), histology and fibrosis (Trichrome) score. Lung function was evaluated using a 7 minute treadmill test. Utilizing the BLM model, myofibroblasts, epithelia, endothelia and macrophage cell populations were enriched, counted and characterized. Results: In the BLM model, we demonstrated dose-dependent and statistically significant reduction in lung weight, collagen deposition and histology and fibrosis scores following ND-L02-s0201 treatment. As a functional measure, statistically significant improvement in lung function determined by running endurance capacity was noted. Following cell enrichment, myofibroblasts contained the highest HSP47 mRNA expression. BLM led to a >5-fold increase in myofibroblasts and ND-L02-s0201 treatment reduced the myofibroblasts to sham levels. Comparable anti-fibrotic efficacy utilizing the endpoints was also observed in the silica model. Conclusions: Given the significant unmet medical need and our results, the safety and efficacy of ND-L02-s0201 warrants evaluation in IPF clinical trials.

Regional water safety systems are affected by social, economic, ecological, hydrological and other factors, and their effects are complicated and variable. Studying water safety systems is crucial to promoting the coordinated development of regional water safety systems and anthropogenic processes. Thus, a similarity cloud model is developed to simulate the evolution mechanisms of fuzzy and complex regional systems of water security and overcome the uncertainty that is associated with the indices that are used in water safety index systems. This cloud generator is used to reciprocally transform a qualitative cloud image with a quantitative cloud characteristic value, and the stochastic weight assignment method is used to determine the weight of the evaluation indices. The results of case studies show that Jiansanjiang's water safety systems were in a safe state in 2002–2011, but the water safety systems in the arid area of Yinchuan City were in a dangerous state in 2006–2007 because of climate factors and a lack of effective water and soil resource protection. The experimental results are consistent with the research subjects' actual situations, and the proposed model provides a tool for decision makers to better understand the security issues that are associated with regional water safety systems.

Lung cancer is the most common form of cancer worldwide and the leading cause of cancer-related deaths. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers, and KRAS mutation occurs in 25-30% of NSCLC. However, to date, direct therapeutic targeting of KRAS has not been achieved. Our approach to developing a KRAS mutant NSCLC therapeutic agent was to identify a selective novel target involved in modulating signaling proteins in the RAS pathway without impacting healthy cells. Numerous studies have shown that glutathione S-transferase P (GSTP) is strongly upregulated in many cancer types, specifically lung, colon, and pancreas. Besides being a well-known Phase II detoxification enzyme, GSTP is also known to influence cell signaling through interaction with MAP kinases such as JNK and c-jun. We therefore hypothesized that GSTP knockdown (KD) could be an effective therapeutic approach to treat KRAS mutant tumors. To test this hypothesis, we designed a series of novel GSTP siRNAs and identified our lead candidate, a highly potent and selective GSTP siRNA (NDT-05-1040) to specifically target and downregulate GSTP protein. A panel of KRAS mutant NSCLC cell lines was utilized to determine the GSTP KD potency and antiproliferative activity of NDT-05-1040. Western blot analysis and co-immunoprecipitation (co-IP) were conducted to identify the proteins that were regulated by GSTP in the proliferation and apoptosis pathways. These studies demonstrated that NDT-05-1040 is a very potent and selective GSTP siRNA. Furthermore, transfection of NDT-05-1040 led to significant growth inhibition and induced apoptosis in NSCLC cells without affecting normal cell viability. Western blot analysis showed that NDT-05-1040 effectively decreased the phosphorylation of CRAF, ERK, MEK, in the MAP kinase pathway. Interestingly, with NDT-05-1040 treatment, the phosphorylation of Akt and mTOR in the PI3K pathway was also decreased. Moreover, the activity of p-JNK, PUMA, caspase-3/7, and p53 in the KRAS mutant cells was upregulated by NDT-05-1040. Co-IP experiments demonstrated that GSTP formed a complex with both p-CRAF and JNK. In summary, GSTP KD by NDT-05-1040 targeted the RAS/MEK/ERK, Akt, mTOR and apoptosis pathways. This selective multipronged attack on the growth and survival pathways of cancer cells makes it a compelling target and could potentially serve as a novel therapeutic agent for KRAS mutant NSCLC. Citation Format: Cima Cina, Jens Harborth, Zhihong O'Brien, Nish Beltran-Raygoza, Jung-kang Jin, Jessica Xu, Sang Jun Lee, Kwok Tsang, Jiping Yao, Roger Adami, Sonya Zabludoff, Wenbin Ying. A novel glutathione S-transferase P (GSTP) siRNA (NDT-05-1040) for the treatment of KRAS-driven non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5918.

To study dynamic change and pathophysiology of airway obstruction of the soft palate in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) during wakefulness and natural sleep.Sixteen patients who were diagnosed as OSAHS by sleep questionnaires, medical examination and polysomnography were enrolled in this study in Shanghai Tenth People' Hospital from May to December during 2007. All patients were requested to keep awake prior to examination. Sequential midline sagittal images of the upper airway were obtained during awake and asleep state with Cine-MRI and been transmitted to portable computer. Morphologic change of the soft palate, the anterior-posterior pendulum angle of the soft palate, the anteroposterior diameter and the length of soft palate were measured. Statistical analysis was performed with paired t-test.During wakefulness: soft palate caused obstruction by floating backwards and widening anteroposterior diameter(distance between hard palate and uvula P0.05, included angle of hard palate and segmental vente of uvula P0.05, included angle of hard palate and segmental dorsum of uvula P0.01, difference of included angle P0.01). Main obstruction site was on retropalatal region. During natural sleep: soft palate caused obstruction by lengthening down and widening anteroposterior diameter (distance between hard palate and uvula P0.01), included angle of hard palate and segmental vente of uvula P0.05, included angle of hard palate and segmental dorsum of uvula P0.05, difference of included angle P0.01). Main obstruction site was on retroglottal region.Morphologic change of soft palate in patients with OSAHS is multiple, and level of obstruction is deeper during natural sleep than during wakefulness. Main reason of airway obstruction is distinct during different state. The obstruction of upper airway of patients with OSAHS during wakefulness can't replace that during natural sleep.

The objective was to explore the optimal b value in diffusion-weighted imaging (DWI) of MRI for differential diagnosis of benign and malignant vertebral fractures.Thirty-four consecutive patients with vertebral compression fractures underwent sagittal diffusion-weighted imaging (DWI) with different b values. The group included 14 patients with 18 benign vertebral fractures due to osteoporosis and/or trauma and 20 patients with 27 malignant vertebral fractures due to malignancy. The quality of the images was analyzed qualitatively on a three-point scale and quantitatively by measurement of the signal-to-noise ratio (SNR). Apparent diffusion coefficient (ADC) values were also calculated.Smaller b values correlated with better DW image quality. We found significant differences in the qualitative points values among the DW images with different b values (F=302.18, p0.001). The mean SNR of the images ranged from 21.75+/-3.64 at a b value of 0 s/mm2 to 5.31+/-3.17 at a b value of 800 s/mm2. The SNR of DWI with a b value of 300 s/mm2 (18.62+/-2.47) was significantly different from that with other b values (p0.01). The mean combined ADC values of malignant fractures were significantly lower than those of benign ones on DWI with a b value of 300 s/mm2 (t=9.097, p0.01). Four cases of benign vertebral fractures were misdiagnosed as being malignant when b values of 0 s/mm2 and 100 s/mm2 were used.When DWI with multiple b values is used to differentiate benign from malignant vertebral compression fractures, b values within the range of around 300 s/mm2 are recommended, taking into account both SNR and diffusion weighting of water molecules.

Purpose: To determine whether autocrine motility factor receptor (AMFR) is detectable in the urine of patients with transitional cell carcinoma (TCC) of the bladder.Materials and Methods: We assayed the urine of 89 patients with bladder pathology and 28 normal controls for AMFR. A monoclonal antibody to AMFR was used.Results: All patients with muscle-invasive TCC tested positive for AMFR. Autocrine motility factor receptor was detectable for 80 percent of superficial tumors, with a correlation between AMFR and tumor grade. Seventy-five percent of control urines tested negative.Conclusions: Autocrine motility factor receptor is detectable in the urine of patients with TCC. Long-term follow-up and refinements in the assay should define the marker's utility for detection and prognosis.

The present day vegetation types on the earth are to a large extent controlled by climatic conditions that are mainly reflected in variations in moisture availability and temperature through the annual cycle. Therefore, fossil plants can be used as a tool to elucidate both spatial and temporal climatic changes. The global climates of the Jurassic can be interpreted with fossil floras because many parts of world have yielded abundant floral localities. Those records not only provide a strong basis for the qualitative depiction of vegetation patterns, but also provide quantitative data for the reconstruction of paleophytogeographic provinces and climatic changes. The computer program known as “Detrended Correspondence Analysis” written by Hill (1979) was used in this study. The floral data for this quantitative approach was assembled at the generic level mainly from the published literature. By definition, it is a method based on ordination scores, that is, the species ordination scores are averages of the sample ordination scores, and vice versa.The scatter diagrams of the first two axes of genera and sample sites derived by detrended correspondence analysis were obtained for the intervals of Early, Middle, and Late Jurassic. The gradient variations of both genera and sample sites are reflected by the scores along axis 1 and 2 because axis 1 and axis 2 maximize the correlation of species and sample sites according to this technique. In the ordination score diagrams, the genera in similar climatic environments and the sample sites in similar paleogeographic regions are relatively close to each other along axis1 and axis2.One of characteristics of the Jurassic vegetation is the taxonomic stability through the period compared with other periods of time. Therefore, the generic scores of axis1 for the Early and Middle, Middle and Late, and Early and Late Jurassic can be plotted against each other. The regression line can be used to assign the scores to the ordered genera. This is the technique used to complement the ordered genera from the gradient score diagrams and to eliminate the effect of some local genera. The genera adjacent to the regression line can be reliably used to reflect climatic gradients. The gradient changes were used to define biomes and to determine phytogeographic patterns on a global scale.The quantitative analysis clearly shows that the use of floral data can achieve fast and satisfactory results in paleoclimatic studies of the Jurassic. For example, the cool-wet temperate climate is reflected by a ginkgophyte dominated deciduous flora, such as Ginkgo, Czekanowskia, Phoenicopsis, and Baiera, whereas the subtropical warm and drier climate is represented by cycad dominated floras, such as Anomozamites, Nilssonia, Pterophylum, Ptilophyllwn, Ctenis, and Otozamites. The general conclusion of earlier workers that Jurassic floras were especially uniform through the earth is true in the relative sense only, and the ordination study allows for the subdivision of the rather shallow gradients that do exist.