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Background: ASP3026 is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has potent in vitro activity against crizotinib-resistant ALK-positive tumors. This open-label, multicenter, first-in-human phase I study (NCT01284192) assessed the safety, pharmacokinetic profile, and antitumor activity of ASP3026. Methods: Advanced solid tumor patients received oral ASP3026 in 3 + 3 dose-escalation cohorts at doses of 25-800 mg once daily in 28-day cycles. The endpoints were to identify the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the pharmacokinetic profile of ASP3026. A phase Ib expansion cohort enrolled patients with metastatic, crizotinib-resistant ALK-positive solid tumors at the RP2D, and response was evaluated by RECIST 1.1. Results: The dose-escalation cohort enrolled 33 patients, including three crizotinib-resistant, ALK-positive patients, and the dose-expansion cohort enrolled another 13 crizotinib-resistant, ALK-positive non-small cell lung cancer (NSCLC) patients. ASP3026 demonstrated both linear pharmacokinetics and dose-proportional exposure for area under the plasma concentration-time curve and maximum concentration observed with a median terminal half-life of 35 h, supporting the daily dosing. Grade 3 rash and elevated transaminase concentrations were dose-limiting toxicities observed at 800 mg; hence, 525 mg daily was the MTD and RP2D. The most common treatment-related adverse events were nausea (38 %), fatigue (35 %), and vomiting (35 %). Among the 16 patients with crizotinib-resistant ALK-positive tumors (15 NSCLC, 1 neuroblastoma), eight patients achieved partial response (overall response rate 50 %; 95 % confidence interval 25-75 %) and seven patients (44 %) achieved stable disease. Conclusions: ASP3026 was well tolerated and had therapeutic activity in patients with crizotinib-resistant ALK-positive advanced tumors. [ABSTRACT FROM AUTHOR]

Urban sprawl significantly impacts ecosystem services and functions. The exact impacts, however are difficult to quantify and are often neglected in policy making. The evaluation of ecosystem services is conducive to clarifying the ecological and environmental changes caused by urbanization. The objective of this study is to investigate variations in ecosystem services in response to land use changes during urbanization. The aim is to provide useful information and advice for policy makers concerned with sustainable development. Shenzhen, one of the fastest growing metropolitan areas in China, is selected as the study area. A fast evaluation method for ecological service values based on land use change was proposed and applied to the city for 1996, 2000 and 2004. The total value of ecosystem services in Shenzhen was 2776.0 million Yuan in 1996, 2911.4 million Yuan in 2000 and 2544.7 million Yuan in 2004 respectively, with a decrease of 231.3 million Yuan from 1996 to 2004 mainly due to the decreasing areas of woodland, wetland and water body. The combined ecosystem service value of woodland, wetland, water body and orchard was over 90% of the total value. Water supply and waste treatment were the top two service functions with high service value, contributing about 40% of the total service value. The results suggest that a reasonable land use plan should be made with emphasis on protecting wetland, water body and woodland, which have the highest ecosystem service value. [Copyright &y& Elsevier]

The epidermal growth factor receptor (EGFR), an N-glycosylated transmembrane protein, is the target of erlotinib, an orally bioavailable agent approved for treatment of patients with non-small cell lung cancer (NSCLC). In this study, we examined whether inhibition of EGFR N-glycosylation and stimulation of endoplasmic reticulum (ER) stress by tunicamycin enhances erlotinib-induced growth inhibition in NSCLC cell lines. We examined the effects of tunicamycin and erlotinib on cytotoxicity of erlotinib-sensitive and resistant NSCLC cell lines, as well its effects on apoptotic pathways and on EGFR activation and subcellular localization. A minimally cytotoxic concentration of tunicamycin (1 μM) resulted in~2.6–2.9 fold and~6.8–13.5 fold increase in erlotinib-induced antiproliferative effects in sensitive (H322 and H358) and resistant cell lines (A549 and H1650), respectively. We found that tunicamycin generated an aglycosylated form of 130 kDa EGFR. Tunicamycin additionally affected EGFR activation and subcellular localization. Interestingly, the combination of tunicamycin and erlotinib caused more inhibitory effect on EGFR phosphorylation than that of erlotinib alone. Moreover, the combination induced apoptosis in H1650 cells through induction of CHOP expression, activation of caspase-12 and caspase-3, cleavage of PARP and bak, and down-regulation of anti-apoptotic proteins bcl-xL and survivin. Overall, our data demonstrate that tunicamycin significantly enhances the susceptibility of lung cancer cells to erlotinib, particularly sensitizing resistant cell lines to erlotinib, and that such sensitization may be associated with activation of the ER stress pathway and with inhibition of EGFR N-glycosylation. [ABSTRACT FROM AUTHOR]

We are concerned with spherically symmetric solutions to Euler equations for multi-dimensional compressible fluids which have many applications in diverse real physical situations. The system can be reduced to one-dimensional isentropic gas dynamics with geometric source terms. Due to the presence of the singularity at the origin, there are few papers devoted to this problem. The present paper proves two existence theorems of global entropy solutions. The first one focuses on a case excluding the origin in which negative velocity is allowed, and the second one corresponds to a case which includes the origin with non-negative velocity. The compensated compactness framework and vanishing viscosity method are applied to prove the convergence of approximate solutions. In the second case, we show that if the blast wave initially moves outwards and the initial densities and velocities decay to zero with certain rates near the origin, then the densities and velocities tend to zero with the same rates near the origin for any positive time. In particular, the entropy solutions in two existence theorems are uniformly bounded with respect to time. [ABSTRACT FROM AUTHOR]

Softening is a key step during fruit ripening that is modulated by the interplay between multiple phytohormones. The antagonistic action of abscisic acid (ABA) and auxin determines the rate of fruit ripening and softening. However, the transcription factors that integrate ABA and auxin signals to regulate fruit softening remain to be determined. In this study, we identified several DNA-binding with One Finger (Dof) transcription factors essential for ABA-promoted fruit softening, based on transcriptome analysis of two sweet cherry (Prunus avium L.) varieties with different fruit firmness. We show that PavDof6 directly binds to the promoters of genes encoding cell wall-modifying enzymes to activate their transcription, while PavDof2/15 directly repress their transcription. Transient overexpression of PavDof6 and PavDof2/15 in sweet cherry fruits resulted in precocious and delayed softening, respectively. In addition, we show that the auxin response factor PavARF8, the expression of whose encoding gene is repressed by ABA, activates PavDof2/15 transcription. Furthermore, PavDof2/6/15 and PavARF8 directly bind to the 9-cis-epoxycarotenoid dioxygenase 1 (PavNCED1) promoter and regulate its expression, forming a feedback mechanism for ABA-mediated fruit softening. These findings unveil the physiological framework of fruit softening and establish a direct functional link between the ABA-PavARF8-PavDofs module and cell-wallmodifying genes in mediating fruit softening. [ABSTRACT FROM AUTHOR]

Activation of EGF receptor (EGFR) triggers signaling pathways regulating various cellular events that contribute to tissue development and function. Aberrant activation of EGFR contributes to tumor progression as well as therapeutic resistance in patients with cancer. C-terminal tensin-like (CTEN; TNS4) is a focal adhesion molecule that is a member of the tensin family. Its expression is upregulated by EGF and elevated CTEN mediates EGF-induced cell migration. In the presence of CTEN, we found that EGF treatment elevated the level of EGFR protein but not mRNA. The extended half-life of activated EGFR sustained its signaling cascades. CTEN reduced ligand-induced EGFR degradation by binding to the E3 ubiquitin ligase c-Cbl and decreasing the ubiquitination of EGFR. The Src homology 2 domain of CTEN is not only required for binding to the phosphorylated tyrosine residue at codon 774 of c-Cbl, but is also essential for the tumorigenicity observed in the presence of CTEN. Public database analyses indicated that CTEN mRNA levels are elevated in breast, colon, lung, and pancreas cancers, but not correlated with EGFR mRNA levels in these cancers. In contrast, immunohistochemistry analyses of lung cancer specimens showed that CTEN and EGFR protein levels were positively associated, in support of our finding that CTEN regulates EGFR protein levels through a posttranslational mechanism. Overall, this work defines a function for CTEN in prolonging signaling from EGFR by reducing its ligand-induced degradation. [ABSTRACT FROM AUTHOR]

With population growth and economic development, urban ecosystems are facing serious ecological risks from multiple pressures. Through a case study of the Shenzhen River-Bay watershed, which had experienced rapid urbanization, a Pressure-Effect-Social Response (PESR) ecological risk assessment indicator system was established based on the Pressure-State-Response (PSR) framework. Risk index for each sub-ecosystem was calculated through Fuzzy Comprehensive Evaluation (FCE). The risk grading and the potential ecological risk for the Shenzhen River-Bay watershed were determined. The results showed that the ecological risk of the Shenzhen River and the Shenzhen Bay watershed remained at high and medium levels from years 2001 to 2005, respectively. Appropriate measures should be implemented to mitigate the ecological risks in this area. The results provide a scientific basis for risk prevention management in the study area and can be of reference for other urbanized areas. [ABSTRACT FROM AUTHOR]

Drought stress severely restricts crop yield and quality. Small noncoding RNAs play critical roles in plant growth, development, and stress responses by regulating target gene expression, but their roles in drought stress tolerance in apple (Malus domestica) are poorly understood. Here, we identified various small noncoding RNAs and their targets from the wild apple species Malus sieversii via high-throughput sequencing and degradome analysis. Forty known microRNAs (miRNAs) and eight new small noncoding RNAs were differentially expressed in response to 2 or 4 h of drought stress treatment. We experimentally verified the expression patterns of five selected miRNAs and their targets. We established that one miRNA, mdm-miR171i, specifically targeted and degraded SCARECROW-LIKE PROTEINS26.1 (MsSCL26.1) transcripts. Both knockout of mdm-miR171i and overexpression of MsSCL26.1 improved drought stress tolerance in the cultivated apple line 'GL-3' by regulating the expression of antioxidant enzyme genes, especially that of MONODEHYDROASCORBATE REDUCTASE, which functions in metabolism under drought stress. Transient expression analysis demonstrated that MsSCL26.1 activates MsMDHAR transcription by positively regulating the activity of the P1 region in its promoter. Therefore, the miR171i-SCL26.1 module enhances drought stress tolerance in apple by regulating antioxidant gene expression and ascorbic acid metabolism. [ABSTRACT FROM AUTHOR]

Polycyclic tetramate macrolactams (PoTeMs) are a growing class of natural products with distinct structure and diverse biological activities. By promoter engineering and heterologous expression of the cryptic cbm gene cluster, four new PoTeMs, combamides A-E (1-4), were identified. Additionally, two new derivatives, combamides E (5) and F (6), were generated via combinatorial biosynthesis. Together, our findings provide a sound base for expanding the structure diversities of PoTeMs through genome mining and combinatorial biosynthesis. [ABSTRACT FROM AUTHOR]

MicroRNA (miRNA) is processed from primary transcripts with hairpin structures (pri-miRNAs) by microprocessors in the nucleus. How cytoplasmic-borne microprocessor components are transported into the nucleus to fulfill their functions remains poorly understood. Here, we report KETCH1 (karyopherin enabling the transport of the cytoplasmic HYL1) as a partner of hyponastic leaves 1 (HYL1) protein, a core component of microprocessor in Arabidopsis and functional counterpart of DGCR8/Pasha in animals. Null mutation of ketch1 is embryonic-lethal, whereas knockdown mutation of ketch1 caused morphological defects, reminiscent of mutants in the miRNA pathway. ketch1 knockdown mutation also substantially reduced miRNA accumulation, but did not alter nuclear-cytoplasmic shuttling of miRNAs. Rather, the mutation significantly reduced nuclear portion of HYL1 protein and correspondingly compromised the pri-miRNA processing in the nucleus. We propose that KETCH1 transports HYL1 from the cytoplasm to the nucleus to constitute functional microprocessor in Arabidopsis. This study provides insight into the largely unknown nuclear-cytoplasmic trafficking process of miRNA biogenesis components through eukaryotes. [ABSTRACT FROM AUTHOR]

Background: Programmed cell death 1 (PD-1) and its ligand 1 (PD-L1) inhibitors have quickly become standard of care for patients with advanced non-small cell lung cancer and increasing numbers of other cancer types. In this report, we discuss the clinical history, pathological evaluation, and genomic findings in a patient with metastatic lung squamous cell cancer (SCC) who developed severe nivolumab-induced pneumonitis preceding durable clinical remission after three doses of nivolumab. Case presentation: A patient with chemotherapy-refractory, metastatic lung SCC developed symptomatic pneumonitis by week 4 after nivolumab treatment, concurrently with onset of a potent antitumor response. Despite discontinuation of nivolumab after three doses and the use of high dose oral corticosteroids for grade 3 pneumonitis, continued tumor response to a complete remission by 3 months was evident by radiographic assessment. At the time of this submission, the patient has remained in clinical remission for 14 months. High PD-L1 expression by immunohistochemistry staining was seen in intra-alveolar macrophages and viable tumor cells in the pneumonitis and recurrent tumor specimens, respectively. Tumor genomic profiling by FoundationOne targeted exome sequencing revealed a very high tumor mutation burden (TMB) corresponding to 95-96 percentile in lung SCC, i.e., 87.4-91.0 and 82.9 mut/Mb, respectively, in pre- and post-nivolumab tumor specimens. Except for one, the 13 functional genomic alterations remained the same in the diagnostic, recurrent, and post-treatment, relapsed tumor specimens, suggesting that nivolumab reset the patient's immune system against one or more preexisting tumor-associated antigens (TAAs). One potential TAA candidate is telomerase reverse transcriptase (TERT) in which an oncogenic promoter -146C>T mutation was detected. Human leukocyte antigen (HLA) typing revealed HLA-A*0201 homozygosity, which is the prevalent HLA class I allele that has been used to develop universal cancer vaccine targeting TERT-derived peptides. Conclusions: Nivolumab could quickly reset and sustain host immunity against preexisting TAA(s) in this chemotherapy-refractory lung SCC patient. Further mechanistic studies are needed to characterize the effective immune cells and define the HLA-restricted TAA(s) and the specific T cell receptor clones responsible for the potent antitumor effect, with the aim of developing precision immunotherapy with improved effectiveness and safety. [ABSTRACT FROM AUTHOR]

Soil erosion by water impacts soil organic carbon stocks and alters CO2 fluxes exchanged with the atmosphere. The role of erosion as a net sink or source of atmospheric CO2 remains highly debated, and little information is available at scales larger than small catchments or regions. This study attempts to quantify the lateral transport of soil carbon and consequent land-atmosphere CO2 fluxes at the scale of China, where severe erosion has occurred for several decades. Based on the distribution of soil erosion rates derived from detailed national surveys and soil carbon inventories, here we show that water erosion in China displaced 180 ± 80 Mt C⋅y-1 of soil organic carbon during the last two decades, and this resulted a net land sink for atmospheric CO2 of 45 ± 25 Mt C⋅y-1, equivalent to 8-37% of the terrestrial carbon sink previously assessed in China. Interestingly, the "hotspots," largely distributed in mountainous regions in the most intensive sink areas (>40 g C⋅m-2⋅y-1), occupy only 1.5% of the total area suffering water erosion, but contribute 19.3% to the national erosion-induced CO2 sink. The erosion-induced CO2 sink underwent a remarkable reduction of about 16% from the middle 1990s to the early 2010s, due to diminishing erosion after the implementation of large-scale soil conservation programs. These findings demonstrate the necessity of including erosion-induced CO2 in the terrestrial budget, hence reducing the level of uncertainty. [ABSTRACT FROM AUTHOR]

Modulating immune inhibitory pathways has been a major recent breakthrough in cancer treatment. Checkpoint blockade antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programed cell-death protein 1 (PD-1) have demonstrated acceptable toxicity, promising clinical responses, durable disease control, and improved survival in some patients with advanced melanoma, non-small cell lung cancer (NSCLC), and other tumor types. About 20 % of advanced NSCLC patients and 30 % of advanced melanoma patients experience tumor responses from checkpoint blockade monotherapy, with better clinical responses seen with the combination of anti-PD-1 and anti-CTLA-4 antibodies. Given the power of these new therapies, it is important to understand the complex and dynamic nature of host immune responses and the regulation of additional molecules in the tumor microenvironment and normal organs in response to the checkpoint blockade therapies. In this era of precision oncology, there remains a largely unmet need to identify the patients who are most likely to benefit from immunotherapy, to optimize the monitoring assays for tumor-specific immune responses, to develop strategies to improve clinical efficacy, and to identify biomarkers so that immune-related adverse events can be avoided. At this time, PD-L1 immunohistochemistry (IHC) staining using 22C3 antibody is the only FDA-approved companion diagnostic for patients with NSCLC-treated pembrolizumab, but more are expected to come to market. We here summarize the current knowledge, clinical efficacy, potential immune biomarkers, and associated assays for immune checkpoint blockade therapies in advanced solid tumors. [ABSTRACT FROM AUTHOR]

Large water diversion projects have extensive impact on the water systems in the receiving areas, where inevitable regional responses are aroused and alert to local environmental carrying capacity. To ensure the water quality of China's eastern South-to-North Water Diversion Project (SNWDP), Shandong Province had issued strict local wastewater discharge standards since 2006. However, some flexibility exists in the enforcement of local standards, which created uncertainty to the outcomes. A system dynamic (SD) model and Water Environmental Carrying Capacity (WECC) method were integrated to dynamically illustrate the interaction between the enforcement of the local standards and the performance of the regional water system. The WECC was calculated based on an indicator system representing the multi-dimensional impact of the local standards on the regional water system. The SD model was constructed to simulate and forecast the variations of those indicators of WECC. The SD-WECC model was trained and validated with yearly data from 2000 to 2020, then four scenarios with different levels of enforcement of local standards were illustrated. The results showed that overall WECC improves during period from 2000 to 2025, and that the SNWDP improves the balance of water supply and demand in Shandong in the long run in the three scenarios that have introduced the local standards. The adoption of the local standard helps the concentration of industrial Chemical Oxygen Demand (COD) discharge to meet the discharging standards earlier by stimulating the investment in pollution control. Therefore, the flexibility in local water environment management enabled the local actors to pursue a balance between environmental protection and economic growth in a dynamic context with multi-objects for local development. [ABSTRACT FROM AUTHOR]

Background: Auxin plays important roles in hormone crosstalk and the plant's stress response. The auxinresponsive Gretchen Hagen3 (GH3) gene family maintains hormonal homeostasis by conjugating excess indole-3 -acetic acid (IAA), salicylic acid (SA), and jasmonic acids (JAs) to amino acids during hormone- and stress-related signaling pathways. With the sequencing of the apple (Malus × domestica) genome completed, it is possible to carry out genomic studies on GH3 genes to indentify candidates with roles in abiotic/biotic stress responses. Results: Malus sieversii Roem., an apple rootstock with strong drought tolerance and the ancestral species of cultivated apple species, was used as the experimental material. Following genome-wide computational and experimental identification of MdGH3 genes, we showed that MdGH3s were differentially expressed in the leaves and roots of M. sieversii and that some of these genes were significantly induced after various phytohormone and abiotic stress treatments. Given the role of GH3 in the negative feedback regulation of free IAA concentration, we examined whether phytohormones and abiotic stresses could alter the endogenous auxin level. By analyzing the GUS activity of DR5::GUS-transformed Arabidopsis seedlings, we showed that ABA, SA, salt, and cold treatments suppressed the auxin response. These findings suggest that other phytohormones and abiotic stress factors might alter endogenous auxin levels. Conclusion: Previous studies showed that GH3 genes regulate hormonal homeostasis. Our study indicated that some GH3 genes were significantly induced in M. sieversii after various phytohormone and abiotic stress treatments, and that ABA, SA, salt, and cold treatments reduce the endogenous level of axuin. Taken together, this study provides evidence that GH3 genes play important roles in the crosstalk between auxin, other phytohormones, and the abiotic stress response by maintaining auxin homeostasis. [ABSTRACT FROM AUTHOR]

A new spectrometric method ultra performance liquid chromatography-tandem mass spectrometric with high precision and rapid analysis was developed to separate 17 phenolic compounds. Different species of cherries, including 10 sweet cherry ( Prunus avium L.) cultivars, a tart cherry ( P. cerasus L.) rootstock (CAB), and a hybrid rootstock 'Colt' ( P. avium × P. pseudocerasus), were analyzed for phenolics contents by this method. The results showed that significant differences were observed among the phenolic compound contents in different cherry species. In 10 sweet cherry cultivars, the contents of neochlorogenic acid and cyanidin-3O-rutinoside were much higher in red-colored fruits (for example, 64.60 and 44.50 mg/100 g fresh weight in Burlat, respectively) than those in bicolored ones. Principal component analysis revealed that cyanidin-3O-rutinoside was an effective index for grouping the cultivars with similar species and fruit colors. Moreover, there were strong positive correlations between phenolics content and antioxidant activity, which was higher in red-colored cherries. [ABSTRACT FROM AUTHOR]

Because aqueous ions can influence the defluoridation of the electrocoagulation (EC) process, the effects of Ca2+ and Mg2+ were investigated. The behaviors and mechanisms of EC defluoridation in Ca2+-containing systems were different from those in Mg2+-containing systems. An increase in Ca2+ concentration improved the defluoridation efficiency (eF), but it could not change the optimal molar ratio of OH- and F- to Al3+ (rOH+F). The highest eF can usually be obtained at rOH+F = 3 for defluoridation. Only a small portion of Ca2+ entered into the flocs, and Ca2+ could not influence the mechanism of EC defluoridation. For the Mg2+-containing system, the optimal rOH+F increased with increasing Mg2+ concentration. The optimal rOH+F was maintained at 3 after the Mg2+ concentration was corrected using the obtained correction coefficient of 0.3435. About 50% to 70% of the total Mg2+ entered into the flocs. From the XRD analysis, it was found that some Mg—Al—F layered double hydroxides (LDHs) were formed by Mg2+, F-, and Al3+ during electrolysis. It is proposed for the first time that the formation of Mg—Al—F LDH is one of the mechanisms for EC defluoridation in systems containing both F- and Mg2+. [ABSTRACT FROM AUTHOR]

Chemotherapy commonly used in the treatment of advanced bladder cancer is only moderately effective and associated with significant toxicity. There has been no appreciable improvement in overall survival over the last three decades. The goal of this project is to develop and characterize bladder cancer-specific nanometer-scale micelles loaded with the chemotherapeutic drug paclitaxel (PTX) and determine the anti-tumor activity and toxicity. Micelle-building-material telodendrimers were synthesized through the stepwise conjugation of eight cholic acid units at one terminus of polyethylene glycol (PEG) and a bladder cancer-specific targeting peptide named PLZ4 at the other terminus. To synthesize disulfide-crosslinked PLZ4 nanomicelles (DC-PNM), cysteine was introduced between the cholic acid and PEG. DC-PNM-PTX was synthesized through the evaporation method by loading PTX in the core. The loading capacity of PTX in DC-PNM was 25% (W/W). The loading efficiency was over 99%. DC-PNM-PTX was spherical with the median size of 25 nm. The stability of DC-PNM-PTX was determined in a solution containing sodium docecyl sulfate (SDS). It was stable in a SDS solution, but dissolved within 5 min after the addition of glutathione at the physiological intracellular concentration of 10 mM. In vivo targeting and anti-tumor activity were determined in immunodeficient mice carrying patient-derived bladder cancer xenografts (PDXs). After intravenous administration, DC-PNM specifically targeted the bladder cancer PDXs, but very little to the lung cancer xenografts in the same mice (p < 0.001). DC-PNM loaded with PTX overcame cisplatin resistance, and improved the median survival from 55 d with free PTX to 69.5 d (p = 0.03) of mice carrying PDXs. In conclusion, DC-PNM remained stable in the SDS solution, specifically targeted the bladder cancer xenografts in vivo, and improved the anti-cancer efficacy of PTX. [ABSTRACT FROM AUTHOR]