The bisindole moiety, as a versatile pharmacophore, is one of the widespread heterocycles in naturally occurring and synthetic bioactive compounds. The bisindole alkaloids derived from natural ...sources possess structural and mechanistic diversity, and they were found to be generally more active than monoindole alkaloids against various cancer cell lines. Moreover, some bisindole alkaloids such as the tubulin inhibitors, vinorelbine and vinblastine, have already been approved for cancer therapy, suggesting that bisindole alkaloids are a significant source of anticancer agents and lead hits. Bisindole hybrids have the potential to overcome drug resistance, enhance efficiency, and reduce severe side effects. The bisindole–lactam hybrid midostaurin has already been approved for the treatment of adult patients with newly diagnosed acute myeloid leukemia who are FLT3 mutation‐positive, highlighting the importance of bisindole hybrids in the development of novel anticancer agents. In this review, we present a brief account of the bisindole alkaloids derived from nature and of synthetic hybrids with potential anticancer activity developed in the recent 10 years.
Bisindole alkaloids were found to be generally more active than monoindole alkaloids against various cancer cell lines. Bisindole hybrids have the potential to overcome drug resistance, enhance efficiency, and reduce severe side effects. This review focuses on the bisindole alkaloids derived from nature and synthetic hybrids with potential anticancer activity developed in the recent 10 years.
Recently, with improvements in computed tomography angiography and digital subtraction angiography, the assessment of certain morphologic traits of anterior communicating artery aneurysms (ACoAA) has ...drawn great attention. The determination of specific factors associated with rupture would provide much-needed guidance for the treatment of unruptured intracranial aneurysms, such as surgical clipping or endovascular coiling. Morphologic factors include, but are not limited to, aneurysm size, number, shape, dome direction, neck/dome ratio, and relationship of the aneurysm to the surrounding vessels. However, the results of previous investigations concerning morphologic parameters have yielded inconsistent results.
This review presents and analyzes the literature on the morphology of ACoAAs and risk of rupture.
This literature review reveals that the strongest predictors of ACoAA rupture are size ratio, direction of the dome, and fenestration. These were the only factors that were either unanimously or near unanimously found to be predictive of rupture across multiple studies.
The size ratio, direction of the dome, and fenestration should be examined most meticulously when deciding when to treat an ACoAA.
Previous projections show consistent increases in river flows of Asian Water Towers under future climate change. Here we find non-monotonic changes in river flows for seven major rivers originating ...from the Tibetan Plateau at the warming levels of 1.5 °C, 2.0 °C, and 3.0 °C based on an observation-constrained hydrological model. The annual mean streamflow for seven rivers at 1.5 °C warming level decreases by 0.1-3.2% relative to the present-day climate condition, and increases by 1.5-12% at 3.0 °C warming level. The shifting river flows for the Yellow, Yangtze, Brahmaputra, and Ganges are mostly influenced by projected increases in rainfall, but those for the Mekong, Salween, and Indus are dictated by the relative changes in rainfall, snowmelt and glacier melt. Reduced river flows in a moderately warmed climate threaten water security in riparian countries, while elevated flood risks are expected with further temperature increases over the Tibetan Plateau.
Summary Background Activating mutations in EGFR are important markers of response to tyrosine kinase inhibitor (TKI) therapy in non-small-cell lung cancer (NSCLC). The OPTIMAL study compared efficacy ...and tolerability of the TKI erlotinib versus standard chemotherapy in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC. Methods We undertook an open-label, randomised, phase 3 trial at 22 centres in China. Patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received either oral erlotinib (150 mg/day) until disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin. Patients were randomly assigned (1:1) with a minimisation procedure and were stratified according to EGFR mutation type, histological subtype (adenocarcinoma vs non-adenocarcinoma), and smoking status. The primary outcome was progression-free survival, analysed in patients with confirmed disease who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov , number NCT00874419 , and has completed enrolment; patients are still in follow-up. Findings 83 patients were randomly assigned to receive erlotinib and 82 to receive gemcitabine plus carboplatin; 82 in the erlotinib group and 72 in the chemotherapy group were included in analysis of the primary endpoint. Median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy (13.1 95% CI 10.58–16.53 vs 4.6 4.21–5.42 months; hazard ratio 0.16, 95% CI 0.10–0.26; p<0.0001). Chemotherapy was associated with more grade 3 or 4 toxic effects than was erlotinib (including neutropenia in 30 42% of 72 patients and thrombocytopenia in 29 40% patients on chemotherapy vs no patients with either event on erlotinib); the most common grade 3 or 4 toxic effects with erlotinib were increased alanine aminotransferase concentrations (three 4% of 83 patients) and skin rash (two 2% patients). Chemotherapy was also associated with increased treatment-related serious adverse events (ten 14% of 72 patients decreased platelet count, n=8; decreased neutrophil count, n=1; hepatic dysfunction, n=1 vs two 2% of 83 patients both hepatic dysfunction). Interpretation Compared with standard chemotherapy, erlotinib conferred a significant progression-free survival benefit in patients with advanced EGFR mutation-positive NSCLC and was associated with more favourable tolerability. These findings suggest that erlotinib is important for first-line treatment of patients with advanced EGFR mutation-positive NSCLC. Funding F Hoffmann-La Roche Ltd (China); Science and Technology Commission of Shanghai Municipality.
Abstract
Transboundary river cooperation provides an effective pathway to maintain regional security and sustainable development; however, its implementation is a pressing and prominent concern due ...to lack of appropriate compensation measures and effective incentive strategies. Here we develop a dual water-electricity cooperation (DWEC) framework that combines water and electricity trading to meet the often-conflicting demands of participating countries. The results from the Lancang-Mekong River Basin reveal that substantial benefits in both economic and social aspects can be achieved through coupling regional water and electricity trades. Economic benefits can be obtained by expanding cooperation space and thereby greatly improving the willingness of countries to participate in basin-wide cooperation. Electricity trading plays a key role in loss compensation for water exporters, ensuring no loss for any party and maximizing basin-wide benefits. Furthermore, the DWEC improves regional water use equality, especially in water shortage periods when there is severe competition among water users. The proposed cooperation framework provides a viable way to implement cooperation in transboundary river basins.
The optimal treatment strategy for stage IB2-IIB cervical cancer is controversial. This systematic review with meta-analysis evaluated the efficacy of concomitant chemoradiotherapy (CCRT) and ...neoadjuvant chemotherapy followed by radical surgery (NACT+S). Studies that evaluated NACT+S versus CCRT for patients with Federation of Gynecology and Obstetrics stage IB2-IIB cervical cancer were searched in MEDLINE, EMBASE, and the Cochrane Library database. Hazard ratios (HRs) with their respective 95% confidence intervals (CIs) were calculated using a random-effects model. Toxicity was also evaluated. Six qualified retrospective studies and one randomized controlled trial (2270 patients) were included in this review. The results suggested that compared with CCRT, NACT+S did not improve overall survival in all patients (HR 0.73, 95% CI 0.52-1.02) or stage IIB patients (HR 0.83, 95% CI 0.61-1.15). NACT+S did not improve disease-free survival (DFS) in stage IIB patients (HR 1.10, 95% CI 0.70-1.71). In the analysis of DFS in all patients, a high degree of heterogeneity was detected (I2 = 84%). Sensitivity analysis that eliminated these heterogeneous data suggested that CCRT could improve DFS over NACT+S (HR 1.47, 95% CI 1.12-1.93). Diarrhea and rectal and bladder complications occurred at a lower rate in the NACT+S group than in the CCRT group. NACT+S had no survival advantage for patients with stage IB2-IIB cervical cancer compared with CCRT but was associated with fewer side effects. Further prospective studies with a larger sample size of treatment protocols for locally advanced cervical cancer are needed.
Nuclear protein Ki-67 indicates the status of cell proliferation and has been regarded as an attractive biomarker for the prognosis of HCC. The aim of this study is to investigate which radiomics ...model derived from different sequences and phases of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI was superior to predict Ki-67 expression in hepatocellular carcinoma (HCC), then further to validate the optimal model for preoperative prediction of Ki-67 expression in HCC.
This retrospective study included 151 (training cohort: n = 103; validation cohort: n = 48) pathologically confirmed HCC patients. Radiomics features were extracted from the artery phase (AP), portal venous phase (PVP), hepatobiliary phase (HBP), and T2-weighted (T2W) images. A logistic regression with the least absolute shrinkage and selection operator (LASSO) regularization was used to select features to build a radiomics score (Rad-score). A final combined model including the optimal Rad-score and clinical risk factors was established. Receiver operating characteristic (ROC) curve analysis, Delong test and calibration curve were used to assess the predictive performance of the combined model. Decision cure analysis (DCA) was used to evaluate the clinical utility.
The AP radiomics model with higher decision curve indicating added more net benefit, gave a better predictive performance than the HBP and T2W radiomic models. The combined model (AUC = 0.922 vs. 0.863) including AP Rad-score and serum AFP levels improved the predictive performance more than the AP radiomics model (AUC = 0.873 vs. 0.813) in the training and validation cohort. Calibration curve of the combined model showed a good agreement between the predicted and the actual probability. DCA of the validation cohort revealed that at a range threshold probability of 30-60%, the combined model added more net benefit compared with the AP radiomics model.
A combined model including AP Rad-score and serum AFP levels based on enhanced MRI can preoperatively predict Ki-67 expression in HCC.
A facile strategy is reported here for synthesis of Zn-Cu-In-S/ZnS (ZCIS/ZnS) core/shell QDs to address the synthetic issues that the unexpected blue-shift of CuInS(2)-based nanocrystals. In this ...strategy, Zn(2+) ions are intentionally employed for the synthesis of alloyed ZCIS core QDs before ZnS shell coating, which contributes to the reduced blue-shift in photoluminescence (PL) emission. The experimental results demonstrate this elaborate facile strategy is effective for the reduction of blue-shift during shell growth. Particularly, a hypothesis is proposed and proved for explanation of this effective strategy. Namely, both cation exchange inhibition and ions accumulation are involved during the synthesis of ZCIS/ZnS QDs. Furthermore, the obtained near infrared (NIR) ZCIS/ZnS QDs are transferred into aqueous phase by a polymer coating technique and coupled with cyclic Arg-Gly-Asp peptide (cRGD) peptides. After confirmation of biocompability by cytotoxicity test on normal 3T3 cells, these QDs are injected via tail vein into nude mice bearing U87 MG tumor. The result indicates that the signals detected in the tumor region are much more distinguishing injected with ZCIS/ZnS-cRGD QDs than that injected with ZCIS/ZnS QDs.
•Soil erosion control is the main cause of sediment reduction in the Yellow River since 2000.•Sediment reduction effects of soil conservation measures exists a critical threshold.•Marginal sediment ...reduction benefits of the soil and water conservation measures is at a low level.
Under the background of large-scale, high-intensity, comprehensive soil erosion control, the sediment discharge of the Yellow River has undergone profound changes. The quantitative evaluation of the influences of soil and water conservation on sediment discharge is not only an inevitable requirement for the objective assessment of the ecological benefits of soil and water conservation projects, but it is also a prerequisite for gaining a scientific understanding of the causes of the drastic changes in the sediment discharge of the Yellow River. Taking the trunk stream in the Toudaoguai-Tongguan section of the middle reaches of the Yellow River and its 24 primary tributaries as the research objects, the Mann-Kendall test and the double mass curve were used to determine the spatial–temporal changes in the sediment discharge over the past 60 years. The results show the following. 1) The average annual sediment discharge in the Toudaoguai-Tongguan section decreased by 81.1% (P < 0.001) over the past 60 years, with a sudden decrease in 2000. 2) From 1956 to 2000, the Toudaoguai-Wubao section, the Wubao-Longmen section, and the Longmen-Tongguan section contributed 34.76%, 30.60%, and 34.64%, respectively, to the sediment discharge measured at Tongguan station. After 2000, the contribution rates were 11.17%, 38.93%, and 49.9%, respectively. 3) Compared with 1956–2000, the average annual sediment discharge of the primary tributaries during 2001–2016 decreased by an average of 85.61%. Marginal benefit analysis indicates that, once the degree of soil erosion control in the study area reached the critical value of 32%, the marginal sediment reduction benefits of the soil and water conservation measures approached 0. Once the degree of soil erosion control exceeded 50%, the sediment discharge in the river basin decreased to a low level. These research results provide a reference for future directions and priorities in soil erosion control planning and implementation on the Loess Plateau.
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