Targeting translation initiation by synthetic rocaglates for treating MYC-driven lymphomas.

MYC-driven lymphomas, especially those with concurrent MYC and BCL2 dysregulation, are currently a challenge in clinical practice due to rapid disease progression, resistance to standard chemotherapy, and high risk of refractory disease. MYC plays a central role by coordinating hyperactive protein synthesis with upregulated transcription in order to support rapid proliferation of tumor cells. Translation initiation inhibitor rocaglates have been identified as the most potent drugs in MYC-driven lymphomas as they efficiently inhibit MYC expression and tumor cell viability. We found that this class of compounds can overcome eIF4A abundance by stabilizing target mRNA-eIF4A interaction that directly prevents translation. Proteome-wide quantification demonstrated selective repression of multiple critical oncoproteins in addition to MYC in B-cell lymphoma including NEK2, MCL1, AURKA, PLK1, and several transcription factors that are generally considered undruggable. Finally, (-)-SDS-1-021, the most promising synthetic rocaglate, was confirmed to be highly potent as a single agent, and displayed significant synergy with the BCL2 inhibitor ABT199 in inhibiting tumor growth and survival in primary lymphoma cells in vitro and in patient-derived xenograft mouse models. Overall, our findings support the strategy of using rocaglates to target oncoprotein synthesis in MYC-driven lymphomas.P30 CA036727 - NCI NIH HHS; R24 GM111625 - NIGMS NIH HHS; R35 GM118173 - NIGMS NIH HHS; LB506 - Nebraska Department of Health and Human Services (Nebraska DHHS)Accepted manuscriptSupporting documentatio

Double-blind comparison of ziprasidone and risperidone in the treatment of Chinese patients with acute exacerbation of schizophrenia

Background: The aim of the study was to evaluate the efficacy and safety of ziprasidone versus risperidone in Chinese subjects with acute exacerbation of schizophrenia. Methods: In patients meeting the Chinese Classification of Mental Disorders criteria for schizophrenia and with a Positive and Negative Syndrome Scale (PANSS) total score >= 60 were randomly assigned to six weeks of double-blind treatment with ziprasidone 40-80 mg twice daily or risperidone 1-3 mg bid, flexibly dosed. Noninferiority was demonstrated if the upper limit of the two-sided 95% confidence interval (CI) for the difference in PANSS total score improvement from baseline in the evaluable population was smaller than the prespecified noninferiority margin of 10 units. Results: The intent-to-treat population comprised 118 ziprasidone-treated and 121 risperidone-treated subjects. Improvement (reduction) from baseline to week 6 in PANSS total score was (-35.6 [95% CI: -38.6, -32.6]) for ziprasidone and (-37.1 [95% CI: -39.9, -34.4]) for risperidone. Noninferiority was demonstrated in the evaluable population with a difference score of 1.5 [95% CI: -2.5, 5.5]. Mean prolactin levels decreased at week 6 compared with baseline for ziprasidone (-3.5 ng/mL), but significantly increased for risperidone (61.1 ng/mL; P < 0.001). More risperidone-treated subjects (14.9%) than ziprasidone-treated subjects (4.2%) reported weight gain >= 7%. Akathisia and somnolence in the ziprasidone group and akathisia and insomnia in the risperidone group were the most common side effects. Treatment-related/treatment-emergent adverse events were reported by 79.7% and 71.1% of ziprasidone-treated and risperidone-treated subjects, respectively. Conclusion: In Chinese subjects, ziprasidone was as effective as risperidone, with less weight gain and less prolactin elevation.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000294955100009&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Clinical NeurologyPsychiatrySCI(E)PubMed3ARTICLE77-85

MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells

Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function of the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in pancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch, implying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination. Restoration of miR-34 may hold significant promise as a novel molecular therapy for human pancreatic cancer with loss of p53-miR34, potentially via inhibiting pancreatic cancer stem cells

Research on the Disequilibrium Development of Output of Regional Innovation Based on R&D Personnel

Regional innovation is of great significance to the sustainable development of a regional economy. However, there exists a disequilibrium development of output of regional innovation in China, which affects the imbalance of regional economic development to a certain extent. In order to explore the process and mechanism of the disequilibrium development in regional innovation, a new perspective is adopted in this paper to analyze the index of R&D (research and development) personnel, which is an important input element of regional innovation output. The regional samples, including 31 provinces in China, are divided into three parts: eastern region, central region, and western region. First, developing the tendency and speed of the disequilibrium of regional innovation output are analyzed by using σ convergent model and β convergent model, respectively, during the period of analyzing the process of the disequilibrium development. Then, the LMDI (logarithmic mean Divisia index) method is used to analyze the character of regional innovation output by using R&D personnel as an important endogenous factor during the period of analyzing the mechanism of the disequilibrium development. At last, we draw the conclusion of the study. We find that: (i) there is a gap in the absolute amount between regions in a long term, but the gap between regions is shrinking and the speed of catching up between regions is different; (ii) the efficiency of R&D personnel is the most positive effect of promoting equilibrium

Effect of sulfur dioxide on vascular biology

Gasotransmitters, such as nitric oxide, carbon monoxide and hydrogen sulfide, can be generated endogenously. These gasotransmitters play important roles in vascular biology, including vasorelaxation and inhibition of vascular smooth muscle cell (VSMC) proliferation. In recent years, sulfur dioxide (SO2) has been considered as the fourth gasotransmitter. SO2 is present in air pollution. Moreover, SO2 toxicity, including oxidative stress and DNA damage, has been extensively reported in previous studies. Recent studies have shown that SO2 can be endogenously generated in various organs and vascular tissues, where it regulates vascular tone, vascular smooth cell proliferation and collagen synthesis. SO2 can decrease blood pressure in rats, inhibit smooth muscle cell proliferation and collagen accumulation and promote collagen degradation, and improve vascular remodelling. SO2 can decrease cardiovascular atherosclerotic plaques by enhancing the antioxidant effect and upregulating nitric oxide/nitric oxide synthase and hydrogen sulfide/ cystathionine-γ-lyase pathways. SO2 can also ameliorate vascular calcification via the transforming growth factor - β1/Smad pathway. The effect of SO2 on vascular regulation has attracted great interest. SO2 may be a novel mediator in vascular biolog

Research on Spatial Correlation in Regional Innovation Spillover in China Based on Patents

Regional innovation is very important for the sustainable development of regional economies. Innovation development between regions is not independent, and there is spatial correlation in innovation spillover. This paper uses the total amount of regional patent authorization as the measure of regional innovation and uses network analysis to study the spatial relationships among different regions. An unstructured vector autoregressive model is established to determine whether there is an association between any two regions, the causal relationship between which is tested by a Granger causality test. Having established the spatial network relationship, network analysis is used to further analyze the overall characteristics of the network, the individual characteristics of the network, and the block model of the network. We find that the provinces are closely related regarding regional innovation spillovers. However, the spatial correlation between the provinces differs greatly. Also, there is an obvious hierarchy between blocks that have different orientations and functions. Finally, the relationship between the interior of each block differs greatly in closeness degree

Electrical Conductivity Evidence for the Existence of a Mantle Plume Beneath Tarim Basin

This paper proposes using a simulated annealing (SA) calculation to perform one-dimensional inversion of Geomagnetic Depth Sounding (GDS) to obtain the conductivity information of the lower mantle beneath the Tarim area, to calculate the temperature of the lower mantle according to the relevant formula of the petrophysical experiment, and to provide evidence of the existence of the Tarim mantle plume. The data used for inversion originate from the China Geomagnetic Network Center. This article uses theoretical data to prove that the simulated annealing algorithm can invert the true conductivity model when the data do not contain noise. However, when the data contain noise, it is more accurate to use the statistical expected value of the high-quality conductivity model during the simulated annealing inversion process as the optimal conductivity model rather than the classic simulated annealing algorithm. The simulated annealing inversion results of only four stations in Tarim area show that the conductivity of the top of the lower mantle and the upper part of the mantle transition zone in Tarim area is higher than the global average, and it is speculated that the temperature is 150k–450k higher than the global average. This is important evidence for the existence of the mantle plume beneath the Tarim Basin