Our recent breakthrough discovery demonstrated that the anticancer drug FL118 tightly binds to and then dephosphorylates and degrades the oncogenic protein DEAD-box helicase 5(DDX5),leading to the inhibition of DDX5 d...Our recent breakthrough discovery demonstrated that the anticancer drug FL118 tightly binds to and then dephosphorylates and degrades the oncogenic protein DEAD-box helicase 5(DDX5),leading to the inhibition of DDX5 downstream targets(e.g.,survivin,myeloid cell leukemia 1(Mcl-1),X-linked inhibitor of apoptosis(XIAP),c-Myc,mutant Kras,etc.)[1].FL118 is a molecular glue(MG)that can alter the interactomes of two or more non-interacting proteins[2].Thus,FL118 exhibits high efficacy against colorectal and pancreatic cancer xenograft tumors[1,3].However,moving FL118 into clinical trials requires a clinically compatible FL118 drug product(DP)that possesses high antitumor efficacy and low toxicity via oral(ideal)or intravenous(iv)administration.Here,we report the development and characterization of a clinically and orally compatible FL118 DP.We show that(1)FL118 drug substances(DS)exhibit high chemical stability under various test conditions;(2)a clinically and orally compatible FL118 DP can be manufactured through the formulation of FL118 DS with 2-hydroxypropyl-bcyclodextrin(HPbCD)using mixed solvents of glacial acetic acid(GAA)with ethanol through microfluidizer-mediated spray dried dispersion(M-SDD).展开更多
Microseismic(MS)events generated during coal and rock hydraulic fracturing(HF)include wet events caused by fracturing fuid injection,in addition to dry events caused by stress perturbations.The mixture of these two ev...Microseismic(MS)events generated during coal and rock hydraulic fracturing(HF)include wet events caused by fracturing fuid injection,in addition to dry events caused by stress perturbations.The mixture of these two events makes efective fracturing MS events pickup difcult.This study is based on physical experiments of diferent coal and rock HF and uniaxial compression.The diferences of waveform characteristic parameters of various coal and rock ruptures were analyzed using the Hilbert–Huang transform,leading to some useful conclusions.The phase characteristics of the acoustic emission(AE)energy difered signifcantly and responded well to the pumping pressure curve.The AE waveforms of HF exhibit similar energy and frequency distribution characteristics after Empirical mode decomposition.The main frequency bands for coal,sandstone,and shale samples are 100–300 kHz,while the mudstone sample is in the range of 50–150 kHz.The decay ratios for coal,sandstone,shale and mudstone samples are 0.78,0.83,0.67 and 0.85,respectively.When compared to the uniaxial compression test,the main frequency bands of HF were reduced for coal,sandstone and mudstone samples,whereas shale remained essentially unchanged.The duration,instantaneous energy,and total energy of the HF waveform are smaller than those of uniaxial compression,while the decay ratio is greater,especially for the mudstone samples.The waveform characteristic parameters,trained using the multilayer perceptron neural network,can efectively identify HF and uniaxial compression events with an accuracy of 96%.展开更多
Objectives:Colorectal cancer(CRC)remains a major contributor to global cancer mortality,ranking second worldwide for cancer-related deaths in 2022,and is characterized by marked heterogeneity in prognosis and therapeu...Objectives:Colorectal cancer(CRC)remains a major contributor to global cancer mortality,ranking second worldwide for cancer-related deaths in 2022,and is characterized by marked heterogeneity in prognosis and therapeutic response.We sought to construct a machine-learning prognosticmodel based on a complement-related risk signature(CRRS)and to situate this signature within the CRC immune microenvironment.Methods:Transcriptomic profiles with matched clinical annotations from TCGA and GEO CRC cohorts were analyzed.Prognostic CRRS genes were screened using Cox proportional hazards modeling alongside machine-learning procedures.A random survival forest(RSF)predictor was trained and externally validated.Comparisons of immune infiltration,mutational burden,pathway enrichment,and drug sensitivity were made between risk groups.The function of FAM84A,a key model gene,was examined in CRC cell lines.Results:The six-gene CRRS model accurately stratified patients by survival outcomes.Low-risk patients exhibited greater immune cell infiltration and higher predicted response to immunotherapy and chemotherapy,while high-risk patients showed enrichment of complement activation and matrix remodeling pathways.FAM84A was shown to promote CRC cell proliferation,migration,and epithelial–mesenchymal transition.Conclusion:CRRS is a critical modulator of the CRC immune microenvironment.The developed model enables precise risk prediction and supports individualized therapeutic decisions in CRC.展开更多
In this paper, we consider the problem of finding sparse solutions for underdetermined systems of linear equations, which can be formulated as a class of L_0 norm minimization problem. By using the least absolute resi...In this paper, we consider the problem of finding sparse solutions for underdetermined systems of linear equations, which can be formulated as a class of L_0 norm minimization problem. By using the least absolute residual approximation, we propose a new piecewis, quadratic function to approximate the L_0 norm.Then, we develop a piecewise quadratic approximation(PQA) model where the objective function is given by the summation of a smooth non-convex component and a non-smooth convex component. To solve the(PQA) model,we present an algorithm based on the idea of the iterative thresholding algorithm and derive the convergence and the convergence rate. Finally, we carry out a series of numerical experiments to demonstrate the performance of the proposed algorithm for(PQA). We also conduct a phase diagram analysis to further show the superiority of(PQA) over L_1 and L_(1/2) regularizations.展开更多
We investigate tail behavior of the supremum of a random walk in the case that Cramer＇s condition fails, namely, the intermediate case and the heavy-tailed ease. When the integrated distribution of the increment of t...We investigate tail behavior of the supremum of a random walk in the case that Cramer＇s condition fails, namely, the intermediate case and the heavy-tailed ease. When the integrated distribution of the increment of the random walk belongs to the intersection of exponential distribution class and O-subexponential distribution class, under some other suitable conditions, we obtain some asymptotic estimates for the tail probability of the supremum and prove that the distribution of the supremum also belongs to the same distribution class. The obtained results generalize some corresponding results of N. Veraverbeke. Finally, these results are applied to renewal risk model, and asymptotic estimates for the ruin probability are presented.展开更多
文摘Our recent breakthrough discovery demonstrated that the anticancer drug FL118 tightly binds to and then dephosphorylates and degrades the oncogenic protein DEAD-box helicase 5(DDX5),leading to the inhibition of DDX5 downstream targets(e.g.,survivin,myeloid cell leukemia 1(Mcl-1),X-linked inhibitor of apoptosis(XIAP),c-Myc,mutant Kras,etc.)[1].FL118 is a molecular glue(MG)that can alter the interactomes of two or more non-interacting proteins[2].Thus,FL118 exhibits high efficacy against colorectal and pancreatic cancer xenograft tumors[1,3].However,moving FL118 into clinical trials requires a clinically compatible FL118 drug product(DP)that possesses high antitumor efficacy and low toxicity via oral(ideal)or intravenous(iv)administration.Here,we report the development and characterization of a clinically and orally compatible FL118 DP.We show that(1)FL118 drug substances(DS)exhibit high chemical stability under various test conditions;(2)a clinically and orally compatible FL118 DP can be manufactured through the formulation of FL118 DS with 2-hydroxypropyl-bcyclodextrin(HPbCD)using mixed solvents of glacial acetic acid(GAA)with ethanol through microfluidizer-mediated spray dried dispersion(M-SDD).
基金supported by the National Natural Science Foundation of China(52074049)Chongqing Natural Science Foundation(cstc2021jcyj-msxmX0764)the Independent Research fund of The State Key Laboratory of Mining Response and Disaster Prevention and Control in Deep Coal Mines(Anhui University of Science and Technology)(SKLMRDPC19KF07).
文摘Microseismic(MS)events generated during coal and rock hydraulic fracturing(HF)include wet events caused by fracturing fuid injection,in addition to dry events caused by stress perturbations.The mixture of these two events makes efective fracturing MS events pickup difcult.This study is based on physical experiments of diferent coal and rock HF and uniaxial compression.The diferences of waveform characteristic parameters of various coal and rock ruptures were analyzed using the Hilbert–Huang transform,leading to some useful conclusions.The phase characteristics of the acoustic emission(AE)energy difered signifcantly and responded well to the pumping pressure curve.The AE waveforms of HF exhibit similar energy and frequency distribution characteristics after Empirical mode decomposition.The main frequency bands for coal,sandstone,and shale samples are 100–300 kHz,while the mudstone sample is in the range of 50–150 kHz.The decay ratios for coal,sandstone,shale and mudstone samples are 0.78,0.83,0.67 and 0.85,respectively.When compared to the uniaxial compression test,the main frequency bands of HF were reduced for coal,sandstone and mudstone samples,whereas shale remained essentially unchanged.The duration,instantaneous energy,and total energy of the HF waveform are smaller than those of uniaxial compression,while the decay ratio is greater,especially for the mudstone samples.The waveform characteristic parameters,trained using the multilayer perceptron neural network,can efectively identify HF and uniaxial compression events with an accuracy of 96%.
文摘Objectives:Colorectal cancer(CRC)remains a major contributor to global cancer mortality,ranking second worldwide for cancer-related deaths in 2022,and is characterized by marked heterogeneity in prognosis and therapeutic response.We sought to construct a machine-learning prognosticmodel based on a complement-related risk signature(CRRS)and to situate this signature within the CRC immune microenvironment.Methods:Transcriptomic profiles with matched clinical annotations from TCGA and GEO CRC cohorts were analyzed.Prognostic CRRS genes were screened using Cox proportional hazards modeling alongside machine-learning procedures.A random survival forest(RSF)predictor was trained and externally validated.Comparisons of immune infiltration,mutational burden,pathway enrichment,and drug sensitivity were made between risk groups.The function of FAM84A,a key model gene,was examined in CRC cell lines.Results:The six-gene CRRS model accurately stratified patients by survival outcomes.Low-risk patients exhibited greater immune cell infiltration and higher predicted response to immunotherapy and chemotherapy,while high-risk patients showed enrichment of complement activation and matrix remodeling pathways.FAM84A was shown to promote CRC cell proliferation,migration,and epithelial–mesenchymal transition.Conclusion:CRRS is a critical modulator of the CRC immune microenvironment.The developed model enables precise risk prediction and supports individualized therapeutic decisions in CRC.
基金supported by National Natural Science Foundation of China (Grant No. 11771275)
文摘In this paper, we consider the problem of finding sparse solutions for underdetermined systems of linear equations, which can be formulated as a class of L_0 norm minimization problem. By using the least absolute residual approximation, we propose a new piecewis, quadratic function to approximate the L_0 norm.Then, we develop a piecewise quadratic approximation(PQA) model where the objective function is given by the summation of a smooth non-convex component and a non-smooth convex component. To solve the(PQA) model,we present an algorithm based on the idea of the iterative thresholding algorithm and derive the convergence and the convergence rate. Finally, we carry out a series of numerical experiments to demonstrate the performance of the proposed algorithm for(PQA). We also conduct a phase diagram analysis to further show the superiority of(PQA) over L_1 and L_(1/2) regularizations.
基金Acknowledgements The authors were grateful to the two reviewers for their valuable comments and suggestions to improve the present paper. This work was supported by the National Natural Science Foundation of China （NO. 11071182） and the Doctor Introduction Foundation of Nantong University （No. 12R066）.
文摘We investigate tail behavior of the supremum of a random walk in the case that Cramer＇s condition fails, namely, the intermediate case and the heavy-tailed ease. When the integrated distribution of the increment of the random walk belongs to the intersection of exponential distribution class and O-subexponential distribution class, under some other suitable conditions, we obtain some asymptotic estimates for the tail probability of the supremum and prove that the distribution of the supremum also belongs to the same distribution class. The obtained results generalize some corresponding results of N. Veraverbeke. Finally, these results are applied to renewal risk model, and asymptotic estimates for the ruin probability are presented.
