Aggressive tumors pose ultra-challenges to drug resistance.Anti-cancer treatments are often unsuccessful,and single-cell technologies to rein drug resistance mechanisms are still fruitless.The National Cancer Institut...Aggressive tumors pose ultra-challenges to drug resistance.Anti-cancer treatments are often unsuccessful,and single-cell technologies to rein drug resistance mechanisms are still fruitless.The National Cancer Institute defines aggressive cancers at the tissue level,describing them as those that spread rapidly,despite severe treatment.At the molecular,foundational level,the quantitative biophysics discipline defines aggressive cancers as harboring a large number of(overexpressed,or mutated)crucial signaling proteins in major proliferation pathways populating their active conformations,primed for their signal transduction roles.This comprehensive review explores highly aggressive cancers on the foundational and cell signaling levels,focusing on the differences between highly aggressive cancers and the more treatable ones.It showcases aggressive tumors as harboring massive,cancer-promoting,catalysis-primed oncogenic proteins,especially through certain overexpression scenarios,as predisposed aggressive tumor candidates.Our examples narrate strong activation of ERK1/2,and other oncogenic proteins,through malfunctioning chromatin and crosslinked signaling,and how they activate multiple proliferation pathways.They show the increased cancer heterogeneity,plasticity,and drug resistance.Our review formulates the principles underlying cancer aggressiveness on the molecular level,discusses scenarios,and describes drug regimen(single drugs and drug combinations)for PDAC,NSCLC,CRC,HCC,breast and prostate cancers,glioblastoma,neuroblastoma,and leukemia as examples.All show overexpression scenarios of master transcription factors,transcription factors with gene fusions,copy number alterations,dysregulation of the epigenetic codes and epithelial-to-mesenchymal transitions in aggressive tumors,as well as high mutation loads of vital upstream signaling regulators,such as EGFR,c-MET,and K-Ras,befitting these principles.展开更多
Double-network(DN)hydrogels,consisting of two contrasting and interpenetrating polymer networks,are considered as perhaps the toughest soft-wet materials.Current knowledge of DN gels from synthesis methods to tougheni...Double-network(DN)hydrogels,consisting of two contrasting and interpenetrating polymer networks,are considered as perhaps the toughest soft-wet materials.Current knowledge of DN gels from synthesis methods to toughening mechanisms almost exclusively comes from chemically-linked DN hydrogels by experiments.Molecular modeling and simulations of inhomogeneous DN structure in hydrogels have proved to be extremely challenging.Herein,we developed a new multiscale simulation platform to computationally investigate the early fracture of physically-chemically linked agar/polyacrylamide(agar/PAM)DN hydrogels at a long timescale.A“random walk reactive polymerization”(RWRP)was developed to mimic a radical polymerization process,which enables to construct a physically-chemically linked agar/PAM DN hydrogel from monomers,while conventional and steered MD simulations were conducted to examine the structural-dependent energy dissipation and fracture behaviors at the relax and deformation states.Collective simulation results revealed that energy dissipation of agar/PAM hydrogels was attributed to a combination of the pulling out of agar chains from the DNs,the disruption of massive hydrogen bonds between and within DN structures,and the strong association of water molecules with both networks,thus explaining a different mechanical enhancement of agar/PAM hydrogels.This computational work provided atomic details of network structure,dynamics,solvation,and interactions of a hybrid DN hydrogel,and a different structural-dependent energy dissipation mode and fracture behavior of a hybrid DN hydrogel,which help to design tough hydrogels with new network structures and efficient energy dissipation modes.Additionally,the RWRP algorithm can be generally applied to construct the radical polymerization-produced hydrogels,elastomers,and polymers.展开更多
Dear Editor,B-Raf,the main effector of Ras in the mitogen-activated protein kinase(MAPK)pathway,is among the most highly mutated kinases in human cancer[1].About 40%-60%of melanoma patients harbor B-Raf mutations,of w...Dear Editor,B-Raf,the main effector of Ras in the mitogen-activated protein kinase(MAPK)pathway,is among the most highly mutated kinases in human cancer[1].About 40%-60%of melanoma patients harbor B-Raf mutations,of which∼90%involve V600E and V600K.B-RafV600E is more frequent(60%-80%)than B-RafV600K(10%-30%).Substitution of a Val codon by Glu requires a single nucleotide change,whereas Val to Lys requires two[2].This is in line with melanoma patients harboring the V600K mutation,who usually suffer from higher sun exposure that may induce increased DNA damage[3].Since both mutations occur at the same position of the kinase domain and are mutated to charged residues,it was believed that the B-Raf V600E and V600K mutantswould share a similar behavior,and in clinical trials,patients with V600E and V600K mutations have been recruited into the same cohort.展开更多
Which signaling pathway and protein to selea to mitigate the patient's expected drug resistance?The number of possibilities facing the physician is massive,and the drug combination should fit the patient status.He...Which signaling pathway and protein to selea to mitigate the patient's expected drug resistance?The number of possibilities facing the physician is massive,and the drug combination should fit the patient status.Here,we briefly review current approaches and data and map an innovative patient-specific strategy to forecast drug resistance targets that centers on parallel(or redundant)proliferation pathways in specialized cells.It considers the availability of each protein in each pathway in the specific cell,its activating mutations,and the chromatin accessibility of its encoding gene.The construction of the resulting Proliferation Pathway Network Atlas will harness the emerging exascale computing and advanced artificial intelligence(Al)methods for therapeutic development.Merging the resulting set of targets,pathways,and proteins,with current strategies will augment the choice for the attending physicians to thwart resistance.展开更多
基金funded in whole or in part with federal funds from the National Cancer Institute,National Institutes of Health,under contract HHSN261201500003I.
文摘Aggressive tumors pose ultra-challenges to drug resistance.Anti-cancer treatments are often unsuccessful,and single-cell technologies to rein drug resistance mechanisms are still fruitless.The National Cancer Institute defines aggressive cancers at the tissue level,describing them as those that spread rapidly,despite severe treatment.At the molecular,foundational level,the quantitative biophysics discipline defines aggressive cancers as harboring a large number of(overexpressed,or mutated)crucial signaling proteins in major proliferation pathways populating their active conformations,primed for their signal transduction roles.This comprehensive review explores highly aggressive cancers on the foundational and cell signaling levels,focusing on the differences between highly aggressive cancers and the more treatable ones.It showcases aggressive tumors as harboring massive,cancer-promoting,catalysis-primed oncogenic proteins,especially through certain overexpression scenarios,as predisposed aggressive tumor candidates.Our examples narrate strong activation of ERK1/2,and other oncogenic proteins,through malfunctioning chromatin and crosslinked signaling,and how they activate multiple proliferation pathways.They show the increased cancer heterogeneity,plasticity,and drug resistance.Our review formulates the principles underlying cancer aggressiveness on the molecular level,discusses scenarios,and describes drug regimen(single drugs and drug combinations)for PDAC,NSCLC,CRC,HCC,breast and prostate cancers,glioblastoma,neuroblastoma,and leukemia as examples.All show overexpression scenarios of master transcription factors,transcription factors with gene fusions,copy number alterations,dysregulation of the epigenetic codes and epithelial-to-mesenchymal transitions in aggressive tumors,as well as high mutation loads of vital upstream signaling regulators,such as EGFR,c-MET,and K-Ras,befitting these principles.
基金J.Z.thanksfinancial supports from NSF grants of 1607475 and 1825122.
文摘Double-network(DN)hydrogels,consisting of two contrasting and interpenetrating polymer networks,are considered as perhaps the toughest soft-wet materials.Current knowledge of DN gels from synthesis methods to toughening mechanisms almost exclusively comes from chemically-linked DN hydrogels by experiments.Molecular modeling and simulations of inhomogeneous DN structure in hydrogels have proved to be extremely challenging.Herein,we developed a new multiscale simulation platform to computationally investigate the early fracture of physically-chemically linked agar/polyacrylamide(agar/PAM)DN hydrogels at a long timescale.A“random walk reactive polymerization”(RWRP)was developed to mimic a radical polymerization process,which enables to construct a physically-chemically linked agar/PAM DN hydrogel from monomers,while conventional and steered MD simulations were conducted to examine the structural-dependent energy dissipation and fracture behaviors at the relax and deformation states.Collective simulation results revealed that energy dissipation of agar/PAM hydrogels was attributed to a combination of the pulling out of agar chains from the DNs,the disruption of massive hydrogen bonds between and within DN structures,and the strong association of water molecules with both networks,thus explaining a different mechanical enhancement of agar/PAM hydrogels.This computational work provided atomic details of network structure,dynamics,solvation,and interactions of a hybrid DN hydrogel,and a different structural-dependent energy dissipation mode and fracture behavior of a hybrid DN hydrogel,which help to design tough hydrogels with new network structures and efficient energy dissipation modes.Additionally,the RWRP algorithm can be generally applied to construct the radical polymerization-produced hydrogels,elastomers,and polymers.
基金the National Cancer Institute,National Institutes of Health,under contract HHSN261201500003I.
文摘Dear Editor,B-Raf,the main effector of Ras in the mitogen-activated protein kinase(MAPK)pathway,is among the most highly mutated kinases in human cancer[1].About 40%-60%of melanoma patients harbor B-Raf mutations,of which∼90%involve V600E and V600K.B-RafV600E is more frequent(60%-80%)than B-RafV600K(10%-30%).Substitution of a Val codon by Glu requires a single nucleotide change,whereas Val to Lys requires two[2].This is in line with melanoma patients harboring the V600K mutation,who usually suffer from higher sun exposure that may induce increased DNA damage[3].Since both mutations occur at the same position of the kinase domain and are mutated to charged residues,it was believed that the B-Raf V600E and V600K mutantswould share a similar behavior,and in clinical trials,patients with V600E and V600K mutations have been recruited into the same cohort.
基金This project has been funded in whole or in part with federal funds from the National Cancer Institute,National Institutes of Health,under contract HHSN261200800001EThis research was supported[in part]by the Intramural Research Program of NIH,National Cancer Institute,Center for Cancer Research.
文摘Which signaling pathway and protein to selea to mitigate the patient's expected drug resistance?The number of possibilities facing the physician is massive,and the drug combination should fit the patient status.Here,we briefly review current approaches and data and map an innovative patient-specific strategy to forecast drug resistance targets that centers on parallel(or redundant)proliferation pathways in specialized cells.It considers the availability of each protein in each pathway in the specific cell,its activating mutations,and the chromatin accessibility of its encoding gene.The construction of the resulting Proliferation Pathway Network Atlas will harness the emerging exascale computing and advanced artificial intelligence(Al)methods for therapeutic development.Merging the resulting set of targets,pathways,and proteins,with current strategies will augment the choice for the attending physicians to thwart resistance.
