RAS mutations occur in approximately 30%of tumors worldwide and have a poor prognosis due to limited therapies.Covalent targeting of KRAS G12C has achieved significant success in recent years,but there is still a lack...RAS mutations occur in approximately 30%of tumors worldwide and have a poor prognosis due to limited therapies.Covalent targeting of KRAS G12C has achieved significant success in recent years,but there is still a lack of efficient therapeutic approaches for tumors with non-G12C KRAS mutations.A highly promising approach is to target the MAPK pathway downstream of RAS,with a particular focus on RAF kinases.First-generation RAF inhibitors have been authorized to treat BRAF mutant tumors for over a decade.However,their use in RAS-mutated tumors is not recommended due to the paradoxical ERK activation mainly caused by RAF dimerization.To address the issue of RAF dimerization,type II RAF inhibitors have emerged as leading candidates.Recent clinical studies have shown the initial effectiveness of these agents against RAS mutant tumors.Promisingly,type II RAF inhibitors in combination with MEK or ERK inhibitors have demonstrated impressive efficacy in RAS mutant tumors.This review aims to clarify the importance of RAF dimerization in cellular signaling and resistance to treatment in tumors with RAS mutations,as well as recent progress in therapeutic approaches to address the problem of RAF dimerization in RAS mutant tumors.展开更多
A new model was established based on the flow model of the drilling fluid in one-dimensional radial fracture to research the influencing factors on conversion time between lost circulation and overflow for multi-press...A new model was established based on the flow model of the drilling fluid in one-dimensional radial fracture to research the influencing factors on conversion time between lost circulation and overflow for multi-pressure system in fractured reservoirs.And the equation of the conversion time between lost circulation and overflow is obtained by solving the mathematical model.The model were validated by reproducing the field data from Sichuan oil field and the simulation results of references.The influences of consistency index,liquidity index,dynamic shear force,drilling fluid density,drilling fluid intrusion depth,pressure of lost circulation layer,crack width,decreased height of annular liquid level,pressure of high-pressure layer were analyzed.Results indicate that conversion time between lost circulation and overflow increases with the increasing consistency index,liquidity index,dynamic shear force,drilling fluid density,drilling fluid intrusion depth,pressure of lost circulation layer.Conversion time between lost circulation and overflow decreases with the increasing crack width,decreased height of annular liquid level,pressure of high-pressure layer.The time interval of“Hang's Muddingoff”operating should be appropriately less than the conversion time between lost circulation and overflow.Under the premise of ensuring wellbore safety,appropriately increasing the consistency index,liquidity index and dynamic shear force of the drilling fluid can effectively increase the conversion time between lost circulation and overflow in large fractured stratum.展开更多
基金This study was supported by the National Natural Science Foundation of China(82073059,82073314)the Sichuan Science and Technology Program(2023NSFSC1838,China)the Sichuan University Postdoctoral Interdisciplinary Innovation Fund(JCXK2212,China).
文摘RAS mutations occur in approximately 30%of tumors worldwide and have a poor prognosis due to limited therapies.Covalent targeting of KRAS G12C has achieved significant success in recent years,but there is still a lack of efficient therapeutic approaches for tumors with non-G12C KRAS mutations.A highly promising approach is to target the MAPK pathway downstream of RAS,with a particular focus on RAF kinases.First-generation RAF inhibitors have been authorized to treat BRAF mutant tumors for over a decade.However,their use in RAS-mutated tumors is not recommended due to the paradoxical ERK activation mainly caused by RAF dimerization.To address the issue of RAF dimerization,type II RAF inhibitors have emerged as leading candidates.Recent clinical studies have shown the initial effectiveness of these agents against RAS mutant tumors.Promisingly,type II RAF inhibitors in combination with MEK or ERK inhibitors have demonstrated impressive efficacy in RAS mutant tumors.This review aims to clarify the importance of RAF dimerization in cellular signaling and resistance to treatment in tumors with RAS mutations,as well as recent progress in therapeutic approaches to address the problem of RAF dimerization in RAS mutant tumors.
基金The authors gratefully acknowledge the financial support of the National Key R&D Program of China(No.2018YFC031020201)the Sichuan Science and Technology Project(2019YFS0045).
文摘A new model was established based on the flow model of the drilling fluid in one-dimensional radial fracture to research the influencing factors on conversion time between lost circulation and overflow for multi-pressure system in fractured reservoirs.And the equation of the conversion time between lost circulation and overflow is obtained by solving the mathematical model.The model were validated by reproducing the field data from Sichuan oil field and the simulation results of references.The influences of consistency index,liquidity index,dynamic shear force,drilling fluid density,drilling fluid intrusion depth,pressure of lost circulation layer,crack width,decreased height of annular liquid level,pressure of high-pressure layer were analyzed.Results indicate that conversion time between lost circulation and overflow increases with the increasing consistency index,liquidity index,dynamic shear force,drilling fluid density,drilling fluid intrusion depth,pressure of lost circulation layer.Conversion time between lost circulation and overflow decreases with the increasing crack width,decreased height of annular liquid level,pressure of high-pressure layer.The time interval of“Hang's Muddingoff”operating should be appropriately less than the conversion time between lost circulation and overflow.Under the premise of ensuring wellbore safety,appropriately increasing the consistency index,liquidity index and dynamic shear force of the drilling fluid can effectively increase the conversion time between lost circulation and overflow in large fractured stratum.
