BACKGROUND Patients harboring gene mutations like KRAS,NRAS,and BRAF demonstrate highly variable responses to chemotherapy,posing challenges for treatment optimization.Multiparametric magnetic resonance imaging(MRI),w...BACKGROUND Patients harboring gene mutations like KRAS,NRAS,and BRAF demonstrate highly variable responses to chemotherapy,posing challenges for treatment optimization.Multiparametric magnetic resonance imaging(MRI),with its noninvasive capability to assess tumor characteristics in detail,has shown promise in evaluating treatment response and predicting therapeutic outcomes.This technology holds potential for guiding personalized treatment strategies tailored to individual patient profiles,enhancing the precision and effectiveness of colorectal cancer care.AIM To create a multiparametric MRI-based predictive model for assessing chemotherapy efficacy in colorectal cancer patients with gene mutations.METHODS This retrospective study was conducted in a tertiary hospital,analyzing 157 colorectal cancer patients with gene mutations treated between August 2022 and December 2023.Based on chemotherapy outcomes,the patients were categorized into favorable(n=60)and unfavorable(n=50)response groups.Univariate and multivariate logistic regression analyses were performed to identify independent predictors of chemotherapy efficacy.A predictive nomogram was constructed using significant variables,and its performance was assessed using the area under the receiver operating characteristic curve(AUC)in both training and validation sets.RESULTS Univariate analysis identified that tumor differentiation,T2 signal intensity ratio,tumor-to-anal margin distance,and MRI-detected lymph node metastasis as significantly associated with chemotherapy response(P<0.05).Multivariate Logistics regression confirmed these four parameters as independent predictors.The predictive model demonstrated strong discrimination,with an AUC of 0.938(sensitivity:86%;specificity:92%)in the training set,and 0.942(sensitivity:100%;specificity:83%)in the validation set.CONCLUSION We established and validated a multiparametric MRI-based model for predicting chemotherapy response in colorectal cancer patients with gene mutations.This model holds promise for guiding individualized treatment strategies.展开更多
Ras homolog enriched in brain(Rheb) is a small GTPase that activates mammalian target of rapamycin complex 1(mTORC1).Previous studies have shown that constitutively active Rheb can enhance the regeneration of sensory ...Ras homolog enriched in brain(Rheb) is a small GTPase that activates mammalian target of rapamycin complex 1(mTORC1).Previous studies have shown that constitutively active Rheb can enhance the regeneration of sensory axons after spinal cord injury by activating downstream effectors of mTOR.S6K1 and4E-BP1 are important downstream effectors of mTORC1.In this study,we investigated the role of Rheb/mTOR and its downstream effectors S6K1 and 4E-BP1in the protection of retinal ganglion cells.We transfected an optic nerve crush mouse model with adeno-associated viral 2-mediated constitutively active Rheb and observed the effects on retinal ganglion cell survival and axon regeneration.We found that overexpression of constitutively active Rheb promoted survival of retinal ganglion cells in the acute(14 days) and chronic(21 and 42 days) stages of injury.We also found that either co-expression of the dominant-negative S6K1mutant or the constitutively active 4E-BP1 mutant together with constitutively active Rheb markedly inhibited axon regeneration of retinal ganglion cells.This suggests that mTORC1-mediated S6K1 activation and 4E-BP1 inhibition were necessary components for constitutively active Rheb-induced axon regeneration.However,only S6K1 activation,but not 4E-BP1 knockdown,induced axon regeneration when applied alone.Furthermore,S6K1 activation promoted the survival of retinal ganglion cells at 14 days post-injury,whereas 4E-BP1 knockdown unexpectedly slightly decreased the survival of retinal ganglion cells at 14 days postinjury.Ove rexpression of constitutively active 4E-BP1 increased the survival of retinal ganglion cells at 14 days post-injury.Likewise,co-expressing constitutively active Rheb and constitutively active 4E-BP1 markedly increased the survival of retinal ganglion cells compared with overexpression of constitutively active Rheb alone at 14 days post-injury.These findings indicate that functional 4E-BP1 and S6K1 are neuroprotective and that 4E-BP1 may exert protective effects through a pathway at least partially independent of Rhe b/mTOR.Together,our results show that constitutively active Rheb promotes the survival of retinal ganglion cells and axon regeneration through modulating S6K1 and 4E-BP1 activity.Phosphorylated S6K1 and 4E-BP1 promote axon regeneration but play an antagonistic role in the survival of retinal ganglion cells.展开更多
The regulating effects of TCM treatments including clearing away heat and toxic materials,promoting blood circulation and removing blood stasis,and strengthening the spleen and regulating qi on the oncogene transcript...The regulating effects of TCM treatments including clearing away heat and toxic materials,promoting blood circulation and removing blood stasis,and strengthening the spleen and regulating qi on the oncogene transcription were observed in the liver cancer model rats.The preliminary results indicated that the mRNA levels of H-ras N-ras and K-ras,and signal molecules correlated with the ras/MAPK signal transduction pathway were down-regulated by the different TCM treatments in varying degrees.Also,the regulating effects of the treatments on differently-displayed genes were discrepant.It is suggested that the molecular mechanisms of the TCM treatments for liver cancer was complex with different target genes.展开更多
This editorial comments on the study by Yang et al,emphasizing the Ras homolog enriched in brain 1(Rheb1)core function in restoring functionalβ-cell mass in diabetes,as crucial forβ-cell proliferation and survival.I...This editorial comments on the study by Yang et al,emphasizing the Ras homolog enriched in brain 1(Rheb1)core function in restoring functionalβ-cell mass in diabetes,as crucial forβ-cell proliferation and survival.It has been revealed that Rheb1 promotesβ-cell regeneration through a dual pathway,activating mammalian target of rapamycin complex 1 and simultaneously inhibiting AMP-activated protein kinase(AMPK).Blocking mammalian target of rapamycin complex 1 while stimulating AMPK was necessary to haltβ-cell expansion,challenging traditional single-target approaches.Rheb1 also supportedβ-cell identity by triggering neurogenic locus notch homolog protein 1 signaling and interacting with hepatocyte nuclear factor 4 alpha,linked to maturity-onset diabetes of the young 1.An age-related decline of Rheb1 in human islets suggests its role in diminished regenerative capacity in adulthood.These findings make Rheb1 a promising therapeutic target for rejuvenatingβ-cells by linking nutrient sensing and energy regulation.Focusing on Rheb1 could alter diabetes treatment,merging proliferation with identity preservation for next-generation therapies.The gaps and translational opportunities,from Rheb1 modulators to biomarkers,were emphasized,advocating for interdisciplinary collaboration to maximize this pathway for positive clinical outcomes.Additional studies are needed to thoroughly investigate AMPK’s involvement in the Rheb1 metabolic biomarker associated with brain health and its possible therapeutic benefits.展开更多
Background and Objective:Idiopathic intracranial hypertension(IIH)is a disorder of raised intracranial pressure(ICP)associated with overweight and obesity,with weight loss being the mainstay of management.Diet and lif...Background and Objective:Idiopathic intracranial hypertension(IIH)is a disorder of raised intracranial pressure(ICP)associated with overweight and obesity,with weight loss being the mainstay of management.Diet and lifestyle changes alone are often unsuccessful at achieving meaningful or sustained weight loss.Glucagon-like peptide-1 receptor agonists(GLP-1RA)are a class of medications developed for the treatment of diabetes but are also highly effective for weight reduction.The objective of this narrative review is to present the current evidence for GLP-1RAs in the management of IIH.Methods:Articles were searched for inclusion through OVID using the following terms:[papilledema OR intracranial hypertension OR idiopathic intracranial hypertension OR brain pseudotumor]and[glucagon like peptide 1 OR glucagon like peptide 1 receptor agonist OR semaglutide OR exendin 4 OR liraglutide OR tirzepatide].Titles and abstracts were screened manually for relevance.There were no exclusion criteria for time frame,language,population or article type,although conference abstracts were not included.An illustrative case of a patient with IIH treated with tirzepatide and semaglutide is also presented.Key Content and Findings:GLP-1RAs have demonstrated the potential for significantly greater weight loss in patients with IIH,with a reduced requirement for IIH medications and improved symptoms,compared to conventional weight management.Treatment with GLP-1RAs has also been shown to result in a rapid and persistent reduction in ICP in both rat and human studies.The side effects of GLP-1RAs are generally well-tolerated,with low rates of discontinuation in clinical trials.However,continuous treatment is likely required to avoid weight rebound and symptom recurrence after cessation.Conclusions:Despite highly promising preliminary evidence,further clinical trials are needed to determine the most effective GLP-1RA medications within this class,appropriate dosing regimens and treatment duration.展开更多
BACKGROUND The combination of anti-epidermal growth factor receptor(EGFR)therapy and chemotherapy is currently a preferred first-line treatment for patients with unre-sectable,RAS and BRAF wild-type,left-sided metasta...BACKGROUND The combination of anti-epidermal growth factor receptor(EGFR)therapy and chemotherapy is currently a preferred first-line treatment for patients with unre-sectable,RAS and BRAF wild-type,left-sided metastatic colorectal cancer(mCRC).Several studies have also demonstrated the benefit of anti-EGFR therapy in sub-sequent line settings for this patient population.However,direct evidence com-paring the effectiveness of frontline vs subsequent anti-EGFR therapy remains limited,leaving a crucial gap in guiding optimal treatment strategies.AIM To compare overall survival(OS)between frontline and subsequent anti-EGFR treatment in patients with unresectable,RAS and BRAF wild-type,left-sided mCRC.METHODS We retrospectively reviewed the medical records of mCRC patients treated at The King Chulalongkorn Memorial Hospital and Songklanagarind Hospital,Thailand,between January 2013 and April 2023.Patients were classified into two groups based on the sequence of their anti-EGFR treatment.The primary endpoint was OS.RESULTS Among 222 patients with a median follow-up of 29 months,no significant difference in OS was observed between the frontline and subsequent-line groups(HR 1.03,95%CI:0.73-1.46,P=0.878).The median OS was 35.53 months(95%CI:26.59-44.47)for the frontline group and 31.60 months(95%CI:27.83-35.37)for the subsequent-line group.In the subsequent-line group,71 patients(32.4%)who ultimately never received anti-EGFR therapy had a significantly worse median OS of 19.70 months(95%CI:12.87-26.53).CONCLUSION Frontline and subsequent-line anti-EGFR treatments provide comparable OS in unresectable,RAS/BRAF wild-type,left-sided mCRC patients,but early exposure is vital for those unlikely to receive subsequent therapy.展开更多
We demonstrate a new polarization smoothing(PS)approach utilizing residual stress birefringence in fused silica to create a spatially random polarization control plate(SRPCP),thereby improving target illumination unif...We demonstrate a new polarization smoothing(PS)approach utilizing residual stress birefringence in fused silica to create a spatially random polarization control plate(SRPCP),thereby improving target illumination uniformity in inertial confinement fusion(ICF)laser systems.The fundamental operating mechanism and key fabrication techniques for the SRPCP are systematically developed and experimentally validated.The SRPCP converts a linearly polarized 3ω incident laser beam into an output beam with a spatially randomized polarization distribution.When combined with a continuous phase plate,the SRPCP effectively suppresses high-intensity speckles at all spatial frequencies in the focal spot.The proposed PS technique is specifically designed for high-fluence large-aperture laser systems,enabling novel polarization control regimes in laser-driven ICF.展开更多
Abnormal activation of the Ras/Raf/Mek/Erk signaling cascade plays an important role in glioma. Inhibition of this aberrant activity could effectively hinder glioma cell proliferation and promote cell apoptosis. To in...Abnormal activation of the Ras/Raf/Mek/Erk signaling cascade plays an important role in glioma. Inhibition of this aberrant activity could effectively hinder glioma cell proliferation and promote cell apoptosis. To investigate the mechanism of gJioblastoma treatment by neural stem ceiJ trans- plantation with respect to the Ras/Raf/Mek/Erk pathway, C6 glioma cells were prepared in sus- pension and then infused into the rat brain to establish a glioblastoma model. Neural stem cells isolated from fetal rats were then injected into the brain of this glioblastoma model. Results showed that Raf-1, Erk and Bcl-2 protein expression significantly increased, while Caspase-3 protein expression decreased. After transplantation of neural stem cells, Raf-1, Erk and Bcl-2 protein expression significantly decreased, while Caspase-3 protein expression significantly in-creased. Our findings indicate that transplantation of neural stem cells may promote apoptosis of glioma cells by inhibiting Ras/Raf/Mek/Erk signaling, and thus may represent a novel treatment approach for glioblastoma.展开更多
基金Supported by Shenzhen High-level Hospital Construction Fund.
文摘BACKGROUND Patients harboring gene mutations like KRAS,NRAS,and BRAF demonstrate highly variable responses to chemotherapy,posing challenges for treatment optimization.Multiparametric magnetic resonance imaging(MRI),with its noninvasive capability to assess tumor characteristics in detail,has shown promise in evaluating treatment response and predicting therapeutic outcomes.This technology holds potential for guiding personalized treatment strategies tailored to individual patient profiles,enhancing the precision and effectiveness of colorectal cancer care.AIM To create a multiparametric MRI-based predictive model for assessing chemotherapy efficacy in colorectal cancer patients with gene mutations.METHODS This retrospective study was conducted in a tertiary hospital,analyzing 157 colorectal cancer patients with gene mutations treated between August 2022 and December 2023.Based on chemotherapy outcomes,the patients were categorized into favorable(n=60)and unfavorable(n=50)response groups.Univariate and multivariate logistic regression analyses were performed to identify independent predictors of chemotherapy efficacy.A predictive nomogram was constructed using significant variables,and its performance was assessed using the area under the receiver operating characteristic curve(AUC)in both training and validation sets.RESULTS Univariate analysis identified that tumor differentiation,T2 signal intensity ratio,tumor-to-anal margin distance,and MRI-detected lymph node metastasis as significantly associated with chemotherapy response(P<0.05).Multivariate Logistics regression confirmed these four parameters as independent predictors.The predictive model demonstrated strong discrimination,with an AUC of 0.938(sensitivity:86%;specificity:92%)in the training set,and 0.942(sensitivity:100%;specificity:83%)in the validation set.CONCLUSION We established and validated a multiparametric MRI-based model for predicting chemotherapy response in colorectal cancer patients with gene mutations.This model holds promise for guiding individualized treatment strategies.
基金National Natural Science Foundation of China,Nos.82070967,81770930the Natural Science Foundation of Hunan Province,No.2020jj4788 (all to BJ)。
文摘Ras homolog enriched in brain(Rheb) is a small GTPase that activates mammalian target of rapamycin complex 1(mTORC1).Previous studies have shown that constitutively active Rheb can enhance the regeneration of sensory axons after spinal cord injury by activating downstream effectors of mTOR.S6K1 and4E-BP1 are important downstream effectors of mTORC1.In this study,we investigated the role of Rheb/mTOR and its downstream effectors S6K1 and 4E-BP1in the protection of retinal ganglion cells.We transfected an optic nerve crush mouse model with adeno-associated viral 2-mediated constitutively active Rheb and observed the effects on retinal ganglion cell survival and axon regeneration.We found that overexpression of constitutively active Rheb promoted survival of retinal ganglion cells in the acute(14 days) and chronic(21 and 42 days) stages of injury.We also found that either co-expression of the dominant-negative S6K1mutant or the constitutively active 4E-BP1 mutant together with constitutively active Rheb markedly inhibited axon regeneration of retinal ganglion cells.This suggests that mTORC1-mediated S6K1 activation and 4E-BP1 inhibition were necessary components for constitutively active Rheb-induced axon regeneration.However,only S6K1 activation,but not 4E-BP1 knockdown,induced axon regeneration when applied alone.Furthermore,S6K1 activation promoted the survival of retinal ganglion cells at 14 days post-injury,whereas 4E-BP1 knockdown unexpectedly slightly decreased the survival of retinal ganglion cells at 14 days postinjury.Ove rexpression of constitutively active 4E-BP1 increased the survival of retinal ganglion cells at 14 days post-injury.Likewise,co-expressing constitutively active Rheb and constitutively active 4E-BP1 markedly increased the survival of retinal ganglion cells compared with overexpression of constitutively active Rheb alone at 14 days post-injury.These findings indicate that functional 4E-BP1 and S6K1 are neuroprotective and that 4E-BP1 may exert protective effects through a pathway at least partially independent of Rhe b/mTOR.Together,our results show that constitutively active Rheb promotes the survival of retinal ganglion cells and axon regeneration through modulating S6K1 and 4E-BP1 activity.Phosphorylated S6K1 and 4E-BP1 promote axon regeneration but play an antagonistic role in the survival of retinal ganglion cells.
文摘The regulating effects of TCM treatments including clearing away heat and toxic materials,promoting blood circulation and removing blood stasis,and strengthening the spleen and regulating qi on the oncogene transcription were observed in the liver cancer model rats.The preliminary results indicated that the mRNA levels of H-ras N-ras and K-ras,and signal molecules correlated with the ras/MAPK signal transduction pathway were down-regulated by the different TCM treatments in varying degrees.Also,the regulating effects of the treatments on differently-displayed genes were discrepant.It is suggested that the molecular mechanisms of the TCM treatments for liver cancer was complex with different target genes.
基金Supported by Zhejiang University Global Partnership Fund,No.BIO-0322023.
文摘This editorial comments on the study by Yang et al,emphasizing the Ras homolog enriched in brain 1(Rheb1)core function in restoring functionalβ-cell mass in diabetes,as crucial forβ-cell proliferation and survival.It has been revealed that Rheb1 promotesβ-cell regeneration through a dual pathway,activating mammalian target of rapamycin complex 1 and simultaneously inhibiting AMP-activated protein kinase(AMPK).Blocking mammalian target of rapamycin complex 1 while stimulating AMPK was necessary to haltβ-cell expansion,challenging traditional single-target approaches.Rheb1 also supportedβ-cell identity by triggering neurogenic locus notch homolog protein 1 signaling and interacting with hepatocyte nuclear factor 4 alpha,linked to maturity-onset diabetes of the young 1.An age-related decline of Rheb1 in human islets suggests its role in diminished regenerative capacity in adulthood.These findings make Rheb1 a promising therapeutic target for rejuvenatingβ-cells by linking nutrient sensing and energy regulation.Focusing on Rheb1 could alter diabetes treatment,merging proliferation with identity preservation for next-generation therapies.The gaps and translational opportunities,from Rheb1 modulators to biomarkers,were emphasized,advocating for interdisciplinary collaboration to maximize this pathway for positive clinical outcomes.Additional studies are needed to thoroughly investigate AMPK’s involvement in the Rheb1 metabolic biomarker associated with brain health and its possible therapeutic benefits.
文摘Background and Objective:Idiopathic intracranial hypertension(IIH)is a disorder of raised intracranial pressure(ICP)associated with overweight and obesity,with weight loss being the mainstay of management.Diet and lifestyle changes alone are often unsuccessful at achieving meaningful or sustained weight loss.Glucagon-like peptide-1 receptor agonists(GLP-1RA)are a class of medications developed for the treatment of diabetes but are also highly effective for weight reduction.The objective of this narrative review is to present the current evidence for GLP-1RAs in the management of IIH.Methods:Articles were searched for inclusion through OVID using the following terms:[papilledema OR intracranial hypertension OR idiopathic intracranial hypertension OR brain pseudotumor]and[glucagon like peptide 1 OR glucagon like peptide 1 receptor agonist OR semaglutide OR exendin 4 OR liraglutide OR tirzepatide].Titles and abstracts were screened manually for relevance.There were no exclusion criteria for time frame,language,population or article type,although conference abstracts were not included.An illustrative case of a patient with IIH treated with tirzepatide and semaglutide is also presented.Key Content and Findings:GLP-1RAs have demonstrated the potential for significantly greater weight loss in patients with IIH,with a reduced requirement for IIH medications and improved symptoms,compared to conventional weight management.Treatment with GLP-1RAs has also been shown to result in a rapid and persistent reduction in ICP in both rat and human studies.The side effects of GLP-1RAs are generally well-tolerated,with low rates of discontinuation in clinical trials.However,continuous treatment is likely required to avoid weight rebound and symptom recurrence after cessation.Conclusions:Despite highly promising preliminary evidence,further clinical trials are needed to determine the most effective GLP-1RA medications within this class,appropriate dosing regimens and treatment duration.
文摘BACKGROUND The combination of anti-epidermal growth factor receptor(EGFR)therapy and chemotherapy is currently a preferred first-line treatment for patients with unre-sectable,RAS and BRAF wild-type,left-sided metastatic colorectal cancer(mCRC).Several studies have also demonstrated the benefit of anti-EGFR therapy in sub-sequent line settings for this patient population.However,direct evidence com-paring the effectiveness of frontline vs subsequent anti-EGFR therapy remains limited,leaving a crucial gap in guiding optimal treatment strategies.AIM To compare overall survival(OS)between frontline and subsequent anti-EGFR treatment in patients with unresectable,RAS and BRAF wild-type,left-sided mCRC.METHODS We retrospectively reviewed the medical records of mCRC patients treated at The King Chulalongkorn Memorial Hospital and Songklanagarind Hospital,Thailand,between January 2013 and April 2023.Patients were classified into two groups based on the sequence of their anti-EGFR treatment.The primary endpoint was OS.RESULTS Among 222 patients with a median follow-up of 29 months,no significant difference in OS was observed between the frontline and subsequent-line groups(HR 1.03,95%CI:0.73-1.46,P=0.878).The median OS was 35.53 months(95%CI:26.59-44.47)for the frontline group and 31.60 months(95%CI:27.83-35.37)for the subsequent-line group.In the subsequent-line group,71 patients(32.4%)who ultimately never received anti-EGFR therapy had a significantly worse median OS of 19.70 months(95%CI:12.87-26.53).CONCLUSION Frontline and subsequent-line anti-EGFR treatments provide comparable OS in unresectable,RAS/BRAF wild-type,left-sided mCRC patients,but early exposure is vital for those unlikely to receive subsequent therapy.
基金supported by the National Natural Science Foundation of China(Grant No.62275235).
文摘We demonstrate a new polarization smoothing(PS)approach utilizing residual stress birefringence in fused silica to create a spatially random polarization control plate(SRPCP),thereby improving target illumination uniformity in inertial confinement fusion(ICF)laser systems.The fundamental operating mechanism and key fabrication techniques for the SRPCP are systematically developed and experimentally validated.The SRPCP converts a linearly polarized 3ω incident laser beam into an output beam with a spatially randomized polarization distribution.When combined with a continuous phase plate,the SRPCP effectively suppresses high-intensity speckles at all spatial frequencies in the focal spot.The proposed PS technique is specifically designed for high-fluence large-aperture laser systems,enabling novel polarization control regimes in laser-driven ICF.
文摘Abnormal activation of the Ras/Raf/Mek/Erk signaling cascade plays an important role in glioma. Inhibition of this aberrant activity could effectively hinder glioma cell proliferation and promote cell apoptosis. To investigate the mechanism of gJioblastoma treatment by neural stem ceiJ trans- plantation with respect to the Ras/Raf/Mek/Erk pathway, C6 glioma cells were prepared in sus- pension and then infused into the rat brain to establish a glioblastoma model. Neural stem cells isolated from fetal rats were then injected into the brain of this glioblastoma model. Results showed that Raf-1, Erk and Bcl-2 protein expression significantly increased, while Caspase-3 protein expression decreased. After transplantation of neural stem cells, Raf-1, Erk and Bcl-2 protein expression significantly decreased, while Caspase-3 protein expression significantly in-creased. Our findings indicate that transplantation of neural stem cells may promote apoptosis of glioma cells by inhibiting Ras/Raf/Mek/Erk signaling, and thus may represent a novel treatment approach for glioblastoma.
