Immune checkpoint inhibitors augment the antitumor activity of T cells by inhibiting the negative regulatory pathway of T cells,leading to notable efficacy in patients with non-small cell lung cancer,melanoma,and othe...Immune checkpoint inhibitors augment the antitumor activity of T cells by inhibiting the negative regulatory pathway of T cells,leading to notable efficacy in patients with non-small cell lung cancer,melanoma,and other malignancies through immunotherapy utilization.However,secondary malignant liver tumors not only lower the liver's sensitivity to immunotherapy but also trigger systemic immune suppression,resulting in reduced overall effectiveness of immune therapy.Patients receiving immunotherapy for non-small cell lung cancer and melanoma experience reduced response rates,progression-free survival,and overall survival when secondary malignant tumors develop in the liver.Through Liu's retrospective analysis,valuable insights are provided for the future clinical management of these patients.Therefore,in patients with gastric cancer(GC),the occurrence of liver metastasis might be indicative of reduced efficacy of immuno-therapy.Overcoming liver immune tolerance mechanisms and their negative impacts allows for the potential benefits of immunotherapy in patients with GC and liver metastasis.INTRODUCTION Gastric cancer(GC)ranks among the prevalent malignancies affecting the digestive system globally.Based on the latest epidemiological data[1,2],it holds the fifth position for incidence and the fourth position for mortality among all malignant tumors.GC cases and fatalities in China make up roughly half of the worldwide figures.Earlier investigations[3]have demonstrated that the median overall survival(mOS)among advanced GC patients left untreated typically ranges from 3 to 4 months.Systemic chemotherapy recipients often experience a mOS of around one year,accompanied by a marked improvement in the quality of life among patients with advanced GC.The mainstay of treatment for advanced GC patients involves chemotherapeutic medications such as fluoropyrimidines,platinum compounds,and taxanes.However,their efficacy in tumor control is constrained by acquired resistance and primary resistance.The rise of personalized precision therapy has propelled immunotherapy into the spotlight as a crucial component of comprehensive treatment[4].By blocking the negative regulatory pathways of T cells,immune checkpoint inhibitors(ICIs)boost the anti-tumor effect of T cells.Immunotherapy has brought about significant therapeutic benefits for patients diagnosed with non-small cell lung cancer,melanoma,and related illnesses[5,6],instilling newfound hope in those with advanced GC[7].However,phase III clinical trial data[8-12]reveals that the incorporation of immunotherapy into chemotherapy regimens improves overall survival(OS)outcomes for patients with advanced GC.The liver's immune-exempt nature renders it less responsive to immunotherapy when secondary malignant tumors are present,fostering systemic immune suppression and yielding unfavorable outcomes in immune therapy[13-15].In retrospective research[16-20]pertaining to non-small cell lung cancer and melanoma,it has been observed that the presence of secondary liver malignancies may lower the response rate,progression-free survival(PFS),and OS rates in patients treated with immunotherapy,independent of factors such as tumor mutation burden and PD-L1 expression.Despite this,there is a paucity of studies examining whether the existence of secondary malignant liver tumors affects the effectiveness of immunotherapy in patients diagnosed with advanced HER-2 negative GC.展开更多
BACKGROUND At present,immune checkpoint inhibitors(ICIs)remain the 1st-line therapy me-thod for patients suffering from high microsatellite instability/deficient misma-tch repair metastatic colorectal cancer(mCRC).How...BACKGROUND At present,immune checkpoint inhibitors(ICIs)remain the 1st-line therapy me-thod for patients suffering from high microsatellite instability/deficient misma-tch repair metastatic colorectal cancer(mCRC).However,ICI treatments demon-strate minimal therapeutic efficacy against microsatellite stable(MSS)/proficient mismatch repair(pMMR)CRC.This is mainly because this type of tumor is a“cold tumor”with almost no lymphocyte infiltration.Anti-angiogenic drugs have been found to improve the immune microenvironment by promoting many immune cells to enter the immune microenvironment,thereby exerting anti-tumor effects.AIM To investigate the effects of ICIs combined with bevacizumab monoclonal anti-body on tumor immune cells in MSS/pMMR advanced CRC patients with first-line treatment failure.METHODS A total of 110 MSS/pMMR patients with advanced CRC after first-line treatment failure in the Affiliated Hospital of Qinghai University were enrolled for a ran-domized controlled trial.In short,patients in the experimental group(n=60)were given sintilimab plus bevacizumab for 4 cycles,and those in the control group(n=50)patients were treated with FOLFIRI combined with bevacizumab for 4 cycles.The expression levels of cluster of differentiation(CD)8(+)T cells,tumor-associated macrophages(TAMs),and cancer-associated fibroblasts(CAFs)were comprehensively evaluated to assess the effects of sintilimab combined with bevacizumab on MSS/pMMR advanced CRC sufferers following failure of 1st-line therapy.RESULTS The positive expression rates of CD8(+)T lymphocytes(30%vs 50%),TAMs(23.30%vs 60%),and CAFs(23.30%vs 50%)before and after treatment in both groups exhibited statistical significance(P<0.05).Additionally,the therapeutic effects of both groups(partial remission:26.67%vs 10%;objective response rate:26.70%vs 10%)were significantly different(P<0.05).Although the experimental group showed a higher progression-free survival,median progression-free survival,and disease control rate than the control group,the difference was not statist-ically significant.Moreover,no significant difference in the occurrence rate of drug-related adverse reactions after treatment between the two groups was found(P>0.05).CONCLUSION ICIs in combination with bevacizumab can not only improve the patient’s prognosis but also yield safe and controllable adverse drug reactions in patients suffering from MSS/pMMR advanced CRC after failure to a 1st-line therapy.展开更多
While emergency medical service (EMS) response time (ERT) is a major factor associated with the survival of patients with cardiovascular disease (CVD), relatively few studies have explored the factors associated with ...While emergency medical service (EMS) response time (ERT) is a major factor associated with the survival of patients with cardiovascular disease (CVD), relatively few studies have explored the factors associated with ERT. This study aimed to assess the current status of ERT and to identify the factors affecting ERT in patients with CVD in China. Between January 1, 2011 and December 31, 2015, EMS responses to CVD incidents in Guangzhou, China, were examined. The primary outcome was ERT, defined as the time from receipt of an emergency call to the arrival of paramedics on the scene. Factors associated with ERT were evaluated by multivariable logistic regression. A total of 44 383 CVD incidents were analysed. The median ERT was 12.58 min (interquartile range=9.98-15.67). Among the risk factors, distance (OR=13.73, 95% CI=11.76- 16.04), level of hospital (OR=1.57, 95% CI=1.40-1.75), and site of the incident (OR=1.53, 95% CI=1.38-1.69) were the top three significant factors affecting the ERT. Our results suggest that greater attention should be given to factors affecting the ERT. It is essential to make continuous efforts to promote the development of effective interventions to reduce the response time.展开更多
A nonlinear controller for disturbances rejection and collision avoidance is proposed for spacecraft formation flying.The formation flying is described by a nonlinear model with the J2 perturbation and atmospheric dra...A nonlinear controller for disturbances rejection and collision avoidance is proposed for spacecraft formation flying.The formation flying is described by a nonlinear model with the J2 perturbation and atmospheric drag. Based on the theory of the state-dependent Riccati equation（SDRE）, a finite time nonlinear control law is developed for the nonlinear dynamics involved in formation flying. Then, a compensative internal mode（IM） control law is added to eliminate disturbances.These two control laws compose a finite time nonlinear tracking controller with disturbances rejection. Moreover, taking safety requirements into account, the repulsive control law is incorporated in the composite controller to perform collision avoidance manoeuvres. A numerical simulation is presented to demonstrate the effectiveness of the proposed method.Compared to the conventional control method, the proposed method provides better performance in the presence of the obstacles and external disturbances.展开更多
The total mesorectal excision(TME)approach has been established as the gold standard for the surgical treatment of middle and lower rectal cancer.This approach is widely accepted to minimize the risk of local recurren...The total mesorectal excision(TME)approach has been established as the gold standard for the surgical treatment of middle and lower rectal cancer.This approach is widely accepted to minimize the risk of local recurrence and increase the long-term survival rate of patients undergoing surgery.However,standardized TME causes urogenital dysfunction in more than half of patients,thus lowering the quality of life of patients.Of note,pelvic autonomic nerve damage during TME is the most pivotal cause of postoperative urogenital dysfunction.The anatomy of the Denonvilliers’fascia(DVF)and its application in surgery have been investigated both nationally and internationally.Nevertheless,controversy exists regarding the basic to clinical anatomy of DVF and its application in surgery.Currently,it is a hotspot of concern and research to improve the postoperative quality of life of patients with rectal cancer through the protection of their urinary and reproductive functions after radical resection.Herein,this study systematically describes the anatomy of DVF and its appli-cation in surgery,thus providing a reference for the selection of surgical treatment modalities and the enhancement of postoperative quality of life in patients with middle and low rectal cancer.展开更多
Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tum...Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tumor effects,they can also trigger immune-related adverse events(irAEs),with ICI-associated colitis being one of the more prevalent forms.This condition can disrupt treatment,necessitate drug discontinuation,and adversely affect therapeutic outcomes.In severe cases,irAEs may even become life-threatening.A recent case report by Hong et al highlights the importance of vigilance for ICI-associated colitis in patients experiencing symptoms such as diarrhea and abdominal pain,which can arise both during and even after completion of ICI treatment.Early identification,multidisciplinary management,and continuous monitoring of patients are essential steps to further improve outcomes.展开更多
The discovery of neuroglobin(Ngb),a brain-or neuron-specific member of the hemoglobin family,has revolutionized our understanding of brain oxygen metabolism.Currently,how Ngb plays such a role remains far from clear.H...The discovery of neuroglobin(Ngb),a brain-or neuron-specific member of the hemoglobin family,has revolutionized our understanding of brain oxygen metabolism.Currently,how Ngb plays such a role remains far from clear.Here,we report a novel mechanism by which Ngb might facilitate neuronal oxygenation upon hypoxia or anemia.We found that Ngb was present in,co-localized to,and co-migrated with mitochondria in the cell body and neurites of neurons.Hypoxia induced a sudden and prominent migration of Ngb towards the cytoplasmic membrane(CM)or cell surface in living neurons,and this was accompanied by the mitochondria.In vivo,hypotonic and anemic hypoxia induced a reversible Ngb migration toward the CM in cerebral cortical neurons in rat brains but did not alter the expression level of Ngb or its cytoplasm/mitochondria ratio.Knock-down of Ngb by RNA interference significantly diminished respiratory succinate dehydrogenase(SDH)and ATPase activity in neuronal N2a cells.Over-expression of Ngb enhanced SDH activity in N2a cells upon hypoxia.Mutation of Ngb at its oxygen-binding site(His64)significantly increased SDH activity and reduced ATPase activity in N2a cells.Taken together,Ngb was physically and functionally linked to mitochondria.In response to an insufficient oxygen supply,Ngb migrated towards the source of oxygen to facilitate neuronal oxygenation.This novel mechanism of neuronal respiration provides new insights into the understanding and treatment of neurological diseases such as stroke and Alzheimer’s disease and diseases that cause hypoxia in the brain such as anemia.展开更多
基金2021 Key Topic of Qinghai Provincial Health System–Guiding Plan Topic,No.2021-WJZDX-43.
文摘Immune checkpoint inhibitors augment the antitumor activity of T cells by inhibiting the negative regulatory pathway of T cells,leading to notable efficacy in patients with non-small cell lung cancer,melanoma,and other malignancies through immunotherapy utilization.However,secondary malignant liver tumors not only lower the liver's sensitivity to immunotherapy but also trigger systemic immune suppression,resulting in reduced overall effectiveness of immune therapy.Patients receiving immunotherapy for non-small cell lung cancer and melanoma experience reduced response rates,progression-free survival,and overall survival when secondary malignant tumors develop in the liver.Through Liu's retrospective analysis,valuable insights are provided for the future clinical management of these patients.Therefore,in patients with gastric cancer(GC),the occurrence of liver metastasis might be indicative of reduced efficacy of immuno-therapy.Overcoming liver immune tolerance mechanisms and their negative impacts allows for the potential benefits of immunotherapy in patients with GC and liver metastasis.INTRODUCTION Gastric cancer(GC)ranks among the prevalent malignancies affecting the digestive system globally.Based on the latest epidemiological data[1,2],it holds the fifth position for incidence and the fourth position for mortality among all malignant tumors.GC cases and fatalities in China make up roughly half of the worldwide figures.Earlier investigations[3]have demonstrated that the median overall survival(mOS)among advanced GC patients left untreated typically ranges from 3 to 4 months.Systemic chemotherapy recipients often experience a mOS of around one year,accompanied by a marked improvement in the quality of life among patients with advanced GC.The mainstay of treatment for advanced GC patients involves chemotherapeutic medications such as fluoropyrimidines,platinum compounds,and taxanes.However,their efficacy in tumor control is constrained by acquired resistance and primary resistance.The rise of personalized precision therapy has propelled immunotherapy into the spotlight as a crucial component of comprehensive treatment[4].By blocking the negative regulatory pathways of T cells,immune checkpoint inhibitors(ICIs)boost the anti-tumor effect of T cells.Immunotherapy has brought about significant therapeutic benefits for patients diagnosed with non-small cell lung cancer,melanoma,and related illnesses[5,6],instilling newfound hope in those with advanced GC[7].However,phase III clinical trial data[8-12]reveals that the incorporation of immunotherapy into chemotherapy regimens improves overall survival(OS)outcomes for patients with advanced GC.The liver's immune-exempt nature renders it less responsive to immunotherapy when secondary malignant tumors are present,fostering systemic immune suppression and yielding unfavorable outcomes in immune therapy[13-15].In retrospective research[16-20]pertaining to non-small cell lung cancer and melanoma,it has been observed that the presence of secondary liver malignancies may lower the response rate,progression-free survival(PFS),and OS rates in patients treated with immunotherapy,independent of factors such as tumor mutation burden and PD-L1 expression.Despite this,there is a paucity of studies examining whether the existence of secondary malignant liver tumors affects the effectiveness of immunotherapy in patients diagnosed with advanced HER-2 negative GC.
基金Supported by the 2021 Key Topic of the Qinghai Provincial Health System-Guiding Plan Topic,No.2021-WJZDX-43.
文摘BACKGROUND At present,immune checkpoint inhibitors(ICIs)remain the 1st-line therapy me-thod for patients suffering from high microsatellite instability/deficient misma-tch repair metastatic colorectal cancer(mCRC).However,ICI treatments demon-strate minimal therapeutic efficacy against microsatellite stable(MSS)/proficient mismatch repair(pMMR)CRC.This is mainly because this type of tumor is a“cold tumor”with almost no lymphocyte infiltration.Anti-angiogenic drugs have been found to improve the immune microenvironment by promoting many immune cells to enter the immune microenvironment,thereby exerting anti-tumor effects.AIM To investigate the effects of ICIs combined with bevacizumab monoclonal anti-body on tumor immune cells in MSS/pMMR advanced CRC patients with first-line treatment failure.METHODS A total of 110 MSS/pMMR patients with advanced CRC after first-line treatment failure in the Affiliated Hospital of Qinghai University were enrolled for a ran-domized controlled trial.In short,patients in the experimental group(n=60)were given sintilimab plus bevacizumab for 4 cycles,and those in the control group(n=50)patients were treated with FOLFIRI combined with bevacizumab for 4 cycles.The expression levels of cluster of differentiation(CD)8(+)T cells,tumor-associated macrophages(TAMs),and cancer-associated fibroblasts(CAFs)were comprehensively evaluated to assess the effects of sintilimab combined with bevacizumab on MSS/pMMR advanced CRC sufferers following failure of 1st-line therapy.RESULTS The positive expression rates of CD8(+)T lymphocytes(30%vs 50%),TAMs(23.30%vs 60%),and CAFs(23.30%vs 50%)before and after treatment in both groups exhibited statistical significance(P<0.05).Additionally,the therapeutic effects of both groups(partial remission:26.67%vs 10%;objective response rate:26.70%vs 10%)were significantly different(P<0.05).Although the experimental group showed a higher progression-free survival,median progression-free survival,and disease control rate than the control group,the difference was not statist-ically significant.Moreover,no significant difference in the occurrence rate of drug-related adverse reactions after treatment between the two groups was found(P>0.05).CONCLUSION ICIs in combination with bevacizumab can not only improve the patient’s prognosis but also yield safe and controllable adverse drug reactions in patients suffering from MSS/pMMR advanced CRC after failure to a 1st-line therapy.
文摘While emergency medical service (EMS) response time (ERT) is a major factor associated with the survival of patients with cardiovascular disease (CVD), relatively few studies have explored the factors associated with ERT. This study aimed to assess the current status of ERT and to identify the factors affecting ERT in patients with CVD in China. Between January 1, 2011 and December 31, 2015, EMS responses to CVD incidents in Guangzhou, China, were examined. The primary outcome was ERT, defined as the time from receipt of an emergency call to the arrival of paramedics on the scene. Factors associated with ERT were evaluated by multivariable logistic regression. A total of 44 383 CVD incidents were analysed. The median ERT was 12.58 min (interquartile range=9.98-15.67). Among the risk factors, distance (OR=13.73, 95% CI=11.76- 16.04), level of hospital (OR=1.57, 95% CI=1.40-1.75), and site of the incident (OR=1.53, 95% CI=1.38-1.69) were the top three significant factors affecting the ERT. Our results suggest that greater attention should be given to factors affecting the ERT. It is essential to make continuous efforts to promote the development of effective interventions to reduce the response time.
基金supported by the National Natural Science Foundation of China(Grant No.11404404)
文摘A nonlinear controller for disturbances rejection and collision avoidance is proposed for spacecraft formation flying.The formation flying is described by a nonlinear model with the J2 perturbation and atmospheric drag. Based on the theory of the state-dependent Riccati equation（SDRE）, a finite time nonlinear control law is developed for the nonlinear dynamics involved in formation flying. Then, a compensative internal mode（IM） control law is added to eliminate disturbances.These two control laws compose a finite time nonlinear tracking controller with disturbances rejection. Moreover, taking safety requirements into account, the repulsive control law is incorporated in the composite controller to perform collision avoidance manoeuvres. A numerical simulation is presented to demonstrate the effectiveness of the proposed method.Compared to the conventional control method, the proposed method provides better performance in the presence of the obstacles and external disturbances.
基金the Key Project of the Qinghai Provincial Health Commission,No.2019-wjzd-06.
文摘The total mesorectal excision(TME)approach has been established as the gold standard for the surgical treatment of middle and lower rectal cancer.This approach is widely accepted to minimize the risk of local recurrence and increase the long-term survival rate of patients undergoing surgery.However,standardized TME causes urogenital dysfunction in more than half of patients,thus lowering the quality of life of patients.Of note,pelvic autonomic nerve damage during TME is the most pivotal cause of postoperative urogenital dysfunction.The anatomy of the Denonvilliers’fascia(DVF)and its application in surgery have been investigated both nationally and internationally.Nevertheless,controversy exists regarding the basic to clinical anatomy of DVF and its application in surgery.Currently,it is a hotspot of concern and research to improve the postoperative quality of life of patients with rectal cancer through the protection of their urinary and reproductive functions after radical resection.Herein,this study systematically describes the anatomy of DVF and its appli-cation in surgery,thus providing a reference for the selection of surgical treatment modalities and the enhancement of postoperative quality of life in patients with middle and low rectal cancer.
基金Supported by 2021 Key Topic of Qinghai Provincial Health System–Guiding Plan Topic,No.2021-WJZDX-43.
文摘Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tumor effects,they can also trigger immune-related adverse events(irAEs),with ICI-associated colitis being one of the more prevalent forms.This condition can disrupt treatment,necessitate drug discontinuation,and adversely affect therapeutic outcomes.In severe cases,irAEs may even become life-threatening.A recent case report by Hong et al highlights the importance of vigilance for ICI-associated colitis in patients experiencing symptoms such as diarrhea and abdominal pain,which can arise both during and even after completion of ICI treatment.Early identification,multidisciplinary management,and continuous monitoring of patients are essential steps to further improve outcomes.
基金This work was supported by the National Natural Science Foundation of China(81972362,82173197,and 81672504).
文摘The discovery of neuroglobin(Ngb),a brain-or neuron-specific member of the hemoglobin family,has revolutionized our understanding of brain oxygen metabolism.Currently,how Ngb plays such a role remains far from clear.Here,we report a novel mechanism by which Ngb might facilitate neuronal oxygenation upon hypoxia or anemia.We found that Ngb was present in,co-localized to,and co-migrated with mitochondria in the cell body and neurites of neurons.Hypoxia induced a sudden and prominent migration of Ngb towards the cytoplasmic membrane(CM)or cell surface in living neurons,and this was accompanied by the mitochondria.In vivo,hypotonic and anemic hypoxia induced a reversible Ngb migration toward the CM in cerebral cortical neurons in rat brains but did not alter the expression level of Ngb or its cytoplasm/mitochondria ratio.Knock-down of Ngb by RNA interference significantly diminished respiratory succinate dehydrogenase(SDH)and ATPase activity in neuronal N2a cells.Over-expression of Ngb enhanced SDH activity in N2a cells upon hypoxia.Mutation of Ngb at its oxygen-binding site(His64)significantly increased SDH activity and reduced ATPase activity in N2a cells.Taken together,Ngb was physically and functionally linked to mitochondria.In response to an insufficient oxygen supply,Ngb migrated towards the source of oxygen to facilitate neuronal oxygenation.This novel mechanism of neuronal respiration provides new insights into the understanding and treatment of neurological diseases such as stroke and Alzheimer’s disease and diseases that cause hypoxia in the brain such as anemia.
