The initiation and progression of colorectal cancer(CRC)are profoundly influenced by the complex interplay between the gut microbiota and the immune system,underscoring the clinical importance of exploring the bidirec...The initiation and progression of colorectal cancer(CRC)are profoundly influenced by the complex interplay between the gut microbiota and the immune system,underscoring the clinical importance of exploring the bidirectional regulatory mechanisms of the microbiota-immune axis within the CRC immune microenvironment.Emerging evidence indicates that the composition and functional capacity of the gut microbiota play a vital role in modulating the host’s immune responses,while the immune system,in turn,can reciprocally regulate the structure and function of the microbiota.Despite significant insights into the role of the microbiota-immune axis in CRC progression,several critical questions remain unanswered-including how microbial heterogeneity affects therapeutic outcomes and the specific consequences of dysregulated regulatory mechanisms on the immune microenvironment.This review aims to provide a comprehensive analysis of the compositional features of the CRC immune microenvironment,examine the bidirectional molecular mechanisms underpinning the microbiotaimmune axis,and evaluate the potential of targeted therapeutic strategies,thereby offering novel research perspectives and clinical applications for CRC treatment.展开更多
Osteoarthritis(OA)is a progressive degenerative joint sickness related with mechanics,obesity,ageing,etc.,mainly characterized by cartilage degeneration,subchondral bone damage and synovium inflammation.Coordinated me...Osteoarthritis(OA)is a progressive degenerative joint sickness related with mechanics,obesity,ageing,etc.,mainly characterized by cartilage degeneration,subchondral bone damage and synovium inflammation.Coordinated mechanical absorption and conduction of the joint play significant roles in the prevalence and development of OA.Subchondral bone is generally considered a load-burdening tissue where mechanosensitive cells are resident,including osteocytes,osteoblast lineage cells,and osteoclast lineage cells(especially less concerned in mechanical studies).Mechano-signaling imbalances affect complicated cellular events and disorders of subchondral bone homeostasis.This paper will focus on the significance of mechanical force as the pathogenesis,involvement of various mechanical force patterns in mechanosensitive cells,and mechanobiology research of loading devices in vitro and in vivo,which are further discussed.Additionally,various mechanosensing structures(e.g.,transient receptor potential channels,gap junctions,primary cilia,podosome-associated complexes,extracellular vesicles)and mechanotransduction signaling pathways(e.g.,Ca^(2+) signaling,Wnt/β-catenin,RhoA GTPase,focal adhesion kinase,cotranscriptional activators YAP/TAZ)in mechanosensitive bone cells.Finally,we highlight potential targets for improving mechanoprotection in the treatment of OA.These advances furnish an integration of mechanical regulation of subchondral bone homeostasis,as well as OA therapeutic approaches by modulating mechanical homeostasis.展开更多
Background Prior randomized trials have shown reduced bleeding with bivalirudin compared with unfractionated heparin （UFH） in patients undergoing percutaneous coronary intervention （PCI）. However, it is not known ...Background Prior randomized trials have shown reduced bleeding with bivalirudin compared with unfractionated heparin （UFH） in patients undergoing percutaneous coronary intervention （PCI）. However, it is not known if this benefit is also present when UFH doses are more tightly controlled （as measured by activated clotting time, ACT）.展开更多
Background: A better understanding of the impact of Targeted Interventions (TI) services on Female Sex Worker (FSW) behaviours can help in informing and strengthening future TI efforts under National AIDS Control Prog...Background: A better understanding of the impact of Targeted Interventions (TI) services on Female Sex Worker (FSW) behaviours can help in informing and strengthening future TI efforts under National AIDS Control Programme (NACP). Methods: National Integrated Biological and Behavioural Survey (IBBS) 2014-15 has been analysed in the paper. Descriptive statistics and logistic regression analysis were used to understand factors affecting condom use. Propensity score matching (PSM) was done to understand the impact of the TI services on condom use at the last act and consistent condom use in the last three months among FSWs. Results: Younger FSWs aged 15 - 25 years were 1.4 times (95% CI: 1.04 - 1.77) more likely to use consistent condoms in the last three months compared to older over 45 years after controlling for other socio-economic and programme variables. The matched samples estimate ATET i.e. the average treatment effect on treated for consistent condom use in the last three months shows that a 6.0% (CI: 4.7 - 7.3) increase in consistent condom use in the last three months in the FSWs who received information on STI/HIV from peer educator and outreach worker. There is also a 6.0% (4.7 - 7.2) increase in condom use in the last act for FSWs who received the referral services at STI clinics, HIV testing, and detox centres. Conclusions: It is evident that the TI programme has a positive impact on behavior change among FSWs which can prove beneficial to curtail the spread of HIV to the partners and onward transmission to the general population.展开更多
Objective: to explore the application of targeted nursing in postoperative treatment of esophageal cancer. Observation method: 74 patients with esophageal cancer admitted to our hospital from February 2020 to February...Objective: to explore the application of targeted nursing in postoperative treatment of esophageal cancer. Observation method: 74 patients with esophageal cancer admitted to our hospital from February 2020 to February 2021 were selected for this study. According to the "random number allocation" method, they were divided into the control group and the observation group. The control group was treated with conventional interventional therapy, and the observation group was treated with targeted care. The postoperative complications and quality of life after care were compared. Results: the incidence of complications after nursing in the observation group was lower than that in the control group to improve the nursing quality and curative effect, which is worthy of clinical promotion.展开更多
Objective: to explore the hospital to family extension of NSCLC intervention after discharge.Methods: after 90 patients with NSCLC were discharged from May 2019 to June 2020, the envelopes were randomized into two gro...Objective: to explore the hospital to family extension of NSCLC intervention after discharge.Methods: after 90 patients with NSCLC were discharged from May 2019 to June 2020, the envelopes were randomized into two groups.The routine care group gave routine care, and the continuing intervention group performed extended hospital-to-family care.The quality of survival and the rate of oral targeted drugs were compared between the two groups.Results: compared of quality of survival, rate of oral targeted drugs and routine intervention group, P <0.05. Conclusion: NSCLC patients continue to control targeted drugs after discharge from hospital, and extending hospital care to family can improve the quality of survival and improve the rate of oral targeted drugs, which is worth promoting.展开更多
Objective: to analyze the application efficiency of emergency surgical nursing in trauma management. Methods: a total of 100 surgical trauma patients who were admitted to the emergency department of our hospital from ...Objective: to analyze the application efficiency of emergency surgical nursing in trauma management. Methods: a total of 100 surgical trauma patients who were admitted to the emergency department of our hospital from July 2020 to July 2021 were selected and divided into a control group and an observation group, with 35 cases in each. The patients in the control group were given basic nursing care, while the patients in this group were observed and targeted nursing intervention in emergency surgery. The time to diagnosis, time to surgery, length of hospital stay, rescue success rate and complications were evaluated. Conclusion: after compared with the observation group, the inspection time, the time to surgery, and the time to hosp ital admission were significantly longer in the control group, and the difference between the two was statistically significant (p<0.05). In the control group, patients’survival rate of first aid was only 74.00%, obviously 96.0% of the patients in the observation group were lower, and the number of failures (deaths) was significantly higher than that of the patients in the observation group (p<0.05). The incidence of comorbidities in the control group was significantly higher than 20.00%, and significantly higher than 4.00% in the observation group (p<0.05). Conclusion: the application effect of surgical targeted nursing intervention in emergency department in trauma treatment is definite and can significantly shortens the diagnosis time of patients, buys precious time for patients surgical operations, reduces the hospitalization time of patients, improves the success rate of rescue, and reduces complications. It is recommended to popularize it in emergency department surgical nursing.展开更多
Precise identification of HIV transmission among populations is a key step in public health responses.However,the HIV transmission network is usually difficult to determine.HIV molecular networks can be determined by ...Precise identification of HIV transmission among populations is a key step in public health responses.However,the HIV transmission network is usually difficult to determine.HIV molecular networks can be determined by phylogenetic approach,genetic distance-based approach,and a combination of both approaches.These approaches are increasingly used to identify transmission networks among populations,reconstruct the history of HIV spread,monitor the dynamics of HIV transmission,guide targeted intervention on key subpopulations,and assess the effects of interventions.Simulation and retrospective studies have demonstrated that these molecular network-based interventions are more cost-effective than random or traditional interventions.However,we still need to address several challenges to improve the practice of molecular network-guided targeting interventions to finally end the HIV epidemic.The data remain limited or difficult to obtain,and more automatic real-time tools are required.In addition,molecular and social networks must be combined,and technical parameters and ethnic issues warrant further studies.展开更多
Epidemics of infectious diseases have been known to recur in time.Diseases like influenza,despite intervention efforts through vaccination and targeted social distancing,continue to persist intermittently in the popul...Epidemics of infectious diseases have been known to recur in time.Diseases like influenza,despite intervention efforts through vaccination and targeted social distancing,continue to persist intermittently in the population.I have undertaken an analysis of a stochastic epidemic model with the hypothesis that intervention drives epidemic cycles.Intervention indeed is found to induce cycles of epidemic activity.Above a minimum intervention rate,however,activity dies out in finite time.The susceptibility structure of a community could be easily infused into the design of existing surveillance protocols.By tracking that structure,early detection of an impending outbreak is enhanced.展开更多
Neutrophils have emerged as key players in tumor progression and are often associated with poor prognosis.Despite ongoing efforts to target neutrophil functions in cancer,therapeutic success has been limited.In this s...Neutrophils have emerged as key players in tumor progression and are often associated with poor prognosis.Despite ongoing efforts to target neutrophil functions in cancer,therapeutic success has been limited.In this study,we addressed the possibility of blocking STAT3 signaling in neutrophils as a targeted therapeutic intervention in cancer.Conditional deletion of Stat3 in a neutrophil-specific manner(Ly6GcreStat3fl/fl mice)significantly impaired tumor growth and metastasis in mice.Neutrophils isolated from these mice exhibited a strong antitumoral phenotype,with increased MHCII,CD80/86 and ICAM-1 expression.Immune profiling of tumors and tumor-draining lymph nodes of these mice revealed significant enrichment of CD8^(+)T cells(granzymeB^(hi),perforin^(hi) and IFN-γ^(hi))with strong cytotoxic activity.To further translate these findings to human settings,we blocked STAT3 signaling in cancer patient neutrophils via the small molecule in^(hi)bitor LLL12 and assessed its effects on patient-derived tumor explants.In agreement with the in vivo mouse data,we observed the expansion and activation of cytotoxic CD8^(+)T cells in such explants.To test the therapeutic applicability of STAT3 targeting,we utilized myeloid cell-selective STAT3 antisense oligonucleotide(CpG-STAT3ASO)to target neutrophils in vivo in tumor-bearing mice.Consistent with previous results,neutrophil-specific STAT3 knockdown impaired tumor growth and enhanced cytotoxic T cell activity in the tumors and tumor-draining lymph nodes of treated mice.These findings highlight STAT3 signaling as a deleterious pathway supporting the protumoral activity of neutrophils and suggest that neutrophil-targeted STAT3 in^(hi)bition is a promising opportunity for cancer immunotherapy,providing novel insights into targeted therapeutic avenues.展开更多
Identification of human immunodeficiency virus(HIV)transmission networks is a critical step in the public health response;however,it is challenging to achieve this through traditional epidemiological surveys alone.The...Identification of human immunodeficiency virus(HIV)transmission networks is a critical step in the public health response;however,it is challenging to achieve this through traditional epidemiological surveys alone.The molecular network approach can provide more accurate information for understanding HIV outbreaks and bring targeted interventions into reality.Based on the current global development of the concept of the molecular network,Chinese scientists have in recent years explored the applications of molecular networks for understanding the HIV-1 transmission trends,for identifying the population acquiring priority interventions,and for evaluating the targeted intervention effectiveness.In this review,we focus on research progress by Chinese scientists in the field of molecular networks and put forward some suggestions for future research of molecular networks.展开更多
Understanding the cellular origins and early evolutionary dynamics that drive the initiation of carcinogenesis is critical to advancing early detection and prevention strategies.By characterizing key molecular,cellula...Understanding the cellular origins and early evolutionary dynamics that drive the initiation of carcinogenesis is critical to advancing early detection and prevention strategies.By characterizing key molecular,cellular and niche events at the precancerous tipping point of early gastric cancer(EGC),we aimed to develop more precise screening tools and design targeted interventions to prevent malignant transformation at this stage.We utilized our AI models to integrate spatial multimodal data from nine EGC endoscopic submucosal dissection(ESD)samples(covering sequential stages from normal to cancer),construct a spatial-temporal profile of disease progression,and identify a critical tipping point(PMC_P)characterized by an immune-suppressive microenvironment during early cancer development.At this stage,inflammatory pit mucous cells with stemness(PMC_2)interact with fibroblasts via NAMPT→ITGA5/ITGB1 and with macrophages via AREG→EGFR/ERBB2 signaling,fostering cancer initiation.We established gastric precancerous cell lines and organoids to demonstrate that NAMPT and AREG promote cellular proliferation in vitro.Furthermore,in the transgenic CEA-SV40 mouse model,targeting AREG and/or NAMPT disrupted key cell interactions,inhibited the JAK-STAT,MAPK,and NFκB pathways,and reduced PD-L1 expression,which was also confirmed by western blot in vitro.These interventions delayed disease progression,reversed the immunosuppressive microenvironment,and prevented malignant transformation.Clinical validation was conducted using endoscopically resected EGC specimens.Our study provides a precise spatiotemporal depiction of EGC development and identifies novel diagnostic markers and therapeutic targets for early intervention.展开更多
文摘The initiation and progression of colorectal cancer(CRC)are profoundly influenced by the complex interplay between the gut microbiota and the immune system,underscoring the clinical importance of exploring the bidirectional regulatory mechanisms of the microbiota-immune axis within the CRC immune microenvironment.Emerging evidence indicates that the composition and functional capacity of the gut microbiota play a vital role in modulating the host’s immune responses,while the immune system,in turn,can reciprocally regulate the structure and function of the microbiota.Despite significant insights into the role of the microbiota-immune axis in CRC progression,several critical questions remain unanswered-including how microbial heterogeneity affects therapeutic outcomes and the specific consequences of dysregulated regulatory mechanisms on the immune microenvironment.This review aims to provide a comprehensive analysis of the compositional features of the CRC immune microenvironment,examine the bidirectional molecular mechanisms underpinning the microbiotaimmune axis,and evaluate the potential of targeted therapeutic strategies,thereby offering novel research perspectives and clinical applications for CRC treatment.
基金supported by the Integration Project of NSFC Joint Fund for Regional Innovation and Development(U23A6008)the Key Programme of National Natural Science Foundation of China(81930067)+2 种基金the Youth Program of National Natural Science Foundation of China(82002316)the General Program of Natural Science Foundation of Chongqing(cstc2019jcyj-msxmX0176)the China Postdoctoral Science Foundation(2021MD703946).
文摘Osteoarthritis(OA)is a progressive degenerative joint sickness related with mechanics,obesity,ageing,etc.,mainly characterized by cartilage degeneration,subchondral bone damage and synovium inflammation.Coordinated mechanical absorption and conduction of the joint play significant roles in the prevalence and development of OA.Subchondral bone is generally considered a load-burdening tissue where mechanosensitive cells are resident,including osteocytes,osteoblast lineage cells,and osteoclast lineage cells(especially less concerned in mechanical studies).Mechano-signaling imbalances affect complicated cellular events and disorders of subchondral bone homeostasis.This paper will focus on the significance of mechanical force as the pathogenesis,involvement of various mechanical force patterns in mechanosensitive cells,and mechanobiology research of loading devices in vitro and in vivo,which are further discussed.Additionally,various mechanosensing structures(e.g.,transient receptor potential channels,gap junctions,primary cilia,podosome-associated complexes,extracellular vesicles)and mechanotransduction signaling pathways(e.g.,Ca^(2+) signaling,Wnt/β-catenin,RhoA GTPase,focal adhesion kinase,cotranscriptional activators YAP/TAZ)in mechanosensitive bone cells.Finally,we highlight potential targets for improving mechanoprotection in the treatment of OA.These advances furnish an integration of mechanical regulation of subchondral bone homeostasis,as well as OA therapeutic approaches by modulating mechanical homeostasis.
文摘Background Prior randomized trials have shown reduced bleeding with bivalirudin compared with unfractionated heparin （UFH） in patients undergoing percutaneous coronary intervention （PCI）. However, it is not known if this benefit is also present when UFH doses are more tightly controlled （as measured by activated clotting time, ACT）.
文摘Background: A better understanding of the impact of Targeted Interventions (TI) services on Female Sex Worker (FSW) behaviours can help in informing and strengthening future TI efforts under National AIDS Control Programme (NACP). Methods: National Integrated Biological and Behavioural Survey (IBBS) 2014-15 has been analysed in the paper. Descriptive statistics and logistic regression analysis were used to understand factors affecting condom use. Propensity score matching (PSM) was done to understand the impact of the TI services on condom use at the last act and consistent condom use in the last three months among FSWs. Results: Younger FSWs aged 15 - 25 years were 1.4 times (95% CI: 1.04 - 1.77) more likely to use consistent condoms in the last three months compared to older over 45 years after controlling for other socio-economic and programme variables. The matched samples estimate ATET i.e. the average treatment effect on treated for consistent condom use in the last three months shows that a 6.0% (CI: 4.7 - 7.3) increase in consistent condom use in the last three months in the FSWs who received information on STI/HIV from peer educator and outreach worker. There is also a 6.0% (4.7 - 7.2) increase in condom use in the last act for FSWs who received the referral services at STI clinics, HIV testing, and detox centres. Conclusions: It is evident that the TI programme has a positive impact on behavior change among FSWs which can prove beneficial to curtail the spread of HIV to the partners and onward transmission to the general population.
文摘Objective: to explore the application of targeted nursing in postoperative treatment of esophageal cancer. Observation method: 74 patients with esophageal cancer admitted to our hospital from February 2020 to February 2021 were selected for this study. According to the "random number allocation" method, they were divided into the control group and the observation group. The control group was treated with conventional interventional therapy, and the observation group was treated with targeted care. The postoperative complications and quality of life after care were compared. Results: the incidence of complications after nursing in the observation group was lower than that in the control group to improve the nursing quality and curative effect, which is worthy of clinical promotion.
文摘Objective: to explore the hospital to family extension of NSCLC intervention after discharge.Methods: after 90 patients with NSCLC were discharged from May 2019 to June 2020, the envelopes were randomized into two groups.The routine care group gave routine care, and the continuing intervention group performed extended hospital-to-family care.The quality of survival and the rate of oral targeted drugs were compared between the two groups.Results: compared of quality of survival, rate of oral targeted drugs and routine intervention group, P <0.05. Conclusion: NSCLC patients continue to control targeted drugs after discharge from hospital, and extending hospital care to family can improve the quality of survival and improve the rate of oral targeted drugs, which is worth promoting.
文摘Objective: to analyze the application efficiency of emergency surgical nursing in trauma management. Methods: a total of 100 surgical trauma patients who were admitted to the emergency department of our hospital from July 2020 to July 2021 were selected and divided into a control group and an observation group, with 35 cases in each. The patients in the control group were given basic nursing care, while the patients in this group were observed and targeted nursing intervention in emergency surgery. The time to diagnosis, time to surgery, length of hospital stay, rescue success rate and complications were evaluated. Conclusion: after compared with the observation group, the inspection time, the time to surgery, and the time to hosp ital admission were significantly longer in the control group, and the difference between the two was statistically significant (p<0.05). In the control group, patients’survival rate of first aid was only 74.00%, obviously 96.0% of the patients in the observation group were lower, and the number of failures (deaths) was significantly higher than that of the patients in the observation group (p<0.05). The incidence of comorbidities in the control group was significantly higher than 20.00%, and significantly higher than 4.00% in the observation group (p<0.05). Conclusion: the application effect of surgical targeted nursing intervention in emergency department in trauma treatment is definite and can significantly shortens the diagnosis time of patients, buys precious time for patients surgical operations, reduces the hospitalization time of patients, improves the success rate of rescue, and reduces complications. It is recommended to popularize it in emergency department surgical nursing.
基金This work was supported in part by the Mega-Projects of the National Science Research for the 13th Five-Year Plan(No.2017ZX10201101),Innovation Team Development Program of the Ministry of Education(No.IRT_16R70)the National Natural Science Foundation of China(No.81871637)Central Publicinterest Scientific Institution Basal Research Fund(No.2018PT31042).
文摘Precise identification of HIV transmission among populations is a key step in public health responses.However,the HIV transmission network is usually difficult to determine.HIV molecular networks can be determined by phylogenetic approach,genetic distance-based approach,and a combination of both approaches.These approaches are increasingly used to identify transmission networks among populations,reconstruct the history of HIV spread,monitor the dynamics of HIV transmission,guide targeted intervention on key subpopulations,and assess the effects of interventions.Simulation and retrospective studies have demonstrated that these molecular network-based interventions are more cost-effective than random or traditional interventions.However,we still need to address several challenges to improve the practice of molecular network-guided targeting interventions to finally end the HIV epidemic.The data remain limited or difficult to obtain,and more automatic real-time tools are required.In addition,molecular and social networks must be combined,and technical parameters and ethnic issues warrant further studies.
基金support from the Ateneo Scholarly Work Grant SOSE 172012the National Research Council of the Philippines(NRCP)Grant B-108.
文摘Epidemics of infectious diseases have been known to recur in time.Diseases like influenza,despite intervention efforts through vaccination and targeted social distancing,continue to persist intermittently in the population.I have undertaken an analysis of a stochastic epidemic model with the hypothesis that intervention drives epidemic cycles.Intervention indeed is found to induce cycles of epidemic activity.Above a minimum intervention rate,however,activity dies out in finite time.The susceptibility structure of a community could be easily infused into the design of existing surveillance protocols.By tracking that structure,early detection of an impending outbreak is enhanced.
基金support from the Open Access Publication Fund of the University of Duisburg-Essensupported by the Deutsche Forschungsgemeinschaft(DFG/JA-2461/7-1)+1 种基金CRC TRR332 project A05 to JJthe Stiftung Tumorforschung Kopf-Hals to CK.
文摘Neutrophils have emerged as key players in tumor progression and are often associated with poor prognosis.Despite ongoing efforts to target neutrophil functions in cancer,therapeutic success has been limited.In this study,we addressed the possibility of blocking STAT3 signaling in neutrophils as a targeted therapeutic intervention in cancer.Conditional deletion of Stat3 in a neutrophil-specific manner(Ly6GcreStat3fl/fl mice)significantly impaired tumor growth and metastasis in mice.Neutrophils isolated from these mice exhibited a strong antitumoral phenotype,with increased MHCII,CD80/86 and ICAM-1 expression.Immune profiling of tumors and tumor-draining lymph nodes of these mice revealed significant enrichment of CD8^(+)T cells(granzymeB^(hi),perforin^(hi) and IFN-γ^(hi))with strong cytotoxic activity.To further translate these findings to human settings,we blocked STAT3 signaling in cancer patient neutrophils via the small molecule in^(hi)bitor LLL12 and assessed its effects on patient-derived tumor explants.In agreement with the in vivo mouse data,we observed the expansion and activation of cytotoxic CD8^(+)T cells in such explants.To test the therapeutic applicability of STAT3 targeting,we utilized myeloid cell-selective STAT3 antisense oligonucleotide(CpG-STAT3ASO)to target neutrophils in vivo in tumor-bearing mice.Consistent with previous results,neutrophil-specific STAT3 knockdown impaired tumor growth and enhanced cytotoxic T cell activity in the tumors and tumor-draining lymph nodes of treated mice.These findings highlight STAT3 signaling as a deleterious pathway supporting the protumoral activity of neutrophils and suggest that neutrophil-targeted STAT3 in^(hi)bition is a promising opportunity for cancer immunotherapy,providing novel insights into targeted therapeutic avenues.
基金This work was supported by Mega-Projects of National Science Research for the 13th Five-Year Plan(2018ZX10721102)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-027)。
文摘Identification of human immunodeficiency virus(HIV)transmission networks is a critical step in the public health response;however,it is challenging to achieve this through traditional epidemiological surveys alone.The molecular network approach can provide more accurate information for understanding HIV outbreaks and bring targeted interventions into reality.Based on the current global development of the concept of the molecular network,Chinese scientists have in recent years explored the applications of molecular networks for understanding the HIV-1 transmission trends,for identifying the population acquiring priority interventions,and for evaluating the targeted intervention effectiveness.In this review,we focus on research progress by Chinese scientists in the field of molecular networks and put forward some suggestions for future research of molecular networks.
基金supported by Shanghai Oriental Talent Youth Program(QNKJ2024006)National Natural Science Foundation of China(82170555,32300523,32570769,and 62132015)+1 种基金Shanghai Academic/Technology Research Leader(22XD1422400)Shuguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission(22SG06).
文摘Understanding the cellular origins and early evolutionary dynamics that drive the initiation of carcinogenesis is critical to advancing early detection and prevention strategies.By characterizing key molecular,cellular and niche events at the precancerous tipping point of early gastric cancer(EGC),we aimed to develop more precise screening tools and design targeted interventions to prevent malignant transformation at this stage.We utilized our AI models to integrate spatial multimodal data from nine EGC endoscopic submucosal dissection(ESD)samples(covering sequential stages from normal to cancer),construct a spatial-temporal profile of disease progression,and identify a critical tipping point(PMC_P)characterized by an immune-suppressive microenvironment during early cancer development.At this stage,inflammatory pit mucous cells with stemness(PMC_2)interact with fibroblasts via NAMPT→ITGA5/ITGB1 and with macrophages via AREG→EGFR/ERBB2 signaling,fostering cancer initiation.We established gastric precancerous cell lines and organoids to demonstrate that NAMPT and AREG promote cellular proliferation in vitro.Furthermore,in the transgenic CEA-SV40 mouse model,targeting AREG and/or NAMPT disrupted key cell interactions,inhibited the JAK-STAT,MAPK,and NFκB pathways,and reduced PD-L1 expression,which was also confirmed by western blot in vitro.These interventions delayed disease progression,reversed the immunosuppressive microenvironment,and prevented malignant transformation.Clinical validation was conducted using endoscopically resected EGC specimens.Our study provides a precise spatiotemporal depiction of EGC development and identifies novel diagnostic markers and therapeutic targets for early intervention.
