Objective:Pancreatic ductal adenocarcinoma(PDAC)is a deadly malignancy,due in large part to its resistance to conventional therapies,including radiotherapy(RT).Despite RT exerting a modest antitumor response,it has al...Objective:Pancreatic ductal adenocarcinoma(PDAC)is a deadly malignancy,due in large part to its resistance to conventional therapies,including radiotherapy(RT).Despite RT exerting a modest antitumor response,it has also been shown to promote an immunosuppressive tumor microenvironment.Previous studies demonstrated that focal adhesion kinase inhibitors(FAKi)in clinical development inhibit the infiltration of suppressive myeloid cells and T regulatory(T regs)cells,and subsequently enhance effector T cell infiltration.FAK inhibitors in clinical development have not been investigated in combination with RT in preclinical murine models or clinical studies.Thus,we investigated the impact of FAK inhibition on RT,its potential as an RT sensitizer and immunomodulator in a murine model of PDAC.Methods:We used a syngeneic orthotopic murine model to study the effect of FAKi on hypofractionated RT.Results:In this study we showed that IN10018,a small molecular FAKi,enhanced antitumor response to RT.Antitumor activity of the combination of FAKi and RT is T cell dependent.FAKi in combination with RT enhanced CD8+T cell infiltration significantly in comparison to the radiation or FAKi treatment alone(P<0.05).FAKi in combination with radiation inhibited the infiltration of granulocytes but enhanced the infiltration of macrophages and T regs in comparison with the radiation or FAKi treatment alone(P<0.01).Conclusions:These results support the clinical development of FAKi as a radiosensitizer for PDAC and combining FAKi with RT to prime the tumor microenvironment of PDAC for immunotherapy.展开更多
The altered lysosomal function can induce drug redistribution which leads to drug resistance and poor prognosis for cancer patients.V-ATPase,an ATP-driven proton pump positioned at lysosomal surfaces,is responsible fo...The altered lysosomal function can induce drug redistribution which leads to drug resistance and poor prognosis for cancer patients.V-ATPase,an ATP-driven proton pump positioned at lysosomal surfaces,is responsible for maintaining the stability of lysosome.Herein,we reported that the potassium voltage-gated channel subfamily J member 15(KCNJ15)protein,which may bind to V-ATPase,can regulate the function of lysosome.The deficiency of KCNJ15 protein in breast cancer cells led to drug aggregation as well as reduction of drug efficacy.The application of the V-ATPase inhibitor could inhibit the binding between KCNJ15 and V-ATPase,contributing to the amelioration of drug resistance.Clinical data analysis revealed that KCNJ15 deficiency was associated with higher histological grading,advanced stages,more metastases of lymph nodes,and shorter disease free survival of patients with breast cancer.KCNJ15 expression level is positively correlated with a high response rate after receiving neoadjuvant chemotherapy.Moreover,we revealed that the small molecule drug CMA/BAF can reverse drug resistance by disrupting the interaction between KCNJ15 and lysosomes.In conclusion,KCNJ15 could be identified as an underlying indicator for drug resistance and survival of breast cancer,which might guide the choice of therapeutic strategies.展开更多
Background: Laying sequence has important effects on eggshell color and embryonic development in birds. Some birds can allocate resources unevenly among the eggs within a clutch, prioritizing those at the beginning of...Background: Laying sequence has important effects on eggshell color and embryonic development in birds. Some birds can allocate resources unevenly among the eggs within a clutch, prioritizing those at the beginning of the laying sequence, in order to maximize reproductive success. The changes in egg color according to laying sequence may be an adaptation to pressure from predators or brood parasites.Methods: In this study, effects of laying sequence on egg color and embryonic heart rate in Russet Sparrows(Passer cinnamomeus) were investigated using artificial nest boxes. The eggs were divided into three groups: first to be laid, intermediate in the laying sequence, and last to be laid. We maintained the eggs in an incubator and measured embryonic heart rates.Results: Avian visual modeling showed that the background color brightness of the last eggs laid was significantly higher(whiter) than those of the other eggs. All eggs were about the same size and hatched around 13 days, indicating that laying sequence significantly affected embryonic development speed; the last eggs to be laid developed significantly faster than did the first in the clutch.Conclusions: Our study quantified the effect of laying sequence on egg color variation and proved that laying sequence has an important effect on embryonic heart rate in Russet Sparrows.展开更多
Object Constraint Language(OCL)is one kind of lightweight formal specification,which is widely used for software verification and validation in NASA and Object Management Group projects.Although OCL provides a simple ...Object Constraint Language(OCL)is one kind of lightweight formal specification,which is widely used for software verification and validation in NASA and Object Management Group projects.Although OCL provides a simple expressive syntax,it is hard for the developers to write correctly due to lacking knowledge of the mathematical foundations of the first-order logic,which is approximately half accurate at the first stage of devel-opment.A deep neural network named DeepOCL is proposed,which takes the unre-stricted natural language as inputs and automatically outputs the best-scored OCL candidates without requiring a domain conceptual model that is compulsively required in existing rule-based generation approaches.To demonstrate the validity of our proposed approach,ablation experiments were conducted on a new sentence-aligned dataset named OCLPairs.The experiments show that the proposed DeepOCL can achieve state of the art for OCL statement generation,scored 74.30 on BLEU,and greatly outperformed experienced developers by 35.19%.The proposed approach is the first deep learning approach to generate the OCL expression from the natural language.It can be further developed as a CASE tool for the software industry.展开更多
Combined sewer overflows represent significant risks to human health as untreated water is discharged to the environment.Municipalities,such as the Metropolitan Sewer District of Greater Cincinnati(MSDGC),recently beg...Combined sewer overflows represent significant risks to human health as untreated water is discharged to the environment.Municipalities,such as the Metropolitan Sewer District of Greater Cincinnati(MSDGC),recently began collecting large amounts of water-related data and considering the adoption of deep learning(DL)solutions like recurrent neural network(RNN)for predicting overflow events.Clearly,assessing the DL's fitness for the purpose requires a systematic understanding of the problem context.In this study,we propose a requirements engineering framework that uses the problem frames to identify and structure the stakeholder concerns,analyses the physical situations in which the highquality data assumptions may not hold,and derives the software testing criteria in the form of metamorphic relations that incorporate both input transformations and output comparisons.Applying our framework to MSDGC's overflow prediction problem enables a principled way to evaluate different RNN solutions in meeting the requirements.展开更多
Erratum to:SCIENCE CHINA Life Sciences,Volume 66,Issue 12:2805-2817(2023),https://doi.org/10.1007/s11427-023-2343-y.This paper contains errors in Figure 1B and Figure 5A,where the representative images of immunohistoc...Erratum to:SCIENCE CHINA Life Sciences,Volume 66,Issue 12:2805-2817(2023),https://doi.org/10.1007/s11427-023-2343-y.This paper contains errors in Figure 1B and Figure 5A,where the representative images of immunohistochemical staining of FSIP1 in TNBC tissues and Western blot band of Nanog in 231-WT and 231-F KO cells were misused.展开更多
CDK4/6 inhibitors are routinely recommended agents for the treatment of advanced HR+HER2-breast cancer.However,their therapeutic effectiveness in triple-negative breast cancer(TNBC)remains controversial.Here,we observ...CDK4/6 inhibitors are routinely recommended agents for the treatment of advanced HR+HER2-breast cancer.However,their therapeutic effectiveness in triple-negative breast cancer(TNBC)remains controversial.Here,we observed that the expression level of fibrous sheath interacting protein 1(FSIP1)could predict the treatment response of TNBC to CDK4/6 inhibitors.High FSIP1 expression level was related to a poor prognosis in TNBC,which was associated with the ability of FSIP1 to promote tumor cell proliferation.FSIP1 downregulation led to slowed tumor growth and reduced lung metastasis in TNBC.FSIP1knockout caused cell cycle arrest at the G0/G1 phase and reduced treatment sensitivity to CDK4/6 inhibitors by inactivating the Nanog/CCND1/CDK4/6 pathway.FSIP1 could form a complex with Nanog,protecting it from ubiquitination and degradation,which may facilitate the rapid cell cycle transition from G0/G1 to S phase and exhibit enhanced sensitivity to CDK4/6 inhibitors.Our findings suggest that TNBC patients with high FSIP1 expression levels may be suitable candidates for CDK4/6 inhibitor treatment.展开更多
Significant heterogeneity exists in hormone receptor(HR)-positive/HER2-positive(HR+/HER2+)breast cancer,contributing to suboptimal pathological complete response rates with conventional neoadjuvant treatment regimens....Significant heterogeneity exists in hormone receptor(HR)-positive/HER2-positive(HR+/HER2+)breast cancer,contributing to suboptimal pathological complete response rates with conventional neoadjuvant treatment regimens.Overcoming this challenge requires precise molecular classification,which is pivotal for the development of targeted therapies.We conducted molecular typing on a cohort of 211 patients with HR^(+)/HER2^(+) breast cancer and performed a comprehensive analysis of the efficacy of various neoadjuvant treatment regimens.Our findings revealed four distinct molecular subtypes,each exhibiting unique characteristics and therapeutic implications.The HER2-enriched subtype,marked by activation of the HER2 signaling and hypoxiainducible factor 1(HIF-1)pathway,may benefit from intensified anti-HER2-targeted therapy.Estrogen receptor(ER)-activated subtype demonstrated potential sensitivity to combined therapeutic strategies targeting both ER and HER2 pathways.Characterized by high immune cell infiltration,the immunomodulatory subtype showed sensitivity to HER2-targeted antibody-drug conjugates(ADCs)and promise for immune checkpoint therapy.The highly heterogeneous subtype requires a multifaceted therapeutic approach.Organoid susceptibility assays suggested phosphoinositide 3-kinase inhibitors may be a potential treatment option.These findings underscore the importance of molecular subtyping in HR^(+)/HER2^(+) breast cancer,offering a framework for developing precise and personalized treatment strategies.By addressing the heterogeneity of the disease,these approaches have the potential to optimize therapeutic outcomes and improve patient care.展开更多
文摘Objective:Pancreatic ductal adenocarcinoma(PDAC)is a deadly malignancy,due in large part to its resistance to conventional therapies,including radiotherapy(RT).Despite RT exerting a modest antitumor response,it has also been shown to promote an immunosuppressive tumor microenvironment.Previous studies demonstrated that focal adhesion kinase inhibitors(FAKi)in clinical development inhibit the infiltration of suppressive myeloid cells and T regulatory(T regs)cells,and subsequently enhance effector T cell infiltration.FAK inhibitors in clinical development have not been investigated in combination with RT in preclinical murine models or clinical studies.Thus,we investigated the impact of FAK inhibition on RT,its potential as an RT sensitizer and immunomodulator in a murine model of PDAC.Methods:We used a syngeneic orthotopic murine model to study the effect of FAKi on hypofractionated RT.Results:In this study we showed that IN10018,a small molecular FAKi,enhanced antitumor response to RT.Antitumor activity of the combination of FAKi and RT is T cell dependent.FAKi in combination with RT enhanced CD8+T cell infiltration significantly in comparison to the radiation or FAKi treatment alone(P<0.05).FAKi in combination with radiation inhibited the infiltration of granulocytes but enhanced the infiltration of macrophages and T regs in comparison with the radiation or FAKi treatment alone(P<0.01).Conclusions:These results support the clinical development of FAKi as a radiosensitizer for PDAC and combining FAKi with RT to prime the tumor microenvironment of PDAC for immunotherapy.
基金supported by the National Natural Science Foundation of China(#81872159,#81902607,and#81874301)the Liaoning Colleges Innovative Talent Support Program(#Cancer Stem Cell Origin and Biology Behavior)+2 种基金the Major Project Construction Foundation of China Medical University(#2017ZDZX05)the Outstanding Scientific Fund of Shengjing Hospital(#201803)the Outstanding Young Scholars of Liaoning Province(#2019-YQ-10).
文摘The altered lysosomal function can induce drug redistribution which leads to drug resistance and poor prognosis for cancer patients.V-ATPase,an ATP-driven proton pump positioned at lysosomal surfaces,is responsible for maintaining the stability of lysosome.Herein,we reported that the potassium voltage-gated channel subfamily J member 15(KCNJ15)protein,which may bind to V-ATPase,can regulate the function of lysosome.The deficiency of KCNJ15 protein in breast cancer cells led to drug aggregation as well as reduction of drug efficacy.The application of the V-ATPase inhibitor could inhibit the binding between KCNJ15 and V-ATPase,contributing to the amelioration of drug resistance.Clinical data analysis revealed that KCNJ15 deficiency was associated with higher histological grading,advanced stages,more metastases of lymph nodes,and shorter disease free survival of patients with breast cancer.KCNJ15 expression level is positively correlated with a high response rate after receiving neoadjuvant chemotherapy.Moreover,we revealed that the small molecule drug CMA/BAF can reverse drug resistance by disrupting the interaction between KCNJ15 and lysosomes.In conclusion,KCNJ15 could be identified as an underlying indicator for drug resistance and survival of breast cancer,which might guide the choice of therapeutic strategies.
基金supported by the National Natural Science Foundation of China(No.31672303 to CY,and 31772453 to WL)
文摘Background: Laying sequence has important effects on eggshell color and embryonic development in birds. Some birds can allocate resources unevenly among the eggs within a clutch, prioritizing those at the beginning of the laying sequence, in order to maximize reproductive success. The changes in egg color according to laying sequence may be an adaptation to pressure from predators or brood parasites.Methods: In this study, effects of laying sequence on egg color and embryonic heart rate in Russet Sparrows(Passer cinnamomeus) were investigated using artificial nest boxes. The eggs were divided into three groups: first to be laid, intermediate in the laying sequence, and last to be laid. We maintained the eggs in an incubator and measured embryonic heart rates.Results: Avian visual modeling showed that the background color brightness of the last eggs laid was significantly higher(whiter) than those of the other eggs. All eggs were about the same size and hatched around 13 days, indicating that laying sequence significantly affected embryonic development speed; the last eggs to be laid developed significantly faster than did the first in the clutch.Conclusions: Our study quantified the effect of laying sequence on egg color variation and proved that laying sequence has an important effect on embryonic heart rate in Russet Sparrows.
基金The National Key Research and Development Program of China,Grant/Award Number:2021YFB2501301。
文摘Object Constraint Language(OCL)is one kind of lightweight formal specification,which is widely used for software verification and validation in NASA and Object Management Group projects.Although OCL provides a simple expressive syntax,it is hard for the developers to write correctly due to lacking knowledge of the mathematical foundations of the first-order logic,which is approximately half accurate at the first stage of devel-opment.A deep neural network named DeepOCL is proposed,which takes the unre-stricted natural language as inputs and automatically outputs the best-scored OCL candidates without requiring a domain conceptual model that is compulsively required in existing rule-based generation approaches.To demonstrate the validity of our proposed approach,ablation experiments were conducted on a new sentence-aligned dataset named OCLPairs.The experiments show that the proposed DeepOCL can achieve state of the art for OCL statement generation,scored 74.30 on BLEU,and greatly outperformed experienced developers by 35.19%.The proposed approach is the first deep learning approach to generate the OCL expression from the natural language.It can be further developed as a CASE tool for the software industry.
基金the National Natural Science Foundation of China,Grant/Award Number:62177003。
文摘Combined sewer overflows represent significant risks to human health as untreated water is discharged to the environment.Municipalities,such as the Metropolitan Sewer District of Greater Cincinnati(MSDGC),recently began collecting large amounts of water-related data and considering the adoption of deep learning(DL)solutions like recurrent neural network(RNN)for predicting overflow events.Clearly,assessing the DL's fitness for the purpose requires a systematic understanding of the problem context.In this study,we propose a requirements engineering framework that uses the problem frames to identify and structure the stakeholder concerns,analyses the physical situations in which the highquality data assumptions may not hold,and derives the software testing criteria in the form of metamorphic relations that incorporate both input transformations and output comparisons.Applying our framework to MSDGC's overflow prediction problem enables a principled way to evaluate different RNN solutions in meeting the requirements.
文摘Erratum to:SCIENCE CHINA Life Sciences,Volume 66,Issue 12:2805-2817(2023),https://doi.org/10.1007/s11427-023-2343-y.This paper contains errors in Figure 1B and Figure 5A,where the representative images of immunohistochemical staining of FSIP1 in TNBC tissues and Western blot band of Nanog in 231-WT and 231-F KO cells were misused.
基金supported by the National Natural Science Foundation of China (82203804,81872159)345 Talent Project of Shengjing Hospital of China Medical University。
文摘CDK4/6 inhibitors are routinely recommended agents for the treatment of advanced HR+HER2-breast cancer.However,their therapeutic effectiveness in triple-negative breast cancer(TNBC)remains controversial.Here,we observed that the expression level of fibrous sheath interacting protein 1(FSIP1)could predict the treatment response of TNBC to CDK4/6 inhibitors.High FSIP1 expression level was related to a poor prognosis in TNBC,which was associated with the ability of FSIP1 to promote tumor cell proliferation.FSIP1 downregulation led to slowed tumor growth and reduced lung metastasis in TNBC.FSIP1knockout caused cell cycle arrest at the G0/G1 phase and reduced treatment sensitivity to CDK4/6 inhibitors by inactivating the Nanog/CCND1/CDK4/6 pathway.FSIP1 could form a complex with Nanog,protecting it from ubiquitination and degradation,which may facilitate the rapid cell cycle transition from G0/G1 to S phase and exhibit enhanced sensitivity to CDK4/6 inhibitors.Our findings suggest that TNBC patients with high FSIP1 expression levels may be suitable candidates for CDK4/6 inhibitor treatment.
基金supported by the National Natural ScienceFoundation of China(Grant Nos.U20A20381,82203804,82403918)the National Natural ScienceFoundation of Liaoning Province(Grant No.2024-MS-053)China Medical Education Association Subject(2016001).
文摘Significant heterogeneity exists in hormone receptor(HR)-positive/HER2-positive(HR+/HER2+)breast cancer,contributing to suboptimal pathological complete response rates with conventional neoadjuvant treatment regimens.Overcoming this challenge requires precise molecular classification,which is pivotal for the development of targeted therapies.We conducted molecular typing on a cohort of 211 patients with HR^(+)/HER2^(+) breast cancer and performed a comprehensive analysis of the efficacy of various neoadjuvant treatment regimens.Our findings revealed four distinct molecular subtypes,each exhibiting unique characteristics and therapeutic implications.The HER2-enriched subtype,marked by activation of the HER2 signaling and hypoxiainducible factor 1(HIF-1)pathway,may benefit from intensified anti-HER2-targeted therapy.Estrogen receptor(ER)-activated subtype demonstrated potential sensitivity to combined therapeutic strategies targeting both ER and HER2 pathways.Characterized by high immune cell infiltration,the immunomodulatory subtype showed sensitivity to HER2-targeted antibody-drug conjugates(ADCs)and promise for immune checkpoint therapy.The highly heterogeneous subtype requires a multifaceted therapeutic approach.Organoid susceptibility assays suggested phosphoinositide 3-kinase inhibitors may be a potential treatment option.These findings underscore the importance of molecular subtyping in HR^(+)/HER2^(+) breast cancer,offering a framework for developing precise and personalized treatment strategies.By addressing the heterogeneity of the disease,these approaches have the potential to optimize therapeutic outcomes and improve patient care.
