AIM： To investigate the mechanisms of sulfasalazine （SASP） in the treatment of ulcerative colitis （UC）.METHODS： Changes of pathological signs and histological grading of 106 patients with active UC were observed...AIM： To investigate the mechanisms of sulfasalazine （SASP） in the treatment of ulcerative colitis （UC）.METHODS： Changes of pathological signs and histological grading of 106 patients with active UC were observed before and after the treatment with SASP, 1 g, thrice daily for 6 wk.RESULTS： The effect of SASP on the vasculitis in lamina propria was 48.2% and 17.4% in the mild active UC （P〈0.001） and 68% and 26.7% in the moderate active UC （P〈0.001） before and after treatment, Fibroid necrosis of vessel wail was found in one case of mild UC and two cases of moderate UC before treatment and was not found after treatment, No thrombosis was found in mild UC before and after treatment, while thrombosis was found in one case of moderate UC before treatment, The effect on mucosal glandular abnormality was 30.4% and 13.0% in mild UC （P〈0.05）, and 42% and 40% in moderate UC （P〉0.05） before and after treatment, The rate of eosinophil infiltration was 98.2% and 80,4% in mild UC （P〈0.01）,and 100% and 91,1% in moderate UC （P〈0.05） before and after treatment, The effect on crypt abscess was 21.4% and 4.4% in mild UC （P〈0.05）, and 48% and 13.3% in moderate UC （P〈0.001） before and after treatment. The effect on mucosal pathohistological grading was 2.00±0.84 and 0.91±0.46 in mild UC （P〈0.001）, and 2.49±0.84 and 1.31±0.75 in moderate UC （P〈0.001） before and after treatment.CONCLUSION： SASP can improve small vessel lesions and crypt abscesses and reduce neutrophilic and eosinophilic leukocyte infiltration in inflammatory mucosa of UC.展开更多
Conversational large language models(LLMs)such as ChatGPT and GPT-4 have recently exhibited remarkable capabilities across various domains,capturing widespread attention from the public.To facilitate this line of rese...Conversational large language models(LLMs)such as ChatGPT and GPT-4 have recently exhibited remarkable capabilities across various domains,capturing widespread attention from the public.To facilitate this line of research,in this paper,we report the development of MOSS,an open-sourced conversational LLM that contains 16 B parameters and can perform a variety of instructions in multi-turn interactions with humans.The base model of MOSS is pre-trained on large-scale unlabeled English,Chinese,and code data.To optimize the model for dialogue,we generate 1.1 M synthetic conversations based on user prompts collected through our earlier versions of the model API.We then perform preference-aware training on preference data annotated from AI feedback.Evaluation results on real-world use cases and academic benchmarks demonstrate the effectiveness of the proposed approaches.In addition,we present an effective practice to augment MOSS with several external tools.Through the development of MOSS,we have established a complete technical roadmap for large language models from pre-training,supervised fine-tuning to alignment,verifying the feasibility of chatGPT under resource-limited conditions and providing a reference for both the academic and industrial communities.Model weights and code are publicly available at https://github.com/OpenMOSS/MOSS.展开更多
The aqueous two-phase system(ATPS)is an all-aqueous system fabricated from two immiscible aqueous phases.It is spontaneously assembled through physical liquid-liquid phase separation(LLPS)and can create suitable templ...The aqueous two-phase system(ATPS)is an all-aqueous system fabricated from two immiscible aqueous phases.It is spontaneously assembled through physical liquid-liquid phase separation(LLPS)and can create suitable templates like the multicompartment of the intracellular environment.Delicate structures containing multiple compartments make it possible to endow materials with advanced functions.Due to the properties of ATPSs,ATPS-based drug delivery systems exhibit excellent biocompatibility,extraordinary loading efficiency,and intelligently controlled content release,which are particularly advantageous for delivering drugs in vivo.Therefore,we will systematically review and evaluate ATPSs as an ideal drug delivery system.Based on the basic mechanisms and influencing factors in forming ATPSs,the transformation of ATPSs into valuable biomaterials is described.Afterward,we concentrate on the most recent cutting-edge research on ATPS-based delivery systems.Finally,the potential for further collaborations between ATPS-based drug-carrying biomaterials and disease diagnosis and treatment is also explored.展开更多
Van Hove singularities in proximity to the Fermi level promote electronic interactions and generate diverse competing instabilities.It is also known that a nontrivial Berry phase derived from spin–orbit coupling can ...Van Hove singularities in proximity to the Fermi level promote electronic interactions and generate diverse competing instabilities.It is also known that a nontrivial Berry phase derived from spin–orbit coupling can introduce an intriguing decoration into the interactions and thus alter correlated phenomena.However,it is unclear how and what type of new physics can emerge in a system featured by the interplay between van Hove singularities(VHSs)and the Berry phase.Here,based on a general Rashba model on the square lattice,we comprehensively explore such an interplay and its significant influence on the competing electronic instabilities by performing a parquet renormalization group analysis.Despite the existence of a variety of comparable fluctuations in the particle–particle and particle-hole channels associated with higher-order VHSs,we find that the chiral p±ip pairings emerge as two stable fixed trajectories within the generic interaction parameter space,namely the system becomes a robust topological superconductor.The chiral pairings stem from the hopping interaction induced by the nontrivial Berry phase.The possible experimental realization and implications are discussed.Our work sheds new light on the correlated states in quantum materials with strong spin–orbit coupling(SOC)and offers fresh insights into the exploration of topological superconductivity.展开更多
FRMD6,a member of the 4.1 ezrin-radixin-moesin domain-containing protein family,has been reported to inhibit tumor progression in multiple cancers.Here,we demonstrate the involvement of FRMD6 in lung cancer progressio...FRMD6,a member of the 4.1 ezrin-radixin-moesin domain-containing protein family,has been reported to inhibit tumor progression in multiple cancers.Here,we demonstrate the involvement of FRMD6 in lung cancer progression.We find that FRMD6 is overexpressed in lung cancer tissues relative to in normal lung tissues.In addition,the enhanced expression of FRMD6 is associated with poor outcomes in patients with lung squamous cell carcinoma(n=75,P=0.0054)and lung adenocarcinoma(n=94,P=0.0330).Cell migration and proliferation in vitro and tumor formation in vivo are promoted by FRMD6 but are suppressed by the depletion of FRMD6.Mechanistically,FRMD6 interacts and colocalizes with mTOR and S6K,which are the key molecules of the mTOR signaling pathway.FRMD6 markedly enhances the interaction between mTOR and S6K,subsequently increasing the levels of endogenous pS6K and downstream pS6 in lung cancer cells.Furthermore,knocking out FRMD6 inhibits the activation of the mTOR signaling pathway in Frmd6^(−/−)gene KO MEFs and mice.Altogether,our results show that FRMD6 contributes to lung cancer progression by activating the mTOR signaling pathway.展开更多
Kindlin-2, an integrin-interacting protein, regulates breast cancer progression. However, currently, no animal model to study the role of Kindlin-2 in the carcinogenesis of mammary gland is available. We established a...Kindlin-2, an integrin-interacting protein, regulates breast cancer progression. However, currently, no animal model to study the role of Kindlin-2 in the carcinogenesis of mammary gland is available. We established a Kindlin-2 transgenic mouse model using a mammary gland-specific promoter, mammary tumor virus(MMTV) long terminal repeat(LTR). Kindlin-2 was overexpressed in the epithelial cells of the transgenic mice. The mammary gland ductal trees were found to grow faster in MMTV-Kindlin-2 transgenic mice than in control mice during puberty. Kindlin-2 promoted mammary gland growth as indicated by more numerous duct branches and larger lumens, and more alveoli were formed in the mammary glands during pregnancy under Kindlin-2 overexpression. Importantly, mammary gland-specific expression of Kindlin-2 induced tumor formation at the age of 55 weeks on average. Additionally, the levels of estrogen receptor and progesterone receptor were decreased, whereas human epidermal growth factor receptor 2 and β-catenin were upregulated in the Kindlin-2-induced mammary tumors. These findings demonstrated that Kindlin-2 induces mammary tumor formation via activation of the Wnt signaling pathway.展开更多
The cyclic oxidation behavior of Hf/Y-doped B2 FeAl intermetallics at 1373 K was investigated.For an undoped FeAl alloy,premature spallation of the alumina film occurs due to the formation of numerous voids at the fil...The cyclic oxidation behavior of Hf/Y-doped B2 FeAl intermetallics at 1373 K was investigated.For an undoped FeAl alloy,premature spallation of the alumina film occurs due to the formation of numerous voids at the film/alloy interface and apparent shrinkage in the film.In contrast to this,doping with either Hf or Y significantly improves the interfacial adhesion between the alumina film and the alloy substrate,particularly with Hf-doping.Microstructural observation in combination with Anger electron spectroscopic analysis suggests that in addition to prohibiting interfacial void formation and alleviating film shrinkage,the addition of Hf in the FeAl alloy could consolidate the film/alloy interface by directly participating in chemical bonding across the interface as a Hf ion.This causes the spallation of alumina film from the equiaxed grains/columnar grains interface rather than the bottom of the film.展开更多
Basal-like breast cancer with a luminal progenitor gene expression profile is an aggressive subtype of breast cancer with a poorer prognosis compared with other subtypes.However,genes that specifically promote basal-l...Basal-like breast cancer with a luminal progenitor gene expression profile is an aggressive subtype of breast cancer with a poorer prognosis compared with other subtypes.However,genes that specifically promote basal-like breast cancer development remain largely unknown.Here,we report that a novel gene C1orf106 plays an important role in maintaining the feature of basal-like/luminal progenitors.C1orf106 is frequently amplified and overexpressed in basal-like breast cancer and is associated with a poor outcome in patients.In human TCGA database,C1orf106 expression was correlated with upregulation of ELF5 and downregulation of GATA3,two transcription factors that regulate mammary gland stem cell fate.Enhanced expression of C1orf106 promotes tumor progression and expression of basal-like/luminal progenitor marker ELF5;depletion of C1orf106 suppresses tumorigenesis and expression of basal-like/luminal progenitor marker GATA3.These findings suggest that C1orf106 maintains the basal-like/luminal progenitor character through balancing the expression of ELF5 and GATA3.Taken together,we demonstrated that C1orf106 is an important regulator for basal-like/luminal progenitors and targeting C1orf106 is of therapeutic value for breast cancer.展开更多
LGR6 is a member of the G protein-coupled receptor family that plays a tumor-suppressive role in colon cancer. However, the relationship between LGR6 expression in patients and clinicopathological factors remains uncl...LGR6 is a member of the G protein-coupled receptor family that plays a tumor-suppressive role in colon cancer. However, the relationship between LGR6 expression in patients and clinicopathological factors remains unclear. This study aimed to clarify whether the expression level of LGR6 is correlated with colon adenocarcinoma progression. Immunohistochemistry was used to detect LGR6 expression in colon adenoma tissues (n = 21), colon adenocarcinoma tissues (n = 156), and adjacent normal tissues (n = 124). The expression levels of LGR6 in colon adenoma and adenocarcinoma were significantly higher than those in normal colon epithelial tissues (P < 0.001). Low LGR6 expression predicted a short overall survival in patients with colon adenocarcinoma (log-rank test, P = 0.016). Univariate and multivariate survival analyses showed that, in addition to N and M classification, LGR6 expression served as an independent prognostic factor. Thus, low expression of LGR6 can be used as an independent prognostic parameter in patients with colon adenocarcinoma.展开更多
Large tumor suppressor 1(LATS1)is the key kinase controlling activation of Hippo signalling pathway.Post-translational modifications of LATS1 modulate its kinase activity.However,detailed mechanism underlying LATS1 st...Large tumor suppressor 1(LATS1)is the key kinase controlling activation of Hippo signalling pathway.Post-translational modifications of LATS1 modulate its kinase activity.However,detailed mechanism underlying LATS1 stability and activation remains elusive.Here we report that LATS1 is acetylated by acetyltransferase CBP at K751 and is deacetylated by deacetylases SIRT3 and SIRT4.Acetylation at K751 stabilized LATS1 by decreasing LATS1 ubiquitination and inhibited LATS1 activation by reducing its phosphorylation.Mechanistically,LATS1 acetylation resulted in inhibition of YAP phosphorylation and degradation,leading to increased YAP nucleus translocation and promoted target gene expression.Functionally,LATS1-K751 Q,the acetylation mimic mutant potentiated lung cancer cell migration,invasion and tumor growth,whereas LATS1-K751 R,the acetylation deficient mutant inhibited these functions.Taken together,we demonstrated a previously unidentified post-translational modification of LATS1 that converts LATS1 from a tumor suppressor to a tumor promoter by suppression of Hippo signalling through acetylation of LATS1.展开更多
Background:Fascin is crucial for cancer cell filopodium formation and tumor metastasis,and is functionally regulated by post-translational modifications.However,whether and how Fascin is regulated by acetylation remai...Background:Fascin is crucial for cancer cell filopodium formation and tumor metastasis,and is functionally regulated by post-translational modifications.However,whether and how Fascin is regulated by acetylation remains unclear.This study explored the regulation of Fascin acetylation and its corresponding roles in filopodium formation and tumor metastasis.Methods:Immunoprecipitation and glutathione-S-transferase pull-down assays were performed to examine the interaction between Fascin and acetyltransferase P300/CBP-associated factor(PCAF),and immunofluorescence was used to investigate their colocalization.An in vitro acetylation assay was performed to identify Fascin acetylation sites by using mass spectrometry.A specific antibody against acetylated Fascin was generated and used to detect the PCAF-mediated Fascin acetylation in esophageal squamous cell carcinoma(ESCC)cells using Western blotting by overexpressing and knocking down PCAF expression.An in vitro cell migration assay was performed,and a xenograft model was established to study in vivo tumor metastasis.Live-cell imaging and fluorescence recovery after photobleaching were used to evaluate the function and dynamics of acetylated Fascin in filopodium formation.The clinical significance of acetylated Fascin and PCAF in ESCC was evaluated using immunohistochemistry.Results:Fascin directly interacted and colocalized with PCAF in the cytoplasm and was acetylated at lysine 471(K471)by PCAF.Using the specific antiAcK471-Fascin antibody,Fascin was found to be acetylated in ESCC cells,and the acetylation level was consequently increased after PCAF overexpression and decreased after PCAF knockdown.Functionally,Fascin-K471 acetylation markedly suppressed in vitro ESCC cell migration and in vivo tumor metastasis,whereas Fascin-K471 deacetylation exhibited a potent oncogenic function.Moreover,Fascin-K471 acetylation reduced filopodial length and density,and lifespan of ESCC cells,while its deacetylation produced the opposite effect.In the filipodium shaft,K471-acetylated Fascin displayed rapid dynamic exchange,suggesting that it remained in its monomeric form owing to its weakened actinbundling activity.Clinically,high levels of AcK471-Fascin in ESCC tissues were strongly associated with prolonged overall survival and disease-free survival of ESCC patients.Conclusions:Fascin interacts directly with PCAF and is acetylated at lysine 471 in ESCC cells.Fascin-K471 acetylation suppressed ESCC cell migration and tumor metastasis by reducing filopodium formation through the impairment of its actin-bundling activity.展开更多
Esophageal cancer （EC） is one of the most lethal malignancies in China, but the etiology and risk factors remain unclear. The integrin-interacting proteins Kindlin-1 and Kindlin-2 are focal adhesion molecules that a...Esophageal cancer （EC） is one of the most lethal malignancies in China, but the etiology and risk factors remain unclear. The integrin-interacting proteins Kindlin-1 and Kindlin-2 are focal adhesion molecules that activate transmembrane receptor integrins and regulate tumor cell growth, invasion, and metastasis. Here, we report that Kindlin-1 and Kindlin-2 are differentially expressed among Chinese EC patients. For this, Kindlin-1 and Kindlin-2 expression was evaluated in 220 EC patients by immunohistochemistry （IHC） and found to be correlated with the EC progression, along with a variety of epidemiologic parameters, including smoking, family EC history, and EC invasion status. Moreover, data downloaded from the Oncomine database revealed that both Kindlin- 1 and Kindlin-2 were upregulated in ECs compared with normal esophageal tissues; although Kindlin-1 was highly expressed in well-differentiated tumors, whereas Kindlin-2 was more prevalent in poorly differentiated tumors. Collectively, these data suggest that Kindlin-1 may inhibit, while Kindlin-2 may promote, EC progression. This study, for the first time, linked the expression of Kindlin-1 and Kindlin-2 with EC family genetic background and living habits, which may help further our understanding of the various causes of EC.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is the ninth most common human malignancy and the sixth leading cause of cancer-related death in China.AcK27-HOXB9 is a newly identified HOXB9 post-transcriptional modification th...Pancreatic ductal adenocarcinoma(PDAC)is the ninth most common human malignancy and the sixth leading cause of cancer-related death in China.AcK27-HOXB9 is a newly identified HOXB9 post-transcriptional modification that can predict the outcome in lung adenocarcinoma and colon cancer well.However,the role of AcK27-HOXB9 in PDAC is unclear.The present study aims to investigate the differential diagnostic role of patients with AcK27-HOXB9 PDAC.Tissue microarrays consisting of 162 pancreatic tumor tissue samples from patients with PDAC and paired normal subjects were used to examine HOXB9 and AcK27-HOXB9 levels and localizations by immunohistochemical analysis and Western blot assay,respectively.HOXB9 was upregulated(P<0.0001),and AcK27-HOXB9(P=0.0023)was downregulated in patients with PDAC.HOXB9 promoted(P=0.0115),while AcK27-HOXB9(P=0.0279)inhibited PDAC progression.AcK27-HOXB9 predicted favorable outcome in patients with PDAC(P=0.0412).AcK27-HOXB9 also suppressed PDAC cell migration in a cell migration assay.The results of this study showed that HOXB9 promoted and AcK27-HOXB9 suppressed PDAC progression.The determination of ratio between HOXB9 and AcK27-HOXB9 exhibited potential diagnostic value in patients with PDAC.展开更多
In this paper,a novel dynamic addressing scheme for wireless sensor networks(WSNs)is proposed by using variable length coding.A WSN is typically composed of numerous tiny energy-constrained sensor nodes with limited i...In this paper,a novel dynamic addressing scheme for wireless sensor networks(WSNs)is proposed by using variable length coding.A WSN is typically composed of numerous tiny energy-constrained sensor nodes with limited information processing and data storage capabilities;thus,the energy-efficient strategy is the key issue in designing protocols for WSN.Traditional addressing strategies adopt flat addressing(static and uniform addresses)for sensor nodes.However,the proposed variable length dynamic addressing(VLDA)for sensor nodes is based on the fact that different nodes in the network have uneven traffic loads.Therefore,nodes with more data to receive or send are allocated with shorter addresses.Whether a node is busy or not is determined by the network traffic distribution(NTD),which is defined as the number of data packets each node has received or sent in a period of time.Sensor nodes’energy is saved by VLDA scheme;hence,the wireless sensor network’s lifetime is extended.In the simulation,a 20%improvement has been achieved through the addressing scheme compared to traditional flat addressing.展开更多
文摘AIM： To investigate the mechanisms of sulfasalazine （SASP） in the treatment of ulcerative colitis （UC）.METHODS： Changes of pathological signs and histological grading of 106 patients with active UC were observed before and after the treatment with SASP, 1 g, thrice daily for 6 wk.RESULTS： The effect of SASP on the vasculitis in lamina propria was 48.2% and 17.4% in the mild active UC （P〈0.001） and 68% and 26.7% in the moderate active UC （P〈0.001） before and after treatment, Fibroid necrosis of vessel wail was found in one case of mild UC and two cases of moderate UC before treatment and was not found after treatment, No thrombosis was found in mild UC before and after treatment, while thrombosis was found in one case of moderate UC before treatment, The effect on mucosal glandular abnormality was 30.4% and 13.0% in mild UC （P〈0.05）, and 42% and 40% in moderate UC （P〉0.05） before and after treatment, The rate of eosinophil infiltration was 98.2% and 80,4% in mild UC （P〈0.01）,and 100% and 91,1% in moderate UC （P〈0.05） before and after treatment, The effect on crypt abscess was 21.4% and 4.4% in mild UC （P〈0.05）, and 48% and 13.3% in moderate UC （P〈0.001） before and after treatment. The effect on mucosal pathohistological grading was 2.00±0.84 and 0.91±0.46 in mild UC （P〈0.001）, and 2.49±0.84 and 1.31±0.75 in moderate UC （P〈0.001） before and after treatment.CONCLUSION： SASP can improve small vessel lesions and crypt abscesses and reduce neutrophilic and eosinophilic leukocyte infiltration in inflammatory mucosa of UC.
基金supported by the National Natural Science Foundation of China(No.62022027).
文摘Conversational large language models(LLMs)such as ChatGPT and GPT-4 have recently exhibited remarkable capabilities across various domains,capturing widespread attention from the public.To facilitate this line of research,in this paper,we report the development of MOSS,an open-sourced conversational LLM that contains 16 B parameters and can perform a variety of instructions in multi-turn interactions with humans.The base model of MOSS is pre-trained on large-scale unlabeled English,Chinese,and code data.To optimize the model for dialogue,we generate 1.1 M synthetic conversations based on user prompts collected through our earlier versions of the model API.We then perform preference-aware training on preference data annotated from AI feedback.Evaluation results on real-world use cases and academic benchmarks demonstrate the effectiveness of the proposed approaches.In addition,we present an effective practice to augment MOSS with several external tools.Through the development of MOSS,we have established a complete technical roadmap for large language models from pre-training,supervised fine-tuning to alignment,verifying the feasibility of chatGPT under resource-limited conditions and providing a reference for both the academic and industrial communities.Model weights and code are publicly available at https://github.com/OpenMOSS/MOSS.
基金This study was supported by National Natural Science Foundation of China Youth Science Fund Project(Grant number 82001107)the Applied Basic Research Project of Sichuan province(Grant number 2022NSFSC1345,China).
文摘The aqueous two-phase system(ATPS)is an all-aqueous system fabricated from two immiscible aqueous phases.It is spontaneously assembled through physical liquid-liquid phase separation(LLPS)and can create suitable templates like the multicompartment of the intracellular environment.Delicate structures containing multiple compartments make it possible to endow materials with advanced functions.Due to the properties of ATPSs,ATPS-based drug delivery systems exhibit excellent biocompatibility,extraordinary loading efficiency,and intelligently controlled content release,which are particularly advantageous for delivering drugs in vivo.Therefore,we will systematically review and evaluate ATPSs as an ideal drug delivery system.Based on the basic mechanisms and influencing factors in forming ATPSs,the transformation of ATPSs into valuable biomaterials is described.Afterward,we concentrate on the most recent cutting-edge research on ATPS-based delivery systems.Finally,the potential for further collaborations between ATPS-based drug-carrying biomaterials and disease diagnosis and treatment is also explored.
基金supports by the Ministry of Science and Technology(2022YFA1403901)the National Natural Science Foundation of China(11920101005,11888101,and 12047503)+2 种基金the New Cornerstone Investigator Programpartially supported by Chinese Academy of Sciences under contract No.JZHKYPT-2021–08supports from China Postdoctoral Science Foundation Fellowship(2022M723112)。
文摘Van Hove singularities in proximity to the Fermi level promote electronic interactions and generate diverse competing instabilities.It is also known that a nontrivial Berry phase derived from spin–orbit coupling can introduce an intriguing decoration into the interactions and thus alter correlated phenomena.However,it is unclear how and what type of new physics can emerge in a system featured by the interplay between van Hove singularities(VHSs)and the Berry phase.Here,based on a general Rashba model on the square lattice,we comprehensively explore such an interplay and its significant influence on the competing electronic instabilities by performing a parquet renormalization group analysis.Despite the existence of a variety of comparable fluctuations in the particle–particle and particle-hole channels associated with higher-order VHSs,we find that the chiral p±ip pairings emerge as two stable fixed trajectories within the generic interaction parameter space,namely the system becomes a robust topological superconductor.The chiral pairings stem from the hopping interaction induced by the nontrivial Berry phase.The possible experimental realization and implications are discussed.Our work sheds new light on the correlated states in quantum materials with strong spin–orbit coupling(SOC)and offers fresh insights into the exploration of topological superconductivity.
基金supported by grants from the National Natural Science Foundation of China(Nos.82172972,81972609,81472734,31170711,81773199,81730071,81972616,81230051,and 81670626)the Beijing Natural Science Foundation(Nos.202084,7171005,7120002,and 7202080).
文摘FRMD6,a member of the 4.1 ezrin-radixin-moesin domain-containing protein family,has been reported to inhibit tumor progression in multiple cancers.Here,we demonstrate the involvement of FRMD6 in lung cancer progression.We find that FRMD6 is overexpressed in lung cancer tissues relative to in normal lung tissues.In addition,the enhanced expression of FRMD6 is associated with poor outcomes in patients with lung squamous cell carcinoma(n=75,P=0.0054)and lung adenocarcinoma(n=94,P=0.0330).Cell migration and proliferation in vitro and tumor formation in vivo are promoted by FRMD6 but are suppressed by the depletion of FRMD6.Mechanistically,FRMD6 interacts and colocalizes with mTOR and S6K,which are the key molecules of the mTOR signaling pathway.FRMD6 markedly enhances the interaction between mTOR and S6K,subsequently increasing the levels of endogenous pS6K and downstream pS6 in lung cancer cells.Furthermore,knocking out FRMD6 inhibits the activation of the mTOR signaling pathway in Frmd6^(−/−)gene KO MEFs and mice.Altogether,our results show that FRMD6 contributes to lung cancer progression by activating the mTOR signaling pathway.
基金supported by grants from the Ministry of Science and Technology of China (2016YFC1302103, 2015CB553906, and 2013CB910501)the National Natural Science Foundation of China (81730071, 81230051, 81472734, and 31170711)+3 种基金the Beijing Natural Science Foundation (7120002 and 7171005)the 111 Project of the Ministry of Education, grants from Peking University (BMU20120314 and BMU20130364)a Leading Academic Discipline Project of Beijing Education Bureau to H.Z.supported by a grant from the National Natural Science Foundation of China (81773199) to J.Z
文摘Kindlin-2, an integrin-interacting protein, regulates breast cancer progression. However, currently, no animal model to study the role of Kindlin-2 in the carcinogenesis of mammary gland is available. We established a Kindlin-2 transgenic mouse model using a mammary gland-specific promoter, mammary tumor virus(MMTV) long terminal repeat(LTR). Kindlin-2 was overexpressed in the epithelial cells of the transgenic mice. The mammary gland ductal trees were found to grow faster in MMTV-Kindlin-2 transgenic mice than in control mice during puberty. Kindlin-2 promoted mammary gland growth as indicated by more numerous duct branches and larger lumens, and more alveoli were formed in the mammary glands during pregnancy under Kindlin-2 overexpression. Importantly, mammary gland-specific expression of Kindlin-2 induced tumor formation at the age of 55 weeks on average. Additionally, the levels of estrogen receptor and progesterone receptor were decreased, whereas human epidermal growth factor receptor 2 and β-catenin were upregulated in the Kindlin-2-induced mammary tumors. These findings demonstrated that Kindlin-2 induces mammary tumor formation via activation of the Wnt signaling pathway.
基金financially supported by the Basic Research Program of State Grid(No.GCB17201600179)
文摘The cyclic oxidation behavior of Hf/Y-doped B2 FeAl intermetallics at 1373 K was investigated.For an undoped FeAl alloy,premature spallation of the alumina film occurs due to the formation of numerous voids at the film/alloy interface and apparent shrinkage in the film.In contrast to this,doping with either Hf or Y significantly improves the interfacial adhesion between the alumina film and the alloy substrate,particularly with Hf-doping.Microstructural observation in combination with Anger electron spectroscopic analysis suggests that in addition to prohibiting interfacial void formation and alleviating film shrinkage,the addition of Hf in the FeAl alloy could consolidate the film/alloy interface by directly participating in chemical bonding across the interface as a Hf ion.This causes the spallation of alumina film from the equiaxed grains/columnar grains interface rather than the bottom of the film.
基金supported by the Ministry of Science and Technology of China (2016YFC1302103 and 2015CB553906)the National Natural Science Foundation of China (81230051, 81472734,31170711, 81321003, and 30830048)+3 种基金the Beijing Natural Science Foundation (7120002)the 111 Project of the Ministry of Education, Peking University (BMU2018JC004, BMU20120314, and BMU20130364)a Leading Academic Discipline Project of Beijing Education Bureau to H.Za grant from the National Natural Science Foundation of China (81773199) to J.Z
文摘Basal-like breast cancer with a luminal progenitor gene expression profile is an aggressive subtype of breast cancer with a poorer prognosis compared with other subtypes.However,genes that specifically promote basal-like breast cancer development remain largely unknown.Here,we report that a novel gene C1orf106 plays an important role in maintaining the feature of basal-like/luminal progenitors.C1orf106 is frequently amplified and overexpressed in basal-like breast cancer and is associated with a poor outcome in patients.In human TCGA database,C1orf106 expression was correlated with upregulation of ELF5 and downregulation of GATA3,two transcription factors that regulate mammary gland stem cell fate.Enhanced expression of C1orf106 promotes tumor progression and expression of basal-like/luminal progenitor marker ELF5;depletion of C1orf106 suppresses tumorigenesis and expression of basal-like/luminal progenitor marker GATA3.These findings suggest that C1orf106 maintains the basal-like/luminal progenitor character through balancing the expression of ELF5 and GATA3.Taken together,we demonstrated that C1orf106 is an important regulator for basal-like/luminal progenitors and targeting C1orf106 is of therapeutic value for breast cancer.
基金This study was supported by grants from the Ministry of Science and Technology ofChina (Nos. 2016YFC1302103,2015CB553906, and 2013CB910501)the National Natural Science Foundation of China (Nos. 81230051, 81472734, 31170711, 81321003, and 30830048)+2 种基金the Beijing Natural Science Foundation (No. 7120002)the 111 Project of the Ministry of Education, Peking University (Nos. BMU20120314 and BMU20130364)and the Leading Academic Discipline Project of Beijing Education Bureau to Hongquan Zhang.
文摘LGR6 is a member of the G protein-coupled receptor family that plays a tumor-suppressive role in colon cancer. However, the relationship between LGR6 expression in patients and clinicopathological factors remains unclear. This study aimed to clarify whether the expression level of LGR6 is correlated with colon adenocarcinoma progression. Immunohistochemistry was used to detect LGR6 expression in colon adenoma tissues (n = 21), colon adenocarcinoma tissues (n = 156), and adjacent normal tissues (n = 124). The expression levels of LGR6 in colon adenoma and adenocarcinoma were significantly higher than those in normal colon epithelial tissues (P < 0.001). Low LGR6 expression predicted a short overall survival in patients with colon adenocarcinoma (log-rank test, P = 0.016). Univariate and multivariate survival analyses showed that, in addition to N and M classification, LGR6 expression served as an independent prognostic factor. Thus, low expression of LGR6 can be used as an independent prognostic parameter in patients with colon adenocarcinoma.
基金supported by the National Natural Science Foundation of China(81730071,81972616,81230051,81472734,31170711 and 81773199)the Ministry of Science and Technology of China(2016YFC1302103 and 2015CB553906)+1 种基金Beijing Natural Science Foundation(7120002 and 7171005)Peking University(BMU2018JC004,BMU20120314 and BMU20130364)。
文摘Large tumor suppressor 1(LATS1)is the key kinase controlling activation of Hippo signalling pathway.Post-translational modifications of LATS1 modulate its kinase activity.However,detailed mechanism underlying LATS1 stability and activation remains elusive.Here we report that LATS1 is acetylated by acetyltransferase CBP at K751 and is deacetylated by deacetylases SIRT3 and SIRT4.Acetylation at K751 stabilized LATS1 by decreasing LATS1 ubiquitination and inhibited LATS1 activation by reducing its phosphorylation.Mechanistically,LATS1 acetylation resulted in inhibition of YAP phosphorylation and degradation,leading to increased YAP nucleus translocation and promoted target gene expression.Functionally,LATS1-K751 Q,the acetylation mimic mutant potentiated lung cancer cell migration,invasion and tumor growth,whereas LATS1-K751 R,the acetylation deficient mutant inhibited these functions.Taken together,we demonstrated a previously unidentified post-translational modification of LATS1 that converts LATS1 from a tumor suppressor to a tumor promoter by suppression of Hippo signalling through acetylation of LATS1.
基金National Natural Science Foundation of China,Grant/Award Numbers:81872372,81902469Natural Science Foundation of China-Guangdong Joint Fund,Grant/Award Number:U0932001+2 种基金National Cohort of Esophageal Cancer of China,Grant/Award Number:2016YFC0901400China Postdoctoral Science Foundation,Grant/Award Number:2018M6431342020 Li Ka Shing Foundation Cross-Disciplinary Research Grant,Grant/Award Number:2020LKSFG07B。
文摘Background:Fascin is crucial for cancer cell filopodium formation and tumor metastasis,and is functionally regulated by post-translational modifications.However,whether and how Fascin is regulated by acetylation remains unclear.This study explored the regulation of Fascin acetylation and its corresponding roles in filopodium formation and tumor metastasis.Methods:Immunoprecipitation and glutathione-S-transferase pull-down assays were performed to examine the interaction between Fascin and acetyltransferase P300/CBP-associated factor(PCAF),and immunofluorescence was used to investigate their colocalization.An in vitro acetylation assay was performed to identify Fascin acetylation sites by using mass spectrometry.A specific antibody against acetylated Fascin was generated and used to detect the PCAF-mediated Fascin acetylation in esophageal squamous cell carcinoma(ESCC)cells using Western blotting by overexpressing and knocking down PCAF expression.An in vitro cell migration assay was performed,and a xenograft model was established to study in vivo tumor metastasis.Live-cell imaging and fluorescence recovery after photobleaching were used to evaluate the function and dynamics of acetylated Fascin in filopodium formation.The clinical significance of acetylated Fascin and PCAF in ESCC was evaluated using immunohistochemistry.Results:Fascin directly interacted and colocalized with PCAF in the cytoplasm and was acetylated at lysine 471(K471)by PCAF.Using the specific antiAcK471-Fascin antibody,Fascin was found to be acetylated in ESCC cells,and the acetylation level was consequently increased after PCAF overexpression and decreased after PCAF knockdown.Functionally,Fascin-K471 acetylation markedly suppressed in vitro ESCC cell migration and in vivo tumor metastasis,whereas Fascin-K471 deacetylation exhibited a potent oncogenic function.Moreover,Fascin-K471 acetylation reduced filopodial length and density,and lifespan of ESCC cells,while its deacetylation produced the opposite effect.In the filipodium shaft,K471-acetylated Fascin displayed rapid dynamic exchange,suggesting that it remained in its monomeric form owing to its weakened actinbundling activity.Clinically,high levels of AcK471-Fascin in ESCC tissues were strongly associated with prolonged overall survival and disease-free survival of ESCC patients.Conclusions:Fascin interacts directly with PCAF and is acetylated at lysine 471 in ESCC cells.Fascin-K471 acetylation suppressed ESCC cell migration and tumor metastasis by reducing filopodium formation through the impairment of its actin-bundling activity.
基金supported by the Ministry of Science and Technology of China (2016YFC1302103, 2015CB553906. 2013CB910501)the National Natural Science Foundation of China (81230051, 81472734, 31170711, 81321003, 81301802, 30830048)+2 种基金Beijing Natural Science Foundation (7120002)the 111 Project of the Ministry of Education, Peking University (BMU20120314, BMU20130364)a Leading Academic Discipline Project of Beijing Education Bureau to Hongquan Zhang
文摘Esophageal cancer （EC） is one of the most lethal malignancies in China, but the etiology and risk factors remain unclear. The integrin-interacting proteins Kindlin-1 and Kindlin-2 are focal adhesion molecules that activate transmembrane receptor integrins and regulate tumor cell growth, invasion, and metastasis. Here, we report that Kindlin-1 and Kindlin-2 are differentially expressed among Chinese EC patients. For this, Kindlin-1 and Kindlin-2 expression was evaluated in 220 EC patients by immunohistochemistry （IHC） and found to be correlated with the EC progression, along with a variety of epidemiologic parameters, including smoking, family EC history, and EC invasion status. Moreover, data downloaded from the Oncomine database revealed that both Kindlin- 1 and Kindlin-2 were upregulated in ECs compared with normal esophageal tissues; although Kindlin-1 was highly expressed in well-differentiated tumors, whereas Kindlin-2 was more prevalent in poorly differentiated tumors. Collectively, these data suggest that Kindlin-1 may inhibit, while Kindlin-2 may promote, EC progression. This study, for the first time, linked the expression of Kindlin-1 and Kindlin-2 with EC family genetic background and living habits, which may help further our understanding of the various causes of EC.
基金supported by grants from the Ministry of Science and Technology of China(Nos.2016YFC1302103 and 2015CB553906)the National Natural Science Foundation of China(Nos.81730071,81230051,81472734,and 31170711)+1 种基金the Beijing Natural Science Foundation(Nos.7120002 and 7171005)This work was also supported by a grant from the National Natural Science Foundation of China(No.81773199)to Jun Zhan.
文摘Pancreatic ductal adenocarcinoma(PDAC)is the ninth most common human malignancy and the sixth leading cause of cancer-related death in China.AcK27-HOXB9 is a newly identified HOXB9 post-transcriptional modification that can predict the outcome in lung adenocarcinoma and colon cancer well.However,the role of AcK27-HOXB9 in PDAC is unclear.The present study aims to investigate the differential diagnostic role of patients with AcK27-HOXB9 PDAC.Tissue microarrays consisting of 162 pancreatic tumor tissue samples from patients with PDAC and paired normal subjects were used to examine HOXB9 and AcK27-HOXB9 levels and localizations by immunohistochemical analysis and Western blot assay,respectively.HOXB9 was upregulated(P<0.0001),and AcK27-HOXB9(P=0.0023)was downregulated in patients with PDAC.HOXB9 promoted(P=0.0115),while AcK27-HOXB9(P=0.0279)inhibited PDAC progression.AcK27-HOXB9 predicted favorable outcome in patients with PDAC(P=0.0412).AcK27-HOXB9 also suppressed PDAC cell migration in a cell migration assay.The results of this study showed that HOXB9 promoted and AcK27-HOXB9 suppressed PDAC progression.The determination of ratio between HOXB9 and AcK27-HOXB9 exhibited potential diagnostic value in patients with PDAC.
文摘In this paper,a novel dynamic addressing scheme for wireless sensor networks(WSNs)is proposed by using variable length coding.A WSN is typically composed of numerous tiny energy-constrained sensor nodes with limited information processing and data storage capabilities;thus,the energy-efficient strategy is the key issue in designing protocols for WSN.Traditional addressing strategies adopt flat addressing(static and uniform addresses)for sensor nodes.However,the proposed variable length dynamic addressing(VLDA)for sensor nodes is based on the fact that different nodes in the network have uneven traffic loads.Therefore,nodes with more data to receive or send are allocated with shorter addresses.Whether a node is busy or not is determined by the network traffic distribution(NTD),which is defined as the number of data packets each node has received or sent in a period of time.Sensor nodes’energy is saved by VLDA scheme;hence,the wireless sensor network’s lifetime is extended.In the simulation,a 20%improvement has been achieved through the addressing scheme compared to traditional flat addressing.
