Gulf War Illness(GWI) encompass a spectrum of maladies specific to troops deployed during the Persian Gulf War(1990–1991). There are several hypothesized factors believed to contribute to GWI, including(but not limit...Gulf War Illness(GWI) encompass a spectrum of maladies specific to troops deployed during the Persian Gulf War(1990–1991). There are several hypothesized factors believed to contribute to GWI, including(but not limited to)exposures to chemical agents and a foreign environment(e.g., dust, pollens, insects, and microbes). Moreover, the inherent stress associated with deployment and combat has been associated with GWI. While the etiology of GWI remains uncertain, several studies have provided strong evidence that chemical exposures, especially neurotoxicants,may be underlying factors for the development of GWI. This mini style perspective article will focus on some of the major evidence linking chemical exposures to GWI development and persistence decades after exposure.展开更多
AIM： To determine the role of Sonic hedgehog （Shh） pathway in colorectal adenocarcinomas through analysis of the expression of Shh pathway-related molecules, Shh, Ptchl, hedgehog-interacting protein （Hip）, Gil1, ...AIM： To determine the role of Sonic hedgehog （Shh） pathway in colorectal adenocarcinomas through analysis of the expression of Shh pathway-related molecules, Shh, Ptchl, hedgehog-interacting protein （Hip）, Gil1, Gli3 and PDGFRα. METHODS： Expression of Shh in 25 colorectal adenocarcinomas was detected by RT-PCR,in situ hybridization and immunohistochemistry. Expression of Ptchl was observed by in situ hybridization and immunohistochemistry. Expression of Hip, Gil1, Gli3 and PDGFRα was analyzed by in situ hybridization. RESULTS： Expression of cytokeratin AE1/AE3 was observed in the cytoplasm of colorectal crypts. Members of the Hh signaling pathway were expressed in colorectal epithelium. Shh was expressed in cytoplasm of dysplastic epithelial cells, while expression of Ptchl, Hip and Gill were mainly detected in the malignant crypts of adenocarcinomas. In contrast, PDGFRα was expressed highly in aberrant crypts and moderately in the stroma. Expression of Gli3 could not be detected in colorectal adenocarcinomas. CONCLUSION： These data suggest that Shh-Ptchl-Gli1 signaling pathway may play a role in the progression of colorectal tumor.展开更多
The majority of the mammalian skeleton is formed through endochondral ossification starting from a cartilaginous template.Cartilage cells, or chondrocytes, survive, proliferate and synthesize extracellular matrix in a...The majority of the mammalian skeleton is formed through endochondral ossification starting from a cartilaginous template.Cartilage cells, or chondrocytes, survive, proliferate and synthesize extracellular matrix in an avascular environment, but the metabolic requirements for these anabolic processes are not fully understood. Here, using metabolomics analysis and genetic in vivo models, we show that maintaining intracellular serine homeostasis is essential for chondrocyte function. De novo serine synthesis through phosphoglycerate dehydrogenase(PHGDH)-mediated glucose metabolism generates nucleotides that are necessary for chondrocyte proliferation and long bone growth. On the other hand, dietary serine is less crucial during endochondral bone formation, as serine-starved chondrocytes compensate by inducing PHGDH-mediated serine synthesis.Mechanistically, this metabolic flexibility requires ATF4, a transcriptional regulator of amino acid metabolism and stress responses.We demonstrate that both serine deprivation and PHGDH inactivation enhance ATF4 signaling to stimulate de novo serine synthesis and serine uptake, respectively, and thereby prevent intracellular serine depletion and chondrocyte dysfunction. A similar metabolic adaptability between serine uptake and de novo synthesis is observed in the cartilage callus during fracture repair.Together, the results of this study reveal a critical role for PHGDH-dependent serine synthesis in maintaining intracellular serine levels under physiological and serine-limited conditions, as adequate serine levels are necessary to support chondrocyte proliferation during endochondral ossification.展开更多
Despite the large size of most communication and transportation systems, there are short paths between nodes in these networks which guarantee the efficient information, data and passenger delivery; furthermore these ...Despite the large size of most communication and transportation systems, there are short paths between nodes in these networks which guarantee the efficient information, data and passenger delivery; furthermore these networks have a surprising tolerance under random errors thanks to their inherent scale-free topology. However, their scale-free topology also makes them fragile under intentional attacks, leaving us a challenge on how to improve the network robustness against intentional attacks without losing their strong tolerance under random errors and high message and passenger delivering capacity. Here We propose two methods （SL method and SH method） to enhance scale-free network＇s tolerance under attack in different conditions.展开更多
Dear Editor,Schwannomas are peripheral nervous system tumors that cause chronic pain,numbness,and potentially lifethreatening organ dysfunction.Surgery is a conventional treatment for schwannoma patients.However,those...Dear Editor,Schwannomas are peripheral nervous system tumors that cause chronic pain,numbness,and potentially lifethreatening organ dysfunction.Surgery is a conventional treatment for schwannoma patients.However,those who undergo surgery may experience neurological deficits.Moreover,the management of schwannomas can be problematic due to their unpredictable growth.Thus,there is a pressing need for nonsurgical treatments to manage both tumor growth and pain control.展开更多
To date,the overall response rate of PD-1 blockade remains unsatisfactory,partially due to limited understanding of tumor immune microenvironment(TIME).B-cell lymphoma 9(BCL9),a key transcription co-activator of the W...To date,the overall response rate of PD-1 blockade remains unsatisfactory,partially due to limited understanding of tumor immune microenvironment(TIME).B-cell lymphoma 9(BCL9),a key transcription co-activator of the Wnt pathway,is highly expressed in cancers.By genetic depletion and pharmacological inhibition of BCL9 in tumors,we found that BCL9 suppression reduced tumor growth.展开更多
The expression of self-antigens in medullary thymic epithelial cells(mTECs)is essential for the establishment of immune tolerance,but the regulatory network that controls the generation and maintenance of the multitud...The expression of self-antigens in medullary thymic epithelial cells(mTECs)is essential for the establishment of immune tolerance,but the regulatory network that controls the generation and maintenance of the multitude of cell populations expressing self-antigens is poorly understood.Here,we show that Insm1,a zinc finger protein with known functions in neuroendocrine and neuronal cells,is broadly coexpressed with an autoimmune regulator(Aire)in mTECs.Insm1 expression is undetectable in most mimetic cell populations derived from mTECs but persists in neuroendocrine mimetic cells.Mutation of Insm1 in mice downregulated Aire expression,dysregulated the gene expression program of mTECs,and altered mTEC subpopulations and the expression of tissue-restricted antigens.Consistent with these findings,loss of Insm1 resulted in autoimmune responses in multiple peripheral tissues.We found that Insm1 regulates gene expression in mTECs by binding to chromatin.Interestingly,the majority of the Insm1 binding sites are co-occupied by Aire and enriched in superenhancer regions.Together,our data demonstrate the important role of Insm1 in the regulation of the repertoire of self-antigens needed to establish immune tolerance.展开更多
Although VEGF-B was discovered as a VEGF-A homolog a long time ago,the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups.Notwithstanding,drugs that inhibit V...Although VEGF-B was discovered as a VEGF-A homolog a long time ago,the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups.Notwithstanding,drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases.It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms.Using comprehensive in vitro and in vivo methods and models,we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed.Mechanistically,we unveil that VEGF-B binds to FGFR1,induces FGFR1/VEGFR1 complex formation,and suppresses FGF2-induced Erk activation,and inhibits FGF2-driven angiogenesis and tumor growth.Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway.Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels,caution is warranted when modulating VEGF-B activity to treat neovascular diseases.展开更多
Melanoma,a type of skin malignancy with a high incidence and poor prognosis,is a global public health issue.The tumorigenesis and pathogenesis of melanoma involve genetic mutations,metabolic disruption,and immune evas...Melanoma,a type of skin malignancy with a high incidence and poor prognosis,is a global public health issue.The tumorigenesis and pathogenesis of melanoma involve genetic mutations,metabolic disruption,and immune evasion.Tumors undergo immune editing to escape immune surveillance,and immune escape has been identified as a critical factor in the development and progression of melanoma.展开更多
Immune checkpoint blockade(ICB)exhibits considerable benefits in malignancies,but its overall response rate is limited.Previous studies have shown that sphingosine kinases(SPHKs)are critical in the tumor microenvironm...Immune checkpoint blockade(ICB)exhibits considerable benefits in malignancies,but its overall response rate is limited.Previous studies have shown that sphingosine kinases(SPHKs)are critical in the tumor microenvironment(TME),but their role in immunotherapy is unclear.We performed integrative analyses including bioinformatics analysis,functional study,and clinical validation to investigate the role of SPHK1 in tumor immunity.Functionally,we demonstrated that the inhibition of SPHK1 significantly suppressed tumor growth by promoting antitumor immunity in immunocompetent melanoma mouse models and tumor T-cell cocultures.A mechanistic analysis revealed that MTA3 functions as the downstream target of SPHK1 in transcriptionally regulating tumor PD-L1.Preclinically,we found that anti-PD-1 monoclonal antibody(mAb)treatment significantly rescued tumor SPHK1 overexpression or tumor MTA3 overexpression-mediated immune evasion.Significantly,we identified SPHK1 and MTA3 as biological markers for predicting the efficacy of anti-PD-1 mAb therapy in melanoma patients.Our findings revealed a novel role for SPHK1 in tumor evasion mediated by regulating the MTA3-PD-L1 axis,identified SPHK1 and MTA3 as predictors for assessing the efficacy of PD-1 mAb treatment,and provided a therapeutic possibility for the treatment of melanoma patients.展开更多
A recent study by Dr.Wickström et al.published in Cell reveals a new mechanism for how genome is protected from mechanical stress-induced damage.The study demonstrates that cells show rapid chromatin mechanorespo...A recent study by Dr.Wickström et al.published in Cell reveals a new mechanism for how genome is protected from mechanical stress-induced damage.The study demonstrates that cells show rapid chromatin mechanoresponse by loss of H3K9me3-marked heterochromatin and tissue-level reorganization to prevent long-term stretch-induced damage(Fig.1).展开更多
基金supported in part by the VA grant(5 I21 BX003760)to JMR.
文摘Gulf War Illness(GWI) encompass a spectrum of maladies specific to troops deployed during the Persian Gulf War(1990–1991). There are several hypothesized factors believed to contribute to GWI, including(but not limited to)exposures to chemical agents and a foreign environment(e.g., dust, pollens, insects, and microbes). Moreover, the inherent stress associated with deployment and combat has been associated with GWI. While the etiology of GWI remains uncertain, several studies have provided strong evidence that chemical exposures, especially neurotoxicants,may be underlying factors for the development of GWI. This mini style perspective article will focus on some of the major evidence linking chemical exposures to GWI development and persistence decades after exposure.
基金grants from National Natural Science Foundation of China, No. 30228031, No. 30671072
文摘AIM： To determine the role of Sonic hedgehog （Shh） pathway in colorectal adenocarcinomas through analysis of the expression of Shh pathway-related molecules, Shh, Ptchl, hedgehog-interacting protein （Hip）, Gil1, Gli3 and PDGFRα. METHODS： Expression of Shh in 25 colorectal adenocarcinomas was detected by RT-PCR,in situ hybridization and immunohistochemistry. Expression of Ptchl was observed by in situ hybridization and immunohistochemistry. Expression of Hip, Gil1, Gli3 and PDGFRα was analyzed by in situ hybridization. RESULTS： Expression of cytokeratin AE1/AE3 was observed in the cytoplasm of colorectal crypts. Members of the Hh signaling pathway were expressed in colorectal epithelium. Shh was expressed in cytoplasm of dysplastic epithelial cells, while expression of Ptchl, Hip and Gill were mainly detected in the malignant crypts of adenocarcinomas. In contrast, PDGFRα was expressed highly in aberrant crypts and moderately in the stroma. Expression of Gli3 could not be detected in colorectal adenocarcinomas. CONCLUSION： These data suggest that Shh-Ptchl-Gli1 signaling pathway may play a role in the progression of colorectal tumor.
基金supported by funding from the Research Foundation-Flanders(FWO:G.0A42.16, G.0B3418 and G0C5120N)the KU Leuven (C24/17/077)supported by long-term structural funding-Methusalem Funding by the Flemish Government and the European Research Council (ERC Advanced Research Grant EU-ERC743074)
文摘The majority of the mammalian skeleton is formed through endochondral ossification starting from a cartilaginous template.Cartilage cells, or chondrocytes, survive, proliferate and synthesize extracellular matrix in an avascular environment, but the metabolic requirements for these anabolic processes are not fully understood. Here, using metabolomics analysis and genetic in vivo models, we show that maintaining intracellular serine homeostasis is essential for chondrocyte function. De novo serine synthesis through phosphoglycerate dehydrogenase(PHGDH)-mediated glucose metabolism generates nucleotides that are necessary for chondrocyte proliferation and long bone growth. On the other hand, dietary serine is less crucial during endochondral bone formation, as serine-starved chondrocytes compensate by inducing PHGDH-mediated serine synthesis.Mechanistically, this metabolic flexibility requires ATF4, a transcriptional regulator of amino acid metabolism and stress responses.We demonstrate that both serine deprivation and PHGDH inactivation enhance ATF4 signaling to stimulate de novo serine synthesis and serine uptake, respectively, and thereby prevent intracellular serine depletion and chondrocyte dysfunction. A similar metabolic adaptability between serine uptake and de novo synthesis is observed in the cartilage callus during fracture repair.Together, the results of this study reveal a critical role for PHGDH-dependent serine synthesis in maintaining intracellular serine levels under physiological and serine-limited conditions, as adequate serine levels are necessary to support chondrocyte proliferation during endochondral ossification.
基金Project supported in part by the China Scholarships Council (Grant No. 2007103794)the Defence Threat Reduction Agency Award HDTRA1-08-1-0027+5 种基金the James S. McDonnell Foundation 21st Century Initiative in Studying Complex Systems,the National Science Foundation within the DDDAS (CNS-0540348)ITR (DMR-0426737)IIS-0513650 programsthe US Office of Naval Research Award N00014-07-Cthe National Natural Science Foundation of China (Grant Nos. 80678605 and 60903157)the National High Technology Research and Development Program of China (Grant No. 2009AA01Z422)
文摘Despite the large size of most communication and transportation systems, there are short paths between nodes in these networks which guarantee the efficient information, data and passenger delivery; furthermore these networks have a surprising tolerance under random errors thanks to their inherent scale-free topology. However, their scale-free topology also makes them fragile under intentional attacks, leaving us a challenge on how to improve the network robustness against intentional attacks without losing their strong tolerance under random errors and high message and passenger delivering capacity. Here We propose two methods （SL method and SH method） to enhance scale-free network＇s tolerance under attack in different conditions.
基金supported by Ub-RASdisease(AS,H2020 ERC,Grant agreement ID:772649)the Young Investigator Award(TI,CTF,award ID:2022-01-004).
文摘Dear Editor,Schwannomas are peripheral nervous system tumors that cause chronic pain,numbness,and potentially lifethreatening organ dysfunction.Surgery is a conventional treatment for schwannoma patients.However,those who undergo surgery may experience neurological deficits.Moreover,the management of schwannomas can be problematic due to their unpredictable growth.Thus,there is a pressing need for nonsurgical treatments to manage both tumor growth and pain control.
基金This study was partially supported by grants from National Natural Science Foundation of China(81872895 and 82073881 to D.Z.,81872915,82073904,and 82011530150 to M.-W.W.)Shanghai Municipal Education Commission(Shanghai Top-Level University Capacity Building Program DGF817029-04 to M.-W.W.)+1 种基金Shanghai Science and Technology Commission(18ZR1403900,20430713600,and 18JC1413800 to D.Z.)Fudan-SIMM Joint Research Fund(FU-SIMM20181010 to D.Z.and D.Y.).
文摘To date,the overall response rate of PD-1 blockade remains unsatisfactory,partially due to limited understanding of tumor immune microenvironment(TIME).B-cell lymphoma 9(BCL9),a key transcription co-activator of the Wnt pathway,is highly expressed in cancers.By genetic depletion and pharmacological inhibition of BCL9 in tumors,we found that BCL9 suppression reduced tumor growth.
基金supported by the National Natural Science Foundation of China(31970856)the Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University(JNU1AF-CFTP-2022-a01236)the Science and Technology Program of Guangzhou(202201020042).
文摘The expression of self-antigens in medullary thymic epithelial cells(mTECs)is essential for the establishment of immune tolerance,but the regulatory network that controls the generation and maintenance of the multitude of cell populations expressing self-antigens is poorly understood.Here,we show that Insm1,a zinc finger protein with known functions in neuroendocrine and neuronal cells,is broadly coexpressed with an autoimmune regulator(Aire)in mTECs.Insm1 expression is undetectable in most mimetic cell populations derived from mTECs but persists in neuroendocrine mimetic cells.Mutation of Insm1 in mice downregulated Aire expression,dysregulated the gene expression program of mTECs,and altered mTEC subpopulations and the expression of tissue-restricted antigens.Consistent with these findings,loss of Insm1 resulted in autoimmune responses in multiple peripheral tissues.We found that Insm1 regulates gene expression in mTECs by binding to chromatin.Interestingly,the majority of the Insm1 binding sites are co-occupied by Aire and enriched in superenhancer regions.Together,our data demonstrate the important role of Insm1 in the regulation of the repertoire of self-antigens needed to establish immune tolerance.
基金This study is supported by the State Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,and Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,P.R.Chinathe National Natural Science Foundation of China(82150710555 and 82220108016 to X.Li,81970823 to Jin Yao and 81830013 to J.O.)+4 种基金a Key Research and Development Plan of Shandong Province(2016GSF201100)the Fundamental Research Funds for the Central Universities(19ykpy151)the long-term structural Methusalem funding by the Flemish Government,Belgiumthe Deutsche Forschungsge-meinschaft(Project No.:394046768-SFB1366)the DZHK partner site Mannheim/Heidelberg to H.F.L.,an ERA PerMed 2020 JTC grant“PROGRESS”.
文摘Although VEGF-B was discovered as a VEGF-A homolog a long time ago,the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups.Notwithstanding,drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases.It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms.Using comprehensive in vitro and in vivo methods and models,we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed.Mechanistically,we unveil that VEGF-B binds to FGFR1,induces FGFR1/VEGFR1 complex formation,and suppresses FGF2-induced Erk activation,and inhibits FGF2-driven angiogenesis and tumor growth.Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway.Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels,caution is warranted when modulating VEGF-B activity to treat neovascular diseases.
基金supported by the National Key Research and Development Program of China(2019YFE0120800 and 2019YFA0111600)the National Natural Science Foundation of China for Innovative Research Group Project(82221002,82130090,81874242,31800979,and 82073145)+2 种基金the Natural Science Foundation of China for Outstanding Young Scholars(82022060)the Natural Science Foundation of Hunan Province for Outstanding Young Scholars(2019JJ30040)Talent Young Scholars of Hunan Province(2019RS2009)。
文摘Melanoma,a type of skin malignancy with a high incidence and poor prognosis,is a global public health issue.The tumorigenesis and pathogenesis of melanoma involve genetic mutations,metabolic disruption,and immune evasion.Tumors undergo immune editing to escape immune surveillance,and immune escape has been identified as a critical factor in the development and progression of melanoma.
基金This work was supported by the National Key Research and Development Program of China(No.2019YFA0111600,No.2019YFE0120800)the Natural Science Foundation of China for Outstanding Young Scholars(No.82022060)+3 种基金the National Natural Science Foundation of China(No.81874242,No.31800979,No.62102455)the Natural Science Foundation of Hunan Province for Outstanding Young Scholars(No.2019JJ30040)China Postdoctoral Science Foundation(No.2020M682587)Hunan Outstanding Postdoctoral Innovative Talents Program(No.2021RC2035).
文摘Immune checkpoint blockade(ICB)exhibits considerable benefits in malignancies,but its overall response rate is limited.Previous studies have shown that sphingosine kinases(SPHKs)are critical in the tumor microenvironment(TME),but their role in immunotherapy is unclear.We performed integrative analyses including bioinformatics analysis,functional study,and clinical validation to investigate the role of SPHK1 in tumor immunity.Functionally,we demonstrated that the inhibition of SPHK1 significantly suppressed tumor growth by promoting antitumor immunity in immunocompetent melanoma mouse models and tumor T-cell cocultures.A mechanistic analysis revealed that MTA3 functions as the downstream target of SPHK1 in transcriptionally regulating tumor PD-L1.Preclinically,we found that anti-PD-1 monoclonal antibody(mAb)treatment significantly rescued tumor SPHK1 overexpression or tumor MTA3 overexpression-mediated immune evasion.Significantly,we identified SPHK1 and MTA3 as biological markers for predicting the efficacy of anti-PD-1 mAb therapy in melanoma patients.Our findings revealed a novel role for SPHK1 in tumor evasion mediated by regulating the MTA3-PD-L1 axis,identified SPHK1 and MTA3 as predictors for assessing the efficacy of PD-1 mAb treatment,and provided a therapeutic possibility for the treatment of melanoma patients.
文摘A recent study by Dr.Wickström et al.published in Cell reveals a new mechanism for how genome is protected from mechanical stress-induced damage.The study demonstrates that cells show rapid chromatin mechanoresponse by loss of H3K9me3-marked heterochromatin and tissue-level reorganization to prevent long-term stretch-induced damage(Fig.1).
