Gain-of-function mutations in fibroblast growth factor receptor(FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, ...Gain-of-function mutations in fibroblast growth factor receptor(FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, we analyzed the impact of Fgfr2- and Fgfr3- activating mutations on mandibular bone formation and endochondral bone repair after non-stabilized mandibular fractures in mouse models of Crouzon syndrome(Crz) and hypochondroplasia(Hch).展开更多
Patients diagnosed with advanced osteosarcoma,often in the form of lung metastases,have abysmal five-year overall survival rates.The complexity of the osteosarcoma immune tumor microenvironment has been implicated in ...Patients diagnosed with advanced osteosarcoma,often in the form of lung metastases,have abysmal five-year overall survival rates.The complexity of the osteosarcoma immune tumor microenvironment has been implicated in clinical trial failures of various immunotherapies.The purpose of this exploratory study was to spatially characterize the immune tumor microenvironment of metastatic osteosarcoma lung specimens.Knowledge of the coordinating cellular networks within these tissues could then lead to improved outcomes when utilizing immunotherapy for treatment of this disease.Importantly,various cell types,interactions,and cellular neighborhoods were associated with five-year survival status.Of note,increases in cellular interactions between T lymphocytes,positive for programmed cell death protein 1,and myeloid-derived suppressor cells were observed in the 5-year deceased cohort.Additionally,cellular neighborhood analysis identified an Immune-Cold Parenchyma cellular neighborhood,also associated with worse 5-year survival.Finally,the Osteosarcoma Spatial Score,which approximates effector immune activity in the immune tumor microenvironment through the spatial proximity of immune and tumor cells,was increased within 5-year survivors,suggesting improved effector signaling in this patient cohort.Ultimately,these data represent a robust spatial multiplexed immunofluorescence analysis of the metastatic osteosarcoma immune tumor microenvironment.Various communication networks,and their association with survival,were described.In the future,identification of these networks may suggest the use of specific,combinatory immunotherapeutic strategies for improved anti-tumor immune responses and outcomes in osteosarcoma.展开更多
BACKGROUND The development of colorectal cancer(CRC) is a complicated multistep process that involves an accumulation of mutations in tumor suppressor genes and oncogenes.In the process of DNA replication, base mismat...BACKGROUND The development of colorectal cancer(CRC) is a complicated multistep process that involves an accumulation of mutations in tumor suppressor genes and oncogenes.In the process of DNA replication, base mismatch often occurs due to various factors leading to abnormal expression of mismatch repair genes(MMR),among which MLH1 and MSH2 are the most important.Recently, numerous studies indicated that MLH1/MSH2 phenotype is associated with CRC.We wanted to elucidate the role of MLH1/MSH2 in the prediction and prognosis of CRC through long-term clinical observation.AIM To evaluate the prognostic and predictive significance of MLH1/MSH2 in patients with stage Ⅱ-Ⅲ CRC using immunohistochemical analysis and GeneScan.METHODS Specimens from 681 patients with CRC(395 stage Ⅱ and 286 stage Ⅲ, 387 males and 294 females) who underwent curative surgical resection from 2013 to 2016 were tested.Immunohistochemistry was used to analyze MMR status and the microsatellite status of 133 patients was determined by GeneScan analysis.RESULTS Five hundred and fifty(80.76%) patients were MLH1/MSH2 positive and 131(19.24%) were negative by immunohistochemistry.MLH1/MSH2-positive tumors were significantly more frequent in the colon than in the rectum, and had poor differentiation and less mucin production(P < 0.05).Patients of different groups did not differ in terms of age, gender, tumor size, tumor stage, lymphocytic infiltration, or circumscribed margin.MLH1/MSH2-negative patients had a more favorable OS than MLH1/MSH2-positive patients(P < 0.001).Univariate and multivariate analyses demonstrated MLH1/MSH2 expression as an independent prognostic and predictive factor for stage Ⅱ/Ⅲ CRC.MLH1/MSH2 expression was a strong prognostic factor in all patients [P < 0.001, hazard ratio(HR) = 4.064,95%CI: 2.241–7.369].Adjuvant chemotherapy had a greater correlation with survival advantage in MLH1/MSH2-negative patients with stage Ⅲ disease(P <0.001, HR = 7.660, 95%CI: 2.974–15.883).However, patients with stage Ⅱ disease or MLH1/MSH2-positive patients with stage Ⅲ disease did not benefit from adjuvant chemotherapy.GeneScan analysis demonstrated that among 133 patients, 105(78.95%) were microsatellite stable, and 28(21.05%) had microsatellite instability(MSI), including 18(13.53%) with high MSI and 10(7.52%) with low MSI.This is consistent with the immunohistochemical results.CONCLUSION MLH1/MSH2 phenotype constitutes a pathologically and clinically distinct subtype of sporadic CRC.MLH1/MSH2 is an independent prognostic and predictive factor for outcome of stage Ⅱ-Ⅲ CRC.展开更多
We previously demonstrated immune activation in the maternal peripheral circulation associated with preterm labor (PTL). There was an elevation in WBC mRNA of anti-inflammatory complement decay-accelerating factor (CD...We previously demonstrated immune activation in the maternal peripheral circulation associated with preterm labor (PTL). There was an elevation in WBC mRNA of anti-inflammatory complement decay-accelerating factor (CD55) and the innate-immune response activating toll-like receptor 4 (TLR4). These findings suggested that collectively, these two molecules might serve as useful biomolecules to aid in the diagnosis of PTL. In this study, we used a combined marker approach to determine whether a dual marker model utilizing both CD55 and TLR4 mRNA levels to classify PTL would increase diagnostic accuracy compared to either molecule alone. Two methods were evaluated;a linear discriminant (LD) method and a distribution free (DF) method, in order to find the optimal linear combination of TLR4 and CD55 data to diagnose PTL accurately. Our results indicated that a combined CD55-TLR4 dual marker model could provide statistically significant improve- ments compared to CD55 or TLR4 single marker models for PTL classification performance.展开更多
Beta-defensin 20(DEFB20)is widely expressed in the epididymis with gene features involved in epididymal sperm maturation.However,the action mechanism and function of DEFB20 in sperm maturation are still unclear.One of...Beta-defensin 20(DEFB20)is widely expressed in the epididymis with gene features involved in epididymal sperm maturation.However,the action mechanism and function of DEFB20 in sperm maturation are still unclear.One of the important roles of beta-defensin is the ion channel activity.The cation channel sperm-associated protein(CatSper)alpha is an ion channel protein found on the sperm surface.This study aimed to investigate the interaction between DEFB20 and CatSper1–4 protein in relation to the sperm maturation process.Protein sequences were obtained from the National Center for Biotechnology Information(NCBI).Protein modeling and validation were carried out by using the Robetta modeling server and the Ramachandran plot method.Rosetta web server was used for the docking analysis.The results revealed a natural interaction between DEFB20 and CatSper1–4.The interaction occurred at the cation channel(close to the casein kinase II),ion transport protein,and kinase c phosphorylation of the CatSper1–4 active site.The DEFB20 region interacting with CatSper2–4 was the beta-defensin domain,while with CatSper1 was the non-beta-defensin domain.Based on the analysis,DEFB20 may interact with CatSperαsubunits,particularly CatsSper1,to affect ion channel activity during sperm maturation.展开更多
Several members of the Juglandaceae family produce juglone,a specialized 1,4-naphthoquinone(1,4-NQ)natural product that is responsible for the notorious allelopathic effects of black walnut(Juglans nigra).Despite its ...Several members of the Juglandaceae family produce juglone,a specialized 1,4-naphthoquinone(1,4-NQ)natural product that is responsible for the notorious allelopathic effects of black walnut(Juglans nigra).Despite its documented ecological roles and potential for being developed as a novel natural product-based herbicide,none of the genes involved in synthesizing juglone have been identified.Based on classical labeling studies,we hypothesized that biosynthesis of juglone’s naphthalenoid moiety is shared with biochemical steps of the phylloquinone pathway.Here,using comparative transcriptomics in combination with targeted metabolic profiling of 1,4-NQs in various black walnut organs,we provide evidence that phylloquinone pathway genes involved in 1,4-dihydroxynaphthoic acid(DHNA)formation are expressed in roots for synthesis of a compound other than phylloquinone.Feeding experiments using axenic black walnut root cultures revealed that stable isotopically labeled L-glutamate incorporates into juglone resulting in the same mass shift as that expected for labeling of the quinone ring in phylloquinone.Taken together,these results indicate that in planta,an intermediate from the phylloquinone pathway provides the naphthalenoid moiety of juglone.Moreover,this work shows that juglone can be de novo synthesized in roots without the contribution of immediate precursors translocated from aerial tissues.The present study illuminates all genes involved in synthesizing the juglone naphthoquinone ring and provides RNA-sequencing datasets that can be used with functional screening studies to elucidate the remaining juglone pathway genes.Translation of the generated knowledge is expected to inform future metabolic engineering strategies for harnessing juglone as a novel natural product-based herbicide.展开更多
BACKGROUND Primary neuroendocrine tumors (NETs) in the presacral region are extremely rare, some of which are caused by other primary tumors or metastatic rectal carcinoids. Nevertheless, cases of NETs have been incre...BACKGROUND Primary neuroendocrine tumors (NETs) in the presacral region are extremely rare, some of which are caused by other primary tumors or metastatic rectal carcinoids. Nevertheless, cases of NETs have been increasing in recent years. This report describes the first primary neuroendocrine tumor in the presacral region that was found at our hospital within the last five years. CASE SUMMARY The patient was identified as a 36-year-old woman with a presacral mass and pelvic floor pain. A digital rectal examination revealed a presacral mass with unclear margins and obvious tenderness. Magnetic resonance imaging (MRI) demonstrated a 57 mm × 29 mm presacral lump. An ultrasound-guided needle biopsy confirmed a well-differentiated neuroendocrine tumor. No other primary or metastatic tumors were found. CONCLUSION Comprehensive consideration of our case report and literature reported by others suggests that a conclusive diagnosis of NETs should be based on computed tomography/MRI and pathological examinations. The treatment of primary NETs in the presacral region mainly relies on surgical procedures with follow-up.展开更多
The divergence and continuous evolution of plants and animals contribute to ecological diversity.Promoters and transcription factors(TFs) are key determinants of gene regulation and transcription throughoutlife.Howeve...The divergence and continuous evolution of plants and animals contribute to ecological diversity.Promoters and transcription factors(TFs) are key determinants of gene regulation and transcription throughoutlife.However,theevolutionary trajectories and relationships of promoters and TFs are still poorly understood. Here, we conducted extensive analysis of large-scale multi-omics sequences in 420 animal species and 223 plant species spanning nearly a billion years of evolutionary history. Results showed that promoter GC-contentandTFisoelectricpoints,as features/signatures that accompany long biological evolution, exhibited increasing growth in animal cells but a decreasing trend in plant cells. Furthermore, the evolutionary trajectories of promoter and TF signatures in the animal kingdom provided further evidence that Mammalia as well as Aves evolved directly from the ancestor Reptilia. The strong correlation between promoter and TF signatures indicates that promoters and TFs formed antagonistic coevolution in the animal kingdom, but mutualistic coevolution in the plant kingdom. The distinct coevolutionary patterns potentially drive the plant-animal divergence, divergent evolution and ecological diversity.展开更多
The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the pre...The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the precise mechanisms remain unclear.In a model of local recurrence(LR),circulating tumor cells(CTC)engrafting in the post-resection tumor bed developed a radioresistant phenotype linked to an ENPP1+-gene signature which was also identified in TNBC patients,suggesting ENPP1´s role in genome integrity.Blockade of ENPP1 using a permeable ENPP1 inhibitor(AVA-NP-695)reduced radioresistance,mechanistically attributed to decreased homologous recombination(HR)resulting in persistent DNA damage,as evidenced by enhanced tail moment and sustainedγH2AX formation.This impaired DNA damage repair(DDR)sensitized tumor cells to ionizing radiation(IR).Notably,several DDR inhibitors(i)(including PARPi and ATMi)showed the highest synergy score in a targeted pharmacological screening.In vivo,dual ENPP1/ATM inhibition heightened radiosensitivity,compromised tumor cell survival and enhanced STINGTBK1 signaling by preventing ENPP1-mediated cGAMP hydrolysis.This resulted in robust innate and long-lasting adaptive antitumor immune memory responses,leading to significant tumor regression.Remarkably,combined treatment post-IR reduced spontaneous metastasis and local recurrence,and induced abscopal effects that impacted distant tumor spread in orthotopic tumor models.Thus,these findings position ENPP1 as a critical link between genome integrity and immunosuppression,offering promising translational opportunities for treating local or distant dissemination in TNBC.展开更多
Human pluripotent stem cells(hPSCs)can in theory give rise to any hematopoietic lineages,thereby offering opportunities for disease modeling,drug screening and cell therapies.However,gaps in our knowledge of the signa...Human pluripotent stem cells(hPSCs)can in theory give rise to any hematopoietic lineages,thereby offering opportunities for disease modeling,drug screening and cell therapies.However,gaps in our knowledge of the signaling requirements for the specification of human hematopoietic stem/progenitor cells(HSPCs),which lie at the apex of all hematopoietic lineages,greatly limit the potential of hPSC in hematological research and application.Transcriptomic analysis reveals aberrant regulation of WNT signaling during maturation of hPSC-derived hematopoietic progenitor cells(hPSC-HPCs),which results in higher mitochondria activity,misregulation of HOX genes,loss of self-renewal and precocious differentiation.These defects are partly due to the activation of the WNT target gene CDX2.Late-stage WNT inhibition improves the yield,self-renewal,multilineage differentiation,and transcriptional and metabolic profiles of hPSC-HPCs.Genome-wide mapping of transcription factor(TF)accessible chromatin reveals a significant overrepresentation of myeloid TF binding motifs in hPSC-HPCs,which could underlie their myeloid-biased lineage potential.Together our findings uncover a previously unappreciated dynamic requirement of the WNT signaling pathway during the specification of human HSPCs.Modulating the WNT pathway with small molecules normalizes the molecular differences between hPSC-HPCs and endogenous hematopoietic stem cells(HSCs),thereby representing a promising approach to improve the differentiation and function of hPSC-HPCs.展开更多
The overexpression of sialic acids on glycans,called hypersialylation,is a common alteration found in cancer cells.Sialylated glycans can enhance immune evasion by interacting with sialic acid-binding immunoglobulin-l...The overexpression of sialic acids on glycans,called hypersialylation,is a common alteration found in cancer cells.Sialylated glycans can enhance immune evasion by interacting with sialic acid-binding immunoglobulin-like lectin(Siglec)receptors on tumorinfiltrating immune cells.Here,we investigated the effect of sialylated glycans and their interaction with Siglec receptors on myeloid-derived suppressor cells(MDSCs).We found that MDSCs derived from the blood of lung cancer patients and tumor-bearing mice strongly express inhibitory Siglec receptors and are highly sialylated.In murine cancer models of emergency myelopoiesis,Siglec-E knockout in myeloid cells resulted in prolonged survival and increased tumor infiltration of activated T cells.Targeting suppressive myeloid cells by blocking Siglec receptors or desialylation strongly reduced their suppressive potential.We further identified CCL2 as a mediator involved in T-cell suppression upon interaction between sialoglycans and Siglec receptors on MDSCs.Our results demonstrated that sialylated glycans inhibit anticancer immunity by modulating CCL2 expression.展开更多
Background and Aims:Alpha-1 antitrypsin deficiency(AATD)is a genetic disorder characterized by the misfolding and accumulation of the mutant variant of alpha-1 antitrypsin(AAT)within hepatocytes,which limits its acces...Background and Aims:Alpha-1 antitrypsin deficiency(AATD)is a genetic disorder characterized by the misfolding and accumulation of the mutant variant of alpha-1 antitrypsin(AAT)within hepatocytes,which limits its access to the circulation and exposes the lungs to protease-mediated tissue damage.This results in progressive liver disease secondary to AAT polymerization and accumulation,and chronic obstructive pulmonary disease(COPD)due to deficient levels of AAT within the lungs.Our goal was to characterize the unique effects of COPD secondary to AATD on liver disease and gene expression.Methods:A subcohort of AATD individuals with COPD(n=33)and AATD individuals without COPD(n=14)were evaluated in this study from our previously reported cross-sectional cohort.We used immunohistochemistry to assess the AATD liver phenotype,and RNA sequencing to explore liver transcriptomics.We observed a distinct transcriptomic profile in liver tissues from AATD individuals with COPD compared to those without.Results:A total of 339 genes were differentially expressed.Canonical pathways related to fibrosis,extracellular matrix remodeling,collagen deposition,hepatocellular damage,and inflammation were significantly upregulated in the livers of AATD individuals with COPD.Histopathological analysis also revealed higher levels of fibrosis and hepatocellular damage in these individuals.Conclusions:Our data supports a relationship between the development of COPD and liver disease in AATD and introduces genes and pathways that may play a role in AATD liver disease when COPD is present.We believe addressing lung impairment and airway inflammation may be an approach to managing AATD-related liver disease.展开更多
Postnatal mammalian cardiomyocytes(CMs)rapidly lose proliferative capacity and exit the cell cycle to undergo further differentiation and maturation.Cell cycle activation has been a major strategy to stimulate postnat...Postnatal mammalian cardiomyocytes(CMs)rapidly lose proliferative capacity and exit the cell cycle to undergo further differentiation and maturation.Cell cycle activation has been a major strategy to stimulate postnatal CM proliferation,albeit achieving modest effects.One impediment is that postnatal CMs may need to undergo dedifferentiation before proliferation,if not simultaneously.Here,we report that overexpression of Hdac7 in neonatal mouse CMs results in significant CM dedifferentiation and proliferation.Mechanistically,we showthat histone deacetylase7(HDAC7)-mediatedCM proliferation is contingent on dedifferentiation,which is accomplished by suppressing myocyte enhancefactor2(MEF2).Hdac7overexpression in CM shifts the chromatin state from binding with MEF2,which favors the transcriptional program toward differentiation,to binding with AP-1,which favors the transcriptional program toward proliferation.Furthermore,we found that HDAC7 interacts with minichromosome maintenance complex components to initiate cell cycleprogression.Ourfindings revealthat HDAC7 promotes CM proliferation byits dual action on CM dedifferentiation and proliferation,uncovering a potential new strategy for heart regeneration/repair.展开更多
WRKYgenee encode transcription factors that are Involved In the regulation of various biological processes. These zinc-finger proteins, especially those members mediating stress responses, are uniquely expanded In pla...WRKYgenee encode transcription factors that are Involved In the regulation of various biological processes. These zinc-finger proteins, especially those members mediating stress responses, are uniquely expanded In plants. To facilitate the study of the evolutionary history and functions of this eupergene family, we performed an exhaustive search for WRKY genes using HMMER and a Hidden Markov Model that was specifically trained for rice. This work resulted In a comprehensive list of WRKYgene models In Oryza sativa L. eep. indica and L. eep. Japonica. Mapping of these genes to Individual chromosomes facilitated elimination of the redundant, leading to the Identification of 98 WRKYgenee In Japonica and 102 In indica rice. These genes were further categorized according to the number and structure of their zinc-finger domains. Based on a phylogenetlc tree of the conserved WRKY domains and the graphic display of WRKY loci on corresponding indica and Japonica chromosomes, we Identified possible WRKY gene duplications within, and losses between the two closely related rice subspecies. Also reviewed are the roles of WRKY genes In disease resistance and responses to salicylic acid and Jaemonlc acid, seed development and germination mediated by glbberelllns, other developmental processes Including senescence, and responses to ablotlc stresses and abeclelc acid In rice and other plants. The signaling pathways mediating WRKY gene expreeelon are also discussed.展开更多
The fast development of next-generation sequencing technology presents a major computational challenge for data processing and analysis.A fast algorithm,de Bruijn graph has been successfully used for genome DNA de nov...The fast development of next-generation sequencing technology presents a major computational challenge for data processing and analysis.A fast algorithm,de Bruijn graph has been successfully used for genome DNA de novo assembly;nevertheless,its performance for transcriptome assembly is unclear.In this study,we used both simulated and real RNA-Seq data,from either artificial RNA templates or human transcripts,to evaluate five de novo assemblers,ABySS,Mira,Trinity,Velvet and Oases.Of these assemblers,ABySS,Trinity,Velvet and Oases are all based on de Bruijn graph,and Mira uses an overlap graph algorithm.Various numbers of RNA short reads were selected from the External RNA Control Consortium(ERCC) data and human chromosome 22.A number of statistics were then calculated for the resulting contigs from each assembler.Each experiment was repeated multiple times to obtain the mean statistics and standard error estimate.Trinity had relative good performance for both ERCC and human data,but it may not consistently generate full length transcripts.ABySS was the fastest method but its assembly quality was low.Mira gave a good rate for mapping its contigs onto human chromosome 22,but its computational speed is not satisfactory.Our results suggest that transcript assembly remains a challenge problem for bioinformatics society.Therefore,a novel assembler is in need for assembling transcriptome data generated by next generation sequencing technique.展开更多
Cancer metastasis is largely incurable and accounts for 90%of breast cancer deaths,especially for the aggressive basal-like or triple negative breast cancer(TNBC).Combining patient database analyses and functional stu...Cancer metastasis is largely incurable and accounts for 90%of breast cancer deaths,especially for the aggressive basal-like or triple negative breast cancer(TNBC).Combining patient database analyses and functional studies,we examined the association of integrin family members with clinical outcomes as well as their connection with previously identified microRNA regulators of metastasis,such as miR-206 that inhibits stemness and metastasis of TNBC.Here we report that the integrin receptor CD49b-encoding ITGA2,a direct target of miR-206,promotes breast cancer stemness and metastasis.ITGA2 knockdown sup-pressed self-renewal related mammosphere formation and pluripotency marker expression,in-hibited cell cycling,compromised migration and invasion,and therefore decreased lung metastasis of breast cancer.ITGA2 overexpression reversed miR-206-caused cell cycle arrest in G1.RNA sequencing analyses revealed that ITGA2 knockdown inhibits genes related to cell cycle regulation and lipid metabolism,including CCND1 and ACLY as representative targets,respectively.Knockdown of CCND1 or ACLY inhibits mammosphere formation of breast cancer cells.Overexpression of CCND1 rescues the phenotype of ITGA2 knockdown-induced cell cycle arrest.ACLY-encoded ATP citrate lyase is essential to maintain cellular acetyl-CoA levels.CCND1 knockdown further mimics 1TGA2 knodkdown in abolishing lung colonization of breast cancer cells.We identified that the low levels of miR-206 as well as high expression levels of 1TGA2,ACLY and CCND1 are associated with an unf avor able relapse-free survival of the pa-tients with estrogen receptor-negative or high grade breast cancer,especially basal-like or TNBC,possibly serving as potential biomarkers of cancer stemness and thera peutic targets of breast cancer metastasis.展开更多
Dear Editor,The global burden of cancer is significant.The list of malignancies regarded as obesity-related continues to expand as evidence accumulates[1,2].Fueled by the ongoing obesity epidemic,obesity has emerged a...Dear Editor,The global burden of cancer is significant.The list of malignancies regarded as obesity-related continues to expand as evidence accumulates[1,2].Fueled by the ongoing obesity epidemic,obesity has emerged as one of the most important preventable causes of cancerworldwide[1,3].Given the long latency periods of many obesity-related adult cancers,risk factors with onset during early age and accumulation of risks during one’s life course are likely to be of importance[4].展开更多
Articular cartilage has a limited capacity to self-heal once damaged.Tissue-specific stem cells are a solution for cartilage regeneration;however,ex vivo expansion resulting in cell senescence remains a challenge as a...Articular cartilage has a limited capacity to self-heal once damaged.Tissue-specific stem cells are a solution for cartilage regeneration;however,ex vivo expansion resulting in cell senescence remains a challenge as a large quantity of high-quality tissue-specific stem cells are needed for cartilage regeneration.Our previous report demonstrated that decellularized extracellular matrix(dECM)deposited by human synovium-derived stem cells(SDSCs),adipose-derived stem cells(ADSCs),urine-derived stem cells(UDSCs),or dermal fibroblasts(DFs)provided an ex vivo solution to rejuvenate human SDSCs in proliferation and chondrogenic potential,particularly for dECM deposited by UDSCs.To make the cell-derived dECM(C-dECM)approach applicable clinically,in this study,we evaluated ex vivo rejuvenation of rabbit infrapatellar fat pad-derived stem cells(IPFSCs),an easily accessible alternative for SDSCs,by the abovementioned C-dECMs,in vivo application for functional cartilage repair in a rabbit osteochondral defect model,and potential cellular and molecular mechanisms underlying this rejuvenation.We found that C-dECM rejuvenation promoted rabbit IPFSCs’cartilage engineering and functional regeneration in both ex vivo and in vivo models,particularly for the dECM deposited by UDSCs,which was further confirmed by proteomics data.RNA-Seq analysis indicated that both mesenchymal-epithelial transition(MET)and inflammation-mediated macrophage activation and polarization are potentially involved in the C-dECM-mediated promotion of IPFSCs’chondrogenic capacity,which needs further investigation.展开更多
基金National Research Agency under the Investments for the Future program (ANR-10-IAHU-01)Filière Nationale TeteCou for financial support。
文摘Gain-of-function mutations in fibroblast growth factor receptor(FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, we analyzed the impact of Fgfr2- and Fgfr3- activating mutations on mandibular bone formation and endochondral bone repair after non-stabilized mandibular fractures in mouse models of Crouzon syndrome(Crz) and hypochondroplasia(Hch).
基金This project used the UPMC Hillman Cancer Center and Tissue and Research Pathology/Pitt Biospecimen Core shared resource,which is supported,in part,by award P30CA047904supported through grant funding by the Pittsburgh Cure Sarcoma Foundationinternal funding by the West Virginia University School of Medicine,Department of Orthopaedics。
文摘Patients diagnosed with advanced osteosarcoma,often in the form of lung metastases,have abysmal five-year overall survival rates.The complexity of the osteosarcoma immune tumor microenvironment has been implicated in clinical trial failures of various immunotherapies.The purpose of this exploratory study was to spatially characterize the immune tumor microenvironment of metastatic osteosarcoma lung specimens.Knowledge of the coordinating cellular networks within these tissues could then lead to improved outcomes when utilizing immunotherapy for treatment of this disease.Importantly,various cell types,interactions,and cellular neighborhoods were associated with five-year survival status.Of note,increases in cellular interactions between T lymphocytes,positive for programmed cell death protein 1,and myeloid-derived suppressor cells were observed in the 5-year deceased cohort.Additionally,cellular neighborhood analysis identified an Immune-Cold Parenchyma cellular neighborhood,also associated with worse 5-year survival.Finally,the Osteosarcoma Spatial Score,which approximates effector immune activity in the immune tumor microenvironment through the spatial proximity of immune and tumor cells,was increased within 5-year survivors,suggesting improved effector signaling in this patient cohort.Ultimately,these data represent a robust spatial multiplexed immunofluorescence analysis of the metastatic osteosarcoma immune tumor microenvironment.Various communication networks,and their association with survival,were described.In the future,identification of these networks may suggest the use of specific,combinatory immunotherapeutic strategies for improved anti-tumor immune responses and outcomes in osteosarcoma.
基金Supported by Medical Science and Technology Development Foundation,Nanjing Department of Health,No.YKK14140(to ShuiMing Wang)and No.ZKX15040(to Bin Jiang)Project of Administration of Traditional Chinese Medicine of Jiangsu Province of China,No.LZ11101(to Zhi-Ming Fang)
文摘BACKGROUND The development of colorectal cancer(CRC) is a complicated multistep process that involves an accumulation of mutations in tumor suppressor genes and oncogenes.In the process of DNA replication, base mismatch often occurs due to various factors leading to abnormal expression of mismatch repair genes(MMR),among which MLH1 and MSH2 are the most important.Recently, numerous studies indicated that MLH1/MSH2 phenotype is associated with CRC.We wanted to elucidate the role of MLH1/MSH2 in the prediction and prognosis of CRC through long-term clinical observation.AIM To evaluate the prognostic and predictive significance of MLH1/MSH2 in patients with stage Ⅱ-Ⅲ CRC using immunohistochemical analysis and GeneScan.METHODS Specimens from 681 patients with CRC(395 stage Ⅱ and 286 stage Ⅲ, 387 males and 294 females) who underwent curative surgical resection from 2013 to 2016 were tested.Immunohistochemistry was used to analyze MMR status and the microsatellite status of 133 patients was determined by GeneScan analysis.RESULTS Five hundred and fifty(80.76%) patients were MLH1/MSH2 positive and 131(19.24%) were negative by immunohistochemistry.MLH1/MSH2-positive tumors were significantly more frequent in the colon than in the rectum, and had poor differentiation and less mucin production(P < 0.05).Patients of different groups did not differ in terms of age, gender, tumor size, tumor stage, lymphocytic infiltration, or circumscribed margin.MLH1/MSH2-negative patients had a more favorable OS than MLH1/MSH2-positive patients(P < 0.001).Univariate and multivariate analyses demonstrated MLH1/MSH2 expression as an independent prognostic and predictive factor for stage Ⅱ/Ⅲ CRC.MLH1/MSH2 expression was a strong prognostic factor in all patients [P < 0.001, hazard ratio(HR) = 4.064,95%CI: 2.241–7.369].Adjuvant chemotherapy had a greater correlation with survival advantage in MLH1/MSH2-negative patients with stage Ⅲ disease(P <0.001, HR = 7.660, 95%CI: 2.974–15.883).However, patients with stage Ⅱ disease or MLH1/MSH2-positive patients with stage Ⅲ disease did not benefit from adjuvant chemotherapy.GeneScan analysis demonstrated that among 133 patients, 105(78.95%) were microsatellite stable, and 28(21.05%) had microsatellite instability(MSI), including 18(13.53%) with high MSI and 10(7.52%) with low MSI.This is consistent with the immunohistochemical results.CONCLUSION MLH1/MSH2 phenotype constitutes a pathologically and clinically distinct subtype of sporadic CRC.MLH1/MSH2 is an independent prognostic and predictive factor for outcome of stage Ⅱ-Ⅲ CRC.
文摘We previously demonstrated immune activation in the maternal peripheral circulation associated with preterm labor (PTL). There was an elevation in WBC mRNA of anti-inflammatory complement decay-accelerating factor (CD55) and the innate-immune response activating toll-like receptor 4 (TLR4). These findings suggested that collectively, these two molecules might serve as useful biomolecules to aid in the diagnosis of PTL. In this study, we used a combined marker approach to determine whether a dual marker model utilizing both CD55 and TLR4 mRNA levels to classify PTL would increase diagnostic accuracy compared to either molecule alone. Two methods were evaluated;a linear discriminant (LD) method and a distribution free (DF) method, in order to find the optimal linear combination of TLR4 and CD55 data to diagnose PTL accurately. Our results indicated that a combined CD55-TLR4 dual marker model could provide statistically significant improve- ments compared to CD55 or TLR4 single marker models for PTL classification performance.
文摘Beta-defensin 20(DEFB20)is widely expressed in the epididymis with gene features involved in epididymal sperm maturation.However,the action mechanism and function of DEFB20 in sperm maturation are still unclear.One of the important roles of beta-defensin is the ion channel activity.The cation channel sperm-associated protein(CatSper)alpha is an ion channel protein found on the sperm surface.This study aimed to investigate the interaction between DEFB20 and CatSper1–4 protein in relation to the sperm maturation process.Protein sequences were obtained from the National Center for Biotechnology Information(NCBI).Protein modeling and validation were carried out by using the Robetta modeling server and the Ramachandran plot method.Rosetta web server was used for the docking analysis.The results revealed a natural interaction between DEFB20 and CatSper1–4.The interaction occurred at the cation channel(close to the casein kinase II),ion transport protein,and kinase c phosphorylation of the CatSper1–4 active site.The DEFB20 region interacting with CatSper2–4 was the beta-defensin domain,while with CatSper1 was the non-beta-defensin domain.Based on the analysis,DEFB20 may interact with CatSperαsubunits,particularly CatsSper1,to affect ion channel activity during sperm maturation.
基金This work was supported by start-up funds and a Showalter Trust Fund award for bioinformatics support from Purdue University to J.R.WThis material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE-1333468 to J.W.C. We thank Jim McKenna (Hardwood Tree Improvement and Regeneration Center, Purdue University) for providing black walnut seedlings and collecting tissues from mature trees, Elena Yakubova for technical assistance, and Jing Yuan for assistance with microscopy.
文摘Several members of the Juglandaceae family produce juglone,a specialized 1,4-naphthoquinone(1,4-NQ)natural product that is responsible for the notorious allelopathic effects of black walnut(Juglans nigra).Despite its documented ecological roles and potential for being developed as a novel natural product-based herbicide,none of the genes involved in synthesizing juglone have been identified.Based on classical labeling studies,we hypothesized that biosynthesis of juglone’s naphthalenoid moiety is shared with biochemical steps of the phylloquinone pathway.Here,using comparative transcriptomics in combination with targeted metabolic profiling of 1,4-NQs in various black walnut organs,we provide evidence that phylloquinone pathway genes involved in 1,4-dihydroxynaphthoic acid(DHNA)formation are expressed in roots for synthesis of a compound other than phylloquinone.Feeding experiments using axenic black walnut root cultures revealed that stable isotopically labeled L-glutamate incorporates into juglone resulting in the same mass shift as that expected for labeling of the quinone ring in phylloquinone.Taken together,these results indicate that in planta,an intermediate from the phylloquinone pathway provides the naphthalenoid moiety of juglone.Moreover,this work shows that juglone can be de novo synthesized in roots without the contribution of immediate precursors translocated from aerial tissues.The present study illuminates all genes involved in synthesizing the juglone naphthoquinone ring and provides RNA-sequencing datasets that can be used with functional screening studies to elucidate the remaining juglone pathway genes.Translation of the generated knowledge is expected to inform future metabolic engineering strategies for harnessing juglone as a novel natural product-based herbicide.
基金Supported by Nanjing Municipal Health Bureau,No.ZKX15040Nanjing Medical Science and Technology Development Foundation,No.NWQR-201702
文摘BACKGROUND Primary neuroendocrine tumors (NETs) in the presacral region are extremely rare, some of which are caused by other primary tumors or metastatic rectal carcinoids. Nevertheless, cases of NETs have been increasing in recent years. This report describes the first primary neuroendocrine tumor in the presacral region that was found at our hospital within the last five years. CASE SUMMARY The patient was identified as a 36-year-old woman with a presacral mass and pelvic floor pain. A digital rectal examination revealed a presacral mass with unclear margins and obvious tenderness. Magnetic resonance imaging (MRI) demonstrated a 57 mm × 29 mm presacral lump. An ultrasound-guided needle biopsy confirmed a well-differentiated neuroendocrine tumor. No other primary or metastatic tumors were found. CONCLUSION Comprehensive consideration of our case report and literature reported by others suggests that a conclusive diagnosis of NETs should be based on computed tomography/MRI and pathological examinations. The treatment of primary NETs in the presacral region mainly relies on surgical procedures with follow-up.
基金supported by the National Key Research and Development Program of China (2017YFA0505500 to L.N.C., 2017YFC0909502 to J.S.Z.)Strategic Priority Research Program of the Chinese Academy of Sciences (XDB38040400 to L.N.C., XDB13000000 to W.W.)+3 种基金National Science Foundation of China (12131020 and 31930022 to L.N.C, 61602460 to J.S.Z.)Major Key Project of PCL (PCL2021A12 to L.N.C.)Special Fund for Science and Technology Innovation Strategy of Guangdong Province(2021B0909050004 and 2021B0909060002 to L.N.C.)Fundamental Research Funds for the Central Universities(3102019JC007 to W.W.)。
文摘The divergence and continuous evolution of plants and animals contribute to ecological diversity.Promoters and transcription factors(TFs) are key determinants of gene regulation and transcription throughoutlife.However,theevolutionary trajectories and relationships of promoters and TFs are still poorly understood. Here, we conducted extensive analysis of large-scale multi-omics sequences in 420 animal species and 223 plant species spanning nearly a billion years of evolutionary history. Results showed that promoter GC-contentandTFisoelectricpoints,as features/signatures that accompany long biological evolution, exhibited increasing growth in animal cells but a decreasing trend in plant cells. Furthermore, the evolutionary trajectories of promoter and TF signatures in the animal kingdom provided further evidence that Mammalia as well as Aves evolved directly from the ancestor Reptilia. The strong correlation between promoter and TF signatures indicates that promoters and TFs formed antagonistic coevolution in the animal kingdom, but mutualistic coevolution in the plant kingdom. The distinct coevolutionary patterns potentially drive the plant-animal divergence, divergent evolution and ecological diversity.
基金supported the Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional“Una manera de hacer Europa”to RMM(PI 19/01884 and PI22/01506)by the Government of Navarra(34/2021)/50%FEDER 2014-2020 and by the Foundation AECC(PRYES211377MART)+7 种基金funded by Cancer Research Thematic Network of the Instituto de Salud Carlos III(RTICC RD12/0036/0066)SAF2015-71606R,RTI2018-094507B-100 financed by MCIN/AEI/10.13039/501100011033/and by FEDER“Una manera de hacer Europa”MICIU PID2021-1226380B-100 and PID2024-156335OB-100supported by FIS(PI22/01253)supported by the Foundation for Applied Medical Research(FIMA)and CIBERONC(CB16/12/00443)funded by the Government of Navarra of the I+D 2022-25,GEMA(GRANATE:Grupo de Radioterapia Avanzada de Navarra,0011-1411-2022-000066 and 0011-1411-2022-000073)supported by a Project PID2023-152755OB-I00 funded by MICIU/AEI/10.13039/501100011033 and by FEDER,EU.K.Vsupported by an Investigator grant from AECC.F.L.and S.V.report research funding from Roche.F.L.and R.M.-M.report consulting fees from Ellipses Life.No potential conflicts of interest were disclosed by the other authors.
文摘The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the precise mechanisms remain unclear.In a model of local recurrence(LR),circulating tumor cells(CTC)engrafting in the post-resection tumor bed developed a radioresistant phenotype linked to an ENPP1+-gene signature which was also identified in TNBC patients,suggesting ENPP1´s role in genome integrity.Blockade of ENPP1 using a permeable ENPP1 inhibitor(AVA-NP-695)reduced radioresistance,mechanistically attributed to decreased homologous recombination(HR)resulting in persistent DNA damage,as evidenced by enhanced tail moment and sustainedγH2AX formation.This impaired DNA damage repair(DDR)sensitized tumor cells to ionizing radiation(IR).Notably,several DDR inhibitors(i)(including PARPi and ATMi)showed the highest synergy score in a targeted pharmacological screening.In vivo,dual ENPP1/ATM inhibition heightened radiosensitivity,compromised tumor cell survival and enhanced STINGTBK1 signaling by preventing ENPP1-mediated cGAMP hydrolysis.This resulted in robust innate and long-lasting adaptive antitumor immune memory responses,leading to significant tumor regression.Remarkably,combined treatment post-IR reduced spontaneous metastasis and local recurrence,and induced abscopal effects that impacted distant tumor spread in orthotopic tumor models.Thus,these findings position ENPP1 as a critical link between genome integrity and immunosuppression,offering promising translational opportunities for treating local or distant dissemination in TNBC.
基金supported by CIRM fellowshipssupported by grants from the G.Harold and Leila Y.Mathers Charitable Foundation,The California Institute of Regenerative Medicine,Ellison Medical Foundation,and The Leona M.and Harry B.Helmsley Charitable Trust grant#2012-PG-MED002supported by the KAUST Office of Sponsored Research(OSR)under Award No.BAS/1/1080-01(ML),URF/1/4716-01(ML)and KAUST Center of Excellence for Smart Health(KCSH)award number 5932.
文摘Human pluripotent stem cells(hPSCs)can in theory give rise to any hematopoietic lineages,thereby offering opportunities for disease modeling,drug screening and cell therapies.However,gaps in our knowledge of the signaling requirements for the specification of human hematopoietic stem/progenitor cells(HSPCs),which lie at the apex of all hematopoietic lineages,greatly limit the potential of hPSC in hematological research and application.Transcriptomic analysis reveals aberrant regulation of WNT signaling during maturation of hPSC-derived hematopoietic progenitor cells(hPSC-HPCs),which results in higher mitochondria activity,misregulation of HOX genes,loss of self-renewal and precocious differentiation.These defects are partly due to the activation of the WNT target gene CDX2.Late-stage WNT inhibition improves the yield,self-renewal,multilineage differentiation,and transcriptional and metabolic profiles of hPSC-HPCs.Genome-wide mapping of transcription factor(TF)accessible chromatin reveals a significant overrepresentation of myeloid TF binding motifs in hPSC-HPCs,which could underlie their myeloid-biased lineage potential.Together our findings uncover a previously unappreciated dynamic requirement of the WNT signaling pathway during the specification of human HSPCs.Modulating the WNT pathway with small molecules normalizes the molecular differences between hPSC-HPCs and endogenous hematopoietic stem cells(HSCs),thereby representing a promising approach to improve the differentiation and function of hPSC-HPCs.
基金supported by funding from the Swiss National Science Foundation(SNSF Grant No.310030-215237/1)the Schoenmakers-Müller Foundation,a research grant from Ono Pharmaceuticals,and the Cancer League of Basel(KlbB).Open access funding provided by University of Basel.
文摘The overexpression of sialic acids on glycans,called hypersialylation,is a common alteration found in cancer cells.Sialylated glycans can enhance immune evasion by interacting with sialic acid-binding immunoglobulin-like lectin(Siglec)receptors on tumorinfiltrating immune cells.Here,we investigated the effect of sialylated glycans and their interaction with Siglec receptors on myeloid-derived suppressor cells(MDSCs).We found that MDSCs derived from the blood of lung cancer patients and tumor-bearing mice strongly express inhibitory Siglec receptors and are highly sialylated.In murine cancer models of emergency myelopoiesis,Siglec-E knockout in myeloid cells resulted in prolonged survival and increased tumor infiltration of activated T cells.Targeting suppressive myeloid cells by blocking Siglec receptors or desialylation strongly reduced their suppressive potential.We further identified CCL2 as a mediator involved in T-cell suppression upon interaction between sialoglycans and Siglec receptors on MDSCs.Our results demonstrated that sialylated glycans inhibit anticancer immunity by modulating CCL2 expression.
基金sponsored by a grant from the Alpha-1 Foundation(AGR00019116).
文摘Background and Aims:Alpha-1 antitrypsin deficiency(AATD)is a genetic disorder characterized by the misfolding and accumulation of the mutant variant of alpha-1 antitrypsin(AAT)within hepatocytes,which limits its access to the circulation and exposes the lungs to protease-mediated tissue damage.This results in progressive liver disease secondary to AAT polymerization and accumulation,and chronic obstructive pulmonary disease(COPD)due to deficient levels of AAT within the lungs.Our goal was to characterize the unique effects of COPD secondary to AATD on liver disease and gene expression.Methods:A subcohort of AATD individuals with COPD(n=33)and AATD individuals without COPD(n=14)were evaluated in this study from our previously reported cross-sectional cohort.We used immunohistochemistry to assess the AATD liver phenotype,and RNA sequencing to explore liver transcriptomics.We observed a distinct transcriptomic profile in liver tissues from AATD individuals with COPD compared to those without.Results:A total of 339 genes were differentially expressed.Canonical pathways related to fibrosis,extracellular matrix remodeling,collagen deposition,hepatocellular damage,and inflammation were significantly upregulated in the livers of AATD individuals with COPD.Histopathological analysis also revealed higher levels of fibrosis and hepatocellular damage in these individuals.Conclusions:Our data supports a relationship between the development of COPD and liver disease in AATD and introduces genes and pathways that may play a role in AATD liver disease when COPD is present.We believe addressing lung impairment and airway inflammation may be an approach to managing AATD-related liver disease.
基金supported by the National Heart,Lung,and Blood Institute R01 grant(HL153406).
文摘Postnatal mammalian cardiomyocytes(CMs)rapidly lose proliferative capacity and exit the cell cycle to undergo further differentiation and maturation.Cell cycle activation has been a major strategy to stimulate postnatal CM proliferation,albeit achieving modest effects.One impediment is that postnatal CMs may need to undergo dedifferentiation before proliferation,if not simultaneously.Here,we report that overexpression of Hdac7 in neonatal mouse CMs results in significant CM dedifferentiation and proliferation.Mechanistically,we showthat histone deacetylase7(HDAC7)-mediatedCM proliferation is contingent on dedifferentiation,which is accomplished by suppressing myocyte enhancefactor2(MEF2).Hdac7overexpression in CM shifts the chromatin state from binding with MEF2,which favors the transcriptional program toward differentiation,to binding with AP-1,which favors the transcriptional program toward proliferation.Furthermore,we found that HDAC7 interacts with minichromosome maintenance complex components to initiate cell cycleprogression.Ourfindings revealthat HDAC7 promotes CM proliferation byits dual action on CM dedifferentiation and proliferation,uncovering a potential new strategy for heart regeneration/repair.
基金Supported by the National Center for Research Resources （NCRR） （P20 RR 016464）, a component of the National Institutes of Health （NIH）, Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH. Publication of this paper is supported by the National Natural Science Foundation of China （30624808）. Acknowledgements The authors thank two former members of our laboratory namely Drs Zhonglin Zhang and Zhen Xie, for stimulating discussions and their contributions in preparing Figure 4 and compiling information for the biological functions of WRKYgenes. Dr Zhang is currently a postdoctoral fellow in Duke and Dr Xie is a postdoctoral fellow in Harvard.
文摘WRKYgenee encode transcription factors that are Involved In the regulation of various biological processes. These zinc-finger proteins, especially those members mediating stress responses, are uniquely expanded In plants. To facilitate the study of the evolutionary history and functions of this eupergene family, we performed an exhaustive search for WRKY genes using HMMER and a Hidden Markov Model that was specifically trained for rice. This work resulted In a comprehensive list of WRKYgene models In Oryza sativa L. eep. indica and L. eep. Japonica. Mapping of these genes to Individual chromosomes facilitated elimination of the redundant, leading to the Identification of 98 WRKYgenee In Japonica and 102 In indica rice. These genes were further categorized according to the number and structure of their zinc-finger domains. Based on a phylogenetlc tree of the conserved WRKY domains and the graphic display of WRKY loci on corresponding indica and Japonica chromosomes, we Identified possible WRKY gene duplications within, and losses between the two closely related rice subspecies. Also reviewed are the roles of WRKY genes In disease resistance and responses to salicylic acid and Jaemonlc acid, seed development and germination mediated by glbberelllns, other developmental processes Including senescence, and responses to ablotlc stresses and abeclelc acid In rice and other plants. The signaling pathways mediating WRKY gene expreeelon are also discussed.
基金supported by grants from the National Center for Research Resources (5P20RR016471-12)the National Institute of General Medical Sciences (8 P20 GM103442-12) from the National Institutes of Healththe seed collaborative research grant from the Odegard School of Aerospace Sciences and the School of Medicine and Health Sciences at University of North Dakota
文摘The fast development of next-generation sequencing technology presents a major computational challenge for data processing and analysis.A fast algorithm,de Bruijn graph has been successfully used for genome DNA de novo assembly;nevertheless,its performance for transcriptome assembly is unclear.In this study,we used both simulated and real RNA-Seq data,from either artificial RNA templates or human transcripts,to evaluate five de novo assemblers,ABySS,Mira,Trinity,Velvet and Oases.Of these assemblers,ABySS,Trinity,Velvet and Oases are all based on de Bruijn graph,and Mira uses an overlap graph algorithm.Various numbers of RNA short reads were selected from the External RNA Control Consortium(ERCC) data and human chromosome 22.A number of statistics were then calculated for the resulting contigs from each assembler.Each experiment was repeated multiple times to obtain the mean statistics and standard error estimate.Trinity had relative good performance for both ERCC and human data,but it may not consistently generate full length transcripts.ABySS was the fastest method but its assembly quality was low.Mira gave a good rate for mapping its contigs onto human chromosome 22,but its computational speed is not satisfactory.Our results suggest that transcript assembly remains a challenge problem for bioinformatics society.Therefore,a novel assembler is in need for assembling transcriptome data generated by next generation sequencing technique.
基金This manuscript has been partially supported by NIH/NCI grants R00CA160638 and R01CA245699(H.L.),and Supple-ment for Diversity(V.A.),T32 CA080621-15(R.T.),and R01CA213843(R.A.K),American Cancer Society grant ACS127951-RSG-15-025-01-CSM(H.L.)the Susan G.Komen Foundation CCR15332826(H.L.)and CCR18548501(X.L.)+3 种基金the Department of Defense W81XWH-16-1-0021(H.L.)the Lynn Sage Cancer Research Foundation(X.L.and H.L.)North-western University’s Endocrinology Training Grant T32DK007169-39(A.H.)and start-up funds fromCaseWestern Reserve University and at Northwestern University(H.L.).
文摘Cancer metastasis is largely incurable and accounts for 90%of breast cancer deaths,especially for the aggressive basal-like or triple negative breast cancer(TNBC).Combining patient database analyses and functional studies,we examined the association of integrin family members with clinical outcomes as well as their connection with previously identified microRNA regulators of metastasis,such as miR-206 that inhibits stemness and metastasis of TNBC.Here we report that the integrin receptor CD49b-encoding ITGA2,a direct target of miR-206,promotes breast cancer stemness and metastasis.ITGA2 knockdown sup-pressed self-renewal related mammosphere formation and pluripotency marker expression,in-hibited cell cycling,compromised migration and invasion,and therefore decreased lung metastasis of breast cancer.ITGA2 overexpression reversed miR-206-caused cell cycle arrest in G1.RNA sequencing analyses revealed that ITGA2 knockdown inhibits genes related to cell cycle regulation and lipid metabolism,including CCND1 and ACLY as representative targets,respectively.Knockdown of CCND1 or ACLY inhibits mammosphere formation of breast cancer cells.Overexpression of CCND1 rescues the phenotype of ITGA2 knockdown-induced cell cycle arrest.ACLY-encoded ATP citrate lyase is essential to maintain cellular acetyl-CoA levels.CCND1 knockdown further mimics 1TGA2 knodkdown in abolishing lung colonization of breast cancer cells.We identified that the low levels of miR-206 as well as high expression levels of 1TGA2,ACLY and CCND1 are associated with an unf avor able relapse-free survival of the pa-tients with estrogen receptor-negative or high grade breast cancer,especially basal-like or TNBC,possibly serving as potential biomarkers of cancer stemness and thera peutic targets of breast cancer metastasis.
基金Thisworkwas supported by the Swedish Research Council and by grants from the Swedish state under the agreement between the Swedish Government and the County Councils,the ALF-agreement(grant numbers 883541,723791 and 238261),Swedish Heart-Lung Foundation,the Lundberg Foundation,the Torsten Soderberg Foundation,the Novo Nordisk Foundation and the Knut and Alice Wallenberg Foundation.None of the funders had any role in the design and conduct of the study,collection,management,analysis,and interpretation of the data,or preparation,review,or approval of the manuscript.
文摘Dear Editor,The global burden of cancer is significant.The list of malignancies regarded as obesity-related continues to expand as evidence accumulates[1,2].Fueled by the ongoing obesity epidemic,obesity has emerged as one of the most important preventable causes of cancerworldwide[1,3].Given the long latency periods of many obesity-related adult cancers,risk factors with onset during early age and accumulation of risks during one’s life course are likely to be of importance[4].
文摘Articular cartilage has a limited capacity to self-heal once damaged.Tissue-specific stem cells are a solution for cartilage regeneration;however,ex vivo expansion resulting in cell senescence remains a challenge as a large quantity of high-quality tissue-specific stem cells are needed for cartilage regeneration.Our previous report demonstrated that decellularized extracellular matrix(dECM)deposited by human synovium-derived stem cells(SDSCs),adipose-derived stem cells(ADSCs),urine-derived stem cells(UDSCs),or dermal fibroblasts(DFs)provided an ex vivo solution to rejuvenate human SDSCs in proliferation and chondrogenic potential,particularly for dECM deposited by UDSCs.To make the cell-derived dECM(C-dECM)approach applicable clinically,in this study,we evaluated ex vivo rejuvenation of rabbit infrapatellar fat pad-derived stem cells(IPFSCs),an easily accessible alternative for SDSCs,by the abovementioned C-dECMs,in vivo application for functional cartilage repair in a rabbit osteochondral defect model,and potential cellular and molecular mechanisms underlying this rejuvenation.We found that C-dECM rejuvenation promoted rabbit IPFSCs’cartilage engineering and functional regeneration in both ex vivo and in vivo models,particularly for the dECM deposited by UDSCs,which was further confirmed by proteomics data.RNA-Seq analysis indicated that both mesenchymal-epithelial transition(MET)and inflammation-mediated macrophage activation and polarization are potentially involved in the C-dECM-mediated promotion of IPFSCs’chondrogenic capacity,which needs further investigation.
