BACKGROUND RNA binding motif 5(RBM5)has emerged as crucial regulators in many cancers.AIM To explore more functional and mechanistic exploration of RBM5 since the lack of research on RBM5 in colorectal cancer(CRC)dict...BACKGROUND RNA binding motif 5(RBM5)has emerged as crucial regulators in many cancers.AIM To explore more functional and mechanistic exploration of RBM5 since the lack of research on RBM5 in colorectal cancer(CRC)dictates that is essential.METHODS Through Gene Expression Profiling Interactive Analysis,we analyzed RBM5 expression in colon adenocarcinoma and rectum adenocarcinoma tissues.For detecting the mRNA expression of RBM5,quantitative real time-polymerase chain reaction was performed.Protein expression levels of RBM5,hexokinase 2,lactate dehydrogenase A,phosphatase and tensin homolog(PTEN),phosphoinositide 3-kinase(PI3K),phosphorylated-protein kinase B(p-AKT),and AKT were determined via Western blot.Functionally,cell counting kit-8 and 5-ethynyl-2’-deoxyuridine(EDU)assay were performed to evaluate proliferation of CRC cells.Invasiveness and migration of CRC cells were evaluated through conducting transwell assays.Glucose consumption,lactate production and adenosinetriphosphate(ATP)production were measured through a glucose assay kit,a lactate assay kit and an ATP production assay kit,respectively.Besides,RNA immunoprecipitation assay,half-life RT-PCR and dual-luciferase reporter assay were applied to detect interaction between RBM5 and PTEN.To establish a xenotypic tumor mice,CRC cells were subcutaneously injected into the right flank of each mouse.Protein expression of RBM5,Ki67,and PTEN in tumor tissues was examined using immunohistochemistry staining.Haematoxylin and eosin staining was used to evaluate tumor liver metastasis in mice.RESULTS We discovered down-regulation of RBM5 expression in CRC tissues and cells.RBM5 overexpression repressed proliferation,migration and invasion of CRC cells.Meantime,RBM5 impaired glycolysis in CRC cells,presenting as decreased glucose consumption,decreased lactate production and decreased ATP production.Besides,RBM5 bound to PTEN mRNA to stabilize its expression.PTEN expression was positively regulated by RBM5 in CRC cells.The protein levels of PI3K and p-AKT were significantly decreased after RBM5 overexpression.The suppressive influences of RBM5 on glycolysis,proliferation and metastasis of CRC cells were partially counteracted by PTEN knockdown.RBM5 suppressed tumor growth and liver metastasis in vivo.CONCLUSION This investigation provided new evidence that RBM5 was involved in CRC by binding to PTEN,expanding the importance of RBM5 in the treatment of CRC.展开更多
Objective:Anlotinib is a novel tyrosine kinase inhibitor blocking angiogenesis.This study was performed to assess the efficacy and safety of anlotinib in patients with metastatic breast cancer.Methods:Patients with HE...Objective:Anlotinib is a novel tyrosine kinase inhibitor blocking angiogenesis.This study was performed to assess the efficacy and safety of anlotinib in patients with metastatic breast cancer.Methods:Patients with HER2-negative breast cancer,who were pre-treated with anthracycline or taxanes in a neoadjuvant,adjuvant,or metastatic setting,and had treatment failure after at least one prior chemotherapy regimen in the metastatic setting were enrolled.Anlotinib was administered at 12 mg daily for 14 days in a 21-day cycle until disease progression or unacceptable toxicity occurred.Simultaneously,5–10 m L of venous blood was collected to perform circulating tumor DNA(ct DNA)testing every 2 treatment cycles.The primary endpoint was the objective response rate(ORR).Secondary endpoints included the disease control rate(DCR),progression-free survival(PFS),overall survival,safety,and biomarkers.Results:Twenty-six eligible patients were enrolled,with a median age of 56(30–75)years.The median follow-up time was 10.5 months.The ORR was 15.4%,the DCR was 80.8%,and the median PFS was 5.22 months(95%confidence interval 2.86–6.24).Fourteen(53.8%)patients survived for more than 10 months.The changes in the detectable ct DNA variant allele frequency were consistent with the tumor response.The most common treatment-related adverse events were hypertension(57.7%),thyroidstimulating hormone elevation(34.6%),and hand-foot syndrome(23.1%).Conclusion:Anlotinib showed objective efficacy with tolerable toxicity in heavily pre-treated,metastatic HER2-negative breast cancer.The dynamic changes in the ct DNA variant allele fraction may be predictive of the tumor response.展开更多
Tetragonal ZrO2-3 mol% Y2O3 （3Y-TZP） coated with CePO4 was synthesized by a co-precipitation method and the effects of CePO4 content and sintering temperature on its mechanical properties were investigated. The micr...Tetragonal ZrO2-3 mol% Y2O3 （3Y-TZP） coated with CePO4 was synthesized by a co-precipitation method and the effects of CePO4 content and sintering temperature on its mechanical properties were investigated. The microstructure and phase composition of the products were characterized using scanning and transmission electron microscopy as well as X-ray diffraction, respectively. The machinability index of CePO4-coated zirconia was calculated to be 1.05 when the CePO4 content is 25 wt.%. The sample hardness, bending strength and fracture toughness are 7.08 GPa, 457.85 MPa and 9.75 MPa m1/2, respectively, when the sintering temperature is 1400°C. The results show that as-prepared CePO4-coated 3Y-TZP ceramics are highly suitable biomaterials for dental applications and are expected to be used in a com-puter-aided design and computer-aided manufacturing （CAD/CAM） system to make dental crowns or bridge prostheses in a one-step sinter-ing process.展开更多
BACKGROUND Kissing molars(KMs)are a scarcely reported form of molar impaction in which the occlusal surfaces contact each other within a single dental follicle and the roots point in opposite directions.The direction ...BACKGROUND Kissing molars(KMs)are a scarcely reported form of molar impaction in which the occlusal surfaces contact each other within a single dental follicle and the roots point in opposite directions.The direction of KMs impaction is generally tilted.KMs with vertical direction impaction have not been reported in the literature.CASE SUMMARY A 25-year-old female visited a dentist for right maxillary wisdom teeth extraction and was diagnosed with two vertically impacted KMs in the left mandible on panoramic radiography.After cone-beam computed tomography examination confirmed no secondary complication,the patient chose to undergo observation and regular follow-up.A literature review of KMs revealed that vertical impacted KMs are rare;high-quality evidence regarding their prevalence is still lacking.At present,the causality of KMs is controversial.In this study,we have tried to provide a detailed definition of KMs to allow an accurate evaluation of their prevalence and classification based on their impaction direction which may be related to their pathogenesis.The treatment plan of KMs depends on the condition and location of the affected teeth and associated complications;they may be either directly extracted or treated using a multidisciplinary approach including maxillofacial surgeons and orthodontists.CONCLUSION KMs are a rare clinical condition of impacted teeth with unclear pathogenesis.Vertically impacted KMs were seldom reported.Reasonable definition and classification of KMs can help in the understanding of their causes and prevalence.展开更多
Objective:Apatinib is an oral TKI targeting VEGFR-2.Single-agent apatinib treatment has been shown to produce an objective response in patients with pretreated m BC.Oral vinorelbine also holds promise as a treatment o...Objective:Apatinib is an oral TKI targeting VEGFR-2.Single-agent apatinib treatment has been shown to produce an objective response in patients with pretreated m BC.Oral vinorelbine also holds promise as a treatment of choice in patients with m BC.This study aimed to investigate the efficacy and safety of the oral vinorelbine-apatinib combination in patients with pretreated m BC.In addition,we detected gene variants in ct DNA to explore the therapeutic implications.Methods:This study enrolled patients with HER2-negative m BC who were pretreated with anthracycline/taxanes.Patients were treated with apatinib at 500 mg/425 mg daily plus oral vinorelbine 60 mg/m2 on days 1,8,and 15 of every cycle(3 weeks).The primary endpoint was PFS.The secondary endpoints were ORR,CBR,OS,and safety.Patients eligible for ct DNA detection were evaluated before and during treatment.Results:Forty patients were enrolled.The median PFS was 5.2 months(95%CI,3.4–7.0 months),and the median OS was 17.4 months(95%CI,8.0–27.0 months).The ORR was 17.1%(6/35),and the CBR was 45.7%(16/35).The most common AEs included gastrointestinal reaction,myelosuppression,and hypertension.In 20 patients,ct DNA was detected at baseline and during treatment.A significant difference was found in PFS for undetected vs.detected baseline ct DNA(13.9 months vs.3.6 months,P=0.018).Conclusions:All-oral therapy with apatinib plus vinorelbine displayed objective efficacy in patients with heavily pretreated HER2-negative m BC,with acceptable and manageable toxicity profiles.Patients with no gene variant detected and lower variant allele frequencies in ct DNA at baseline showed longer PFS.展开更多
The Wnt/β-catenin signaling pathway is the main target of tooth regeneration regulation.Treatment of cells with AZD2858 stimulates the Wnt/β-catenin signaling pathway,yet the function of this pathway in tooth regene...The Wnt/β-catenin signaling pathway is the main target of tooth regeneration regulation.Treatment of cells with AZD2858 stimulates the Wnt/β-catenin signaling pathway,yet the function of this pathway in tooth regeneration remains unclear.Here,we found that AZD2858 promotes the accumulation ofβ-catenin in the nuclei of stem cells from the apical papilla(SCAPs)and enhances cell proliferation.Single-cell sequencing was performed on SCAPs treated with AZD2858.Eight clusters were identified,namely SCAPs-CNTNAP2,SCAPs-DTL,SCAPs-MYH11,SCAPs-MKI67,SCAPs-CXCL8,SCAPs-TPM2,SCAPs-IFIT2 and SCAPs-NEK10.The pseudo-time trajectory analysis showed that AZD2858 enhanced the evolution of SCAPs from SCAPs-TMP2 clusters to SCAPs-MYH11,SCAPs-CNTNAPs and SCAPs-NEK10 clusters via up-regulation of PRKCA,SMURF2,MAGI2,RBMS3,EXT1,CAMK2D,PLCB4,and PLCB1.These results demonstrate that AZD2858 enhances the proliferation of SCAPs-TPM2 cluster by activating the non-canonical Wnt/β-catenin signaling pathway.展开更多
Objective:Endocrine therapy with fulvestrant has shown synergistic antitumor effects with some chemotherapy drugs in vitro.This study evaluated the efficacy and safety of fulvestrant with vinorelbine in patients with ...Objective:Endocrine therapy with fulvestrant has shown synergistic antitumor effects with some chemotherapy drugs in vitro.This study evaluated the efficacy and safety of fulvestrant with vinorelbine in patients with hormone receptor positive(HR+)/human epidermal growth factor receptor-2-negative(HER2−)recurrent or metastatic breast cancer.Methods:Patients were intramuscularly administered fulvestrant 500 mg(day 1 per cycle for 28 days)and oral vinorelbine(60 mg/m2 on days 1,8,and 15 of each cycle).The primary endpoint was progression-free survival(PFS).Secondary endpoints included overall survival,objective response rate,disease control rate,duration of response,and safety.Results:A total of 38 patients with HR+/HER2−advanced breast cancer included in the study were followed up for a median time of 25.1 months.The overall median PFS was 9.86 months[95%confidence interval(CI)7.2-23.13],and the median PFS of the first-line and the second-line treatment population was 20.73 months(95%CI 9.82 to NR)and 4.27 months(95%CI 3.68 to NR),respectively.Most adverse events reported were of grade 1/2,and none were of grade 4/5.Conclusions:This is the first exploratory study of a fulvestrant and oral vinorelbine regimen in the treatment of HR+/HER2−recurrent and metastatic breast cancer.The combination chemo-endocrine therapy was efficacious,safe,and promising for patients with HR+/HER2−advanced breast cancer.展开更多
Treatment of breast cancer with low expression of human epidermal growth factor receptor 2(HER2;HER2-low)has drawn much attention in recent years.With the proven therapeutic effect of trastuzumab deruxtecan(T-DXd)in p...Treatment of breast cancer with low expression of human epidermal growth factor receptor 2(HER2;HER2-low)has drawn much attention in recent years.With the proven therapeutic effect of trastuzumab deruxtecan(T-DXd)in patients with HER2-low(immunohistochemistry[IHC]1+,or IHC2+/in situ hybridization[ISH]-)breast cancer,HER2-low may become a new subtype of targeted therapy for breast cancer.The expert committee formulated this consensus based on the current clinical studies and clinical medication experience.The current consensus is the collaborative work of an interdisciplinary working group,including experts in the fields of pathology and oncology.The purpose of this consensus was to guide the clinical diagnosis and treatment of HER2-low breast cancer,thereby prolonging the overall survival of patients.展开更多
Background:Breast cancer is a highly heterogeneous disease,characterized by tumor and nontumor cells at various cell states.Ecotyper is an innovative machine learning framework that quantifies the tumor microenvironme...Background:Breast cancer is a highly heterogeneous disease,characterized by tumor and nontumor cells at various cell states.Ecotyper is an innovative machine learning framework that quantifies the tumor microenvironment and delineates the tumor ecosystem,demonstrating clinical significance.However,further validation is needed in breast cancer.Methods:Ecotyper was applied to identify multiple cellular states and tumor ecotypes using large-scale breast cancer bulk sequencing data,followed by a detailed analysis of their associations with clinical classification,molecular subtypes,survival prognosis,and immunotherapy response.Identified subtypes were further characterized using single-cell and spatial data sets to reveal molecular profiles.Results:In a comprehensive analysis of 6578 breast cancer samples from four data sets,Ecotyper identified 69 cellular states and 10 tumor ecotypes.Of these,37 cellular states significantly correlated with overall survival.Notably,specific states within epithelial cells,macrophages/monocytes,and fibroblasts were linked to a worse prognosis.CE2 abundance was identified as the most significant marker indicating unfavorable prognosis and was further validated in an additional data set of 116 HER2-negative patients.These biomarkers also indicated the efficacy of neoadjuvant immunotherapy in breast cancer.CE2-high cancers were characterized by an abundance of basal-like epithelial cells,scant lymphocytic infiltration,and activation of hypoxia signaling.Single-cell analysis showed that CE2-high areas were rich in SPP1-positive tumor-associated macrophages(TAM),basal-like epithelial cells,and hypoxic cancer-associated fibroblasts(CAF).Spatially,these regions were often peripheral in triple-negative breast cancer,adjacent to fibrotic/necrotic zones.Multiplex immunofluorescence confirmed the enrichment of SPP1+CD68+TAM and HIF1A+SMA+CAF in hypoxic triple-negative breast cancer(TNBC)regions.展开更多
Objective:The choice of chemotherapeutic regimen for triple-negative breast cancer(TNBC)remains controversial.Homologous recombination deficiency(HRD)has attracted increasing attention in informing chemotherapy treatm...Objective:The choice of chemotherapeutic regimen for triple-negative breast cancer(TNBC)remains controversial.Homologous recombination deficiency(HRD)has attracted increasing attention in informing chemotherapy treatment.This study was aimed at investigating the feasibility of HRD as a clinically actionable biomarker for platinum-containing and platinum-free therapy.Methods:Chinese patients with TNBC who received chemotherapy between May 1,2008 and March 31,2020 were retrospectively analyzed with a customized 3D-HRD panel.HRD positivity was defined by an HRD score≥30 or deleterious BRCA1/2 mutation.A total of 386 chemotherapy-treated patients with TNBC were screened from a surgical cohort(NCT01150513)and a metastatic cohort,and 189 patients with available clinical and tumor sequencing data were included.Results:In the entire cohort,49.2%(93/189)of patients were identified as HRD positive(40 with deleterious BRCA1/2 mutations and 53 with BRCA1/2 intact with an HRD score of≥30).In the first-line metastatic setting,platinum therapy was associated with longer median progression-free survival(mPFS)than platinum-free therapy[9.1 vs.3.0 months;hazard ratio(HR),0.43;95%confidence interval 0.22–0.84;P=0.01].Among HRD-positive patients,the mPFS was significantly longer in those treated with platinum rather than platinum-free therapy(13.6 vs.2.0 months;HR,0.11;P=0.001).Among patients administered a platinum-free regimen,HRD-negative patients showed a PFS significantly superior to that of HRD-positive patients(P=0.02;treatment-biomarker P-interaction=0.001).Similar results were observed in the BRCA1/2-intact subset.In the adjuvant setting,HRD-positive patients tended to benefit more from platinum chemotherapy than from platinum-free chemotherapy(P=0.05,P-interaction=0.02).Conclusions:HRD characterization may guide decision-making regarding the use of platinum treatment in patients with TNBC in both adjuvant and metastatic settings.展开更多
Background:This study was conducted to evaluate the efficacy and safety of docetaxel/S-1(TS)compared with docetaxel/capecitabine(TX)as a first-line treatment for advanced breast cancer.Methods:Patients with advanced m...Background:This study was conducted to evaluate the efficacy and safety of docetaxel/S-1(TS)compared with docetaxel/capecitabine(TX)as a first-line treatment for advanced breast cancer.Methods:Patients with advanced metastatic breast cancer were randomly divided into the TS group(n=54)and the TX group(n=57)for first-line chemotherapy from August 2015 to April 2019(ClinicalTrials.org registration no.NCT02947061).Following the completion of combination therapy,patients without progression received S-1 or capecitabine maintenance treatment.The primary end point was progression-free survival(PFS).Results:Among 111 enrolled patients,the median PFS did not differ significantly between the TS group and the TX group(TS vs.TX,9.0 vs.7.4 months,P=0.365,95%confidence interval[CI]:0.50-1.11,hazard ratio[HR]:0.75).There was also no statistically significant difference in median overall survival(OS)between the two groups(TS vs.TX,40.2 vs.41.3 months,P=0.976).In addition,visceral metastasis and metastasis sites,such as the liver or lung,did not lead to a significant effect on PFS and OS.The two regimens showed no significant difference in adverse events,except hand-foot syndrome,which predominated in the TX group(38.6%vs.7.4%,P=0.001),and diarrhea(24.1%vs.3.6%,P=0.003)and elevation of aspartate aminotransferase(AST)/alanine aminotransferase(ALT)levels(14.8%vs.3.5%,P=0.049),which were more frequent in the TS group.Conclusions:The TS and TX regimens demonstrated similar efficacy and safety for the first-line treatment of advanced breast cancer.The TS regimen had fewer cases of severe hand-foot syndrome than the TX regimen,representing an effective alternative option to the TX regimen.Further studies are warranted to define the efficacy and safety of this strategy in real-world settings.展开更多
Breast cancer is the most prevalent female malignant tumor and significantly threatens the health of affected individuals.1 Recent progress in the identification of the molecular subtypes of breast cancer has ensured ...Breast cancer is the most prevalent female malignant tumor and significantly threatens the health of affected individuals.1 Recent progress in the identification of the molecular subtypes of breast cancer has ensured more personalized and precise treatment strategies.2 This has presented new challenges and opportunities in treatment options and disease prognosis.This Special Issue,titled"Recent advances in breast cancer research",highlights the latest advances in clinical,basic,and translational research on breast cancer.It explores tumor resistance mechanisms and microenvironments to enhance our understanding of drug efficacy and safety.展开更多
Background:Breast cancer is a global problem,and a large number of new cases are diagnosed every year.Capecit-abine is effective in patients with metastatic breast cancer(MBC).Hand-foot syndrome(HFS)is a common advers...Background:Breast cancer is a global problem,and a large number of new cases are diagnosed every year.Capecit-abine is effective in patients with metastatic breast cancer(MBC).Hand-foot syndrome(HFS)is a common adverse effect of capecitabine.In this study,we investigated the association between single nucleotide polymorphisms(SNPs)in genes involved in capecitabine metabolism pathways and capecitabine-induced HFS in Chinese patients with MBC to identify some predictive genetic biomarkers.Methods:We selected 3 genes involved in capecitabine metabolism and screened genetic variants in these target genes.We genotyped a total of 22 SNPs in the thymidylate synthase gene(TYMS),the methylene tetrahydrofolate reductase gene(MTHFR),and the ribonucleotide reductase M1 gene(RRM1)in 342 MBC patients treated with capecit-abine-based chemotherapy.The genotype distributions of each SNP in patients with and without HFS were assessed using Pearson’sχ^(2)test,and the relationship between HFS and genotypes of SNPs was determined using logistic regression analysis.The association between SNPs and their corresponding gene expression was analyzed using the Blood expression quantitative trait loci(eQTL)browser online tools.Results:We found 4 positive sites for HFS in the TYMS and MTHFR genes:TYMS rs2606241(P=0.022),TYMS rs2853741(P=0.019),MTHFR rs3737964(P=0.029),and MTHFR rs4846048(P=0.030).Logistic regression analyses showed that the genotype AG of MTHFR rs3737964[odds ratio(OR)=0.54,95%confidence interval(CI)0.31-0.97,P=0.038]and MTHFR rs4846048(OR=0.54,95%CI 0.30-0.98,P=0.042)were protective factors of HFS,whereas the genotype CT of TYMS rs2853741(OR=2.25,95%CI 1.31-3.87,P=0.012)increased the risk of HFS.The association between the genotype GT of TYMS rs2606241(OR=1.27,95%CI 0.73-2.23,P=0.012)and HFS was uncertain.Further eQTL analyses confirmed that the alleles of rs3737964 and rs4846048 affected the gene expression levels of MTHFR in cis.Conclusions:We have identified four potentially useful pharmacogenetic markers,TYMS rs2606241,TYMS rs2853741,MTHFR rs3737964,and MTHFR rs4846048 to predict capecitabine-induced HFS in MBC patients.展开更多
Background and objectives:Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease(NAFLD).However,whether and how hepatic steatosis and liver inflammation are differentially regu...Background and objectives:Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease(NAFLD).However,whether and how hepatic steatosis and liver inflammation are differentially regulated remains to be elucidated.Considering that disruption of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(Pfkfb3/iPfk2)dissociates fat deposition and inflammation,the present study examined a role for Pfkfb3/iPfk2 in hematopoietic cells in regulating hepatic steatosis and inflammation in mice.Methods:Pfkfb3-disrupted(Pfkfb3^(+/-))mice and wild-type(WT)littermates were fed a high-fat diet(HFD)and examined for NAFLD phenotype.Also,bone marrow cells isolated from Pfkfb3^(+/-)mice andWT mice were differentiated into macrophages for analysis of macrophage activation status and for bone marrow transplantation(BMT)to generate chimeric(WT/BMT-Pfkfb3^(+/-))mice in which Pfkfb3 was disrupted only in hematopoietic cells and control chimeric(WT/BMT-WT)mice.The latter were also fed an HFD and examined for NAFLD phenotype.In vitro,hepatocytes were co-cultured with bone marrowderived macrophages and examined for hepatocyte fat deposition and proinflammatory responses.Results:After the feeding period,HFD-fed Pfkfb3^(+/-)mice displayed increased severity of liver inflammation in the absence of hepatic steatosis compared with HFD-fed WT mice.When inflammatory activation was analyzed,Pfkfb3^(+/-)macrophages revealed increased proinflammatory activation and decreased anti-proinflammatory activation.When NAFLD phenotype was analyzed in the chimeric mice,WT/BMT-Pfkfb3^(+/-) mice displayed increases in the severity of HFD-induced hepatic steatosis and inflammation compared with WT/BMT-WT mice.At the cellular level,hepatocytes co-cultured with Pfkfb3^(+/-) macrophages revealed increased fat deposition and proinflammatory responses compared with hepatocytes co-cultured with WT macrophages.Conclusions:Pfkfb3 disruption only in hematopoietic cells exacerbates HFD-induced hepatic steatosis and inflammation whereas the Pfkfb3/iPfk2 in nonhematopoietic cells appeared to be needed for HFD feeding to induce hepatic steatosis.As such,the Pfkfb3/iPfk2 plays a unique role in regulating NAFLD pathophysiology.展开更多
Cellular strategies remain a crucial component in bone tissue engineering （BTE）. So far, the outcome of cell-based strategies from initial clinical trials is far behind compared to animal studies, which is suggested...Cellular strategies remain a crucial component in bone tissue engineering （BTE）. So far, the outcome of cell-based strategies from initial clinical trials is far behind compared to animal studies, which is suggested to be related to insufficient nutrient and oxygen supply inside the Ussue-engineered constructs. Cocultures, by introducing angiogenic cells into osteogenic cell cultures, might provide a solution for improving vascularization and hence increasing bone formation for cell-based constructs. So far, pre-clinical studies demonstrated that cocultures enhance vascularization and bone formation compared to monocultures. However, there has been no report on the application of cocultures in clinics. Therefore, this mini-review aims to provide an overview regarding （i） critical parameters in cocultures and the outcomes of cocultures compared to monocultures in the currently available pre-clinical studies using human mesenchymal stem cells implanted in orthotopic animal models; and （ii） the usage of monocultures in clinical application in BTE.展开更多
The synchronized development of mineralized bone and blood vessels is a fundamental requirement for successful bone tissue regeneration.Adequate energy production forms the cornerstone supporting new bone formation.ET...The synchronized development of mineralized bone and blood vessels is a fundamental requirement for successful bone tissue regeneration.Adequate energy production forms the cornerstone supporting new bone formation.ETS variant 2(ETV2)has been identified as a transcription factor that promotes energy metabolism reprogramming and facilitates the coordination between osteogenesis and angiogenesis.In vitro molecular experiments have demonstrated that ETV2 enhances osteogenic differentiation of dental pulp stem cells(DPSCs)by regulating the ETV2-prolyl hydroxylase 2(PHD2)-hypoxia-inducible factor-1α(HIF-1α)-vascular endothelial growth factor A(VEGFA)axis.Notably,ETV2 achieves the rapid reprogramming of energy metabolism by simultaneously accelerating mitochondrial aerobic respiration and glycolysis,thus fulfilling the energy requirements essential to expedite osteogenic differentiation.Furthermore,decreasedα-ketoglutarate release from ETV2-modified DPSCs contributes to microcirculation reconstruction.Additionally,we engineered hydroxyapatite/chitosan microspheres(HA/CS MS)with biomimetic nanostructures to facilitate multiple ETV2-DPSC functions and further enhanced the osteogenic differentiation.Animal experiments have validated the synergistic effect of ETV2-modified DPSCs and HA/CS MS in promoting the critical-size bone defect regeneration.In summary,this study offers a novel treatment approach for vascularized bone tissue regeneration that relies on energy metabolism activation and the maintenance of a stable local hypoxia signaling state.展开更多
Tricho-dento-osseous(TDO)syndrome is a rare autosomal dominant disease resulting from distal-less homeobox 3(DLX3)mutation.1,2 Accumulative bone density in alveolar bone is a clinically favorable phenotype for TDO pat...Tricho-dento-osseous(TDO)syndrome is a rare autosomal dominant disease resulting from distal-less homeobox 3(DLX3)mutation.1,2 Accumulative bone density in alveolar bone is a clinically favorable phenotype for TDO patients.However,the limited number of bone marrow mesenchymal stem cells(BMSCs)in TDO patients restricts their application.展开更多
Homeostasis is essential for the maintenance of health,and how it is maintained is the focus of attention in homeostatic medicine.As a natural dietary nutrient,nitrate is critical in regulating homeostasis.This articl...Homeostasis is essential for the maintenance of health,and how it is maintained is the focus of attention in homeostatic medicine.As a natural dietary nutrient,nitrate is critical in regulating homeostasis.This article summarizes nitrate's cognitive his-tory,sources,and metabolism.It discusses the relationship and possible mechanism between nitrate and organism homeostasis from three aspects:flora homeostasis,inflammation-immunity homeostasis,and energy metabolism homeostasis,as well as the clinical application scenarios of nitrate as a promising new generation of drugs,including preventing and treating multi-system diseases,reducing organism injury,improving exercise ability,regulating glucose and lipid metabolism,and assisting tumor treatment.An increased understanding of nitrate's impact on body home-ostasis could foster a new research concept for its application in disease prevention and treatment.展开更多
Breast cancer is a multistep, multifactorial, and heterogeneous disease. Significant transformations have occurred in the sys-temic management of breast cancer in the past decade. Due to the further understanding of p...Breast cancer is a multistep, multifactorial, and heterogeneous disease. Significant transformations have occurred in the sys-temic management of breast cancer in the past decade. Due to the further understanding of pathogenesis, scientists have found plenty of signaling pathways and correspondingly therapeutic targets in breast cancer, such as hormone receptor, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), phos-phoinositide-3-kinase (PI3K), v-akt murine thymoma viral oncogene homolog (AKT), mechanistic target of rapamycin (mTOR), cyclin-dependent kinase 4/6 (CDK4/6), poly (adenosine diphosphate-ribose) polymerase (PARP), and programmed death-1 (PD-1). Targeted therapy, which optimizes the accuracy of antitumor activity and minimizes toxicity to normal tissues, plays a crucial role in breast cancer treatment in the era of precision medicine. In this review, we aimed to summarize the latest developments in targeted therapy for breast cancer and discuss the existing problems.展开更多
Treating patients with esophageal squamous cell carcinoma(ESCC)is challenging due to the high chemoresistance.Growth differentiation factor 15(GDF15)is crucial in the development of various types of tumors and negativ...Treating patients with esophageal squamous cell carcinoma(ESCC)is challenging due to the high chemoresistance.Growth differentiation factor 15(GDF15)is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research.In this study,the link between GDF15 and chemotherapy resistance in ESCC was further explored.The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies.ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response.GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2.Through an in vivo study,we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin.Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A.AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A,indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin.The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy,resulting in beneficial therapeutic outcomes.展开更多
文摘BACKGROUND RNA binding motif 5(RBM5)has emerged as crucial regulators in many cancers.AIM To explore more functional and mechanistic exploration of RBM5 since the lack of research on RBM5 in colorectal cancer(CRC)dictates that is essential.METHODS Through Gene Expression Profiling Interactive Analysis,we analyzed RBM5 expression in colon adenocarcinoma and rectum adenocarcinoma tissues.For detecting the mRNA expression of RBM5,quantitative real time-polymerase chain reaction was performed.Protein expression levels of RBM5,hexokinase 2,lactate dehydrogenase A,phosphatase and tensin homolog(PTEN),phosphoinositide 3-kinase(PI3K),phosphorylated-protein kinase B(p-AKT),and AKT were determined via Western blot.Functionally,cell counting kit-8 and 5-ethynyl-2’-deoxyuridine(EDU)assay were performed to evaluate proliferation of CRC cells.Invasiveness and migration of CRC cells were evaluated through conducting transwell assays.Glucose consumption,lactate production and adenosinetriphosphate(ATP)production were measured through a glucose assay kit,a lactate assay kit and an ATP production assay kit,respectively.Besides,RNA immunoprecipitation assay,half-life RT-PCR and dual-luciferase reporter assay were applied to detect interaction between RBM5 and PTEN.To establish a xenotypic tumor mice,CRC cells were subcutaneously injected into the right flank of each mouse.Protein expression of RBM5,Ki67,and PTEN in tumor tissues was examined using immunohistochemistry staining.Haematoxylin and eosin staining was used to evaluate tumor liver metastasis in mice.RESULTS We discovered down-regulation of RBM5 expression in CRC tissues and cells.RBM5 overexpression repressed proliferation,migration and invasion of CRC cells.Meantime,RBM5 impaired glycolysis in CRC cells,presenting as decreased glucose consumption,decreased lactate production and decreased ATP production.Besides,RBM5 bound to PTEN mRNA to stabilize its expression.PTEN expression was positively regulated by RBM5 in CRC cells.The protein levels of PI3K and p-AKT were significantly decreased after RBM5 overexpression.The suppressive influences of RBM5 on glycolysis,proliferation and metastasis of CRC cells were partially counteracted by PTEN knockdown.RBM5 suppressed tumor growth and liver metastasis in vivo.CONCLUSION This investigation provided new evidence that RBM5 was involved in CRC by binding to PTEN,expanding the importance of RBM5 in the treatment of CRC.
基金supported by the National Natural Science Foundation of China(Grant No.81672634)National Key Research and Development Program of China(Grant No.2018YFC0115204)+2 种基金Capital Health Development Scientific Research Project(Grant No.2018-2-4023)Clinical Translation and Medical Research Fund of Chinese Academy of Medical Sciences(Grant No.12019XK320071)Peking Union Medical College Graduate Innovation Fund(Grant No.2018-1002-02-25)。
文摘Objective:Anlotinib is a novel tyrosine kinase inhibitor blocking angiogenesis.This study was performed to assess the efficacy and safety of anlotinib in patients with metastatic breast cancer.Methods:Patients with HER2-negative breast cancer,who were pre-treated with anthracycline or taxanes in a neoadjuvant,adjuvant,or metastatic setting,and had treatment failure after at least one prior chemotherapy regimen in the metastatic setting were enrolled.Anlotinib was administered at 12 mg daily for 14 days in a 21-day cycle until disease progression or unacceptable toxicity occurred.Simultaneously,5–10 m L of venous blood was collected to perform circulating tumor DNA(ct DNA)testing every 2 treatment cycles.The primary endpoint was the objective response rate(ORR).Secondary endpoints included the disease control rate(DCR),progression-free survival(PFS),overall survival,safety,and biomarkers.Results:Twenty-six eligible patients were enrolled,with a median age of 56(30–75)years.The median follow-up time was 10.5 months.The ORR was 15.4%,the DCR was 80.8%,and the median PFS was 5.22 months(95%confidence interval 2.86–6.24).Fourteen(53.8%)patients survived for more than 10 months.The changes in the detectable ct DNA variant allele frequency were consistent with the tumor response.The most common treatment-related adverse events were hypertension(57.7%),thyroidstimulating hormone elevation(34.6%),and hand-foot syndrome(23.1%).Conclusion:Anlotinib showed objective efficacy with tolerable toxicity in heavily pre-treated,metastatic HER2-negative breast cancer.The dynamic changes in the ct DNA variant allele fraction may be predictive of the tumor response.
基金supported by the National High-Technology Research and Development Program of China (No.2009AA03Z422)
文摘Tetragonal ZrO2-3 mol% Y2O3 （3Y-TZP） coated with CePO4 was synthesized by a co-precipitation method and the effects of CePO4 content and sintering temperature on its mechanical properties were investigated. The microstructure and phase composition of the products were characterized using scanning and transmission electron microscopy as well as X-ray diffraction, respectively. The machinability index of CePO4-coated zirconia was calculated to be 1.05 when the CePO4 content is 25 wt.%. The sample hardness, bending strength and fracture toughness are 7.08 GPa, 457.85 MPa and 9.75 MPa m1/2, respectively, when the sintering temperature is 1400°C. The results show that as-prepared CePO4-coated 3Y-TZP ceramics are highly suitable biomaterials for dental applications and are expected to be used in a com-puter-aided design and computer-aided manufacturing （CAD/CAM） system to make dental crowns or bridge prostheses in a one-step sinter-ing process.
基金Supported by Strategic Cooperation Project between Sichuan University and Luzhou Municipal Government,No. 2018CDLZ-14Aba Tibetan and Qiang Autonomous Prefecture Science and Technology Bureau,No. 21YYJSYJ0052
文摘BACKGROUND Kissing molars(KMs)are a scarcely reported form of molar impaction in which the occlusal surfaces contact each other within a single dental follicle and the roots point in opposite directions.The direction of KMs impaction is generally tilted.KMs with vertical direction impaction have not been reported in the literature.CASE SUMMARY A 25-year-old female visited a dentist for right maxillary wisdom teeth extraction and was diagnosed with two vertically impacted KMs in the left mandible on panoramic radiography.After cone-beam computed tomography examination confirmed no secondary complication,the patient chose to undergo observation and regular follow-up.A literature review of KMs revealed that vertical impacted KMs are rare;high-quality evidence regarding their prevalence is still lacking.At present,the causality of KMs is controversial.In this study,we have tried to provide a detailed definition of KMs to allow an accurate evaluation of their prevalence and classification based on their impaction direction which may be related to their pathogenesis.The treatment plan of KMs depends on the condition and location of the affected teeth and associated complications;they may be either directly extracted or treated using a multidisciplinary approach including maxillofacial surgeons and orthodontists.CONCLUSION KMs are a rare clinical condition of impacted teeth with unclear pathogenesis.Vertically impacted KMs were seldom reported.Reasonable definition and classification of KMs can help in the understanding of their causes and prevalence.
基金funded by the National Natural Science Foundation of China(Grant No.81472753 and 81672634)。
文摘Objective:Apatinib is an oral TKI targeting VEGFR-2.Single-agent apatinib treatment has been shown to produce an objective response in patients with pretreated m BC.Oral vinorelbine also holds promise as a treatment of choice in patients with m BC.This study aimed to investigate the efficacy and safety of the oral vinorelbine-apatinib combination in patients with pretreated m BC.In addition,we detected gene variants in ct DNA to explore the therapeutic implications.Methods:This study enrolled patients with HER2-negative m BC who were pretreated with anthracycline/taxanes.Patients were treated with apatinib at 500 mg/425 mg daily plus oral vinorelbine 60 mg/m2 on days 1,8,and 15 of every cycle(3 weeks).The primary endpoint was PFS.The secondary endpoints were ORR,CBR,OS,and safety.Patients eligible for ct DNA detection were evaluated before and during treatment.Results:Forty patients were enrolled.The median PFS was 5.2 months(95%CI,3.4–7.0 months),and the median OS was 17.4 months(95%CI,8.0–27.0 months).The ORR was 17.1%(6/35),and the CBR was 45.7%(16/35).The most common AEs included gastrointestinal reaction,myelosuppression,and hypertension.In 20 patients,ct DNA was detected at baseline and during treatment.A significant difference was found in PFS for undetected vs.detected baseline ct DNA(13.9 months vs.3.6 months,P=0.018).Conclusions:All-oral therapy with apatinib plus vinorelbine displayed objective efficacy in patients with heavily pretreated HER2-negative m BC,with acceptable and manageable toxicity profiles.Patients with no gene variant detected and lower variant allele frequencies in ct DNA at baseline showed longer PFS.
基金the fund of National Natural Science Foundation of China(82170951)Beijing Natural Science Foundation(7222079).
文摘The Wnt/β-catenin signaling pathway is the main target of tooth regeneration regulation.Treatment of cells with AZD2858 stimulates the Wnt/β-catenin signaling pathway,yet the function of this pathway in tooth regeneration remains unclear.Here,we found that AZD2858 promotes the accumulation ofβ-catenin in the nuclei of stem cells from the apical papilla(SCAPs)and enhances cell proliferation.Single-cell sequencing was performed on SCAPs treated with AZD2858.Eight clusters were identified,namely SCAPs-CNTNAP2,SCAPs-DTL,SCAPs-MYH11,SCAPs-MKI67,SCAPs-CXCL8,SCAPs-TPM2,SCAPs-IFIT2 and SCAPs-NEK10.The pseudo-time trajectory analysis showed that AZD2858 enhanced the evolution of SCAPs from SCAPs-TMP2 clusters to SCAPs-MYH11,SCAPs-CNTNAPs and SCAPs-NEK10 clusters via up-regulation of PRKCA,SMURF2,MAGI2,RBMS3,EXT1,CAMK2D,PLCB4,and PLCB1.These results demonstrate that AZD2858 enhances the proliferation of SCAPs-TPM2 cluster by activating the non-canonical Wnt/β-catenin signaling pathway.
基金supported by grants from the National Key R&D Program of China(Grant No.2018YFC0115204)the National Natural Science Foundation of China(Grant No.81672634)+3 种基金the Chinese Society of Clinical Oncology Foundation(Grant No.Y-2019AZMS-0377)the Beijing Medical Award Foundation(Grant No.YXJL-2020-0941-0763)Beijing Hope Run Special Fund of Cancer Foundation of China(Grant No.LC2019B16)Beijing Xisike Clinical Oncology Research Foundation(Grant No.Y-pirrefabre202101-0008).
文摘Objective:Endocrine therapy with fulvestrant has shown synergistic antitumor effects with some chemotherapy drugs in vitro.This study evaluated the efficacy and safety of fulvestrant with vinorelbine in patients with hormone receptor positive(HR+)/human epidermal growth factor receptor-2-negative(HER2−)recurrent or metastatic breast cancer.Methods:Patients were intramuscularly administered fulvestrant 500 mg(day 1 per cycle for 28 days)and oral vinorelbine(60 mg/m2 on days 1,8,and 15 of each cycle).The primary endpoint was progression-free survival(PFS).Secondary endpoints included overall survival,objective response rate,disease control rate,duration of response,and safety.Results:A total of 38 patients with HR+/HER2−advanced breast cancer included in the study were followed up for a median time of 25.1 months.The overall median PFS was 9.86 months[95%confidence interval(CI)7.2-23.13],and the median PFS of the first-line and the second-line treatment population was 20.73 months(95%CI 9.82 to NR)and 4.27 months(95%CI 3.68 to NR),respectively.Most adverse events reported were of grade 1/2,and none were of grade 4/5.Conclusions:This is the first exploratory study of a fulvestrant and oral vinorelbine regimen in the treatment of HR+/HER2−recurrent and metastatic breast cancer.The combination chemo-endocrine therapy was efficacious,safe,and promising for patients with HR+/HER2−advanced breast cancer.
文摘Treatment of breast cancer with low expression of human epidermal growth factor receptor 2(HER2;HER2-low)has drawn much attention in recent years.With the proven therapeutic effect of trastuzumab deruxtecan(T-DXd)in patients with HER2-low(immunohistochemistry[IHC]1+,or IHC2+/in situ hybridization[ISH]-)breast cancer,HER2-low may become a new subtype of targeted therapy for breast cancer.The expert committee formulated this consensus based on the current clinical studies and clinical medication experience.The current consensus is the collaborative work of an interdisciplinary working group,including experts in the fields of pathology and oncology.The purpose of this consensus was to guide the clinical diagnosis and treatment of HER2-low breast cancer,thereby prolonging the overall survival of patients.
基金supported by National Natural Science Foundation of China(Grant No.82172650)Chinese Academy of Medical Sciences Clinical Translational and Medical Research Fund(Grant No.2022-I2M-C&T-A-014)+2 种基金Beijing Hospitals Authority Youth Programme(Grant No.QML20231110)Natural Science Foundation of Shandong Province(Grant No.ZR2023QH359)the Taishan Scholars Young Experts Fund(Grant No.tsqn202306388).
文摘Background:Breast cancer is a highly heterogeneous disease,characterized by tumor and nontumor cells at various cell states.Ecotyper is an innovative machine learning framework that quantifies the tumor microenvironment and delineates the tumor ecosystem,demonstrating clinical significance.However,further validation is needed in breast cancer.Methods:Ecotyper was applied to identify multiple cellular states and tumor ecotypes using large-scale breast cancer bulk sequencing data,followed by a detailed analysis of their associations with clinical classification,molecular subtypes,survival prognosis,and immunotherapy response.Identified subtypes were further characterized using single-cell and spatial data sets to reveal molecular profiles.Results:In a comprehensive analysis of 6578 breast cancer samples from four data sets,Ecotyper identified 69 cellular states and 10 tumor ecotypes.Of these,37 cellular states significantly correlated with overall survival.Notably,specific states within epithelial cells,macrophages/monocytes,and fibroblasts were linked to a worse prognosis.CE2 abundance was identified as the most significant marker indicating unfavorable prognosis and was further validated in an additional data set of 116 HER2-negative patients.These biomarkers also indicated the efficacy of neoadjuvant immunotherapy in breast cancer.CE2-high cancers were characterized by an abundance of basal-like epithelial cells,scant lymphocytic infiltration,and activation of hypoxia signaling.Single-cell analysis showed that CE2-high areas were rich in SPP1-positive tumor-associated macrophages(TAM),basal-like epithelial cells,and hypoxic cancer-associated fibroblasts(CAF).Spatially,these regions were often peripheral in triple-negative breast cancer,adjacent to fibrotic/necrotic zones.Multiplex immunofluorescence confirmed the enrichment of SPP1+CD68+TAM and HIF1A+SMA+CAF in hypoxic triple-negative breast cancer(TNBC)regions.
基金granted by Capital’s Funds for Health Improvement and Research(Grant No.2018-2-4023)the National Natural Science Foundation of China(Grant No.82001559)。
文摘Objective:The choice of chemotherapeutic regimen for triple-negative breast cancer(TNBC)remains controversial.Homologous recombination deficiency(HRD)has attracted increasing attention in informing chemotherapy treatment.This study was aimed at investigating the feasibility of HRD as a clinically actionable biomarker for platinum-containing and platinum-free therapy.Methods:Chinese patients with TNBC who received chemotherapy between May 1,2008 and March 31,2020 were retrospectively analyzed with a customized 3D-HRD panel.HRD positivity was defined by an HRD score≥30 or deleterious BRCA1/2 mutation.A total of 386 chemotherapy-treated patients with TNBC were screened from a surgical cohort(NCT01150513)and a metastatic cohort,and 189 patients with available clinical and tumor sequencing data were included.Results:In the entire cohort,49.2%(93/189)of patients were identified as HRD positive(40 with deleterious BRCA1/2 mutations and 53 with BRCA1/2 intact with an HRD score of≥30).In the first-line metastatic setting,platinum therapy was associated with longer median progression-free survival(mPFS)than platinum-free therapy[9.1 vs.3.0 months;hazard ratio(HR),0.43;95%confidence interval 0.22–0.84;P=0.01].Among HRD-positive patients,the mPFS was significantly longer in those treated with platinum rather than platinum-free therapy(13.6 vs.2.0 months;HR,0.11;P=0.001).Among patients administered a platinum-free regimen,HRD-negative patients showed a PFS significantly superior to that of HRD-positive patients(P=0.02;treatment-biomarker P-interaction=0.001).Similar results were observed in the BRCA1/2-intact subset.In the adjuvant setting,HRD-positive patients tended to benefit more from platinum chemotherapy than from platinum-free chemotherapy(P=0.05,P-interaction=0.02).Conclusions:HRD characterization may guide decision-making regarding the use of platinum treatment in patients with TNBC in both adjuvant and metastatic settings.
文摘Background:This study was conducted to evaluate the efficacy and safety of docetaxel/S-1(TS)compared with docetaxel/capecitabine(TX)as a first-line treatment for advanced breast cancer.Methods:Patients with advanced metastatic breast cancer were randomly divided into the TS group(n=54)and the TX group(n=57)for first-line chemotherapy from August 2015 to April 2019(ClinicalTrials.org registration no.NCT02947061).Following the completion of combination therapy,patients without progression received S-1 or capecitabine maintenance treatment.The primary end point was progression-free survival(PFS).Results:Among 111 enrolled patients,the median PFS did not differ significantly between the TS group and the TX group(TS vs.TX,9.0 vs.7.4 months,P=0.365,95%confidence interval[CI]:0.50-1.11,hazard ratio[HR]:0.75).There was also no statistically significant difference in median overall survival(OS)between the two groups(TS vs.TX,40.2 vs.41.3 months,P=0.976).In addition,visceral metastasis and metastasis sites,such as the liver or lung,did not lead to a significant effect on PFS and OS.The two regimens showed no significant difference in adverse events,except hand-foot syndrome,which predominated in the TX group(38.6%vs.7.4%,P=0.001),and diarrhea(24.1%vs.3.6%,P=0.003)and elevation of aspartate aminotransferase(AST)/alanine aminotransferase(ALT)levels(14.8%vs.3.5%,P=0.049),which were more frequent in the TS group.Conclusions:The TS and TX regimens demonstrated similar efficacy and safety for the first-line treatment of advanced breast cancer.The TS regimen had fewer cases of severe hand-foot syndrome than the TX regimen,representing an effective alternative option to the TX regimen.Further studies are warranted to define the efficacy and safety of this strategy in real-world settings.
文摘Breast cancer is the most prevalent female malignant tumor and significantly threatens the health of affected individuals.1 Recent progress in the identification of the molecular subtypes of breast cancer has ensured more personalized and precise treatment strategies.2 This has presented new challenges and opportunities in treatment options and disease prognosis.This Special Issue,titled"Recent advances in breast cancer research",highlights the latest advances in clinical,basic,and translational research on breast cancer.It explores tumor resistance mechanisms and microenvironments to enhance our understanding of drug efficacy and safety.
基金This work was supported by the Chinese Academic of Medical Sciences Initiative for Innovative Medicine(CAMS-12M-1-010)Beijing Municipal Science&Technology Commission(Z151100004015024)
文摘Background:Breast cancer is a global problem,and a large number of new cases are diagnosed every year.Capecit-abine is effective in patients with metastatic breast cancer(MBC).Hand-foot syndrome(HFS)is a common adverse effect of capecitabine.In this study,we investigated the association between single nucleotide polymorphisms(SNPs)in genes involved in capecitabine metabolism pathways and capecitabine-induced HFS in Chinese patients with MBC to identify some predictive genetic biomarkers.Methods:We selected 3 genes involved in capecitabine metabolism and screened genetic variants in these target genes.We genotyped a total of 22 SNPs in the thymidylate synthase gene(TYMS),the methylene tetrahydrofolate reductase gene(MTHFR),and the ribonucleotide reductase M1 gene(RRM1)in 342 MBC patients treated with capecit-abine-based chemotherapy.The genotype distributions of each SNP in patients with and without HFS were assessed using Pearson’sχ^(2)test,and the relationship between HFS and genotypes of SNPs was determined using logistic regression analysis.The association between SNPs and their corresponding gene expression was analyzed using the Blood expression quantitative trait loci(eQTL)browser online tools.Results:We found 4 positive sites for HFS in the TYMS and MTHFR genes:TYMS rs2606241(P=0.022),TYMS rs2853741(P=0.019),MTHFR rs3737964(P=0.029),and MTHFR rs4846048(P=0.030).Logistic regression analyses showed that the genotype AG of MTHFR rs3737964[odds ratio(OR)=0.54,95%confidence interval(CI)0.31-0.97,P=0.038]and MTHFR rs4846048(OR=0.54,95%CI 0.30-0.98,P=0.042)were protective factors of HFS,whereas the genotype CT of TYMS rs2853741(OR=2.25,95%CI 1.31-3.87,P=0.012)increased the risk of HFS.The association between the genotype GT of TYMS rs2606241(OR=1.27,95%CI 0.73-2.23,P=0.012)and HFS was uncertain.Further eQTL analyses confirmed that the alleles of rs3737964 and rs4846048 affected the gene expression levels of MTHFR in cis.Conclusions:We have identified four potentially useful pharmacogenetic markers,TYMS rs2606241,TYMS rs2853741,MTHFR rs3737964,and MTHFR rs4846048 to predict capecitabine-induced HFS in MBC patients.
基金This work was supported in part by the Hickam Endowed Chair,Gastroenterology,Medicine,Indiana University and the Indiana University Health e Indiana University School of Medicine Strategic Research Initiative,the Research Career Scientist to Dr.Alpini from the United States Department of Veteran’s Affairs,Biomedical Laboratory Research and Development Service and National Institutes of Health(NIH)grants DK054811,DK110035,and DK076898 to Drs.G.Alpini and S.Glaser.In addition,this work was supported in whole or in part by grants from the American Diabetes Association(ADA)(1-10-BS-76 to C.Wu)the National Institutes of Health(DK095828 and DK124854 to C.Wu).
文摘Background and objectives:Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease(NAFLD).However,whether and how hepatic steatosis and liver inflammation are differentially regulated remains to be elucidated.Considering that disruption of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(Pfkfb3/iPfk2)dissociates fat deposition and inflammation,the present study examined a role for Pfkfb3/iPfk2 in hematopoietic cells in regulating hepatic steatosis and inflammation in mice.Methods:Pfkfb3-disrupted(Pfkfb3^(+/-))mice and wild-type(WT)littermates were fed a high-fat diet(HFD)and examined for NAFLD phenotype.Also,bone marrow cells isolated from Pfkfb3^(+/-)mice andWT mice were differentiated into macrophages for analysis of macrophage activation status and for bone marrow transplantation(BMT)to generate chimeric(WT/BMT-Pfkfb3^(+/-))mice in which Pfkfb3 was disrupted only in hematopoietic cells and control chimeric(WT/BMT-WT)mice.The latter were also fed an HFD and examined for NAFLD phenotype.In vitro,hepatocytes were co-cultured with bone marrowderived macrophages and examined for hepatocyte fat deposition and proinflammatory responses.Results:After the feeding period,HFD-fed Pfkfb3^(+/-)mice displayed increased severity of liver inflammation in the absence of hepatic steatosis compared with HFD-fed WT mice.When inflammatory activation was analyzed,Pfkfb3^(+/-)macrophages revealed increased proinflammatory activation and decreased anti-proinflammatory activation.When NAFLD phenotype was analyzed in the chimeric mice,WT/BMT-Pfkfb3^(+/-) mice displayed increases in the severity of HFD-induced hepatic steatosis and inflammation compared with WT/BMT-WT mice.At the cellular level,hepatocytes co-cultured with Pfkfb3^(+/-) macrophages revealed increased fat deposition and proinflammatory responses compared with hepatocytes co-cultured with WT macrophages.Conclusions:Pfkfb3 disruption only in hematopoietic cells exacerbates HFD-induced hepatic steatosis and inflammation whereas the Pfkfb3/iPfk2 in nonhematopoietic cells appeared to be needed for HFD feeding to induce hepatic steatosis.As such,the Pfkfb3/iPfk2 plays a unique role in regulating NAFLD pathophysiology.
文摘Cellular strategies remain a crucial component in bone tissue engineering （BTE）. So far, the outcome of cell-based strategies from initial clinical trials is far behind compared to animal studies, which is suggested to be related to insufficient nutrient and oxygen supply inside the Ussue-engineered constructs. Cocultures, by introducing angiogenic cells into osteogenic cell cultures, might provide a solution for improving vascularization and hence increasing bone formation for cell-based constructs. So far, pre-clinical studies demonstrated that cocultures enhance vascularization and bone formation compared to monocultures. However, there has been no report on the application of cocultures in clinics. Therefore, this mini-review aims to provide an overview regarding （i） critical parameters in cocultures and the outcomes of cocultures compared to monocultures in the currently available pre-clinical studies using human mesenchymal stem cells implanted in orthotopic animal models; and （ii） the usage of monocultures in clinical application in BTE.
基金supported by the National Natural Science Foundation of China (grants 82301039)the Natural Science Foundation of the Anhui Higher Education Institutions of China (grant 2022AH050758)+2 种基金Anhui Institute of Translational Medicine,Natural Sciences (grant 2022zhyx-C87)National Natural Science Foundation of China (82170951)Beijing Municipal Natural Science Foundation (7222079).
文摘The synchronized development of mineralized bone and blood vessels is a fundamental requirement for successful bone tissue regeneration.Adequate energy production forms the cornerstone supporting new bone formation.ETS variant 2(ETV2)has been identified as a transcription factor that promotes energy metabolism reprogramming and facilitates the coordination between osteogenesis and angiogenesis.In vitro molecular experiments have demonstrated that ETV2 enhances osteogenic differentiation of dental pulp stem cells(DPSCs)by regulating the ETV2-prolyl hydroxylase 2(PHD2)-hypoxia-inducible factor-1α(HIF-1α)-vascular endothelial growth factor A(VEGFA)axis.Notably,ETV2 achieves the rapid reprogramming of energy metabolism by simultaneously accelerating mitochondrial aerobic respiration and glycolysis,thus fulfilling the energy requirements essential to expedite osteogenic differentiation.Furthermore,decreasedα-ketoglutarate release from ETV2-modified DPSCs contributes to microcirculation reconstruction.Additionally,we engineered hydroxyapatite/chitosan microspheres(HA/CS MS)with biomimetic nanostructures to facilitate multiple ETV2-DPSC functions and further enhanced the osteogenic differentiation.Animal experiments have validated the synergistic effect of ETV2-modified DPSCs and HA/CS MS in promoting the critical-size bone defect regeneration.In summary,this study offers a novel treatment approach for vascularized bone tissue regeneration that relies on energy metabolism activation and the maintenance of a stable local hypoxia signaling state.
基金supported by the National Nature Science Foundation of China(No.81970920,81900983)the Natural Science Foundation of Beijing Municipality,China(No.7232218)the Shanghai Science and Technology Committee Youth Sailing Program(China)(No.19YF1442500).
文摘Tricho-dento-osseous(TDO)syndrome is a rare autosomal dominant disease resulting from distal-less homeobox 3(DLX3)mutation.1,2 Accumulative bone density in alveolar bone is a clinically favorable phenotype for TDO patients.However,the limited number of bone marrow mesenchymal stem cells(BMSCs)in TDO patients restricts their application.
基金supported by the National Natural Science Foundation of China(92049201,82030031,81991504,92149301,L2224038,82001067,and 82170951)National Key Research and Development Program(2022YFA1104401)+9 种基金Beijing Municipal Govermment(Beijing Laboratory of Oral Health,PXM2021_014226_000041Beijing Scholar Program,PXM2020_014226_000005 and PXM2021_014226_000020)Beijing Municipal Science and Technology Commission(Z181100001718208)Beijing Municipal Education Commission(119207020201)Innovation Research Team Project of Beijing Stomatological Hospital,Capital Medical University(CXTD202201)Research Unit of Tooth Development and Regeneration,Chinese Academy of Medical Sciences(2019-12M-5-031)Beijing Advanced Innovation Center for Big Data-based Precision Medicine(PXM2021_014226_000026)Beijing Municipal Colleges and Universities High Level Talents Introduction and Cultivate Project-Beijing Great Wall Scholar Program(CIT&TCD 20180332)Scientific Research Common Program of Beijing Municipal Commission of Education(KM202110025009)Beijing Municipal Natural Science Foundation(7232071 and 7222079).
文摘Homeostasis is essential for the maintenance of health,and how it is maintained is the focus of attention in homeostatic medicine.As a natural dietary nutrient,nitrate is critical in regulating homeostasis.This article summarizes nitrate's cognitive his-tory,sources,and metabolism.It discusses the relationship and possible mechanism between nitrate and organism homeostasis from three aspects:flora homeostasis,inflammation-immunity homeostasis,and energy metabolism homeostasis,as well as the clinical application scenarios of nitrate as a promising new generation of drugs,including preventing and treating multi-system diseases,reducing organism injury,improving exercise ability,regulating glucose and lipid metabolism,and assisting tumor treatment.An increased understanding of nitrate's impact on body home-ostasis could foster a new research concept for its application in disease prevention and treatment.
基金the National Natu-ral Science Foundation of China(81672634 and 81472753).
文摘Breast cancer is a multistep, multifactorial, and heterogeneous disease. Significant transformations have occurred in the sys-temic management of breast cancer in the past decade. Due to the further understanding of pathogenesis, scientists have found plenty of signaling pathways and correspondingly therapeutic targets in breast cancer, such as hormone receptor, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), phos-phoinositide-3-kinase (PI3K), v-akt murine thymoma viral oncogene homolog (AKT), mechanistic target of rapamycin (mTOR), cyclin-dependent kinase 4/6 (CDK4/6), poly (adenosine diphosphate-ribose) polymerase (PARP), and programmed death-1 (PD-1). Targeted therapy, which optimizes the accuracy of antitumor activity and minimizes toxicity to normal tissues, plays a crucial role in breast cancer treatment in the era of precision medicine. In this review, we aimed to summarize the latest developments in targeted therapy for breast cancer and discuss the existing problems.
基金the National Key R&D Program of China(No.2021YFC2501004)the National Natural Science Foundation of China(Nos.82172988,81772490 and 81502023)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(CIFMS)(Nos.2021-1-I2M-014 and 2021-1-I2M-067).
文摘Treating patients with esophageal squamous cell carcinoma(ESCC)is challenging due to the high chemoresistance.Growth differentiation factor 15(GDF15)is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research.In this study,the link between GDF15 and chemotherapy resistance in ESCC was further explored.The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies.ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response.GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2.Through an in vivo study,we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin.Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A.AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A,indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin.The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy,resulting in beneficial therapeutic outcomes.
