Discontinuation of tyrosine kinase inhibitor(TKI)therapy after achieving a persistent deep molecular response(DMR)is an urgently needed treatment goal for chronic myeloid leukemia(CML)patients and has been included in...Discontinuation of tyrosine kinase inhibitor(TKI)therapy after achieving a persistent deep molecular response(DMR)is an urgently needed treatment goal for chronic myeloid leukemia(CML)patients and has been included in the National Comprehensive Cancer Network(NCCN)guidelines(version 2.2017)for CML.Indeed,various studies have confirmed the feasibility of discontinuing TKI therapy.In this study,we analyzed data from 45 CML patients who had discontinued TKI therapy.Univariate analysis was performed to predict factors that were potentially related to treatment-free remission(TFR)and identify the differences between early relapse and late relapse.Out of the 45 patients,20 exhibited molecular relapse after a median follow-up of 18 months(range,1-54 months),and the estimated TFR at 24 months was 40%.The univariate analysis revealed that a high Sokal score and interruptions or dose reductions during TKI treatment were the only baseline factors associated with poor outcomes.Our results indicate that TKI discontinuation could be successfully put into practice in China.展开更多
Objective:To investigate the effect of vascular endothelial growth factor(VEGF),P53 and telomerase on angiogenesis in gastric carcinoma tissue.Methods:A total of 95 surgical resection samples of gastric cancer tissue ...Objective:To investigate the effect of vascular endothelial growth factor(VEGF),P53 and telomerase on angiogenesis in gastric carcinoma tissue.Methods:A total of 95 surgical resection samples of gastric cancer tissue after pathological diagnosis are collected to observe the VEGF,P53 and telomerase expression using immunohistochemical methods.Relationship between their expression and its influence on angiogenesis in gastric carcinoma tissue were analyzed.Results:Microvascular density(MVD)and the expression of VEGF,P53 and telomerase were positively correlated.Expression of VEGF and P53 protein were related to tumor type and lymph metastasis,and also a correlation was observed between P53 and VEGF.The telomerase expression had no correlation with VEGF,and P53.Conclusions:VEGF angiogenesis has a angiogenesis promoting effect on gastric cancer tissue development and plays an important role in tumor generation and metastasis.Mutant P53 promotes the tumor angiogenesis generation by adjusting VEGF.Telomerase has a certain role in promoting activity of angiogenesis through different way rather than P53.展开更多
In the present study, human umbilical cord blood mesenchymal stem cells were injected into a rat model of traumatic brain injury via the tail vein. Results showed that 5-bromodeoxyuridine-labeled cells aggregated arou...In the present study, human umbilical cord blood mesenchymal stem cells were injected into a rat model of traumatic brain injury via the tail vein. Results showed that 5-bromodeoxyuridine-labeled cells aggregated around the injury site, surviving up to 4 weeks post-transplantation. In addition, transplantation-related death did not occur, and neurological functions significantly improved. Histological detection revealed attenuated pathological injury in rat brain tissues following human umbilical cord blood mesenchymal stem cell transplantation. In addition, the number of apoptotic cells decreased. Immunohistochemistry and in situ hybridization showed increased expression of brain-derived neurotrophic factor, nerve growth factor, basic fibroblast growth factor, and vascular endothelial growth factor, along with increased microvessel density in surrounding areas of brain injury. Results demonstrated migration of transplanted human umbilical cord blood mesenchymal stem cells into the lesioned boundary zone of rats, as well as increased angiogenesis and expression of related neurotrophic factors in the lesioned boundary zone.展开更多
Objective:To investigate the expression of targeting protein for Xenopus kinesin-like protein 2(TPX2) in breast cancer tissue and to explore its role in proliferation,migration and invasion of breast cancer cells.Meth...Objective:To investigate the expression of targeting protein for Xenopus kinesin-like protein 2(TPX2) in breast cancer tissue and to explore its role in proliferation,migration and invasion of breast cancer cells.Methods:The mRNA and protein expressions of TPX2 in breast cancer tissue and cell lines were assessed by quantitative RT-PCR and Western blot.The effect of TPX2 with RNA interference on proliferation,invasion and migration of breast cancer cells was observed by MTT and Transwell assays.Results:Both mRNA and protein expressions of TPX2 were upregulated in breast cancer tissues compared to tumor-adjacent tissue.TPX2 expression was also upregulated in breast cancer cell lines,and the TPX2 interfered by small interfering RNA could inhibit the proliferation,invasion and migration of breast cancer cells by inhibiting matrix metalloproteinase-2 and matrix metalloproteinase-9.Conclusions:Significantly upregulated TPX2 expression is observed in breast cancer tissue and cells,and contributes to promote the proliferation,migration and invasion of breast cancer cells.展开更多
Oculocutaneous albinism (OCA)is an autosomal recessive pigmentation abnormality,characterized by variable hair,skin,and ocular hypopigmentation.OCA1 is the most frequent subtype of OCA,caused by mutations in the tyros...Oculocutaneous albinism (OCA)is an autosomal recessive pigmentation abnormality,characterized by variable hair,skin,and ocular hypopigmentation.OCA1 is the most frequent subtype of OCA,caused by mutations in the tyrosinase gene (TYR). In this study,we investigated the genetic mutation of a Chinese family with a female OCA patient who came for genetic counseling before pregnancy.Complete physical examination was performed,and DNA from blood samples was collected from the family members.Mutations of TYR,OCA2,and SLC45A2 genes were examined in the proband, and verified in her parents by Sanger sequencing.Large deletion or duplication of TYR and OCA2 genes was detected by multiplex ligation-dependent probe amplification (MLPA).A homozygous TYR c.307T>C (p.Cys103Arg)missense mutation was identified in the proband,and both parents were heterozygous carriers.No large deletion or duplication was found in the proband.This mutation was absent in 1000G,ExAC,or HGMD database,and multiple lines of in silico tools supported a deleterious effect.These results suggest that TYR c.307T>C mutation might be responsible for OCA1,and our study further expands the mutation spectrum of OCA1 in the Chinese population.展开更多
BACKGROUND Graft-vs-host disease (GVHD) is a major cause of mortality after allogeneic hematopoietic stem cell transplantation.Some patients have steroid-refractory(SR) GVHD.AIM To evaluate the effect and safety of ru...BACKGROUND Graft-vs-host disease (GVHD) is a major cause of mortality after allogeneic hematopoietic stem cell transplantation.Some patients have steroid-refractory(SR) GVHD.AIM To evaluate the effect and safety of ruxolitinib add-on in the treatment of patients with SR acute (a) and chronic (c) GVHD.METHODS We retrospectively analyzed 38 patients administered ruxolitinib add-on to standard immunosuppressive therapy for SR-aGVHD or SR-cGVHD following allogeneic hematopoietic stem cell transplantation.Ruxolitinib was administered5-10 mg/d depending on disease severity,patient status,and the use of antifungal drugs.Overall response rate,time to best response,malignancy relapse rate,infection rate,and treatment-related adverse events were assessed.RESULTS The analysis included 10 patients with SR-aGVHD (gradeⅢ/Ⅳ,n=9) and 28patients with SR-cGVHD (moderate/severe,n=24).For the SR-aGVHD and SRcGVHD groups,respectively:Median number of previous GVHD therapies was 2(range:1-3) and 2 (1-4);median follow-up was 2.5 (1.5-4) and 5 (1.5-10) mo;median time to best response was 1 (0.5-2.5) and 3 (1-9.5) mo;and overall response rate was 100%(complete response:80%) and 82.1%(complete response:10.7%) with a response observed in all GVHD-affected organs.The malignancy relapse rates for the SR-aGVHD and SR-cGVHD groups were 10.0%and 10.7%,respectively.Reactivation rates for cytomegalovirus,Epstein-Barr virus,and varicella-zoster virus,respectively,were 30.0%,10.0%,and 0%for the SR-aGVHD group and 0%,14.3%,and 7.1%for the SR-cGVHD group.CONCLUSION Ruxolitinib add-on was effective and safe as salvage therapy for SR-GVHD.展开更多
The key to improve the therapeutic efficacy for cancer treatment is to increase the delivery of drugs to tumors.For this purpose, tumor-microenvironment stimuliresponsive materials have great potential. Here, we prepa...The key to improve the therapeutic efficacy for cancer treatment is to increase the delivery of drugs to tumors.For this purpose, tumor-microenvironment stimuliresponsive materials have great potential. Here, we prepared a new nanomedicine by bonding the conjugate of honokiol(HNK) and 5,6-dimethylxanthenone-4-acetic acid(DMXAA)to a glutathione(GSH)-responsive nanocarrier, poly(α-lipoic acid) polyethylene glycol. The nanomedicine would disintegrate due to the high level of GSH at the tumor sites,achieving the co-delivery of HNK and DMXAA, and realizing the combination therapy through close-range killing by HNK and long-range striking by DMXAA together. In a murine 4T1 breast tumor model, this strategy exhibited high tumor inhibition rate of 93%, and provided a valuable therapeutic choice for cancer therapy.展开更多
Unsaturated fatty acids are widely distributed in natural edible resources,and have various uses and biological activities.However,no relevant review on unsaturated fat acids from natural edible resources has been fou...Unsaturated fatty acids are widely distributed in natural edible resources,and have various uses and biological activities.However,no relevant review on unsaturated fat acids from natural edible resources has been found.Therefore,this paper reviewed unsaturated fatty acids in natural edible resources,including the classification and resources of unsaturated fatty acids,biosynthetic pathway,biological activities and application.It was found that unsaturated fatty acids have good therapeutic value in preventing oxidative stress,inflammation,cardiovascular and cerebrovascular diseases,cancer and osteoporosis.This paper will provide reference for the study of unsaturated fatty acids in natural edible resources.展开更多
We report a reactive oxygen species(ROS)-stimulus-responsive phenylboronic acid pinacol ester nanocarrier,loaded with guanidine-modified 10-hydroxycamptothecin(HCPT)prodrug,to create a drug delivery-base nanomedicine....We report a reactive oxygen species(ROS)-stimulus-responsive phenylboronic acid pinacol ester nanocarrier,loaded with guanidine-modified 10-hydroxycamptothecin(HCPT)prodrug,to create a drug delivery-base nanomedicine.The prodrug was stuck tightly in the nanocarrier with over 99%drug-loading efficiency due to the superposition of hydrogen bonds from guanidine and carboxyl,hydrophobic interaction,π–πstacking interaction from phenylboronic acid pinacol ester,and the HCPT prodrug.The aqueous stability of the phenylboronic acid pinacol ester nanocarrier improved remarkably after drug loading because of the interaction between the prodrug and the nanocarrier.Thus,the nanomedicine could realize ROS-triggered disassembly at the tumor sites,release the cell-penetrating prodrug,and achieve improved cellular uptake than the HCPT alone.The results of in vivo antitumor determination demonstrated three-fold inhibition of tumor growth rate of the ROS-stimulus-responsive nanomedicine,compared with HCPT,and the side effects of the prodrug complex reduced significantly.Therefore,our approach offers a promising strategy for the enhancement of antitumor efficacy.展开更多
Using organizational flexibility as a research lens, we investigate how private firms, especially SMEs, in China cope with the 2008 financial crisis. Testing data from a large sample of private firms （N=3,459） by di...Using organizational flexibility as a research lens, we investigate how private firms, especially SMEs, in China cope with the 2008 financial crisis. Testing data from a large sample of private firms （N=3,459） by difference-indifferences analysis, we find that firms with industrial diversification, geographic expansion and political connections perform better during the crisis than those without. These results are less affected by self-selection problems （as the abrupt crisis provides a natural experiment） and hold up against endogeneity and several other challenges in robustness tests. The findings offer important implications for researchers, business owners, policy makers and future research.展开更多
Background Synaptic degeneration occurs in the early stage of Alzheimer’s disease(AD)before devastating symptoms,strongly correlated with cognitive decline.Circular RNAs(circRNAs)are abundantly enriched in neural tis...Background Synaptic degeneration occurs in the early stage of Alzheimer’s disease(AD)before devastating symptoms,strongly correlated with cognitive decline.Circular RNAs(circRNAs)are abundantly enriched in neural tissues,and aberrant expression of circRNAs precedes AD symptoms,significantly correlated with clinical dementia severity.However,the direct relationship between circRNA dysregulation and synaptic impairment in the early stage of AD remains poorly understood.Methods Hippocampal whole-transcriptome sequencing was performed to identify dysregulated circRNAs and miRNAs in 4-month-old wild-type and APP/PS1 mice.RNA antisense purification and mass spectrometry were utilized to unveil interactions between circRIMS2 and methyltransferase 3,N6-adenosine-methyltransferase complex catalytic subunit(METTL3).The roles of circRIMS2/miR-3968 in synaptic targeting of UBE2K-mediated ubiquitination of GluN2B subunit of NMDA receptor were evaluated via numerous lentiviruses followed by morphological staining,co-immunoprecipitation and behavioral testing.Further,a membrane-permeable peptide was used to block the ubiquitination of K1082 on GluN2B in AD mice.Results circRIMS2 was significantly upregulated in 4-month-old APP/PS1 mice,which was mediated by METTL3-dependent N6-methyladenosine(m6A)modification.Overexpression of circRIMS2 led to synaptic and memory impairments in 4-month-old C57BL/6 mice.MiR-3968/UBE2K was validated as the downstream of circRIMS2.Elevated UBE2K induced synaptic dysfunction of AD through ubiquitinating K1082 on GluN2B.Silencing METTL3 or blocking the ubiquitination of K1082 on GluN2B with a short membrane-permeable peptide remarkably rescued synaptic dysfunction in AD mice.Conclusions In conclusion,our study demonstrated that m6A-modified circRIMS2 mediates the synaptic and memory impairments in AD by activating the UBE2K-dependent ubiquitination and degradation of GluN2B via sponging miR-3968,providing novel therapeutic strategies for AD.展开更多
Osteosarcoma is a high-class malignant bone cancer with a less than 20% five-year survival rate due to its early metastasis potential. There is an urgent need to develop a versatile and innoxious drug to treat metasta...Osteosarcoma is a high-class malignant bone cancer with a less than 20% five-year survival rate due to its early metastasis potential. There is an urgent need to develop a versatile and innoxious drug to treat metastatic osteosarcoma.Curcumin（Cur） has shown its potential for the treatment of many cancers; however,the clinical implication of native curcumin is severely hindered by its intrinsic property. In this study,a mixed system of monomethoxy（polyethylene glycol）-poly（d,l-lactide-co-glycolide）/poly（ε-caprolactone）（m PEGPLGA/PCL） was used to build a formulation of curcuminencapsulated nanoparticles（Cur-NPs）,which significantly improved the solubility,stability and cellular uptake of curcumin. Moreover,the Cur-NPs were superior to free curcumin in the matter of inhibition on the proliferation,migration and invasion of osteosarcoma 143B cells. It was found that both free curcumin and Cur-NPs could decrease the expressions of c-Myc and MMP7 in the level of mRNA and protein,which explained why free curcumin and Cur-NPs could inhibit the proliferation and invasion of metastatic osteosarcoma 143B cells. The Cur-NPs provided a promising strategy for metastatic osteosarcoma treatment.展开更多
In the version of the article originally published in the volume 63,issue 2,2020 of Sci China Mater(2020,63(2):307–315,https://doi.org/10.1007/s40843-019-1183-0),the affiliations of two of the authors(Zhaohui Tang an...In the version of the article originally published in the volume 63,issue 2,2020 of Sci China Mater(2020,63(2):307–315,https://doi.org/10.1007/s40843-019-1183-0),the affiliations of two of the authors(Zhaohui Tang and Xuesi Chen)were incompletely labeled.The corrected version of the authors’affiliations is as below.展开更多
Background： Brain acid soluble protein 1 （BASPI） is identified as a novel potential tumor suppressor in several cancers. However, its role in thyroid cancer has not been investigated yet. In the present study, the ...Background： Brain acid soluble protein 1 （BASPI） is identified as a novel potential tumor suppressor in several cancers. However, its role in thyroid cancer has not been investigated yet. In the present study, the antitumor activities of BASP1 against the growth and migration of thyroid cancer cells were evaluated. Methods： BASP1 expression in thyroid cancer tissues and normal tissues were examined by immunohistochemical staining and the association between its expression and prognosis was analyzed, pcDNA-BASP 1 carrying full length of BASP1 cDNA was constructed to restore the expression of BASP1 in thyroid cancer cell lines （BHT- I 01 and KMH-2）. The cell proliferation in vitro and in vivo was evaluated by WST-1 assay and xenografl tumor models, respectively. Cell cycle distribution after transfection was analyzed using flow cytometry. Cell apoptosis after transfection was examined by annexin V/propidium iodide assay. The migration was examined using transwell assay. Results： BASP1 expression was abundant in normal tissues while it is significantly decreased in cancer tissues （P = 0.000）. pcDNA-BASP1 restored the expression of BASPI and significantly inhibited the growth of BHT-101 and KMH-2 cells as well as xenograft tumors in nude mice （P = 0.000）. pcDNA-BASPI induced G1 arrest and apoptosis in BHT-101 and KMH-2 cells. In addition, pcDNA-BASP1 significantly inhibited the cell migration. Conclusions： Downregulation of BASP1 expression may play a role in the tumorigenesis of thyroid cancer. Restoration of BASPI expression exerted extensive antitumor activities against growth and migration of thyroid cancer cells, which suggested that BASPI gene might act as a potential therapeutic agent for the treatment of thyroid cancer.展开更多
Physical encapsulation of drugs into polymer micelles is a common method of loading hydrophobic drugs.Methoxy polyethylene glycol-poly(D,L.-lactide)(mPEG-PDLLA)is one of the most commonly used drug carrier.At present,...Physical encapsulation of drugs into polymer micelles is a common method of loading hydrophobic drugs.Methoxy polyethylene glycol-poly(D,L.-lactide)(mPEG-PDLLA)is one of the most commonly used drug carrier.At present,whether a carrier is suitable for the loading of a certain drug is determined by drug loading experiments.This process costs a lot of time.Therefore,an efficient predicting method to avoid time-consuming tests is critical.In this study,we prepared mPEG5k-PDLLA5k and used it to load a series of drugs.Three parameters were used to test the miscibility of mPEG5k-PDLLA5k with drugs,including absolute difference in Hildebrand solubility parameters(|△δ|),Flory-Huggins interaction parameter(x)and the distance(D value)calculated from the two-dimensional solubility parameters.We found the two-dimensional solubility parameters obtained from JB2013 group contribution(GC)method was useful.By comparing the drug loading content(DLC)with the D value,we found that when the D value was less than 5.0(MJ/m3)1/2,the miscibility of drug and mPEGSk-PDLLASk was good and drug loading capability was high;when the D value was more than 8.0(MJ/m3)1/2,the drug was barely loaded.Thus,this work provided a rationale to qualitatively predict the loading capability of mPEGSk-PDLLA5k for hydrophobic drugs.展开更多
β-Lapachone (β-Lap) is a promising orthonaphthoquinone drug for cancer treatment and has been inclinical trials. Its application is constrained by the low aqueoussolubility, and severe side effects. Even prodrug des...β-Lapachone (β-Lap) is a promising orthonaphthoquinone drug for cancer treatment and has been inclinical trials. Its application is constrained by the low aqueoussolubility, and severe side effects. Even prodrug designation isan effective approach to render it with tumor selectivity, it islimited by the lack of modifiable groups on β-Lap. Herein, anovel azo bond primary cleavage and carbon–carbon (C–C)bond secondary cleavage-based polymeric β-Lap prodrug(Azo-Lap NP) is designed, in which the self-immolated paraaminobenzyl linker is connected to poly(L-glutamic acid)(PGlu) via azo linkage and the responsive drug release of β-Lapagainst tumors can be achieved under high NAD(P)H:quinoneoxidoreductase 1 (NQO1) expression and low pH environmentin tumors. The effective covalent loading of β-Lap by Azo-LapNPs permitted a high administration dose of β-Lap and enabled significant tumor retention time. Moreover, Azo-LapNPs markedly reduced the side effects of β-Lap by avoidinghemolysis and the production of methemoglobin. The safety ofAzo-Lap NPs administration is validated in the antitumorexperiment of mice. In the 4T1 model, Azo-Lap NPs exhibiteda markedly higher tumor suppression rate than β-Lap. Thiswork provides an effective and safe polymeric prodrug fortumor selective delivery of β-Lap.展开更多
基金the National Natural Science Foundation of China(No.81500136 and No.81670145).
文摘Discontinuation of tyrosine kinase inhibitor(TKI)therapy after achieving a persistent deep molecular response(DMR)is an urgently needed treatment goal for chronic myeloid leukemia(CML)patients and has been included in the National Comprehensive Cancer Network(NCCN)guidelines(version 2.2017)for CML.Indeed,various studies have confirmed the feasibility of discontinuing TKI therapy.In this study,we analyzed data from 45 CML patients who had discontinued TKI therapy.Univariate analysis was performed to predict factors that were potentially related to treatment-free remission(TFR)and identify the differences between early relapse and late relapse.Out of the 45 patients,20 exhibited molecular relapse after a median follow-up of 18 months(range,1-54 months),and the estimated TFR at 24 months was 40%.The univariate analysis revealed that a high Sokal score and interruptions or dose reductions during TKI treatment were the only baseline factors associated with poor outcomes.Our results indicate that TKI discontinuation could be successfully put into practice in China.
基金supported by Handan City Technology Bureau Scientific Research Project(No 1023108101-8)
文摘Objective:To investigate the effect of vascular endothelial growth factor(VEGF),P53 and telomerase on angiogenesis in gastric carcinoma tissue.Methods:A total of 95 surgical resection samples of gastric cancer tissue after pathological diagnosis are collected to observe the VEGF,P53 and telomerase expression using immunohistochemical methods.Relationship between their expression and its influence on angiogenesis in gastric carcinoma tissue were analyzed.Results:Microvascular density(MVD)and the expression of VEGF,P53 and telomerase were positively correlated.Expression of VEGF and P53 protein were related to tumor type and lymph metastasis,and also a correlation was observed between P53 and VEGF.The telomerase expression had no correlation with VEGF,and P53.Conclusions:VEGF angiogenesis has a angiogenesis promoting effect on gastric cancer tissue development and plays an important role in tumor generation and metastasis.Mutant P53 promotes the tumor angiogenesis generation by adjusting VEGF.Telomerase has a certain role in promoting activity of angiogenesis through different way rather than P53.
基金supported by Medical Scientific Research Program of Hebei Province in 2010, Hebei Provincial Health Department, No. 20100131
文摘In the present study, human umbilical cord blood mesenchymal stem cells were injected into a rat model of traumatic brain injury via the tail vein. Results showed that 5-bromodeoxyuridine-labeled cells aggregated around the injury site, surviving up to 4 weeks post-transplantation. In addition, transplantation-related death did not occur, and neurological functions significantly improved. Histological detection revealed attenuated pathological injury in rat brain tissues following human umbilical cord blood mesenchymal stem cell transplantation. In addition, the number of apoptotic cells decreased. Immunohistochemistry and in situ hybridization showed increased expression of brain-derived neurotrophic factor, nerve growth factor, basic fibroblast growth factor, and vascular endothelial growth factor, along with increased microvessel density in surrounding areas of brain injury. Results demonstrated migration of transplanted human umbilical cord blood mesenchymal stem cells into the lesioned boundary zone of rats, as well as increased angiogenesis and expression of related neurotrophic factors in the lesioned boundary zone.
基金Supported by National Science Foundation(81502322)
文摘Objective:To investigate the expression of targeting protein for Xenopus kinesin-like protein 2(TPX2) in breast cancer tissue and to explore its role in proliferation,migration and invasion of breast cancer cells.Methods:The mRNA and protein expressions of TPX2 in breast cancer tissue and cell lines were assessed by quantitative RT-PCR and Western blot.The effect of TPX2 with RNA interference on proliferation,invasion and migration of breast cancer cells was observed by MTT and Transwell assays.Results:Both mRNA and protein expressions of TPX2 were upregulated in breast cancer tissues compared to tumor-adjacent tissue.TPX2 expression was also upregulated in breast cancer cell lines,and the TPX2 interfered by small interfering RNA could inhibit the proliferation,invasion and migration of breast cancer cells by inhibiting matrix metalloproteinase-2 and matrix metalloproteinase-9.Conclusions:Significantly upregulated TPX2 expression is observed in breast cancer tissue and cells,and contributes to promote the proliferation,migration and invasion of breast cancer cells.
基金This project was supported by the National Natural Science Foundation of China (No.81500925).
文摘Oculocutaneous albinism (OCA)is an autosomal recessive pigmentation abnormality,characterized by variable hair,skin,and ocular hypopigmentation.OCA1 is the most frequent subtype of OCA,caused by mutations in the tyrosinase gene (TYR). In this study,we investigated the genetic mutation of a Chinese family with a female OCA patient who came for genetic counseling before pregnancy.Complete physical examination was performed,and DNA from blood samples was collected from the family members.Mutations of TYR,OCA2,and SLC45A2 genes were examined in the proband, and verified in her parents by Sanger sequencing.Large deletion or duplication of TYR and OCA2 genes was detected by multiplex ligation-dependent probe amplification (MLPA).A homozygous TYR c.307T>C (p.Cys103Arg)missense mutation was identified in the proband,and both parents were heterozygous carriers.No large deletion or duplication was found in the proband.This mutation was absent in 1000G,ExAC,or HGMD database,and multiple lines of in silico tools supported a deleterious effect.These results suggest that TYR c.307T>C mutation might be responsible for OCA1,and our study further expands the mutation spectrum of OCA1 in the Chinese population.
文摘BACKGROUND Graft-vs-host disease (GVHD) is a major cause of mortality after allogeneic hematopoietic stem cell transplantation.Some patients have steroid-refractory(SR) GVHD.AIM To evaluate the effect and safety of ruxolitinib add-on in the treatment of patients with SR acute (a) and chronic (c) GVHD.METHODS We retrospectively analyzed 38 patients administered ruxolitinib add-on to standard immunosuppressive therapy for SR-aGVHD or SR-cGVHD following allogeneic hematopoietic stem cell transplantation.Ruxolitinib was administered5-10 mg/d depending on disease severity,patient status,and the use of antifungal drugs.Overall response rate,time to best response,malignancy relapse rate,infection rate,and treatment-related adverse events were assessed.RESULTS The analysis included 10 patients with SR-aGVHD (gradeⅢ/Ⅳ,n=9) and 28patients with SR-cGVHD (moderate/severe,n=24).For the SR-aGVHD and SRcGVHD groups,respectively:Median number of previous GVHD therapies was 2(range:1-3) and 2 (1-4);median follow-up was 2.5 (1.5-4) and 5 (1.5-10) mo;median time to best response was 1 (0.5-2.5) and 3 (1-9.5) mo;and overall response rate was 100%(complete response:80%) and 82.1%(complete response:10.7%) with a response observed in all GVHD-affected organs.The malignancy relapse rates for the SR-aGVHD and SR-cGVHD groups were 10.0%and 10.7%,respectively.Reactivation rates for cytomegalovirus,Epstein-Barr virus,and varicella-zoster virus,respectively,were 30.0%,10.0%,and 0%for the SR-aGVHD group and 0%,14.3%,and 7.1%for the SR-cGVHD group.CONCLUSION Ruxolitinib add-on was effective and safe as salvage therapy for SR-GVHD.
基金supported by the Ministry of Science and Technology of China (2018ZX09711003-012)the National Natural Science Foundation of China (51873206, 51673189, 51829302, 51503202, 51833010 and 51520105004)the Program of Scientific Development of Jilin Province (20190103033JH)
文摘The key to improve the therapeutic efficacy for cancer treatment is to increase the delivery of drugs to tumors.For this purpose, tumor-microenvironment stimuliresponsive materials have great potential. Here, we prepared a new nanomedicine by bonding the conjugate of honokiol(HNK) and 5,6-dimethylxanthenone-4-acetic acid(DMXAA)to a glutathione(GSH)-responsive nanocarrier, poly(α-lipoic acid) polyethylene glycol. The nanomedicine would disintegrate due to the high level of GSH at the tumor sites,achieving the co-delivery of HNK and DMXAA, and realizing the combination therapy through close-range killing by HNK and long-range striking by DMXAA together. In a murine 4T1 breast tumor model, this strategy exhibited high tumor inhibition rate of 93%, and provided a valuable therapeutic choice for cancer therapy.
基金supported by National Natural Science Foundation of China(82204762)China Postdoctoral Science Foundation(2022M721984)+1 种基金Shandong Province Postdoctoral Innovative Talent Support Program(SDBX2022062)Introduction Project of High-level doctoral Talents of Linyi University(LYDX2019BS055).
文摘Unsaturated fatty acids are widely distributed in natural edible resources,and have various uses and biological activities.However,no relevant review on unsaturated fat acids from natural edible resources has been found.Therefore,this paper reviewed unsaturated fatty acids in natural edible resources,including the classification and resources of unsaturated fatty acids,biosynthetic pathway,biological activities and application.It was found that unsaturated fatty acids have good therapeutic value in preventing oxidative stress,inflammation,cardiovascular and cerebrovascular diseases,cancer and osteoporosis.This paper will provide reference for the study of unsaturated fatty acids in natural edible resources.
基金support for this work was provided by the Ministry of Science and Technology of China(no.2018ZX09711003-012)National Natural Science Foundation of China(Project nos.51503202,51673189,51873206,51833010,and 51520105004).
文摘We report a reactive oxygen species(ROS)-stimulus-responsive phenylboronic acid pinacol ester nanocarrier,loaded with guanidine-modified 10-hydroxycamptothecin(HCPT)prodrug,to create a drug delivery-base nanomedicine.The prodrug was stuck tightly in the nanocarrier with over 99%drug-loading efficiency due to the superposition of hydrogen bonds from guanidine and carboxyl,hydrophobic interaction,π–πstacking interaction from phenylboronic acid pinacol ester,and the HCPT prodrug.The aqueous stability of the phenylboronic acid pinacol ester nanocarrier improved remarkably after drug loading because of the interaction between the prodrug and the nanocarrier.Thus,the nanomedicine could realize ROS-triggered disassembly at the tumor sites,release the cell-penetrating prodrug,and achieve improved cellular uptake than the HCPT alone.The results of in vivo antitumor determination demonstrated three-fold inhibition of tumor growth rate of the ROS-stimulus-responsive nanomedicine,compared with HCPT,and the side effects of the prodrug complex reduced significantly.Therefore,our approach offers a promising strategy for the enhancement of antitumor efficacy.
文摘Using organizational flexibility as a research lens, we investigate how private firms, especially SMEs, in China cope with the 2008 financial crisis. Testing data from a large sample of private firms （N=3,459） by difference-indifferences analysis, we find that firms with industrial diversification, geographic expansion and political connections perform better during the crisis than those without. These results are less affected by self-selection problems （as the abrupt crisis provides a natural experiment） and hold up against endogeneity and several other challenges in robustness tests. The findings offer important implications for researchers, business owners, policy makers and future research.
基金supported by the National Natural Science Foundation of China(82372337,81500925 to Xiong Wang,81801062 to Xiaoguang Li)Tongji Hospital(HUST)Foundation for Excellent Young Scientist(2020YQ01-11 to Xiong Wang)the Natural Science Foundation of Hubei Province(2022CFB150 to Huijun Li).
文摘Background Synaptic degeneration occurs in the early stage of Alzheimer’s disease(AD)before devastating symptoms,strongly correlated with cognitive decline.Circular RNAs(circRNAs)are abundantly enriched in neural tissues,and aberrant expression of circRNAs precedes AD symptoms,significantly correlated with clinical dementia severity.However,the direct relationship between circRNA dysregulation and synaptic impairment in the early stage of AD remains poorly understood.Methods Hippocampal whole-transcriptome sequencing was performed to identify dysregulated circRNAs and miRNAs in 4-month-old wild-type and APP/PS1 mice.RNA antisense purification and mass spectrometry were utilized to unveil interactions between circRIMS2 and methyltransferase 3,N6-adenosine-methyltransferase complex catalytic subunit(METTL3).The roles of circRIMS2/miR-3968 in synaptic targeting of UBE2K-mediated ubiquitination of GluN2B subunit of NMDA receptor were evaluated via numerous lentiviruses followed by morphological staining,co-immunoprecipitation and behavioral testing.Further,a membrane-permeable peptide was used to block the ubiquitination of K1082 on GluN2B in AD mice.Results circRIMS2 was significantly upregulated in 4-month-old APP/PS1 mice,which was mediated by METTL3-dependent N6-methyladenosine(m6A)modification.Overexpression of circRIMS2 led to synaptic and memory impairments in 4-month-old C57BL/6 mice.MiR-3968/UBE2K was validated as the downstream of circRIMS2.Elevated UBE2K induced synaptic dysfunction of AD through ubiquitinating K1082 on GluN2B.Silencing METTL3 or blocking the ubiquitination of K1082 on GluN2B with a short membrane-permeable peptide remarkably rescued synaptic dysfunction in AD mice.Conclusions In conclusion,our study demonstrated that m6A-modified circRIMS2 mediates the synaptic and memory impairments in AD by activating the UBE2K-dependent ubiquitination and degradation of GluN2B via sponging miR-3968,providing novel therapeutic strategies for AD.
基金supported by the National Natural Science Foundation of China (51520105004,51673189,51390484,51403204,51673185,51473029 and 51503202)Science and Technology Service Network Initiative (KFJ-SW-STS-166)the Chinese Academy of Sciences Youth Innovation Promotion Association
文摘Osteosarcoma is a high-class malignant bone cancer with a less than 20% five-year survival rate due to its early metastasis potential. There is an urgent need to develop a versatile and innoxious drug to treat metastatic osteosarcoma.Curcumin（Cur） has shown its potential for the treatment of many cancers; however,the clinical implication of native curcumin is severely hindered by its intrinsic property. In this study,a mixed system of monomethoxy（polyethylene glycol）-poly（d,l-lactide-co-glycolide）/poly（ε-caprolactone）（m PEGPLGA/PCL） was used to build a formulation of curcuminencapsulated nanoparticles（Cur-NPs）,which significantly improved the solubility,stability and cellular uptake of curcumin. Moreover,the Cur-NPs were superior to free curcumin in the matter of inhibition on the proliferation,migration and invasion of osteosarcoma 143B cells. It was found that both free curcumin and Cur-NPs could decrease the expressions of c-Myc and MMP7 in the level of mRNA and protein,which explained why free curcumin and Cur-NPs could inhibit the proliferation and invasion of metastatic osteosarcoma 143B cells. The Cur-NPs provided a promising strategy for metastatic osteosarcoma treatment.
文摘In the version of the article originally published in the volume 63,issue 2,2020 of Sci China Mater(2020,63(2):307–315,https://doi.org/10.1007/s40843-019-1183-0),the affiliations of two of the authors(Zhaohui Tang and Xuesi Chen)were incompletely labeled.The corrected version of the authors’affiliations is as below.
文摘Background： Brain acid soluble protein 1 （BASPI） is identified as a novel potential tumor suppressor in several cancers. However, its role in thyroid cancer has not been investigated yet. In the present study, the antitumor activities of BASP1 against the growth and migration of thyroid cancer cells were evaluated. Methods： BASP1 expression in thyroid cancer tissues and normal tissues were examined by immunohistochemical staining and the association between its expression and prognosis was analyzed, pcDNA-BASP 1 carrying full length of BASP1 cDNA was constructed to restore the expression of BASP1 in thyroid cancer cell lines （BHT- I 01 and KMH-2）. The cell proliferation in vitro and in vivo was evaluated by WST-1 assay and xenografl tumor models, respectively. Cell cycle distribution after transfection was analyzed using flow cytometry. Cell apoptosis after transfection was examined by annexin V/propidium iodide assay. The migration was examined using transwell assay. Results： BASP1 expression was abundant in normal tissues while it is significantly decreased in cancer tissues （P = 0.000）. pcDNA-BASP1 restored the expression of BASPI and significantly inhibited the growth of BHT-101 and KMH-2 cells as well as xenograft tumors in nude mice （P = 0.000）. pcDNA-BASPI induced G1 arrest and apoptosis in BHT-101 and KMH-2 cells. In addition, pcDNA-BASP1 significantly inhibited the cell migration. Conclusions： Downregulation of BASP1 expression may play a role in the tumorigenesis of thyroid cancer. Restoration of BASPI expression exerted extensive antitumor activities against growth and migration of thyroid cancer cells, which suggested that BASPI gene might act as a potential therapeutic agent for the treatment of thyroid cancer.
基金the Ministry of Science and Technology of China(No.2018ZX09711003-012)the National Natural Science Foundation of China(Nos.51673189,51873206,51829302)Department of Science and Technology of Jilin Province(No.20190103033JH).
文摘Physical encapsulation of drugs into polymer micelles is a common method of loading hydrophobic drugs.Methoxy polyethylene glycol-poly(D,L.-lactide)(mPEG-PDLLA)is one of the most commonly used drug carrier.At present,whether a carrier is suitable for the loading of a certain drug is determined by drug loading experiments.This process costs a lot of time.Therefore,an efficient predicting method to avoid time-consuming tests is critical.In this study,we prepared mPEG5k-PDLLA5k and used it to load a series of drugs.Three parameters were used to test the miscibility of mPEG5k-PDLLA5k with drugs,including absolute difference in Hildebrand solubility parameters(|△δ|),Flory-Huggins interaction parameter(x)and the distance(D value)calculated from the two-dimensional solubility parameters.We found the two-dimensional solubility parameters obtained from JB2013 group contribution(GC)method was useful.By comparing the drug loading content(DLC)with the D value,we found that when the D value was less than 5.0(MJ/m3)1/2,the miscibility of drug and mPEGSk-PDLLASk was good and drug loading capability was high;when the D value was more than 8.0(MJ/m3)1/2,the drug was barely loaded.Thus,this work provided a rationale to qualitatively predict the loading capability of mPEGSk-PDLLA5k for hydrophobic drugs.
基金financially supported by the Ministry of Science and Technology of the People’s Republic of China (2022YFE0110200)the National Natural Science Foundation of China (52025035, 52273157, and 52073279)+1 种基金the Department of Science and Technology of Jilin Province (20240305041YY and 20230508102RC)the Youth Innovation Promotion Association of the Chinese Academy of Sciences (2022224)。
文摘β-Lapachone (β-Lap) is a promising orthonaphthoquinone drug for cancer treatment and has been inclinical trials. Its application is constrained by the low aqueoussolubility, and severe side effects. Even prodrug designation isan effective approach to render it with tumor selectivity, it islimited by the lack of modifiable groups on β-Lap. Herein, anovel azo bond primary cleavage and carbon–carbon (C–C)bond secondary cleavage-based polymeric β-Lap prodrug(Azo-Lap NP) is designed, in which the self-immolated paraaminobenzyl linker is connected to poly(L-glutamic acid)(PGlu) via azo linkage and the responsive drug release of β-Lapagainst tumors can be achieved under high NAD(P)H:quinoneoxidoreductase 1 (NQO1) expression and low pH environmentin tumors. The effective covalent loading of β-Lap by Azo-LapNPs permitted a high administration dose of β-Lap and enabled significant tumor retention time. Moreover, Azo-LapNPs markedly reduced the side effects of β-Lap by avoidinghemolysis and the production of methemoglobin. The safety ofAzo-Lap NPs administration is validated in the antitumorexperiment of mice. In the 4T1 model, Azo-Lap NPs exhibiteda markedly higher tumor suppression rate than β-Lap. Thiswork provides an effective and safe polymeric prodrug fortumor selective delivery of β-Lap.
