ABSTRACT
Aging poses a major risk factor for cardiovascular diseases, the leading cause of death in the aged population. However, the cell type-specific changes underlying cardiac aging are far from being clear. Here, we performed single-nucleus RNA-sequencing analysis of left ventricles from young and aged cynomolgus monkeys to define cell composition changes and transcriptomic alterations across different cell types associated with age. We found that aged cardiomyocytes underwent a dramatic loss in cell numbers and profound fluctuations in transcriptional profiles. Via transcription regulatory network analysis, we identified FOXP1, a core transcription factor in organ development, as a key downregulated factor in aged cardiomyocytes, concomitant with the dysregulation of FOXP1 target genes associated with heart function and cardiac diseases. Consistently, the deficiency of FOXP1 led to hypertrophic and senescent phenotypes in human embryonic stem cell-derived cardiomyocytes. Altogether, our findings depict the cellular and molecular landscape of ventricular aging at the single-cell resolution, and identify drivers for primate cardiac aging and potential targets for intervention against cardiac aging and associated diseases.
Subject(s)
Aged , Animals , Humans , Aging/genetics , Forkhead Transcription Factors/metabolism , Myocytes, Cardiac/metabolism , Primates/metabolism , Repressor Proteins/metabolism , Transcriptome , Macaca fascicularis/metabolismABSTRACT
Objective:To investigate the efficacy and adverse effects of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in preventing neutropenia in patients undergoing sequential adjuvant radiotherapy after postoperative chemotherapy for breast cancer.Methods:A total of 43 female patients with breast cancer from January 2017 to January 2019 in Shandong Cancer Hospital and Institute were analyzed prospectively. Twenty-one patients in the experimental group were given 6 mg of PEG-rhG-CSF subcutaneously 1-3 days before radiotherapy. In the control group, 22 patients were enrolled without PEG-rhG-CSF utilization. The lowest absolute neutrophil count (ANC), the number of days of radiotherapy interruption due to neutropenia, the number of recombinant human granulocyte colony-stimulating factor (rhG-CSF) used during radiotherapy and the occurrence of drug-induced skeletal muscle pain in the two groups were statistically analyzed.Results:No neutropenia fever was observed in the two groups during radiotherapy. In the experimental group, there was no case of grade Ⅲ neutropenia; while in the control group, there were 3 cases of grade Ⅲ neutropenia. The median value of the lowest ANC in the experimental group was 1.56×10 9/L, higher than that in the control group (1.37×10 9/L), with a statistically significant difference ( Z=-2.261, P=0.023). The median number of rhG-CSF used in the experimental group was 1, which was smaller than 2 in the control group, and the difference was statistically significant ( Z=-2.498, P=0.012). The median numbers of days of radiotherapy interruption due to neutropenia were 0 and 3 in the experimental group and the control group, with a statistically significant difference ( Z=-3.117, P=0.001). One case (4.8%) of drug-induced skeletal muscle pain was found in the experimental group and 5 cases (22.7%) in the control group, with no statistically significant difference ( χ2=1.586, P=0.208). Conclusion:PEG-rhG-CSF can effectively prevent neutropenia caused by radiotherapy after postoperative chemotherapy for patients with breast cancer, and can reduce the interruption of radiotherapy and the use of rhG-CSF during radiotherapy, which is helpful to the smooth process of radiotherapy.
ABSTRACT
Many human genetic diseases, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by single point mutations. HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutation in the LMNA gene. Base editors (BEs) composed of a cytidine deaminase fused to CRISPR/Cas9 nickase are highly efficient at inducing C to T base conversions in a programmable manner and can be used to generate animal disease models with single amino-acid substitutions. Here, we generated the first HGPS monkey model by delivering a BE mRNA and guide RNA (gRNA) targeting the LMNA gene via microinjection into monkey zygotes. Five out of six newborn monkeys carried the mutation specifically at the target site. HGPS monkeys expressed the toxic form of lamin A, progerin, and recapitulated the typical HGPS phenotypes including growth retardation, bone alterations, and vascular abnormalities. Thus, this monkey model genetically and clinically mimics HGPS in humans, demonstrating that the BE system can efficiently and accurately generate patient-specific disease models in non-human primates.
Subject(s)
Animals , Female , Humans , Disease Models, Animal , Gene Editing , Lamin Type A/metabolism , Macaca fascicularis , Progeria/pathologyABSTRACT
Objective To survey on smoking related knowledge and intention of quitting among smoking patients with diabetes mellitus .Methods A questionnaire survey on smoking related knowledge and intention of quitting was conducted among 146 smoking patients with type 2 diabetes mellitus ( T2DM) in Beijing Yangfangdian Community Health Service Center from September 2016 to October.The questionnaire included general information ( 6 items ) , smoking status ( 3 items ) , awareness of smoking hazards ( 11 items), smoking cessation (5 items).Of the 146 patients, 82 were face-to-face surveyed, and 64 were telephone surveyed.Among 141 respondents who completed the questionnaire , there were 135 males (95.7%) and 6 females (4.3%) aged 32-74 (58.9 ±7.9) years, 4 cases (2.8%) with primary school education,46 cases (32.6%) with junior high school,63 cases (44.7%) with secondary school or high school education , 28 cases (19.9%) with college degree or above .The duration of diabetes ranged from 1 to 35 years with an average of (7.7 ±5.9) years.There was 2 cases (1.4%) with 1-5 years of smoking , 2 cases (1.4%) with 6-10 years of smoking, 25 cases (17.8%) with 11-20 years of smoking, 112 cases (79.4%) with more than 20 years of smoking.Results 99.3% (140/141) of the participants knew that smoking could lead to chronic bronchitis and emphysema , 46.8% ( 66/141 ) thought that smoking could lead to diabetes, 51.1%(72/141) thought that smoking affected blood glucose control , 65.2%(92/141) knew that smoking increased the incidence of cardiovascular and cerebrovascular diseases .The intention of quitting smoking was significantly correlated with the awareness of above knowledge in smoking diabetic patients.Conclusion The awareness rate of smoking causing diabetes , blood glucose control and diabetic chronic complications is relatively low .The awareness of smoking related knowledge can significantly facilitate patients to quit smoking .
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Objective To investigate the association of vitamin D receptor gene (Apa1,Bsm1,Taq1) polymorphisms with autoimmune liver diseases risk.Metiods Case control test documents were retrieved through Pubmed,Ovid,Medline,and Web of science databases,according to the inclusion and exclusion criteria included in this study.The design of experiments,the characteristics of the object of study,research results was excerpted,STATA version 12.0 software were used.The correlation intensity was demonstrated with odds ratio (OR) and 95％ confidence interval (CI).Results A total of 6 publications containing 9 studies (7 studies about primary biliary cirrhosis,2 studies about autoimmune hepatitis) published from January 2000 to February 2012 were identified and 844 cases and 1 522 controls were included.The combined results based on all studies showed that there was a statistically significant link between Apa 1 and autoimmune liver diseases (OR =0.85,95％ CI 0.74-0.96,P =0.058,for a vs.A; OR =0.75,95％ CI 0.58-0.97,P =0.212,for aa vs.AA;OR =0.78,95％ CI 0.63-0.98,P =0.235,for Aa vs.AA; OR =0.77,95％ CI 0.63-0.94,P =0.231,for Aa/aa vs.AA),while the Bsm 1 and Taq 1 didn' t show the association with autoimmune liver diseases.Conclusion The current meta-analysis shows that Apal may be a low-penetrant risk factor for autoimmune liver diseases.Bsm1 and Taq1 don't show the association with autoimmune liver diseases.
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Objective To observe the therapeutic effectiveness and safety of autologous peripheral blood stem cell transplantation (APBSCT) for poor-risk non-Hodgkin lymphoma (NHL). Methods Ten patients with poor-prognosis NHL were enrolled from October 2003 to October 2008 in our institute. Ten patients were treated by APBSCT with CY+TBI conditioning regimen (Two patients of them were treated by Double-APBSCT with MEC conditioning regimen). Results Hematopoietic reconstitution was observed in all patients.The time of neutrophil count ≥0.5×109L and platelet≥20×109/L were at day 10 (range: 7-14) and day 16 (range: 10-37), respectively. All patients achieved complete remission (CR) after transplantation. Severe toxicity and transplant related mortality were not observed. After a median follow-up of 24 (10-84) months,seven cases were in event-free survival and three cases relapsed. One of three relapsed patients died from progression of disease, the other was still alive after treatment. Conclusion APBSCT in the treatment of patients with poor-prognosis NHL is a safe, convenient and efficient treatment.
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Objective To investigate the effect and hematopoietic reconstitution as well as survival of diffierent kinds of allogeneic hematopoietic stem cell transplantation(allo-HSCT)in the treatment of leukemia.Methods allo-HSCT was used to treat 20 cases of leukemia from March 2003 to July 2006 in my hospital.Twelve of them received allo-PBSCT from HLA matched sibling donors.Four of them received HLA-mismatched unrelated umbilical cord blood transplantation.Three of them received allo-PBSCT from unrelated donors.One of them received bone marrow transplantion from unrelated donors.Results Totally 19 recipients acheived hematopoietic reconstitution.The median time of hematopoietic reconstitution after UCBT was longer than that of HLA matched sibling PBSCT.Seven patients received aGVHD after allo-HSCT,and 4 among them were Ⅰ~Ⅱ degree and 3 cases Ⅲ~Ⅳ degree.Two patients died of relapse,and 3 patients died of GVHD.One patient was puzzled by cGVHD.The others are disease-free survival now.The median time of survival is 30(1~41)months.Conclusion allo-HSCT is effective for the cure of patients with leukemia.UCBT with enough cells and 1~2 mismatched loci is safe and effective for the patients who have no HLA matched sibling donors.