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Over-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer (CRC) samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by re-activating the dormant human-reverse-transcriptase (hTERT) subunit of telomerase holoenzyme in an iron-(Fe3+)-dependent-manner and thereby drives CRCs. Chemical genetic screens combined with isothermal-dose response fingerprinting and mass-spectrometry identified a small molecule SP2509, that specifically inhibits Pirin-mediated hTERT reactivation in CRCs by competing with iron-(Fe3+) binding. Our findings, first to document how metal ions reactivate telomerase, provide a molecular mechanism for the well-known association between red meat, and increased incidence of CRCs. Small molecules like SP2509 represent a novel modality to target telomerase that acts as driver of 90% human cancers and is yet to be targeted in clinic.
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Interactions between brain-resident and peripheral infiltrated immune cells are thought to contribute to neuroplasticity after cerebral ischemia. However, conventional bulk sequencing makes it challenging to depict this complex immune network. Using single-cell RNA sequencing, we mapped compositional and transcriptional features of peri-infarct immune cells. Microglia were the predominant cell type in the peri-infarct region, displaying a more diverse activation pattern than the typical pro- and anti-inflammatory state, with axon tract-associated microglia (ATMs) being associated with neuronal regeneration. Trajectory inference suggested that infiltrated monocyte-derived macrophages (MDMs) exhibited a gradual fate trajectory transition to activated MDMs. Inter-cellular crosstalk between MDMs and microglia orchestrated anti-inflammatory and repair-promoting microglia phenotypes and promoted post-stroke neurogenesis, with SOX2 and related Akt/CREB signaling as the underlying mechanisms. This description of the brain's immune landscape and its relationship with neurogenesis provides new insight into promoting neural repair by regulating neuroinflammatory responses.
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Humanos , AVC Isquêmico , Encéfalo/metabolismo , Macrófagos , Isquemia Encefálica/metabolismo , Microglia/metabolismo , Perfilação da Expressão Gênica , Anti-Inflamatórios , Plasticidade Neuronal/fisiologia , Infarto/metabolismoRESUMO
Objective:To investigate the role of miR-146a in regulating the homeostasis and function of epidermal Langerhans cells (LCs).Methods:Fresh and in vitro cultured epidermal LCs were isolated and purified by flow cytometry (FCM). The expression of miR-146a in LCs was detected by quantitative PCR (qPCR). The percentages of epidermal LCs in wild-type (WT) and miR-146a conventional knockout (miR-146a cKO) mice were analyzed by FCM. The expression of major histocompatibility complex Ⅱ (MHCⅡ) and co-stimulatory molecules (CD86 and CD80) was analyzed by FCM to evaluate the effect of miR-146a on the maturation of LCs. The percentage of Dextran-FITC + LCs was detected by FCM to evaluate the effect of miR-146a on the phagocytic function of LCs. In vitro and in vivo experiments were used to analyze the ability of miR-146a-deficient and -sufficient LCs to stimulate the proliferation of CD8 + OT-ⅠT cells and CD4 + OT-Ⅱ T cells. Results:The expression of miR-146a was significantly increased in mature LCs than in the freshly isolated LCs. There was no significant difference in the number of epidermal LCs between wild-type (WT) and miR-146a cKO mice. After a 48 h culture in vitro, the expression of MHCⅡ, CD86 and CD80 in the epidermal LCs of miR-146a cKO mice was similar to that of WT mice. Moreover, miR-146a deletion had no significant influence on antigen uptake by LCs. However, miR-146a deficiency enhanced the antigen-presenting ability of LCs that could stimulate the proliferation of OVA-specific CD8 + OT-Ⅰ T cells and CD4 + OT-Ⅱ T cells. Conclusions:miR-146a had no influence on the homeostasis, maturation and phagocytosis of LCs, but enhanced the antigen-presenting function.
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Spinal infection is a serious health-threatening clinical condition, which more frequently occurs in solid organ transplantation receipients than in non transplant receipients. With the increase of solid organ transplantation, the incidence of secondary spinal infection has been increased in recent years. The symptoms and signs of secondary spinal infection are not obvious, and early diagnosis and treatment are difficult, leading to recurrent attacks and protracted disease courses. This article reviews the progress in the diagnosis and treatment of secondary spinal infection after solid organ transplantation.
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Bipolar disorder and obsessive-compulsive disorder comorbidity is becoming more and more common and has aroused clinical physicians' increasing interest. This review summarizes the epidemiology, clinical characteristics, neurobiochemistry, and treatment of comorbid bipolar disorder and obsessive-compulsive disorder and discusses the neurobiochemical mechanism. Findings from this review will provide evidence for identifying the clinical symptoms of bipolar disorder and obsessive-compulsive disorder comorbidity and for treatment of the comorbidity.
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Teaching practice is an important link in the process of postgraduate training. This paper analyzes the current situation and existing problems of postgraduate teaching practice, and discusses the influence of new teaching practice mode on postgraduate training. Aiming at the problems existing in the teaching practice of postgraduate students, this paper carries out the reform from five aspects: subject course learning, teaching preparation, theoretical teaching, experimental teaching participation and teaching management participation, and evaluates the implementation effect of the reform. Through the reform of postgraduate teaching practice, the teaching ability and social competitiveness of postgraduate students have been effectively improved. The new teaching practice mode provides new ideas and methods for the cultivation of postgraduate students' teaching ability.
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Objective To study the different ischemic characteristics of cerebral gray matter and deep white matter in patients with chronic cerebral artery severe stenosis or occlusion. Methods A retrospective study was conducted on 30 patients with chronic unilateral cerebral artery severe stenosis or occlusion from April 2014 to April 2018 in our hospital. Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time of peak time (TTP) and time to delay(TTD) of cerebral cortex gray matter and deep white matter in the blood supply area of the responsible artery (the affected side) and the contralateral hemisphere (the healthy side) were measured. Statistical analysis of the perfusion parameters of cerebral cortex gray matter and deep white matter in the affected side and contralateral side were performed using SPSS13.0 software package. T test was used for variance homogeneity, and t′test was used for variance discrepancy, and P<0.05 was statistically significant. Results The average values of CBF and CBV of the ipsilateral and contralateral cerebral cortex were increased than those of ipsilateral and contralateral cerebral deep white matter respectively(P<0.01). MTT, TTP and TTD of the ipsilateral and contralateral cerebral cortex were decreased than that of ipsilateral and contralateral cerebral deep white matter (P<0.01); CBF of ipsilateral cerebral cortex and CBV of ipsilateral cerebral deep white matter were not different from those of the contralateral cerebral cortex and deep white matter respectively, but CBF of ipsilateral cerebral deep white matter is decreased than that of the contralateral deep white matter (P<0.01). CBV of ipsilateral cerebral cortex is increased than that of the contralateral cerebral cortex (P<0.01). MTT, TTP and TTD of ipsilateral cerebral cortex and deep white matter were increased than those of contralateral cerebral cortex and deep white matter respectively(P<0.01). Conclusion Deep cerebral white matter perfusion decreased more significantly than cortical gray matter in the supply region of chronic cerebral artery severe stenosis or occlusion. CT perfusion imaging can quantify the degree of chronic cerebral ischemia and can provide quantitative diagnostic information for clinical treatment and efficacy evaluation.
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Objective@#To study the different ischemic characteristics of cerebral gray matter and deep white matter in patients with chronic cerebral artery severe stenosis or occlusion.@*Methods@#A retrospective study was conducted on 30 patients with chronic unilateral cerebral artery severe stenosis or occlusion from April 2014 to April 2018 in our hospital. Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time of peak time (TTP) and time to delay(TTD) of cerebral cortex gray matter and deep white matter in the blood supply area of the responsible artery (the affected side) and the contralateral hemisphere (the healthy side) were measured. Statistical analysis of the perfusion parameters of cerebral cortex gray matter and deep white matter in the affected side and contralateral side were performed using SPSS13.0 software package. T test was used for variance homogeneity, and t′ test was used for variance discrepancy, and P<0.05 was statistically significant.@*Results@#The average values of CBF and CBV of the ipsilateral and contralateral cerebral cortex were increased than those of ipsilateral and contralateral cerebral deep white matter respectively(P<0.01). MTT, TTP and TTD of the ipsilateral and contralateral cerebral cortex were decreased than that of ipsilateral and contralateral cerebral deep white matter (P<0.01); CBF of ipsilateral cerebral cortex and CBV of ipsilateral cerebral deep white matter were not different from those of the contralateral cerebral cortex and deep white matter respectively, but CBF of ipsilateral cerebral deep white matter is decreased than that of the contralateral deep white matter (P<0.01). CBV of ipsilateral cerebral cortex is increased than that of the contralateral cerebral cortex (P<0.01). MTT, TTP and TTD of ipsilateral cerebral cortex and deep white matter were increased than those of contralateral cerebral cortex and deep white matter respectively(P<0.01).@*Conclusion@#Deep cerebral white matter perfusion decreased more significantly than cortical gray matter in the supply region of chronic cerebral artery severe stenosis or occlusion. CT perfusion imaging can quantify the degree of chronic cerebral ischemia and can provide quantitative diagnostic information for clinical treatment and efficacy evaluation.
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OBJECTIVE@#To investigate the metabolic profiles of urine from mice with early-stage Alzheimer's disease (AD).@*METHODS@#Urine samples were collected from 13 mice of 16 weeks and 15 wild-type mice. H-NMR spectroscopy was acquired with a one-dimensional NOESY pulse sequence, and the integral values were imported to SIMCA-P+12.0 software for analysis.@*RESULTS@#The metabonomic analysis showed that the metabolic profiles of the mice were significantly different from that of age-matched wild-type mice. The levels of 3-hydroxybutyrate, 2-hydroxybutyrate, succinic acid, 2-ketoglutaric acid, citric acid, cis-aconitic acid, fumaric acid decreased, and those of acetic acid, trimethylamine, taurine, creatinine, hippuric acid, formic acid, trigonelline, urea increased (all <0.05).@*CONCLUSIONS@#Metabolic pathways including glucose metabolism and methylamine metabolism may be involved in the pathogenesis of early AD.
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Animais , Camundongos , Doença de Alzheimer , Urina , Modelos Animais de Doenças , Espectroscopia de Ressonância Magnética , Metaboloma , Metabolômica , Camundongos Endogâmicos C57BLRESUMO
Objective@#To investigate the imaging diagnosis, treatment and prognosis of primary hepatic neuroendocrine tumors.@*Methods@#The clinical features, imaging manifestations, histopathological and immunohistochemical findings and interventional therapy of 6 patients identified with pathologically confirmed primary hepatic neuroendocrine tumors were retrospectively analyzed, and the related literatures were reviewed.@*Results@#All 6 patients presented with symptoms of abdominal pain. 4 patients had solitary hepatic mass and 2 patients had multiple hepatic masses. Magnetic resonance imaging showed low signal intensity on T1 weighted imaging, high signal intensity on T2 weighted imaging and clear boundary; the arterial phase of enhancement scan was uneven and enhanced, and portal venous phase or delayed phase showed continuous enhancement, surrounded by ring enhanced capsule. A pathological diagnosis was primary neuroendocrine tumor of the liver. After interventional treatment, 6 patients had some therapeutic effects. Among them, 4 patients underwent multiple interventional therapies, followed by 4 years of follow-up has shown satisfactory results.@*Conclusion@#Primary hepatic neuroendocrine tumors are very rare and their imaging manifestations are specific. Eventually, relies on pathological and immunohistochemical diagnosis. Transarterial chemoembolization therapy can bring satisfactory results in the treatment of primary hepatic neuroendocrine tumor.
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Objective@#To observe the therapeutic effects and related mechanism of hemin on the progression of hepatic fibrosis in rats.@*Methods@#Sixty male Wistar rats were randomly divided into normal control group, 4-week model group, 6-week model group, hemin inhibitor zinc protoporphyrin-IX (ZnPP-IX) intervention group and hemin intervention group. Hemin intervention group in complex liver fibrosis model was intraperitonealy administered ZnPP-IX or hemin every other day for 2 weeks from the fourth week. The mRNA expression of HO-1, α-smooth muscle actin (α-SMA) and nuclear factor-κB (NF-κB) in the liver tissue was detected by real-time polymerase chain reaction. Immunohistochemistry was used to detect HO-1 and localization of α-SMA expression. Serum hyaluronic acid, propeptide of type III collagen and hepatic transforming growth factor beta (TGFβ), and interleukin 6 (IL-6) expressions were detected by enzyme-linked immunosorbent assay. The content of hydroxyproline in hepatic tissues was measured by alkaline hydrolysis method. One-way ANOVA was used to compare the mean of each group. The difference between the two groups was compared by independent samples t- test. P-values < 0.05 was considered statistically significant.@*Results@#Compared with model groups and ZnPP-IX intervention group, Hemin's intervention significantly increased the expression of HO-1 mRNA (P < 0.01) and protein distribution in liver tissues, while the expression of alpha-SMA mRNA was significantly decreased (P < 0.05) in portal space and areas around the fibrotic septum, and hepatic sinus. Hyp content and serum hyaluronic acid and propeptide of type III collagen decreased significantly (P < 0.05). Meanwhile, NF-κB p65 mRNA expression and the downstream production of TGFβ and IL-6 in Hemin intervention group were also inhibited (P < 0.05).@*Conclusion@#Hemin can significantly inhibit the progression of hepatic fibrosis in rats by up-regulating HO-1 expression, and the inhibiting activity of NF-κB p65 leads to downstream of the inflammatory factors.
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Objective To detect the frequency of BRAF/ KRAS and PIK3CA mutations in the small cell lung cancer (SCLC) specimens from a large population of Chinese patients and to analyze the gene mutation and clinical characteristics. Methods A total of 557 samples were collected from SCLC patients from 2009 to 2014.BRAF,KRAS,PIK3CA,NRAS and MEK1 gene mutations were detected by the dideoxy sequencing. Chi-square test was adopted to analyze the correlation between clinical factors and gene mutation. Kaplan-Meier method was utilized for survival analysis. Cox model was used for multivariate prognostic analysis. Results BRAF mutations were detected in 13 out of 557 specimens. The mutation types included V600E (n= 5) ,V600A (n= 2) ,V600M (n= 1) ,D594G (n= 1),G464E (n= 1),K601R (n= 2) and S605N (n= 1).KRAS mutation was detected in 6 cases including G12C (n= 3),G12A (n= 1),G12D (n=1) andG13D (n= 1).PIK3CA mutation was observed in 4 samples including E545G (n= 2) and H1047R (n= 2).Besides,NRAS mutation (Q61R) was detected in 1 case and MEK1 mutation (D61Y) was noted in 1 case. These gene mutations were not significantly correlated with the age, gender, smoking status and clinical staging of the patients. Univariate survival analysis demonstrated the median survival time of patients with gene mutation was (10.30±0. 751) months (95%CI:8. 829-11. 771 months),significantly shorter than (12.80±0. 543) months (95%CI:11. 736-13. 864 months) of their counterparts without gene mutation (P=0. 011). Conclusions BRAF/ KRAS and PIK3CA gene mutation is detected in a small proportion of SCLC patients. These gene mutations are not significantly correlated with the clinical characteristics. Univariate survival analysis demonstrates that negative these gene mutations are negatively correlated with the clinical prognosis of SCLC patients.
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Vascular cell functionality is critical to blood vessel homeostasis. Constitutive NF-κB activation in vascular cells results in chronic vascular inflammation, leading to various cardiovascular diseases. However, how NF-κB regulates human blood vessel homeostasis remains largely elusive. Here, using CRISPR/Cas9-mediated gene editing, we generated RelA knockout human embryonic stem cells (hESCs) and differentiated them into various vascular cell derivatives to study how NF-κB modulates human vascular cells under basal and inflammatory conditions. Multi-dimensional phenotypic assessments and transcriptomic analyses revealed that RelA deficiency affected vascular cells via modulating inflammation, survival, vasculogenesis, cell differentiation and extracellular matrix organization in a cell type-specific manner under basal condition, and that RelA protected vascular cells against apoptosis and modulated vascular inflammatory response upon tumor necrosis factor α (TNFα) stimulation. Lastly, further evaluation of gene expression patterns in IκBα knockout vascular cells demonstrated that IκBα acted largely independent of RelA signaling. Taken together, our data reveal a protective role of NF-κB/RelA in modulating human blood vessel homeostasis and map the human vascular transcriptomic landscapes for the discovery of novel therapeutic targets.
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Humanos , Vasos Sanguíneos , Biologia Celular , Metabolismo , Sistemas CRISPR-Cas , Células-Tronco Embrionárias , Biologia Celular , Técnicas de Inativação de Genes , Homeostase , NF-kappa B , Metabolismo , Fator de Transcrição RelA , MetabolismoRESUMO
The adenosine triphosphate (ATP)-binding cassette transporter G1 (ABCG1),a member of the superfamily of ATP-binding cassette transporters,is involved in the efflux of cholesterol and phospholipids from cells,and it maintains the intracellular hpid homeostasis.ABCG1 deficiency results in foam cell formation,endothelial dysfunction,and inflammatory reaction,and it further leads to the development and progression of atherosclerosis.However,the role of ABCG1 in atherosclerosis in animal experiments and human studies is still a debatable matter.In this paper,the recent findings on the role of ABCG1 in atherosclerotic disease are reviewed.
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Objective:Living organ transplantation prolongs the life of many dying patients, but there are many disputes, especially the definition ofliving organ transplantation between non relatives. The definition of this ter-minology is closely related to medical students′cognitive ofliving organ transplantation between non relatives. The medical students are the main reserve army of medical staff and the executor of living donor organ transplantation in the future, who directly determine the organ transplantation and affect the doctor-patient relationship. This paper is to investigate and analyze the status of the medical students′recognition of cross transplantation between non rela-tives. Methods:A total of 450 medical students of Qingdao university were selected with cluster method and were investigated using self-designed questionnaire. Data were analyzed by SPSS 22. 0. Results:The overall recogni-tion rate toliving organ cross transplantation between non relatives was relatively low. The difference was statisti-cally significant (P<0. 05), namely that students in higher grade had lower recognition. The difference was statis-tically significant (P < 0. 05) between different specialties, and the recognition degree of students majoring in clinical medicine and ecsomatics was higher. Conclusion:The medical students of Qingdao University understand the concept of living organ cross transplantation between non relativesfuzzily, and the recognition degree is low.
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Objective To investigate the relationship between single nucleotide polymorphism (SNP) at position + 10225 in adiponectin receptor 1 gene and type 2 diabetes.Methods The genotypes of + 10225C/G of adiponectin receptor 1 were detected by polymerase chain reaction with sequence specific primers (PCR-SSP) in 200 type 2 diabetes and 100 health controls.Fasting blood samples of all cases were obtained to extract DNA and detect genotype.Statistical software spss 13.0 was used to analyzed.Results Frequency of G-type allele in type 2 diabetes was 40.5%,that in normal controls was 23.5%,there was significant diffierences in the genotype frequencies of SNP+10225 between type 2 diabetes and health controls (x2 =128.0,P<0.01).Conclusion AdipoR1 + 10225C/G polymorphism was probably associated with type 2 diabetes,G-type allele might be a genetic risk factor of type 2 diabetes.
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Objective:To determine the effects of Jinlong capsule combined with interventional therapy on the immune functions of primary hepatocellular carcinoma patients. Methods:Sixty randomly selected cases of clinically diagnosed primary hepatocellular carcinoma were divided into the observation group and the control group. Three days after operation, the observation group was given four Jinlong capsules three times a day for 30 days (one treatment). Meanwhile, the control group received interventional therapy after the operation. One to four days following one treatment, peripheral blood specimens were collected from the two groups to determine the cellular immune function indices. Results:The cell numbers (mean) of the peripheral blood components CD3, CD4, NK, SIL-2R, TSGF, and SIL-2R and the CD4/CD8 ratio in the observation group showed no significant difference before and after treatment. In the control group, these indices were significantly different before and after treatment. Conclusion:The Jinlong capsule facilitates the cellu-lar immunity recovery of patients with primary hepatocellular carcinoma after interventional therapy.
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OBJECTIVE To study the characteristics of drug resistance and infection of mycoplasma. METHODS The mycoplasma was detected by culture,with an observation of drug susceptibility to 10 antibiotics. RESULTS The total positive rate of mycoplasma was 36.79%;of them Ureaplasma urealyticum(Uu) was 76.71%,Uu+ Mycoplasma hominis(Mh) was 19.87%,and Mh was 3.42%.The resistance rates to other antimicrobials were over 50.00% except JOS,CLA,MIN,DOX and OFL which were lower.The resistant rate to antibiotics for the mixed infection of Uu+Mh was significantly higher than Uu affection alone,from them to 6 antibiotics was over 60.00%. CONCLUSIONS The detection of mycoplasma infection and its drug resistance play an important guide role in the clinical treatment of urogential tract infection.
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Objective To establish a method for the determination of Alkaloid in cut crude drug of aconite root.Method Contents of aconitine,hypaconitine and mesaconitine incrude drug of aconite root were determined by LC-MS.It was carried out on Inertsil ODS-3 column(150 mm?4.6 mm,5 ?m),with acetonitrile-ammonium acetate buffer solution(60:40) as mobile phase,at a flow rate of 0.2 mL/min and temperature of 30 ℃.Result The method of determining Alkaloid content in crude drug of aconite root was established and 25 lots of crude drugs were determined.Conclusion The method was sensitive and specifical,can be used to control the quality of cut crude drug from aconite root.
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Objective To evaluate the clinical value of arterial chemotherapy and embolization in the treatment of advanced uterine carcinoma.Methods In this study,52 cases of uterine carcinoma(including 43 carcinoma of cervix and 9 cases carcinoma of endonetrium)were treated interventional therapy.In these cases,after one or two times interventional therapy and after 10-14 days,45 cases followed by uterectomy and pelvic lymphadenectomy. 7 cases that can't operated continue followed by interventional therapy. Results Curative effect was obvious,the clinical symptoms were alleviated,the bleed in operation was decreased and the tumor was divided easily.In 45 cases followed by operation,the one-year and three-year survival rate are 100% and 92%.In 7 cases treated by interventional therapy alone,the one-year and three-year survival rate are 100% and 85%.Conlusion The interventional therapy preoperation can reduce the clinical stage and metastasis of lymph,improve the ectomy by operation and survival rate of patients obviously,so it can be used as a routine treatment in uterine carcinoma.