Colorectal cancer(CRC)stands among the top prevalent cancers worldwide and holds a prominent position as a major contributor to cancer-related mortality globally.Absent in melanoma 2(AIM2),a constituent of the interfe...Colorectal cancer(CRC)stands among the top prevalent cancers worldwide and holds a prominent position as a major contributor to cancer-related mortality globally.Absent in melanoma 2(AIM2),a constituent of the interferoninducible hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeats protein family,contributes to both cancer progression and inflammasome activation.Despite this understanding,the precise biological functions and molecular mechanisms governed by AIM2 in CRC remain elusive.Consequently,this study endeavors to assess AIM2’s expression levels,explore its potential antitumor effects,elucidate associated cancer-related processes,and decipher the underlying signaling pathways in CRC.Our findings showed a reduced AIM2 expression in most CRC cell lines.Elevation of AIM2 levels suppressed CRC cell proliferation and migration,altered cell cycle by inhibiting G1/S transition,and induced cell apoptosis.Further research uncovered the participation of P38 mitogen-activated protein kinase(P38MAPK)in AIM2-mediated modulation of CRC cell apoptosis and proliferation.Altogether,our achievements distinctly underscored AIM2’s antitumor role in CRC.AIM2 overexpression inhibited proliferation and migration and induced apoptosis of CRC cells via activating P38MAPK signaling pathway,indicating AIM2 as a prospective and novel therapeutic target for CRC.展开更多
In traumatic brain injury, absent in melanoma 2(AIM2) has been demonstrated to be involved in pyroptotic neuronal cell death. Although the pathophysiological mechanism of spinal cord injury is similar to that of brain...In traumatic brain injury, absent in melanoma 2(AIM2) has been demonstrated to be involved in pyroptotic neuronal cell death. Although the pathophysiological mechanism of spinal cord injury is similar to that of brain injury, the expression and cellular localization of AIM2 after spinal cord injury is still not very clear. In the present study, we used a rat model of T9 spinal cord contusive injury, produced using the weight drop method. The rats were randomly divided into 1-hour, 6-hour, 1-day, 3-day and 6-day(post-injury time points) groups. Sham-operated rats only received laminectomy at T9 without contusive injury. Western blot assay revealed that the expression levels of AIM2 were not significantly different among the 1-hour, 6-hour and 1-day groups. The expression levels of AIM2 were markedly higher in the 1-hour, 6-hour and 1-day groups compared with the sham, 3-day and 7-day groups. Double immunofluorescence staining demonstrated that AIM2 was expressed by NeuN+(neurons), GFAP+(astrocytes), CNPase+(oligodendrocytes) and CD11 b+(microglia) cells in the sham-operated spinal cord. In rats with spinal cord injury, AIM2 was also found in CD45+(leukocytes) and CD68+(activated microglia/macrophages) cells in the spinal cord at all time points. These findings indicate that AIM2 is mainly expressed in neurons, astrocytes, microglia and oligodendrocytes in the normal spinal cord, and that after spinal cord injury, its expression increases because of the infiltration of leukocytes and the activation of astrocytes and microglia/macrophages.展开更多
For severe cubital tunnel syndrome, patients with absent sensory nerve action potential tend to have more severe nerve damage than those without. Thus, it is speculated that such patients generally have a poor prognos...For severe cubital tunnel syndrome, patients with absent sensory nerve action potential tend to have more severe nerve damage than those without. Thus, it is speculated that such patients generally have a poor prognosis. How absent sensory nerve action potential affects surgical outcomes remains uncertain owing to a scarcity of reports and conflicting results. This retrospective study recruited one hundred and fourteen cases(88 patients with absent sensory nerve action potential and 26 patients with present sensory nerve action potential) undergoing either subcutaneous transposition or in situ decompression. The minimum follow-up was set at 2 years. Primary outcome measures of overall hand function included their McGowan grade, modified Bishop score, and Disabilities of the Arm, Shoulder, and Hand Questionnaire(DASH) score. For patients with absent sensory nerve action potential, 71 cases(80.7%) achieved at least one McGowan grade improvement, 76 hands(86.4%) got good or excellent results according to the Bishop score, and the average DASH score improved 49.5 points preoperatively to 13.1 points postoperatively. When compared with the present sensory nerve action potential group, they showed higher postoperative McGowan grades and DASH scores, but there was no statistical difference between the modified Bishop scores of the two groups. Following in situ decompression or subcutaneous transposition, great improvement in hand function was achieved for severe cubital tunnel syndrome patients with absent sensory nerve action potential. The functional outcomes after surgery for severe cubital tunnel syndrome are worse in patients with absent sensory nerve action potential than those without. This study was approved by the Ethical Committee of Huashan Hospital, Fudan University, China(approval No. 2017142).展开更多
The famous American writer MarkTwain was well—known for his absent-mind-edness.One day,when he was riding in a train,the conductor asked him for his ticket.MarkTwain looked for the ticket in all his pockets.but 11e d...The famous American writer MarkTwain was well—known for his absent-mind-edness.One day,when he was riding in a train,the conductor asked him for his ticket.MarkTwain looked for the ticket in all his pockets.but 11e didn’t find it.At last,the展开更多
Background The prognosis of tetralogy of Fallot with absent pulmonary valve (TOF/APV) without operation is poor. We evaluated the surgical outcome of TOF/APV in a single center. Methods Twenty-two TOF/APV patients und...Background The prognosis of tetralogy of Fallot with absent pulmonary valve (TOF/APV) without operation is poor. We evaluated the surgical outcome of TOF/APV in a single center. Methods Twenty-two TOF/APV patients underwent complete surgical correction in our hospital. Right ventricular outflow tract reconstruction was performed using bovine jugular vein (BJV)-valved conduit implantation (n=10), homograft-valved conduit implantation (n=2), or monocusp-valve patch (n=10). Health-related quality of life (QOL) was evaluated during follow-up. Results The overall survival at 5 and 10 years was 86.4±7.3% (confidence interval 69.4–97.2%). The survival rates were significantly different between patients with and without bronchial stenosis (40 and 100%, P=0.0003, log-rank test). The survival of patients aged>6 months was higher than those≤6 months (100 vs. 40%, P=0.0003, log-rank test). Patients with BJV-valved conduits had higher systolic gradients from the right ventricle to the pulmonary artery (RV–PA) compared to those with monocusp-valve patches. BJV-valved conduit implantation was a risk factor for post-operative pulmonary-valve stenosis. The QOL score for patients with BJV-valved conduits was lower than those with monocusp-valve patches (P<0.05). No reoperation was performed during follow-up. Conclusions Bronchial stenosis and lower age (≤6 months) were the main factors influencing post-operative survival. The use of a BJV-valved conduit was a main reason for RV–PA restenosis;thus, the use of a BJV-valved conduit may increase the need for repeat intervention and decrease the post-operative quality of life.展开更多
Background:Emerging evidence indicates that the sineoculis homeobox homolog 1−eyes absent homolog 1(SIX1–EYA1)transcriptional complex significantly contributes to the pathogenesis of multiple cancers by mediating the...Background:Emerging evidence indicates that the sineoculis homeobox homolog 1−eyes absent homolog 1(SIX1–EYA1)transcriptional complex significantly contributes to the pathogenesis of multiple cancers by mediating the expression of genes involved in different biological processes,such as cell-cycle progression and metastasis.However,the roles of the SIX1–EYA1 transcriptional complex and its targets in colorectal cancer(CRC)are still being investigated.This study aimed to investigate the roles of SIX1–EYA1 in the pathogenesis of CRC,to screen inhibitors disrupting the SIX1–EYA1 interaction and to evaluate the efficiency of small molecules in the inhibition of CRC cell growth.Methods:Real-time quantitative polymerase chain reaction and western blotting were performed to examine gene and protein levels in CRC cells and clinical tissues(collected from CRC patients who underwent surgery in the Department of Integrated Traditional and Western Medicine,West China Hospital of Sichuan University,between 2016 and 2018,n=24).In vivo immunoprecipitation and in vitro pulldown assays were carried out to determine SIX1–EYA1 interaction.Cell proliferation,cell survival,and cell invasion were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay,clonogenic assay,and Boyden chamber assay,respectively.The Amplified Luminescent Proximity Homogeneous Assay Screen(AlphaScreen)method was used to obtain small molecules that specifically disrupted SIX1–EYA1 interaction.CRC cells harboring different levels of SIX1/EYA1 were injected into nude mice to establish tumor xenografts,and small molecules were also injected into mice to evaluate their efficiency to inhibit tumor growth.Results:Both SIX1 and EYA1 were overexpressed in CRC cancerous tissues(for SIX1,7.47±3.54 vs.1.88±0.35,t=4.92,P=0.008;for EYA1,7.61±2.03 vs.2.22±0.45,t=6.73,P=0.005).The SIX1/EYA1 complex could mediate the expression of two important genes including cyclin A1(CCNA1)and transforming growth factor beta 1(TGFB1)by binding to the myocyte enhancer factor 3 consensus.Knockdown of both SIX1 and EYA1 could decrease cell proliferation,cell invasion,tumor growth,and in vivo tumor growth(all P<0.01).Two small molecules,NSC0191 and NSC0933,were obtained using AlphaScreen and they could significantly inhibit the SIX1–EYA1 interaction with a half-maximal inhibitory concentration(IC50)of 12.60±1.15μmol/L and 83.43±7.24μmol/L,respectively.Administration of these two compounds could significantly repress the expression of CCNA1 and TGFB1 and inhibit the growth of CRC cells in vitro and in vivo.Conclusions:Overexpression of the SIX1/EYA1 complex transactivated the expression of CCNA1 and TGFB1,causing the pathogenesis of CRC.Pharmacological inhibition of the SIX1–EYA1 interaction with NSC0191 and NSC0933 significantly inhibited CRC cell growth by affecting cell-cycle progression and metastasis.展开更多
Micro RNAs(mi RNAs) can be found in a wide range of tissues and body ?uids, and their speci?c signatures can be used to determine diseases or predict clinical courses. The mi RNA pro?les in biological samples(tissue, ...Micro RNAs(mi RNAs) can be found in a wide range of tissues and body ?uids, and their speci?c signatures can be used to determine diseases or predict clinical courses. The mi RNA pro?les in biological samples(tissue, serum, peripheral blood mononuclear cells or other body ?uids) differ signi?cantly even in the same patient and therefore have their own speci?city for the presented condition. Complex pro?les of deregulated mi RNAs are of high interest, whereas the importance of non-expressed mi RNAs was ignored. Since mi RNAs regulate gene expression rather negatively,absent mi RNAs could indicate genes with unaltered expression that therefore are normally expressed in speci?c compartments or under speci?c disease situations. For the ?rst time,non-detectable mi RNAs in different tissues and body ?uids from patients with different diseases(cardiomyopathies, Alzheimer's disease, bladder cancer, and ocular cancer) were analyzed and compared in this study. mi RNA expression data were generated by microarray or Taq Man PCR-based platforms. Lists of absent mi RNAs of primarily cardiac patients(myocardium, blood cells, and serum) were clustered and analyzed for potentially involved pathways using two prediction platforms, i.e., mi RNA enrichment analysis and annotation tool(mi EAA) and DIANA mi RPath.Extensive search in biomedical publication databases for the relevance of non-expressed mi RNAs in predicted pathways revealed no evidence for their involvement in heart-related pathways as indicated by software tools, con?rming proposed approach.展开更多
BACKGROUND Congenital agenesis of the gallbladder(CAGB)is a rare condition often misdiagnosed as cholecystolithiasis,leading to unnecessary surgeries.Accurate diagnosis and surgical exploration are crucial in patients...BACKGROUND Congenital agenesis of the gallbladder(CAGB)is a rare condition often misdiagnosed as cholecystolithiasis,leading to unnecessary surgeries.Accurate diagnosis and surgical exploration are crucial in patients with suspected CAGB or atypical gallbladder stone symptoms.Preoperative imaging,such as magnetic resonance cholangiopancreatography(MRCP),plays a vital role in confirming the diagnosis.Careful intraoperative dissection is necessary to avoid iatrogenic injuries and misdiagnosis.Multidisciplinary consultations and collaboration,along with the use of various diagnostic methods,can minimize associated risks.CASE SUMMARY We present the case of a 34-year-old female with suspected gallbladder stones,ultimately diagnosed with CAGB through surgical exploration.The patient underwent laparoscopic examination followed by open exploratory surgery,which confirmed absence of the gallbladder.Subsequent imaging studies supported the diagnosis.The patient received appropriate postoperative care and experienced a successful recovery.CONCLUSION This case highlights the rarity of CAGB and the importance of considering this condition in the differential diagnosis of patients with gallbladder stone symptoms.Accurate diagnosis using preoperative imaging,such as MRCP,is crucial to prevent unnecessary surgeries.Surgeons should exercise caution and conduct meticulous dissection during surgery to avoid iatrogenic injuries and ensure accurate diagnosis.Multidisciplinary collaboration and utilization of various diagnostic methods are essential to minimize the risk of misdiagnosis.Selection of the optimal treatment strategy should prioritize minimizing trauma and maintaining open communication with the patient and their family members.展开更多
目的探讨血清黑色素瘤缺乏因子2(absent in melanoma 2,AIM2)和白三烯B4(leukotriene B4,LTB4)水平与急性缺血性脑卒中(acute ischemic stroke,AIS)患者预后的相关性。方法收集2020年2月~2021年2月期间于西安交通大学第一附属医院、西...目的探讨血清黑色素瘤缺乏因子2(absent in melanoma 2,AIM2)和白三烯B4(leukotriene B4,LTB4)水平与急性缺血性脑卒中(acute ischemic stroke,AIS)患者预后的相关性。方法收集2020年2月~2021年2月期间于西安交通大学第一附属医院、西安交通大学附属红会医院、咸阳市第一人民医院和泾阳县医院接受组织型纤溶酶原激活剂(tissue plasminogen activator,tPA)进行静脉溶栓治疗的138例AIS患者的临床资料进行回顾性分析。收集患者治疗三月后的改良Rankin评分量表(modified Rankin rating scale,mRS)评价其神经功能情况。依据mRS评分将AIS患者分为预后良好组(mRS评分≤2分,n=87)和预后不良组(mRS评分>2分,n=51)。采用酶联免疫吸附试验检测血清AIM2和LTB4水平。收集患者入院时的美国国立卫生研究院卒中患者神经功能缺损(neurological deficits in stroke patients at the National Institutes of Health,NIHSS)评分、梗死体积和侧支循环建立状况等信息。分析血清AIM2和LTB4水平、入院NIHSS评分、梗死体积和侧支循环建立状况与AIS患者预后的相关性。建立多因素Logistic回归模型分析rt-PA静脉溶栓后AIS患者预后不良的危险因素。结果与预后良好组比较,预后不良组的血清AIM2(1161.51±338.56pg/ml vs 964.77±171.94pg/ml)和LTB4水平(137.99±35.49pg/ml vs 117.85±21.60pg/ml)明显增高,差异具有统计学意义(t=4.638,4.148,均P<0.01)。Logistic回归分析发现AIS患者血清AIM2和LTB4水平增高、梗死体积增大、入院NIHSS评分增高及侧支循环建立状况较差均为AIS患者预后不良的独立危险因素(均P<0.05)。相关性分析显示AIS患者的血清AIM2和LTB4水平分别与梗死体积和入院NIHSS评分呈正相关性(r=0.374,0.334;0.233,0.304,均P<0.05)。AIM2和LTB4水平增高患者的侧支循环建立状况较差(均P<0.01)。受试者工作特征(receiver operating characteristic,ROC)曲线分析显示AIM2,LTB4及联合检测诊断AIS预后不良的曲线下面积(area under curve,AUC)分别为0.706(95%CI:0.607~0.806,P=0.000),0.745(95%CI:0.655~0.835,P=0.000)和0.740(95%CI:0.648~0.833,P=0.000);约登系数分别为0.424,0.386和0.422;敏感度和特异度分别为60.80%,81.60%;62.70%,75.90%;68.60%,75.80%。AIM2和LTB4诊断AIS预后不良的截断值分别为1065.93pg/ml和130.68pg/ml。结论血清AIM2和LTB4水平增高可能增加AIS患者rt-PA静脉溶栓后预后不良的风险,因此检测患者血清AIM2和LTB4水平可以为AIS患者的预后评估提供依据。展开更多
黑色素瘤缺乏因子-2(Absent in melanoma-2,AIM2)是存在于细胞质中的模式识别受体,它能够识别内源性或外源性的双链DNA并组装一种称为炎症小体的蛋白聚合物,介导白介素-1β(Interleukin-1β,IL-1β)、白介素-18(Interleukin-18,IL-18)...黑色素瘤缺乏因子-2(Absent in melanoma-2,AIM2)是存在于细胞质中的模式识别受体,它能够识别内源性或外源性的双链DNA并组装一种称为炎症小体的蛋白聚合物,介导白介素-1β(Interleukin-1β,IL-1β)、白介素-18(Interleukin-18,IL-18)的成熟与释放,促使细胞发生炎症性的程序性死亡—细胞焦亡。AIM2对外源性DNA的识别有助于宿主抵抗各类病原微生物的感染,例如各种细菌、病毒、真菌以及寄生虫。本文就AIM2炎症小体在感染中的作用机制研究进展进行综述。展开更多
基金supported by the Gusu Medical Key Talent Project of Suzhou City of China(GSWS2020005)the New Pharmaceutics and Medical Apparatuses Project of Suzhou City of China(SLJ2021007)+3 种基金the Suzhou City Key Clinical Disease Diagnosis and Treatment Technology Special Project,China(LCZX202129)Wujiang Science and Educational Health Revitalization Fund Project,Suzhou,China(WWK202015)the Scientific Research Project of Suzhou Ninth People’s Hospital,Suzhou,China(YK202008)and Suzhou“Science and Education”Youth Science and Technology Project,Suzhou,China(KJXW2020075).
文摘Colorectal cancer(CRC)stands among the top prevalent cancers worldwide and holds a prominent position as a major contributor to cancer-related mortality globally.Absent in melanoma 2(AIM2),a constituent of the interferoninducible hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeats protein family,contributes to both cancer progression and inflammasome activation.Despite this understanding,the precise biological functions and molecular mechanisms governed by AIM2 in CRC remain elusive.Consequently,this study endeavors to assess AIM2’s expression levels,explore its potential antitumor effects,elucidate associated cancer-related processes,and decipher the underlying signaling pathways in CRC.Our findings showed a reduced AIM2 expression in most CRC cell lines.Elevation of AIM2 levels suppressed CRC cell proliferation and migration,altered cell cycle by inhibiting G1/S transition,and induced cell apoptosis.Further research uncovered the participation of P38 mitogen-activated protein kinase(P38MAPK)in AIM2-mediated modulation of CRC cell apoptosis and proliferation.Altogether,our achievements distinctly underscored AIM2’s antitumor role in CRC.AIM2 overexpression inhibited proliferation and migration and induced apoptosis of CRC cells via activating P38MAPK signaling pathway,indicating AIM2 as a prospective and novel therapeutic target for CRC.
基金supported by the National Natural Science Foundation of China,No.81772321(to HZL),81571194(to HZL),81471277(to JGH)a grant from the Key Program of Anhui Province for Outstanding Talents in Universities in China,No.gxbjZD2016071(to HZL),2014H012(to HZL)
文摘In traumatic brain injury, absent in melanoma 2(AIM2) has been demonstrated to be involved in pyroptotic neuronal cell death. Although the pathophysiological mechanism of spinal cord injury is similar to that of brain injury, the expression and cellular localization of AIM2 after spinal cord injury is still not very clear. In the present study, we used a rat model of T9 spinal cord contusive injury, produced using the weight drop method. The rats were randomly divided into 1-hour, 6-hour, 1-day, 3-day and 6-day(post-injury time points) groups. Sham-operated rats only received laminectomy at T9 without contusive injury. Western blot assay revealed that the expression levels of AIM2 were not significantly different among the 1-hour, 6-hour and 1-day groups. The expression levels of AIM2 were markedly higher in the 1-hour, 6-hour and 1-day groups compared with the sham, 3-day and 7-day groups. Double immunofluorescence staining demonstrated that AIM2 was expressed by NeuN+(neurons), GFAP+(astrocytes), CNPase+(oligodendrocytes) and CD11 b+(microglia) cells in the sham-operated spinal cord. In rats with spinal cord injury, AIM2 was also found in CD45+(leukocytes) and CD68+(activated microglia/macrophages) cells in the spinal cord at all time points. These findings indicate that AIM2 is mainly expressed in neurons, astrocytes, microglia and oligodendrocytes in the normal spinal cord, and that after spinal cord injury, its expression increases because of the infiltration of leukocytes and the activation of astrocytes and microglia/macrophages.
基金supported by the National Natural Science Foundation of China,No.81371374(to ZD)
文摘For severe cubital tunnel syndrome, patients with absent sensory nerve action potential tend to have more severe nerve damage than those without. Thus, it is speculated that such patients generally have a poor prognosis. How absent sensory nerve action potential affects surgical outcomes remains uncertain owing to a scarcity of reports and conflicting results. This retrospective study recruited one hundred and fourteen cases(88 patients with absent sensory nerve action potential and 26 patients with present sensory nerve action potential) undergoing either subcutaneous transposition or in situ decompression. The minimum follow-up was set at 2 years. Primary outcome measures of overall hand function included their McGowan grade, modified Bishop score, and Disabilities of the Arm, Shoulder, and Hand Questionnaire(DASH) score. For patients with absent sensory nerve action potential, 71 cases(80.7%) achieved at least one McGowan grade improvement, 76 hands(86.4%) got good or excellent results according to the Bishop score, and the average DASH score improved 49.5 points preoperatively to 13.1 points postoperatively. When compared with the present sensory nerve action potential group, they showed higher postoperative McGowan grades and DASH scores, but there was no statistical difference between the modified Bishop scores of the two groups. Following in situ decompression or subcutaneous transposition, great improvement in hand function was achieved for severe cubital tunnel syndrome patients with absent sensory nerve action potential. The functional outcomes after surgery for severe cubital tunnel syndrome are worse in patients with absent sensory nerve action potential than those without. This study was approved by the Ethical Committee of Huashan Hospital, Fudan University, China(approval No. 2017142).
文摘The famous American writer MarkTwain was well—known for his absent-mind-edness.One day,when he was riding in a train,the conductor asked him for his ticket.MarkTwain looked for the ticket in all his pockets.but 11e didn’t find it.At last,the
基金The study was supported by the National Natural Science Foundation of China(81400242 and 81525002)from ESW and HZ,and Program for Distinguished Professor in PUMC from HZ.
文摘Background The prognosis of tetralogy of Fallot with absent pulmonary valve (TOF/APV) without operation is poor. We evaluated the surgical outcome of TOF/APV in a single center. Methods Twenty-two TOF/APV patients underwent complete surgical correction in our hospital. Right ventricular outflow tract reconstruction was performed using bovine jugular vein (BJV)-valved conduit implantation (n=10), homograft-valved conduit implantation (n=2), or monocusp-valve patch (n=10). Health-related quality of life (QOL) was evaluated during follow-up. Results The overall survival at 5 and 10 years was 86.4±7.3% (confidence interval 69.4–97.2%). The survival rates were significantly different between patients with and without bronchial stenosis (40 and 100%, P=0.0003, log-rank test). The survival of patients aged>6 months was higher than those≤6 months (100 vs. 40%, P=0.0003, log-rank test). Patients with BJV-valved conduits had higher systolic gradients from the right ventricle to the pulmonary artery (RV–PA) compared to those with monocusp-valve patches. BJV-valved conduit implantation was a risk factor for post-operative pulmonary-valve stenosis. The QOL score for patients with BJV-valved conduits was lower than those with monocusp-valve patches (P<0.05). No reoperation was performed during follow-up. Conclusions Bronchial stenosis and lower age (≤6 months) were the main factors influencing post-operative survival. The use of a BJV-valved conduit was a main reason for RV–PA restenosis;thus, the use of a BJV-valved conduit may increase the need for repeat intervention and decrease the post-operative quality of life.
基金supported by the grant from scientific research fund of the Science and Technology Department of Sichuan Province(Nos.2017SZ0151 and 2018SZ0113).
文摘Background:Emerging evidence indicates that the sineoculis homeobox homolog 1−eyes absent homolog 1(SIX1–EYA1)transcriptional complex significantly contributes to the pathogenesis of multiple cancers by mediating the expression of genes involved in different biological processes,such as cell-cycle progression and metastasis.However,the roles of the SIX1–EYA1 transcriptional complex and its targets in colorectal cancer(CRC)are still being investigated.This study aimed to investigate the roles of SIX1–EYA1 in the pathogenesis of CRC,to screen inhibitors disrupting the SIX1–EYA1 interaction and to evaluate the efficiency of small molecules in the inhibition of CRC cell growth.Methods:Real-time quantitative polymerase chain reaction and western blotting were performed to examine gene and protein levels in CRC cells and clinical tissues(collected from CRC patients who underwent surgery in the Department of Integrated Traditional and Western Medicine,West China Hospital of Sichuan University,between 2016 and 2018,n=24).In vivo immunoprecipitation and in vitro pulldown assays were carried out to determine SIX1–EYA1 interaction.Cell proliferation,cell survival,and cell invasion were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay,clonogenic assay,and Boyden chamber assay,respectively.The Amplified Luminescent Proximity Homogeneous Assay Screen(AlphaScreen)method was used to obtain small molecules that specifically disrupted SIX1–EYA1 interaction.CRC cells harboring different levels of SIX1/EYA1 were injected into nude mice to establish tumor xenografts,and small molecules were also injected into mice to evaluate their efficiency to inhibit tumor growth.Results:Both SIX1 and EYA1 were overexpressed in CRC cancerous tissues(for SIX1,7.47±3.54 vs.1.88±0.35,t=4.92,P=0.008;for EYA1,7.61±2.03 vs.2.22±0.45,t=6.73,P=0.005).The SIX1/EYA1 complex could mediate the expression of two important genes including cyclin A1(CCNA1)and transforming growth factor beta 1(TGFB1)by binding to the myocyte enhancer factor 3 consensus.Knockdown of both SIX1 and EYA1 could decrease cell proliferation,cell invasion,tumor growth,and in vivo tumor growth(all P<0.01).Two small molecules,NSC0191 and NSC0933,were obtained using AlphaScreen and they could significantly inhibit the SIX1–EYA1 interaction with a half-maximal inhibitory concentration(IC50)of 12.60±1.15μmol/L and 83.43±7.24μmol/L,respectively.Administration of these two compounds could significantly repress the expression of CCNA1 and TGFB1 and inhibit the growth of CRC cells in vitro and in vivo.Conclusions:Overexpression of the SIX1/EYA1 complex transactivated the expression of CCNA1 and TGFB1,causing the pathogenesis of CRC.Pharmacological inhibition of the SIX1–EYA1 interaction with NSC0191 and NSC0933 significantly inhibited CRC cell growth by affecting cell-cycle progression and metastasis.
基金supported by grants from the German Research Foundation, the Transregional Collaborative Research Centre (Inflammatory Cardiomyopathy–Molecular Pathogenesis and Therapy) [SFB/TR19]the Federal Ministry of Education and Research for the Small and Medium-sized Enterprises Innovative Program (Grant No. 616 0315296) of Germany
文摘Micro RNAs(mi RNAs) can be found in a wide range of tissues and body ?uids, and their speci?c signatures can be used to determine diseases or predict clinical courses. The mi RNA pro?les in biological samples(tissue, serum, peripheral blood mononuclear cells or other body ?uids) differ signi?cantly even in the same patient and therefore have their own speci?city for the presented condition. Complex pro?les of deregulated mi RNAs are of high interest, whereas the importance of non-expressed mi RNAs was ignored. Since mi RNAs regulate gene expression rather negatively,absent mi RNAs could indicate genes with unaltered expression that therefore are normally expressed in speci?c compartments or under speci?c disease situations. For the ?rst time,non-detectable mi RNAs in different tissues and body ?uids from patients with different diseases(cardiomyopathies, Alzheimer's disease, bladder cancer, and ocular cancer) were analyzed and compared in this study. mi RNA expression data were generated by microarray or Taq Man PCR-based platforms. Lists of absent mi RNAs of primarily cardiac patients(myocardium, blood cells, and serum) were clustered and analyzed for potentially involved pathways using two prediction platforms, i.e., mi RNA enrichment analysis and annotation tool(mi EAA) and DIANA mi RPath.Extensive search in biomedical publication databases for the relevance of non-expressed mi RNAs in predicted pathways revealed no evidence for their involvement in heart-related pathways as indicated by software tools, con?rming proposed approach.
文摘BACKGROUND Congenital agenesis of the gallbladder(CAGB)is a rare condition often misdiagnosed as cholecystolithiasis,leading to unnecessary surgeries.Accurate diagnosis and surgical exploration are crucial in patients with suspected CAGB or atypical gallbladder stone symptoms.Preoperative imaging,such as magnetic resonance cholangiopancreatography(MRCP),plays a vital role in confirming the diagnosis.Careful intraoperative dissection is necessary to avoid iatrogenic injuries and misdiagnosis.Multidisciplinary consultations and collaboration,along with the use of various diagnostic methods,can minimize associated risks.CASE SUMMARY We present the case of a 34-year-old female with suspected gallbladder stones,ultimately diagnosed with CAGB through surgical exploration.The patient underwent laparoscopic examination followed by open exploratory surgery,which confirmed absence of the gallbladder.Subsequent imaging studies supported the diagnosis.The patient received appropriate postoperative care and experienced a successful recovery.CONCLUSION This case highlights the rarity of CAGB and the importance of considering this condition in the differential diagnosis of patients with gallbladder stone symptoms.Accurate diagnosis using preoperative imaging,such as MRCP,is crucial to prevent unnecessary surgeries.Surgeons should exercise caution and conduct meticulous dissection during surgery to avoid iatrogenic injuries and ensure accurate diagnosis.Multidisciplinary collaboration and utilization of various diagnostic methods are essential to minimize the risk of misdiagnosis.Selection of the optimal treatment strategy should prioritize minimizing trauma and maintaining open communication with the patient and their family members.
文摘目的探讨血清黑色素瘤缺乏因子2(absent in melanoma 2,AIM2)和白三烯B4(leukotriene B4,LTB4)水平与急性缺血性脑卒中(acute ischemic stroke,AIS)患者预后的相关性。方法收集2020年2月~2021年2月期间于西安交通大学第一附属医院、西安交通大学附属红会医院、咸阳市第一人民医院和泾阳县医院接受组织型纤溶酶原激活剂(tissue plasminogen activator,tPA)进行静脉溶栓治疗的138例AIS患者的临床资料进行回顾性分析。收集患者治疗三月后的改良Rankin评分量表(modified Rankin rating scale,mRS)评价其神经功能情况。依据mRS评分将AIS患者分为预后良好组(mRS评分≤2分,n=87)和预后不良组(mRS评分>2分,n=51)。采用酶联免疫吸附试验检测血清AIM2和LTB4水平。收集患者入院时的美国国立卫生研究院卒中患者神经功能缺损(neurological deficits in stroke patients at the National Institutes of Health,NIHSS)评分、梗死体积和侧支循环建立状况等信息。分析血清AIM2和LTB4水平、入院NIHSS评分、梗死体积和侧支循环建立状况与AIS患者预后的相关性。建立多因素Logistic回归模型分析rt-PA静脉溶栓后AIS患者预后不良的危险因素。结果与预后良好组比较,预后不良组的血清AIM2(1161.51±338.56pg/ml vs 964.77±171.94pg/ml)和LTB4水平(137.99±35.49pg/ml vs 117.85±21.60pg/ml)明显增高,差异具有统计学意义(t=4.638,4.148,均P<0.01)。Logistic回归分析发现AIS患者血清AIM2和LTB4水平增高、梗死体积增大、入院NIHSS评分增高及侧支循环建立状况较差均为AIS患者预后不良的独立危险因素(均P<0.05)。相关性分析显示AIS患者的血清AIM2和LTB4水平分别与梗死体积和入院NIHSS评分呈正相关性(r=0.374,0.334;0.233,0.304,均P<0.05)。AIM2和LTB4水平增高患者的侧支循环建立状况较差(均P<0.01)。受试者工作特征(receiver operating characteristic,ROC)曲线分析显示AIM2,LTB4及联合检测诊断AIS预后不良的曲线下面积(area under curve,AUC)分别为0.706(95%CI:0.607~0.806,P=0.000),0.745(95%CI:0.655~0.835,P=0.000)和0.740(95%CI:0.648~0.833,P=0.000);约登系数分别为0.424,0.386和0.422;敏感度和特异度分别为60.80%,81.60%;62.70%,75.90%;68.60%,75.80%。AIM2和LTB4诊断AIS预后不良的截断值分别为1065.93pg/ml和130.68pg/ml。结论血清AIM2和LTB4水平增高可能增加AIS患者rt-PA静脉溶栓后预后不良的风险,因此检测患者血清AIM2和LTB4水平可以为AIS患者的预后评估提供依据。
文摘黑色素瘤缺乏因子-2(Absent in melanoma-2,AIM2)是存在于细胞质中的模式识别受体,它能够识别内源性或外源性的双链DNA并组装一种称为炎症小体的蛋白聚合物,介导白介素-1β(Interleukin-1β,IL-1β)、白介素-18(Interleukin-18,IL-18)的成熟与释放,促使细胞发生炎症性的程序性死亡—细胞焦亡。AIM2对外源性DNA的识别有助于宿主抵抗各类病原微生物的感染,例如各种细菌、病毒、真菌以及寄生虫。本文就AIM2炎症小体在感染中的作用机制研究进展进行综述。
