清金得生片治疗老年晚期非小细胞肺癌的临床和实验研究
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摘要
一、研究目的
原发性支气管肺癌是一种严重威胁人类健康和生命的疾病。在20世纪末,肺癌已成为各种癌症死亡的首要原因。肺癌的发病随年龄增长呈上升趋势,在40岁后开始迅速升高,直到约70岁时达到高峰,而非小细胞肺癌占绝大多数。随着人口的平均寿命延长,社会老年化日益严重,老年肺癌的发病率逐年增加,对晚期老年NSCLC患者的研究逐步引起重视。
目前西医学认为,对于老年非小细胞肺癌的治疗,单纯年龄因素不是肿瘤三大治疗手段——手术、化疗、放疗的禁忌症。但老年人由于脏器储备功能低下,常规的三大治疗手段受到限制,效果并不理想。老年人对治疗的耐受性以及维持较好的生活质量是治疗中必须重视的首要问题。在中国,中医药是治疗老年肺癌的一个重要手段,在肺癌的综合治疗中发挥了独特的作用,已被认为是肺癌综合治疗的五大治疗手段之一。中医中药在稳定瘤灶、调节机体功能、增加免疫力、改善临床症状、增加食欲、减轻放、化疗毒副作用、提高生活质量、延长带瘤生存期等方面有独特疗效。老年非小细胞肺癌患者是中医药治疗的优势人群,本研究拟观察益气除痰法的代表方药清金得生片治疗老年晚期非小细胞肺癌的各项指标,为评价中医药治疗老年非小细胞肺癌的临床疗效,规范、合理地治疗老年肺癌探索道路。
转移是恶性肿瘤的基本生物学特征之一,是导致肿瘤治疗失败和患者死亡的最重要因素。随着肿瘤细胞生物学及分子生物学的研究进展,新的肿瘤治疗途径和靶点被发现,为中医药抗癌转移研究提供了新的思路和方法。中医药抗癌转移的研究仍处于起步阶段,尤其是对中药诱导失巢凋亡的研究。在实验方面,本论文拟研究清金得生片含药血清对人A549肺腺癌细胞失巢状态的影响,并探讨其对失巢凋亡密切相关的P-akt表达的调节作用。
二、研究方法
(一)临床研究:共完成合格病例48例,其中治疗组(清金得生片组)24例,对照组(安康欣胶囊组)24例,治疗前两组患者性别、年龄、病理类型、分化程度、临床分期、纳入前体重、卡氏评分和接受治疗情况相比较,经统计学处理,P＞0.05,差异无显著性,具有可比性。治疗组采用清金得生片治疗,对照组采用安康欣胶囊治疗,疗程2个月。观察两组瘤体、症状评分及体重等变化情况,检测两组治疗前后的CEA和ESR的变化,并进行药物毒性分析。
(二)实验研究:采用多聚-HEMA悬浮培养A549腺癌细胞,模拟体内癌细胞失巢状态,以高中低含药血清、空白血清、顺铂分别作用于A549腺癌细胞,用流式细胞仪检测各组细胞的凋亡率,Western-blot免疫印迹法检测各组细胞P-akt的表达。
三、研究结果
1、临床研究:(1)治疗后,两组患者瘤体变化情况比较,均未有病例达到CR和PR,但治疗组和对照组的瘤体稳定率分别达到79.17%和75%,经统计学处理,差异无显著性,但说明中药在稳定瘤体方面有一定优势。(2)两组患者临床症状的改善情况比较,治疗组在症状改善方面,有效率为54.17%,稳定率为29.17%,无效为16.67%,对照组在症状改善方面,有效率为50.00%,稳定率为33.33%,无效为16.67%,经χ~2检验,P＞0.05,差异无显著性。治疗组在改善口干、缓解胸痛方面,疗效较对照组明显(P＜0.05)。(3)两组患者体力状况的比较,在改善患者体力方面,治疗组和对照组的显效率和无效率相同,分别为4.17%和12.5%,治疗组有效率为33.33%,稳定率为50.00%;对照组有效率为20.83%,稳定率为62.50%,两组比较,经统计学处理,P＞0.05,差异无显著性。(4)两组体重均无恶化病例,治疗组和对照组患者的体重稳定率分别为83.33%和87.50%,经统计学处理,P＞0.05,两组比较差异无显著性;两组体重好转率分别为16.67%和12.5%;经统计学处理,P＞0.05,两组比较差异无显著性。(5)两组患者肿瘤指标CEA和ESR的比较,经统计处理,治疗组和对照组治疗前CEA、ESR相比,差异无统计学意义;治疗组和对照组CEA治疗后都有下降趋势,但P＞0.05,无统计学意义,治疗组治疗前后和对照组治疗前后的ESR相比较,P＜0.01,有统计学意义。说明治疗后,两组患者的血沉有明显的下降,病情趋于稳定。(6)对清金得生片药物不良反应的观察发现,清金得生片治疗前后患者血分析(WBC、NEU、HGB、PLT)、肝功能(AST、ALT)、肾功能(BUN、Cr)相比,经t检验,P＞0.05,差异无显著性,说明清金得生片治疗后未见明显的血液毒性和肝肾功能损害。(7)临床研究未发生严重不良事件和严重不良反应。
综合本临床研究的结果,我们可以看出无论清金得生片还是安康欣胶囊对晚期老年非小细胞肺癌患者具有稳定瘤体作用、改善临床症状及评分,降低肿瘤指标CEA和ESR,稳定病情,而且无明显毒副反应,较好反映了中医药治疗癌症稳定病情,改善生活质量的优势。清金得生片组在改善口干、缓解胸痛方面,疗效较安康欣胶囊组明显。
2、实验研究:(1)流式细胞仪检测结果:各中药含药血清组A549细胞的凋亡率均高于空白血清组,中药含药血清组随着剂量的增加,凋亡率也逐渐增加,说明中药清金得生片具有诱A549细胞凋亡的作用,而化疗药顺铂组的凋亡率最高。(2)Western-blot免疫印迹法检测结果:顺铂组的P-akt表达最低,为32,与空白血清组和低剂量组比较,均显著性降低;高剂量(30%)含药血清组P-akt表达为59,与空白血清组和低剂量组比较,均显著性降低(p＜0.05);中剂量组(20%)的P-akt表达为69,低剂量(10%)含药血清组的最高,为127,空白血清组的蛋白相对表达为122;在中药含药血清组中,随着浓度的逐渐降低,P-akt表达呈逐渐增高趋势。
结合既往研究,分析认为清金得生片有诱导A549人腺癌细胞失巢凋亡的作用,其机制可能为中药含药血清通过抑制P-akt的活化,降低了下游端粒酶活性,下调了抗凋亡基因bcl-2的表达,从而诱导癌细胞的凋亡。
Objective:
Primary lung bronchogenic carcinoma is one kind of the diseases threatening human being health and life gravely.In the 20th,the end of the century,lung cancer has become the leading cause of death in various types of carcinoma.The lung cancer morbidity increases with age,going up rapidly after 40-year old and reaches a peak until when being about 70-year old. Non-small cell lung cancer accounts for the vast majority of them.The issue of cancer in the elderly is of growing concern given the aging population. It is a particular issue in lung cancer,where the median age of patients is over 60.The issue of lung cancer treatment in the elderly has been the subject of recent comprehensive reviews.
At present,the age alone has not been considered a significant contraindication factor to three treatments---surgery,radiotherapy, chemotherapy in the older patients with non-small lung cancer.However,as the prevalence of dysfunction and comorbidity increase with age,the results of three main treatments are not satisfactory.Elderly tolerance to treatment and to maintain a better quality of life is of the primary issues that must be given attention.In china,traditional Chinese medicine plays a very important role in treating elderly patients with NSCLC.As one of five main methods in treating lung cancer,TCM can stabilize the tumor,regulate body functions,increase immunity,relieve the clinical symptoms,increase appetite,reduce the side effects of radiotherapy and chemotherapy,improve the quality of life and prolong survival with a unique effect and so on.TCM have unique advantages in treating the elderly patient with advanced NSCLC.
Metastasis is one of the fundamental biology characters for the malignant tumor and it is the most important factor leading to the cure failure and patient death.With the cell biology and the molecular biology development, the new methods have been approached,which has provided the new thoughts and methods for the anticancer metastasis of traditional Chinese medicine studies. Research for prevent cancer from metastasis in TCM is still in its infancy, especially for traditional Chinese medicine-induced anoikis studies.
This study will investigate the clinical efficacy of Qingjin Desheng Tablets on behalf of Yi-qi-chu-tan principles on elderly patients with advanced NSCLC and explore a reasonal,standard and economic way for the treatment of the elder lung cancer.In the field of the experiment,the thesis intends to study the effects of Qingjin Desheng Tablets on anoikis resistance in human lung cancer cell—AS49 and investigate the expression of signaling protein phosphor-AKT.
Methods:
Clinical part:48 elderly patients with NSCLC were selected and divided into 2 groups randomly:24 cases of treatment group and 24 cases control group. There is no significant difference in sex,age,pathology,differentiation grade,weight,performance states and the treatment before between the treatment group and the control group(P> 0.05).The two groups accepted the same supporting treatment.Meanwhile,the treated group was treated with Qingjin Desheng Tablets;the control group was treated with An-kang-xin capsule,last 60 days.The therapeutic efficiency and adverse effect of the two groups were evaluated after curing 60 days,then estimated it clinical effect and safety.
Experiment part:We cultivated adenocarcinoma cell-AS49 in suspension state by using poly-HEMA and simulate the state of anoikis of cancer cells in vivo.The cell apoptosis and period were measured by FCM after adenocarcinoma cell-A549 treated with serum containing Qingjin Desheng Tablets.The expression of P-akt in each group of cells was detected by Western-blot.
Results:
Clinical part:(1) No cases reached CR or PR equally in the two groups. The treatment group and control group tumors reached a stable rate of 79.17% and 75%respectively.Although there being no notable difference,it had showed certain advantage of stabilizing the tumor with traditional Chinese medicine treatment.(2) Both treatment group and control group were no improvement in clinic symptoms.In treatment group,effective rate was 54.17%,stable rate was 29.17%and invalid rate was 16.67%.In control group effective rate was 50.00%,stable rate was 33.33%and invalid rate was 16.67%.There were no significant difference between two groups(P>0.05 ).Through further observation,we found that Qingjin Desheng Tablets in alleviating the symptoms of chest pain and dry mouth,were better than An-kang-xin capsule.(3) After treatment,there were no striking difference between two groups in KPS (P >0.05)(4) There was no deterioration of body weight in two groups.The patients with stable weight were 83.33%and 87.50%respectively in treatment group and control group.The difference between the two groups was not significant(P> 0.05).(5) There were no significant difference to CEA and ESR in two groups before observation.After treatment,both CEA and ESR in two groups had obvious gone down.There were striking difference between two groups in ESR(P < 0.01),which showed that state of illness was to tend to stability.(6) There were no obvious blood toxicity and damage to liver and kidney functions after the treatment.(7) No serious adverse events and serious adverse reactions was found in clinical studies.
According to the results of this clinical study,we found whether Qing-jin-de-sheng tablet or An-kang-xin capsule in treat elderly patients with advanced non-small cell lung cancer could stabilize tumor,relieve the clinical symptoms,reduce tumor marker CEA and maintain the patient's condition etc.There were no significant toxicity,and better reflects the advantage of TCM.
Experiment part:(1) The cell apoptosis in every serum containing Qingjin Desheng Tablets was higher than blank space serum.With the serum containing Chinese medicine going up with the concentration,the apoptosis rate increased gradually.Chemotherapy drug-cisplatin group achieved the highest rate of apoptosis.(2) P-akt expression in the platinum group was lowest,32.It showed a significant reduces comparable with the blank blood serum group and the low monitoring group P-akt expression in the high dose group was 59,which showed a significant reduces comparable with the blank blood serum group and the low monitoring group too(p<0.05 ).Relative expression of P-akt among the monitoring team(20%),the low dose(10%) and the blank blood serum group were 69,127 and 122 respectively.The serum containing traditional Chinese medicine group,along with density gradual reduction,the P-akt expression had the tendency of increase gradually.
Combined with previous research,we concluded that Qingjin Desheng tablets have the function of leading A549 cells in suspension state to death.The mechanism may be for traditional Chinese medicine containing serum by blocking the anti-apoptotic gene bcl-2's role.Qingjin Desheng Tablets exerted the anti-tumor action thought inhibiting the P-akt activation and expression, which reduced the telomerase activity and modulating the expression of bcl-2 and bax2 protein.
原发性支气管肺癌是一种严重威胁人类健康和生命的疾病。在20世纪末,肺癌已成为各种癌症死亡的首要原因。肺癌的发病随年龄增长呈上升趋势,在40岁后开始迅速升高,直到约70岁时达到高峰,而非小细胞肺癌占绝大多数。随着人口的平均寿命延长,社会老年化日益严重,老年肺癌的发病率逐年增加,对晚期老年NSCLC患者的研究逐步引起重视。
目前西医学认为,对于老年非小细胞肺癌的治疗,单纯年龄因素不是肿瘤三大治疗手段——手术、化疗、放疗的禁忌症。但老年人由于脏器储备功能低下,常规的三大治疗手段受到限制,效果并不理想。老年人对治疗的耐受性以及维持较好的生活质量是治疗中必须重视的首要问题。在中国,中医药是治疗老年肺癌的一个重要手段,在肺癌的综合治疗中发挥了独特的作用,已被认为是肺癌综合治疗的五大治疗手段之一。中医中药在稳定瘤灶、调节机体功能、增加免疫力、改善临床症状、增加食欲、减轻放、化疗毒副作用、提高生活质量、延长带瘤生存期等方面有独特疗效。老年非小细胞肺癌患者是中医药治疗的优势人群,本研究拟观察益气除痰法的代表方药清金得生片治疗老年晚期非小细胞肺癌的各项指标,为评价中医药治疗老年非小细胞肺癌的临床疗效,规范、合理地治疗老年肺癌探索道路。
转移是恶性肿瘤的基本生物学特征之一,是导致肿瘤治疗失败和患者死亡的最重要因素。随着肿瘤细胞生物学及分子生物学的研究进展,新的肿瘤治疗途径和靶点被发现,为中医药抗癌转移研究提供了新的思路和方法。中医药抗癌转移的研究仍处于起步阶段,尤其是对中药诱导失巢凋亡的研究。在实验方面,本论文拟研究清金得生片含药血清对人A549肺腺癌细胞失巢状态的影响,并探讨其对失巢凋亡密切相关的P-akt表达的调节作用。
二、研究方法
(一)临床研究:共完成合格病例48例,其中治疗组(清金得生片组)24例,对照组(安康欣胶囊组)24例,治疗前两组患者性别、年龄、病理类型、分化程度、临床分期、纳入前体重、卡氏评分和接受治疗情况相比较,经统计学处理,P＞0.05,差异无显著性,具有可比性。治疗组采用清金得生片治疗,对照组采用安康欣胶囊治疗,疗程2个月。观察两组瘤体、症状评分及体重等变化情况,检测两组治疗前后的CEA和ESR的变化,并进行药物毒性分析。
(二)实验研究:采用多聚-HEMA悬浮培养A549腺癌细胞,模拟体内癌细胞失巢状态,以高中低含药血清、空白血清、顺铂分别作用于A549腺癌细胞,用流式细胞仪检测各组细胞的凋亡率,Western-blot免疫印迹法检测各组细胞P-akt的表达。
三、研究结果
1、临床研究:(1)治疗后,两组患者瘤体变化情况比较,均未有病例达到CR和PR,但治疗组和对照组的瘤体稳定率分别达到79.17%和75%,经统计学处理,差异无显著性,但说明中药在稳定瘤体方面有一定优势。(2)两组患者临床症状的改善情况比较,治疗组在症状改善方面,有效率为54.17%,稳定率为29.17%,无效为16.67%,对照组在症状改善方面,有效率为50.00%,稳定率为33.33%,无效为16.67%,经χ~2检验,P＞0.05,差异无显著性。治疗组在改善口干、缓解胸痛方面,疗效较对照组明显(P＜0.05)。(3)两组患者体力状况的比较,在改善患者体力方面,治疗组和对照组的显效率和无效率相同,分别为4.17%和12.5%,治疗组有效率为33.33%,稳定率为50.00%;对照组有效率为20.83%,稳定率为62.50%,两组比较,经统计学处理,P＞0.05,差异无显著性。(4)两组体重均无恶化病例,治疗组和对照组患者的体重稳定率分别为83.33%和87.50%,经统计学处理,P＞0.05,两组比较差异无显著性;两组体重好转率分别为16.67%和12.5%;经统计学处理,P＞0.05,两组比较差异无显著性。(5)两组患者肿瘤指标CEA和ESR的比较,经统计处理,治疗组和对照组治疗前CEA、ESR相比,差异无统计学意义;治疗组和对照组CEA治疗后都有下降趋势,但P＞0.05,无统计学意义,治疗组治疗前后和对照组治疗前后的ESR相比较,P＜0.01,有统计学意义。说明治疗后,两组患者的血沉有明显的下降,病情趋于稳定。(6)对清金得生片药物不良反应的观察发现,清金得生片治疗前后患者血分析(WBC、NEU、HGB、PLT)、肝功能(AST、ALT)、肾功能(BUN、Cr)相比,经t检验,P＞0.05,差异无显著性,说明清金得生片治疗后未见明显的血液毒性和肝肾功能损害。(7)临床研究未发生严重不良事件和严重不良反应。
综合本临床研究的结果,我们可以看出无论清金得生片还是安康欣胶囊对晚期老年非小细胞肺癌患者具有稳定瘤体作用、改善临床症状及评分,降低肿瘤指标CEA和ESR,稳定病情,而且无明显毒副反应,较好反映了中医药治疗癌症稳定病情,改善生活质量的优势。清金得生片组在改善口干、缓解胸痛方面,疗效较安康欣胶囊组明显。
2、实验研究:(1)流式细胞仪检测结果:各中药含药血清组A549细胞的凋亡率均高于空白血清组,中药含药血清组随着剂量的增加,凋亡率也逐渐增加,说明中药清金得生片具有诱A549细胞凋亡的作用,而化疗药顺铂组的凋亡率最高。(2)Western-blot免疫印迹法检测结果:顺铂组的P-akt表达最低,为32,与空白血清组和低剂量组比较,均显著性降低;高剂量(30%)含药血清组P-akt表达为59,与空白血清组和低剂量组比较,均显著性降低(p＜0.05);中剂量组(20%)的P-akt表达为69,低剂量(10%)含药血清组的最高,为127,空白血清组的蛋白相对表达为122;在中药含药血清组中,随着浓度的逐渐降低,P-akt表达呈逐渐增高趋势。
结合既往研究,分析认为清金得生片有诱导A549人腺癌细胞失巢凋亡的作用,其机制可能为中药含药血清通过抑制P-akt的活化,降低了下游端粒酶活性,下调了抗凋亡基因bcl-2的表达,从而诱导癌细胞的凋亡。
Objective:
Primary lung bronchogenic carcinoma is one kind of the diseases threatening human being health and life gravely.In the 20th,the end of the century,lung cancer has become the leading cause of death in various types of carcinoma.The lung cancer morbidity increases with age,going up rapidly after 40-year old and reaches a peak until when being about 70-year old. Non-small cell lung cancer accounts for the vast majority of them.The issue of cancer in the elderly is of growing concern given the aging population. It is a particular issue in lung cancer,where the median age of patients is over 60.The issue of lung cancer treatment in the elderly has been the subject of recent comprehensive reviews.
At present,the age alone has not been considered a significant contraindication factor to three treatments---surgery,radiotherapy, chemotherapy in the older patients with non-small lung cancer.However,as the prevalence of dysfunction and comorbidity increase with age,the results of three main treatments are not satisfactory.Elderly tolerance to treatment and to maintain a better quality of life is of the primary issues that must be given attention.In china,traditional Chinese medicine plays a very important role in treating elderly patients with NSCLC.As one of five main methods in treating lung cancer,TCM can stabilize the tumor,regulate body functions,increase immunity,relieve the clinical symptoms,increase appetite,reduce the side effects of radiotherapy and chemotherapy,improve the quality of life and prolong survival with a unique effect and so on.TCM have unique advantages in treating the elderly patient with advanced NSCLC.
Metastasis is one of the fundamental biology characters for the malignant tumor and it is the most important factor leading to the cure failure and patient death.With the cell biology and the molecular biology development, the new methods have been approached,which has provided the new thoughts and methods for the anticancer metastasis of traditional Chinese medicine studies. Research for prevent cancer from metastasis in TCM is still in its infancy, especially for traditional Chinese medicine-induced anoikis studies.
This study will investigate the clinical efficacy of Qingjin Desheng Tablets on behalf of Yi-qi-chu-tan principles on elderly patients with advanced NSCLC and explore a reasonal,standard and economic way for the treatment of the elder lung cancer.In the field of the experiment,the thesis intends to study the effects of Qingjin Desheng Tablets on anoikis resistance in human lung cancer cell—AS49 and investigate the expression of signaling protein phosphor-AKT.
Methods:
Clinical part:48 elderly patients with NSCLC were selected and divided into 2 groups randomly:24 cases of treatment group and 24 cases control group. There is no significant difference in sex,age,pathology,differentiation grade,weight,performance states and the treatment before between the treatment group and the control group(P> 0.05).The two groups accepted the same supporting treatment.Meanwhile,the treated group was treated with Qingjin Desheng Tablets;the control group was treated with An-kang-xin capsule,last 60 days.The therapeutic efficiency and adverse effect of the two groups were evaluated after curing 60 days,then estimated it clinical effect and safety.
Experiment part:We cultivated adenocarcinoma cell-AS49 in suspension state by using poly-HEMA and simulate the state of anoikis of cancer cells in vivo.The cell apoptosis and period were measured by FCM after adenocarcinoma cell-A549 treated with serum containing Qingjin Desheng Tablets.The expression of P-akt in each group of cells was detected by Western-blot.
Results:
Clinical part:(1) No cases reached CR or PR equally in the two groups. The treatment group and control group tumors reached a stable rate of 79.17% and 75%respectively.Although there being no notable difference,it had showed certain advantage of stabilizing the tumor with traditional Chinese medicine treatment.(2) Both treatment group and control group were no improvement in clinic symptoms.In treatment group,effective rate was 54.17%,stable rate was 29.17%and invalid rate was 16.67%.In control group effective rate was 50.00%,stable rate was 33.33%and invalid rate was 16.67%.There were no significant difference between two groups(P>0.05 ).Through further observation,we found that Qingjin Desheng Tablets in alleviating the symptoms of chest pain and dry mouth,were better than An-kang-xin capsule.(3) After treatment,there were no striking difference between two groups in KPS (P >0.05)(4) There was no deterioration of body weight in two groups.The patients with stable weight were 83.33%and 87.50%respectively in treatment group and control group.The difference between the two groups was not significant(P> 0.05).(5) There were no significant difference to CEA and ESR in two groups before observation.After treatment,both CEA and ESR in two groups had obvious gone down.There were striking difference between two groups in ESR(P < 0.01),which showed that state of illness was to tend to stability.(6) There were no obvious blood toxicity and damage to liver and kidney functions after the treatment.(7) No serious adverse events and serious adverse reactions was found in clinical studies.
According to the results of this clinical study,we found whether Qing-jin-de-sheng tablet or An-kang-xin capsule in treat elderly patients with advanced non-small cell lung cancer could stabilize tumor,relieve the clinical symptoms,reduce tumor marker CEA and maintain the patient's condition etc.There were no significant toxicity,and better reflects the advantage of TCM.
Experiment part:(1) The cell apoptosis in every serum containing Qingjin Desheng Tablets was higher than blank space serum.With the serum containing Chinese medicine going up with the concentration,the apoptosis rate increased gradually.Chemotherapy drug-cisplatin group achieved the highest rate of apoptosis.(2) P-akt expression in the platinum group was lowest,32.It showed a significant reduces comparable with the blank blood serum group and the low monitoring group P-akt expression in the high dose group was 59,which showed a significant reduces comparable with the blank blood serum group and the low monitoring group too(p<0.05 ).Relative expression of P-akt among the monitoring team(20%),the low dose(10%) and the blank blood serum group were 69,127 and 122 respectively.The serum containing traditional Chinese medicine group,along with density gradual reduction,the P-akt expression had the tendency of increase gradually.
Combined with previous research,we concluded that Qingjin Desheng tablets have the function of leading A549 cells in suspension state to death.The mechanism may be for traditional Chinese medicine containing serum by blocking the anti-apoptotic gene bcl-2's role.Qingjin Desheng Tablets exerted the anti-tumor action thought inhibiting the P-akt activation and expression, which reduced the telomerase activity and modulating the expression of bcl-2 and bax2 protein.
引文
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