重组人甲状旁腺激素(1-34)对骨质疏松患者血清Cbfa-1和MMP-13水平的影响

探讨重组人甲状旁腺素[rhPTH(1-34)]对绝经后骨质疏松患者血清核心结合因子a-1(Cbfa-1)和基质金属蛋白酶13(MMP-13)水平的影响.rhPTH(1-34)治疗6个月后,血清Cbfa~(-1)[(54.0±2.4)对(62.2±2.8)μg/L,P<0.05]、MMP-13[(2.51±0.15)对(3.96±0.24)μg/L,P<0.01]显著降低;相关性分析显示治疗前血清Cbfa-1与MMP-13呈正相关(r=0.74,P<0.01).提示小剂量rhPTH(1-34)皮下注射能促进骨的合成,并使血清Cbfa-1和MMP-13水平下降.     

重组人甲状旁腺激素(1-34)与依降钙素治疗绝经后骨质疏松症妇女多中心、随机对照研究

目的 比较重组人甲状旁腺激素(rhPTH)(1-34)和依降钙素在治疗绝经后骨质疏松症(OP)妇女中的疗效和安全性.方法 205例绝经后OP妇女,被随机分为rhPTH(1-34)组和依降钙素组,其中前者接受rhPTH(1-34)20μg(200 U)每天皮下注射1次,后者接受依降钙素20 U每周肌肉注射1次.治疗前和治疗后3个月、6个月分别检测腰椎1～4(L1～4)和股骨颈的骨密度(BMD)以及骨形成和骨吸收生化指标,同时记录治疗过程中所出现的不良反应.结果 治疗结束时,rhPTH(1-34)组和依降钙素组L1～4的BMD均增加,股骨颈的BMD没有明显变化.治疗3个月和6个月时,rhPTH(1-34)组L1～4、股骨颈的BMD较基线分别增加2.2%(P<0.05)、0.37%和5.51%(P<0.01)、0.65%;依降钙素组分别增加0.41%、-0.10%和1.55%(P<0.05)、0.11%;与依降钙素组相比,rhPTH(1-34)组在3个月和6个月时L1～4 BMD改善更明显.治疗3个月和6个月时,rhPTH(1-34)组和依降钙素组的血清骨碱性磷酸酶(BSAP)分别增加36.79%和0.31%及92.42%和-0.17%,尿I型胶原N末端肽与肌酐比值(NTX/Cr)分别增加48.91%和-5.32%及68.82%和-10.86%.在整个治疗过程中,两种药物均具有较好耐受性,两组在不良反应方面差异无统计学意义.结论 与依降钙素相比,rhPTH(1-34)治疗绝经后妇女OP,能更好地促进骨形成,提高BMD,并具有较好耐受性、副作用少,对肝、肾功能均无不良影响.     

合成的人血浆甲状旁腺素(1-34)放射免疫测定法及其临床应用

用合成的人甲状旁腺素(1-34)肽段(hPTH_(1-34))免疫动物,产生特异抗体,制备标记物,建立了放射免疫测定法(RIA)。不同hPTH_(1-34)浓度平均回收率为93.0％,灵敏度为1.1pmol/L,批内和批间变异系数分别为6.0％及13.0％。与另外3种肽段的交叉反应均<0.05％。测定100例正常受试者,生理参考值为11.8±4.5pmol/L。与用hPTH_(1-84)和PTH_(44-68)肽段进行比较,该法具有很好相关性,可用于临床诊断。     

重组人甲状旁腺素（1-34）治疗原发性骨质疏松症疗效观察

目的 观察对比重组人甲状旁腺素（1-34）[PTH（1-34）]和降钙素对原发性骨质疏松症的疗效.方法 将20例原发性骨质疏松症患者随机分为试验组和对照组.试验组皮下注射PTH（1-34）20μg,每天1次;对照组肌肉注射降钙素20 IU,每周1次,两组均每日口服钙尔奇D 600mg,连续治疗6个月.所有患者于治疗前后枪测腰椎（L2～L4）、股骨颈骨密度、血钙及血清骨特异性碱性磷酸酶（BSAP）、血清I型胶原交基C端肽（CTX）、PTH等指标及观察有无不良反应.结果 治疗后PTH组和降钙素组腰椎（L2～L4）骨密度变化较治疗前均有明显增加,且有统计学意义.治疗后两组股骨颈骨密度变化较治疗前无明显改善（P〉0.05）,两组间比较无明显差异（P〉0.05）.PTH组BSAP变化值明显高于对照组,两组间比较差异有统计学意义（P〈0.01）;两组治疗后血、尿常规、肝、肾功能均未见明显异常.结论 PTH（1-34）与降钙素都能显著提高腰椎（L2～L4）骨密度,对于原发性骨质疏松症治疗安全有效.     

重组人甲状旁腺激素氨基端1-34对绝经后骨质疏松症的作用

重组人甲状旁腺激素氨基端1-34(rh PTH1-34)是促骨形成的代表性药物,具有提高绝经后骨质疏松症患者骨密度,降低发生脆性骨折风险的作用。本文介绍rh PTH1-34抗骨质疏松机制、临床疗效、对骨转换标志物的影响、疗效的影响因素和不良反应,并对临床应用提出建议。     

重组人成骨蛋白-1骨修复材料的毒性研究

目的探讨重组人成骨蛋白-1（rhOP-1）明胶海绵骨修复材料的体内毒性反应，为其临床应用奠定基础。方法选用昆明种小鼠80只，雌雄各半。随机分成对照组和观察Ⅰ、Ⅱ、Ⅲ组，每组20只，均予乙醚麻醉，无菌条件下将rhOP-1／明胶海绵复合物置于观察Ⅰ、Ⅱ、Ⅲ组小鼠股部肌间隙。剂量分别为3、10、25mg，术后不用抗生素。正常饲养2、4周时观察各组血液、血生化指标改变及主要脏器的组织形态和脏器系数变化。结果各观察组术后3d活动力差，食欲减少，7d后恢复。观察组与对照组各血液学指标结果无统计学差异；血生化指标中除蛋白含量、ALT、AST观察组与对照组差异有统计学意义（P〈0．05）外，其余指标未见异常；4周时两组血液、血生化指标及组织学形态、脏器系数差异无统计学意义（P均〉0．05）。结论rhOP-1明胶海绵骨修复材料体内使用无毒、安全、可靠。     

重组人甲状旁腺激素(1-84)对去卵巢大鼠骨质疏松模型的影响

目的观察重组人甲状旁腺激素(1-84)对卵巢摘除骨质疏松大鼠的治疗作用。方法 36只4月龄的SD健康雌性大鼠,26只行双侧卵巢摘除术,10只作为假手术组,6 w后各处死6只检测造模效果。余20只骨质疏松模型鼠随机分为PTH组和安慰剂组。PTH组肌肉注射rhPTH(1-84)40μg/kg,每周3次。安慰剂组肌肉注射等量生理盐水,每周3次。治疗8 w后,测定并比较子宫湿重、股骨骨密度(BMD)、血清碱性磷酸酶(ALP)及吡啶酚(PYD)/Cr水平。结果双侧卵巢摘除6 w后,大鼠股骨BMD明显低于假手术组。8 w治疗后,PTH治疗组大鼠股骨BMD明显高于安慰剂组,血ALP及PYD/Cr也高于安慰剂组。结论 rhPTH(1-84)可显著增加BMD,对卵巢摘除诱导的大鼠骨质疏松有效。     

国产rhPTH1-34治疗绝经后骨质疏松症的有效性和安全性:随机对照、多中心临床研究

目的 以原研特立帕肽和鲑鱼降钙素为阳性对照,观察国产基因重组人甲状旁腺素氨基端1-34片段(recombinant human parathyroid hormone N-terminal 1-34 fragment, rhPTH1-34)治疗绝经后骨质疏松症的有效性和安全性。方法 纳入绝经后骨质疏松症女性214例,按照1∶1∶1∶0.5比例,随机分为4组：rhPTH1-34 20μg组(n=59)及40μg组(n=62)分别每天注射国产rhPTH1-34 20及40μg;降钙素组(n=61)给予鼻喷鲑鱼降钙素200 IU;特立帕肽组(n=32)给予原研特立帕肽注射20μg/d;疗程均为24周。观察治疗前后腰椎(L1-4)和髋部骨密度(bone mineral density, BMD)的变化率,骨转换生化指标的变化率,包括血清Ⅰ型前胶原N-端肽(procollagen typeⅠN-terminal propeptide, P1NP)和Ⅰ型胶原交联C-末端肽(β-cross linked C-telopeptide of typeⅠcollagen,β-CTX),以及药物治疗的安全性。结果 治疗24周后,rhPTH1-34 20μg及40μg组L1-4 BMD较基线分别增加3.42%和4.82%,特立帕肽组L1-4 BMD增加3.66%(均P<0.05),rhPTH1-34治疗组间骨密度变化率无明显差异;降钙素组腰椎骨密度变化率为-0.01%,骨密度无明显增加(P>0.05)。国产及原研特立帕肽的疗效均优于鼻喷降钙素组。国产与原研rhPTH1-34 20μg组治疗24周使血清P1NP分别升高534.22%和277.86%,使β-CTX水平分别升高247.88%和202.25%(均P<0.001),P1NP增幅大于β-CTX。国产与原研rhPTH1-34组的安全性较好。结论 每天皮下注射20μg国产rhPTH1-34治疗24周能够显著提升腰椎BMD,促进骨形成,疗效及安全性与原研特立帕肽相当,且优于降钙素鼻喷剂。     

血管紧张素-(1-7)与脂质代谢研究进展

脂质代谢是人体主要代谢之一,包括脂肪代谢、胆固醇代谢和磷脂代谢。脂质代谢紊乱主要为甘油三酯、总胆固醇、低密度脂蛋白胆固醇升高,以及高密度脂蛋白胆固醇降低,是引发急性冠脉综合征和脑卒中等心脑血管疾病的重要原因。血管紧张素-(1-7)作为肾素-血管紧张素系统中一种新的生物活性肽,近年来被国内外学者研究发现,其在降压、抗心肌纤维化、抗心律失常和改善动脉粥样硬化等心血管疾病中发挥作用,同时研究发现,血管紧张素-(1-7)通过抑制脂肪合成,促进脂肪分解,改善脂肪变性和调节胆固醇转运等参与脂质代谢。现就血管紧张素-(1-7)与脂质代谢的研究进展做一综述。     

甲状旁腺素1-34对新生Wistar大鼠心肌成纤维细胞增殖的影响

目的观察人甲状旁腺素1-34(hPTH)对原代培养新生Wistar大鼠心肌成纤维细胞(CFs)增殖的影响,通过细胞内钙离子([Ca~(2 )]i)的变化,探讨诱导CFs增殖的发生机制。方法培养新生Wistar大鼠心肌成纤维细胞,根据加入不同浓度的hPTH(10~(-10)、10~(-9)、10~(-8)mol/L)分组、同时设维拉帕米(L型钙通道拈抗剂)组。四氮唑盐比色法(MTT)、~3H-TdR掺入法检测细胞增殖；激光共聚焦显微镜(LSCM)测定细胞内[Ca~(2 )]i。结果①CFs增殖活性组间比较,差异有统计学意义(F=9．20,P＜0．01)。随着hPTH的增加,CFs增殖活性呈明显递增性升高,10~(-10)、10~(-9)、10~(-8) mol/L组CFs增殖活性分别为(0．408±0．016)、(0．518±0．019)、(0．778±0．034),与对照组(0．365±0．013)比较,差异有统计学意义(P＜0．01)。②~3H-TdR的掺入量组间比较差异有统计学意义(F=8．82,P＜0．01)；~3H-TdR的掺入量也随着hPTH的升高而呈递增趋势,10~(-10)、10~(-9)、10~(-8) mol/L组分别为(36．79±2．03)、(39．13±1．98)、(45．51±2．64)Bq,与对照组(24．08±1．23)Bq比较,差异有统计学意义(P＜0．01)；维拉帕米组~3H-TdR掺入量(41．68±2．72) Bq,明显低于10~(-8) mol/L组(P＜0．01)。③CFs内[Ca~(2 )]j组间比较,差异有统计学意义(F=9．16,P＜0．01)；10~(-10)、10~(-9)、10~(-8) mol/L组CFs内[Ca~(2 )]i(38．28±4．40、63．78±5．15、78．39±6．87)也明显高于对照组(36．18±3．57)；维拉帕米组CFs内[Ca~(2 )]i为(52．14±4．69),明显低于单独应用hPTH 10~(-8) mol/L组。结论PTH能刺激CFs增殖,增殖活性与PTH浓度有关,L型钙通道开放引起的细胞外钙内流增加为其重要的机制之一。     

甲状旁腺素1-34对骨质疏松大鼠治疗作用的实验研究

目的探讨甲状旁腺素134(hPTH134)对骨质疏松的治疗作用以及与血钙、磷、维生素D代谢和生长因子的关系。方法用摘除大鼠双侧卵巢的方式制备骨质疏松模型(OVX),实验动物分为4个组:模型对照组(OVX组,摘除大鼠双侧卵巢不作任何处理);hPTH134治疗组(PTH组,摘除大鼠双侧卵巢12w后用hPTH134治疗8w);盐酸雷洛昔芬治疗组(摘除大鼠双侧卵巢12w后用雷洛昔芬治疗8w);假手术组(Sham组,仅切除卵巢周围的脂肪组织约3g,术后12w纳入实验)。应用HOLOGIC第4代双能X线4500W骨密度仪测大鼠腰椎、股骨上段骨密度值(BMD);以骨形态计量学测股骨骨小梁面积、矿化沉积率;用ELISA法测定血清IGF1水平和血清25OHVitD浓度以及血淋巴细胞VitD受体(VDR)含量。结果hPTH134治疗组、盐酸雷洛昔芬治疗组均较OVX组腰椎、股骨上段骨密度增高,组间比较差异有显著性(P<0.01)。hPTH134治疗组较盐酸雷洛昔芬治疗组股骨上段骨密度增高,两组之间差异有显著性(P<0.01)。hPTH134治疗组骨小梁面积明显增加、矿化沉积率增高。hPTH134治疗组、盐酸雷洛昔芬治疗组血清IGF1浓度值、血清25OHVitD浓度值升高,与OVX组比较差异有显著性(P<0.01)。各组血淋巴细胞VDR含量无明显变化,与OVX组比较差异无显著性(P>0.05)。结论hPTH134能够预防腰椎、股骨上段骨密度丢失,使骨小梁面积明显增加、矿化沉积率增高并且血清IGF1及血清25OHVitD浓度值升高,但对VDR含量无明显作用。     

人甲状旁腺激素相关蛋白片段对骨质疏松大鼠股骨和腰椎骨密度的影响

目的观察人甲状旁腺激素相关蛋白（PTHrP1-34）对去卵巢的骨质疏松大鼠股骨、腰椎骨密度（BMD）的影响。方法80只4月龄Wistar健康雌性大鼠。其中60只行双侧卵巢摘除术，20只做假手术，6w后各处死10只证实骨质疏松造模成功。剩余50只骨质疏松模型鼠随机分为5个治疗组，每组10只，其他10只假手术组作对照。PTHrP治疗组（PTHrP20组，PTHrP40组，PTHrP80组）分别用20、40、80μg／kg剂量，每日皮下注射1次PTHrP1-04；雌二醇治疗组（E2组）用苯甲酸雌二醇40μg/kg，每3天注射1次；安慰荆组及假手术对照组分别用生理盐水，每3d注射1次。治疗3个月后，测定并比较股骨、腰椎不同部位BMD及血清钙、磷、碱性磷酸酶（ALP）水平。结果双侧卵巢摘除6W后，大鼠腰椎BMD明显低于假手术组（P〈0．05）。3个月治疗后，PTHrP40组和PTHrP80组大鼠股骨、腰椎BMD明显高于安慰剂组，与E2组无显著差异，腰椎BMD较PTHrP20组明显升商（P〈0．05）；PTHrP40组与PTHrP80组无明显差异。结论每日每公斤体重皮下注射40和80μg PTHrP1-34对左卵巢骨质疏松大鼠股骨、腰椎BMD均有增高作用。对腰椎作用更为明显。     

The high stromal SPARC expression is independently associated with poor survival of patients with resected pancreatic ductal adenocarcinoma treated with adjuvant gemcitabine in combination with S-1 or adjuvant gemcitabine alone

Background

Although postoperative adjuvant chemotherapy for pancreatic ductal adenocarcinoma (PDAC) improves survival, its efficacy varies among individuals. Identification of biomarkers that can predict the efficacy of adjuvant chemotherapy for PDAC is essential.

Comparison between recombinant human parathyroid hormone(1-34) and elcatonin in treatment of primary osteoporosis

Objective:To evaluate the efficacy and safety of rhPTH(1-34) vs.elcatonin.Methods:Sixty palients with primary OP were randomly divided into two groups according to the ratio of 3:1.rhPTH(1-34) group(PTH group) was treated with subcutaneous injection of rhPTH(1-34) 20 μg daily for 18 months,and the elcalonin group(CT group) was treated with intramuscular injection of elcatonin 20 U weekly for 12 months.Bone mineral density(BMD) of the lumbar spine 2-4(L_(2-4))and femoral neck,serum calcium and phosphorus,urinary calcium,serum hone specific alkaline phosphatase(BSAP).and urinary c-terminal telopeptides of type Ⅰ collagen/creatinine(uCTX-Ⅰ /Cn were tested at baseline,and 6.12.and 18 months after treatment.Results:In PTH group.HMD of L_(2-4),at 6,12.and 18 months,BDM of Femoral neck at 18 month,BSAP at 6 and 12 months and uCTX- Ⅰ /Cr at 6.12 and 18 months were all significantly raised.In CT group.HMD of L_(2-4) at12 month and that of femoral neck at 12 and 18 months were significantly elevated,while HSAP was significantly decreased at 12 and 18 months,and no significant difference on CTX- Ⅰ /Cr was observed.When BMD growth and growth rate between two groups were compared.PTH group had better improvement in L_(2-4) BMD and growth rate than CT group at 6.12.and 18 months.BMD growth and growth rale of femoral neck al 12 month and its growth at 18 month in CT group were higher than in PTH group,hut there was no significant difference between two groups regarding the growth rates at 18 month.Besides,there were no significant differences regarding the rales ol adverse reactions between two groups.Conclusions:rhPTH(1—34),is safe and effective in the treatment of primary OP.It is superior to elcatonin in improving vertebral HMD at onset time,growth rate and growth range,but inferior to elcatonin at HMD of femoral neck.     

Atorvastatin enhances bone density in ovariectomized rats given 17beta-estradiol or human parathyroid hormone(1-34)

We investigated the in vivo effect of atorvastatin on bone mineral density (BMD) in ovariectomized (OVX) rats. Eight-week-old female rats underwent either a sham operation or ovariectomy, and treatments with vehicle, atorvastatin, 17β-estradiol (E₂) and human parathyroid hormone(1–34) [hPTH(1–34)] were initiated 6 wk after the surgery. E₂ (10 μg/kg) treatment for 12 wk significantly increased lumbar BMD (L2–L4), whereas atorvastatin did not affect lumbar BMD. The combination of atorvastatin (2 mg/kg) and E₂ significantly enhanced the BMD of lumbar vertebrae (L2–L4) and femoral metaphyseal area (2/10–4/10 segments from the most proximal point) compared to that of either E₂ or atorvastatin alone. A low dose 1 μg/kg of hPTH (1–34) did not alter lumbar or femoral BMD, whereas a high dose 17.5 μg/kg of the peptide significantly increased BMD. Concomitant injections of atorvastatin (2 mg/kg) with hPTH(1–34) (1 μg/kg) for 8 wk significantly enhanced the BMD of lumbar vertebrae and the metaphyseal area of the femur in OVX rats. These findings demonstrate that chronic administration of atorvastatin appears to modestly enhance the BMD of the lumbar vertebrae and femoral metaphysis of OVX rats treated with submaximal doses of E₂ and hPTH(1–34).     

富含半胱氨酸的酸性分泌蛋白在肺癌和肺纤维化中的研究进展

富含半胱氨酸的酸性分泌蛋白(SPARC)可调控细胞基本功能如黏附、增殖和分化,同时也调控生长因子以及细胞外基质(ECM)降解和转化必需的基质金属蛋白酶(MMPs)的表达和活性。在非小细胞肺癌(NSCLC)和特发性肺纤维化(IPF)中,SPARC通过促进微血管改造和ECM中蛋白过度沉积发挥作用。而SPARC在慢性呼吸道疾病如哮喘和慢性阻塞性肺疾病(COPD)中的作用一直不被重视。为此,本文综述了SPARC在NSCLC和IPF中的作用研究,并提出未来应研究SPARC在哮喘和COPD中的作用。     

Secreted protein acidic and rich in cysteine (SPARC) gene polymorphism association with hepatocellular carcinoma in Italian patients

Background and Aim: Hepatocellular carcinoma (HCC) is a multifactorial disease driven by both genetic and epigenetic factors. Infection, inflammation and the immune response against hepatitis B virus and hepatitis C virus have been shown to play an important role in increasing cancer risk and promoting tumor development. In order to investigate the genetic component influencing HCC development, we analyzed 50 single nucleotide polymorphisms (SNP) spanning 34 different genes in 230 Italian patients affected by HCC and 230 controls. Methods: Genes were selected on the basis of their known biological function and their possible involvement in the progression or in the susceptibility to HCC was considered. SNP genotyping was performed using allelic‐specific fluorescent probes. Results: For most SNP, no differences were identified between HCC patients and controls, with the exception of rs2304052, localized on the secreted protein acidic and rich in cysteine (SPARC) gene, which was significantly associated to the disease. The C allele was significantly more frequent in the HCC patients than in the healthy controls (23% vs 10%, corrected P < 0.001), as well as the CC genotype (13% vs 1%, corrected P < 0.001). Conclusion: Since the presence of the rs2304052 C allele is associated with an increased risk (odds ratio: 2.76) of developing hepatocarcinoma, our results allowed us to identify a SNP in the SPARC gene correlating to HCC susceptibility.