环氧合酶-2对乳腺癌淋巴管形成的影响

目的探讨环氧合酶-2（COX-2）对人乳腺癌淋巴管形成的影响。方法1998年11月至2002年3月行手术治疗并经病理证实的乳腺癌患者94例,随访83例,失访11例。免疫组织化学方法检测COX-2、血管内皮生长因子-C（VEGF—C）及D2-40在乳腺癌中的表达。逆转录聚合酶链式反应（RT-PCR）和Western印迹法分别检测加入不同浓度COX-2抑制剂尼美舒利后VEGF-CmRNA及蛋白的变化。Western印迹法检测加入外源性前列腺素E2（PGE2）和曲妥珠单抗后VEGF—C蛋白的变化。结果46．8％的乳腺癌组织呈COX-2高表达,51．1％呈VEGF—C高表达。COX-2与VEGF—C（P〈0．01）、淋巴管密度（P=0．032）和淋巴结转移（P＝0．035）呈正相关,与乳腺癌患者的无病生存率（P=0．010）和总生存率（P＝0．040）呈负相关。尼美舒利以剂量依赖性方式下调VEGF-CmRNA及蛋白表达,而PGE2上调其蛋白表达。曲妥珠单抗可显著降低VEGF—C的蛋白表达。结论COX-2可通过上调VEGF—C的表达,促进乳腺癌的淋巴管形成和淋巴结转移,并影响乳腺癌患者的预后。     

膀胱移行细胞癌中Survivin基因的检测及临床意义

目的：探讨Survivin基因在膀胱移行细胞癌中的表达及其临床意义。方法：通过逆转录一聚合酶链反应（RT-PCR）检测40例膀胱癌和12例非膀胱癌组织及尿液标本中Survivin基因mRNA的表达,采用免疫组织化学方法（SP法）复检Survivin基因的表达并确定其临床病理分期和分级。结果：40例膀胱癌组织中Survivin基因的阳性表达率为67．5％,mRNA表达结果与免疫组织化学结果一致;在尿液中的阳性表达率为55．5％。12例非膀胱癌组织中Survivin基因的阳性表达率仅为8．3％;尿液中未见Survivin基因表达。显示Survivin基因在膀胱癌中的表达显著高于在非膀胱癌中的表达（P〈0．05）;而组织标本与尿液标本对Survivin基因的检出率无明显差异（P〉0．05）;Survivin的阳性表达与膀胱癌的恶性程度、临床病理分级或是否复发关系密切（P〈0．05）,Survivin基因的阳性表达与患者年龄、性别、肿瘤的分期无明显相关性。结论：Survivin基因在膀胱癌的恶性程度、肿瘤转移及预后等方面可能有较大的临床意义,而检测尿液中Survivin基因的表达可作为膀胱癌的早期发现、早期诊断、术后复查的新方法。     

不同类型膀胱癌组织中环氧化酶-2的表达及意义

目的探时环氧化酶-2（COX-2）在不同类型膀胱癌组织中的表达及临床意义。方法应用免疫组化染色方法检测52例膀胱移行细胞癌组织（其中T，18例、T2 14例、T3 14例、T4 6例，G1 13例、G2 25例、G3 14例，肿瘤单发37例、多发15例）、20例膀胱腺癌组织、10例膀胱鳞状细胞癌组织及17例正常膀胱黏膜组织中COX-2蛋白表达情况，根据染色阳性细胞所占比例，分为（-）、（＋）、（＋＋）、（＋＋＋）4个等级，用等级资料x^2检验进行统计学分析。结果82例肿瘤组织COX-2蛋白表达率（82．9％，68／82）高于正常黏膜（23．5％，4／17）（P〈0．05），不同类型肿瘤COX-2蛋白表达率也有差别，鳞状细胞癌最强（100％，10／10），腺癌次之（90．0％，18／20），移行细胞癌相对较弱（76．9％，40／52）（P〈0．05）；在52例移行细胞癌标夺中，COX-2表达率与肿瘤分级、分期相关（P〈0．05）。结论COX-2在不同类型膀胱癌组织中呈岛表达，在鳞状细胞癌表达最强，可能成为膀胱癌化学预防的一个靶点。     

乳腺癌组织中survivin及其剪接体与VEGF的表达及临床意义

目的 研讨抗凋亡蛋白survivin及其剪接体survivin—△Ex3、survivin-2B与血管内皮生长因子（VEGF）在乳腺癌组织中表达情况及其与临床病理学指标的关系。方法以RT—PCR法检测100例乳腺癌及癌旁5cm正常乳腺组织标本中survivin及其剪接体survivin—△Ex3、survivin-2B与VEGF基因的mRNA表达,半定量分析电泳结果。以免疫组化法检测乳腺癌石蜡标本中的雌激素受体（ER）、孕激素受体（PR）和HER-2基因状态。结果Survivin及其剪接体survivin—△Ex3、survivin-2BmRNA在乳腺癌组织中均有较高表达,在癌旁5cm正常乳腺组织中均低表达,差异有统计学意义（P〈0．05）;VEGFmRNA在乳腺癌组织中均有较高表达,在正常乳腺组织中均低表达,差异有统计学意义（P〈0．05）;淋巴结转移与survivin-△Ex3、survivin-2B的表达相关（P〈0．05）。结论Survivin及其剪接体survivin—△Ex3、sur-vivin-2B与VEGF的表达与乳腺癌发生、发展有关,与其他预后指标ER、PR、HER-2等的联合检测可望对患者的预后作出更准确的预测。     

利用RNA干扰阻抑膀胱癌细胞Survivin基因表达和诱导凋亡

目的 探讨RNA干扰下调Survivin基因表达后膀胱癌细胞生物学行为变化及Survivin基因抗凋亡机制。方法设计、合成一对Survivin编码基因序列特异的小分子干扰RNA（siRNA），用脂质体包裹转染T24膀胱癌细胞，分不同的浓度组（50～200nmol／L）。噻唑蓝（MTT）法检测细胞生长情况，流式细胞仪测定细胞凋亡率，实时定量聚合酶链反应（PCR）检测Survivin基因和Caspase-3基因mRNA表达。结果 Survivin编码基因序列特异性siRNA能有效下调Survivin基因表达水平，并呈剂量和时间依赖性，最大效应浓度为100nmol／L，此时与对照比较Survivin表达水平下调75．91％，并显著的抑制了细胞生长，抑制率达55．29％，差异有统计学意义（P＜0．05）。同时，Caspase-3 mRNA表达水平明显上升达239．80％，细胞凋亡率亦增加至45．70％，与对照相比差异有统计学意义（P＜0．05）。结论RNA干扰显著下调Survivin基因表达后，能明显促进T24膀胱癌细胞凋亡并抑制其增殖；Survivin基因可能是通过下调Caspase-3表达来抑制凋亡。     

前列腺素E2在肾脏球旁器调节肾素分泌中的作用

目的 观察前列腺素E2（PGE2）对肾脏球旁器颗粒细胞（JGG）肾素分泌的调节作用。 方法 将小鼠肾脏致密斑细胞株（MMDD1）种植在特殊滤器上,滤器上下（细胞顶侧和基底侧）分别用不同培养基培养细胞,改变细胞顶侧培养基中钠离子、氯离子和血管紧张素Ⅱ（AngⅡ）浓度,分别测定不同时间点滤器上、下PGE2浓度。腹腔注射卡托普利（30 mg/kg）前后,放射免疫法测定野生型和环氧化酶基因敲除（COX-2-/-）小鼠血浆肾素活性(PRA)变化;原代分离COX-2-/-小鼠JGG,测定细胞上清肾素活性及其对PGE2刺激的反应。实时定量PCR测定低肾素（JGG细胞特异性Gsα基因缺失）小鼠肾脏皮质COX-2 mRNA表达。免疫组化法检测肾皮质COX-2蛋白表达。代谢笼中留取24 h尿,ELISA方法测定PGE2水平。 结果 (1)低氯刺激能使致密斑细胞分泌PGE2,不论基底侧还是细胞顶端PGE2浓度均显著增加（均P < 0.05）;但AngⅡ对致密斑分泌PGE2没有显著影响;(2)COX-2-/-小鼠基础PRA[（378.3±96.4）比（1115.0±210.0） ng AngI&#8226;ml-1&#8226;h-1,P ＝ 0.0051,n＝10]和JGG细胞肾素分泌[（153.7±14.7）比（672.4±129.0） ng AngI&#8226;ml-1&#8226;h-1,P ＝ 0.0162,n＝3]显著低于相同遗传背景的野生型小鼠;卡托普利能刺激COX-2-/-小鼠PRA增加32.8倍;PGE2能部分恢复COX-2-/-小鼠原代JGG细胞分泌肾素功能;(3)PGE2受体EP4耦联的Gsα基因敲除的低肾素小鼠,肾脏皮质COX-2 mRNA表达增加（8.07±1.08)倍（n=6,P = 0.0022),免疫组化显示致密斑和远端小管COX-2蛋白表达增加,24 h尿PGE2分泌增加[（1235±152） pg/24 h 比（385±140） pg/24 h,P = 0.0065]。 结论 致密斑PGE2直接受低氯调节,COX-2-/-小鼠基础肾素减少;下游的AngⅡ能直接作用于JGG细胞而不是致密斑负反馈调节肾素分泌。阻断JGG细胞自身的肾素产生（Gsα基因敲除）后,能负反馈上调致密斑的COX-2表达,故COX-2-PGE2-肾素在球旁器存在近距离精确调控机制。     

脱氧核酶抑制COX-2基因表达并促进人肝癌细胞的凋亡

目的探讨利用脱氧核酶切割环氧化酶-2（COX-2）mRNA来抑制其基因表达以及对人肝癌细胞凋亡的影响。方法合成针对COX-2基因的“10～23”型脱氧核酶及其类似物，提取人肝癌细胞总RNA在胞外切割COX-2mRNA，检测其胞外切割活性；转染肝癌细胞，检测其在细胞内的切割活性及对细胞凋亡的影响。用RT-PCR检测COX-2和凋亡相关基因bcl-2、bax的mRNA水平，用荧光免疫方法测定相应的蛋白水平。结果非修饰脱氧核酶DzT和修饰的脱氧核酶DzTi（在DzT的3′末端添加倒位连接的T碱基）在胞外切割反应中能够有效地切割COX-2mRNA；在转染进入肝癌细胞后，DzTi比DzT显示更强的切割活性，显著地下调细胞内COX-2蛋白水平（P〈0.01）和bcl-2蛋白水平（P〈0.05），上调bax蛋白的表达（P〈0.01），抑制肝癌细胞的生长（P〈0．05）。脱氧寡核苷酸DzT′和DzTi′是由对DzT和DzTi的催化区进行碱基替换而成，在胞外和胞内均不能切割COX-2mRNA和促进肝癌细胞的凋亡。结论脱氧核酶能够有效切割COX-2mRNA，抑制COX-2蛋白表达和促进肝癌细胞凋亡，有可能作为COX-2抑制剂用于医学临床。     

PTEN和COX-2在病理性瘢痕中的表达及其相关性研究

目的研究抑癌基因PTEN和COX-2在病理性瘢痕中的表达及其相关性。方法应用免疫组化SP法检测正常皮肤24例、扁平瘢痕20例、增生性瘢痕32例和瘢痕疙瘩16例组织中PTEN、COX-2蛋白的表达。结果病理性瘢痕（瘢痕疙瘩、增生性瘢痕）组织中PTEN蛋白表达显著低于正常皮肤、扁平瘢痕（P〈0．05）,而COX-2蛋白表达显著高于正常皮肤、扁平瘢痕（P〈0．05）;4类组织中PTEN蛋白和COX-2蛋白呈负相关（P〈0．05）。结论COX-2及PTEN是病理性瘢痕发生发展中重要的调控因子,两者呈负相关。     

反义寡核苷酸抑制Survivin基因表达对移植静脉内膜增生的影响

目的研究反义寡脱氧核苷酸（ASODN）抑制Survivin基因表达对移植静脉内膜增生的抑制作用。方法Wistar大鼠60只，建立自体静脉移植模型，术后随机分为：对照组、Survivin ASODN 50、200μg组、正义对照组、Lipofectin＋pluronic等五个组，施加不同的处理因素，在移植后1、2周取材。组织形态学方法比较内膜增生程度，逆转录．聚合酶链反应（RT-PCR）检测Survivin基因的mRNA表达，Westem blot检测Survivin基因的蛋白产物表达，免疫组织化学方法检测Survivin及增殖细胞核抗原（PCNA）的表达，脱氧核苷酸转移酶末端标记法（TUNEL）检测血管平滑肌细胞（VSMC）凋亡的变化。结果移植后1、2周内膜增生明显，局部转染50μg Survivin ASODN组内膜增生明显受抑制（P〈0．05），200μg组受抑制程度更为明显（P〈0．05）；与对照组相比，Survivln ASODN组Survivin的mRNA及蛋白产物表达显著减少（P〈0．05），PCNA阳性表达同时减少，而TUNEL阳性细胞却明显增加。结论Survivin ASODN可显著抑制移植静脉的内膜增生，其作用可能是通过抑制Survivin基因及其蛋白产物表达，从而抑制VSMC增殖、促进其凋亡而实现的。     

丝裂霉素C对人膀胱癌T24细胞Mta-1 mRNA、Mta-1蛋白表达的影响及意义

目的研究人膀胱癌T24细胞株中Mta-1 mRNA和Mta-1蛋白的表达,及丝裂霉素C（MMC）对人膀胱癌T24细胞株中Mta-1 mRNA和Mat-1蛋白表达的影响。方法人膀胱癌T24细胞株培养,MMC干预,用原位杂交和免疫组化检测Mta-1 mRNA和Mta-1蛋白的表达。结果人膀胱癌T24细胞株中Mta-1 mRNA阳性细胞表达率MMC组（35.1±9.0）%明显低于对照组组（61.9±12.8）%;Mta-1蛋白阳性细胞表达率MMC组（36.0±8.03）%亦明显低于对照组（57.7±10.1）%,P〈0.01。结论人膀胱癌T24细胞株中存在Mta-1 mRNA和Mta-1蛋白的高表达,MMC对人膀胱癌T24细胞株中Mta-1 mRNA和Mta-1蛋白的表达具有抑制作用。     

Subchondral pO2, pCO2, pressure, pH, and lactate in human osteoarthritis of the hip

The pathogenesis of primary human osteoarthritis is unknown. It has been suggested that hypoxia caused by reduced subchondral blood flow plays a central role in the development of tissue damages in osteoarthritis. This hypothesis was investigated using an in situ technique based on mass spectrometry to measure subchondral pO2 and pCO2 in both femoral heads of patients with late stage unilateral osteoarthritis and the normal opposite hip. Intraosseous pressure was recorded and lactate concentrations and pH were measured in blood samples obtained from the two femoral heads. The subchondral pO2 in the diseased hip was significantly lower than pO2 in the normal hip (43 torr versus 63 torr). The intraosseous pressure was significantly higher in the diseased than in the normal hip. The lactate concentration showed a 50% increase in the diseased hip. There were no differences in pCO2 and pH between the two locations.     

Continuous measurement of intraarterial pHa, PaCO2, and PaO2 in the operating room

Miniaturized sensors based upon the principles of optical fluorescence can measure the pH, PCO2, and PO2 of liquid or gas media. A prototype of a three-component fiberoptic sensor has been developed for intraarterial application by CDI, 3M Health Care, Irvine, California. We report the first study of this continuous intraarterial monitor in patients undergoing surgical procedures under general anesthesia. Fourteen patients participated in the study. The fiberoptic sensor was calibrated before insertion and then passed through an existing 18-gauge radial artery cannula. Blood samples were drawn at frequent intervals through the same cannula for in vitro blood gas analysis. For each of the 87 arterial blood gas samples obtained, the in vitro values of pHa, PaCO2, and PaO2 were compared with simultaneous readings from the fiberoptic sensor. For pHa, the mean error (error = fiberoptic value minus in vitro value) or "bias" of the fiberoptic data was -0.032 and the standard deviation of error or "precision" was 0.042. For PaCO2, the bias was -3.8 mm Hg and the precision was 4.7 mm Hg. For PaO2, the bias was -9.0 mm Hg and the precision was 23.3 mm Hg. For PaO2 values less than 175 mm Hg, the bias was -8.5 mm Hg and the precision was 8.3 mm Hg. Expressed in terms of percentage errors, the bias +/- precision values were -11.5% +/- 13.3% for PaCO2, and -6.2% +/- 10.0% for PaO2. The duration of the surgical procedures ranged from 1.6 to 8 h with an average of 4.2 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lrig2 and Hpse2, mutated in urofacial syndrome,pattern nerves in the urinary bladder

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Impact of Common Variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 on the Risk of Type 2 Diabetes in 5,164 Indians

OBJECTIVE

Common variants in PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 genes have been shown to be associated with type 2 diabetes in European populations by genome-wide association studies. We have studied the association of common variants in these eight genes with type 2 diabetes and related traits in Indians by combining the data from two independent case–control studies.

RESEARCH DESIGN AND METHODS

We genotyped eight single nucleotide polymorphisms (PPARG-rs1801282, KCNJ11-rs5219, TCF7L2-rs7903146, SLC30A8-rs13266634, HHEX-rs1111875, CDKN2A-rs10811661, IGF2BP2-rs4402960, and CDKAL1-rs10946398) in 5,164 unrelated Indians of Indo-European ethnicity, including 2,486 type 2 diabetic patients and 2,678 ethnically matched control subjects.

RESULTS

We confirmed the association of all eight loci with type 2 diabetes with odds ratio (OR) ranging from 1.18 to 1.89 (P = 1.6 × 10⁻³ to 4.6 × 10⁻³⁴). The strongest association with the highest effect size was observed for TCF7L2 (OR 1.89 [95% CI 1.71–2.09], P = 4.6 × 10⁻³⁴). We also found significant association of PPARG and TCF7L2 with homeostasis model assessment of β-cell function (P = 6.9 × 10⁻⁸ and 3 × 10⁻⁴, respectively), which looked consistent with recessive and under-dominant models, respectively.

CONCLUSIONS

Our study replicates the association of well-established common variants with type 2 diabetes in Indians and shows larger effect size for most of them than those reported in Europeans.Type 2 diabetes is a complex metabolic disorder with both genetic and environmental factors such as food habits and lifestyle contributing to its pathogenesis (1). Due to its complex etiology, the progress of discovery of genetic components for type 2 diabetes had been very slow until the advent of high throughput genome-wide association (GWA) studies (2). Until recently, only a few common variants in PPARG (3), KCNJ11 (4), and TCF7L2 (5) were shown to be associated with type 2 diabetes. With the advent of GWA studies, there are at least 20 loci identified today that are associated with the risk of type 2 diabetes (6). The first GWA study in the French population revealed SLC30A8 and HHEX as new loci for type 2 diabetes in addition to replicating the strong association with TCF7L2 (7). Further, GWA studies added several new genes including CDKAL1, CDKN2A, IGF2BP2, and FTO to the list of type 2 diabetes–associated loci and confirmed the associations for PPARG, KCNJ11, and TCF7L2 (8–12).India harbors the maximum number of diabetic patients, which is projected to double by the year 2030 (13). Indians are diagnosed with diabetes a decade earlier and at a lower BMI than Europeans, which may be partly explained by their excess central obesity (14,15). Hence, determination of genetic risk factors predicting the risk of type 2 diabetes in the Indian population is highly desirable. Recent evidence suggests that the genetic basis of several diseases in Indians might be different from that of Europeans (16,17), which could be due to differences in the risk allele frequency and pattern of linkage disequilibrium. A report from the Indian Genome Variation Consortium also suggested that most of the populations in the Indian subcontinent are distinct from HapMap populations (18). Hence, genes associated with a disease in other populations need to be assessed for their role in the Indian population. The present study evaluated the association of eight most replicated and well-established genetic variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 with type 2 diabetes and related quantitative traits in Indians. We also performed allele dosage analysis of these variants and investigated their influence on quantitative metabolic traits related to type 2 diabetes.     

Cross-reactivity among the products of three nonallelic H-2 loci, H-2Ld, H-2Dq, and H-2Kk

Cross-reactions of the products of three nonallelic H-2 loci, H-2K, H-2D, and H-2L, have been studied by serological, immunochemical, and cellular immune techniques. Immunoprecipitation experiments revealed a determinant shared between Ld and Dq molecules but absent on Dd molecules, By cytotoxic screening of sera from individual mice an exceptional anti-Ld serum was found which cross-reacted with an H-2k antigen. Genetic mapping studies suggested that the basis of this activity was an Ld-Kk serological cross-reaction. Cytotoxic T cells generated to Ld alloantigens were also found to recognize a cross-reacting Kk determinant. These studies therefore suggest that L, D, and K are three structurally homologous cell surface glycoproteins that have evolved from a common primordial gene.     

Variation of venous admixture,SF6 shunt,PaO2, and the PaO2/FIO2 ratio with FIO2

Background. Measures of impairment of oxygenation can be affectedby the inspired oxygen fraction. Methods. We used a mathematical model of an inhomogenous lungto predict the effect of increasing inspired oxygen concentration(FI_O2) on: (1) venous admixture (Q^·va/Q^·t); (2)arterial oxygen partial pressure (Pa_O2); (3) the Pa_O2/FI_O2 indexof hypoxaemia; and (4) sulphur hexafluoride (SF₆) retention(often taken to be true right-to-left shunt). This model predictswhether or not atelectasis will occur. Results. For lungs with regions of low V^·/Q^·,increasing the inspired oxygen concentration can cause theseregions to collapse. In the absence of atelectasis, the modelpredicts that Q^·va/Q^·t will decrease and arterialoxygen partial pressure increase as FI_O2 is increased. However,when atelectasis occurs, Q^·va/Q^·t rises to a constantvalue, whilst Pa_O2 falls at first, but then begins to rise again,with increasing FI_O2. The SF₆ retention increased markedly insome cases at high FI_O2. Conclusions. Venous admixture will estimate true right-to-leftshunt at high FI_O2, even when oxygen consumption is raised.This model can explain the way that the P_a/FI ratio changeswith increasing inspired oxygen concentration. Br J Anaesth 2002; 88: 771–8     

Intracompartmental pressure, PO2, PCO2 and blood flow in the human skeletal muscle

Measurement of PO2, PCO2, and blood flow in skeletal muscle could be a supplement to examination in clinical practice. Mass spectrometry was utilized to measure these parameters in the resting anterior tibial muscle of healthy adults. The partial pressures of oxygen and carbon dioxide were 21 +/- 3.6 and 46 +/- 2.5 Torr, respectively. The intracompartmental pressure was 8 +/- 1.1 Torr. The oxygen tension in muscle varied only slightly when arterial partial pressure was increased. The blood flow (tissue perfusion coefficient) estimated by washout of an inert gas was 5.4 +/- 0.8 ml/100 g/min. The results are in accordance with those from animal studies of skeletal muscle. The study demonstrates the feasibility of measuring PO2, PCO2, and blood flow in skeletal muscle by mass spectrometry.     

Cyclooxygenase-2, prostaglandin synthases,and prostaglandin H2 metabolism in traumatic brain injury in the rat

Inflammatory mediators are important in traumatic brain injury (TBI). The objective of the present study was to investigate the expression of cyclooxygenase-2 (COX-2), prostaglandin E (PGE) and PGD synthases, and PGH2 metabolism in two rat models of TBI. Fluid percussion injury (FPI) resulted in bilateral induction of COX-2 mRNA in the dentate gyri and the cortex, whereas controlled cortical contusion injury (CCC) induced COX-2 mRNA in the ipsilateral dentate gyrus and intensely in the cortex as judged by in situ hybridization. The induction subsided within 24 h. COX-2 immunoreactivity was detectable in these areas and persisted in the ipsilateral cortex for at least 72 h after CCC. Regions with COX-2 induction co-localized with TUNEL staining, suggesting a link between COX-2 expression and cell damage. COX-2 forms PGH2, which can be isomerized to PGD2, PGE2, and PGF2alpha by enzymatic and non-enzymatic mechanisms. In situ hybridization showed that mRNA of PGD synthase and microsomal PGE synthase were present in the choroid plexus. The microsomal PGE synthase was induced bilaterally after FPI and unilaterally after CCC. Liquid chromatography-mass spectrometry showed that low speed supernatant of normal and traumatized cortex and hippocampus transformed PGH2 to PGD2 as main product. PGD2 was dehydrated in brain homogenates to biological active compounds, for example, 15-deoxy-delta12,14-PGJ2. Thus COX-2 increases in certain neurons following TBI without neuronal induction of PGD and microsomal PGE synthases, suggesting that PGH2 may decompose to PGD2 and its dehydration products by nonenzymatic mechanisms or to PGD2 by low constitutive levels of PGD synthase.     

Expression of pS2, c-erbB-2, and cathepsin D during the menstrual cycle in human breast cancers

Background: Many studies have addressed the effect of the timing of surgery for breast cancer relative to menstrual cycle phase, with conflicting results. Explanations for the possibility that survival could be altered by the appropriate timing of breast cancer surgery in humans remain speculative. Methods: We examined the expression of three estrogen related proteins (c-erbB-2, cathepsin D, pS2) in the breast tumors from 69 premenopausal women sampled in different phases of the menstrual cycle. Data on S-phase fraction and hormone receptor expression were also analyzed. Immunohistochemical assays were used to measure the proteins of interest. S-phase fraction was determined by flow cytometry. Analyses were performed based on fraction of cells staining positive for the protein, density of stain, and a histoscore that combined both fraction of positive cells and density. Results: We found no differences in c-erbB-2, cathepsin D, hormone receptor, or S-phase levels in tumors sampled in the follicular versus luteal phase, or perimenstrual versus periovulatory phase. The exception was pS2, which was expressed at greater levels during the luteal than during the follicular phase of the cycle (p<0.01); but there was no difference in pS2 expression when the patients were classified as periovulatory versus perimenstrual. Conclusions: Our findings do not support a variation in c-erbB-2, cathepsin D, S-phase fraction, or receptor expression as an explanation for the differences in breast cancer prognosis when surgery is timed by menstrual cycle phase. The finding that pS2 (an indicator of hormone sensitivity, and possibly better prognosis) is expressed at higher levels in tumor samples during the luteal phase suggests that the biologic profile of breast tumors may vary with the menstrual cycle and that these variations deserve further study.