荧光原位杂交与免疫组织化学检测胃癌组织中HER-2基因及蛋白表达一致性

目的探讨荧光原位杂交(fluorescence in situ hybridization,FISH)与免疫组织化学(immunohistochemistry,IHC)检测胃癌组织中HER-2基因扩增及与C-erbB-2蛋白表达结果的一致性。方法采用FISH和IHC法分别检测50例胃癌组织中HER-2基因扩增和C-erbB-2蛋白表达,并采用SPSS 19.0进行统计学分析。结果 50例胃癌标本进行IHC检测结果 11例为(﹢),9例为(),4例为(),26例为(-);50例胃癌标本进行FISH检测结果 11例为(+),39例为(-);其中,FISH检测阳性标本中IHC检测有2例(﹢),5例(),4例()。IHC检测C-erbB-2蛋白为()的病例FISH检测均为(+),而IHC检测C-erbB-2蛋白()的9位患者中有4例经FISH检测证实HER-2呈(-),5例呈(+)。结论 IHC与FISH检测HER-2状态结果的符合率为95.1%(39/41),具有高度一致性(Kappa系数=0.773,P<0.001)。当IHC检测C-erbB-2蛋白表达为(-)或()时IHC和FISH检测结果有较高符合率,可作为临床是否应用Herceptin治疗的依据,而C-erbB-2蛋白表达为()的病例则必须进一步行HER-2基因扩增检测。     

新旧两版指南对浸润性乳腺癌HER-2基因扩增的判读影响

目的探讨2014版与2019版《乳腺癌HER-2检测指南》对浸润性乳腺癌HER-2基因扩增的判读影响。方法收集698例浸润性乳腺癌石蜡标本,采用免疫组化(immunohistochemistry, IHC)法和荧光原位杂交(fluorescence in situ hybridization, FISH)法对HER-2蛋白表达和基因扩增进行检测,并用2014和2019版指南分别对检测结果进行判读。结果根据2014版指南FISH判读法检测HER-2基因扩增的阳性检出率为40.7%(284/698),阴性检出率为52.1%(364/698),不确定为7.2%(50/698)。根据2019版指南FISH判读法检测HER-2基因扩增的阳性检出率为40.0%(279/698),阴性检出率为60.0%(419/698)。两版指南中IHC与FISH法检测HER-2蛋白表达与基因扩增的总一致率分别为54.7%、55.7%;两版检测结果具有一致性(Kappa=0.277,P0.001;Kappa=0.251,P0.001),且均呈正相关(r=0.608,P0.001;r=0.641,P0.001)。结论 2019版指南取消FISH法检测HER-2基因扩增的不确定结果,使其阴性率有所增加,更加明确了HER-2基因状态,为临床靶向治疗提供参考。     

进展期乳腺浸润性导管癌HER-2/neu蛋白表达的稳定性分析

目的探讨HER-2/neu蛋白在进展期乳腺浸润性导管癌原发灶和同期腋窝淋巴结转移灶中的表达,指导临床检测标本的选择以及检测报告的分析与应用。方法收集进展期乳腺浸润性导管癌标本100例制备全信息组织芯片,采用免疫组化法检测HER-2/neu蛋白表达,FISH法检测HER-2/neu基因扩增状态,分析其特点、稳定性及其相互关系。结果 69%病例HER-2/neu蛋白呈均质性表达,与同期腋窝淋巴结转移灶相比,原发灶蛋白均质阴性病例一致性最强,均质阳性病例次之,均质不确定病例最差;三者相比差异有统计学意义(P0.000 1)。36例HER-2/neu蛋白不确定和异质性病例的FISH检测显示20例为基因均质扩增,13例为基因均质非扩增,3例为基因异质性,其中31.65%的蛋白阴性位点HER-2/neu基因扩增。结论乳腺浸润性导管癌HER-2/neu蛋白表达在肿瘤原发灶和同期腋窝淋巴结转移灶之间稳定性较高,尤以阴性病例最稳定;免疫组化与FISH同步检测及对比分析可能为乳腺癌患者的治疗及预后提供更为精准的信息;应用全信息组织芯片更能全面检测HER-2/neu蛋白表达及基因状态,并可用于深入分析乳腺癌基因分型及其它相关指标在肿瘤进展中的变化。     

胃癌组织中HER-2基因扩增和K-ras基因突变的关系

目的探讨胃癌组织中HER-2蛋白表达和基因扩增与K-ras基因突变的关系及其意义。方法采用免疫组化、FISH和焦磷酸测序技术对67例胃癌组织中HER-2蛋白表达、HER-2基因扩增与K-ras基因的突变率进行了检测。结果 HER-2蛋白阳性率为40.3%(27/67),其中HER-2蛋白3+者9.0%(6/67),HER-2蛋白2+者13.4%(9/67),HER-2蛋白1+者17.9%(12/67)。FISH检测HER-2基因扩增率为18.5%(5/27),HER-2基因拷贝数增加和基因扩增者共48.1%(13/27)。K-ras基因突变定量检测为7.5%(5/67),均为K-ras基因第12密码子突变,其中低于10%低丰度突变2例,高于10%高丰度突变3例(突变数值分别为:17、29、30)。除1例为GGT→GAT突变型外,其它均为GGT→GTT突变型。本组K-ras基因突变5例中除1例既有K-ras基因突变,又有HER-2基因扩增,另外4例HER-2基因均无扩增。结论检测胃癌中HER-2扩增时选用抗肿瘤药物治疗的靶点曲妥珠单抗,同时可选用K-ras基因突变的抗肿瘤药物治疗的靶点西妥昔单抗;联合检测胃癌组织中HER-2基因扩增和K-ras基因突变为靶向抗肿瘤药物治疗过程中受益提供参考指标。     

胃癌单、双蜡块中HER-2的表达及其临床意义

目的探讨免疫组化双蜡块法检测胃癌中HER-2蛋白的实用性,分析HER-2过表达与胃癌临床病理特征的相关性。方法采用免疫组化法检测胃癌中HER-2表达,将2 500例胃癌标本分为两组:(1)单蜡块组956例标本使用1个组织蜡块,(2)双蜡块组中1 544例使用2个组织蜡块。在双蜡块组中,将HER-2评分较高者作为最终判读结果,并对两组数据相应的临床病理特征进行综合分析。结果单蜡块组:HER-2评分为0、1+、2+、3+的患者分别为582例(60.9%)、158例(16.5%)、122例(12.8%)、94例(9.8%);双蜡块组:HER-2评分为0、1+、2+、3+的患者分别为815例(52.8%)、377例(24.4%)、160例(10.4%)、192例(12.4%),其中有412例(26.7%)双蜡块出现不一致结果。双蜡块组检测胃癌HER-2阳性率(3+)高于单蜡块组。胃癌HER-2表达与肿瘤部位、组织学类型和分化程度相关(P0.05);与患者性别、年龄、肿瘤大小、浸润深度、淋巴结转移及远处转移等无明显相关(P0.05)。结论双蜡块法HER-2阳性率高于单蜡块法,免疫组化双蜡块法是一种更加高效、经济、实用的胃癌HER-2检测法。HER-2过表达与肿瘤部位、组织学类型和分化程度密切相关。     

食管鳞状细胞癌中HER-2基因扩增和蛋白表达

目的探讨食管鳞状细胞癌(esophageal squamous cell carcinoma,ESCC)中HER-2基因扩增和蛋白表达状况以及与临床病理指标的关系。方法收集96例ESCC组织,采用免疫组化法检测HER-2蛋白表达,采用FISH法检测HER-2基因扩增,并对患者进行随访。结果免疫组化结果显示3例HER-2呈3+,15例2+,11例1+,67例-,3+的病例中2例HER-2基因扩增,15例2+的病例中1例拷贝数6.0。HER-2蛋白过表达与基因扩增存在显著相关性(P0.000 1)。HER-2基因扩增/蛋白过表达与肿瘤组织无坏死(P=0.012)、低临床分期(P=0.040)存在一定相关性。HER-2基因扩增/蛋白过表达患者呈预后好的趋势,但差异无统计学意义(P0.05)。结论 HER-2在ESCC中有一定的基因扩增率和蛋白过表达率,两者具有相关性,且HER-2基因/蛋白过表达是潜在预后好的指标。     

208例内镜活检胃癌组织中HER-2蛋白的表达及意义

目的：分析内镜活检胃癌组织中HER-2蛋白的表达及意义。方法应用免疫组织化学( immunohistochemistry, IHC)法检测208例内镜活检胃癌组织中HER-2蛋白表达,采用荧光原位杂交( fluorescence in situ hybridization, FISH)技术检测IHC 2+胃镜活检组织中HER-2基因扩增,并对相应的临床病理特征(性别、年龄、肿瘤发生部位及Lauren分型)进行综合分析。结果208例内镜活检胃癌组织中HER-2 IHC 3+阳性率为7．7%(16/208),IHC 2+为13．5%(28/208),IHC 1+为45．7%(95/208),IHC 0为33．2%(69/208)。 IHC 2+的胃癌活检组织中 FISH 阳性率为14．2%(4/28)。 HER-2总体阳性率为9．6%；HER-2蛋白过表达与患者性别、年龄均无关( P>0．05),与发生部位及Lauren分型密切相关(P<0．05)。结论内镜活检胃癌组织中HER-2蛋白过表达与胃癌发生部位、Lauren分型密切相关。     

采用双蜡块检测胃癌中HER-2蛋白的表达

目的探讨双蜡块检测胃癌中HER-2蛋白的表达,分析该方法的实用性。方法收集259例胃癌手术标本,每个病例用2个蜡块检测HER-2蛋白表达,统计学分析双蜡块和单蜡块免疫表型的差异。结果所有病例1号蜡块中HER-2呈1+、2+和3+分别为64例(24.7%)、100例(38.6%)、29例(11.2%)。2号蜡块中HER-2呈1+、2+、和3+分别为54例(20.8%)、106例(40.9%)、38例(14.7%)。联合1号和2号蜡块,HER-2呈1+、2+和3+分别为45例(17.4%)、122例(47.1%)、40例(15.4%)。1号和2号蜡块检测结果不一致为75例,占29.0%。结论在胃癌手术切除标本中,用双蜡块检测HER-2蛋白表达,能提高HER-2的阳性率,减少肿瘤异质性造成的假阴性。     

结直肠癌组织中EGFR及HER-2的表达及临床意义

目的：探讨结直肠癌组织中表皮生长因子受体（ epiderma1 growth factor receptor,EGFR）和人类表皮生长因子受体-2（ hu-man epiderma1 receptor-2,HER-2）蛋白的表达,并分析二者与临床病理特征的关系。方法采用免疫组化PV-9000两步法检测78例结直肠癌组织中EGFR和HER-2的表达,分析二者表达与结直肠癌临床病理特征的关系;应用银染原位杂交（ si1ver in situ hybridization,SISH）法检测结直肠癌组织中HER-2基因扩增情况。结果 EGFR在结直肠癌组织中的阳性率为69.23%（54/78）,EGFR表达与结直肠癌浸润深度、淋巴结转移呈正相关,与患者性别、年龄、肿瘤大小、细胞分化程度、Dukes分期无关;HER-2在结直肠癌组织中的阳性率为25.64%（20/78）,HER-2表达与结直肠癌浸润深度、淋巴结转移呈正相关,与患者性别、年龄、肿瘤大小、细胞分化程度、Dukes分期无关。EGFR与HER-2蛋白表达呈正相关。20例HER-2蛋白阳性者中,10例HER-2基因扩增;其中15例HER-2蛋白（~）中有10例HER-2基因扩增,占高表达组的66.67%;5例HER-2蛋白（+）者无HER-2基因扩增。结论 EGFR和HER-2蛋白在结直肠癌中均呈高表达,EGFR和HER-2的表达与结直肠癌侵袭、转移密切相关,二者可能存在协同作用。HER-2蛋白（~）与HER-2基因扩增密切相关,故该类患者可考虑先行免疫组化初步筛选,再行SISH法检测确认,从而为结直肠癌分子的靶向治疗提供有价值的信息。     

HER-2基因及蛋白的检测在乳腺癌临床诊断中的价值

目的探讨用免疫组化（immunohistochemistry,IHC）和显色原位杂交技术（chromogenic in situ hybridization,CISH）检测乳腺癌HER-2蛋白表达和基因扩增在临床病理诊断及分子靶向治疗中的应用及意义。方法用免疫组化（IHC）和显色原位杂交技术（CISH）检测60例乳腺癌石蜡包埋组织标本中HER-2蛋白的表达及基因扩增情况,比较两种方法的结果以及与临床病理的关系。结果 HER-2蛋白过表达与HER-2基因扩增之间密切相关。结论两者综合结果的判定对乳腺癌患者的临床治疗有明确的指导意义,可用于临床赫塞汀（Herceptin）分子靶向治疗病例的筛选。     

Renal dysplasia and asplenia in two sibs

A family is reported in which two sibs, one male and the other female, both died within 24 hours of birth with enlarged polycystic kidneys. Postmortem histology in the second child showed gross renal dysplasia. In both children the pancreas was enlarged, nodular and cystic but the liver appeared macroscopically normal. In the second child, histological examination confirmed pancreatic fibrosis with cystic dilation of ducts, but showed portal fibrosis with bile duct proliferation in the liver.
This combination of findings is very reminiscent of those in a girl and her brother reported by Ivemark et al. (1959). The children reported here also showed absence or hypoplasia of the spleen, cardiac anomalies and other features of the Ivemark syndrome (Ivemark 1955), a quite different, usually sporadic, congenital disorder. It is suggested that the children described here have a distinct lethal congenital disorder, probably inherited in an autosomal recessive manner.     

Schizophrenia in a North Swedish geographical isolate, 1900–1977. Epidemiology, genetics and biochemistry

Over 200 schizophrenic patients belonging to three major and interrelated pedigree complexes have been investigated over the past 30 years in a North Swedish geographically isolated population, presently numbering about 6,000. An intensive investigation of a number of biochemical correlates and genetic markers in a few selected families belonging to one of the major pedigrees has indicated new strategies for the current research program.
Schizophrenia, as defined operationally, is significantly associated with decreased activities of two enzymes (1) blood platelet monoamine oxidase, (2) plasma dopamine-β-hydroxylase, and (3) with the genetic marker Gc² (group specific antigen). Both enzymes are subject to genetic variation. A positive score for linkage between schizophrenia and low plasma DBH activity has been calculated, but, so far, available data are insufficient for discrimination between linkage and partial contribution of genetically controlled low plasma DBH to the pathogenesis of the disease. Alternatively, both mechanisms could be involved.
As a model for continued research, schizophrenia is explained as based on a double dominant-recessive genotype (Aabb), representing a vulnerability which in about 50 % of cases develops into clinical schizophrenia. It is suggested that the dominant mutation (A) operates on or affects MAO activity, and that the recessive genotype (bb) is instrumental in low variates of DBH activity and very likely such variates within the normal range of physiological variation. Moreover, it is suggested that the combined effects of MAO- and DBH-reduced efficiency on the metabolism of e.g. dopamine could be an essential pathogenic mechanism for the schizophrenic illness which is segregating in this population.     

What will studies of Fulani individuals naturally exposed to malaria teach us about protective immunity to malaria?

There are an estimated over 200 million yearly cases of malaria worldwide. Despite concerted international effort to combat the disease, it still causes approximately half a million deaths every year, the majority of which are young children with Plasmodium falciparum infection in sub-Saharan Africa. Successes are largely attributed to malaria prevention strategies, such as insecticide-treated mosquito nets and indoor spraying, as well as improved access to existing treatments. One important hurdle to new approaches for the treatment and prevention of malaria is our limited understanding of the biology of Plasmodium infection and its complex interaction with the immune system of its human host. Therefore, the elimination of malaria in Africa not only relies on existing tools to reduce malaria burden, but also requires fundamental research to develop innovative approaches. Here, we summarize our discoveries from investigations of ethnic groups of West Africa who have different susceptibility to malaria.     

The universal muscular chain reaction,muscle spasm,Torsions, ruptures and extravasations. Chameleons of pathology and some manifestations of simple muscular disorders

Most bodily functions require the coordinated actions of complementary and supplementary paired muscle groups. Where this essential muscular cooperation is lacking, hollow organs may burst and others become literally screwed up, giving rise to many similar spastic diseases such as Torticollis, Twisted ovarian cyst, Torsion of the Testis, Volvulus of the intestines, Varicose Veins, Megacolon, Aortamegaly, Scoliosis, Erb's Palsy, Peyronie's Disease, Main-en-Griffe, Undescended Foot (Pes Cavus), Talipes, Strabismus. Spasm is “panenepidemic” and unclassified examples of Torsion Dystonia and Dyskinesia really are as common as debt and taxes.     

Class II HLA in Georgia Caucasus Tbilisi Georgians and their Mediterranean ancestry: The Usko Mediterranean languages

Georgia (or Sakartvelo in its own language) is a South Caucasus Mts. country with its easternmost part is enigmatically named Iberia, like the Iberian Peninsula, which may refer to rivers “Kura” and “Ebro” or their valleys respectively. Most of their inhabitants speak Georgian which is included within Dene-Caucasian group and Usko-Mediterranean subgroup of languages. The latter includes Basque, Berber, ancient Iberian-Tartessian, Etruscan, Hittite, Minoan Lineal A and others. In the present paper, HLA class II -DRB1 and -DQB1 alleles has been studied and extended haplotypes calculated. Most frequent haplotypes are also of Mediterranean origin (i. e.: (A*02-B*51)-DRB1*11:01-DQB1*03:01, (A*02-B*51)-DRB1*13:01-DQB1*06:03, or (A*24-B*35)-DRB1*01:01-DQB1*05:01) and DA genetic distances show that closest world populations to Georgians are Mediterraneans. Georgians also show common extended haplotypes ((A*02-B*51)-DRB1*11:01-DQB1*03:01, (A*02-B*13)-DRB1*07:01-DQB1*02:01 and (A*03-B*35)-DRB1*11:01-DQB1*03:01) with Svan people, a secluded population in North Georgia mountains. We can conclude that Georgians belong to a very old Mediterranean substratum according to both linguistics (Usko Mediterranean languages) and HLA genetics.     

Hypo- und Hypermagnesämie aus kardiologischer Sicht

Zusammenfassung Eine Reihe pathologischer Zustände bedingen Magnesiummangel. Zustände mit Hypermagnesämie sind ebenfalls bekannt, doch wesentlich seltener. Für den Kardiologen beachtenswert ist, daß unter Therapie mit bestimmten Diuretica bei Herzinsuffizienz, bei Herzinfarkt, Kardiomyopathie, Digitalisintoxikation und bestimmten Herzrhythmusstörungen Hypomagnesämie beobachtet wurde. Leider kann in der klinischen Routine nur ein extracelluläres Magnesiumdefizit durch Serumbestimmungen gemessen werden; über Magnesiummangel einzelner Organe kann nichts ausgesagt werden. Hinweise für Magnesiummangel geben aber neben der Messung des Serumspiegels Anamnese, klinischer Befund, bestimmte EKG-Veränderungen wie auch evtl. Hypokalämie, ein Zustand, bei dem sich oft — besonders bei Aldosteronismus — parallele Veränderungen zeigten.Tierexperimente deuten darauf hin, daß infarktähnliche Läsionen unter Magnesiummangel entstehen, doch ob Herzinfarkt beim Menschen durch Magnesiummangel ausgelöst werden kann, ist noch ungeklärt. In Leichenherzen zeigte sich im Infarktgebiet neben Calciumakkumulation signifikanter Magnesiumverlust, wobei unklar blieb, ob sich Ursache oder Folge des Infarktes widerspiegelten. Falls ein ursächlicher Zusammenhang besteht, ist er im Myokardstoffwechsel selbst zu suchen, wie bei der Alkoholkardiomyopathie, wo myokardialer Magnesiummangel zumindest als pathogenetischer Teilfaktor anerkannt wird. Andererseits versucht man aber auch Beziehungen zwischen Atherosklerose, Blutgerinnung und Hypomagnesämie herzustellen, in der Meinung, daß Magnesiummangel auch über den coronaren Pathomechanismus des Herzinfarktes wirken könnte. Sicher scheint, daß gewisse EKG-Veränderungen und Herzrhythmusstörungen durch einen irritierten Magnesiumhaushalt bedingt sein können, da sie bei Gabe bzw. Entzug von Magnesium verschwinden. Daß Magnesiummangel die Glykosidtoleranz verringert, wird tierexperimentell bestätigt. Unter Hypomagnesämie bewirkt Acetylstrophanthidin eher und länger Rhythmusstörungen als ohne, außerdem lassen diese sich durch Magnesiumgaben eliminieren. Da in gewissen Fällen spontane und digitalisinduzierte Herzrythmusstörungen durch Magnesiuminjektionen beseitigt wurden, scheint Magnesium als Therapeuticum angebracht. Einsatz verschiedener Magnesiumsalze bei Angina pectoris, degenerativen Herzerkrankungen und Herzinsuffizienz ohne geprüften und offensichtlich gestörten Magnesiumhaushalt ist fragwürdig, weil keine eindeutigen klinischen Erfolgsbeweise vorliegen. Immerhin mag es aber larvierte, durch Serumbestimmungen nicht erfaßbare Mangelzustände geben. Allgemein erscheint es aus kardiologischer Sicht ratsam, den Magnesiumhaushalt zu überwachen und in entsprechenden Fällen auszugleichen, um möglichen Myokardläsionen oder fatalen Herzrhythmusstörungen entgegenzuwirken.     

HLA in North Colombia Chimila Amerindians

HLA-A,-B,-C,-DRB1 and -DQB1 alleles have been studied in Chimila Amerindians from Sabana de San Angel (North Colombian Coast) by using high resolution molecular typing. A frequent extended haplotype was found:HLA-A*24:02-B*51:10-C*15:02-BRB1*04:07-DQB1*03:02 (28.7%) which has also been described in Amerinndian Mayos Mexican population (Mexico, California Gulf, Pacific Ocean). Other haplotypes had already been found in Amerindians from Mexico (Pacific and Atlantic Coast), Peru (highlands and Amazon Basin), Bolivia and North USA. A geographic pattern according to HLA allele or haplotype frequencies is lacking in Amerindians, as already known. Also, five new extended haplotypes were found in Chimila Amerindians. Their HLA-A*24:02 high frequencies characteristic is shared with aboriginal populations of Taiwan; also, HLA-C*01:02 high frequencies are found in New Zealand Maoris, New Caledonians and Kimberly Aborigines from Australia. Finally, this study may show a model of evolutionary factors acting and rising one HLA allele frequency (-A*24:02), but not in others that belong to the same or different HLA loci.     

Environmental risk factors and their role in the management of atopic dermatitis

Introduction: The etiology of atopic dermatitis (AD) is multifactorial with interaction between genetics, immune and environmental factors.

Areas covered: We review the role of prenatal exposures, irritants and pruritogens, pathogens, climate factors, including temperature, humidity, ultraviolet radiation, outdoor and indoor air pollutants, tobacco smoke exposure, water hardness, urban vs. rural living, diet, breastfeeding, probiotics and prebiotics on AD.

Expert commentary: The increased global prevalence of AD cannot be attributed to genetics alone, suggesting that evolving environmental exposures may trigger and/or flare disease in predisposed individuals. There is a complex interplay between different environmental factors, including individual use of personal care products and exposure to climate, pollution, food and other exogenous factors. Understanding these complex risk factors is crucial to developing targeted interventions to prevent the disease in millions. Moreover, patients require counseling on optimal regimens for minimization of exposure to irritants and pruritogens and other harmful exposures.     

Functional role of fertility α2

Fertility α₂-microglobulin is one of the main proteins expressed between the late lutein phase of the menstrual cycle and the first gestation trimester. It is produced by endometrial secretory glandular epithelium and decidual membrane. It is believed to be involved in the preparation to gestation, conception, normal development of the fetoplacental system, and initiation of labor. The immunomodulating, effect of fertility α₂-microglobulin and its possible involvement in the regulation of fertilization by blocking the spermatozoon reaction with the ovocyte lucid membrane were demonstratedin vitro. The data of structural analysis (appurtenance to lipocalines and unique pattern of N-glycosylation) and analysis of the spatial and temporal parameters of the expression in connection with other events in the organism within the same system of coordinates propated us to investigate the probability of realization of other, so far unknown functions of α₂-microglobulin. The probable mechanisms of realization of the immunomodulating function are analyzed. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 126, No. 10, pp. 364–373, October 1998