肿瘤微环境中免疫细胞与肿瘤逃逸

肿瘤微环境是肿瘤细胞赖以生存和发展的内环境,肿瘤免疫逃逸机制与肿瘤微环境密切相关。文章综述了肿瘤微环境中的免疫细胞,如调节性T细胞、骨髓来源的抑制性细胞、选择性活化的巨噬细胞及功能受损的树突状细胞对肿瘤免疫逃逸的作用,以及如何逆转这种肿瘤微环境的免疫治疗策略。     

干扰素介导肿瘤免疫分子机制的研究进展

干扰素(IFNs)是一类具有多种生物活性的细胞因子,在肿瘤微环境中调节细胞免疫和体液免疫,发挥重要的抗病毒和抗肿瘤免疫作用.免疫治疗已成为肿瘤手术治疗及放化疗之后的重要治疗方式,但在某些肿瘤中,免疫治疗的作用效果甚微,其原因可能是耐药及免疫逃逸,因此探究肿瘤免疫逃逸的具体机制意义重大.     

PD-L1 在恶性肿瘤中的表达及研究进展

正癌症严重威胁着人类的健康,已是一个非常重要的世界性公共健康问题。随着科学的进步、肿瘤相关学科的发展,肿瘤免疫研究得到了爆炸式的发展,肿瘤的免疫治疗备受广泛学者的关注,认为免疫逃逸是肿瘤发生、发展的重要机制之,其机制可分为源于肿瘤细胞自身的逃逸机制和源于肿瘤微环境中免疫细胞的逃逸机制,T细胞在免疫逃逸中起着重要的作用~([1])。越来越多的学者用免疫检查点来解     

髓系来源抑制性细胞在肿瘤免疫和肿瘤免疫治疗中作用的研究进展

髓系来源抑制性细胞（MDSCs）是由多种具有抑制功能的细胞构成的群体,是肿瘤免疫逃逸的关键因素.一方面,MDSCs主要通过抑制宿主固有免疫及适应性免疫减弱对肿瘤的免疫监视,促进肿瘤血管形成,参与肿瘤免疫逃逸.另一方面,肿瘤细胞又分泌多种细胞因子诱导MDSCs产生及活化,形成恶性循环.基于MDSCs进行相关靶向治疗,将有助于减弱MDSCs对宿主肿瘤微环境的抑制作用,可能为肿瘤的免疫治疗提供新思路和策略.     

光动力疗法治疗肿瘤的免疫机制研究进展

光动力疗法(photodynamic therapy,PDT)是治疗肿瘤的有效手段之一,PDT治疗可导致肿瘤细胞的死亡和凋亡,并损伤肿瘤相关血管.近年来,PDT的免疫机制越来越受到关注.肿瘤细胞的免疫逃逸是肿瘤发生发展的重要因素.PDT治疗肿瘤时,可通过免疫原性细胞死亡(immunogenic cell death,ICD)诱导肿瘤细胞表达损伤相关分子模式(damage associated molecular patterns,DAMPs),从而活化树突状细胞,诱导机体特异性抗肿瘤免疫.同时,PDT还可影响肿瘤微环境中的相关免疫细胞和因子,进而增强机体抗肿瘤反应.光动力治疗和其他免疫治疗联合应用亦能增强疗效.故光动力治疗的免疫机制研究将为肿瘤治疗提供可能的新思路.     

CRISPR/Cas9基因编辑技术及其在肿瘤免疫治疗中的应用

正肿瘤的治疗依旧是医学上的难题,由于其发生发展复杂,往往伴随着免疫逃逸和免疫抑制性肿瘤微环境的形成,且肿瘤细胞易于扩散和迁移~([1])。因此,阻止肿瘤细胞的免疫逃逸是一项重要的治疗途径。肿瘤免疫治疗是指通过增强特异性免疫细胞对肿瘤的防御能力,并阻遏其他调节性免疫细胞对肿瘤的保护作用~([2]),从免疫防御的角度来控制肿瘤细胞     

髓源性抑制细胞与肿瘤

髓源性抑制细胞(myeloid-derived suppressor cells,MDSCs)是一类具有显著免疫抑制活性的异质细胞群,其通过抑制效应T细胞功能从而介导肿瘤免疫逃逸,促进肿瘤生长.该文就MDSCs在肿瘤免疫逃逸中的作用机制、肿瘤微环境中的各种细胞因子对MDSCs的影响及各种免疫活性细胞与MDSCs间的相互作用作一综述.     

LAG-3的生物学特点及其在肿瘤免疫中的研究进展

免疫治疗已成为肿瘤治疗的主要方式之一。CTLA-4和PD-1在肿瘤免疫逃逸中起关键作用,然而PD-1和CTLA-4的低反应率是目前肿瘤免疫治疗面临的主要挑战。新一代抑制性免疫检查点淋巴细胞活化基因3(lymphocyte activation gene 3, LAG-3)在人体免疫系统中发挥重要的调节作用。LAG-3在各种类型的TIL上高表达,通过多种机制介导肿瘤免疫逃逸。LAG-3还可以和PD-1在TIL中共表达,联合阻断LAG-3和PD-1对抑制免疫逃逸、增加抗肿瘤反应、增强T细胞增殖具有协同作用,已成为改善当前肿瘤免疫治疗缺陷最有希望的免疫疗法之一。因此,深入了解LAG-3的生物学特点并进一步探究其作用机制具有重要意义。该文就LAG-3的结构、功能及其在肿瘤免疫中的研究进展进行综述。     

肿瘤干细胞免疫逃逸机制的研究进展

肿瘤干细胞是肿瘤发生、发展、转移及复发的根源。虽然机体有严密的免疫监视机制,但肿瘤干细胞可以通过改变表面抗原、表达免疫逃逸相关基因及逃逸相关的表面标志物,或诱导具有免疫抑制能力的细胞或细胞因子的分泌等多种机制有效地逃避免疫系统的监视。此外,肿瘤干细胞免疫逃逸与其微环境中的各种间质细胞和细胞外因子的作用也密切相关。这些机制的研究有助于加深对肿瘤干细胞的认识,为肿瘤的预防和治疗提供新的理论指导。     

基于自然杀伤(NK)细胞的肿瘤免疫治疗研究新进展

针对程序性死亡蛋白1/程序性死亡蛋白1配体1(PD-1/PD-L1)和细胞毒性T淋巴细胞相关蛋白4(CTLA4)等免疫检查点分子的抑制剂在肿瘤临床治疗中的成功应用，开辟了肿瘤免疫治疗的全新领域。近年来，如何维持肿瘤微环境中的免疫细胞活性始终是肿瘤免疫治疗领域热点问题。随着研究的深入，自然杀伤(NK)细胞在肿瘤免疫治疗中的作用正在被逐步阐明。NK细胞在固有免疫应答和适应性免疫应答中都发挥关键作用，具有多种细胞毒作用机制，并能够通过产生细胞因子调节免疫反应。NK细胞作为肿瘤微环境中重要的效应细胞之一，其活化、增殖和杀伤效应依赖于多种受体间活化与抑制信号的协调与平衡，不受主要组织相容性复合体(MHC)表达限制，是T细胞肿瘤免疫治疗策略的重要补充手段。我们着重总结了基于NK细胞的肿瘤免疫治疗策略，并讨论了NK细胞免疫卡控分子作为新的肿瘤免疫治疗靶点的可能性。     

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.     

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.     

The dominant diseases of modernized societies as omega-3 essential fatty acid deficiency syndrome: Substrate beriberi

About 1900, modern food selection and processing caused widespread $\text{epidemics}$ of the B vitamin deficiency diseases of beriberi and pellagra which, for genetic reasons, often expressed as different diseases ranging from bowel and heart disease to dermatoses and psychoses. But the B vitamins merely help convert essential fatty acids (EFA) into the prostaglandin (PG) tissue regulators and it now turns out that, through hydrogenation, milling and selection of w3-poor southern foods, we have also been systematically depleting, by as much as 90%, a newly discovered trace Nordic EFA (w3) of special importance to primates and sole precursor of the PG3(4) series, even as a concurrent fiber deficiency increases body demand for EFA. Since substrate EFA is processed by many B vitamin catalysts, an EFA deficiency will mimic a $\text{panh}$ypovitaminosis B, i.e., a mixture of $\text{substrate}$ beriberi and $\text{substrate}$ pellagra resembling vitamin beriberi and pellagra but exhibiting as even more diverse $\text{endemic}$ disease. This would consitute a second stage of the Modern Malnutrition and explain why some workers now hold the dominant diseases of modermized societies to be new, nutritionally based, pellagraform yet lipid-related and to range, once again, from heart disease to psychosis. It is an assumption that our dominant diseases are unrelated to each other or are merely revealed by our diagnostic acumen and therapeutic success; and that hydrogenating millions of tons of food oils annually, to destroy the rancidity producing w3-EFA, is safe for $\text{primates}$. Extensive beriberiform disease is reported here in 32 typical cases taken from medical practice which responds strikingly to linseed oil supplements (60% w3-EFA) in confirmation of identical results in Capuchins.     

'Very sore nights and days': the child's experience of illness in early modern England, c.1580-1720

Sick children were ubiquitous in early modern England, and yet they have received very little attention from historians. Taking the elusive perspective of the child, this article explores the physical, emotional, and spiritual experience of illness in England between approximately 1580 and 1720. What was it like being ill and suffering pain? How did the young respond emotionally to the anticipation of death? It is argued that children’s experiences were characterised by profound ambivalence: illness could be terrifying and distressing, but also a source of emotional and spiritual fulfilment and joy. This interpretation challenges the common assumption amongst medical historians that the experiences of early modern patients were utterly miserable. It also sheds light on children’s emotional feelings for their parents, a subject often overlooked in the historiography of childhood. The primary sources used in this article include diaries, autobiographies, letters, the biographies of pious children, printed possession cases, doctors’ casebooks, and theological treatises concerning the afterlife.     

Guidelines for the Validation and Use of Immunoassays for Determination of Introduced Proteins in Biotechnology Enhanced Crops and Derived Food Ingredients

Recent advancements in agricultural biotechnology have created a need for analytical techniques to determine introduced proteins in crops enhanced through modern biotechnology techniques. These proteins are expressed in plant tissues and may be present in food ingredients. Immunoassays are ideally suited for protein detection and may be used as both quantitative and threshold methods. Microplate ELISA and lateral flow devices are two of the most commonly used immunoassay formats for agricultural biotechnology applications. This paper provides general background information and a discussion of criteria for the validation and application of immunochemical methods to the analysis of proteins introduced into plants and food ingredients using biotechnology methods. It is the result of a collaborative effort of members of the Analytical Environmental Immunochemical Consortium. This collaborative effort represents the combined expertise of several organizations to reach consensus on establishing guidelines for the validation and use of immunoassays. Further, the paper offers developers and users a consistent approach to adopting the technology as well as aid in producing accurate and meaningful results.     

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.     

Ultracryotomy: development and application (with examples from the yeast cytology) (author's transl)

The preparation steps usually necessary for obtaining ultrathin frozen sections of biological material (chemical prefixation, enclosing, cryoprotective treatment, freezing, sectioning, and post-staining the sections for transmission electron microscopy) are submitted to a critical analysis. The application of cryo-ultramicrotomy, in particularly for cytochemical purposes, is reviewed. Fundamental considerations of chemical prefixation and poststaining are supported by examples from yeast cytology. Furthermore, the efficiency of the cryo-ultramicrotomy (electron optical resolution of ultrastructural details) is demonstrated on yeast cells and protoplasts.     

The universal muscular chamber. A basic unit of the genitourinary, cardiovascular, gastro-intestinal, skeletal, cutaneous, respiratory and other systems, endocameral hypertension; and spasm, the key to their idiopathic diseases and arthropathies

Starting with the integument, we see many organs are contractile sacs or multiples thereof, which tubes or bags constitute the major part of the entire body. Recognition of this basic unit and its characteristics sheds new light, individually and collectively, on many disorders previously considered unrelated. Muscular tears and perforations develop in the walls of these chambers, being no way peculiar to those organs, wherein, hydrochloric acid occurs. So, it is not necessary to explain the absence of excessive acid from patients who exhibit holes in the gastric, uterine, aortic, duodenal, rectal, pulmonary, retina, and other walls. Muscle, not acid is the great common factor relating idiopathic disorders in the gastrointestinal tract to each other and to similar diseases in other systems. When the units are linked together, the lesions tend to appear as arthropathies, i.e. at the joints. Rephrasing common-place observations, frees us from conventional, conceptual cul-de-sacs. An observation is only as good as its interpretation, so all possibilities must be considered, otherwise, we will remain blinded by our misconceptions.     

Der Einfluß von Nahrungsmitteln und Rauchen auf die klinisch-chemische Diagnostik von Phäochromozytom,Neuroblastom und Karzinoid-Syndrom

Zusammenfassung Der Einfluß von verschiedenen Nahrungsmitteln auf Methoden zur Bestimmung von Adrenalin (AD), Noradrenalin (NA), Vanillinmandelsäure (VMS), Metanephrinen (MN), Homovanillinsäure (HVS) und 5-Hydroxyindolessigsäure (5-HIE) im 24 h-Harn zur Diagnose des Phäochromozytoms bzw. Karzinoid-Syndroms wurde untersucht. Die in die Untersuchung einbezogenen Nahrungsmittel waren: Tee, Kaffee, Mandeln, Ananas, Käse, Walnüsse, Vanillepudding, Bananen, Tomaten und Milchschokolade. Außerdem wurde der Einfluß des Zigarettenrauchens auf die Bestimmung von AD, NA, VMS und MN untersucht.Walnüsse führten zu einer starken Erhöhung der 5-HIE-Ausscheidung. Bananen erhöhten die Ausscheidung von AD, NA, VMS, MN und 5-HIE. Kaffee und Ananas bewirkten eine geringe Zunahme der MN-Werte. Rauchen von 20–30 Zigaretten/Tag beeinflußte keine der vier Variablen.Wenn die beschriebenen Methoden benutzt werden, sollte lediglich auf den Verzehr von Bananen und Walnüssen vor und während der Harnsammelperioden verzichtet werden, da die oberen Normgrenzen im Harn überschritten werden könnten. Ein Verzicht auf Kaffee und Ananas in normalen Mengen ist nicht erforderlich. Es besteht kein Anlaß, weiterhin die bisherigen umfangreichen Restriktionen der übrigen Nahrungsmittel beizubehalten.