Rudolf G. Wagner

Beta2-microglobulin mutations in microsatellite unstable colorectal tumors

Defects of DNA mismatch repair (MMR) cause the high level microsatellite instability (MSI‐H) phenotype. MSI‐H cancers may develop either sporadically or in the context of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome that is caused by germline mutations of MMR genes. In colorectal cancer (CRC), MSI‐H is characterized by a dense lymphocytic infiltration, reflecting a high immunogenicity of these cancers. As a consequence of immunoselection, MSI‐H CRCs frequently display a loss of human leukocyte antigen (HLA) class I antigen presentation caused by mutations of the β2‐microglobulin (β2m) gene. To examine the implications of β2m mutations during MSI‐H colorectal tumor development, we analyzed the prevalence of β2m mutations in MSI‐H colorectal adenomas (n = 38) and carcinomas (n = 104) of different stages. Mutations were observed in 6/38 (15.8%) MSI‐H adenomas and 29/104 (27.9%) MSI‐H CRCs. A higher frequency of β2m mutations was observed in MSI‐H CRC patients with germline mutations of MMR genes MLH1 or MSH2 (36.4%) compared with patients without germline mutations (15.4%). The high frequency of β2m mutations in HNPCC‐associated MSI‐H CRCs is in line with the hypothesis that immunoselection may be particularly pronounced in HNPCC patients with inherited predisposition to develop MSI‐H cancers. β2m mutations were positively related to stage in tumors without distant metastases (UICC I‐III), suggesting that loss of β2m expression may promote local progression of colorectal MSI‐H tumors. However, no β2m mutations were observed in metastasized CRCs (UICC stage IV, p = 0.04). These results suggest that functional β2m may be necessary for distant metastasis formation in CRC patients.

Lack of HLA class II antigen expression in microsatellite unstable colorectal carcinomas is caused by mutations in HLA class II regulatory genes

Colorectal cancers (CRCs) develop on the basis of a deficient DNA mismatch repair (MMR) system in about 15% of cases. MMR‐deficient CRC lesions show high‐level microsatellite instability (MSI‐H) and accumulate numerous mutations located at coding microsatellite loci that lead to the generation of immunogenic neopeptides. Consequently, the hosts antitumoral immune response is of high importance for the course of the disease in MSI‐H CRC patients. Accordingly, immune evasion mediated by impairment of HLA class I antigen presentation is frequently observed in these cancers. In this study, we aimed at a systematic analysis of alterations affecting HLA class II antigen expression in MSI‐H CRC. HLA class II antigens are expressed by only two‐thirds of MSI‐H CRCs. The mechanisms underlying the lack of HLA class II antigens in a subset of MSI‐H CRCs remain unknown. We here screened HLA class II regulatory genes for the presence of coding microsatellites and identified mutations of the essential regulator genes RFX5 in 9 (26.9%) out of 34 and CIITA in 1 (2.9%) out of 34 MSI‐H CRCs. RFX5 mutations were related to lack of or faint HLA class II antigen expression (p = 0.006, Fishers exact test). Transfection with wild‐type RFX5 was sufficient to restore interferon gamma‐inducible HLA class II antigen expression in the RFX5‐mutant cell line HDC108. We conclude that somatic mutations of the RFX5 gene represent a novel mechanism of loss of HLA class II antigen expression in tumor cells, potentially contributing to immune evasion in MSI‐H CRCs.

The Role of the Foreign Community in the Chinese Public Sphere

The last years have seen lively international sinological and domestic Chinese debates oDn the structure and development of the Chinese public sphere. The international discussion has been largely analytical in orientation, prompted by developments in late Qing social history research and the new availability in English and French of Habermass seminal study. The Chinese discussion has been more strategic, suggesting or legitimizing paths for Chinas further development: PRC government-directed research in the context of the Seventh Five-Year Plan focused on those aspects in the development experiences of cities like Shanghai which might be of use for the citys further development, especially regarding its relationship with the developed world. Independent critics writing outside the PRC felt prompted to join the discussion about the Chinese public sphere by the growing conflict between a society in the process of rapid diversification and development on the one hand and a political leadership rigidly maintaining the ideal of the peoples uniformity in thought and attitude on the other. These differences notwithstanding, the international and domestic branches of the discussion share, for different reasons, an endogenous perspective explaining modern developments from the internal dynamics of Chinese society rather than from the impact from or the response to the West. The international sinological discussion has searched for elements of a self-assertive Chinese public sphere in traditional areas such as guilds, associations or landsmannschaften , in the new private social welfare institutions set up by reconstruction activists after the Taiping rebellion, in the late Qing qingyi discussions within the bureaucracy, or in more modern areas such as labour unions or chambers of commerce.

Signet ring stomach cancer: Morphological characterization and antigenic profile of a newly established cell line (Mz-Sto-1)

A human gastric signet ring cancer cell line (Mz-Sto-1) was established in tissue culture from the ascites fluid of a 54-year-old patient. The tumor cells growing in tissue culture exhibit the morphological characteristics of signet ring cells in phase contrast and transmission electron microscopy. Mz-Sto-1 cells grow as monolayer with a population doubling time of 28-36 hr during exponential growth phase and show a chromosome number between 72 and 74. In the cellular DNA of Mz-Sto-1 cells no amplification of 19 oncogenes studied is observed, c-myc included. Mz-Sto-1 cells secrete 150-250 ng CEA per 10(7) cell in 3 days, but no AFP. In addition Mz-Sto-1 cells and 2 already established gastric cancer cell lines MKN-28 and MKN-45 express HLA- and blood group related antigens (A, Lewis). HLA-DR antigens, which are regularly detected on normal stomach epithelium, are not found on any of the 3 cultured gastric cell lines. Mz-Sto-1 cells represent the first human gastric cancer cell characterized ultrastructurally as signet ring cells. This line will be a valuable tool to study the biology and genetics of gastric carcinoma, to test cytostatic drugs and to define new antigenic markers for stomach cancer.

Colonic carcinogenesis along different genetic routes: glycophenotyping of tumor cases separated by microsatellite instability/stability

Different genetic routes account for colonic carcinogenesis. However, when analyzing colon cancer specimens, separation into different groups based on genetic alterations is commonly not performed. Thus, we here initiate the comparative phenotyping considering microsatellite instability/stability for clinical specimens. The focus is given to glycan epitopes, expression of which is known to be modulated by signal-transducing proteins that act as key regulators of normal colon epithelial growth and differentiation. In addition to six plant lectins used as sensors, the presence of two adhesion/growth-regulatory galectins is studied. Overall, a considerable level of intra- and interindividual heterogeneity is revealed. Alterations in the proportion of stained cells between tumor-adjacent and malignant epithelia concerned plant lectins, which bind substituted N-glycan cores, α2,6-sialylated branch ends, core 1 O-glycans and N-acetylgalactosamine. A tendency for changes was noted between microsatellite-unstable and microsatellite-stable cases for core substitution (bisected N-glycan, presence of β1,6-branching) and status of α2,6-sialylation. Statistical significance was reached for presence of galectin-3, found to be elevated in microsatellite-stable compared to microsatellite-unstable tumors. These results emphasize the potential of distinct signaling pathways to regulate certain aspects of the glycophenotype in vivo and thus delineate a perspective to discern functionally relevant deviations in expression of endogenous lectins and their counter-receptors.

The Early Chinese Newspapers and the Chinese Public Sphere

The European Community and many of its member states have incorporated the goal of promoting the development of ‘civil society’ in China into their China policy guidelines.1 By this they mean supporting more vigorous and independent articulation and organisation of society in an environment where the Party, and the State under its control, claim a monopoly by right in both fields, and have set up powerful machinery to secure this monopoly. The guidelines contain the implicit and certainly not uncontested claim that foreign nations have a stake in the development of such articulation and organisation, and that they consider this to be beneficial to the stability and predictability of this big country, both domestically and in the international environment. In terms of helping towards independent articulation. Some of these nations, such as the UK, France and Germany, have already been taking practical steps for many years by supporting radio and TV stations broadcasting in Chinese into China. These broadcasts are in no way restricted to news about these foreign countries, but often include news about China that is unavailable from official sources inside China, or opinions by Chinese living in China itself or abroad who do not find an avenue of articulation through the official media. In their day-to-day practice, these stations function as a part of the Chinese public sphere, and are recognised as such by the Chinese authorities, albeit generally as illegitimate imperialistic intrusions into the sacred Chinese national space/public sphere. In normal times, selected portions of programmes from these foreign stations might be rebroadcast by official stations in China, and, in times of crisis, as in May and June 1989, these stations (and others such as the Voice of America) might be the only ones to provide any detailed information about developments on the ground in China. When the

Can We Speak of East/West Ways of Knowing?

C an we speak of distinct Eastern andWestern ways of knowing? Or of more or less undifferentiated East/West ways of knowing? Or of East/West ways of knowing of which we can speak, as opposed to North/South ways of knowing, of which we cannot really speak? All three propositions exist in the real world. As the essentialization of East andWest implied in thefirst proposition leads to a predictable faith-based outcome that is not really attractive, and as I have never worked on North-South transcultural interaction say, between Eurasia and Africa, allow me to deal with the second. There can be no question that since time immemorial, knowledge has traveled as something consciously adopted across Eurasia, whether this refers to domesticated plants and animals and the techniques of their handling, to leisure pursuits, to the idea of writing, to features of governance, or to ways to secure the functionality of the body, the mind, or the surrounding life-world. Below this conscious level of interaction, the hidden forces of nature do their own interaction, which one might call trans-natural, be it in the domain of genes, of diseases

Chinese Encyclopaedias of new global knowledge (1870 - 1930)

In this paper, I will explore the process by which news and newspaper articles became a recognised source for Chinese encyclopaedic works of new knowledge in the late nineteenth century. At first sight, the assumption itself seems self-contradictory: we commonly think of newspapers and encyclopaedias as serving different purposes, as being manufactured under different premises, and as produced by different social actors. While we assume that journalists produce quick ephemeral news to be sold on a daily basis, encyclopaedists produce standardised and sustainable summaries of up-to-date learning. In times of rapid change, these might even serve as introductory reference works for a new order of knowledge or a new educational system. Again, while publishers of newspapers or encyclopaedias pursue similar goals—marketing information for the purpose of educating the common people—their understanding of how to achieve this differs fundamentally. In order to provide the latest information, but also to overcome the numbing reiteration of certain standardized statements, newspapers produce and disseminate new knowledge daily. Encyclopaedists, however, seem to aim for the exact opposite, namely to standardise the most recent knowledge and turn it into a canon authorised by either secular or religious authorities.

The Formation of Encyclopaedic Commonplaces During the Late Qing: Entries on the Newspaper

This paper proposes to do two things: sketch out the development of a stock of shared information and judgment on a given topic—“the newspaper”—through the various late Qing encyclopaedias; and sketch out the actual use of late Qing encyclopaedias as an information base for the new form of examinations that came with the “Reform of Governance,” Xinzheng 新政, beginning in 1901. In the Chinese entries the term bao 報 refers to a periodical publication. The word “newspaper” will here be used as shorthand for “periodical publication.”

Chinese Encyclopaedias of New Global Knowledge (1870–1930): Changing Ways of Thought

Many aspects of the rapidly evolving engagement between China and the West during the nineteenth and early twentieth centuries have been well enough explored to have entered schoolbook knowledge. These include war, trade, diplomacy, and missionary endeavors. The present volume explores what went on in Chinese minds during this turbulent process. It does so through a series of case studies on the Chinese adaptation of the increasingly globalized canon of modern knowledge and the shifts in the equally globalized software through which this process was articulated: in the taxonomy of knowledge, the hierarchy of relevance and usefulness, the standards for the reliability of information, and the tools to enhance the terminological precision of language. The footprints of these articulations are best visible in Chinese encyclopaedic works of what was called “new” or “Western” knowledge. They were published between the 1880s and the 1930s and were produced against the background of and in a critical debate with a well-established, traditional encyclopaedia culture. While present at the time in great diversity and in large print runs, the shelf life of these new works was short because they were quickly superseded by ever-newer works. These works have neither been reprinted, nor studied in any detail.