Gastric cancer: basic aspects

Gastric cancer (GC) is a world health burden, ranging as the second cause of cancer death worldwide. Etiologically, GC arises not only from the combined effects of environmental factors and susceptible genetic variants but also from the accumulation of genetic and epigenetic alterations. In the last years, molecular oncobiology studies brought to light a number of genes that are implicated in gastric carcinogenesis. This review is intended to focus on the recently described basic aspects that play key roles in the process of gastric carcinogenesis. Genetic variants of the genes IL-10, IL-17, MUC1, MUC6, DNMT3B, SMAD4, and SERPINE1 have been reported to modify the risk of developing GC. Several genes have been newly associated with gastric carcinogenesis, both through oncogenic activation (GSK3β, CD133, DSC2, P-Cadherin, CDH17, CD168, CD44, metalloproteinases MMP7 and MMP11, and a subset of miRNAs) and through tumor suppressor gene inactivation mechanisms (TFF1, PDX1, BCL2L10, XRCC, psiTPTE-HERV, HAI-2, GRIK2, and RUNX3). It also addressed the role of the inflammatory mediator cyclooxygenase-2 (COX-2) in the process of gastric carcinogenesis and its importance as a potential molecular target for therapy.     

Review: Gastric cancer: Basic aspects

Gastric cancer is still one of the most prevalent and deadliest cancers in the world. Although our knowledge about the disease has progressed extraordinarily, this has not been accompanied by our capacity to effectively treat the disease. In the last years, immunotherapy made its way into the cancer field and was responsible for major changes in the treatment success rates for several cancer types. Although gastric cancer was not among the first successful targets of this type of therapy, the relationship between this type of cancer, immunosurveillance and immunotherapy is now being actively researched. In this article, we review the literature of the past year regarding the relationship between gastric cancer, its immune microenvironment and response to immunotherapy. Published data indicate that the immune microenvironment influences the clinical behaviour of gastric cancer, and is correlated with its histologic and molecular subtypes with an emphasis on the microsatellite‐ and EBV‐positive tumour subgroups. Although the literature regarding response to immunotherapy is scarce, there is good evidence that patient stratification for immunotherapy is going to become a reality in gastric cancer.     

Gastric cancer: clinical aspects, epidemiology and molecular background

The validity and usefulness of the 7th edition of the UICC tumor node metastasis classification in the context of clinical management of gastric cancer are discussed. The most relevant new agent in gastric cancer therapy is trastuzumab for HER2-positive gastric carcinomas. This marks the success of continuous effort of translational research. Trastuzumab, initially applied in palliative settings, is currently being evaluated also in neoadjuvant treatment regimens. Several new meta-analyses support the carcinogenic effect of high salt intake and smoking in the context of Helicobacter pylori infection. Further data have become available on the efficacy of protective agents, acetyl salicylic acid/nonsteroidal anti-inflammatory drugs, and antioxidants. In search for a successful prevention strategy, the focus is on the identification of individuals at high risk who demand screening (testing) and surveillance. Serological assessment of gastric mucosal abnormalities with increased risk for gastric cancer development is extensively studied, and new data are presented from Asia as well as from Europe. New high-throughput techniques combined with bioinformatic vector analysis open the gate to the identification of new potential diagnostic and therapeutic targets. Furthermore, these approaches allow us to elucidate the interplay of bacterial virulence factors and the host's immune response as well as H. pylori-associated alterations of mucosal gene expression.     

Review: Gastric malignancies: Basic aspects

Gastric cancer is the third deadliest cancer in the world, and the absolute number of cases is increasing every year due to aging and growing of high‐risk populations. This disease is a consequence of the complex interaction of microbial agents, with environmental and host factors, resulting in the dysregulation of multiple oncogenic and tumor‐suppressing signaling pathways. Despite the advances in our understanding of carcinogenesis, there are still reduced therapeutic options for patients with gastric cancer. In recent years, genomic analyses of gastric tumors have emphasized their molecular heterogeneity. The distinction of gastric cancer molecular subtypes may be a key to identify novel therapeutic targets, to predict patient outcome and response to therapy, and to guide early diagnosis strategies. In this review, we summarize the most recent updates on the relationship between microbial agents and gastric cancer, in particular, Helicobacter pylori, the non‐H pylori microbiome, and Epstein‐Barr virus. We also highlight the main advances made in the past year regarding the molecular characterization of gastric cancer, especially the signatures with potential clinical utility.     

Review: Gastric cancer—Clinical aspects

Gastric cancer (GC) was responsible for over 1 000 000 new cases in 2018 and an estimated 783 000 deaths, making it still the fifth most frequently diagnosed cancer and the third leading cause of cancer deaths in both sexes worldwide. Divergent trends for GC incidence were observed in the USA. Incidence rates, particularly for non‐cardia GC, were stable or increasing among persons aged <50 years. In an analysis of data from a public hospital database in Hong Kong, treatment of Helicobacter pylori infection was associated with a lower risk of GC, particularly in older subjects who received treatment ≥10 years before. Based on the results of a 16‐year endoscopy‐based follow‐up eradication trial, patients with incomplete‐type intestinal metaplasia (IM) should receive endoscopic surveillance upon H. pylori eradication therapy. Updated guidelines on the endoscopic surveillance of preneoplastic conditions of the stomach (MAPS II) have been published. In the RAINFALL trial, the addition of ramucirumab to a backbone chemotherapy as a first‐line regimen failed to improve overall survival (OS) of patients with metastatic disease. Also, pembrolizumab did not prolong OS when compared to paclitaxel in the second‐line treatment of patients with advanced GC or esophagogastric junction (EGJ) cancer. Trifluridine/tipiracil improved OS by 2.1 months in the third or further treatment line of patients with advanced GC. In a systematic investigation conducted on Chinese patients with GC, CLDN18‐ARHGAP26/6 fusion was associated with signet‐ring cell content and was prognostic for a worse outcome and predictive for no benefit from oxaliplatin/fluoropyrimidine‐based chemotherapy. Organoid cultures represent an appealing model that may be applied for therapy response testing in the near future.     

Tumour-stroma interactions in carcinogenesis: basic aspects and perspectives

In contrast to the conventional notion regarding tumour development as a cell autonomous process in which the major participants were the cancer cells, increasing evidence attributes important role in the stromal components, namely fibroblasts, and view the tumour as a heterogenous mixture of different cell types. These different types of cells, being cancer cells, fibroblasts, endothelial cells, and others, interact reciprocally and play an almost equally important role in the manifestation of certain aspects of the malignant phenotype. The elucidation of the mechanistic base of such interactions, besides the contribution to understand fundamental aspects of tumour cell biology, promises important applications in diagnosis, prognosis and therapy of the disease.     

The general mechanism of chromosomal mutagenesis: basic and applied aspects

Based on the analysis of literature and the findings of the present work, it is assumed that there are two main mechanisms of formation of structural chromosome mutations in eukaryotic cells: 1) homologous recombinations, resulting in the formation of all kinds of chromosome exchanges; 2) the process of telomere formation, resulting in the generation of true deletions. Some chromosome breaks registered in the first K-mitosis of cells after exposure to mutagens reflect temporary disturbance of chromatin condensation. These aberrations can be repaired in the next nuclear cycle. Data are presented that argue in favour of the existence of a minor fraction of DNA sequences that serve as the molecular basis of specific targets of chromosome mutagenesis. These sequences can play an essential role in the normal structural and functional organization of the nucleus.     

Neuroendocrine regulation of ovulation in fishes: basic and applied aspects

This review summarizes the major neuroendocrine mechanisms regulating ovulation, thus providing a basis for understanding the various environmental and hormonal techniques for induction of ovulation of cultured teleosts. The secretion of gonadotrophin-ii(GtH-ii) is stimulated by gonadotrophin-releasing hormone (GnRH), and, although some teleosts have three different forms of GnRH regionally distributed in the brain, in most species investigated, only one form is present in the pituitary and apparently involved in GtH-ii secretion. In nearly all species investigated, dopamine (DA) inhibits GtH-ii secretion by direct actions on gonadotrophs, as well as by inhibition of GnRH release. Sex steroids act at both brain and pituitary levels to regulate GtH-ii secretion through a combination of positive and negative feedback actions; one important positive feedback action is that sex steroids enhance the responsiveness of the pituitary to GnRH and an important negative feedback action is to increase DA turnover, thereby increasing the overall DA inhibitory tone on GtH-ii secretion. The preovulatory surge of release of GtH-ii is stimulated by a surge release of GnRH. A decrease in DA turnover also occurs to disinhibit GnRH and GtH-ii release. Environmental factors including photoperiod, temperature and spawning substrate may cue ovulation and spawning. Social and pheromonal interactions play a very important role in synchronizing preovulatory endocrine changes, ovulation and spawning behaviour in many species. A widely used technique for inducing ovulation of cultured fishes is injection of the combination of a GnRH superactive analogue, to stimulate GtH-ii release, and a DA receptor antagonist, to block the inhibitory actions of DA. This is termed the Linpe technique and has proven particularly useful with those species having synchronous or group synchronous follicular development and a large preovulatory surge of GtH-ii. In other groups of teleosts, particularly those species having asynchronous ovarian development and multiple spawnings over an extended period, treatment with a sustained-release preparation of a GnRH superactive analogue to cause a prolonged, somewhat enhanced release of GtH-ii has proven highly successful in inducing multiple ovulations and spawnings. However, the lack of specific radioimmunoassays for GtH-ii in many of these species has hindered progress, as the precise pattern of GtH-ii release necessary for the recruitment of vitellogenic oocytes into final maturation and ovulation in these multiple spawners remains an intriguing neuroendocrine question     

Comparative aspects of basic chromatin proteins in dinoflagellates

Previous work on histone-like proteins in dinoflagellates is summarized, together with some new data to give an overview of basic proteins in these algae. The first two dinoflagellates studied were both found to contain one major acid-soluble protein that migrated to the same position in acidic-urea gels. When several other genera were studied however, it became apparent that the histone-like proteins from different dinoflagellates were similar but not identical. In view of the great diversity of living dinoflagellates it is speculated that further differences in dinoflagellate basic chromatin proteins will be revealed. Electrophoretic data from the eukaryotic (endosymbiont) nucleus of Peridinium balticum showed the presence of five major components. It is speculated that two of these proteins represent an H1-like doublet and two others correspond to the highly conserved histones H3 and H4. The fifth component is a new histone that may substitute for H2A and H2B in the nucleosome. Because histones and nucleosomes are present in all higher organisms but completely lacking in procaryotes, studies on basic proteins in dinoflagellates will provides insights into the evolution of histones and eucaryotic chromatin organization.     

胃癌与胃微生态的研究进展

胃癌(gastric cancer)是我国常见恶性肿瘤之一,有着较高的发病率和死亡率。胃癌的发生是一个相对缓慢、多步骤、复杂的过程,可能与幽门螺杆菌(Helicobacter pylori,H.pylori)感染、环境、基因、吸烟等因素相关。随着高通量测序技术和宏基因组学等技术的发展和运用,大量研究表明胃肠道微生物与消化道系统疾病息息相关,其中胃微生物中H.pylori已被明确列为I类致癌因子。除了H.pylori,胃内其他共生菌与胃癌的发生也有密切的联系。本文将通过胃癌与H.pylori感染、胃癌与H.pylori根除、H.pylori与胃微生态、胃癌与胃微生态四个方面综述胃癌与胃微生物的关系,为日后胃癌的研究提供参考。     

Towards an ecosystem semiotics: Some basic aspects for a new research programme

The paper argues that ecosystem should be recognized as semiotic systems and that it is necessary to carry out studies of the ongoing semiotic processes in addition to traditional ecosystem research. It is suggested that interpretation of ecosystems within such a semiotic framework is of utmost importance and essential if we want to fully understand the complexity issue and how complex behaviour comes about at this level of biological hierarchy. This area—called ecosystem semiotics—is suggested to become a new direction of study dedicated to this understanding.As a consequence of the ontic character of ecosystem complexity, studies on the importance of semiotic processes can only be synthesized through modelling efforts. Hitherto, this type of process with a few exceptions has been neglected or at best only implicitly integrated and accounted for in ecosystem models. In the future, ecosystem models will need to integrate this type of behaviour in order to get full insight into the causal mechanisms behind the emergence of their complex behaviour. In addition, the concept of exergy in its classical form derived by Evans is suggested as a platform to integrate thermodynamic information of the systems as a complexity measure. The thermodynamic information may be split into parts that causally originate in the ontic existence of various ecosystem elements. Ecosystem semiotics is thought to considerably increase the thermodynamic efficiency of the ecosystem, leading to an increase in thermodynamic information and for instance ascendancy that would not have existed if it was not emerging from the semiotic processes.In other words, by incorporating semiotics, we add a “metaphysical” layer to our models, which may be referred to as the semiotype of the system. The semiotype acts as downward causation on the lower layers of interactions and allows for modification and adaptations of existing genotype or phenotype possibilities that would not be possible without the existence of semiosis and cognitive processes.     

Gastric cancer: a curable disease in Britain.

OBJECTIVE--To determine whether more vigorous efforts aimed at earlier diagnosis allied to radical surgical resection lead to improved survival of patients with gastric cancer. DESIGN--Prospective audit of all cases of gastric cancer treated during 1970-89. SETTING--Department of surgery, general hospital. SUBJECTS--493 consecutive patients with gastric adenocarcinoma. MAIN OUTCOME MEASURES--Operative mortality, postoperative morbidity, and five year survival after radical potentially curative resection. RESULTS--207 (42%) patients underwent potentially curative resection. The proportion of all patients in whom this was possible increased significantly (p < 0.01) from 31% in the first five year period to 53% in the last five year period. The proportion of patients who had early gastric cancer rose from 1% to 15% (p < 0.01) and stage I disease rose from 4% to 26% (p < 0.001). After potentially curative resection, mortality 30 days after operation was 6%. Operative mortality decreased from 9% in the 1970s to 5% in the 1980s. Likewise, the incidence of serious postoperative complications decreased from 33% in the 1970s to 17% in the 1980s (p < 0.01). Five year survival was 60% in patients who underwent curative resection, 98% in patients with early gastric cancer, and 93%, 69%, and 28% in stage I, II, and III disease respectively. By the late 1980s five year survival after operation was about 70%. CONCLUSIONS--These findings suggest that an increasing proportion of patients with gastric cancer could be diagnosed at a relatively early pathological stage when about two thirds are curable by means of radical surgery.     

Endocrine aspects of cancer: an epidemiological approach

Over the last 2 decades epidemiologists have increasingly used parameters of endocrine function in their studies. Prospective cohort studies offer methodological advantages in view of the latency between the relevant hormonal exposure and the clinical onset of cancer. Examples from the author's experience are provided. Evidence is mounted for an important "time window" for breast cancer development between menarche and the birth of a first child.