Role of Gastrokine 1 in Gastric Cancer

Gastric cancer (GC) has high incidence (> 1.000.000 new cases/year) and mortality rate in several countries and is still one of the most frequent and lethal (> 600.000 dead/year) neoplasia with an average surviving of five years (less than 20%) (Pisani et al., 1990; Lands et al., 1998). It is already well known that infection of gastric antrum mucosal with the bacterium Helicobacter pylori is the cause of the chronic inflammation that leads to intestinal-type gastric cancer in the majority of the cases. The H. pylori infection is widespread but only a small number of the total population of infected individuals might eventually develop adenocarcinoma (around 3/10,000 individuals per year or 2.1% for lifetime infection) 27 (Correa & Piazuelo, 2008). Risk factors influencing the outcome of H. pylori–associated pathology include bacterial cytotoxic heterogeneity, diet, and geographic differences. The phenomenon of decreased gastric cancer incidence in Africa compared with other regions where H. pylori is endemic 28 (Holcombe, 1992) is probably due to the different diet of these populations compared to the western countries. This discrepancy has been partially attributed to helminth co-infection that likely modifies the characteristic proinflammatory type 1 T-helper 1 cell response, to a T-helper 2–predominant response 29 (Whary et al., 2005), typified by the release of non-inflammatory cytokines and reduced incidence of H. pylori–associated glandular atrophy, an early marker of cancer development. The identification of novel genes regulated by H. pylori in vivo, particularly those contributing to these early stages of gastric cancer, would facilitate improved understanding of the differential susceptibility to this pathogen. The different susceptibility among individuals to H. pylori infection is still not yet defined. Some works, however, suggested that the polymorphisms in host genetic factors like the proinflammatory cytokines interleukin-1, interleukin-8, and tumor necrosis factor may play a relevant role 30 (El-Omar et al., 2003). The evolution of intestinal tumours is characterized by a progression of several sequential steps that starts with gastritis and then progresses to mucosal atrophy (atrophic gastritis), intestinal metaplasia, dysplasia and carcinoma with subsequent metastatic dissemination (Correa, 1992, 1995). The diffuse-type has instead a poorer prognosis and develops through unknown genetic and morphological events from normal gastric epithelium. No preceding steps have been identi_ed in the pathogenesis of diffuse carcinoma other than the chronic gastritis. The pathogenesis of gastric cancer remains poorly understood although it is evident that several environmental factors, such as H. pylori infection can be one of the causes leading to this disease. In fact, the risk to develop gastric cancer is increased in patients with H. pylori infections probably as the result of a combination of genetic and environmental factors in which the infection by H. pylori is of particular relevance, especially when the inflammation involves the gastric body region with respect to the antrum (Correa, 1995; Goldstone et al., 1996; Nabewera & Logan, 1999). Generally, this condition is associated to different degrees of atrophy and alterations of the secretor function that, in the long term, became associated to gastric carcinoma (Forman et al., 1991; Parsonnet et al., 1997; Watanabe et al., 1998). Diffuse adenocarcinoma shows an increased propensity for intra and transmural spread and is therefore associated with a poorer prognosis. Unfortunately, the histological classification of an individual gastric adenocarcinoma is not clear-cut with a tumour often comprising a mixture of intestinal and diffuse tissue types. Under these considerations, we think that there is an urgent necessity to dispose of an efficient tool for the detection of early stage gastric cancer like the identification of highly sensitive and specific biomarkers that will aid disease diagnosis and ensure early clinical intervention, thereby preventing mortality and reducing morbidity (Boussioutas & Taupin, 2001). Since most of GC (around 73%) is developed at antrum/pylorus, proteins secreted by antrum/pylorus mucosa might play a critical role in maintaining normal gastric mucosa structure and function

Gastric Cancer: Molecular Pathology State

Despite the progressive decrease observed in the past fifty years, gastric cancer (GC) is the fourth of the world rankings incidence of various types of cancer and is the second as a cause of cancer-related death. There is distinct geographical variation in gastric cancer incidence with the highest rates reported from Japan, Korea and Eastern Asia. Other high incidence areas are Eastern Europe and parts of Latin America, while Western Europe, Africa, Australia and the US generally have low incidence rates. In the last decade there has been a downward trend in the incidence and mortality from this cancer. The reasons are to be found in the improvement of food both as regards its preservation procedures and the variability in the diet and for the decrease of infection by Helicobacter pylori (H. pylori). H. pylori infection is strongly associated with risk for stomach cancer. Likely, this association is supported by the strong link between this bacterium infections and precancerous lesions, including chronic atrophic gastritis and dysplasia. The development of gastric cancer is characterized by multistage process in which several alterations of genetic and epigenetic nature accumulate. These alterations are mainly related to abnormalities of growth factors and receptors, DNA mismatch repair genes, angiogenic factors, transcription factors, adaptor proteins, cell cycle regulators, and many other macromolecular cell components. All these abnormalities identify from one side the molecular and biological aspect of gastric cancer cells and from the other might suggest possible strategies for therapeutic intervention

Translational Control in Tumour Progression and Drug Resistance

Protein biosynthesis is a multi-step process that starts with the transcription of nuclear DNA, depository of genetic information, into messenger RNA (mRNA) that is used as template for the following polypeptide chain synthesis, also known as translation. Each step of this essential process is highly controlled in order to modulate any specific protein requirement of the cell in response to different stimuli and cellular events. This regulatory process is called translational control. Deregulation of the core signalling network in translational control, the phosphatidyl inositol trisphosphate kinase (PI3K), Protein Kinase B (PKB or Akt), mammalian target of rapamycin (mTOR) and RAS mitogen-activated protein kinase (MAPK)/MAPK-interacting Kinases (MNK) pathways, frequently occurs in human cancers and leads to aberrant modulation of mRNA translation. However, investigations on the contribution of these two pathways to translational regulation led to the interesting finding that translation factors are also substrate of signalling molecules. Post-translational modifications, including cleavage and phosphorylation, usually affect translational factors activity in protein biosynthesis; on the other hand, direct interaction of translational components with signalling mediators can either activate the pathway in which the mediator is involved or redirect translation factors to other activities, such as cytoskeletal rearrangements. These findings shed light on new functions of translation factors, different from their canonical role in protein synthesis. Taken together, these new functions are an intriguing step forward to the discovery of molecular mechanisms at the base of cellular response during “special” conditions such as cancer and drug resistance

An enhanced procedure for the analysis of organic binders in Pompeian's wall paintings from Insula Occidentalis

Abstract Quantitation of paint powders of ancient wall paintings is often hindered by the calcite contamination during samples withdrawal. To overcome this problem, a new approach was explored based on the mechanical pulverization of the paint powder followed by the evaluation of its true concentration, namely binders, pigments, and decaying compounds, from the comparison of the calcite FT-IR peak area at 2510 cm−1 with that of the corresponding underlying calcite used as calibrator. After extraction of the pulverized paint powder with polar and nonpolar solvents, liquid chromatography, gas chromatography with flame ionization detection, and gas chromatography–mass spectrometry were used to estimate the free amino acids, and fatty acids profiles. Compared to our previous investigation, the results obtained showed a better yield of the extracted organic materials as mg/kg of powder and also a qualitative improvement of the lipids profile

The ligand-receptor interactions based on silicon technology

We explored the use of porous silicon (pSi) technology for the construction of a biotechnological device, in which the ligand-receptor interactions are revealed by means of laser optical measurements. Here we report the settling of chemical procedures for the functionalization of the silicon wafers and for the subsequent anchoring of biological molecules such as a purified murine monoclonal antibody (UN1 mAb), an antibody anti-P8 protein of M13 phage and an antibody anti-A20 murine lymphoma cell line. The optical analysis of the interaction on the biochips between the bound biomolecules and their corresponding ligands indicated that the pSi is suitable for thi

silicon based technology for ligand receptor molecular identification

One of the most important goals in the fields of biology and medicine is the possibility to dispose of efficient tools for the characterization of the extraordinary complexity of ligand-receptor interactions. To approach this theme, we explored the use of crystalline silicon (cSi) technology for the realization of a biotechnological device in which the ligand-receptor interactions are revealed by means of optical measurements. Here, we describe a chemical procedure for the functionalization of microwell etched on silicon wafers, and the subsequent anchoring of biological molecules like an antibody anti-A20 murine lymphoma cell line. The optical analysis of the interaction on the biochips between the bound biomolecule and their corresponding ligand indicated that the functionalized cSi is suitable for this application

Polar and non-polar organic binder characterization in Pompeian wall paintings: comparison to a simulated painting mimicking an a secco technique.

The use of Fourier transform infrared spectromicroscopy and mass spectrometry (MS) allowed us to characterize the composition of polar and non-polar binders present in sporadic wall paint fragments taken from Pompeii's archaeological excavation. The analyses of the polar and non-polar binder components extracted from paint powder layer showed the presence of amino acids, sugars, and fatty acids but the absence of proteinaceous material. These results are consistent with a water tempera painting mixture composed of pigments, flours, gums, and oils and are in agreement with those obtained from a simulated wall paint sample made for mimicking an ancient "a secco" technique. Notably, for the first time, we report the capability to discriminate by tandem MS the presence of free amino acids in the paint layer

Bioengineered Surfaces for Real-Time Label-Free Detection of Cancer Cells

Biosensing technology is an advancing field that benefits from the properties of biological processes combined to functional materials. Recently, biosensors have emerged as essential tools in biomedical applications, offering advantages over conventional clinical techniques for diagnosis and therapy. Optical biosensors provide fast, selective, direct, and cost-effective analyses allowing label-free and real-time tests. They have also shown exceptional potential for integration in lab-on-a-chip (LOC) devices. The major challenge in the biosensor field is to achieve a fully operative LOC platform that can be used in any place at any time. The choice of an appropriate strategy to immobilize the biological element on the sensor surface becomes the key factor to obtain an applicable analytical tool. In this chapter, after a brief description of the main biofunctionalization procedures on silicon devices, two silicon-based chips that present an (i) IgG antibody or (ii) an Id-peptide as molecular probe, directed against the B-cell receptor of lymphoma cancer cells, will be presented. From a comparison in detecting cells, the Id-peptide device was able to detect lymphoma cells also at low cell concentrations (8.5 × 10−3 cells/μm2) and in the presence of a large amount of non-specific cells. This recognition strategy could represent a proof-of-concept for an innovative tool for the targeting of patient-specific neoplastic B cells during the minimal residual disease; in addition, it represents an encouraging starting point for the construction of a lab-on-a-chip system for the specific recognition of neoplastic cells in biological fluids enabling the follow-up of the changes of cancer cells number in patients, highly demanded for therapy monitoring applications

Cellular Interaction of Human Eukaryotic Elongation Factor 1A Isoforms

Besides its canonical role in protein synthesis, the eukaryotic translation elongation factor 1A (eEF1A) is also involved in many other cellular processes such as cell survival and apoptosis. We showed that eEF1A phosphorylation by C-Raf in vitro occurred only in the presence of eEF1A1 and eEF1A2, thus suggesting that both isoforms interacted in cancer cells (heterodimer formation). This hypothesis was recently investigated in COS-7 cells where fluorescent recombinant eEF1A isoforms colocalized at the level of cytoplasm with a FRET signal more intense at plasma membrane level. Here, we addressed our attention in highlighting and confirming this interaction in a different cell line, HEK 293, normally expressing eEF1A1 but lacking the eEF1A2 isoform. To this end, His-tagged eEF1A2 was expressed in HEK 293 cells and found to colocalize with endogenous eEF1A1 in the cytoplasm, also at the level of cellular membranes. Moreover, FRET analysis showed, in this case, the appearance of a stronger signal mainly at the level of the plasma membrane. These results confirmed what was previously observed in COS-7 cells and strongly reinforced the interaction among eEF1A isoforms. Moreover, the formation of eEF1A heterodimer in cancer cells could also be important for cytoskeleton rearrangements rather than for phosphorylation, most likely occurring during cell survival and apoptosis

Exploring the influence of takotsubo syndrome on oncologic patients' mortality

It has been reported that patients affected by takotsubo syndrome (TTS) with a concurrent diagnosis of cancer suffer from greater mortality as compared to their non-cancer counterpart. It remains unclear whether TTS worsens the prognosis of cancer patients as well. Aim of this study was to compare outcomes of cancer patients with and without TTS. We combined data from two independent cohorts: one consisted of a prospective multicentre TTS registry; the second cohort consisted of all oncologic patients from two Cardio-Oncology Outpatient Clinics, who did not have cardiovascular conditions at the time of the cardio-oncologic visit. From the TTS registry, we selected patients with cancer (cancer-TTS patients). Next, we matched these patients with those from the cardio-oncologic cohort (cancer non-TTS patients) in a 1:2 fashion by age, sex, and type and cancer staging. Study endpoint was all-cause mortality. Among 318 TTS patients, 42 (13%) had a concurrent diagnosis of cancer. Characteristics of cancer-TTS patients and of the 84 matched cancer non-TTS subjects were comparable with the exception of diabetes mellitus, which was more common in cancer non-TTS patients. All-cause mortality was similar between cancer-TTS and cancer non-TTS patients. At Cox regression analysis TTS was not associated with mortality (OR 1.4, 95% CI 0.6-3.3, p = 0.43). Our findings show that even in the presence of acute heart failure due to TTS, the prognosis of oncologic patients is driven by the malignancy itself. Our results may prove useful for integrated management of cardio-oncologic patients