Correlation between Helicobacter pylori infection and IL-18 mRNA expression in human gastric biopsy specimens.

Our data indicate that H. pylori infection is associated with active interleukin-18 production in patients with chronic gastritis. Different cell types appear to be involved in this activity and may play a role in the development of immunopathologic damage.

Nerve growth factor receptor immunoreactivity in breast cancer patients.

Nerve growth factor receptor (NGF-R) has been shown to have antiproliferative, differentiative, or apoptotic effects on some types of tumor cells, whereas in others it may have mitogenic activity. The immunohistochemical distribution of NGF-R was analyzed in a series of tissue samples from breast cancer patients and its relationship with other clinical and pathological parameters was studied. The distribution of NGF-R was evaluated by immunohistochemistry in frozen tissue samples of 46 breast cancer patients (ME20-4 monoclonal anti-NGF-R). NGF-R immunoreactivity was localized in the plasma membrane of myoepithelial cells, differentiated ducts, neoplastic cells, blood vessels, and nerve fibers in 26 patients (57%). Less differentiated neoplastic tissues were usually NGF-R negative. NGF-R immunoreactivity was associated with estrogen receptor (ER) status (p = 0.02), small tumor dimension (pT) (p = 0.04), low histologic grade (G1-G2) (p < 0.05), old age (p = 0.02), menopause (p = 0.02), and long disease-free survival (DFS) (median follow up 86 months; p = 0.03; independently from ER, pT, age, menopause by multivariate analysis, p = 0.0078). The expression of NGF-R immunoreactivity by breast cancer patients with long DFS may represent a crucial step both in the differentiation status of neoplasia and in the host immune mechanism controlling tumor growth and metastasization.

Immunohistochemical TRF1 expression in human primary intracranial tumors.

BACKGROUND: The telomeric-repeat binding factor (TRF1) participates in a physiological homeostatic mechanism controlling telomere shortening by inhibiting telomerase activity: down-regulation of TRF1 expression results in telomere elongation and may be involved in cell immortalization. PATIENTS AND METHODS: To determine the TRF1 expression by immunohistochemistry (IHC) in human brain tumors, a cohort of 20 consecutive flash-frozen surgical specimens (14 meningiomas and 6 anaplastic astrocytomas (AA)) were collected. RESULTS: Variable levels of TRF1 expression in 12 out of the 14 (87.5%) meningioma samples were observed. By contrast, no expression of TRF1 in tissue samples from AA (p = 0.008) was detected. Positive TRF1 cells were usually more differentiated (less atypical features) and Ki67 negative (inverse statistical association, chi2 = p < 0.001). CONCLUSION: We demonstrated, for the first time, that routine IHC techniques are capable of identifying TRF1 expression in intracranial tumors, which is heterogeneously expressed in meningiomas, but absent in AA. Although these preliminary observations need confirmation from larger studies, the TRF1 status in intracranial tumors might become of prognostic value.

Telomere length maintenance in aging and carcinogenesis.

Normal somatic cells have a finite number of divisions, a limited capacity to proliferate. Human telomeres, the long DNA TTAGGG repeats at the ends of chromosomes, are considered a molecular clock marker. The gradual and progressive telomere shortening at each replicative cycle is associated, through the activation of pRB and p53 pathways and genomic instability, to the replicative senescence, a non-dividing state and widespread cell death. Activation of telomere maintenance [telomerase; or alternative lengthening of telomeres mechanisms (ALT), or other adaptive responses] can revert this program. Although not completely known, several mechanisms and modulating agents may be able to up and down-regulate telomere length and its maintenance. Chemopreventive therapies for the up-regulation of telomerase activity, able to prolong the life of cell cultures in a phenotypically youthful state, could have important applications in research and medicine. On the contrary the therapeutic down-regulation of telomerase activity may be used in cancer therapy. Telomerase expression per se is not oncogenic, but telomere shortening and maintenance seem to be crucial events in tumor formation. Thus a particular focus has been pointed out relatively to the immortalization of normal or potential pre-cancerous cells. With the extension of life span the probability to get in contact with carcinogens increases, genetic instability, oncogene activation and/or onco-suppressor gene inactivation (i.e. p53, pRB, ras): the cancer transformation can be then induced in predisposed cells, depending on their genetic context, by the activation of telomere maintenance. Pharmacological intervention may be able to modulate the rate of living, by increasing life span of few specific target cells, or decreasing it in proliferating . Because of the unknown state of the enormous cell number of the human organism, is it safe to extend the human life span by therapeutic agents?

Immunohistochemical telomeric-repeat binding factor-1 expression in gastrointestinal tumors.

The maintenance of telomere length has been hypothesized to be involved in the early steps of cancerogenesis. A physiologic modulation of telomere maintenance is exerted by TRF1 (telomeric-repeat binding factor-1), which deletion permits telomere elongation. Gastrointestinal neoplastic (n=19) and non-neoplastic tissues (six inflammatory disease and six normal mucosa distant from tumor at least 5 cm) were studied, by immunohistochemistry, for TRF1 expression, by using a polyclonal antibody anti-TRF1. Differentiated and not proliferating epithelial secretory cells (Ki67 and p53 negative cells) were stained by anti-TRF1, which did not stain tumor cells in all cases but one (p<0.0001). p53 was expressed by 26% of tumor cases. Inflammatory gastrointestinal non-tumor tissues showed lower expression of TRF1 in epithelial secreting cells compared to normal tissues (p=0.008). These preliminary data suggest that down-regulation of the TRF1 expression in tumor cells may be involved in cell immortalization as an initial step in gastrointestinal carcinogenesis (before p53 alteration), and may open new perspectives, when confirmed, in gastrointestinal tumor prognosis.

[Importance of chemoprevention in oncology]. / Importanza della chemioprevenzione in oncologia.

The therapeutic approach to cancer is generally limited to the advanced phases of disease. The preventive strategies aim at eliminating or reducing the exposition to known carcinogenes. We act with pharmacological and/or with an accurate dietary education to induce cellular differentiation phenomena, cytostasis and apoptosis. Chemoprevention acts both on the inductive phase (metabolic activation, DNA adducts), as well as on the promotion/proliferation of the long pre-clinical period of latency (antioxidants, anti-inflammatory, retinoids, carotenoids, vitamins and micronutrients, hormones and hormonal inhibitors, polyamine inhibitors, ditholetions, isothiocyanates, telomerase inhibitors, etc). Unanimous agreement has been reached on the preventive role of retinoids in head and neck tumors and of the cervical uterus, of hormonal inhibitors in breast and prostate cancer, and of anti-inflammatory in colorectal cancer. New and more accurate parameters for the evaluation of results and individual applications of chemopreventive strategies are linked to the biological research of high-risk subjects (genetic damage) or increased individual susceptibility. Caution, instead, should be applied in the clinical trial planning. An increased risk in developing and dying of lung tumor in smokers has been shown for the use vitamin A. Many clinical studies have been started in order to establish an efficient chemoprevention in oncology, and with the early diagnostic programs, and the evaluation of genotypic and phenotypic alterations, encouraging results will be reached for the next millennium.

[The role of telomere-binding proteins in carcinogenesis]. / Ruolo delle proteine associate ai telomeri nella cancerogenesi.

Normal somatic cells have a defined number of divisions, a limited capacity to proliferative. The telomeres, sequences of TTAGGG repeats at the ends of chromosomes, are considered the direct responsible of the control of the cellular cycle. In fact, the progressive shortening of telomere length at each cellular division, causes the entrance of the cells in a phase of senescence and than apoptosis. The maintenance of the length of telomeres is carried out through: the telomerase, a DNA polymerase reverse transcriptase that extends sequence TTAGGG repeats, or the alternative lengthening of telomeres (ALT), between which the adaptive mechanisms, inactivation of TRF1, a protein bound to the telomeres with the functions of inhibiting the telomerase activity and Tankirase-PARP, an enzymatic complex that ADP-ribosylate TRF1 and reduce its binding to DNA. The alteration of the mechanism of maintenance of the telomeres length (Telomerase, TRF1, Tankirase-PARP) may represent a first step toward the cell immortalization and cancerogenesis. Together with the alteration of the control mechanisms of the telomere length, also the cell genic contest should be considered. In fact, the oncogene activation and/or oncosuppressor gene inactivation (p53, Rb, ras) may allow or reduce the cancerogenesis. From this point of view, the telomerase, the TRF1, Tanchirase-PARP and other proteins involved in telomere length could be, in a near future, used as new indicators of prognosis and as markers for new anti-cancer therapies.

Lymphocyte number and stress parameter modifications in untreated breast cancer patients with depressive mood and previous life stress.

Depressive mood disorders and severe, chronic stressful life events (DSM-III-R criteria) were more frequently diagnosed in 106 breast cancer patients with respect to 37 patients with benign breast diseases (control group) (p < 0.001), during a stressful period such as hospital admission, diagnosis uncertainty, and when awaiting surgery. The study was performed 5 +/- 3 days before histological diagnosis had been done. Controls showed reduced 24-h diuresis and low catecholamine excretion (norepinephrine, NE; and epinephrine, E) that positively correlated with 24-h diuresis (p < 0.001) and CD3+ lymphocytes (p = 0.056), as during a normal stress response. In contrast, breast cancer patients showed increased 24-h diuresis (with respect to controls p < 0.001) and catecholamine values (p < 0.05). Patients' 24-h diuresis correlated positively with NE (p = 0.02) and 17-ketosteroids (p = 0.004); blood cortisol correlated positively with CD3+ (p = 0.01), CD4+ (p = 0.02), CD8+ (p < 0.01), CD16+ (p = 0.01) lymphocytes and negatively with E (p < 0.03); catecholamines correlated negatively with CD8+ (p = 0.006). These preliminary data are discussed in relation to upregulation of the adrenergic system and the different mechanisms of immune system regulation involved in breast cancer patients, compared with those in subjects with benign breast disease. The differences in these mechanisms may be a result of an imbalance of the bi-directional regulatory circuit of the psycho-neuro-endocrine-immune system, caused by previous life stress or the presence of the tumor mass.