Circulating immunocomplexes and laryngeal carcinoma

Serum levels of circulating immunocomplexes (CIC) were studied in a group of 37 patients with laryngeal carcinoma using two polyethylene glycol-precipitation methods. The preoperative values of this group showed higher levels of CIC when compared with 140 normal controls. No correlation was noted between tumoral stage, oncotype, and serum levels of CIC. Previous studies have shown that the status of several different types of human tumors can be monitored by serial determinations of levels of CIC. We believe that this technique can be used to evaluate the efficacy of therapy and to detect the recurrence of laryngeal carcinoma.     

Persistent high plasma levels of interleukins 18 and 4 in children with recurrent infections of the upper respiratory tract

The aim of this study was to examine whether children with recurrent infections of the upper respiratory tract might have alterations in the systemic immune response to viral infections as compared with healthy control children. We quantitated plasma levels of interferon-gamma, interleukin-12, interleukin-18, interleukin-4, lymphocyte subpopulations, serum immunoglobulins, and subclasses of immunoglobulin G in 30 children under the age of 6 years with recurrent infections of the upper respiratory tract, both during the acute phase of the infection and 4 weeks later, when clinical symptoms had resolved, as well as in 20 normal controls. We found elevated levels of immunoglobulin G primarily due to increased levels of immunoglobulin G(1). Moreover, significantly higher levels of interleukin-18 and interleukin-4 were noted during the acute phase of infection among children with an increased incidence of respiratory infections as compared with the controls (P =.022 and P =.0001, respectively), while plasma levels of interferon-gamma and interleukin-12 were significantly lower (P =.034 and P =.0001, respectively) than in controls. We suggest that an imbalance between T-cell helper type-1 and T-cell helper type-2 immune responses might be responsible for the perpetuation of recurrent infections of the upper respiratory tract.     

Second-line chemotherapy and new drugs for ovarian carcinoma

Epithelial ovarian carcinoma represents a prototypic example of neoplastic disease sharing at the same time good chemosensitivity as well as marked propensity to relapse. If in one hand the definition of almost clear-cut guidelines has been reached in the setting of first-line therapy (i.e., cytoreductive surgery followed by first-line chemotherapy), more difficult to discern for the oncologist remains the choice of treatment in the occasion(s) of relapse(s). This article focuses on this particular setting of disease, analyzing the specific criteria of choice of drug or their combinations; the definite criteria followed for the use of platinum compounds in the second line of treatment, even if already utilized in the front line therapy, are also analyzed. Specific attention has also been paid in the definition of the role of single parameter as a "prognosticator" and/or as "predictor" of response. The Authors emphasize how clinical definitions remain the more reliable, simple, reproducible tools in therapeutical decision making.     

Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

Preclinical studies have shown that nitric oxide (NO)-donating nonsteroidal anti-inflammatory drugs possess anticancer activities. Here, we report in vitro and in vivo studies showing the antitumor effect of the NO-donating isoxazole derivative (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid (GIT-27NO). GIT-27NO, but not the NO-deprived parental compound VGX-1027, significantly affected viability of both rodent (L929, B16, and C6) and human (U251, BT20, HeLa, and LS174) tumor cell lines. GIT-27NO triggered either apoptotic cell death (e.g., L929 cells) or autophagic cell death (C6 and B16 cells). Moreover, GIT-27NO hampered the viability of cisplatin-resistant B16 cells. NO scavenger hemoglobin completely prevented GIT-27NO-induced death, indicating that NO release mediated the tumoricidal effect of the compound. Increase in intracellular NO upon on the treatment was associated with intensified production of reactive oxygen species, whereas their neutralization by antioxidant N-acetylcysteine resulted in partial recovery of cell viability. The antitumor activity of the drug was mediated by the selective activation of mitogen-activated protein kinases in a cell-specific manner and was neutralized by their specific inhibitors. In vivo treatment with GIT-27NO significantly reduced the B16 melanoma growth in syngeneic C57BL/6 mice. The therapeutic effect occurred at dose (0.5 mg/mouse) up to 160 times lower than those needed to induce acute lethality (80 mg/mouse). In addition, a dose of GIT-27NO five times higher than that found effective in the melanoma model was well tolerated by the mice when administered for 4 consecutive weeks. These data warrant additional studies to evaluate the possible translation of these findings to the clinical setting.     

Inflammatory status in patients with chronic renal failure: the role of PTX3 and pro-inflammatory cytokines

Increased plasma levels of several acute phase proteins, such as C-reactive protein (CRP), have been documented among different patients with chronic renal failure (CRF). The aim of the present study was to determine whether pentraxin-3 (PTX3) is a reliable marker of inflammation in CRF. Plasma samples and monocytes were taken from 43 patients before and after undergoing haemodialysis (HD), from 45 uraemic patients (UR) without HD treatment and from 25 healthy controls. Plasma and monocyte samples were analyzed by ELISA for levels of PTX3, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6); all of these protein levels were higher in CRF patients with respect to the controls. After HD, plasma PTX3 and cytokine levels increased. Inter- and intra-individual variations in CRP were observed in HD patients, while PTX3 plasma levels were stable. Release of PTX3, TNF-alpha, IL-1beta and IL-6 by unstimulated monocytes from patients, before and after HD, was higher with respect to UR patients and controls. After lipopolysaccharide stimulation, all values were higher in patients before HD than those in UR patients, but lower when compared to those in the controls. In contrast, no changes were observed after HD. A significant correlation among plasma PTX3 versus fibrinogen, TNF-alpha and IL-1beta was observed in HD and UR patients. Collectively, these data suggest that PTX3 protein may represent an additional and stable marker of inflammation in CRF.     

Long pentraxin 3: a marker of inflammation in untreated psoriatic patients

Psoriasis is a common cutaneous disorder characterized by abnormal epidermal differentiation, proliferation and inflammation mediated by dermal infiltrates, such as T cells, neutrophils, dendritic cells and macrophages. There are renewed interest in the role of components of the innate immune system. Cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6, and -1beta involved in pathogenic phenomena in psoriasis are known as inducers of the acute phase response. Among the large group of acute phase reactants, C-reactive protein (CRP) and fibrinogen are of special interest in psoriasis. The PTX-3, a long pentraxin sharing similarities with the classical short proteins. Thus, considering the numerous biological roles of inflammatory cytokines and their relationship with inflammatory markers, such as CRP and fibrinogen we have investigated the role of PTX3 in psoriasis. To this aim PTX3, TNF-alpha, IL-6 and IL-1beta in plasma and in monocytic cultures by enzyme linked immunosorbent assay (ELISA) in 44 patients including severe and mild psoriasis were measured. An increased production of PTX3, both in supernatant of purified monocytes and in plasma from patients with severe psoriasis, was found. The significant correlation, between cellular production and plasma levels of PTX3 in psoriasis was found as a sign of cellular activation by monocytes/macrophages that first infiltrate the psoriatic lesion. In severe psoriasis, a significant correlation between psoriasis area and severity index (PASI) score and TNF-alpha and IL-6 levels in both supernatant of monocytes and plasma was found. In contrast, no correlation was found for IL-1beta. By immunohistochemistry and immunofluorescence, a strong PTX3 staining in fibroblasts, endothelial cells and monocytes/macrophages in severe psoriatic lesional skin was detected. Finally, a positive correlation between PTX3 and disease activity of psoriasis was observed as PASI score was elevated. These findings suggest that PTX3 could be used as a further marker of disease activity of psoriasis.     

Association of TIMP-1 +372 SNP with digital ulcer manifestation in female systemic sclerosis patients

A candidate gene for TIMP-1 gene located on the X-chromosome (rs4898) was selected for a control case study to investigate a possible association of this SNP with the susceptibility to systemic sclerosis and its digit ulcer manifestation. A total of 461 individuals of Italian Caucasian origin (228 SSc patients and 233 healthy control subjects) were genotyped for TIMP-1 +372 T/C single nucleotide polymorphism rs4898. Subgroups were analyzed according to the presence or absence of digital ulcers. The CC genotype and C allele frequencies were significantly lower in female SSc patients than in controls (OR 0.53, CI 0.29-0.96, p=0.03 and OR 0.72, CI 0.53-0.98 p=0.04, respectively). CC genotypes frequency was lower also in female patients with ulcers than those without ulcers (OR 0.37, CI 0.14-1.00, p=0.03). Furthermore, CC genotype and C allele frequencies were lower also in female patients with ulcers in comparison to female healthy control subjects (OR 0.27, CI 0.10-0.70, p=0.004; OR 0.60, CI 0.40-0.89, p=0.01, respectively). The TIMP-1 rs4898 polymorphism may play a protective role in the susceptibility to SSC in females, and in particular to digital ulcer formation.     

Analysis of matrix metalloproteinase-9 gene polymorphism -1562 C/T in patients suffering from systemic sclerosis with and without ulcers

The objective of this study was to determine whether the matrix metalloproteinase-9 (MMP-9) rs3918242 single nucleotide polymorphism may confer susceptibility to systemic sclerosis (SSc) with and without ulcers in an Italian Caucasian population. The MMP-9 rs3918242 functional polymorphism was genotyped in 461 subjects of Italian Caucasian origin: 228 patients with SSc (92 with and 136 without ulcers) and 233 unrelated healthy individuals. The SNP under study was in Hardy-Weinberg equilibrium in the control population. Genotype and allele distributions between SSc patients, with or without ulcers, were not statistically significant (p>0.05). A significant increase of the genotype C/T was observed in male SSc patients without ulcers when compared to patients with ulcers (P=0.04). The MMP-9 rs3918242 functional polymorphism is not associated with susceptibility to SSc. However, the presence of the polymorphism may have a protective effect on the development of ulcers in SSc male patients.     

Analysis of G(-174)C IL-6 polymorphism and plasma concentrations of inflammatory markers in patients with type 2 diabetes and peripheral arterial disease

AIMS: To determine whether the G(-174)C interleukin 6 (IL-6) polymorphism influences the development of peripheral arterial disease (PAD) in individuals with type 2 diabetes. This was investigated by comparing the distribution of G(-174)C genotypes between patients with type 2 diabetes and PAD (PAD+) and those with type 2 diabetes but without PAD (PAD-). Plasma concentrations of IL-6, fibrinogen, C reactive protein (CRP), and vascular endothelial growth factor (VEGF) were also compared in PAD+ and PAD- patients. METHODS: Blood samples were collected from 146 PAD+ and 144 PAD- patients. SfaNI was used to determine the G(-174)C genotype. Plasma concentrations of IL-6, fibrinogen, CRP, and VEGF were measured by an enzyme linked immunosorbent assay. RESULTS: The GG genotype was more common in PAD+ patients than in PAD- patients. PAD+ patients also had increased mean plasma concentrations of IL-6, fibrinogen, CRP, and VEGF compared with PAD- patients. Mean plasma concentrations of IL-6, fibrinogen, and CRP in both PAD+ and PAD- patients were higher in those with the GG genotype than in those with the GC or CC genotypes. In contrast, mean plasma concentrations of VEGF in PAD+ and PAD- patients were not significantly different between those with different G(-174)C genotypes. CONCLUSIONS: These results support a model in which the GG genotype promotes PAD development among individuals with type 2 diabetes by inducing increased release of IL-6. Higher concentrations of IL-6 among those with the GG genotype is associated with increased plasma concentrations of fibrinogen and CRP.