Inflammation, ageing and cancer

Cancer is generally recognized as an age-related disease. In fact, incidence and mortality rates of most human cancers increase consistently with age up to 90 years, but they plateau and decline thereafter. A low-grade systemic inflammation characterizes ageing and this pro-inflammatory status underlies biological mechanisms responsible for age-related inflammatory diseases. On the other hand, clinical and epidemiological studies show a strong association between chronic infection, inflammation and cancer and indicate that even in tumours not directly linked to pathogens, the microenvironment is characterized by the presence of a smouldering inflammation, fuelled primarily by stromal leukocytes. In this review, we have briefly mentioned inflammatory mediators involved in cancer although we decided to choose the ones which show a strict association with ageing and longevity. Inflammation is necessary to manage with damaging agents and is crucial for survival. But, in our opinion, the pro-inflammatory status of ageing might be one of the mechanisms which relate cancer to ageing. The most appropriate inflammatory genes have been selected to survive and to reproduce. Paradoxically, inflammatory age-related diseases (including cancer) are the marks of the same evolutionistic trait. Centenarians are characterized by a higher frequency of genetic markers associated with better control of inflammation. The reduced capacity of centenarians to mount inflammatory responses appears to exert a protective effect towards the development of those age-related pathologies having a strong inflammatory pathogenetic component, including cancer. All in all, centenarians seem to carry a genetic background with a peculiar resistance to cancer which is also an anti-inflammatory profile.     

Albumin adsorption onto pyrolytic carbon: a molecular mechanics approach.

A number of implants of cardiac valve prosthesis, vascular prosthesis, and coronary stents present a pyrolytic carbon interface to blood. Plasma protein adsorption is essential for the hemocompatibility of the implanted devices. This work quantitatively evaluates the molecular interaction force between a biomaterial surface (pyrolytic carbon) and plasma protein (albumin) binding sites through a simplified molecular model of the interface consisting of (i) multioriented graphite microcrystallites; (ii) selected fragments of albumin; and (iii) a water environment. A number of simplifying assumptions were made in the calculation: the albumin molecule was divided into hydrophobic and hydrophilic subunits (helices); an idealized clean, nonoxidized polycrystalline graphite surface was assumed to approximate the surface of pyrolytic carbon. The interaction forces between albumin helices and pyrolytic carbon surfaces are evaluated from potential energy data. These forces are decomposed into a normal and a tangential component. The first one is calculated using a docking procedure (F( perpendicular tot MAX) = 4.16 x 10(-20) N). The second one (F( parallel)), calculated by mean of geometric models estimating the energy variation associated with the protein sliding on the material surface, varies within the range +/-9.62 x 10(-21) N. The molecular simulations were performed using the commercial software package Hyperchem 5.0 (Hyperchem, Hypercube, Canada).     

Clinical and molecular spectrum of Wiedemann-Steiner syndrome,an emerging member of the chromatinopathy family

Wiedemann-Steiner syndrome (OMIM #605130) is a rare congenital malformation syndrome characterized by hypertrichosis cubiti associated with short stature; consistent facial features, including long eyelashes, thick or arched eyebrows with a lateral flare, wide nasal bridge, and downslanting and vertically narrow palpebral fissures; mild to moderate intellectual disability; behavioral difficulties; and hypertrichosis on the back. It is caused by heterozygous pathogenic variants in KMT2A. This gene has an established role in histone methylation, which explains the overlap of Wiedemann-Steiner syndrome with other chromatinopathies, a heterogeneous group of syndromic conditions that share a common trigger: The disruption of one of the genes involved in chromatin modification, leading to dysfunction of the epigenetic machinery.     

Identification of new Th peptides from the cytomegalovirus protein pp65 to design a peptide library for generation of CD4 T cell lines for cellular immunoreconstitution

CD8 and CD4 lymphocytes control cytomegalovirus (CMV) infection in immunocompetent individuals, while patients with defective cellular immunity are prone to endogenous reactivation of latent CMV or, like seronegative subjects, prone to primary infection. Administration of CMV-specific CD8 lymphocytes was beneficial for immunocompromised hemopoietic stem cell (HSC) graft recipients. Since CD4 cells contribute to expansion of cytotoxic T lymphocytes (CTL), we defined new T(h) peptides on the immunodominant protein pp65 recognized by CD4 cells from HLA-typed subjects, in the perspective of complementing CTL administration with CMV-specific T(h) cells. Screening by ELISPOT on CD4 and CD8 subsets using overlapping peptides identified 10 novel CD4 peptides. To simplify procedures to generate T cell lines, we used a CD4 peptide library for T cell stimulation instead of ill-defined viral lysates, without the requirement of dendritic cells. This library stimulated CMV-specific CD4 cells. In fact, peptide-induced CD4 cells responded to pp65 and to the viral lysate. These cells were also devoid of alloreactivity after one stimulation cycle. Since Good Manufacturing Procedure-grade peptides can be synthesized, culture conditions are simplified and alloreactivity is rapidly lost, these procedures based on peptide stimulation can facilitate implementation of adoptive reconstitution of CD4 responses in immunocompromised patients also in the case when the HSC allodonor is available for generation of the T cell line.     

Relationship between MUC5AC and altered expression of MLH1 protein in mucinous and non-mucinous colorectal carcinomas

The main purpose of this study was to examine the expression of mucins and mismatch repair proteins in colorectal carcinomas. The immunohistochemical distribution of apomucins MUC2, MUC5AC, and the expression of MLH1 and MSH2 proteins were examined in 76 mucinous and 60 non-mucinous colorectal carcinomas. MUC2 was noted in all mucinous carcinomas, whereas MUC5AC was present in 41 cases only (54%). In non-mucinous carcinomas, MUC2 was expressed in 61.7% of the tumors; by contrast, MUC5AC was present in 20% of the cases. The expression level of apomucins was significantly different in mucinous and non-mucinous lesions (p<0.001). Twenty-seven (35.5%) of the mucinous carcinomas showed no MLH1 expression, whereas 11 (18.3%) of the non-mucinous tumors did. This difference was statistically significant (p<0.005). Altered expression of MSH2 protein was never observed. The lack of MLH1 expression was considerably more frequent in carcinomas with secretion of MUC5AC (p<0.005). Our study has demonstrated this close relationship by immunohistochemical methods. In summary, our data show: (1) differences in the expression of mucins between mucinous and non-mucinous tumors; (2) a high frequency of altered MLH1 protein expression (35.5%) in mucinous carcinomas; (3) a significant relationship between the presence of MUC5AC and the altered expression of MLH1 protein in colorectal carcinomas.     

Cytokine production pathway in the elderly

It is well known that aging is associated with various alterations in lymphoid cell functions, particularly with a progressive decline in immune responsiveness to exogenous antigens and increasing incidence of autoimmune phenomena. Many studies have been focused on the mechanisms of the immunologic features of aging. This review describes our results of studies performed to determine the influence of age on the capacity to produce interleukin-2 (IL-2), interferon-γ (IFN-γ), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6) and tumor necrosis factor (TNF). Mitogen-stimulated cultures of mononuclear cells (MNC) from human beings were assessed for cytokine-producing capacity. A significant decrease in IFN-γ and IL-2 production by MNC cultures from elderly individuals was observed. No significant difference was instead observed between cultures from elderly individuals and those from young ones as regards TNF-α, IL-4 and IL-6 production. Mitogen or antigen-stimulated cultures of MNC from aged mice also displayed a significant decrease in IFN-γ and IL-2 production as well as TNF-β. Instead IL-4 and IL-5 production significantly increased in these cultures. We suggest that this imbalanced cytokine production may well account for the pattern of immune response which may be observed in the elderly, i.e. a normal or increased humoral response (including autoimmune responses) in face of a low T cell immune responsiveness.     

Interaction between NH(2)-tau fragment and Aβ in Alzheimer's disease mitochondria contributes to the synaptic deterioration

Although amyloid beta (Aβ) peptide can promote tau pathology and its toxicity is concurrently tau-dependent, the underlying mechanisms of the in vivo interplay of these proteins remain unsolved. Structural and functional mitochondrial alterations play an early, precipitating role in synaptic failure of Alzheimer's disease (AD) pathogenesis and an aggravated mitochondrial impairment has been described in triple APP/PS/tau transgenic mice carrying both plaques and tangles, if compared with mice overexpressing tau or amyloid precursor protein (APP) alone. Here, we show that a neurotoxic aminoterminal (NH(2))-derived tau fragment mapping between 26 and 230 amino acids of the human tau40 isoform (441 amino acids)-but not the physiological full-length protein-preferentially interacts with Aβ peptide(s) in human AD synapses in association with mitochondrial adenine nucleotide translocator-1 (ANT-1) and cyclophilin D. The two peptides-Aβ 1-42 and the smaller and more potent NH(2)-26-44 peptide of the longest 20-22 kDa NH(2)-tau fragment-inhibit the ANT-1-dependent adenosine diphosphate-adenosine triphosphate (ADP/ATP) exchange in a noncompetitive and competitive manner, respectively, and together further aggravate the mitochondrial dysfunction by exacerbating the ANT-1 impairment. Taken together, these data establish a common, direct and synergistic toxicity of pathological APP and tau products on synaptic mitochondria and suggest potential, new pathway(s) and target(s) for a combined, more efficient therapeutic intervention of early synaptic dysfunction in AD.     

Somatoform and psychoform dissociation among women with orgasmic and sexual pain disorders

Since the 20th century, psychogenic female sexual dysfunctions (FSD), like some somatoform and conversion disorders, have been considered an expression of somatoform dissociation. Several studies have reported dissociative symptoms in different somatoform and conversion disorders, but limited data are available on dissociation among patients with FSD. The aim of this study was to assess somatoform and psychoform dissociation among patients with women's orgasmic disorder, dyspareunia, and vaginismus. A battery of self-administered questionnaires (Somatoform Dissociation Questionnaire, Dissociative Experiences Scale, Hospital Anxiety and Depression Scale, Impact of Event Scale-Revised) was given to 200 gynecological outpatients to assess psychoform and somatoform dissociation and their association with FSD. A strong association between somatoform dissociation and FSD was observed (adjusted odds ratio [OR] = 5.39, 95% confidence interval [CI] = 1.15-25.32), the association between somatoform and psychoform dissociation being estimated by an adjusted OR of 4.83 (95% CI = 1.17-19.91). Our results are compatible with the idea that some forms of FSD could be regarded as somatoform dissociative disorders.     

Pro‐B cells propagated in stromal cell‐free cultures reconstitute functional B‐cell compartments in immunodeficient mice

Up to now long‐term in vitro growth of pro‐B cells was thought to require stromal cells. However, here we show that fetal liver (FL) and bone marrow (BM) derived pro‐B cells can be propagated long‐term in stromal cell‐free cultures supplemented with IL‐7, stem cell factor and FLT3 ligand. Within a week, most cells expressed surface CD19, CD79A, λ5, and VpreB antigens and had rearranged immunoglobulin D‐J heavy chain genes. Both FL and BM pro‐B cells reconstituted the B‐cell compartments of immuno‐incompetent Rag2‐deficient mice, with FL pro‐B cells generating follicular, marginal zone (MZB) and B1a B cells, and BM pro‐B cells giving rise mainly to MZB cells. Reconstituted Rag2‐deficient mice generated significant levels of IgM and IgG antibodies to a type II T‐independent antigen; mice reconstituted with FL pro‐B cells generated surprisingly high IgG₁ titers. Finally, we show for the first time that mice reconstituted with mixtures of pro‐B and pro‐T cells propagated in stromal cell‐free in vitro cultures mounted a T‐cell‐dependent antibody response. This novel stromal cell‐free culture system facilitates our understanding of B‐cell development and might be applied clinically.