Individuals with presumably hereditary uveal melanoma do not harbour germline mutations in the coding regions of either the P16INK4A, P14ARF or cdk4 genes

In familial cutaneous malignant melanoma (CMM), disruption of the retinoblastoma (pRB) pathway frequently occurs through inactivating mutations in the p16 (p16INK4A/CDKN2A/MTS1) gene or activating mutations in the G1-specific cyclin dependent kinase 4 gene (CDK4). Uveal malignant melanoma (UMM) also occurs in a familial setting, or sometimes in association with familial or sporadic CMM. Molecular studies of sporadic UMM have revealed somatic deletions covering the INK4A-ARF locus (encoding P16INK4Aand P14ARF) in a large proportion of tumours. We hypothesized that germline mutations in the p16INK4A, p14ARFor CDK4 genes might contribute to some cases of familial UMM, or to some cases of UMM associated with another melanoma. Out of 155 patients treated at the Institut Curie for UMM between 1994 and 1997, and interviewed about their personal and familial history of melanoma, we identified seven patients with a relative affected with UMM (n = 6) or CMM (n = 1), and two patients who have had, in addition to UMM, a personal history of second melanoma, UMM (n = 1), or CMM (n = 1). We screened by polymerase chain reaction single-strand conformation polymorphism the entire coding sequence of the INK4A-ARF locus (exon 1α from p16INK4A, exon 1β from p14ARF, and exons 2 and 3, common to both genes), as well as the exons 2, 5 and 8 of the CDK4 gene, coding for the functional domains involved in p16 and/or cyclin D1 binding. A previously reported polymorphism in exon 3 of the INK4A-ARF locus was found in one patient affected with bilateral UMM, but no germline mutations were detected, either in the p16INK4A, p14ARFor CDK4 genes. Our data support the involvement of other genes in predisposition to uveal melanoma. © 2000 Cancer Research Campaig

Experience of safety monitoring in the context of a prospective observational study of artemether-lumefantrine in rural Tanzania: lessons learned for pharmacovigilance reporting

<p>Abstract</p> <p>Objectives</p> <p>To identify and implement strategies that help meet safety monitoring requirements in the context of an observational study for artemether-lumefantrine (AL) administered as first-line treatment for uncomplicated malaria in rural Tanzania.</p> <p>Methods</p> <p>Pharmacovigilance procedures were developed through collaboration between the investigating bodies, the relevant regulatory authority and the manufacturer of AL. Training and refresher sessions on the pharmacovigilance system were provided for healthcare workers from local health facilities and field recorders of the Ifakara Health Demographic Surveillance System (IHDSS). Three distinct channels for identification of adverse events (AEs) and serious adverse events (SAEs) were identified and implemented. Passive reporting took place through IHDSS and health care facilities, starting in October 2007. The third channel was through solicited reporting that was included in the context of a survey on AL as part of the ALIVE (<b>A</b>rtemether-<b>L</b>umefantrine <b>I</b>n <b>V</b>ulnerable patients: <b>E</b>xploring health impact) study (conducted only in March-April 2008).</p> <p>Results</p> <p>Training was provided for 40 healthcare providers (with refresher training 18 months later) and for six field recorders. During the period 1^stSeptember 2007 to 31^stMarch 2010, 67 AEs were reported including 52 under AL, five under sulphadoxine-pyrimethamine, one under metakelfin, two after antibiotics; the remaining seven were due to anti-pyretic or anti-parasite medications. Twenty patients experienced SAEs; in 16 cases, a relation to AL was suspected. Six of the 20 cases were reported within 24 hours of occurrence.</p> <p>Discussion</p> <p>Safety monitoring and reporting is possible even in settings with weak health infrastructure. Reporting can be enhanced by regular and appropriate training of healthcare providers. SMS text alerts provide a practical solution to communication challenges.</p> <p>Conclusion</p> <p>Experience gained in this setting could help to improve spontaneous reporting of AEs and SAEs to health authorities or marketing authorization holders.</p

Second malignant neoplasms after a first cancer in childhood: temporal pattern of risk according to type of treatment

The variation in the risk of solid second malignant neoplasms (SMN) with time since first cancer during childhood has been previously reported. However, no study has been performed that controls for the distribution of radiation dose and the aggressiveness of past chemotherapy, which could be responsible for the observed temporal variation of the risk. The purpose of this study was to investigate the influence of the treatment on the long-term pattern of the incidence of solid SMN after a first cancer in childhood. We studied a cohort of 4400 patients from eight centres in France and the UK. Patients had to be alive 3 years or more after a first cancer treated before the age of 17 years and before the end of 1985. For each patient in the cohort, the complete clinical, chemotherapy and radiotherapy history was recorded. For each patient who had received external radiotherapy, the dose of radiation received by 151 sites of the body were estimated. After a mean follow-up of 15 years, 113 children developed a solid SMN, compared to 12.3 expected from general population rates. A similar distribution pattern was observed among the 1045 patients treated with radiotherapy alone and the 2064 patients treated with radiotherapy plus chemotherapy; the relative risk, but not the excess absolute risk, of solid SMN decreased with time after first treatment; the excess absolute risk increased during a period of at least 30 years after the first cancer. This pattern remained after controlling for chemotherapy and for the average dose of radiation to the major sites of SMN. It also remained when excluding patients with a first cancer type or an associated syndrome known to predispose to SMN. When compared with radiotherapy alone, the addition of chemotherapy increases the risk of solid SMN after a first cancer in childhood, but does not significantly modify the variation of this risk during the time after the first cancer. © 1999 Cancer Research Campaig

Atorvastatin Improves Survival in Septic Rats: Effect on Tissue Inflammatory Pathway and on Insulin Signaling

The aim of the present study was to investigate whether the survival-improving effect of atorvastatin in sepsis is accompanied by a reduction in tissue activation of inflammatory pathways and, in parallel, an improvement in tissue insulin signaling in rats. Diffuse sepsis was induced by cecal ligation and puncture surgery (CLP) in male Wistar rats. Serum glucose and inflammatory cytokines levels were assessed 24 h after CLP. The effect of atorvastatin on survival of septic animals was investigated in parallel with insulin signaling and its modulators in liver, muscle and adipose tissue. Atorvastatin improves survival in septic rats and this improvement is accompanied by a marked improvement in insulin sensitivity, characterized by an increase in glucose disappearance rate during the insulin tolerance test. Sepsis induced an increase in the expression/activation of TLR4 and its downstream signaling JNK and IKK/NF-κB activation, and blunted insulin-induced insulin signaling in liver, muscle and adipose tissue; atorvastatin reversed all these alterations in parallel with a decrease in circulating levels of TNF-α and IL-6. In summary, this study demonstrates that atorvastatin treatment increased survival, with a significant effect upon insulin sensitivity, improving insulin signaling in peripheral tissues of rats during peritoneal-induced sepsis. The effect of atorvastatin on the suppression of the TLR-dependent inflammatory pathway may play a central role in regulation of insulin signaling and survival in sepsis insult

Ovarian cancer

Ovarian cancer is not a single disease and can be subdivided into at least five different histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically diagnosed at a late stage and has no effective screening strategy. Standard treatments for newly diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent cancer, chemotherapy, anti-angiogenic agents and poly(ADP-ribose) polymerase inhibitors are used, and immunological therapies are currently being tested. High-grade serous carcinoma (HGSC) is the most commonly diagnosed form of ovarian cancer and at diagnosis is typically very responsive to platinum-based chemotherapy. However, in addition to the other histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy. Consequently, understanding the mechanisms underlying platinum resistance and finding ways to overcome them are active areas of study in ovarian cancer. Substantial progress has been made in identifying genes that are associated with a high risk of ovarian cancer (such as BRCA1 and BRCA2), as well as a precursor lesion of HGSC called serous tubal intraepithelial carcinoma, which holds promise for identifying individuals at high risk of developing the disease and for developing prevention strategies

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

metabolic bone disease and osteoporosis in children

To understand the basics of pediatric bone metabolism and mechanisms underlying osteoporosi