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This is a personal, informal and non-sponsored commentary on papers recently published by the Italian biomedical research community.
The purpose is to draw attention not only to good Italian research,
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The selection of articles is purely subjective, but your suggestions are welcome. Write to me, Valerie Matarese, at vmatarese@ uptoit.org; copies of non-OA papers are welcome.
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Up To it! Home > Italian biomedical research highlights > July-December 2009
The vascularization of neoplastic lesions is essential for tumor growth and metastasis. Therefore, tumor neoangiogenesis has been a major area of study in the attempt to design effective anticancer therapies. Initial efforts have focused on blocking dysregulated pro-angiogenic factors such as VEGF, yet vessel formation depends on a balance of pro- and anti-angiogenic factors in both normal and cancerous tissues. Therefore, researchers from Turin, Milan and Trieste hypothesized that cancer progression also involved a loss of normal anti-angiogenic factors. They tested their hypothesis in three transgenic mouse models of multistage tumorigenesis.
The researchers focused on the secreted chemorepulsive class 3 semaphorins (Sema3s), proteins that bind endothelial cell receptors involved in down-regulating angiogenesis and integrin-mediated adherence. They studied the expression of seven Sema3 proteins and several of their receptors (neuropilins and plexins) during the different stages of tumor formation, compared to normal tissues. In the RipTag2 model of pancreatic cancer, levels of Sema3 mRNA in hyperplastic islets were similar to those in normal tissue but, in angiogenic islets and in developed tumors, Sema3 expression was dysregulated: many genes were down-regulated but Sema3a and Sema3f (and to a lesser extent Sema3e) were up-regulated in angiogenic islets. A similar pattern emerged in the HPV/E2 mouse, with up-regulation of Sema3a, 3e and 3f in high-grade dysplasia followed by strong down-regulation in advanced squamous cell carcinoma. Differential expression of transcripts of Sema3 receptors, during the various stages of cancer, was also observed. These gene expression findings were confirmed at the protein level by immunofluorescence studies.
Since Sema3A is less characterized than Sema3F, the researchers continued their work by focusing on the former. Briefly, they found similar expression patterns of Sema3A in specimens of human uterine cervical cancer taken at different stages of progression. In RipTag2 mice already with tumors, re-expression of Sema3A, driven by exogenous gene delivery, reduced tumor volume, induced stable disease and prolonged survival. Moreover, overexpression of Sema3A in young RipTag2 mice, before tumor development, had a protective effect. Other experiments provided insight into the molecular functions of Sema3A signalling. Altogether, these experiments document that Sema3A has strong anti-angiogenic properties and is dysregulated during cancer progression. The complex research reported in this well written paper, published in the Journal of Clinical Investigation (PMID: 19809158), opens the possibility of developing novel anticancer therapies by reestablishing the natural anti-angiogenic signalling of the Sema3A pathway. Posted 12 November 2009.
Very low-birth-weight neonates (<1.5 kg) who survive the first perinatal days remain at high risk of nosocomial infections until they are discharged home. The Italian Task Force for the Study and Prevention of Neonatal Fungal Infections (part of the Italian Society of Neonatology) conducted a multicenter randomized controlled trial to test the effectiveness of supplementation with lactoferrin in reducing the incidence of late-onset sepsis. In the trial, 472 newborn infants were randomized to receive bovine lactoferrin, without or with the probiotic Lactobacillus rhamnosus GG, or placebo (all supplied by Dicofarm Spa); treatment began on day 3 of life and continued for up to 45 days or until discharge. During the study period, 45 infants had sepsis and 22 died (9 deaths were attributable to sepsis). There were significantly fewer cases of sepsis among neonates who received lactoferrin, with or without the probiotic. Supplementation with lactoferrin also significantly reduced mortality: there was no death among infants receiving lactoferrin, one death among those receiving lactoferrin and probiotic, and 8 deaths in the control group. The authors concluded that lactoferrin supplementation is a safe and effective prophylaxis for these high-risk infants. Following international standards for the proper conduction of a clinical trial, the researchers had registered the study at the ISRCTN Register and obtained an independent statistical analysis without interference by the sponsoring company. These factors, together with the quality conduction of the trial and the important topic, helped this Italian study be published in JAMA (PMID: 19809023). Posted 23 October 2009.
Marine mucilage, a floating, gelatinous aggregate of polymeric compounds derived from stressed and dying marine organisms, can extend for hundreds of kilometers in coastal waters. Mostly observed in the Mediterranean Sea, mucilage has known detrimental effects on fishing and tourism. Researchers from Ancona and Trieste hypothesized that marine mucilage favors the growth of pathogenic microorganisms. They therefore identified and quantified viruses and prokaryotes in the Adriatic Sea, and found that mucilage was not only highly enriched in microorganisms, compared to normal seawater, but also had a different biotic profile. In particular, mucilage was enriched in coliform bacteria and contained pathologic species (such as Vibrio harveyi) absent from seawater. In further analyses, the authors found an association between mucilage outbreaks and the warming of surface seawater over 60 years. The study, published in PLoS One (PMID: 19759910), suggests that mucilage will be an increasing phenomenon in the Mediterranean Sea, due to climate change and abuse of marine resources, and will pose serious risks for marine and human health. Posted 14 October 2009.
Endometriosis is a common disease that causes pain and infertility in women of childbearing age. It is thought to have a multifactorial etiology involving genetic factors and exposure to endocrine-disrupting or immunotoxic agents, particularly halogenated organic industrial pollutants like dioxins and polychlorinated biphenyls (PCBs).
Researchers from Rome, in a continued effort to understand the risks these compound pose, did a case-control study in which PCBs and other persistent pollutants were measured in women with or without endometriosis. Serum levels of 8 of 11 tested PCBs were significantly higher in cases with endometriosis than in controls; total PCB levels were 50% higher and levels of DDE, a metabolite of the pesticide dichlorodiphenyltrichloroetha ne (DDT), were 45% higher in cases than controls. High concentrations of total PCBs gave a 5.6-fold increased risk and high levels of DDE gave a 2.1-fold increased risk of endometriosis. These data strengthen the evidence base for an association between accumulated organohalogenated pollutants and endometriosis. Since no evidence for increased exposure to the pollutants among cases was found, this study suggests that the disease may manifest in women less able to eliminate or detoxify these compounds; molecular studies into this aspect of endometriosis are warranted. The study was published in Environmental Health Perspectives (PMID: 19654915), a highly selective journal (acceptance rate, 20%) of the US National Institute of Environmental Health Sciences. Posted 28 August 2009.
The June 17th issue of JAMA, a leading general medical journal published by the American Medical Association, reported the results of two Italian multicenter trials. Interest in these studies was such that the journal dedicated to them two 2-page editorials and a "JAMA patient page".
Daniele Regge and colleagues from 11 Italian centers and one Belgian center carried out a cross-sectional study to assess the diagnostic accuracy of CT colonography as a screening tool for colorectal cancer (CRC) in high-risk patients. CT colonography has already been shown to be accurate in the general population and is recommended for use as an alternative screening method in patients who cannot undergo colonoscopy, but its use had not yet been studied in a high-risk population. The study enrolled persons with a family history of CRC or a personal history suggestive of cancer, such as positive results at fecal occult blood testing or the previous removal of a colorectal adenoma. Altogether, 937 persons underwent CT colonography and, as a reference test, optical colonoscopy; this later test identified 177 persons (18.9%) with advanced neoplastic lesions 6 mm or larger. Screening noninvasively with CT colonography correctly identified 151 of these persons (sensitivity, 85.3%) and correctly indicated no disease in 667 of the remaining 760 persons with normal colonoscopy findings (specificity, 87.8%). The authors concluded that CT colonoscopy could be used as an alternative screening test also in high-risk persons. (PMID: 19531785)
Dinna N. Cruz and coworkers from 10 Italian intensive care units reported the results of a randomized controlled trial called "Early use of polymyxin B hemoperfusion in abdominal septic shock" (EUPHAS). Their study tested the clinical impact of removing endotoxin from the blood of persons with intra-abdominal infections causing severe sepsis or septic shock and requiring surgical treatment. Such infections are often caused by gram-negative bacteria that produce endotoxin. This toxin can be removed from blood by extracorporeal hemoperfusion over polymyxin-covered beads. In the study, patients underwent emergency abdominal surgery and then were randomized to receive either conventional care for sepsis (n=30) or to undergo two sessions of hemoperfusion (n=34), and then were followed until discharge or death. At the 72-hour follow-up, the hemoperfusion group had significant improvements in arterial pressure, ionotropic scores and vasopressor dependency index compared to baseline values, whereas in the control group these parameters did not change significantly. The hemoperfusion group had a significantly lower mortality rate at 28 days (adjusted hazards ratio, 0.36). This result caused the researchers to terminate the trial early, before enrolling the projected 120 patients, because it was unethical to continue randomizing patients to the control group when the conventional sepsis treatment had been proved less effective in saving lives. Further studies of this emergency therapy are warranted to determine its applicability in other critical patient groups and to identify the best treatment schedule. (PMID: 19531784)
Posted 16 July 2009.
The Italian Society of Neonatology, through its pain study group, has recently established guidelines on preventing and controlling pain during invasive procedures on neonates. Newborn infants - whose nervous system is still developing - are highly sensitive to pain and respond to such stimuli with hormonal and metabolic reactions that may have long-term behavioral effects. To develop the guidelines, the pain study group conducted a systematic review of the literature for evidence on pharmacological, non-pharmacological, environmental and behavioral strategies to reduce pain during ten common neonatal procedures. Each strategy was discussed by the writing group until a consensus was reached regarding the level of evidence (scored according to the SIGN classification, ). The guidelines were then critically appraised by practitioners and parents before being endorsed by the Italian Society of Neonatology. The document, published in Acta Paediatrica (PMID: 19484828) and freely available under the Wiley-Blackwell "online open" option, should guide neonatologists in understanding and managing pain in newborn infants. Posted 16 July 2009.
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