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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,
but also to good scientific reporting and publishing from Italy.
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 > January-June 2009
To a Lancet subscriber, the article type called "seminar" is a clearly written and well documented overview of an important medical topic. Italian authors Di Sabatino and Corazza, from the Policlinico San Matteo at the University of Pavia, maintained the usual Lancet quality in their recent paper on coeliac disease, calling on their own clinical research experience and a review of the literature.
In their paper, the authors reviewed the epidemiology, etiology and pathophysiology of coeliac disease, described its clinical presentation and natural course, explained current diagnostic approaches and dietary treatments, and discussed possible complications such as enteropathy-associated lymphoma due to the proliferation of T cell clones in the disturbed intestinal epithelium. They concluded by highlighting innovative approaches to managing the disease, through both the use of novel medicines and the development of grains and foods with less immunotoxicity. The paper appeared in the 25 April issue of Lancet (PMID: 19394538). Posted 11 May 2009.
Cancer progression from a microscopic lesion to a large, aggressive tumor requires the induction of neoangiogenesis and the development of an intratumoral vascular network. Nonetheless, tumoral vessels are morphologically and functionally abnormal, resulting in the characteristic hypoxia (and necrosis) within areas of viable tissue. Intratumoral hypoxia promotes cellular processes necessary for cancer progression, such as induction of anaerobic metabolism and maintenance of an undifferentiated state, and thus has been thought to be a determinant – rather than an epiphenomenon – of neoplasia. However, experimental demonstration of the role of hypoxia in neoplasia has been lacking.
Researchers from Turin developed a novel cellular approach to manipulating tumor tissue oxygenation in order to directly study the effects of hypoxia. They expressed myoglobin, a protein that binds, stores, buffers and transports oxygen, in A549 human lung carcinoma cells. Cells expressing myoglobin were more resistant to hypoxia and manifested an attenuated response in terms of anaerobic metabolism and induction of hypoxia-inducible factor (HIF)-1α. When injected into mice, myoglobin-expressing carcinoma cells took longer to implant and form tumors, which grew more slowly than those from control A549 cells. Tumors formed by myoglobin-expressing cells had greater tissue oxygenation, fewer hypoxic areas, more normal vasculature architecture, lower HIF-1α expression and decreased metastatic potential than control tumors. These and other findings in this well-executed research provide experimental support for the hypothesis that hypoxia is not simply a byproduct of neoplasia but serves a determining role in cancer progression and invasiveness. The study was published in the Journal of Clinical Investigation (PMID: 19307731). Posted 20 April 2009.
Until recently, mutations causing familial forms of Alzheimer's disease (AD) have all been characterized by a autosomal dominant inheritance pattern. Now, researchers in Milan (together with a colleague in New York) have identified a recessive mutation causing familial AD only in homozygous state. Their study, published in Science (PMID: 19286555), sheds light on the mechanism of disease and opens new avenues for the design of therapeutic agents.
The newly identified mutation is a C-to-T transition that results in an alanine-to-valine substitution at position 673 of the β-amyloid precursor protein (APP). When APP is proteolytically processed, the altered residue takes position 2 of the β-amyloid (Aβ) protein. This mutation caused severe, early onset dementia in the proband; his younger sibling, also homozygous, is beginning to show cognitive impairment, but heterozygous family members have no symptoms. The mutation increased APP processing into Aβ in primary cultures and in transiently transfected cells, while in vitro it accelerated the aggregation kinetics of Aβ, increased the size of Aβ agglomerates, and increased the toxicity of Aβ towards cultured neuroblastoma cells. Unexpectedly, when the in vitro experiments were performed with equimolar amounts of mutant and wildtype Aβ, the researchers found opposite results: delayed aggregation leading to the formation of small, unstable agglomerates and significantly reduced neurotoxicity (even in comparison to wildtype Aβ). These latter results explain why the disease does not manifest in heterozygous carriers of mutations at position 673 of APP (position 2 of Aβ). Moreover, they intriguingly suggest that treatment with modified Aβ peptides or peptide mimics may similarly interfere with amyloidogenesis. Posted 19 March 2009.
The quality of a research report depends on both the research and the reporting. Quality in clinical research requires careful design and precise execution of the study to avoid bias and to maximize the strength of the evidence. Quality in reporting means clear and rigorous analysis of the data and logical interpretation of the results. The range of quality of published reports is wide and, as is beginning to emerge, there is a puzzling relationship between quality and conclusions favorable to the use of certain therapies.
Researchers at the Cochrane Vaccines Field, in Alessandria, did a systematic review of clinical trials on the effectiveness of influenza vaccines. Their aim was to understand the nature of the evidence base in this field and to identify the aspects of research and reporting associated with conclusions supporting or not the use of such vaccines. They identified 259 papers, of which 70% supported influenza vaccine use, and evaluated them for methodological quality, concordance between results and conclusions, type of funding (industry vs. government or nonprofit) and other aspects, such as study size, citation index and the journal's impact factor. Overall, quality of the included papers was low: 56% of papers were at high risk of bias (research quality) and 82% had some problem in concordance between results and conclusions (reporting quality). A conclusion in favor of vaccine use was 5-times less likely among studies with good methodological quality and 25-times less likely in papers with good concordance; studies with government funding were 2-times less likely to support vaccine use than those with industry funding. Curiously, studies published in high-impact-factor journals did not have higher quality in either research or reporting but they were more likely to have industry funding than papers published in other journals.
This study, published in BMJ (PMID: 19213766), draws a number of interesting and important conclusions. Despite the wealth of information on how to design a clinical trial, poor quality trials with inherent biases are still being conducted and published. Moreover, results of clinical trials are not always fairly and accurately interpreted by authors. Readers of the scientific literature - in particular clinicians and policy makers - must rely on their own critical appraisal of primary research reports; not even restricting our reading to prestigious journals can guarantee quality findings and honest interpretation. Posted: 23 February 2009.
Tick-borne encephalitis (TBE) is caused by a flavivirus that is transmitted to humans by ticks (Ixodes ricinus in Europe). The disease is often biphasic, with an early viremic stage causing flu-like symptoms and a second stage in which symptoms may range from mild meningitis to severe encephalitis, causing permanent neurological sequelae in some patients. Although the disease is rare, its incidence in Europe is increasing in a heterogeneous manner, characterized by outbreaks clustered in foci.
Rizzoli and colleagues, at the Edmund Mach Foundation (Trento), wanted to identify the factors responsible for the upsurge of this zoonotic disease in certain parts of northern Italy. They based their study on the observation that the 198 TBE cases in Italy since 1990 have been clustered in 7 alpine provinces yet absent from another 10 provinces with similar characteristics in terms of forest and pasture lands and ungulate populations. They therefore compared these two sets of provinces in terms of climate, ungulate populations, and forest cover. They used a generalized linear model with binomial error distribution to analyze the relationships of these variables with the incidence of TBE, and used Akaike's information criterion to select a model in which TBE was best predicted by the environmental variables. The analysis showed that the growing incidence of TBE in the 7 provinces depended on both the relative amount of high-stand forest compared to coppice (forest from root sprouts of cut trees) and the density of roe deer; climatic variables did not explain the clustered outbreaks of TBE. These results suggest that modern forestry management practices, permitting the growth of mature trees, also provide habitat for deer and rodents in which the tick and TBE virus propagate. This study, published in PLoS ONE (PMID: 19183811), provides not only insight into the recent clustering of TBE in Italy, but also sets out a systematic method for assessing TBE risk. The authors encouraged the longitudinal recording of relevant biotic and clinical data for a more accurate assessment of TBE in these areas. Posted: 7 February 2009.
During neoplasia, genomic alterations (i.e. deletions, amplifications and loss of heterozygosity) result in altered gene expression patterns. Molecular methods that reveal both genomic and transcriptomic aberrations are considered the state-of-the-art for understanding carcinogenesis and for identifying cancer-related genes. In particular, genes whose expression levels increase in association with increased copy number (due to amplification) are likely to be involved in the initiation and progression of a tumor.
Researchers from Milan applied such a dual genomic-transcriptomic approach, using high-density SNP mapping and gene expression microarrays, to study renal cell carcinoma (RCC). The comparison between tumoral and normal cortical tissues identified 71 differentially expressed genes associated with genomic alterations. Differentially expressed genes in amplified genomic areas were predominantly upregulated. Some of these genes are known to be associated with RCC, confirming the validity of this approach, while others represent novel findings. The next step of this important research is to investigate whether the genes associated for the first time with RCC have direct roles in carcinogenesis and if they can serve as specific biomarkers of the disease. The research was published this month in the open access journal Molecular Cancer (PMID: 18194544). Posted: 20 January 2009.
Rituximab is a chimeric monoclonal antibody used in the treatment of B cell tumors and autoimmune diseases; it exerts its cytotoxic effects by binding the integral membrane protein CD20. Since not all antibodies that bind the same epitope of CD20 have the same efficacy, researchers from Bari and Catania investigated the molecular determinants of rituximab's immunotherapeutic activity. They did this by testing peptide mimics of the CD20 epitope in a series of cellular and biochemical experiments, and supported their findings with molecular modelling. The study, published in the Journal of Immunology (PMID: 19109173), suggests that this monoclonal antibody recognizes two structurally different CD20-associated epitopes, an unexpected but fascinating result. The biological interpretation and therapeutic importance of these results are yet to be solved. Posted 15 January 2009.
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