San Giovanni Rotondo, Italy
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Cordani N.,Scientific Institute | Pisa V.,University of Milan | Pozzi L.,Scientific Institute | Sciorati C.,San Raffaele Scientific Institute | And 2 more authors.
Stem Cells | Year: 2014

Duchenne muscular dystrophy (DMD) is an hereditary disease characterized by loss of muscle fibers and their progressive substitution by fat and fibrous tissue. Mesenchymal fibro-adipogenic progenitors (FAPs) expressing the platelet-derived growth factor receptor alpha (PDGFRα) are an important source of fibrosis and adipogenesis in dystrophic skeletal muscle. Among the therapies suggested for dystrophy are those based on nitric oxide (NO) donating drugs, the administration of which slows disease progression. NO has been shown to act by enhancing the regenerative potential of the diseased muscle. Whether it acts also by inhibiting fibrosis and adipogenesis was not known. Here, we show in vitro that NO regulates FAP fate through inhibition of their differentiation into adipocytes. In mdx mice, an animal model of DMD, treatment with the NO donating drug molsidomine reduced the number of PDGFRα + cells as well as the deposition of both skeletal muscle fat and connective tissues. Inhibition of adipogenesis was due to NO-induced increased expression of miR-27b leading to downregulation of peroxisome proliferator-activated receptors gamma (Pparγ1) expression in a pathway independent of cGMP generation. These findings reveal an additional effect of NO in dystrophic muscle that conceivably synergizes with its known effects on regeneration improvement and explain why NO-based therapies appear effective in the treatment of muscular dystrophy. © AlphaMed Press 2013.


Casartelli L.,University of Geneva | Casartelli L.,Scientific Institute | Molteni M.,Scientific Institute
Neuroscience and Biobehavioral Reviews | Year: 2014

The relationships between mirror neurons (MNs) and motor imitation, and its clinical implications in autism spectrum disorder (ASD) have been widely investigated; however, the literature remains - at least partially - controversial. In this review we support a multi-level action understanding model focusing on the mirror-based understanding. We review the functional role of the parieto-frontal MNs (PFMN) network claiming that PFMNs function cannot be limited to imitation nor can imitation be explained solely by the activity of PFMNs. The distinction between movement, motor act and motor action is useful to characterize deeply both act(ion) understanding and imitation of act(ion). A more abstract representation of act(ion) may be crucial for clarifying what, why and how an imitator is imitating. What counts in social interactions is achieving goals: it does not matter which effector or string of motor acts you eventually use for achieving (proximal and distal) goals. Similarly, what counts is the ability to recognize/imitate the style of act(ion) regardless of the way in which it is expressed. We address this crucial point referring to its potential implications in ASD. © 2014 Elsevier Ltd. All rights reserved.


Casartelli L.,University of Geneva | Casartelli L.,Scientific Institute | Chiamulera C.,University of Verona
Current Opinion in Psychiatry | Year: 2013

PURPOSE OF REVIEW: In the last decade, a number of studies have been published to shed light on the interaction between neuroscience and the law, notably on the introduction of neuroscience data in forensic psychiatric evaluation (FPE). Even if there is a growing consensus on the relevance of neuroscience in clinical practice, the role of neuroscience in FPE is still controversial. RECENT FINDINGS: The use of neuroscience data in FPE can support the detection of psychopathological disabilities (e.g. deficit of self-control, aggressiveness) that may be involved in criminal action. Traumatic brain injury-related clinical disorders that may lead to misconduct have a relevant role in the debate. Traditionally, literature refers also to rare and weird cases in which brain tumours, infections and morphological abnormalities were supposed to be significantly associated with disorders leading to criminal action. SUMMARY: After reviewing recent literature from both legal and neuroscientific perspectives, we consider a broader range of clinical conditions (e.g. disorders of consciousness in sleepwalking, dopamine replacement therapy in Parkinson's disease, misattributions of self in delusional experience) that may have implications in legal settings. Obviously, it would be possible to consider also different clinical conditions. We conclude by suggesting further experimental and theoretical analysis. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Ruffino M.,Scientific Institute | Gori S.,Scientific Institute | Gori S.,University of Padua | Boccardi D.,University of Padua | And 3 more authors.
Frontiers in Human Neuroscience | Year: 2014

Although the dominant view posits that developmental dyslexia (DD) arises from a deficit in phonological processing, emerging evidence suggest that DD could result from a more basic cross-modal letter-to-speech sound integration deficit. Letters have to be precisely selected from irrelevant and cluttering letters by rapid orienting of visual attention before the correct letter-to-speech sound integration applies. In the present study the time-course of spatial attention was investigated measuring target detection reaction times (RTs) in a cuing paradigm, while temporal attention was investigated by assessing impaired identification of the first of two sequentially presented masked visual objects. Spatial and temporal attention were slower in dyslexic children with a deficit in pseudoword reading (N = 14) compared to chronological age (N = 43) and to dyslexics without a deficit in pseudoword reading (N = 18), suggesting a direct link between visual attention efficiency and phonological decoding skills. Individual differences in these visual attention mechanisms were specifically related to pseudoword reading accuracy in dyslexics. The role of spatial and temporal attention in the graphemic parsing process might be related to a basic oscillatory temporal sampling" dysfunction. © 2014 Ruffino, Gori, Boccardi, Molteni and Facoetti.


Gori S.,University of Padua | Gori S.,Scientific Institute | Facoetti A.,University of Padua | Facoetti A.,Scientific Institute
Journal of Vision | Year: 2015

Developmental dyslexia (DD) is the most common neurodevelopmental disorder (about 10% of children across cultures) characterized by severe difficulties in learning to read. According to the dominant view, DD is considered a phonological processing impairment that might be linked to a cross-modal, letter-to-speech sound integration deficit. However, new theories-supported by consistent data-suggest that mild deficits in low-level visual and auditory processing can lead to DD. This evidence supports the probabilistic and multifactorial approach for DD. Among others, an interesting visual deficit that is often associated with DD is excessive visual crowding. Crowding is defined as difficulty in the ability to recognize objects when surrounded by similar items. Crowding, typically observed in peripheral vision, could be modulated by attentional processes. The direct consequence of stronger crowding on reading is the inability to recognize letters when they are surrounded by other letters. This problem directly translates to reading at a slower speed and being more prone to making errors while reading. Our aim is to review the literature supporting the important role of crowding in DD. Moreover, we are interested in proposing new possible studies in order to clarify whether the observed excessive crowding could be a cause rather than an effect of DD. Finally, we also suggest possible remediation and even prevention programs that could be based on reducing the crowding in children with or at risk for DD without involving any phonological or orthographic training. © 2015 ARVO.


News Article | November 18, 2015
Site: www.nature.com

Descriptions of a drug as revolutionary, transformative or a home run are usually reserved for press releases or presentations to investors. But oncologists are embracing such language to describe two drugs that allow them to offer some people with breast cancer a cure rather than a consolation. The drugs are trastuzumab (Herceptin) and pertuzumab (Perjeta). Both are antibody-based agents that target the signalling protein HER2, which is produced in abundance in 20–25% of breast tumours. The high levels result in poorly controlled cell growth and proliferation. For decades, the protein has been regarded as the hallmark of a dire prognosis, says oncologist Luca Gianni, at the San Raffaele Hospital Scientific Institute in Milan, Italy. Today, many patients with HER2-positive tumours are essentially having their cancer eradicated by receiving a double-hit of targeted therapy before surgery. Even patients diagnosed with late-stage, metastatic disease — once seen as an imminent death sentence — are living much longer than ever before. In a few exceptional cases, the duration of these benefits can be remarkable. “We never use the 'c-word' with metastatic disease, but I have one patient in my practice who has been in complete remission for 13 years,” says Shanu Modi, a medical oncologist at New York's Memorial Sloan Kettering Cancer Center. “I think of her as a cured person who just comes by my clinic to visit every three months.” These two agents exemplify the modern model of targeted therapy in oncology — give patients personalized treatments that selectively hit tumours based on their specific set of mutations, rather than conventional chemotherapy, which is broadly toxic to healthy as well as dangerous cells. Nevertheless, cancers will return in many people who receive prompt treatment. “I still don't think we're curing the vast majority of patients,” says Modi. New agents in the clinical pipeline could improve the effectiveness of these targeted agents and help doctors and patients to achieve more and longer-lasting victories, although some worry that soaring costs (see 'Crippling costs') will limit the reach of these next-generation therapeutics. Trastuzumab was the first HER2-targeting drug to reach the market, following a phase 3 clinical trial that showed that the drug improved the odds of survival by 20% in women with metastatic HER2-positive breast cancer1. Subsequent data showed that giving people the drug after the surgical removal of early-stage tumours cut the risk of the cancer returning in half2. “That's an absolute home run,” says Elizabeth Mittendorf, a surgical oncologist at Houston's MD Anderson Cancer Center. “We don't see numbers like that often in oncology.” In 2012, data from the CLEOPATRA clinical trial showed that oncologists could expect an even better return by pairing trastuzumab with pertuzumab3. Both drugs are antibodies that specifically bind HER2, but each recognizes a different site on the protein, and their combined effects (along with conventional chemotherapy) resulted in even greater tumour shrinkage and further improvements in prognosis for people with metastatic breast cancer. The combination prolonged median survival by well over a year relative to trastuzumab alone. “We give that combination to all of our metastatic patients as first-line treatment if we can,” says Modi, “and they're being treated for three or four years on average.” In two further trials4, 5, by using the trastuzumab–pertuzumab combination to shrink tumours before surgery — an approach known as neoadjuvant therapy — clinicians discovered that they could eradicate all traces of cancer from the breast and lymph nodes (known as a pathological complete response) in roughly half of patients. That is not the same as a cure, however, and these trials are too recent to confirm how durable the benefits are. Still, physicians are already seeing clear benefits in other domains. Mittendorf says she can now perform less-invasive operations that leave the breast largely intact, and neoadjuvant treatment can eliminate lymph node growths that previously required surgical removal. Oncologists are now eagerly awaiting the results from the recently concluded APHINITY trial, which measured survival and recurrence in patients given the combined therapy after surgery. Other HER2-targeted therapies have reached the clinic, but without offering such a clear patient benefit. Lapatinib, for example, delays tumour progression by interfering with HER2 signalling, but also exhibits more toxicity and is generally less effective as a first line of treatment than its antibody-based counterparts. As a result, lapatinib is generally reserved for late-stage treatment of patients whose tumours acquire resistance to trastuzumab or pertuzumab. Importantly, this treatment may also be effective at limiting metastatic growth in the brain — a particular threat to patients who are HER2-positive (see 'Staving off a deadly invasion'). Another HER2-targeted drug called T-DM1 (Kadcyla) mitigates the severe toxicity associated with conventional chemotherapy agents by physically tethering the chemotherapeutic agent DM1 to trastuzumab. This restricts the toxic effect to HER2-expressing cells. “There's no hair loss and very little neuropathy,” says Modi. “I think patients are enjoying a much better quality of life on T-DM1.” As one of the first antibody–drug conjugates to reach the clinic, T-DM1 extends median survival by more than five months in patients with recurrent HER2-positive breast cancer relative to lapatinib. A recently concluded trial called MARIANNE examined whether T-DM1 could replace trastuzumab and chemotherapy as the first line of treatment. Although less toxic than the standard drug combination, T-DM1 proved no more effective at delaying disease progression, and so will probably remain a second-line option. Gianni hopes that these results will not prevent clinicians from finding smart ways to incorporate this safe and generally effective drug into their regimens. “T-DM1 was presented as the solution to all of our problems, and now it's being demonized as an expensive failure — but this is not so,” he says. “It is simply a drug that requires some better thinking and a different approach.” The ability to target HER2 has been a life saver for many patients, but it is far from a complete victory. Many people who receive neoadjuvant treatment will not have their cancer eradicated. And although oncologists can keep cancer in people with metastatic disease at bay for years, this requires multiple rounds of therapeutic attack with a shifting arsenal of drugs. “The chance of having a durable response is much higher, and we're seeing patients with metastatic disease go through five, six or seven lines of treatment,” says Nancy Lin, an oncologist at the Dana-Farber Cancer Institute in Boston, Massachusetts. “But the disease is generally not curable.” The mechanisms by which HER2-positive tumours acquire resistance to the drugs that once laid them low are poorly understood. Gianni sees the tumour environment, which contains a diverse mixture of cells with distinct mutational profiles, as part of the problem. “If 30% of the cells in a tumour overexpress HER2, that's a HER2-positive tumour,” he says, “but many cells still do not express that target.” Thus, killing off trastuzumab-vulnerable cells will still leave a large cancerous community. This highlights the value of generalized chemotherapy, and Francisco Esteva at New York University's Langone Medical Center suggests that this phenomenon may also be to blame for T-DM1's modest performance in MARIANNE. “If you target too much, the other clones can escape,” he says. However, Thomas Bachelot, a medical oncologist at the Centre Léon Bérard, in Lyon, France, does not believe that this is the only mechanism by which tumours can recur after an initial therapeutic victory. “I do a lot of biopsies, and they always remain HER2-positive — they don't lose it,” he says, adding that even if the tumour rebounds while patients are taking trastuzumab or pertuzumab, they still draw some benefit from those drugs. If HER2-targeted therapies are halted, he says, patients tend to fare even worse than if they had stayed the course. This outcome hints at other cellular pathways and processes that amplify or mitigate the effects of HER2-targeted treatment. These pathways might therefore serve as useful biomarkers to guide therapy. The trial data point to sub-populations with strong responses in both directions — one neoadjuvant trial4 found that nearly 17% of patients had a pathological complete response from targeted drugs without any chemotherapy, a result that suggests that some patients could skip the most toxic components of treatment. Other tumours remain stubbornly unresponsive. “About 10% of our HER2-positive patients do not respond at all to trastuzumab and pertuzumab,” says Bachelot. “There is this huge primary resistance, and we don't know why.” Another apparent pathway to resistance arises from hyperactivation of a signalling cascade known as the phosphoinositide 3-kinase (PI3K) pathway. Preliminary clinical studies suggested that everolimus, a drug that interferes with PI3K signalling, might increase the effectiveness of trastuzumab against metastatic breast cancer. Although results from two phase 3 trials proved disappointing, subsequent examination of the data revealed that everolimus may delay progression in patients with mutations that affect PI3K activity6. However, Modi believes that future studies should hit this pathway through alternate means. “You can get a few weeks improvement from everolimus, but with a lot of toxicity,” she says. “There have got to be better drugs for targeting PI3K.” Her team is evaluating one such drug, BYL719, and has also seen promising results from another approach to bolstering HER2-targeted treatment. Tumour cells rely on a molecule called heat-shock protein 90 (HSP90) to manage the production of HER2, and Modi and colleagues have found that chemical inhibition of HSP90 can stall HER2-dependent tumour growth7. “In our first phase 2 trial, we combined an HSP90 inhibitor with Herceptin and saw a nearly 25% response rate from just these two agents, without any chemo,” she says. Her team is working with two different HSP90 inhibitors, including a compound that can be isotopically labelled so that the extent to which tumours are taking up the drug can be directly monitored. Most breast tumours also show excessive activity by the receptors that respond to the reproductive hormones oestrogen and progesterone, and numerous studies suggest that these hormone receptors influence the response to HER2-targeted drugs. Data from dual-therapy neoadjuvant trials indicate that the pathological complete response rate jumps from around 50% to more than 80% in patients with hormone receptor-negative tumours5. A growing body of data demonstrate that these two signalling pathways collaborate to promote growth8, suggesting that multiple hits may be necessary to limit the tumour's escape routes. Ultimately, combinations of highly targeted treatments with more broadly active therapy regimens may hold the key to ensuring that no patient with cancer gets left behind, Gianni says. “We now have plenty of drugs that exploit different mechanisms of action,” he says. “The challenge is to use them in the optimal way.” For now, these targeted therapies are giving some patients the opportunity to live cancer-free, and giving many others the prospect of additional years of life — and a chance to think differently about their futures. “It's completely changed the conversation in my office,” Mittendorf says.


Pellegrino P.,University of Milan | Clementi E.,University of Milan | Clementi E.,Scientific Institute | Capuano A.,The Second University of Naples | Radice S.,University of Milan
Pharmacological Research | Year: 2015

Vaccines are safe and efficacious in reducing the burden of several serious infections affecting children and adults. Due to their efficacy, vaccines are often administered in patients with chronic diseases, likely to be under poly-therapy. Because of several case reports indicating changes in drug metabolism after vaccination, the hypothesis of an interaction between vaccines and specific drugs has been put forward. These interactions are conceivably of great concern, especially in patients treated with molecules characterised by a narrow therapeutic index. Herein, we review and systematise the available evidence on vaccine-drug interactions. The picture that emerges indicates that reduction in the activity of specific CYPs following vaccination may occur, most likely via interferon γ overproduction, and for specific drugs such as anticonvulsivant and theophylline may have significant clinical relevance. Clinical interaction between vaccines and drugs that are metabolised by cytochromes uninfluenced by INFγ levels, such as warfarin, are instead unlikely to happen. Further studies are however needed to gain a complete picture of vaccine-drug interactions and define their relevance in terms of possible negative clinical impact. © 2014 Elsevier Ltd. All rights reserved.


Kele B.,University of Szeged | Lengyel G.,Scientific Institute | Deak J.,University of Szeged
Diagnostic Microbiology and Infectious Disease | Year: 2011

Noroviruses are uncultivable; ELISA and reverse transcription polymerase chain reaction (RT-PCR) methods are therefore widely used for their detection. Sixty-one sporadic, diarrhoeal stool samples from various university hospital wards and from outpatients in Szeged, Hungary, were examined. Three methods were compared: two RT-PCR methods (the Argene Calici/Astrovirus Consensus kit and the Cepheid Norovirus Primer and Probe Set) and one ELISA method (the IDEIA™ Norovirus ELISA Test). Sensitivities of 78.9%, 92.8%, and 91.2%, and specificities of 100%, 100%, and 100% were found for the IDEIA™ Norovirus ELISA, the Argene kit, and the Cepheid kit, respectively. The PCR and ELISA systems detected 52 norovirus-positive samples, one of which belonged to genogroup I and all the others to genogroup II. Although the ELISA kit has a lower sensitivity compared to the PCR ones, it can be useful for large-scale testing. However, ELISA-negative outbreaks should be retested by RT-PCR methods. Our results suggest that noroviruses, and predominantly genogroup II of the norovirus genera, play an important role in outbreaks and sporadic cases of acute gastroenteritis, not only in infants and young children, but also in adults. © 2011 Elsevier Inc.


Ponticelli C.,Scientific Institute
Nephrology Dialysis Transplantation | Year: 2014

Ischaemia-reperfusion injury (IRI) is a frequent event in kidney transplantation, particularly when the kidney comes from a deceased donor. The brain death is usually associated with generalized ischaemia due to a hyperactivity of the sympathetic system. In spite of this, most donors have profound hypotension and require administration of vasoconstrictor agents. Warm ischaemia after kidney vessels clamping and the cold ischaemia after refrigeration also reduce oxygen and nutrients supply to tissues. The reperfusion further aggravates the state of oxidation and inflammation created by ischaemia. IRI first attacks endothelial cells and tubular epithelial cells. The lesions may be so severe that they lead to acute kidney injury (AKI) and delayed graft function (DGF), which can impair the graft survival. The unfavourable impact of DGF is worse when DGF is associated with acute rejection. Another consequence of IRI is the activation of the innate immunity. Danger signals released by dying cells alarm Toll-like receptors that, through adapter molecules and a chain of kinases, transmit the signal to transcription factors which encode the genes regulating inflammatory cells and mediators. In the inflammatory environment, dendritic cells (DCs) intercept the antigen, migrate to lymph nodes and present the antigen to immunocompetent cells, so activating the adaptive immunity and favouring rejection. Attempts to prevent IRI include optimal management of donor and recipient. Calcium-channel blockers, l-arginine and N-acetylcysteine could obtain a small reduction in the incidence of post-transplant DGF. Fenoldopam, Atrial Natriuretic Peptide, Brain Natriuretic Peptide and Dopamine proved to be helpful in reducing the risk of AKI in experimental models, but there is no controlled evidence that these agents may be of benefit in preventing DGF in kidney transplant recipients. Other antioxidants have been successfully used in experimental models of AKI but only a few studies of poor quality have been made in clinical transplantation with a few of these agents and we still lack of unambiguous demonstration that pre-treatment with these antioxidants can attenuate the impact of IRI in kidney transplantation. Interference with the signals leading to activation of innate immunity, inactivation of complement or manipulation of DCs is a promising therapeutic option for the near future. © 2013 The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.


Beri S.,Scientific Institute | Bonaglia M.C.,Scientific Institute | Giorda R.,Scientific Institute
European Journal of Human Genetics | Year: 2013

Submicroscopic structural variations, including deletions, duplications, inversions and more complex rearrangements, are widespread in normal human genomes. Inverted segmental duplications or highly identical low-copy repeat (LCR) sequences can mediate the formation of inversions and more complex structural rearrangements through non-allelic homologous recombination. In a patient with 7q36 inverted duplication/terminal deletion, we demonstrated the central role of a pair of short inverted LCRs in the vasoactive intestinal peptide receptor gene (VIPR2)-LCRs in generating the rearrangement. We also revealed a relatively common VIPR2-LCR-associated inversion polymorphism disrupting the gene in almost 1% of healthy subjects, and a small number of complex duplications/triplications. In genome-wide studies of several thousand patients, a significant association of rare microduplications with variable size, all involving VIPR2, with schizophrenia was recently described, suggesting that altered vasoactive intestinal peptide signaling is likely implicated in the pathogenesis of schizophrenia. Genetic testing for VIPR2-LCR-associated inversions should be performed on available cohorts of psychiatric patients to evaluate their potential pathogenic role. © 2013 Macmillan Publishers Limited. All rights reserved.

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