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Researchers at Turku Centre for Biotechnology have invented new tools for decoding and controlling signalling circuits in living cells with flashes of light. In principle, any cellular circuit can now be targeted with the new method. By using this approach, the researchers discovered that major biological signalling circuits can be made to resonate when driven at their resonant frequency. Resonance is a familiar concept in music, physics and engineering and underlies technical approaches in chemistry, biology and medicine. - Our discovery that signalling circuits of mammalian cells can made to resonate is new and likely to have a relevance in the treatment of diseases. With this method we can control when the signalling pathway is on or off, says Senior Researcher Michael Courtney from Turku Centre for Biotechnology at the University of Turku and Åbo Akademi University, Finland. The team developed optogenetic inhibitors for protein kinases such as JNK which is a central regulator of cell function. - JNK protein in the cell cytoplasm was not thought to regulate gene expression in the nucleus and continuous inhibition in the cytoplasm is ineffective. However, the team found that delivering a specific frequency of inhibition pulses to JNK in the cytoplasm drove inhibition of gene expression in the nucleus. This indicates that cell signalling circuits can be controlled in previously unforeseen ways once the appropriate time-code has been identified, says Courtney. He explains that not only might cell circuit resonance play an unexpected role in degenerative disease processes, but it could even guide the discovery of new therapeutic approaches. Interestingly, the only previous report on cell circuit resonance in the scientific literature showed it can be used to prevent microbial cells from growing. This new discovery of similar behaviour in mammalian cells suggests it could potentially be used to stop cancer cells from growing. - Currently, the development of resistance to new drugs is a major problem in cancer, as it cost billions of dollars to develop and approve new drugs, and yet they can rapidly become ineffective as a treatment. With this new research information, we can perhaps change the frequency instead of using the same drug and in this way achieve a better outcome, says Courtney. The research team's newly discovered phenomenon of circuit resonance in mammalian cells might offer a way to avoid or work around drug resistance. The researchers have now assembled a research consortium which has applied for funding in order to begin the evaluation of this idea. The team started developing light-regulated tools while at the University of Eastern Finland. The project was funded primarily by the Academy of Finland's Photonics programme. The mammalian circuit resonance was discovered and characterised by the team after moving to the University of Turku. The team received support from the Turku BioImaging Screening Unit and funding from the National Cancer Institute in the Uniteds States, the EU-Marie Skłodowska-Curie programme, and Finnish foundations including the Magnus Ehrnrooth, Alfred Koredelin, Instrumentarium and Orion Foundations. This work was published in the Nature Communications journal on 12 May 2017. More information: Senior Researcher Michael Courtney, University of Turku, Turku Centre for Biotechnology, tel. +358 (0)504649827 , e-mail miccou@utu.fi


Pacchiarotti A.,Lega Italiana per la Lotta Ai Tumori | Ferrari F.,Epidemiology Unit | Bellardini P.,Screening Unit | Chini F.,Public Health Agency Rome | And 8 more authors.
International Journal of Cancer | Year: 2014

P16-INK4A overexpression has been proposed as a prognostic marker to manage the follow up of women with positive cytology and/or HPV test but without high-grade cervical intraepithelial neoplasia (CIN2+). This study measures the relative risk (RR) of CIN2+ of p16 positive versus negative in these women. All the women referred to colposcopy from October 2008 to September 2010 with negative or CIN1 colposcopy-guided biopsy were included in the study; women surgically treated or having a CIN2-3 were excluded. All baseline biopsies were dyed with hematoxylin and eosin and p16. Women were followed up according to screening protocols, with cytology or colposcopy at 6 or 12 months. CIN2/3 RRs and 95% confidence intervals (95%CI) were computed. Of 442 eligible women, 369 (83.5%) had at least one follow-up episode. At baseline, 113 (30.6%) were CIN1, 248 (67.2%) negative, and 8 (2.2%) inadequate histology; 293 (79.4%) were p16-negative, 64 (17.3%) p16 positive and 12 (3.2%) not valid. During follow up, we found ten CIN2 and three CIN3; of these, six were p16 positive (sensitivity 46%, 95% CI 19-75). The absolute risk among p16 positives was 9.4/100 compared to 1.7/100 of the p16 negatives (RR 5.5; 95% CI 1.7-17.4). The risk was also higher for CIN1 than for histologically negative women (RR 4.4; 95% CI 1.3-14.3). The RR for p16 in CIN1 did not change (RR 5.2; 95% CI 0.6-47.5). P16 overexpression is a good candidate for modulating follow-up intensity after a negative colposcopy but is limited by its low prospective sensitivity. What's new? Women with low-grade cervical intraepithelial neoplasia 1 (CIN1) detected by positive Pap smear but accompanied by negative colposcopic biopsy present unique challenges for follow-up, especially since CIN1 is known to often regress. The situation could be helped in part through the use of a biomarker for CIN1 progression, such as p16 overexpression. This study shows that p16 has low prognostic sensitivity for patients with CIN2+ (CIN2 or worse) but is associated with elevated risk for these advanced conditions. The data suggest that p16 overexpression may be useful in evaluating the intensity of follow-up needed after a negative colposcopy. © 2013 UICC.


Regge D.,Candiolo Cancer Institute FPO | Iussich G.,Ospedale Regionale di Locarno La Carita | Segnan N.,AOU S Giovanni Battista CPO Piemonte | Correale L.,im3D S.p.A. | And 23 more authors.
Gut | Year: 2016

Importance and aims The role of CT colonography (CTC) as a colorectal cancer (CRC) screening test is uncertain. The aim of our trial was to compare participation and detection rate (DR) with sigmoidoscopy (flexible sigmoidoscopy (FS)) and CTC in a screening setting. Design setting and participants We conducted two randomised clinical trials (RCTs). (1) Participation RCT: individuals, aged 58 years, living in Turin (Italy), were randomly assigned to be invited to FS or CTC screening; (2) detection RCT: residents in northern Italy, aged 58-60, giving their consent to recruitment, were randomly allocated to CTC or FS. Polyps =6 mm at CTC, or 'high-risk' distal lesions at FS, were referred for colonoscopy (TC). Main outcome measures Participation rate ( proportion of invitees examined); DR of advanced adenomas or CRC (advanced neoplasia (AN)). Results Participation was 30.4% (298/980) for CTC and 27.4% (267/976) for FS (relative risk (RR) 1.1; 95% CI 0.98 to 1.29). Among men, participation was higher with CTC than with FS (34.1% vs 26.5%, p=0.011). In the detection RCT, 2673 subjects had FS and 2595 had CTC: the AN DR was 4.8% (127/2673, including 9 CRCs) with FS and 5.1% (133/2595, including 10 CRCs) with CTC (RR 1.08; 95% CI 0.85 to 1.37). Distal AN DR was 3.9% (109/2673) with FS and 2.9% (76/2595) with CTC (RR 0.72; 95% CI 0.54 to 0.96); proximal AN DR was 1.2% (34/2595) for FS vs 2.7% (69/2595) for CTC (RR 2.06; 95% CI 1.37 to 3.10). Conclusions and relevance Participation and DR for FS and CTC were comparable. AN DR was twice as high in the proximal colon and lower in the distal colon with CTC than with FS. Men were more likely to participate in CTC screening. Trial registration number NCT01739608; Preresults. © 2016 BMJ Publishing Group Ltd & British Society of Gastroenterology.


Zorzi M.,Instituto Oncologico Veneto IRCCS | Fedato C.,Instituto Oncologico Veneto IRCCS | Grazzini G.,Cancer Prevention and Research Institute ISPO | Stocco F.C.,Instituto Oncologico Veneto IRCCS | And 7 more authors.
Gut | Year: 2011

Objective: Although guaiac-based faecal occult blood test screening has been shown to be effective in reducing colorectal cancer (CRC) mortality, it has been criticised mostly for its low sensitivity. Italian CRC screening programmes are based on immunochemical tests (iFOBT). We collected and analysed the interval cancers (ICs) found by five screening programmes to estimate their sensitivity. Methods: ICs were identified in subjects who had a negative result in a screening examination from 2002 to 2007 (N=267 789); data were linked with 2002-2008 hospital discharge records. Analysis was based on the follow up of 468 306 person-years. The proportional incidence-based sensitivity was estimated overall and by sex, age class, time since last negative iFOBT result, anatomical site, and history of screening (first or subsequent test). Results: Overall, 126 ICs were identified, compared to 572 expected cancers. The proportional incidences were 15.3% and 31.0% in the first and the second interval-years, respectively, with an overall episode sensitivity of 78.0% (95% CI: 73.8 to 81.6). Sensitivity was higher for males than females (80.1% vs 74.8%); no differences were observed by age, anatomical site or between programmes. The test sensitivity of iFOBT was 82.1% (95% CI 78.1% to 85.3%). Conclusions: iFOBT-based screening programmes showed a high performance in terms of sensitivity as estimated through the IC rates. The screening schedule utilised in our programmes (single iFOBT, positivity threshold of 100 ng Hb/ml of sample solution, inter-screening interval of 2 years) shows low rates of missed cancers that are diagnosed during the interval. HDR are a convenient and reliable source of data for IC studies.


News Article | December 12, 2016
Site: www.eurekalert.org

The slightest touch can evoke intense pain in patients suffering from nerve injuries or conditions such as diabetic neuropathy. A team of researchers of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) has found a way to suppress pain in mice by applying a newly identified chemical agent to the skin of the animals. The substance blocked the action of an ion channel in nerves which is responsible for the perception of light touch. The activation of this channel also leads to severe pain after injuries, which the substance eliminated. The method could work in humans. An anesthetic injection like that given by a dentist numbs all feeling in the surrounding tissue. This is often the only approach for treating people who suffer from a painful hypersensitivity that often accompanies nerve damage. Anesthetics that shut down all the functions of mechanosensory nerves reduce pain, but they also prevent other important signals from getting through. Collaborating with the Screening Unit at the Leibniz-Institut für Molekulare Pharmakologie (FMP), which is jointly operated by the MDC and FMP, Cécile-Vogt fellow Dr. Kate Poole, Dr. Christiane Wetzel and their colleagues in the research team of Prof. Gary Lewin at the MDC and the Charité - Universitätsmedizin Berlin have now identified a substance that suppresses pain from mechanical stimuli without disturbing other sensations. Very light touch is detected by a molecular sensor in the skin, an ion channel called "Piezo2". Such channels are like tiny valves in the membranes of neurons which open once they experience stress from movement in the skin. When open, electrically charged particles pass through the valve. This creates an electrical signal which the cell then amplifies and forwards to the spine. The protein STOML3 tunes the mechanical sensitivity of Piezo2 ion channel. The researchers subjected the STOML3 protein to a drug screen, testing 35,000 different chemicals in large-scale in vitro experiments. They identified a substance called OB-1 which prevents STOML3 from forming clusters and thereby inhibits its function. Further electrochemical measurements of cells confirmed that when this didn't happen, the Piezo2 ion channel remained closed. Most importantly, the chemical effectively suppressed only this type of mechanical sensation in mice without affecting other types of sensation. Under the influence of OB-1, the animals' sensitivity to light touch was significantly reduced. After the effects of the drug had worn off, the animals' sensitivity returned to normal levels. "Colleagues at the MDC designed a set of behavioral experiments in which the animals could 'talk' to us," Lewin says. "Small amounts of the substance were administered to the mouse paw. The paw was then gently tapped. The mice had been trained to reach for a reward when they felt it. The OB-1 drug had a dramatic effect on animals suffering from touch-evoked pain caused by nerve injuries or diabetes. Treating the skin with OB-1 completely eliminated this type of pain. This indicates that its cause might be an increase in STOML3's modulation of Piezo2, which means that dampening it would be a way of treating the condition. "The results are encouraging for many reasons," Prof. Lewin says. "What this represents is a new strategy that arose from understanding the mechanisms that turn sensations of touch into pain. From what we can tell so far, the substance only affects a very specific type of mechanoreceptor that has both STOML3 proteins and Piezo2 channels. It dampens the perception of painful stimuli in a way that doesn't affect other signals that the animal needs. And the effects are reversible." Prof. Lewin says that developing the substance into a treatment will be a long process. But at some point it should be ready for trials in people. If human patients respond the same way, this will represent a major step in treating a neuropathology that has a devastating effect on the lives of many people. The Max Delbrück Center for Molecular Medicine in the Helmholtz Association was founded in January 1992 with the goal of linking basic science to clinical research. The MDC was named for Max Delbrück, a physicist, biologist, and Nobel Prize winner. Currently the institute employs more than 1600 people from nearly 60 countries; over 1300 of those are directly involved in research. The MDC's annual budget is over 80 million Euros, along with substantial third-party funding obtained by individual scientific groups. For more information, please visit http://www. With a total of 3,001 beds, Charité - Universitätsmedizin Berlin is one of the largest university hospitals in Europe. Charité spans 4 campuses and comprises approximately 100 Departments and Institutes. In 2015, Charité treated more than 142,000 outpatient and more than 663,000 inpatient cases. With approximately 16,900 staff employed across the Charité group of companies, Charité is one of the largest employers in Berlin. In 2015, the Charité university hospital recorded a turnover of more than €1.6 billion. The areas of research, teaching, and health care delivery are intricately linked, resulting in a working relationship that is characterized by interdisciplinary cooperation. In 2015, Charité was able to secure more than €149 million in third-party funding, as well as approximately €202 million in state funding for research and teaching. With approximately 7,000 future physicians and dentists currently enrolled in degree courses, Charité is one of the largest medical faculties in Germany. http://www.


Schroder D.,Institute For Biochemie Und Signaltransduktion | Rehbach C.,Institute For Biochemie Und Signaltransduktion | Seyffarth C.,Screening Unit | Neuenschwander M.,Screening Unit | And 2 more authors.
Biochemical and Biophysical Research Communications | Year: 2013

Ectopic expression of the neuron-specific inositol-1,4,5-trisphosphate-3-kinase A (ITPKA) in lung cancer cells increases their metastatic potential because the protein exhibits two actin regulating activities; it bundles actin filaments and regulates inositol-1,4,5-trisphosphate (InsP3)-mediated calcium signals by phosphorylating InsP3. Thus, in order to inhibit the metastasis-promoting activity of ITPKA, both its actin bundling and its InsP3kinase activity has to be blocked. In this study, we performed a high throughput screen in order to identify specific and membrane-permeable substances against the InsP3kinase activity. Among 341,44 small molecules, 237 compounds (0.7%) were identified as potential InsP3kinase inhibitors. After determination of IC50-values, the three compounds with highest specificity and highest hydrophobicity (EPPC-3, BAMB-4, MEPTT-3) were further characterized. Only BAMB-4 was nearly completely taken up by H1299 cells and remained stable after cellular uptake, thus exhibiting a robust stability and a high membrane permeability. Determination of the inhibitor type revealed that BAMB-4 belongs to the group of mixed type inhibitors. Taken together, for the first time we identified a highly membrane-permeable inhibitor against the InsP3kinase activity of ITPKA providing the possibility to partly inhibit the metastasis-promoting effect of ITPKA in lung tumor cells. © 2013 Elsevier Inc.


PubMed | Screening Unit, Local Health Care Center, A Manzoni Hospital and Local Health Care Center Lecco
Type: Comparative Study | Journal: Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver | Year: 2014

Colorectal cancer screening may reduce disease-related mortality by early-stage detection of cancers.To study the effect of a single immunochemical faecal occult blood test (i-FOBt) screening round on reduction in colorectal cancer-related-mortality among average risk subjects.Comparison of 5-year mortality rates in 3 cohorts from a Northern Italian province: (1) colorectal cancers detected at the 1st biennial round of a mass-screening programme targeting 50-69 years old subjects, (2) non-screening cancers symptomatically diagnosed during the same time period, and (3) cancers detected in the pre-screening biennium. Multivariate analyses were performed with the Cox regression model including tumour node metastasis (TNM) stage at diagnosis, anatomical distribution of cancers, age at diagnosis, gender and patient group. Kaplan-Meyer survival estimates and log-rank test for equality of survivor functions were calculated.Stage distribution significantly differed between screening and non-screening colorectal cancers: 73% of screen-detected colorectal cancers were stages I and II versus 43% and 40% of non-screening and pre-screening colorectal cancers. Cumulative 5-year mortality rate was significantly lower in screening compared to non-screening or pre-screening colorectal cancers patients (19% versus 37% and 41%, p < 0.001).Colorectal cancers were detected at earlier stages in i-FOBT-positive subjects in comparison with non-screening patients; colorectal cancers found at screening had a significantly improved 5-year survival.


Rossi P.G.,Laziosanita Agency for Public Health | Grazzini G.,Cancer Prevention and Research Institute ISPO | Anti M.,Screening Unit | Baiocchi D.,Laziosanita Agency for Public Health | And 10 more authors.
Journal of Medical Screening | Year: 2011

Background: Sending faecal occult blood tests (FOBT) by mail has been proposed both as a method to increase participation and a way to reduce staff costs in colorectal cancer screening. Methods: Two multicentre randomized controlled trials (ISRCTN10351276) were performed: one randomly assigned 3196 individuals who had previously participated in colorectal screening to receive a FOBT kit at home or a standard invitation; in the second, 4219 people aged 50-69 years who did not respond to a screening invitation were either sent a FOBT or a standard recall letter. The cost per returned kit was calculated in each arm. Results: Participation was higher with direct FOBT mailing in both trials: relative risk 1.11 (95% CI 1.06-1.17) and 1.36 (95% CI 1.16-1.60) for previous responders and non-responders, respectively. The cost per returned kit for previous responders ranged from 4.24€ to 16.10€, and from 3.29€ to 7.36€ with FOBT mailing and standard invitation, respectively, not including staff costs; for non-responders it ranged from 17.13€ to 46.80€, and from 7.36€ to 18.30€ with FOBT mailing and standard recall, respectively. Conclusions The FOBT mailing strategy modestly increased participation. This method can be used on a population of previous responders to reduce personnel costs and workload. When used as a reminder to non-responders, this method increases costs.


Chiappetta C.,University of Rome La Sapienza | Puggioni C.,University of Rome La Sapienza | Lendaro E.,University of Rome La Sapienza | Cacciotti J.,University of Rome La Sapienza | And 6 more authors.
International Journal of Clinical and Experimental Pathology | Year: 2015

With cervical cancer screening the choice of 1-year as a period of follow-up in positive high-risk HPV women without cytological lesions is still under discussion. We evaluated the management of these women and the role of HPV genotyping test. We did a cervical cancer screening study of women aged 35-64 with primary high-risk HPV test. Women positive for high-risk HPV with negative cytology were followed-up after 1 year. In this study we selected women with high-risk HPV+/PapTest- resulted high-risk HPV+ at recall and performed the PapTest and HPV genotyping test. The detection rate of squamous high grade (CIN2+) relative to the total screened cohort was 2.1%, and it was 0.2% at the 1-year recall. The colposcopy performed in women referred at the 1-year recall accounted for 48.8% of the total (baseline + 1-year recall), and 84.3% of these women had no cytological lesions. The most frequent hr-HPV genotype detected was HPV16 and 66.7% of co-infections were due to HPV16 and HPV18. 54.5% of women presented a persistent infection at 1-year recall with the same HPV subtype, 50% of persistent infections was due to HPV16 and 16.7% of these were determined to be CIN2+ histological lesions. Our data show that it may be useful to extend the period of follow-up for women hr-HPV+/PapTest- so as to reduce the number of unnecessary colposcopies due to the transitory infections and that the genotyping test could help to identify the persistent infections in which HPV16 is involved.


PubMed | University of Rome La Sapienza and Screening Unit
Type: Journal Article | Journal: International journal of clinical and experimental pathology | Year: 2016

With cervical cancer screening the choice of 1-year as a period of follow-up in positive high-risk HPV women without cytological lesions is still under discussion. We evaluated the management of these women and the role of HPV genotyping test. We did a cervical cancer screening study of women aged 35-64 with primary high-risk HPV test. Women positive for high-risk HPV with negative cytology were followed-up after 1 year. In this study we selected women with high-risk HPV+/PapTest- resulted high-risk HPV+ at recall and performed the PapTest and HPV genotyping test. The detection rate of squamous high grade (CIN2+) relative to the total screened cohort was 2.1, and it was 0.2 at the 1-year recall. The colposcopy performed in women referred at the 1-year recall accounted for 48.8% of the total (baseline + 1-year recall), and 84.3% of these women had no cytological lesions. The most frequent hr-HPV genotype detected was HPV16 and 66.7% of co-infections were due to HPV16 and HPV18. 54.5% of women presented a persistent infection at 1-year recall with the same HPV subtype, 50% of persistent infections was due to HPV16 and 16.7% of these were determined to be CIN2+ histological lesions. Our data show that it may be useful to extend the period of follow-up for women hr-HPV+/PapTest- so as to reduce the number of unnecessary colposcopies due to the transitory infections and that the genotyping test could help to identify the persistent infections in which HPV16 is involved.

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