Showing papers by "University of Turin published in 2010"
University of Turin1, Aix-Marseille University2, National Health Service3, University Hospital of South Manchester NHS Foundation Trust4, University of Ljubljana5, Karolinska University Hospital6, Centre Hospitalier Universitaire de Grenoble7, University of Aberdeen8, The Royal Marsden NHS Foundation Trust9, VU University Medical Center10, University of Salamanca11, Katholieke Universiteit Leuven12, University Hospital of Lausanne13
TL;DR: The ESMO Guidelines Committee concluded that current state-of-the-art oncology practices in France, Belgium, and the Netherlands are suitable for frontline use and recommend further research into these practices.
2,349 citations
15 Apr 2010
TL;DR: Systematic studies of more than 25,000 cancer genomes will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
Abstract: The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
2,041 citations
Katholieke Universiteit Leuven1, Swiss Institute of Bioinformatics2, Aristotle University of Thessaloniki3, Paris Descartes University4, University of Auvergne5, Università Campus Bio-Medico6, University of Turin7, Hebron University8, French Institute of Health and Medical Research9, Seconda Università degli Studi di Napoli10, University of Southern Denmark11, Odense University Hospital12, Cliniques Universitaires Saint-Luc13, University Hospital of Lausanne14
TL;DR: This is the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era and confirmed that, if KRAS is not mutated, assessing BRAF, NRAS, and PIK3CA population response rates confirmed that.
Abstract: Background Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era. Methods 1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy. Findings 40.0% (299/747) of the tumours harboured a KRAS mutation, 14.5% (108/743) harboured a PIK3CA mutation (of which 68.5% [74/108] were located in exon 9 and 20.4% [22/108] in exon 20), 4.7% (36/761) harboured a BRAF mutation, and 2.6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6.7% (17/253) versus 35.8% (126/352; odds ratio [OR] 0.13, 95% CI 0.07-0.22; p<0.0001), a median PFS of 12. weeks versus 24 weeks (hazard ratio [HR] 1 98, 1.66-2.36; p<0.0001), and a median overall survival of 32 weeks versus 50 weeks (1.75, 1.47-2.09; p<0.0001). In KRAS wild types, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild types, with a response rate of 8.3% (2/24) in carriers of BRAF mutations versus 38.0% in BRAF wild types (124/326; OR 0.15, 95% CI 0.02-0.51; p=0.0012); and 7.7% (1/13) in carriers of NRAS mutations versus 38.1% in NRAS wild types (110/289; OR 0.14, 0.007-0.70; p=0.013). PIK3CA exon 9 mutations had no effect, whereas exon 20 mutations were associated with a worse outcome compared with wild types, with a response rate of 0.0% (0/9) versus 36.8% (121/329; OR 0.00,0.00-0.89; p=0.029), a median PFS of 11.5 weeks versus 24 weeks (HR 2.52, 1.33-4.78; p=0.013), and a median overall survival of 34 weeks versus 51 weeks (3.29, 1.60-6.74; p=0.0057). Multivariate analysis and conditional inference trees confirmed that, if KRAS is not mutated, assessing BRAF, NRAS, and PIK3CA exon 20 mutations (in that order) gives additional information about outcome. Objective response rates in our series were 24.4% in the unselected population, 36.3% in the KRAS wild-type selected population, and 41.2% in the KRAS, BRAF, NRAS, and PIK3CA exon 20 wild-type population. Interpretation While confirming the negative effect of KRAS mutations on outcome after cetuximab, we show that BRAF, NRAS, and PIK3CA,exon 20 mutations are significantly associated with a low response rate. Objective response rates could be improved by additional genotyping of BRAF, NRAS, and PIK3CA exon 20 mutations in a KRAS wild-type population.
1,940 citations
TL;DR: The Cholesky decomposition method applied to some quantum chemical methods is described, and the ElectroStatic Potential Fitted scheme, a version of a quantum mechanics/molecular mechanics hybrid method implemented in MOLCAS, is described and discussed.
Abstract: Some of the new unique features of the MOLCAS quantum chemistry package version 7 are presented inthis report. In particular, the Cholesky decomposition method applied to some quantum chemical methods is described. This approach is used both in the context of a straight forward approximation of the two-electron integrals and in the generation of so-called auxiliary basis sets. The article describes how the method is implemented for most known wave functions models: self-consistent field, density functional theory, 2nd order perturbation theory, complete-active space self-consistent field multiconfigurational reference 2nd order perturbation theory, and coupled-cluster methods. The report further elaborates on the implementation of a restricted-active space self-consistent field reference function in conjunction with 2nd order perturbation theory. The average atomic natural orbital basis for relativistic calculations, covering the whole periodic table, are described and associated unique properties are demonstrated. Furthermore, the use of the arbitrary order Douglas-Kroll-Hess transformation for one-component relativistic calculations and its implementation are discussed. This section especially focuses on the implementation of the so-called picture-change-free atomic orbital property integrals. Moreover, the ElectroStatic Potential Fitted scheme, a version of a quantum mechanics/molecular mechanics hybrid method implemented in MOLCAS, is described and discussed. Finally, the report discusses the use of the MOLCAS package for advanced studies of photo chemical phenomena and the usefulness of the algorithms for constrained geometry optimization in MOLCAS in association with such studies. (c) 2009 Wiley Periodicals, Inc. J Corn put Chem 31: 224-247, 2010
1,492 citations
TL;DR: Nilotinib at a dose of either 300 mg or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia chromosome-positive CML, and no patient with progression to the accelerated phase or blast crisis had a major molecular response.
Abstract: Background Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (CML) in the chronic phase. Methods In this phase 3, randomized, open-label, multicenter study, we assigned 846 patients with chronic-phase Philadelphia chromosome–positive CML in a 1:1:1 ratio to receive nilotinib (at a dose of either 300 mg or 400 mg twice daily) or imatinib (at a dose of 400 mg once daily). The primary end point was the rate of major molecular response at 12 months. Results At 12 months, the rates of major molecular response for nilotinib (44% for the 300-mg dose and 43% for the 400-mg dose) were nearly twice that for imatinib (22%) (P<0.001 for both comparisons). The rates of complete cytogenetic response by 12 months were significantly higher for nilotinib (80% for the 300-mg dose and 78% for the 400-mg dose) than for imatinib (65%) (P<0.001 for both comparisons). Patients receiving either the 300-mg dose or the 400-mg dose of nilotinib twice daily had a significant improvement in the time to progression to the accelerated phase or blast crisis, as compared with those receiving imatinib (P = 0.01 and P = 0.004, respectively). No patient with progression to the accelerated phase or blast crisis had a major molecular response. Gastrointestinal and fluid-retention events were more frequent among patients receiving imatinib, whereas dermatologic events and headache were more frequent in those receiving nilotinib. Discontinuations due to aminotransferase and bilirubin elevations were low in all three study groups. Conclusions Nilotinib at a dose of either 300 mg or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia chromosome–positive CML. (ClinicalTrials.gov number, NCT00471497.)
1,486 citations
TL;DR: In this article, a family of isoreticular MOFs, based on the UiO-66 structure, was obtained from the three different linker ligands H2N−H2BDC, O2N −H2BDDC, and Br−H 2BDC and the physicochemical and chemical investigation of these materials demonstrate that this class of MOFs retains high thermal and chemical stabilities, even with functional groups present at the linker units.
Abstract: The development in the field MOF materials is moving from the discovery of new structures toward applications of the most promising materials. In most cases, specialized applications require incorporation of functional chemical groups. This work is a systematic investigation of the effect that simple substituents attached to the aromatic linker have on the stability and property to the parent MOF. A family of isoreticular MOFs, based on the UiO-66 structure was obtained from the three different linker ligands H2N−H2BDC, O2N−H2BDC, and Br−H2BDC. The physicochemical and chemical investigation of these materials demonstrate that this class of MOFs retains high thermal and chemical stabilities, even with functional groups present at the linker units. The results demonstrate the possibility of incorporating active functional groups into the UiO-66 structure almost without losing its exceptionally high thermal and chemical stability. It has been established that the functional groups, at least in the amino func...
1,430 citations
Sapienza University of Rome1, Charité2, University of Barcelona3, University of Erlangen-Nuremberg4, University of Trieste5, Institut national de la recherche agronomique6, Sahlgrenska University Hospital7, Uppsala University8, University of Turin9, University of Edinburgh10, University of Parma11, University of Nice Sophia Antipolis12, Maastricht University13
TL;DR: The definition of cachexia, pre-cachexia and sarc Openia as well as the criteria for the differentiation between cachexia and other conditions associated with sarcopenia, which have been developed in cooperation with the ESPEN SIG on nutrition in geriatrics are reported.
1,380 citations
TL;DR: Clinical practice guidelines for congenital adrenal hyperplasia (CAH) recommend universal newborn screening for severe steroid 21-hydroxylase deficiency followed by confirmatory tests and recommend judicious use of medication during pregnancy and in symptomatic patients with nonclassic CAH.
Abstract: Objective: We developed clinical practice guidelines for congenital adrenal hyperplasia (CAH).
Participants: The Task Force included a chair, selected by The Endocrine Society Clinical Guidelines Subcommittee (CGS), ten additional clinicians experienced in treating CAH, a methodologist, and a medical writer. Additional experts were also consulted. The authors received no corporate funding or remuneration.
Consensus Process: Consensus was guided by systematic reviews of evidence and discussions. The guidelines were reviewed and approved sequentially by The Endocrine Society’s CGS and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments.
Conclusions: We recommend universal newborn screening for severe steroid 21-hydroxylase deficiency followed by confirmatory tests. We recommend that prenatal treatment of CAH continue to be regarded as experimental. The diagnosis rests on clinical and hormonal data; genotyping is reserved for equivocal cases and genetic counseling. Glucocorticoid dosage should be minimized to avoid iatrogenic Cushing’s syndrome. Mineralocorticoids and, in infants, supplemental sodium are recommended in classic CAH patients. We recommend against the routine use of experimental therapies to promote growth and delay puberty; we suggest patients avoid adrenalectomy. Surgical guidelines emphasize early single-stage genital repair for severely virilized girls, performed by experienced surgeons. Clinicians should consider patients’ quality of life, consulting mental health professionals as appropriate. At the transition to adulthood, we recommend monitoring for potential complications of CAH. Finally, we recommend judicious use of medication during pregnancy and in symptomatic patients with nonclassic CAH.
1,114 citations
University of North Carolina at Chapel Hill1, University of Texas Health Science Center at Houston2, University of Cambridge3, University of Pavia4, University of Milan5, Stanford University6, Kaiser Permanente7, National Institutes of Health8, University of Washington9, Wake Forest University10, Cedars-Sinai Medical Center11, Group Health Cooperative12, Lund University13, University of Michigan14, National Institute for Health and Welfare15, University of Helsinki16, Boston University17, University of Chicago18, International Agency for Research on Cancer19, Charles University in Prague20, Institut Gustave Roussy21, French Institute of Health and Medical Research22, University of Padua23, University of Glasgow24, Palacký University, Olomouc25, Trinity College, Dublin26, National and Kapodistrian University of Athens27, Newcastle University28, University of Aberdeen29, University of Turin30, Nofer Institute of Occupational Medicine31, Russian Academy32, University of Exeter33, Harvard University34, Massachusetts Institute of Technology35, Broad Institute36, VU University Amsterdam37, Erasmus University Rotterdam38, University of Virginia39, Virginia Commonwealth University40, University of Pennsylvania41, Duke University42, Tufts University43, University of Ioannina44
TL;DR: A meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium found the strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3, and three loci associated with number of cigarettes smoked per day were identified.
Abstract: Consistent but indirect evidence has implicated genetic factors in smoking behavior1,2. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], b = 1.03, standard error (s.e.) = 0.053, beta = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], b = 0.367, s. e. = 0.059, beta = 5.7 x 10(-10); and rs1028936[A], b = 0.446, s. e. = 0.074, beta = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], b = 0.333, s. e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.
1,104 citations
TL;DR: The MET tyrosine kinase receptor promotes tissue remodelling, which underlies developmental morphogenesis, wound repair, organ homeostasis and cancer metastasis, by integrating growth, survival and migration cues in response to environmental stimuli or cell-autonomous perturbations.
Abstract: The MET tyrosine kinase receptor (also known as the HGF receptor) promotes tissue remodelling, which underlies developmental morphogenesis, wound repair, organ homeostasis and cancer metastasis, by integrating growth, survival and migration cues in response to environmental stimuli or cell-autonomous perturbations. The versatility of MET-mediated biological responses is sustained by qualitative and quantitative signal modulation. Qualitative mechanisms include the engagement of dedicated signal transducers and the subcellular compartmentalization of MET signalling pathways, whereas quantitative regulation involves MET partnering with adaptor amplifiers or being degraded through the shedding of its extracellular domain or through intracellular ubiquitylation. Controlled activation of MET signalling can be exploited in regenerative medicine, whereas MET inhibition might slow down tumour progression.
1,057 citations
University of Modena and Reggio Emilia1, Emory University2, University of Pennsylvania3, National Institutes of Health4, University College London5, Johns Hopkins University6, The Catholic University of America7, University of Turin8, Seconda Università degli Studi di Napoli9, University of Siena10, University of Palermo11, University of Cagliari12, Georgetown University13
TL;DR: Exome sequencing data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ∼1%-2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neurons degeneration.
TL;DR: Promotion and integration of laboratory and clinical research will allow advances in the ethical use of placebo mechanisms that are inherent in routine clinical care, and encourage the use of treatments that stimulate placebo effects.
TL;DR: Signalling pathways between plants and fungi have now been described and the identification of several novel nutrient transporters has revealed some of the cellular processes that underlie symbiosis.
Abstract: Mycorrhizal fungi are a heterogeneous group of diverse fungal taxa, associated with the roots of over 90% of all plant species. Recently, state-of-the-art molecular and genetic tools, coupled to high-throughput sequencing and advanced microscopy, have led to the genome and transcriptome analysis of several symbionts. Signalling pathways between plants and fungi have now been described and the identification of several novel nutrient transporters has revealed some of the cellular processes that underlie symbiosis. Thus, the contributions of each partner in a mycorrhizal association are starting to be unravelled. This new knowledge is now available for use in agricultural practices.
TL;DR: Understanding the neural bases of the non-conscious perception of emotional signals will clarify the phylogenetic continuity of emotion systems across species and the integration of cortical and subcortical activity in the human brain.
Abstract: Many emotional stimuli are processed without being consciously perceived. Recent evidence indicates that subcortical structures have a substantial role in this processing. These structures are part of a phylogenetically ancient pathway that has specific functional properties and that interacts with cortical processes. There is now increasing evidence that non-consciously perceived emotional stimuli induce distinct neurophysiological changes and influence behaviour towards the consciously perceived world. Understanding the neural bases of the non-conscious perception of emotional signals will clarify the phylogenetic continuity of emotion systems across species and the integration of cortical and subcortical activity in the human brain.
TL;DR: HPV-based screening is more effective than cytology in preventing invasive cervical cancer, by detecting persistent high-grade lesions earlier and providing a longer low-risk period, but in younger women, HPV screening leads to over-diagnosis of regressive CIN2.
Abstract: Summary Background Human papillomavirus (HPV) testing is known to be more sensitive, but less specific than cytology for detecting cervical intraepithelial neoplasia (CIN). We assessed the efficacy of cervical-cancer screening policies that are based on HPV testing. Methods Between March, 2004, and December, 2004, in two separate recruitment phases, women aged 25–60 years were randomly assigned to conventional cytology or to HPV testing in combination with liquid-based cytology (first phase) or alone (second phase). Randomisation was done by computer in two screening centres and by sequential opening of numbered sealed envelopes in the remaining seven centres. During phase one, women who were HPV-positive and aged 35–60 years were referred to colposcopy, whereas women aged 25–34 years were referred to colposcopy only if cytology was also abnormal or HPV testing was persistently positive. During phase two, women in the HPV group were referred for colposcopy if the HPV test was positive. Two rounds of screening occurred in each phase, and all women had cytology testing only at the second round. The primary endpoint was the detection of grade 2 and 3 CIN, and of invasive cervical cancers during the first and second screening rounds. Analysis was done by intention to screen. This trial is registered, number ISRCTN81678807. Findings In total for both phases, 47 001 women were randomly assigned to the cytology group and 47 369 to HPV testing. 33 851 women from the cytology group and 32 998 from the HPV-testing group had a second round of screening. We also retrieved the histological diagnoses from screening done elsewhere. The detection of invasive cervical cancers was similar for the two groups in the first round of screening (nine in the cytology group vs seven in the HPV group, p=0·62); no cases were detected in the HPV group during round two, compared with nine in the cytology group (p=0·004). Overall, in the two rounds of screening, 18 invasive cancers were detected in the cytology group versus seven in the HPV group (p=0·028). Among women aged 35–60 years, at round one the relative detection (HPV vs cytology) was 2·00 (95% CI 1·44–2·77) for CIN2, 2·08 (1·47–2·95) for CIN3, and 2·03 (1·60–2·57) for CIN2 and 3 together. At round two the relative detection was 0·54 (0·23–1·28) for CIN2, 0·48 (0·21–1·11) for CIN3, and 0·51 (0·28–0·93) for CIN2 and 3 together. Among women aged 25–34 years, there was significant heterogeneity between phases in the relative detection of CIN3. At round one the relative detection was 0·93 (0·52–1·64) in phase one and 3·91 (2·02–7·57) in phase two. At round two the relative detection was 1·34 (0·46–3·84) in phase one and 0·20 (0·04–0·93) in phase two. Pooling both phases, the detection ratio of CIN2 for women aged 25–34 years was 4·09 (2·24–7·48) at round one and 0·64 (0·23–1·27) at round two. Interpretation HPV-based screening is more effective than cytology in preventing invasive cervical cancer, by detecting persistent high-grade lesions earlier and providing a longer low-risk period. However, in younger women, HPV screening leads to over-diagnosis of regressive CIN2. Funding European Union, Italian Ministry of Health, Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia-Romagna, and Public Health Agency of Lazio.
TL;DR: In the largest series of Brugada syndrome patients thus far, event rates in asymptomatic patients were low and gender, familial history of SCD, inducibility of ventricular tachyarrhythmias during electrophysiological study, and the presence of an SCN5A mutation were not predictive of arrhythmic events.
Abstract: BACKGROUND: Brugada syndrome is characterized by ST-segment elevation in the right precordial leads and an increased risk of sudden cardiac death (SCD). Fundamental questions remain on the best strategy for assessing the real disease-associated arrhythmic risk, especially in asymptomatic patients. The aim of the present study was to evaluate the prognosis and risk factors of SCD in Brugada syndrome patients in the FINGER (France, Italy, Netherlands, Germany) Brugada syndrome registry. METHODS AND RESULTS: Patients were recruited in 11 tertiary centers in 4 European countries. Inclusion criteria consisted of a type 1 ECG present either at baseline or after drug challenge, after exclusion of diseases that mimic Brugada syndrome. The registry included 1029 consecutive individuals (745 men; 72%) with a median age of 45 (35 to 55) years. Diagnosis was based on (1) aborted SCD (6%); (2) syncope, otherwise unexplained (30%); and (3) asymptomatic patients (64%). During a median follow-up of 31.9 (14 to 54.4) months, 51 cardiac events (5%) occurred (44 patients experienced appropriate implantable cardioverter-defibrillator shocks, and 7 died suddenly). The cardiac event rate per year was 7.7% in patients with aborted SCD, 1.9% in patients with syncope, and 0.5% in asymptomatic patients. Symptoms and spontaneous type 1 ECG were predictors of arrhythmic events, whereas gender, familial history of SCD, inducibility of ventricular tachyarrhythmias during electrophysiological study, and the presence of an SCN5A mutation were not predictive of arrhythmic events. CONCLUSIONS: In the largest series of Brugada syndrome patients thus far, event rates in asymptomatic patients were low. Inducibility of ventricular tachyarrhythmia and family history of SCD were not predictors of cardiac events.
Vardan Khachatryan, Albert M. Sirunyan, Armen Tumasyan, Wolfgang Adam1 +2197 more•Institutions (149)
TL;DR: The pre-print version of the Published Article can be accessed from the link below - Copyright @ 2010 Springer Verlag as discussed by the authors, which can be viewed as a preprint of the published article.
Abstract: This is the pre-print version of the Published Article, which can be accessed from the link below - Copyright @ 2010 Springer Verlag
TL;DR: Criteria to define active acromegaly and disease control were agreed, and several significant changes were made to the 2000 guidelines.
Abstract: Objective: The Acromegaly Consensus Group met in April 2009 to revisit the guidelines on criteria for cure as defined in 2000. Participants: Participants included 74 neurosurgeons and endocrinologists with extensive experience of treating acromegaly. Evidence/Consensus Process: Relevant assays, biochemical measures, clinical outcomes, and definition of disease control were discussed, based on the available published evidence, and the strength of consensus statements was rated. Conclusions: Criteria to define active acromegaly and disease control were agreed, and several significant changes were made to the 2000 guidelines. Appropriate methods of measuring and achieving disease control were summarized.
TL;DR: Challenges for CEST Agents and Hyperpolarized Probes: Use of Gd Contrast Agents with HyperPolarized Substances 3038.
Abstract: 3.3. Magnetic Particle Imaging 3029 4. Challenges for CEST Agents 3029 4.1. Technical Issues 3029 4.2. Chemical Issues 3031 4.3. Biological Issues 3032 5. Challenges for Heteronuclear MR Imaging 3033 5.1. F-Based Probes 3033 6. Challenges for Hyperpolarized Probes 3034 6.1. Brute Force 3034 6.2. Optical Pumping and Spin Exchange 3035 6.3. Dynamic Nuclear Polarization (DNP) 3035 6.4. para-Hydrogen Induced Polarization (PHIP) 3037 6.5. Use of Gd Contrast Agents with Hyperpolarized Substances 3038
TL;DR: Sex differences in incidence may be explained by the higher incidence of spinal onset ALS among men, and the age related disease pattern suggests that ALS occurs within a susceptible group within the population rather than being a disease of ageing.
Abstract: Background Geographical differences in the incidence of amyotrophic lateral sclerosis (ALS) have been reported in the literature but comparisons across previous studies are limited by different methods in case ascertainment and by the relatively small size of the studied populations. To address these issues, the authors undertook a pooled analysis of European population based ALS registries. Methods All new incident ALS cases in subjects aged 18 years old and older were identified prospectively in six population based registries in three European countries (Ireland, UK and Italy) in the 2 year period 1998–1999, with a reference population of almost 24 million. Results Based on 1028 identified incident cases, the crude annual incidence rate of ALS in the general European population was 2.16 per 100 000 person years; 95% CI 2.0 to 2.3), with similar incidence rates across all registries. The incidence was higher among men (3.0 per 100 000 person years; 95% CI 2.8 to 3.3) than among women (2.4 per 100 000 person years; 95% CI 2.2 to 2.6). Spinal onset ALS was more common among men compared with women, particularly in the 70–80 year age group. Disease occurrence decreased rapidly after 80 years of age. Conclusions ALS incidence is homogeneous across Europe. Sex differences in incidence may be explained by the higher incidence of spinal onset ALS among men, and the age related disease pattern suggests that ALS occurs within a susceptible group within the population rather than being a disease of ageing.
Katholieke Universiteit Leuven1, Ottawa Hospital Research Institute2, University of Turin3, University of Bern4, Cliniques Universitaires Saint-Luc5, Bristol-Myers Squibb6, University of Melbourne7, Peter MacCallum Cancer Centre8, University of Sydney9, Flinders University10, Catholic University of Leuven11
TL;DR: In this paper, the authors studied the association between KRAS mutation status (p.G13D vs other KRAS mutations) and response and survival in a pooled data set of 579 patients with metastatic colorectal cancer treated with cetuximab between 2001 and 2008.
Abstract: Context Patients with metastatic colorectal cancer who have KRAS codon 12- or KRAS codon 13-mutated tumors are presently excluded from treatment with the anti-epidermal growth factor receptor monoclonal antibody cetuximab. Objective To test the hypothesis that KRAS codon 13 mutations are associated with a better outcome after treatment with cetuximab than observed with other KRAS mutations. Design, Setting, and Patients We studied the association between KRAS mutation status (p.G13D vs other KRAS mutations) and response and survival in a pooled data set of 579 patients with chemotherapy-refractory colorectal cancer treated with cetuximab between 2001 and 2008. Patients were included in the CO. 17, BOND, MABEL, EMR202600, EVEREST, BABEL, or SALVAGE clinical trials or received off-study treatment. Univariate and multivariate analyses, adjusting for possible prognostic factors and data set, were performed. The effect of the different mutations was studied in vitro by constructing isogenic cell lines with wild-type KRAS, p.G12V, or p.G13D mutant alleles and treating them with cetuximab. Main Outcome Measures The main efficacy end point was overall survival. Secondary efficacy end points were response rate and progression-free survival. Results In comparison with patients with other KRAS-mutated tumors, patients with p.G13D-mutated tumors (n=32) treated with cetuximab had longer overall survival (median, 7.6 [95% confidence interval {CI}, 5.7-20.5] months vs 5.7 [95% CI, 4.9-6.8] months; adjusted hazard ratio [HR], 0.50; 95% CI, 0.31-0.81; P=.005) and longer progression-free survival (median, 4.0 [95% CI, 1.9-6.2] months vs 1.9 [95% CI, 1.8-2.8] months; adjusted HR, 0.51; 95% CI, 0.32-0.81; P=.004). There was a significant interaction between KRAS mutation status (p.G13D vs other KRAS mutations) and overall survival benefit with cetuximab treatment (adjusted HR, 0.30; 95% CI, 0.14-0.67; P=.003). In vitro and mouse model analysis showed that although p.G12V-mutated colorectal cells were insensitive to cetuximab, p.G13D-mutated cells were sensitive, as were KRAS wild-type cells. Conclusions In this analysis, use of cetuximab was associated with longer overall and progression-free survival among patients with chemotherapy-refractory colorectal cancer with p.G13D-mutated tumors than with other KRAS-mutated tumors. Evaluation of cetuximab therapy in these tumors in prospective randomized trials may be warranted. JAMA. 2010; 304(16): 1812-1820
TL;DR: The evidence that mCRCs respond differently to EGFR-targeted agents and that the tumor-specific response has a genetic basis is discussed and it is suggested that CRCs lacking oncogenic alterations in these four genes have the highest probability of response to anti-EGFR therapies and are defined as "quadruple negative".
Abstract: Personalized cancer medicine based on the genetic milieu of individual colorectal tumors has long been postulated, but until recently this concept was not supported by clinical evidence. The advent of the epidermal growth factor receptor (EGFR) -targeted monoclonal antibodies cetuximab and panitumumab has paved the way to the individualized treatment of metastatic colorectal cancer (mCRC). Here we discuss the evidence that mCRCs respond differently to EGFR-targeted agents and that the tumor-specific response has a genetic basis. We outline how, from the initial observation that cetuximab or panitumumab as monotherapy is effective only in 10% to 20% of mCRCs, knowledge has being gained on the molecular mechanisms underlying primary resistance to these agents. The role of oncogenic activation of EGFR downstream effectors such as KRAS, BRAF, PIK3CA, and PTEN on response to therapy is discussed. We suggest that CRCs lacking oncogenic alterations in these four genes have the highest probability of response to anti-EGFR therapies and are defined as "quadruple negative." The rapid and effective translation of these findings into predictive biomarkers to couple EGFR-targeted antibodies to the patients who benefit from them is presented as a paradigm of modern clinical oncology. Finally, unresolved questions such as understanding the molecular basis of response as well the mechanisms of secondary resistance are presented as the future fundamental goals in this research field.
Mayo Clinic1, Cedars-Sinai Medical Center2, National Institutes of Health3, University of Würzburg4, Rutgers University5, National and Kapodistrian University of Athens6, Spanish National Research Council7, Masaryk University8, Harvard University9, Erasmus University Rotterdam10, University of Turin11, University of Arkansas for Medical Sciences12, Lund University13
TL;DR: Monoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of residents of Olmsted County, Minnesota, 50 years of age or older and is characterized by having an M protein <15 g/l, IgG type and a normal free light chain (FLC) ratio.
Abstract: Monoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is approximately 1% per year. Low-risk MGUS is characterized by having an M protein <15 g/l, IgG type and a normal free light chain (FLC) ratio. Patients should be followed with serum protein electrophoresis at six months and, if stable, can be followed every 2-3 years or when symptoms suggestive of a plasma cell malignancy arise. Patients with intermediate and high-risk MGUS should be followed in 6 months and then annually for life. The risk of smoldering (asymptomatic) multiple myeloma (SMM) progressing to multiple myeloma or a related disorder is 10% per year for the first 5 years, 3% per year for the next 5 years and 1-2% per year for the next 10 years. Testing should be done 2-3 months after the initial recognition of SMM. If the results are stable, the patient should be followed every 4-6 months for 1 year and, if stable, every 6-12 months.
TL;DR: This survey identifies several less-common species of Candida with decreased susceptibility to azoles, which may pose a future threat to optimal antifungal therapy and underscore the importance of prompt and accurate species identification and antIFungal susceptibility testing.
Abstract: Fluconazole in vitro susceptibility test results for 256,882 isolates of Candida spp. were collected from 142 sites in 41 countries from June 1997 to December 2007. Data were collected for 197,619 isolates tested with voriconazole from 2001 to 2007. A total of 31 different species of Candida were isolated. Increased rates of isolation of the common non-albicans species C. glabrata (10.2% to 11.7%), C. tropicalis (5.4% to 8.0%), and C. parapsilosis (4.8% to 5.6%) were noted when the time periods 1997 to 2000 and 2005 to 2007 were compared. Investigators tested clinical isolates of Candida spp. by the CLSI M44-A disk diffusion method. Overall, 90.2% of Candida isolates tested were susceptible (S) to fluconazole; however, 13 of 31 species identified exhibited decreased susceptibility (<75% S), similar to that seen with the resistant (R) species C. glabrata and C. krusei. Among 197,619 isolates of Candida spp. tested against voriconazole, 95.0% were S and 3% were R. About 30% of fluconazole-R isolates of C. albicans, C. glabrata, C. tropicalis, C. rugosa, C. lipolytica, C. pelliculosa, C. apicola, C. haemulonii, C. humicola, C. lambica, and C. ciferrii remained S to voriconazole. An increase in fluconazole resistance over time was seen with C. parapsilosis, C. guilliermondii, C. lusitaniae, C. sake, and C. pelliculosa. Among the emerging fluconazole-R species were C. guilliermondii (11.4% R), C. inconspicua (53.2% R), C. rugosa (41.8% R), and C. norvegensis (40.7% R). The rates of isolation of C. rugosa, C. inconspicua, and C. norvegensis increased by 5- to 10-fold over the 10.5-year study period. C. guilliermondii and C. rugosa were most prominent in Latin America, whereas C. inconspicua and C. norvegensis were most common in Eastern European countries. This survey identifies several less-common species of Candida with decreased susceptibility to azoles. These organisms may pose a future threat to optimal antifungal therapy and underscore the importance of prompt and accurate species identification and antifungal susceptibility testing.
TL;DR: In this article, a combination of the inclusive deep inelastic cross sections measured by the H1 and ZEUS Collaborations in neutral and charged current unpolarised e(+/-)p scattering at HERA during the period 1994-2000 is presented.
Abstract: A combination is presented of the inclusive deep inelastic cross sections measured by the H1 and ZEUS Collaborations in neutral and charged current unpolarised e(+/-)p scattering at HERA during the period 1994-2000. The data span six orders of magnitude in negative four-momentum-transfer squared, Q(2), and in Bjorken x. The combination method used takes the correlations of systematic uncertainties into account, resulting in an improved accuracy. The combined data are the sole input in a NLO QCD analysis which determines a new set of parton distributions, HERAPDF1.0, with small experimental uncertainties. This set includes an estimate of the model and parametrisation uncertainties of the fit result.
TL;DR: It was demonstrated that MVs contained ribonucleoproteins involved in the intracellular traffic of RNA and selected pattern of miRNAs, suggesting a dynamic regulation of RNA compartmentalization in MVs.
Abstract: Background: Cell-derived microvesicles (MVs) have been described as a new mechanism of cell-to-cell communication. MVs after internalization within target cells may deliver genetic information. Human bone marrow derived mesenchymal stem cells (MSCs) and liver resident stem cells (HLSCs) were shown to release MVs shuttling functional mRNAs. The aim of the present study was to evaluate whether MVs derived from MSCs and HLSCs contained selected micro-RNAs (miRNAs). Methodology/Principal Findings: MVs were isolated from MSCs and HLSCs. The presence in MVs of selected ribonucleoproteins involved in the traffic and stabilization of RNA was evaluated. We observed that MVs contained TIA, TIAR and HuR multifunctional proteins expressed in nuclei and stress granules, Stau1 and 2 implicated in the transport and stability of mRNA and Ago2 involved in miRNA transport and processing. RNA extracted from MVs and cells of origin was profiled for 365 known human mature miRNAs by real time PCR. Hierarchical clustering and similarity analysis of miRNAs showed 41 co-expressed miRNAs in MVs and cells. Some miRNAs were accumulated within MVs and absent in the cells after MV release; others were retained within the cells and not secreted in MVs. Gene ontology analysis of predicted and validated targets showed that the high expressed miRNAs in cells and MVs could be involved in multi-organ development, cell survival and differentiation. Few selected miRNAs shuttled by MVs were also associated with the immune system regulation. The highly expressed miRNAs in MVs were transferred to target cells after MV incorporation. Conclusions: This study demonstrated that MVs contained ribonucleoproteins involved in the intracellular traffic of RNA and selected pattern of miRNAs, suggesting a dynamic regulation of RNA compartmentalization in MVs. The observation that MV-highly expressed miRNAs were transferred to target cells, rises the possibility that the biological effect of stem cells may, at least in part, depend on MV-shuttled miRNAs. Data generated from this study, stimulate further functional investigations on the predicted target genes and pathways involved in the biological effect of human adult stem cells.
25 Jul 2010
TL;DR: A novel topic detection technique that permits to retrieve in real-time the most emergent topics expressed by the community, under user-specified time constraints is proposed.
Abstract: Twitter is a user-generated content system that allows its users to share short text messages, called tweets, for a variety of purposes, including daily conversations, URLs sharing and information news. Considering its world-wide distributed network of users of any age and social condition, it represents a low level news flashes portal that, in its impressive short response time, has the principal advantage.In this paper we recognize this primary role of Twitter and we propose a novel topic detection technique that permits to retrieve in real-time the most emergent topics expressed by the community. First, we extract the contents (set of terms) of the tweets and model the term life cycle according to a novel aging theory intended to mine the emerging ones. A term can be defined as emerging if it frequently occurs in the specified time interval and it was relatively rare in the past. Moreover, considering that the importance of a content also depends on its source, we analyze the social relationships in the network with the well-known Page Rank algorithm in order to determine the authority of the users. Finally, we leverage a navigable topic graph which connects the emerging terms with other semantically related keywords, allowing the detection of the emerging topics, under user-specified time constraints. We provide different case studies which show the validity of the proposed approach.
TL;DR: In patients with NAFLD, adiponutrin rs738409 C→G genotype, encoding for I148M, is associated with the severity of steatosis and fibrosis and the presence of nonalcoholic steatohepatitis.
National Technological University1, Technical University of Lisbon2, University of Turin3, University of Paris4, National Scientific and Technical Research Council5, New York University6, University of Naples Federico II7, University of Wisconsin–Milwaukee8, INAF9, Complutense University of Madrid10, University of California, Los Angeles11, Pierre-and-Marie-Curie University12, Karlsruhe Institute of Technology13, University of Chicago14, National University of La Plata15, Ohio State University16, Colorado State University17, Joseph Fourier University18, University of Alcalá19, Istituto Nazionale di Fisica Nucleare20, University of Salento21, University of Rome Tor Vergata22, Polish Academy of Sciences23, University of Leeds24, University of Siegen25, University of Granada26, Max Planck Society27, University of Catania28, Fermilab29, Academy of Sciences of the Czech Republic30, Radboud University Nijmegen31, University of Paris-Sud32, Pennsylvania State University33
TL;DR: The measurement of the depth of maximum, X{max}, of the longitudinal development of air showers induced by cosmic rays is described and the interpretation of these results in terms of the cosmic ray mass composition is briefly discussed.
Abstract: We describe the measurement of the depth of maximum, Xmax, of the longitudinal development of air showers induced by cosmic rays. Almost four thousand events above 10^18 eV observed by the fluorescence detector of the Pierre Auger Observatory in coincidence with at least one surface detector station are selected for the analysis. The average shower maximum was found to evolve with energy at a rate of (106 +35/-21) g/cm^2/decade below 10^(18.24 +/- 0.05) eV and (24 +/- 3) g/cm^2/decade above this energy. The measured shower-to-shower fluctuations decrease from about 55 to 26 g/cm^2. The interpretation of these results in terms of the cosmic ray mass composition is briefly discussed.
University of Málaga1, Centre national de la recherche scientifique2, Ege University3, University of Genoa4, Spanish National Research Council5, Adnan Menderes University6, University of Turin7, Ca' Foscari University of Venice8, Autonomous University of Madrid9, University of Alicante10, University of Bari11, Stazione Zoologica Anton Dohrn12
TL;DR: The state-of-art on alien species in the Mediterranean Sea is presented, making distinctions among the four subregions defined in the EU Marine Strategy Framework Directive; the WMED hosts most invasive macrophytes, whereas the EMED has the lion’s share in polychaetes, crustaceans, molluscs and fish.
Abstract: The state-of-art on alien species in the Mediterranean Sea is presented, making distinctions among the four subregions defined in the EU Marine Strategy Framework Directive: (i) the Western Mediterranean Sea (WMED); (ii) the Central Mediterranean Sea (CMED); (iii) the Adriatic Sea (ADRIA); and (iv) the Eastern Mediterranean Sea (EMED). The updated checklist (December 2010) of marine alien species within each subregion, along with their acclimatization status and origin, is provided. A total of 955 alien species is known in the Mediterranean, the vast majority of them having being introduced in the EMED (718), less in the WMED (328) and CMED (267) and least in the Adriatic (171). Of these, 535 species (56%) are established in at least one area. Despite the collective effort of experts who attempted in this work, the number of introduced species remains probably underestimated. Excluding microalgae, for which knowledge is still insufficient, aliens have increased the total species richness of the Mediterranean Sea by 5.9%. This figure should not be directly read as an indication of higher biodiversity, as spreading of so many aliens within the basin is possibly causing biotic homogenization. Thermophilic species, i.e. Indo-Pacific, Indian Ocean, Red Sea, Tropical Atlantic, Tropical Pacific, and circum(sub)tropical, account for 88.4% of the introduced species in the EMED, 72.8% in the CMED, 59.3% in the WMED and 56.1% in the Adriatic. Cold water species, i.e. circumboreal, N Atlantic, and N Pacific, make up a small percentage of the introduced species, ranging between 4.2% and 21.6% and being more numerous in the Adriatic and less so in the EMED. Species that are classified as invasive or potentially invasive are 134 in the whole of the Mediterranean: 108 are present in the EMED, 76 in the CMED, 53 in the Adriatic and 64 in the WMED. The WMED hosts most invasive macrophytes, whereas the EMED has the lion’s share in polychaetes, crustaceans, molluscs and fish.