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1.
Constitutively active receptor tyrosine kinases (RTKs) are known oncogenic drivers and provide valuable therapeutic targets in many cancer types. However, clinical efficacy of RTK inhibitors is limited by intrinsic and acquired resistance. To identify genes conferring resistance to inhibition of the MET RTK, we conducted a forward genetics screen in the GTL-16 gastric cancer cell line, carrying MET amplification and exquisitely sensitive to MET inhibition. Cells were transduced with three different retroviral cDNA expression libraries and selected for growth in the presence of the MET inhibitor PHA-665752. Selected cells displayed robust and reproducible enrichment of library-derived cDNAs encoding truncated forms of RAF1 and BRAF proteins, whose silencing reversed the resistant phenotype. Transduction of naïve GTL-16 cells with truncated, but not full length, RAF1 and BRAF conferred in vitro and in vivo resistance to MET inhibitors, which could be reversed by MEK inhibition. Induction of resistance by truncated RAFs was confirmed in other MET-addicted cell lines, and further extended to EGFR-addicted cells. These data show that truncated RAF1 and BRAF proteins, recently described as products of genomic rearrangements in gastric cancer and other malignancies, have the ability to render neoplastic cells resistant to RTK-targeted therapy.  相似文献   
2.
European Journal of Nuclear Medicine and Molecular Imaging - To compare the incremental diagnostic value of amyloid-PET and CSF (Aβ42, tau, and phospho-tau) in AD diagnosis in patients with...  相似文献   
3.
ObjectiveTo determine whether the risk of colorectal cancer (CRC) decreases after colonoscopy compared with sigmoidoscopy or no lower endoscopy.Patients and MethodsPatients 67 to 80 years old in the 5% random Medicare sample of the Surveillance, Epidemiology and End Results and Medicare–linked database were grouped into those who underwent colonoscopy or flexible sigmoidoscopy from January 1, 1998, through December 31, 2002, and those who did not undergo lower endoscopy. We excluded patients with inflammatory bowel disease, history of colon polyps, or family history of CRC. All patients were followed up until the diagnosis of CRC or carcinoma in situ, death, or December 31, 2005. The risk of CRC after colonoscopy was compared with the risk after sigmoidoscopy or no lower endoscopy. The multivariate Cox proportional hazards model was used in statistical analysis.ResultsIn the colonoscopy group (n=12,266), 58 CRCs (0.5%) were diagnosed during follow-up compared with 66 CRCs (1.0%) in the sigmoidoscopy group (n=6402) and 634 (1.5%) in the control group (n=41,410) (all P<.001). In the sigmoidoscopy group, 771 patients (12.0%) underwent colonoscopy within the next 12 months. In multivariate Cox regressions, colonoscopy was associated with a decreased risk of distal CRC (hazard ratio [HR], 0.266; 95% CI, 0.161-0.437) and proximal CRC (HR, 0.451; 95% CI, 0.305-0.666); sigmoidoscopy was associated with a decreased risk of distal CRC (HR, 0.409; 95% CI, 0.207-0.809) but not proximal CRC.ConclusionAmong older patients, the risk of distal CRC decreased after both colonoscopy and sigmoidoscopy; the risk of proximal CRC decreased after colonoscopy but not sigmoidoscopy.  相似文献   
4.

Aim

To examine the association between mental disorders and work disability in the adult resident population in Singapore.

Method

Data are from the Singapore Mental Health Study, which was a household survey of a nationally representative sample. The main instrument used was the Composite International Diagnostic Interview (CIDI). Employment-related information was collected using the modified employment module of the CIDI.

Results

A total of 6,429 respondents were included in the analysis, 71 % (n = 4,594) were employed, 24.5 % (n = 1,522) were economically inactive and 4.5 % (n = 313) were unemployed. Among the employed, 2.3 % had a 12-month prevalence of at least one mental disorder, while 5.3 % of the unemployed had at least one mental disorder. The average number of work loss days (absenteeism) per capita among those with a mental disorder was 0.5 per month that is equivalent to an annualized national projection of approximately 0.3 million productivity days. The average work-cutback days (presenteeism) were 0.4 days among this group. Of the mentally ill in the workforce, a high proportion (86.5 %) did not ever seek help for problems related to mental health.

Conclusion

Our findings provide information on the significant consequences of mental disorders on the workforce in terms of lost work productivity, which could pave the way for a more rational allocation of scarce resources.  相似文献   
5.
Alzheimer’s disease (AD) is characterized by a non-linear progressive course and several aspects influence the relationship between cerebral amount of AD pathology and the clinical expression of the disease. Brain cognitive reserve (CR) refers to the hypothesized capacity of an adult brain to cope with brain damage in order to minimize symptomatology. CR phenomenon contributed to explain the disjunction between the degree of neurodegeneration and the clinical phenotype of AD. The possibility to track brain amyloidosis (Aβ) in vivo has huge relevance for AD diagnosis and new therapeutic approaches. The clinical repercussions of positron emission tomography (PET)-assessed Aβ load are certainly mediated by CR thus potentially hampering the prognostic meaning of amyloid PET in selected groups of patients. Similarly, amyloid PET and cerebrospinal fluid amyloidosis biomarkers have recently provided new evidence for CR. The present review discusses the concept of CR in the framework of available neuroimaging studies and specifically deals with the reciprocal influences between amyloid PET and CR in AD patients and with the potential consequent interventional strategies for AD.  相似文献   
6.
Rocco Marchitelli  Ludovico Minati  Moira Marizzoni  Beatriz Bosch  David Bartrés‐Faz  Bernhard W. Müller  Jens Wiltfang  Ute Fiedler  Luca Roccatagliata  Agnese Picco  Flavio Nobili  Oliver Blin  Stephanie Bombois  Renaud Lopes  Régis Bordet  Julien Sein  Jean‐Philippe Ranjeva  Mira Didic  Hélène Gros‐Dagnac  Pierre Payoux  Giada Zoccatelli  Franco Alessandrini  Alberto Beltramello  Núria Bargalló  Antonio Ferretti  Massimo Caulo  Marco Aiello  Carlo Cavaliere  Andrea Soricelli  Lucilla Parnetti  Roberto Tarducci  Piero Floridi  Magda Tsolaki  Manos Constantinidis  Antonios Drevelegas  Paolo Maria Rossini  Camillo Marra  Peter Schönknecht  Tilman Hensch  Karl‐Titus Hoffmann  Joost P. Kuijer  Pieter Jelle Visser  Frederik Barkhof  Jorge Jovicich 《Human brain mapping》2016,37(6):2114-2132
Understanding how to reduce the influence of physiological noise in resting state fMRI data is important for the interpretation of functional brain connectivity. Limited data is currently available to assess the performance of physiological noise correction techniques, in particular when evaluating longitudinal changes in the default mode network (DMN) of healthy elderly participants. In this 3T harmonized multisite fMRI study, we investigated how different retrospective physiological noise correction (rPNC) methods influence the within‐site test‐retest reliability and the across‐site reproducibility consistency of DMN‐derived measurements across 13 MRI sites. Elderly participants were scanned twice at least a week apart (five participants per site). The rPNC methods were: none (NPC), Tissue‐based regression, PESTICA and FSL‐FIX. The DMN at the single subject level was robustly identified using ICA methods in all rPNC conditions. The methods significantly affected the mean z‐scores and, albeit less markedly, the cluster‐size in the DMN; in particular, FSL‐FIX tended to increase the DMN z‐scores compared to others. Within‐site test‐retest reliability was consistent across sites, with no differences across rPNC methods. The absolute percent errors were in the range of 5–11% for DMN z‐scores and cluster‐size reliability. DMN pattern overlap was in the range 60–65%. In particular, no rPNC method showed a significant reliability improvement relative to NPC. However, FSL‐FIX and Tissue‐based physiological correction methods showed both similar and significant improvements of reproducibility consistency across the consortium (ICC = 0.67) for the DMN z‐scores relative to NPC. Overall these findings support the use of rPNC methods like tissue‐based or FSL‐FIX to characterize multisite longitudinal changes of intrinsic functional connectivity. Hum Brain Mapp 37:2114–2132, 2016. © 2016 Wiley Periodicals, Inc.  相似文献   
7.
Sleep disturbances and nocturnal disabilities are common in Parkinson’s Disease (PD). The PD sleep scale, second version (PDSS-2), has been proposed as a helpful tool for measuring sleep disorders in PD. We aimed to validate the Italian version of the PDSS-2. One hundred and twenty-three consecutive PD outpatients (76 males) were evaluated by means of PDSS-2, Epworth Sleepiness Scale, Hamilton Depression Rating Scale, Parkinson’s Disease Quality of Life Questionnaire (self-administered scales), Unified Parkinson’s Disease Rating (motor section) and Hoehn and Yahr Scales, and Mini Mental State Examination. PDSS-2 internal consistency was satisfactory (Cronbach’s α: 0.77) with significant item to total score correlation and high intra-class correlation coefficient for test–retest reliability (0.943). Total PDSS-2 score was correlated with the scores on all other clinical scales. The factor analysis identified five factors, related to five areas of nocturnal disturbances, similarly as the original PDSS-2. The five factors mainly reflected: (1) nocturnal movement-related problems, (2) quality of sleep, (3) dreaming distress, (4) fragmentation of sleep and (5) insomnia symptoms. The PDSS-2 scale has confirmed its usefulness in evaluating sleep problems in Italian PD patients.  相似文献   
8.
Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterized by fragmented and mineralized elastic fibers in the mid-dermis of the skin, eye, digestive tract and cardiovascular system. Clinical presentation includes typical skin lesions, ocular angioid streaks, and multisystem vasculopathy. The age of onset varies considerably from infancy to old age, but the diagnosis is usually made in young adults due to frequent absence of pathognomonic skin and ocular manifestations in early childhood. We report two children with PXE presenting with isolated multisystem vasculopathy and early-onset stroke. In the first patient, diagnosis was delayed until typical dermatologic alterations appeared; in the second patient, next-generation sequencing (NGS) study led to early diagnosis and specific follow-up, underlying the crucial role in idiopathic pediatric stroke of early genetic testing using NGS-based panels.  相似文献   
9.
10.
Aims To establish the prevalence, correlates, comorbidity and treatment gap of alcohol use disorders in the Singapore resident population. Design The Singapore Mental Health Study is a cross‐sectional epidemiological survey. Setting A nationally representative survey of the resident (citizens and permanent residents) population in Singapore. Participants A total of 6616 Singaporean adults aged 18 years and older. Measurements The diagnoses were established using the World Mental Health Composite International Diagnostic Interview (WMH‐CIDI) diagnostic modules for life‐time and 12‐month prevalence of selected mental illnesses including alcohol use disorders. Findings The life‐time prevalence of alcohol abuse and alcohol dependence was 3.1% and 0.5%, while the 12‐month prevalence of alcohol abuse and alcohol dependence was 0.5% and 0.3%, respectively. The life‐time and 12‐month prevalence of alcohol use disorders was 3.6% and 0.8%, respectively. Those with alcohol use disorder had significantly higher odds of having major depressive disorder [odds ratio (OR) 3.1] and nicotine dependence (OR 4.5). Compared to the rest of the population, those with an alcohol use disorder had significantly higher odds of having gastric ulcers (OR 3.0), respiratory conditions (OR 2.1) and chronic pain (OR 2.1). Only one in five of those with alcohol use disorder had ever sought treatment. Conclusions The prevalence of alcohol use disorders is relatively low in the Singapore adult population. Comorbidity with mental and physical disorders is significant, emphasizing the need to screen people with alcohol use disorders for these comorbidities.  相似文献   
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