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81.
Richard B. Lanman Stefanie A. Mortimer Oliver A. Zill Dragan Sebisanovic Rene Lopez Sibel Blau Eric A. Collisson Stephen G. Divers Dave S. B. Hoon E. Scott Kopetz Jeeyun Lee Petros G. Nikolinakos Arthur M. Baca Bahram G. Kermani Helmy Eltoukhy AmirAli Talasaz 《PloS one》2015,10(10)
Next-generation sequencing of cell-free circulating solid tumor DNA addresses two challenges in contemporary cancer care. First this method of massively parallel and deep sequencing enables assessment of a comprehensive panel of genomic targets from a single sample, and second, it obviates the need for repeat invasive tissue biopsies. Digital SequencingTM is a novel method for high-quality sequencing of circulating tumor DNA simultaneously across a comprehensive panel of over 50 cancer-related genes with a simple blood test. Here we report the analytic and clinical validation of the gene panel. Analytic sensitivity down to 0.1% mutant allele fraction is demonstrated via serial dilution studies of known samples. Near-perfect analytic specificity (> 99.9999%) enables complete coverage of many genes without the false positives typically seen with traditional sequencing assays at mutant allele frequencies or fractions below 5%. We compared digital sequencing of plasma-derived cell-free DNA to tissue-based sequencing on 165 consecutive matched samples from five outside centers in patients with stage III-IV solid tumor cancers. Clinical sensitivity of plasma-derived NGS was 85.0%, comparable to 80.7% sensitivity for tissue. The assay success rate on 1,000 consecutive samples in clinical practice was 99.8%. Digital sequencing of plasma-derived DNA is indicated in advanced cancer patients to prevent repeated invasive biopsies when the initial biopsy is inadequate, unobtainable for genomic testing, or uninformative, or when the patient’s cancer has progressed despite treatment. Its clinical utility is derived from reduction in the costs, complications and delays associated with invasive tissue biopsies for genomic testing. 相似文献
82.
Jessica AB van Nies Rute B Marques Stella Trompet Zuzana de Jong Fina AS Kurreeman Rene EM Toes J Wouter Jukema Tom WJ Huizinga Annette HM van der Helm-van Mil 《Arthritis research & therapy》2010,12(2):R38
Introduction
Recently an association between a genetic variation in TRAF1/C5 and mortality from sepsis or cancer was found in rheumatoid arthritis (RA). The most prevalent cause of death, cardiovascular disease, may have been missed in that study, since patients were enrolled at an advanced disease stage. Therefore, we used an inception cohort of RA patients to investigate the association between TRAF1/C5 and cardiovascular mortality, and replicate the findings on all-cause mortality. As TRAF1/C5 associated mortality may not be restricted to RA, we also studied a large cohort of non-RA patients. 相似文献83.
Bert Vander Cruyssen Patrick Durez Rene Westhovens Filip De Keyser 《Arthritis research & therapy》2010,12(3):1-8
Introduction
This study is based on the results from a Belgian expanded access program in which patients with active refractory and erosive rheumatoid arthritis (RA) were treated with intravenous infusions of infliximab in combination with methotrexate. The objectives of this study were to evaluate the continuation rate of infliximab and its clinical effect over a 7-year period and to document the reasons for discontinuation.Methods
Between 2000 and 2001, 511 patients with severe and refractory RA were enrolled and treated with infliximab. After 7 years, apart from routine clinical follow-up, treating rheumatologists were asked to complete a questionnaire designed specifically for the present study to evaluate the current therapy with infliximab, the level of disease activity (Disease Activity Score in 28 joints [DAS28]) and the reasons for infliximab discontinuation.Results
After 7 years, 160 of 511 patients (31%) were still on infliximab treatment. The major reasons for infliximab discontinuation included lack of efficacy (104 patients), adverse events (107 patients) and elective change of therapy (70 patients). The majority of cases of treatment discontinuation for safety reasons occurred during the first 2 years. In contrast, discontinuation due to ineffectiveness showed a more constant rate over the 7-year period. Mean DAS for patients still on treatment with infliximab decreased from 5.7 (standard error [SE] 0.1) at baseline to 3.0 (SE 0.1) at year 4 and remained that low until year 7 (3.0 [SE 0.1]). Low disease activity (defined as DAS28 <3.2) was present in 60.9% of patients, and 45.5% achieved remission (DAS28 <2.6). DAS28 at the time of treatment discontinuation due to ineffectiveness decreased over the 7-year period from 5.6 (SE 0.3) in 2001 to 4.8 (SE 0.3) in 2008.Conclusions
This observational study revealed that patients who continue to receive infliximab experience sustained clinical benefit. The majority of safety issues occurred during the first 2 years of infliximab therapy. We observed that the DAS at the time of therapy discontinuation showed a trend to decrease over time. 相似文献84.
Phagosomes fuse with late endosomes and/or lysosomes by extension of membrane protrusions along microtubules: role of Rab7 and RILP 下载免费PDF全文
Harrison RE Bucci C Vieira OV Schroer TA Grinstein S 《Molecular and cellular biology》2003,23(18):6494-6506
Nascent phagosomes must undergo a series of fusion and fission reactions to acquire the microbicidal properties required for the innate immune response. Here we demonstrate that this maturation process involves the GTPase Rab7. Rab7 recruitment to phagosomes was found to precede and to be essential for their fusion with late endosomes and/or lysosomes. Active Rab7 on the phagosomal membrane associates with the effector protein RILP (Rab7-interacting lysosomal protein), which in turn bridges phagosomes with dynein-dynactin, a microtubule-associated motor complex. The motors not only displace phagosomes in the centripetal direction but, strikingly, promote the extension of phagosomal tubules toward late endocytic compartments. Fusion of tubules with these organelles was documented by fluorescence and electron microscopy. Tubule extension and fusion with late endosomes and/or lysosomes were prevented by expression of a truncated form of RILP lacking the dynein-dynactin-recruiting domain. We conclude that full maturation of phagosomes requires the retrograde emission of tubular extensions, which are generated by activation of Rab7, recruitment of RILP, and consequent association of phagosomes with microtubule-associated motors. 相似文献
85.
86.
Mahalingam S Schwarze J Zaid A Nissen M Sloots T Tauro S Storer J Alvarez R Tripp RA 《Microbes and infection / Institut Pasteur》2006,8(1):285-293
Human metapneumovirus (HMPV) is a recently discovered pathogen first identified in respiratory specimens from young children suffering from clinical respiratory syndromes ranging from mild to severe lower respiratory tract illness. HMPV has worldwide prevalence, and is a leading cause of respiratory tract infection in the first years of life, with a spectrum of disease similar to respiratory syncytial virus (RSV). The disease burden associated with HMPV infection has not been fully elucidated; however, studies indicate that HMPV may cause upper or lower respiratory tract illness in patients between ages 2 months and 87 years, may co-circulate with RSV, and HMPV infection may be associated with asthma exacerbation. The mechanisms and effector pathways contributing to immunity or disease pathogenesis following infection are not fully understood; however, given the clinical significance of HMPV, there is a need for a fundamental understanding of the immune and pathophysiological processes that occur following infection to provide the foundation necessary for the development of effective vaccine or therapeutic intervention strategies. This review provides a current perspective on the processes associated with HMPV infection, immunity, and disease pathogenesis. 相似文献
87.
Whether present-day European genetic variation and its distribution patterns can be attributed primarily to the initial peopling of Europe by anatomically modern humans during the Paleolithic, or to latter Near Eastern Neolithic input is still the subject of debate. Southeastern Europe has been a crossroads for several cultures since Paleolithic times and the Balkans, specifically, would have been part of the route used by Neolithic farmers to enter Europe. Given its geographic location in the heart of the Balkan Peninsula at the intersection of Central and Southeastern Europe, Serbia represents a key geographical location that may provide insight to elucidate the interactions between indigenous Paleolithic people and agricultural colonists from the Fertile Crescent. In this study, we examine, for the first time, the Y-chromosome constitution of the general Serbian population. A total of 103 individuals were sampled and their DNA analyzed for 104 Y-chromosome bi-allelic markers and 17 associated STR loci. Our results indicate that approximately 58% of Serbian Y-chromosomes (I1-M253, I2a-P37.2 and R1a1a-M198) belong to lineages believed to be pre-Neolithic. On the other hand, the signature of putative Near Eastern Neolithic lineages, including E1b1b1a1-M78, G2a-P15, J1-M267, J2-M172 and R1b1a2-M269 accounts for 39% of the Y-chromosome. Haplogroup frequency distributions in Western and Eastern Europe reveal a spotted landscape of paleolithic Y chromosomes, undermining continental-wide generalizations. Furthermore, an examination of the distribution of Y-chromosome filiations in Europe indicates extreme levels of Paleolithic lineages in a region encompassing Serbia, Bosnia-Herzegovina and Croatia, possibly the result of Neolithic migrations encroaching on Paleolithic populations against the Adriatic Sea. 相似文献
88.
Tenzin Gayden Maria Regueiro Slavica Vujovic Danica Popovic Marija Djuric Oliver Stojkovic Rene J. Herrera 《American journal of physical anthropology》2010,142(3):380-390
Southeastern Europe and, particularly, the Balkan Peninsula are especially useful when studying the mechanisms responsible for generating the current distribution of Paleolithic and Neolithic genetic signals observed throughout Europe. In this study, 404 individuals from Montenegro and 179 individuals from Serbia were typed for 17 Y‐STR loci and compared across 9 Y‐STR loci to geographically targeted previously published collections to ascertain the phylogenetic relationships of populations within the Balkan Peninsula and beyond. We aim to provide information on whether groups in the region represent an amalgamation of Paleolithic and Neolithic genetic substrata, or whether acculturation has played a critical role in the spread of agriculture. We have found genetic markers of Middle Eastern, south Asian and European descent in the area, however, admixture analyses indicate that over 80% of the Balkan gene pool is of European descent. Altogether, our data support the view that the diffusion of agriculture into the Balkan region was mostly a cultural phenomenon although some genetic infiltration from Africa, the Levant, the Caucasus, and the Near East has occurred. Am J Phys Anthropol, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
89.
Tenzin Gayden Annabel Perez Patrice J. Persad Areej Bukhari Shilpa Chennakrishnaiah Tanya Simms Trisha Maloney Kristina Rodriguez Rene J. Herrera 《American journal of physical anthropology》2013,151(2):169-182
The Himalayan mountain range is strategically located at the crossroads of the major cultural centers in Asia, the Middle East and Europe. Although previous Y‐chromosome studies indicate that the Himalayas served as a natural barrier for gene flow from the south to the Tibetan plateau, this region is believed to have played an important role as a corridor for human migrations between East and West Eurasia along the ancient Silk Road. To evaluate the effects of the Himalayan mountain range in shaping the maternal lineages of populations residing on either side of the cordillera, we analyzed mitochondrial DNA variation in 344 samples from three Nepalese collections (Newar, Kathmandu and Tamang) and a general population of Tibet. Our results revealed a predominantly East Asian‐specific component in Tibet and Tamang, whereas Newar and Kathmandu are both characterized by a combination of East and South Central Asian lineages. Interestingly, Newar and Kathmandu harbor several deep‐rooted Indian lineages, including M2, R5, and U2, whose coalescent times from this study (U2, >40 kya) and previous reports (M2 and R5, >50 kya) suggest that Nepal was inhabited during the initial peopling of South Central Asia. Comparisons with our previous Y‐chromosome data indicate sex‐biased migrations in Tamang and a founder effect and/or genetic drift in Tamang and Newar. Altogether, our results confirm that while the Himalayas acted as a geographic barrier for human movement from the Indian subcontinent to the Tibetan highland, it also served as a conduit for gene flow between Central and East Asia. Am J Phys Anthropol 151:169–182, 2013. © 2013 Wiley Periodicals, Inc. 相似文献
90.
A progressive hydrolysis of phospholipids was observed during the mineralization process mediated by extracellular matrix vesicles. Increasing levels of different hydrolysis products revealed phospholipase A and D activities. The importance of these enzymes for the mineralization process lies in a high rate of hydrolysis of neutral phospholipids and lower rate of degradation of anionic phospholipids, which may favor mineral formation in vesicular membrane and membrane breakdown necessary for the release of mineral deposits into extracellular matrix. In this report, we focus on the phosphorylation-dependent phospholipase D activity during mineral formation initiated by chicken embryo matrix vesicles. 相似文献