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Dhillon N.,Mount Sinai School of Medicine | Walsh L.,Mount Sinai School of Medicine | Kruger B.,Mount Sinai School of Medicine | Kruger B.,Ruhr University Bochum | And 7 more authors.
Liver Transplantation | Year: 2010

The complement system has been implicated in the pathogenesis of liver diseases. Human complement component C3 (C3) exists as 2 allotypes, fast (F) and slow (S). We conducted a study to address the influence of these alleles on ischemia-reperfusion (IR) injury and graft survival in liver transplant recipients. Four hundred thirty patients receiving liver transplants from 2000 to 2004 were included. C3 allotypes of 296 donor-recipient pairs were determined and correlated with clinical outcomes. Four groups were analyzed according to the C3 genotype: C3 SS donor and recipient, C3 FS or C3 FF donor and C3 SS recipient, C3 SS donor and C3 FS or C3 FF recipient, and C3 FS or C3 FF donor and recipient. Baseline characteristics of the 4 groups were similar. The mean follow-up time was 4.3 ± 2.2 years. The 4 groups had similar rates of IR injury (P = 0.16). The hazard ratios for liver allograft survival in the C3 SS donor and recipient group in comparison with the other 3 groups (C3 FS or C3 FF donor and C3 SS recipient, C3 SS donor and C3 FS or C3 FF recipient, and C3 FS or C3 FF donor and recipient) were not significantly different: 1.13 (P = 0.60), 0.99 (P = 0.97), and 1.02 (P = 0.95), respectively. In conclusion, donor and recipient C3 genotypes are not associated with liver transplantation outcomes. © 2010 AASLD.

Antonescu C.R.,Sloan Kettering Cancer Center | Le Loarer F.,Sloan Kettering Cancer Center | Mosquera J..-M.,New York Medical College | Sboner A.,New York Medical College | And 10 more authors.
Genes Chromosomes and Cancer | Year: 2013

Conventional epithelioid hemangioendotheliomas (EHE) have a distinctive morphologic appearance and are characterized by a recurrent t(1;3) translocation, resulting in a WWTR1-CAMTA1 fusion gene. We have recently encountered a fusion-negative subset characterized by a somewhat different morphology, including focally well-formed vasoformative features, which was further investigated for recurrent genetic abnormalities. Based on a case showing strong transcription factor E3 (TFE3) immunoreactivity, fluorescence in situ hybridization (FISH) analysis for TFE3 gene rearrangement was applied to the index case as well as to nine additional cases, selected through negative WWTR1-CAMTA1 screening. A control group, including 18 epithelioid hemangiomas, nine pseudomyogenic HE, and three epithelioid angiosarcomas, was also tested. TFE3 gene rearrangement was identified in 10 patients, with equal gender distribution and a mean age of 30 years old. The lesions were located in somatic soft tissue in six cases, lung in three and one in bone. One case with available frozen tissue was tested by RNA sequencing and FusionSeq data analysis to detect novel fusions. A YAP1-TFE3 fusion was thus detected, which was further validated by FISH and reverse transcription polymerase chain reaction (RT-PCR). YAP1 gene rearrangements were then confirmed in seven of the remaining nine TFE3-rearranged EHEs by FISH. No TFE3 structural abnormalities were detected in any of the controls. The TFE3-rearranged EHEs showed similar morphologic features with at least focally, well-formed vascular channels, in addition to a variably solid architecture. All tumors expressed endothelial markers, as well as strong nuclear TFE3. In summary, we are reporting a novel subset of EHE occurring in young adults, showing a distinct phenotype and YAP1-TFE3 fusions. © 2013 Wiley Periodicals, Inc.

Kissin E.Y.,Boston University | Nishio J.,Rheumatology | Yang M.,Boston University | Backhaus M.,Charite University Hospital | And 16 more authors.
Arthritis Care and Research | Year: 2010

Objective. Because musculoskeletal ultrasound (MSUS) is highly user dependent, we aimed to establish whether non-mentored learning of MSUS is sufficient to achieve the same level of diagnostic accuracy and scanning reliability as has been achieved by rheumatologists recognized as international experts in MSUS. Methods. A group of 8 rheumatologists with more experience in MSUS and 8 rheumatologists with less experience in MSUS participated in an MSUS exercise to assess patients with musculoskeletal abnormalities commonly seen in a rheumatology practice. Patients' established diagnoses were obtained from chart review (gout, osteoarthritis, rotator cuff syndrome, rheumatoid arthritis, and seronegative arthritis). Two examining groups were formed, each composed of 4 less experienced and 4 more experienced examiners. Each group scanned 1 predefined body region (hand, wrist, elbow, shoulder, knee, or ankle) in each of 8 patients, blinded to medical history and physical examination. Structural abnormalities were noted with dichotomous answers, and an open-ended answer was used for the final diagnosis. Results. Less experienced and more experienced examiners achieved the same diagnostic accuracy (US-established diagnosis versus chart review diagnosis). The interrater reliability for tissue pathology was slightly higher for more experienced versus less experienced examiners (κ = 0.43 versus κ = 0.34; P = 0.001). Conclusion. Non-mentored training in MSUS can lead to the achievement of diagnostic accuracy in MSUS comparable to that achieved by highly experienced international experts. Reliability may increase slightly with additional experience. Further study is needed to determine the minimal training requirement to achieve proficiency in MSUS. © 2010, American College of Rheumatology.

Kissin E.Y.,Boston University | Niu J.,Boston University | Balint P.,National Institute of Rheumatology and Physiotherapy | Bong D.,Instituto Poal Of Reumatlogia | And 10 more authors.
Journal of Ultrasound in Medicine | Year: 2013

Objectives-The purpose of this study was to establish standards for musculoskeletal ultrasound competency through knowledge and skills testing using criterion-referenced methods. Methods-Two groups of rheumatology fellows trained in musculoskeletal ultrasound through a standardized curriculum, which required submission of ultrasound studies for review over 8 months. Both groups then completed written and practical examinations in musculoskeletal ultrasound. Instructors, advanced users, and intermediate users of musculoskeletal ultrasound served as comparison groups. A passing score (competency) was established for the written examination by the Angoff procedure and for the practical examination by the borderline method. Results-Thirty-eight fellows (19 in each group) took the final examination. Five fellows failed the written examination, and 1 failed the practical examination, whereas none of the advanced users failed. Written examination scores did not differ between the two fellow groups (74% versus 70%; P > .05), were reliable, and were able to discriminate between the intermediate and advanced groups. Practical and written examination results correlated in both groups (first group, r = 0.70; P = .0008; second group, r = 0.59; P = .009). Conclusions-Criterion-referenced methods were used for the first time to determine fellow musculoskeletal ultrasound competency. The examination used to determine competency was reproducible, was reliable, and could differentiate musculoskeletal ultrasound users with different levels of experience. Most rheumatology fellows completing our program passed the written and practical examinations, suggesting achievement of basic musculoskeletal ultrasound competency. © 2013 by the American Institute of Ultrasound in Medicine.

Zhang Y.,University of Washington | Zhang Y.,Raritan Bay Medical Center | Otero J.E.,University of Iowa | Abu-Amer Y.,University of Washington
Calcified Tissue International | Year: 2013

The transcription factor NF-κB family is central for osteoclastogenesis and inflammatory osteolysis. Activation of NF-κB dimers is regulated by a kinase complex predominantly containing IKKα (IKK1), IKKβ (IKK2), and a regulatory subunit, IKKγ/NEMO. IKKα and IKKβ catalyze the cytoplasmic liberation and nuclear translocation of various NF-κB subunits. The requirement of IKKα and IKKβ for normal bone homeostasis has been established. Congruently, mice devoid of IKKα or IKKβ exhibit in vitro and in vivo defects in osteoclastogenesis, and IKKβ-null mice are refractory to inflammatory arthritis and osteolysis. To better understand the molecular mechanism underlying IKKβ function in bone homeostasis and bone pathologies, we conducted structure-function analysis to determine IKKβ functional domains in osteoclasts. IKKβ encompasses several domains, of which the ubiquitination-like domain (ULD) has been shown essential for IKKβ activation. In this study, we examined the role of ULD in IKKβ-mediated NF-κB activation in osteoclast precursors and its contribution to osteoclastogenesis and osteolysis. We generated and virally introduced IKKβ in which the ULD domain has been deleted (IKKβ-ULD) into osteoclast progenitors. The results show that deletion of ULD diminishes IKKβ activity and that IKKβ-ULD strongly inhibits osteoclastogenesis. In addition, unlike wild type (WT)-IKKβ, IKKβ-ULD fail to restore RANKL-induced osteoclastogenesis by IKKβ-null precursors. Finally, we provide evidence that IKKβ-ULD blocks inflammatory osteolysis in a model of murine calvarial osteolysis. Thus, we identified the ULD as crucial for IKKβ activity and osteoclastogenesis and found that ULD-deficient IKKβ is a potent inhibitor of osteoclastogenesis and osteolysis. © 2013 Springer Science+Business Media New York.

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