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Near universal detection of alterations in CTNNB1 and Wnt pathway regulators in desmoid‐type fibromatosis by whole‐exome sequencing and genomic analysis 下载免费PDF全文
Aimee M. Crago Juliann Chmielecki Mara Rosenberg Rachael O'Connor Caitlin Byrne Fatima G. Wilder Katherine Thorn Phaedra Agius Deborah Kuk Nicholas D. Socci Li‐Xuan Qin Matthew Meyerson Meera Hameed Samuel Singer 《Genes, chromosomes & cancer》2015,54(10):606-615
CTNNB1 mutations or APC abnormalities have been observed in ~85% of desmoids examined by Sanger sequencing and are associated with Wnt/β‐catenin activation. We sought to identify molecular aberrations in “wild‐type” tumors (those without CTNNB1 or APC alteration) and to determine their prognostic relevance. CTNNB1 was examined by Sanger sequencing in 117 desmoids; a mutation was observed in 101 (86%) and 16 were wild type. Wild‐type status did not associate with tumor recurrence. Moreover, in unsupervised clustering based on U133A‐derived gene expression profiles, wild‐type and mutated tumors clustered together. Whole‐exome sequencing of eight of the wild‐type desmoids revealed that three had a CTNNB1 mutation that had been undetected by Sanger sequencing. The mutation was found in a mean 16% of reads (vs. 37% for mutations identified by Sanger). Of the other five wild‐type tumors sequenced, two had APC loss, two had chromosome 6 loss, and one had mutation of BMI1. The finding of low‐frequency CTNNB1 mutation or APC loss in wild‐type desmoids was validated in the remaining eight wild‐type desmoids; directed miSeq identified low‐frequency CTNNB1 mutation in four and comparative genomic hybridization identified APC loss in one. These results demonstrate that mutations affecting CTNNB1 or APC occur more frequently in desmoids than previously recognized (111 of 117; 95%), and designation of wild‐type genotype is largely determined by sensitivity of detection methods. Even true CTNNB1 wild‐type tumors (determined by next‐generation sequencing) may have genomic alterations associated with Wnt activation (chromosome 6 loss/BMI1 mutation), supporting Wnt/β‐catenin activation as the common pathway governing desmoid initiation. © 2015 Wiley Periodicals, Inc. 相似文献
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Juliann Saquib Nouf Abdulrahman AlRomaih Hanadi Mufakkir Al-Mutairi Renad Nasser Alenazi Reef Deyf Allah Al-Mutairi Dona Jamal AlHtlani Fatemah Saleh Al-Theyab Mnahel Ali Alhsaon Mohammed Imran Hassan Khalaf Nazmus Saquib 《Journal of the Saudi Heart Association》2018,30(3):240-246
Background
After myocardial infarction (MI), patients have an elevated risk for depression, which has a negative impact on morbidity and mortality for patients. As depression and memory function are associated, we examined them in the context of one another. Our objectives were to determine the proportion of patients with either depression only, memory loss only, or both depression and memory loss and to examine the correlates with each outcome.Methods
This study was a cohort of 264 patients who had myocardial infarction. Data sources included medical records and phone interviews.Results
The participants’ mean age was 62?±?12.2?years and mean body mass index was 28.4?±?5.8?kg/m2. Of the participants, 6.4% had memory loss alone, 23.17% had depression alone, and 6.1% had combined memory loss and depression. Activity level and poor health were significantly associated with depression only (p?<?0.05). Poor health was significantly associated with combined memory loss and depression (p?<?0.05).Conclusion
Activity level and poor health were identified as correlates of depression as well as combined memory loss and depression. Future studies should aim to improve screening for depression among post-MI patients and develop appropriate interventions to raise the level of activity. 相似文献5.
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Comprehensive Genomic Profiling of Advanced Penile Carcinoma Suggests a High Frequency of Clinically Relevant Genomic Alterations 下载免费PDF全文
Siraj M. Ali Kai Wang Norma A. Palma Eric Sanford Mark Bailey Jie He Julia A. Elvin Juliann Chmielecki Rachel Squillace Edward Dow Deborah Morosini Jamie Buell Roman Yelensky Doron Lipson Garrett M. Frampton Peter Howley Jeffrey S. Ross Philip J. Stephens Vincent A. Miller 《The oncologist》2016,21(1):33-39
Background.
Advanced penile squamous cell carcinoma (PSCC) is associated with poor survival due to the aggressiveness of the disease and lack of effective systemic therapies. Comprehensive genomic profiling (CGP) was performed to identify clinically relevant genomic alterations (CRGAs).Materials and Methods.
DNA was extracted from 40 μm of formalin-fixed, paraffin-embedded sections in patients with advanced PSCC. CGP was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of 692× for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. CRGAs were defined as genomic alterations (GAs) linked to targeted therapies on the market or under evaluation in mechanism-driven clinical trials.Results.
Twenty male patients with a median age of 60 years (range, 46–87 years) were assessed. Seventeen (85%) cases were stage IV and three cases (15%) were stage III. CGP revealed 109 GAs (5.45 per tumor), 44 of which were CRGAs (2.2 per tumor). At least one CRGA was detected in 19 (95%) cases, and the most common CRGAs were CDKN2A point mutations and homozygous deletion (40%), NOTCH1 point mutations and rearrangements (25%), PIK3CA point mutations and amplification (25%), EGFR amplification (20%), CCND1 amplification (20%), BRCA2 insertions/deletions (10%), RICTOR amplifications (10%), and FBXW7 point mutations (10%).Conclusion.
CGP identified CRGAs in patients with advanced PSCC, including EGFR amplification and PIK3CA alterations, which can lead to the rational administration of targeted therapy and subsequent benefit for these patients.Implications for Practice:
Few treatment options exist for patients with advanced penile squamous cell carcinoma (PSCC). Outcomes are dismal with platinum-based chemotherapy, with median survival estimated at 1 year or less across multiple series. Biological studies of patients with PSCC to date have principally focused on human papillomavirus status, but few studies have elucidated molecular drivers of the disease. To this end, comprehensive genomic profiling was performed in a cohort of 20 patients with advanced PSCC. Findings of frequent mutations in CDKN2A, NOTCH1, PIK3CA, and EGFR (all in excess of 20%) point to potential therapeutic avenues. Trials of targeted therapies directed toward these mutations should be explored. 相似文献8.
Menglin Ma Abhijit Gurjar James R. Theoret Jorge P. Garcia Juliann Beingesser John C. Freedman Derek J. Fisher Bruce A. McClane Francisco A. Uzal 《Infection and immunity》2014,82(7):2958-2970
The ability of Clostridium perfringens type C to cause human enteritis necroticans (EN) is attributed to beta toxin (CPB). However, many EN strains also express C. perfringens enterotoxin (CPE), suggesting that CPE could be another contributor to EN. Supporting this possibility, lysate supernatants from modified Duncan-Strong sporulation (MDS) medium cultures of three CPE-positive type C EN strains caused enteropathogenic effects in rabbit small intestinal loops, which is significant since CPE is produced only during sporulation and since C. perfringens can sporulate in the intestines. Consequently, CPE and CPB contributions to the enteropathogenic effects of MDS lysate supernatants of CPE-positive type C EN strain CN3758 were evaluated using isogenic cpb and cpe null mutants. While supernatants of wild-type CN3758 MDS lysates induced significant hemorrhagic lesions and luminal fluid accumulation, MDS lysate supernatants of the cpb and cpe mutants caused neither significant damage nor fluid accumulation. This attenuation was attributable to inactivating these toxin genes since complementing the cpe mutant or reversing the cpb mutation restored the enteropathogenic effects of MDS lysate supernatants. Confirming that both CPB and CPE are needed for the enteropathogenic effects of CN3758 MDS lysate supernatants, purified CPB and CPE at the same concentrations found in CN3758 MDS lysates also acted together synergistically in rabbit small intestinal loops; however, only higher doses of either purified toxin independently caused enteropathogenic effects. These findings provide the first evidence for potential synergistic toxin interactions during C. perfringens intestinal infections and support a possible role for CPE, as well as CPB, in some EN cases. 相似文献
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Abhishek Chatterjee Jennifer Gass M. Barbara Burke Katherine Kopkash Mahmoud B. El-Tamer Dennis R. Holmes Patricia Clark Juliann Reiland 《Annals of surgical oncology》2018,25(10):2790-2794
Introduction
Oncoplastic surgery is emerging as a validated, safe, patient-centric approach to breast cancer surgery in the United States. The American Society of Breast Surgeons Oncoplastic Surgery Committee (ASBrS-OSC) conducted a survey to assess the scope of practice and level of interest in oncoplastic surgery among its members. Furthermore, the group sought to identify barriers to incorporating oncoplastic skills in a surgeon’s practice.Methods
A 10-question survey was administered in March 2017 to the entire ASBrS membership using an online format. Three solicitations were sent. Unique identifiers allowed a single response.Results
Of the 2655 surveys sent out, 708 members responded. Nearly all (99%) respondents had at least some interest in oncoplastic surgery. The current rates of performing nipple-sparing mastectomy, adjacent tissue transfer, and breast reduction with lumpectomy were 80, 60, and 51%, respectively. A minority of respondents reported independently performing breast reductions/mammaplasties (19%) or contralateral symmetrization (10%). Barriers to learning oncoplastic surgery included surgeon’s time and access to oncoplastic educational material/courses. Most respondents felt that training courses and videos may allow them to better incorporate oncoplastic techniques in their practices.Conclusions
The interest in oncoplastic surgery among U.S. surgeons is significant, yet there are barriers to incorporate these surgical techniques into a breast surgeon’s practice. As professional organizations provide access to effective training and enduring educational resources, breast surgeons will be enabled to develop their oncoplastic skill set and safely offer these techniques to their patients.10.
Juliann G. Sebastian Eileen T. Breslin Deborah E. Trautman Ann H. Cary Robert J. Rosseter David Vlahov 《Journal of Professional Nursing》2018,34(2):110-116
In 2016 the American Association of Colleges of Nursing issued a report, Advancing Healthcare Transformation: A New Era for Academic Nursing that included recommendations for more fully integrating nursing education, research, and practice. The report calls for a paradigm shift in how nursing leaders in academia and practice work together and with other leaders in higher education and clinical practice. Only by doing so can we realize the full benefits of academic nursing in this new era in which integration and collaboration are essential to success. In this paper we: 1) examine how academic nursing can contribute to healthcare innovation across environments; 2) explore leadership skills for deans of nursing to advance the goals of academic nursing in collaboration with clinical nursing partners, other health professions and clinical service leaders, academic administrators, and community members; and, 3) consider how governance structures and policy initiatives can advance this work. 相似文献