The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair.

Cell-based therapies, using multipotent mesenchymal stem cells (MSCs) for organ regeneration, are being pursued for cardiac disease, orthopedic injuries and biomaterial fabrication. The molecular pathways that regulate MSC-mediated regeneration or enhance their therapeutic efficacy are, however, poorly understood. We compared MSCs isolated from MRL/MpJ mice, known to demonstrate enhanced regenerative capacity, to those from C57BL/6 (WT) mice. Compared with WT-MSCs, MRL-MSCs demonstrated increased proliferation, in vivo engraftment, experimental granulation tissue reconstitution, and tissue vascularity in a murine model of repair stimulation. The MRL-MSCs also reduced infarct size and improved function in a murine myocardial infarct model compared with WT-MSCs. Genomic and functional analysis indicated a downregulation of the canonical Wnt pathway in MRL-MSCs characterized by significant up-regulation of specific secreted frizzled-related proteins (sFRPs). Specific knockdown of sFRP2 by shRNA in MRL-MSCs decreased their proliferation and their engraftment in and the vascular density of MRL-MSC-generated experimental granulation tissue. These results led us to generate WT-MSCs overexpressing sFRP2 (sFRP2-MSCs) by retroviral transduction. sFRP2-MSCs maintained their ability for multilineage differentiation in vitro and, when implanted in vivo, recapitulated the MRL phenotype. Peri-infarct intramyocardial injection of sFRP2-MSCs resulted in enhanced engraftment, vascular density, reduced infarct size, and increased cardiac function after myocardial injury in mice. These findings implicate sFRP2 as a key molecule for the biogenesis of a superior regenerative phenotype in MSCs.

Extrapulmonic presentation of tuberculosis: An atypical urogenital presentation of a common disease.

Mycobacterium tuberculosis is the leading cause of infectious disease-related death worldwide. However, it is less frequently encountered in developed countries, and 90% of cases are reported in adults, making it a less commonly encountered entity in pediatric radiology. The disease is treatable, but symptoms of renal disease are nonspecific and should be identified early. A high index of clinical suspicion and supportive imaging studies, particularly in immigrant or exposed children, is prudent to prevent irreversible organ damage. We report a rare case of a 16-year-old Mexican immigrant male who presented with chronic dysuria, urinary frequency, intermittent hematuria, hydronephrosis, ureteral stenosis, and evolving autonephrectomy secondary to renal M. tuberculosis.

Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages.

BACKGROUND: Solid tumors residing in tissues and organs leave footprints in circulation through circulating tumor cells (CTCs) and circulating tumor DNAs (ctDNA). Characterization of the ctDNA portraits and comparison with tumor DNA mutational portraits may reveal clinically actionable information on solid tumors that is traditionally achieved through more invasive approaches. METHODS: We isolated ctDNAs from plasma of patients of 103 lung cancer and 74 other solid tumors of different tissue origins. Deep sequencing using the Guardant360 test was performed to identify mutations in 73 clinically actionable genes, and the results were associated with clinical characteristics of the patient. The mutation profiles of 37 lung cancer cases with paired ctDNA and tumor genomic DNA sequencing were used to evaluate clonal representation of tumor in circulation. Five lung cancer cases with longitudinal ctDNA sampling were monitored for cancer progression or response to treatments. RESULTS: Mutations in TP53, EGFR, and KRAS genes are most prevalent in our cohort. Mutation rates of ctDNA are similar in early (I and II) and late stage (III and IV) cancers. Mutation in DNA repair genes BRCA1, BRCA2, and ATM are found in 18.1% (32/177) of cases. Patients with higher mutation rates had significantly higher mortality rates. Lung cancer of never smokers exhibited significantly higher ctDNA mutation rates as well as higher EGFR and ERBB2 mutations than ever smokers. Comparative analysis of ctDNA and tumor DNA mutation data from the same patients showed that key driver mutations could be detected in plasma even when they were present at a minor clonal population in the tumor. Mutations of key genes found in the tumor tissue could remain in circulation even after frontline radiotherapy and chemotherapy suggesting these mutations represented resistance mechanisms. Longitudinal sampling of five lung cancer cases showed distinct changes in ctDNA mutation portraits that are consistent with cancer progression or response to EGFR drug treatment. CONCLUSIONS: This study demonstrates that ctDNA mutation rates in the key tumor-associated genes are clinical parameters relevant to smoking status and mortality. Mutations in ctDNA may serve as an early detection tool for cancer. This study quantitatively confirms the hypothesis that ctDNAs in circulation is the result of dissemination of aggressive tumor clones and survival of resistant clones. This study supports the use of ctDNA profiling as a less-invasive approach to monitor cancer progression and selection of appropriate drugs during cancer evolution.

Mutational Landscapes of Smoking-Related Cancers in Caucasians and African Americans: Precision Oncology Perspectives at Wake Forest Baptist Comprehensive Cancer Center.

Background: Cancers related to tobacco use and African-American ancestry are under-characterized by genomics. This gap in precision oncology research represents a major challenge in the health disparities in the United States. Methods: The Precision Oncology trial at the Wake Forest Baptist Comprehensive Cancer Center enrolled 431 cancer patients from March 2015 to May 2016. The composition of these patients consists of a high representation of tobacco-related cancers (e.g., lung, colorectal, and bladder) and African-American ancestry (13.5%). Tumors were sequenced to identify mutations to gain insight into genetic alterations associated with smoking and/or African-American ancestry. Results: Tobacco-related cancers exhibit a high mutational load. These tumors are characterized by high-frequency mutations in TP53, DNA damage repair genes (BRCA2 and ATM), and chromatin remodeling genes (the lysine methyltransferases KMT2D or MLL2, and KMT2C or MLL3). These tobacco-related cancers also exhibit augmented tumor heterogeneities. Smoking related genetic mutations were validated by The Cancer Genome Atlas dataset that includes 2,821 cases with known smoking status. The Wake Forest and The Cancer Genome Atlas cohorts (431 and 7,991 cases, respectively) revealed a significantly increased mutation rate in the TP53 gene in the African-American subgroup studied. Both cohorts also revealed 5 genes (e.g. CDK8) significantly amplified in the African-American population. Conclusions: These results provide strong evidence that tobacco is a major cause of genomic instability and heterogeneity in cancer. TP53 mutations and key oncogene amplifications emerge as key factors contributing to cancer outcome disparities among different racial/ethnic groups.

Highly cited works in radiology: the top 100 cited articles in radiologic journals.

RATIONALE AND OBJECTIVES: The number of citations a publication receives can be used to show its impact on a field of study. It may indicate the educational interest in a given population or underline a perceived or real educational gap. This article identifies and characterizes the 100 top cited publications in radiologic journals as of May 2013. MATERIALS AND METHODS: All clinical radiologic journals listed by Thomson Reuters Journal Citation Reports in 2011 were identified. A total of 46 journals were identified, and all articles published within these journals were analyzed for citation counts. The top 100 highly cited articles were recorded. RESULTS: The most frequently cited radiologic articles appeared in 9 of the 46 journals. These included 59 articles in Radiology, 17 in Journal of Nuclear Medicine, 9 in the American Journal of Roentgenology, 5 in the British Journal of Radiology, 4 in Investigative Radiology, 2 in American Journal of Neuroradiology, 2 in European Radiology, 2 in Radiologic Clinics of North America, 1 in the Seminars in Nuclear Medicine, and 1 in Pediatric Radiology. The citation values ranged from 422 to 7506 with a mean of 751. Publication dates ranged from 1967 to 2006 with the 5-year period between 1986 and 1990 accounting for the largest percentage of articles. The most frequently studied radiologic modality was magnetic resonance imaging (MRI; 28 articles), followed by vascular/interventional (19 articles) and nuclear medicine (13 articles). The central nervous system was the most frequently studied organ system (22 articles), followed by mixed organ systems (14 articles) and liver (12 articles). CONCLUSIONS: The top cited articles in radiologic journals span a wide range of imaging modalities, subspecialties, and organ systems. Topics that occurred frequently in the top 100 cited articles included contrast and radiopharmaceutical characterization, MRI of motion, percutaneous radiofrequency ablation in the liver and percutaneous vertebroplasty. We present a methodology that uses citation analysis to identify and characterize these articles. Its use may aid radiologists, academic organization, and editorial staff in determining areas of imaging interest or perceived educational gap. It also highlights the importance of including classic articles in current imaging education.