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Doherty L.,The Manton Center for Orphan Disease Research | Sheen M.R.,The Manton Center for Orphan Disease Research | Vlachos A.,Feinstein Institute for Medical Research | Vlachos A.,Yeshiva University | And 23 more authors.
American Journal of Human Genetics | Year: 2010

Diamond-Blackfan anemia (DBA), an inherited bone marrow failure syndrome characterized by anemia that usually presents before the first birthday or in early childhood, is associated with birth defects and an increased risk of cancer. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital malformations, in particular craniofacial, upper limb, heart, and urinary system defects that are present in ∼30%-50% of patients. DBA has been associated with mutations in seven ribosomal protein (RP) genes, RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, and RPS7, in about 43% of patients. To continue our large-scale screen of RP genes in a DBA population, we sequenced 35 ribosomal protein genes, RPL15, RPL24, RPL29, RPL32, RPL34, RPL9, RPL37, RPS14, RPS23, RPL10A, RPS10, RPS12, RPS18, RPL30, RPS20, RPL12, RPL7A, RPS6, RPL27A, RPLP2, RPS25, RPS3, RPL41, RPL6, RPLP0, RPS26, RPL21, RPL36AL, RPS29, RPL4, RPLP1, RPL13, RPS15A, RPS2, and RPL38, in our DBA patient cohort of 117 probands. We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands. Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E pre-rRNA. This accumulation is consistent with the phenotype observed in HeLa cells after knockdown of RPS10 or RPS26 expression with siRNAs, which indicates that mutations in the RPS10 and RPS26 genes in DBA patients affect the function of the proteins in rRNA processing. © 2010 The American Society of Human Genetics. Source


Paller C.J.,Kimmel Comprehensive Cancer Center | Antonarakis E.S.,Kimmel Comprehensive Cancer Center
Clinical Advances in Hematology and Oncology | Year: 2013

Among men treated with prostatectomy or radiation therapy for localized prostate cancer, the state of an increasing prostate-specific antigen (PSA) level is known as biochemical recurrence (BCR). BCR can be predictive of the development of subsequent distant metastases and ultimately death, but BCR often predates other signs of clinical progression by several years. Although patients may be concerned about their rising PSA levels, physicians attempting to address patient anxiety must inform them that BCR is not typically associated with imminent death from disease, and that the natural history of biochemical progression may be prolonged. Misinterpretation of the significance of early changes in PSA may cause patients to receive androgen deprivation therapy (ADT) prematurely, especially in settings where the disease is unlikely to impact survival. In addition, knowledge of the morbidities associated with ADT (hot flashes, impotence, sarcopenia, metabolic syndrome, bone loss, and increased risk of vascular disease) has accelerated the search for alternative treatment options for these patients. Clinical trials investigating when and how to best use and supplement hormonal therapies in this patient population are under way, as are trials of novel nonhormonal targeted agents, immunotherapies, natural products, and other pharmaceuticals that have been approved by the US Food and Drug Administration (FDA) for other indications. This review will summarize the acceptable standards of care for the management of biochemically recurrent prostate cancer, and will also outline some novel experimental approaches for the treatment of this disease state. Source


Wu P.-H.,Johns Hopkins University | Giri A.,Johns Hopkins University | Wirtz D.,Johns Hopkins University | Wirtz D.,Kimmel Comprehensive Cancer Center
Nature Protocols | Year: 2015

Cell migration through 3D extracellular matrices (ECMs) is crucial to the normal development of tissues and organs and in disease processes, yet adequate analytical tools to characterize 3D migration are lacking. The motility of eukaryotic cells on 2D substrates in the absence of gradients has long been described using persistent random walks (PRWs). Recent work shows that 3D migration is anisotropic and features an exponential mean cell velocity distribution, rendering the PRW model invalid. Here we present a protocol for the analysis of 3D cell motility using the anisotropic PRW model. The software, which is implemented in MATLAB, enables statistical profiling of experimentally observed 2D and 3D cell trajectories, and it extracts the persistence and speed of cells along primary and nonprimary directions and an anisotropic index of migration. Basic computer skills and experience with MATLAB software are recommended for successful use of the protocol. This protocol is highly automated and fast, taking <30 min to analyze trajectory data per biological condition. © 2015 Nature America, Inc. Source

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