777 research outputs found
A recital
No full textProgram notes and recording of the recital, performed by the Kansas State University Chamber Choir; Jess Wade, piano; the author, conductor.Digitized by Kansas Correctional Industrie
Interactive Multi-Submission Deposit Workflows for Desktop Applications
No full textOnline submission and publishing is the norm for academic researchers. With the pressure on these authors to submit their work to conferences, journals and Institutional Repositories, this leads to demands on the author to go through multiple web based interfaces, filling in forms with the same information multiple times before they can submit. At the same time, each of these services in turn will have made policy decisions on what types of format they allow and what templates the content has to conform to. The amount of work expected of the author does not adding up to the potential gain, thus most authors will only submit into the repository or publication where they foresee the most benefit. In this paper we propose a solution to this problem that embeds the workflow for multiple submissions into the desktop application of the author, most commonly Microsoft Word. We also propose extending the work done on the Microsoft Word Author Add-in tool to allow two-way negotiation between each repository and the desktop application
A 2 h periodic variation in the low-mass X-ray binary Ser X-1
No full textSpectroscopy of the low-mass X-ray binary Ser X-1 using the Gran Telescopio Canarias have revealed a ?2 h periodic variability that is present in the three strongest emission lines. We tentatively interpret this variability as due to orbital motion, making it the first indication of the orbital period of Ser X-1. Together with the fact that the emission lines are remarkably narrow, but still resolved, we show that a main-sequence K dwarf together with a canonical 1.4 M? neutron star gives a good description of the system. In this scenario, the most likely place for the emission lines to arise is the accretion disc, instead of a localized region in the binary (such as the irradiated surface or the stream-impact point), and their narrowness is due instead to the low inclination (?10°) of Ser X-1
A Synthetic Lethal shRNA Screen and Genetic Proof of Concept Identifies RAC1 as a Novel Target to Disrupt Plexiform Neurofibroma Formation
No full textIndiana University-Purdue University Indianapolis (IUPUI)Neurofibromatosis Type 1 (NF1) is a highly penetrant autosomal dominant
genetic disorder where mutations in the tumor suppressor gene NF1 leads to decreased
neurofibromin. The most debilitating manifestation is the presence of complex multilineage
Schwann cell-derived plexiform neurofibromas (PN). Historically, little clinical
success has been achieved targeting PN through surgery or chemotherapies. I performed
an shRNA library screen of patient-derived Schwann cell lines to identify novel
therapeutic targets to disrupt PN formation and progression. An shRNA library screen of
human kinases and Rho-GTPases was performed in NF1-/- and paired NF1 competent
immortalized Schwann cell lines. Following sequencing, candidates were identified. We
previously developed a novel mouse model of NF1 wherein a neural crest specific Postncre
targeted loxp-flanked Nf1 that replicated the PN found in patients. Additional cohorts
of mice were generated with biallelic deletion of Rac1 (Nf1f/fRac1f/f Postn-Cre+; DKO ).
Mice were aged for 9 months and peripheral nerves were harvested and fixed in formalin.
Peripheral nerve size was measured and tumors were identified through blinded analysis
of hematoxylin and eosin and Masson’s Trichrome (collagen) stained slides. Rho family
members, including RAC1, were identified as candidates through an shRNA library
screen. Genetic disruption of Rac1 in the Schwann cell lineage resulted in the prevention
of tumor formation in DKO mice, as observed by peripheral nerve size and histological
analysis. I observed an average of 14.8 +/- 2.65 tumors per mouse in the Nf1f/f Postnviii
Cre+ cohort compared to 0 tumors in the DKO (p<0.0001). Following an shRNA library
screen, RAC1 was identified as a candidate to modulate PN formation. Biallelic deletion
of Rac1 in vivo prevented PN formation. I demonstrate that a candidate identified in an
shRNA library screen can translate to an biological effect in a mouse model of PN
Abstract IA24: Identification of therapies for plexiform neurofibromas, a precursor of malignant peripheral nerve sheath tumors
No full textA Mechanistic Approach to Identify Novel Therapeutic Drugs for Targeting FA-Disrupted Malignancies
No full textIndiana University-Purdue University Indianapolis (IUPUI)The Fanconi anemia (FA) signaling network plays a critical role in maintaining genomic integrity during interphase and mitosis. Biallelic germline mutation of any of the 22 genes that constitute this pathway (FANCA-FANCW) results in Fanconi Anemia, a cancer predisposition syndrome characterized by congenital malformations, bone marrow failure, and pediatric acute myeloid leukemias (AMLs). Among the general population, acquired genetic disruptions of the FA pathway are found in 30% of all sporadic cancers and over 15% of sporadic pediatric AMLs underscoring the importance of this pathway in the prevention of malignant transformation. Therefore, the identification of precision therapies for FA-deficient AML is a critical need. The canonical tumor suppressive role of FA proteins in the repair of DNA damage during interphase is well established. We and others have uncovered the roles of FA proteins in mitotic regulation, suggesting additional mechanisms by which the FA pathway prevents genomic instability. Mutation of FANCA is the most common cause of FA and is one of the most frequently disrupted FA pathway genes in sporadic AML. To identify synthetic lethal targets of FANCA, we previously identified mitotic phospho-signaling pathways required for the survival of FANCA-/- patient-derived fibroblasts through a kinome-wide shRNA screen. We identified mitotic kinases CHEK1, PLK1, SLK, and TTK as potential targets, which suggests a mitosis-specific vulnerability of FA-deficient cells. These findings corroborate work by others who have identified synthetic lethal interactions between PLK1 and the FA pathway members, FANCG and BRCA1, suggesting that inactivation of the FA pathway may sensitize cancers to PLK1 inhibition. A more thorough understanding of FA pathway function in mitosis provides new insight into AML pathogenesis and suggests that genetic disruptions of the FA pathway may be predictive of sensitivity to PLK1 inhibition, providing a preclinical rationale for the development of precision therapies
A Mechanistic Approach to Identify Novel Therapeutic Drugs for Targeting FA-Disrupted Malignancies
No full textIndiana University-Purdue University Indianapolis (IUPUI)The Fanconi anemia (FA) signaling network plays a critical role in maintaining genomic integrity during interphase and mitosis. Biallelic germline mutation of any of the 22 genes that constitute this pathway (FANCA-FANCW) results in Fanconi Anemia, a cancer predisposition syndrome characterized by congenital malformations, bone marrow failure, and pediatric acute myeloid leukemias (AMLs). Among the general population, acquired genetic disruptions of the FA pathway are found in 30% of all sporadic cancers and over 15% of sporadic pediatric AMLs underscoring the importance of this pathway in the prevention of malignant transformation. Therefore, the identification of precision therapies for FA-deficient AML is a critical need. The canonical tumor suppressive role of FA proteins in the repair of DNA damage during interphase is well established. We and others have uncovered the roles of FA proteins in mitotic regulation, suggesting additional mechanisms by which the FA pathway prevents genomic instability. Mutation of FANCA is the most common cause of FA and is one of the most frequently disrupted FA pathway genes in sporadic AML. To identify synthetic lethal targets of FANCA, we previously identified mitotic phospho-signaling pathways required for the survival of FANCA-/- patient-derived fibroblasts through a kinome-wide shRNA screen. We identified mitotic kinases CHEK1, PLK1, SLK, and TTK as potential targets, which suggests a mitosis-specific vulnerability of FA-deficient cells. These findings corroborate work by others who have identified synthetic lethal interactions between PLK1 and the FA pathway members, FANCG and BRCA1, suggesting that inactivation of the FA pathway may sensitize cancers to PLK1 inhibition. A more thorough understanding of FA pathway function in mitosis provides new insight into AML pathogenesis and suggests that genetic disruptions of the FA pathway may be predictive of sensitivity to PLK1 inhibition, providing a preclinical rationale for the development of precision therapies
Expression of Human Papillomavirus Type 16 E7 Is Sufficient To Significantly Increase Expression of Angiogenic Factors But Is Not Sufficient To Induce Endothelial Cell Migration
No full textIndiana University-Purdue University Indianapolis (IUPUI)Human papillomavirus 16 (HPV 16) causes cancer. Two viral oncoproteins of HPV 16, E6 and E7, are consistently expressed in these cancers. HPV 16 E6 and E7 proteins target p53 and Rb family members, respectively, for degradation thus inactivating the functiond of these tumor suppressor proteins. Tumor development requires the acquisition of a blood supply, a process known as angiogenesis. Tumor suppressors negatively regulate angigogenesis. Expression of HPV 16 E6 and E7 together in human foreskin keratinocytes (HFKs) increases the level of angiogenic inducers vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). Further, conditioned media from such cells are sufficient to alter endothelial cell behavior both in vitro and in vivo. To determine the individual contributions of HPV E6 and E7 to angiogenesis, translational termination linkers (TTLs) were inserted into the coding region of E6 or E7. Following retroviral transduction of the mutated cassette into HFKs, the ability of E7 in the context of the E6TTL mutation (E6TTLE7) and E6 in the context of the E7TTL mutation (E6E7TTL) to induce VEGF and IL-8 was compared to the LXSN control retrovirus. E7 and, to a lesser extent E6, increased the expression of VEGF and IL-8. Migration of human microvascular endothelial cells was not induced using conditioned media from either E6 or E7 expressing cells. Since the increased levels of VEGF and IL-8 induced by HPV 16E6ETTLE7 were not sufficient to alter endothelial cell behavior, immunological depletion experiments were used to determine whether either angiogenic factor was required for HPV 16E6 and E7 together to induce HMVEC migration. Only VEGF was required. Preliminary data suggest that the ability of HPV 16 E7 to induce angiogenic factors is dependent upon degradation of a specific Rb family member
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