Academic literature on the topic 'Adair County'

On July 4, 1986, a Cherokee tribal member was shot in the leg and arrested by a deputy in Adair County, Oklahoma. In a subsequent civil action, the Tenth Circuit Court of Appeals ruled that absent a statutory grant of authority by Congress or consent from the tribe itself, Oklahoma law enforcement officers have no criminal jurisdiction “in Indian country” unless the crime is committed by a non-Indian against another non-Indian or the crime is a victimless crime committed by a non-Indian. Realizing that they were no longer protected by the state, the Cherokee Nation responded by creating its own Marshal Service. This article describes the evolution of that agency, checkerboard jurisdiction, and the need for cross deputization. In particular, the article addresses the recent political tribal crisis that almost devastated the newly formed Marshal Service and the tribe's current struggle to regain stability in the politically charged aftermath.

The present paper reads David Malouf’s 1996 novel The Conversations at Curlow Creek as portraying a vivid and realistic picture of events relating to crime and punishment in colonial Australia in the early nineteenth century. The depiction of death penalty accorded to the bushranger Daniel Carney under the supervision of the Irish sheriff Michael Adair in New South Wales thus resonates with numerous historical accounts of incidents that actually happened. The novel, however, does more than only provide accurate historical representation as it also presents Adair as having undergone a rather dramatic transformation in the process of conversing with Carney before the latter’s execution. The paper, drawing on the views of the German philosopher Martin Heidegger, argues that a realization of inevitable mortality, of facing certain death characterizes this change in Adair’s nature and worldview. It concludes by suggesting that Adair’s acceptance of his finitude intimates of a way of being in the world that not only subverts procedures of administering punishment to convicts in colonial Australia but also indicates the limits of polarized identity politics that shapes the country in the present times.

Abstract We propose a quantitative metric (called relative assortativity index, RAI) to assess the extent with which a real-world network would become relatively more assortative due to link addition(s) using a link prediction technique. Our methodology is as follows: for a link prediction technique applied on a particular real-world network, we keep track of the assortativity index values incurred during the sequence of link additions until there is negligible change in the assortativity index values for successive link additions. We count the number of network instances for which the assortativity index after a link addition is greater or lower than the assortativity index prior to the link addition and refer to these counts as relative assortativity count and relative dissortativity count, respectively. RAI is computed as (relative assortativity count − relative dissortativity count) / (relative assortativity count + relative dissortativity count). We analyzed a suite of 80 real-world networks across different domains using 3 representative neighborhood-based link prediction techniques (Preferential attachment, Adamic Adar and Jaccard coefficients [JACs]). We observe the RAI values for the JAC technique to be positive and larger for several real-world networks, while most of the biological networks exhibited positive RAI values for all the three techniques.

The chromosomes are the carriers of the geometric information, any alteration in the structure or number of these chromosomes is termed as genetic defect. These alterations cause malfunctioning in the proteins and are cause of the various underlying medical conditions that are hard to cure or detect by normal clinical procedures. In order to detect the underlying causes of these defects, the cells of the humans need to be imaged during the mitosis phase of cell division. During this phase, the chromosomes are the longest and can be easily studied and the alterations in the structure and count of the chromosomes can be analyzed easily. The chromosomes are non-rigid objects, due to which they appear in varied orientations, which makes them hard to be analyzed for the detection of structural defects. In order to detect the genetic abnormalities due to structural defects, the chromosomes need to be in straight orientation. Therefore, in this work, we propose to classify the segmented chromosomes from the metaspread images into straight, bent, touching overlapping or noise, so that the bent, touching, overlapping chromosomes can be preprocessed and straightened and the noisy objects be discarded. The classification has been done using a set of 17 different geometric features. We have proposed a Multilayer Perceptron-based classification approach to classify the chromosomes extracted from metaspread images into five distinct categories considering their orientation. The results of the classification have been analyzed using the segmented objects of the Advance Digital Imaging Research (ADIR) dataset. The proposed technique is capable of classifying the segmented chromosomes with 94.28% accuracy. The performance of the proposed technique has been compared with seven other state-of-the-art classifiers and superior results have been achieved by the proposed method.

Abstract One hallmark of the rare, monogenic disorder called Fanconi anemia (FA) is an accelerated decline in hematopoietic stem cells (HSCs) leading to bone marrow (BM) failure. Long-term treatment requires successful bone marrow transplant (BMT) from an unaffected donor. However, BMT success is limited if the donor is not a matched sibling and ~70% of FA patients lack such donors. Gene therapy could be an alternative, correcting the genetic defect in the patient's own HSCs, and negating the need for a BMT donor. Based on lessons learned in previous FA gene therapy studies, we developed an optimized protocol for lentivirus (LV)-mediated FANCA gene transfer into HSCs from FA-A patients. This phase I clinical trial incorporates vector recommendations from the International FA Gene Therapy Working Group. Two patients have been treated on this trial to date (National Clinical Trials Registry ID: NCT01331018). This protocol harvests BM to collect unmanipulated HSC and does not include conditioning prior to cell infusion. Patient 1 is a 22-year old male with confirmed FA-A resulting from a splice variant in exon 22 of the FANCA gene (c. 1827-1 G>A). Baseline ANC averaged 0.5-1.0 K/mcL and baseline platelet counts averaged 40 K/mcL. A total of 3.2 x 107 CD34+ cells were present in 1.1L of BM, but only 9.4 x 106 total CD34+ cells were successfully isolated by magnetic bead separation, due to low level CD34 expression. LV transduction at 10 infectious units (IU)/cell resulted in a vector copy number (VCN) of 0.33 per cell and 18.4% of colony-forming cells transduced. Patient 2 is a 10-year old male with confirmed FA-A resulting from gross deletion of exons 6-31 of the FANCA gene. Baseline ANC and platelets declined over a 4.5-year interval prior to gene therapy and were 0.67 K/mcL and 82 K/mcL, respectively, in the 6 months prior to treatment. A total of 400mL of BM was collected, containing a total of 30.6 x 106 CD34+ cells. To avoid excessive CD34+ cell loss, the CD34+ cell magnetic bead purification step was omitted and the entire red blood cell depleted BM product was subjected to LV transduction at 10 IU/cell. We observed a VCN of 1.83 per cell and 43% of colony-forming cells transduced, suggesting more efficient transduction of the mixed cell population. Both patients tolerated the harvest and infusion procedures but displayed low and declining levels of transduced cells in peripheral blood after infusion. For future subjects, use of pre-infusion conditioning may be required to achieve long-term engraftment in vivo. Interestingly, both patients have maintained stable blood cell counts since gene therapy. These data demonstrate that LV gene therapy in FA patients is safe and suggest that avoidance of direct CD34 selection is advantageous for transduction and gene transfer. However, one complicating factor is the volume of concentrated LV vector required to transduce the non-purified cell product infused in Patient 2. To address these barriers, we developed a modified clinical protocol which utilizes depletion of mature cell lineages including CD3+, CD14+, CD16+ and CD19+ cells. Using healthy donor bone marrow we demonstrate that this protocol efficiently depletes >85% of cells expressing each lineage marker, reducing the volume of LV vector required for gene transfer by 60-70%. Most importantly, we demonstrate that this protocol preserves >90% of CD34+ cells present in the starting bone marrow product, and that these cells are efficiently transduced and capable of engrafting in a xenotransplant model. This protocol is currently being implemented for subjects in the ongoing phase I trial. Disclosures Adair: Rocket Pharmaceuticals: Consultancy, Equity Ownership. Kiem:Rocket Pharmaceuticals: Consultancy, Equity Ownership, Research Funding.

Abstract In both humans and canines, X-linked severe combined immunodeficiency disease (XSCID) is caused by mutations in the interleukin-2 receptor gamma chain gene (IL2RG) which results in a lack of response to common gamma-chain (gammaC) dependent cytokines and abnormal development of T and B lymphocytes, and natural killer (NK) cells. Death from infections usually occurs before 1 year of age unless allogeneic hematopoietic cell transplantation (HCT) is performed. While HCT is successful if an HLA-matched sibling donor is available, transplants from mismatched and unrelated donors are associated with greater morbidity and overall survival can be as low as 50%. To circumvent these complications, several clinical trials are testing the possibility of utilizing blood and marrow stem cells from the patient for ex vivo gene therapy to treat X-SCID. Although these trials show promising results, they require expensive GMP cell manufacturing that are not accessible to many patients, and may also necessitate low level of conditioning to improve engraftment of gene-corrected cells. With these limitations in mind, we have explored in vivo gene therapy as a treatment for X-SCID. We previously showed that foamy virus vectors (FVs), exhibit a potentially more favorable integration profile compared to lenti- and gamma-retroviral vectors. In vivo delivery of a gammaC-FV in dogs resulted in immune reconstitution with gene-corrected T cells in dogs but the treated animals still developed infections and had low levels of immunoglobulin levels. We hypothesized that an increased transduction of hematopoietic stem/progenitor cells in vivo might result in more rapid and sustained immune reconstitution. Thus, in the current study, we used cG-CSF and AMD3100 to mobilize hematopoietic stem/progenitor cells into the peripheral blood prior to in vivo injection with a FV expressing the gammaC gene driven by a PGK promoter (PGK-gammaC-FV). We mobilized two X-SCID dogs at ~3 weeks of age with 5ug/kg of cG-CSF bi-daily from day -4 to -1 prior to FV injection, and with 4mg/kg of AMD3100 on the morning of the injection with 4x10e8 IU of PGK-gammaC-FV. Our mobilization protocol resulted in a 10-fold increase in CD34+ cells in the peripheral blood of mobilized X-SCID dogs as compared to a unmobilized normal littermate control (Figure 1 A). Lymphocyte recovery and gene marking in the mobilized animals was significantly improved as compared to animals that were previously injected with similar doses of either PGK-gammaC-FV or EF1a-gammaC-FV but without mobilization. As illustrated in Figure 1B-C, lymphocyte counts expanded to ~3000 cells/uL with ~75% gene marking in the mobilized animals treated with PGK-gammC-FV within 30 days, as compared to <1500 cells/uL with <5% gene marking in unmobilized dogs treated with EF1a-gammaC-FV and to <1000 cells/uL with <50% gene marking in unmobilized dogs treated with PGK-gammaC-FV at all time points post-therapy. The expansion of CD3+ T-cells at 6 weeks post injection for the mobilized dogs was about 2700 cells/uL, as compared to <380 cells/uL in the PGK-gammaC-FV and <210 cells/uL in the EF1a-gammaC-FV unmobilized dogs. Notably, in human clinical trials, CD3 T cell counts were <250 cells/uL following transplantation with autologous CD34+ cells modified with EF1a-gammaC-SIN gamma-retrovirus (Hacein-Bey-Abina, NEJM, 2014). In conclusion, mobilization with cG-CSF and AMD3100 prior to in vivo injection of PGK-gammaC-FV substantially improved the lymphocyte expansion and immune reconstitution in X-SCID dogs and resulted in a higher level of gene marking in myeloid cells (about 1%) at one-month post injection than seen in our previous studies in unmobilized dogs. These results suggest remarkable potential for an accessible and portable approach for treatment of human X-SCID clinical trials using combination of hematopoietic stem/progenitor cells mobilization and in vivo foamy viral vector delivery. Disclosures Adair: Rocket Pharmaceuticals: Consultancy, Equity Ownership. Scharenberg:bluebird bio: Consultancy, Equity Ownership, Research Funding; Alpine Immune Sciences: Consultancy. Kiem:Rocket Pharmaceuticals: Consultancy, Equity Ownership, Research Funding.

Introduction: Hematopoietic stem cell (HSC) gene therapy/editing is a viable treatment option for various hematological diseases and disorders including hemoglobinopathies and HIV/AIDS. Most if not all currently available approaches target CD34-enriched cell fractions, a heterogeneous mix of mostly committed progenitor cells and only very few true HSCs with long-term multilineage engraftment potential. As a consequence, gene therapy/editing approaches are currently limited in their HSC targeting efficiency, very expensive consuming huge quantities of modifying reagents, and can lead to unwanted side-effects in non-target cells. We recently described a novel HSC-enriched CD34 subset (CD90+CD45RA-) that is exclusively responsible for rapid recovery onset, robust long-term multilineage engraftment, as well as entire reconstitution of the bone marrow stem cell compartment in the nonhuman primate (NHP) stem cell transplantation and gene therapy model (Radtke et al. 2017, STM). Most importantly, we demonstrate that this CD34 subset reduces the number of target cells, modifying reagents and costs by more than 10-fold without compromising the long-term efficiency of gene-modification in the NHP (Humbert and Radtke et al. 2019, STM). Here, we aimed to develop a clinical protocol to reliably purify and efficiently gene-modify human HSC-enriched CD90+ cell fractions. Methods: Large-scale enrichment of CD34+ cells from GCSF-mobilized leukapheresis products was initially performed on the Miltenyi CliniMACS Prodigy according to previously established protocols (Adair et al. 2017, Nat. Comm.). Yield, purity, quality, and feasibility of CD90 sorting was then comprehensively tested on two different commercially available cell sorting systems comparing the jet-in-air sorter FX500 from Sony and the cartridge-based closed-system sorter MACSQuant Tyto from Miltenyi Biotech with our clinically approved gold-standard CD34-mediated gene therapy approach. Sorted CD90+ and bulk CD34+ cells were transduced with a clinical-grade lentivirus encoding for GFP and the multilineage differentiation as well as engraftment potential tested using in vitro assays and the NSG mouse xenograft model, respectively. Results: Flow-cytometric sort-purification of CD90+ cells was similarly efficient in purity and yield using either the FX500 or Tyto (Figure A,B). Both approaches reliably reduced the overall target cell count by 10 to 15-fold without impacting the cells viability and in vitro colony-forming cell potential. Unexpectedly, the transduction efficiency of sort-purified CD90+ cells was significantly improved compared to bulk-transduced CD34+ cells and especially the CD34+CD90+ subset (Figure C). All cell fractions demonstrated robust mouse xenograft potential (Figure D). Most importantly, significantly higher levels of GFP+ expression in the peripheral blood, bone marrow, spleen and thymus were observed after transplantation of gene-modified CD90+ compared to bulk CD34+ cells in NSG mice (Figure E). Conclusion: Here, we show that sort-purification of our HSC-enriched CD34+CD90+ cell subset is technically feasible and highly reproducible in two different systems. Purification of human CD90+ cell fractions significantly increased the gene-modification efficiency of primitive human HSCs with multilineage mouse engraftment potential. These findings should have important implications for currently available as well as future HSC gene therapy and gene editing protocols. Isolation of an HSC-enriched phenotype will allow more targeted gene modification and thus likely reduce unwanted off target effects. Our approach further reduced the overall costs for gene modifying reagents, can be combined with a closed transduction system, increase the portability and ultimately make HSC gene therapy GMP-facility independent and affordable. Finally, this stem cell selection strategy may also allow efficient and effective depletion of donor T cells in the setting of allogeneic stem cell or organ transplantation. Figure: A) Purity and B) yield of CD90+ cells after sort-purification. C) Transduction efficiency of bulk-transduced CD34+CD90+ cells and sort-purified CD90+ cells. Frequency of D) human chimerism and E) GFP+ human CD45+ cells in the peripheral blood (PB), bone marrow, spleen and thymus after transplantation of gene-modified bulk CD34+ or sort-purified CD90+ cells. Figure Disclosures Kiem: CSL Behring: Consultancy; Rocket Pharma: Consultancy, Equity Ownership; Homology Medicines: Consultancy, Equity Ownership; Magenta Therapeutics: Consultancy.