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This chapter details a mixed-methods investigation of the experiences and\ud effectiveness of a soft brace for adults with degenerative scoliosis. Study 1 explored\ud patients’ experiences of living with scoliosis, together with the pain and quality of\ud life they experienced as a result of scoliosis. The secondary aims of the qualitative\ud aspect of the study were to explore patient perceptions of wearing the soft brace\ud together with the overall functionality and practicalities of the brace design. We\ud found the main experiences of living with scoliosis in people over 50 were one\ud of constant pain and limited activity. The interviews also identified the benefits\ud of wearing the brace along with design issues associated with the comfort and\ud practicalities of wearing the brace. Study 2 investigated the quantitative effects\ud the brace had on adults with degenerative scoliosis. The quantitative questionnaire\ud results were compared with those from the control group who did not receive the\ud brace. Overall, we found that patients in interviews reported improvements in their\ud quality of life, although these improvements were not reflected in the quantitative\ud results. Implications of our findings for the treatment of adults with scoliosis by\ud bracing, and directions for future work are discussed.

This article highlights the U.S. Armed Forces’ appointment of the YMCA to train American soldiers in boxing during World War I and so contributes to scholarly research on religion and war as well as religion and sports. As the YMCA taught the fistic art to white regiments in stateside military camps and to the American Expeditionary Forces on the Western Front, I argue that World War I was a watershed moment for both Muscular Christianity and boxing. Religious, political, and military leaders announced boxing to be ideal for the close-proximity encounters in the trenches, and they championed the YMCA as being best equipped to turn newly enlisted recruits into hardened trench-pugs. To the YMCA-military, the practical benefits of boxing were that soldiers would not just be “good with their hands” but also have a good manly character, a “fighting spirit.” In the establishment of a new world order, boxing thereby became a bellicose technique for unmaking evil others and a Christian method for remaking “overcivilized” white men. Immediately after the war—because of the Y—the sport of boxing, previously believed unscrupulous, was redeemed. Protestant Christians and a larger public recast boxing as less an activity for the morally corrupt and the criminal underworld and more an enlightened pursuit in the realization of an authentic, God-given human nature. Legalized, mainstreamed, and backed by antimodern logic, Christian theology, and white fears of racial devolution, boxing was for “character” more than crime.

Leadership is a word that seemingly needs no definition but is generally misunderstood or misused as a concept. Confusion is common between the functions of leadership and those of management. However, the immediate assistants reported a gap between the chiefs’ values and behaviors, particularly with respect to the leadership items. Changing times call for changing approaches to leadership and leadership development. Educational institutions have broadened applied science degree programs that incorporate cybercrime and public leadership as featured majors. Along with these progressions came a shift in police leadership typology. Police culture is unique in that it operates and is responsible to specific government policies, yet can only fulfill its mission by allowing officers to operate with the greatest amount of discretion. Properly trained police psychologists, especially those with backgrounds in industrial/organizational psychology, can be very useful in devising and improving leadership development programs in law enforcement agencies.

Interest into the area of working memory has increased in recent years. However, there is a lack of empirical exploration regarding how memory contributes directly to forensic investigations. It is suggested a more complete analysis of the nuances involved with working memory is needed in order to bridge the gap between past human behavior and criminogenic outcomes. Practitioners of cognitive, applied, and police psychology have generally asserted that memory is malleable; meaning retrieval outcomes relative to the brain are both delicate and prone to inaccuracies. Yet, the concept of memory has proven to be a staple of the criminal justice system. It is memory that oftentimes serves as the impetus for the advancement of a valid defense to prosecution. Conversely, the accurate, corroborated retrieval of past events can lead to the successful imprisonment of a violent offender. This paper examines the neural bases of memory, and discusses how forensic professionals can enhance the efficacy of retrieval within interview contexts. False and repressed memories will be discussed due to their relevance in criminal investigations. Age considerations and clinical pathology affecting memory will be appraised, as will a section detailing procedural safeguards for practitioners when interviewing involves a memory component.

In American Apocalypse, Matthew Sutton ambitiously tasks himself with accounting for the history of American evangelicalism in the long 20th century. The payoff is nothing less than a story of what...

With a promising farewell, George Whitefield assured his Charleston audience in 1740, ‘the fields here … are white, ready to harvest’ (p. 143). In The Origins of Southern Evangelicalism, Thomas J. ...

2604 Background: AB928, a selective, small-molecule A2aR/A2bR antagonist, potently blocks the immunosuppressive effects of high adenosine concentrations in the tumor microenvironment. Preclinically, combining adenosine receptor inhibition with either chemotherapy or anti-PD-1 resulted in greater tumor control, suggesting AB928 may have additive activity when paired with either of these agents in cancer pts. Methods: Three dose-escalation (3+3 design) studies are assessing the safety, pharmacokinetics (PK), pharmacodynamics, and clinical activity of increasing doses of AB928 (75, 150, 200 mg orally once daily) in combination with: standard pegylated liposomal doxorubicin in triple-negative breast cancer (TNBC) and ovarian cancer (OC); standard mFOLFOX6 in gastroesophageal cancer (GEC) and colorectal cancer (CRC); and AB122 (240 mg every 2 weeks) in various advanced tumors. Following identification of the recommended phase 2 dose of AB928 in combination with chemotherapy or AB122 in dose escalation, the following tumor cohorts may be expanded (15-40 pts/cohort) to further test the combinations: TNBC and OC, GEC and CRC, and renal cell carcinoma. Results: As of 01Feb2019, 9 pts were treated across the 3 studies, and time on treatment ranged from 1-182 days (table). Overall, AB928 combination therapy was well tolerated. Two pts underwent post-baseline disease assessment; both had stable disease. Preliminary data indicate that AB928 PK and adenosine receptor coverage in cancer pts are similar to what was previously assessed in healthy volunteers. AB122 PK and PD-1 coverage are equally unaffected by AB928 co-administration. Updated data, including biomarker data, will be presented at the meeting. Conclusions: Early results showed a favorable safety profile of AB928 combination therapy. All 3 studies are actively recruiting pts. Clinical trial information: NCT03719326; NCT03720678; NCT03629756. [Table: see text]

Corporal Knowledge: Early Christian Bodies, by Jennifer A. Glancy, Oxford University Press: New York, 2010, xi + 189pp. ISBN 978 0 19 532815 8, US$45 (cloth) Foregrounding the role of the body in r...

INTRODUCTION: CD73 converts extracellular adenosine monophosphate (AMP), derived from adenosine triphosphate, into adenosine (ADO). ADO suppresses immune responses, including those of T cells, natural killer (NK) cells and dendritic cells, via A2aR and A2bR receptors. Activation of these receptors results in increased intracellular levels of cyclic AMP (cAMP) and phosphorylation of the cAMP response element-binding protein (CREB). Monitoring the degree of pCREB induced by activation of the Aa2R and A2bR receptors in peripheral blood allows for a specific measurement of target engagement by AB928. In mice, the pCREB assay, coupled with changes in immune cell infiltrate and tumor growth rates, allows for a fuller understanding of the drug's PK/PD relationship. METHODS: Mouse and human whole blood was stimulated with the adenosine agonist NECA (5'-N-Ethylcarboxamidoadenosine) following in vitro spike in or in vivo dosing with AB928. Multi-color phospho-flow cytometry was used to assess levels of pCREB on immune cells. AB928 levels in plasma samples were determined using LC-MS-MS after protein precipitation. RESULTS: A2aR mRNA was the most prevalent adenosine receptor in CD4+ and CD8+ T cells. NK cells also express primarily A2aR, although A2bR was also detected. Dendritic cells and CD14+ monocytes expressed both A2aR and A2bR. NECA stimulation of mouse whole blood resulted in a significant increase in the levels of pCREB within CD8+ T cells with an EC50 of 100 nM, while in human whole blood the EC50 was higher at 700 nM. AB928 (100 nM) exhibited comparable shifts in the NECA dose response between human and murine whole blood, 15 and 16-fold, respectively. Due to the high level of adenosine in the tumor microenvironment, doses of AB928 associated with plasma levels that significantly inhibited 5 μM NECA in the whole-blood pCREB assay were selected for mouse efficacy studies. At these doses, significant reductions in tumor growth were noted. In human whole blood, approximately 90 nM AB928 was required to inhibit 50% of the 5 μM NECA-induced pCREB signal. Inhibition was observed on both CD4+ and CD8+ T cells. NECA-induced pCREB elevations were observed in CD14+ cells less frequently than T cells; however, when the signal was observed, AB928 inhibited it. The human pCREB assay is being utilized to monitor the PD responses in an ongoing clinical trial. Preliminary PK/PD results from this study will be presented. CONCLUSIONS: Systemic extent of receptor (A2aR and A2bR) occupancy by the novel dual antagonist AB928 can be assessed in humans and mice based on the extent of receptor-mediated CREB phosphorylation in blood lymphocytes. AB928 retains much of its inherent potency when competing against high concentrations of adenosine under physiologically relevant conditions (i.e., whole blood). Citation Format: Lisa Seitz, Devika Ashok, Manmohan R. Leleti, Jay P. Powers, Brandon Rosen, Dillon Miles, Lixia Jin, Adam Park, Tim Park, Steve Young, Ferdie Soriano, Aimee Rieger, Ulrike Schindler, Joyson Karakunnel, Matt J. Walters. Pharmacokinetic-pharmacodynamic relationship for AB928, a dual antagonist of the A2aR and A2bR adenosine receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3769.

Faith in the Fight: Religion and the American Soldier in the Great War , by Jonathan H. Ebel, Princeton University Press: Princeton, 2010, xi + 253pp. ISBN 978 0 691 13992 0, US$35.00 (cloth) Looki...

Tumor necrosis factor receptor 1 (TNF-R1) mediates most of the biological properties of TNF including activation of the transcription factor NF-kappaB and programmed cell death. An approximately 80-amino acid region within the intracellular domain of the receptor, termed the death domain, is required for signaling NF-kappaB activation and cytotoxicity. A TNF-R1-associated protein TRADD has been discovered that interacts with the death domain of the receptor. Elevated expression of TRADD in cells triggers both NF-kappaB activation and programmed cell death pathways. The biological activities of TRADD have been mapped to a 111-amino acid region within the carboxyl-terminal half of the protein. This region shows sequence similarity to the death domain of TNF-R1 and can self-associate and bind to the TNF-R1 death domain. We have performed an alanine scanning mutagenesis of TRADD's death domain to explore the relationship among its various functional properties. Mutations affecting the different activities of TRADD do not map to discrete regions but rather are spread over the entire death domain, suggesting that the death domain is a multifunctional unit. A mutant that separates cell killing from NF-kappaB activation by the TRADD death domain has been identified indicating that these two signaling pathways diverge with TRADD. Additionally, one of the TRADD mutants that fails to activate NF-kappaB was found to act as dominant negative mutant capable of preventing induction of NF-kappaB by TNFalpha. Such observations provide evidence that TRADD performs an obligate role in TNF-induced NF-kappaB activation.

Acquired secondary resistance mutations in FLT3 have been shown to limit the therapeutic benefit of FLT3 inhibitors in FLT3-ITD mutated AML. Multiple strategies have been pursued to address such resistance, including the development of kinase inhibitors that use alternate binding modes or by simultaneously targeting additional pathways. This latter approach may be focused on suppression of parallel oncogenic pathways to treat the acquired resistance, or on strategies to reduce or delay the acquisition of resistance. Here, we describe a rationally conceived next generation FLT3 inhibitor, FLX925, that was prospectively designed to address or avoid common resistance mechanisms with a unique binding mode and potent activity against CDK4/CDK6. We contextualize our findings by comparing FLX925 to other FLT3 inhibitors (quizartinib and gilteritinib) currently in late-stage clinical development and demonstrate that FLX925 has a superior resistance profile. FLX925 is a potent and selective type-1 inhibitor of FLT3 that retains its cellular potency against clinically relevant secondary resistance mutations in FLT3. This was evaluated in multiple experimental systems including isogenic Ba/F3 cells engineered to express FLT3-ITD with, or without, various known secondary FLT3 mutations. In addition, these data were extended to the human setting using both the MOLM13 and MOLM14 FLT3-ITD mutated AML cell lines and subclones of these lines harboring well-characterized resistance mutations described elsewhere. Data have been published previously demonstrating a superior resistance profile for FLX925 when compared to quizartinib and sorafenib. When compared to gilteritinib, FLX925 had a favorable profile of relative potencies against a range of FLT3-ITD resistance mutations. In addition to the isogenic murine and human models of FLT3 inhibitor resistance, with engineered known genetic alterations, we explored the activity of FLX925 and other FLT3 inhibitors in a model of in vitro acquired resistance. Using MOLM13 cells and standard protocols for the generation of drug resistance, we demonstrate that the magnitude of resistance to quizartinib and gilteritinib greatly exceeds that observed with FLX925 during the same timeframe. Pools of resistant cells from each compound treatment are being analyzed by next-generation sequencing in an effort to better understand the mechanism of resistance associated with each compound. We hypothesize that the CDK4/6 inhibitory activity, which is unique to FLX925, contributes to its superior resistance profile. Whether this is solely linked to an impact on the cell cycle or more recent findings of CDK6-driven transcription of FLT3 and PIM1 is an active area of investigation. Nonetheless, the CDK4/6 activity of FLX925 potentially broadens the utility of this compound to FLT3 wild-type AML. Here, we show FLX925, in contrast to other FLT3 inhibitors, potently suppresses the proliferation of a panel of AML cell lines. These data have been extended to FLT3 wild-type AML patient samples in which FLX925, but not gilteritnib, induced a desirable pharmacodynamic effects. The totality of the preclinical data suggest FLX925 may be a best-in-class inhibitor for the treatment of AML with, or without, FLT3-ITD mutations. FLX925 is currently being investigated in a Ph1/b dose-escalation study in subject with relapsed or refractory AML (NCT02335814). Disclosures Marubayashi: FLX Bio: Employment, Equity Ownership. Park:FLX Bio: Employment, Equity Ownership. Noubade:FLX Bio: Employment, Equity Ownership. Phan:FLX Bio: Employment. Cutler:FLX Bio: Employment, Equity Ownership; Amgen, Inc: Equity Ownership. Kassner:FLX Bio: Employment, Equity Ownership. Fridman:FLX Bio: Employment, Equity Ownership.

The Large Hadron Collider (LHC) cryogenic system comprises eight independent refrigeration and distribution systems that supply the eight 3.3 km long accelerator sectors with cryogenic refrigeration power as well as four refrigeration systems for the needs of the detectors ATLAS and CMS. In order to ensure the highest possible reliability of the installations, it is important to apply a reliability centred approach for the maintenance. Even though large scale cryogenic refrigeration exists since the mid 20th century, very little third party reliability data is available today. CERN has started to collect data with its computer aided maintenance management system (CAMMS) in 2009, when the accelerator has gone into normal operation. This paper presents the reliability observations from the operation and the maintenance side, as well as statistical data collected by the means of the CAMMS system.

A new natural product, stawamycin ( 1 ), has been isolated from the liquid cultures of Streptomyces sp. as an inhibitor against the Epstein-Barr virus BZLF1 transcription factor. The novel chemical structure was established by a combination of spectroscopic data analysis and chemical derivatization.

G-protein-coupled receptors (GPCRs) represent one of the largest gene families in the human genome and have long been regarded as valuable targets for small-molecule drugs. The authors describe a new functional assay that directly monitors GPCR activation. It is based on the interaction between beta-arrestin and ligand-activated GPCRs and uses enzyme fragment complementation technology. In this format, a GPCR of interest is fused to a small (approximately 4 kDa), optimized alpha fragment peptide (termed ProLink) derived from beta-galactosidase, and beta-arrestin is fused to an N-terminal deletion mutant of beta-galactosidase (termed the enzyme acceptor [EA]). Upon activation of the receptor, the beta-arrestin-EA fusion protein binds the activated GPCR. This interaction drives enzyme fragment complementation, resulting in an active beta-galactosidase enzyme, and thus GPCR activation can be determined by quantifying beta-galactosidase activity. In this report, the authors demonstrate the utility of this technology to monitor GPCR activation and validate the approach using a Galphai-coupled GPCR, somatostatin receptor 2. Potential application to high-throughput screens in both agonist and antagonist screening modes is exemplified.

The IDO1 pathway has been proposed to mediate immunosuppressive effects in the tumor microenvironment through its role in the catabolism of tryptophan, resulting in effects on the differentiation and proliferation of T cells. IDO1 inhibition has shown promising clinical benefit as well as exacerbated toxicity in the treatment of melanoma, when combined with the anti-CTLA-4 antibody ipilimumab. We have discovered a novel class of highly selective small molecule inhibitors of IDO1 which surpass the potency of the compounds currently in clinical development. These compounds potently inhibit IDO1 activity in IFN-γ stimulated HeLa cells with single digit nM potency. Importantly, they also retain their potency in the presence of human serum, with IC50 values ranging between 5 and 15 nM in this more physiologically relevant media. Consistent with the role of IDO1+ dendritic cells in the suppression of T cell proliferation, this series of molecules is capable of restoring the proliferative capacity of human T cells (which is inhibited by allogeneic IDO1+ dendritic cells) with EC50 values of 2-3 nM. The molecules exhibit preclinical PK characteristics that are suitable for assessing the contribution of IDO1 to tumor growth in murine models, both alone and in combination with other therapeutic agents. The compounds have high metabolic stability against cultured human hepatocytes and exhibit preclinical PK and ADME characteristics consistent with once-daily dosing in humans. The full preclinical profile of one of these molecules, selected for clinical evaluation, will be the focus of this presentation. In conclusion, we have discovered a novel class of small molecule inhibitors of IDO1, which provides a preclinical basis for the clinical evaluation of a next generation IDO1 inhibitor in combination with other therapeutic agents. Citation Format: Jay P. Powers, Matthew J. Walters, Rajkumar Noubade, Stephen W. Young, Lisa Marshall, Jan Melom, Adam Park, Nick Shah, Pia Bjork, Jordan S. Fridman, Hilary P. Beck, David Chian, Jenny V. McKinnell, Maksim Osipov, Maureen K. Reilly, Hunter P. Shunatona, James R. Walker, Mikhail Zibinsky, Juan C. Jaen. Potent and selective next generation inhibitors of indoleamine-2,3-dioxygenase (IDO1) for the treatment of cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4290. doi:10.1158/1538-7445.AM2015-4290

The project investigates how public perception of interstitial urban spaces could be elicited and recorded through Performing the City - participatory ‘walkabout’ performance practices produced and staged for specific urban sites. Interstitial urban spaces are ‘forgotten’ underused spaces awaiting public re-imagination and interventions. Following an ethnographic study of the UK theatre company Slung Low's Mapping the City production in May 2011, the authors reflect on how the research propositions should be refined to better capture the transient transformative potential of spatial urban mapping through performing the city.

Transcription of the vascular cell adhesion molecule-1 (VCAM-1) gene in endothelial cells is induced by the inflammatory cytokines interleukin-1 beta, tumor necrosis factor-alpha, and lipopolysaccharide. Previous studies demonstrated that the cytokine-response region in the VCAM1 promoter contains binding sites for the transcription factors nuclear factor-kappa B (NF-kappa B) and interferon regulatory factor-1. Using a saturation mutagenesis approach, we report that the cytokine-inducible enhancer consists of these previously characterized elements and a novel region located 3' of the NF-kappa B sites. Electrophoretic mobility shift assays and DNase I footprint studies with endothelial nuclear extracts and recombinant protein revealed that the transcriptional activator Sp1 interacts with this novel element in a specific manner. Transient transfection assays using vascular endothelial cells revealed that site-directed mutations in the Sp1 binding element decreased tumor necrosis factor-alpha-induced activity of the VCAM1 promoter. The cytokine-induced enhancer of the VCAM1 gene requires constitutively bound Sp1 and induced heterodimeric NF-kappa B for maximal promoter activity.