Richard Sparks Research Articles

A talk with Ian Loader and Richard Sparks

A talk with Ian Loader and Richard Sparks

Review of Exploring L1-L2 relationships: The impact of individual differences by Richard Sparks

This paper is a review of Richard Sparks' latest position, Exploring L1-L2 relationships. The impact of individual differences, which summarizes 30 years of his research in the field of SLA. The author is the originator of the Linguistic Coding Deficit Hypothesis (LCDH), later modified to the Linguistic Coding Differences Hypothesis, which is one of the most cited theories in the context of research into foreign language aptitude. The volume contains 7 chapters representing different strands of research.

Rethinking Individual Differences in SLA: A Special Issue in Honour of Richard Sparks

Richard Sparks is currently Professor Emeritus of Special Education in Mount St. Joseph University's Department of Graduate Education in Cincinnati, USA. For over 40 years, Richard has had a celebratory career in teaching, researching, and servicing language education. His broad research interests and academic influence span various sub-domains of individual differences in L1 and L2 reading and writing, language learning difficulties, and language aptitude. Richard has published extensively in top journals of language and education, producing an impressive list of empirical studies and thought-provoking theoretical position papers related to key topics and issues in foreign language education, educational psychology, and learning disability. Scholars and practitioners in both language and psychology have read his works with interest and cited frequently many of his influential works on language, education, psychology, dyslexia, hyperlexia, and in particular language aptitude.

Reflections on a 40-year Career in Language, Education, and Psychology: An Interview with Richard Sparks

The current paper is an interview with Professor Richard Sparks, who has contributed his teaching, research, and consultancy service to academia and the broader community at large for over 40 years. In this paper, the two guest editors of this special issue (Edward and Hassan) had prepared a list of questions and invited Prof Sparks to answer them in written form. Key issues covered in the interview include some general background information, as well as more in-depth discussions of specific academic issues related to the major themes included in the special issue.

Some Thoughts on Richard Sparks’ report to the Economic and Social Research Council

Some Thoughts on Richard Sparks’ report to the Economic and Social Research Council

Crime and justice research: The current landscape and future possibilities

The contributions in this themed section developed from conversations that took place at an event hosted by the British Society of Criminology and Criminology & Criminal Justice in April 2019. The papers that follow respond to a ‘think-piece’ presented by Richard Sparks at that event, and engage with the subsequent debate about the future of funding for crime and justice research. Contributors reflect on the opportunities and challenges arising from recent shifts in funding allocations and priorities, from their different vantage points. Highlighting the importance of interdisciplinary and international work, they consider priorities for future investment in crime and justice research and draw attention to the impact of an increasingly restrictive and risk-averse climate on critical research. The papers explore the consequences for criminology as a discipline and warn of the potential reinforcement of existing inequalities in academia unless action is taken to support the development of future researchers.

The Myth of Mob Rule: Violent Crime and Democratic Politics. Lisa L. Miller. New York: Oxford University Press (2016). 272pp. £26.49hb ISBN 9780190228705

The Myth of Mob Rule: Violent Crime and Democratic Politics. Lisa L. Miller. New York: Oxford University Press (2016). 272pp. £26.49hb ISBN 9780190228705

Abstract 4904: The BET inhibitor INCB054329 enhances the activity of checkpoint modulation in syngeneic tumor models

Abstract Inhibitors of the BET family of bromodomain proteins have been shown to be growth inhibitory across a spectrum of tumor types due to their ability to regulate the expression of key survival and cell fate determining genes such as c-myc. In addition to their role in cancer, studies using genetic knockdown and small molecule inhibitors have demonstrated that targeting BET proteins controls the expression of pro-inflammatory cytokine genes in macrophages and is therapeutic in models of acute inflammation. These data suggest that in addition to their tumor intrinsic effects, BET inhibitors may also regulate the cytokine milieu within the tumor microenvironment and have immunomodulatory activity in cancer. To study this aspect, we evaluated INCB054329, a novel and selective BET inhibitor currently in Phase 1 trials, alone and in combination either with epacadostat, a highly selective IDO1 inhibitor, or with PD-1/PD-L1 axis blockade in syngeneic tumor models using immunocompetent animals. When used alone, INCB054329 suppressed a panel of cytokines and chemokines in a whole blood assay, confirming that INCB054329 can antagonize a pro-inflammatory response. The potency of INCB054329 in reducing the levels of these inflammatory mediators in the whole blood assay was similar to that for inhibition of c-myc, suggesting that the effects were on-target. INCB054329 was capable of inhibiting the growth of multiple syngeneic tumor models in immunocompetent mice, whereas only modest tumor growth inhibition was observed in immunodeficient mice and a lack of activity was observed in vitro, supporting the immunomodulatory activity of the compound. Because maximal in vivo tumor growth inhibition required an intact immune system, we investigated the impact of INCB054329 on various immune cell subsets, both in vitro and in vivo. Of note, increases in effector T cell populations were observed and efforts are ongoing to further characterize the tumor infiltrating immune cells following INCB054329 treatment. The mechanistic complimentarity of this novel BET inhibitor-mediated immunomodulation was also evaluated in combination with other therapeutically relevant mechanisms, including IDO1 inhibition and PD-1 axis blockade. Enhanced efficacy was observed with all INCB054329-containing regimens. These data demonstrate for the first time that BET inhibition can suppress tumor growth through both tumor-intrinsic and immune modulatory mechanisms, and support the potential of epigenetic-based, immunotherapy combinations as a novel approach to cancer therapy. Citation Format: Holly K. Koblish, Michael Hansbury, Leslie Hall, Liang-Chuan Wang, Yue Zhang, Maryanne Covington, Timothy Burn, Mark Rupar, Christine Gardiner, Thomas Condamine, Kerri Lasky, Matthew C. Stubbs, Eddy Yue, Richard Sparks, Richard Sparks, Thomas Maduskuie, Andrew P. Combs, Gregory Hollis, Reid Huber, Phillip CC Liu, Peggy Scherle. The BET inhibitor INCB054329 enhances the activity of checkpoint modulation in syngeneic tumor models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4904.

Abstract 3780: Activity of the BET inhibitor INCB054329 in models of lymphoma

Abstract Inhibitors of the BET family of Bromodomain proteins have been shown to be growth inhibitory across a spectrum of tumor types due to their ability to regulate expression of key survival and cell fate determining genes such as c-myc. Among the various tumor histologies, hematologic malignancies are among the most sensitive cancers to BET inhibition. INCB054329 is a novel, non-benzodiazepine, selective BET inhibitor that is undergoing Phase 1 clinical trials and that has shown encouraging in vitro and in vivo preclinical activity in several models of hematologic malignancy. In the current study, the activity of INCB054329 was evaluated in models of B cell malignancy. INCB54329 effectively inhibited the in vitro growth of a panel of cell lines representing both Hodgkin and non-Hodgkin lymphoma. Treated cells arrested primarily in G1 with sensitive lines also exhibiting dose and time-dependent apoptosis. Within a panel of double-hit lymphoma cell lines, which have activating chromosomal rearrangements in both c-myc and bcl-2, INCB054329 potently inhibited cell growth and was more effective than antagonists of BTK, bcl-2, PIM and PI3Kδ. INCB054329 also showed in vivo efficacy in models of diffuse large B-cell lymphoma (DLBCL). As a single agent, oral administration of INCB054329 inhibited tumor growth in Pfeiffer (GBC) and WILL-2 (GCB, double-hit) subcutaneous xenograft models. The in vivo combination of bendamustine with INCB054329 enhanced anti-tumor efficacy compared with either agent alone in the Pfeiffer model, and the combination was well tolerated. A rational, targeted combination strategy was evaluated involving INCB054329 and a selective, orally active PI3Kδ inhibitor, INCB050465, which is currently in clinical trials in B cell malignancies. Combining INCB054329 with PI3Kδ inhibition markedly enhanced anti-tumor efficacy, increasing the incidence of partial tumor regressions in vivo. In this model, both INCB054329 and INCB050465 treatment led to a reduction in c-Myc protein levels, suggesting a convergence between modulation of BET transcriptional regulation and the PI3Kδ pathway. These data suggest that clinical investigation of INCB054329, both as monotherapy and in combination with standard of care or novel targeted therapies, in several classes of B cell lymphoma, including high risk double hit lymphoma, is warranted. Citation Format: Matthew Stubbs, Robert Collins, Alla Volgina, Mike Liu, Margaret Favata, Mark Rupar, Xiaomng Wen, Richard Sparks, Thomas Maduskuie, Maryanne Covington, Timothy Burn, Bruce Ruggeri, Andrew P. Combs, Wenqing Yao, Reid Huber, Gregory Hollis, Peggy Scherle, Phillip CC Liu. Activity of the BET inhibitor INCB054329 in models of lymphoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3780.

Abstract 3525: The BET inhibitor INCB054329 is efficacious as a single agent or in combination with targeted agents in colorectal cancer models

Abstract The Bromodomain and extra-terminal (BET) family of proteins consists of BRD2, BRD3, BRD4 and BRDT. Each BET protein contains two bromodomains (BD1 and BD2) that recognize acetylated histones at enhancer and promoter regions of a select number of genes. BET proteins function as transcriptional regulators that are critical for the expression of oncogenes such as c-Myc; thus, BET proteins are important for cancer cell proliferation and survival. We have identified INCB054329, a potent and selective BET protein inhibitor that targets BD1 and BD2 of BRD2, BRD3 and BRD4. In this study, we characterized the pharmacology of INCB054329 in solid tumor cell lines. In a panel of colon cancer cell lines, more than 50% are sensitive to INCB054329 treatment with IC50 values below 500 nM in cell proliferation assays. INCB054329 down-regulated c-Myc expression, and induced cell cycle arrest and apoptosis in sensitive colon cancer cell lines. Moreover, INCB54329 was efficacious in the RKO colon cancer xenograft model. To understand whether BRD inhibition would synergize with other signaling pathway inhibitors and standard of care agents for colon cancer, we employed a high throughput combination screening strategy. Several combinations were active in a panel of colon cancer cell lines and demonstrated synergistic interactions based on combination index values. As an example, strong synergy was observed between INCB054329 and MEK inhibitors. The combination of INCB054329 and MEK inhibitors synergistically blocked expression of c-Myc protein and inhibited the MEK/ERK signaling pathway. Our data suggest the potential utilization of INCB054329 as a single agent or in combination with other targeted therapies for the treatment of colon cancer. Citation Format: Xuesong Liu, Jun Li, Xin He, Matthew Stubbs, Margaret Favata, Xiaoming Wen, Hong Chang, Beth R. Rumberger, Yanlong Li, Thomas Maduskuie, Richard Sparks, Nikoo Falahatpisheh, Padmaja Polam, Andrew P. Combs, Reid Huber, Gregory Hollis, Peggy Scherle, Phillip C. Liu. The BET inhibitor INCB054329 is efficacious as a single agent or in combination with targeted agents in colorectal cancer models. [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 3525. doi:10.1158/1538-7445.AM2015-3525

Abstract 692: The BET inhibitor INCB054329 is synergistic with JAK1 inhibition in models of multiple myeloma

Abstract Bromodomain and Extra Terminal (BET) protein inhibitors have emerged as a potentially effective therapeutic option for multiple tumor types, through their ability to regulate expression of genes necessary for proliferation and survival. For example, multiple myeloma (MM) cells have been shown to be highly sensitive to BET inhibition due in large part to the ability of BET proteins to control transcription of c-myc, an oncogene known to be dysregulated in MM. Likewise, some inflammatory response and cytokine signaling pathways associated with MM (eg. IL-6/JAK/STAT pathway) have also been shown to be reliant on BET proteins. Therefore, inhibition of both BET proteins and the JAK/STAT signaling pathway may be beneficial to MM patients. Here we assess the in vitro and in vivo effects of combining clinical compounds that target BET proteins and JAK in multiple myeloma cell lines. Studies were performed using the potent pan-BET inhibitor INCB054329 and selective JAK1 inhibitors. When tested in cell proliferation assays, the combination of BET and JAK1 inhibitors displayed strong synergistic effects in the IL-6 dependent INA-6 MM cell line in vitro. Western blots also revealed that several pharmacodynamic (PD) markers including c-MYC, PIM-2 and phospho-STAT3 were further repressed with the combination than with single agents alone. Likewise, the c-MYC and p-STAT3 PD markers could also be increasingly repressed in vivo by combined administration of BET and JAK1 inhibitors in the INA-6 mouse xenograft model. In vivo efficacy experiments in the INA-6 model resulted in enhanced, synergistic tumor growth inhibition in the BET/JAK inhibitor cohort as compared with the single drug cohorts. Interestingly, the cytokine independent MM1.S cell line was also sensitive to the BET/JAK inhibitor combination in vivo, while being far less sensitive to JAK1 inhibition as a monotherapy. In the MM1.S model, the c-MYC and p-STAT3 PD markers also behaved as seen in the INA-6 model. Our data indicate that the pharmacological inhibition of BET proteins and JAK1 yields strong combinatorial effects in MM cell lines both in vitro and in vivo. Therefore, dual inhibition of BET proteins and the JAK/STAT signaling pathway may offer a novel therapeutic approach and suggest a potential clinical utility for this drug combination in MM. Citation Format: Matthew C. Stubbs, Xuesong M. Liu, Xiaoming Wen, Jun Li, Valerie Dostalik, Sybil O'Connor, Eian Caulder, Margaret Favata, Mark Rupar, Yu Li, Beth Rumberger, Thomas Maduskuie, Richard Sparks, Nikoo Falahatpisheh, Padmaja Polam, Kris Vaddi, Timothy Burn, Andrew P. Combs, Wenqing Yao, Reid Huber, Gregory Hollis, Peggy Scherle, Phillip CC Liu. The BET inhibitor INCB054329 is synergistic with JAK1 inhibition in models of multiple myeloma. [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 692. doi:10.1158/1538-7445.AM2015-692

Abstract 691: Activity of the BET inhibitor INCB054329 in models of multiple myeloma

Abstract Multiple myeloma (MM) is a disease of plasma cell transformation. Current therapy for MM is initially effective, but nearly all tumors relapse, making new therapeutic options a necessity. Due to their efficacy in MM models, small molecule inhibitors of Bromodomain and Extra Terminal (BET) proteins have generated much interest as potential therapeutic agents for MM. Efficacy from BET inhibitors in MM is thought to be driven by their ability to reduce transcript levels of the c-myc oncogene. Current MM standard of care (SoC) therapeutics include lenalidomide (Revlimid, Celgene), bortezomib (Velcade, Takeda), and Melphalan (Alkeran, GlaxoSmithKline). In preparation for potential clinical studies, these MM SoC agents were each combined with a potent pan-BET inhibitor, INCB054329, for in vitro and in vivo studies. In vitro, treatment of MM cell lines with INCB054329 inhibited expression of c-MYC, induced HEXIM1 levels and inhibited cell growth with potencies less than 200 nM. Combination of INCB054329 with SoC therapeutics showed synergistic effects in blocking MM cell proliferation. INA-6 and MM1.S mouse xenograft models of MM were utilized to study the effects of the combination of INCB054329 with the MM SoC agents in vivo. In each instance (INCB054329/lenalidomide, INCB054329/bortezomib, INCB054329/melphalan), additive to synergistic effects, as measured by inhibition of subcutaneous tumor growth, were seen in both models of MM. Since lenalidomide has recently been shown to bind the ubiquitin ligase cereblon (CRBN), leading to the degradation of two Ikaros family members, IKZF1 and IKZF3, that are essential to B cell fate and survival, we examined whether there could be functional overlap between BET inhibition and the downstream effects of lenalidomide. From MM1.S xenograft pharmacodynamic assays, we found a synergistic repression of c-MYC protein levels at 3hr post dose for the combination of INCB054329 and lenalidomide. Interestingly, the sharp decline in c-MYC protein levels in the MM1.S model appears to be independent of the IRF4 pathway, as IRF4 protein levels do not decrease until 24 hrs post dose of lenalidomide. Overall, our data indicate that INCB054329 may provide a novel combination partner with current standard of care therapies for MM, and support the clinical evaluation of the compound within the anti-myeloma treatment landscape. Citation Format: Matthew Stubbs, Xiaoming Wen, Valerie Dostalik, Sybil O'Connor, Eian Caulder, Alla Vogina, Thomas Maduskuie, Richard Sparks, Taisheng Huang, Nikoo Falahatpisheh, Padmaja Polam, Chu-Biao Xue, Xuesong M. Liu, Timothy Burn, Kris Vaddi, Andrew P. Combs, Reid Huber, Gregory Hollis, Peggy Scherle, Phillip CC Liu. Activity of the BET inhibitor INCB054329 in models of multiple myeloma. [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 691. doi:10.1158/1538-7445.AM2015-691

Abstract 3523: Discovery of a novel BET inhibitor INCB054329

Abstract Bromodomains (BD) are protein modules that bind acetylated lysine residues and are components of many epigenetic modifiers and transcription factors. The BET (Bromodomain and extra-terminal) family is composed of four members each harboring two tandem BDs. BET proteins are critical regulators of transcription through interactions with complexes including Mediator and p-TEFb at gene promoter and enhancer elements. Studies using genetic knockdown and small molecule inhibitors have demonstrated that targeting BET proteins is therapeutic in models of cancer and acute inflammation. We describe the preclinical activity of a novel BET inhibitor INCB054329 for the potential treatment of malignant diseases. INCB054329 inhibited binding of BRD2, BRD3 and BRD4 to an acetylated histone H4 peptide with low nanomolar potency. In myeloma cell lines, treatment with INCB054329 inhibited expression of c-MYC and induced HEXIM1. The majority of myeloma, AML, and lymphoma cell lines tested were growth inhibited by INCB054329 with potencies less than 200 nM. Selectivity was seen when compared with nontransformed cells as the potency for growth inhibition of IL-2 stimulated T-cells from normal donors was greater than 1300 nM. Cell cycle analysis revealed treatment-induced G1 arrest. Furthermore in both AML and lymphoma cell lines, INCB054329 induced apoptosis consistent with increased expression of pro-apoptotic regulators. In vivo, oral administration of INCB054329 inhibited tumor growth in several models of hematologic cancers. In the MM1.S multiple myeloma xenograft model, inhibition of tumor growth was correlated with reduction of c-MYC levels. PK-PD analysis showed c-MYC suppression was associated with an IC50 value of less than 100 nM in vivo. In summary these studies demonstrate that INCB054329 is a potent inhibitor of BET transcriptional regulators in models of hematologic malignancies in vitro and in vivo and support its clinical development for the treatment of cancer. Citation Format: Phillip CC Liu, Xuesong Mike Liu, Matthew C. Stubbs, Thomas Maduskuie, Richard Sparks, Nina Zolotarjova, Jun Li, Xiaoming Wen, Margaret Favata, Patricia Feldman, Alla Volgina, Darlise DiMatteo, Robert Collins, Nikoo Falahatpisheh, Padmaja Polam, Yu Li, Maryanne Covington, Sharon Diamond-Fosbenner, Richard Wynn, Timothy Burn, Kris Vaddi, Swamy Yeleswaram, Andrew P. Combs, Wenqing Yao, Reid Huber, Peggy Scherle, Gregory Hollis. Discovery of a novel BET inhibitor INCB054329. [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 3523. doi:10.1158/1538-7445.AM2015-3523

Book Review: Ian Loader and Richard Sparks, Public Criminology?

Book Review: Ian Loader and Richard Sparks, <i>Public Criminology?</i>

Stephen Farrall, Mike Hough, Shadd Maruna and Richard Sparks (eds), Escape Routes: Contemporary Perspectives on Life After Punishment

Stephen Farrall, Mike Hough, Shadd Maruna and Richard Sparks (eds), <i>Escape Routes: Contemporary Perspectives on Life After Punishment</i>

Book review: Ian Loader and Richard Sparks, Public Criminology?

Book review: Ian Loader and Richard Sparks, Public Criminology?

Milton Okun, as told to Richard Sparks. Along the Cherry Lane: Tales from the Life of Music Industry Legend Milton Okun

Milton Okun, as told to Richard Sparks. Along the Cherry Lane: Tales from the Life of Music Industry Legend Milton Okun

Escape Routes: Contemporary Perspectives on Life after Punishment. Edited by Stephen Farrall, Mike Hough, Shadd Maruna and Richard Sparks (London: Routledge, 2011, 2178pp. 75.00 hb)

Escape Routes: Contemporary Perspectives on Life after Punishment. Edited by Stephen Farrall, Mike Hough, Shadd Maruna and Richard Sparks (London: Routledge, 2011, 2178pp. 75.00 hb)

Ian Loader and Richard Sparks, Public Criminology?

Ian Loader and Richard Sparks, <i>Public Criminology?</i>

A Symposium of Reviews oF Public Criminology?: By Ian Loader and Richard Sparks (Oxford: Key Ideas in Criminology, Routledge, 2010, 196pp.) with contributions from Nils Christie, Elliott Currie, Helena Kennedy, Gloria Laycock, Rod Morgan, Joe Sim, Jacqueline Tombs and Reece Walters

A Symposium of Reviews oF Public Criminology?: By Ian Loader and Richard Sparks (Oxford: Key Ideas in Criminology, Routledge, 2010, 196pp.) with contributions from Nils Christie, Elliott Currie, Helena Kennedy, Gloria Laycock, Rod Morgan, Joe Sim, Jacqueline Tombs and Reece Walters