Abstract
Coronaviruses can evolve and spread rapidly to cause severe disease morbidity and mortality, as exemplified by SARS-CoV-2 variants of the COVID-19 pandemic. Although currently available ...vaccines remain mostly effective against SARS-CoV-2 variants, additional treatment strategies are needed. Inhibitors that target essential viral enzymes, such as proteases and polymerases, represent key classes of antivirals. However, clinical use of antiviral therapies inevitably leads to emergence of drug resistance. In this study we implemented a strategy to pre-emptively address drug resistance to protease inhibitors targeting the main protease (M
pro
) of SARS-CoV-2, an essential enzyme that promotes viral maturation. We solved nine high-resolution cocrystal structures of SARS-CoV-2 M
pro
bound to substrate peptides and six structures with cleavage products. These structures enabled us to define the substrate envelope of M
pro
, map the critical recognition elements, and identify evolutionarily vulnerable sites that may be susceptible to resistance mutations that would compromise binding of the newly developed M
pro
inhibitors. Our results suggest strategies for developing robust inhibitors against SARS-CoV-2 that will retain longer-lasting efficacy against this evolving viral pathogen.
Elotuzumab is a monoclonal antibody in development for multiple myeloma (MM) that targets CS1, a cell surface glycoprotein expressed on MM cells. In preclinical models, elotuzumab exerts anti-MM ...efficacy via natural killer (NK)-cell-mediated antibody-dependent cellular cytotoxicity (ADCC). CS1 is also expressed at lower levels on NK cells where it acts as an activating receptor. We hypothesized that elotuzumab may have additional mechanisms of action via ligation of CS1 on NK cells that complement ADCC activity. Herein, we show that elotuzumab appears to induce activation of NK cells by binding to NK cell CS1 which promotes cytotoxicity against CS1(+) MM cells but not against autologous CS1(+) NK cells. Elotuzumab may also promote CS1–CS1 interactions between NK cells and CS1(+) target cells to enhance cytotoxicity in a manner independent of ADCC. NK cell activation appears dependent on differential expression of the signaling intermediary EAT-2 which is present in NK cells but absent in primary, human MM cells. Taken together, these data suggest elotuzumab may enhance NK cell function directly and confer anti-MM efficacy by means beyond ADCC alone.
Multiple myeloma (MM) patients who receive killer cell Ig–like receptor (KIR) ligand–mismatched, T cell–depleted, allogeneic transplantation may have a reduced risk of relapse compared with patients ...who receive KIR ligand–matched grafts, suggesting the importance of this signaling axis in the natural killer (NK) cell-versus-MM effect. Expanding on this concept, IPH2101 (1-7F9), an anti-inhibitory KIR mAb, enhances NK-cell function against autologous MM cells by blocking the engagement of inhibitory KIR with cognate ligands, promoting immune complex formation and NK-cell cytotoxicity specifically against MM cell targets but not normal cells. IPH2101 prevents negative regulatory signals by inhibitory KIR, whereas lenalidomide augments NK-cell function and also appears to up-regulate ligands for activating NK-cell receptors on MM cells. Lenalidomide and a murine anti-inhibitory NK-cell receptor Ab mediate in vivo rejection of a lenalidomide-resistant tumor. These mechanistic, preclinical data support the use of a combination of IPH2101 and lenalidomide in a phase 2 trial for MM.
The phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) axis plays a central role in attenuating inflammation upon macrophage stimulation with toll-like receptor (TLR) ligands. The mechanistic ...target of rapamycin complex 2 (mTORC2) relays signal from PI3K to Akt but its role in modulating inflammation in vivo has never been investigated. To evaluate the role of mTORC2 in the regulation of inflammation in vivo, we have generated a mouse model lacking Rictor, an essential mTORC2 component, in myeloid cells. Primary macrophages isolated from myeloid-specific Rictor null mice exhibited an exaggerated response to TLRs ligands, and expressed high levels of M1 genes and lower levels of M2 markers. To determine whether the loss of Rictor similarly affected inflammation in vivo, mice were either fed a high fat diet, a situation promoting chronic but low-grade inflammation, or were injected with lipopolysaccharide (LPS), which mimics an acute, severe septic inflammatory condition. Although high fat feeding contributed to promote obesity, inflammation, macrophage infiltration in adipose tissue and systemic insulin resistance, we did not observe a significant impact of Rictor loss on these parameters. However, mice lacking Rictor exhibited a higher sensitivity to septic shock when injected with LPS. Altogether, these results indicate that mTORC2 is a key negative regulator of macrophages TLR signalling and that its role in modulating inflammation is particularly important in the context of severe inflammatory challenges. These observations suggest that approaches aimed at modulating mTORC2 activity may represent a possible therapeutic approach for diseases linked to excessive inflammation.
A configuration of the High-Altitude Long-Range Research Aircraft (HALO) as a remote sensing cloud observatory is described, and its use is illustrated with results from the first and second ...Next-Generation Aircraft Remote Sensing for Validation (NARVAL) field studies. Measurements from the second NARVAL (NARVAL2) are used to highlight the ability of HALO, when configured in this fashion, to characterize not only the distribution of water condensate in the atmosphere, but also its impact on radiant energy transfer and the covarying large-scale meteorological conditions—including the large-scale velocity field and its vertical component. The NARVAL campaigns with HALO demonstrate the potential of airborne cloud observatories to address long-standing riddles in studies of the coupling between clouds and circulation and are helping to motivate a new generation of field studies.
Is Moses Maimonides an unacknowledged ancestor of the psychoanalytic movement? In this book, David Bakan, Dan Merkur, and David S. Weiss look at the great medieval Jewish philosopher's prescription ...for the cure of souls and its psychological significance. In the Guide of the Perplexed, Maimonides, who was also a physician, describes the soul's illness: when sinners rationalize evil as good, they limit their capacities to reason, imagine, and behave well, which also produces physical symptoms. The cure depends on repentance in love and fear of God that is attained through philosophical knowledge, the interpretation of dreams and visions, and mystical contemplation. The authors look at the Aristotelian background of Maimonides' psychology, Maimonidean mysticism, his beliefs about prophecy and sexuality, and what is known of Maimonides' client population. A final chapter discusses Maimonides and Freud, noting that many distinctive features of the cure of souls are shared by Freud's original formulation of psychoanalysis. Indeed, the many points of convergence suggest Freud's direct or indirect contact with Maimonides' legacy.
Introduction: Multiple myeloma (MM) is associated with profound and widespread disarray of both the adaptive and innate arms of the immune system including loss of effector T cell function, humoral ...immune deficiency, and natural killer (NK) cell immunity. This immunosuppressive milieu is crucial to promoting disease progression. Standard treatment options (immunomodulators (IMIDs) and proteosome inhibitors, radiation, and high-dose corticosteroids) offer modest benefit, but also contribute to further immune suppression. Little is known regarding the mechanisms by which immune dysfunction and immunoevasion occur. Our group has characterized an important role for the programmed death receptor-1 (PD-1) / PD-L1 signaling axis in these processes. MDV9300 (formerly CT-011 / Pidilizumab) is a novel IgG1 humanized monoclonal antibody (mAb) that modulates the immune response through interaction with PD-1. Lenalidomide (Len) an IMID exerts efficacy in MM in part through enhancement of NK cell versus MM effect - an effect likely mediated through T cell production of interleukin (IL)-2. In our in-vitro study, pretreatment of NK cells with MDV9300 with or without Len enhanced immune complex formation between NK cells and MM tumor targets and also augmented NK cell activation and cytotoxicity against MM. We sought to determine the safety, tolerability and any early signs of efficacy in relapsed or refractory MM patients using MDV9300 in combination with Len.
Methods: In the phase I portion, the primary endpoint is to determine the maximum tolerated dose (MTD) of the combination. Key eligibility criteria are relapsed or refractory disease but not progressed on Len 25 mg; ≥2 prior lines of therapy, absolute neutrophil count ≥ 1000/µL; Platelets ≥60,000/µL; and creatinine clearance of ≥ 40ml/min. Patients are treated with escalating doses of MDV9300 and Len utilizing a 3x3 escalation design (Table 1). If stable disease is the best response after 4 cycles, patients have the option of adding dexamethasone (20-40mg weekly). Len dose may be modified independently of MDV9300. Patients can receive a maximum of 12 cycles of therapy.
Results: Twelve patients are evaluable to date. The median age was 68.5 (range 49-82) and the median time from diagnosis 4.98 years (range 1.54-12.62). At study entry, 67% had high risk cytogenetics (del 17p, complex karyotype, gain 1q) and the median number of prior treatment lines was 2 (range 2-11). 100% of patients had received prior Len, bortezomib and Dex, 50% alkylating agents (cyclophosphamide, oral melphalan, bendamustine), 75% autologous stem cell transplant, 25% pomalidomide and 33% carfilzomib. MDV9300 infusion has been well tolerated with only one grade 2 infusion related toxicity with sore throat. The patient received hydrocortisone with no further reaction observed. Grade 3/4 Anemia, neutropenia, and thrombocytopenia attributable to therapy have been seen in 25%, 23%, and 34% of patients, respectively. Other common grade 2-3 therapy related adverse events are fatigue (50%), anorexia (17%), and hypophosphatemia (17%). There has been no grade 3 or higher infection and no worsening of neuropathy from baseline. Len dose was reduced in 3 patients (25%) and increased in one. There has been no dose reduction in MDV9300. Dex 20 mg or less was added in 2 patients for muscle cramps and < PR after 3 cycles. To date 7 patients are off therapy; 1 due to grade 3 fatigue and 6 due to disease progression. Five patients continue on therapy at respective 12, 11, 9, 5 and 3 months. Responses to date have been 3 Very good partial response,1 partial response, 2 minimal response and 2 stable disease.
Conclusion: The combination of steroid sparing MDV9300 and Len regimen has demonstrated an acceptable toxicity profile to date with evidence of anti-myeloma activity. This is the first reported combination anti-PD-1 based immune therapy for MM. Updated results will be presented at the meeting including the MTD dose for phase II.
Table 1MDV9300- mg/kg Intravenously given on day 3 every 28 daysLenalidomide- mg orally days 1-21 every 28 daysDLT EvaluableDLTsCohort 11.5156Grade 3 fatigue. Cohort extended to 6Cohort 23153noneCohort 33253noneCohort 46250
Acknowledgments: Drug has been provided by Medivation; The study is sponsored by the American Cancer Society
No relevant conflicts of interest to declare.
The election of Ronald Reagan as President of the United States in November 1980 opened a new chapter in international relations; U.S. foreign policy shifted from an alliance-based, consensual ...approach to one based on a more overt use of its immense economic and, above all, military power. This policy entailed some stark choices for the U.S.A.'s allies and neighbours and, above all, for the small countries of Central America and the Caribbean. This revealing book tells the story of the Caribbean Basin Initiative (CBI), through which the new assertion of U.S. hegemony in the region was expressed. The CBI entitled "friendly" countries of the region (i.e., excluding Cuba, pre-invasion Grenada and Nicaragua) to military and economic aid plus incentives, modelled on the so-called "Puerto Rican miracle, " so as to reorient their trade towards the U.S.A. The authors carefully compare the claims made for the CBI with its underlying political objectives and examine its actual impact on regional development through detailed case studies of the Eastern Caribbean and Trinidad. Also examined are the impact of the CBI on Caribbean regional integration and the responses of Canada and Britain, the two other major countries with long- standing political and economic interests in the Caribbean. What emerges from this investigation is the way the CBI reflects the U.S.A.'s historic quest for regional dominance, rather than a new era in Caribbean development.
Surveillance is always a means to an end, whether that end is influence, management or entitlement. This book examines the several layers of surveillance that control the Palestinian population in ...Israel and the Occupied Territories, showing how they operate, how well they work, how they are augmented, and how in the end their chief purpose is population control.
Showing how what might be regarded as exceptional elsewhere is here regarded as the norm, the book looks not only at the political economy of surveillance and its technological and military dimensions, but also at the ordinary ways that Palestinians in Israel and the occupied territories are affected in their everyday lives. Written in a clear and accessible style by experts in the field, this book will have large appeal for academic faculty as well as graduate and senior undergraduate students in sociology, political science, international relations, surveillance studies and Middle East studies.
Preface Elia Zureik, David Lyon and Yasmeen Abu-Laban Part I: Introduction 1. Colonialism, Surveillance and Population Control: Israel/Palestine Elia Zureik Part II: Theories of Surveillance in Conflict Zones 2. Identification, Colonialism and Control: Surveillant Sorting in Israel/Palestine David Lyon 3. Making Place for the Palestinians in the Altneuland: Herzl, Anti-Semitism, and the Jewish State Glenn Bowman Part III: Civilian Surveillance 4. Ominous Designs: Israel’s Strategies and Tactics of Controlling the Palestinians during the First Two Decades Ahmad Sa'di 5. The Matrix of Surveillance in Times of National Conflict: The Israeli-Palestinian Case Hillel Cohen 6. The Changing Patterns of Disciplining Palestinian National Memory in Israel Tamir Sorek Part IV: Political Economy and Globalization of Surveillance 7. Laboratories of War: Surveillance and US-Israeli Collaboration in War and Security Steven Graham 8. Israel’s Emergence as a Homeland Security Capital Neve Gordon 9. From Tanks to Wheelchairs: Unmanned Aerial Vehicles, Zionist Battlefield Experiments, and the Transparency of the Civilian Nick Denes Part V: Citizenship Criteria and State Construction 10. Legal Analysis and Critique of Some Surveillance Methods Used by Israel Usama Halabi 11. Orange, Green, and Blue: Colour-Coded Paperwork for Palestinian Population Control Helga Tawil-Souri 12. "You Must Know Your Stock": Census as Surveillance Practice in 1948 and 1967 Anat E. Leibler Part VI: Surveillance, Racialization, and Uncertainty 13. Exclusionary Surveillance and Spatial Uncertainty in the Occupied Palestinian Territories Ariel Handel 14. "Israelization" of Social Sorting and the "Palestinianization" of the Racial Contract: Reframing Israel/Palestine and The War on Terror Yasmeen Abu-Laban and Abigail B. Bakan Part VII: Territory and Population Management in Conflict Zones 15. British and Zionist Data Gathering on Palestinian Arab Land Ownership and Population during the Mandate Michael Fischbach 16. Surveillance and Spatial Flows in the Occupied Palestinian Territories Nurhan Abujidi 17. Territorial Dispossession and Population Control of the Palestinians Rassem Khamaisi Part VIII: Social Ordering, Biopolitics and Profiling 18. The Palestinian Authority Security Apparatus: Biopolitics, Surveillance and Resistance in the Occupied Palestinian Territories Nigel Parsons 19. Behavioural Profiling in Israeli Aviation Security as a Tool for Social Control Reg Whitaker
"This stimulating edited collection is a valuable contribution to the growing corpus of scholarship that takes Israel’s over forty-year occupation regime as its central object of analysis, research, and comparative theoretical reflection... this important volume provides a sound basis for further comparative studies in the technologies of power that are transforming the globe at this time." - Steve Niva; Journal of Palestine Studies, Vol. 41, No. 1 (Autumn 2011)
Elia Zureik is Emeritus Professor of Sociology at Queen’s University, Canada. His published work covers the Middle East, with special reference to the Israeli--Palestinian conflict, and surveillance.
David Lyon is Director of the Surveillance Studies Centre at Queen’s University, Canada. He is the author of Surveillance Studies: An Overview (2007) and Identifying Citizens: ID Cards as Citizenship (2009), and is currently researching the global growth of national ID systems.
Yasmeen Abu-Laban is Professor and Associate Chair (Research) in the Department of Political Science at the University of Alberta, Canada. She specializes in the politics of gender, racialization, migration and citizenship. She is co-author of Selling Diversity (2002), co-editor of Politics in North America (2008), and editor of Gendering the Nation-State (2008).
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