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Background Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 virus-specific cytotoxic T-cell lymphocytes (vCTLs) could provide a promising modality in COVID-19 treatment. We aimed to screen, manufacture, and characterize SARS-CoV-2–vCTLs generated from convalescent COVID-19 donors using the CliniMACS Cytokine Capture System (CCS). Methods Donor screening was done by stimulation of convalescent COVID-19 donor peripheral blood mononuclear cells with viral peptides and identification of interferonγ (IFN-γ)+ CD4 and CD8 T cells using flow cytometry. Clinical-grade SARS-CoV-2–vCTLs were manufactured using the CliniMACS CCS. The enriched SARS-CoV-2–vCTLs were characterized by T-cell receptor sequencing, mass cytometry, and transcriptome analysis. Results Of the convalescent donor blood samples, 93% passed the screening criteria for clinical manufacture. Three validation runs resulted in enriched T cells that were 79% (standard error of the mean 21%) IFN-γ+ T cells. SARS-CoV-2–vCTLs displayed a highly diverse T-cell receptor repertoire with enhancement of both memory CD8 and CD4 T cells, especially in CD8 TEM, CD4 TCM, and CD4 TEMRA cell subsets. SARS-CoV-2–vCTLs were polyfunctional with increased gene expression in T-cell function, interleukin, pathogen defense, and tumor necrosis factor superfamily pathways. Conclusions Highly functional SARS-CoV-2–vCTLs can be rapidly generated by direct cytokine enrichment (12 hours) from convalescent donors. Clinical Trials Registration NCT04896606.

Opinion statementNatural killer (NK) cells have played a critical—if largely unrecognized or ignored—role in the treatment of B cell non-Hodgkin lymphoma (NHL) since the introduction of CD20-directed immunotherapy with rituximab as a cornerstone of therapy over 25 years ago. Engagement with NK cells leading to lysis of NHL targets through antibody-dependent cellular cytotoxicity (ADCC) is a critical component of rituximab’s mechanism of action. Despite this important role, the only aspect of B cell NHL therapy that has been adopted as standard therapy that even indirectly augments or restores NK cell function is the introduction of obinutuzumab, a CD20 antibody with enhanced ability to engage with NK cells. However, over the last 5 years, adoptive immunotherapy with effector lymphocytes of B cell NHL has experienced tremendous growth, with five different CAR T cell products now licensed by the FDA, four of which target CD19 and have approved indications for some subtype of B cell NHL—axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, and tisagenlecleucel. These T cell-based immunotherapies essentially mimic the recognition, activation pathway, and cytotoxic machinery of a CD19 antibody engaging NK cells and lymphoma targets. Despite their efficacy, these T cell-based immunotherapies have been difficult to implement because they require 4–6 weeks of manufacture, are costly, and have significant toxicities. This renewed interest in the potential of cellular immunity—and the manufacturing, supply chain, and administration logistics that have been addressed with these new agents—have ignited a new wave of enthusiasm for NK cell-directed therapies in NHL. With high safety profiles and proven anti-lymphoma efficacy, one or more new NK cell-directed modalities are certain to be introduced into the standard toolbox of NHL therapy within the next few years, be it function-enhancing cytokine muteins, multi-domain NK cell engagers, or adoptive therapy with expanded or genetically modified NK cells.

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 virus-specific cytotoxic T-cell lymphocytes (vCTLs) could provide a promising modality in COVID-19 treatment. We aimed to screen, manufacture, and characterize SARS-CoV-2-vCTLs generated from convalescent COVID-19 donors using the CliniMACS® Cytokine Capture System (CCS).Donor screening was done by stimulation of convalescent COVID-19 donor peripheral blood mononuclear cells with viral peptides and identification of IFN-γ+ CD4 and CD8 T-cells using flow cytometry. Clinical-grade SARS-CoV-2-vCTLs were manufactured using the CliniMACS® CCS. The enriched SARS-CoV-2-vCTLs were characterized by T-cell receptor sequencing, mass cytometry, and transcriptome analysis.93% of convalescent donor blood samples passed the screening criteria for clinical manufacture. Three validation runs resulted in enriched T-cells that were 79% ± 21% IFN-γ+ T-cells. SARS-CoV-2-vCTLs displayed a highly diverse TCR repertoire with enhancement of both memory CD8 and CD4 T-cells, especially in CD8 TEM, CD4 TCM and CD4 TEMRA cell subsets. SARS-CoV-2-vCTLs were polyfunctional with increased gene expression in T-cell function, interleukin, pathogen defense, and tumor necrosis factor superfamily pathways.Highly functional SARS-CoV-2-vCTLs can be rapidly generated by direct cytokine enrichment (12 hours) from convalescent donors.NCT04896606, NCT03266627, NCT03266640, NCT03266653, NCT04197596.

BACKGROUND A standard-of-care has not been established for the management of DS patients who develop primary CNS GCTs – the most common CNS neoplasm in DS – despite being more susceptible to treatment-related adverse events. METHODS A review of the English-language medical literature between 1960 and 2020 was conducted. RESULTS Thirty-one cases of CNS GCTs in DS patients (median nine-years-old; 21 males) were reported; the majority (23/31) originated from East Asia. Twelve had germinomas (39%), 12 had non-germinomatous germ cell tumors (NGGCTs) (39%), and seven had teratomas (22%). Four patients (13%) died from tumor progression (one germinoma versus three teratoma). Seven patients (23%) died from treatment-related complications (four germinoma versus three NGGCT). Of the germinoma patients, two died from chemotherapy-related sepsis, one from post-surgery cardiopulmonary failure, and one from Moyamoya following radiation-therapy (RT) only. Of the NGGCT patients, one died from chemotherapy-related sepsis, one from post-surgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival (OS) was 58.1% for all patients, 52.5% for germinoma, 64.8% for NGGCT, and 60% for teratoma. Three-year OS for patients who received RT or chemotherapy was 63.6% and 59.6% respectively. Twenty patients (65%) remain alive (seven germinoma versus nine NGCCT versus four teratoma). Ten patients (32%) experienced serious treatment-related complications (five germinoma versus five NGGCT). CONCLUSIONS Patients with DS and CNS GCTs are at an increased risk of treatment-related complications. Therefore, a different therapeutic approach may need to be considered for this patient population in order to mitigate the treatment-related complications and long-term neurocognitive sequelae.

CRISPR/Cas9 technology is accelerating genome engineering in many cell types, but so far, gene delivery and stable gene modification have been challenging in primary NK cells. For example, transgene delivery using lentiviral or retroviral transduction resulted in a limited yield of genetically-engineered NK cells due to substantial procedure-associated NK cell apoptosis. We describe here a DNA-free method for genome editing of human primary and expanded NK cells using Cas9 ribonucleoprotein complexes (Cas9/RNPs). This method allowed efficient knockout of the TGFBR2 and HPRT1 genes in NK cells. RT-PCR data showed a significant decrease in gene expression level, and a cytotoxicity assay of a representative cell product suggested that the RNP-modified NK cells became less sensitive to TGFβ. Genetically modified cells could be expanded post-electroporation by stimulation with irradiated mbIL21-expressing feeder cells.

References to "customers‟ have become commonplace in the policy discourses within UK government and other public sector bodies. It is a working assumption of UK public sector management that the concept of the "customer‟ can be applied to any public sector service agency or department; this paper analyses how the UK government‟s revenue department, formerly titled the Inland Revenue (IR), re-characterised firstly taxpayers and latterly tax claimants as "customers," rather than "users," of IR services. This paper identifies some problems, dilemmas and ambiguities associated with this reconceptualisation in the context of an organisation that is predominantly a regulating department. Far from being merely a reclassification of the taxpayer as customer, the emerging discourse and associated practices of the IR were in part embedded in organisational change including the merger with HM Customs and Excise to form the present-day HMRC. Thus, this case analysis illustrates the limits of consumerism as a strategic tool of a government revenue department and raises wider questions for public management.

Genetic modification of NK cells to enhance cancer immunotherapy has potential application to treat a wide range of cancers. Recently, we developed a new strategy in which CRISPR/Cas9 elements are introduced into NK cells as ribonucleoproteins (RNPs) via electroporation, followed by expansion on feeder cells expressing 4-1BBL and membrane-bound IL-21 to generate large numbers of genetically modified NK cells. This method was used to genetically modify several genes in primary and expanded NK cells including suppressor of cytokine signaling 3 (SOCS3). SOCS3 negatively regulates cytokine signaling through the JAK/STAT pathway. We hypothesized that disruption of SOCS3 in primary NK cells using Cas9/RNPs could potentially maintain STAT3 signaling levels and subsequently increase their proliferation and cytotoxic function. We designed gRNAs to target exon 2 of the SOCS3 gene and electroporated them along with Cas9 protein as Cas9/RNPs into primary NK cells using the Lonza 4D electroporator. We tested 6 different conditions of gRNAs alone or in combination. The NK cells in the control group were electroporated with no Cas9/RNPs. After electroporation, the cells were rested in culture media supplemented with 100 IU of human IL-2 for 48 hours and then expanded using irradiated feeder cells. At day 7, an equal number of cells were restimulated with irradiated feeder cells to test the effect of SOCS3 KO on proliferation. Western blot was used to assay the knock out efficacy at the protein level. Calcein assay and IncuCyte Zoom (Essen) were performed to measure cytotoxicity against two cancer cell lines, K562 and Daoy. Our results showed a significant reduction in SOCS3 protein levels in 3 conditions (gRNA1, gRNA3 and gRNA1+ gRNA3) in comparison to the control group. The calcein assay and IncuCyte zoom showed the modified SOCS3 KO NK cells could kill the tumors more efficiently in comparison to the control. Proliferation data showed the SOCS3 KO cells can grow faster than the control group. In conclusion, our data demonstrate the role of SOCS3 and JAK/STAT pathway in NK cell function and suggests that SOCS3 may be a good target for genetic modification to improve cancer immunotherapy using NK cells. Disclosures Lee: CytoSen Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck, Sharp, and Dohme: Consultancy; Courier Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

BACKGROUND: There is a well-known association between central nervous system (CNS) germ cell tumors (GCTs) and Down syndrome (DS). Current standard of care for CNS GCTs includes surgery, chemotherapy and radiation therapy (RT). We describe our institutional experience regarding the management of DS patients with CNS GCT. Additionally, we have performed a comprehensive literature review of CNS GCTs in DS patients. RESULTS: Patient # 1: An infant with posterior fossa immature teratoma is currently without any evidence of disease two years following gross total resection of the tumor without requiring any adjuvant therapy. Patient #2: A 17-year-old female with suprasellar CD30 positive embryonal carcinoma underwent subtotal resection of the tumor. RT was spared by using an induction chemotherapy regimen followed by myeloablative chemotherapy with autologous stem cell support. Moreover, she received six cycles of the anti-CD30 antibody-drug conjugate Brentuximab-vedotin. She is 16 months off therapy with no evidence of disease. Twenty-four cases were reported in the literature; diagnosed at 1 month-35 years of age (median 10 years). Of the 24 cases; 10 were germinoma (42%), 7 yolk sac tumor (29%), 3 immature teratoma (12.5%), 3 mature teratoma (12.5%), 1 embryonal carcinoma (4%). Five-year overall survival for all cases was 53%. Four patients died from infectious complications of chemotherapy while four died from tumor progression. CONCLUSIONS: Patients with DS have an increased risk of mortality from cerebrovascular disease following RT. Treatment-related toxicities should be considered while planning the management of GCTs in DS patients.

This review essay suggests considerations to be addressed in research design if research on a taxation subject is to succeed as rigorous accounting research, well grounded in relevant historical scholarship. Tax research must focus on substantive subjects that are recognizable as “accounting”; the methods, approach, and exposition must be “historical” to an acceptable standard; and the research must engage with relevant portions of the existing body of accounting historical scholarship. Further, scholarly engagement with the best researchers and liveliest debates that the disciplines of accounting and history have to offer will enrich the treatment of tax in accounting history

Seven British income tax disputes over depreciation (1875–1897) are analyzed in this contextual study. The legal cases reveal how uncertainty over meanings for “depreciation,” “profits,” and “capital” reflected social and political tensions which had commercial accounting implications. Case analysis yields evidence of how judicial support reinforced the Inland Revenue's technical authority over a competing tax administration institution and enabled its modern regulatory control over taxpayers to be constructed. The British example illustrates the ways in which technical and administrative practices may emerge from the contestation of meanings that takes place both in a wide political context and within particular institutional settings.

In 1855 Jane Carlyle, wife of historian Thomas Carlyle, appeared before the General Commissioners of Income Tax to appeal against her husband's assessment. Moulded around her memoire of the appeal, this paper explores the process of and social context for mid-nineteenth century English income taxation of profits, and the associated accountings and processes of accountability. It reveals how local tax authorities employed sovereign powers as the basis for regulatory control. The paper outlines conditions of possibility for the emergence of modern Inland Revenue powers based on disciplinary technologies.

Taxation practice represents a significant part of what may be classed as accounting practice. In contrast, taxation research represents a very small part of the accounting research field. This pap...

This paper constructs a method for assessing the degree of connection between tax rules and practices and financial reporting rules and practices in a country. Five types of connection and disconnection are suggested, and 15 arenas of accounting are proposed for assessment on this basis. The method is applied to four countries, partly in order to test the claim of a clear distinction between Anglo-Saxon and continental European countries.

The relationship between accounting and taxation in the United Kingdom is explored in this article. The first section considers historical reasons for the relative independence of contemporary calculations of accounting profits and taxable profits. Despite the formal independence of important aspects of the calculation regimes, effective interdependence of practice is a feature of the United Kingdom's tax and accounting histories. The second section outlines the current law and practice governing the recognition of taxable profits, and reviews the financial reporting standards and practices that have been developed to deal with tax/accounting differences. Finally, recent developments in financial report-ing and taxation are identified that are likely to have an impact on the character of the relationship between tax and accounting in the future.

has long been recognized that the immense growth of hostility towards Russia displayed by the British press in the 1830s was largely the result of a deliberate campaign organized by a few ardent Russophobes. Contemporaries singled out David Urquhart as the main, if not the only, instigator, but historians have recognized that others were intimately involved; they have generally included Sir John McNeill and James Baillie Fraser as leading participants. The British ambassador at Constantinople, Viscount Ponsonby; the private secretary to the king, Sir Herbert Taylor; and the foreign secretary, Viscount Palmerston, have all been regarded as having some connection with the campaign, but there has not been agreement about the extent of their involvement.1 Palmerston's role in particular has been a matter of dispute and his most recent biographer, Kenneth Bourne, believes that the extent of the foreign secretary's involvement 'will surely never be known'.2 Bourne accepts Palmerston's own account of his activities without much question and Sir Charles Webster is almost as uncritical. J.H. Gleason and G.H. Bolsover, however, suggest that the foreign secretary was more deeply involved than he was later prepared to admit. With the comparatively recent availability of the private papers of McNeill and of Ponsonby, there seems room to investigate further the extent of the responsibility of all the participants and the motivation for their actions.3

In the decade between the signing of the major peace treaties and the onset of the Great Depression, the statesmen of Europe attempted to come to terms with the major changes which had occurred and to reconstruct the economic and political life of the continent on the basis of the new settlement. The outbreak of another major war only ten years later suggests that the statesmen of the 1920s were not successful in laying the basis for a stable lasting peace. Some historians argue that considerable progress had been made in solving disputes and easing tensions and that it was the Great Depression of the early 1930s which produced new economic and political causes of international instability. Others believe that the tensions and disputes of the Great War era were never resolved and that there was a mere ‘illusion of peace’.1 All agree, however, that the difficulties that the statesmen faced were immense. In the aftermath of the war all governments needed to restore national finances, stimulate economic growth and maintain domestic political and social stability. Foreign policy had to respond to and reflect these domestic needs and pressures.

In the spring of 1940, Britain and France on one side and Germany on the other began military measures which brought to an end the so-called ‘phoney war’. Both sides began operations in Scandinavia. In an extension their strategy of blockade, Britain and France were anxious to deprive Germany of supplies of Swedish iron ore. They had originally contemplated sending troops across northern Norway and Sweden to help the Finns in their war against Russia and hoped, in the process, to obtain control of the export of the iron ore fields. When the Finns capitulated, the British and French adopted the alternative plan of laying mines in Norwegian territorial waters to block the ice-free route down the Norwegian coast which the Germans used. Unprepared themselves to go so far as violating Norwegian neutral territory, they anticipated that their measures could provoke a German attack upon the Scandinavian countries, to which they could respond by seizing the iron ore fields. Anglo-French disagreements delayed the operation. The mine laying began on 8 April, but the Germans had already despatched forces to occupy Denmark and Norway.

The hopes at the end of the First World War for a new era in international relations and an end to war had been based on the concept of ‘collective security’, of which the twin pillars were disarmament and the League of Nations. The developments of the first few years of the 1930s seriously undermined these hopes. The long-awaited Disarmament Conference had failed to reach an agreement on land armaments limitation. Despite the Washington and London conferences, agreement on naval limitation was by no means complete. Germany was firmly under the control of a regime which had openly expansionist aims and was blatantly rearming. The messages emanating from the other major fascist state, Italy, were somewhat confusing, but Mussolini’s constant incitement of the Italians to warlike attitudes, his glorying in the instruments of war, the savage nature of the Italian reprisals on the rebels against their rule in Libya and their fomenting of discord in Yugoslavia led some foreign diplomats to see Mussolini as ‘one of the chief existing dangers to European peace’.1 While the hopes for disarmament and for a growing commitment to peace were disappointed in Europe, the League had also failed to curb Japanese aggression in Manchuria.

The statesmen who met in Paris in 1919 to draw up a peace settlement faced a daunting task. Lloyd George, the leader of the British delegation, claimed that ‘it is not one continent that is engaged — every continent is affected’.1 The collapse of the four empires of Germany, Austria-Hungary, Russia and Turkey and the demands of previously subject national groups necessitated a major redrawing of the map in Europe and the Middle East. In Africa, China and the Pacific, the future of Germany’s former possessions had to be considered. Many diverse and often conflicting hopes and aspirations depended on the outcome of the negotiations. Some were inevitably disappointed and those disappointments fuelled the criticism of contemporaries and have influenced the judgement of historians. The fact that the settlement was followed twenty years later by another major war has led to the assumption that it must have been fatally flawed. There has been less agreement on the nature of the flaws. Its treatment of Germany has been criticised both as too harsh and as not severe enough. The peacemakers have been accused of failing to appreciate the full strength of nationalist aspirations but they have also been blamed for too easily acquiescing in the break-up of the multinational Austro-Hungarian empire. Most frequently the settlement has been criticised for failing to fulfil expectations that it would be the first major act of the new open diplomacy of which Wilson had been the advocate.

Britain was the most successful of the nineteenth-century European powers in expanding its territory overseas, but that very success brought an increasing nervousness and sense of vulnerability as well as prestige and status as a world power. As early as the 1830s, the possession of India had led to growing fears about the threat of Russian expansion in Central Asia. The development of intense imperial rivalry with France in Africa and Asia, disagreements with the United States over the Canadian-American boundary and over Central America, pressures from Germany to make colonial concessions, and the perception that the Russian threat had extended to Manchuria and China as well as the Middle East caused the British to reconsider their whole diplomatic position. They decided that they were no longer able to stand aloof from the alliances of the other European powers and alone defend their interests against a number of potential enemies. When the attempt to conclude an agreement with Germany failed, they made an alliance with Japan in 1902 to help protect their interests in the Far East and settled their differences with the United States in 1902 and 1903, with France in 1904 and with Russia in 1907. Although the memories of years of rivalry and friction could not be expunged, Britain’s relations with France and the USA steadily improved.

'the policy of Russia has long been impregnated with the spirit of deadly hostility to England' asserted the leader writer in the Morning Herald in October 1838.1 Similar comments about Russia were a regular feature of the editorials of almost all of the major daily and periodical publications in England at that time. From small indications of suspicion and antipathy in the 1 820s, a nearly universally expressed fear and hatred of Russia had emerged ten years later. So intense was this feeling that less convinced contemporaries, recognizing that it was much more than the usual dislike of all that was strange and foreign, referred to it as Russophobia.2 Historians have studied this phenomenon in various ways. They have sought to investigate its effect upon the formulation of British foreign policy; they have tried to explain its origins and what fed and stimulated it during the 1830s and at subsequent periods during the nineteenth century. Some have put great emphasis upon the conflicting economic policies of the two states, others on the growing rivalry in the Near East and Central Asia, and others on the different internal political systems.3 On one point, however, there has been widespread agreement, that in the 1830s one man and his collaborators were largely responsible for the initial surge of Russophobia. That man was David Urquhart. One of the few contemporaries who tried to stem the tide of Urquhart's influence, Richard Cobden, wrote in 1836: 'One active mind [i.e.

In a review for Ms. (December 1973), the poet Yvonne contrasted the musical Raisin with Lorraine Hansberry's original play, in which theThree Younger women formed the most complex, thoroughly honest portrait of the archetypal black woman to have appeared on the American stage…. The spine of Hansberry's original plot was provocative and clear-cut. It was the conflict between life and the profit motive, a conflict in which a black man, Walter Lee Younger (Mama's son, Ruth's husband, Beneatha's brother), having chosen money as his god, becomes his family's moral antagonist. In the new musical, the dramatic focus is switched from the women to the man. The total production—script, music, lyrics, direction, choreography, sets—is created by everybody but the black woman. The women's most intense speeches are cut, their stage movements made awkward and their personalities made shallow or reversed. Many of their lines and dramatic gestures, particularly those showing warmth and depth, are given to Walter to make him a less vindictive and more likeable character.

After speech, reading is the most important of the basic skills, involving as it does recognition of a visual pattern, and the ability to pronounce it. Reading readiness has been the subject of much investigation and varies considerably from country to country, but in Great Britain it is now fairly generally accepted that the age at which a child is ready to read depends upon intelligence, home influence and teaching methods. The latter have varied very much in the last decade and much investigation is still going on to determine the best methods. To combine maximum comprehension with rapid or effective reading, more early practice in ‘silent’ as opposed to oral reading is probably necessary.