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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.

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.

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.

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

'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 Hugh got sick and went back to England, Amy was content to live without a man. It was partly that the afterglow lasted, in remembered scenes that replayed ceaselessly, illuminating resignation. And then, the old friendly-fun-sophisticated love affair had always ended wretchedly for her: half-love, not enough to marry on, too much to break off, dwindling in half-life for ages. When friends reported their romantic syndromes"Amy, I fucked it up the same way again!" -she listened with the swamp closing over her head. How could people manufacture the causes of their suffering ? She rarely spoke of Hugh, and her pride increased in isolation. She promised herself: no man until he's right. "You can do it, lead a chaste life," she told herself. "You've had the disadvantages of being Irish Catholic, might as well get the good of it too." No more squandering Sunday on a walk in the park with some nice guy, when she could be writing. No more staring at the big black telephone. Then she met Francis. It was the graduate Shakespeare class, no hey nonny no, but a tired collection of Ph.D. commuters. One night a tall young man with redgold hair and beard livened it by describing Olivier's Othello in an enthusiastic rush of words, big gestures. Afterwards, waiting for the elevator, the young man was doing a slow heel-to-toe dance, his blue eyes abstracted. Amy spoke to him. He went into more detail. He spoke well. Amy tried to imagine the long powerful line of a great performance, like the path of a night plane shot in time delay.