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Neutrophils help to clear pathogens and cellular debris, but can also cause collateral damage within inflamed tissues. Prolonged neutrophil residency within an inflammatory niche can exacerbate tissue pathology. Using both genetic and pharmacological approaches, we show that BCL-XL is required for the persistence of neutrophils within inflammatory sites in mice. We demonstrate that a selective BCL-XL inhibitor (A-1331852) has therapeutic potential by causing apoptosis in inflammatory human neutrophils ex vivo. Moreover, in murine models of acute and chronic inflammatory disease, it reduced inflammatory neutrophil numbers and ameliorated tissue pathology. In contrast, there was minimal effect on circulating neutrophils. Thus, we show a differential survival requirement in activated neutrophils for BCL-XL and reveal a new therapeutic approach to neutrophil-mediated diseases.

© 2020 The Authors. British Journal of Social Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society In the current project, we examined how perceived group memberships (number, and characteristics, of), social and relational identification, and social identity leadership are associated with resilience in Royal Air Force (RAF) personnel. Based on social identity theorizing, we hypothesized positive associations between the number of groups, perceptions of their characteristics (e.g., positivity), and how they relate to each other (i.e., compatibility) and resilience (H1). We also hypothesized positive associations between both social identity leadership (H2) and resilience, and social and relational identification (H3) and resilience. Two hundred and forty-three personnel from 18 RAF bases completed an identity mapping exercise and measures of leadership, social and relational identification, and resilience. Our findings highlighted the importance of the association between positive group memberships and resilience, and social identification and resilience. Counter to our hypothesis, belonging to more groups was negatively associated with resilience, and there were non-significant relationships between three principles of social identity leadership and resilience, with embedding identity being significantly negatively associated with resilience. In support of social identity theorizing, the number of positive groups was positively associated with resilience, as was social identification. These findings indicate that, for RAF personnel, it is belonging to positive groups, both within and outside work, along with social identification, that is positively associated with resilience.

© 2020 The Authors. British Journal of Social Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society In the current project, we examined how perceived group memberships (number, and characteristics, of), social and relational identification, and social identity leadership are associated with resilience in Royal Air Force (RAF) personnel. Based on social identity theorizing, we hypothesized positive associations between the number of groups, perceptions of their characteristics (e.g., positivity), and how they relate to each other (i.e., compatibility) and resilience (H1). We also hypothesized positive associations between both social identity leadership (H2) and resilience, and social and relational identification (H3) and resilience. Two hundred and forty-three personnel from 18 RAF bases completed an identity mapping exercise and measures of leadership, social and relational identification, and resilience. Our findings highlighted the importance of the association between positive group memberships and resilience, and social identification and resilience. Counter to our hypothesis, belonging to more groups was negatively associated with resilience, and there were non-significant relationships between three principles of social identity leadership and resilience, with embedding identity being significantly negatively associated with resilience. In support of social identity theorizing, the number of positive groups was positively associated with resilience, as was social identification. These findings indicate that, for RAF personnel, it is belonging to positive groups, both within and outside work, along with social identification, that is positively associated with resilience.

Improving survival outcomes in adult B-cell acute lymphoblastic leukemia (B-ALL) remains a clinical challenge. Relapsed disease has a poor prognosis despite the use of tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome positive (Ph+ ALL) cases and immunotherapeutic approaches, including blinatumomab and chimeric antigen receptor T cells. Targeting aberrant cell survival pathways with selective small molecule BH3-mimetic inhibitors of BCL-2 (venetoclax, S55746), BCL-XL (A1331852), or MCL1 (S63845) is an emerging therapeutic option. We report that combined targeting of BCL-2 and MCL1 is synergistic in B-ALL in vitro. The combination demonstrated greater efficacy than standard chemotherapeutics and TKIs in primary samples from adult B-ALL with Ph+ ALL, Ph-like ALL, and other B-ALL. Moreover, combined BCL-2 or MCL1 inhibition with dasatinib showed potent killing in primary Ph+ B-ALL cases, but the BH3-mimetic combination appeared superior in vitro in a variety of Ph-like ALL samples. In PDX models, combined BCL-2 and MCL1 targeting eradicated ALL from Ph- and Ph+ B-ALL cases, although fatal tumor lysis was observed in some instances of high tumor burden. We conclude that a dual BH3-mimetic approach is highly effective in diverse models of high-risk human B-ALL and warrants assessment in clinical trials that incorporate tumor lysis precautions.

Novel targets are required to improve the outcomes for patients with colorectal cancers. In this regard, the selective inhibitor of the pro-survival protein BCL2, venetoclax, has proven highly effective in several hematological malignancies. In addition to BCL2, potent and highly selective small molecule inhibitors of its relatives, BCLxL and MCL1, are now available, prompting us to investigate the susceptibility of colorectal cancers to the inhibition of one or more of these pro-survival proteins. While targeting BCLxL, but not BCL2 or MCL1, on its own had some impact, most (15/17) of the immortalized colorectal cancer cell lines studied were efficiently killed by the combined targeting of BCLxL and MCL1. Importantly, these in vitro findings were confirmed in a xenograft model and, interestingly, in all (5/5) patient derived tumor organoids evaluated. Our results lend strong support to the notion that BCLxL and MCL1 are highly promising targets for further evaluation in efforts to improve the treatment of colorectal cancers.

Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 antagonist has revealed emergence of a drug-selected BCL-2 mutation (G101V) in some patients failing therapy. To understand the molecular basis of this acquired resistance we describe the crystal structures of venetoclax bound to both BCL-2 and the G101V mutant. The pose of venetoclax in its binding site on BCL-2 reveals small but unexpected differences as compared to published structures of complexes with venetoclax analogues. The G101V mutant complex structure and mutant binding assays reveal that resistance is acquired by a knock-on effect of V101 on an adjacent residue, E152, with venetoclax binding restored by a E152A mutation. This provides a framework for considering analogues of venetoclax that might be effective in combating this mutation.

[6], 73, [1] p., Imperfect: copy at 1800:6 stained, and torn, with loss of text; t.p. and preface bound at end., No copy of a first edition is known. Cf. Evans., Reproductions of the originals in the Henry E. Huntington Library and Art Gallery (1800:6) and Boston Public Library (2915:8a)., Item at reel 2915:8a with: The possibility of Gods forsaking a people ... / By Mr. Joseph Rowlandson. Boston in New-England : Printed for John Ratcliffe, & John Griffin., 1682., (DLPS) B09906.0001.001, (vid) 192319, http://quod.lib.umich.edu/t/text/accesspolicy.html

80 p. ; 15 cm. (8vo), (DLPS) N01835.0001.001, (tcp) N01835, http://quod.lib.umich.edu/t/text/accesspolicy.html, To the extent possible under law, the Text Creation Partnership has waived all copyright and related or neighboring rights to this keyboarded and encoded edition of the work described above, according to the terms of the CC0 1.0 Public Domain Dedication (http://creativecommons.org/publicdomain/zero/1.0/). This waiver does not extend to any page images or other supplementary files associated with this work, which may be protected by copyright or other license restrictions. Please go to http://www.textcreationpartnership.org/ for more information.

[6], 73, [1] p. ; 15 cm. (8vo), Edition statement transposed; precedes "Written by her own hand ..." on title page., The first impression. A second impression corrects "addition" to "edition"; in the second impression the first half of the book has been reset. Cf. Vail, R.W.G. The voice of the old frontier, p. 168., Issued both separately and with Rolandson, Joseph. The possibility of Gods forsaking a people ... (Cambridge, 1682; Bristol B60, Shipton & Mooney 39221)., Signatures: A-E^8 (E8 verso blank)., Two states noted. In the first, p. 64-65 are misnumbered 54-55. In the second, they are correctly numbered., (DLPS) N00261.0001.001, (tcp) N00261, http://quod.lib.umich.edu/t/text/accesspolicy.html, To the extent possible under law, the Text Creation Partnership has waived all copyright and related or neighboring rights to this keyboarded and encoded edition of the work described above, according to the terms of the CC0 1.0 Public Domain Dedication (http://creativecommons.org/publicdomain/zero/1.0/). This waiver does not extend to any page images or other supplementary files associated with this work, which may be protected by copyright or other license restrictions. Please go to http://www.textcreationpartnership.org/ for more information.

[6], 73, [1] p., Imperfect: copy at 1800:6 stained, and torn, with loss of text; t.p. and preface bound at end., No copy of a first edition is known. Cf. Evans., Reproductions of the originals in the Henry E. Huntington Library and Art Gallery (1800:6) and Boston Public Library (2915:8a)., Item at reel 2915:8a with: The possibility of Gods forsaking a people ... / By Mr. Joseph Rowlandson. Boston in New-England : Printed for John Ratcliffe, & John Griffin., 1682., (DLPS) B09906.0001.001, (vid) 192319, http://quod.lib.umich.edu/t/text/accesspolicy.html