Modelling the evolution of distributions : an application to major league baseball

We develop Bayesian techniques for modelling the evolution of entire distributions over time and apply them to the distribution of team performance in Major League baseball for the period 1901-2000. Such models offer insight into many key issues (e.g. competitive balance) in a way that regression-based models cannot. The models involve discretizing the distribution and then modelling the evolution of the bins over time through transition probability matrices. We allow for these matrices to vary over time and across teams. We find that, with one exception, the transition probability matrices (and, hence, competitive balance) have been remarkably constant across time and over teams. The one exception is the Yankees, who have outperformed all other teams

On the Dialectics of Global Governance in the Twenty-first Century : A Polanyian Double Movement?

Following decades of economic globalisation and market-oriented reforms across the world, Karl Polanyi’s double movement has been invoked not only to explain what is happening but also to give reasons for being hopeful about a different future. Some have suggested a pendulum model of history: a swing from markets to society leading, in the next phase, to a swing from society to markets, and so on. The double movement can also be understood dialectically as a description of an irreversible historical development following its own inner laws or schemes of development. Going beyond a thesis – antithesis – synthesis pattern, I maintain that conceptions and schemes drawn from dialectics, and especially dialectical critical realism, can provide better geo-historical hypotheses for explaining past changes and for building scenarios about possible future changes. I analyse political economy contradictions and tendencies, and focus on normative rationality, to assess substantial claims about rational tendential directionality of world history. I argue that democratic global Keynesianism would enable processes of decommodification and new syntheses concerning the market/social nexus. A learning process towards qualitatively higher levels of reflexivity can help develop global transformative agency. Existing contradictions can be resolved by means of rational collective actions and building more adequate common institutions. These collective actions are likely to involve new forms of political agency such as world political parties.Peer reviewe

The ASCIZ-DYNLL1 axis promotes 53BP1-dependent non-homologous end joining and PARP inhibitor sensitivity

53BP1 controls a specialized non-homologous end joining (NHEJ) pathway that is essential for adaptive immunity, yet oncogenic in BRCA1 mutant cancers. Intra-chromosomal DNA double-strand break (DSB) joining events during immunoglobulin class switch recombination (CSR) require 53BP1. However, in BRCA1 mutant cells, 53BP1 blocks homologous recombination (HR) and promotes toxic NHEJ, resulting in genomic instability. Here, we identify the protein dimerization hub—DYNLL1—as an organizer of multimeric 53BP1 complexes. DYNLL1 binding stimulates 53BP1 oligomerization, and promotes 53BP1’s recruitment to, and interaction with, DSB-associated chromatin. Consequently, DYNLL1 regulates 53BP1-dependent NHEJ: CSR is compromised upon deletion of Dynll1 or its transcriptional regulator Asciz, or by mutation of DYNLL1 binding motifs in 53BP1; furthermore, Brca1 mutant cells and tumours are rendered resistant to poly-ADP ribose polymerase (PARP) inhibitor treatments upon deletion of Dynll1 or Asciz. Thus, our results reveal a mechanism that regulates 53BP1-dependent NHEJ and the therapeutic response of BRCA1-deficient cancers

Preclinical mouse models for BRCA1-associated breast cancer

A substantial part of all hereditary breast cancer cases is caused by BRCA1 germline mutations. In this review, we will discuss the insights into BRCA1 functions that we obtained from mouse models with conventional and conditional mutations in Brca1. The most advanced models closely resemble human BRCA1-related breast cancer and may therefore be useful for addressing clinically relevant questions

Tumour microenvironment characterisation to stratify patients for hyperthermic intraperitoneal chemotherapy in high-grade serous ovarian cancer (OVHIPEC-1).

BACKGROUND Hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival in patients with Stage III ovarian cancer following interval cytoreductive surgery (CRS). Optimising patient selection is essential to maximise treatment efficacy and avoid overtreatment. This study aimed to identify biomarkers that predict HIPEC benefit by analysing gene signatures and cellular composition of tumours from participants in the OVHIPEC-1 trial. METHODS Whole-transcriptome RNA sequencing data were retrieved from high-grade serous ovarian cancer (HGSOC) samples from 147 patients obtained during interval CRS. We performed differential gene expression analysis and applied deconvolution methods to estimate cell-type proportions in bulk mRNA data, validated by histological assessment. We tested the interaction between treatment and potential predictors on progression-free survival using Cox proportional hazards models. RESULTS While differential gene expression analysis did not yield any predictive biomarkers, the cellular composition, as characterised by deconvolution, indicated that the absence of macrophages and the presence of B cells in the tumour microenvironment are potential predictors of HIPEC benefit. The histological assessment confirmed the predictive value of macrophage absence. CONCLUSION Immune cell composition, in particular macrophages absence, may predict response to HIPEC in HGSOC and these hypothesis-generating findings warrant further investigation. CLINICAL TRIAL REGISTRATION NCT00426257

The Inclusive Leader, The Smart Strategist and The Forced Altruist: Subject Positions for Men as Gender Equality Partner

This article explores how men are conceptualised as partners in gender equality processes in organisations against the backdrop of a postfeminist sensibility. Drawing on interviews that formed part of organisational ethnographies, the article highlights three subject positions that men are encouraged to adopt: the inclusive leader, the smart strategist, and the forced altruist. All three subject positions entail the construction of men as disadvantaged through a focus on women. While theorists of postfeminism have shown how women are made responsible for their own success and failure with structural gender inequalities being disavowed, the opposite logic seems to operate for men; if men do not succeed, it is due to unequal gender structures that favour women. Alternative subject positions could focus on making men’s privilege visible or on that men who support gender equality might accelerate their careers. The article also shows that gender equality is still seen as a women’s issue rather than an issue that concerns both women and men