A novel anti-B7-H3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers

B7-H3 (CD276) has emerged as a target for cancer immunotherapy by virtue of consistent expression in many malignancies, relative absence from healthy tissues, and an emerging role as a driver of tumor immune inhibition. Recent studies have reported B7-H3 to be a suitable target for chimeric antigen receptor-modified T cell (CAR-T) therapy using CARs constructed from established anti-B7-H3 antibodies converted into single-chain Fv format (scFv). We constructed and screened binders in an scFv library to generate a new anti-B7-H3 CAR-T with favorable properties. This allowed access to numerous specificities ready formatted for CAR evaluation. Selected anti-human B7-H3 scFvs were readily cloned into CAR-T and evaluated for anti-tumor reactivity in cytotoxicity, cytokine, and proliferation assays. Two binders with divergent complementarity determining regions were found to show optimal antigen-specific cytotoxicity and cytokine secretion. One binder in second-generation CD28-CD3ζ CAR format induced sustained in vitro proliferation on repeat antigen challenge. The lead candidate CAR-T also demonstrated in vivo activity in a resistant neuroblastoma model. An empirical approach to B7-H3 CAR-T discovery through screening of novel scFv sequences in CAR-T format has led to the identification of a new construct with sustained proliferative capacity warranting further evaluation

The Performance of Private Equity Funds: Does Diversification Matter?

This paper is the first systematic analysis of the impact of diversification on the performance of private equity funds. A unique data set allows the exact evaluation of diversification across the dimensions financing stages, industries, and countries. Very different levels of diversification can be observed across sample funds. While some funds are highly specialized others are highly diversified. The empirical results show that the rate of return of private equity funds declines with diversification across financing stages, but increases with diversification across industries. Accordingly, the fraction of portfolio companies which have a negative return or return nothing at all, increase with diversification across financing stages. Diversification across countries has no systematic effect on the performance of private equity funds

Constructing female entrepreneurship policy in the UK : is the US a relevant benchmark?

Successive UK governments have introduced a range of policy initiatives designed to encourage more women to start new firms. Underpinning these policies has been an explicit ambition for the UK to achieve similar participation rates as those in the US where it is widely reported that women own nearly half the stock of businesses. The data underlying these objectives are critically evaluated and it is argued that the definitions and measures of female enterprise used in the UK and the US restrict meaningful comparisons between the two. It is suggested that the expansion of female entrepreneurship in the US is historically and culturally specific to that country. UK policy goals should reflect the national socioeconomic context, while drawing upon good practice examples from a range of other countries. The paper concludes by discussing the economic and social viability of encouraging more women in the UK to enter self-employment without fully recognising the intensely competitive sectors in which they are often located

A terminal assessment of stages theory : introducing a dynamic states approach to entrepreneurship

Stages of Growth models were the most frequent theoretical approach to understanding entrepreneurial business growth from 1962 to 2006; they built on the growth imperative and developmental models of that time. An analysis of the universe of such models (N=104) published in the management literature shows no consensus on basic constructs of the approach, nor is there any empirical confirmations of stages theory. However, by changing two propositions of the stages models, a new dynamic states approach is derived. The dynamic states approach has far greater explanatory power than its precursor, and is compatible with leading edge research in entrepreneurship

Life After Succession in the Family Business: Is It Really the End of Problems?

The succession processes in family business are well chronicled in the business literature. Most of the research focuses on the process of transferring power within the business-family. What has not been as closely examined is the after-succession environment that exists when the management and leadership of the family business are passed on to the next generation. This article addresses that organizational climate and the potential for additional problems in the business-family if post-succession issues are not identified and addressed and suggests some steps that will be helpful in producing complete succession success.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

"Aye, but it were wasted on thee": Cricket, British Asians, ethnic identities, and the 'magical recovery of community'

People in sport tend to possess rather jaded perceptions of its colour-blindness and thus, they are reluctant to confront the fact that, quite often racism is endemic. Yorkshire cricket in particular, has faced frequent accusations from minority ethnic communities of inveterate and institutionalised racism and territorial defensiveness. Drawing upon semi-structured interviews conducted with amateur white and British Asian cricketers, this paper examines the construction of regional identities in Yorkshire at a time when traditional myths and invented traditions of Yorkshire and 'Yorkshireness' are being deconstructed. This is conceptualised through a reading of John Clarke's 'magical recovery of community'. Although cricket has been multiracial for decades, I argue that some people's position as insiders is more straightforward than others. I present evidence to suggest that, regardless of being committed to Yorkshire and their 'Yorkshireness', white Yorkshire people may never fully accept British Asians as 'one of us'. Ideologically and practically, white Yorkshire people are engaged in constructing British Asians as anathema to Yorkshire culture. The paper concludes by advocating that, for sports cultures to be truly egalitarian, the ideology of sport itself has to change. True equality will only ever be achieved within a deracialised discourse that not only accepts difference, but embraces it

The Impact of Timing and Mode of Entry on Successor Development and Successful Succession

Family businesses frequently are disrupted by the process of succession of leadership and ownership. This article focuses on causes of conflict and how to manage success after siblings have entered the business.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Environmental Determinants of Infectious Disease: A Framework for Tracking Causal Links and Guiding Public Health Research

BACKGROUND: Discoveries that emerging and re-emerging pathogens have their origin in environmental change has created an urgent need to understand how these environmental changes impact disease burden. In this article we present a framework that provides a context from which to examine the relationship between environmental changes and disease transmission and a structure from which to unite disparate pieces of information from a variety of disciplines. METHODS: The framework integrates three interrelated characteristics of environment–disease relationships: a) Environmental change manifests in a complex web of ecologic and social factors that may ultimately impact disease; these factors are represented as those more distally related and those more proximally related to disease. b) Transmission dynamics of infectious pathogens mediate the effects that environmental changes have on disease. c) Disease burden is the outcome of the interplay between environmental change and the transmission cycle of a pathogen. RESULTS: To put this framework into operation, we present a matrix formulation as a means to define important elements of this system and to summarize what is known and unknown about the these elements and their relationships. The framework explicitly expresses the problem at a systems level that goes beyond the traditional risk factor analysis used in public health, and the matrix provide

Role of Personal Networks in the Growth of Entrepreneurship Ventures of Ethnic Minority Female Entrepreneurs

The main objective of the paper is to explore and explain the differences/similarities in personal networks of, and their use by, immigrant and British born Pakistani female entrepreneurs for business growth.A broad range of studies has explored the social context of ethnic minority and immigrant entrepreneurship by assuming all minority entrepreneurs as a cohesive group without taking into account intergroup (geographical categorisation) and intra-group (generational) differences. These differences are explained by socio-economic and cultural factors such as family background and support, ethnicity, religion, education, and more importantly personal network (Metcalf et. al., 1996; Basu, 1998). The blend of culture and religion depicted in entrepreneurial practices of Pakistani entrepreneurs is an interesting but under-researched area. Our particular interest is to explore the scope, depth, variations and limitations of the personal networks of Pakistani female entrepreneurs in their effort to grow their business