Prolonged and tunable residence time using reversible covalent kinase inhibitors.

Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo

British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice

BACKGROUND: Testosterone deficiency (TD) is an increasingly common problem with significant health implications, but its diagnosis and management can be challenging. AIM: To review the available literature on TD and provide evidence-based statements for UK clinical practice. METHODS: Evidence was derived from Medline, EMBASE, and Cochrane searches on hypogonadism, testosterone (T) therapy, and cardiovascular safety from May 2005 to May 2015. Further searches continued until May 2017. OUTCOMES: To provide a guideline on diagnosing and managing TD, with levels of evidence and grades of recommendation, based on a critical review of the literature and consensus of the British Society of Sexual Medicine panel. RESULTS: 25 statements are provided, relating to 5 key areas: screening, diagnosis, initiating T therapy, benefits and risks of T therapy, and follow-up. 7 statements are supported by level 1, 8 by level 2, 5 by level 3, and 5 by level 4 evidence. CLINICAL IMPLICATIONS: To help guide UK practitioners on effectively diagnosing and managing primary and age-related TD. STRENGTHS AND LIMITATIONS: A large amount of literature was carefully sourced and reviewed, presenting the best evidence available at the time. However, some statements provided are based on poor-quality evidence. This is a rapidly evolving area of research and recommendations are subject to change. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions and take personal values and preferences and individual circumstances into account. Many issues remain controversial, but in the meantime, clinicians need to manage patient needs and clinical expectations armed with the best clinical evidence and the multidisciplinary expert opinion available. CONCLUSION: Improving the diagnosis and management of TD in adult men should provide somatic, sexual, and psychological benefits and subsequent improvements in quality of life. Hackett G, Kirby M, Edwards D, et al. British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice. J Sex Med 2017;14:1504-1523

Inferring causal molecular networks: empirical assessment through a community-based effort

It remains unclear whether causal, rather than merely correlational, relationships in molecular networks can be inferred in complex biological settings. Here we describe the HPN-DREAM network inference challenge, which focused on learning causal influences in signaling networks. We used phosphoprotein data from cancer cell lines as well as in silico data from a nonlinear dynamical model. Using the phosphoprotein data, we scored more than 2,000 networks submitted by challenge participants. The networks spanned 32 biological contexts and were scored in terms of causal validity with respect to unseen interventional data. A number of approaches were effective, and incorporating known biology was generally advantageous. Additional sub-challenges considered time-course prediction and visualization. Our results suggest that learning causal relationships may be feasible in complex settings such as disease states. Furthermore, our scoring approach provides a practical way to empirically assess inferred molecular networks in a causal sense

Inferring causal molecular networks: empirical assessment through a community-based effort

Inferring molecular networks is a central challenge in computational biology. However, it has remained unclear whether causal, rather than merely correlational, relationships can be effectively inferred in complex biological settings. Here we describe the HPN-DREAM network inference challenge that focused on learning causal influences in signaling networks. We used phosphoprotein data from cancer cell lines as well as in silico data from a nonlinear dynamical model. Using the phosphoprotein data, we scored more than 2,000 networks submitted by challenge participants. The networks spanned 32 biological contexts and were scored in terms of causal validity with respect to unseen interventional data. A number of approaches were effective and incorporating known biology was generally advantageous. Additional sub-challenges considered time-course prediction and visualization. Our results constitute the most comprehensive assessment of causal network inference in a mammalian setting carried out to date and suggest that learning causal relationships may be feasible in complex settings such as disease states. Furthermore, our scoring approach provides a practical way to empirically assess the causal validity of inferred molecular networks

Trends in the Market for Entrepreneurship Faculty, 1989-1998

The last decade has seen a dramatic rise in the number and status of entrepreneurship programs in schools of business and management. The popularity of entrepreneurship courses has increased dramatically among both graduate and undergraduate students. Alumni and external constituencies of schools of business have generally been supportive of the development of entrepreneurship programs, and in fact in many instances it has been the demands of these constituencies that have led to the creation or expansion of entrepreneurship programs within these schools. The growth in entrepreneurship programs has been fostered by an increase in the popularity of entrepreneurship, an increase in the status accorded entrepreneurs, as well as an increase in the recognition by the business press of the importance of entrepreneurship in the larger economy. Despite the increase in popularity within the field, there has also been considerable resistance from within the faculties of many institutions to the expansion of entrepreneurship programs. Faculty outside the field have been, and many remain, very skeptical about the validity of entrepreneurship as an academic field, the quality and rigor of entrepreneurship research and the need to hire academic faculty to teach and research in the field. The last decade has seen the confluence of these opposing forces. This disparity has created the question of whether the external forces supporting entrepreneurship are overcoming the inertia inherent in academic institutions and succeeding in institutionalizing the study of entrepreneurship within schools of business and management. This study hopes to shed some light on which of these forces is winning by addressing the question of whether the field of entrepreneurship is moving toward or has been institutionalized as part of the curriculum and research within schools of business and management. It also examines the institutionalization of the field by analyzing the change in the number and level of entrepreneurship positions, the quality of the recruiting institutions as well as the number, level and training of entrepreneurship candidates during the years 1989–1998. Data was obtained from the Academy of Management Placement Roster and The Chronicle of Higher Education for the years 1989–1998. Previous entrepreneurship education researchers have examined the number of endowed chairs and professorships, conferences, journals, programs and various centers for entrepreneurial education, however sparse research, if any, has been performed on the trends and characteristics of candidates and positions in the field of entrepreneurship. The results of this study are very encouraging. Both the demand for and the supply of entrepreneurship faculty have increased spectacularly during the last nine years. Between 1989/90 and 1997/98 the number of entrepreneurship positions increased 253% while the number of candidates increased by 94%. During this period the number of positions that list entrepreneurship as the primary field has increased ten-fold from 5 to 50 and the number of candidates that list entrepreneurship as their primary field has increased four-fold from 5 to 20. During the same period the number of secondary and tertiary positions have increased 116% and 78%, respectively, and the number of secondary and tertiary candidates have increased by 67% and 53%. The percentage of entrepreneurship positions listing entrepreneurship as the primary field has increased from 19% in 89/90 to 54% in 1997/98. Overall, the growth in the number of primary entrepreneurship positions is very encouraging. In the end, the results of this study are very encouraging. Both the demand and the supply of entrepreneurship faculty have increased spectacularly during the last nine years. The field has clearly made significant progress toward being institutionalized. However, it is still too soon to conclude that the commitment to entrepreneurship by schools of business and management is irreversible. One clear indication of the tenuous status is that, unlike strategy and international business, there has been no mandate from the American Assembly of Collegiate Schools of Business that entrepreneurship be incorporated into the curriculum of all accredited schools. Entrepreneurship remains an elective subject in most schools and therefore depends on student interest. The field has made great strides during the 1990s, but a couple of hurdles remain