Improving Antibody-Tubulysin Conjugates through Linker Chemistry and Site-Specific Conjugation

Tubulysins have emerged in recent years as a compelling drug class for delivery to tumor cells via antibodies. The ability of this drug class to exert bystander activity while retaining potency against multidrug-resistant cell lines differentiates them from other microtubule-disrupting agents. Tubulysin M, a synthetic analogue, has proven to be active and well tolerated as an antibody-drug conjugate (ADC) payload, but has the liability of being susceptible to acetate hydrolysis at the C11 position, leading to attenuated potency. In this work, we examine the ability of the drug-linker and conjugation site to preserve acetate stability. Our findings show that, in contrast to a more conventional protease-cleavable dipeptide linker, the β-glucuronidase-cleavable glucuronide linker protects against acetate hydrolysis and improves ADC activity in vivo. In addition, site-specific conjugation can positively impact both acetate stability and in vivo activity. Together, these findings provide the basis for a highly optimized delivery strategy for tubulysin M.     

Adolescents' participation in organized activities and developmental success 2 and 8 years after high school: Do sponsorship, duration, and intensity matter?

Using data from the National Education Longitudinal Study, the authors examined relations between educational, civic, and occupational success in young adulthood and the duration and intensity of participation in organized activities during high school. They also examined these relations as a function of sponsorship (i.e., school- vs. community-sponsored organized activities). They found that youths who participated in organized activities for 2 years demonstrated more favorable educational and civic outcomes in young adulthood than those who participated for 1 year. More intensive participation was also associated with greater educational, civic, and occupational success in young adulthood--particularly among youths who participated in activities for 2 years. Educational attainment often mediated the relations between temporal measures of participation and young adult civic and occupational outcomes. With the exception of analyses examining occupational success, findings varied little as a function of sponsorship. Of note, analyses revealed that both temporal measures of participation were positively associated with young adult outcomes as many as 8 years after high school. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A unified sample preparation protocol for proteomic and genomic profiling of cervical swabs to identify biomarkers for cervical cancer screening

Cervical cancer screening is ideally suited for the development of biomarkers due to the ease of tissue acquisition and the well-established histological transitions. Furthermore, cell and biologic fluid obtained from cervix samples undergo specific molecular changes that can be profiled. However, the ideal manner and techniques for preparing cervical samples remains to be determined. To address this critical issue a patient screening protein and nucleic acid collection protocol was established. RNAlater was used to collect the samples followed by proteomic methods to identify proteins that were differentially expressed in normal cervical epithelial versus cervical cancer cells. Three hundred ninety spots were identified via 2-D DIGE that were expressed at either higher or lower levels (>three-fold) in cervical cancer samples. These proteomic results were compared to genes in a cDNA microarray analysis of microdissected neoplastic cervical specimens to identify overlapping patterns of expression. The most frequent pathways represented by the combined dataset were: cell cycle: G2/M DNA damage checkpoint regulation; aryl hydrocarbon receptor signaling; p53 signaling; cell cycle: G1/S checkpoint regulation; and the ER stress pathway. HNRPA2B1 was identified as a biomarker candidate with increased expression in cancer compared to normal cervix and validated by Western blot.     

Letter from Approximately Milton Keynes

The literature on local government reform has seen a vociferous and ongoing debate surrounding the merits of compulsory structural change through local council consolidation. A central theme in the local government amalgamation debate centres on potential trade-offs between the economic efficiency of local government and the vibrancy of local democracy. This review develops a simple conceptual schema for deconstructing and differentiating between alternative views on the relationship between local democracy and local efficiency. It is argued that three different views can be identified in the scholarly literature, together with an as yet unarticulated fourth view.     

Ground Control to Tony Blair …!

Emphasis on the creative class as promoters of economic prosperity is based on two main claims: first, people working in occupations dependent on the exercise of creativity (the ‘creative class’) make a disproportionate contribution to wealth generation; second, creative class professionals are highly mobile and have a preference for localities that are tolerant of social diversity and rich in creative resources. In essence, bohemia is good for business as creative class professionals are stimulated by and supporters of the creative arts. These propositions have encouraged cities and regions around the industrial world to assess their attractiveness to the creative class and to invest in amenities appealing to creative workers. A core challenge for the creative class thesis is to demonstrate that the openness and tolerance of communities is the causal agent of enhanced business performance. Pending confirmation of actual interaction between, on the one hand, creative people and activities, and on the other hand with entrepreneurship and business growth, this review identifies three areas where the creative class thesis has application to urban policy: art sector support based on industry-specific policies; the attraction of migrant professionals, including return migrants; application of the interest in diversity and tolerance to reduce racial segregation.     

Peer Influence on Risk Taking, Risk Preference, and Risky Decision Making in Adolescence and Adulthood: An Experimental Study.

In this study, 306 individuals in 3 age groups--adolescents (13-16), youths (18-22), and adults (24 and older)--completed 2 questionnaire measures assessing risk preference and risky decision making, and 1 behavioral task measuring risk taking. Participants in each age group were randomly assigned to complete the measures either alone or with 2 same-aged peers. Analyses indicated that (a) risk taking and risky decision making decreased with age; (b) participants took more risks, focused more on the benefits than the costs of risky behavior, and made riskier decisions when in peer groups than alone; and (c) peer effects on risk taking and risky decision making were stronger among adolescents and youths than adults. These findings support the idea that adolescents are more inclined toward risky behavior and risky decision making than are adults and that peer influence plays an important role in explaining risky behavior during adolescence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

1909 and all that: reflections on the Housing,Town Planning,Etc. Act 1909

As the pioneering legislation for town planning in Britain, the Housing, Town Planning Etc. Act 1909 has been the subject of analysis and discussion over the past half century. However, many commentators have argued that the Act was a timid measure that failed to achieve its intentions. The purpose of this study is to question that argument by re-examining both the Act and the commentaries on it. It does so by charting the historiography of the Act and then returning to the debates in Parliament and within the profession at the time the legislation was introduced and finally given Royal assent. It concludes that to regard the Act as a failure is to misunderstand its purpose as primarily concerned with the house and its surroundings, to which the broader question of land-use planning was effectively seen as an adjunct.     

Not quite right.

Comments on the L. B. Silverstein and C. F. Auerbach (see record 1999-05337-001) examination of the essentialist perspective on fathering, family structure, and child development. It is stated that Silverstein and Auerbach misrepresented what is known about rates of child abuse at the hands of stepparents vs genetic parents. (PsycINFO Database Record (c) 2010 APA, all rights reserved)