Synthesis and Biological Evaluation of a Carbamate-Containing Tubulysin Antibody-Drug Conjugate.

Antibody-drug conjugates (ADCs) use antibodies to deliver cytotoxic payloads directly into tumor cells via specifically binding to the target cell surface antigens. ADCs can enhance the anti-tumor effects of antibodies, and increase the delivery of cytotoxic payloads to cancer cells with a better therapeutic index. An ADC was prepared with a potent carbamate-containing tubulysin analogue attached to an anti-mesothelin antibody via a Cit-Val dipeptide linker. An aniline functionality in the tubulysin analogue was created to provide a site of linker attachment via an amide bond that would be stable in systemic circulation. Upon ADC internalization into antigen-positive cancer cells, the Cit-Val dipeptide linker was cleaved by lysosomal proteases, and the drug was released inside the tumor cells. The naturally occurring acetate of tubulysin was modified to a carbamate to reduce acetate hydrolysis of the ADC in circulation and to increase the hydrophilicity of the drug. The ADC bearing the monoclonal anti-mesothelin antibody and the carbamate-containing tubulysin was highly potent and immunologically specific to H226 human lung carcinoma cells in vitro, and efficacious at well-tolerated doses in a mesothelin-positive OVCAR3 ovarian cancer xenograft mouse model.

Where Have All the Children Gone?

Despite declining infant-mortality rates and a cottage industry of publications devoted to improving parenting/childcare, birthrates in the U.S. and Western Europe continue to fall. But the present inquiry is directed less to the disappearance of actual children than to that more fragile and contested state of childhood. Changes in the spaces reserved for childhood might be compared to the erosion of Arctic ice due to climate change. In both, human factors play a contentious role. The examples cited below will show how children are susceptible not just to parental influences but also to other adults in the community and especially now to unprecedented cultural changes. How these transformations impact the evolution of parenting modes laid out by Lloyd deMause will be assessed in due course.

Political Leaders and Psychohistorical Approaches in a Time of Borderline Polarization.

Since the breakup of the Soviet Empire in 1989, followed by Yugoslavia, many otherwise secure countries have been collapsing and splitting apart. The maps in the Middle East are continually being redrawn, more often than not, in blood. Scotland is poised to break away from the UK, Catalonia from Spain, and here at home several states toy around with secession. Much of this turmoil on the macro level seems to dovetail with my present focus on the micro. Whether the two are related in some fashion is tantalizingly beyond the present scope. In this paper my micro-purpose is to delve into the deeper recesses of our public life and explore the intra-psychic fissures. The key concept for this quest is a relative newcomer to psychoanalytic nomenclature: the borderline. Coming to the fore in the 1970s, the term addresses the widespread splitting both within the self and in relationships, manifest in either-or, all-or-nothing ideation, along with an impulsivity that further distances actions from consequences. These and related features-are conducive to an anything-goes politics of us-against-them. Richard Hofstadter's 1965 "paranoid style," of political leaders is recalled and modified to a borderline-mode factored into a psychohistorical dynamic which construes politicians as delegates for group-fantasy. Recent presidential elections offer a rich field for testing the aptness of this approach. Then, after brief detours into how Freud and Darwin disrupted polarizing forces in their own cultures, we revisit political turmoil during the Woodrow Wilson years for historical similarities and differences in which repeated recourse to purity serves as a bridge word. The inquiry closes with reflections on how psychohistory may avoid pitfalls in further probing this vexing state of affairs and primes the reader to ponder whether the disaffected young males drawn to ISIS are functioning on borderline levels. If so, we have a plausible bridge between macro and micro realms.