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This paper is principally concerned with reappraising some of the major disagreements that separated the Viennese and the London Kleinians during the British Psychoanalytical Society's Controversial Discussions. Of particular focus are questions pertaining to the genesis of ego development, the beginnings of object-relating, and the role of unconscious phantasy in respect of these phenomena. The aim of the investigation is to inquire into the light that may be shed on the once intractable conflicts surrounding these questions by bringing to bear more recent developments from psychoanalysis and the neurosciences. First, various key issues from the Controversial Discussions are outlined, before the paper turns to work by Jaak Panksepp and Mark Solms that bears on these older arguments and the Freudian theories that underpinned them. With these conceptual foundations established, three questions are posed and discussed with a view to understanding the implications of recent neuropsychoanalytic thinking for some of the entrenched conflicts that divided the British Society. These questions include: (1) what does it mean for the ego if the id is conscious? (2) What does recent neuroscientific knowledge tell us about whether the ego should be thought of as present from birth? (3) How can we understand and locate unconscious phantasy if the main part of the mind that Freud thought of as unconscious is not so? Research from the arena of infant development-particularly the material and analysis of infant observation-is drawn on to illustrate various conclusions. The paper ultimately concludes that taking such an interdisciplinary approach can reveal renewed justification for aspects of the Kleinian metapsychology., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mellor.)

With the publication of Wilfred Bion's text 'Learning from Experience,' psychoanalysis was afforded a new schema for understanding the processes and implications involved in an infant's contact with their caregivers. As a result, our conception of some of the most fundamental phenomena of psychic life was significantly enriched. By proposing his theory of alpha-functioning, Bion mapped out how meaningful connexions to the internal and external worlds become established in the mind. In contrast, and through working clinically with psychotic patients, Bion revealed how these ties can catastrophically come undone. It is with these ideas, as well as their links to a corresponding set of neuroscientific constructs relating to the Markov blanket and principally developed by Karl Friston, that this paper is concerned. Through an investigation of the psychic functioning originally dubbed 'dream-work-alpha,' the paper's first section focuses on how Bion conceived of the creation of a 'contact-barrier' that allows for the differentiation of consciousness from an unconscious mind. Casting the ramifications of this organisation in sharp relief, the psychotic disorganisation of the contact-barrier is then explored. The discussion subsequently broadens to incorporate contemporary theories from free energy neuroscience that bear significant and illuminating relations to the psychoanalytic ideas espoused by Bion over half a century ago. Finally, through posing a series of three questions with accompanying discussions, a superimposition of these theoretical schemas is attempted. These suggestions directly address, (1) whether there is an intimate connexion between the interoceptive contact-barrier and the exteroceptive Markov blanket, (2) whether a disobjectalising of the contact-barrier may be reflected as a tear in the functional fabric of the Markov blanket, and (3) what the clinical implications are of working at the level of the projected surface. Ultimately, the aim of the paper is to expose relevant points of contact within and between the varying conceptual frameworks; frameworks that ultimately derive from disciplines that are both concerned with examining the underlying mechanisms of the mind-brain.

Osimertinib (AZD9291) is a potent, selective, irreversible inhibitor of EGFR-sensitizing (exon 19 and L858R) and T790M-resistant mutation. In vivo, in the mouse, it is metabolized to an active des-methyl metabolite, AZ5104. To understand the therapeutic potential in patients, this study aimed to assess the relationship between osimertinib pharmacokinetics, the pharmacokinetics of the active metabolite, the pharmacodynamics of phosphorylated EGFR reduction, and efficacy in mouse xenograft models of EGFR-driven cancers, including two NSCLC lines. Osimertinib was dosed in xenografted models of EGFR-driven cancers. In one set of experiments, changes in phosphorylated EGFR were measured to confirm target engagement. In a second set of efficacy studies, the resulting changes in tumor volume over time after repeat dosing of osimertinib were observed. To account for the contributions of both molecules, a mathematical modeling approach was taken to integrate the resulting datasets. The model was able to describe the pharmacokinetics, pharmacodynamics, and efficacy in A431, PC9, and NCI-H1975 xenografts, with the differences in sensitivity described by the varying potency against wild-type, sensitizing, and T790M-mutant EGFR and the phosphorylated EGFR reduction required to reduce tumor volume. It was inferred that recovery of pEGFR is slower after chronic dosing due to reduced resynthesis. It was predicted and further demonstrated that although inhibition is irreversible, the resynthesis of EGFR is such that infrequent intermittent dosing is not as efficacious as once daily dosing. Mol Cancer Ther; 15(10); 2378-87. ©2016 AACR., (©2016 American Association for Cancer Research.)

The fibroblast growth factor (FGF) signaling axis is increasingly implicated in tumorigenesis and chemoresistance. Several small-molecule FGF receptor (FGFR) kinase inhibitors are currently in clinical development; however, the predominant activity of the most advanced of these agents is against the kinase insert domain receptor (KDR), which compromises the FGFR selectivity. Here, we report the pharmacologic profile of AZD4547, a novel and selective inhibitor of the FGFR1, 2, and 3 tyrosine kinases. AZD4547 inhibited recombinant FGFR kinase activity in vitro and suppressed FGFR signaling and growth in tumor cell lines with deregulated FGFR expression. In a representative FGFR-driven human tumor xenograft model, oral administration of AZD4547 was well tolerated and resulted in potent dose-dependent antitumor activity, consistent with plasma exposure and pharmacodynamic modulation of tumor FGFR. Importantly, at efficacious doses, no evidence of anti-KDR-related effects were observed, confirming the in vivo FGFR selectivity of AZD4547. Taken together, our findings show that AZD4547 is a novel selective small-molecule inhibitor of FGFR with potent antitumor activity against FGFR-deregulated tumors in preclinical models. AZD4547 is under clinical investigation for the treatment of FGFR-dependent tumors.