Exploring Retrograde Trafficking: Mechanisms and Consequences in Cancer and Disease.

Retrograde trafficking (RT) orchestrates the intracellular movement of cargo from the plasma membrane, endosomes, Golgi or endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) in an inward/ER-directed manner. RT works as the opposing movement to anterograde trafficking (outward secretion), and the two work together to maintain cellular homeostasis. This is achieved through maintaining cell polarity, retrieving proteins responsible for anterograde trafficking and redirecting proteins that become mis-localised. However, aberrant RT can alter the correct location of key proteins, and thus inhibit or indeed change their canonical function, potentially causing disease. This review highlights the recent advances in the understanding of how upregulation, downregulation or hijacking of RT impacts the localisation of key proteins in cancer and disease to drive progression. Cargoes impacted by aberrant RT are varied amongst maladies including neurodegenerative diseases, autoimmune diseases, bacterial and viral infections (including SARS-CoV-2), and cancer. As we explore the intricacies of RT, it becomes increasingly apparent that it holds significant potential as a target for future therapies to offer more effective interventions in a wide range of pathological conditions.

4D printed multipurpose smart implants for breast cancer management.

Breast-conserving surgery (BCS) is the primary strategy for treating early-stage breast cancer; however, the incidence of local recurrence and breast tissue loss negatively impacts patients and survivors. Furthermore, radiotherapy and/or systemic therapies are frequently advised to avoid recidivism and increase the patient's chance of survival, resulting in longer duration of treatments, and unpleasant systemic side effects. Given the poor prognosis and the heterogeneity between individuals and tumors, a patient-centered approach is fundamental. Herein we developed a multipurpose 4D printed implant made of a blend of carboxymethyl cellulose sodium salt (CMC) and cellulose nanocrystals (CNC), loaded with doxorubicin (DOX). To predict printability performance, full rheological characterization was carried out. The smart device was programmed to change size, under swelling, to better fit in the tissue cavity, resulting in a great potential for personalization, thus improving the aesthetic outcomes. The influence of the formulation and printing parameters on the morpho transformation was investigated through the swelling test, confirming the possibility to program the 4D shape. The manufactured implants were characterized by a variety of methods, including in vitro release studies. Lastly, the anticancer activity was conducted in vitro, on MDA-MB-231 cells. Implants promoted an anticancer effect of -58% viability after 72 h incubation, even when tested 4 weeks after the printing process. Overall, the morpho transformation and the in vitro studies have shown that the implant could represent a potential strategy for breast cancer following resection, to fill the void in the breast resulting from the surgery and provide an anticancer effect to avoid recurrence.

Debate: The concept of culture has outlived its usefulness for psychiatry.

This paper presents a debate in which the authors participated at the World Psychiatric Association conference in Cape Town, South Africa in November 2016. Professor van Staden acted as chair and here, as at the debate, provides a rationale for debating a topic that many of those involved in mental health believe to be decided. The discussion that ensued demonstrated, however, that while the arguments have moved on they have not ceased. Who won? Well that depends how you look at it. A few in the audience shifted position towards the motion but the majority remained opposed. What do you think? Declaration of interest None.

The definition of mental disorder: evolving but dysfunctional?

Extensive and diverse conceptual work towards developing a definition of 'mental disorder' was motivated by the declassification of homosexuality from the Diagnostic and Statistical Manual in 1973. This highly politicised event was understood as a call for psychiatry to provide assurances against further misclassification on the basis of discrimination or socio-political deviance. Today, if a definition of mental disorder fails to exclude homosexuality, then it fails to provide this safeguard against potential abuses and therefore fails to do an important part of the work it was intended to do. We argue that fact-based definitions of mental disorder, relying on scientific theory, fail to offer a robust definition of mental disorder that excludes homosexuality. Definitions of mental disorder based on values do not fare better: these definitions are silent on questions about the diagnostic status of individuals in oppressive societies and over-inclusive of mental or behavioural states that happen to be negatively valued in the individual's social context. We consider the latest definition proposed for the Diagnostic and Statistical Manual-5 (DSM-5) in light of these observations. We argue that definition fails to improve on these earlier deficiencies. Its inclusion in the manual may offer false reassurance against repetition of past misclassifications. We conclude with a provocation that if candidate definitions of mental disorder are unable to exclude homosexuality, it might perhaps be preferable not to attempt a definition at all.

The gap between voluntary admission and detention in mental health units.

This paper presents the case of a young man with a diagnosis of schizophrenia, who agreed to inpatient treatment primarily to avoid being formally detained. I draw on Peter Breggin's early critique of coercion of informal patients to supply an updated discussion of the ethical issues raised. Central questions are whether the admission was coercive, and if so, whether unethical. Whether or not involuntary admission would be justified, moral discomfort surrounds its appearance as a threat. This arises in part from ambivalence about autonomy: although a 'choice' is made, the threat of detention impinges on the patient's choice. Recent legal developments provide some experience of safeguarding those whose consent is not obtained. This highlights the lack of safeguards in this 'gap' and suggests that we have the tools with which to begin to deal with the problem.