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High rates of failure, exorbitant costs, and the sluggish pace of new drug discovery and development have led to a growing interest in repurposing “old” drugs to treat both common and rare diseases, particularly cancer. Cancer, a complex and heterogeneous disease, often necessitates a combination of different treatment modalities to achieve optimal outcomes. The intrinsic polygenicity of cancer, intricate biological signalling networks, and feedback loops make the inhibition of a single target frequently insufficient for achieving the desired therapeutic impact. As a result, addressing these complex or “smart” malignancies demands equally sophisticated treatment strategies. Combinatory treatments that target the multifaceted oncogenic signalling network hold immense promise. Repurposed drugs offer a potential solution to this challenge, harnessing known compounds for new indications. By avoiding the prohibitive costs and long development timelines associated with novel cancer drugs, this approach holds the potential to usher in more effective, efficient, and cost-effective cancer treatments. The pursuit of combinatory therapies through drug repurposing may hold the key to achieving superior outcomes for cancer patients. However, drug repurposing faces significant commercial, technological and regulatory challenges that need to be addressed. This review explores the diverse approaches employed in drug repurposing, delves into the challenges faced by the drug repurposing community, and presents innovative solutions to overcome these obstacles. By emphasising the significance of combinatory treatments within the context of drug repurposing, we aim to unlock the full potential of this approach for enhancing cancer therapy. The positive aspects of drug repurposing in oncology are underscored here; encompassing personalized treatment, accelerated development, market opportunities for shelved drugs, cancer prevention, expanded patient reach, improved patient access, multi-partner collaborations, increased likelihood of approval, reduced costs, and enhanced combination therapy.

Recent controversies have arisen regarding claims of uncritical positive regard and hype surrounding psychedelic drugs and their therapeutic potential. Criticisms have included that study designs and reporting styles bias positive over negative outcomes. The present study was motivated by a desire to address this alleged bias by intentionally focusing exclusively on negative outcomes, defined as self-perceived ‘negative’ psychological responses lasting for at least 72 h after psychedelic use. A strong justification for this selective focus was that it might improve our ability to capture otherwise missed cases of negative response, enabling us to validate their existence and better examine their nature, as well as possible causes, which could inspire risk-mitigation strategies. Via advertisements posted on social media, individuals were recruited who reported experiencing negative psychological responses to psychedelics (defined as classic psychedelics plus MDMA) lasting for greater than 72 h since using. Volunteers were directed to an online questionnaire requiring quantitative and qualitative input. A key second phase of this study involved reviewing all of the submitted cases, identifying the most severe—e.g., where new psychiatric diagnoses were made or pre-existing symptoms made worse post psychedelic-use—and inviting these individuals to participate in a semi-structured interview with two members of our research team, during which participant experiences and backgrounds were examined in greater depth. Based on the content of these interviews, a brief summary of each case was compiled, and an explorative thematic analysis was used to identify salient and consistent themes and infer common causes. 32 individuals fully completed an onboarding questionnaire (56% male, 53% < age 25); 37.5% of completers had a psychiatric diagnosis that emerged after their psychedelic experience, and anxiety symptoms arose or worsened in 87%. Twenty of the seemingly severer cases were invited to be interviewed; of these, 15 accepted an in-depth interview that lasted on average 60 min. This sample was 40% male, mean age = 31 ± 7. Five of the 15 (i.e., 33%) reported receiving new psychiatric diagnoses after psychedelic-use and all fifteen reported the occurrence or worsening of psychiatric symptoms post use, with a predominance of anxiety symptoms (93%). Distilling the content of the interviews suggested the following potential causal factors: unsafe or complex environments during or surrounding the experience, unpleasant acute experiences (classic psychedelics), prior psychological vulnerabilities, high- or unknown drug quantities and young age. The current exploratory findings corroborate the reality of mental health iatrogenesis via psychedelic-use but due to design limitations and sample size, cannot be used to infer on its prevalence. Based on interview reports, we can infer a common, albeit multifaceted, causal mechanism, namely the combining of a pro-plasticity drug—that was often ‘over-dosed’—with adverse contextual conditions and/or special psychological vulnerability—either by young age or significant psychiatric history. Results should be interpreted with caution due to the small sample size and selective sample and study focus.

Computerized clinical decision support systems, or CDSS, represent a paradigm shift in healthcare today. CDSS are used to augment clinicians in their complex decision-making processes. Since their first use in the 1980s, CDSS have seen a rapid evolution. They are now commonly administered through electronic medical records and other computerized clinical workflows, which has been facilitated by increasing global adoption of electronic medical records with advanced capabilities. Despite these advances, there remain unknowns regarding the effect CDSS have on the providers who use them, patient outcomes, and costs. There have been numerous published examples in the past decade(s) of CDSS success stories, but notable setbacks have also shown us that CDSS are not without risks. In this paper, we provide a state-of-the-art overview on the use of clinical decision support systems in medicine, including the different types, current use cases with proven efficacy, common pitfalls, and potential harms. We conclude with evidence-based recommendations for minimizing risk in CDSS design, implementation, evaluation, and maintenance.

Reactive oxygen species (ROS)-induced apoptosis is a promising treatment strategy for malignant neoplasms. However, current systems are highly dependent on oxygen status and/or external stimuli to generate ROS, which greatly limit their therapeutic efficacy particularly in hypoxic tumors. Herein, we develop a biomimetic nanoflower based on self-assembly of nanozymes that can catalyze a cascade of intracellular biochemical reactions to produce ROS in both normoxic and hypoxic conditions without any external stimuli. In our formulation, PtCo nanoparticles are firstly synthesized and used to direct the growth of MnO 2 . By adjusting the ratio of reactants, highly-ordered MnO 2 @PtCo nanoflowers with excellent catalytic efficiency are obtained, where PtCo behaves as oxidase mimic and MnO 2 functions as catalase mimic. In this way, the well-defined MnO 2 @PtCo nanoflowers not only can relieve hypoxic condition but also induce cell apoptosis significantly through ROS-mediated mechanism, thereby resulting in remarkable and specific inhibition of tumor growth. Hypoxic tumors are resistant to dynamic therapy, limiting potential treatment options. Here, the authors describe a nanoflower where oxidase mimicking PtCo nanoparticles are decorated with catalase mimicking MnO 2 to reverse tumor hypoxia and generate reactive oxygen species for dynamic therapy.

The Wnt/β-catenin pathway comprises a family of proteins that play critical roles in embryonic development and adult tissue homeostasis. The deregulation of Wnt/β-catenin signalling often leads to various serious diseases, including cancer and non-cancer diseases. Although many articles have reviewed Wnt/β-catenin from various aspects, a systematic review encompassing the origin, composition, function, and clinical trials of the Wnt/β-catenin signalling pathway in tumour and diseases is lacking. In this article, we comprehensively review the Wnt/β-catenin pathway from the above five aspects in combination with the latest research. Finally, we propose challenges and opportunities for the development of small-molecular compounds targeting the Wnt signalling pathway in disease treatment.

The US Food and Drug Administration (FDA) has approved the first drug, resmetirom, for metabolic dysfunction-associated steatohepatitis (MASH), but much work remains for the industry, practitioners and health systems so that this approval will benefit all patients.

The pharmaceutical industry and its global regulators have routinely used frequentist statistical methods, such as null hypothesis significance testing and p values, for evaluation and approval of new treatments. The clinical drug development process, however, with its accumulation of data over time, can be well suited for the use of Bayesian statistical approaches that explicitly incorporate existing data into clinical trial design, analysis and decision-making. Such approaches, if used appropriately, have the potential to substantially reduce the time and cost of bringing innovative medicines to patients, as well as to reduce the exposure of patients in clinical trials to ineffective or unsafe treatment regimens. Nevertheless, despite advances in Bayesian methodology, the availability of the necessary computational power and growing amounts of relevant existing data that could be used, Bayesian methods remain underused in the clinical development and regulatory review of new therapies. Here, we highlight the value of Bayesian methods in drug development, discuss barriers to their application and recommend approaches to address them. Our aim is to engage stakeholders in the process of considering when the use of existing data is appropriate and how Bayesian methods can be implemented more routinely as an effective tool for doing so.Bayesian statistical approaches that explicitly incorporate existing data into clinical trial design, analysis and decision-making have the potential to substantially reduce the time and cost of bringing new medicines to patients in some contexts, but remain underused. This Perspective highlights the value of Bayesian methods in drug development, discusses barriers to their application and recommends approaches to address them.

The 21st Century Cures Act, approved in the USA in December 2016, has encouraged the establishment of the national Precision Medicine Initiative and the augmentation of efforts to address disease prevention, diagnosis and treatment on the basis of a molecular understanding of disease. The Act adopts into law the formal process, developed by the FDA, of qualification of drug development tools, including biomarkers and clinical outcome assessments, to increase the efficiency of clinical trials and encourage an era of molecular medicine. The FDA and European Medicines Agency (EMA) have developed similar processes for the qualification of biomarkers intended for use as companion diagnostics or for development and regulatory approval of a drug or therapeutic. Biomarkers that are used exclusively for the diagnosis, monitoring or stratification of patients in clinical trials are not subject to regulatory approval, although their qualification can facilitate the conduct of a trial. In this Review, the salient features of biomarker discovery, analytical validation, clinical qualification and utilization are described in order to provide an understanding of the process of biomarker development and, through this understanding, convey an appreciation of their potential advantages and limitations.

Neurodevelopmental disorders such as fragile X syndrome (FXS) result in lifelong cognitive and behavioural deficits and represent a major public health burden. FXS is the most frequent monogenic form of intellectual disability and autism, and the underlying pathophysiology linked to its causal gene, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches. These robust preclinical findings have led to the implementation of the most comprehensive drug development programme undertaken thus far for a genetically defined neurodevelopmental disorder, including phase IIb trials of metabotropic glutamate receptor 5 (mGluR5) antagonists and a phase III trial of a GABAB receptor agonist. However, none of the trials has been able to unambiguously demonstrate efficacy, and they have also highlighted the extent of the knowledge gaps in drug development for FXS and other neurodevelopmental disorders. In this Review, we examine potential issues in the previous studies and future directions for preclinical and clinical trials. FXS is at the forefront of efforts to develop drugs for neurodevelopmental disorders, and lessons learned in the process will also be important for such disorders.