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Cancer manifests through a spectrum of mutations, including gene fusions termed oncofusions. These structural alterations influence tumorigenesis across various cancer types. Oncofusions arise primarily from genomic rearrangements and operate through deregulation or hybrid gene formation mechanisms. Notable examples such as BCR::ABL and EWS::FLI1 underscore their clinical significance. Several case studies exemplify the role of identifying and targeting oncofusions in guiding treatment decisions and improving patient outcomes. However, challenges persist in discerning drivers from passenger mutations and addressing acquired resistance. Despite advancements, the complexity of oncofusions warrants further exploration of their full potential as therapeutic targets, requiring a multidisciplinary approach integrating genomics, functional studies, and innovative drug discovery strategies to achieve precision in medicine., (© The Author(s) 2024. Published by Oxford University Press.)

CMGC kinases, encompassing cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAPKs), glycogen synthase kinases (GSKs), and CDC-like kinases (CLKs), play pivotal roles in cellular signaling pathways, including cell cycle regulation, proliferation, differentiation, apoptosis, and gene expression regulation. The dysregulation and aberrant activation of these kinases have been implicated in cancer development and progression, making them attractive therapeutic targets. In recent years, kinase inhibitors targeting CMGC kinases, such as CDK4/6 inhibitors and BRAF/MEK inhibitors, have demonstrated clinical success in treating specific cancer types. However, challenges remain, including resistance to kinase inhibitors, off-target effects, and the need for better patient stratification. This review provides a comprehensive overview of the importance of CMGC kinases in cancer biology, their involvement in cellular signaling pathways, protein-protein interactions, and the current state of kinase inhibitors targeting these kinases. Furthermore, we discuss the challenges and future perspectives in targeting CMGC kinases for cancer therapy, including potential strategies to overcome resistance, the development of more selective inhibitors, and novel therapeutic approaches, such as targeting protein-protein interactions, exploiting synthetic lethality, and the evolution of omics in the study of the human kinome. As our understanding of the molecular mechanisms and protein-protein interactions involving CMGC kinases expands, so too will the opportunities for the development of more selective and effective therapeutic strategies for cancer treatment.

Cancer-associated gene fusions, also known as oncofusions, have emerged as influential drivers of oncogenesis across a diverse range of cancer types. These genetic events occur via chromosomal translocations, deletions, and inversions, leading to the fusion of previously separate genes. Due to the drastic nature of these mutations, they often result in profound alterations of cellular behavior. The identification of oncofusions has revolutionized cancer research, with advancements in sequencing technologies facilitating the discovery of novel fusion events at an accelerated pace. Oncofusions exert their effects through the manipulation of critical cellular signaling pathways that regulate processes such as proliferation, differentiation, and survival. Extensive investigations have been conducted to understand the roles of oncofusions in solid tumors, leukemias, and lymphomas. Large-scale initiatives, including the Cancer Genome Atlas, have played a pivotal role in unraveling the landscape of oncofusions by characterizing a vast number of cancer samples across different tumor types. While validating the functional relevance of oncofusions remains a challenge, even non-driver mutations can hold significance in cancer treatment. Oncofusions have demonstrated potential value in the context of immunotherapy through the production of neoantigens. Their clinical importance has been observed in both treatment and diagnostic settings, with specific fusion events serving as therapeutic targets or diagnostic markers. However, despite the progress made, there is still considerable untapped potential within the field of oncofusions. Further research and validation efforts are necessary to understand their effects on a functional basis and to exploit the new targeted treatment avenues offered by oncofusions. Through further functional and clinical studies, oncofusions will enable the advancement of precision medicine and the drive towards more effective and specific treatments for cancer patients.

Background: Like most living organisms, the fruit fly Drosophila melanogaster exhibits strong and diverse behavioural reactions to light. Drosophila is a diurnal animal that displays both short- and long-term responses to light, important for, instance, in avoidance and light wavelength preference, regulation of eclosion, courtship, and activity, and provides an important model organism for understanding the regulation of circadian rhythms both at molecular and circuit levels. However, the assessment and comparison of light-based behaviours is still a challenge, mainly due to the lack of a standardised platform to measure behaviour and different protocols created across studies. Here, we describe the Drosophila Interactive System for Controlled Optical manipulations (DISCO), a low-cost, automated, high-throughput device that records the flies' activity using infrared beams while performing LED light manipulations., Results: To demonstrate the effectiveness of this tool and validate its potential as a standard platform, we developed a number of distinct assays, including measuring the locomotor response of flies exposed to sudden darkness (lights-off) stimuli. Both white-eyed and red-eyed wild-type flies exhibit increased activity after the application of stimuli, while no changes can be observed in Fmr1 null allele flies, a model of fragile X syndrome. Next, to demonstrate the use of DISCO in long-term protocols, we monitored the circadian rhythm of the flies for 48 h while performing an alcohol preference test. We show that increased alcohol consumption happens intermittently throughout the day, especially in the dark phases. Finally, we developed a feedback-loop algorithm to implement a place preference test based on the flies' innate aversion to blue light and preference for green light. We show that both white-eyed and red-eyed wild-type flies were able to learn to avoid the blue-illuminated zones., Conclusions: Our results demonstrate the versatility of DISCO for a range of protocols, indicating that this platform can be used in a variety of ways to study light-dependent behaviours in flies., (© 2022. The Author(s).)

Type 2 diabetes mellitus (T2DM) continues to be a substantial medical problem due to its increasing global prevalence and because chronic hyperglycemic states are closely linked with obesity, liver disease and several cardiovascular diseases. Since the early discovery of insulin, numerous antihyperglycemic drug therapies to treat diabetes have been approved, and also discontinued, by the United States Food and Drug Administration (FDA). To provide an up-to-date account of the current trends of antidiabetic pharmaceuticals, this review offers a comprehensive analysis of the main classes of antihyperglycemic compounds and their mechanisms: insulin types, biguanides, sulfonylureas, meglitinides (glinides), alpha-glucosidase inhibitors (AGIs), thiazolidinediones (TZD), incretin-dependent therapies, sodium-glucose cotransporter type 2 (SGLT2) inhibitors and combinations thereof. The number of therapeutic alternatives to treat T2DM are increasing and now there are nearly 60 drugs approved by the FDA. Beyond this there are nearly 100 additional antidiabetic agents being evaluated in clinical trials. In addition to the standard treatments of insulin therapy and metformin, there are new drug combinations, e.g., containing metformin, SGLT2 inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors, that have gained substantial use during the last decade. Furthermore, there are several interesting alternatives, such as lobeglitazone, efpeglenatide and tirzepatide, in ongoing clinical trials. Modern drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists, DPP4 inhibitors and SGLT2 inhibitors have gained popularity on the pharmaceutical market, while less expensive over the counter alternatives are increasing in developing economies. The large heterogeneity of T2DM is also creating a push towards more personalized and accessible treatments. We describe several interesting alternatives in ongoing clinical trials, which may help to achieve this in the near future., Competing Interests: The authors declare 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 © 2022 Dahlén, Dashi, Maslov, Attwood, Jonsson, Trukhan and Schiöth.)

Objectives: To describe postgraduate emergency medicine (EM) residents' perceptions of simulation-based curriculum immediately post-simulation training., Methods: This interpretive qualitative study explores residents' reflections on a city-wide, adult EM simulation-based curriculum. Focus group interviews gather residents' insights immediately post-simulation. Postgraduate trainees from the University of Toronto EM residency program were eligible to participate. We explored participants' perceptions of how well learning objectives were addressed, helpful/challenging aspects of the simulations, feelings during sessions, debriefing/pre-briefing, simulation integration into the broader EM curriculum, and anticipated changes in practice after the session., Results: Our findings indicate that EM residents' learning goals for the simulation sessions evolve as they progress through residency training. Junior trainees report performance-oriented goals while senior trainees report learning-oriented goals. Differing motivations may affect residents' perceptions of the quality of the simulation experience. Junior residents want to feel prepared for the scenario and primed with the appropriate knowledge to manage the case. Senior residents focus on developing teamwork competencies and on mastering new clinical skills in the simulation environment., Conclusions: Junior and senior emergency medicine residents differ in their goal orientation during simulation-based training. Educators who develop simulation-based curricula should be mindful that junior residents may benefit from preparatory materials while senior residents prefer to be challenged. Resident reflections may significantly contribute to improvement of simulation-based curricula.

Background: Methemoglobinemia and carbon monoxide poisoning are potentially life-threatening conditions that can present with nonspecific clinical features. This lack of specificity increases the probability of misdiagnosis or avoidable delays in diagnosis and management. These conditions are both treatable with antidotes of methylene blue and oxygen, respectively. Modern blood gas analyzers have the ability to measure carboxyhemoglobin (COHb) and methemoglobin (MetHb) levels without any additional resources. However, these results, although readily available from the machine used to perform the analysis, are not fully reported by some hospital clinical laboratories., Case Report: A 49-year-old male presented with shortness of breath and cyanosis after inhaling cocaine via a nasal route ("snorting"). Methemoglobinemia was not initially considered in the differential diagnosis. However, the diagnosis of methemoglobinemia was made once newly routinely reported laboratory results revealed an elevated MetHb level. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Routinely reporting MetHb and COHb levels with arterial and venous blood gas results will facilitate making the diagnoses of these infrequently diagnosed causes of hypoxia more quickly so that early treatment of these uncommon but potentially lethal conditions can be initiated promptly., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: A key task of the team leader in a medical emergency is effective information gathering. Studying information gathering patterns is readily accomplished with the use of gaze-tracking glasses. This technology was used to generate hypotheses about the relationship between performance scores and expert-hypothesized visual areas of interest in residents across scenarios in simulated medical resuscitation examinations., Methods: Emergency medicine residents wore gaze-tracking glasses during two simulation-based examinations (n=29 and 13 respectively). Blinded experts assessed video-recorded performances using a simulation performance assessment tool that has validity evidence in this context. The relationships between gaze patterns and performance scores were analyzed and potential hypotheses generated. Four scenarios were assessed in this study: diabetic ketoacidosis, bradycardia secondary to beta-blocker overdose, ruptured abdominal aortic aneurysm and metabolic acidosis caused by antifreeze ingestion., Results: Specific gaze patterns were correlated with objective performance. High performers were more likely to fixate on task-relevant stimuli and appropriately ignore task-irrelevant stimuli compared with lower performers. For example, shorter latency to fixation on the vital signs in a case of diabetic ketoacidosis was positively correlated with performance (r=0.70, p<0.05). Conversely, total time spent fixating on lab values in a case of ruptured abdominal aortic aneurysm was negatively correlated with performance (r= −0.50, p<0.05)., Conclusions: There are differences between the visual patterns of high and low-performing residents. These findings may allow for better characterization of expertise development in resuscitation medicine and provide a framework for future study of visual behaviours in resuscitation cases.