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Molecular Metabolism Jun 2024Bioenergetic remodeling of core energy metabolism is essential to the initiation, survival, and progression of cancer cells through exergonic supply of adenosine... (Review)
Review
Bioenergetic remodeling of core energy metabolism is essential to the initiation, survival, and progression of cancer cells through exergonic supply of adenosine triphosphate (ATP) and metabolic intermediates, as well as control of redox homeostasis. Mitochondria are evolutionarily conserved organelles that mediate cell survival by conferring energetic plasticity and adaptive potential. Mitochondrial ATP synthesis is coupled to the oxidation of a variety of substrates generated through diverse metabolic pathways. As such, inhibition of the mitochondrial bioenergetic system by restricting metabolite availability, direct inhibition of the respiratory Complexes, altering organelle structure, or coupling efficiency may restrict carcinogenic potential and cancer progression. Here, we review the role of bioenergetics as the principal conductor of energetic functions and carcinogenesis while highlighting the therapeutic potential of targeting mitochondrial functions.
PubMed: 38876266
DOI: 10.1016/j.molmet.2024.101966 -
JMIR AI Jan 2024ChatGPT (Open AI) is a state-of-the-art large language model that uses artificial intelligence (AI) to address questions across diverse topics. The American Society of...
BACKGROUND
ChatGPT (Open AI) is a state-of-the-art large language model that uses artificial intelligence (AI) to address questions across diverse topics. The American Society of Clinical Oncology Self-Evaluation Program (ASCO-SEP) created a comprehensive educational program to help physicians keep up to date with the many rapid advances in the field. The question bank consists of multiple choice questions addressing the many facets of cancer care, including diagnosis, treatment, and supportive care. As ChatGPT applications rapidly expand, it becomes vital to ascertain if the knowledge of ChatGPT-3.5 matches the established standards that oncologists are recommended to follow.
OBJECTIVE
This study aims to evaluate whether ChatGPT-3.5's knowledge aligns with the established benchmarks that oncologists are expected to adhere to. This will furnish us with a deeper understanding of the potential applications of this tool as a support for clinical decision-making.
METHODS
We conducted a systematic assessment of the performance of ChatGPT-3.5 on the ASCO-SEP, the leading educational and assessment tool for medical oncologists in training and practice. Over 1000 multiple choice questions covering the spectrum of cancer care were extracted. Questions were categorized by cancer type or discipline, with subcategorization as treatment, diagnosis, or other. Answers were scored as correct if ChatGPT-3.5 selected the answer as defined by ASCO-SEP.
RESULTS
Overall, ChatGPT-3.5 achieved a score of 56.1% (583/1040) for the correct answers provided. The program demonstrated varying levels of accuracy across cancer types or disciplines. The highest accuracy was observed in questions related to developmental therapeutics (8/10; 80% correct), while the lowest accuracy was observed in questions related to gastrointestinal cancer (102/209; 48.8% correct). There was no significant difference in the program's performance across the predefined subcategories of diagnosis, treatment, and other (P=.16, which is greater than .05).
CONCLUSIONS
This study evaluated ChatGPT-3.5's oncology knowledge using the ASCO-SEP, aiming to address uncertainties regarding AI tools like ChatGPT in clinical decision-making. Our findings suggest that while ChatGPT-3.5 offers a hopeful outlook for AI in oncology, its present performance in ASCO-SEP tests necessitates further refinement to reach the requisite competency levels. Future assessments could explore ChatGPT's clinical decision support capabilities with real-world clinical scenarios, its ease of integration into medical workflows, and its potential to foster interdisciplinary collaboration and patient engagement in health care settings.
PubMed: 38875575
DOI: 10.2196/50442 -
Medicine Jun 2024Ultrasound (US) can guide and confirm percutaneous release of the achilles tendon in the clubfoot. However, this technique may not always be available; therefore,... (Observational Study)
Observational Study
Reproducibility of pop sensation, Thompson sign in achillotomy, and final Pirani score to predict clubfoot relapse: Achillotomy clinical signs and Pirani predictive ability.
Ultrasound (US) can guide and confirm percutaneous release of the achilles tendon in the clubfoot. However, this technique may not always be available; therefore, surgeons' reported feelings of tendon release ("click" or "pop") and the Thompson sign could demonstrate that they are sensitive and reliable for confirming complete tendon release. The purpose of this study was to compare the reproducibility of clinical maneuvers that aim to detect the reported "click" or "pop" sensation by the surgeon and the Thompson sign after surgical release in percutaneous achilles tenotomy compare with US in patients with clubfoot. A cross-sectional reproducibility study of consecutive patients with idiopathic clubfoot was conducted. All the patients were scheduled to undergo tenotomy in the operating room using the standard percutaneous achilles tenotomy technique under sedation. The surgeon's reported surgical sensation ("click" or "pop") and Thompson signs were compared to the US assessment of the cut. The final Pirani score was used to predict recurrence risk and was correlated with the number of plaster casts and age. Forty-five feet were affected in 30 patients. Eighteen (60%) men. Age range: 1 to 60 months. The sensation of "click" or "pop" was recorded in 38 patients, and complete release was confirmed by US in 37 patients, for a sensitivity (Se) of 0.95 and specificity (Sp) of 0.63. Thompson signs were positive in 33 and 36 patients at 2 evaluations, with Se values of 0.87 and 0.92 and Sp values of 0.88 and 0.75, respectively. The Pirani final score, a predictor of recurrence risk, had an area under the curve of 0.80 (95% CI = 0.63-0.97; P = .005), Se = 0.78, and Sp = 0.56, with a cutoff point of 2.75. The feeling of achilles tendon release and Thompson sign had high sensitivity, prevalence, accuracy, and posttest probability. The confirmation of tendon release based on clinical signs could prevent the use of US.
Topics: Humans; Clubfoot; Male; Female; Recurrence; Achilles Tendon; Cross-Sectional Studies; Infant; Tenotomy; Reproducibility of Results; Child, Preschool; Ultrasonography; Predictive Value of Tests
PubMed: 38875390
DOI: 10.1097/MD.0000000000038377 -
Medicine Jun 2024Bone cement implantation syndrome (BCIS) is a critical and potentially life-threatening condition that manifests during implantation. Characterized by a constellation of... (Review)
Review
Bone cement implantation syndrome (BCIS) is a critical and potentially life-threatening condition that manifests during implantation. Characterized by a constellation of symptoms, including hypoxemia, hypotension, cardiac arrhythmias, elevated pulmonary vascular resistance, and occasionally cardiac arrest, BCIS typically ensues shortly after cement introduction, albeit with rare instances of delayed onset. Primarily attributed to the exothermic reaction of bone cement implantation, this syndrome is caused by local tissue damage, histamine and prostaglandin release, and microemboli formation, ultimately triggering a systemic immune response that culminates in respiratory and circulatory failure. The current hypotheses regarding BCIS include embolism, allergic reactions, and cement autotoxicity. BCIS management emphasizes preventative strategies, encompassing meticulous patient risk assessment, comprehensive preoperative and intraoperative evaluations, and precise cement application techniques. Treatment primarily involves symptomatic therapy and life-support measures to address the systemic effects of the syndrome.
Topics: Humans; Bone Cements; Syndrome; Postoperative Complications
PubMed: 38875363
DOI: 10.1097/MD.0000000000038624 -
PloS One 2024Pro-inflammatory changes contribute to multiple neuropsychiatric illnesses. Understanding how these changes are involved in illnesses and identifying strategies to alter...
Pro-inflammatory changes contribute to multiple neuropsychiatric illnesses. Understanding how these changes are involved in illnesses and identifying strategies to alter inflammatory responses offer paths to potentially novel treatments. We previously found that acute pro-inflammatory stimulation with high (μg/ml) lipopolysaccharide (LPS) for 10-15 min dampens long-term potentiation (LTP) in the hippocampus and impairs learning. Effects of LPS involved non-canonical inflammasome signaling but were independent of toll-like receptor 4 (TLR4), a known LPS receptor. Low (ng/ml) LPS also inhibits LTP when administered for 2-4 h, and here we report that this LPS exposure requires TLR4. We also found that effects of low LPS on LTP involve the oxysterol, 25-hydroxycholesterol, akin to high LPS. Effects of high LPS on LTP are blocked by inhibiting synthesis of 5α-reduced neurosteroids, indicating that neurosteroids mediate LTP inhibition. 5α-Neurosteroids also have anti-inflammatory effects, and we found that exogenous allopregnanolone (AlloP), a key 5α-reduced steroid, prevented effects of low but not high LPS on LTP. We also found that activation of TLR2, TLR3 and TLR7 inhibited LTP and that AlloP prevented the effects of TLR2 and TLR7, but not TLR3. The enantiomer of AlloP, a steroid that has anti-inflammatory actions but low activity at GABAA receptors, prevented LTP inhibition by TLR2, TLR3 and TLR7. In vivo, both AlloP enantiomers prevented LPS-induced learning defects. These studies indicate that neurosteroids play complex roles in network effects of acute neuroinflammation and have potential importance for development of AlloP analogues as therapeutic agents.
Topics: Animals; Hippocampus; Lipopolysaccharides; Long-Term Potentiation; Male; Neurosteroids; Toll-Like Receptors; Learning; Mice; Neuronal Plasticity; Toll-Like Receptor 4; Inflammation; Mice, Inbred C57BL; Hydroxycholesterols; Pregnanolone
PubMed: 38875235
DOI: 10.1371/journal.pone.0304481 -
Biology Open Jun 2024The neural crest (NC) is an embryonic multipotent and transitory population of cells that appears during late gastrulation/early neurulation in the developing embryos of...
The neural crest (NC) is an embryonic multipotent and transitory population of cells that appears during late gastrulation/early neurulation in the developing embryos of vertebrate organisms. Often called "the fourth germ layer", the NC is characterised by incredible mobility, which allows the NC cells to migrate throughout the whole embryo, giving rise to an astonishing number of different derivatives in the adult organism, such as craniofacial skeleton, adrenal gland, enteric nervous system and melanocytes. Because of these properties, neurocristopathies (NCPs), which is the term used to classify genetic diseases associated with NC developmental defects, are often syndromic and, taken all together, are the most common type of genetic disease. The NEUcrest consortium is an EU funded innovative training network (ITN) that aims to study the NC and NCPs. In March 2024, the early stage researchers (ESRs) in the NEUcrest consortium organised an in-person conference for well-established and early career researchers to discuss new advances in the NC and NCPs field, starting from the induction of the NC, and then moving on to migration and differentiation processes they undergo. The conference focused heavily on NCPs associated with each of these steps. The conference also included events, such as a round table to discuss the future of the NC research, plus a talk by a person living with an NCP. This 3-day conference aimed to bring together the past, present and future of this field to try and unravel the mysteries of this unique cell population.
Topics: Neural Crest; Humans; Animals; Cell Differentiation; Cell Movement
PubMed: 38874999
DOI: 10.1242/bio.060530 -
ELife Jun 2024Epithelial to mesenchymal transition (EMT) is a cellular process that converts epithelial cells to mesenchymal cells with migratory potential in developmental and...
Epithelial to mesenchymal transition (EMT) is a cellular process that converts epithelial cells to mesenchymal cells with migratory potential in developmental and pathological processes. Although originally considered a binary event, EMT in cancer progression involves intermediate states between a fully epithelial and a fully mesenchymal phenotype, which are characterized by distinct combinations of epithelial and mesenchymal markers. This phenomenon has been termed epithelial to mesenchymal plasticity (EMP), however, the intermediate states remain poorly described and it's unclear whether they exist during developmental EMT. Neural crest cells (NCC) are an embryonic progenitor cell population that gives rise to numerous cell types and tissues in vertebrates, and their formation and delamination is a classic example of developmental EMT. However, whether intermediate states also exist during NCC EMT and delamination remains unknown. Through single-cell RNA sequencing of mouse embryos, we identified intermediate NCC states based on their transcriptional signature and then spatially defined their locations in situ in the dorsolateral neuroepithelium. Our results illustrate the importance of cell cycle regulation and functional role for the intermediate stage marker in facilitating mammalian cranial NCC delamination and may provide new insights into mechanisms regulating pathological EMP.
Topics: Neural Crest; Animals; Epithelial-Mesenchymal Transition; Mice; Single-Cell Analysis
PubMed: 38873887
DOI: 10.7554/eLife.92844 -
Neurorehabilitation and Neural Repair Jun 2024Actual and imagined cued gait trainings have not been compared in people with multiple sclerosis (MS).
BACKGROUND
Actual and imagined cued gait trainings have not been compared in people with multiple sclerosis (MS).
OBJECTIVE
To analyze the effects of cued motor imagery (CMI), cued gait training (CGT), and combined CMI and cued gait training (CMI-CGT) on motor, cognitive, and emotional functioning, and health-related quality of life in people with MS.
METHODS
In this double-blind randomized parallel-group multicenter trial, people with MS were randomized (1:1:1) to CMI, CMI-CGT, or CGT for 30 minutes, 4×/week for 4 weeks. Patients practiced at home, using recorded instructions, and supported by ≥6 phone calls. Data were collected at weeks 0, 4, and 13. Co-primary outcomes were walking speed and distance, analyzed by intention-to-treat. Secondary outcomes were global cognitive impairment, anxiety, depression, suicidality, fatigue, HRQoL, motor imagery ability, music-induced motivation, pleasure and arousal, self-efficacy, and cognitive function. Adverse events and falls were continuously monitored.
RESULTS
Of 1559 screened patients, 132 were randomized: 44 to CMI, 44 to CMI-CGT, and 44 to CGT. None of the interventions demonstrated superiority in influencing walking speed or distance, with negligible effects on walking speed (η = 0.019) and distance (η = 0.005) observed in the between-group comparison. Improvements in walking speed and walking distance over time corresponded to large effects for CMI, CMI-CGT, and CGT (η = 0.348 and η = 0.454 respectively). No severe study-related adverse events were reported.
CONCLUSIONS
CMI-GT did not lead to improved walking speed and distance compared with CMI and CGT alone in people with MS. Lack of a true control group represents a study limitation.
TRIAL REGISTRATION
German Clinical Trials Register, DRKS00023978.
PubMed: 38873806
DOI: 10.1177/15459683241260724 -
Heliyon Jun 2024In principle, after all manufacturing processes are performed, a set of residual stresses occur in the product that have their particular distribution given the...
In principle, after all manufacturing processes are performed, a set of residual stresses occur in the product that have their particular distribution given the manufacturing process performed. The residual stresses must be removed to achieve the desired dimensional accuracy and quality. Among stress-relieving processes performed for a following the manufacturing process, we can refer to thermal and vibratory stress relief (VSR). Both methods perform the same function as they enter into the plastic phase, causing a fracture of residual stresses to be released with local plastic deformations. The process is as follows: The stress induced by thermal or vibratory loads is added to the residual stresses and exceeds the yield stress. This research, which is focused on VSR, aims to evaluate the effect of the main parameters of the VSR method, including load amplitude or amount, load application frequency, and cycle numbers. The general trend of the problem is that the VSR process is performed for a piece with residual stress, and the effect of the abovementioned parameters on reducing its residual stresses is evaluated.
PubMed: 38873681
DOI: 10.1016/j.heliyon.2024.e32052 -
EClinicalMedicine Jul 2024Access to gender-affirming medical care has life-saving effects on transgender and gender diverse (TGD) individuals. An increasing number of TGD individuals seek care...
BACKGROUND
Access to gender-affirming medical care has life-saving effects on transgender and gender diverse (TGD) individuals. An increasing number of TGD individuals seek care which led to waiting times of years. We assessed the duration and effects of excessive waiting for gender-affirming care.
METHODS
In this mixed-methods cross-sectional population study, conducted in the Netherlands between June and August 2019, all TGD individuals with experiences with receiving/applying for gender-affirming medical care could participate. Data of participants waiting for care was primarily analyzed. Demographic characteristics and requested care (multiple-choice questions) and the effects of waiting on health were surveyed (open-ended questions). Descriptive statistics were calculated per treatment, and differences in participant characteristics between those waiting for and already in care were assessed through Chi squared tests and post-hoc testing of residuals. Open text answers were thematically analyzed.
FINDINGS
Of all 975 participants, 431 (44.2%) waited for gender-affirming medical care. For 10 out of 20 treatment modalities, the median waiting period was more than a year. Participants already in care were on average higher educated and less-frequently non-binary. Subjective effects of waiting were (very) negative for most treatments. Qualitative findings showed that long waiting was associated with a range of psychosocial distress, poorer health, increasing healthcare consumption, and increased inequality between TGD individuals.
INTERPRETATION
Findings confirm that TGD individuals encounter long waiting times in multiple stages of their gender-affirming medical care. Waiting affects both physical and psychosocial health. Individual resilience and resources can mitigate these experiences, which increase inequality within this already marginalized group.
FUNDING
Ministry of Health, Welfare and Sport of the Netherlands and Zorgverzekeraars Nederland (Healthcare Insurers Netherlands).
PubMed: 38873631
DOI: 10.1016/j.eclinm.2024.102657