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Life Science Alliance Aug 2024Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the...
Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology of (SOD1)- and in particular (FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)-both putative products of the Parkinson's disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization.
Topics: Humans; Amyotrophic Lateral Sclerosis; RNA-Binding Protein FUS; Glycolates; Mitochondria; Protein Deglycase DJ-1; Lactic Acid; Superoxide Dismutase-1; Membrane Potential, Mitochondrial; Motor Neurons; Lysosomes
PubMed: 38760174
DOI: 10.26508/lsa.202302535 -
BMJ Open May 2024DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in...
Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children (MARVEL- PIC): protocol for a national randomised controlled trial of pharmacogenomics implementation.
INTRODUCTION
DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in paediatric oncology remains sparse.
METHODS AND ANALYSIS
Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children is a national prospective, multicentre, randomised controlled trial assessing the impact of pre-emptive PGx testing for actionable PGx variants on adverse drug reaction (ADR) incidence in patients with a new cancer diagnosis or proceeding to haematopoetic stem cell transplant. All ADRs will be prospectively collected by surveys completed by parents/patients using the National Cancer Institute Pediatric Patient Reported [Ped-PRO]-Common Terminology Criteria for Adverse Events (CTCAE) (weeks 1, 6 and 12). Pharmacist will assess for causality and severity in semistructured interviews using the CTCAE and Liverpool Causality Assessment Tool. The primary outcome is a reduction in ADRs among patients with actionable PGx variants, where an ADR will be considered as any CTCAE grade 2 and above for non-haematological toxicities and any CTCAE grade 3 and above for haematological toxicities Cost-effectiveness of pre-emptive PGx (secondary outcome) will be compared with standard of care using hospital inpatient and outpatient data along with the validated Childhood Health Utility 9D Instrument. Power and statistics considerations: A sample size of 440 patients (220 per arm) will provide 80% power to detect a 24% relative risk reduction in the primary endpoint of ADRs (two-sided α=5%, 80% vs 61%), allowing for 10% drop-out.
ETHICS AND DISSEMINATION
The ethics approval of the trial has been obtained from the Royal Children's Hospital Ethics Committee (HREC/89083/RCHM-2022). The ethics committee of each participating centres nationally has undertaken an assessment of the protocol and governance submission.
TRIAL REGISTRATION NUMBER
NCT05667766.
Topics: Humans; Child; Drug-Related Side Effects and Adverse Reactions; Pharmacogenetics; Prospective Studies; Randomized Controlled Trials as Topic; Neoplasms; Multicenter Studies as Topic; Precision Medicine; Hematopoietic Stem Cell Transplantation
PubMed: 38760050
DOI: 10.1136/bmjopen-2024-085115 -
BMJ Open May 2024(STEPS) is a digital application (app) designed to help parents manage behaviour of their children who are referred to mental health services and are waiting for an...
INTRODUCTION
(STEPS) is a digital application (app) designed to help parents manage behaviour of their children who are referred to mental health services and are waiting for an assessment or treatment. STEPS is currently being evaluated in the Online Parent Training for the Initial Management of Attention-Deficit/Hyperactivity Disorder randomised controlled trial. Alongside the examination of STEPS' clinical and cost-effectiveness, we are conducting a process evaluation to better understand the contextual factors that may influence study outcomes. The purpose of this protocol is to describe the aims, objectives and methodology of the process evaluation prior to it taking place to add to the fidelity and rigour of the trial process and outcomes. Our goal is to adapt STEPS to optimise its benefits in future applications.
METHODS
In line with the Medical Research Council guidelines for evaluating complex interventions, the process evaluation will adopt a mixed method design using qualitative data collected from clinicians and parent interviews and app usage data from participants assigned to the intervention arm.
ANALYSIS
Qualitative data from semistructured interviews and free text box responses included in trial questionnaires will be analysed thematically using framework analysis to better understand how parents use STEPS, how it works and key factors that could aid or hinder its effective implementation in routine clinical practice.
ETHICS
The application for ethical approval for the study was submitted to the North West-Liverpool Central Research Ethics Committee and received a favourable opinion on further information on 26 November 2021, reference number 21/NW/0319.
DISSEMINATION
The process evaluation aims to explore how a digital app might support parents in managing their child's behaviour. Implications for policy and research will be explored and the clinical implications of offering the app to a wider audience to address the lack of support to parents as highlighted in this paper. We plan to publish findings in international, peer-reviewed journals as well as present at conferences.
TRIAL REGISTRATION NUMBER
The trial has been prospectively registered on 18 November 2021; ISRCTN816523503. https://www.isrctn.com/ISRCTN16523503.
Topics: Humans; Parenting; Parents; Child; Attention Deficit Disorder with Hyperactivity; Randomized Controlled Trials as Topic; Mobile Applications; Research Design
PubMed: 38760045
DOI: 10.1136/bmjopen-2023-081563 -
Medicine May 2024Amniotic fluid embolism (AFE) is a fatal obstetric condition that often rapidly leads to severe respiratory and circulatory failure. It is complicated by obstetric... (Review)
Review
RATIONALE
Amniotic fluid embolism (AFE) is a fatal obstetric condition that often rapidly leads to severe respiratory and circulatory failure. It is complicated by obstetric disseminated intravascular coagulation (DIC) with bleeding tendency; therefore, the introduction of venoarterial extracorporeal membrane oxygenation (VA-ECMO) is challenging. We report the case of a patient with AFE requiring massive blood transfusion, rescued using VA-ECMO without initial anticoagulation.
PATIENTS CONCERNS
A 39-year-old pregnant patient was admitted with a complaint of abdominal pain. An emergency cesarean section was performed because a sudden decrease in fetal heart rate was detected in addition to DIC with hyperfibrinolysis. Intra- and post-operatively, the patient had a bleeding tendency and required massive blood transfusions. After surgery, the patient developed lethal respiratory and circulatory failure, and VA-ECMO was introduced.
DIAGNOSIS
Based on the course of the illness and imaging findings, the patient was diagnosed with AFE.
INTERVENTIONS
By controlling the bleeding tendency with a massive transfusion and tranexamic acid administration, using an antithrombotic ECMO circuit, and delaying the initiation of anticoagulation and anti-DIC medication until the bleeding tendency settled, the patient was managed safely on ECMO without complications.
OUTCOMES
By day 5, both respiration and circulation were stable, and the patient was weaned off VA-ECMO. Mechanical ventilation was discontinued on day 6. Finally, she was discharged home without sequelae.
LESSONS
VA-ECMO may be effective to save the lives of patients who have AFE with lethal circulatory and respiratory failure. For safe management without bleeding complications, it is important to start VA-ECMO without initial anticoagulants and to administer anticoagulants and anti-DIC drugs after the bleeding tendency has resolved.
Topics: Humans; Female; Embolism, Amniotic Fluid; Extracorporeal Membrane Oxygenation; Adult; Pregnancy; Cesarean Section; Blood Transfusion; Tranexamic Acid; Disseminated Intravascular Coagulation; Anticoagulants
PubMed: 38758915
DOI: 10.1097/MD.0000000000038176 -
Medicine May 2024Microorganisms, including bacteria, viruses, and fungi, coexist in the human body, forming a symbiotic microbiota that plays a vital role in human health and disease.... (Review)
Review
Microorganisms, including bacteria, viruses, and fungi, coexist in the human body, forming a symbiotic microbiota that plays a vital role in human health and disease. Intratumoral microbial components have been discovered in various tumor tissues and are closely linked to the occurrence, progression, and treatment results of cancer. The intratumoral microbiota can enhance antitumor immunity through mechanisms such as activating the stimulator of interferon genes signaling pathway, stimulating T and NK cells, promoting the formation of TLS, and facilitating antigen presentation. Conversely, the intratumoral microbiota might suppress antitumor immune responses by increasing reactive oxygen species levels, creating an anti-inflammatory environment, inducing T cell inactivation, and enhancing immune suppression, thereby promoting cancer progression. The impact of intratumoral microbiota on antitumor immunity varies based on microbial composition, interactions with cancer cells, and the cancer's current state. A deep understanding of the complex interactions between intratumoral microbiota and antitumor immunity holds the potential to bring new therapeutic strategies and targets to cancer immunotherapy.
Topics: Humans; Neoplasms; Immunotherapy; Microbiota; Tumor Microenvironment
PubMed: 38758914
DOI: 10.1097/MD.0000000000038078 -
Medicine May 2024Thrombotic thrombocytopenic purpura (TTP) is a syndrome characterized by widespread blood vessel clotting and bleeding. It can affect individuals of any age but is more... (Review)
Review
RATIONALE
Thrombotic thrombocytopenic purpura (TTP) is a syndrome characterized by widespread blood vessel clotting and bleeding. It can affect individuals of any age but is more commonly observed in females, particularly during pregnancy. Pregnancy combined with TTP is a critical and rapidly progressing condition that is often misdiagnosed as an obstetric disorder like severe preeclampsia or HELLP syndrome. To deepen the understanding of TTP during pregnancy with the help of a clinical case.
PATIENT CONCERNS
A 20-year-old patient, is pregnancy 1 birth 0, 32 weeks dated by her last menstrual period, presented chest tightness, and shortness of breath after physical activity for 3 days.
DIAGNOSES
TTP.
INTERVENTIONS
At present, there are no preventive measures. Timely diagnosis and treatment are useful. Plasma exchange and treat to the patient hinder autoantibodies, such as gamma globulin, methylprednisolone, rituximab, and cyclosporine were effective.
OUTCOMES
The patient exhibited stable vital signs, normal examination results, and experienced no complications. We continued to monitor her progress after she was discharged.
LESSONS SUBSECTIONS
The acute onset of TTP is often associated with pregnancy, as it is a triggering factor. Timely identification, accurate diagnosis, and a comprehensive treatment approach involving plasma exchange, immunosuppressants, and the termination of pregnancy can lead to remission and a favorable outlook for the majority of patients.
Topics: Humans; Female; Pregnancy; Purpura, Thrombotic Thrombocytopenic; Plasma Exchange; Young Adult; Pregnancy Complications, Hematologic
PubMed: 38758904
DOI: 10.1097/MD.0000000000038112 -
Medicine May 2024Soft tissue sarcoma (STS) incidence, progression, and metastasis are tightly linked to the tumor microenvironment (TME). The modification patterns mediated by...
Soft tissue sarcoma (STS) incidence, progression, and metastasis are tightly linked to the tumor microenvironment (TME). The modification patterns mediated by pyroptosis-related genes (PRGs) in STS are unknown regarding the immune cell infiltration landscape of TME, immunotherapy effect, and prognostic value. First, we downloaded STS samples from the Cancer Genome Atlas (TCGA) and gene-expression omnibus (GEO) databases. Based on 52 PRGs, 2 pyroptosis modification patterns were analyzed, and the associations of pyroptosis modification patterns with immune cell infiltration in the TME were elucidated systematically. To quantify PRG modification patterns in STS patients, we generated a pyroptosis scoring system using principal component analysis (PCA). We identified 2 distinct pyroptosis modification patterns in STS. Compared to PRG cluster A, the prognosis of cluster B was better. These 2 pyroptosis modification patterns corresponded to different characteristics of immune cell infiltration in the TME and biological behaviors. In the pyroptosis scoring system, a high pyroptosis score was connected to higher immune cell infiltration, stronger immune surveillance, immune-killing effects on tumor cells, and better clinical benefits. The results from 3 anti-PD1/PD-L1-treated immune cohorts demonstrated that higher pyroptosis scores are also closely connected to better immunotherapy results. We demonstrated that pyroptosis modification is essential to the STS microenvironment. Moreover, the pyroptosis score is a reliable and independent prognostic factor in STS patients, enabling a richer understanding of the STS microenvironment and the screening of immunotherapy candidates, predicting the immunotherapeutic effects for individual STS patients, and guiding the use of chemotherapy drugs.
Topics: Humans; Tumor Microenvironment; Pyroptosis; Sarcoma; Immunotherapy; Prognosis; Gene Expression Regulation, Neoplastic
PubMed: 38758862
DOI: 10.1097/MD.0000000000038173 -
Medicine May 2024To explore the therapeutic mechanism of Mori Cortex against osteosarcoma (OS), we conducted bioinformatics prediction followed by in vitro experimental validation.
OBJECTIVE
To explore the therapeutic mechanism of Mori Cortex against osteosarcoma (OS), we conducted bioinformatics prediction followed by in vitro experimental validation.
METHODS
Gene expression data from normal and OS tissues were obtained from the GEO database and underwent differential analysis. Active Mori Cortex components and target genes were extracted from the Traditional Chinese Medicine System Pharmacology database. By intersecting these targets with differentially expressed genes in OS, we identified potential drug action targets. Using the STRING database, a protein-protein interaction network was constructed. Subsequent analyses of these intersected genes, including Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment, were performed using R software to elucidate biological processes, molecular functions, and cellular components, resulting in the simulation of signaling pathways. Molecular docking assessed the binding capacity of small molecules to signaling pathway targets. In vitro validations were conducted on U-2 OS cells. The CCK8 assay was used to determine drug-induced cytotoxicity in OS cells, and Western Blotting was employed to validate the expression of AKT, extracellular signal-regulated kinases (ERK), Survivin, and Cyclin D1 proteins.
RESULTS
Through differential gene expression analysis between normal and OS tissues, we identified 12,364 differentially expressed genes. From the TCSMP database, 39 active components and 185 therapeutic targets related to OS were derived. The protein-protein interaction network indicated that AKT1, IL-6, JUN, VEGFA, and CASP3 might be central targets of Mori Cortex for OS. Molecular docking revealed that the active compound Morusin in Mori Cortex exhibits strong binding affinity to AKT and ERK. The CCK8 assay showed that Morusin significantly inhibits the viability of U-2 OS cells. Western Blot demonstrated a reduction in the p-AKT/AKT ratio, the p-ERK/ERK ratio, Survivin, and Cyclin D1.
CONCLUSION
Mori Cortex may exert its therapeutic effects on OS through multiple cellular signaling pathways. Morusin, the active component of Mori Cortex, can inhibit cell cycle regulation and promote cell death in OS cells by targeting AKT/ERK pathway.
Topics: Osteosarcoma; Humans; Computational Biology; Molecular Docking Simulation; Cell Line, Tumor; Drugs, Chinese Herbal; Morus; Bone Neoplasms; Protein Interaction Maps; Signal Transduction; Gene Expression Regulation, Neoplastic; Medicine, Chinese Traditional; Survivin; Cyclin D1
PubMed: 38758844
DOI: 10.1097/MD.0000000000038261 -
Medicine May 2024To investigate the mechanism by which high-dose vitamin C (HVC) promotes ferroptosis in tumor cells via network pharmacology, vitamin C-related and ferroptosis-related... (Review)
Review
To investigate the mechanism by which high-dose vitamin C (HVC) promotes ferroptosis in tumor cells via network pharmacology, vitamin C-related and ferroptosis-related targets were obtained from the PharmMapper and GeneCards databases, respectively, and their common targets were compared using the Venn diagram. Common targets were imported into the STRING database for protein-protein interaction analysis, and core targets were defined. Core targets were enriched for Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways using the R language packages. A map of the core target-based interaction network and a map of the mechanism by which HVC regulates ferroptosis were constructed. A total of 238 vitamin C-related and 721 ferroptosis-related targets were identified, of which 21 targets were common to both. Furthermore, ALDOA, AHCY, LDHB, HSPA8, LGALS3, and GSTP1 were identified as core targets. GO enrichment analysis suggested that the main biological processes included the extrinsic apoptotic signaling pathway and pyruvate metabolic process. KEGG enrichment analysis suggested that HVC regulates ferroptosis mainly through the amino acid and carbohydrate metabolic pathways. The targets were validated by molecular docking. In conclusion, HVC may promote ferroptosis in tumor cells by regulating metabolic pathways, and there is a synergistic effect between HVC and type I ferroptosis inducers. Glycolysis-dependent tumors may be beneficial for HVC therapy. Our study provides a reference for further clinical studies on HVC antitumor therapy.
Topics: Ferroptosis; Humans; Molecular Docking Simulation; Ascorbic Acid; Network Pharmacology; Neoplasms; Protein Interaction Maps
PubMed: 38758839
DOI: 10.1097/MD.0000000000038189 -
Journal of Medical Internet Research May 2024Artificial intelligence is increasingly being applied to many workflows. Large language models (LLMs) are publicly accessible platforms trained to understand, interact... (Comparative Study)
Comparative Study
Utility of Large Language Models for Health Care Professionals and Patients in Navigating Hematopoietic Stem Cell Transplantation: Comparison of the Performance of ChatGPT-3.5, ChatGPT-4, and Bard.
BACKGROUND
Artificial intelligence is increasingly being applied to many workflows. Large language models (LLMs) are publicly accessible platforms trained to understand, interact with, and produce human-readable text; their ability to deliver relevant and reliable information is also of particular interest for the health care providers and the patients. Hematopoietic stem cell transplantation (HSCT) is a complex medical field requiring extensive knowledge, background, and training to practice successfully and can be challenging for the nonspecialist audience to comprehend.
OBJECTIVE
We aimed to test the applicability of 3 prominent LLMs, namely ChatGPT-3.5 (OpenAI), ChatGPT-4 (OpenAI), and Bard (Google AI), in guiding nonspecialist health care professionals and advising patients seeking information regarding HSCT.
METHODS
We submitted 72 open-ended HSCT-related questions of variable difficulty to the LLMs and rated their responses based on consistency-defined as replicability of the response-response veracity, language comprehensibility, specificity to the topic, and the presence of hallucinations. We then rechallenged the 2 best performing chatbots by resubmitting the most difficult questions and prompting to respond as if communicating with either a health care professional or a patient and to provide verifiable sources of information. Responses were then rerated with the additional criterion of language appropriateness, defined as language adaptation for the intended audience.
RESULTS
ChatGPT-4 outperformed both ChatGPT-3.5 and Bard in terms of response consistency (66/72, 92%; 54/72, 75%; and 63/69, 91%, respectively; P=.007), response veracity (58/66, 88%; 40/54, 74%; and 16/63, 25%, respectively; P<.001), and specificity to the topic (60/66, 91%; 43/54, 80%; and 27/63, 43%, respectively; P<.001). Both ChatGPT-4 and ChatGPT-3.5 outperformed Bard in terms of language comprehensibility (64/66, 97%; 53/54, 98%; and 52/63, 83%, respectively; P=.002). All displayed episodes of hallucinations. ChatGPT-3.5 and ChatGPT-4 were then rechallenged with a prompt to adapt their language to the audience and to provide source of information, and responses were rated. ChatGPT-3.5 showed better ability to adapt its language to nonmedical audience than ChatGPT-4 (17/21, 81% and 10/22, 46%, respectively; P=.03); however, both failed to consistently provide correct and up-to-date information resources, reporting either out-of-date materials, incorrect URLs, or unfocused references, making their output not verifiable by the reader.
CONCLUSIONS
In conclusion, despite LLMs' potential capability in confronting challenging medical topics such as HSCT, the presence of mistakes and lack of clear references make them not yet appropriate for routine, unsupervised clinical use, or patient counseling. Implementation of LLMs' ability to access and to reference current and updated websites and research papers, as well as development of LLMs trained in specialized domain knowledge data sets, may offer potential solutions for their future clinical application.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Health Personnel; Artificial Intelligence; Language
PubMed: 38758582
DOI: 10.2196/54758