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Journal of Gynecologic Oncology Jun 2024In ovarian cancer (OvCa), tumor cell high glucocorticoid receptor (GR) has been associated with poor patient prognosis. In vitro, GR activation inhibits...
OBJECTIVE
In ovarian cancer (OvCa), tumor cell high glucocorticoid receptor (GR) has been associated with poor patient prognosis. In vitro, GR activation inhibits chemotherapy-induced OvCa cell death in association with transcriptional upregulation of genes encoding anti-apoptotic proteins. A recent randomized phase II study demonstrated improvement in progression-free survival (PFS) for heavily pre-treated OvCa patients randomized to receive therapy with a selective GR modulator (SGRM) plus chemotherapy compared to chemotherapy alone. We hypothesized that SGRM therapy would improve carboplatin response in OvCa patient-derived xenograft (PDX).
METHODS
Six high-grade serous (HGS) OvCa PDX models expressing GR mRNA () and protein were treated with chemotherapy +/- SGRM. Tumor size was measured longitudinally by peritoneal transcutaneous ultrasonography.
RESULTS
One of the 6 GR-positive PDX models showed a significant improvement in PFS with the addition of a SGRM. Interestingly, the single model with an improved PFS was least carboplatin sensitive. Possible explanations for the modest SGRM activity include the high carboplatin sensitivity of 5 of the PDX tumors and the potential that SGRMs activate the tumor invasive immune cells in patients (absent from immunocompromised mice). The level of tumor GR protein expression alone appears insufficient for predicting SGRM response.
CONCLUSION
The significant improvement in PFS shown in 1 of the 6 models after treatment with a SGRM plus chemotherapy underscores the need to determine predictive biomarkers for SGRM therapy in HGS OvCa and to better identify patient subgroups that are most likely to benefit from adding GR modulation to chemotherapy.
PubMed: 38909640
DOI: 10.3802/jgo.2025.36.e4 -
Parkinsonism & Related Disorders May 2024Botulinum toxin (BoNT) is first-line treatment for cervical dystonia (CD). Treatment of CD with BoNT usually requires injections every 3-4 months for as long as symptoms... (Review)
Review
INTRODUCTION
Botulinum toxin (BoNT) is first-line treatment for cervical dystonia (CD). Treatment of CD with BoNT usually requires injections every 3-4 months for as long as symptoms persist, which can be for the lifetime of the individual. Duration of BoNT effect can impact quality of life since it is important that efficacy is maintained throughout an injection cycle to avoid fluctuations of effect after each injection. There is currently no consensus on how to assess duration of BoNT effect in patients with CD.
METHODS
A scoping review was conducted to summarize the available evidence from phase 3 clinical trials of BoNT in CD and on the interpretation of the reported duration of effect. The available evidence was analyzed in the context of clinical experience and real-world treatment practices of CD.
RESULTS
Methods for estimating duration of effect varied across publications; most were based on artificial constructs developed for clinical trials (time until a pre-specified efficacy endpoint was reached) and are not appropriate to apply in clinical practice. Clinical trial outcomes in CD were not objectively evaluated, and did not prioritize patients' needs or focus on factors that impact patients' daily living activities and quality of life.
CONCLUSION
Better evidence and consistency of reporting for duration of effect for BoNT in CD is needed to help guide clinicians on when reinjection is likely to be required. The goal should be to keep patients as symptom-free as possible with flexible reinjection intervals tailored to individual needs.
PubMed: 38909588
DOI: 10.1016/j.parkreldis.2024.107011 -
Scientific Reports Jun 2024Intoeing in children is a common parental concern, but our understanding of the impact of foot progression angle (FPA) in these children leaves remains limited. This...
Intoeing in children is a common parental concern, but our understanding of the impact of foot progression angle (FPA) in these children leaves remains limited. This study examines the relationship between FPA and plantar loading pattern, as well as gait symmetry in children with intoeing. The sample included 30 children with intoeing caused by internal tibial torsion, uniformly divided into three groups: unilateral intoeing, bilateral mild intoeing, and bilateral mild-moderate intoeing. The relationship between FPA and plantar loading pattern, and gait symmetry within and among groups were assessed using dynamic pedobarographic and spatiotemporal data. Results indicated a significant correlation between FPA and peak pressure, maximum force, and plantar impulse in the medial and central forefoot, and also the medial and lateral heel zones for both bilateral intoeing groups. Significant differences were observed only in subdivided stance phase, including loading response, single support, and pre-swing phases, between the unilateral intoeing and bilateral mild intoeing groups. These findings suggest that FPA significantly affects the forefoot and heel zones, potentially increasing the load on the support structures and leading to transverse arch deformation. While children with intoeing demonstrate a dynamic self-adjustment capability to maintain gait symmetry, this ability begins to falter as intoeing becomes more pronounced.
Topics: Humans; Child; Gait; Female; Male; Foot; Weight-Bearing; Biomechanical Phenomena
PubMed: 38909161
DOI: 10.1038/s41598-024-65422-5 -
BMJ Open Jun 2024Globally, transgender ('trans') women experience extreme social and economic marginalisation due to intersectional stigma, defined as the confluence of stigma that...
Reducing intersectional stigma among transgender women in Brazil to promote uptake of HIV testing and PrEP: study protocol for a randomised controlled trial of Manas por Manas.
INTRODUCTION
Globally, transgender ('trans') women experience extreme social and economic marginalisation due to intersectional stigma, defined as the confluence of stigma that results from the intersection of social identities and positions among those who are oppressed multiple times. Among trans women, gender-based stigma intersects with social positions such as engagement in sex work and substance use, as well as race-based stigma to generate a social context of vulnerability and increased risk of HIV acquisition. In Brazil, trans women are the 'most at-risk' group for HIV, with 55 times higher estimated odds of HIV infection than the general population; further, uptake of HIV testing and pre-exposure prophylaxis (PrEP) among trans women is significantly lower than other at-risk groups. Through extensive formative work, we developed Manas por Manas, a multilevel intervention using HIV prevention strategies with demonstrated feasibility and acceptability by trans women in Brazil, to address intersectional stigma and increase engagement in the HIV prevention continuum.
METHODS AND ANALYSIS
We are conducting a two-arm randomised wait-list controlled trial of the intervention's efficacy in São Paulo, Brazil, to improve uptake of HIV testing and PrEP among transgender women (N=400). The primary outcomes are changes in HIV testing (self-testing and clinic based), changes in PrEP uptake and changes in PrEP persistence at baseline and follow-up assessment for 12 months at 3-month intervals.
ETHICS AND DISSEMINATION
This study was approved by University of California, San Francisco Institutional Review Board (15-17910) and Comissão Nacional de Ética em Pesquisa (Research Ethics National Commission, CAAE: 25215219.8.0000.5479) in Brazil. Participants provided informed consent before enrolment. We are committed to collaboration with National Institutes of Health officials, other researchers, and health and social services communities for rapid dissemination of data and sharing of materials. The results will be published in peer-reviewed academic journals and scientific presentations.
TRIAL REGISTRATION NUMBER
NCT03081559.
Topics: Humans; Transgender Persons; Brazil; Female; HIV Infections; Pre-Exposure Prophylaxis; Social Stigma; Male; Adult; HIV Testing; Randomized Controlled Trials as Topic; Young Adult; Adolescent; Patient Acceptance of Health Care
PubMed: 38908840
DOI: 10.1136/bmjopen-2023-076878 -
Molecular Metabolism Jun 2024Cachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all...
OBJECTIVES
Cachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all cancer deaths. In acute myeloid leukemia, somatic mutations of the metabolic enzyme isocitrate dehydrogenase 1 and 2 cause the production of the oncometabolite D2-hydroxyglutarate (D2-HG). Increased production of D2-HG is associated with heart and skeletal muscle atrophy, but the mechanistic links between metabolic and proteomic remodeling remain poorly understood. Therefore, we assessed how oncometabolic stress by D2-HG activates autophagy and drives skeletal muscle loss.
METHODS
We quantified genomic, metabolomic, and proteomic changes in cultured skeletal muscle cells and mouse models of IDH-mutant leukemia using RNA sequencing, mass spectrometry, and computational modeling.
RESULTS
D2-HG impairs NADH redox homeostasis in myotubes. Increased NAD+ levels drive activation of nuclear deacetylase Sirt1, which causes deacetylation and activation of LC3, a key regulator of autophagy. Using LC3 mutants, we confirm that deacetylation of LC3 by Sirt1 shifts its distribution from the nucleus into the cytosol, where it can undergo lipidation at pre-autophagic membranes. Sirt1 silencing or p300 overexpression attenuated autophagy activation in myotubes. In vivo, we identified increased muscle atrophy and reduced grip strength in response to D2-HG in male vs. female mice. In male mice, glycolytic intermediates accumulated, and protein expression of oxidative phosphorylation machinery was reduced. In contrast, female animals upregulated the same proteins, attenuating the phenotype in vivo. Network modeling and machine learning algorithms allowed us to identify candidate proteins essential for regulating oncometabolic adaptation in mouse skeletal muscle.
CONCLUSIONS
Our multi-omics approach exposes new metabolic vulnerabilities in response to D2-HG in skeletal muscle and provides a conceptual framework for identifying therapeutic targets in cachexia.
PubMed: 38908793
DOI: 10.1016/j.molmet.2024.101969 -
European Journal of Paediatric... May 2024Inflammation related to influenza virus infection can lead to multiple neurological presentations. Encephalitis is one of them, mostly accompanied by seizures, with...
INTRODUCTION
Inflammation related to influenza virus infection can lead to multiple neurological presentations. Encephalitis is one of them, mostly accompanied by seizures, with different profiles depending on the epidemics and previous medical conditions.
MATERIALS AND METHODS
All children presenting neurological symptoms and positive for influenza virus RNA detection in a respiratory sample between November 2018 and April 2023, hospitalized in the Department of Paediatric Neurology of Toulouse Children's Hospital, were retrospectively analysed.
RESULTS
Among the 1,277 children diagnosed with influenza in our centre, 131 (10.3 %) were hospitalized for neurological features. The year 2020-2021 was marked by zero incidence of positive influenza tests, associated with the COVID-19 pandemic. Among the 131 patients included, 71.6 % were under 5 years old. Most of them (80.9 %) were infected by influenza A virus. The first neurological symptoms were mainly seizures in 73.3 % of patients. Possible or confirmed encephalitis was observed in 29 % of cases, including one acute necrotizing encephalopathy. Few children (6.1 %) presented with acute myositis. Twenty-seven patients (20.6 %) had a personal history of significant previous neurological disorders. Most patients (88.5 %) displayed a rapid favourable outcome, marked by the disappearance of their neurological symptoms within the first 2 days. Anti-epileptic drugs were introduced in 1.5 % of cases, and adapted in 16.8 %, mainly in patients with febrile status epilepticus and an abnormal EEG.
CONCLUSION
Neurological features were frequently associated with influenza infection in children; most were transient. Effects on long-term neurodevelopmental outcomes need to be clarified as our follow-up was limited, especially in children with pre-existing neurological conditions.
PubMed: 38908343
DOI: 10.1016/j.ejpn.2024.05.012 -
Acta Neuropathologica Communications Jun 2024Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs)....
snRNA-seq of human cutaneous neurofibromas before and after selumetinib treatment implicates role of altered Schwann cell states, inter-cellular signaling, and extracellular matrix in treatment response.
Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs). Currently the only approved therapeutic for NF1 is selumetinib, a mitogen -activated protein kinase (MEK) inhibitor. The purpose of this study was to analyze the transcriptome of cNF tumors before and on selumetinib treatment to understand both tumor composition and response. We obtained biopsy sets of tumors both pre- and on- selumetinib treatment from the same individuals and were able to collect sets from four separate individuals. We sequenced mRNA from 5844 nuclei and identified 30,442 genes in the untreated group and sequenced 5701 nuclei and identified 30,127 genes in the selumetinib treated group. We identified and quantified distinct populations of cells (Schwann cells, fibroblasts, pericytes, myeloid cells, melanocytes, keratinocytes, and two populations of endothelial cells). While we anticipated that cell proportions might change with treatment, we did not identify any one cell population that changed significantly, likely due to an inherent level of variability between tumors. We also evaluated differential gene expression based on drug treatment in each cell type. Ingenuity pathway analysis (IPA) was also used to identify pathways that differ on treatment. As anticipated, we identified a significant decrease in ERK/MAPK signaling in cells including Schwann cells but most specifically in myeloid cells. Interestingly, there is a significant decrease in opioid signaling in myeloid and endothelial cells; this downward trend is also observed in Schwann cells and fibroblasts. Cell communication was assessed by RNA velocity, Scriabin, and CellChat analyses which indicated that Schwann cells and fibroblasts have dramatically altered cell states defined by specific gene expression signatures following treatment (RNA velocity). There are dramatic changes in receptor-ligand pairs following treatment (Scriabin), and robust intercellular signaling between virtually all cell types associated with extracellular matrix (ECM) pathways (Collagen, Laminin, Fibronectin, and Nectin) is downregulated after treatment. These response specific gene signatures and interaction pathways could provide clues for understanding treatment outcomes or inform future therapies.
Topics: Humans; Schwann Cells; Skin Neoplasms; Benzimidazoles; Extracellular Matrix; Signal Transduction; Neurofibroma; Female; Male; RNA-Seq; Middle Aged; Adult; Neurofibromatosis 1; Protein Kinase Inhibitors; Transcriptome
PubMed: 38907342
DOI: 10.1186/s40478-024-01821-z -
Cardiovascular Diabetology Jun 2024Circulating atherogenic index of plasma (AIP) levels has been proposed as a novel biomarker for dyslipidemia and as a predictor of insulin resistance (IR) risk. However,... (Comparative Study)
Comparative Study
BACKGROUND
Circulating atherogenic index of plasma (AIP) levels has been proposed as a novel biomarker for dyslipidemia and as a predictor of insulin resistance (IR) risk. However, the association between AIP and the incidence of new-onset stroke, particularly in individuals with varying glucose metabolism status, remains ambiguous.
METHODS
A total of 8727 participants aged 45 years or older without a history of stroke from the China Health and Retirement Longitudinal Study (CHARLS) were included in this study. The AIP was calculated using the formula log [Triglyceride (mg/dL) / High-density lipoprotein cholesterol (mg/dL)]. Participants were divided into four groups based on their baseline AIP levels: Q1 (AIP ≤ 0.122), Q2 (0.122 < AIP ≤ 0.329), Q3 (0.329 < AIP ≤ 0.562), and Q4 (AIP > 0.562). The primary endpoint was the occurrence of new-onset stroke events. The Kaplan-Meier curves, multivariate Cox proportional hazard models, and Restricted cubic spline analysis were applied to explore the association between baseline AIP levels and the risk of developing a stroke among individuals with varying glycemic metabolic states.
RESULTS
During an average follow-up of 8.72 years, 734 participants (8.4%) had a first stroke event. The risk for stroke increased with each increasing quartile of baseline AIP levels. Kaplan-Meier curve analysis revealed a significant difference in stroke occurrence among the AIP groups in all participants, as well as in those with prediabetes mellitus (Pre-DM) and diabetes mellitus (DM) (all P values < 0.05). After adjusting for potential confounders, the risk of stroke was significantly higher in the Q2, Q3, and Q4 groups than in the Q1 group in all participants. The respective hazard ratios (95% confidence interval) for stroke in the Q2, Q3, and Q4 groups were 1.34 (1.05-1.71), 1.52 (1.19-1.93), and 1.84 (1.45-2.34). Furthermore, high levels of AIP were found to be linked to an increased risk of stroke in both pre-diabetic and diabetic participants across all three Cox models. However, this association was not observed in participants with normal glucose regulation (NGR) (p > 0.05). Restricted cubic spline analysis also demonstrated that higher baseline AIP levels were associated with higher hazard ratios for stroke in all participants and those with glucose metabolism disorders.
CONCLUSIONS
An increase in baseline AIP levels was significantly associated with the risk of stroke in middle-aged and elderly individuals, and exhibited distinct characteristics depending on the individual's glucose metabolism status.
Topics: Humans; Male; Female; Middle Aged; Risk Factors; Aged; Blood Glucose; Biomarkers; China; Risk Assessment; Incidence; Stroke; Time Factors; Longitudinal Studies; Prognosis; Insulin Resistance; Triglycerides; Cholesterol, HDL; Dyslipidemias; Atherosclerosis; Prospective Studies
PubMed: 38907337
DOI: 10.1186/s12933-024-02314-y -
Journal of Nanobiotechnology Jun 2024Osteosarcoma (OS) derived small extracellular vesicles (OS-sEVs) have been shown to induce the formation of cancer-associated fibroblasts (CAFs), characterized by...
Osteosarcoma (OS) derived small extracellular vesicles (OS-sEVs) have been shown to induce the formation of cancer-associated fibroblasts (CAFs), characterized by elevated pro-inflammatory factor expression and enhanced migratory and contractile abilities. These CAFs play a crucial role in priming lung metastasis by orchestrating the pre-metastatic niche (PMN) in the lung. Disrupting the communication between OS-sEVs and lung fibroblasts (LFs) emerges as a potent strategy to hinder OS pulmonary metastasis. Our previously established saponin-mediated cargo-elimination strategy effectively reduces the cancer-promoting ability of tumor-derived small extracellular vesicles (TsEVs) while preserving their inherent targeting capability. In this study, we observed that cargo-eliminated OS-sEVs (CE-sEVs) display minimal pro-tumoral and LFs activation potential, yet retain their ability to target LFs. The uptake of OS-sEVs by LFs can be concentration-dependently suppressed by CE-sEVs, preventing the conversion of LFs into CAFs and thus inhibiting PMN formation and pulmonary metastasis of OS. In summary, this study proposes a potential strategy to prevent LFs activation, PMN formation in the lung, and OS pulmonary metastasis through competitive inhibition of OS-sEVs' function by CE-sEVs.
Topics: Osteosarcoma; Extracellular Vesicles; Lung Neoplasms; Animals; Humans; Mice; Cell Line, Tumor; Bone Neoplasms; Cancer-Associated Fibroblasts; Mice, Inbred BALB C; Saponins; Mice, Nude; Cell Movement; Lung
PubMed: 38907233
DOI: 10.1186/s12951-024-02636-9 -
BMC Medical Research Methodology Jun 2024As evidence related to the COVID-19 pandemic surged, databases, platforms, and repositories evolved with features and functions to assist users in promptly finding the...
BACKGROUND
As evidence related to the COVID-19 pandemic surged, databases, platforms, and repositories evolved with features and functions to assist users in promptly finding the most relevant evidence. In response, research synthesis teams adopted novel searching strategies to sift through the vast amount of evidence to synthesize and disseminate the most up-to-date evidence. This paper explores the key database features that facilitated systematic searching for rapid evidence synthesis during the COVID-19 pandemic to inform knowledge management infrastructure during future global health emergencies.
METHODS
This paper outlines the features and functions of previously existing and newly created evidence sources routinely searched as part of the NCCMT's Rapid Evidence Service methods, including databases, platforms, and repositories. Specific functions of each evidence source were assessed as they pertain to searching in the context of a public health emergency, including the topics of indexed citations, the level of evidence of indexed citations, and specific usability features of each evidence source.
RESULTS
Thirteen evidence sources were assessed, of which four were newly created and nine were either pre-existing or adapted from previously existing resources. Evidence sources varied in topics indexed, level of evidence indexed, and specific searching functions.
CONCLUSION
This paper offers insights into which features enabled systematic searching for the completion of rapid reviews to inform decision makers within 5-10 days. These findings provide guidance for knowledge management strategies and evidence infrastructures during future public health emergencies.
Topics: COVID-19; Humans; Public Health; SARS-CoV-2; Databases, Factual; Pandemics; Emergencies; Information Storage and Retrieval
PubMed: 38907198
DOI: 10.1186/s12874-024-02246-x