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1.
Article En | MEDLINE | ID: mdl-38843933

OBJECTIVES: This study investigates retreatment rates in single-fraction radiation therapy (SFRT) for painful bone metastasis in patients with limited life expectancy. We compared retreatment-free survival (RFS) in patients from a rapid access bone metastases clinic (RABC) and non-RABC patients, identifying factors associated with retreatment. METHODS: In this observational study, we analysed RABC patients who received SFRT between April 2018 and November 2019, using non-RABC SFRT patients as a comparison group. Patients with prior or perioperative radiation therapy (RT) were excluded. The primary endpoint was same-site and any-site retreatment with RT or surgery. Patient characteristics were compared using χ2 and Student's t-tests, with RFS estimates based on a multistate model considering death as a competing risk using Aalen-Johansen estimates. RESULTS: We identified 151 patients (79 RABC, 72 non-RABC) with 225 treatments (102 RABC, 123 non-RABC) meeting eligibility criteria. Of the 22 (10.8%) same-site retreatments, 5 (22.7%) received surgery, 14 (63.6%) received RT and 3 (13.6%) received both RT and surgery. We found no significant differences in any-site RFS (p=0.97) or same-site RFS (p=0.11). CONCLUSIONS: RFS is high and similar comparable in the RABC and non-RABC cohorts. Retreatment rates are low, even in patients with low Eastern Cooperative Oncology Group scores.

2.
Cells ; 13(10)2024 May 16.
Article En | MEDLINE | ID: mdl-38786066

Immune cell migration is required for the development of an effective and robust immune response. This elegant process is regulated by both cellular and environmental factors, with variables such as immune cell state, anatomical location, and disease state that govern differences in migration patterns. In all cases, a major factor is the expression of cell surface receptors and their cognate ligands. Rapid adaptation to environmental conditions partly depends on intrinsic cellular immune factors that affect a cell's ability to adjust to new environment. In this review, we discuss both myeloid and lymphoid cells and outline key determinants that govern immune cell migration, including molecules required for immune cell adhesion, modes of migration, chemotaxis, and specific chemokine signaling. Furthermore, we summarize tumor-specific elements that contribute to immune cell trafficking to cancer, while also exploring microenvironment factors that can alter these cellular dynamics within the tumor in both a pro and antitumor fashion. Specifically, we highlight the importance of the secretome in these later aspects. This review considers a myriad of factors that impact immune cell trajectory in cancer. We aim to highlight the immunotherapeutic targets that can be harnessed to achieve controlled immune trafficking to and within tumors.


Cell Movement , Neoplasms , Tumor Microenvironment , Humans , Neoplasms/immunology , Neoplasms/pathology , Tumor Microenvironment/immunology , Animals , Lymphocytes/immunology , Lymphocytes/metabolism , Signal Transduction
3.
Materials (Basel) ; 17(9)2024 Apr 24.
Article En | MEDLINE | ID: mdl-38730775

The utilization of triboelectric materials has gained considerable attention in recent years, offering a sustainable approach to energy harvesting and sensing technologies. Biomass-derived materials, owing to their abundance, renewability, and biocompatibility, offer promising avenues for enhancing the performance and versatility of triboelectric devices. This paper explores the synthesis and characterization of biomass-derived materials, their integration into triboelectric nanogenerators (TENGs), and their applications in energy harvesting, self-powered sensors, and environmental monitoring. This review presents an overview of the emerging field of advanced triboelectric applications that utilize the unique properties of biomass-derived materials. Additionally, it addresses the challenges and opportunities in employing biomass-derived materials for triboelectric applications, emphasizing the potential for sustainable and eco-friendly energy solutions.

4.
Nat Genet ; 56(5): 889-899, 2024 May.
Article En | MEDLINE | ID: mdl-38741018

The extent of cell-to-cell variation in tumor mitochondrial DNA (mtDNA) copy number and genotype, and the phenotypic and evolutionary consequences of such variation, are poorly characterized. Here we use amplification-free single-cell whole-genome sequencing (Direct Library Prep (DLP+)) to simultaneously assay mtDNA copy number and nuclear DNA (nuDNA) in 72,275 single cells derived from immortalized cell lines, patient-derived xenografts and primary human tumors. Cells typically contained thousands of mtDNA copies, but variation in mtDNA copy number was extensive and strongly associated with cell size. Pervasive whole-genome doubling events in nuDNA associated with stoichiometrically balanced adaptations in mtDNA copy number, implying that mtDNA-to-nuDNA ratio, rather than mtDNA copy number itself, mediated downstream phenotypes. Finally, multimodal analysis of DLP+ and single-cell RNA sequencing identified both somatic loss-of-function and germline noncoding variants in mtDNA linked to heteroplasmy-dependent changes in mtDNA copy number and mitochondrial transcription, revealing phenotypic adaptations to disrupted nuclear/mitochondrial balance.


Cell Nucleus , DNA Copy Number Variations , DNA, Mitochondrial , Genome, Mitochondrial , Neoplasms , Single-Cell Analysis , Humans , DNA, Mitochondrial/genetics , Single-Cell Analysis/methods , DNA Copy Number Variations/genetics , Cell Nucleus/genetics , Neoplasms/genetics , Neoplasms/pathology , Cell Line, Tumor , Animals , Mitochondria/genetics , Whole Genome Sequencing/methods , Mice , Heteroplasmy/genetics
5.
Biomed Pharmacother ; 175: 116770, 2024 Jun.
Article En | MEDLINE | ID: mdl-38772154

Patients with inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), often have concomitant mental disorders such as depression and anxiety. Therefore, a bidirectional approach involving the gut and brain axes is necessary for the prevention and treatment thereof. In this study, we explored the potential of Poncirus trifoliata extract (PT), traditionally known for its neuroprotective effects against gastrointestinal diseases, as a natural treatment agent for IBD in a dextran sulfate sodium (DSS)-induced colitis model. Oral administration of PT ameliorated weight loss and inflammatory responses in mice with DSS-induced colitis. Furthermore, PT treatment effectively restored the colon length and ameliorated enterocyte death by inhibiting DSS-induced reactive oxygen species (ROS)-mediated necroptosis. The main bioactive components of PT, poncirin and naringin, confirmed using ultra-performance liquid chromatography-quadrupole time-of-flight (UPLC-qTOF), can be utilized to regulate necroptosis. The antidepressant-like effects of PT were confirmed using open field test (OFT) and tail suspension test (TST). PT treatment also restored vascular endothelial cell integrity in the hippocampus. In the Cornu Ammonis 1 (CA1) and dentate gyrus (DG) regions of the hippocampus, PT controlled the neuroinflammatory responses of proliferated microglia. In conclusion, PT, which contains high levels of poncirin and naringin, has potential as a bidirectional therapeutic agent that can simultaneously improve IBD-associated intestinal and mental disorders.


Colitis , Depression , Dextran Sulfate , Flavanones , Mice, Inbred C57BL , Plant Extracts , Poncirus , Animals , Poncirus/chemistry , Plant Extracts/pharmacology , Plant Extracts/isolation & purification , Male , Mice , Depression/drug therapy , Flavanones/pharmacology , Flavanones/isolation & purification , Colitis/drug therapy , Colitis/chemically induced , Colitis/pathology , Behavior, Animal/drug effects , Disease Models, Animal , Antidepressive Agents/pharmacology , Antidepressive Agents/isolation & purification , Flavonoids/pharmacology , Flavonoids/isolation & purification , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/pathology , Reactive Oxygen Species/metabolism
6.
Science ; 384(6698): eadh7688, 2024 May 24.
Article En | MEDLINE | ID: mdl-38781356

RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, the role of cell type-specific splicing and transcript-isoform diversity during human brain development has not been systematically investigated. In this work, we leveraged single-molecule long-read sequencing to deeply profile the full-length transcriptome of the germinal zone and cortical plate regions of the developing human neocortex at tissue and single-cell resolution. We identified 214,516 distinct isoforms, of which 72.6% were novel (not previously annotated in Gencode version 33), and uncovered a substantial contribution of transcript-isoform diversity-regulated by RNA binding proteins-in defining cellular identity in the developing neocortex. We leveraged this comprehensive isoform-centric gene annotation to reprioritize thousands of rare de novo risk variants and elucidate genetic risk mechanisms for neuropsychiatric disorders.


Mental Disorders , Neocortex , Neurogenesis , Protein Isoforms , RNA Splicing , Single-Cell Analysis , Transcriptome , Humans , Alternative Splicing , Genetic Predisposition to Disease , Mental Disorders/genetics , Molecular Sequence Annotation , Neocortex/metabolism , Neocortex/embryology , Protein Isoforms/genetics , Protein Isoforms/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Neurogenesis/genetics
7.
Science ; 384(6698): eadh0829, 2024 May 24.
Article En | MEDLINE | ID: mdl-38781368

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.


Alternative Splicing , Brain , Gene Expression Regulation, Developmental , Mental Disorders , Humans , Atlases as Topic , Autism Spectrum Disorder/genetics , Brain/metabolism , Brain/growth & development , Brain/embryology , Gene Regulatory Networks , Genome-Wide Association Study , Protein Isoforms/genetics , Protein Isoforms/metabolism , Quantitative Trait Loci , Schizophrenia/genetics , Transcriptome , Mental Disorders/genetics
8.
Shock ; 2024 May 23.
Article En | MEDLINE | ID: mdl-38813923

BACKGROUND: The recruitment of neutrophils to sites of localized injury or infection is initiated by changes on the surface of endothelial cells located in proximity to tissue damage. Inflammatory mediators, such as TNF-α, increase surface expression of adhesive ligands and receptors on the endothelial surface to which neutrophils tether and adhere. Neutrophils then transit through the activated endothelium to reach sites of tissue injury with little lasting vascular injury. However, in cases of sepsis, the interaction of endothelial cells with highly activated neutrophils can cause damage vascular damage. The identification of molecules that are essential for neutrophil diapedesis may reveal targets of therapeutic opportunity for preservation of endothelial function in the presence of critical illness. We tested the hypothesis that inhibition of neutrophil ß1 integrin Very Late Antigen-3 (VLA-3; α3ß1) and/or inhibition of the Tetraspanin (TM4) family member CD151 would protect against neutrophil-mediated loss of endothelial function. METHODS: Blood was obtained from septic patients or healthy donors. Neutrophils were purified and aliquots were treated with/without proinflammatory molecules. Confluent Human Umbilical Vascular Endothelial Cells (HUVECs) were activated with tumor necrosis factor (TNF-α). Electric Cell Impedance Sensing (ECIS) was used to determine monolayer resistance over time after the addition of neutrophils that were treated with blocking antibodies against VLA-3 and/or CD151 or isotype controls. Groups (depending on relevancy) were analyzed by Mann-Whitney test, Wilcoxon test, or repeated measures one-way analysis of variance (ANOVA). RESULTS: Neutrophils from septic patients and neutrophils activated ex vivo reduced endothelial monolayer resistance to a greater extent than neutrophils from healthy donors. Antibody blockade of VLA-3 and/or CD151 significantly reduced activation-associated endothelial damage. Similar findings were demonstrated on fibronectin, collagen I, collagen IV and laminin suggesting that neutrophil surface VLA-3 and CD151 are responsible for endothelial damage regardless of substrata and are likely to be operative in all bodily tissues. CONCLUSION: This report identifies VLA-3 and CD151, on the activated human neutrophil that are responsible for damage to endothelial function. Targeting these molecules in vivo may demonstrate preservation of organ function during critical illness.

9.
Front Pharmacol ; 15: 1352842, 2024.
Article En | MEDLINE | ID: mdl-38590637

Introduction: Fusion of the fragment crystallizable (Fc) to protein therapeutics is commonly used to extend the circulation time by enhancing neonatal Fc-receptor (FcRn)-mediated endosomal recycling and slowing renal clearance. This study applied kinetic modeling to gain insights into the cellular processing contributing to the observed pharmacokinetic (PK) differences between the novel recombinant ADAMTS13 fragment (MDTCS) and its Fc-fusion protein (MDTCS-Fc). Methods: For MDTCS and MDTCS-Fc, their plasma PK profiles were obtained at two dose levels following intravenous administration of the respective proteins to mice. The plasma PK profiles of MDTCS were fitted to a kinetic model with three unknown protein-dependent parameters representing the fraction recycled (FR) and the rate constants for endocytosis (kup, for the uptake into the endosomes) and for the transfer from the plasma to the interstitial fluid (kpi). For MDTCS-Fc, the model was modified to include an additional parameter for binding to FcRn. Parameter optimization was done using the Cluster Gauss-Newton Method (CGNM), an algorithm that identifies multiple sets of approximate solutions ("accepted" parameter sets) to nonlinear least-squares problems. Results: As expected, the kinetic modeling results yielded the FR of MDTCS-Fc to be 2.8-fold greater than that of MDTCS (0.8497 and 0.3061, respectively). In addition, MDTCS-Fc was predicted to undergo endocytosis (the uptake into the endosomes) at a slower rate than MDTCS. Sensitivity analyses identified the association rate constant (kon) between MDTCS-Fc and FcRn as a potentially important factor influencing the plasma half-life in vivo. Discussion: Our analyses suggested that Fc fusion to MDTCS leads to changes in not only the FR but also the uptake into the endosomes, impacting the systemic plasma PK profiles. These findings may be used to develop recombinant protein therapeutics with extended circulation time.

10.
Clin Pharmacol Ther ; 2024 Apr 26.
Article En | MEDLINE | ID: mdl-38666606

Fibroblast growth factor (FGF)-21 analogs are potential therapeutic candidates for metabolic dysfunction-associated steatohepatitis (MASH). This systematic review and meta-analysis aimed to assess the efficacy and safety of the FGF-21 analogs, efruxifermin, pegbelfermin, and pegozafermin for MASH treatment. A comprehensive systematic review and meta-analysis of randomized controlled trials from five major databases was conducted. Primary efficacy outcomes focused on liver histological improvement, while secondary efficacy outcomes encompassed reductions in liver fat content and improvements in biochemical parameters. Safety outcomes examined included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, TEAEs leading to discontinuation, and serious TEAEs. Eight eligible studies involving 963 patients were included in this review. Compared with the placebo group, the FGF-21 analog-treated group exhibited significantly improved primary efficacy outcomes, specifically ≥1 stage improvement in fibrosis with no worsening of MASH (risk ratio [RR] = 1.83; 95% confidence interval [CI] = 1.27-2.62) and at least two-point improvement in the non-alcoholic fatty liver disease activity score with no worsening of fibrosis (RR = 2.85; 95% CI = 2.06-3.95). Despite an increased risk of TEAEs (RR = 1.17; 95% CI = 1.08-1.27) and treatment-related adverse events (RR = 1.75; 95% CI = 1.40-2.19), FGF-21 analogs exhibited an acceptable safety profile. FGF-21 analogs were significantly better in achieving liver histological improvements and beneficial biochemical outcomes compared with placebo, with a tolerable safety pattern. These findings shed light on the efficacy and safety of FGF-21 analogs and provide valuable evidence for their application as MASH therapeutics.

11.
Korean J Pain ; 37(2): 119-131, 2024 Apr 01.
Article En | MEDLINE | ID: mdl-38557654

There are growing concerns regarding the safety of long-term treatment with opioids of patients with chronic non-cancer pain. In 2017, the Korean Pain Society (KPS) developed guidelines for opioid prescriptions for chronic non-cancer pain to guide physicians to prescribe opioids effectively and safely. Since then, investigations have provided updated data regarding opioid therapy for chronic non-cancer pain and have focused on initial dosing schedules, reassessment follow-ups, recommended dosage thresholds considering the risk-benefit ratio, dose-reducing schedules for tapering and discontinuation, adverse effects, and inadvertent problems resulting from inappropriate application of the previous guidelines. Herein, we have updated the previous KPS guidelines based on a comprehensive literature review and consensus development following discussions among experts affiliated with the Committee on Hospice and Palliative Care in the KPS. These guidelines may assist physicians in prescribing opioids for chronic non-cancer pain in adult outpatient settings, but should not to be regarded as an inflexible standard. Clinical judgements by the attending physician and patient-centered decisions should always be prioritized.

12.
Biomedicines ; 12(4)2024 Apr 07.
Article En | MEDLINE | ID: mdl-38672167

Ischemic stroke poses a significant global health challenge, necessitating ongoing exploration of its pathophysiology and treatment strategies. This comprehensive review integrates various aspects of ischemic stroke research, emphasizing crucial mechanisms, therapeutic approaches, and the role of clinical imaging in disease management. It discusses the multifaceted role of Netrin-1, highlighting its potential in promoting neurovascular repair and mitigating post-stroke neurological decline. It also examines the impact of blood-brain barrier permeability on stroke outcomes and explores alternative therapeutic targets such as statins and sphingosine-1-phosphate signaling. Neurocardiology investigations underscore the contribution of cardiac factors to post-stroke mortality, emphasizing the importance of understanding the brain-heart axis for targeted interventions. Additionally, the review advocates for early reperfusion and neuroprotective agents to counter-time-dependent excitotoxicity and inflammation, aiming to preserve tissue viability. Advanced imaging techniques, including DWI, PI, and MR angiography, are discussed for their role in evaluating ischemic penumbra evolution and guiding therapeutic decisions. By integrating molecular insights with imaging modalities, this interdisciplinary approach enhances our understanding of ischemic stroke and offers promising avenues for future research and clinical interventions to improve patient outcomes.

13.
Food Chem ; 451: 139437, 2024 Sep 01.
Article En | MEDLINE | ID: mdl-38678653

This study explores the potential for optimizing a sustainable manufacturing process that maintains the essential characteristics of conventional liposomes using food-grade solvents and components. The focus was comparing the physicochemical, morphological, and interfacial properties of liposomes produced with these food-grade ingredients to those made by conventional methods. It was found that there was no significant difference in particle size (195.87 ± 1.40 nm) and ζ-potential (-45.13 ± 0.65 mV) between liposomes made from food-grade and conventional materials. The manufacturing process for liposomes, utilizing food-grade solvents and components, was optimized through the application of Plackett-Burman design and response surface methodology. This approach helped identify key parameters (soy lecithin, ß-sitosterol, W/O ratio) and their optimal values (3.17 g, 0.25 g, 1:2.59). These findings suggest that it is possible to enhance the use of liposomes as an effective and safe delivery system in the food industry, adhering to the strict guidelines set by regulatory agencies.


Lecithins , Liposomes , Particle Size , Liposomes/chemistry , Lecithins/chemistry , Sitosterols/chemistry , Microfluidics/instrumentation , Glycine max/chemistry
14.
J Exp Med ; 221(6)2024 Jun 03.
Article En | MEDLINE | ID: mdl-38607370

Cytokine release syndrome (CRS) is a frequently observed side effect of chimeric antigen receptor (CAR)-T cell therapy. Here, we report self-regulating T cells that reduce CRS severity by secreting inhibitors of cytokines associated with CRS. With a humanized NSG-SGM3 mouse model, we show reduced CRS-related toxicity in mice treated with CAR-T cells secreting tocilizumab-derived single-chain variable fragment (Toci), yielding a safety profile superior to that of single-dose systemic tocilizumab administration. Unexpectedly, Toci-secreting CD19 CAR-T cells exhibit superior in vivo antitumor efficacy compared with conventional CD19 CAR-T cells. scRNA-seq analysis of immune cells recovered from tumor-bearing humanized mice revealed treatment with Toci-secreting CD19 CAR-T cells enriches for cytotoxic T cells while retaining memory T-cell phenotype, suggesting Toci secretion not only reduces toxicity but also significantly alters the overall T-cell composition. This approach of engineering T cells to self-regulate inflammatory cytokine production is a clinically compatible strategy with the potential to simultaneously enhance safety and efficacy of CAR-T cell therapy for cancer.


Cytokine Release Syndrome , Cytokines , Animals , Mice , Cytokine Release Syndrome/etiology , Adaptor Proteins, Signal Transducing , Antigens, CD19 , Cell- and Tissue-Based Therapy
15.
Materials (Basel) ; 17(3)2024 Jan 29.
Article En | MEDLINE | ID: mdl-38592009

The depletion of reliable energy sources and the environmental and climatic repercussions of polluting energy sources have become global challenges. Hence, many countries have adopted various renewable energy sources including hydrogen. Hydrogen is a future energy carrier in the global energy system and has the potential to produce zero carbon emissions. For the non-fossil energy sources, hydrogen and electricity are considered the dominant energy carriers for providing end-user services, because they can satisfy most of the consumer requirements. Hence, the development of both hydrogen production and storage is necessary to meet the standards of a "hydrogen economy". The physical and chemical absorption of hydrogen in solid storage materials is a promising hydrogen storage method because of the high storage and transportation performance. In this paper, physical hydrogen storage materials such as hollow spheres, carbon-based materials, zeolites, and metal-organic frameworks are reviewed. We summarize and discuss the properties, hydrogen storage densities at different temperatures and pressures, and the fabrication and modification methods of these materials. The challenges associated with these physical hydrogen storage materials are also discussed.

16.
Pharmacol Res Perspect ; 12(2): e1194, 2024 Apr.
Article En | MEDLINE | ID: mdl-38573021

The SARS-CoV-2 caused COVID-19 pandemic has posed a global health hazard. While some vaccines have been developed, protection against viral infection is not perfect because of the urgent approval process and the emergence of mutant SARS-CoV-2 variants. Here, we employed UDCA as an FXR antagonist to regulate ACE2 expression, which is one of the key pathways activated by SARS-CoV-2 Delta variant infection. UDCA is a well-known reagent of liver health supplements and the only clinically approved bile acid. In this paper, we investigated the protective efficacy of UDCA on Omicron variation, since it has previously been verified for protection against Delta variant. When co-housing with an Omicron variant-infected hamster group resulted in spontaneous airborne transmission, the UDCA pre-supplied group was protected from weight loss relative to the non-treated group at 4 days post-infection by more than 5%-10%. Furthermore, UDCA-treated groups had a 3-fold decrease in ACE2 expression in nasal cavities, as well as reduced viral expressing genes in the respiratory tract. Here, the data show that the UDCA serves an alternative option for preventive drug, providing SARS-CoV-2 protection against not only Delta but also Omicron variant. Our results of this study will help to propose drug-repositioning of UDCA from liver health supplement to preventive drug of SARS-CoV-2 infection.


COVID-19 , SARS-CoV-2 , Animals , Cricetinae , Humans , Ursodeoxycholic Acid/pharmacology , Ursodeoxycholic Acid/therapeutic use , Angiotensin-Converting Enzyme 2/genetics , Pandemics
17.
Nature ; 628(8009): 741-745, 2024 Apr.
Article En | MEDLINE | ID: mdl-38658686

Extensive efforts have been undertaken to combine superconductivity and the quantum Hall effect so that Cooper-pair transport between superconducting electrodes in Josephson junctions is mediated by one-dimensional edge states1-6. This interest has been motivated by prospects of finding new physics, including topologically protected quasiparticles7-9, but also extends into metrology and device applications10-13. So far it has proven challenging to achieve detectable supercurrents through quantum Hall conductors2,3,6. Here we show that domain walls in minimally twisted bilayer graphene14-18 support exceptionally robust proximity superconductivity in the quantum Hall regime, allowing Josephson junctions to operate in fields close to the upper critical field of superconducting electrodes. The critical current is found to be non-oscillatory and practically unchanging over the entire range of quantizing fields, with its value being limited by the quantum conductance of ballistic, strictly one-dimensional, electronic channels residing within the domain walls. The system described is unique in its ability to support Andreev bound states at quantizing fields and offers many interesting directions for further exploration.

18.
Cancers (Basel) ; 16(6)2024 Mar 16.
Article En | MEDLINE | ID: mdl-38539508

Triple-negative breast cancer (TNBC) is a significant clinical challenge due to its aggressive nature and limited treatment options. In search of new treatment targets, not only single genes but also gene pairs involved in protein interactions, we explored the tumor microenvironment (TME) of TNBC from a retrospective point of view, using public single-cell RNA sequencing datasets. A High-resolution Cell type Annotation Tool, HiCAT, was used first to identify the cell type in 3-level taxonomies. Tumor cells were then identified based on the estimates of copy number variation. With the annotation results, differentially expressed genes were analyzed to find subtype-specific markers for each cell type, including tumor cells, fibroblast, and macrophage. Cell-cell interactions were also inferred for each cell type pair. Through integrative analysis, we could find unique TNBC markers not only for tumor cells but also for various TME components, including fibroblasts and macrophages. Specifically, twelve marker genes, including DSC2 and CDKN2A, were identified for TNBC tumor cells. Another key finding of our study was the interaction between the DSC2 and DSG2 genes among TNBC tumor cells, suggesting that they are more tightly aggregated with each other than those of other subtypes, including normal epithelial cells. The overexpression of DSC2 in TNBC and its prognostic power were verified by using METABRIC, a large bulk RNA-seq dataset with clinical information. These findings not only corroborate previous hypotheses but also lay the foundation for a new structural understanding of TNBC, as revealed through our single-cell analysis workflow.

19.
J Med Virol ; 96(4): e29558, 2024 Apr.
Article En | MEDLINE | ID: mdl-38533898

Human papillomavirus (HPV) infection poses a significant risk to women's health by causing cervical cancer. In addition to HPV, cervical cancer incidence rates can be influenced by various factors, including human immunodeficiency virus and herpes, as well as screening policy. In this study, a mathematical model with stochastic processes was developed to analyze HPV transmission between genders and its subsequent impact on cervical cancer incidence. The model simulations suggest that both-gender vaccination is far more effective than female-only vaccination in preventing an increase in cervical cancer incidence. With increasing stochasticity, the difference between the number of patients in the vaccinated group and the number in the nonvaccinated group diminishes. To distinguish the patient population distribution of the vaccinated from the nonvaccinated, we calculated effect size (Cohen's distance) in addition to Student's t-test. The model analysis suggests a threshold vaccination rate for both genders for a clear reduction of cancer incidence when significant stochastic factors are present.


Papillomavirus Infections , Papillomavirus Vaccines , Uterine Cervical Neoplasms , Humans , Female , Male , Vaccination , Models, Biological , Human Papillomavirus Viruses , Stochastic Processes
20.
Am J Case Rep ; 25: e941169, 2024 Mar 30.
Article En | MEDLINE | ID: mdl-38553814

BACKGROUND Erdheim-Chester disease (ECD) is a rare neoplasm of histiocytes that is characterized by prominent involvement of the long bones. Approximately 1500 cases have been reported since the disease was first described in 1930. The imaging appearance of ECD can be highly variable given the numerous systems it can affect. In this case report we discuss a patient whose ECD was occult on multiple imaging modalities. CASE REPORT We report the case of a 60-year-old woman who presented with sub-acute left knee and calf pain that led to an MRI. She was found to have innumerable marrow-replacing lesions in the axial and appendicular skeleton visualized on the initial MRI, as well as on an ¹8F-FDG PET/CT scan. The patient did not have extraosseous abnormal uptake on the PET/CT. Subsequently, a lesion from the left iliac bone was histologically confirmed as ECD on the basis of positive staining for CD68 and CD163 and negative staining for CD1a. Osseous lesions in ECD have a distinct imaging appearance and are typically detected by radiography and bone scintigraphy, among other modalities; however, the lesions in this case were unexpectedly absent from those studies. CONCLUSIONS If there is a high degree of suspicion for ECD, 18F-FDG PET/CT and/or MRI may be necessary for adequate visualization of bone lesions, given that those lesions can have an infiltrative nature that may be difficult to image with other anatomic imaging modalities. Use of 18F-FDG PET/CT and/or MRI may also lead to adequate guidance of confirmatory biopsy.


Erdheim-Chester Disease , Positron Emission Tomography Computed Tomography , Female , Humans , Middle Aged , Fluorodeoxyglucose F18 , Erdheim-Chester Disease/diagnostic imaging , Erdheim-Chester Disease/pathology , Magnetic Resonance Imaging , Tomography, X-Ray Computed
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