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Scientific Reports Jul 2024The tumor microenvironment (TME) plays a fundamental role in tumorigenesis, tumor progression, and anti-cancer immunity potential of emerging cancer therapeutics....
The tumor microenvironment (TME) plays a fundamental role in tumorigenesis, tumor progression, and anti-cancer immunity potential of emerging cancer therapeutics. Understanding inter-patient TME heterogeneity, however, remains a challenge to efficient drug development. This article applies recent advances in machine learning (ML) for survival analysis to a retrospective study of NSCLC patients who received definitive surgical resection and immune pathology following surgery. ML methods are compared for their effectiveness in identifying prognostic subtypes. Six survival models, including Cox regression and five survival machine learning methods, were calibrated and applied to predict survival for NSCLC patients based on PD-L1 expression, CD3 expression, and ten baseline patient characteristics. Prognostic subregions of the biomarker space are delineated for each method using synthetic patient data augmentation and compared between models for overall survival concordance. A total of 423 NSCLC patients (46% female; median age [inter quantile range]: 67 [60-73]) treated with definite surgical resection were included in the study. And 219 (52%) patients experienced events during the observation period consisting of a maximum follow-up of 10 years and median follow up 78 months. The random survival forest (RSF) achieved the highest predictive accuracy, with a C-index of 0.84. The resultant biomarker subtypes demonstrate that patients with high PD-L1 expression combined with low CD3 counts experience higher risk of death within five-years of surgical resection.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Tumor Microenvironment; Machine Learning; Female; Male; Aged; Middle Aged; Lung Neoplasms; Prognosis; Retrospective Studies; Biomarkers, Tumor; B7-H1 Antigen; Survival Analysis
PubMed: 38951567
DOI: 10.1038/s41598-024-64977-7 -
Scientific Reports Jul 2024Digital positron emission tomography/computed tomography (PET/CT) has shown enhanced sensitivity and spatial resolution compared with analog PET/CT. The present study... (Comparative Study)
Comparative Study
Digital positron emission tomography/computed tomography (PET/CT) has shown enhanced sensitivity and spatial resolution compared with analog PET/CT. The present study compared the diagnostic performance of digital and analog PET/CT with [Ga]Ga-PSMA-11 in prostate cancer patients who experienced biochemical recurrence (BCR) after prostatectomy. Forty prostate cancer patients who experienced BCR, defined as serum prostate-specific antigen (PSA) concentrations exceeding 0.2 ng/mL after prostatectomy, were prospectively recruited. These patients were stratified into three groups based on their serum PSA levels. [Ga]Ga-PSMA-11 was injected into each patient, and images were acquired using both analog and digital PET/CT scanners. Analog and digital PET/CT showed comparable lesion detection rate (71.8% vs. 74.4%), sensitivity (85.0% vs. 90.0%), and positive predictive value (PPV, 100.0% vs. 100.0%). However, digital PET/CT detected more lesions (139 vs. 111) and had higher maximum standardized uptake values (SUVmax, 14.3 vs. 10.3) and higher kappa index (0.657 vs. 0.502) than analog PET/CT, regardless of serum PSA levels. On both analog and digital PET/CT, lesion detection rates and interrater agreement increased with increasing serum PSA levels. Compared with analog PET/CT, digital PET/CT detected more lesions with a higher SUVmax and better interrater agreement in prostate cancer patients who experienced BCR after prostatectomy.
Topics: Humans; Male; Prostatic Neoplasms; Prostatectomy; Positron Emission Tomography Computed Tomography; Aged; Prospective Studies; Gallium Radioisotopes; Middle Aged; Neoplasm Recurrence, Local; Gallium Isotopes; Prostate-Specific Antigen; Edetic Acid; Oligopeptides
PubMed: 38951530
DOI: 10.1038/s41598-024-65399-1 -
NPJ Parkinson's Disease Jun 2024Idiopathic rapid eye movement sleep behaviour disorder (iRBD)-a Parkinson's disease (PD) prodrome-might exhibit neural changes similar to those in PD. Substantia nigra...
Idiopathic rapid eye movement sleep behaviour disorder (iRBD)-a Parkinson's disease (PD) prodrome-might exhibit neural changes similar to those in PD. Substantia nigra pars compacta (SNc) degeneration underlies motor symptoms of PD. In iRBD and early PD (ePD), we measured diffusion MRI (dMRI) in the caudal motor SNc, which overlaps the nigrosome-1-the earliest-degenerating dopaminergic neurons in PD-and in the striatum. Nineteen iRBD, 26 ePD (1.7 ± 0.03 years), and 46 age-matched healthy controls (HCs) were scanned at Western University, and 47 iRBD, 115 ePD (0.9 ± 0.01 years), and 56 HCs were scanned through the Parkinson's Progression Markers Initiative, using 3T MRI. We segmented the SNc and striatum into subregions using automated probabilistic tractography to the cortex. We measured mean diffusivity (MD) and fractional anisotropy (FA) along white-matter bundles and subregional surfaces. We performed group-level and classification analyses. Increased caudal motor SNc surface MD was the only iRBD-HCs and ePD-HCs difference replicating across datasets (p < 0.05). No iRBD-ePD differences emerged. Caudal motor SNc surface MD classified patient groups from HCs at the single-subject level with good-to-excellent balanced accuracy in an independent sample (0.91 iRBD and 0.86 iRBD and ePD combined), compared to fair performance for total SNc surface MD (0.72 iRBD and ePD). Caudal motor SNc surface MD correlated significantly with MDS-UPDRS-III scores in ePD patients. Using dMRI and automated segmentation, we detected changes suggesting altered microstructural integrity in iRBD and ePD in the nigrostriatal subregion known to degenerate first in PD. Surface MD of the caudal motor SNc presents a potential measure for inclusion in neuroimaging biomarkers of iRBD and PD.
PubMed: 38951528
DOI: 10.1038/s41531-024-00731-0 -
Nature Communications Jun 2024Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying...
Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.
Topics: Drug Resistance, Neoplasm; Humans; Cell Line, Tumor; Antineoplastic Agents; Oxaliplatin; Irinotecan; CRISPR-Cas Systems; Protein Serine-Threonine Kinases; Colorectal Neoplasms; Animals; Neoplasms; Clustered Regularly Interspaced Short Palindromic Repeats; Mice; Gene Expression Regulation, Neoplastic
PubMed: 38951519
DOI: 10.1038/s41467-024-49673-4 -
Scientific Reports Jun 2024Glioblastoma (GBM) continues to exhibit a discouraging survival rate despite extensive research into new treatments. One factor contributing to its poor prognosis is the...
Glioblastoma (GBM) continues to exhibit a discouraging survival rate despite extensive research into new treatments. One factor contributing to its poor prognosis is the tumor's immunosuppressive microenvironment, in which the kynurenine pathway (KP) plays a significant role. This study aimed to explore how KP impacts the survival of newly diagnosed GBM patients. We examined tissue samples from 108 GBM patients to assess the expression levels of key KP markers-tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenase (IDO1/2), and the aryl hydrocarbon receptor (AhR). Using immunohistochemistry and QuPath software, three tumor cores were analyzed per patient to evaluate KP marker expression. Kaplan-Meier survival analysis and stepwise multivariate Cox regression were used to determine the effect of these markers on patient survival. Results showed that patients with high expression of TDO2, IDO1/2, and AhR had significantly shorter survival times. This finding held true even when controlling for other known prognostic variables, with a hazard ratio of 3.393 for IDO1, 2.775 for IDO2, 1.891 for TDO2, and 1.902 for AhR. We suggest that KP markers could serve as useful tools for patient stratification, potentially guiding future immunomodulating trials and personalized treatment approaches for GBM patients.
Topics: Humans; Kynurenine; Glioblastoma; Female; Male; Prognosis; Middle Aged; Indoleamine-Pyrrole 2,3,-Dioxygenase; Receptors, Aryl Hydrocarbon; Biomarkers, Tumor; Tryptophan Oxygenase; Aged; Adult; Brain Neoplasms; Kaplan-Meier Estimate; Tumor Microenvironment; Aged, 80 and over; Basic Helix-Loop-Helix Transcription Factors
PubMed: 38951170
DOI: 10.1038/s41598-024-65907-3 -
The Journal of Rheumatology Jul 2024Rheumatoid arthritis (RA) is prevalent in many Indigenous North American First Nations (FN) and tends to be seropositive, familial, and disabling, as well as associated... (Review)
Review
Rheumatoid arthritis (RA) is prevalent in many Indigenous North American First Nations (FN) and tends to be seropositive, familial, and disabling, as well as associated with highly unfavorable outcomes such as early mortality. The risk of developing RA is based on a perfect storm of gene-environment interactions underpinning this risk. The gene-environment interactions include a high frequency of shared epitope encoding HLA alleles, particularly , in the background population, and prevalent predisposing environmental factors such as smoking and periodontal disease. Together, these provide a compelling rationale for an RA prevention agenda in FN communities. Our research team has worked in partnership with several FN communities to prospectively follow the first-degree relatives of FN patients with RA, with the aim of better understanding the preclinical stages of RA in this population. We have focused on specific features of the anticitrullinated protein antibodies (ACPA) and other proteomic biomarkers as predictors of future development of RA. These studies have now led us to consider interventions having a favorable risk-benefit ratio if applied at a stage prior to a hypothetical "point of no return," when the autoimmunity potentially becomes irreversible. Based on a supportive mouse model and available human studies of curcumin, omega-3, and vitamin D supplements, we are undertaking studies where we screen communities using dried blood spot technology adapted for the detection of ACPA, and then enrolling ACPA-positive individuals in studies that use a combination of these supplements. These studies are guided by shared decision-making principles.
Topics: Humans; Anti-Citrullinated Protein Antibodies; Arthritis, Rheumatoid; Biomarkers; Gene-Environment Interaction; HLA-DRB1 Chains; Indians, North American
PubMed: 38950968
DOI: 10.3899/jrheum.2024-0369_dunlop-dottridge -
PloS One 2024The placenta is a transient organ critical for fetal development. Disruptions of normal placental functions can impact health throughout an individual's entire life....
BACKGROUND
The placenta is a transient organ critical for fetal development. Disruptions of normal placental functions can impact health throughout an individual's entire life. Although being recognized by the NIH Human Placenta Project as an important organ, the placenta remains understudied, partly because of a lack of non-invasive tools for longitudinally evaluation for key aspects of placental functionalities.
OBJECTIVE
Our goal is to create a non-invasive preclinical imaging pipeline that can longitudinally probe murine placental health in vivo. We use advanced imaging processing schemes to establish functional biomarkers for non-invasive longitudinal evaluation of placental development.
METHODOLOGY
We implement dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) and analysis pipeline to quantify uterine contraction and placental perfusion dynamics. We use optic flow and time-frequency analysis to quantify and characterize contraction-related placental motion. Our novel imaging and analysis pipeline uses subcutaneous administration of gadolinium for steepest slope-based perfusion evaluation, enabling non-invasive longitudinal monitoring.
RESULTS
We demonstrate that the placenta exhibits spatially asymmetric contractile motion that develops from E14.5 to E17.5. Additionally, we see that placental perfusion, perfusion delivery rate, and substrate delivery all increase from E14.5 to E17.5, with the High Perfusion Chamber (HPC) leading the placental changes that occur from E14.5 to E17.5.
DISCUSSION
We advance the placental perfusion chamber paradigm with a novel, physiologically based threshold model for chamber localization and demonstrate spatially varying placental chambers using multiple functional metrics that assess mouse placental development and remodeling throughout gestation.
CONCLUSION
Our pipeline enables the non-invasive, longitudinal assessment of multiple placenta functions from a single imaging session. Our pipeline serves as a key toolbox for advancing research in mouse models of placental disease and disorder.
Topics: Animals; Female; Pregnancy; Magnetic Resonance Imaging; Mice; Placenta; Uterine Contraction; Contrast Media; Mice, Inbred C57BL
PubMed: 38950083
DOI: 10.1371/journal.pone.0303957 -
Endocrine Connections Jul 2024Epigenetics, which involves regulatory modifications that do not alter the DNA sequence itself, is crucial in the development and progression of thyroid cancer. This...
BACKGROUND
Epigenetics, which involves regulatory modifications that do not alter the DNA sequence itself, is crucial in the development and progression of thyroid cancer. This study aims to provide a comprehensive analysis of the epigenetic research landscape in thyroid cancer, highlighting current trends, major research areas, and potential future directions.
METHODS
A bibliometric analysis was performed using data from the Web of Science Core Collection (WOSCC) up to November 1, 2023. Analytical tools such as VOSviewer, CiteSpace, and the R package "bibliometrix" were employed for comprehensive data analysis and visualization. This process identified principal research themes, along with influential authors, institutions, and countries contributing to the field.
RESULTS
The analysis reveals a marked increase in thyroid cancer epigenetics research over the past two decades. Emergent key themes include the exploration of molecular mechanisms and biomarkers, various subtypes of thyroid cancer, implications for therapeutic interventions, advancements in technologies and methodologies, and the scope of translational research. Research hotspots within these themes highlight intensive areas of study and the potential for significant breakthroughs.
CONCLUSION
This study presents an in-depth overview of the current state of epigenetics in thyroid cancer research. It underscores the potential of epigenetic strategies as viable therapeutic options and provides valuable insights for researchers and clinicians in advancing the understanding and treatment of this complex disease. Future research is vital to fully leverage the therapeutic possibilities offered by epigenetics in the management of thyroid cancer.
PubMed: 38949925
DOI: 10.1530/EC-24-0087 -
Microbiology Spectrum Jul 2024
PubMed: 38949384
DOI: 10.1128/spectrum.01017-24 -
The Journal of Clinical Investigation Jul 2024Type 3 innate lymphoid cells (ILC3s) are key regulators of intestinal homeostasis and epithelial barrier integrity. In this issue of the JCI, Cao and colleagues found...
Type 3 innate lymphoid cells (ILC3s) are key regulators of intestinal homeostasis and epithelial barrier integrity. In this issue of the JCI, Cao and colleagues found that a sensor of endoplasmic reticulum (ER) stress, the inositol-requiring kinase 1α/X-box-binding protein 1 (IRE1α/XBP1) pathway, fine-tuned the functions of ILC3s. Activation of IRE1α and XBP1 in ILC3s limited intestinal inflammation in mice and correlated with the efficacy of ustekinumab, an IL-12/IL-23 blocker, in patients with Crohn's disease. These results advance our understanding in the use of ILCs as biomarkers not only to predict disease outcomes but also to indicate the response to biologicals in patients with inflammatory bowel disease.
Topics: X-Box Binding Protein 1; Animals; Endoribonucleases; Protein Serine-Threonine Kinases; Humans; Mice; Endoplasmic Reticulum Stress; Lymphocytes; Signal Transduction; Crohn Disease; Immunity, Innate; Inflammation
PubMed: 38949019
DOI: 10.1172/JCI182204