-
British Journal of Cancer Jun 2024This study aimed to investigate the distribution and changes of HER2 status in untreated tumours, in residual disease and in metastasis, and their long-term prognostic...
BACKGROUND
This study aimed to investigate the distribution and changes of HER2 status in untreated tumours, in residual disease and in metastasis, and their long-term prognostic implications.
METHODS
This is a population-based cohort study of patients treated with neoadjuvant chemotherapy for breast cancer during 2007-2020 in the Stockholm-Gotland region which comprises 25% of the entire Swedish population. Information was extracted from the National Breast Cancer Registry and electronic patient charts to minimize data missingness and misclassification.
RESULTS
In total, 2494 patients received neoadjuvant chemotherapy, of which 2309 had available pretreatment HER2 status. Discordance rates were 29.9% between primary and residual disease (kappa = 0.534), 31.2% between primary tumour and metastasis (kappa = 0.512) and 33.3% between residual disease to metastasis (kappa = 0.483). Adjusted survival curves differed between primary HER2 0 and HER2-low disease (p < 0.001), with the former exhibiting an early peak in risk for death which eventually declined below the risk of HER2-low. Across all disease settings, increasing the number of biopsies increased the likelihood of detecting HER2-low status.
CONCLUSION
HER2 status changes during neoadjuvant chemotherapy and metastatic progression, and the long-term behaviours of HER2 0 and HER2-low disease differ, underscoring the need for obtaining tissue biopsies and for extended follow-up in breast cancer studies.
PubMed: 38942987
DOI: 10.1038/s41416-024-02777-6 -
Communications Biology Jun 2024Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of renal cancer, accounting for over 75% of cases. The asymptomatic nature of the disease contributes...
Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of renal cancer, accounting for over 75% of cases. The asymptomatic nature of the disease contributes to late-stage diagnoses and poor survival. Highly vascularized and immune infiltrated microenvironment are prominent features of ccRCC, yet the interplay between vasculature and immune cells, disease progression and response to therapy remains poorly understood. Using droplet-based single-cell RNA sequencing we profile 50,236 transcriptomes from paired tumor and healthy adjacent kidney tissues. Our analysis reveals significant heterogeneity and inter-patient variability of the tumor microenvironment. Notably, we discover a previously uncharacterized vasculature subpopulation associated with epithelial-mesenchymal transition. The cell-cell communication analysis reveals multiple modes of immunosuppressive interactions within the tumor microenvironment, including clinically relevant interactions between tumor vasculature and stromal cells with immune cells. The upregulation of the genes involved in these interactions is associated with worse survival in the TCGA KIRC cohort. Our findings demonstrate the role of tumor vasculature and stromal cell populations in shaping the ccRCC microenvironment and uncover a subpopulation of cells within the tumor vasculature that is associated with an angiogenic phenotype.
Topics: Humans; Carcinoma, Renal Cell; Kidney Neoplasms; Single-Cell Analysis; Tumor Microenvironment; Gene Expression Profiling; Phenotype; Gene Expression Regulation, Neoplastic; Endothelial Cells; Transcriptome; Epithelial-Mesenchymal Transition; Male; Female
PubMed: 38942917
DOI: 10.1038/s42003-024-06478-x -
Scientific Reports Jun 2024Prostate cancer (PCa) is the most common cancer among men in the United States and the leading cause of cancer-related death. The Solute Carrier Family 14 Member 1...
Prostate cancer (PCa) is the most common cancer among men in the United States and the leading cause of cancer-related death. The Solute Carrier Family 14 Member 1 (SLC14A1) is a member of urea transporters which are important for the regulation of urine concentration. However, the physiological significance of SLC14A1 in PCa still remains unclear. In the present study, via bioinformatics analysis and experiments, we found that expression of SLC14A1 is significantly decreased in PCa progression, which could be attributed to hypermethylation on SLC14A1 promoter region. Moreover, its low expression and hypermethylation on SLC14A1 promoter are closely related to the poor prognosis of PCa patients. On the other hand, overexpression of SLC14A1 inhibited cell proliferation and metastasis while its overexpression also suppressed CDK1/CCNB1 pathway and mTOR/MMP-9 signaling pathway. Additionally, SLC14A1 expression is enriched in prostate basal-type cells. In summary, our study indicates that its low expression level and promoter hypermethylation of SLC14A1 may represent novel indicators for PCa progression and prognosis, and SLC14A1 could inhibit the progression of PCa.
Topics: Humans; Male; Prostatic Neoplasms; TOR Serine-Threonine Kinases; Gene Expression Regulation, Neoplastic; Disease Progression; Signal Transduction; Cell Line, Tumor; CDC2 Protein Kinase; DNA Methylation; Promoter Regions, Genetic; Cell Proliferation; Down-Regulation; Prognosis; Cell Movement
PubMed: 38942821
DOI: 10.1038/s41598-024-66020-1 -
Cell Death & Disease Jun 2024The role of mitochondria peptides in the spreading of glioblastoma remains poorly understood. In this study, we investigated the mechanism underlying intracranial...
The role of mitochondria peptides in the spreading of glioblastoma remains poorly understood. In this study, we investigated the mechanism underlying intracranial glioblastoma progression. Our findings demonstrate that the mitochondria-derived peptide, humanin, plays a significant role in enhancing glioblastoma progression through the intratumoral activation of the integrin alpha V (ITGAV)-TGF beta (TGFβ) signaling axis. In glioblastoma tissues, humanin showed a significant upregulation in the tumor area compared to the corresponding normal region. Utilizing multiple in vitro pharmacological and genetic approaches, we observed that humanin activates the ITGAV pathway, leading to cellular attachment and filopodia formation. This process aids the subsequent migration and invasion of attached glioblastoma cells through intracellular TGFβR signaling activation. In addition, our in vivo orthotopic glioblastoma model provides further support for the pro-tumoral function of humanin. We observed a correlation between poor survival and aggressive invasiveness in the humanin-treated group, with noticeable tumor protrusions and induced angiogenesis compared to the control. Intriguingly, the in vivo effect of humanin on glioblastoma was significantly reduced by the treatment of TGFBR1 inhibitor. To strengthen these findings, public database analysis revealed a significant association between genes in the ITGAV-TGFβR axis and poor prognosis in glioblastoma patients. These results collectively highlight humanin as a pro-tumoral factor, making it a promising biological target for treating glioblastoma.
Topics: Glioblastoma; Humans; Transforming Growth Factor beta; Animals; Signal Transduction; Disease Progression; Cell Line, Tumor; Integrin alphaV; Mice; Brain Neoplasms; Cell Movement; Mice, Nude; Receptor, Transforming Growth Factor-beta Type I; Neoplasm Invasiveness; Gene Expression Regulation, Neoplastic
PubMed: 38942749
DOI: 10.1038/s41419-024-06790-8 -
Radiography (London, England : 1995) Jun 2024Alzheimer's disease (AD), the most common cause of dementia, presents a global health crisis with its prevalence expected to triple worldwide by 2050, emphasizing the...
INTRODUCTION
Alzheimer's disease (AD), the most common cause of dementia, presents a global health crisis with its prevalence expected to triple worldwide by 2050, emphasizing the urgent need for early diagnosis to delay progression and improve patient quality of life. Our project aims to detect AD in its early phase by identifying subtle neuroanatomical changes with Radiomics features, offering a more accurate diagnosis.
METHODS
The AssemblyNet segmentation model was used to analyze brain changes by employing anonymized T1 MRI scans from 416 patients. For each segmented label we extracted Radiomic features. After preprocessing of Radiomic features we trained four models, Gradient Booster, Random Forest, Support Vector Classifier, and XGBoost, in a 70%/20%/10% train, validation and test split. All models were hyperparameter tuned with GridSearch, Cross validation and evaluated with accuracy on the test data.
RESULTS
208 T1-weighted MRI scans were segmented, with 132 segmentation labels per patient, 1130 Radiomic features per segmentation, totalling in over 31 million features. For all four models we achieved accuracies between 0.71 and 0.86, and the machine learning model with highest accuracy were XGBoost, achieving an accuracy at 0.86 on the segmentation of the left inferior lateral ventricle.
CONCLUSION
Our study's use of segmentation on T1-weighted MRI scans resulted promising accuracies for early AD diagnosis with the machine learning model XGBoost, peaking at 0.86 accuracy. Future research should aim to expand datasets and refine methodologies for broader applicability.
IMPLICATION FOR PRACTICE
Implementing Radiomics for early AD detection using T1-weighted MRI scans could substantially improve diagnostic accuracy, enabling earlier interventions that may delay disease progression and improve outcomes, thereby requiring radiographers to adopt more advanced imaging techniques and analysis tools, as well as additional training to effectively interpret complex Radiomic data.
PubMed: 38942647
DOI: 10.1016/j.radi.2024.06.016 -
Aging Jun 2024Down Syndrome (DS) is a common genetic disorder characterized by an extra copy of chromosome 21, leading to dysregulation of various metabolic pathways. Oxidative stress...
Down Syndrome (DS) is a common genetic disorder characterized by an extra copy of chromosome 21, leading to dysregulation of various metabolic pathways. Oxidative stress in DS is associated with neurodevelopmental defects, neuronal dysfunction, and a dementia onset resembling Alzheimer's disease. Additionally, chronic oxidative stress contributes to cardiovascular diseases and certain cancers prevalent in DS individuals. This study investigates the impact of ageing on oxidative stress and liver fibrosis using a DS murine model (Ts2Cje mice). Our results show that DS mice show increased liver oxidative stress and impaired antioxidant defenses, as evidenced by reduced glutathione levels and increased lipid peroxidation. Therefore, DS liver exhibits an altered inflammatory response and mitochondrial fitness as we showed by assaying the expression of HMOX1, CLPP, and the heat shock proteins Hsp90 and Hsp60. DS liver also displays dysregulated lipid metabolism, indicated by altered expression of PPARα, PPARγ, FATP5, and CTP2. Consistently, these changes might contribute to non-alcoholic fatty liver disease development, a condition characterized by liver fat accumulation. Consistently, histological analysis of DS liver reveals increased fibrosis and steatosis, as showed by Col1a1 increased expression, indicative of potential progression to liver cirrhosis. Therefore, our findings suggest an increased risk of liver pathologies in DS individuals, particularly when combined with the higher prevalence of obesity and metabolic dysfunctions in DS patients. These results shed a light on the liver's role in DS-associated pathologies and suggest potential therapeutic strategies targeting oxidative stress and lipid metabolism to prevent or mitigate liver-related complications in DS individuals.
PubMed: 38942607
DOI: 10.18632/aging.205970 -
Neuroimaging Clinics of North America Aug 2024Multiple sclerosis (MS) is increasingly understood not only as a white matter disease but also involving both the deep and cortical gray matter (GM). GM pathology in... (Review)
Review
Multiple sclerosis (MS) is increasingly understood not only as a white matter disease but also involving both the deep and cortical gray matter (GM). GM pathology in people with MS (pwMS) includes the presence of lesions, leptomeningeal inflammation, atrophy, altered iron concentration, and microstructural changes. Studies using 7T and 3T MR imaging with optimized protocols established that GM damage is a principal driver of disease progression in pwMS. Future work is needed to incorporate the assessment of these GM imaging biomarkers into the clinical workup of pwMS and the assessment of treatment efficacy.
Topics: Humans; Multiple Sclerosis; Gray Matter; Magnetic Resonance Imaging; Neuroimaging; Brain
PubMed: 38942527
DOI: 10.1016/j.nic.2024.03.007 -
Neuroimaging Clinics of North America Aug 2024Concepts of multiple sclerosis (MS) biology continue to evolve, with observations such as "progression independent of disease activity" challenging traditional... (Review)
Review
Concepts of multiple sclerosis (MS) biology continue to evolve, with observations such as "progression independent of disease activity" challenging traditional phenotypic categorization. Iron-sensitive, susceptibility-based imaging techniques are emerging as highly translatable MR imaging sequences that allow for visualization of at least 2 clinically useful biomarkers: the central vein sign and the paramagnetic rim lesion (PRL). Both biomarkers demonstrate high specificity in the discrimination of MS from other mimics and can be seen at 1.5 T and 3 T field strengths. Additionally, PRLs represent a subset of chronic active lesions engaged in "smoldering" compartmentalized inflammation behind an intact blood-brain barrier.
Topics: Humans; Multiple Sclerosis; Magnetic Resonance Imaging; Brain; Biomarkers; Inflammation; Neuroimaging; Cerebral Veins
PubMed: 38942521
DOI: 10.1016/j.nic.2024.03.004 -
Life Sciences Jun 2024Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality globally and the risk of developing lung cancer is six times greater in individuals... (Review)
Review
Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality globally and the risk of developing lung cancer is six times greater in individuals with COPD who smoke compared to those who do not smoke. Matrix metalloproteinases (MMPs) play a crucial role in the pathophysiology of respiratory diseases by promoting inflammation and tissue degradation. Furthermore, MMPs are involved in key processes like epithelial-to-mesenchymal transition (EMT), metastasis, and invasion in lung cancer. While EMT has traditionally been associated with the progression of lung cancer, recent research highlights its active involvement in individuals with COPD. Current evidence underscores its role in orchestrating airway remodeling, fostering airway fibrosis, and contributing to the potential for malignant transformation in the complex pathophysiology of COPD. The precise regulatory roles of diverse MMPs in steering EMT during COPD progression needs to be elucidated. Additionally, the less-understood aspect involves how these MMPs bi-directionally activate or regulate various EMT-associated signaling cascades during COPD progression. This review article explores recent advancements in understanding MMPs' role in EMT during COPD progression and various pharmacological approaches to target MMPs. It also delves into the limitations of current MMP inhibitors and explores novel, advanced strategies for inhibiting MMPs, potentially offering new avenues for treating respiratory diseases.
PubMed: 38942362
DOI: 10.1016/j.lfs.2024.122874 -
Pharmacological Research Jun 2024Transfer RNA-derived small RNAs (tsRNAs) are a class of small non-coding RNA (sncRNA) molecules derived from tRNA, including tRNA derived fragments (tRFs) and tRNA halfs... (Review)
Review
Transfer RNA-derived small RNAs (tsRNAs) are a class of small non-coding RNA (sncRNA) molecules derived from tRNA, including tRNA derived fragments (tRFs) and tRNA halfs (tiRNAs). tsRNAs can affect cell functions by participating in gene expression regulation, translation regulation, intercellular signal transduction, and immune response. They have been shown to play an important role in various human diseases, including cardiovascular diseases (CVDs). Targeted regulation of tsRNAs expression can affect the progression of CVDs. The tsRNAs induced by pathological conditions can be detected when released into the extracellular, giving them enormous potential as disease biomarkers. Here, we review the biogenesis, degradation process and related functional mechanisms of tsRNAs, and discuss the research progress and application prospects of tsRNAs in different CVDs, to provide a new perspective on the treatment of CVDs.
PubMed: 38942340
DOI: 10.1016/j.phrs.2024.107279