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Cancer Science May 2024Histological diagnosis of sarcomas (malignant bone and soft tissue tumors) is challenging due to their rarity, morphological diversity, and constantly evolving...
Histological diagnosis of sarcomas (malignant bone and soft tissue tumors) is challenging due to their rarity, morphological diversity, and constantly evolving diagnostic criteria. In this study, we aimed to assess the concordance in histological diagnosis of bone and soft tissue tumors between referring hospitals and a tertiary sarcoma center and analyzed the clinical impact of the diagnostic alteration. We analyzed 628 consecutively accessioned specimens from 624 patients who visited a specialized sarcoma center for treatment. The diagnoses at referring hospitals and those at the sarcoma center were compared and classified into four categories: agreed, disagreed, specified, and de-specified. Of the 628 specimens, the diagnoses agreed in 403 (64.2%) specimens, whereas some changes were made in 225 (35.8%) specimens: disagreed in 153 (24.3%), specified in 52 (8.3%), and de-specified in 20 (3.2%) cases. The benign/intermediate/malignant judgment changed for 92 cases (14.6%). The diagnostic change resulted in patient management modification in 91 cases (14.5%), including surgical and medical treatment changes. The main inferred reason for the diagnostic discrepancies was a different interpretation of morphological findings of the tumor, which accounted for 48.9% of the cases. This was followed by the unavailability of specialized immunohistochemical antibodies and the unavailability of genetic analysis. In summary, our study clarified the actual clinical impact of diagnostic discrepancy in bone and soft tissue tumors. This may underscore the value of pathology consultation, facilitating access to specialized diagnostic tools, and continued education. These measures are expected to improve diagnostic precision and ultimately benefit patients.
PubMed: 38763523
DOI: 10.1111/cas.16211 -
NeuroImage. Clinical May 2024The main objective was to characterize the tracer uptake kinetics of [F]fluoromethylcholine ([F]F-CHO) in high-grade gliomas (HGG) through a full PET kinetic modeling...
PURPOSE
The main objective was to characterize the tracer uptake kinetics of [F]fluoromethylcholine ([F]F-CHO) in high-grade gliomas (HGG) through a full PET kinetic modeling approach. Secondarily, we aimed to explore the relationship between the PET uptake measures and the HGG molecular features.
MATERIALS AND METHODS
Twenty-four patients with a suspected diagnosis of HGG were prospectively included. They underwent a dynamic brain [F]F-CHO-PET/CT, from which a tumoral time-activity curve was extracted. The plasma input function was obtained through arterial blood sampling with metabolite correction. These data were fitted to 1- and 2-tissue-compartment models, the best of which was selected through the Akaike information criterion. We assessed the correlation between the kinetic parameters and the conventional static PET metrics (SUV, SUV and tumor-to-background ratio TBR). We explored the association between the [F]F-CHO-PET quantitative parameters and relevant molecular biomarkers in HGG.
RESULTS
Tumoral time-activity curves in all patients showed a rapid rise of [F]F-CHO uptake followed by a plateau-like shape. Best fits were obtained with near-irreversible 2-tissue-compartment models. The perfusion-transport constant K and the net influx rate K showed strong correlation with SUV (r = 0.808-0.861), SUV (r = 0.794-0.851) and TBR (r = 0.643-0.784), p < 0.002. HGG was confirmed in 21 patients, of which those with methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter showed higher mean K (p = 0.020), K (p = 0.025) and TBR (p = 0.001) than the unmethylated ones.
CONCLUSION
[F]F-CHO uptake kinetics in HGG is best explained by a 2-tissue-compartment model. The conventional static [F]F-CHO-PET measures have been validated against the perfusion-transport constant (K) and the net influx rate (K) derived from kinetic modeling. A relationship between [F]F-CHO uptake rate and MGMT methylation is suggested but needs further confirmation.
PubMed: 38763039
DOI: 10.1016/j.nicl.2024.103616 -
World Journal of Surgical Oncology May 2024Human endogenous retrovirus subfamily H long terminal repeat associating protein 2, (HHLA2), a member of B7 family, exhibits heightened expression in various malignant...
BACKGROUND
Human endogenous retrovirus subfamily H long terminal repeat associating protein 2, (HHLA2), a member of B7 family, exhibits heightened expression in various malignant tumors. However, the exact functions of HHLA2 in pancreatic cancer (PC) remain incompletely elucidated.
METHODS
We initially conducted an analysis of the B7 family members' expression pattern in pancreatic tumor samples and adjacent normal tissues using The Cancer Genome Atlas (TCGA) database. Subsequently, immunohistochemistry, RT-qPCR and western blot methods were used to assess HHLA2 expression levels in PC tissues and cell lines. Furthermore, after silencing HHLA2 in PC cell lines, cell migration and proliferation of PC cells were detected by wound healing and CCK-8 assays, and cell invasion of PC cells was detected by transwell assays. We also investigated the regulation of epithelial-mesenchymal transition (EMT) markers and levels of EGFR, MEK, ERK1/2, mTOR and AKT via western blot analysis. Finally, the correlation between HHLA2 expression and immune infiltration was further explored.
RESULTS
Silencing of HHLA2 resulted in the inhibition of PC cell proliferation, migration and invasion, potentially through the suppression of the EGFR/MAPK/ERK and mTOR/AKT signaling pathway. Additionally, silencing HHLA2 led to the inhibition of M2-type polarization of tumor associated macrophages (TAMs).
CONCLUSION
The knockdown of HHLA2 was observed to inhibit the migration and invasion of PC cells through the regulation of the EMT process and EGFR/MAPK/ERK and mTOR/AKT pathway. Furthermore, silencing HHLA2 was found to modulate M2 polarization of TAMs. These finding suggest that HHLA2 could be a promising therapeutic target for Pancreatic cancer.
Topics: Humans; Pancreatic Neoplasms; TOR Serine-Threonine Kinases; ErbB Receptors; Cell Proliferation; Proto-Oncogene Proteins c-akt; Cell Movement; Epithelial-Mesenchymal Transition; Disease Progression; Prognosis; Macrophages; Tumor Cells, Cultured; Signal Transduction; Male; Biomarkers, Tumor; MAP Kinase Signaling System; Apoptosis; THP-1 Cells; Gene Expression Regulation, Neoplastic; Female; Immunoglobulins
PubMed: 38762741
DOI: 10.1186/s12957-024-03409-2 -
Cellular & Molecular Biology Letters May 2024The role of the scavenger receptor CD36 in cell metabolism and the immune response has been investigated mainly in macrophages, dendritic cells, and T cells. However,...
BACKGROUND
The role of the scavenger receptor CD36 in cell metabolism and the immune response has been investigated mainly in macrophages, dendritic cells, and T cells. However, its involvement in B cells has not been comprehensively examined.
METHODS
To investigate the function of CD36 in B cells, we exposed Cd36MB1 mice, which lack CD36 specifically in B cells, to apoptotic cells to trigger an autoimmune response. To validate the proteins that interact with CD36 in primary B cells, we conducted mass spectrometry analysis following anti-CD36 immunoprecipitation. Immunofluorescence and co-immunoprecipitation were used to confirm the protein interactions.
RESULTS
The data revealed that mice lacking CD36 in B cells exhibited a reduction in germinal center B cells and anti-DNA antibodies in vivo. Mass spectrometry analysis identified 30 potential candidates that potentially interact with CD36. Furthermore, the interaction between CD36 and the inhibitory Fc receptor FcγRIIb was first discovered by mass spectrometry and confirmed through immunofluorescence and co-immunoprecipitation techniques. Finally, deletion of FcγRIIb in mice led to decreased expression of CD36 in marginal zone B cells, germinal center B cells, and plasma cells.
CONCLUSIONS
Our data indicate that CD36 in B cells is a critical regulator of autoimmunity. The interaction of CD36-FcγRIIb has the potential to serve as a therapeutic target for the treatment of autoimmune disorders.
Topics: Animals; CD36 Antigens; Receptors, IgG; B-Lymphocytes; Autoimmune Diseases; Mice; Germinal Center; Mice, Inbred C57BL; Protein Binding; Mice, Knockout; Autoimmunity
PubMed: 38762740
DOI: 10.1186/s11658-024-00593-7 -
Communications Medicine May 2024Adolescents and young adult (AYA) patients with soft tissue tumours including sarcomas are an underserved group with disparities in treatment outcomes.
BACKGROUND
Adolescents and young adult (AYA) patients with soft tissue tumours including sarcomas are an underserved group with disparities in treatment outcomes.
METHODS
To define the molecular features between AYA and older adult (OA) patients, we analysed the proteomic profiles of a large cohort of soft tissue tumours across 10 histological subtypes (AYA n = 66, OA n = 243), and also analysed publicly available functional genomic data from soft tissue tumour cell lines (AYA n = 5, OA n = 8).
RESULTS
Biological hallmarks analysis demonstrates that OA tumours are significantly enriched in MYC targets compared to AYA tumours. By comparing the patient-level proteomic data with functional genomic profiles from sarcoma cell lines, we show that the mRNA splicing pathway is an intrinsic vulnerability in cell lines from OA patients and that components of the spliceosome complex are independent prognostic factors for metastasis free survival in AYA patients.
CONCLUSIONS
Our study highlights the importance of performing age-specific molecular profiling studies to identify risk stratification tools and targeted agents tailored for the clinical management of AYA patients.
PubMed: 38762630
DOI: 10.1038/s43856-024-00522-x -
Nature Communications May 2024The naked mole-rat (Heterocephalus glaber) is a long-lived rodent species showing resistance to the development of cancer. Although naked mole-rats have been reported to...
The naked mole-rat (Heterocephalus glaber) is a long-lived rodent species showing resistance to the development of cancer. Although naked mole-rats have been reported to lack natural killer (NK) cells, γδ T cell-based immunity has been suggested in this species, which could represent an important arm of the immune system for antitumor responses. Here, we investigate the biology of these unconventional T cells in peripheral tissues (blood, spleen) and thymus of the naked mole-rat at different ages by TCR repertoire profiling and single-cell gene expression analysis. Using our own TCR annotation in the naked mole-rat genome, we report that the γδ TCR repertoire is dominated by a public invariant Vγ4-2/Vδ1-4 TCR, containing the complementary-determining-region-3 (CDR3)γ CTYWDSNYAKKLF / CDR3δ CALWELRTGGITAQLVF that are likely generated by short-homology-repeat-driven DNA rearrangements. This invariant TCR is specifically found in γδ T cells expressing genes associated with NK cytotoxicity and is generated in both the thoracic and cervical thymus of the naked mole-rat until adult life. Our results indicate that invariant Vγ4-2/Vδ1-4 NK-like effector T cells in the naked mole-rat can contribute to tumor immunosurveillance by γδ TCR-mediated recognition of a common molecular signal.
Topics: Animals; Mole Rats; Receptors, Antigen, T-Cell, gamma-delta; Thymus Gland; Killer Cells, Natural; Spleen; Complementarity Determining Regions; Natural Killer T-Cells
PubMed: 38762584
DOI: 10.1038/s41467-024-48652-z -
Scientific Reports May 2024Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies. Tissue microarrays (TMA) are an established method of high throughput...
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies. Tissue microarrays (TMA) are an established method of high throughput biomarker interrogation in tissues but may not capture histological features of cancer with potential biological relevance. Topographic TMAs (T-TMAs) representing pathophysiological hallmarks of cancer were constructed from representative, retrospective PDAC diagnostic material, including 72 individual core tissue samples. The T-TMA was interrogated with tissue hybridization-based experiments to confirm the accuracy of the topographic sampling, expression of pro-tumourigenic and immune mediators of cancer, totalling more than 750 individual biomarker analyses. A custom designed Next Generation Sequencing (NGS) panel and a spatial distribution-specific transcriptomic evaluation were also employed. The morphological choice of the pathophysiological hallmarks of cancer was confirmed by protein-specific expression. Quantitative analysis identified topography-specific patterns of expression in the IDO/TGF-β axis; with a heterogeneous relationship of inflammation and desmoplasia across hallmark areas and a general but variable protein and gene expression of c-MET. NGS results highlighted underlying genetic heterogeneity within samples, which may have a confounding influence on the expression of a particular biomarker. T-TMAs, integrated with quantitative biomarker digital scoring, are useful tools to identify hallmark specific expression of biomarkers in pancreatic cancer.
Topics: Humans; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Biomarkers, Tumor; Tissue Array Analysis; High-Throughput Nucleotide Sequencing; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Retrospective Studies; Transcriptome; Male; Female; Middle Aged; Aged
PubMed: 38762572
DOI: 10.1038/s41598-024-62031-0 -
Immunity & Ageing : I & A May 2024Research has suggested significant correlations among ageing, immune microenvironment, inflammation and tumours. However, the relationships among ageing, immune...
BACKGROUND
Research has suggested significant correlations among ageing, immune microenvironment, inflammation and tumours. However, the relationships among ageing, immune microenvironment, cystitis and bladder urothelial carcinoma (BLCA) in the bladder have rarely been reported.
METHODS
Bladder single-cell and transcriptomic data from young and old mice were used for immune landscape analysis. Transcriptome, single-cell and The Cancer Genome Atlas Program datasets of BLCA and interstitial cystitis/bladder pain syndrome (IC/BPS) were used to analyse immune cell infiltration and molecular expression. Bladder tissues from mice, IC/BPS and BLCA were collected to validate the results.
RESULTS
Eight types of immune cells (macrophages, B-cells, dendritic cells, T-cells, monocytes, natural killer cells, γδ T-cells and ILC2) were identified in the bladder of mice. Aged mice bladder tissues had a significantly higher number of T-cells, γδ T-cells, ILC2 and B-cells than those in the young group (P < 0.05). Three types of T-cells (NK T-cells, γδ T-cells and naïve T-cells) and three types of B-cells (follicular B-cells, plasma and memory B-cells) were identified in aged mice bladder. Chemokine receptor 7 (CCR7) is highly expressed in aged bladder, IC/BPS and BLCA (P < 0.05). CCR7 is likely to be involved in T- and B-cell infiltration in aged bladder, IC/BPS and BLCA. Interestingly, the high CCR7 expression on BLCA cell membranes was a prognostic protective factor.
CONCLUSIONS
In this study, we characterised the expression profiles of immune cells in bladder tissues of aged and young mice and demonstrated that CCR7-mediated T- and B-cell filtration contributes to the development of bladder ageing, IC/BPS and BLCA.
PubMed: 38762550
DOI: 10.1186/s12979-024-00432-5 -
Scientific Reports May 2024Glioblastoma (GB) is a devastating tumor of the central nervous system characterized by a poor prognosis. One of the best-established predictive biomarker in...
Glioblastoma (GB) is a devastating tumor of the central nervous system characterized by a poor prognosis. One of the best-established predictive biomarker in IDH-wildtype GB is O6-methylguanine-DNA methyltransferase (MGMT) methylation (mMGMT), which is associated with improved treatment response and survival. However, current efforts to monitor GB patients through mMGMT detection have proven unsuccessful. Small extracellular vesicles (sEVs) hold potential as a key element that could revolutionize clinical practice by offering new possibilities for liquid biopsy. This study aimed to determine the utility of sEV-based liquid biopsy as a predictive biomarker and disease monitoring tool in patients with IDH-wildtype GB. Our findings show consistent results with tissue-based analysis, achieving a remarkable sensitivity of 85.7% for detecting mMGMT in liquid biopsy, the highest reported to date. Moreover, we suggested that liquid biopsy assessment of sEV-DNA could be a powerful tool for monitoring disease progression in IDH-wildtype GB patients. This study highlights the critical significance of overcoming molecular underdetection, which can lead to missed treatment opportunities and misdiagnoses, possibly resulting in ineffective therapies. The outcomes of our research significantly contribute to the field of sEV-DNA-based liquid biopsy, providing valuable insights into tumor tissue heterogeneity and establishing it as a promising tool for detecting GB biomarkers. These results have substantial implications for advancing predictive and therapeutic approaches in the context of GB and warrant further exploration and validation in clinical settings.
Topics: Humans; Glioblastoma; Extracellular Vesicles; Liquid Biopsy; DNA Modification Methylases; DNA Repair Enzymes; DNA Methylation; Male; Female; Biomarkers, Tumor; Middle Aged; Tumor Suppressor Proteins; Brain Neoplasms; Aged; Adult; Prognosis
PubMed: 38762534
DOI: 10.1038/s41598-024-62061-8 -
Scientific Reports May 2024Acute liver injury, there is a risky neurological condition known as hepatic encephalopathy (HE). Herbacetin is a glycosylated flavonoid with many pharmacological...
Neuroprotective and cognitive enhancing effects of herbecetin against thioacetamide induced hepatic encephalopathy in rats via upregulation of AMPK and SIRT1 signaling pathways.
Acute liver injury, there is a risky neurological condition known as hepatic encephalopathy (HE). Herbacetin is a glycosylated flavonoid with many pharmacological characteristics. The purpose of this study was to assess the ability of herbacetin to protect against the cognitive deficits associated with thioacetamide (TAA) rat model and delineate the underlying behavioral and pharmacological mechanisms. Rats were pretreated with herbacetin (20 and 40 mg/kg) for 30days. On 30th day, the rats were injected with TAA (i.p. 350 mg/kg) in a single dose. In addition to a histpathological studies, ultra-structural architecture of the brain, liver functions, oxidative stress biomarkers, and behavioral tests were evaluated. Compared to the TAA-intoxicated group, herbacetin improved the locomotor and cognitive deficits, serum hepatotoxicity indices and ammonia levels. Herbacetin reduced brain levels of malodialdeyde, glutamine synthetase (GS), tumor necrosis factor- alpha (TNF-α), interleukin 1 B (IL-1β), annexin v, and increased brain GSH, Sirtuin 1 (SIRT1), and AMP-activated kinase (AMPK) expression levels. Also, herbacetin improve the histopathological changes and ultra- structure of brain tissue via attenuating the number of inflammatory and apoptotic cells. Herbacetin treatment significantly reduced the toxicity caused by TAA. These findings suggest that herbacetin might be taken into account as a possible neuroprotective and cognitive enhancing agent due to its ability to reduce oxidative stress, inflammation and apoptosis associated with TAA.
Topics: Animals; Thioacetamide; Sirtuin 1; Hepatic Encephalopathy; Rats; Neuroprotective Agents; Signal Transduction; AMP-Activated Protein Kinases; Male; Oxidative Stress; Up-Regulation; Cognition; Brain; Rats, Wistar; Liver; Disease Models, Animal
PubMed: 38762495
DOI: 10.1038/s41598-024-61639-6