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Cell Death & Disease Jun 2024Lung cancer stands as the leading cause of mortality among all types of tumors, with over 40% of cases being lung adenocarcinoma (LUAD). Family with sequence similarity...
Lung cancer stands as the leading cause of mortality among all types of tumors, with over 40% of cases being lung adenocarcinoma (LUAD). Family with sequence similarity 83 member A (FAM83A) emerges as a notable focus due to its frequent overexpression in LUAD. Despite this, the precise role of FAM83A remains elusive. This study addresses this gap by unveiling the crucial involvement of FAM83A in maintaining the cancer stem cell-like (CSC-like) phenotype of LUAD. Through a global proteomics analysis, the study identifies human epidermal growth factor receptor 2 (HER2 or ErbB2) as a crucial target of FAM83A. Mechanistically, FAM83A facilitated ErbB2 expression at the posttranslational modification level via the E3 ubiquitin ligase STUB1 (STIP1-homologous U-Box containing protein 1). More importantly, the interaction between FAM83A and ErbB2 at Arg241 promotes calcineurin (CALN)-mediated dephosphorylation of ErbB2, followed by inhibition of STUB1-mediated ubiquitin-proteasomal ErbB2 degradation. The maintenance of the CSC-like phenotype by FAM83A, achieved through the posttranslational regulation of ErbB2, offers valuable insights for identifying potential therapeutic targets for LUAD.
Topics: Humans; Receptor, ErbB-2; Adenocarcinoma of Lung; Lung Neoplasms; Neoplastic Stem Cells; Neoplasm Proteins; Phenotype; Animals; Mice; Cell Line, Tumor; Ubiquitin-Protein Ligases
PubMed: 38942760
DOI: 10.1038/s41419-024-06853-w -
RMD Open Jun 2024Discontinuation or continuation of maintenance immunosuppressive therapy (MIST) after a severe lupus nephritis (LN) requires measuring the risk of relapse but reliable... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Discontinuation or continuation of maintenance immunosuppressive therapy (MIST) after a severe lupus nephritis (LN) requires measuring the risk of relapse but reliable clinical and biological markers are lacking. The WIN-IgE study assesses the value of serum anti-dsDNA IgE autoantibodies as a biomarker for the prediction of relapse in severe LN.
METHODS
WIN-IgE is an ancillary study of the WIN-Lupus study (NCT01284725), a prospective controlled clinical trial which evaluated the discontinuation of MIST after 2-3 years in class III or IV±V LN with active lesions. WIN-IgE included all patients with available serum collected at randomisation for continuation or discontinuation of MIST. In these sera, anti-dsDNA antibodies, IgE and IgG, were quantified by ELISA and compared between patients who experienced LN relapse and those who did not during the 24 months of follow-up.
RESULTS
52 patients were included, 25 in the MIST continuation group and 27 in the MIST discontinuation group, 12 experienced a biopsy-proven relapse of LN. Initial anti-dsDNA IgE antibodies levels were higher in patients with subsequent LN relapse. Anti-dsDNA IgG was not associated with relapse. Survival without LN relapse was lower in patients with anti-dsDNA IgE levels above vs below a threshold of 1.9 arbitrary units (p=0.019), particularly in the subgroup of patients randomised to discontinue MIST (p=0.002). In all patients, anti-dsDNA IgE above 1.9 arbitrary units had a positive predictive value of 0.8 for severe LN relapse.
CONCLUSIONS
These results suggest blood anti-dsDNA IgE as a non-invasive predictive marker of LN relapse.
Topics: Humans; Lupus Nephritis; Female; Male; Recurrence; Adult; Biomarkers; Immunoglobulin E; Antibodies, Antinuclear; Middle Aged; Prognosis; Prospective Studies; DNA; Immunosuppressive Agents
PubMed: 38942591
DOI: 10.1136/rmdopen-2024-004255 -
RMD Open Jun 2024The nature of the relationship between inflammation, cardiovascular (CV) risk factors and atherosclerosis in axial spondyloarthritis (axSpA) remains largely unknown and...
INTRODUCTION
The nature of the relationship between inflammation, cardiovascular (CV) risk factors and atherosclerosis in axial spondyloarthritis (axSpA) remains largely unknown and sex differences in this regard are yet to be assessed.
METHODS
Study including 611 men and 302 women from the Spanish multicentre AtheSpAin cohort to assess CV disease in axSpA. Data on CV disease risk factors were collected both at disease diagnosis and at enrolment, and data on disease activity, functional indices and carotid ultrasonography only at enrolment.
RESULTS
After a median disease duration of 9 years, patients of both sexes who at disease diagnosis had elevated acute phase reactants (APRs), more frequently had hypertension and obesity. The same occurred with dyslipidaemia in men and with diabetes mellitus in women. At enrolment, CV risk factors were independently associated with APR and with activity and functional indices, with various sex differences. C reactive protein (CRP) values were inversely associated with HDL-cholesterol in men (β coefficient: -1.2 (95% CI: -0.3 to -0.07) mg/dL, p=0.001), while erythrocyte sedimentation rate values were positively associated with triglycerides in women (β coefficient: 0.6 (95% CI: 0.04 to 1) mg/dL, p=0.035). Furthermore, only women showed an independent relationship between insulin resistance parameters and APR or disease activity. Both men and women with high-very high CV risk according to the Systematic Assessment of Coronary Risk Evaluation 2 and CRP levels higher than 3 mg/L at diagnosis of the disease presented carotid plaques significantly more frequently than those with normal CRP levels at disease diagnosis.
CONCLUSION
Inflammation is associated with atherosclerosis and CV disease in axSpA. A gender-driven effect is observed in this relationship.
Topics: Humans; Male; Female; Atherosclerosis; Middle Aged; Inflammation; Adult; Heart Disease Risk Factors; Sex Factors; Axial Spondyloarthritis; Risk Factors; Biomarkers; Cardiovascular Diseases; C-Reactive Protein
PubMed: 38942590
DOI: 10.1136/rmdopen-2024-004187 -
Korean Journal of Radiology Jul 2024To develop and validate a preoperative risk score incorporating carbohydrate antigen (CA) 19-9, CT, and fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT variables to...
Predicting Recurrence-Free Survival After Upfront Surgery in Resectable Pancreatic Ductal Adenocarcinoma: A Preoperative Risk Score Based on CA 19-9, CT, and F-FDG PET/CT.
OBJECTIVE
To develop and validate a preoperative risk score incorporating carbohydrate antigen (CA) 19-9, CT, and fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT variables to predict recurrence-free survival (RFS) after upfront surgery in patients with resectable pancreatic ductal adenocarcinoma (PDAC).
MATERIALS AND METHODS
Patients with resectable PDAC who underwent upfront surgery between 2014 and 2017 (development set) or between 2018 and 2019 (test set) were retrospectively evaluated. In the development set, a risk-scoring system was developed using the multivariable Cox proportional hazards model, including variables associated with RFS. In the test set, the performance of the risk score was evaluated using the Harrell C-index and compared with that of the postoperative pathological tumor stage.
RESULTS
A total of 529 patients, including 335 (198 male; mean age ± standard deviation, 64 ± 9 years) and 194 (103 male; mean age, 66 ± 9 years) patients in the development and test sets, respectively, were evaluated. The risk score included five variables predicting RFS: tumor size (hazard ratio [HR], 1.29 per 1 cm increment; < 0.001), maximal standardized uptake values of tumor ≥ 5.2 (HR, 1.29; = 0.06), suspicious regional lymph nodes (HR, 1.43; = 0.02), possible distant metastasis on F-FDG PET/CT (HR, 2.32; = 0.03), and CA 19-9 (HR, 1.02 per 100 U/mL increment; = 0.002). In the test set, the risk score showed good performance in predicting RFS (C-index, 0.61), similar to that of the pathologic tumor stage (C-index, 0.64; = 0.17).
CONCLUSION
The proposed risk score based on preoperative CA 19-9, CT, and F-FDG PET/CT variables may have clinical utility in selecting high-risk patients with resectable PDAC.
Topics: Humans; Male; Fluorodeoxyglucose F18; Female; Positron Emission Tomography Computed Tomography; Middle Aged; Carcinoma, Pancreatic Ductal; Aged; Pancreatic Neoplasms; Retrospective Studies; Radiopharmaceuticals; CA-19-9 Antigen; Tomography, X-Ray Computed; Neoplasm Recurrence, Local; Risk Assessment; Disease-Free Survival; Predictive Value of Tests
PubMed: 38942458
DOI: 10.3348/kjr.2023.1235 -
Korean Journal of Radiology Jul 2024This study systematically reviewed the role of diffusion-weighted imaging (DWI) in the assessment of molecular prognostic biomarkers in breast cancer, focusing on the... (Meta-Analysis)
Meta-Analysis Review
This study systematically reviewed the role of diffusion-weighted imaging (DWI) in the assessment of molecular prognostic biomarkers in breast cancer, focusing on the correlation of apparent diffusion coefficient (ADC) with hormone receptor status and prognostic biomarkers. Our meta-analysis includes data from 52 studies examining ADC values in relation to estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and Ki-67 status. The results indicated significant differences in ADC values among different receptor statuses, with ER-positive, PgR-positive, HER2-negative, and Ki-67-positive tumors having lower ADC values compared to their negative counterparts. This study also highlights the potential of advanced DWI techniques such as intravoxel incoherent motion and non-Gaussian DWI to provide additional insights beyond ADC. Despite these promising findings, the high heterogeneity among the studies underscores the need for standardized DWI protocols to improve their clinical utility in breast cancer management.
Topics: Humans; Breast Neoplasms; Diffusion Magnetic Resonance Imaging; Female; Biomarkers, Tumor; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Ki-67 Antigen
PubMed: 38942456
DOI: 10.3348/kjr.2023.1188 -
Pharmacological Research Jun 2024Heart failure (HF) is the leading cause of morbidity and mortality in cardiovascular diseases, being responsible for many hospitalizations annually. HF is considered a... (Review)
Review
Heart failure (HF) is the leading cause of morbidity and mortality in cardiovascular diseases, being responsible for many hospitalizations annually. HF is considered a public health problem with significant economic and social impact, which makes searches essential for strategies that improve the ability to predict and diagnose HF. In this way, biomarkers can help in risk stratification for a more personalized approach to patients with HF. Preclinical and clinical evidence shows the participation of matrix metalloproteinase 9 (MMP-9) in the HF process. In this review, we will demonstrate the critical role that MMP-9 plays in cardiac remodeling and dysfunction. We will also show its importance as a blood biomarker in acute and chronic HF patients.
PubMed: 38942342
DOI: 10.1016/j.phrs.2024.107285 -
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 -
Annals of Oncology : Official Journal... Jun 2024Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant...
Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.
BACKGROUND
Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups.
PATIENTS AND METHODS
This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR).
RESULTS
Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004].
CONCLUSIONS
Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.
PubMed: 38942080
DOI: 10.1016/j.annonc.2024.05.541 -
EBioMedicine Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC,...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC, different oncolytic viruses (OVs) are currently investigated in clinical trials. However, systematic comparisons of these different OVs in terms of efficacy against PDAC and biomarkers predicting therapeutic response are lacking.
METHODS
We screened fourteen patient-derived PDAC cultures which reflect the intra- and intertumoural heterogeneity of PDAC for their sensitivity to five clinically relevant OVs, namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC, measles vaccine strain MV-NIS, reovirus jin-3, and protoparvovirus H-1PV. Live cell analysis, quantification of viral genome/gene expression, cell viability as well as cytotoxicity assays and titration of viral progeny were conducted. Transcriptome profiling was employed to identify potential predictive biomarkers for response to OV treatment.
FINDINGS
Patient-derived PDAC cultures showed individual response patterns to OV treatment. Twelve of fourteen cultures were responsive to at least one OV, with no single OV proving superior or inferior across all cultures. Known host factors for distinct viruses were retrieved as potential biomarkers. Compared to the classical molecular subtype, the quasi-mesenchymal or basal-like subtype of PDAC was found to be more sensitive to H-1PV, jin-3, and T-VEC. Generally, expression of viral entry receptors did not correlate with sensitivity to OV treatment, with one exception: Expression of Galectin-1 (LGALS1), a factor involved in H-1PV entry, positively correlated with H-1PV induced cell killing. Rather, cellular pathways controlling immunological, metabolic and proliferative signaling appeared to determine outcome. For instance, high baseline expression of interferon-stimulated genes (ISGs) correlated with relative resistance to oncolytic measles virus, whereas low cyclic GMP-AMP synthase (cGAS) expression was associated with exceptional response. Combination treatment of MV-NIS with a cGAS inhibitor improved tumour cell killing in several PDAC cultures and cells overexpressing cGAS were found to be less sensitive to MV oncolysis.
INTERPRETATION
Considering the heterogeneity of PDAC and the complexity of biological therapies such as OVs, no single biomarker can explain the spectrum of response patterns. For selection of a particular OV, PDAC molecular subtype, ISG expression as well as activation of distinct signaling and metabolic pathways should be considered. Combination therapies can overcome resistance in specific constellations. Overall, oncolytic virotherapy is a viable treatment option for PDAC, which warrants further development. This study highlights the need for personalised treatment in OVT. By providing all primary data, this study provides a rich source and guidance for ongoing developments.
FUNDING
German National Science Foundation (Deutsche Forschungsgemeinschaft, DFG), German Cancer Aid (Deutsche Krebshilfe), German National Academic Scholarship Foundation (Studienstiftung des deutschen Volkes), Survival with Pancreatic Cancer Foundation.
PubMed: 38941955
DOI: 10.1016/j.ebiom.2024.105219 -
Archives of Gerontology and Geriatrics Jun 2024To examine the associaiton between environmental measures and brain volumes and its potential mediators.
OBJECTIVES
To examine the associaiton between environmental measures and brain volumes and its potential mediators.
STUDY DESIGN
This was a prospective study.
METHODS
Our analysis included 34,454 participants (53.4% females) aged 40-73 years at baseline (between 2006 and 2010) from the UK Biobank. Brain volumes were measured using magnetic resonance imaging between 2014 and 2019.
RESULTS
Greater proximity to greenspace buffered at 1000 m at baseline was associated with larger volumes of total brain measured 8.8 years after baseline assessment (standardized β (95% CI) for each 10% increment in coverage: 0.013(0.005,0.020)), grey matter (0.013(0.006,0.020)), and white matter (0.011(0.004,0.017)) after adjustment for covariates and air pollution. The corresponding numbers for natural environment buffered at 1000 m were 0.010 (0.004,0.017), 0.009 (0.004,0.015), and 0.010 (0.004,0.016), respectively. Similar results were observed for greenspace and natural environment buffered at 300 m. The strongest mediator for the association between greenspace buffered at 1000 m and total brain volume was smoking (percentage (95% CI) of total variance explained: 7.9% (5.5-11.4%)) followed by mean sphered cell volume (3.3% (1.8-5.8%)), vitamin D (2.9% (1.6-5.1%)), and creatinine in blood (2.7% (1.6-4.7%)). Significant mediators combined explained 18.5% (13.2-25.3%) of the association with total brain volume and 32.9% (95% CI: 22.3-45.7%) of the association with grey matter volume. The percentage (95% CI) of the association between natural environment and total brain volume explained by significant mediators combined was 20.6% (14.7-28.1%)).
CONCLUSIONS
Higher coverage percentage of greenspace and environment may benefit brain health by promoting healthy lifestyle and improving biomarkers including vitamin D and red blood cell indices.
PubMed: 38941948
DOI: 10.1016/j.archger.2024.105546