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Frontiers in Immunology 2023Chondroitin sulfate proteoglycan 4 (CSPG4), also known as high molecular weight-melanoma associated antigen, is expressed in melanoma but also other tumor entities and...
INTORDUCTION
Chondroitin sulfate proteoglycan 4 (CSPG4), also known as high molecular weight-melanoma associated antigen, is expressed in melanoma but also other tumor entities and constitutes an attractive target for immunotherapeutic approaches. While recent preclinical reports focused on anti-CSPG4 chimeric antigen receptors (CAR), we here explore T-cell receptor (TCR)-based approaches targeting CSPG4.
METHODS
The TCRs of two CSPG4-reactive T-cell clones (11C/73 and 2C/165) restricted by the highly prevalent HLA-C*07:01 allele were isolated and the respective αβTCR pairs were retrovirally expressed in CRISPR/Cas9-edited TCR-knockout T cells for functional testing. We also combined alpha and beta TCR chains derived from 11C/73 and 2C/165 in a cross-over fashion to assess for hemichain dominance. CSPG4 melanoma, glioblastoma and lung cancer cell lines were identified and, if negative, retrovirally transduced with HLA-C*07:01.
RESULTS
Functional tests confirmed specific recognition of CSPG4HLA-C*07:01 target cells by the αβTCR retrieved from the parental T-cell clones and in part also by the cross-over TCR construct 2Cα-11Cβ. Despite high surface expression, the 11Cα-2Cβ combination, however, was not functional.
DISCUSSION
Collectively, 11C/73- and 2C/165-expressing T cells specifically and efficiently recognized CSPG4HLA-C*07:01 cancer cells which warrants further preclinical and clinical evaluation of these TCRs.
Topics: Humans; HLA-C Antigens; Receptors, Antigen, T-Cell; Melanoma; T-Lymphocytes; Membrane Proteins; Chondroitin Sulfate Proteoglycans
PubMed: 37849763
DOI: 10.3389/fimmu.2023.1245559 -
Medicine Oct 2023Major orthopedic surgery, including hip and knee replacement and lower extremity trauma fractures surgery, is associated with a high risk of venous thromboembolism... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Major orthopedic surgery, including hip and knee replacement and lower extremity trauma fractures surgery, is associated with a high risk of venous thromboembolism (VTE), especially proximal deep vein thrombosis (DVT), and pulmonary embolism (PE), and is linked with high morbidity and mortality rates. Chemical anticoagulation is routinely used to prevent VTE, with previous meta-analyses reporting on the efficacy and safety of aspirin and other anticoagulants, however, opinions are divided. In the past 2 years, several large randomized controlled trials have been published, therefore, we reanalyzed aspirin efficacy and safety when compared with other anticoagulants in preventing VTE in major orthopedic surgery.
METHODS
Using PubMed, The Cochrane Library, Embase, and Web of Science databases, we conducted a RCT search in August 2023. The main outcomes included VTE, proximal DVT or PE. Additional outcomes included bleeding events, wound complications, wound infections, blood transfusions, and death events.
RESULTS
In total, 17 eligible articles, involving 29,522 patients (15,253 aspirin vs 14,269 other anticoagulant cases), were included. Primary outcomes showed that VTE incidence was more high in the aspirin group when compared with other anticoagulants (risk ratio [RR] = 1.45, 95% confidence interval [CI] = 1.18-1.77, P = .0004) and proximal in the aspirin group the DVT and/or PE incidence was significantly higher in the aspirin group when compared with other anticoagulants (RR = 1.19, 95% CI = 1.02-1.39, P = .03). No significant secondary outcome differences were identified in the aspirin group when compared with other anticoagulants (bleeding events [RR] = 0.83, 95% CI = 0.63-1.10, P = .20); wound complications (RR = 0.45, 95% CI = 0.20-1.04, P = .06); wound infection (RR = 1.08, 95% CI = 0.85-1.38, P = .53); blood transfusion events (RR = 1.00, 95% CI = 0.84-1.19, P = 1.00) and death events (RR = 1.11, 95% CI = 0.78-1.57, P = .55).
CONCLUSIONS
Our updated meta-analysis showed that aspirin was inferior to when compared with other anticoagulants in VTE-related orthopedic major surgery, including proximal DVT and/or PE, and was more likely to form VTE. No differences between groups were identified for bleeding, wound complications, wound infections, transfusion, or death events.
Topics: Humans; Aspirin; Venous Thromboembolism; Randomized Controlled Trials as Topic; Venous Thrombosis; Anticoagulants; Hemorrhage; Pulmonary Embolism; Orthopedic Procedures; Wound Infection; Heparin, Low-Molecular-Weight
PubMed: 37861503
DOI: 10.1097/MD.0000000000035602 -
Respiratory Research Nov 2023Quantitative interstitial abnormalities (QIA) are an automated computed tomography (CT) finding of early parenchymal lung disease, associated with worse lung function,...
BACKGROUND
Quantitative interstitial abnormalities (QIA) are an automated computed tomography (CT) finding of early parenchymal lung disease, associated with worse lung function, reduced exercise capacity, increased respiratory symptoms, and death. The metabolomic perturbations associated with QIA are not well known. We sought to identify plasma metabolites associated with QIA in smokers. We also sought to identify shared and differentiating metabolomics features between QIA and emphysema, another smoking-related advanced radiographic abnormality.
METHODS
In 928 former and current smokers in the Genetic Epidemiology of COPD cohort, we measured QIA and emphysema using an automated local density histogram method and generated metabolite profiles from plasma samples using liquid chromatography-mass spectrometry (Metabolon). We assessed the associations between metabolite levels and QIA using multivariable linear regression models adjusted for age, sex, body mass index, smoking status, pack-years, and inhaled corticosteroid use, at a Benjamini-Hochberg False Discovery Rate p-value of ≤ 0.05. Using multinomial regression models adjusted for these covariates, we assessed the associations between metabolite levels and the following CT phenotypes: QIA-predominant, emphysema-predominant, combined-predominant, and neither- predominant. Pathway enrichment analyses were performed using MetaboAnalyst.
RESULTS
We found 85 metabolites significantly associated with QIA, with overrepresentation of the nicotinate and nicotinamide, histidine, starch and sucrose, pyrimidine, phosphatidylcholine, lysophospholipid, and sphingomyelin pathways. These included metabolites involved in inflammation and immune response, extracellular matrix remodeling, surfactant, and muscle cachexia. There were 75 metabolites significantly different between QIA-predominant and emphysema-predominant phenotypes, with overrepresentation of the phosphatidylethanolamine, nicotinate and nicotinamide, aminoacyl-tRNA, arginine, proline, alanine, aspartate, and glutamate pathways.
CONCLUSIONS
Metabolomic correlates may lend insight to the biologic perturbations and pathways that underlie clinically meaningful quantitative CT measurements like QIA in smokers.
Topics: Humans; Smokers; Niacin; Lung; Pulmonary Emphysema; Emphysema; Niacinamide; Pulmonary Disease, Chronic Obstructive
PubMed: 37925418
DOI: 10.1186/s12931-023-02576-2 -
Journal of Global Health Mar 2024This study was designed to evaluate the effects of body mass index (BMI) and weight change on the risk of developing cancer overall and cancer at different sites. (Meta-Analysis)
Meta-Analysis
BACKGROUND
This study was designed to evaluate the effects of body mass index (BMI) and weight change on the risk of developing cancer overall and cancer at different sites.
METHODS
We searched PubMed and other databases up to July 2023 using the keywords related to 'risk', 'cancer', 'weight', 'overweight', and 'obesity'. We identified eligible studies, and the inclusion criteria encompassed cohort studies in English that focused on cancer diagnosis and included BMI or weight change as an exposure factor. Multiple authors performed data extraction and quality assessment, and statistical analyses were carried out using RevMan and R software. We used random- or fixed-effects models to calculate the pooled relative risk (RR) or hazard ratio along with 95% confidence intervals (CIs). We used the Newcastle-Ottawa Scale to assess study quality.
RESULTS
Analysis included 66 cohort studies. Compared to underweight or normal weight, overweight or obesity was associated with an increased risk of endometrial cancer, kidney cancer, and liver cancer but a decreased risk of prostate cancer and lung cancer. Being underweight was associated with an increased risk of gastric cancer and lung cancer but not that of postmenopausal breast cancer or female reproductive cancer. In addition, weight loss of more than five kg was protective against overall cancer risk.
CONCLUSIONS
Overweight and obesity increase the risk of most cancers, and weight loss of >5 kg reduces overall cancer risk. These findings provide insights for cancer prevention and help to elucidate the mechanisms underlying cancer development.
REGISTRATION
Reviewregistry1786.
Topics: Male; Female; Humans; Body Mass Index; Overweight; Thinness; Obesity; Cohort Studies; Breast Neoplasms; Lung Neoplasms; Weight Loss
PubMed: 38547495
DOI: 10.7189/jogh.14.04067 -
Respiratory Research Nov 2023Interstitial lung disease (ILD) and pulmonary hypertension (PH) represent the major causes of mortality in systemic sclerosis (SSc). Patients with systemic sclerosis and...
BACKGROUND
Interstitial lung disease (ILD) and pulmonary hypertension (PH) represent the major causes of mortality in systemic sclerosis (SSc). Patients with systemic sclerosis and combined PH and ILD (SSc-PH-ILD) generally have a poor prognosis. Predictors of survival and of potential benefit of treatment are lacking in patients with SSc-PH-ILD.
OBJECTIVE
To identify specific plasma protein expression patterns associated with survival in patients with SSc-PH-ILD.
MATERIALS AND METHODS
Post-hoc analysis of a prospective multicenter French study in patients with PH-ILD. An untargeted proteomic analysis using mass spectrometry was performed to identify plasma protein changes associated with long-term overall survival in patients with SSc-PH-ILD.
RESULTS
Thirty two patients were included in the analysis, of whom 13 died during follow-up (median survival: 76.5 months). At baseline, survivors had less severe hemodynamic impairment [pulmonary vascular resistance of 4.4 Wood Units (IQR 3-5.2) vs. 6.2 Wood Units (IQR 4.2-10.7)] and higher carbon monoxide diffusing capacity [median 39% (IQR 35-44%) vs. 25% (IQR 22-30.5%)], than the 13 patients who died. Seven proteins, associated with haemostasis and fibrosis, were differentially expressed according to patients' survival. In the survivor group, two proteins were increased (ADAMTS13, SERPIND1) and five were decreased (PTGDS, OLFM1, C7, IGFBP7, FBN1) compared to the non-survivor groups.
CONCLUSION
The prognosis of SSc-PH-ILD patients is poor. This proteomic approach found 7 plasma proteins (involved in haemostasis and fibrosis pathways) associated with survival. These potential biomarkers may be good candidates to prognostic enrichment.
Topics: Humans; Hypertension, Pulmonary; Prospective Studies; Proteomics; Scleroderma, Systemic; Lung Diseases, Interstitial; Biomarkers; Pulmonary Arterial Hypertension; Fibrosis; Blood Proteins; Lung
PubMed: 37936223
DOI: 10.1186/s12931-023-02578-0 -
Aging Dec 2023Aging usually causes lung-function decline and susceptibility to chronic lung diseases, such as pulmonary fibrosis. However, how aging affects the lung-fibrosis pathways...
Aging usually causes lung-function decline and susceptibility to chronic lung diseases, such as pulmonary fibrosis. However, how aging affects the lung-fibrosis pathways and leads to the occurrence of pulmonary fibrosis is not completely understood. Here, mass spectrometry-based proteomics was used to chart the lung proteome of young and old mice. Micro computed tomography imaging, RNA immunoprecipitation, dual-fluorescence mRFP-GFP-LC3 adenovirus monitoring, transmission electron microscopy, and other experiments were performed to explore the screened differentially expressed proteins related to abnormal ferroptosis, autophagy, mitochondria, and mechanical force , , and in healthy people. Combined with our previous studies on pulmonary fibrosis, we further demonstrated that these biological processes and underlying molecular players were also involved in the aging process. Our work depicted a comprehensive cellular and molecular atlas of the aging lung and attempted to explain why aging is a risk factor for pulmonary fibrosis and the role that aging plays in the progression of pulmonary fibrosis. The abnormalities of aging triggered an increase in mechanical force and ferroptosis, autophagy blockade, and mitochondrial dysfunction, which often appear during pulmonary fibrogenesis. We hope that the elucidation of these anomalies will help to enhance our understanding of senescence-inducing pulmonary fibrosis, thereby guiding the use of anti-senescence as an entry point for early intervention in pulmonary fibrosis and age-related diseases.
Topics: Humans; Animals; Mice; Proteomics; X-Ray Microtomography; Idiopathic Pulmonary Fibrosis; Lung; Aging; MicroRNAs; Cellular Senescence
PubMed: 38147026
DOI: 10.18632/aging.205355 -
American Journal of Respiratory and... Nov 2023CFTR (cystic fibrosis transmembrane conductance regulator) modulator drugs restore function to mutant channels in patients with cystic fibrosis (CF) and lead to...
CFTR (cystic fibrosis transmembrane conductance regulator) modulator drugs restore function to mutant channels in patients with cystic fibrosis (CF) and lead to improvements in body mass index and lung function. Although it is anticipated that early childhood treatment with CFTR modulators will significantly delay or even prevent the onset of advanced lung disease, lung neutrophils and inflammatory cytokines remain high in patients with CF with established lung disease despite modulator therapy, underscoring the need to identify and ultimately target the sources of this inflammation in CF lungs. To determine whether CF lungs, like chronic obstructive pulmonary disease (COPD) lungs, harbor potentially pathogenic stem cell "variants" distinct from the normal p63/Krt5 lung stem cells devoted to alveolar fates, to identify specific variants that might contribute to the inflammatory state of CF lungs, and to assess the impact of CFTR genetic complementation or CFTR modulators on the inflammatory variants identified herein. Stem cell cloning technology developed to resolve pathogenic stem cell heterogeneity in COPD and idiopathic pulmonary fibrosis lungs was applied to end-stage lungs of patients with CF (three homozygous CFTR:F508D, one CFTR F508D/L1254X; FEV, 14-30%) undergoing therapeutic lung transplantation. Single-cell-derived clones corresponding to the six stem cell clusters resolved by single-cell RNA sequencing of these libraries were assessed by RNA sequencing and xenografting to monitor inflammation, fibrosis, and mucin secretion. The impact of CFTR activity on these variants after CFTR gene complementation or exposure to CFTR modulators was assessed by molecular and functional studies. End-stage CF lungs display a stem cell heterogeneity marked by five predominant variants in addition to the normal lung stem cell, of which three are proinflammatory both at the level of gene expression and their ability to drive neutrophilic inflammation in xenografts in immunodeficient mice. The proinflammatory functions of these three variants were unallayed by genetic or pharmacological restoration of CFTR activity. The emergence of three proinflammatory stem cell variants in CF lungs may contribute to the persistence of lung inflammation in patients with CF with advanced disease undergoing CFTR modulator therapy.
Topics: Humans; Child, Preschool; Animals; Mice; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Lung; Pulmonary Disease, Chronic Obstructive; Inflammation
PubMed: 37695863
DOI: 10.1164/rccm.202305-0818OC -
Journal of Virology Sep 2023The continued evolution and emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have resulted in challenges to vaccine and antibody...
The continued evolution and emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have resulted in challenges to vaccine and antibody efficacy. The emergence of each new variant necessitates the need to re-evaluate and refine animal models used for countermeasure testing. Here, we tested a recently circulating SARS-CoV-2 Omicron lineage variant, BQ.1.1, in multiple rodent models including K18-human ACE2 (hACE2) transgenic, C57BL/6J, and 129S2 mice, and Syrian golden hamsters. In contrast to a previously dominant BA.5.5 Omicron variant, inoculation of K18-hACE2 mice with BQ.1.1 resulted in substantial weight loss, a characteristic seen in pre-Omicron variants. BQ.1.1 also replicated to higher levels in the lungs of K18-hACE2 mice and caused greater lung pathology than the BA.5.5 variant. However, in C57BL/6J mice, 129S2 mice, and Syrian hamsters, BQ.1.1 did not cause increased respiratory tract infection or disease compared to animals administered BA.5.5. Moreover, the rates of direct contact or airborne transmission in hamsters were not significantly different after BQ.1.1 and BA.5.5 infections. Taken together, these data suggest that the BQ.1.1 Omicron variant has increased virulence in rodent species that express hACE2, possibly due to the acquisition of unique spike mutations relative to earlier Omicron variants. IMPORTANCE As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, there is a need to rapidly assess the efficacy of vaccines and antiviral therapeutics against newly emergent variants. To do so, the commonly used animal models must also be re-evaluated. Here, we determined the pathogenicity of the BQ.1.1 SARS-CoV-2 variant in multiple SARS-CoV-2 animal models including transgenic mice expressing human ACE2 (hACE2), two strains of conventional laboratory mice, and Syrian hamsters. While BQ.1.1 and BA.5.5 infection resulted in similar levels of viral burden and clinical disease in hamsters and the conventional strains of laboratory mice tested, increases in lung infection were detected in hACE2-expressing transgenic mice, which corresponded with greater levels of pro-inflammatory cytokines and lung pathology. Taken together, our data highlight important differences in two closely related Omicron SARS-CoV-2 variant strains and provide a foundation for evaluating countermeasures.
Topics: Animals; Cricetinae; Humans; Mice; COVID-19; Disease Models, Animal; Lung; Mesocricetus; Mice, Inbred C57BL; Mice, Transgenic; SARS-CoV-2; Viral Load; Virulence
PubMed: 37676002
DOI: 10.1128/jvi.00628-23 -
Cancer Imaging : the Official... Dec 2023We aim to compare the differences in growth characteristics between part-solid and solid lung adenocarcinoma, and to investigate the value of volume doubling time (VDT)...
BACKGROUND
We aim to compare the differences in growth characteristics between part-solid and solid lung adenocarcinoma, and to investigate the value of volume doubling time (VDT) or mass doubling time (MDT) in predicting lymph node (LN) metastasis and preoperative evaluation in patients of early-stage (IA) non-small cell lung cancer (NSCLC).
METHOD
We reviewed 8,653 cases of surgically resected stage IA lung adenocarcinoma between 2018 and 2022, with two follow-up visits at least 3 months apart, comparing diameter, volume, and mass growth of pSN and SN. VDT and MDT calculations for nodules with a volume change of at least 25%. Univariable or multivariable analysis was used to identify the risk factors. The area under the curve (AUC) for the receiver operating characteristic (ROC) curves was used to evaluate the diagnostic value.
RESULTS
A total of 144 patients were included 114 with solid nodules (SN) and 25 with part-solid nodules (pSN). During the follow-up period, the mean VDTt and MDTt of SN were shorter than those of pSN, 337 vs. 541 days (p = 0.005), 298 vs. 458 days (p = 0.018), respectively. Without considering the ground-glass component, the mean VDTc and MDTc of SN were shorter than the solid component of pSN, 337 vs. 498 days (p = 0.004) and 298 vs. 453 days (p = 0.003), respectively. 27 nodules were clinically and pathologically diagnosed as N1/N2. Logistic regression identified initial diameter (p < 0.001), consolidation increase (p = 0.019), volume increase (p = 0.020), mass increase (p = 0.021), VDTt (p = 0.002), and MDTt (p = 0.004) were independent factors for LN metastasis. The ROC curves showed that the AUC for VDTt was 0.860 (95% CI, 0.778-0.943; p < 0.001) and for MDTt was 0.848 (95% CI, 0.759-0.936; p < 0.001).
CONCLUSIONS
Our study showed significant differences in the growth characteristics of pSN and SN, and the application of VDT and MDT could be a valid predictor LN metastasis in patients with early-stage NSCLC.
Topics: Humans; Adenocarcinoma of Lung; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Neoplasm Staging; Retrospective Studies; Tomography, X-Ray Computed
PubMed: 38041175
DOI: 10.1186/s40644-023-00631-1 -
Open Life Sciences 2023Meningiomas are extra-axial neoplasms that originate from the arachnoid cap cells located on the inner surface of the meninges. Approximately 36% of central nervous... (Review)
Review
Meningiomas are extra-axial neoplasms that originate from the arachnoid cap cells located on the inner surface of the meninges. Approximately 36% of central nervous system tumors are meningiomas. Based on earlier findings to be benign in most cases, they are categorized as slow-growing tumors that form gradually over time. Meningiomas are usually asymptomatic and discovered inadvertently. They rarely present with immediate clinical symptoms or abrupt hemorrhagic strokes. However, tumor hemorrhage can be fatal in high-grade meningiomas, particularly those with vascularization. We describe a 58-year-old man who was hospitalized after experiencing an unexpectedly acute headache. The right cerebellar hemisphere and vermis cerebellar hemorrhage were detected on computed tomography (CT), and the cerebellar hemorrhage was explained by a diagnosis of hypertension. When additional analysis of the patient's chest CT indicated lung mass lesions, we assumed that the lung cancer had spread to the brain. However, the pathological outcomes of a guided definite pulmonary aspiration biopsy, in conjunction with resection of the cerebellar tumor, suggested a subtentorial meningioma with ruptured hemorrhage and pulmonary meningioma metastasis. The patient was transferred to a hospital closer to home for ongoing follow-up and, after 2 months, he had recovered well.
PubMed: 37941787
DOI: 10.1515/biol-2022-0745