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Journal of the National Cancer Institute Dec 2023Though obesity, measured by body mass index (BMI), is an established risk factor for several cancer sites, there is conflicting evidence on whether obesity increases...
BACKGROUND
Though obesity, measured by body mass index (BMI), is an established risk factor for several cancer sites, there is conflicting evidence on whether obesity increases prostate cancer risk or mortality and, if it does, whether it increases risk directly or indirectly by affecting prostate cancer screening efficacy.
METHODS
We examined associations between BMI and prostate cancer screening outcomes, incidence, and mortality in men randomly assigned to the intervention arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (n = 36 756) between 1993 and 2001. Participants received annual screening with the prostate-specific antigen test and digital rectal exam. Associations between baseline BMI and screening outcomes were assessed via multinomial logistic regression, and associations with prostate cancer incidence and mortality were assessed via Cox proportional hazards regression.
RESULTS
Individuals with higher BMI were less likely to screen positive via the prostate-specific antigen test and/or digital rectal exam and more likely to have an inadequate screen (all Ptrend < .01). Higher BMI was inversely associated with prostate cancer incidence (per 5 kg/m2 BMI increase: hazard ratio [HR] = 0.94, 95% confidence interval [CI] = 0.91 to 0.97), including incidence of early stage (HR = 0.94, 95% CI = 0.90 to 0.97) and advanced-stage (HR = 0.91, 95% CI = 0.82 to 1.02) disease, but positively associated with prostate cancer mortality (HR = 1.21, 95% CI = 1.06 to 1.37). The association with mortality was not modified by screening outcome (Pinteraction = .13).
CONCLUSIONS
Within this screened population, individuals with higher BMI had lower risk of prostate cancer diagnosis but higher risk of prostate cancer mortality. As higher BMI was not positively associated with advanced-stage prostate cancer risk, the increased mortality is unlikely to be due to delayed prostate cancer detection.
Topics: Male; Humans; Prostatic Neoplasms; Prostate; Prostate-Specific Antigen; Incidence; Early Detection of Cancer; Obesity; Colorectal Neoplasms; Lung; Ovarian Neoplasms; Body Mass Index
PubMed: 37382561
DOI: 10.1093/jnci/djad113 -
International Immunopharmacology Nov 2023Keratin 7 (Krt7) is a member of the keratin family and is primarily involved in cytoskeleton composition. It has been shown that Krt7 is able to influence its own...
Keratin 7 (Krt7) is a member of the keratin family and is primarily involved in cytoskeleton composition. It has been shown that Krt7 is able to influence its own remodeling and interactions with other signaling molecules via phosphorylation at specific sites unique to Krt7. However, its molecular mechanism in acute lung injury (ALI) remains unclear. In this study, differential proteomics was used to analyze lung samples from the receptor for advanced glycation end products (RAGE)-deficient and (wild-type)WT-septic mice. We screened for the target protein Krt7 and identified Ser53 as the phosphorylation site using mass spectrometry (MS), and this phosphorylation further triggered the deformation and disintegration of Desmoplakin (Dsp), ultimately leading to epithelial barrier dysfunction. Furthermore, we demonstrated that in sepsis, mDia1/Cdc42/p38 MAPK signaling activation plays a role in septic lung injury. We also explored the mechanism of alveolar dysfunction of the Krt7-Dsp complex in the epithelial cell barrier. In summary, the present findings increase our understanding of the pathogenesis of septic acute lung injury.
Topics: Animals; Mice; Acute Lung Injury; Desmoplakins; Lung; Receptor for Advanced Glycation End Products; Sepsis
PubMed: 37660597
DOI: 10.1016/j.intimp.2023.110867 -
Journal of Rural Medicine : JRM Jul 2023To identify the prevalence of risk factors for pulmonary non-tuberculous mycobacterial (NTM) disease in a Japanese population. We reviewed 337 consecutive Japanese...
To identify the prevalence of risk factors for pulmonary non-tuberculous mycobacterial (NTM) disease in a Japanese population. We reviewed 337 consecutive Japanese patients (210 women) with pulmonary NTM disease, including 225 patients with Mycobacterium avium complex (MAC) disease (95.8%) at our hospital during 2006-2017. We calculated the prevalence of risk factors reported in Western countries among mycobacterial species. Pulmonary MAC disease cases comprised 78.2% of pulmonary NTM patients in their 40s, increasing to 100% at age ≥80 years. Body mass index (BMI) was <18.5 in approximately 40% of patients, which was significantly higher than the prevalence of underweight in the Japanese population. The percentage of male heavy smokers (Brinkman index ≥600) was 58.2% of pulmonary NTM disease and was high for all mycobacterial species. In pulmonary MAC disease, systemic factors were observed in the order of malignant tumors (other than lung cancer), diabetes, rheumatoid arthritis, and tuberculosis. Local factors were observed in the order of bronchiectasis, chronic obstructive pulmonary disease, lung cancer, and bronchial asthma. The risk factors reported in Western countries were relatively highly prevalent among Japanese pulmonary NTM disease patients. This observation may help elucidate disease onset mechanisms.
PubMed: 37448701
DOI: 10.2185/jrm.2023-001 -
Thoracic Cancer Aug 2023Lung adenocarcinoma (LUAD) is the leading cause of death among cancer diseases. The tumorigenic functions of AHNAK2 in LUAD have attracted more attention in recent...
BACKGROUND
Lung adenocarcinoma (LUAD) is the leading cause of death among cancer diseases. The tumorigenic functions of AHNAK2 in LUAD have attracted more attention in recent years, while there are few studies which have reported its high molecular weight.
METHODS
The mRNA-seq data of AHNAK2 and corresponding clinical data from UCSC Xena and GEO was analyzed. LUAD cell lines were transfected with sh-NC and sh-AHNAK2, and cell proliferation, migration and invasion were then detected by in vitro experiments. We performed RNA sequencing and mass spectrometry analysis to explore the downstream mechanism and interacting proteins of AHNAK2. Finally, western blot, cell cycle analysis and CO-IP were used to confirm our assumptions regarding previous experiments.
RESULTS
Our study revealed that AHNAK2 expression was significantly higher in tumors than in normal lung tissues and higher AHNAK2 expression led to a poor prognosis, especially in patients with advanced tumors. AHNAK2 suppression via shRNA reduced the LUAD cell lines proliferation, migration and invasion and induced significant changes in DNA replication, NF-kappa B signaling pathway and cell cycle. AHNAK2 knockdown also caused G1/S phase cell cycle arrest, which could be attributed to the interaction of AHNAK2 and RUVBL1. In addition, the results from gene set enrichment analysis (GSEA) and RNA sequencing suggested that AHNAK2 probably plays a part in the mitotic cell cycle.
CONCLUSION
AHNAK2 promotes proliferation, migration and invasion in LUAD and regulates the cell cycle via the interaction with RUVBL1. More studies of AHNAK2 are still needed to reveal its upstream mechanism.
Topics: Humans; Adenocarcinoma of Lung; ATPases Associated with Diverse Cellular Activities; Carrier Proteins; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; DNA Helicases; Down-Regulation; Lung Neoplasms
PubMed: 37349884
DOI: 10.1111/1759-7714.14989 -
Nature Communications Nov 2023Single cell spatial interrogation of the immune-structural interactions in COVID -19 lungs is challenging, mainly because of the marked cellular infiltrate and...
Single cell spatial interrogation of the immune-structural interactions in COVID -19 lungs is challenging, mainly because of the marked cellular infiltrate and architecturally distorted microstructure. To address this, we develop a suite of mathematical tools to search for statistically significant co-locations amongst immune and structural cells identified using 37-plex imaging mass cytometry. This unbiased method reveals a cellular map interleaved with an inflammatory network of immature neutrophils, cytotoxic CD8 T cells, megakaryocytes and monocytes co-located with regenerating alveolar progenitors and endothelium. Of note, a highly active cluster of immature neutrophils and CD8 T cells, is found spatially linked with alveolar progenitor cells, and temporally with the diffuse alveolar damage stage. These findings offer further insights into how immune cells interact in the lungs of severe COVID-19 disease. We provide our pipeline [Spatial Omics Oxford Pipeline (SpOOx)] and visual-analytical tool, Multi-Dimensional Viewer (MDV) software, as a resource for spatial analysis.
Topics: Humans; Neutrophils; COVID-19; CD8-Positive T-Lymphocytes; Lung; T-Lymphocytes, Cytotoxic
PubMed: 37940670
DOI: 10.1038/s41467-023-42421-0 -
Cancers Sep 2023Cancer-associated thrombosis (CAT) is a leading cause of death among patients with cancer. CAT can manifest itself as venous thromboembolism (VTE), in the form of deep... (Review)
Review
Cancer-associated thrombosis (CAT) is a leading cause of death among patients with cancer. CAT can manifest itself as venous thromboembolism (VTE), in the form of deep vein thrombosis or pulmonary embolism, or arterial thromboembolism. The pathophysiology of CAT is complex and depends on cancer-, patient-, treatment- and biomarkers-related factors. Treatment of VTE in patients with cancer is complex and includes three major classes of anticoagulant agents: heparin and its derivatives, e.g., low molecular weight heparins, direct oral anticoagulants (DOACs), and vitamin K inhibitors. Given the tremendous heterogeneity of clinical situations in patients with cancer and the challenges of CAT, there is no single universal treatment option for patients suffering from or at risk of CAT. Initial studies suggested that patients seemed to prefer an anticoagulant that would not interfere with their cancer treatment, suggesting the primacy of cancer over VTE, and favoring efficacy and safety over convenience of route of administration. Recent studies show that when the efficacy and safety aspects are similar, patients prefer the oral route of administration. Despite this, injectables are a valid option for many patients with cancer.
PubMed: 37760609
DOI: 10.3390/cancers15184640 -
Journal of Biomedical Science Nov 2023Patients with metastatic triple-negative breast cancer (mTNBC) have a higher probability of developing visceral metastasis within 5 years after the initial diagnosis....
BACKGROUND
Patients with metastatic triple-negative breast cancer (mTNBC) have a higher probability of developing visceral metastasis within 5 years after the initial diagnosis. Therefore, a deeper understanding of the progression and spread of mTNBC is urgently needed.
METHODS
The isobaric tag for relative and absolute quantitation (iTRAQ)-based LC-MS/MS proteomic approach was applied to identify novel membrane-associated proteins in the lung-tropic metastatic cells. Public domain datasets were used to assess the clinical relevance of the candidate proteins. Cell-based and mouse models were used for biochemical and functional characterization of the protein molecule Sciellin (SCEL) identified by iTRAQ to elucidate its role and underlying mechanism in promoting lung colonization of TNBC cells.
RESULTS
The iTRAQ-based LC-MS/MS proteomic approach identified a membrane-associated protein SCEL that was overexpressed in the lung-tropic metastatic cells, and its high expression was significantly correlated with the late-stage TNBC and the shorter survival of the patients. Downregulation of SCEL expression significantly impaired the 3D colony-forming ability but not the migration and invasion ability of the lung colonization (LC) cells. Knockdown of SCEL reduced TNF-α-induced activation of the NF-κB/c-FLIP pro-survival and Akt/Erk1/2 growth signaling pathways in the LC cells. Specifically, knockdown of SCEL expression switched TNF-α-mediated cell survival to the caspase 3-dependent apoptosis. Conversely, ectopic expression of SCEL promoted TNF-α-induced activation of NF-κB/c-FLIP pro-survival and Akt/Erk1/2 pro-growth signaling pathway. The result of co-immunoprecipitation (Co-IP) and GST pull-down assay showed that SCEL could interact with TNFR1 to promote its protein stability. The xenograft mouse model experiments revealed that knockdown of SCEL resulted in increase of caspase-3 activity, and decrease of ki67 and TNFR1 expression as well as increase of tumor-associated macrophages in the metastatic lung lesions. Clinically, SCEL expression was found to be positively correlated with TNFR1 in TNBC tissues. Lastly, we showed that blocking TNF-α-mediated cell survival signaling by adalimumab effectively suppressed the lung colonization of the SCEL-positive, but not the SCEL-downregulated LC cells in the tail-vein injection model.
CONCLUSIONS
Our findings indicate that SCEL plays an essential role in the metastatic lung colonization of TNBC by promoting the TNF-α/TNFR1/NF-κB/c-FLIP survival and Akt/Erk1/2 proliferation signaling. Thus, SCEL may serve as a biomarker for adalimumab treatment of TNBC patients.
Topics: Humans; Animals; Mice; NF-kappa B; Receptors, Tumor Necrosis Factor, Type I; Triple Negative Breast Neoplasms; Tumor Necrosis Factor-alpha; Proto-Oncogene Proteins c-akt; Adalimumab; Chromatography, Liquid; Proteomics; Cell Line, Tumor; Tandem Mass Spectrometry; Apoptosis; Lung; Carrier Proteins
PubMed: 38037106
DOI: 10.1186/s12929-023-00986-4 -
Neuro-oncology Aug 2023Patients with diffuse glioma are at high risk of developing venous thromboembolism (VTE) over the course of the disease, with up to 30% incidence in patients with...
Patients with diffuse glioma are at high risk of developing venous thromboembolism (VTE) over the course of the disease, with up to 30% incidence in patients with glioblastoma (GBM) and a lower but nonnegligible risk in lower-grade gliomas. Recent and ongoing efforts to identify clinical and laboratory biomarkers of patients at increased risk offer promise, but to date, there is no proven role for prophylaxis outside of the perioperative period. Emerging data suggest a higher risk of VTE in patients with isocitrate dehydrogenase (IDH) wild-type glioma and the potential mechanistic role of IDH mutation in the suppression of production of the procoagulants tissue factor and podoplanin. According to published guidelines, therapeutic anticoagulation with low molecular weight heparin (LMWH) or alternatively, direct oral anticoagulants (DOACs) in patients without increased risk of gastrointestinal or genitourinary bleeding is recommended for VTE treatment. Due to the elevated risk of intracranial hemorrhage (ICH) in GBM, anticoagulation treatment remains challenging and at times fraught. There are conflicting data on the risk of ICH with LMWH in patients with glioma; small retrospective studies suggest DOACs may convey lower ICH risk than LMWH. Investigational anticoagulants that prevent thrombosis without impairing hemostasis, such as factor XI inhibitors, may carry a better therapeutic index and are expected to enter clinical trials for cancer-associated thrombosis.
Topics: Humans; Heparin, Low-Molecular-Weight; Venous Thromboembolism; Retrospective Studies; Anticoagulants; Neoplasms; Glioma; Glioblastoma; Biology
PubMed: 37100086
DOI: 10.1093/neuonc/noad059 -
Frontiers in Oncology 2024MUC21, also known as Epiglycanin, is a high-molecular-weight glycoprotein with transmembrane mucin properties. It consists of a tandem repeat domain, a stem domain, a... (Review)
Review
MUC21, also known as Epiglycanin, is a high-molecular-weight glycoprotein with transmembrane mucin properties. It consists of a tandem repeat domain, a stem domain, a transmembrane domain and a cytoplasmic tail. MUC21 is expressed is observed in normal tissues in organs like the thymus, testes, lungs, and large intestine. Research has shown that MUC21 is expressed in esophageal squamous cell carcinoma, lung adenocarcinoma, glioblastoma, thyroid cancer, melanoma, and various other malignant tumors in distinctive manner. Additionally, tumor invasion, metastasis, and poor prognosis are linked to it. Some researchers believe that MUC21 has the potential to become a new target in cancer treatment. This review aims to deliver a comprehensive overview of the glycosylation, function, and research progress of MUC21 in multiple types of cancer and infectious diseases.
PubMed: 38933439
DOI: 10.3389/fonc.2024.1410761 -
BMJ Open Respiratory Research Nov 2023Cholesterol is an irreplaceable nutrient in pulmonary metabolism; however, studies on high-density lipoprotein cholesterol (HDL-C) levels have shown conflicting results...
Association between serum high-density lipoprotein cholesterol and lung function in adults: three cross-sectional studies from US and Korea National Health and Nutrition Examination Survey.
INTRODUCTION
Cholesterol is an irreplaceable nutrient in pulmonary metabolism; however, studies on high-density lipoprotein cholesterol (HDL-C) levels have shown conflicting results regarding lung function. Therefore, we investigated the association between lung function and HDL-C levels in three cross-sectional studies conducted in the USA and South Korea.
METHODS
US National Health and Nutrition Examination Survey (NHANES) III, US NHANES 2007-2012, and Korea National Health and Nutrition Examination Survey (KNHANES) IV-VII performed spirometry and met the American Thoracic Society recommendations. Multiple linear regression models were used to determine the relationship between serum lipid levels and lung function. The models were adjusted for age, sex, household income, body mass index, smoking pack year, use of lipid-lowering medication and race. Serum HDL-C levels were classified into three groups to assess the dose-response relationship according to the guideline from the National Cholesterol Education Program-Adult Treatment Panel III.
RESULTS
The adult participants of the KNHANES (n=31 288), NHANES III (n=12 182) and NHANES 2007-2012 (n=9122) were analysed. Multivariate linear regression analysis of the serum cholesterol profiles revealed that only serum HDL-C was associated with forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV) in all three studies. A 1 SD increase in the HDL-C level increased the percent predicted FVC by 0.5%-1.5% p, and the per cent predicted FEV by 0.5%-1.7% p. In terms of HDL-C levels, correlations between the HDL-C groups and the per cent predicted FVC and FEV showed dose-response relationships. Compared with the normal group, high HDL-C levels increased FVC by 0.75%-1.79% p and FEV by 0.55%-1.90% p, while low levels led to 0.74%-2.19% p and 0.86%-2.68% p reductions in FVC and FEV, respectively. Subgroup analyses revealed weaker associations in females from KNHANES and NHANES III.
CONCLUSION
In the three nationwide cross-sectional studies, high HDL-C levels were associated with improved FVC and FEV. However, future studies are needed to confirm this correlation and elucidate the underlying mechanisms.
Topics: Female; Humans; Adult; United States; Nutrition Surveys; Cross-Sectional Studies; Cholesterol; Republic of Korea; Lung; Lipoproteins, HDL
PubMed: 37940356
DOI: 10.1136/bmjresp-2023-001792