Controversy remains regarding the relationship between bone health and sleep. In the literature, the effect of sleep on bone density in the clinical setting varies depending on the definition of ...normal sleep duration, sleep quality, selected population, and diagnostic tools for bone density. The aim of this study was to examine the association between bone mineral density (BMD)assessed by dual-energy X-ray absorptiometry and sleep duration/quality in the defined adult population from the National Health and Nutrition Examination Survey (NHANES) (a national household survey) within a 6-year period (2005-2010) and explore age differences. The basic variables, metabolic diseases, and bone density in the femoral neck as determined through dual-energy X-ray absorptiometry, were segregated, and analyzed according to different sleep durations (1-4, 5-6,7-8, and > 9 h/day) and sleep quality using multinomial regression models. A total of 12,793 subjects were analyzed. Our results reveal that women aged > 50 years with sleep duration < 5 h/day had a 7.35 (CI 3.438-15.715) odds of osteoporosis than those in other groups. This analysis is based on a nationally representative sample using survey and inspection data and clarifies the relationship between bone density and the effect of the combination of sleep quality and duration.
Oral squamous cell carcinoma (OSCC) is an extremely common head and neck cancer with a poor 5‐year survival rate, especially in cases of metastatic disease. Interleukin (IL)‐11 reportedly promotes ...cell growth and the epithelial–mesenchymal transition process in metastasis. However, the molecular mechanisms of IL‐11 in OSCC metastasis are unclear. This study found that IL‐11 upregulates matrix metalloproteinase 13 (MMP‐13) expression in OSCC via the IL‐11 receptor alpha subunit/glycoprotein 130 receptors that activate phosphatidyl‐inositol 3‐kinase, Ak strain transforming, and activator protein 1 signaling, which subsequently enhance MMP‐13‐induced tumor metastasis. TIMER2.0 analysis revealed a positive correlation between MMP‐13 and IL‐11 levels (r = 0.454). Moreover, a strong positive association was observed between higher levels of IL‐11 expression in OSCC tissue (p < 0.01), lymph node metastasis (p = 0.0154), and clinical disease stage (p = 0.0337). IL‐11 knockdown suppressed the migration of OSCC cells (p < 0.05). The evidence indicates that IL‐11 can serve as a new molecular therapeutic target in OSCC metastasis.
Targeting the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) axis with monoclonal antibodies (mAbs) represents a crucial breakthrough in anticancer therapy, but mAbs are ...limited by their poor oral bioavailability, adverse events in multiple organ systems, and primary, adaptive, and acquired resistance, amongst other issues. More recently, the advent of small molecule inhibitors that target the PD-1/PD-L1 axis have shown promising cellular inhibitory activity and the potential to counteract the disadvantages of mAbs. In this study, structure-based virtual screening identified small molecule inhibitors that effectively inhibited the PD-1/PD-L1 interaction. Six of those small molecule inhibitors were applied to cell-based experiments targeting PD-1: CH-1, CH-2, CH-3, CH-4, CH-5, and CH-6. Of all 6, CH-4 displayed the lowest cytotoxicity and strongest inhibitory activity towards the PD-1/PD-L1 interaction. The experiments revealed that CH-4 inhibited the interaction of soluble form PD-L1 (sPD-L1) with PD-1 surface protein expressed by KG-1 cells. Investigations into CH-4 analogs revealed that CH-4.7 effectively blocked the PD-1/sPD-L1 interaction, but sustained the secretion of interleukin-2 and interferon-γ by Jurkat cells. Our experiments revealed a novel small molecule inhibitor that blocks the interaction of PD-1/sPD-L1 and potentially offers an alternative PD-1 target for immune checkpoint therapy.
Abstract Chondrosarcoma is a primary malignant bone cancer, with a potent capacity to invade locally and cause distant metastasis. Angiogenesis is a critical step in tumor growth and metastasis. ...Chemokine CCL5 (previously called RANTES) has been shown to facilitate tumor progression and metastasis. However, the relationship of CCL5 with vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma is mostly unknown. In this study, CCL5 increased VEGF expression and also promoted chondrosarcoma medium-mediated angiogenesis in vitro as well as angiogenesis effects in the chick chorioallantoic membrane and Matrigel plug nude mice model in vivo . MicroRNA analysis was performed in CCL5-treated chondrosarcoma cells versus control cells to investigate the mechanism of CCL5-mediated promotion of chondrosarcoma angiogenesis. Among the miRNAs regulated by CCL5, miR-199a was the most downregulated miRNA after CCL5 treatment. In addition, co-transfection with miR-199a mimic reversed the CCL5-mediated VEGF expression and angiogenesis in vitro and in vivo . Moreover, overexpression of CCL5 increased tumor-associated angiogenesis and tumor growth by downregulating miR-199a in the xenograft tumor angiogenesis model. Taken together, these results demonstrated that CCL5 promotes VEGF-dependent angiogenesis in human chondrosarcoma cells by downregulating miR-199a.
Osteosarcoma is characterized by a high malignant and metastatic potential. Angiogenesis is essential for the caner metastasis. Interleukin-6 (IL-6) is a multifunctional cytokine that is associated ...with the disease status and outcomes of cancers. However, the relationship between IL-6 and vascular endothelial growth factor (VEGF) expression in human osteosarcoma is mostly unknown. Here we found that the IL-6 and VEGF expression was correlated with tumor stage and significantly higher than that in normal bone. Incubation of osteosarcoma cells with IL-6 increased VEGF mRNA and protein expression. Pretreatment of cells with IL-6R antibody reduced IL-6-mediated VEGF production. The apoptosis signal-regulating kinase 1 (ASK1)/p38/AP-1 pathway was activated after IL-6 treatment, and IL-6-induced VEGF expression was abolished by the specific inhibitor and siRNA of ASK1, p38, and AP-1 cascades. Importantly, knockdown IL-6 reduced VEGF expression and abolished osteosarcoma conditional medium-mediated angiogenesis. Taken together, these results indicate that IL-6 occurs through ASK1 and p38, which in turn activates AP-1, resulting in the activations of VEGF expression and contributing the angiogenesis of human osteosarcoma cells.
Chondrosarcoma is a malignancy of soft tissue and bone that has a high propensity to metastasize to distant organs. Nerve growth factor (NGF) is critical for neuronal cell growth, apoptosis, and ...differentiation, and also appears to promote the progression and metastasis of several different types of tumors, although the effects of NGF upon chondrosarcoma mechanisms are not very clear. We report that NGF facilitates lysyl oxidase (LOX)-dependent cellular migration and invasion in human chondrosarcoma cells, and that NGF overexpression enhances lung metastasis in a mouse model of chondrosarcoma. NGF-induced stimulation of LOX production and cell motility occurs through the inhibition of miR-149-5p expression, which was reversed by PI3K, Akt, and mTOR inhibitors and their respective short interfering RNAs. Notably, levels of NGF and LOX expression correlated with tumor stage in human chondrosarcoma samples. Thus, NGF appears to be a worthwhile therapeutic target for metastatic chondrosarcoma.
Osteosarcoma is a highly mortal bone tumor, with a high metastatic potential, promoted in part by the enzyme procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2). Increasing level of PLOD2 in ...osteosarcoma tissue correlates with lymphatic and distant metastasis. The adipokine apelin (APLN) is also found in different cancers and APLN upregulation promotes angiogenesis and metastasis, but its effects on osteosarcoma metastasis are uncertain. We explored APLN functioning in metastatic osteosarcoma. An analysis of records from the Gene Expression Omnibus (GEO) database showed higher levels of APLN expression in osteosarcoma tissue than in normal tissue. Similarly, levels of
and
mRNA synthesis were upregulated in osteosarcoma tissue. Levels of APLN and PLOD2 protein correlated positively with osteosarcoma clinical stages. APLN increased PLOD2 expression in human osteosarcoma cell lines and cell migration via the mammalian Sterile 20-like kinase 1 (MST1), monopolar spindle-one-binder protein (MOB)1, and YAP cascades, and through hsa_circ_0000004 functioning as a sponge of miR-1303. We also found that knockdown of APLN antagonized lung metastasis in mice with osteosarcoma. APLN may be a therapeutic target in osteosarcoma metastasis.
Summary
Most studies investigating the association between physical activity and osteoporosis prevention only focused on specific types of physical activity. This study’s evidence regarding the ...combined effects or interaction of sleep duration and physical activity. The findings emphasize the role of sleep duration and physical activity in association with osteoporosis.
Purpose
The associations between physical activity, sleep duration, and prevalent osteoporosis in Taiwanese adults were studied in this cross-sectional study.
Methods
The Taiwan Biobank enrolled a community-based cohort of ~ 120,000 volunteers (as of April 30, 2020) between 30 and 76 years of age with no history of cancer. Amongst, bone mineral density (BMD) measures by dual-energy X-ray absorptiometry (DXA) were available in 22,402 participants. After excluding individuals who had no complete data of BMI (
n
= 23), MET score (
n
= 207), T-score (
n
= 8,826), and sleep duration (
n
= 16), 13,330 subjects were included as the primary cohort. Univariate and multivariable regression analyses were performed to determine the associations between the presence of osteoporosis, physical activity level, sleep duration, and other variables.
Results
The results showed that after adjustment, subjects with physical activity < 20 METs/week and ≥ 20 METs/week (aOR = 1.017 and 0.767, respectively) were associated with risk of osteoporosis than those with zero MET. The odds of osteoporosis were not significantly lower in subjects who slept for ≥ 8 h/day (aOR = 0.934,p=0.266). In addition, compared to short sleepers with no physical activity, adults with increased physical activity ≥ 20 METs/week and sleep ≥ 8 h/day had a significantly lowest likelihood of osteoporosis (aOR = 0.702). Those with medium physical activity (< 20 METs/week) plus average sleep duration (6.5–8 h/day) did not have significant higher odds of osteoporosis (aOR = 1.129,p=0.151).
Conclusion
The findings emphasize the joint role of sleep duration and physical activity in association with osteoporosis. Adults with high physical activity plus high sleep hours have the highest BMD and lowest risk of osteoporosis.
Abstract
Background
Approximately 25% of patients with early-stage breast cancer experience cancer progression throughout the disease course. Alterations in
TMEM240
in breast cancer were identified ...and investigated to monitor treatment response and disease progression.
Methods
Circulating methylated
TMEM240
in the plasma of breast cancer patients was used to monitor treatment response and disease progression. The Cancer Genome Atlas (TCGA) data in Western countries and Illumina methylation arrays in Taiwanese breast cancer patients were used to identify novel hypermethylated CpG sites and genes related to poor hormone therapy response. Quantitative methylation-specific PCR (QMSP), real-time reverse transcription PCR, and immunohistochemical analyses were performed to measure DNA methylation and mRNA and protein expression levels in 394 samples from Taiwanese and Korean breast cancer patients.
TMEM240
gene manipulation, viability, migration assays, RNA-seq, and MetaCore were performed to determine its biological functions and relationship to hormone drug treatment response in breast cancer cells.
Results
Aberrant methylated
TMEM240
was identified in breast cancer patients with poor hormone therapy response using genome-wide methylation analysis in the Taiwan and TCGA breast cancer cohorts. A cell model showed that TMEM240, which is localized to the cell membrane and cytoplasm, represses breast cancer cell proliferation and migration and regulates the expression levels of enzymes involved in estrone and estradiol metabolism. TMEM240 protein expression was observed in normal breast tissues but was not detected in 88.2% (67/76) of breast tumors and in 90.0% (9/10) of metastatic tumors from breast cancer patients. QMSP revealed that in 54.5% (55/101) of Taiwanese breast cancer patients, the methylation level of
TMEM240
was at least twofold higher in tumor tissues than in matched normal breast tissues. Patients with hypermethylation of TMEM240 had poor 10-year overall survival (
p
= 0.003) and poor treatment response, especially hormone therapy response (
p
< 0.001). Circulating methylated
TMEM240
dramatically and gradually decreased and then diminished in patients without disease progression, whereas it returned and its levels in plasma rose again in patients with disease progression. Prediction of disease progression based on circulating methylated
TMEM240
was found to have 87.5% sensitivity, 93.1% specificity, and 90.2% accuracy.
Conclusions
Hypermethylation of
TMEM240
is a potential biomarker for treatment response and disease progression monitoring in breast cancer.
Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with high mortality. To date, there is no comprehensive population-based analysis of patients with AML in Asia, including ...Taiwan.
This is a retrospective cohort study using three population-based databases, namely, the Taiwan Cancer Registry, Taiwanese National Health Insurance Research Database, and Taiwan Death Registry, between 2001 and 2015 to provide detailed information on patients with AML and relevant clinical variables, such as sex, age, year of diagnosis, socioeconomic status (SES) level, hospital level, treatment location, and Deyo-Charlson Comorbidity Index (Deyo-CCI) score.
Patients with newly diagnosed AML (n = 9949) were included in the study. The median age was 60 years, and the overall age-adjusted AML incidence over 15 years was 2.44 per 100,000 person-years. The median overall survival (OS) of patients younger than 65 years was 18 months, whereas the OS of patients older than age 65 was only 5 months. AML patients with a prior cancer history had the worst outcomes, and the acute promyelocytic leukemia subtype predicted better survival. Patients who were older, male and a higher Deyo-CCI score had a significantly higher risk of death. In contrast, patients with a higher SES level and receiving treatment in a medical center had a lower risk of mortality than their respective counterparts.
Our study results could enable clinicians to obtain a comprehensive picture of the epidemiology, survival outcomes and unmet medical needs of AML patients in Taiwan.
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