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"Cheng, S-Y"
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Geographic trends in incidence of hip fractures: a comprehensive literature review
Summary
A comprehensive review of literature was conducted to investigate variation in hip fracture incident rates around the world. The original crude incidence rates were standardized for age and sex for comparability. After standardization, the highest rates of hip fracture were found in Scandinavia and the lowest rates in Africa.
Introduction
This study was conducted to investigate the geographic trends of the incidence of osteoporotic hip fractures through a comprehensive review of literature.
Methods
Studies were identified for inclusion in the review by searching the MEDLINE database via PubMed and applying strict inclusion and exclusion criteria. Age-specific incidence rates were extracted from the articles, and in order to provide a common platform for analysis, we used directly age-standardized and age–sex-standardized rates (using the 2005 United Nations estimates of the world population as standard) to complete the analysis.
Results
Forty-six full text articles spanning 33 countries/regions were included in the review. For ease of comparison, the results were analyzed by geographic regions: North America, Latin America, Scandinavia, Europe (excluding Scandinavia), Africa, Asia, and Australia. The highest hip fracture rates were found in Scandinavia and the lowest in Africa. We found comparable rates from countries in North America, Australia, and Europe outside of Scandinavia. The diverse makeup of the Asian continent also resulted in quite variable hip fracture rates: ranging from relatively high rates in Iran to low rates, comparable to those from Africa, in mainland China.
Conclusions
Given the aging of populations globally, and in the industrialized countries specifically, hip fractures will become a progressively larger public health burden. The geographic trends observed in hip fracture incidence rates can provide important clues to etiology and prevention.
Journal Article
Coexpression of NOS2 and COX2 accelerates tumor growth and reduces survival in estrogen receptor-negative breast cancer
Proinflammatory signaling pathways are commonly up-regulated in breast cancer. In estrogen receptor-negative (ER⁻) and triple-negative breast cancer (TNBC), nitric oxide synthase-2 (NOS2) and cyclooxygenase-2 (COX2) have been described as independent predictors of disease outcome. We further explore these findings by investigating the impact of their coexpression on breast cancer survival. Elevated coexpression of NOS2/COX2 proteins is a strong predictor of poor survival among ER⁻ patients (hazard ratio: 21). Furthermore, we found that the key products of NOS2 and COX2, NO and prostaglandin E2 (PGE2), respectively, promote feed-forward NOS2/COX2 crosstalk in both MDA-MB-468 (basal-like) and MDA-MB-231 (mesenchymal-like) TNBC cell lines in which NO induced COX2 and PGE2 induced NOS2 proteins. COX2 induction by NO involved TRAF2 activation that occurred in a TNFα-dependent manner in MDA-MB-468 cells. In contrast, NO-mediated TRAF2 activation in the more aggressive MDA-MB-231 cells was TNFα independent but involved the endoplasmic reticulum stress response. Inhibition of NOS2 and COX2 using amino-guanidine and aspirin/indomethacin yielded an additive reduction in the growth of MDA-MB-231 tumor xenografts. These findings support a role of NOS2/COX2 crosstalk during disease progression of aggressive cancer phenotypes and offer insight into therapeutic applications for better survival of patients with ER⁻ and TNBC disease.
Journal Article
Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression
Inflammation is widely recognized as an inducer of cancer progression. The inflammation-associated enzyme, inducible nitric oxide synthase (NOS2), has emerged as a candidate oncogene in estrogen receptor (ER)-negative breast cancer, and its increased expression is associated with disease aggressiveness and poor survival. Although these observations implicate NOS2 as an attractive therapeutic target, the mechanisms of both NOS2 induction in tumors and nitric oxide (NO)-driven cancer progression are not fully understood. To enhance our mechanistic understanding of NOS2 induction in tumors and its role in tumor biology, we used stimulants of NOS2 expression in ER ⁻ and ER ⁺ breast cancer cells and examined downstream NO-dependent effects. Herein, we show that up-regulation of NOS2 occurs in response to hypoxia, serum withdrawal, IFN-γ, and exogenous NO, consistent with a feed-forward regulation of NO production by the tumor microenvironment in breast cancer biology. Moreover, we found that key indicators of an aggressive cancer phenotype including increased S100 calcium binding protein A8, IL-6, IL-8, and tissue inhibitor matrix metalloproteinase-1 are up-regulated by these NOS2 stimulants, whereas inhibition of NOS2 in MDA-MB-231 breast cancer cells suppressed these markers. Moreover, NO altered cellular migration and chemoresistance of MDA-MB-231 cells to Taxol. Most notably, MDA-MB-231 tumor xenographs and cell metastases from the fat pad to the brain were significantly suppressed by NOS2 inhibition in nude mice. In summary, these results link elevated NOS2 to signals from the tumor microenvironment that arise with cancer progression and show that NO production regulates chemoresistance and metastasis of breast cancer cells.
Journal Article
Artificial intelligence significantly improves the diagnostic accuracy of deep myxoid soft tissue lesions in histology
Deep myxoid soft tissue lesions have posed a diagnostic challenge for pathologists due to significant histological overlap and regional heterogeneity, especially when dealing with small biopsies which have profoundly low accuracy. However, accurate diagnosis is important owing to difference in biological behaviors and response to adjuvant therapy, that will guide the extent of surgery and the need for neo-adjuvant therapy. Herein, we trained two convolutional neural network models based on a total of 149,130 images representing diagnoses of extra skeletal myxoid chondrosarcoma, intramuscular myxoma, low-grade fibromyxoid sarcoma, myxofibrosarcoma and myxoid liposarcoma. Both AI models outperformed all the pathologists, with a significant improvement of accuracy up to 97% compared to average pathologists of 69.7% (p < 0.00001), corresponding to 90% reduction in error rate. The area under curve of the best AI model was on average 0.9976. It could assist pathologists in clinical practice for accurate diagnosis of deep soft tissue myxoid lesions, and guide clinicians for precise and optimal treatment for patients.
Journal Article
CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model
CD97, a member of the adhesion family of G-protein-coupled receptors (GPCRs), complexes with and potentiates lysophosphatidic acid (LPA) receptor signaling to the downstream effector RHOA. We show here that CD97 was expressed in a majority of thyroid cancers but not normal thyroid epithelium and that the level of CD97 expression was further elevated with progression to poorly differentiated and undifferentiated carcinoma. Intratumoral progression also showed that CD97 expression correlates with invasiveness and dedifferentiation. To determine the functional role of CD97, we produced a transgenic model of thyroglobulin promoter-driven CD97 expression. Transgenic CD97 in combination with
Thrb
PV
, an established mouse model of thyroid follicular cell carcinogenesis, significantly increased the occurrence of vascular invasion and lung metastasis. Expression of transgenic CD97 in thyroid epithelium led to elevated ERK phosphorylation and increased numbers of Ki67+ cells in developing tumors. In addition, tumor cell cultures derived from CD97 transgenic as compared with non-transgenic mice demonstrated enhanced, constitutive and LPA-stimulated ERK activation. In human thyroid cancer cell lines, CD97 depletion reduced RHO-GTP and decreased LPA-stimulated invasion but not EGF-stimulated invasion, further suggesting that CD97 influences an LPA-associated mechanism of progression. Consistent with the above, CD97 expression in human thyroid cancers correlated with LPA receptor and markers of aggressiveness including Ki67 and pAKT. This study shows an autonomous effect of CD97 on thyroid cancer progression and supports the investigation of this GPCR as a therapeutic target for these cancers.
Journal Article
Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer
The addition of pembrolizumab to chemotherapy for metastatic lung cancer without
EGFR
or
ALK
mutations resulted in better progression-free and overall survival than chemotherapy alone. Immune-related adverse effects were more common with the combination.
Journal Article
EGFRvIII promotes glioma angiogenesis and growth through the NF-κB, interleukin-8 pathway
Sustaining a high growth rate requires tumors to exploit resources in their microenvironment. One example of this is the extensive angiogenesis that is a typical feature of high-grade gliomas. Here, we show that expression of the constitutively active mutant epidermal growth factor receptor, ΔEGFR (EGFRvIII, EGFR*, de2-7EGFR) is associated with significantly higher expression levels of the pro-angiogenic factor interleukin (IL)-8 in human glioma specimens and glioma stem cells. Furthermore, the ectopic expression of ΔEGFR in different glioma cell lines caused up to 60-fold increases in the secretion of IL-8. Xenografts of these cells exhibit increased neovascularization, which is not elicited by cells overexpressing wild-type (wt)EGFR or ΔEGFR with an additional kinase domain mutation. Analysis of the regulation of IL-8 by site-directed mutagenesis of its promoter showed that ΔEGFR regulates its expression through the transcription factors nuclear factor (NF)-κB, activator protein 1 (AP-1) and CCAAT/enhancer binding protein (C/EBP). Glioma cells overexpressing ΔEGFR showed constitutive activation and DNA binding of NF-κB, overexpression of c-Jun and activation of its upstream kinase c-Jun N-terminal kinase (JNK) and overexpression of C/EBPβ. Selective pharmacological or genetic targeting of the NF-κB or AP-1 pathways efficiently blocked promoter activity and secretion of IL-8. Moreover, RNA interference-mediated knock-down of either IL-8 or the NF-κB subunit p65, in ΔEGFR-expressing cells attenuated their ability to form tumors and to induce angiogenesis when injected subcutaneously into nude mice. On the contrary, the overexpression of IL-8 in glioma cells lacking ΔEGFR potently enhanced their tumorigenicity and produced highly vascularized tumors, suggesting the importance of this cytokine and its transcription regulators in promoting glioma angiogenesis and tumor growth.
Journal Article
Neuropilin-1 promotes human glioma progression through potentiating the activity of the HGF/SF autocrine pathway
Neuropilin-1 (NRP1) functions as a coreceptor through interaction with plexin A1 or vascular endothelial growth factor (VEGF) receptor during neuronal development and angiogenesis. NRP1 potentiates the signaling pathways stimulated by semaphorin 3A and VEGF-A in neuronal and endothelial cells, respectively. In this study, we investigate the role of tumor cell-expressed NRP1 in glioma progression. Analyses of human glioma specimens (WHO grade I–IV tumors) revealed a significant correlation of NRP1 expression with glioma progression. In tumor xenografts, overexpression of NRP1 by U87MG gliomas strongly promoted tumor growth and angiogenesis. Overexpression of NRP1 by U87MG cells stimulated cell survival through the enhancement of autocrine hepatocyte growth factor/scatter factor (HGF/SF)/c-Met signaling. NRP1 not only potentiated the activity of endogenous HGF/SF on glioma cell survival but also enhanced HGF/SF-promoted cell proliferation. Inhibition of HGF/SF, c-Met and NRP1 abrogated NRP1-potentiated autocrine HGF/SF stimulation. Furthermore, increased phosphorylation of c-Met correlated with glioma progression in human glioma biopsies in which NRP1 is upregulated and in U87MG NRP1-overexpressing tumors. Together, these data suggest that tumor cell-expressed NRP1 promotes glioma progression through potentiating the activity of the HGF/SF autocrine c-Met signaling pathway, in addition to enhancing angiogenesis, suggesting a novel mechanism of NRP1 in promoting human glioma progression.
Journal Article
EGFRvIII stimulates glioma growth and invasion through PKA-dependent serine phosphorylation of Dock180
Glioblastomas (GBMs), the most common and malignant brain tumors, are highly resistant to current therapies. The failure of targeted therapies against aberrantly activated oncogenic signaling, such as that of the EGFR-PI3K/Akt pathway, underscores the urgent need to understand alternative downstream pathways and to identify new molecular targets for the development of more effective treatments for gliomas. Here, we report that EGFRvIII (ΔEGFR/de2-7EGFR), a constitutively active EGFR mutant that is frequently co-overexpressed with EGFR in clinical GBM tumors, promotes glioma growth and invasion through protein kinase A (PKA)-dependent phosphorylation of Dock180, a bipartite guanine nucleotide exchange factor (GEF) for Rac1. We demonstrate that EGFRvIII induces serine phosphorylation of Dock180, stimulates Rac1 activation and glioma cell migration. Treatments of glioma cells using the PKA inhibitors H-89 and KT5720, overexpression of a PKA inhibitor (PKI), and
in vitro
PKA kinase assays show that EGFRvIII induction of serine phosphorylation of Dock180 is PKA-dependent. Significantly, PKA induces phosphorylation of Dock180 at amino acid residue S1250 that resides within its Rac1-activating DHR-2 domain. Expression of the Dock180
S1250L
mutant, but not wild type Dock180
WT
, protein in EGFRvIII-expressing glioma cells inhibited receptor-stimulated cell proliferation, survival, migration
in vitro
and glioma tumor growth and invasion
in vivo
. Together, our findings describe a novel mechanism by which EGFRvIII drives glioma tumorigenesis and invasion through PKA-dependent phosphorylation of Dock180, thereby suggesting that targeting EGFRvIII-PKA-Dock180-Rac1 signaling axis could provide a novel pathway to develop potential therapeutic strategies for malignant gliomas.
Journal Article