The incidence of colorectal cancer (CRC) is increasing in China. Here, we aimed to evaluate the latest demographic trends and KRAS/BRAF mutations status of Chinese CRC. Five thousand five hundred and ...forty‐six CRC patients diagnosed from 2010 to 2017 were involved. KRAS exon 2 and BRAFV600E mutations were detected by Sanger sequencing and high‐resolution melting analysis or allelic‐specific probe method. Gene mutation profiles and clinicopathologic characteristics of 5495 patients were analyzed. The joinpoint regression model was used to predict the demographic data in 2018. We found KRAS exon 2 and BRAFV600E mutation rates were 37.7 and 2.8% in CRC patients. Tumors with KRAS exon 2 mutations were more likely to be present in female and patients aged older than 75 years, right colon and have well‐differentiated histology. Tumors with BRAFV600E mutations were more likely to be present in the female, right colon and have poorly differentiated histology. From 2010 to 2017, the percentage of colon cancer and tubular adenocarcinoma in CRC increased substantially (from 39.3 to 51.8%, from 78.6 to 93.4%, respectively). The percentage of right colon cancer increased from 18.3 to 20.5%, which predictively may keep at 22.6% in 2018. The rise trends for patients with moderate differentiation tumor or KRAS exon 2 mutated tumor were apparent (from 50.3 to 78.6%, from 32.8 to 39.7%, respectively). In conclusion, in recent 8 years, there is a shift to the colon, especially right colon in the incidence of Chinese CRC. Moreover tubular adenocarcinoma is becoming the primary histology type.
What's new?
Colorectal carcinoma (CRC) is on the rise in China due to a westernized lifestyle but a thorough molecular characterization of these tumors is lacking. Here the authors determined mutation rates of KRAS and BRAF, two critical growth‐control factors, in a large study of CRC patients in China. Both mutations occurred more frequently in female patients with right‐sided CRCs but significantly differed in their differentiation state, underscoring the need for comprehensive molecular diagnostics in the management of CRC patients in China.
Background
Chronic radiation proctitis (CRP), a common complication after radiotherapy for pelvic malignancies, compromises patient quality of life. Vascular damage and aberrant angiogenesis in the ...mucosal layer are essential histological features, but changes to the submucosal layer are unclear. Thus, we evaluated the histological characteristics and distribution changes of key angiogenic factors in full-layered human CRP samples.
Methods
Thirty paraffin-embedded CRP and twenty-nine non-CRP tissues were used to evaluate histopathological changes. Immunohistochemistry with anti-CD34 antibody was performed to calculate microvascular density (MVD). Frozen tissues from eight CRP patients and five non-CRP controls were collected and analyzed by antibody array, which contained sixty human angiogenesis-related factors. Quality controls with positive and negative controls were performed during antibody array analysis. Two differentially expressed factors were confirmed by ELISA.
Results
CRP lesions showed vasculopathy, fibrosis, mucosal ulceration, edema, and inflammatory cell infiltration. Human angiogenesis antibody array and ELISA confirmed the increased angiostatin in CRP lesions. Immunohistochemical staining showed dispersed distribution of angiostatin throughout the mucosal and submucosal layers in CRP lesions, while angiostatin accumulated within the vessel lumens in non-CRP tissues. MVD significantly decreased in the submucosal layer of CRP, suggesting a potential association with increased angiostatin.
Conclusions
Angiostatin increased and had a distinct distribution in CRP lesions. Compensatory telangiectasia in the mucosa, vessel stenosis, and reduced MVD might attenuate blood flow in the submucosa and contribute to CRP progression. Restoration of vascular functionality by promoting angiogenesis in the submucosal layer may help alleviate CRP in clinical practice.
Vitamin D deficiency is associated with complications of pregnancy such as pre-eclampsia, fetal growth restriction, and miscarriage, all of which are also associated with incomplete spiral artery ...(SpA) remodeling. We have previously shown that both uterine natural killer (uNK) cells and extravillous trophoblast cells (EVT) are required for successful SpA remodeling, but whether their activity in this process is modulated by vitamin D is not known. In the current study, we use a previously described chorionic plate artery (CPA)
model of vascular remodeling to determine the effects of 1,25(OH)
D treated uNK cell, placental explant (PEx), and uNK/PEx conditioned medium (CM) on vascular smooth muscle cell (VSMC) disorganization and phenotypic switching. Significant results were followed up in VSMCs
. We demonstrate that 1,25(OH)
D can enhance the ability of PEx to induce SpA remodeling,
a mechanism associated with increased secretion of granulocyte-colony stimulating factor (G-CSF). G-CSF appears able to increase VSMC disorganization and phenotypic switching in both an
vascular model and
VSMC cultures. The clinical relevance of these findings are still to be determined. G-CSF may have differential effects depending on dose and vascular bed, and vitamin D may play a role in potentiating these actions. G-CSF may be an interesting potential therapeutic target for facilitating physiological vascular remodeling for the prevention of adverse obstetric outcomes.
The economic effects of tourism industry during periods of crisis, such as the COVID-19 pandemic, have received significant attention in recent years. The future is likely to pose a range of new ...challenges and opportunities to sustainable tourism. This paper employs the Markov-switching vector autoregressions (MSVAR) model to investigate the sustainability of tourism's economic effects in Hong Kong, both during periods of crisis and in the absence of crises. The empirical results show that: (1) The MSVAR model is effective in capturing the nonlinear relationship between the economy and tourism and allows for the categorizing of this relationship into four regimes, for example, the "major event crises" regime and the "economic crises" regime; (2) The economic effects of tourism differ noticeably across the four different regimes, and sustainability varies depending on the presence and type of crisis; (3) The Hong Kong economy, and the tourism industry in particular, exhibits high levels of stability and sustainability. In short, economic growth in Hong Kong's tourism industry is capable of rapid recovery following major crisis events, and it has the capacity to rebound quickly into new periods of rapid growth.
Due to the limitations of existing tourism demand forecasting models, data with frequencies lower than those of the tourism demand need to be processed in advance and cannot be directly used in a ...model, which leads to the loss of timeliness and accuracy in tourism demand forecasting. Taking the inbound tourism of the United States prior to and during the COVID-19 pandemic as an example, this study systematically examines the impact of data frequency processing on tourism demand modeling and forecasting, through the construction and comparison of three categories of models, with a particular focus on the first developed multiple mixed-frequency specification of reverse mixed-data sampling (RMIDAS) model. The results confirm the positive effect of multiple mixed-frequency models, which can directly use various original data frequencies, in improving the accuracy of tourism demand forecasting. This study also provides important guidance for future research on high-frequency tourism variables forecasting.
P16 inactivation is frequently accompanied by telomerase reverse transcriptase (TERT) amplification in human cancer genomes. P16 inactivation by DNA methylation often occurs automatically during ...immortalization of normal cells by TERT. However, direct evidence remains to be obtained to support the causal effect of epigenetic changes, such as P16 methylation, on cancer development. This study aimed to provide experimental evidence that P16 methylation directly drives cancer development.
A zinc finger protein-based P16-specific DNA methyltransferase (P16-Dnmt) vector containing a "Tet-On" switch was used to induce extensive methylation of P16 CpG islands in normal human fibroblast CCD-18Co cells. Battery assays were used to evaluate cell immortalization and transformation throughout their lifespan. Cell subcloning and DNA barcoding were used to track the diversity of cell evolution.
Leaking P16-Dnmt expression (without doxycycline-induction) could specifically inactivate P16 expression by DNA methylation. P16 methylation only promoted proliferation and prolonged lifespan but did not induce immortalization of CCD-18Co cells. Notably, cell immortalization, loss of contact inhibition, and anchorage-independent growth were always prevalent in P16-Dnmt&TERT cells, indicating cell transformation. In contrast, almost all TERT cells died in the replicative crisis. Only a few TERT cells recovered from the crisis, in which spontaneous P16 inactivation by DNA methylation occurred. Furthermore, the subclone formation capacity of P16-Dnmt&TERT cells was two-fold that of TERT cells. DNA barcoding analysis showed that the diversity of the P16-Dnmt&TERT cell population was much greater than that of the TERT cell population.
P16 methylation drives TERT-mediated immortalization and transformation of normal human cells that may contribute to cancer development.
Extravillous trophoblast cell (EVT) invasion is tightly controlled, and its dysregulation can lead to altered spiral artery remodeling and contribute to a number of different pregnancy complications. ...Angiopoietin-2 (Ang-2) is expressed by trophoblast cells and various cells in the decidua, and trophoblast cells express its receptor, Tie2. Ang-2 has been shown to play roles in tumor progression and metastasis but it is not known if it also regulates EVT invasion. Here, we show that both the HTR-8/SVneo cell line and primary isolates of human EVT expressed various integrins and the Tie2 receptor, and Ang-2 stimulated their migration and/or invasion. Ang-2 increased expression of matrix metalloproteinase (MMP)2 and MMP9, altered the cytoskeleton of HTR-8/SVneo cells and also induced phosphorylation of Tie2, JNK and c-Jun. Inhibition of p-JNK (using SP600125) blocked the Ang-2 induced invasion of HTR-8/SVneo cells. In addition, inhibition of Tie2 (pexmetinib) and integrin signaling (RGDS and ATN-161) also blocked Ang-2-induced invasion. In conclusion, we demonstrate that Ang-2 can stimulate EVT invasion via a mechanism associated with activation of both the Tie2 receptor and integrins, which appear to work through different pathways; Tie2 through the JNK/c-JUN pathway and integrins through an as yet unidentified pathway(s). We therefore propose that any alterations in Ang-2 expression in the decidua would lead to an imbalance in pro- and anti-invasive factors, disrupting regulation of EVT invasion and spiral artery remodeling and thereby contribute to the etiology of several complications of pregnancy.
Endometrial cancer (EC) is the most common gynecological cancer, and one of the most important causes of cancer‑related deaths in women worldwide. The long‑term survival rate is lower in ...advanced‑stage and recurrent EC, therefore it is important to identify new anticancer drugs. Garcinol, a polyisoprenylated benzophenone, is a promising anticancer drug for various cancer types but its effects on EC remain unclear. To investigate the anticancer effects of garcinol on EC, cell proliferation and cell cycle were assessed by real‑time cell proliferation, cell counting, and colony formation assays, flow cytometric analysis, and 5‑ethynyl‑2'‑deoxyuridine (EdU) incorporation assay, in EC Ishikawa (ISH) and HEC‑1B cell lines. Western blotting was used to evaluate the expression of cell cycle‑related protein cyclins, cyclin‑dependent kinase and tumor suppression proteins. Garcinol inhibited ISH and HEC‑1B cell proliferation in a dose‑dependent manner, and induced ISH and HEC‑1B cell cycle arrest at the G1 phase and G2/M phase, respectively, and decreased the S phase and DNA synthesis in these two cell lines. Following garcinol treatment the expression levels of p53 and p21 were increased, while the expression levels of CDK2, CDK4, cyclin D1 and cyclin B1 were gradually decreased in a dose‑dependent manner in both ISH and HEC‑1B cells. In addition, the expression levels of phosphorylated c‑JUN N‑terminal kinase (JNK) and p‑c‑JUN were significantly increased in both types of cells. Collectively, garcinol can induce EC cell cycle arrest and may be a promising candidate for EC chemotherapy.
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