Although early detection and treatment of prostate cancer (PCa) improves outcomes, many patients still die of metastatic PCa. Here, we report that metastatic PCa exhibits reduced levels of the ...microRNAsmiR-101 and miR-27a. These micro-RNAs (miRNAs) negatively regulate cell invasion and inhibit the expression of FOXM1 and CENPF, two master regulators of metastasis in PCa. Interestingly, the repression of FOXM1 and CENPF by these miRNAs occurs through COUP-TFII, a member of the orphan nuclear receptors family. Loss of miR-101 positively correlates with the increase of COUP-TFII-FOXM1-CENPF activity in clinical PCa data sets, implicating clinical relevance of such regulation. Further studies show that COUP-TFII is a critical factor controlling metastatic gene networks to promote PCa metastasis. Most importantly, this miRNA-COUP-TFII-FOXM1-CENPF regulatory axis is also involved in the development of enzalutaminde resistance. Taken together, our findings highlight the contribution of specific miRNAs through the regulation of the COUP-TFII-FOXM1-CENPF cascade in PCa metastasis and drug resistance.
The roles of Oct4 and Nanog in maintaining self-renewal and undifferentiated status of adult stem cells are unclear. Here, increase in Oct4 and Nanog expression along with increased proliferation and ...differentiation potential but decreased spontaneous differentiation were observed in early-passage (E), hypoxic culture (H), and p21 knockdown (p21KD) mesenchymal stem cells (MSCs) compared to late-passage (L), normoxic culture (N), and scrambled shRNA-overexpressed (Scr) MSCs. Knockdown of Oct4 and Nanog in E, H, and p21KD MSCs decreased proliferation and differentiation potential and enhanced spontaneous differentiation, whereas overexpression of Oct4 and Nanog in L, N, and Scr MSCs increased proliferation and differentiation potential and suppressed spontaneous differentiation. Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation. These data demonstrate the important roles of Oct4 and Nanog in maintaining MSC properties.
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► Increases in stem cell properties correlate with Oct4 and Nanog expression in MSCs ► Knockdown of Oct4 and Nanog decreases stem cell properties in early-passage MSCs ► Overexpression of Oct4 and Nanog increases stem cell properties in late-passage MSCs ► Oct4 and Nanog upregulate Dnmt1 to maintain self-renewal and undifferentiated state
Oxygen is essentially required by most eukaryotic organisms as a scavenger to remove harmful electron and hydrogen ions or as a critical substrate to ensure the proper execution of enzymatic ...reactions. All nucleated cells can sense oxygen concentration and respond to reduced oxygen availability (hypoxia). When oxygen delivery is disrupted or reduced, the organisms will develop numerous adaptive mechanisms to facilitate cells survived in the hypoxic condition. Normally, such hypoxic response will cease when oxygen level is restored. However, the situation becomes complicated if hypoxic stress persists (chronic hypoxia) or cyclic normoxia-hypoxia phenomenon occurs (intermittent hypoxia). A series of chain reaction-like gene expression cascade, termed hypoxia-mediated gene regulatory network, will be initiated under such prolonged or intermittent hypoxic conditions and subsequently leads to alteration of cellular function and/or behaviors. As a result, irreversible processes occur that may cause physiological disorder or even pathological consequences. A growing body of evidence implicates that hypoxia plays critical roles in the pathogenesis of major causes of mortality including cancer, myocardial ischemia, metabolic diseases, and chronic heart and kidney diseases, and in reproductive diseases such as preeclampsia and endometriosis. This review article will summarize current understandings regarding the molecular mechanism of hypoxia in these common and important diseases.
ABSTRACT
Objective
Both low serum albumin (SA) concentration and coronary microvascular dysfunction (CMD) are risk factors for the development of heart failure (HF). We hypothesized that SA ...concentration is associated with myocardial flow reserve (MFR) and implicated in pathophysiological mechanism of HF.
Methods
We retrospectively studied 454 patients undergoing dynamic cardiac cadmium‐zinc‐telluride myocardial perfusion imaging from April 2018 to February 2020. The population was categorized into three groups according to SA level (g/dL): Group 1: >4, Group 2: 3.5–4, and Group 3: <3.5. Myocardial blood flow (MBF) and myocardial flow reserve (MFR, defined as stress/rest MBF ratio) were compared.
Results
The mean age of the whole cohort was 66.2 years, and 65.2% were men. As SA decreased, stress MBF (mL min−1 g−1) and MFR decreased (MBF: 3.29 ± 1.03, MFR: 3.46 ± 1.33 in Group 1, MBF: 2.95 ± 1.13, MFR: 2.51 ± 0.93 in Group 2, and MBF: 2.64 ± 1.16, MFR: 1.90 ± 0.50 in Group 3), whereas rest MBF (mL min−1 g−1) increased (MBF: 1.05 ± 0.42 in Group 1, 1.27 ± 0.56 in Group 2, and 1.41 ± 0.61 in Group 3). After adjusting for covariates, compared with Group 1, the odds ratios for impaired MFR (defined as MFR < 2.5) were 3.57 (95% CI: 2.32–5.48) for Group 2 and 34.9 (95% CI: 13.23–92.14) for Group 3. The results would be similar if only regional MFR were assessed. The risk prediction for CMD using SA was acceptable, with an AUC of 0.76.
Conclusion
Low SA concentration was associated with the severity of CMD in both global and regional MFR as well as MBF.
Although low-density culture provides an efficient method for rapid expansion of human mesenchymal stem cells (MSCs), MSCs enriched by this method undergo senescence and lose their stem cell ...properties, which could be preserved by combining low-density and hypoxic culture. The mechanism was mediated through direct down-regulation of E2A-p21 by the hypoxia-inducible factor–1α (HIF-1α)–TWIST axis. Expansion under normoxia induced E2A and p21 expression, which were abrogated by overexpression of TWIST, whereas siRNA against TWIST up-regulated E2A and p21 in hypoxic cells. Furthermore, siRNA against p21 in normoxic cells enhanced proliferation and increased differentiation potential, whereas overexpression of p21 in hypoxic cells induced a decrease in proliferation and a loss of differentiation capacity. More importantly, MSCs expanded under hypoxic conditions by up to 100 population doublings, exhibited telomerase activity with maintained telomere length, normal karyotyping, and intact genetic integrity, and did not form tumors. These results support low-density hypoxic culture as a method for efficiently expanding MSCs without losing stem cell properties or increasing tumorigenicity.
Solar power is an attractive alternative source of electricity. Solar cells, which form the basis of a solar power system, are mainly based on crystalline silicon. Many defects cannot be visually ...observed with the conventional CCD imaging system. This paper presents defect inspection of multicrystalline solar cells in electroluminescence (EL) images. A solar cell charged with electrical current emits infrared light, whose intensity is lower at intrinsic crystal grain boundaries and extrinsic defects of small cracks, breaks, and finger interruptions. The EL image can distinctly highlight barely visible defects as dark objects, but it also shows random dark regions in the background, which makes automatic inspection in EL images very difficult.
A self-reference scheme based on the Fourier image reconstruction technique is proposed for defect detection of solar cells with EL images. The target defects appear as line- or bar-shaped objects in the EL image. The Fourier image reconstruction process is applied to remove the possible defects by setting the frequency components associated with the line- and bar-shaped defects to zero and then back-transforming the spectral image into a spatial image. The defect region can then be easily identified by evaluating the gray-level differences between the original image and its reconstructed image. The reference image is generated from the inspection image itself and, thus, can accommodate random inhomogeneous backgrounds. Experimental results on a set of various solar cells have shown that the proposed method performs effectively for detecting small cracks, breaks, and finger interruptions. The computation time of the proposed method is also fast, making it suitable for practical implementation. It takes only 0.29s to inspect a whole solar cell image with a size of 550×550pixels.
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►The method can detect micro-cracks, breaks, and finger interruptions in solar cells. ► The defects are sensed and highlighted in Electroluminescence (EL) images. ► The algorithm is based on image reconstruction with Fourier transforms.
Articular cartilage has a very limited capacity for self-repair, and mesenchymal stem cells (MSCs) have the potential to treat cartilage defects and osteoarthritis. However, in-depth mechanistic ...studies regarding their applications are required. Here we demonstrated the use of chitosan film culture for promoting chondrogenic differentiation of MSCs. We found that MSCs formed spheres 2 days after seeding on dishes coated with chitosan. When MSCs were induced in a chondrogenic induction medium on chitosan films, the size of the spheres continuously increased for up to 21 days. Alcian blue staining and immunohistochemistry demonstrated the expression of chondrogenic proteins, including aggrecan, type II collagen, and type X collagen at 14 and 21 days of differentiation. Importantly, chitosan, with a medium molecular weight (size: 190–310 kDa), was more suitable than other sizes for inducing chondrogenic differentiation of MSCs in terms of sphere size and expression of chondrogenic proteins and endochondral markers. We identified that the mechanistic target of rapamycin (mTOR) signaling and its downstream S6 kinase (S6K)/S6 were activated in chitosan film culture compared to that of monolayer culture. The activation of mTOR/S6K was continuously upregulated from days 2 to 7 of differentiation. Furthermore, we found that mTOR/S6K signaling was required for chondrogenic differentiation of MSCs in chitosan film culture through rapamycin treatment and mTOR knockdown. In conclusion, we showed the suitability of chitosan film culture for promoting chondrogenic differentiation of MSCs and its potential in the development of new strategies in cartilage tissue engineering.
Solar power has become an attractive alternative of electricity energy. Solar cells that form the basis of a solar power system are mainly based on multicrystalline silicon. A set of solar cells are ...assembled and interconnected into a large solar module to offer a large amount of electricity power for commercial applications. Many defects in a solar module cannot be visually observed with the conventional CCD imaging system. This paper aims at defect inspection of solar modules in electroluminescence (EL) images. The solar module charged with electrical current will emit infrared light whose intensity will be darker for intrinsic crystal grain boundaries and extrinsic defects including micro-cracks, breaks and finger interruptions. The EL image can distinctly highlight the invisible defects but also create a random inhomogeneous background, which makes the inspection task extremely difficult. The proposed method is based on independent component analysis (ICA), and involves a learning and a detection stage. The large solar module image is first divided into small solar cell subimages. In the training stage, a set of defect-free solar cell subimages are used to find a set of independent basis images using ICA. In the inspection stage, each solar cell subimage under inspection is reconstructed as a linear combination of the learned basis images. The coefficients of the linear combination are used as the feature vector for classification. Also, the reconstruction error between the test image and its reconstructed image from the ICA basis images is also evaluated for detecting the presence of defects. Experimental results have shown that the image reconstruction with basis images distinctly outperforms the ICA feature extraction approach. It can achieve a mean recognition rate of 93.4% for a set of 80 test samples.
CD133 (prominin-1), a 5-transmembrane glycoprotein, has recently been considered to be an important marker that represents the subset population of cancer stem-like cells. Herein we report the ...isolation of CD133-positive cells (LC-CD133(+)) and CD133-negative cells (LC-CD133(-)) from tissue samples of ten patients with non-small cell lung cancer (LC) and five LC cell lines. LC-CD133(+) displayed higher Oct-4 expressions with the ability to self-renew and may represent a reservoir with proliferative potential for generating lung cancer cells. Furthermore, LC-CD133(+), unlike LC-CD133(-), highly co-expressed the multiple drug-resistant marker ABCG2 and showed significant resistance to chemotherapy agents (i.e., cisplatin, etoposide, doxorubicin, and paclitaxel) and radiotherapy. The treatment of Oct-4 siRNA with lentiviral vector can specifically block the capability of LC-CD133(+) to form spheres and can further facilitate LC-CD133(+) to differentiate into LC-CD133(-). In addition, knock-down of Oct-4 expression in LC-CD133(+) can significantly inhibit the abilities of tumor invasion and colony formation, and increase apoptotic activities of caspase 3 and poly (ADP-ribose) polymerase (PARP). Finally, in vitro and in vivo studies further confirm that the treatment effect of chemoradiotherapy for LC-CD133(+) can be improved by the treatment of Oct-4 siRNA. In conclusion, we demonstrated that Oct-4 expression plays a crucial role in maintaining the self-renewing, cancer stem-like, and chemoradioresistant properties of LC-CD133(+). Future research is warranted regarding the up-regulated expression of Oct-4 in LC-CD133(+) and malignant lung cancer.
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