As central nodes in cardiomyocyte signaling, nuclear AKT appears to play a cardio-protective role in cardiovascular disease. Here we describe a circular RNA, circ-Amotl1 that is highly expressed in ...neonatal human cardiac tissue, and potentiates AKT-enhanced cardiomyocyte survival. We hypothesize that circ-Amotl1 binds to PDK1 and AKT1, leading to AKT1 phosphorylation and nuclear translocation. In primary cardiomyocytes, epithelial cells, and endothelial cells, we found that forced circ-Amotl1 expression increased the nuclear fraction of pAKT. We further detected increased nuclear pAKT in circ-Amotl1-treated hearts. In vivo, circ-Amotl1 expression was also found to be protective against Doxorubicin (Dox)-induced cardiomyopathy. Putative PDK1- and AKT1-binding sites were then identified
. Blocking oligonucleotides could reverse the effects of exogenous circ-Amotl1. We conclude that circ-Amotl1 physically binds to both PDK1 and AKT1, facilitating the cardio-protective nuclear translocation of pAKT.
TP53 mutations occur in many different types of cancers that produce mutant p53 proteins. The mutant p53 proteins have lost wild-type p53 activity and gained new functions that contribute to ...malignant tumor progression. Different p53 mutations create distinct profiles in loss of wild-type p53 activity and gain of functions. Targeting the consequences generated by the great number of p53 mutations would be extremely complex. Therefore, in this study we used a workaround and took advantage of the fact that mutant p53 cannot bind H2AX. Using this, we developed a new approach to repress the acquisition of mutant p53 functions. We show here that the delivery of a circular RNA circ-Ccnb1 inhibited the function of three p53 mutations. By microarray analysis and real-time PCR, we detected decreased circ-Ccnb1 expression levels in patients bearing breast carcinoma. Ectopic delivery of circ-Ccnb1 inhibited tumor growth and extended mouse viability. Using proteomics, we found that circ-Ccnb1 precipitated p53 in p53 wild-type cells, but instead precipitated Bclaf1 in p53 mutant cells. Further experiments showed that H2AX serves as a bridge, linking the interaction of circ-Ccnb1 and wild-type p53, thus allowing Bclaf1 to bind Bcl2 resulting in cell survival. In the p53 mutant cells, circ-Ccnb1 formed a complex with H2AX and Bclaf1, resulting in the induction of cell death. We found that this occurred in three p53 mutations. These results shed light on the possible development of new approaches to inhibit the malignancy of p53 mutations.
Systematic review.
The aim of this study was to review the current spine surgery literature to establish a definition for adequate spine decompression using intraoperative ultrasound (IOUS) imaging.
...IOUS remains one of the few imaging modalities that allows spine surgeons to continuously monitor the spinal cord in real-time, while also allowing visualization of surrounding soft tissue anatomy during an operation. Although this has valuable applications for decompression surgery in spinal canal stenosis, it remains unclear how to best characterize adequacy of spinal decompression using IOUS.
We conducted a systematic search of multiple databases including: Medline, Embase, and Cochrane Central Register of Controlled Trials Strategy. Our search terms were spine, spinal cord diseases, decompression surgery, ultrasonogra-phy, and intraoperative period. We were interested in studies that used intraoperative use of ultrasound imaging in spinal decompression surgery for the cervical, thoracic, and lumbar spine. Study quality was evaluated using the Methodological Index for Non-Randomized Studies (MINORS).
Our search strategy yielded 985 of potentially relevant publications, 776 underwent title and abstract screening, and 31 full-text articles were reviewed. We found IOUS to be useful in spine surgery for decompression of degenerative cases in all regions of the spine. The thoracic spine was unique for IOUS-guided decompression of fractures, and the lumbar spine for decompressing nerve roots. Although we did not identify a universal definition for adequate decompression, there was common description of decompression that qualitatively described the ventral aspect of the spinal cord being "free floating" within the cerebrospinal fluid. Other measurable definitions, such as spinal cord diameter or spinal cord pulsatility, were not good definitions given there was insufficient evidence and/or poor reliability.
The systematic review examines the current literature on IOUS and spinal decompression surgery. We identified a common qualitative definition for adequate decompression involving a "free floating" spinal cord within the cerebrospinal fluid which indicates that the spinal cord is free from contact of the anterior elements.Level of Evidence: 1.
Circular RNAs (circRNAs) represent a large group of non-coding RNAs that are widely detected in mammalian cells. Although most circRNAs are generated in a sense orientation, there is a group of ...circRNAs that are synthesized in an antisense orientation. High-throughput analysis of breast cancer specimens revealed a significant enrichment of 209 antisense circRNAs. The tumor suppressor SCRIB was shown to potentially produce thirteen circRNAs, three of which are in an antisense orientation. Among these three circRNAs, circSCRIB (hsa_circ_0001831) was the most enriched in the breast cancer panel. This antisense SCRIB circRNA was shown to span one intron and two exons. We hypothesized that this circRNA could decrease pre-mRNA splicing and mRNA translation. To test this, we generated a hsa_circ_0001831 expression construct. We found that there was decreased SCRIB mRNA production but increased cancer cell proliferation, migration, and invasion. In comparison, an exonic sequence construct did not affect mRNA splicing but decreased protein translation, leading to increased E-cadherin expression and decreased expression of N-cadherin and vimentin. Thus, there was increased cell migration, invasion, proliferation, colony formation, and tumorigenesis. Our study suggests a novel modulatory role of antisense circRNAs on their parental transcripts. This may represent a promising approach for developing circRNA-directed therapy.
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The tumor suppressor SCRIB can generate thirteen circRNAs. Three are in an antisense orientation. hsa_circ_0001831 is highly upregulated in breast cancer. This antisense circRNA spans one intron and two exons and can inhibit pre-mRNA splicing and mRNA translation leading to increased tumorigenesis and may be targeted for cancer intervention.
► Versican V2 isoform promotes angiogenesis by modulating the activities of endothelial cells. ► Fibronectin is up-regulated by V2 isoform and mediated V2 function. ► Our study suggests that V2 could ...be a potential target for intervention of tumor angiogenesis.
Versican is a proteoglycan expressed in the extracellular matrix, where it regulates a variety of cell activities and affects tumor development. With alternative splicing, there are four versican isoforms, denoted V0, V1, V2 and V3. The V2 isoform is highly expressed in the mature brain but its function in the mature brain has not yet been elucidated. Since brain tumors are among the most angiogenic of human tumors, we investigated whether or not the V2 isoform plays a role in angiogenesis and found that the glioblastoma cell line U87 stably transfected with V2 formed tumors containing extensive vasculature. Although the V2-expressing cells grew slowly, they survived well in serum-free medium. They also displayed high adhesive ability to endothelial cells and facilitated tube-like structure formation. Importantly, fibronectin was up-regulated by V2 and mediated V2 function. Thus, versican V2 could be a potential target for intervention of brain tumor angiogenesis.
Introduction
Bones are frequent sites of metastatic disease, observed in 30–75% of advanced cancer patients. Quality of life (QoL) is an important endpoint in studies evaluating the treatments of ...bone metastases (BM), and many patient-reported outcome tools are available. The primary objective of this systematic review was to compile a list of QoL issues relevant to BM and its interventions. The secondary objective was to identify common tools used to assess QoL in patients with BM, and the QoL issues they fail to address.
Methods
A search was conducted on Ovid MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases between 1946 and 27 January 2023 with the keywords “bone metastases”, “quality of life”, and “patient reported outcomes”. Specific QoL issues in original research studies and the QoL tools used were extracted.
Results
The review identified the QoL issues most prevalent to BM in the literature. Physical and functional issues observed in patients included pain, interference with ambulation and daily activities, and fatigue. Psychological symptoms, such as helplessness, depression, and anxiety were also common. These issues interfered with patients’ relationships and social activities. Items not mentioned in existing QoL tools were related to newer treatments of BM, such as pain flare, flu-like symptoms, and jaw pain due to osteonecrosis.
Conclusions
This systematic review highlights that QoL issues for patients with BM have expanded over time due to advances in BM-directed treatments. If they are relevant, additional treatment-related QoL issues identified need to be validated prospectively by patients and added to current assessment tools.
MicroRNAs are known to play regulatory roles in gene expression associated with cancer development. We analyzed levels of the microRNA miR-24 in patients with breast carcinoma and found that miR-24 ...was higher in breast carcinoma samples than in benign breast tissues. We generated constructs expressing miR-24 and studied its functions using both in vitro and in vivo techniques. We found that the ectopic expression of miR-24 promoted breast cancer cell invasion and migration. In vivo experiments in mice indicated that the expression of miR-24 enhanced tumor growth, invasion into local tissues, metastasis to lung tissues and decreased overall mouse survival. In the miR-24-expressing cells and tumors, EGFR was highly phosphorylated, whereas expression of the phosphatases tyrosine-protein phosphatase non-receptor type 9 (PTPN9) and receptor-type tyrosine-protein phosphatase F (PTPRF) were repressed. We confirmed that miR-24 could directly target both PTPN9 and PTPRF. Consistent with this, we found that the levels of phosphorylated epidermal growth factor receptor (pEGFR) were higher whereas the levels of PTPN9 and PTPRF were lower in the patients with metastatic breast carcinoma. Ectopic expression of PTPN9 and PTPRF decreased pEGFR levels, cell invasion, migration and tumor metastasis. Furthermore, we found that MMP2, MMP11, pErk, and ADAM15 were upregulated, whereas TIMP2 was downregulated; all of which supported the roles of miR-24 in tumor invasion and metastasis. Our results suggest that miR-24 plays a key role in breast cancer invasion and metastasis. miR-24 could potentially be a target for cancer intervention.
Biomechanical, in vitro, and initial in vivo evaluation of a thiol-modified hyaluronan (TM-HA) and elastin-like polypeptide (ELP) composite hydrogel for nucleus pulposus (NP) tissue engineering.
To ...investigate the utility of a TM-HA and ELP composite material as a potential tissue-engineering scaffold to reconstitute the NP in early degenerative disc disease (DDD) on the basis of both biomechanical and biologic parameters.
DDD is a common ailment with enormous medical, psychosocial, and economic ramifications. Only end-stage surgical therapies are currently widely available. A less invasive, early stage therapy may provide a clinically relevant treatment option.
TM-HA and ELP were combined in various concentrations and cross-linked using poly (ethylene glycol) diacrylate. Resulting materials were evaluated biomechanically using confined compression to determine biphasic material properties. In vitro cell culture with human intervertebral disc (IVD) cells seeded within TM-HA/ELP scaffolds was analyzed for cell viability and phenotype. The hydrogels' materials were evaluated in an established New Zealand White (NZW) rabbit model of DDD.
The addition of ELP to TM-HA-based hydrogels resulted in a stiffer construct, which is less stiff than native NP but has time-dependant loading characteristics that may be desirable when injected into the IVD. In vitro experiments demonstrated 70% cell viability at 3 weeks with apparent maintenance of phenotype on the basis of morphologic and immunohistochemical data. The addition of ELP had a positive desirable biomechanical effect but did not have a significant positive or negative biologic effect on cell activity. The in vivo feasibility study demonstrated favorable material characteristics and biocompatibility for application as a minimally invasive injectable NP supplement.
TM-HA-based hydrogels provide a hospitable environment for human IVD cells and have material characteristics, particularly when supplemented with ELPs that are attractive for potential application as an injectable NP supplement.
Versican, a large extracellular matrix proteoglycan accumulates in tumor stroma and plays a key role in both malignant transformation and tumor progression. Increased versican expression has been ...observed in a wide range of malignant tumors, and has been associated with both cancer relapse and poor patient outcomes in breast, prostate, and many other cancer types. Through negatively-charged chondroitin and dermatan sulfate side chains or interactions of the G1 and G3 domains, versican is able to regulate many cellular processes including cell adhesion, proliferation, apoptosis, migration, angiogenesis, invasion and metastasis. In this review, the biological roles that versican plays in cancer development are presented. Therapeutic targeting of versican in malignant tumors is also discussed.
This study was designed to explore the role of versican in the development of hepatocellular carcinoma (HCC). Ectopic expression of the versican 3′‐untranslated region (3′‐UTR) was studied as a ...competitive endogenous RNA for regulating miRNA functions. We used this approach to modulate the expression of versican and its related proteins in 3′‐UTR transgenic mice and in the liver cancer cell line HepG2, stably transfected with the 3′‐UTR or a control vector. We demonstrated that transgenic mice expressing the versican 3′‐UTR developed HCC and increased expression of versican isoforms V0 and V1. HepG2 cells transfected with versican 3′‐UTR displayed increased proliferation, survival, migration, invasion, colony formation, and enhanced endothelial cell growth, but decreased apoptosis. We found that versican 3′‐UTR could bind to miRNAs miR‐133a, miR‐199a*, miR‐144, and miR‐431 and also interacted with CD34 and fibronectin. As a consequence, expression of versican, CD34, and fibronectin was up‐regulated by ectopic transfection of the versican 3′‐UTR, which was confirmed in HepG2 cells and in transgenic mice as compared with wild‐type controls. Transfection with siRNAs targeting the versican 3′‐UTR abolished the effects of the 3′‐UTR. Taken together, these results demonstrate that versican V0 and V1 isoforms play important roles in HCC development and that versican mRNAs compete with endogenous RNAs in regulating miRNA functions.—Fang, L., Du, W. W., Yang, X., Chen, K., Ghanekar, A., Levy, G., Yang, W., Yee, A. J., Lu, W.‐Y., Xuan, J. W., Gao, Z., Xie, F., He, C., Deng, Z., Yang, B. B. Versican 3′‐untranslated region (3′‐UTR) functions as a ceRNA in inducing the development of hepatocellular carcinoma by regulating miRNA activity. FASEB J. 27, 907–919 (2013). www.fasebj.org
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