The receptor tyrosine kinase HER2 is an oncogene amplified in invasive breast cancer and its overexpression in mammary epithelial cell lines is a strong determinant of a tumorigenic phenotype. Accordingly, HER2-overexpressing mammary tumors are commonly indicative of a poor prognosis in patients. Several quantitative proteomic studies have employed two-dimensional gel electrophoresis in combination with MS/MS, which provides only limited information about the molecular mechanisms underlying HER2/neu signaling. In the present study, we used a SILAC-based approach to compare the proteomic profile of normal breast epithelial cells with that of Her2/neu-overexpressing mammary epithelial cells, isolated from primary mammary tumors arising in mouse mammary tumor virus-Her2/neu transgenic mice. We identified 23 proteins with relevant annotated functions in breast cancer, showing a substantial differential expression. This included overexpression of creatine kinase, retinol-binding protein 1, thymosin 4 and tumor protein D52, which correlated with the tumorigenic phenotype of Her2-overexpressing cells. The differential expression pattern of two genes, gelsolin and retinol binding protein 1, was further validated in normal and tumor tissues. Finally, an in silico analysis of published cancer microarray data sets revealed a 23-gene signature, which can be used to predict the probability of metastasis-free survival in breast cancer patients.
Abstract HER2 overexpression is linked with poor prognosis and outcome in breast cancer. In our previous study, we have found miR-489 was specifically down regulated by HER2 overexpression. Restoration of miR-489 in multiple breast cancer cell lines significantly inhibited cell growth in vitro and decreased tumor growth in xenograft mice. To study role of miR-489 in Her2 mediated tumorigenesis, for the first time we generated MMTV-miR-489 transgenic mice, which overexpress miR-489 specifically in mammary gland. Our qRT-PCR data has confirmed transgenic mice have significantly more miR-489 expression than FVB mice. We used western blot to further validate our model system and found significant downregulation of miR-489 targets DEK and PTPN11. To find out whether miR-489 has any role in mammary gland development, mammary gland whole mount was performed from wild type FVB mice and MMTV-miR-489 mice at different age. Mammary gland from MMTV-miR-489 mice demonstrated reduction in growth at early age. Our immunohistochemistry staining demonstrated significantly reduction in Ki-67 positive cells in MMTV-miR-489 mammary gland at early age, further confirming reduced growth in MMTV-miR-489 mice. However, we found no significant effect on weight of litters of MMTV-miR-489 female since after 8-week mammary gland was able to recover growth. To find out effect of miR-489 overexpression on Her2 mediated tumorigenesis, we generated double transgenic mice MMTV-Her2/miR-489 by crossing MMTV-miR-489 mice with MMTV-Her2 mice. We have observed significant delay in tumor onset and reduced tumor growth in MMTV-Her2/ miR-489 mice compare to MMTV-Her2 mice. We have also observed less number of metastatic site in lung by performing H and E staining of lung. Our IHC data showed reduction in PTPN11 and DEK in miR-489 overexpress mammary tumor. Surprisingly, we found significant reduction of miR-489 expression in mammary tumors of MMTV-Her2-miR-489 when compared with normal mammary gland of same mice. Overall, our results indicated miR-489 overexpression suppresses mammary gland development at early age, reduced mammary tumorigenesis and decrease lung metastasis by targeting PTPN11 and DEK. Citation Format: Yogin Patel, Mithil Soni, Shou Liu, Hexin Chen. Role of miR-489 in mammary gland development and Her2 mediated tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3424. doi:10.1158/1538-7445.AM2017-3424
Objective To observe the optimal timing of operation and the therapeutic effect of endoscopic optic nerve decompression for traumatic optic neuropathy （TON）. Methods The clinical records of 90 consecutive patients with TON （93 eyes） after head and/or maxillofacial trauma from April 1998 to March 2007 were reviewed and analyzed. All patients were either unresponsive or intolerant to medication before they underwent intranasal endoscopic optic nerve decompression. The time interval between the injury and operation ranged from one day to 97 days （median 5.5 days）. Among the 93 eyes, there were 71 eyes with no visual acuity before operation and 22 eyes with residue visual acuity, including light perception in 1 eye, hand movement in 5 eyes, counting fingers in t3 eyes, 0. 04 in 1 eye, and 0. 1 in 2 eyes. Duration of follow-up ranged from 6 days to two years （median 8 days ）. Results After decompression, 35 patients （36/93 eyes, 38.7% ） showed improvement of visual acuity, 53 patients （55 eyes, 59. 1%） remained the same as before operation, while 2 patients （2 eyes, 2.2%） showed decreased visual acuity. Among patients with visual acuity beyond light perception before decompression, 68.2% of them （ 15/22 eyes） experienced visual improvement ,whereas only 22.9% （8/35 eyes, 0. 02 in two eyes） among patients who lost visual acuity immediately after injury, and 36. 1% （ 13/36 eyes, 0. 02 in five eyes） among those who lost visual acuity gradually after injury. There was a significant difference in visual improvement between group with visual acuity and group with no visual acuity （ X^2 = 11. 864, P 0. 05 ）. When comparing different sites of fracture, the effect of surgery was the most desirable （55.6%, 10/18 eyes improved） if the fracture occurred simultaneously in both exterior and interior walls of optic canal, followed by the interior wall fracture （45.7%, 21/46 eyes）. The operation was less effective if there was no fraction （20%, 4/20 eyes） or if the fracture occurred in exterior wall alone （ 11. 1%, 1/9 eyes）. Conclusions Endoscopic optic nerve decompression is a minimally invasive procedure with no adverse cosmetic effects. Early operation is recommended for saving vision, even though visual acuity is lost immediately after injury. However, the satisfactory clinical effects of endoscopic optic nerve decompression require further study.
Key words:
Optic nerve injuries; Decompression, surgical; Endoscopy; Treatment outcome
This paper presents a new video compression method based on the three-dimensional matrix DCT (3D-MDCT). This method adequately considers the correlation between the intraframe and interframe while regards them as a whole and makes them into a single mathematics model. 3D-MDCT algorithm is used in video system to eliminate the need for motion vectors computations or motion compensation computations. Experiments based on the parallel DSP system show that the proposed method can compress video image in real-time and the compression performance is better than MC/2D-DCT used in MPEG.
In this paper, an image coding approach is developed based on the quadtree classified method. It can solve the problem that some range blocks cannot be coded under the conventional fractal coding method. Experimental results show that compared to the conventional automatic fractal coding method, this approach can obtain high compression ratio with no apparent depression on the quality of the reconstructed image.
Audio-video synchronization is the key technology in applications such as digital TV broadcasting and multimedia communication. This paper proposes an audio-video synchronization method based on AVS and embedding technique. It embeds compressed audio data into AVS video coding system to keep synchronization all the time between audio and video during transmission or storage,decoding at the receiver and playback. Experimental results show that this method can achieve synchronization between audio and video,and reduce overhead for synchronization.
Our previous research discovered that combining the PDA-PEG polymer with copper ions can selectively kill cancer cells. However, the precise mechanism by which this combination functions was not fully understood. This study revealed that the PDA-PEG polymer and copper ions form complementary PDA-PEG/copper (Poly/Cu) nanocomplexes by facilitating copper ion uptake and lysosomal escape. An
The phosphatidylinositol-3,4,5-triphosphate (PIP3) binding function of pleckstrin homology (PH) domain is essential for the activation of oncogenic Akt/PKB kinase. Following the PIP3-mediated activation at the membrane, the activated Akt is subjected to other regulatory events, including ubiquitination-mediated deactivation. Here, by identifying and characterizing an allosteric inhibitor, SC66, we show that the facilitated ubiquitination effectively terminates Akt signaling. Mechanistically, SC66 manifests a dual inhibitory activity that directly interferes with the PH domain binding to PIP3 and facilitates Akt ubiquitination. A known PH domain-dependent allosteric inhibitor, which stabilizes Akt, prevents the SC66-induced Akt ubiquitination. A cancer-relevant Akt1 (e17k) mutant is unstable, making it intrinsically sensitive to functional inhibition by SC66 in cellular contexts in which the PI3K inhibition has little inhibitory effect. As a result of its dual inhibitory activity, SC66 manifests a more effective growth suppression of transformed cells that contain a high level of Akt signaling, compared with other inhibitors of PIP3/Akt pathway. Finally, we show the anticancer activity of SC66 by using a soft agar assay as well as a mouse xenograft tumor model. In conclusion, in this study, we not only identify a dual-function Akt inhibitor, but also demonstrate that Akt ubiquitination could be chemically exploited to effectively facilitate its deactivation, thus identifying an avenue for pharmacological intervention in Akt signaling.
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