Inhibition of MDM2 homodimerization by XIAP IRES stabilizes MDM2, influencing cancer cell survival

BACKGROUND: It is known that the MDM2 protein is stabilized when it forms a heterodimer with its partner MDM4, but MDM2 protein stability in its homodimer form is not known. The MDM2 protein contains a C-terminal RING domain that not only functions as an E3 ligase to regulate ubiquitination of p53 and MDM2 itself, but also is characterized to be able to bind several specific cellular mRNAs to regulate gene expression. In this study, we evaluate whether the MDM2 protein stability is regulated by the binding of a specific small RNA (XIAP IRES mRNA). METHODS: We performed chemical cross-linking and bimolecular fluorescence complementation (BiFC) assay to measure the human MDM2 protein stability in its homodimer form and the effect of XIAP IRES on MDM2 homodimerization and protein stabilization. Ubiquitination and pulse-chase assays were used to detect MDM2 self-ubiquitination and protein turn-over. Fluorescent titration and ITC were used to examine the binding between MDM2 RING protein and XIAP IRES. Western blot assay was used for determining protein expression. Clonogenic assay, WST and flow cytometry were used to test the effects of XIAP IRES, siXIAP and IR on cancer cell growth and apoptosis. RESULTS: We found that self-association (homodimerization) of MDM2 occurs through the C-terminal RING domain of MDM2 and that the MDM2 protein becomes unstable when it is homodimerized. MDM2 homodimerization resulted in an increased function of the RING domain for MDM2 self-ubiquitination. Binding of XIAP IRES to the RING domain inhibited MDM2 homodimerization and self-ubiquitination, which resulted in stabilization of MDM2, as well as increased XIAP expression. Upregulation of XIAP and MDM2 that led to inhibition of p53 by the XIAP IRES resulted in cell growth and survival in both p53-normal and -deficient cancer cells. CONCLUSIONS: Our study identified a new IRES RNA that interacts with MDM2 protein and regulates its stabilization, which suggested that targeting of MDM2 through disruption of MDM2 protein-RNA interaction might be a useful strategy for developing novel anti-cancer therapeutics

Antifibrotic effects of crocetin in scleroderma fibroblasts and in bleomycin-induced sclerotic mice

OBJECTIVE: To investigate the antifibrotic effects of crocetin in scleroderma fibroblasts and in sclerotic mice. METHODS: Skin fibroblasts that were isolated from three systemic scleroderma (SSc) patients and three healthy subjects were treated with crocetin (0.1, 1 or 10 μM). Cell proliferation was measured with an MTT assay. Alpha-smooth muscle actin was detected via an immunohistochemical method. Alpha 1 (I) procollagen (COL1A1), alpha 1 (III) procollagen (COL3A1), matrix metalloproteinase (MMP)-1 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 mRNA levels were measured using real-time PCR. SSc mice were established by the subcutaneous injection of bleomycin. Crocetin (50 mg/kg/d) was injected intraperitoneally for 14 days. Dermal thickness and lung fibrosis were assessed with Masson's trichrome staining. Plasma ET-1 was detected with an enzyme-linked immunosorbent assay (ELISA). Skin and lung ET-1 and COL1A1 mRNA levels were measured via real-time PCR. RESULTS: Crocetin inhibited the proliferation of SSc and normal fibroblasts, an effect that increased with crocetin concentration and incubation time. Crocetin decreased the expression of α-SMA and the levels of mRNA for COL1A1, COL3A1 and matrix metalloproteinase-1, while crocetin increased TIMP-1 mRNA levels in both SSc and normal fibroblasts. Skin and lung fibrosis was induced, and the levels of ET-1 in the plasma, skin and lungs were elevated in bleomycin-injected mice. Crocetin alleviated the thickening of the dermis and lung fibrosis; decreased COL1A1 mRNA levels in the skin and lung; and simultaneously decreased ET-1 concentrations in the plasma and ET-1 mRNA levels in the skin and lungs of the bleomycin-induced sclerotic mice, especially during the early phase (weeks 1-3). CONCLUSION: Crocetin inhibits cell proliferation, differentiation and collagen production in SSc fibroblasts. Crocetin alleviates skin and lung fibrosis in a bleomycin-induced SSc mouse model, in part due to a reduction in ET-1

BOTT: Box Only Transformer Tracker for 3D Object Tracking

Tracking 3D objects is an important task in autonomous driving. Classical Kalman Filtering based methods are still the most popular solutions. However, these methods require handcrafted designs in motion modeling and can not benefit from the growing data amounts. In this paper, Box Only Transformer Tracker (BOTT) is proposed to learn to link 3D boxes of the same object from the different frames, by taking all the 3D boxes in a time window as input. Specifically, transformer self-attention is applied to exchange information between all the boxes to learn global-informative box embeddings. The similarity between these learned embeddings can be used to link the boxes of the same object. BOTT can be used for both online and offline tracking modes seamlessly. Its simplicity enables us to significantly reduce engineering efforts required by traditional Kalman Filtering based methods. Experiments show BOTT achieves competitive performance on two largest 3D MOT benchmarks: 69.9 and 66.7 AMOTA on nuScenes validation and test splits, respectively, 56.45 and 59.57 MOTA L2 on Waymo Open Dataset validation and test splits, respectively. This work suggests that tracking 3D objects by learning features directly from 3D boxes using transformers is a simple yet effective way

Research progress on medical imaging-based artificial intelligence in precision diagnosis and treatment of pancreatic cancer

Pancreatic cancer is a highly malignant tumor of the digestive tract， and its precision diagnosis and treatment is a major challenge in clinical practice. With the development of science and technology， artificial intelligence has been applied in the early diagnosis， treatment and prognosis prediction of some diseases， which has high clinical value. Medical imaging is a disciplie to evaluate human health， which consists of two relatively independent directions of medical imaging system and medical image processing. Artificial intelligence based on medical imaging plays an important role in the clinical diagnosis and treatment of pancreatic cancer. In this article， research progress in the application of artificial intelligence in precision diagnosis and treatment of pancreatic cancer was reviewed from the aspects of imaging diagnosis， efficacy evaluation， survival prediction and radiogenomics， etc

Boosting the stimulated emission properties of host:guest polymer blends by inserting chain twists in the host polymer

Conjugated polymer blends coupled by Förster resonance energy transfer(FRET) have been widely exploited to achieve optically pumped lasers oper-ating at very low pumping thresholds. Among the plaid of conjugated poly-mers and molecules exploited for optical gain, fluorene-based polymers areconsidered front-runners, based on their high photoluminescence quantumyields, large optical gain coefficients, and their processability assets in filmsof high optical quality. Two archetypes of polymers with these properties arepoly(9,9-dioctyl-fluorene) and its green-emitting relative poly(9,9-dioctylflu-orene-alt-benzothiadiazole) that work as excellent FRET-coupled blends butunexpectedly do not exhibit stimulated emission. In this study, light is shedupon the optical gain limiting factors of these blends. Upon investigatinga series of poly(diarylfluorene-co-N-phenyl) polymers bearing a differentnumber of phenyl units inserted between the fluorenes (NPhs, N = 1, 2, 3),important improvements are revealed in the photoluminescence quantumyields and stimulated emission properties, as well as harnessing of exciton-exciton annihilation. These effects are ascribed to disruption of exciton trans-port in NPhs motivated by changes in chain conformation and molecularpacking upon phenyl-insertionThe work in Madrid was supported by the Spanish Ministry of Science and Innovation (RTI2018-097508−B-I00, CTQ2017-87054, PGC2018-096444-B-I00), by the Regional Government of Madrid through projects NMAT2D-CM (S2018/NMT-4511), the program Proyectos Sinérgicos de I+D (Grant Y2018/NMT-5028 FULMATEN-CM), NANOCOV-CM(REACT-UE), and by the Campus of International Excellence (CEI)UAM+CSI