Retinoic acid receptors (RARs) are ligand-dependent transcription factors which are members of the steroid/ thyroid hormone receptor gene family. RAR-agonists inhibit the proliferation of many human breast cancer cell lines, particularly those whose growth is stimulated by estradiol (E2) or growth factors. PCR-amplified subtractive hybridization was used to identify candidate retinoidregulated genes that may be involved in growth inhibition. One candidate gene identified was SOX9, a member of the high mobility group (HMG) box gene family of transcription factors. SOX9 gene expression is rapidly stimulated by RAR-agonists in T-47D cells and other retinoidinhibited breast cancer cell lines. In support of this finding, a database search indicates that SOX9 is expressed as an EST in breast tumor cells. SOX9 is known to be expressed in chondrocytes where it regulates the transcription of type II collagen and in testes where it plays a role in male sexual differentiation. RAR pan-agonists and the RARa-selective agonist Am580, but not RXR agonists, stimulate the expression of SOX9 in a wide variety of retinoid-inhibited breast cancer cell lines. RAR-agonists did not stimulate SOX9 in breast cancer cell lines which were not growth inhibited by retinoids. Expression of SOX9 in T-47D cells leads to cycle changes similar to those found with RARagonists while expression of a dominant negative form of SOX9 blocks RA-mediated cell cycle changes, suggesting a role for SOX9 in retinoid-mediated growth inhibition.

PD-1 (CD279)-PD-L1 (CD274) inhibitory signaling is critical for cancer immune evasion, and thus has become one of the major targets in anticancer immunotherapy. There are several studies that demonstrate the potent effects of posttranslational modifications of CD274 on immune inactivation and suppression, such as ubiquitination, phosphorylation, glycosylation, and palmitoylation. However, the regulatory mechanisms for CD274 deubiquitination are still largely unclear. Here, we identified ubiquitin-specific protease 22 (USP22) as a novel deubiquitinase of CD274. USP22 directly interacted with the C terminus of CD274, inducing its deubiquitination and stabilization. Across multiple cancer types, USP22 was highly expressed and frequently altered in liver cancer, closely correlating with poor prognosis of these patients. Genetic depletion of USP22 inhibited liver cancer growth in an immune system-dependent manner, increased tumor immunogenicity and tumor-infiltrating lymphocytes, and improved therapeutic efficacy of CD274targeted immunotherapy and CDDP-based chemotherapy in mice. We demonstrate that targeting USP22 is a promising strategy to potentiate anticancer immunity for CD274amplified cancer.

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Background/aimsTo evaluate the efficacy of antivascular endothelial growth factor (anti-VEGF) agents pretreatment before vitrectomy for patients with complicated proliferative diabetic retinopathy (PDR).MethodsThe PubMed, Embase and the Cochrane Central Register of Controlled Trials were searched up to June 2017 to identify related studies. The Peferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed. The StataSE V.12.0 software was used to analyse the relevant data. The weighted mean difference, relative risk and their 95% CIs were used to assess the strength of the association.Results14 randomised controlled trials involving 613 patients were assessed, the anti-VEGF pretreatment group included 289 patients and the control group included 324 patients. Our analysis indicated that anti-VEGF pretreatment before vitrectomy for complicated PDR could facilitate much easier surgery regarding less intraoperative bleeding, less endodiathermy, shorter duration of surgery, less iatrogenic retinal breaks, less frequency of using silicone oil and relaxing retinotomy (P<0.05). Additionally, anti-VEGF pretreatment could also achieve better postoperative best-corrected visual acuity, less early recurrent vitreous haemorrhage (VH) and quicker absorption of recurrent VH (P<0.05). However, the incidence of late recurrent VH, recurrent retinal detachment or related secondary surgery could not be reduced (P>0.05).ConclusionThe pretreatment of anti-VEGF agents before vitrectomy for patients with complicated PDR might facilitate much easier surgery and better visual rehabilitation, reduce the rate of early recurrent VH and accelerate its absorption. Moreover, future better-designed studies with larger sample sizes are required to further evaluate the efficacy of different anti-VEGF agents and reach a firmer conclusion.

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Osteocytes are mechanosensitive bone cells, but little is known about their effects on tumor cells in response to mechanical stimulation. We treated breast cancer cells with osteocyte-derived conditioned medium (CM) and fluid flow-treated conditioned medium (FFCM) with 0.25 Pa and 1 Pa shear stress. Notably, CM and FFCM at 0.25 Pa induced the mesenchymal-to-epithelial transition (MET), but FFCM at 1 Pa induced the epithelial-to-mesenchymal transition (EMT). This suggested that the effects of fluid flow on conditioned media depend on flow intensity. Fluorescence resonance energy transfer (FRET)-based evaluation of Src activity and vinculin molecular force showed that osteopontin was involved in EMT and MET switching. A mouse model of tumorinduced osteolysis was tested using dynamic tibia loadings of 1, 2, and 5 N. The low 1 N loading suppressed tumor-induced osteolysis, but this beneficial effect was lost and reversed with loads at 2 and 5 N, respectively. Changing the loading intensities in vivo also led to changes in serum TGFβ levels and the composition of tumor-associated volatile organic compounds in the urine. Collectively, this study demonstrated the critical role of intensity-dependent mechanotransduction and osteopontin in tumorosteocyte communication, indicating that a biophysical factor can tangibly alter the behaviors of tumor cells in the bone microenvironment.

Skin problems not only injure physical health but also induce psychological problems, especially for patients whose faces have been damaged or even disfigured. Using smart devices, most of the people are able to obtain convenient clinical images of their face skin condition. On the other hand, the convolutional neural networks (CNNs) have achieved near or even better performance than human beings in the imaging field. Therefore, this paper studied different CNN algorithms for face skin disease classification based on the clinical images. First, from Xiangya-Derm, which is, to the best of our knowledge, China's largest clinical image dataset of skin diseases, we established a dataset that contains 2656 face images belonging to six common skin diseases [seborrheic keratosis (SK), actinic keratosis (AK), rosacea (ROS), lupus erythematosus (LE), basal cell carcinoma (BCC), and squamous cell carcinoma (SCC)]. We performed studies using five mainstream network algorithms to classify these diseases in the dataset and compared the results. Then, we performed studies using an independent dataset of the same disease types, but from other body parts, to perform transfer learning on our models. Comparing the performances, the models that used transfer learning achieved a higher average precision and recall for almost all structures. In the test dataset, which included 388 facial images, the best model achieved 92.9%, 89.2%, and 84.3% recalls for the LE, BCC, and SK, respectively, and the mean recall and precision reached 77.0% and 70.8%. INDEX TERMS Deep learning, CNN, facial skin disease, medical image processing.

ObjectivesTo provide an up-to-date overview of long-term trends of liver cancer mortality and evaluate the effects attributable to age, period and cohort in Chinese population stratified by gender and urban/rural areas.MethodsPopulation and liver cancer mortality data were obtained based on the Disease Surveillance Points in China from 1991 to 2014. To examine the time trends of liver cancer mortality by gender in urban and rural areas in China, Joinpoint analysis was used to estimate the annual per cent change. The intrinsic estimator, a method of age-period-cohort analysis to estimate age, period and cohort effects simultaneously, was used to analyse the underlying mechanisms for liver cancer mortality trends in the aforementioned four groups.ResultsWe observed a significant decline in liver cancer mortality for urban men (average annual per cent change (AAPC)=−1.1%, P<0.05) and urban women (AAPC=−1.4%, P<0.05), while the liver cancer mortality remained stable for rural men (AAPC=−0.1%, P>0.05) and rural women (AAPC=−0.9%, P>0.05). Compared with the 15–19 age group, the liver cancer mortality risk of the 85 and above age group increased 65 and 42 times for urban and rural men, and 102 and 70 times for urban and rural women. From the 1990–1994 period to the 2005–2009 period, the risk increased 56% and 92% for urban and rural men, and 30% and 74% for urban and rural women. Compared with period and cohort effects, age effects were the most influential factor in liver cancer mortality.ConclusionsAs the status of ageing population in China gets worse, the burden caused by liver cancer mortality could still be a great challenge for China in the future. The disparity of liver cancer mortality trends between urban and rural residents can be attributed to period effects, referring to the unequal medical levels and resources between urban and rural areas.