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Background There is an obvious correlation between ulcerative colitis and colorectal cancer, and the risk of colorectal cancer in patients with ulcerative colitis is increasing. Therefore, the combination therapy of anti-inflammatory and anti-tumor drugs may show promising to inhibit colon cancer. 5-aminosalicylic acid (5-ASA) with anti-inflammatory function is effective for maintaining remission in patients with ulcerative colitis and may also reduce colorectal cancer risk. Histone deacetylase (HDAC) plays an essential role in the progression of colon cancer. Butyric acid (BA) is a kind of HDAC inhibitor and thus shows tumor suppression to colon cancer. However, the volatile and corrosive nature of BA presents challenges in practical application. In addition, its clinical application is limited due to its non-targeting ability and low bioavailability. We aimed to synthesize a novel dual-prodrug of 5-ASA and BA, referred as BBA, to synergistically inhibit colon cancer. Further, based on the fact that folate receptor (FR) is over-expressed in most solid tumors and it has been identified to be a cancer stem cell surface marker in colon cancer, we took folate as the targeting ligand and used carboxymethyl-β-cyclodextrin (CM-β-CD) to carry BBA and thus prepared a novel inclusion complex of BBA/FA-PEG-CM-β-CD. Results It was found that BBA/FA-PEG-CM-β-CD showed significant inhibition in cell proliferation against colon cancer cells SW620. It showed a pro-longed in vivo circulation and mainly accumulated in tumor tissue. More importantly, BBA/FA-PEG-CM-β-CD gave great tumor suppression effect against nude mice bearing SW620 xenografts. Conclusions Therefore, BBA/FA-PEG-CM-β-CD may have clinical potential in colon cancer therapy. Graphical Abstract

Objective: This study aimed to assess neoplasm risk in patients with rheumatoid arthritis (RA) treated with fostamatinib.Methods: Studies were collected from electronic databases of OVID Medline, OVID EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science. We included studies that reported neoplasms in patients with RA treated with fostamatinib. Study selection was repeated by two reviewers based on the study selection criteria. Data were collected and methodological quality assessment was performed. Data were pooled using the Peto odds ratio (OR) with a 95% confidence interval (CI). Subgroup analyses of the fostamatinib dose, trial duration, neoplasm nature, and neoplasm-originating systems were conducted. A funnel plot was used to estimate publication bias, and sensitivity analysis was performed to test the robustness of the results.Results: Seven trials involving 4,971 participants showing low to moderate risk of bias were included. Compared with the placebo, fostamatinib use was not associated with the risks of overall neoplasms (Peto OR = 2.62, 95%CI 0.97–7.10), malignant neoplasms (Peto OR = 3.08, 95%CI 0.96–9.91), or benign neoplasms (Peto OR = 1.71, 95%CI 0.26–11.36). Nevertheless, compared with the placebo, a longer duration of fostamatinib use had a higher risk of malignant neoplasms (Peto OR = 4.49, 95%CI 1.03–19.60) at 52 weeks. As for malignant neoplasms in the digestive system, lower doses of fostamatinib reduced the neoplasm risk (100 mg bid vs 150 mg qd: Peto OR = 0.06, 95%CI 0.01–0.59). Sensitivity analysis showed no significant differences in the effective trends, and no publication bias was found.Conclusion: Fostamatinib is not associated with the risks of overall neoplasms as compared to placebo. Nevertheless, a longer duration of fostamatinib use may be associated with a risk of malignant neoplasms and higher doses of fostamatinib may increase malignant neoplasms in the digestive system. Further well-planned cohort studies with a larger study population are needed to elucidate these outcomes.Systematic ReviewRegistration: PROSPERO (CRD42020202121).

Background Farnesol is a sesquiterpene from propolis and citrus fruit that shows promising anti-bacterial activity for caries treatment and prevention, but its hydrophobicity limits the clinical application. We aimed to develop the novel polymeric micelles (PMs) containing a kind of derivative of farnesol and a ligand of pyrophosphate (PPi) that mediated PMs to adhere tightly with the tooth enamel. Results Farnesal (Far) was derived from farnesol and successfully linked to PEG via an acid-labile hydrazone bond to form PEG-hyd-Far, which was then conjugated to PPi and loaded into PMs to form the aimed novel drug delivery system, PPi-Far-PMs. The in vitro test about the binding of PPi-Far-PMs to hydroxyapatite showed that PPi-Far-PMs could bind rapidly to hydroxyapatite and quickly release Far under the acidic conditions. Results from the mechanical testing and the micro-computed tomography indicated that PPi-Far-PMs could restore the microarchitecture of teeth with caries. Moreover, PPi-Far-PMs diminished the incidence and severity of smooth and sulcal surface caries in rats that were infected with Streptococcus mutans while being fed with a high-sucrose diet. The anti-caries efficacy of free Far can be improved significantly by PPi-Far-PMs through the effective binding of it with tooth enamel via PPi. Conclusions This novel drug-delivery system may be useful for the treatment and prevention of dental caries as well as the targeting therapy of anti-bacterial drugs in the oral disease.

Additional file 1: Figure S1.1H NMR and 13C NMR spectra of synthetic compound 1: tert-butyl 2-(2-(2-hydroxyethoxy)acetyl)hydrazine-1-carboxylate (HO-PEG-NHNH-Boc). Figure S2.1H NMR, 13C NMR and 31P NMR spectra of synthetic compound 2: sodium 2,2-dimethyl-4,7,13-trioxo-3,9,12-trioxa-5,6-diazatetradecan-14-yl hydrogen diphosphate (PPi-PEG-NHNH-Boc). Figure S3.1H NMR and 13C NMR spectra of synthetic compound 3: sodium 2-(2-(2-hydrazinyl-2-oxoethoxy)ethoxy)-2-oxoethyl hydrogen diphosphate (PPi-PEG-NHNH2). Figure S4.1H NMR and 13C NMR spectra of synthetic compound 4: sodium 2-oxo-2-(2-(2-oxo-2-(2-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ylidene)hydrazinyl)ethoxy)ethoxy)ethyl hydrogen diphosphate (PPi-PEG-hyd-Far)) is available in the online version of this article.

Deregulation of the tyrosine kinase signalling is often associated with tumour progression and drug resistance, but its underlying mechanisms are only partly understood. In this study, we investigated the effects of the receptor tyrosine kinase AXL on the stability of the MDMX-MDM2 heterocomplex and the activity of p53 in melanoma cells. Our data demonstrated that AXL overexpression or activation through growth arrest-specific 6 (Gas6) ligand stimulation increases MDMX and MDM2 protein levels and decreases p53 activity. Upon activation, AXL stabilizes MDMX through a post-translational modification that involves phosphorylation of MDMX on the phosphosite Ser314, leading to increased affinity between MDMX and MDM2 and favouring MDMX nuclear translocation. Ser314 phosphorylation can also protect MDMX from MDM2-mediated degradation, leading to stabilization of the MDMX-MDM2 complex. We identified CDK4/6 and p38 MAPK as the two kinases mediating AXL-induced modulation of the MDMX-MDM2 complex, and demonstrated that suppression of AXL, either through siRNA silencing or pharmacological inhibition, increases expression levels of p53 target genes P21, MDM2, and PUMA, improves p53 pathway response to chemotherapy, and sensitizes cells to both Cisplatin and Vemurafenib. Our findings offer an insight into a novel signalling axis linking AXL to p53 and provide a potentially druggable pathway to restore p53 function in melanoma.

According to diagnostic criteria, skin tumors can be divided into three categories: benign, low degree and high degree malignancy. For high degree malignant skin tumors, if not detected in time, they can do serious harm to patients' health. However, in clinical practice, identifying malignant degree requires biopsy and pathological examination which is time costly. Furthermore, in many areas, due to the severe shortage of dermatologists, it's inconvenient for patients to go to hospital for examination. Therefore, an easy to access screening method of malignant skin tumors is needed urgently. Firstly, we spend 5 years to build a dataset which includes 4,500 images of 10 kinds of skin tumors. All instances are verified pathologically thus trustworthy; Secondly, we label each instance to be either low-risk, high-risk or dangerous in which Junctional nevus, Intradermal nevus, Dermatofibroma, Lipoma and Seborrheic keratosis are low-risk, Basal cell carcinoma, Bowen's disease and Actinic keratosis are high-risk, Squamous cell carcinoma and Malignant melanoma are dangerous; Thirdly, we apply the Xception architecture to build the risk degree classifier. The area under the curve (AUC) for three risk degrees reach 0.959, 0.919 and 0.947 respectively. To further evaluate the validity of the proposed risk degree classifier, we conduct a competition with 20 professional dermatologists. The results showed the proposed classifier outperforms dermatologists. Our system is helpful to patients in preliminary screening. It can identify the patients who are at risk and alert them to go to hospital for further examination.

// Jianglin Zhang 1, 2, * , Zhou Lei 1, 2, * , Zunnan Huang 3, * , Xu Zhang 1, 2 , Youyou Zhou 1, 2 , Zhongling Luo 1, 2 , Weiqi Zeng 1, 2 , Juan Su 1, 2 , Cong Peng 1, 2 , Xiang Chen 1, 2 1 The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China 2 Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China 3 Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, Guangdong, China * These authors have contributed equally to this work Correspondence to: Cong Peng, email: pengcongxy@csu.edu.cn Xiang Chen, email: chenxiangck@126.com Keywords: EGCG, TRAF6, ubiquitination, melanoma Received: August 24, 2016 Accepted: October 07, 2016 Published: October 24, 2016 ABSTRACT TRAF6 (TNF Receptor-Associated Factor 6) is an E3 ubiquitin ligase that contains a Ring domain, induces K63-linked polyubiquitination, and plays a critical role in signaling transduction. Our previous results demonstrated that TRAF6 is overexpressed in melanoma and that TRAF6 knockdown dramatically attenuates tumor cell growth and metastasis. In this study, we found that EGCG can directly bind to TRAF6, and a computational model of the interaction between EGCG and TRAF6 revealed that EGCG probably interacts with TRAF6 at the residues of Gln54, Gly55, Asp57 ILe72, Cys73 and Lys96. Among these amino acids, mutation of Gln54, Asp57, ILe72 in TRAF6 could destroy EGCG bound to TRAF6, furthermore, our results demonstrated that EGCG significantly attenuates interaction between TRAF6 and UBC13(E2) and suppresses TRAF6 E3 ubiquitin ligase activity in vivo and in vitro . Additionally, the phosphorylation of IκBα, p-TAK1 expression are decreased and the nuclear translocation of p65 and p50 is blocked by treatment with EGCG, leading to inactivation of the NF-κB pathway. Moreover, EGCG significantly inhibits cell growth as well as the migration and invasion of melanoma cells. Taken together, these findings show that EGCG is a novel E3 ubiquitin ligase inhibitor that could be used to target TRAF6 for chemotherapy or the prevention of melanoma.

// Zhongling Luo 1 , Xu Zhang 1 , Weiqi Zeng 1 , Juan Su 1 , Keda Yang 2 , Lixia Lu 1 , Chuan Bian Lim 3 , Wen Tang 4 , Lisha Wu 5 , Shuang Zhao 1 , Xuekun Jia 1 , Cong Peng 1 , Xiang Chen 1 1 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China 2 Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China 3 Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA 4 Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China 5 Institute of Medical Science Research, Xiangya Hospital, Central South University, Changsha, Hunan, China Correspondence to: Cong Peng, e-mail: pengchongpeng@hotmail.com Xiang Chen, e-mail: chenxiangck@126.com Keywords: TRAF6, melanoma, invasion and metastasis, Basigin, ubiquitination Received: September 07, 2015 Accepted: January 02, 2016 Published: January 12, 2016 ABSTRACT TRAF6 plays a crucial role in the regulation of the innate and adaptive immune responses. Although studies have shown that TRAF6 has oncogenic activity, the role of TRAF6 in melanoma is unclear. Here, we report that TRAF6 is overexpressed in primary as well as metastatic melanoma tumors and melanoma cell lines. Knockdown of TRAF6 with shRNA significantly suppressed malignant phenotypes including cell proliferation, anchorage-independent cell growth and metastasis in vitro and in vivo . Notably, we demonstrated that Basigin (BSG)/CD147, a critical molecule for cancer cell invasion and metastasis, is a novel interacting partner of TRAF6. Furthermore, depletion of TRAF6 by shRNA reduced the recruitment of BSG to the plasma membrane and K63-linked ubiquitination, in turn, which impaired BSG-dependent MMP9 induction. Taken together, our findings indicate that TRAF6 is involved in regulating melanoma invasion and metastasis, suggesting that TRAF6 may be a potential target for therapy or chemo-prevention in melanoma.

Both sunitinib, a multi-target tyrosine kinase inhibitor (TKI) and propranolol, a non-selective β-blocker, have proven therapeutic effects on malignant melanoma (MM). This study reports a synergistic effect of propranolol and sunitinib upon A375, P8 MM cell lines and mice xenografts. Cell viability assays detected a significant decrease of sunitinib IC50 in combination with propranolol, which was confirmed by a colony formation assay. Western blot showed that propranolol and sunitinib combination significantly down-regulated phospho-Rb, phospho-ERK, Cyclin D1, and Cyclin E, but had no effect on Bax, Bcl-2, or cleaved PARP expression. The average tumor size of propranolol and low-dose sunitinib (Sun L) combination treated mice was reduced and similar to high-dose sunitinib treated A375 xenografts. The Ki67 index was significantly reduced in propranolol and Sun L combination treated group compared with single Sun L treated group. This synergistic effect between propranolol and sunitinib to inhibit MM proliferation was through suppressing ERK/Cyclin D1/Rb/Cyclin E pathways and inducing G0/G1/S phase arrest, rather than by inducing tumor cell apoptosis.

Psoriasis is a chronic inflammatory skin disease characterized by abnormal keratinocyte proliferation and terminal differentiation. Interleukin-22 (IL-22) and the transcription factor Stat3 play pivotal roles in the pathogenesis of psoriasis. CD147 is a transmembrane glycosylation protein that belongs to the immunoglobulin superfamily. Our previous studies have shown that CD147 is a marker of high keratinocyte proliferation and poor keratinocyte differentiation as well as a psoriasis susceptibility gene. The current study demonstrates that CD147 is highly expressed in psoriatic skin lesions. Specific CD147 over-expression in the epidermis of K5-promoter transgenic mice promotes imiquimod (IMQ)-induced psoriasis-like inflammation characterized by acanthosis, granular layer loss and inflammatory cell infiltration. We also found that IL-22 increases CD147 transcription in vitro and in vivo and that Stat3 binds directly to the CD147 promoter between positions −854 and −440, suggesting that CD147 expression is up-regulated in patients with psoriasis through Stat3 activation. In addition, CD147 knockdown dramatically blocks IL-22-mediated Stat3 activation as well as IL-22-induced cytokine, chemokine and antimicrobial factor expression. Together, these findings show that CD147 is a novel and key mediator of IL-22-induced psoriatic alterations in the epidermis and might be a therapeutic target in patients with psoriasis.

Background Methotrexate (MTX) is a drug used to treat psoriasis due to inducing immune cell apoptosis. However, certain patients show MTX resistant. CD147, highly expressed by psoriatic PBMCs, is assumed to regulate MTX sensitivity. The underlining mechanism is still relatively understudied. Objective To understand the mechanisms of that CD147 promotes MTX resistance in immune cells. Methods The expression of CD147 and ABCG2 in PBMCs from psoriatic patients, cellular apoptosis and intracellular MTX amount were measured. We also checked the cellular drug sensitivity of CHO (Chinese Hamster Ovary) cell lines with introduced CD147 and Jurkat T cells depeleted CD147. By immunoprecipitation, we detected the interaction between CD147 and ABCG2. Results Both ABCG2 and CD147 are highly expressed in psoriatic PBMCs. Cultured in vitro, the PBMCs from psoriatic patients were more resistant to MTX-induced apoptosis comparing to PBMCs from healthy people. Further studies demonstrated that exogenous overexpression of CD147 in CHO cells increased ABCG2 protein level. After MTX treatment, CD147 overexpressing CHO cells showed lower apoptosis rate and lower intracellular MTX concentration. On the contrary, knockdown of CD147 by shRNA in Jurkat T cells decreased ABCG2 expression, as well as increased MTX-induced apoptosis and decreased MTX efflux. Immunoprecipitation experiment revealed that the trans-membrane domain of CD147 conferred its’ interaction with ABCG2. Conclusion Our study suggests a role of CD147 in regulating ABCG2 transportation of MTX in immune cells. Strategies involving targeting CD147 could be considered in clinical treatment of psoriatic patients resistant to MTX.

To evaluate the application of a high-frequency electrosurgical scalpel and methylene blue staining in the endonasal dacryocystorhinostomy.This retrospective study included 37 patients (43 eyes) undergoing endonasal dacryocystorhinostomy in our hospital between 2011 and 2013 using methylene blue staining of the lacrimal sac and a high-frequency electrosurgical scalpel for cutting nasal mucosa, intraoperative stanch, and fixation of lacrimal sac and nasal mucosal flaps. Surgical efficacy, intraoperative challenges, and corresponding handling methods were evaluated and summarized.Among 43 eyes, 42 were successfully cured (97.7%) and the symptoms in 1 eye were improved (2.3%). Total efficacy rate was 100%. All surgeries were successfully performed. No severe intraoperative complications were observed.A high-frequency electrosurgical scalpel, combined with methylene blue staining of the lacrimal sac, is efficacious for nasal mucosal cutting, intraoperative stanch, and fixation of mucosal flap by cauterization, which significantly alleviates intraoperative complications and enhances surgical success rate. It deserves widespread application in clinical practice.

To describe the study design, methodology and baseline characteristics of the Dongguan Eye Study.Population-based, cross-sectional studyA total of 8952 rural-dwelling residents aged 40 years or older in Hengli, Dongguan.The Dongguan Eye Study was conducted from September 2011 to February 2012. The interview covered demographic data, socio-economic status and health- and vision-related quality of life. Physical measurements included height, weight, waist and hip circumference, heart rate and blood pressure. Laboratory tests included fasting blood glucose, haemoglobin A1c, oral glucose tolerance, serum total cholesterol, triglycerides, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, serum creatinine, blood urea nitrogen and uric acid. Ophthalmic examinations included visual acuity and autorefraction testing, intraocular pressure measurement, slit-lamp examination, ocular biometry, gonioscopy, fundus photography, retinal nerve fibre layer imaging and visual field testing.Prevalence and risk factors for visual impairment, blindness, eye diseases and their associations with systemic medical indicators or health-related lifestyles, as well as epidemiological data on diabetic subjects. Methodology, response rates and baseline characteristics are presented.Of the 11 357 individuals eligible for the Dongguan Eye Study, 8952 (78.82%) subjects participated. All participants were self-identified Han Chinese. The average age was 54.0 years, 59.9% were female, 48.4% were farmers and 77.2% had elementary or junior middle school educational levels. The average body mass index and waist-hip ratio were 24.6 ± 3.9 kg/m(2) and 0.9 ± 0.2.Data from the Dongguan Eye Study provide information concerning the prevalence, risk factors and impacts of eye diseases in rural residents undergoing urbanization in southern China.

Intracellular free calcium is a ubiquitous second messenger regulating a multitude of normal and pathogenic cellular responses, including the development of melanoma. Upstream signaling pathways regulating the intracellular free calcium concentration ([Ca2+]i) may therefore have a significant impact on melanoma growth and metastasis. In this study, we demonstrate that the endoplasmic reticulum (ER)-associated protein calcium-modulating cyclophilin ligand (CAML) is bound to Basigin, a widely expressed integral plasma membrane glycoprotein and extracellular matrix metalloproteinase inducer (EMMPRIN, or CD147) implicated in melanoma proliferation, invasiveness, and metastasis. This interaction between CAML and Basigin was first identified using yeast two-hybrid screening and further confirmed by co-immunoprecipitation. In human A375 melanoma cells, CAML and Basigin were co-localized to the ER. Knockdown of Basigin in melanoma cells by siRNA significantly decreased resting [Ca2+]i and the [Ca2+]i increase induced by the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor thapsigargin (TG), indicating that the interaction between CAML and Basigin regulates ER-dependent [Ca2+]i signaling. Meanwhile upregulating the [Ca2+]i either by TG or phorbol myristate acetate (PMA) could stimulate the production of MMP-9 in A375 cells with the expression of Basigin. Our study has revealed a previously uncharacterized [Ca2+]i signaling pathway that may control melanoma invasion, and metastasis. Disruption of this pathway may be a novel therapeutic strategy for melanoma treatment.