The oxidative stress response regulates DKK1 expression through the JNK signaling cascade in multiple myeloma plasma cells

Multiple myeloma (MM) plasma cells, but not those from healthy donors and patients with monoclonal gammopathy of undetermined significance or other plasma cell dyscrasias involving the bone marrow, express the Wnt-signaling antagonist DKK1. We previously reported that secretion of DKK1 by MM cells likely contributes to osteolytic lesions in this disease by inhibiting Wnt signaling, which is essential for osteoblast differentiation and survival. The mechanisms responsible for activation and regulation of DKK1 expression in MM are not known. Herein, we could trace DKK1 expression changes in MM cells to perturbations in the JNK signaling cascade, which is differentially modulated through oxidative stress and interactions between MM cells with osteoclasts in vitro. Despite its role as a tumor suppressor and mediator of apoptosis in other cell types including osteoblasts, our data suggest that DKK1, a stress-responsive gene in MM, does not mediate apoptotic signaling, is not activated by TP53, and its forced overexpression could not inhibit cell growth or sensitize MM cells to apoptosis following treatment with thalidomide or lenalidomide. We conclude that specific strategies to modulate persistent activation of the JNK pathway may be beneficial in preventing disease progression and treating myeloma-associated bone disease by inhibiting DKK1 expression.     

CKS1B, overexpressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms

Overexpression of CKS1B, a gene mapping within a minimally amplified region between 153 to 154 Mb of chromosome 1q21, is linked to a poor prognosis in multiple myeloma (MM). CKS1B binds to and activates cyclin-dependent kinases and also interacts with SKP2 to promote the ubiquitination and proteasomal degradation of p27(Kip1). Overexpression of CKS1B or SKP2 contributes to increased p27(Kip1) turnover, cell proliferation, and a poor prognosis in many tumor types. Using 4 MM cell lines harboring MAF-, FGFR3/MMSET-, or CCND1-activating translocations, we show that lentiviral delivery of shRNA directed against CKS1B resulted in ablation of CKS1B mRNA and protein with concomitant stabilization of p27(Kip1), cell cycle arrest, and apoptosis. Although shRNA-mediated knockdown of SKP2 and forced expression of a nondegradable form of p27(Kip1) (p27(T187A)) led to cell cycle arrest, apoptosis was modest. Of importance, while knockdown of SKP2 or overexpression of p27(T187A) induced cell cycle arrest in KMS28PE, an MM cell line with biallelic deletion of CDKN1B/p27(Kip1), CKS1B ablation induced strong apoptosis. These data suggest that CKS1B influences myeloma cell growth and survival through SKP2- and p27(Kip1)-dependent and -independent mechanisms and that therapeutic strategies aimed at abolishing CKS1B function may hold promise for the treatment of high-risk disease for which effective therapies are currently lacking.     

Profiles of tamoxifen-related side effects by race and smoking status in women with breast cancer

Background: Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) that is widely used as adjuvant therapy in breast cancer patients; however, it is also associated with undesirable side effects. The goal of this study was to investigate TAM-related side effects, and determine profiles of side effects by race and by smoking status. Methods: A secondary data analysis was conducted using cross-sectional study data from 138 African American and Caucasian women with breast cancer taking TAM 20 mg daily for at least 30 days prior to enrollment. Participants completed questionnaires that obtained information about demographic characteristics, reproductive history, health and lifestyle characteristics, TAM use and its related side effects. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals. Results: Compared to never smokers, a significantly greater percentage of current smokers reported ever experiencing TAM-related nausea (28.0% versus 5.0%, P = 0.007), depression (40.0% versus 7.1%, P = 0.001) and migraines (19.2% versus 1.7%, P = 0.02). These differences remained statistically significant after controlling for race, age, obesity, tumor stage, and duration of TAM treatment. No significant differences by race were noted in women reporting TAM side effects. Conclusion: The findings from this study suggest that current smokers with breast cancer should be informed of the increased probability of reporting TAM-related side effects such as nausea, depression and migraines, and counseled about smoking cessation which may reduce the incidence of these side effects.     

Coronary artery spasm treated with intracoronary bioresorbable scaffold implantation under the guidance of treadmill test and optical coherence tomography: A case report

Coronary artery spasm (CAS) can cause unstable angina, and the treatment of this disease is controversial. We report an elderly male patient who was admitted to hospital due to chest tightness. CAG showed that 70% stenosis in the middle of the right coronary artery (RCA). A bioresorbable scaffold (BRS) was implanted in the lesion under the guidance of optical coherence tomography (OCT). One year later, the patient's symptoms were relieved. The repeated CAG showed that the stent was good. BRS implantation under the guidance of treadmill test and OCT is one of treatment options for CAS patients.     

Two new clerodane diterpenoids and a new pyran-2-one derivative with anti-neuroinflammatory activities from Croton crassifolius

Journal of Natural Medicines - Two new clerodane diterpenoids (1 and 2), a new pyran-2-one derivative (3), along with five known compounds (4?8), were isolated from Croton...     

LncRNA MEG3 restrained pulmonary fibrosis induced by NiO NPs via regulating hedgehog signaling pathway-mediated autophagy

Long noncoding RNA maternally expressed gene 3 (lncRNA MEG3) was down-regulated in pulmonary fibrosis of rats induced by Nickel oxide nanoparticles (NiO NPs), while the downstream regulatory mechanisms of MEG3 remain unclear. This study aimed to investigate the relationship among MEG3, Hedgehog (Hh) signaling pathway and autophagy in pulmonary fibrosis caused by NiO NPs. The pulmonary fibrosis model in rats was constructed by intratracheal instillation of 0.015, 0.06, and 0.24 mg/kg NiO NPs twice a week for 9 weeks. Collagen deposition model was established by treating A549 cells with 25, 50, and 100 μg/mL NiO NPs for 24 h. Our results indicated that NiO NPs activated Hh pathway, down-regulated the expression of MEG3, and reduced autophagy activity in vivo and in vitro. Meanwhile, the autophagy process was promoted by Hh pathway inhibitor (CDG-0449), while the collagen formation in A549 cells was reduced by autophagy activator (Rapamycin). Furthermore, the overexpressed MEG3 inhibited the activation of Hh pathway, resulting in autophagy activity enhancement along with collagen formation reduction. In summary, lncRNA MEG3 can restrain pulmonary fibrosis induced by NiO NPs via regulating hedgehog signaling pathway-mediated autophagy, which may serve as a potential therapeutic strategy for pulmonary fibrosis.     

Contamination,risk and quantitative identification of nutrients and potentially toxic elements in the surface sediments of Baiyangdian Lake,North China

Ecotoxicology - Potentially toxic elements (PTEs) in lake sediments are concerning because of their toxic effects on lacustrine ecosystems and human health. Baiyangdian Lake (BYDL), the...     

Treatment of intracerebral glioblastomas with G422 tumour cell vaccine in a mouse model

The aim of this study was to develop a tumour vaccine with the ability to induce and expand higher affinity cytotoxic T lymphocytes and stimulate an effective antitumour immune response. The hypothesis tested was that G422 glioblastoma cells modified with B7-1 and interferon (IFN)-gamma genes could serve as a tumour vaccine. It was found that therapeutic subcutaneous immunizations with this tumour vaccine significantly induced a cytotoxic T-cell response and prolonged the survival of female Kuming mice with intracerebral G422 tumour isografts. The data collectively suggested that G422 glioblastoma cells genetically modified with B7-1 and IFN-gamma genes could serve as a tumour vaccine.     

Surgical Education in China

A highly skilled surgical team relies on a standardized training system and the most important subject in the development of general surgery in China is to set up standardized education and training systems for surgeons. This article reviews the history of the training of residents, delineates the current situation and problems of residency training in general surgery, and discusses reform and future development of surgical training systems and assessment of competence in surgical practice, in order to put forward the solutions and countermeasures. China needs a large number of highly trained surgeons to improve its medical care system, and some fundamental changes of its residency training system, especially in the field of surgical education, have been made. All of the experts working in this area sum up the historical experience and apply the advanced experience of foreign countries as a reference to build up a surgical education system with Chinese characteristics to achieve a continuous, sound, and rapid development of surgical education in China.     

Reversal of Diabetes in Mice by Intrahepatic Injection of Bone-derived GFP-murine Mesenchymal Stem Cells Infected with the Recombinant Retrovirus-carrying Human Insulin Gene

Background The objective of this study was to assess the effect of intrahepatic injection of bone-derived green fluorescent protein (GFP)-transgenic murine mesenchymal stem cells (GFP-mMSCs) containing the human insulin(ins) gene in streptozotocin-induced diabetic mice. Methods GFP-mMSCs were isolated from the bone marrow of GFP transgenic mice, expanded, and transfected with a recombinant retrovirus MSCV carrying the human insulin gene. C57BL/6J mice were made diabetic by an intraperitoneal administration of 160 mg/kg streptozotocin (STZ), followed by intrahepatic injection of transfected GFP-mMSCs. The variations in body weight and the blood glucose and serum insulin levels were determined after cell transplantation. GFP-mMSCs survival and human insulin expression in liver tissues were examined by fluorescent microscopy and immunohistochemistry. Results The body weight in diabetic mice that received GFP-mMSCs harboring the human insulin gene was increased by 6% within 6 weeks after treatment, and the average blood glucose levels in these animals were 10.40 ± 2.80 mmol/l (day 7) and 6.50 ± 0.89 mmol/l (day 42), respectively, while the average values of blood glucose in diabetic animals without treatment were 26.80 ± 2.49 mmol/l (day 7) and 25.40 ± 4.10 mmol/l (day 42), showing a significant difference (p < 0.05). Moreover, secretion of human insulin of GFP-mMSCs in serum and animal liver was detected by radioimmunoassay (RIA) and immunohistochemistry (IHC). Conclusions Experimental diabetes could be relieved effectively for up to 6 weeks by intrahepatic transplantation of murine mesenchymal stem cells expressing human insulin. This study implies a novel approach of gene therapy for type I diabetes.