FAM129B, an antioxidative protein, reduces chemosensitivity by competing with Nrf2 for Keap1 binding.

BackgroundThe transcription factor Nrf2 is a master regulator of antioxidant response. While Nrf2 activation may counter increasing oxidative stress in aging, its activation in cancer can promote cancer progression and metastasis, and confer resistance to chemotherapy and radiotherapy. Thus, Nrf2 has been considered as a key pharmacological target. Unfortunately, there are no specific Nrf2 inhibitors for therapeutic application. Moreover, high Nrf2 activity in many tumors without Keap1 or Nrf2 mutations suggests that alternative mechanisms of Nrf2 regulation exist.MethodsInteraction of FAM129B with Keap1 is demonstrated by immunofluorescence, colocalization, co-immunoprecipitation and mammalian two-hybrid assay. Antioxidative function of FAM129B is analyzed by measuring ROS levels with DCF/flow cytometry, Nrf2 activation using luciferase reporter assay and determination of downstream gene expression by qPCR and wester blotting. Impact of FAM129B on in vivo chemosensitivity is examined in mice bearing breast and colon cancer xenografts. The clinical relevance of FAM129B is assessed by qPCR in breast cancer samples and data mining of publicly available databases.FindingsWe have demonstrated that FAM129B in cancer promotes Nrf2 activity by reducing its ubiquitination through competition with Nrf2 for Keap1 binding via its DLG and ETGE motifs. In addition, FAM129B reduces chemosensitivity by augmenting Nrf2 antioxidative signaling and confers poor prognosis in breast and lung cancer.InterpretationThese findings demonstrate the important role of FAM129B in Nrf2 activation and antioxidative response, and identify FMA129B as a potential therapeutic target. FUND: The Chang Gung Medical Foundation (Taiwan) and the Ministry of Science and Technology (Taiwan)

GPER-induced signaling is essential for the survival of breast cancer stem cells.

G protein-coupled estrogen receptor-1 (GPER), a member of the G protein-coupled receptor (GPCR) superfamily, mediates estrogen-induced proliferation of normal and malignant breast epithelial cells. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non-BCSCs of three patient-derived xenografts of ER- /PR+ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER-mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD-Ser118 to sustain BCSC characteristics. Transfection with a dominant-negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs

Sialylation of vasorin by ST3Gal1 facilitates TGF-β1-mediated tumor angiogenesis and progression.

ST3Gal1 is a key sialyltransferase which adds α2,3-linked sialic acid to substrates and generates core 1 O-glycan structure. Upregulation of ST3Gal1 has been associated with worse prognosis of breast cancer patients. However, the protein substrates of ST3Gal1 implicated in tumor progression remain elusive. In our study, we demonstrated that ST3GAL1-silencing significantly reduced tumor growth along with a notable decrease in vascularity of MCF7 xenograft tumors. We identified vasorin (VASN) which was shown to bind TGF-β1, as a potential candidate that links ST3Gal1 to angiogenesis. LC-MS/MS analysis of VASN secreted from MCF7, revealed that more than 80% of its O-glycans are sialyl-3T and disialyl-T. ST3GAL1-silencing or desialylation of VASN by neuraminidase enhanced its binding to TGF-β1 by 2- to 3-fold and thereby dampening TGF-β1 signaling and angiogenesis, as indicated by impaired tube formation of HUVECs, suppressed angiogenesis gene expression and reduced activation of Smad2 and Smad3 in HUVEC cells. Examination of 114 fresh primary breast cancer and their adjacent normal tissues showed that the expression levels of ST3Gal1 and TGFB1 were high in tumor part and the expression of two genes was positively correlated. Kaplan Meier survival analysis showed a significantly shorter relapse-free survival for those with lower expression VASN, notably, the combination of low VASN with high ST3GAL1 yielded even higher risk of recurrence (p = 0.025, HR = 2.967, 95% CI = 1.14-7.67). Since TGF-β1 is known to transcriptionally activate ST3Gal1, our findings illustrated a feedback regulatory loop in which TGF-β1 upregulates ST3Gal1 to circumvent the negative impact of VASN

A Parkinson’s Disease Measurement System Using Laser Lines and a CMOS Image Sensor

This paper presents a non-invasive, non-contact system for the measurement of the arterial dorsum manus vibration waveforms of Parkinson disease patients. The laser line method is applied to detect the dorsum manus vibration in rest and postural situations. The proposed measurement system mainly consists of a laser diode and a low cost complementary metal-oxide semiconductor (CMOS) image sensor. Laser line and centroid methods are combined with the Fast Fourier Transform (FFT) in this study. The shape and frequency and relative frequency of the dorsum manus vibration waveforms can be detected rapidly using our Parkinson’s disease measurement system. A laser line near the wrist joint is used as the testing line. The experimental results show an obvious increase in the amplitude and frequency of dorsum manus variation in the measured region in patients suffering from Parkinson’s disease, indicating the obvious effects of the disease. Both in postural and rest state measurements, as the patient disease age increases the vibration frequency increases. The measurement system is well suited for evaluating and pre-diagnosing early stage Parkinson’s disease

San-Huang-Xie-Xin-Tang Prevents Rat Hearts from Ischemia/Reperfusion-Induced Apoptosis through eNOS and MAPK Pathways

San-Huang-Xie-Xin-Tang (SHXT) is a traditional Chinese medication consisting of three herbs, namely Coptidis rhizome, Scutellariae radix and Rhei rhizome. This study aimed to examine the cardioprotective effects of SHXT in a rat model of acute myocardial apoptosis induced by ischemia/reperfusion (I/R). Vehicle (intravenous saline) or SHXT (intravenous or oral) was administered prior to I/R (occlusion of left coronary artery for 45 min followed by reperfusion for 2 h). In the vehicle group, myocardial I/R caused myocardial infarction with increased plasma cardiac enzymes, severe arrhythmia and mortality. Myocardial apoptosis was induced by I/R as evidenced by DNA ladder and Bcl-2/Bax ratio. In the SHXT group, we found that SHXT significantly reduced plasma levels of cardiac enzymes, arrhythmia scores (from 5 ± 1 to 2 ± 1, P < .01) and mortality rate (from 53 to 0%, P < .01). In addition, pretreatment with intravenous SHXT reduced the infarct size dose-dependently when compared with the vehicle group (10 mg kg−1: 14.0 ± 0.2 versus 44.5 ± 5.0%, and 30 mg kg−1: 6.2 ± 1.2% versus 44.5 ± 5.0%, both P < .01). Similarly, oral administration of SHXT reduced the infarct size dose-dependently. Furthermore, SHXT markedly decreased the apoptosis induced by I/R with increased Bcl-2/Bax ratio. Finally, we found that SHXT counteracted the I/R-induced downstream signaling, resulting in increased myocardial eNOS expression and plasma nitrite, and decreased activation of ERK1/2, p38 and JNK. These data suggest that SHXT has cardioprotective effects against I/R-induced apoptosis, and that these effects are mediated, at least in part, by eNOS and MAPK pathways

Initial Presentations Predict Mortality in Pulmonary Tuberculosis Patients - A Prospective Observational Study

Despite effective anti-TB treatments, tuberculosis remains a serious threat to public health and is associated with high mortality. Old age and multiple co-morbidities are known risk factors for death. The association of clinical presentations with mortality in pulmonary tuberculosis patients remains an issue of controversy.This prospective observational study enrolled newly diagnosed, culture-proven pulmonary tuberculosis patients from five medical centers and one regional hospital, which were referral hospitals of TB patients. Radiographic findings and clinical symptoms were determined at the time of diagnosis. Patients who died for any reason during the course of anti-TB treatment were defined as mortality cases and death that occurred within 30 days of initiating treatment was defined as early mortality. Clinical factors associated with overall mortality and early mortality were investigated.A total of 992 patients were enrolled and 195 (19.7%) died. Nearly one-third (62/195, 31.8%) of the deaths occurred before or within 30 days of treatment initiation. Older age (RR = 1.04, 95%CI: 1.03–1.05), malignancy (RR = 2.42, 95%CI: 1.77–3.31), renal insufficiency (RR = 1.77, 95%CI: 1.12–2.80), presence of chronic cough (RR = 0.63, 95%CI: 0.47–0.84), fever (RR = 1.45, 95%CI: 1.09–1.94), and anorexia (RR = 1.49, 95%CI: 1.07–2.06) were independently associated with overall mortality. Kaplan-Meier survival analysis demonstrated significantly higher mortality in patients present with fever (p<0.001), anorexia (p = 0.005), and without chronic cough (p<0.001). Among patients of mortality, those with respiratory symptoms of chronic cough (RR = 0.56, 95%CI: 0.33–0.98) and dyspnea (HR = 0.51, 95%CI: 0.27–0.98) were less likely to experience early mortality. The radiological features were comparable between survivors and non-survivors.In addition to demographic characteristics, clinical presentations including the presence of fever, anorexia, and the absence of chronic cough, were also independent predictors for on-treatment mortality in pulmonary tuberculosis patients