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

Effect of younger age on survival outcomes in T1N0M0 breast cancer: A propensity score matching analysis

Purpose We evaluated the effect of younger age on recurrence risk in Chinese women diagnosed with T1N0M0 breast cancer (BC), using propensity score matching (PSM) analysis. Methods We included 365 women who were diagnosed with T1N0M0 BC between 2003 and 2016, and who received surgery at our center. They were classified as younger (≤40 years) and older (>40 years). We used PSM to balance clinicopathologic characteristics between the two age groups. Survival was analyzed by the Kaplan–Meier method, before and after PSM. Results Over a median follow‐up period of 79 months, 54 patients developed recurrences. Before PSM, younger patients had worse recurrence‐free survival (RFS) than older patients. Significantly worse RFS was seen in younger patients with HER2+ BC compared with their older counterparts. Younger patients had higher rates of locoregional recurrence rather than metastasis, especially in the first 5 years after diagnosis. After PSM, the two age groups still significantly differed in 5‐year RFS. Conclusion Among PSM pairs with T1N0M0 BC, with equal baselines and treatment conditions, we found that patients who presented at younger ages had worse outcomes, independently of other pathological features. Younger patients with BC may require more individualized therapy to improve their prognosis

Study of Local Inner Ear Gene Therapy for Controlling Autoimmune Sensorineural Hearing Loss

Bone marrow mesenchymal stem cells (BMSCs) expressing recombinant IL-4 have the potential to remediate inflammatory diseases. We thus investigated whether BMSCs expressing exogenous IL-4 could alleviate autoimmune sensorineural hearing loss. BMSCs isolated from guinea pigs were transfected with recombinant lentivirus expressing IL-4. A total of 33 animals were divided into three groups. Group A received scala tympani injection of IL-4-expressing BMSCs, and Group B received control vectorexpressing BMSCs, and Group C received phosphate-buffered saline. The distribution of implanted BMSCs in the inner ears was assessed by immunohistochemistry and fluorescence microscopy. Auditory brain-stem response (ABR) was monitored to evaluate the auditory changes. Following BMSCs transplantation, the threshold levels of ABR wave III decreased in Groups A and B and significant differences were observed between these two groups ( < 0.05). Transplanted BMSCs distributed in the scala tympani and scala vestibuli. In some ears with hearing loss, there was a decrease in the number of spiral ganglion cells and varying degrees of endolymphatic hydrops or floccule. Following transplantation, the lentivirus-infected BMSCs migrated to the inner ear and produced IL-4. Our results demonstrate that, upon transplantation, BMSCs and BMSCs expressing recombinant IL-4 have the ability to remediate the inflammatory injury in autoimmune inner ear diseases

MOAP-1 Mediates Fas-Induced Apoptosis in Liver by Facilitating tBid Recruitment to Mitochondria

SummaryFas apoptotic signaling regulates diverse physiological processes. Acute activation of Fas signaling triggers massive apoptosis in liver. Upon Fas receptor stimulation, the BH3-only protein Bid is cleaved into the active form, tBid. Subsequent tBid recruitment to mitochondria, which is facilitated by its receptor MTCH2 at the outer mitochondrial membrane (OMM), is a critical step for commitment to apoptosis via the effector proteins Bax or Bak. MOAP-1 is a Bax-binding protein enriched at the OMM. Here, we show that MOAP-1-deficient mice are resistant to Fas-induced hepatocellular apoptosis and lethality. In the absence of MOAP-1, mitochondrial accumulation of tBid is markedly impaired. MOAP-1 binds to MTCH2, and this interaction appears necessary for MTCH2 to engage tBid. These findings reveal a role for MOAP-1 in Fas signaling in the liver by promoting MTCH2-mediated tBid recruitment to mitochondria

Tree model guided candidate generation for mining frequent subtrees from XML

Due to the inherent flexibilities in both structure and semantics, XML association rules mining faces few challenges, such as: a more complicated hierarchical data structure and ordered data context. Mining frequent patterns from XML documents can be recast as mining frequent tree structures from a database of XML documents. In this study, we model a database of XML documents as a database of rooted labeled ordered subtrees. In particular, we are mainly coneerned with mining frequent induced and embedded ordered subtrees. Our main contributions arc as follows. We describe our unique embedding list representation of the tree structure, which enables efficient implementation ofour Tree Model Guided (TMG) candidate generation. TMG is an optimal, non-redundant enumeration strategy which enumerates all the valid candidates that conform to the structural aspects of the data. We show through a mathematical model and experiments that TMG has better complexity compared to the commonly used join approach. In this paper, we propose two algorithms, MB3Miner and iMB3-Miner. MB3-Miner mines embedded subtrees. iMB3-Miner mines induced and/or embedded subtrees by using the maximum level of embedding constraint. Our experiments with both synthetic and real datasets against two well known algorithms for mining induced and embedded subtrees, demonstrate the effeetiveness and the efficiency of the proposed techniques

Circular RNA hsa_circ_001783 regulates breast cancer progression via sponging miR-200c-3p

Increasing evidence suggests circular RNAs (circRNAs) exert critical functions in tumor progression via sponging miRNAs (microRNAs). However, the role of circRNAs in breast cancer remains unclear. Here we systematically analyzed the circular RNAs in breast cancer based on their characteristic in sponging disease-specific miRNAs and identified hsa_circ_001783 as a top ranked circRNA in our computation and verified its high expression in both breast cancer cells and cancer tissue. A higher level of hsa_circ_001783 was significantly correlated with heavier tumor burden and poorer prognosis of patients with breast cancer. Knockdown of this circRNA remarkably inhibited the proliferation and invasion of breast cancer cells. Importantly, hsa_circ_001783 promoted progression of breast cancer cells via sponging miR-200c-3p. Taken together, hsa_circ_001783 may serve as a novel prognostic and therapeutic target for breast cancer

Programmed Cell Death and Aerenchyma Formation in Water-Logged Sunflower Stems and Its Promotion by Ethylene and ROS

Previous studies have shown that waterlogging/ hypoxic conditions induce aerenchyma formation to facilitate gas exchange. Ethylene (ET) and reactive oxygen species (ROS), as regulatory signals, might also be involved in these adaptive responses. However, the interrelationships between these signals have seldom been reported. Herein, we showed that programmed cell death (PCD) was involved in aerenchyma formation in the stem of Helianthus annuus. Lysigenous aerenchyma formation in the stem was induced through waterlogging (WA), ethylene and ROS. Pre-treatment with the NADPH oxidase inhibitor diphenyleneiodonium (DPI) partially suppressed aerenchyma formation in the seedlings after treatment with WA, ET and 3-amino-1, 2, 4-triazole (AT, catalase inhibitor). In addition, pre-treatment with the ethylene perception inhibitor 1-methylcyclopropene (1-MCP) partially suppressed aerenchyma formation induced through WA and ET in the seedlings, but barely inhibited aerenchyma formation induced through ROS. These results revealed that ethylene-mediated ROS signaling plays a role in aerenchyma formation, and there is a causal and interdependent relationship during WA, ET and ROS in PCD, which regulates signal networks in the stem of H. annuus

Incorporating MicroRNA into molecular phenotypes of circulating tumor cells enhances the prognostic accuracy for patients with metastatic breast cancer

Background. The molecular phenotype of circulating tumor cells (CTCs) was associated with clinical outcome of patients with breast cancer. CTCs isolated from patients with metastatic breast cancer (MBC) display a unique microRNA (miRNA) expression profile. The aim of this study was to enhance the prognostic accuracy of the CTC phenotype in patients with MBC, by incorporating miRNA into a combined prediction model. Subjects, Materials, and Methods. CTCs were detected by CellSearch and enriched by magnetic cell sorting. miRNA deep sequencing and quantitative polymerase chain reaction were used to screen and verify potentially CTC‐specific miRNA candidates. Patients with MBC were enrolled from two independent cohorts, and overall survival (OS) and chemotherapy response were analyzed. Results. We screened and identified that miR‐106b was an upregulated molecule in patients with MBC with CTC ≥5/7.5 mL (n = 16) compared with patients with CTC = 0/7.5 mL (n = 16) and healthy donors (n = 8). The expression of CTC‐specific miR‐106b correlated with vimentin and E‐cadherin in CTC and acted as an independent factor for predicting OS (hazard ratio 2.157, 95% confidence interval [CI] 1.098–4.239, p = .026). Although CTC‐specific miR‐106b, E‐cadherin, and vimentin showed a prognostic potential independently, the prognostic performance for OS based on the combination of three markers was significantly enhanced in Cohort 1 (area under the curve [AUC] 0.752, 95% CI 0.658–0.847, n = 128) and further validated in Cohort 2 (AUC 0.726, 95% CI 0.595–0.856, n = 91). Besides, a combined model incorporating miR‐106b was associated with therapy response. Conclusion. The phenotypic assemblies of CTC incorporating miR‐106b show enhanced prognostic accuracy of overall survival in patients with MBC