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The reaction between hydroxyl radical (

Mobile Crowdsensing (MCS) has attained much attention for gathering distributed mobile users to complete large-scale sensing tasks. To ensure the task completion, enough users should be motivated to perform tasks. Thus, many existing works in MCS focus on proposing incentive mechanism in the offline scenario, where the information of all users is available to the platform. However, we argue that the actual MCS is usually an online scenario, where the platform does not know the user's information until they establish connections with the platform. Meanwhile, users connect to the platform randomly and will cut off the connection at any time. Hence, when accessed by a user, the platform needs to make an irrevocable decision instantly about whether to select the user or not, and decides a remuneration for the user without knowing future information. In this paper, we first propose a reverse-auction framework to model the interaction between the platform and users. Then, we present an online truthful incentive mechanism (OTIM) to motivate users, including online winner selection and remuneration determination strategies. Finally, massive simulations are conducted based on three real traces and the results illustrate that OTIM achieves truthfulness, individual rationality, computational efficiency and an approximately full budget utilization.

In e-commerce, online retailers are usually suffering from professional malicious users (PMUs), who utilize negative reviews and low ratings to their consumed products on purpose to threaten the retailers for illegal profits. Specifically, there are three challenges for PMU detection: 1) professional malicious users do not conduct any abnormal or illegal interactions (they never concurrently leave too many negative reviews and low ratings at the same time), and they conduct masking strategies to disguise themselves. Therefore, conventional outlier detection methods are confused by their masking strategies. 2) the PMU detection model should take both ratings and reviews into consideration, which makes PMU detection a multi-modal problem. 3) there are no datasets with labels for professional malicious users in public, which makes PMU detection an unsupervised learning problem. To this end, we propose an unsupervised multi-modal learning model: MMD, which employs Metric learning for professional Malicious users Detection with both ratings and reviews. MMD first utilizes a modified RNN to project the informational review into a sentiment score, which jointly considers the ratings and reviews. Then professional malicious user profiling (MUP) is proposed to catch the sentiment gap between sentiment scores and ratings. MUP filters the users and builds a candidate PMU set. We apply a metric learning-based clustering to learn a proper metric matrix for PMU detection. Finally, we can utilize this metric and labeled users to detect PMUs. Specifically, we apply the attention mechanism in metric learning to improve the model's performance. The extensive experiments in four datasets demonstrate that our proposed method can solve this unsupervised detection problem. Moreover, the performance of the state-of-the-art recommender models is enhanced by taking MMD as a preprocessing stage., Comment: Accepted by IEEE Transactions on Knowledge and Data Engineering (TKDE)

A visible-light-promoted nickel/photoredox-catalyzed reductive cross-coupling reaction between vinyl bromides and benzyl chlorides is reported. A diverse array of enantioenriched allylic centers containing products could be achieved in good yields (up to 90%) and high enantioselectivities (up to 95% ee). The mechanistic studies show that this reductive cross-coupling involves a radical pathway.

Checkpoint kinase 1 (CHK1) is critical for cell survival under replication stress (RS). CHK1 inhibitors (CHK1i’s) in combination with chemotherapy have shown promising results in preclinical studies but minimal efficacy with substantial toxicity in clinical trials. To explore novel combinational strategies that can overcome these limitations, we performed an unbiased high-throughput screen in a non-small cell lung cancer (NSCLC) cell line and identified thioredoxin1 (Trx1), a major component of the mammalian antioxidant-system, as a novel determinant of CHK1i sensitivity. We established a role for redox recycling of RRM1, the larger subunit of ribonucleotide reductase (RNR), and a depletion of the deoxynucleotide pool in this Trx1-mediated CHK1i sensitivity. Further, the TrxR1 inhibitor auronafin, an anti-rheumatoid arthritis drug, shows a synergistic interaction with CHK1i via interruption of the deoxynucleotide pool. Together, these findings identify a new pharmacological combination to treat NSCLC that relies on a redox regulatory link between the Trx system and mammalian RNR activity.

Fig.S15 POU3F2 and SMARCA5 are positively correlated with each other in GBM cohorts

Table S4. Multivariable analyses of clinic-pathologic parameters with MGMT methylation status in patient with GBM

Supplemental table S1 shows siRNA sequences. Table S2 shows primer sequences used for RTPCR. Figure S1 shows sensitivity of various cells to olaparib. Figure S2 shows the effect of olaparib on ALDHbr population. Figure S3 shows expression of ALDH isoforms at mRNA level. Figure S4 shows mRNA level of ALDH isoforms in PARPi-resistance cancer cells. Figure S5 shows the effect of ALDH1A1 expression on the sensitivity of EOC cells to olaparib. Figure S6 shows DNA repair ability in ALDH+ cells. Figure S7 shows the effect of ALDH1A1 on homologous recombination repair. Figure S8 shows the effect of NCT-501 on cell viability and ALDH activity. Figure S9 shows BRCA2 expression in various EOC cells. Figure S10 shows the combined effect of olaparib and NCT-501 on BRCA2-wt cells. Figure S11 shows the effect of NCT-501 on DNA repair in PARPi-resistant cells.

Elevated expression of the antiapoptotic factor Bcl-2 is believed to be one of the contributing factors to an increased relapse rate associated with multiple cisplatin-resistant cancers. DNA damage-binding protein complex subunit 2 (DDB2) has recently been revealed to play an important role in sensitizing human ovarian cancer cells to cisplatin-induced apoptosis through the downregulation of Bcl-2, but the underlying molecular mechanism remains poorly defined. Here, it is report that DDB2 functions as a transcriptional repressor for Bcl-2 in combination with DDB1. Quantitative ChIP and EMSA analysis revealed that DDB2 binds to a specific cis-acting element at the 5′-end of Bcl-2 P1 promoter. Overexpression of DDB2 resulted in marked losses of histone H3K9,14 acetylation along the Bcl-2 promoter and enhancer regions, concomitant with a local enrichment of HDAC1 to the Bcl-2 P1 core promoter in ovarian cancer cells. Coimmunoprecipitation and in vitro binding analyses identified a physical interaction between DDB1 and HDAC1, whereas downregulation of HDAC1 significantly enhanced Bcl-2 promoter activity. Finally, in comparison with wild-type DDB2, mutated DDB2, which is unable to repress Bcl-2 transcription, mediates a compromised apoptosis upon cisplatin treatment. Taken together, these data support a model wherein DDB1 and DDB2 cooperate to repress Bcl-2 transcription. DDB2 recognizes and binds to the Bcl-2 P1 promoter, and HDAC1 is recruited through the DDB1 subunit associated with DDB2 to deacetylate histone H3K9,14 across Bcl-2 regulatory regions, resulting in suppressed Bcl-2 transcription.Implications: Increasing the expression of DDB complex may provide a molecular strategy for cancer therapy. Mol Cancer Res; 12(3); 370–80. ©2013 AACR.

PDF file - 440K, Supplementary Figure 1. DDB2 expression is inversely correlated with Bcl-2 expression in human ovarian cancer cells and tissues. Supplementary Figure 2. Recruitment of transcription factor E2F1 and Sp1 to the bcl-2 promoter. Supplementary Figure 3: Purification of DDB1, DDB2 and GST-HDAC1. Table S1:Antibodies used for ChIP, IP and Immunoblotting. Table S2: Primers for ChIP and RT-PCR.

Supplementary Materials

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved to treat recurrent ovarian cancer with BRCA1 or BRCA2 mutations, and as maintenance therapy for recurrent platinum-sensitive ovarian cancer (BRCA wild-type or mutated) after treatment with platinum. However, the acquired resistance against PARPi remains a clinical hurdle. Here, we demonstrated that PARP inhibitor (olaparib)–resistant epithelial ovarian cancer (EOC) cells exhibited an elevated aldehyde dehydrogenase (ALDH) activity, mainly contributed by increased expression of ALDH1A1 due to olaparib-induced expression of BRD4, a member of bromodomain and extraterminal (BET) family protein. We also revealed that ALDH1A1 enhanced microhomology-mediated end joining (MMEJ) activity in EOC cells with inactivated BRCA2, a key protein that promotes homologous recombination (HR) by using an intrachromosomal MMEJ reporter. Moreover, NCT-501, an ALDH1A1-selective inhibitor, can synergize with olaparib in killing EOC cells carrying BRCA2 mutation in both in vitro cell culture and the in vivo xenograft animal model. Given that MMEJ activity has been reported to be responsible for PARPi resistance in HR-deficient cells, we conclude that ALDH1A1 contributes to the resistance to PARP inhibitors via enhancing MMEJ in BRCA2−/− ovarian cancer cells. Our findings provide a novel mechanism underlying PARPi resistance in BRCA2-mutated EOC cells and suggest that inhibition of ALDH1A1 could be exploited for preventing and overcoming PARPi resistance in EOC patients carrying BRCA2 mutation.

Rapid tumor growth, widespread brain-invasion, and therapeutic resistance critically contribute to glioblastoma (GBM) recurrence and dismal patient outcomes. Although GBM stem cells (GSC) are shown to play key roles in these processes, the molecular pathways governing the GSC phenotype (GBM-stemness) remain poorly defined. Here, we show that epigenetic silencing of miR-146a significantly correlated with worse patient outcome and importantly, miR-146a level was significantly lower in recurrent tumors compared with primary ones. Further, miR-146a overexpression significantly inhibited the proliferation and invasion of GBM patient-derived primary cells and increased their response to temozolomide (TMZ), both in vitro and in vivo. Mechanistically, miR-146a directly silenced POU3F2 and SMARCA5, two transcription factors that mutually regulated each other, significantly compromising GBM-stemness and increasing TMZ response. Collectively, our data show that miR-146a–POU3F2/SMARCA5 pathway plays a critical role in suppressing GBM-stemness and increasing TMZ-response, suggesting that POU3F2 and SMARCA5 may serve as novel therapeutic targets in GBM.Implications:miR-146a predicts favorable prognosis and the miR-146a–POU3F2/SMARCA5 pathway is important for the suppression of stemness in GBM.

Supplementary Data from Targeting Squalene Epoxidase Interrupts Homologous Recombination via the ER Stress Response and Promotes Radiotherapy Efficacy

PDF file - 1721KB, Detailed methods for cell culture, retroviral transfection, generation of RPMI-8226 cells expressing CS1. Figure S1, killing of 293T cells expressing CS1. Figure S2, activation of T cell subsets. Figure S3, IM-9 in vivo experiment. Figure S4, interaction of normal cells and CAR T cells. Figure S5, activation induced cell death. Figure S6, CAR T cells survival and proliferation.

Supplementary Materials and Methods.

microRNA expression assay, primers and antibodies used in this study, as well as supplementary tables and figures showing the relationship among miR328, ERK, and ROS in CSCs.

Over 50% of all patients with cancer are treated with radiotherapy. However, radiotherapy is often insufficient as a monotherapy and requires a nontoxic radiosensitizer. Squalene epoxidase (SQLE) controls cholesterol biosynthesis by converting squalene to 2,3-oxidosqualene. Given that SQLE is frequently overexpressed in human cancer, this study investigated the importance of SQLE in breast cancer and non–small cell lung cancer (NSCLC), two cancers often treated with radiotherapy. SQLE-positive IHC staining was observed in 68% of breast cancer and 56% of NSCLC specimens versus 15% and 25% in normal breast and lung tissue, respectively. Importantly, SQLE expression was an independent predictor of poor prognosis, and pharmacologic inhibition of SQLE enhanced breast and lung cancer cell radiosensitivity. In addition, SQLE inhibition enhanced sensitivity to PARP inhibition. Inhibition of SQLE interrupted homologous recombination by suppressing ataxia-telangiectasia mutated (ATM) activity via the translational upregulation of wild-type p53-induced phosphatase (WIP1), regardless of the p53 status. SQLE inhibition and subsequent squalene accumulation promoted this upregulation by triggering the endoplasmic reticulum (ER) stress response. Collectively, these results identify a novel tumor-specific radiosensitizer by revealing unrecognized cross-talk between squalene metabolites, ER stress, and the DNA damage response. Although SQLE inhibitors have been used as antifungal agents in the clinic, they have not yet been used as antitumor agents. Repurposing existing SQLE-inhibiting drugs may provide new cancer treatments.Significance:Squalene epoxidase inhibitors are novel tumor-specific radiosensitizers that promote ER stress and suppress homologous recombination, providing a new potential therapeutic approach to enhance radiotherapy efficacy.

Cancer stem cells (CSC) play a central role in cancer metastasis and development of drug resistance. miRNA are important in regulating CSC properties and are considered potential therapeutic targets. Here we report that miR-328–3p (miR-328) is significantly upregulated in ovarian CSC. High expression of miR-328 maintained CSC properties by directly targeting DNA damage binding protein 2, which has been shown previously to inhibit ovarian CSC. Reduced activity of ERK signaling in ovarian CSC, mainly due to a low level of reactive oxygen species, contributed to the enhanced expression of miR-328 and maintenance of CSC. Inhibition of miR-328 in mouse orthotopic ovarian xenografts impeded tumor growth and prevented tumor metastasis. In summary, our findings provide a novel mechanism underlying maintenance of the CSC population in ovarian cancer and suggest that targeted inhibition of miR-328 could be exploited for the eradication of CSC and aversion of tumor metastasis in ovarian cancer.Significance:These findings present inhibition of miR-328 as a novel strategy for efficient elimination of CSC to prevent tumor metastasis and recurrence in patients with epithelial ovarian cancer.

TGFβ pretreatment decreases NK cell cytotoxicity against o-HSV infected glioblastoma cell lines and patient-derived glioblastoma stem-like cells (S1); TGFβ mediated inhibition of NK cell and macrophages/microglia intracranial infiltration persists 2 days after oHSV infection (S2); TGFβ pretreatment decreases spleen NK cell activity in 4C8 B6D2F1 mouse model in the presence of oHSV (S3); Virus titer, macrophages/microglia infiltration levels remain similar after NK cell depletion with an asialo-GM1 antibody (S4); A single dose TGFβ treatment in the absence of oHSV is not oncogenic (S5).

XPC protein is a critical DNA damage recognition factor in nucleotide excision repair for which genetic deficiency confers a predisposition to cancer. In this study, we show that XPC has a function that is independent of its canonical function in DNA repair, potentially altering the interpretation of how XPC deficiency leads to heightened cancer susceptibility. XPC enhances apoptosis induced by DNA damage in a p53 nullizygous background, acting downstream of mitochondrial permeabilization and upstream of caspase-9 activation in the DNA damage–induced apoptosis cascade. We found that deficiency in XPC upregulated production of the short isoform of caspase-2 (casp-2S). This upregulation occurred at both protein and mRNA levels through repression of the caspase-2 promoter by XPC protein. Targeted RNAi-mediated downregulation of casp-2S–enhanced UV-induced apoptosis as well as activation of caspase-9 and caspase-6 in XPC-deficient cells, but not in XPC-proficient cells. In addition, XPC overexpression in various p53-deficient cancer cells resistant to cisplatin improved their sensitivity to cisplatin-induced apoptosis. Given that casp-2S functions as an antiapoptotic protein, our findings suggest that XPC enhances DNA damage–induced apoptosis through inhibition of casp-2S transcription. Together, these findings offer a mechanistic foundation to overcome the resistance of highly prevalent p53-deficient tumors to cell death induced by DNA-damaging therapeutic agents, by targeting strategies that inhibit the expression or function of casp-2S. Cancer Res; 72(3); 666–75. ©2011 AACR.

PDF file - 411K

Description of additional methods and procedures used in the study. Also includes Supplementary References.