<p>PDF file - 668KB, Pin1 inhibition suppresses the expansion of BCSC enriched populations (S1). Pin1 knockdown in MCF7 cells reverts EMT phenotype (S2). Pin1 promotes the expansion of BCSC-enriched populations, as well as basal/myoepithelial and luminal progenitors in primary nonmal human MECs (S3).</p>

<p>PDF file - 35KB, Patient Information for Isolation of Lin-CD24-CD44+ Cells from Human Breast Cancer.</p>

Supplementary Figures 1-8 from The Ability of Versican to Simultaneously Cause Apoptotic Resistance and Sensitivity

We conducted a phase II clinical trial to develop an autologous EBV-specific T cell product (baltaleucel T) for advanced, relapsed ENKTL. Among 47 patients who provided whole blood starting material for manufacturing the product, 15 patients received a median of 4 doses of baltaleucel T. Thirty-two (68%) patients did not receive baltaleucel-T due to manufacturing failure, rapid disease progression, and death. Of the 15 patients, 10 patients had measurable disease at baseline (salvage cohort), and 5 patients had no disease at baseline assessment (adjuvant cohort). In the 15 patients, the median follow-up duration was 10.2 months (range 2.0–23.5 months), median progression-free survival (PFS) was 3.9 months, and the median overall survival (OS) was not reached. Patients in the salvage cohort achieved a 30% complete response (CR) and a 50% overall response rate (ORR). In the adjuvant cohort, disease progression was reported in three patients and two patients did not relapse during study follow-up. When we compared survival outcomes of seven responders and eight non-responders, the PFS (P = 0.001) and OS (P = 0.014) of responders proved statistically superior to that of non-responders. Baltaleucel-T was well tolerated. We have performed a phase II clinical trial of autologous EBV-specific T cell treatment (baltaleucel-T) in R/R ENKTL. Autologous EBV-specific T cells were well tolerated and demonstrated single-agent activity in R/R ENTKL.

This paper examines the role of ethical leadership in managing purchasing agents’ unethical practices. By focusing on the manager-purchasing agent relationship within a firm's purchasing function, we investigate the effect of the manager's ethical leadership on purchasing agents’ unethical behaviors, and explore the moderating role of purchasing agents’ ethical ideology in this relationship. Our scenario-based experiment and survey-based empirical study show that a manager's ethical leadership in a purchasing team plays a critical role in reducing purchasing agents’ unethical behaviors. More importantly, the results reveal that the negative impact of ethical leadership on unethical behaviors is strengthened when the level of purchasing agents’ idealism or relativism is high. In addition, we found that ethical leadership has the strongest negative effect on the unethical behavior of purchasing agents when the agents have high levels of both idealism and relativism.

Purpose Transforming growth factor-β (TGF-β) production in the tumor microenvironment is a potent and ubiquitous tumor immune evasion mechanism that inhibits the expansion and function of tumor-directed responses; therefore, we conducted a clinical study to discover the effects of the forced expression of a dominant-negative TGF-β receptor type 2 (DNRII) on the safety, survival, and activity of infused tumor-directed T cells. Materials and Methods In a dose escalation study, eight patients with Epstein Barr virus-positive Hodgkin lymphoma received two to 12 doses of between 2 × 107 and 1.5 × 108 cells/m2 of DNRII-expressing T cells with specificity for the Epstein Barr virus-derived tumor antigens, latent membrane protein (LMP)-1 and LMP-2 (DNRII-LSTs). Lymphodepleting chemotherapy was not used before infusion. Results DNRII-LSTs were resistant to otherwise inhibitory concentrations of TGF-β in vitro and retained their tumor antigen-specific activity. After infusion, the signal from transgenic T cells in peripheral blood increased up to 100-fold as measured by quantitative polymerase chain reaction for the transgene, with a corresponding increase in the frequency of functional LMP-specific T cells. Expansion was not associated with any acute or long-term toxicity. DNRII-LSTs persisted for up to ≥ 4 years. Four of the seven evaluable patients with active disease achieved clinical responses that were complete and ongoing in two patients at > 4 years, including in one patient who achieved only a partial response to unmodified tumor-directed T cells. Conclusion TGF-β-resistant tumor-specific T cells safely expand and persist in patients with Hodgkin lymphoma without lymphodepleting chemotherapy before infusion. DNRII-LSTs can induce complete responses even in patients with resistant disease. Expression of DNRII may be useful for the many other tumors that exploit this potent immune evasion mechanism.

Introduction: Extranodal NK/T-cell lymphoma (ENKTL) is a rare lymphoma that is highly associated with EBV expression and an aggressive course in advanced stages. Standard treatment for advanced disease involves multiagent asparaginase based regimens. However, this treatment is often toxic and relapses are common; hence there is an unmet medical need. We are presenting early results from a global phase 2 open label study, CITADEL (NCT01948180), that investigates the safety and efficacy of autologous EBV-specific T cells (CMD-003) for the treatment of aggressive ENKTL.

This article investigates the effects of National Football League (NFL) games on crime. Using a panel data set that includes daily crime incidences in eight large cities with NFL teams, we examine how various measurements of criminal activities change on game day compared with nongame days. Our findings from both ordinary least squares and negative binomial regressions indicate that NFL home games are associated with a 2.6% increase in total crimes, while financially motivated crimes such as larceny and motor vehicle theft increase by 4.1% and 6.7%, respectively, on game days. However, we observe that play-off games are associated with a decrease in financially motivated crimes. The effects of game time (afternoon vs. evening) and upset wins and losses on crime are also considered.

In globalised and uncertain business environments, many firms have turned their attention to logistics in order to make their business processes more efficient and cost-effective. In this paper, we identify critical factors that affect logistics performance at the macro level by surveying current literature. The factors include industrial policy priorities, strategic infrastructure development, public-private logistics market growth, and communication network configurations. We also compare the logistics of three East Asian countries (China, Japan, and Korea), using relevant macro-level data. These three countries are increasingly important in global logistics with their aggregate GDP accounting for approximately 21% of the world GDP. Finally, to facilitate future research, we offer eight propositions regarding relationships among critical factors and logistics outcomes. Critical issues facing the three nations' logistics industries are also discussed.

This study uses a large data set to analyze and predict recidivism of juvenile offenders in Pennsylvania. We employ a split-population duration model to determine the effect of covariates on (1) the probability of failure, defined as a second referral to juvenile court, and (2) the time to failure, given that it occurs. A test of the predictive power of our estimates finds a false positive rate of 18.5% and a false negative rate of 20.7%, which compares favorably to the performance of other models in the literature.

Abstract Breast cancer stem–like cells (BCSC) have been implicated in tumor growth, metastasis, drug resistance, and relapse but druggable targets in appropriate subsets of this cell population have yet to be identified. Here we identify a fundamental role for the prolyl isomerase Pin1 in driving BCSC expansion, invasiveness, and tumorigenicity, defining it as a key target of miR200c, which is known to be a critical regulator in BCSC. Pin1 overexpression expanded the growth and tumorigenicity of BCSC and triggered epithelial–mesenchymal transition. Conversely, genetic or pharmacological inhibition of Pin1 reduced the abundance and self-renewal activity of BCSC. Moreover, moderate overexpression of miR200c-resistant Pin1 rescued the BCSC defect in miR200c-expressing cells. Genetic deletion of Pin1 also decreased the abundance and repopulating capability of normal mouse mammary stem cells. In human cells, freshly isolated from reduction mammoplasty tissues, Pin1 overexpression endowed BCSC traits to normal breast epithelial cells, expanding both luminal and basal/myoepithelial lineages in these cells. In contrast, Pin1 silencing in primary breast cancer cells freshly isolated from clinical samples inhibited the expansion, self-renewal activity, and tumorigenesis of BCSC in vitro and in vivo. Overall, our work demonstrated that Pin1 is a pivotal regulator acting downstream of miR200c to drive BCSC and breast tumorigenicity, highlighting a new therapeutic target to eradicate BCSC. Cancer Res; 74(13); 3603–16. ©2014 AACR.

Adoptive transfer of primary T cells genetically modified to have desired specificity can exert an anti-tumor response in some patients. To improve our understanding of their therapeutic potential we have developed a clinically-appealing approach to reveal their in vivo biodistribution using nanoparticles that serve as a radiotracer for imaging by positron emission tomography (PET). T cells electroporated with DNA plasmids from the Sleeping Beauty transposon-transposase system to co-express a chimeric antigen receptor (CAR) specific for CD19 and Firefly luciferase (ffLuc) were propagated on CD19(+) K562-derived artificial antigen presenting cells. The approach to generating our clinical-grade CAR(+) T cells was adapted for electro-transfer of gold nanoparticles (GNPs) functionalized with (64)Cu(2+) using the macrocyclic chelator (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTA) and polyethyleneglycol (GNP-(64)Cu/PEG2000). MicroPET/CT was used to visualize CAR(+)EGFPffLucHyTK(+)GNP-(64)Cu/PEG2000(+) T cells and correlated with bioluminescence imaging. These data demonstrate that GNPs conjugated with (64)Cu(2+) can be prepared as a radiotracer for PET and used to image T cells using an approach that has translational implications.

This study investigates the educational attainment of children of immigrants in the United States. By employing a more detailed classification of children of immigrants, we examine whether a foreign place of birth of either parent or child affects the child's educational attainment. Our results indicate that the full-second generation (U.S.-born children with both foreign-born parents) achieves the highest educational attainment, while the full-first generation (foreign-born children with both foreign-born parents) achieves the second highest educational attainment compared to the other groups of children of immigrants and native children. Full-first and full-second generation females also achieve higher educational attainment than their native female peers. The results support the optimism theory of assimilation in which the educational attainment of children of immigrants relies on the combination of their foreign-born parents' strong values on education and the children's English proficiency. (C) 2013 Elsevier Ltd. All rights reserved.

Due to an altered expression of oncogenic factors and tumor suppressors, aggressive cancer cells have an intrinsic or acquired resistance to chemotherapeutic agents. This typically contributes to cancer recurrence after chemotherapy. microRNAs are short non-coding RNAs that are involved in both cell self-renewal and cancer development. Here we report that tumor cells transfected with miR-378 acquired properties of aggressive cancer cells. Overexpression of miR-378 enhanced both cell survival and colony formation, and contributed to multiple drug resistance. Higher concentrations of chemotherapeutic drugs were needed to induce death of miR-378-transfected cells than to induce death of control cells. We found that the biologically active component isolated from Ganoderma lucidum could overcome the drug-resistance conferred by miR-378. We purified and identified the biologically active component of Ganoderma lucidum as ergosterol peroxide. We demonstrated that ergosterol peroxide produced greater activity in inducing death of miR-378 cells than the GFP cells. Lower concentrations of ergosterol peroxide were needed to induce death of the miR-378-transfected cells than in the control cells. With further clinical development, ergosterol peroxide represents a promising new reagent that can overcome the drug-resistance of tumor cells.

OBJECTIVE. A theranostic system integrates some form of diagnostic testing to determine the presence of a molecular target for which a specific drug is intended. Molecular imaging serves this diagnostic function and provides powerful means for noninvasively detecting disease. We briefly review the paradigms rooted in nuclear medicine and highlight recent advances in this field. We also explore how nanometer-sized complexes, called nanomedicines, present an excellent theranostic platform applicable to both drug discovery and clinical use.CONCLUSION. For imagers, molecular theranostics represents a powerful emerging platform that intimately couples targeted therapeatic entities with noninvasive imaging that yields information on the presence of defined molecular targets before, during, and after cognate therapy.

Recent advances in the study of microRNAs indicate that they have an important role in regulating cellular activities such as proliferation, morphogenesis, apoptosis and differentiation by regulating the expression of various genes. MiR-199a-3p is highly expressed in hair follicles and in some tumor cells, suggesting its participation in tumor progression, but it is significantly underexpressed in hepatocellular carcinoma and in bladder cancer. The mechanism underlying these effects is not yet known. Here, we dissect the effects of miR-199a-3p on YPEN-1 endothelial cells, and MDA-MB-231 and MT-1 breast cancer cell lines. We found that expression of miR-199a-3p promotes proliferation and survival of endothelial cells as well as breast cancer cells. Remarkably, miR-199a-3p inhibited both endogenous caveolin-2 activity and exogenous caveolin-2 activity, which was confirmed by a reporter construct bearing the 3′-untranslated region of caveolin-2. However, overexpression of caveolin-2 completely counteracted the enhancement of miR-199a-3p-mediated activities on cell proliferation, survival and sensitivity of tumor cells to anticancer drugs. Our findings suggest that MiR-199a-3p targeting of caveolin-2 might have an important role in breast cancer tumor progression, making it a potential candidate for intervention in cancer.

BACKGROUND:Mature microRNAs (miRNAs) are single-stranded RNAs that regulate post-transcriptional gene expression. In our previous study, we have shown that versican 3'UTR, a fragment of non-coding transcript, has the ability to antagonize miR-199a-3p function thereby regulating expression of the matrix proteins versican and fibronectin, and thus resulting in enhanced cell-cell adhesion and organ adhesion. However, the impact of this non-coding fragment on tumorigenesis is yet to be determined. METHODS AND FINDINGS:Using computational prediction confirmed with in vitro and in vivo experiments, we report that the expression of versican 3'UTR not only antagonizes miR-199a-3p but can also lower its steady state expression. We found that expression of versican 3'UTR in a mouse breast carcinoma cell line, 4T1, decreased miR-199a-3p levels. The decrease in miRNA activity consequently translated into differences in tumor growth. Computational analysis indicated that both miR-199a-3p and miR-144 targeted a cell cycle regulator, Rb1. In addition, miR-144 and miR-136, which have also been shown to interact with versican 3'UTR, was found to target PTEN. Expression of Rb1 and PTEN were up-regulated synergistically in vitro and in vivo, suggesting that the 3'UTR binds and modulates miRNA activities, freeing Rb1 and PTEN mRNAs for translation. In tumor formation assays, cells transfected with the 3'UTR formed smaller tumors compared with cells transfected with a control vector. CONCLUSION:Our results demonstrated that a 3'UTR fragment can be used to modulate miRNA functions. Our study also suggests that miRNAs in the cancer cells are more susceptible to degradation, due to its interaction with a non-coding 3'UTR. This non-coding component of mRNA may be used retrospectively to modulate miRNA activities.

To probe the in vivo role of stress response factors in normal physiology and in solid tumors we have designed a stable (18)F-labeled molecular imaging agent based on a ligand for heat shock protein 70 (HSP70). We describe the synthesis of [(18)F] fluorodeoxymethylspergualin ([(18)F]MeDSG) as a new radiopharmaceutical probe using a prosthetic group, [(18)F]SFB, for efficient and rapid radiolabeling. Ongoing molecular imaging studies are under way to detect HSP70 expression in tumors by positron emission tomography.