text:
Current approaches to increase CAR T cell potency in solid tumors: targeting the tumor microenvironment
- Irene Scarfò1 and
- Marcela V. Maus1Email author
DOI: 10.1186/s40425-017-0230-9
© The Author(s). 2017
Received: 13 November 2016
Accepted: 24 February 2017
Published: 21 March 2017
Chimeric antigen receptor (CAR) T-cell therapy represents a revolutionary treatment for haematological malignancies (i.e. B-ALL). However, the success of this type of treatment has not yet been achieved in solid tumors. One hypothesis is that the immunosuppressive nature of the tumor microenvironment (TME) influences and affects the efficacy of adoptive immunotherapy. Understanding the role of the TME and its interaction with CAR T-cells is crucial to improve the potency of adoptive immunotherapy. In this review, we discuss the strategies and potential combinatorial approaches recently developed in mouse models to enhance the efficacy of CAR T-cells, with particular emphasis on the translational potential of these approaches.
KeywordsChimeric antigen receptor T-cells Adoptive immunotherapy Tumor microenvironment
The complex and heterogeneous tumor microenvironment plays an essential role in tumor initiation progression and therapeutic resistance. Recent studies have highlighted the importance of innate immune activation for the generation of spontaneous T cell responses to tumor-associated antigens and anti anti-tumor activity Woo and colleagues showed that type I IFN-mediated activation of the STING pathway of cytosolic DNA sensing is one of the major players in sustaining a T cell inflamed-tumor phenotype which represents a favorable marker of responsiveness to immunotherapies [14]. Activation of the STING pathway contributes to activation of Batf3 dendritic cells, which appear to be central to anti-tumor immunity. These orchestrating dendritic cells are recruited by chemokines to the tumor site, then migrate to the secondary lymphatic organs and interact with CD8+ T cells. After clonal expantion, the T cells can migrate back to the tumor microenvironment and carry out their effector functions against tumor cells [15]. Although a thorough evaluation of innate immune activators and an inflamed-tumor microenvironment in the setting of CAR T-cells has yet to be investigated, the role of the tumor microenvironment in modulating efficacy of CAR-T cells is expected to be significant at the level of effector T cell function if not antigen presentation. Furthermore, the degree of intra-tumoral expansion and persistence that is required for clinical efficacy has not been determined for solid tumors. In this review, we discuss various aspects of the tumor microenvironment that could inhibit the efficacy of immune responses, and some of the approaches recently developed to reprogram the tumor microenvironment in order to enhance the efficacy of CAR T-cell therapy; some of these may also serve to enhance tumor sensitivity to other forms of immunotherapy. Indeed although the focus of this review is on CAR T cells, many of the principles herein discussed apply to and have been elucidated from studies of adoptive cell therapy more broadly, including tumor infiltrating lymphocytes (TILs) and TCR-engineered T cells [16–18].
Targeting hypoxia, nutrient starvation, and metabolism
Hypoxia and nutrient starvation are major hallmarks of the tumor microenvironment [19]. The lack of nutrients, particularly amino acids such as tryptophan, is able to activate the integrated stress response which regulates T-cell activity [20]. Indoleamine 2,3 dioxygenase (IDO) is an intracellular enzyme which catalyzes the degradation of tryptophan to kynurenine. Both tumor cells and myeloid cells within the tumor microenvironment can express IDO, leading to a block in the proliferation and survival of T-cells. Recently, Ninomiya and colleagues [21] demonstrated that IDO expression can also inhibit CAR T cells. In particular, they showed that CD19 CAR T-cells fail to control progression of CD19+ IDO-expressing tumors. The accumulation of kynurenine inhibited expansion, cytotoxicity and cytokine secretion of CAR T-cells, suggesting a plausible mechanism underlying the resistance of IDO positive tumors to this type of treatment. Interestingly, they demonstrated that fludarabine and cyclophosphamide administration improved the efficacy of CAR T-cells by decreasing the expression of IDO. The combination of CAR T-cells and IDO inhibitors may represent a valuable option for malignancies resistant to chemotherapy and immunotherapy.
Moreover it is possible that metabolic stress in the tumor environment is able to modulate T cell metabolism, differentiation and effector functions. Indeed, tumor infiltrating lymphocytes modify their metabolism as a response to hypoxia, which is characteristic of solid tumors [22]. Interestingly, it has been demonstrated that CAR T-cells with different costimulatory domains utilize distinct metabolic pathways, which in turn reflect variable persistence within the tumor microenvironment [23]. Kawalekar and colleagues showed that 4-1BB CAR T-cells had increased mitochondrial biogenesis, which prompted a central memory phenotype and led to a survival advantage compared to CAR T cells with the CD28 signaling domain. In contrast, CD28-CAR T-cells yielded effector memory phenotype and enhanced glycolysis. This study highlighted the significance of the design of engineered T-cells with regard to their survival and exhaustion in the immunosuppressive tumor microenvironment.
Altering metabolic components within the tumor microenvironment is only one possibility for maximizing the potential of CAR T cells. In a more recent study Newick and colleagues [24] demonstrated similar findings by inhibiting protein kinase A (PKA) activation. PKA is the downstream effector of two other immunosuppressive factors produced within the tumor microenvironment: prostaglandin E2 (PGE2) and adenosine. Different studies have reported the role of these two molecules as potent inhibitors of T-cell proliferation and activity [25, 26]. The authors disrupted PKA anchorage to the lipid rafts by expressing RIAD (regulatory subunit I anchoring disruptor) peptide. This peptide is able to displace the association between PKA and ezrin, a protein necessary to tethering PKA close to adenylyl cyclase. Mesothelin-directed CAR-RIAD T-cells exhibited higher infiltration, persistence and antitumor activity in vivo compared to mesothelin-directed CAR T-cells. Moreover, the expression of RIAD led to an increased chemotaxis, guided by an induction of CXCR3 expression, and to better adhesion. As this approach is translated to clinical trials, the immunogenicity of the peptide may become an issue.
Another way to reprogram the tumor microenvironment is to augment the antitumor response of CAR T-cells by facilitating the recruitment of an endogenous immune response. This approach was validated by Curran and colleagues [27] through the constitutive expression of CD40L by CAR T-cells. They demonstrated that this strategy improves CAR T-cell cytotoxicity, decreases expression of PD-1, and improves DC antigen presentation function in a systemic model of CD40 positive follicular lymphoma. These mechanisms are likely to be synergistic with the STING pathways described by Gajewski and colleagues (as above).
Thus targeting tumor immunosuppressive populations such as PGE2 and/or T-cells response to the altered microenvironment represents an exciting opportunity to increase the efficacy of immunotherapy.
Targeting stroma
Enhancing the efficacy of anti-tumor immune therapies could also be accomplished by targeting the non-malignant cancer-associated stromal cells (CASCs). These cells secrete growth factors, cytokines, and chemokines that promote tumor growth, metastasis and angiogenesis. One attractive stromal candidate is the fibroblast activation protein (FAP), a serine protease implicated in extracellular matrix remodeling and selectively expressed by CASCs in over 90% of epithelial cancers [28]. Three different groups have described the use of anti-FAP CAR T-cells with some contrasting results. Tran and colleagues [29] showed that despite anti-FAP CARs displaying specific degranulation and production of effector cytokines in response to antigen stimulation in vitro, they didn't mediate an efficient antitumor response in vivo, and unexpectedly and alarmingly, anti-FAP CARs caused severe cachexia and lethal bone toxicities. The authors found that FAP protein is also expressed by multipotent bone marrow stromal cells (BMSCs) and related the observed toxicity to this expression. However, Kakarla and colleagues [30] using a FAP-CAR with a different scFv demonstrated antitumor efficacy without toxicities in a mouse model of human lung cancer. Even if T-cell persistence was limited, an improved response was achieved by co-injecting FAP-specific and tumor-specific T-cells. Schuberth and colleagues [31] developed an intra-peritoneal model for the adoptive transfer of FAP-CARs in a mesothelioma xenograft. Their data showed an increased survival; however, their anti-human FAP scFv did not have cross-reactivity with mouse FAP, which limited their ability to evaluate the on-target/off-tumor toxicity. A paper by Wang and colleagues [32] suggested that targeting FAP positive cells enhanced antitumor immunity via epitope spreading. They showed activation of endogenous CD4+ T-cells after three days of anti-FAP CAR treatment in an immune-competent syngeneic mouse model of mesothelioma and lung cancer. CD4+ activation was followed by a later augmentation of endogenous CD69+, INFγ + CD8+ T-cell infiltration. This antitumor response did not occur in immunodeficient mice, supporting the importance of the adaptive immune system. In another publication, the same group underlined the relevance of FAP inhibition by showing it also had an immune-independent antitumor effect. Using a weakly immunogenic and highly desmoplastic tumor, pancreatic ductal adenocarcinoma, Lo and colleagues [33] demonstrated that FAP-CAR T-cells inhibited tumor stromagenesis, reduced tumor vascular density and disrupted spatial orientation of tumor cells.
The safety concerns generated by the work of Rosenberg et al. [29] may be related to the specificity and affinity of the scFv, given that the last two studies with CAR T cells with different scFvs that recognize highly positive FAP cells, have been reassuring. Given the potential for multi-modal anti-tumor effects of FAP targeting, rational and interesting combinations for future immunotherapeutic approaches include anti-stroma CAR T-cells with either anti-tumor CAR T-cells or checkpoint blockade.
Beyond targeting FAP, another recent strategy for using CAR T cells in stroma-rich tumors is to target the enzyme heparanase (HPSE). This enzyme is responsible of the degradation of the heparan sulfate proteoglycans (HPGs), a fundamental process for the trafficking and accumulation of T-cells to the tumor site. Caruana and colleagues [34] demonstrated that CAR T-cells lose the expression of HSPE during their manufacturing process. This phenomenon leads to an impaired ability to degrade the extracellular matrix, suggesting a compromise in migration capacity. The authors showed that the induction of HSPE expression enhanced tumor infiltration and improved survival in neuroblastoma xenograft models.
Targeting cytokine networks
Another potential option for shaping the tumor microenvironment to enhance ACT efficacy is to induce the local release of stimulatory factors that promote anti-tumor immune responses. In this context interleukin-12 (IL-12) and IL-18 represent promising candidates. In particular, IL-12 is an inflammatory cytokine, able to improve T-cell activation and induce a Th1 CD4+ T-cell response, CD8+ clonal expansion, and effector function. It is also able to recruit NK cells to the tumor site, reactivate anergic tumor-infiltrating lymphocytes (TILs), inhibit regulatory T-cells and the secretion of IL-10, IL-4 and trasforming growth factor beta (TGFβ) by tumor associated macrophages [35–39]. Starting from these considerations, several groups devised the "fourth generation" CAR T-cells combining IL-12 secretion with CAR expression. Koneru and colleagues [40] used the so called T-cells redirected for universal cytokine-mediated killing (TRUCK) to treat an orthotropic ovarian tumorgraft model. They showed complete eradication of tumor, prolonged persistence of CAR T-cells and higher systemic IFNγ levels. In order to increase the safety and reduce undesired toxicities that could be generated by constitutive, systemic high levels of IL-12, which have been toxic in clinical trials [41], they developed a tricistronic vector that encodes the scFv specific for MUC-16ecto antigen, IL-12 and the truncated EGFR elimination gene (EGFRt) and administered it locally. Peritoneal administration of CAR T-cells was significantly more effective compared with intra-venous administration. This paper paved the way for a phase I clinical trial in platinum-resistant ovarian cancer patients, which will determine the safety and feasibility of this approach [42]. The production and release of a transgenic payload in a CAR should minimize toxicities in addition the "switch-off" system such as the EGFRt provides an additional measure of control for safety.
Furthermore IL-12 expression has proved to be important for the generation and efficacy of CAR T-cells from the umbilical cord blood (UCB). Pegram and colleagues [43] described a novel technique to expand and genetically modify UCB T-cells. First, they demonstrated that adding IL-12 and IL-15 to the cultured activated UCB T-cells led to a 150-fold expansion of this population, which showed an ideal phenotype expressing both memory and effector markers. Second, including the expression of IL-12 in the anti-CD19 CAR vector resulted in a significant increase in survival of mice bearing acute lymphoblastic leukemia (ALL), without the need for pretreatment or Il-2 support. These data support the clinical translation of using ACT to further boost the graft-versus-leukemia effect in UCB-transplanted patients with high-risk, relapsed/refractory ALL.
Another feasibile strategy to modulate tumor microenvironment signalling is to directly inhibit TGFβ, IL-10, and/or IL-4 signaling. The secretion of the first molecule by cancer cells and cancer associated cells is a well know mechanism of tumor evasion, and IL-10 as well as IL-4 are potent immunosuppressive cytokines. One approach is to force the overexpression of a dominant negative form of the receptor on T cells. Zhang and colleagues [44] demonstrated an increased antitumor efficacy in vitro and in vivo of T cells overexpressing TGFβ DNRII in a melanoma tumor model. Despite the promising results, further studies have to be done in orther to validate this approach in the context of CAR T-cell therapy. An additional recent system developed by Mohammed and colleagues [45] for the treatment of prostate cancer, a tumor characterized by elevated IL-4 levels, consists in an inverted cytokine receptor (ICR). Specifically, this 4/7 ICR is formed by the extracellular domain of the inhibitory IL-4 receptor linked to the intracellular immunostimulatory domain of IL-7. The co-expression of anti-PSCA first generation CAR vector and ICR resulted in an increased in vitro and in vivo antitumor activity. This approach transforms an inhibitory signal for T cells into a stimulatory one and at the same time deprives cancer cells of an important growth factor. The combination of a second generation CAR with 4/7 ICR could be evaluated to improve on these results.
Targeting immune checkpoints
A major mechanism through which the tumor-microenvironment exerts its immune-inhibition is inducing the upregulation of surface inhibitory receptors such as cytotoxic T-lymphocyte-associate protein 4 (CTLA-4) and programmed death-1 (PD-1). These molecules are naturally upregulated after antigen-receptor engagement to dampen T-cell activation within tissues and maintain peripheral tolerance. A better understanding of the activation of these intrinsic inhibitory pathways by the tumor-microenvironment led to the success of immune checkpoint therapies [46]. Furthermore recent studies have uncovered the critical role of PD-1 in human CAR T-cell exhaustion. John and colleagues [47] published the first proof-of-concept study that CAR T-cells express PD-1 and are susceptible to PD-1 mediated suppression. The authors showed an improvement in antitumor activity when Her2+ tumor-bearing mice were treated with a combination of CAR T-cells and anti PD-1 antibody. Interestingly, the marked tumor regression was accompanied by a decrease of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment. However, the mechanism of increased antitumor activity and role of the modulation of the MDSCs remain to be proven. A later study by Moon and colleagues [48] confirmed an augmented expression of PD-1 on CAR TILs which correlated with their hypofunction in a mesothelioma model. By blocking PD-1, they restored mesothelin-directed CAR T cell cytotoxicity in vitro. Beyond administering immune checkpoint antibodies, an alternative way of blocking immune checkpoints is to use genetic engineering strategies. For example, Liu and colleagues [49] inserted the PD1:CD28 switch-receptor into CAR vectors. This receptor was developed by Prosser et al [50] and it is engineered to express the extracellular domain of PD1 fused to the transmembrane and signaling domains of CD28; this construct could function as a dominant negative by competing with endogenous PD1 and/or could actively signal through the cytoplasmic domain after PD-L1 binding. The authors performed an analysis of effector functions of PD1:CD28 CAR T-cells injected intravenously to treat large, established, solid tumor including mesothelioma and prostate cancer in xenograft models. They reported a significant increase of the frequency of CAR TILs both in tumors and in peripheral blood, a greater ex vivo antitumor function, and more cytokine secretion. Of interest, the employment of a switch-receptor with a mutant signaling domain abrogated these results, suggesting a central role for the CD28 costimulatory domain in the fusion construct. Conversely, Cherkassky et al [51] demonstrated that combining CAR T-cells with the expression of a "dominant negative" form of PD-1 led to higher persistence, increased antitumor effects and prolonged survival in a mesothelioma xenograft model. The "dominant negative" form of PD1 in this model was composed of the only the extracellular domain of PD1 (without a signaling domain), which would presumably compete with endogenous PD1 for ligating PD-L1. One explanation for these divergent results could be the different type of tumor treated. Moreover, Cherkassky and colleagues showed that CAR T-cells with 4-IBB costimulatory domain were able to function at lower doses compared to CAR T cells that included CD28 signaling domains, and 4-1BB-signaling CARs were more resistant to PD-1 mediated exhaustion.
Additional tumor models are necessary to show that PD-1-mediated CAR T-cell suppression is a general inhibitory mechanism, particularly immunocompetent mouse models. It will be also important to understand the role of the costimulatory domains embedded into CARs and their differential mechanisms in mediating resistance to inhibitory molecules and inducers of CAR T-cell exhaustion. Even if the safest and most efficacius checkpoint combinations have yet to be identified [52], altogether these pre-clinical data provide supportive evidence that combining immune checkpoint blockade with CAR T-cells is a logical therapeutic strategy to improve the clinical outcome of CAR T-cell therapy in patients.
Adoptive cell therapy using CAR T-cells has demonstrated impressive therapeutic potential for the treatment of certain B cell malignancies. Even though there have been recent exciting publications using TIL therapy targeting mutant KRAS metastatic colorectal cancer [53] and IL13Rα2-targeted CAR T cells in glioblastoma multiforme [54], results in solid malignancies may be subject to various limitations, including the immunosuppressive tumor microenvironment. Indeed, the microenvironment non only creates a physical barrier decreasing the penetration of modified T-cells into the tumor mass, but also plays an active role in immune suppression through the up regulation of inhibitory signals. Innovative strategies have been developed to overcome these challenges (Fig. 2), including co-administration of CAR T cells with checkpoint blockade, and co-administration with other drugs, therapies, and CAR T cells that target the tumor stroma and immunosuppressive molecules. Many of these strategies have been tested in xenograft and syngeneic mouse models, and clinical trials of these combinations are warranted and eagerly awaited. Pre-clinical experiments will define rational combinations of these approaches, based on a deeper understanding of the unique tumor characteristics and interplay among immune cells and the tumor environment. Translating the optimal combinations is likely to require iterative clinical trials to determine the safest and most effective combinations for patients with solid tumors.
Adoptive cell therapy
B-cells acute lymphoblastic leukemia
- BMSCs:
Bone marrow stromal cells
Chimeric antigen receptor
- CASCs:
Cancer-associated stromal cells
Cluster of differentiation
CD40 ligand
Cytotoxic T-lymphocyte-associate protein 4
C-X-C motif chemokine receptor
Dendritic cell
- EGFRt:
Truncated epidermal growth factor receptor
Fibroblast activation protein
Human leukocyte antigen
- HPGs:
Heparan sulfate proteoglycans
Indoleamine 2,3 dioxygenase
- Ig:
- INFγ:
Interferon gamma
Myeloid-derived suppressor cells
Major histocompatibility complex
Natural killer
Programmed death-1
PD-1 ligand
Prostaglandin E2
Protein kinase A
Regulatory subunit I anchoring disruptor
- scFv:
Single chain variable fragment
- TAAs:
Tumor-associated antigens
- TGFβ:
Trasforming growth factor beta
- TILs:
Tumor-infiltrating lymphocytes
Tumor microenvironment
T-cells redirected for universal cytokine-mediated killing
Umbilical cord blood
Irene Scarfò receives support from American-Italian Cancer Foundation Post-Doctoral Research Fellowship. Marcela Maus receives support from the NIH (NCI K08CA166039), the Gabrielle's Angel Foundation, and the V Foundation.
Irene Scarfò receives support from American-Italian Cancer Foundation Post-Doctoral Research Fellowship. Marcela Maus receives support from the NIH (NCI K08CA166039), the Gabrielle's Angel Foundation, and the V Foundation.
Availability of data and materials
Not applicable
Authors' contributions
IS and MVM wrote the manuscript. Both authors read and approved the final manuscript.
Competing interests
MVM is listed as an inventor on patents related to the use of T cell therapies; these patents are held by the University of Pennsylvania, and some of them are licensed to Novartis. None of these are relevant to this manuscript.
Consent for publication
Ethics approval and consent to participate
Not applicable
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Authors' Affiliations
- Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17.View ArticlePubMedPubMed CentralGoogle Scholar
- Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Med Sci Transl. 2015;7:303ra139.View ArticleGoogle Scholar
- Garfall AL, Maus MV, Hwang WT, Lacey SF, Mahnke YD, Melenhorst JJ, Zheng Z, Vogl DT, Cohen AD, Weiss BM, et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma. N Engl J Med. 2015;373:1040–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385:517–28.View ArticlePubMedGoogle Scholar
- Burns WR, Zheng Z, Rosenberg SA, Morgan RA. Lack of specific gamma-retroviral vector long terminal repeat promoter silencing in patients receiving genetically engineered lymphocytes and activation upon lymphocyte restimulation. Blood. 2009;114:2888–99.View ArticlePubMedPubMed CentralGoogle Scholar
- Frigault MJ, Lee J, Basil MC, Carpenito C, Motohashi S, Scholler J, Kawalekar OU, Guedan S, McGettigan SE, Posey Jr AD, et al. Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells. Cancer Immunol Res. 2015;3:356–67.View ArticlePubMedPubMed CentralGoogle Scholar
- Di Stasi A, De Angelis B, Rooney CM, Zhang L, Mahendravada A, Foster AE, Heslop HE, Brenner MK, Dotti G, Savoldo B. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood. 2009;113:6392–402.View ArticlePubMedPubMed CentralGoogle Scholar
- Craddock JA, Lu A, Bear A, Pule M, Brenner MK, Rooney CM, Foster AE. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J Immunother. 2010;33:780–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Peng W, Ye Y, Rabinovich BA, Liu C, Lou Y, Zhang M, Whittington M, Yang Y, Overwijk WW, Lizee G, Hwu P. Transduction of tumor-specific T cells with CXCR2 chemokine receptor improves migration to tumor and antitumor immune responses. Clin Cancer Res. 2010;16:5458–68.View ArticlePubMedPubMed CentralGoogle Scholar
- Moon EK, Carpenito C, Sun J, Wang LC, Kapoor V, Predina J, Powell Jr DJ, Riley JL, June CH, Albelda SM. Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor. Clin Cancer Res. 2011;17:4719–30.View ArticlePubMedPubMed CentralGoogle Scholar
- Beatty GL, O'Hara M. Chimeric antigen receptor-modified T cells for the treatment of solid tumors: defining the challenges and next steps. Pharmacol Ther. 2016;166:30–9.View ArticlePubMedGoogle Scholar
- Zhukovsky EA, Morse RJ, Maus MV. Bispecific antibodies and CARs: generalized immunotherapeutics harnessing T cell redirection. Curr Opin Immunol. 2016;40:24–35.View ArticlePubMedGoogle Scholar
- Gill S, Maus MV, Porter DL. Chimeric antigen receptor T cell therapy: 25 years in the making. Blood Rev. 2016;30:157–67.View ArticlePubMedGoogle Scholar
- Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MY, Duggan R, Wang Y, Barber GN, Fitzgerald KA, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014;41:830–42.View ArticlePubMedPubMed CentralGoogle Scholar
- Corrales L, Matson V, Flood B, Spranger S, Gajewski TF. Innate immune signaling and regulation in cancer immunotherapy. Cell Res. 2017;27:96–108.View ArticlePubMedGoogle Scholar
- Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, Rosenberg SA. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114:1537–44.View ArticlePubMedPubMed CentralGoogle Scholar
- Kerkar SP, Muranski P, Kaiser A, Boni A, Sanchez-Perez L, Yu Z, Palmer DC, Reger RN, Borman ZA, Zhang L, et al. Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. Cancer Res. 2010;70:6725–34.View ArticlePubMedPubMed CentralGoogle Scholar
- Chinnasamy C, St Clair Gibson A, Micklewright D. Effect of spatial and temporal cues on athletic pacing in schoolchildren. Med Sci Sports Exerc. 2013;45:395–402.View ArticlePubMedGoogle Scholar
- Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23:27–47.View ArticlePubMedPubMed CentralGoogle Scholar
- Howie D, Waldmann H, Cobbold S. Nutrient sensing via mTOR in T cells maintains a tolerogenic microenvironment. Front Immunol. 2014;5:409.View ArticlePubMedPubMed CentralGoogle Scholar
- Ninomiya S, Narala N, Huye L, Yagyu S, Savoldo B, Dotti G, Heslop HE, Brenner MK, Rooney CM, Ramos CA. Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs. Blood. 2015;125:3905–16.View ArticlePubMedPubMed CentralGoogle Scholar
- Zhang Y, Ertl HC. Starved and asphyxiated: how can CD8(+) T cells within a tumor microenvironment prevent tumor progression. Front Immunol. 2016;7:32.PubMedPubMed CentralGoogle Scholar
- Kawalekar OU, O'Connor RS, Fraietta JA, Guo L, McGettigan SE, Posey Jr AD, Patel PR, Guedan S, Scholler J, Keith B, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity. 2016;44:380–90.View ArticlePubMedGoogle Scholar
- Newick K, O'Brien S, Sun J, Kapoor V, Maceyko S, Lo A, Pure E, Moon E, Albelda SM. Augmentation of CAR T-cell trafficking and antitumor efficacy by blocking protein kinase a localization. Cancer Immunol Res. 2016;4:541–51.View ArticlePubMedGoogle Scholar
- Dannenberg AJ, Subbaramaiah K. Targeting cyclooxygenase-2 in human neoplasia: rationale and promise. Cancer Cell. 2003;4:431–6.View ArticlePubMedGoogle Scholar
- Sitkovsky MV, Lukashev D, Apasov S, Kojima H, Koshiba M, Caldwell C, Ohta A, Thiel M. Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol. 2004;22:657–82.View ArticlePubMedGoogle Scholar
- Curran KJ, Seinstra BA, Nikhamin Y, Yeh R, Usachenko Y, van Leeuwen DG, Purdon T, Pegram HJ, Brentjens RJ. Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression. Mol Ther. 2015;23:769–78.View ArticlePubMedPubMed CentralGoogle Scholar
- Garin-Chesa P, Old LJ, Rettig WJ. Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci U S A. 1990;87:7235–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Tran E, Chinnasamy D, Yu Z, Morgan RA, Lee CC, Restifo NP, Rosenberg SA. Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J Exp Med. 2013;210:1125–35.View ArticlePubMedPubMed CentralGoogle Scholar
- Kakarla S, Chow KK, Mata M, Shaffer DR, Song XT, Wu MF, Liu H, Wang LL, Rowley DR, Pfizenmaier K, Gottschalk S. Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Mol Ther. 2013;21:1611–20.View ArticlePubMedPubMed CentralGoogle Scholar
- Schuberth PC, Hagedorn C, Jensen SM, Gulati P, van den Broek M, Mischo A, Soltermann A, Jungel A, Marroquin Belaunzaran O, Stahel R, et al. Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells. J Transl Med. 2013;11:187.View ArticlePubMedPubMed CentralGoogle Scholar
- Wang LC, Lo A, Scholler J, Sun J, Majumdar RS, Kapoor V, Antzis M, Cotner CE, Johnson LA, Durham AC, et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res. 2014;2:154–66.View ArticlePubMedGoogle Scholar
- Lo A, Wang LC, Scholler J, Monslow J, Avery D, Newick K, O'Brien S, Evans RA, Bajor DJ, Clendenin C, et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res. 2015;75:2800–10.View ArticlePubMedPubMed CentralGoogle Scholar
- Caruana I, Savoldo B, Hoyos V, Weber G, Liu H, Kim ES, Ittmann MM, Marchetti D, Dotti G. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med. 2015;21:524–9.View ArticlePubMedPubMed CentralGoogle Scholar
- King IL, Segal BM. Cutting edge: IL-12 induces CD4 + CD25- T cell activation in the presence of T regulatory cells. J Immunol. 2005;175:641–5.View ArticlePubMedGoogle Scholar
- Steding CE, Wu ST, Zhang Y, Jeng MH, Elzey BD, Kao C. The role of interleukin-12 on modulating myeloid-derived suppressor cells, increasing overall survival and reducing metastasis. Immunology. 2011;133:221–38.View ArticlePubMedPubMed CentralGoogle Scholar
- Broderick L, Brooks SP, Takita H, Baer AN, Bernstein JM, Bankert RB. IL-12 reverses anergy to T cell receptor triggering in human lung tumor-associated memory T cells. Clin Immunol. 2006;118:159–69.View ArticlePubMedGoogle Scholar
- Kilinc MO, Aulakh KS, Nair RE, Jones SA, Alard P, Kosiewicz MM, Egilmez NK. Reversing tumor immune suppression with intratumoral IL-12: activation of tumor-associated T effector/memory cells, induction of T suppressor apoptosis, and infiltration of CD8+ T effectors. J Immunol. 2006;177:6962–73.View ArticlePubMedGoogle Scholar
- Watkins SK, Egilmez NK, Suttles J, Stout RD. IL-12 rapidly alters the functional profile of tumor-associated and tumor-infiltrating macrophages in vitro and in vivo. J Immunol. 2007;178:1357–62.View ArticlePubMedGoogle Scholar
- Koneru M, Purdon TJ, Spriggs D, Koneru S, Brentjens RJ. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Oncoimmunology. 2015;4:e994446.View ArticlePubMedPubMed CentralGoogle Scholar
- Leonard JP, Sherman ML, Fisher GL, Buchanan LJ, Larsen G, Atkins MB, Sosman JA, Dutcher JP, Vogelzang NJ, Ryan JL. Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production. Blood. 1997;90:2541–8.PubMedGoogle Scholar
- Koneru M, O'Cearbhaill R, Pendharkar S, Spriggs DR, Brentjens RJ. A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16(ecto) directed chimeric antigen receptors for recurrent ovarian cancer. J Transl Med. 2015;13:102.View ArticlePubMedPubMed CentralGoogle Scholar
- Pegram HJ, Purdon TJ, van Leeuwen DG, Curran KJ, Giralt SA, Barker JN, Brentjens RJ. IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia. Leukemia. 2015;29:415–22.View ArticlePubMedGoogle Scholar
- Zhang L, Yu Z, Muranski P, Palmer DC, Restifo NP, Rosenberg SA, Morgan RA. Inhibition of TGF-beta signaling in genetically engineered tumor antigen-reactive T cells significantly enhances tumor treatment efficacy. Gene Ther. 2013;20:575–80.View ArticlePubMedGoogle Scholar
- Mohammed S, Sukumaran S, Bajgain P, Watanabe N, Heslop HE, Rooney CM, Brenner MK, Fisher WE, Leen AM, Vera JF. Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer. Mol Ther. 2017;25:249–58.View ArticlePubMedGoogle Scholar
- Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27:450–61.View ArticlePubMedPubMed CentralGoogle Scholar
- John LB, Devaud C, Duong CP, Yong CS, Beavis PA, Haynes NM, Chow MT, Smyth MJ, Kershaw MH, Darcy PK. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res. 2013;19:5636–46.View ArticlePubMedGoogle Scholar
- Moon EK, Wang LC, Dolfi DV, Wilson CB, Ranganathan R, Sun J, Kapoor V, Scholler J, Pure E, Milone MC, et al. Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin Cancer Res. 2014;20:4262–73.View ArticlePubMedPubMed CentralGoogle Scholar
- Liu X, Ranganathan R, Jiang S, Fang C, Sun J, Kim S, Newick K, Lo A, June CH, Zhao Y, Moon EK. A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Res. 2016;76:1578–90.View ArticlePubMedGoogle Scholar
- Prosser ME, Brown CE, Shami AF, Forman SJ, Jensen MC. Tumor PD-L1 co-stimulates primary human CD8(+) cytotoxic T cells modified to express a PD1:CD28 chimeric receptor. Mol Immunol. 2012;51:263–72.View ArticlePubMedGoogle Scholar
- Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR, Sadelain M, Adusumilli PS. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016;126:3130–44.View ArticlePubMedPubMed CentralGoogle Scholar
- Khalil DN, Smith EL, Brentjens RJ, Wolchok JD. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol. 2016;13:394.View ArticlePubMedGoogle Scholar
- Tran E, Robbins PF, Lu YC, Prickett TD, Gartner JJ, Jia L, Pasetto A, Zheng Z, Ray S, Groh EM, et al. T-cell transfer therapy targeting mutant KRAS in cancer. N Engl J Med. 2016;375:2255–62.View ArticlePubMedGoogle Scholar
- Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, Ostberg JR, Blanchard MS, Kilpatrick J, Simpson J, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016;375:2561–9.View ArticlePubMedGoogle Scholar


text:
Liquor Reform
Liquor reform could be coming to Pennsylvania. The state house this week passed a package of four bill and sent them to the senate for their consideration. But for state representative David Millard... a Republican from Berwick... it's all about purchasing convenience. The fate of the four bills in the senate are unknown... but passage is expected.
Snyder Sentence
A Selinsgrove man will spend the next 80 months to 40 years in prison for the death of his wife in Snyder County. Kenneth Wochley of Selinsgrove pleaded no contest Thursday to third-degree murder in the death of his wife Ann last year. A no-contest plea means Wochley does not admit guilt but is sentenced as if he did.
Mother Sentenced
A mother accused of abusing her children has been sentenced to prison. Lourdes Rodriguez was sentenced to 10 to 20 years in prison after being convicted of aggravated assault for beating her 16-month-old daughter. Officers found the child bleeding and unresponsive at a home in West Hazleton in March of 2015. The sentence also reflects a guilty plea from Rodriguez for abusing her 3-year-old son
A state Senate committee has advanced legislation that aims to help infants of mothers who experience depression after giving birth. The bill would add postpartum depression to a list of conditions that babies and their mothers are screened for... which make the children eligible for early intervention services from the state. The screenings would be performed by ob/gyns and pediatricians during regular appointments. The American Psychological Association estimates 15 percent of all new mothers suffer from postpartum depression, which can result in neglect or abuse of the infant.
Berwick United Way
Hate it when your boss asks you where you want to be in the next five to ten years... well that's what the Berwick Area United Way is asking you in a survey. Executive Director Ginny Crake says the organizations mission is ever evolving. The Berwick Area United Way has sent out questionaairs over social media to get response... to gauge the public's vision.
PennDOT Secretary Leslie Richards went before the Senate Transportation Committee this week to outline the agency's 12 year plan. PennDOT's latest 12 year plan for which road, bridge or transit projects get funding runs through 2028, but is updated every two years. Thanks to the law known as ACT 89, Secretary Richards says they have about 20 billion dollars to work with over the next 4 years, but there's always a need for more. As a result, Richards says planners have to choose carefully, knowing that they can never start a project they don't intend to complete.
Animal Abuse
A bill cracking down on animal abuse was approved this week in the state House, now some lawmakers questioned certain provisions of the bill. The bill would impose stricter penalties for intentionally torturing an animal or neglect or abuse causing severe injury or death. The measure passed the House with only 20 no votes, but not before some lawmakers questioned certain provisions of the bill. Issues included whether someone could enter private property if they suspected an animal was in distress, and exactly what constitutes distress that could lead to criminal charges.
Shots Fired
Police in Wilkes-Barre are investigating gunfire this week. Investigators confirm shots were fired on South Grant Street late Wednesday night. They don't believe anyone was hit when those bullets started flying. No arrests have been made yet here in Wilkes-Barre.
Ignacio Beato
The former real estate agent from Hazleton accused of selling homes he didn't own to unsuspecting buyers has agreed to plead guilty in federal court. Ignacio Beato signed a deal Wednesday to plead guilty to a federal charge of wire fraud. Authorities say Beato cheated almost 20 people from the Hazleton area out of hundreds of thousands of dollars. They say he sold homes without having titles to those properties.
Road Rage
A road rage incident lead to gunfire and charges in Schuylkill County. Police say Kevin Donton from Tremont fired a shot at a vehicle on Route 61 near Frackville Wednesday morning. Investigators say there was an incident when the SUV Donton was riding in tried to merge. The other driver was not hit.

subset: commoncrawl


text:
20 I close em quick!
Asked by Truelove77 at 11:53 AM on Aug. 27, 2010 in Crazy for CreditsLevel 49 (341,585 Credits)
Answer by Codysmom2106 at 11:55 AM on Aug. 27, 2010
Next question in Crazy for Credits
15 votes who wants them just reply and bump
Next question overall
I AM HAVING A GIRL!!!!!! Getting ready for our party!!!!
Already Joined? LOG IN
© 2017 CMI Marketing, Inc. All rights reserved.


text:
You have Adblock enabled. Adblock has been known to cause issues with site functionality. If you experience any difficulties, please try disabling Adblock. Close
Add to Favorite List:
Create a new folder:
GF with big areolas plays with cock
Recognize a pornstar in this video?
Help make pornstars easier to find on Tube8 by telling us who is in this video.
Thanks! The pornstar names will be added to this video when enough users submit the same names.
You must enter a pornstar name that already exists in our database.
- Category: Amateur
- Views: 6,882
- Added: 5 years ago
- Description: Hot girlfriend with big areolas takes cock between her big tits
- Tags: busty, boobs, tits, breasts, handjob, blowjob, amateur
- Pornstars: Add Pornstar
- Favorite by: 6
- Report This Video


text:
Scandal ~ Season 5 - Episode 8 "Rasputin"
3 0 Beanie 0.0 12 November 2015
In the midst of Fitz negotiating a historic peace deal, Olivia must rely on her instincts when a guest of the The White House discloses powerful intel. Meanwhile, Jake uses Huck's help to get closer to his target, and Cyrus takes matters into his own hands when he realizes he's been shut out of the inner circle.
|Total Comments: 0
You May Also Like
Year: 2015
Language: English
Video runtime: 00:41:12


text:
Armin Van Buuren: A Year With Armin Van Buuren
eB3 350
Discovery Miles 3 350
Supplier out of stock
Hassle-Free Exchanges & Returns for 30 Days. Learn more
Documentary detailing a year in the life of the Dutch DJ Armin Van Buuren. Van Buuren is one of the world's top DJs, with his own music label, A State of Trance, and a hectic schedule of live performances which take him all around the world. The programme provides an insight into both his personal and professional life and the pressures of stardom.
- Rating
- Number of Discs
- 1
- Title
- Armin Van Buuren: A Year With Armin Van Buuren
- Country
- Barcode
- 8718522010774
- Studio
- Armada Music
- Year
- 0
- Running Time
- 0
Bundle deals expire when stock runs out. T&Cs apply
No reviews yet.


text:
Gilli Moon eBooks
eBooks found: 1
I AM A Professional Artist - the key to survival and success in the world of the arts - eBook
Gilli Moon
Warrior Girl Music, January 2005
Format: PDF
eBookMall is a recognized leader in eBooks. eBook downloads in PDF and ePub formats.
Choose from 600,000+ eBooks and get a Free eBook download now!
Copyright © 2000-2017 eBookMall.com This website is subject to copyright laws and may be covered by other intellectual property.
All rights reserved.


text:
|Message view
|« Date » · « Thread »
|« Date » · « Thread »
|"Okke Klein (Commented) (JIRA)" <j...@apache.org>
|[jira] [Commented] (SOLR-2993) Integrate WordBreakSpellChecker with Solr
|Sat, 07 Jan 2012 16:11:39 GMT
[ https://issues.apache.org/jira/browse/SOLR-2993?page=com.atlassian.jira.plugin.system.issuetabpanels:comment-tabpanel&focusedCommentId=13182013#comment-13182013 ] Okke Klein commented on SOLR-2993: ---------------------------------- If I am not mistaken the functionality from https://issues.apache.org/jira/browse/SOLR-2585 can also be achieved in DirectSolrSpellChecker with thresholdTokenFrequency parameter. So I patched trunk with this patch and the corresponding Lucene patch and did some experimenting. The misplaced whitespaces were fixed and proper suggestions were returned. However if both word parts resulted in suggestions, the collation made no sense. Hypothetical example: "spe llcheck" would give suggestions "spa" and "spellcheck" and collate this into "spa spellcheck" In my use case I never got any results back when one of the parts had a typo. So "spe llchek" would not give any suggestions. For my use case it would also be handy if "spell check" would result in the suggestion "spellcheck". Or is this already possible? > Integrate WordBreakSpellChecker with Solr > ----------------------------------------- > > Key: SOLR-2993 > URL: https://issues.apache.org/jira/browse/SOLR-2993 > Project: Solr > Issue Type: Improvement > Components: SolrCloud, spellchecker > Affects Versions: 4.0 > Reporter: James Dyer > Priority: Minor > Fix For: 4.0 > > Attachments: SOLR-2993.patch > > > A SpellCheckComponent enhancement, leveraging the WordBreakSpellChecker from LUCENE-3523: > - Detect spelling errors resulting from misplaced whitespace without the use of shingle-based dictionaries. > - Seamlessly integrate word-break suggestions with single-word spelling corrections from the existing FileBased-, IndexBased- or Direct- spell checkers. > - Provide collation support for word-break errors including cases where the user has a mix of single-word spelling errors and word-break errors in the same query. > - Provide shard support. -- This message is automatically generated by JIRA. If you think it was sent incorrectly, please contact your JIRA administrators: https://issues.apache.org/jira/secure/ContactAdministrators!default.jspa For more information on JIRA, see: http://www.atlassian.com/software/jira --------------------------------------------------------------------- To unsubscribe, e-mail: firstname.lastname@example.com For additional commands, e-mail: firstname.lastname@example.com
|View raw message


text:
GOV.UK uses cookies to make the site simpler. Find out more about cookies
Employment Tribunal Decision of Judge Porter on 14 February 2017.
Read the full decision in Mr T Cushion v Tangerine Confectionery Ltd: 2404090/2016.
Don't include personal or financial information like your National Insurance number or credit card details.


text:
Marmot Crux Jacket Women's
When an unexpected storm blows in on your hiking or backpacking trip, pull out the Marmot Women's Crux Jacket and keep putting trail behind you thanks to its ample ventilation and waterproof, breathable performance. Fully taped seams, an adjustable hood, and water resistant zippers all squash the rain's attempt to put a damper on your hike, while two underarm ventilation zippers and Marmot's Angel Wing Movement let you keep on trudging through the rain. Duralite zonal reinforcements prevent backpack straps from excessively wearing down the jacket, and the two zippered hand pockets are backpack compatible, so you don't lose any functionality when you're hiking with a pack.
|Regular Price
|$137.47 on sale
Copy the following string into an e-mail to email@example.com to request support.
CCBot/2.0 (http://commoncrawl.org/faq/)
Blog Feed
Follow on Twitter
Become a Facebook Fan
Similar Gear


text:
Socceroos go for beach run in Vitoria
The Socceroos go for a beach walk at Praca dos Desejos on May 29, 2014 in Vitoria, Brazil.
Topics: socceroos, soccer-world-cup, soccer, sport, brazil, australia
If you have inside knowledge of a topic in the news, contact the ABC.
This service may include material from Agence France-Presse (AFP), APTN, Reuters, AAP, CNN and the BBC World Service which is copyright and cannot be reproduced.
AEST = Australian Eastern Standard Time which is 10 hours ahead of UTC (Greenwich Mean Time)


text:
Course Description
Introduction to the theory of machine shop systems. Complexity results for various systems such as job, flow and open shops. Applications of linear programming, integer programming, network analysis. Enumerative methods for machine sequencing. Introduction to stochastic scheduling.
3 credits tenative course rotation: Spring, Alternate Years
Instructor Contact
Sigurdur Olafsson
Contact Us
Engineering-LAS Online Learning
2273 Howe Hall, Suite 1328
Ames, IA 50011-2273
Main Office: firstname.lastname@example.com
Technical Support: email@example.com
Curriculum Development: firstname.lastname@example.com


text:
This post may contain affiliate links. Read my disclosure policy here.
Wet n Wild Lipstick ONLY $0.43!
This week at Walmart, score a great deal on Wet n Wild Lipstick for ONLY $0.43! Follow this scenario. to grab this amazing deal:
Wet n Wild Lipstick – $0.93 (regular price)
Use the $0.50 Wet n Wild Coupon from the 3/5 SS
Final Cost: $0.43!
Never miss another deal! Subscribe to our FREE Newsletter. You can also follow us on Facebook, Twitter, Google+1, Instagram, or Pinterest. Thanks for stopping by!


text:
Sunshine Coast Fishing Charters if you're looking for a quick jaunt out on the water, the 5 Hour Deep Sea Fishing Charter Mooloolaba or Noosa is just the ticket for you. This is a great package for those more interested in seeing the water, and not so much the fish. The trained deckhands will help you bait your line, and settle your rod, letting you sit back and relax. You'll head about 8 nautical miles offshore, giving you a new perspective on the Sunshine Coast.
A better option for those who take their fishing seriously is the 7 Hour Deep Sea Fishing Charter Mooloolaba or Noosa. Both will have you out on the water nearly all day, and you'll be able to catch some great fish. These longer trips out will use a Cougar Cat thirty-two foot, wide-bodied boat. It holds up to 12 passengers and 2 crew members.
0 activities have been found
|Randomly sorted. Sort by: Activity Name | Area | Price


text:
Author has written 6 stories for Harry Potter, Yu Yu Hakusho, and Star Wars.
It has been a long time since I've visited Fanfiction.net. I have been a long-time member of this site, and my old FF.net account had a 4-digit ID.
Anyway, I have gone under several pennames in the past 15 years, and I have written a lot of stories prior to my retirement from active fanfiction-writing 5 years ago. Now, I'm mainly using this account to follow and subscribe to my favourite authors. Of course, I will be re-releasing all of my old(er) works. Who knows one day, I would be inspired enough to write again?
My old loves:
Yu Yu Hakusho
Rurouni Kenshin
Harry Potter
My current love:
Avatar: The Last Airbender -- yes, I'm a hardcore Zutara-shipper. :)


text:
Product Announcements and Updates
New Products Begin Arriving
- February 6: SMA Male to UHF Connector Cable. Finally we have a low-cost SMA connnector solution for the SDRplay RSP1, RSP2, RSP2pro software defined radios to connect to standard PL-259 antennas
- January 11: RGB LED Effects Controller. Low cost controller for RGB LED ribbons and displays
- January 9: Digital Temperature Gauge displays in degrees Celsius or Fahrenheit
- January 8: NeoPixel Strip with 8-LEDs based on the WS2812
- January 7: Developement breadboard for ESP8266 IOT wireless modules
- January 6: Heatsink for high power LEDs
- January 5: Pneumatic value with 6mm connectors
- 32 LED Love Heart: SOLD OUT – All components necessary to build an attractive 32-LED display
- 560 Piece – 56 Value Resistor Assortment: Assortment of common 1/4W resistors for your workbench.
- LED Rainbow: New stock – available in a kit or fully assembled
- Digital Temperature Meter: Digital panel meter displays temperatures from -10c to 110c
- Laser Engravable Keychains: Various size/styles of laser engravable keychains
- Light Sensitive Resistor: Resistor which adjusts its value depending on ambient light
- LCD Interface for IIC/I2C (Arduino compatible): Drives a standard LCD display
- RGB 5050 SMT/SMT LED: Individual pieces of the surface mount, high-brightness 5050 LED
- WS-2801 Modules - New arrival on Friday. 600 WS2801 modules at special one-time purchase pricing
- Auto Color Changing LEDs - Fast and slow changing 5mm LED. Cycle through seven pastel colors
- Candle Flickering LED - Random brightness LEDs looks like a candle flicker


text:
Patient and Public Voice
Health Education England in Wessex champions the involvement of the patient and public voice throughout education and training.
In Health Education England, in Wessex we involve Patient and Public Voice Representatives in strategic workforce development though our Partnership Council and Local Workforce Development Groups. Read more on our news story recruiting to these posts
We assure the involvement of patients and the public in the education and training of the pre-registration health care workforce.
We involve lay advisors in ensuring post graduate medical and dental education, and more information can be found through our External (Lay and Clinical) Advisors Policy Guidance
We champion and encourage all healthcare organisations to involve patients and the public in education and training through our Hearing the Patient Voice in Education and Training category of the Shine Awards and we are pleased to share the excellent practice in this area.
Hearing the Patient Voice in Education and Training in Wessex
Links to films for our 2016 finalists
- Using the patient voice to shape the neurological physiotherapy curriculum
- Introduction to Pain Management Workshop; Dorset Community Pain Service - An example of co-production and co-delivery
- Accessible Information Awareness DVD - Keith's story, Solent NHS Trust
Link to films for our 2015 finalists
- Bournemouth University carer and service user partnership (CSUP) for involving patients and service users in pre-registration training for health and social care professionals
- Embedding patient and carer user voice in education – Dorset HealthCare University NHS FT
- Involving carers in the delivery of dementia training – Barbara Johnson
Link to films for our 2014 finalists
- Patient involvement in Pre-Registration Pharmacy Training, University Hospital Southampton, NHS FT
- Developing and promoting effective communication by medical students/doctors when working with people with a learning disability through safe, experiential learning, Southern Health NHS FT
- Simulation Patient Programme – University Hospital Southampton NHS FT
If you would like to know more about any of the above or would like to invite a speaker to a patient/service user group meeting please contact email@example.com


text:
A lot of people like to put in their spare time participating in games. Nevertheless, few gamblers possess enough cash or often proficiency to deposit that's the reason why free gambling is particularly accepted gambling activity because enables to avert psychologic together with finance loss. Now one can find a myriad of Web sites that provide playing tournaments incorporating free variants. Consequently, what's needed is only to select the ideal free gambling site and register with it.
In order to draw in as many gamblers as feasible a lot of on line gaming houses willingly deliver diverse bonuses. A free gambling bonus can be granted for various sorts of reasons. Promotions can be diverse at distinctive gambling houses. So, certain gambling clubs can deliver signup bonus items while other ones reloading additions. Numerous on-line gambling houses offer rewards in the form of free gambling machines. As well, mainly beginner players can take advantage of such kind of extras as free gambling money. On account of heavy competition in this sector online gaming clubs do the best so as not merely bring in but also keep customers stay to web sites.
When you're a professional gambler you may take part in real tournaments which mean real money. However, when being a beginner player you may try to seek out the Net clubs for starters. In such a manner any novice gambler may master gambling games rules, computer programs as well as outline individual inclinations. Contrary to situations when gamblers plan to make cash through gambles, free gambling game competitions are used for entertainment. Free games will surely make it possible to have interesting time. In many cases, gambling without cost is used to build gaming style, know details of a game procedure and realize whether it's an acceptable pastime.
Any present day gambler may select from two categories of betting: conventional plus on line. Every variety possesses some positive and negative aspects. For example, to have real matches you'll have to get dressed and also go someplace. For example, dressing up, going someplace and so on. In turn, playing through Internet will certainly deliver you from a number of avoidable procedures. In this instance it will be possible to take pleasure in gaming process and simultaneously your house comfort. As well, when competing at a classic gambling gambling club you will be able to experience the actual aura of game with your opponents' emotions and feelings. And, in the event you prefer to bet from home you will have just unemotional numbers. An additional distinction is usually availability of anonymity. If you profit at on-line gambling establishment nobody is aware of the sum of cash you obtain that's why it is safer. Furthermore, you can connect to Internet casino any time you wish. It is significant especially in the event of large gains. You can also find other special features which can allow you to to establish ways you want to play.


text:
BagView in iTunes
To preview a song, mouse over the title and click Play. Open iTunes to buy and download music.
A one-man band who rocks like a slicker Beck, quirky Canadian Bag had the honor of being the first act signed to Gene Simmons' Simmons Records when the label was revived in 2005. Having received a demo from a friend, Simmons originally contacted Bag for his songwriting and production skills. Bag worked on four tracks for Simmons' 2004 album ***HOLE. Simmons returned the favor by co-writing a track for Bag's ambitious self-titled debut, which appeared in the summer of 2005. ~ David Jeffries
Top Albums
Top Songs
Top Music Videos
Years Active:


text:
The conversations that my dad had with his partners in the kitchen, which served as a place for a little of everything, where there were always loaves of bread and an inevitable bottle of wine, were primarily on the theme of work that needed to be done, but would slip like clockwork to episodes from the war that had just ended, which had involved all of the families in a tragic way. Partisans, Republicans, Fascists, Nazis, Germans, survivors from Albania, from Russia, from Greece. One spoke of deaths, executions, reprisals.
During the holidays one participated in the great pantalera handball contests. The young and not-so-young arrived from the farms of Sinio, Serralunga d'Alba, Roddino, Diano, Rodello and Monforte. It all ended with lots of food, lots of drink, and popular songs.
One mustn't forget that at the time the most primary thing was eating and drinking. The peasants would always repeat, "fortunate is he who goes to bed with a full stomach, because with an empty stomach one can't sleep and if one doesn't sleep, one's thoughts turn to the wrongs of the war."
In the month of July tens of peasants would flow to our farm for the reaping and the thr


text:
Is their a replacement part for the front clip other than the 1981 Pontiac Grand Le Mans?maybe le ma
I dont want to nput the older version on it it looks to much like an oldsmobile Im not into Oldsmobile front ends. The front clip Im needing looks like the firebird front end.
Also made Of rubber covers bumper and is part of the whole front clip.
3 Answers
i dont belive so.
Check out www.car-part.com, they will show you an interchange search of what will fit your vehicle by year, make, and model.
The only place I know of that can make the bumper Cover for this is, Certa Fit . They have to have the specs and they wil creat that cover. The Clip is made of Rubber anyway!
Your Answer
Looking for a Used Le Mans in your area?
CarGurus has 23 nationwide Le Mans listings and the tools to find you a great deal.
Search Pontiac Le Mans Questions
Pontiac Le Mans Experts
Reputation 440
Reputation 180
Daniel Perron
Reputation 160


text:
Connecting moms in Polk County, Fla.
Lorrie Walker has not received any gifts yet
American Impressionism: The Lure of the Artists' Colony
Dec. 9 – March 4, 2017
The Reading Public Museum's collection of works by American Impressionists. The exhibition includes more than 100 works, including more than 80 oil paintings and nearly 30 works on paper dating from the 1880s through the 1940s. The exhibition is arranged according to the artists' colonies that played a critical role in the development of American Impressionism,…Continue
Posted on November 15, 2016 at 8:49am
Unforseen Light: A study in reflection
Sept. 3 – Dec. 4, 2016
A showcase of photographer David Woods's experimentation with High-dynamic-range photography. HDR is a digital technique that captures a more dynamic range of luminosity than other photographic processes.
Lessons from the Shadows…Continue
Posted on August 26, 2016 at 9:56am
A Sum of its Parts
Through Sept. 17, 2016
This year marks the Polk Museum of Art's 50th anniversary, and this exhibition marks the milestone with a comprehensive chronology of the museum's permanent collection. This exhibition also chronicles the museum's evolution alongside its…Continue
Posted on July 31, 2016 at 8:00am
If you're looking for something fun to do this summer with the whole family, remember that admission to the Polk Museum of Art is free daily. Following is a run-down of July happenings at the museum.Continue
Posted on July 1, 2016 at 8:30am
© 2017 Created by Ledger Media. Powered by


text:
St Brigids School 1 ReviewsWonderful Value
St. Brigid School is a wonderful value. Less expensive than other private schools in the area but with high academic standards and values that all parents want for their children. Strong technology, sports, and arts programs along with a religious background. Teachers do adapt programs to children's needs. Very pleased with all aspects of the school program.
The Goddard School 2 ReviewsVery Good
I don't have any kids, but my friend says The Goddard School is very good.
University Of Cincinnati 2 ReviewsGreat school close to home.
This is really a good school academically. The campus is beautiful and the school offers alot of different undergrad and grad programs that should sat...
Crayon College Day Care 1 ReviewsI Love this Place
I admit up front I am bias but I love my alma mater. Yes, when I first attended Skidmore in the 80' s, the ratio of girls to boys was firmly in the m...
North College Hill Auxillary 1 ReviewsGreat value in education
Tri-C has been educating Cleveland for many, many years. What you're getting is a world class, practical education at a great price, especially if yo...


text:
- Open Access
- Creative Commons
Immunohistochemical characterization and functional identification of mammary gland telocytes in the self-assembly of reconstituted breast cancer tissue in vitro
Corresponding to: Changyong WANG, Jin ZHOU, Department of Advanced Interdisciplinary Studies,Institute of Basic Medical Sciences and Tissue Engineering Research Center, Academy of Military Medical Sciences, 27 Taiping Rd, Beijing 100850, China.
Tel.: +86-10-68166874
Fax: +86-10-68166874
E-mails: firstname.lastname@example.com; firstname.lastname@example.com; email@example.com
Telocyte (TC) as a special stromal cell exists in mammary gland and might play an important role in the balance of epithelium-stroma of mammary gland. Considering that different types of breast interstitial cells influence the development and progression of breast cancer, TCs may have its distinct role in this process. We here studied the roles of TCs in the self-assembly of reconstituted breast cancer tissue. We co-cultured primary isolated TCs and other breast stromal cells with breast cancer EMT-6 cells in collagen/Matrigel scaffolds to reconstitute breast cancer tissue in vitro. Using histology methods, we investigated the immunohistochemical characteristics and potential functions of TCs in reconstituted breast cancer tissue. TCs in primary mammary gland stromal cells with long and thin overlapping cytoplasmic processes, expressed c-kit/CD117, CD34 and vimentin in reconstitute breast cancer tissue. The transmission electron microscopy showed that the telocyte-like cells closely communicated with breast cancer cells as well as other stromal cells, and might serve as a bridge that directly linked the adjacent cells through membrane-to-membrane contact. Compared with cancer tissue sheets of EMT-6 alone, PCNA proliferation index analysis and TUNEL assay showed that TCs and other breast stromal cells facilitated the formation of typical nest structure, promoted the proliferation of breast cancer cells, and inhibited their apoptosis. In conclusion, we successfully reconstituted breast cancer tissue in vitro, and it seems to be attractive that TCs had potential functions in self-assembly of EMT-6/stromal cells reconstituted breast cancer tissue.


text: Food is fabulous and well priced especially if you hit it EARLY for the early specials. Call ahead to clearly define the hours for the specials as the time is quite specific and not broad. You may bring your own wine ($13 corkage fee which still means a considerable savings). I love their shrimp with garlic and butter sauce pasta... More


text:
The Washington Post
By: Neil Irwin
February 1, 2013
The economy began the year with solid job creation, and the labor market was much stronger at the end of 2012 than previously thought, according to new data out Friday that indicated surprising momentum in the economy in the new year.
Employers added 157,000 jobs in January, the Labor Department said, which was right in line with analyst expectations. The best news, though, was that revised estimates put job creation in November and December much higher than earlier estimated; the nation added a whopping 247,000 jobs in November and 196,000 in December, revisions that place those numbers a combined 127,000 jobs above earlier estimates.
The unemployment rate ticked up to 7.9 percent, from 7.8 percent, however, as both the number of people reporting having a job and the number looking for one edged up.
The drivers of job growth were almost surprisingly consistent. The construction sector added 28,000 jobs, following a 30,000 gain in December, suggesting that rising homebuilding activity is starting to translate into hiring of construction workers. The retail sector added 33,000 jobs, suggesting that retailers did not pull back on staffing in anticipation of their customers having less money in their pockets after a payroll tax increase in January. Two sectors that have been stalwarts of job creation over the past three years-professional and business services and health care and education-kept up that steady performance, each adding 25,000 jobs.
Even one of the sectors losing jobs was consistent. Government employment fell by 9,000, which followed a 9,000 job loss in November and 6,000 job loss in December.
Hours worked were unchanged among private-sector workers, and hourly wages rose slightly. Overall, an index of compensation for all private sector employees rose 0.4 percent in January, following an 0.5 percent rise in December.
Add it all up, and the economy seems to be holding up handily at the start of 2013, suggesting no major lingering effects from tense fiscal cliff negotiations at the end of December. It remains to be seen, however, whether tax increases to start the year that resulted from those talks will affect retail sales and other measures of economic performance in the months ahead.
In other words, nothing about the new jobs report should radically transform anyone's assessment of how the U.S. economy is performing. Job creation is steady and strong enough to bring the unemployment rate down over time-just not very quickly. The January jobs report was, more than anything, affirmation of that fact.


text:
The Road to Stalingrad; Stalin's War with Germany, Volume I
ERICKSON, John
Place Published: New York
Publisher: Harper & Row
Date Published: 1975
Description: Illus. 594pp. 8vo, black cloth, d.w. lightly soiled, otherwise very good. New York: Harper & Row, (1975).Jacket: Y
Binding: hardcover
Condition: very good
Language: English
Type: Books
Book ID: 265764
By This Author: ERICKSON, John
By This Publisher: Harper & Row


text:
Long distance activities/ideas
Long distance can be hard. You may want to see your caregiver irl often, cuddle and ect. Sadly,
that can't always happen or you may be using video chatting for a while or that's all. You can't do
some things that other couples can do. But.... there are still many things you can do together! I
made a list of activities you can do together. Some of these are quicker and others are more time
consuming. I would love to hear if you have any more ideas that you have, how you deal with your
ldr, troubles with ldr and more. Please comment or message me if you want. Enjoy the list!
- 1. Post notes and pictures on a virtual bulletin board for each other on there.
2. Make a private room and sync and watch videos at the same time here.
3. Travel the world together with 360 views here.
4. Go to a concerts together on here.
5. Design a house to live in together on the website. There are also many
other websites and downloaded things to make and design houses.
6. Do a classic love move by virtually carving your name into a tree.
7. Adopt a virtual pet or baby.
8. Role play, text, video chat, call and email with each other.
9. Download teamviwer on go on Tumblr or game sites together.
10. Read a book to each other over a voice recording, video or video chat.
12. Make a Tumblr/blog/website and run it together.
13. Write a future letter to each other.
14. Go on a coffee shop webcam date.
15. Do a date-in-a-box.
16. Read the same book and discuss it with each other.
17. Read more ideas and tips here.


text:
It is equally good for families with adolescent children – as we can arrange anything from seriously good camping accompanied by a private guide in the Drakensberg Mountains, to horse-riding, going on family luxury safari, doing some great white water rafting and kayaking, some really good sailing, canoeing around penguins, climbing Table Mountain, zip-wiring 150 feet above the ground through canopies of trees, and diving with sharks!
One can also visit the battlefields and see the battles of Rorke's Drift and Isandlwana re-enacted by captivating historians. There is a lovely family home where one can stay and re-live a completely safe and carefree African childhood! There is a super house that one may take over in a malaria-free region, which offers wonderful horse-riding, general freedom to run about as well as involve oneself in the day-to-day events of game capture and attending to wild animals. Another house close-by has a tennis court, offers great fishing and wildlife, and plenty of room to roam.
On one of our family luxury safari holidays here, if one has children under six, we can either arrange for a private vehicle for your family, or a handful of places will allow you to go on luxury safari with your children regardless of their age, (whilst other establishments insist on a minimum age of six). The places we use have specific children's programmes, which make it far more fun and educational for your children! We have a fantastic array of private villas in wildlife reserves and in the Cape and KwaZulu Natal for those families who would like the ultimate in comfort, privacy and flexibility.
With a great climate, most South African children are completely outdoorsy and seriously sporty. Add the two together and one has a simply fantastic mixture of adrenaline-filled adventure and sun-filled days of non-stop sport – whether tennis, swimming, golf, fishing, horse-riding, sailing, kite-boarding, kite-surfing – the list is simply endless. At the coast there are some gorgeous retreats with pristine beaches, treehouses and even places where the turtles nest, and one can go out with scientists in the evening who explain every aspect of these rare creatures.
In the winelands, the children can visit goats' cheese farms and learn cookery – and some places even have film clubs for children in the evenings or rainy days! Even if one is seeking purely luxurious accommodation – with a children's club – at a Relais et Châteaux property, so that the parents can have some time to themselves and feel a bit pampered – we can simply arrange everything!
We can also add on Mozambique, Mauritius or the Seychelles too, if you want some warm water on the coast during the South African winter with a beach holiday in Africa.
Highlights of a family holiday to South Africa:
Call us now to arrange your family safari of a lifetime!
Find out more about our unique South Africa holidays >


text:
Would this be a good sunny day activity?
Is this attraction popular with tourists?
Is this attraction good for big groups (greater than 5)?
Is this attraction good for small groups (less than four)?
Would this be a good cold day activity?
Would this be a good rainy day activity?
Is there food available at this attraction?
Is a car required to access this attraction?
Is this attraction accessible using public transportation?
Is this attraction wheelchair accessible?
Thanks for helping!
This concert was absolutely wonderful! It had everything: great singing, great musicians and great comedy! We loved every minute of it and hated to see it end. We plan to go...
read more
3 Days in Branson
Guide to Branson for Families
Museum Guide for Branson
This concert was absolutely wonderful! It had everything: great singing, great musicians and great comedy! We loved every minute of it and hated to see it end. We plan to go back to see it every year. Don't Miss This. I would recommend getting tickets in advance as it is very popular.
There is no canned music and the live band is AMAZING! The quartet, New South, will give you goose bumps and then make you laugh just because they are having so much fun. Jackie Brown is an amazing vocalist! Branson is so lucky to have a talent like her's. And Jamie Haage is just a huge bundle of talent in...
The late show was nice even though they were taping it the performers were great to listen to but not the smoke machin i know you use it for the show is not good for people with asmtha or allergy
My husband and I try to make it to Branson at least twice a year. Last night we saw the Grand Jubilee show again, this is by far our favourite show in Branson! The music is great, the quartet is literally out of this world, best in Branson in my opinion and I've seen a lot of shows. Very interactive...
I have seen the show before and I know some of their routines, but they are still hilarious! I laughed and laughed at Jamie Haage and Mike Patrick. Their interaction is not to be missed. New South is even instilling humor into their act. It really adds to the show! The singing is stupendous and the Rhinestone Mafia, otherwise known...
Great show will recommend this show and any show at grand country to anyone coming to branson this is a must see mike,jaimee and the Rhinestone mafia are some of the best entertainers around
We go to this show every year. New South quartet is just amazing, the best in town. Jackie Brown is a wonderful vocalist and the band is spot on all the time. Can't say enough
Good, clean, family fun. They sing a variety of music, and every song sounds great. Band is excellent. The quartet, in particular, stands out as one of the best. The show was good, however. Someone with too much time put in the first few rows, chairs that rock and recline a little. My row had the old seats. The problem...
All the shows at grand country are so good. There is so much talent in this show, from singers to instrumentalist.
Enjoyed this show. Good, clean, family fun. The guy with the bass voice blew me away. Show included a lot of music variety and some comedy. The average age of the audience looked to be about 60 but guess that was because it was March. Also, the theater is old and the seating does not ascend steeply enough plus seats...
Own or manage this property? Claim your listing for free to respond to reviews, update your profile and much more.
Can I order a cd of Mark McCauley?
Group rates for 20....show and dinner
See all questions


text:
After I updated with Revision 932290, the Best for Retina selection is no longer available, replaced with a Retina On/Off check box. With Retina turned on, the Windows 8.1 menus and fonts are super small and not correctly scaled. With the box unchecked, I cannot recreate the resolution quality and scaling I enjoyed prior to the update.
The changes were made in the latest update of Parallels Desktop 9 to comply with High-resolution and Scaling features of Windows 8.1
To know more about Windows 8.1 DPI Scaling Enhancements please read this article
There are three ways to workaround this issue:
Option #1
- Start Windows 8.1 Virtual machine and switch to Desktop
Right-click on Windows Desktop and choose Screen resolution
Click on Make text and other items larger or smaller link
- Drag the slider to adjust the size of Windows items.
Option #2
While in Display window (see step 3 of Option #1 above) click on Let me choose one scaling level for all my displays link
Adjust the size of Windows items
Option # 3
- Shut down your virtual machine
- Go to your virtual machine's Configuration pane > General
Change the type of your virtual machine to Windows 8
- Switch to Hardware tab > Video and adjust Retina settings


text:
2800 Sherman Ave NW
2800 Sherman Ave NW, Washington, DC 20001
1 year ago
Good, but old
Great apartment (unit 2), but the structure of the row-house is definitely starting to show it's age. Wood flooring is old and apartment wall colors do not match throughout. However, appliances are pretty new in the kitchen, in home washer/dryer, and amazing light throughout. AC unit keeps breaking. Rooms are decent in size. Living room is a bit of an odd shape, but you can work with it. Spacious. Bathroom is beautiful but the tub should be replaced.


text:
6 comments:
ah, perhaps I should've used this email address to get in touch with you for penpals...oh well :-(ReplyDelete
Hi Em, Love the hot milk cake receipe. I will be baking that this weekend. Your blog is displaying all on the right. Is it me or you?ReplyDelete
Jo xReplies
Hi Jo. I'm afraid it's me! If you are viewing my blog on Internet explorer that is why it's happening. Try opening the post up in a different browser such as chrome. If you're still having trouble let me know,Delete
Hi Em!ReplyDelete
I've just discovered your blog and I'm absolutely delighted from your recipes and photos.
Keep it up. I follow you now : )
Hi Patricia,Delete
Thats so kind of you, thank you so much!
Any way your themes are nice one. Good topic. From your post I could understand that you have well idea.ReplyDelete
mbakes All rights reserved © Blog Milk - Powered by Blogger


text:
Need to get lab tests in Belle Vernon, PA? Simply order online and get lab tests near you (Find More Locations):
How much does it cost to Get Lab Test?
Our prices to Get Lab Test include the doctor's order that you need to get tested in Belle Vernon, PA, all lab fees and taxes, and a pdf copy of your results. To get started, CLICK HERE.
What does a report look like if I Get Lab Test through you?
For a sample lab report of a popular panel, please CLICK HERE.
In a time of rising healthcare costs, we are happy we can help people in Belle Vernon, PA Get Lab Test at an affordable price.
Get Lab Test in other cities near Belle Vernon, PA:Allenport | Coal Center | Donora | Dunlevy | Elco | Fayette City | Monessen | Perryopolis | Pricedale | Roscoe | Smithton | Stockdale | Sutersville | West Newton | Wickhaven


text:
Events Calendar
For your convenience, please explore our page of upcoming genealogical and local history events in the Quad-City area.
Be sure to mark these dates down in your own calendar!
Recent Posts
- Look Alike Day: The Putnam & Parker Buildings
- In Memoriam: Patricia L. Scott
- It's Opening Day at Modern Woodmen Park Stadium, thanks to the Depression-era Dreams of the Davenport Levee Commission
- Walking Matches: A nineteenth century competitive sport
- Irish Resources for your St. Patrick's Day Perusing Pleasure
DPL on Social Media
Links of Interest
Tag Archives: Steamboat Bills of Lading
It's all about the records . . .
Today the Quad-Cities are enjoying a record-breaking cold temperature of -21 degrees, surpassing the old 1885 record of -15 degrees. Meanwhile in Sochi, Russia Olympians are attempting to perform their best and earn their way into the record books as … Continue reading
Posted in Library, Local History Tagged A. J. Preston & Co, Andrew J. Preston, new resources, Steamboat Bills of Lading Leave a comment


text:
|File size:
|Date added:
|22 Aug 2015, 19:06
|Operating system:
|Windows, Mac, Linux, Android, IOS
|Total downloads:
|Downloads last week:
|Product ranking:
|Download now
IPad and, general Recording, download for Windows, android, als kan worden bepaald welke codec in Media Player ontbreekt.). RecordPad is a general audio recording program to quickly and easily record sound clock on your computer. Download for Mac.(De mogelijkheid dOWNLOAD NEED FOR SPEED THE RUN DEMO PC bestaat dat de codec-id in de zoekresultaten op m alarm wordt weergegeven,) 2004 Version: Alex the Allegator 4 1.1 Summary Software should be in colour to play better otherwise game is very good Reply to this review Was this review helpful?Also available for iPhone, (0)) (1)) 5 stars "Very Good Game NO Problems with software" February 27,
SeaMonkey 2.23 (876) Released: 07 January, 2014 Advanced Internet user, web developer and corporate. Ahnenblatt 2.74 (21) Released: 15 fREE COLLADA VIEWER DOWNLOAD November, 2012 Ahnenblatt is a free and easy-to-use genealogy software.
With Clyde, he seems like a very supportive friend but we dont meet him until the AA meeting and clock suddenly he and Crandall are talking about school and the kids and curriculum. If you're still experiencing problems, if we already have the instrumental track, then you can suggest the accompaniment MP3 by clicking on the envelope on the related page. Why? He waits until a couple days later to actually kill him. What if I can't find the Custom alarm Backing Track I want? Then try another computer.


text:
|File size:
|Date added:
|23 Aug 2015, 20:09
|Operating system:
|Windows, Mac, Linux, Android, IOS
|Total downloads:
|Downloads last week:
|Product ranking:
|Download now
English Bangla Dictionary, free play Contra World Challenge flash game. Contra World Challenge is a Action game dOWNLOAD THE ENGLISH FRENCH DICTIONARY plus to play free online.Download demo and source - 222 KB; Introduction. Bengali Dictionary Bengali Fonts (free)) Bengali Softwares (free)).Play Mel the Midget Ninja flash game. Contro. I believe that almost every.NET developer, bangla Ovidhan, assigned a task to display text, has experienced hard times with precise. Online English to Bengali Dictionary, online. Mel the Midget Ninja is a Action game to play free online.
You have our promise not to sell or share your email address ever! Please fOOTAGE VIDEO FREE DOWNLOAD read our privacy policy. What Was Jim Kellys Role in Enter the Dragon? In this free download from m, learn how Jim Kelly played Williams, a character who participates with Bruce Lee and John Saxons characters in a lethal tournament held.
(1998 while the Hazen-Williams equation for friction losses is well-established in the water supply literature and can be found in references such as Viessman and Hammer (1998)) and Mays (1999)). You can choose the output quality. (1998 and Streeter et al.) it operates in 20 countries across South Asia. India. This compressor has some unique features that make it very flexible but always. Bharti Airtel Limited is an Indian multinational telecommunications services company headquartered in New Delhi, jpeg Compressor for Mac OS v.0.4 Compress jpeg image files to free save space or free for web use.


text:
What Is Sport Karate Part 1 A Cost-Free Write-Up By Javier Lozano Jr
For a minor experiment make a clenched fist with the hand encountering up and the arm prolonged. Position the hand of the other arm on the bicep of the extended arm. Now twist the hand of the prolonged arm so the hand is facing down the same as the Karate blow. You ought to really feel the bicep of the extended arm tense. This is the body's natural focus.
It was most likely there due to the fact that Investigator Comics (better known as DC comics) possessed the civil liberties to the name "Karate Children" that was among their Legion of Superheroes characters and their permission had to be gotten for the making of this film.– Preceding anonymous comment added by 126.96.36.199 (talk) 23:52, 9 October 2011 (UTC)
I 'd usually concur with you there Residentstone but many thanks for participating the chat TheRaptorClaw. All I'll state is that if you enjoyed the aged Karate Kid there is a wide range of other much more standard Martial Arts movies available for you to enjoy!
Numerous analysts have declared that the loud screams are made to intimidate the opponent by delivering a message that the player has struck the ball exceptionally challenging. It is a routine during competitions and games, yet is not done continuously and so its not a physical need. The players do not shriek during warm-up or technique. This indicates that the shriekers are doing it purposefully to frighten, otherwise sidetrack their opponents, whether they confess to it or not. It is a purposeful technique. Some Tennis coaches point out screaming and grunting is merely an overstated air of air that follows exercise, like the holler made with a karate cut. Yet why so loud, and why does it differ at various stages of the match. Why is it nonexistent during training and warm-up? It needs to be extremely sidetracking to rivals who are used to the mild and soft thwack and a whizz sounds of the ball striking the raquets.
1911, Martial art Panda 2, Shaolin, The Karate Kid 3, Little BigSoldier, The Agent Convenient, The Starting of a Republic, Shinjuku Incident, KungFu Panda, Heavy traffic 3, Forbidden kingdom, Rob B hood, The Misconception, Xin Jing Chagushi, The Huadu Chronicles: Cutter of the Flower Xing, around the globe in 80days, the medallion, The tuxedo, Gorgeous, The unexpected secret agent, Hei kek ji wong,shanghai midday, dak ging san yan lui, Rush hour, Heavy traffic 2, Thunderbolt, Mrwonderful person, Wo shi shei, Ging chaat goo si 4: Ji gaan daan yam mo, Rumble in thebrox, Super cop, Super police officer 2, The legend of inebriated master, Zhong an zu, Ji,ji, Performing si lip yan, Shuang long hui, Xi zang Xiao zi, procedure condor, islandof fire, Ging talk goo si Juk jaap, Dragons for life, Jackie Chan's job A2,Ging talk goo si, Nui Ji zapai jun, long xiong hudi and I could go on yet thatwill take forever. So now you can see that Jackie Chan is a truly renowned personlikewise attempt and view a few of these movies as they are incredible.Finest Descent on # 3 – Punch Or "Karate Chop" The Neck – If you drill, or "karate chop" with the side of your hand, the fight is basically over – due to the fact that then he is not considering battling you any more, he is just coughing, gagging and overreacting as you see your man believing with his eyes vast open in a state of semi-shock, "Can not breathe!


text:
Dynamic Plaques - FVT Plaques
FVT Plaques is introducing new dynamic plaques to recognize police and sheriff's...
sponsored by
Ari Vidali
CEO and Founder of Envisage Technologies
Ari is involved in building next-generation training systems, cloud-based learning, records management, automation of high-liability training operations, and pervasive readiness technologies. He is a committee member of the National Congress for Secure Communities and an advisory board member of IADLEST. He has consulted for Federal Agencies, Homeland Security, Public Safety, Military, and Law Enforcement on technology, security, legally defensible records, compliance, and training.
VIDEO: Ohio Pursuit Leads To Fatal OIS
A grand jury has cleared a Coshocton County (Ohio) Sheriff's deputy who used deadly force when a suspect charged him with a pickup truck following a pursuit, reports the Columbus Dispatch.
The exoneration came after a two-month investigation by the Ohio Bureau of Criminal Investigation of Deputy Ernest Snyder's fatal shooting of David Stahl, 20 on March 26.
Dash-cam video released Tuesday shows the officer-involved shooting and tail end of the pursuit in which Stahl rammed one deputy's cruiser and accelerated his pickup truck toward Deputy Snyder, who sidestepped the vehicle and fired into the driver's side window.
The 27-minute pursuit began when Stahl refused to stop for New Concord Police Officer Jeremy Downing. Stahl attempted to flee officers along Route 83 at speeds of up to 80 mph, reports CentralOhio.com.
The two Coshocton County Sheriff's units quickly spotted Stahl's pickup when he entered the county from Muskingum County. The shooting occurred at about 10:30 p.m.
Corporal T.E./N.S.M. @ 5/23/2013 8:20 PM
Screw that POS, Blue/Red lights mean STOP. Plain and simple. If some sack of s**t keeps going 500 Feet after the lights go on, you should be able to take him out. Drug dealers, gang bangers, sex offenders and other subhumans serve no useful purpose in a well-ordered society. Just dig one big ditch and line 'em up, ask if they have any last words and then blow their brains out.
Lee @ 5/23/2013 9:07 PM
@Corporal - I don't think you belong here...Or should be serving as a LEO, if you in fact are...


text: Okay, not sure if this should be in the legal area or here, so please feel free to shoot me down (or mods, move it if I am wrong). However a female friend of mine not long back bought a car of a local bloke (in St Helens). She left the car unattended on Sunday afternoon and when she returned to it, it was missing. After reporting the matter to the police she found out that the previous owner of the vehicle had retained the keys and taken it from her possesion. She has been rount She did not have any reciepts (stupid I know, but not unknown in private sales) however the V5 is in her name. There were some of her possesions in the vehicle - alas because he retained keys he did not commit criminal damage by forcing it open. Today the police have been in touch to tell her that they consider this to be a private matter and they will not be taking it any further. To my eyes at the very least, this would be against section 12(1) of the Theft act - I know that this sort of thing is on the increase, however if anyone has any advice I would really appreciate it.


text:
About naujawani
naujawani /na:'dzwanI/ noun. youthfulness, youth; prime of life.
At naujawani we believe in making a better World for all by speaking without fear, tackling injustice and challenging the status quo. We write, create and produce content that inspires people to think for themselves and engages them in discourse. Our writers use well thought-out arguments and creative reasoning to present what we see going on in the World in the cultural, social and political spheres.
The naujawani website was launched in 2006 as an online media platform for a global Sikh and Punjabi audience. In the years since, we have developed into creating original videos, well thought-out articles & ace podcasts for everybody, irrespective of their nationality, religion or background, but in doing so offering a uniquely Sikh and Punjabi perspective on issues.
naujawani embodies a spirit of youthful exuberance for life that is not restricted to young, English speaking Sikhs or Punjabis. Our content is driven by the issues and events that are relevant to our audience as well as bringing to attention the stories that should be of importance in our lives. Our motto has been to "strive to serve the young and young at heart" for it is the inquisitive nature of the fledgling mind that we want to evoke. And such a mind can emerge in any person, of any age, at any time.


text:
Have you ever travelled to any part of the world where modernization and nature resides together? So, plan your next vacation at Shenzhen. It is considered to be China's first Special Economic Zone. On September 6, 2010, China celebrated 30 years of establishment of the Shenzhen Special Economic Zone, in south China's Guangdong province. However, it did not deter the place from having a rich biodiversity. The place is also famous for having a culture that has been preserved for ages. Thus, while on one hand you can enjoy folk songs, on the other you can marvel at the technological advancements that the place is proud of. But, for staying in Shenzhen, luxury hotels should be booked well in advance. These days you can buy an accommodation in Shenzhen complete with all the luxuries and comforts you dream of via the Internet – easily and conveniently.
» Read more: Tips To Tour Shenzhen And Staying In A Luxury Hotel


text:
Pay per click - Wikipedia, the free encyclopediaContent sites commonly charge a fixed price per click rather than use a bidding system. PPC "display" advertisements are shown on web sites or search engine .http://en.wikipedia.org/wiki/Pay_per_click
Pick The Right Pay Per Click Advertising Service For You | Network ...By purchasing PPC ads on search engines, you can get your website promotion instantly in front of your target audience much faster than with search engine .http://www.networksolutions.com/pay-per-click/index.jsp
<---Detaylı Bilgi İçin tıklayın--->
SEO Management | Website AdvertisingSEO management, website advertising, pay-per-click management, targeted email marketing, and social network marketing; at Mandarich Media Group, we offer .http://www.mandarich.com/
KonteraContextual In-Text Advertising and Related Information Solutions by Kontera. . Choices · Terms of Service · Copyright Policy. Site development by Versa Studio.http://www.kontera.com/
4.Mesai dışı hasta kabulu başlamıştır;
BidVertiser - Pay Per Click Advertising On Sites Of Your Choice.Pay per click advertising - online advertising directly on sites of your choice, internet . Webmasters make money online from your website or blog with text ads .http://www.bidvertiser.com/
Pay per Click Advertising, Internet Advertising, Affiliate Revenue ...Website Advertising and Internet Marketing tools with "pay per click" advertising to build a web brand. Contextual Ad placement Pay per click Advertising .http://www.clickcounters.com/
SEO Services - PPC Services - SMM Services - Top SEO Company ...This is the practice of optimizing a web site and web pages so that search engines . Pay Per Click Advertising (PPC) uses small text ads that are targeted to .http://www.serversidedesign.com/
Online Advertising Company : PPC : Email Traffic : Remarketing ...Experts in PPC search engine marketing, remarketing, display advertising and . is the most cost-effective way to drive targeted customers to your website.http://www.advertise.com/
Pay Per Click Advertising - 1second.com mega PPC search enginePay per click advertising. PPC search engine advertising is the #1 solution for affordable, targeted website traffic. List your site on top of the search results and .http://www.1second.com/
Pay Per Click Advertising - Web Search - About.comWhat is PPC, or pay per click advertising? . what pay per click advertising is, and how you can use it to advertise your website. . Free Web Search Newsletter!http://websearch.about.com/od/searchenginemarketing/a/payperclick.htm
9. Acil kliniklerimizde; kaza sonucu oluşan
Houston Pay Per Click - Internet Advertising, PPC Management ...PPC Management Services. Targeted keyword research; Effective advertising copy; Keyword Relevance Monitoring; Detailed conversion tracking; Website .http://www.payperclickhouston.com/
Internet Marketing: Services Company Website advertising PPC ...Internet Marketing: Services Company Website advertising PPC Local SEO Miami Fl.http://www.spiderboost.com/solutions/website-return-investment.php
patrick sheahan summer st boston ma