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ABSTRACT KEYWORDS Integrating additive or synergistic antitumor effects that focus on distinct elements of tumor biology are breast cancer; carbohydrate the most rational strategies for cancer treatment. Treatments for breast cancer have increased overall mimetic peptide; survival, but remain limited by lack of efficacy in a subset of breast cancer patients. The real challenge is to pathological complete define what elements of tumor biology make the most sense to be integrated. An emerging strategy is to response; tumor glycans; TACA; tumor vaccine consider a systems biology approach to impact multiple interactions in networks as compare with hitting a specific protein-protein interaction target. In this review, we consider how targeting tumor associated carbohydrate antigens (TACA) that are fundamental to signal pathways might be tailored to harness benefit from combination therapy of sustained immunity with chemotherapy. An approach we are developing makes use of a carbohydrate mimetic peptide (CMP) to induce polyspecific antibodies, which by their nature have numerous on and off target effects. Linking multi-target TACA recognition with mechanisms affecting tumor growth in the context of network heterogeneity and concepts of immune surveillance to tumor cells and the type of breast cancer patients that would benefit from such an approach provides a novel integrative treatment.
Introduction rebound activation of backup pathways that bypass targetedPharmacological treatment is a standard approach in the adju- molecules. Hence, targeting a specific, overexpressed, protein invant and neoadjuvant therapy of breast cancer to reduce the a malignant cell may not result in an optimal outcome exceptrisk of disease recurrence.1 But the majority of women with for instances such as Her2 overexpression in breast cancer8 orrelapsed or disseminated disease ultimately still expire from BCR-Abl expression in chronic myelogenous leukemia.9 Com-this disease.2,3 This should not be surprising. Common sense binations of the anti-human epidermal growth factor receptorwould dictate that any finding of residual cancer—in situ, inva- 2 (HER2 or c-erbB2) antibody trastuzumab and chemotherapysive, or in axillary lymph nodes following neoadjuvant ther- lengthen survival in metastatic HER2-overexpressing breastapy—is likely associated with a worse prognosis compared with cancer.10 However, progressive disease typically occurs becauseabsolutely no evidence of residual disease. Not withstanding of genetic mutation of the single target.that cancer is often molecularly and clinically a heterogeneous There is a need to counter the heterogeneity and evolution ofdisease, cells may be resistant to drugs, forming the rational for tumors. Mutation or a genetic event affecting the target of theboth combinations of modalities of treatment as well as combi- drug renders the drug useless where a pathway is still able tonation of molecular therapeutic strategies.4 drive the growth of the tumor, despite the continued presence of The treatment of cancer by chemotherapy causes tumor cell the drug. Interestingly, the epitome of targeted therapy is to iden-death, mostly by apoptosis.5 Molecular mechanisms that regu- tify a mutated oncogene and target it with a small molecule. Thislate apoptosis and the mediators that either prevent or trigger has led to the conceptual addiction to oncogenes.11,12 This con-cell death are an area of intense research. Consequently, apo- cept was invoked to explain how some cancers that contain mul-ptosis regulators have emerged as key targets for the design of tiple genetic, epigenetic, and chromosomal abnormalities aretherapeutic strategies aimed at modulating cellular life- dependent on or 'addicted' to one or a few genes for both main-and-death decisions.6 Proof-of-principle evidence obtained in tenance of the malignant phenotype and cell survival. Genomicsseveral animal models confirms the validity of strategies was developed with this in mind. So every disease was dividedtargeting apoptosis, revealing the potential for therapeutic into a large number of diseases based on this premise and theintervention. Nevertheless, there is a high failure and relapse search commenced for "The Agent" for this mutated oncogene.rate for single-agent targeted therapies because most cancers In vitro models supported this concept but clinical trials disap-have multiple inputs into cellular pathways that serve to bypass pointed. Since every patient may have a different mutation orthe intended outcome of single target therapies. mutations the term "personalized medicine" was born from this Cellular pathways have complex interactions and when per- practical and intellectual bottle-neck.13turbed exhibit redundant mechanisms for survival.7 Developing It is clear a new approach is needed to harness the benefit oftargeted agents for one pathway or target at a time often causes cell death. In contrast to targeting singular proteins we are
CONTACT Thomas Kieber-Emmons email@example.com University of Arkansas for Medical Sciences, 4301 West Markham St., #824, Little Rock, AR 72205, USA.© 2017 Taylor & Francis324 T. KIEBER-EMMONS ET AL.
pursuing the strategy of pan immunotherapy, with roots in sys- presenting cells and presented to immune cells. The adaptivetems immunobiology and in understanding how Tumor Asso- immune response that follows is considered crucial for cancerciated Carbohydrate Antigens (TACA) can be effective-targets control and it is perhaps one of the most important mecha-to mediate cancer cell death. This innovative concept is coinci- nisms through which chemotherapeutics exert their effect, asdent with mounting evidence that combination targeted thera- this effect may be abrogated in case of defective adaptive immu-pies will be more effective than single agents. Systems biology, nity.26 However, not all types of chemotherapy-induced cellhas revealed that human cells and tissues are composed of com- death are immunogenic. Immunogenic cell death (ICD),27 aplex, networked systems with redundant, convergent and diver- special case of regulated cell death, can trigger an adaptivegent signaling pathways.14-18 For example, the redundant immune response and is associated with the translocation offunction of proteins involved in cell-cycle regulation19 has calreticulin to the plasma membrane and the release of type Iinspired efforts to intervene simultaneously at multiple points interferon, High-mobility group box 1 protein and Adenosinein these signaling pathways.20,21 An approach consonant with a triphosphate that can induce the production of proinflamma-systems biology framework, and complementary to the target- tory cytokines leading to the recruitment and activation of anti-based approach, entails identification of pathway points that gen presenting cells and local T-cells against the tumorcan be targeted to perturb cellular signaling networks associ- associated antigens. These signals are collectively called "dam-ated with apoptosis. age associated molecular patterns - DAMPs" and were recently One set of molecular targets associated with a variety of bio- used to predict response to chemotherapeutics in the clinicallogical functions is TACA. Interestingly, TACAs and glycans in setting.28general can be described as pan antigens as they are found on Combining biologic and chemotherapies are now consid-many proteins and lipids on many cancer cells. Aberrant glyco- ered to aim at multiple therapeutic targets to improve treat-sylation of proteins and lipids is one of the characteristic fea- ment response, minimize development of resistance ortures of malignantly transformed cells, expanding the diversity minimize adverse events.29 Considering the multiplicity of con-of the proteome enormously. So how do we target TACA to stitutively activated pathways and the possibility of redundancyinterrupt cell survival signaling? A lesson can be learned from in most cancer it becomes a daunting task to find combinationsthe polyspecific nature of natural antibodies and from lectins.22 of biological agents that are likely to cure cancer. This repre- The polyspecific characteristics of natural antibodies see sents a major advantage to immune and chemotherapy becauseTACA as pan tumor antigens since natural antibody can recog- both can act in a mutation agnostic way provided that thenize multiple glycans as part of the innate immune surveillance appropriate cell death mechanisms are operational.system. Naturally arising IgM antibodies to apoptotic cell deter- Many different combinational cancer immunotherapies areminants are present from birth and can be further induced by being tested in various cancer models.30-32 Most tumor immu-apoptotic cell challenge. Efficient clearance of cells undergoing nologists focus on the establishment of a durable pool of T cellsapoptotic death is crucial for normal tissue homeostasis and for that have potent antitumor activity.32 The underlying causesthe prevention of autoimmunity.23 Natural polyreactive IgM for the failure of current immune therapies are 1) the failure ofautoantibodies, encoded by unmutated germline Immunoglob- the immune system to recognize the cancer as abnormal, 2) theulin (Ig) V genes, represent a major fraction of the normal persistent of immune suppression in the tumor microenviron-circulating IgM repertoire. Studies have suggested a role for ment that drives paralysis of pre-existing antitumor T cells andnormal IgM in controlling cell death and proliferation, and 3) the failure of cell death mechanisms. The interplay of immu-imply a possible therapeutic role for IgM in autoimmune and notherapy and chemotherapy as a means to harness potentiallymphoproliferative disorders,24 which can be extended to synergies therefore principally focus on T cells and checkpointtargeting TACA.25 blockade32 but combination therapy with immune modulatory Harnessing the polyspecific nature of antibodies overcomes drugs might also prove effective.33,34 These drug types, likethe singular nature of targeted therapeutics as well as the draw- Lenalidomide, can stimulate Natural Killer (NK) cell activityback from genetic mutations because TACA are a necessary that could be highly effective in combination with therapeuticcomponent of all proteins and lipids. Targeting the multiple monoclonal antibodies capable of inducing NK-cell-mediateddrivers of pathways simultaneously should therefore aid in antibody dependent cell cytotoxicity thereby enhancing the effi-removal of malignant cells and cancerous cells in the tumor cacy of the monoclonal antibody. Bortezomib, a novel protea-microenvironment as well as being oncogene mutation-agnos- some inhibitor, causes G2–M cell cycle arrest and apoptosis.tic. A vaccine targeting TACA is likely to elicit an immune But it also enhances anti-tumor T cell immunity via deathresponse that should be able to spread to other antigens that receptor-mediated apoptosis.35carry some similarity with the original epitope that was initially Combination of chemotherapy and immunotherapy shouldselected, something that "targeted therapy" could never do, strive to maximize the immunogenic effects of chemothera-leading to improved patient survival. The possibility to use this peutics. Many questions should be raised when such combina-rationale for creating immunotherapies for cancer is examined. tions are being considered; 1) since the immunogenic effects of chemotherapeutics are pleotropic (ICD, antigen presenta- tion, adaptive and innate immune effector cells, antibodyPerspective on combination therapy response etc.) it is important to know all of them in order toThe idea that chemotherapy may increase tumor immunoge- create synergy between the chemotherapy and the immuno-nicity leading to better efficacy is old. Following cancer cell therapy, 2) what doses of the chemotherapeutics should bedeath, tumor antigens are released then processed by antigen used, 3) what is the optimal sequence of chemotherapeutics HUMAN VACCINES & IMMUNOTHERAPEUTICS 325
and immunotherapy and 4) what end points we should use to In contrast, other lectins mediate cytotoxicity through cellassess the efficacy of the intervention? Surrogate biological, internalization.41 The mechanisms of cytotoxic activity of Grif-immunological, radiological or pathological markers should be fonia Simplicifolia 1-B4 (GS1B4) and wheat germ agglutinindeveloped but ultimately, it is by proving that these interven- (WGA) lectins against various murine tumor cell lines havetions are capable of improving survival and decrease disease been described.41 Interestingly, Tumor cells that lack lectin-recurrence that they can be validated. binding carbohydrates can be resistant to lysis by these lectins. However, some cells that do express GS1B4 lectin-binding sites display low sensitivity to lysis, suggesting that the presence ofGlycans as targeted antigens for cell death lectin-binding epitopes, while essential, is not sufficient forGlycans and lectins govern cell fate.36 Among glycans are simple tumor cell lysis. Such results suggest that some intracellularones like O-GlcNAcylation with more than 1,000 O-GlcNAcy- mechanisms are involved in the regulation of lectin-mediatedlated proteins identified suggesting that targeting this epitope cytotoxicity and lectin internalization is probably required formight impact on multiple signaling pathways.37 Growing evi- their lysis.dence reveals that O-GlcNAcylation has extensive crosstalk with Natural lectin models are the Galectin family. Galectins canphosphorylation either on the same or adjacent sites of various act either extracellular or intracellular to exert effects on cellproteins.38 O-GlcNAc modifies proteins in a similar time scale as growth and apoptosis. The Galectin family uses different mech-phosphorylation; modifications that may regulate the cellular sig- anisms associated with their proapoptotic activity. On cancernaling pathways involved in cell death.39 However, there can be cells O-glycans on cell-surface glycoproteins regulate cell sensi-differences in the expression of glycans dependent on types of tivity to Galectin-1 (Gal-1) induced cell death.44 Gal-1 binds totumors.40 The GalNAcb 1 ! 4GlcNAc (LacdiNAc or LDN) LacNAc and polyLacNac ligands that constitute attractive tar-group at the nonreducing termini of both N- and O-glycans is gets for molecular imaging and potential biomarkers for can-not generally found in mammalian cells but whose expression is cer.45 In contrast, several lines of evidence indicate thatassociated with the progression of human prostate, ovarian, and galectin-7 (Gal-7) effect on apoptosis is not due to the lectinpancreatic cancers but not with breast cancer.40 functioning extracellular through interactions with cell surface In tumor cells, alterations of the components comprising the glycoconjugates.46 In fact, this lectin is found to localize in'glycosylation machinery' generate aberrant O-glycans and N- nuclei and cytoplasm of the transfectants and the transformedglycans on Fas and TRAIL receptors, which modulate apopto- keratinocyte line HaCaT. Therefore, galectin-7 is a pro-apopto-sis. Upregulation of GALNT3, FUT and GDP-FUC, as a result tic protein that functions intracellular upstream of JNK activa-of aberrant DNA methylation, increases tumor cell sensitivity tion and cytochrome c release.46to extrinsic apoptosis through TRAIL. a2–6-linked sialic acid Binding of galectin-8 modulates integrin interactions withdecorating Fas receptor on tumor cells is known to block Fas the extracellular matrix and thus regulates cell adhesion andligand internalization, Fas–FADD complex formation and acti- cell survival.47 It was proposed that galectin-8 acts as an integ-vation of caspase-8 and ¡3, thus attenuating cell death via the rin binding-protein that exerts down-modulatory effects onextrinsic pathway. Intracellular and extracellular galectins can integrin receptor functions.47 Several signal transduction path-modulate survival and apoptotic signaling pathways in tumor ways were implicated in mediating anti-adhesive example, by acells. Intracellular galectin-1 decreases Akt activity and induces Ras/Raf- initiated MAP kinase pathway that suppresses integrinapoptosis. By contrast, intracellular galectin-3 either free or activation.48 In Jurkat T cells Gal 8 induces a complex phos-associated with C2-ceramide cooperates with PI3K/Akt to pholipase D/phosphatidic acid signaling pathway.49 It wasincrease tumor cell survival. demonstrated that Gal-8 increases phosphatidic signaling, Understanding how lectins regulate cell viability and func- which enhances the activity of both ERK1/2 and type 4 phos-tion can broaden our knowledge of the roles of such molecules phodiesterases (PDE4), with a subsequent decrease in basalin basic biological processes but can also facilitate development protein kinase A activity. The resulting strong ERK1/2 activa-of therapeutic applications. Models for triggering apoptosis of tion was purposed for the expression of the death factor Fastumor cells mediated by glycan recognition are those associated ligand and caspase-mediated apoptosis.49with lectins.22,41,42 For example, Mistletoe lectins are reported Galectin-9 (Gal 9) possess the anticancer properties by regu-to induce apoptosis in different cancer cell lines in vitro and to lating various cellular functions, such as cell adhesion, cellshow antitumor activity against a variety of tumors in animal proliferation, and induces apoptosis through the calcium-models. Viscum album var coloratum, (VCA)-induces apopto- calpain- caspase-1 pathway.50 It has been suggestedsis by downregulation of Bcl-2 and telomerase activity and by Gal9-induced apoptosis is mediated by the activating transcrip-upregulation of Bax through p53- and p21-independent path- tion factor 3 (ATF)-Noxa pathway, but is independent of p53way in hepatoma cells.42 In other studies it was observed that or Bcr-Abl.51the induction of apoptotic cell death could be mediated throughactivation of caspase-3 and the inhibition of telomerase activity Antibodies as mimics of lectinsthrough transcriptional downregulation of hTERT in VCA-treated cells.43 Choi et all also demonstrated that the dephos- Numerous studies have shown that antibodies can substitutephorylation of Akt leads to inhibition of telomerase activity for lectins and mediate tumor cell death.24,25,52 There is anand concluded that VCA induces apoptotic cell death through emerging awareness that immune surveillance mechanismsAkt signaling pathway, correlated with the inhibition of telome- that include antibodies and effector cells are intimately relatedrase activity, and the activation of caspase-3.43 to TACA reactivity that provides a template for developing326 T. KIEBER-EMMONS ET AL.
strategies for cancer immunotherapy because of the display of Immunization with a common ligand would then induce subpo-glycans in the context of pattern recognition. Both natural anti- pulations of antibodies that could see a variety of carbohydratebodies and vaccine-induced antibodies with reactivity to TACA epitopes on various determinates. This approach would thereforehave demonstrated oncolytic properties.24,25,52-54 The fact that induce a broad-spectrum of antibodies with varying specificitiesmultiple proteins and lipids on cancer cells are modified with that would recognize a distinct yet relevant set of TACA.the same carbohydrate structure creates a powerful advantage We tested the hypothesis that mimicking the hydrogen bondfor TACAs as cancer targets in immunotherapy strategies. pattern through amino acid substitutions in a CMP, to be coin-Most anti-glycan antibodies recognize epitopes of 2 or 3 sugars. cident with that for the carbohydrate ligand, will enhance theConsequently, antibodies can cross-react with various terminal ability of CMPs to elicit the desired anti-TACA antibodies withstructures. This property of recognizing epitopes "shared" by high titers and association constants.60 In this exercise wedifferent molecules is characteristic of anti-glycan antibodies, developed the CMP, termed P10 with primary structure,and can be considered an example of "antigen mimicry." GVVWRYTAPVHLGD from a random peptide library screen Human hybridoma technology for isolating antibodies from using the anti-GD2/GD3 antibody ME36.1.59 Conformationalcancer patients indicated that tumor-specific antibodies were and docking studies suggested that variants of P10 could formgerm-line coded and belonged nearly exclusively to the IgM more hydrogen bonds with ME36.1 that are in common withclass.25 Furthermore, they all bound to new carbohydrates on the GD2 hydrogen bond interaction pattern with ME36.1. Thispost-translationally modified cell surface receptors on malig- increased level of mimicry would suggest that a more specificnant cells. The IgM induced cell death involves classical fea- immune response to GD2 should be enhanced. Subsequently, atures of apoptosis such as nuclear fragmentation and activation shortened version of the CMP P10 (WRYTAPVHLGDG)of caspases.24,25,52 Monoclonal antibodies, such as anti-GD2 developed which showed anti-tumor activity in mice.62 Still, weantibodies, can mediate apoptotic pathways extracellularly, observed that P10s reacted also with various lectins and withwhereby apoptosis signals were transduced via reduction in the an anti-LeY antibody. This indicated that P10s, as an immuno-phosphorylation levels of focal adhesion kinase (FAK) and the gen, could have induced a broad spectrum of antibodies withactivation of a MAPK family member, p38, upon the antibody TACA reactivity's suitable for pan immunotherapy.binding.55 Knock down of FAK resulted in apoptosis and p38 In our studies P10s was shown to bind to human antibodyactivation. fractions with polyspecificity for a mistletoe determinate, in The inhibition of p38 activity blocked antibody-induced addition to lactose, fucosyl-lactose, sulfate fucosyl-lactose,apoptosis, indicating that p38 is involved in this process. sLNLex, Tn, blood group B, blood group A, GD3, GD2, GM2Immunoprecipitation-immunoblotting analysis of immune and LeX, LeY along with several more glycans.63 The antibodyprecipitates with anti-FAK or anti-integrin antibodies using an fraction isolated by the mimetic peptide also block migration ofanti-GD2 mAb revealed that GD2 could be precipitated with cancer cells.63 In a phase I clinical trial P10s immunization ledintegrin and/or FAK. These results suggested that GD2, integ- to antibodies that mediated cell death extracellularly.54 Otherrin, and FAK form a huge molecular complex across the plasma CMPs where shown to mediate apoptosis of cancer cells intra-membrane. Taken together with the fact that GD2C cells cellularly, meaning the antibodies are internalized.53 Conse-showed marked detachment from the plate during apoptosis, quently, P10s and CMPs can induce antibodies that functionGD2C small cell lung cancer cells seemed to undergo anoikis like lectins mediating cell death.through the conformational changes of integrin molecules and Extracellular mediation of cell death may be through severalsubsequent FAK dephosphorylation.55 pathways. Since the mimetic peptide reacts and induces antibod- Gangliosides are also sialic containing moieties. Ganglio- ies reactive with GD2/GD3/GM2 reactivity it is hypothesizedsides are ubiquitous membrane glycosphingolipids modulate that these antibodies might be associated with mechanisms asso-cell proliferation, adhesion, migration, and differentiation ciated with anti-GD2 monoclonal antibodies operating throughprobably through their effects on transmembrane signaling. FAK or through down regulation of BCL¡2. It is possible thatExogenous expression of sialic acid binding Haliotis discus dis- peptide-induced antibodies play a role in sensitizing tumor cellscus lectin (HddSBL) induced apoptosis in several cancer cell for more efficient activity of some therapies.54 Docetaxel notlines, probably through down-regulating anti-apoptosis factor only inhibits microtubule formation but can also downregulateBcl¡2.56 The same is observed for VCA that binds to galactose- expression of Bcl¡2, a known antiapoptotic oncogene. It is possi-and N-acetyl-D-galactosamine. Combining VCA with doxoru- ble that peptide reactive antibodies contribute to downregulatingbicin (DOX) suggests that downregulating Bcl¡2 makes cells BCL¡2 and/or FAK silencing known to promote the in vitro effi-susceptible to chemotherapy.57 Therefore, downregulating cacy of docetaxel in both taxane-sensitive and taxane-resistantBcl¡2 by a panspecific response – reactivity to sialic acid cell lines and may serve as a novel therapeutic approach. Themoieties that includes gangliosides and/or galactose- and same is observed for Pertuzumab and for Trastuzumab. Combi-N-acetyl-D-galactosamine would be an approach to make these nation of antibodies induced by P10s-PADRE and at least doce-cells susceptible to chemotherapeutics. taxel might have a clear beneficial result. We have taken an active therapy approach to targeting TACAusing carbohydrate mimetic peptides (CMPs).53,58-61 In the devel- Picking patient populations to benefit from TACAopment of our CMPs we reasoned that CMPs function as pan targetingimmunogens inducing antibodies that recognize multipleTACAs. Immunization with a CMP functions like a polyvalent Breast cancer diagnosis and clinical trials have provided insightTACA-based vaccine but the immunogen is a single entity. on the molecular characteristics of breast cancer. Treatment HUMAN VACCINES & IMMUNOTHERAPEUTICS 327
combinations targeting receptor signaling that block the cross- represent a valid surrogate end-point for long-term outcomes,talk between pathways and eliminate escape routes have been including progression-free survival and overall survival thatproven highly effective in preclinical models. Results of recent usually serve as primary end-points in trials in adjuvant or met-clinical studies, while partly supporting this approach, also astatic disease settings.71 Changing the pCR rate can affect stan-highlight the need to better identify a priori the appropriate dard of care. The FDA has accepted the proof of activity of anpatients whose tumors are most likely to benefit from specific experimental agent in neoadjuvant trials with PCR as the pri-co-targeting strategies. Cancer cells on the brink of apoptosis mary end-point as the evidence for approval,74 as exemplifiedare more likely to respond to certain chemotherapy agents than for subcutaneous trastuzumab by the HannaH trial.75 Morecancer cells that have yet to reach that stage.64 It has been pro- recently, the FDA used the findings from a meta-analysis show-posed that tumor growth may be more accurately determined ing an increase percentage of pCR rates71 to support theby the outcome of the balance between tumor cell proliferation approval of pertuzumab (Perjeta) in the neoadjuvant setting.76as indicated by the high expression of the proliferative marker There is an important practical consideration for neoadju-Ki67 on the one side and apoptosis as indicated by elevated vant therapy. FDA guidance renders pCR as an adequate pre-activation of caspase-3 on the other.64 dictor for studying combination therapy in high-risk Gene expression profiling has led to the molecular classifica- populations comprised compare with those that hormonetion of breast cancer characterized by 4 intrinsic subtypes: receptor positive but of low grade. Triple Negative andbasal-like, HER2-positive, luminal-A, and luminal-B.65,66 luminal-B populations typically have Ki67 expression levels ofAlthough luminal-A and B subtypes are frequently treated as > 14% in keeping with the idea that chemotherapy is mostsimilar entities, there are obvious differences in the tumor's bio- effective at killing cells that are rapidly dividing. While display-logical and prognostic characteristics. An important major dif- ing a high cell proliferation rate as determined by the Ki67 bio-ference is that luminal-B has lower expression of estrogen marker, the emphasis on this population is because of thereceptor (ER)-related genes and higher expression of prolifer- unfavorable prognosis with existing therapy compare with low-ative genes.67,68 Traditional classification systems regarding grade, hormone receptor-positive tumors (so called luminal-A)biological characteristics, such as tumor size, lymph node that have a more favorable long-term prognosis and are moreinvolvement, histological grade, patient's age, ER, progesterone likely to do well with currently available therapy. The luminal-receptors (PR) and HER2 or c-erbB2 status, may have limita- A tumors have low proliferation rate (Ki67 <14%), hence ittions for patient-tailored treatment strategies. Among ER-posi- takes longer to acquire all the needed changes and to reach thetive types of breast cancer, the luminal-A subtype breast cancer clinical detectability level while the triple negative is morehas been shown to exhibit good clinical outcomes with endo- proliferative.crine therapy, whereas the luminal-B subtype represents the Luminal-A cancers, however, represent a significant con-more complicated type, diagnostically as well as therapeutically. tinuing challenge, because if patients with these tumors presentThis subtype has a higher recurrence rate and lower survival with a high tumor burden with 4 or more positive nodes, theirrates after relapse compare with luminal-A subtype. For lumi- outcome with endocrine therapy remains largely unsatisfactory.nal-A type breast cancers, the most common subtype that rep- The benefit from chemotherapy is either very minimal or non-resents 50–60% of all breast cancers, the addition of existent suggesting that luminal-A tumor's and some luminal-Bchemotherapy to endocrine therapy generally provides little tumors are de novo resistant to chemotherapies. The effective-benefit.69 ness of endocrine therapy is limited by high rates of de novo or An effort to associate clinical benefit of treatment strategies intrinsic resistance (existing before any treatment is given) andrelative to molecular subtype is perhaps best typified by studies acquired resistance during treatment (resistance that developsin the neoadjuvant setting. Neoadjuvant systemic therapy is a during a given therapy after an initial period of response). Onestandard of care for patients with inflammatory and locally third of patients will have recurrent disease within 15 y afteradvanced breast cancer, and is increasingly being used for being treated with tamoxifen for 5 y. About 50% of patientsearly-stage disease70; mostly with the aim of increasing the with metastatic disease do not respond to initial endocrinechance of achieving breast-conserving surgery. Moreover, the treatment77 Inevitably the vast majority of patients with ER-neoadjuvant setting is being increasingly used to study the positive advanced breast cancer will become refractory to endo-activity of new drugs or new regimens because the primary crine therapy. Consequently, luminal-A tumors do not deriveendpoint of the trial is reached earlier in a neoadjuvant study much benefit from chemotherapy, and pCRs in this subgroupcompare with adjuvant trials or trials in patients with meta- are not very predictive of outcomes. If we were to find a way tostatic breast cancer. sensitize tumor cells to standard chemotherapy will pCR for Prominent for clinical benefit is the shrinkage of a tumor, i.e. this subpopulation become predictive?pathological response, prior to its removal. Studies have dem- TACA are involved in tumor cell dissemination and in dor-onstrated that pathological complete response (pCR) is the mancy.78 Circulating Tumor cells can evolve with the expres-most significant prognostic factor in patients with breast cancer sion of different TACA moieties that affect distant tumor celltreated with neoadjuvant therapy.71,72 Overall, patients with dissemination and organ colonization. These disseminatedbreast cancer who experience a pCR with neoadjuvant chemo- tumor cells (DTCs) carry the same indolent nature of the pri-therapy have significant improvements in both disease-free sur- mary tumor but as they are evolving independently from thevival (HR 0.48, 95% CI: 0.37–0.63) and overall survival (HR primary tumor and are undergoing different environmental0.48, 95% CI: 0.33–0.69) compared with patients with residual pressures they end up acquiring different genetic/epigeneticinvasive disease.73 Therefore, pCR is considered by some to changes; so, even if you have a treatment that kills all the328 T. KIEBER-EMMONS ET AL.
primary cancer you may not be able to eradicate the DTCs or studies of lectins used to explore particular signaling pathwaysmicrometastases. that are important to cancer cell survival. Improving pCR in Altered sialylation has long been associated with metastatic populations whose pCR rates are intrinsically low is a validcell behaviors including invasion and enhanced cell survival; strategy in the development of new treatment regimens thathowever, there is limited information regarding the molecular may correlate with clinically meaningful improvement in can-details of how distinct sialylated structures or sialylated carrier cer therapies.proteins regulate cell signaling to control responses such asadhesion/migration or resistance to specific apoptotic path- Abbreviationsways.79 Sialic acid-binding lectin (SBL) is a multi-functionalprotein that is isolated from oocytes of Rana catesbeiana which TACA Tumor Associated Carbohydrate Antigensdisplays caspase 3 dependent killing of cancer cells.80 Selective NK cellpCR Natural Killertreatment of cell lines with SBL revealed that SBL induces cell ICD Immunogenic cell deathdeath on estrogen receptor (ER)-positive breast tumors but not DAMPs Damage associated molecular patternson ER-negative breast tumors.81 The anti-tumor effect of SBL- DOX Doxorubicintreated ER-positive breast tumors is accompanied by the down- ER Estrogen receptorregulation of ER and Bcl-2.81 They also showed that Bcl-2 over- VCA Viscum album var. coloratumexpression, but not Bcl-XL overexpression, significantly GS1B4 Griffonia Simplicifolia 1-B4inhibits the effect.81 WGA Wheat germ agglutinin Gene expression profiling of luminal-A type cells suggest FAK Focal adhesion kinasethat Bcl-2 is upregulated in these cells, which indicates that HddSBL Haliotis discus discus lectinthey are perhaps resistant to cytotoxic chemotherapy. Reduced SBL Sialic acid-binding lectinsensitivity to various chemotherapeutic drugs is well known to CMPs Carbohydrate mimetic peptidesbe mediated by high levels of the anti-apoptotic protein Bcl-282 PR Progesterone receptorsand a low Ki67 expression profile, typical for luminal-A. If we HER2 or c-erbB2 Human epidermal growth factor receptor 2can overcome Bcl-2 resistance we can optimize for other breast Ig Immunoglobulincancer subtypes. Breast tumor cells overexpressing Bcl-2 ishypothesized to become more resistant to chemotherapy, butthey have a less aggressive behavior (they are less able to pro- Disclosure of potential conflicts of interestduce metastasis), and for this reason primary tumors contain- TKE, BMK, and UAMS have a financial interest in the technology dis-ing Bcl-2 overexpression can be related to a better survival. cussed in this manuscript. This interest has been reviewed and approvedWhile Bcl-2 inhibits apoptosis, its overexpression is associated in accordance with the UAMS conflict of interest policies. The otherwith hormone refractory cancer.83 The antagonism of Bcl-2 in authors have no financial interest to declare. A patent has been filed onERC tumors might enhance the effectiveness of predominately the vaccine.proapoptotic treatments even more than it does from combina-tion with endocrine therapies. Targeting sialic acid moieties Acknowledgmentsusing antibodies that function like SBL or using SBL directlymight be synergistic with chemotherapies or with targeted ther- We thank the subjects that participate in clinical trials.apies. Because diminished Bcl-2 expression in cancer confersincreased sensitivity to cytotoxic chemotherapy, it is possible Fundingthat breast cancer patients with endocrine-resistant diseasecould achieve significant therapeutic benefit from cytotoxic A Clinical Translational Award from the Department of Defense Breastagents when used as a second-line treatment. Sensitizing tumor Cancer Program (W81XWH-06–1–0542) to TKE supported this work. Also supported by the UAMS Translational Research Institute (TRI),cells with TACA reactive antibodies that facilitates downregula- UL1TR000039 through the NIH National Center for Research Resourcestion of Bcl-2 or interrupts survival-signaling pathways to and National Center for Advancing Translational Sciences and the UAMSenhance the cytotoxicity of standard Chemotherapy would pro- Center for Microbial Pathogenesis and Host Inflammatory Responses, P20vide a new molecular platform for the development of thera- GM103625. 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Cheap Flights from New York to Beijing - Get Upto 40% Off
Winning Position: Unresolved
89 days ago
Beijing is the capital of China and here you will find a perfect amalgamation of the modern and old civilization. You can visit the Summer Palace here which was once used to be an imperial garden belonged to Qing dynasty. So, to visit such places get Cheap Flights From New York To Beijing from our website. If you also want to enjoy and experience the rich culture of Beijing then make a call on our toll-free number to consult with our expert's team for any of your queries. We ensure low rates on hotel reservation, holiday packages and on Cheap Flight Tickets Get Upto 50% Discount It is one of the leading top online flight booking site which basically hails from USA & . Get assistance 24/7 Call at +1 (877) 728 8804 on any kind of travel related query. We are happy to assist you.
Cheap Flights from Amsterdam To London - Get Upto 50% Off
Winning Position: Unresolved
84 days ago
London is one of the most popular and richest cities in the world. It is the capital of England and United Kingdom .If you want to book Cheap Flights From Amsterdam To London. You will not forget the journey in your life when you reach us by dialing our mentioned toll-free number to book. Schiphol airport has a single large terminal which is split into three distinct departure halls. If you are ready to visit Amsterdam call on our reservation Phone Number +1 (877) 728 8804 to book Cheap Airline Tickets from Amsterdam to London and get the help you need.
Book Flight With United Airlines Phone Number - Get Upto 30% Off
Winning Position: Unresolved
80 days ago
If you wish to fly with the United Airlines and benefit from its premium services, here is a chance to save up to 30%. In case getting any issues then call us at United Airlines Phone Number any time.Our helpline is accessible 24/7. You can reach our experts and tell them the required details. They will give you a variety of options to choose from. Select an option and make your payments for Buy Cheap Airline Tickets and Get Upto 30% Off . You can either use a credit card or payment gateway for the same purpose. You can Dial +1 844 516 2170 this number for any kind of help.
Cheap Flights From New York To Oslo Norway – Get Upto 45% Off
Winning Position: Unresolved
76 days ago
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That a change in Fortnite item
Winning Position: Unresolved
347 days ago
fortnite weapons
Fortnite items
Sony was reluctant to guarantee that a change in Fortnite items its coverage, and a former Sony studio venture recently came forward to say that based on his time inthe company, the choice was about cash.Battle Royale' Leak Tell Us What's Happening With the Missile?Many people thought the thing was heading for Tilted Towers as part of a broad-scale map rebalancing to reduce the city's significance in the present meta. The theory was that it would level tilted and afterwards activate some type of dinosaur or post-apocalyptic-themed Season 4. Certainly, that didn't happen, but one Reddit user was telling us all along. InternetAdam turned out to have some real intel on Season 4, right forecasting both the Dusty Depot impact along with the superhero motif. And so we wonder:nternetAdam's other prediction about Season 4 was that the map was about to start changing weekly in small ways rather than all at the same time, and that came true. And so with a batting average of 1000, we flip into the Cheap fortnite materials oracle's final prediction: that Moisty Mire would seem totally different by season's end. With the missile now threatening to launch any time out of theirsupervillain lair near Snobby Shores, the idea that it could blow up the film series now sitting at the swamp?All FortNite STW products 50% OFF :https://www.mmogo.com/News/christmas-2018-carnival.html
Lufthansa Airlines Cheap Flights
Winning Position: Unresolved
163 days ago
Lufthansa Airlines offering cheap cost flight ticket and providing one of the best option to reserve your flight seat cheaper like flight deals, ticket on sale, coupon code, reward points and several travel packages and offers to get flight ticket on discount rates. for more information, visit here - https://www.godhelpu.com/lufthansa-airlines-cheap-flights
Barcelona tourist area
Winning Position: Unresolved
101 days ago
If you're not familiar with Barcelona, the first place to head out to is Las Ramblas, the medieval Old Town district, with narrow little streets. It's a busy Barcelona tourist area during the day with shops and street musicians, but popular at night for its many restaurants, clubs, and bars. A few popular clubs are Kiosk La Cazalla, Sports Bar Rambles, and the Boadas Cocktail Bar.
Cheap Flights From Chicago to New York - Get Up to 60% Off
Winning Position: Unresolved
90 days ago
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text: Looking for ideas to be able to have a CB radio on my trike. I have been using a hand-held Cobra with plug-in ear-bud with microphone - hard to use the PTT button on the microphone while riding and some messages are hard to hear. I would like to go to using in-helmet ear pieces and microphone with push-to-talk controls on the handlebars. This would probably mean installing a radio unit somewhere on the trike (possibly in the very small trunk) and wiring controls to the handle bars with a plug-in to the headset or possibly using a blue-tooth connection for the headset. Reports I get suggest that having such a radio installed in costly. So I am hoping to find a compact CB unit that I can fit to my trike and complete the connections. I am sure there riders who have done something like this. Look forward to feedback.


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Will climate change cause earthquakes?
Bill McGuire, author of 'Waking the Giant: How a changing climate triggers earthquakes, tsunamis, and volcanoes', discusses the topics raised in his book. Twenty thousand years ago our planet was an icehouse. Temperatures were down six degrees; ice sheets kilometres thick buried much of Europe and North America and sea levels were 130m lower. The … Continue reading Will climate change cause earthquakes?
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text: Kinetic Concealment posted an update in the group Giveaways 1 year, 12 months ago Guys, here is a giveaway we found with Crosman Airguns. https://app.viralsweep.com/sweeps/full/1bb4c0-28561&framed=1 5 people like this. David Brown replied 1 year, 12 months ago This isn't one of those I signup and just get loaded with emails things is it?


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The biggest change in the new Apple TV is that it can finally run third-party apps. That means you'll be able to download popular iPhone apps and games that have been optimised for the big screen.
Apple gave a preview of a few apps that will work on its set-top box in September, like the shopping app Gilt, but now we have larger list of apps and games that will be available on the device from day one.
For example, the hit iOS game "Alto's Adventure" will be ready for the Apple TV when it goes on sale in stores Friday.
Here's a list of 23 apps that will be ready:
- Periscope
- Zillow
- Airbnb
- Houzz
- Craftsy
- Gilt
- Kitchen Stories Cookbook
- Yummly
- Gaia
- Madefire Motion Books
- Sing! Karoke
- Storehouse
- Newsy: Video News
- WATCH Disney Junior
- Rayman Adventures
- Beat Sports
- Galaxy on Fire
- Oceanhorn
- Duet Game
- Mr. Crab
- SweetLand — Family Board Game
- Alto's Adventure
NOW WATCH: You can talk to the new Apple TV — here's what it looks like
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Site highlights each day to your inbox.
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Kalnciema iela 52,
Pearl of Agenskalns is located in a quiet area of Riga on the left bank of the Daugava River, 3 km from the Old Town. It offers self-catering accommodation with free Wi-Fi and private parking. The apartment was renovated in a contemporary style, but with some original elements remaining, for example exposed brickwork or a tiled stove. It is situated on the 3rd floor, without lift. The rooms are classically furnished and decorated in pastel colours. There is a bathroom with a shower and a well-equipped kitchen. The Botanical Garden is 2 km away. The Riga International Airport is about 7 km away. Pearl of Agenskalns is 1.5 km from the Spice Shopping Centre.Please let Pearl of Agenskalns know your expected arrival time in advance. You can use the Special Requests box when booking or contact the property.


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Throughout every trilogy and movie in the Star Wars universe, Chewbacca has been a constant character who symbolizes trust and friendship. Whether it be working with Han Solo or flying the millennium falcon for the cause of the resistance, Chewie has always been a force for good. Now in the form of this collectible Geeki Tikis tumbler, Chewbacca once again is the ever diligent companion in the war against dehydration. Load this tumbler up with your favorite drink or some ice cold water and Chewbacca will make sure that you always have a delicious beverage on hand! Complete with a matching lid and straw, take home this magnificent piece of the Geeki Tikis Star Wars collection today!
Combining the popular fashion of tiki cups with amazing pop culture icons, Geeki Tikis has created a product line for geeks, nerds, and super-fans to enjoy their favorite drinks with their favorite characters! Made from durable quality plastic, each cup is designed to deliver stunning details while also being durable enough to quench your thirst round after round! Enjoy the magic of Geeki Tikis tumblers and collect the complete set of your favorite series!


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Browsing Lean Advancement Initiative (LAI) by Title
Now showing items 655-674 of 1027
Measuring the Efficiency of Commonality Implementation: Application to Commercial Aircraft Cockpits (2007-04-17)Increasing commonality across their models allows commercial aircraft manufacturers to reduce the product development cycle time and tailor their models to their customers' needs. The cockpit is an area where commonality ...
Mechanisms for Interteam Integration: Findings from Five Case Studies (1997-08-03)Many product development programs consist of multiple integrated product teams (IPTs) and functional groups. Interteam information dependencies greatly affect program success. Program integration has thus become an ...
Merging Lean and Six Sigma Programs to Realize Enterprise Excellence (2009-04-01)LAI Annual Conference presentation, Baltimore, Maryland
A methodology for implementing total productive maintenance in the commercial aircraft industry (Massachusetts Institute of Technology, 1996)
Methodology for sizing finished goods inventories for a vinyl siding extrusion plant (Massachusetts Institute of Technology, 1999)
Methods of Integrating Design and Cost Information to Achieve Enhanced Manufacturing Cost/Performance Trade-offs (1995)In this paper we address problems which arise when large organizations attempt a tight integration of design and cost while developing complex products. Topics include the sources of cost and design data, the arrangement ...
Metric Commonality Across an Operating Life Cycle (2010-03-23)Student research poster, LAI Annual Meeting, Dana Point, CA
Metrics for enterprise transformation (Massachusetts Institute of Technology, 2009)The objective of this thesis is to depict the role of metrics in the evolving journey of enterprise transformation. To this end, three propositions are explored: (i) metrics and measurement systems drive transformation, ...
The micro-foundations of alignment among sponsors and contractors on large engineering projects (Massachusetts Institute of Technology, 2006)Large engineering projects design, engineer and construct much of the world's energy, transportation and defense infrastructure. These large scale engineering endeavors are highly visible, have long lasting impacts and are ...
Mission Emphasis and the Determination of Needs for New Weapon Systems (2009)Student research poster
Mission emphasis and the determination of needs for new weapon systems (Massachusetts Institute of Technology, 2009)Efforts to understand the determination of needs of new weapon systems must take into account inputs and actions beyond the formally documented requirements generation process. This study analyzes three recent historical ...
Mitigating the risk of a new workforce by reducing rework and rightsizing on hand inventory (Massachusetts Institute of Technology, 2009)Dramatically increasing the hourly workforce at a rapid pace to support accelerated product demand in an aircraft manufacturing facility in a short amount of time resulted in: (1) increased rework, and (2) increased part ...
Modeling and analyzing cost, schedule, and performance in complex system product development (Massachusetts Institute of Technology, 1999)
Modeling and Understanding Complex Enterprise Behavior using a Hybrid Simulation Approach (2009-01-21)Today, the design of enterprises is much more art than science. The complex structure and behavior of enterprises makes it difficult to untangle cause and effect amidst the enterprise's components and their relationships. ...
Modeling the Product Development Enterprise Methods, Decisions and Metrics (2006-04-18)Presentation on modeling the product development enterprise
Models for Analyzing Complex System Development Cost, Schedule, and Performance Risks (1998-10-14)Lean Aerospace Initiative Plenary Workshop presentation


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Genesis Counseling Services Ltd
Genesis Counseling Services Ltd is a Dual Diagnosis Substance Abuse Rehab in Janesville, WI
Address: 1 South Main Street , Janesville, WI, 53545
Phone Number: 608-757-0404
Intake Line:
Website: http://www.genesiscounselingservices.com
Primary Focus: Dual Diagnosis Substance Abuse Rehab
Treatment Type: Outpatient, Regular outpatient treatment
Treatment Approaches: Cognitive/behavioral therapy, Substance abuse counseling approach, Trauma-related counseling, Rational emotive behavioral therapy
Payment/Insurance Accepted
- Cash or self-payment, Medicaid, Medicare, Private health insurance, Military insurance (e.g., TRICARE)
Payment Assistance
- Payment assistance (check with facility for details)
Type of Care:
- Substance abuse treatment , Naltrexone (oral), Accepts clients on opioid medication
Facility Operation:
- Private organization
Special Programs Provided:
No information available, please contact the facility directly.
We have made our best effort to provide you with all of the information we have pertaining to Genesis Counseling Services Ltd. This includes all contact information such as phone numbers and links to websites.
Other Rehabs Near Genesis Counseling Services Ltd
Lutheran Social Services Alcohol and Drug Treatment Unit
612 North Randall Avenue
Suite A
Janesville, WI, 53545
Janesville Psychiatric Clinic
15 West Milwaulkee Street
Suite 207
Janesville, WI, 53548
Mercy Options Addictions Day Treatment
903 Mineral Point
Janesville, WI, 53548
Rock Valley Community Programs Inc
203 West Sunny Lane Road
Janesville, WI, 53546
Beloit Health Systems Counseling Care
1969 West Hart Road
Beloit, WI, 53511
Quality Addiction Management (QAM)
2240 Prairie Avenue
Beloit, WI, 53511
Mercy Options Behavioral Health Clinic
2825 Prairie Avenue
Beloit, WI, 53511
Oceanhawk Counseling Alternatives LLC
135 West Main Street
Suite 207
Stoughton, WI, 53589
Fort Healthcare Behavioral Health
500 McMillen Street
Fort Atkinson, WI, 53538
Walworth County Health and Human Servs
West 4051 County Road NN
Elkhorn, WI, 53121
Jefferson County Human Services Dept
1541 Annex Road
Jefferson, WI, 53549
Credence Counseling Therapy Associates
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Elkhorn, WI, 53121
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Hosanna! to host women's event on human trafficking
At 7 p.m. Friday, April 5, Hosanna! Lutheran Church in St. Charles will be hosting a women's event featuring guest speaker Sharmila Wijeyakumar, founder of Rahab's Daughters.
She will present information on human trafficking. The organization specializes in rescue, rehabilitation, and reintegration of survivors of trafficking. They offer survivors of human trafficking shelter, clothing, education, vocational training, and the ability to create a dream plan that empowers them to start making choices for their own lives and break free from being controlled by someone else.
All women over 18 years old are welcome to attend this free event; please register in advance. For more information about Rahab's Daughters go to rahabsdaughters.org.
To register to attend or to get more information, call the church office at (630) 584-6434, email at email@example.com or visit www.HosannaChurch.com. Hosanna is located at 36W925 Red Gate Road, with the entrance just east of Randall Road, in St. Charles.
Hosanna! is located just east of Randall Road in St. Charles.


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My favorite season is just around the corner. I am so ready to say hello to chilly weather, football games, and pumpkin flavored everything! It's so fun to switch out decor this time of year to make your home feel more cozy. I'm not super into the over-the-top rustic and harvest look since it doesn't really fit my space, but I've pulled together some of my favorite fall inspo that keeps it clean and modern.
To help you decorate, I've also created 3 adorable free fall printables for you! You can download your favorite at the end of this post!


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Taxis in CW98
- 1
Time & PlaceLocal taxis in cw9801606 88268401606 88268428 St. Marys Drive , Northwich , CW82EZ
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Friendly and Reliable Taxi serviceThe purpose of Time @ Place is to provide a quality Taxi service within Vale Royal offering competitive pricing. We pride ourselves on smart, reliable, and experience drivers. Time & Place uses an all leather vehicle with full air con that can carry six passengers.Latest reviews
Best taxi company in the Cheshire area by a mile. Lyndon is a fantastic driver and the consummate professional and always punctual, helpful, polite and friendly. Don't travel by any other taxi company.THANKSRegular traveller in Northwich11 Mar 16
I never write reviews but felt compelled to write this one. He was absolutely professional, punctual and courteous. Carried all the cases, asked what radio station I preferred as it was a long journey. We chatted and I asked what he used to do and he said he said used to work in the service industry. Well it shows.. Couldn't recommend enough and he deserves his five stars.Fi in Sale19 Jan 16
When I was let down by another company Time & Place stepped in and delivered impeccable service! Punctual, helpful, polite and friendly! The taxi was clean, journey was comfortable and it is clear that there is a real pride in great quality service! I could not recommend more highly!Rescued Lawyer25 May 15
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Exxon Mobil Makes Monster Profit
Exxon Mobil Corp. on Friday posted the largest annual profit by a U.S. company - $40.6 billion - as the world's largest publicly traded oil company benefited from historic crude prices at year's end.
Exxon Mobil also set a U.S. record for the biggest quarterly profit, posting net income of $11.7 billion for the final three months of 2007, besting its own mark of $10.71 billion in the fourth quarter of 2005.
The previous record for annual profit was $39.5 billion, which Exxon Mobil reported for 2006.
The eye-popping results weren't a surprise given record prices for a barrel of oil at the end of 2007. For much of the fourth quarter, they hovered around $90 a barrel, more than 50 percent higher than a year ago.
Crude prices reached an all-time trading high of $100.09 on Jan. 3 but have fallen about 10 percent since.
The record profit for the October-December period amounted to $2.13 a share versus $1.76 a share in 2006. Year-ago net income was $10.25 billion.
Also extraordinary was Exxon Mobil's revenue, which rose 30 percent in the fourth quarter to $116.6 billion from $90 billion a year ago.
For the year, sales rose to $404.5 billion - the most ever for the Irving, Texas-based company - from the $377.64 billion it posted in 2006.
In a statement, Exxon Mobil Chairman Rex Tillerson said the company continued to meet the world's energy needs through its "globally diverse resource base."
"Our long-term investment program, in projects often far from major consuming nations, continued to provide resources essential to the increasingly interdependent global energy supply network," Tillerson said.
Exxon Mobil produces about 3 percent of the world's oil.


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Last year could hardly be called a failure for the Staples football team. The Wreckers went 7-3, reaching the state playoffs before being routed by eventual champion Darien in the opening round.
But coach Marce Petroccio holds his program to the highest standards, the result of five league and three state titles during his 23 years at the school. The trophy case has had no new additions since 2012.
That could change this fall. The Wreckers have their most experienced team in years, one that should compete for the best record in the FCIAC. The lone setback was the news last week that star running back Ethan Burger will sit out this season after suffering a torn ACL in the loss to the Blue Wave.
Staples will have to navigate a tough back-end schedule, but the pieces are in place to handle the challenge.
The Wreckers opted not to have spring practice and started conditioning practice on Monday. We caught up with Petroccio Monday night to discuss the state of the team.
The Ruden Report: You have been pretty upbeat talking to you several times in the past month. Are you a poker player holding a strong hand and not trying to hide it?
Marce Petroccio: We're excited by the fact that we have a lot of returning starters on the offensive side of the ball. This group is hungry to try to prove something. Not that every other group is not hungry but they just go about it a little bit differently. I think the team chemistry is very good. These kids want to do well. We're excited for the season to start.
TRR: Even though it is not with pads on is the first day of conditioning a big deal?
MP: We went to some camps and the conditioning today we did extra hard. We conditioned all summer and we put more on the kids and I think they responded well. It's football and I'm excited that football is back. It seems like yesterday we just played Greenwich and Darien. I'm excited to be back, the coaches are excited to be back, the kids are excited. It's a great feeling to go to practice every day.
TRR: Other than the injury to Ethan Burger we haven't heard a lot out of Staples in the offseason. Have there been any major changes?
MP: We did a 7 on 7 in league in Norwalk and we had a lot of success there. What's going on with our kids is we can take our time now and work on fundamentals. It was strange not having spring football but starting early is good for us. I'm excited to see how we compete. We are going to have a scrimmage with New Canaan, Hand and possibly Southington. We will see exactly where we stand. We have a lot of depth at a lot of positions.
TRR: Not in a cocky way but in recent weeks you have given off an air that you have a lot of confidence in what this team can do. Is that accurate?
MP: I do. Potential is just another word for haven't done anything yet but listen, I think we have some experience at key positions. We haven't had that in a while. This senior group with the senior leadership is special. The chemistry is just unbelievable. I have been coaching here 24 years and I can tell when that team has a certain kind of it factor going for it. Unless I am reading this thing wrong, which I could be, I think we are just a different football team than in past years.
We're excited by the fact that we have a lot of returning starters on the offensive side of the ball. This group is hungry to try to prove something.
TRR: Now that you all have had a little time to digest it what is the feeling about losing Ethan?
MP: Everyone on this team including the staff thought that this could possibly happen. Everyone was prepared for it. There wasn't a shock factor we just all felt bad for Ethan and what he is going through. He did everything the right way. He's still part of our program. It's just an unfortunate thing that the injury happened late in the season. Sometimes they go smooth and sometimes they don't. He has a tremendous career in lacrosse. The doctor made a suggestion that he shouldn't play. That's fine. It's a tough decision that he and his family had to make, we realize it was hard and we are really going to miss him. It's really so unfortunate he can't enjoy his senior year.
TRR: What part of your team right now that we don't know that much about has the potential to be very strong?
MP: I think defensively we should be better than we've been in the past. We have some skill kids, the defensive line is going to be pretty deep. We have six kids to play four positions so we are going to keep moving them around to keep them fresh. The most surprising part for us will be our linebacking corp. They are going to be pretty good. If we play defense against some of these top teams we will have a chance to win.
TRR: You reached the state playoffs so you are not coming off a bad year but you measure success maybe a little differently than some of your colleagues based on what you've done in the past. Are you excited about the prospect of getting back to the playoffs and going farther than you did last year?
MP: We talked about the team goals today and one of those goals is getting back to that state championship game. We know it is a long road. There are a lot of good teams out there and a lot of them are in our league.


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Kern's Kitchen head sues Courier Journal for trademark infringement
Andrei Mincov's commentary on the original article
A trademark will not help you stop others from publishing the recipe of your pies. A trademark will surely help you stop others from naming their pies similarly to yours. The question is, will you be able to stop others from publishing the recipe of your pies while mentioning the name of your pie. It all boils down to the likelihood of confusion. Will readers be confused into believing that the recipes originate from the brand owner? A secondary question here is, is the publication of a recipe that refers to the name of the pie in a generic fashion (i.e. "Derby chocolate-walnut pie" vs. "Derby-Pie® chocolate-walnut pie") dilutes and devalues the trademarked brand.