text:
HER2 therapy: Molecular mechanisms of trastuzumab resistance
- Rita Nahta1Email author and
- Francisco J Esteva1, 2, 3Email author
DOI: 10.1186/bcr1612
© BioMed Central Ltd 2006
Published: 06 November 2006
Trastuzumab is a monoclonal antibody targeted against the HER2 tyrosine kinase receptor. The majority of patients with metastatic breast cancer who initially respond to trastuzumab develop resistance within one year of treatment initiation, and in the adjuvant setting 15% of patients still relapse despite trastuzumab-based therapy. In this review, we discuss potential mechanisms of antitumor activity by trastuzumab, and how these mechanisms become altered to promote therapeutic resistance. We also discuss novel therapies that may improve the efficacy of trastuzumab, and that offer hope that the survival of breast cancer patients with HER2-overexpressing tumors can be vastly improved.
Approximately 20% to 25% of invasive breast cancers exhibit overexpression of the human epidermal growth factor receptor (HER)2 tyrosine kinase receptor [1, 2]. As elevated HER2 levels are associated with reduced disease-free and overall survival in metastatic breast cancer (MBC) [1, 3], therapeutic strategies are being developed to target this oncoprotein. Trastuzumab (Herceptin®; Genentech, South San Francisco, CA, USA), a recombinant humanized monoclonal antibody (rhumAb 4D5) directed against an extracellular region of HER2 [4], was the first HER2-targeted therapy approved by the United States Food and Drug Administration (FDA) for the treatment of HER2-overexpressing MBC. In addition, trastuzumab with adjuvant chemotherapy (either in sequence or in combination) significantly improved disease-free and overall survival rates in patients with early stage HER2-overexpressing breast cancer [5–7].
Trastuzumab: mechanisms of antitumor effects
The mechanisms by which trastuzumab induces regression of HER2-overexpressing tumors are still being elucidated, but several molecular and cellular effects have been reported in the literature [8].
Trastuzumab reduces signaling mediated by HER2 through the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) cascades. Reduced downstream signaling through these pathways induces the cyclin-dependent kinase inhibitor p27kip1, which promotes cell-cycle arrest and apoptosis [9, 10].
Trastuzumab rapidly dissociates the non-receptor tyrosine kinase Src from HER2, reducing Src activity such that the phosphatase and tensin homolog deleted on chromosome ten (PTEN) is dephosphorylated and translocated to the plasma membrane where it is active [11]. The PI3K downstream effectors Akt and mammalian target of rapamycin (mTOR) are then inhibited.
The efficacy of trastuzumab may also depend upon its ability to induce an immune response. HER2-targeted antibodies, including trastuzumab, were shown to promote apoptosis in multiple breast cancer cell lines via antibody-dependent cellular cytotoxicity (ADCC) [12–15]. Importantly, mice that were null for the Fc gamma receptor expressed on natural killer cells, which are important for ADCC, lost much of the antitumor effect of trastuzumab, with only 29% tumor growth inhibition observed versus 96% in control mice expressing the Fc gamma receptor and with intact natural killer cell function [13]. Thus, an active immune response to trastuzumab may be partially responsible for cytotoxic activity. Furthermore, a higher in situ infiltration of leukocytes and ADCC activity were observed in patients achieving complete or partial remission after receiving preoperative trastuzumab relative to those who did not respond to this regimen [14]. Since patients with advanced MBC are immunosuppressed, it is difficult to appreciate the magnitude of the contribution of ADCC to trastuzumab-mediated tumor inhibition. More in-depth in vivo studies are required to grasp exactly how important the contribution of ADCC is to mediating the response to trastuzumab and whether other targeted antibodies used against solid tumors also rely upon immune modulation to achieve response.
Trastuzumab has also been shown to inhibit angiogenesis, resulting in decreased microvessel density in vivo [16–18] and reduced endothelial cell migration in vitro [17]. Expression of pro-angiogenic factors was reduced, while expression of anti-angiogenic factors was increased in trastuzumab-treated tumors relative to control-treated tumors in vivo [16–18]. Combining trastuzumab with the chemotherapeutic agent paclitaxel actually inhibited angiogenesis more potently than did trastuzumab alone [17], perhaps due to trastuzumab-mediated normalization of the tumor vasculature allowing for better drug delivery [16].
Trastuzumab: clinical efficacy and resistance
Proposed mechanisms of trastuzumab resistance
Therapeutic agent cannot recognize molecular target: disrupted interaction between HER2 and trastuzumab
Overexpression of MUC4 sterically hinders antibody from binding HER2 surface receptor and may mediate cross-talk to activate HER2. Knockdown of MUC4 restored trastuzumab sensitivity of breast cancer cells in vitro
Compensatory signaling: increased signaling from HER family members
Growth factor ligands of EGFR, HER3, or HER4 (EGF, betacellulin, heregulin) reduced growth inhibitory effect of trastuzumab by 57, 84, and 90 percent, respectively. Trastuzumab binds domain IV of HER2 and domain II is involved in dimerization with ligand-activated family members; trastuzumab did not block heregulin-activated HER3/HER2 interaction in SKBR3 cells
Compensatory signaling: increased signaling from other receptor types
Overexpression of IGF-IR reduced trastuzumab-mediated growth arrest. Inhibition of IGF-I signaling by IGFBP3 increased sensitivity. IGF-IR interacts with and cross-talks to HER2 in trastuzumab-resistant cells but not in sensitive cells. Inhibition of IGF-IR increased trastuzumab sensitivity
Altered downstream signaling
PTEN deficiency correlated with resistance in clinical samples
Increased Akt activity
P27kip1 downregulation
Competition for binding therapeutic agent
Increased circulating HER2 ECD
Trastuzumab: mechanisms of resistance
Steric hindrance of receptor-antibody interaction: overexpression of MUC4
A potential mechanism by which resistance to targeted antibodies may develop is via disruption of the interaction between the therapeutic agent and the target protein. Resistance to trastuzumab was associated with increased expression of the membrane-associated glycoprotein MUC4 [26]. MUC4 was shown to bind and sterically hinder HER2 from binding to trastuzumab [26, 27]. MUC4 has been suggested to contribute to cancer because of its ability to inhibit immune recognition of cancer cells, promote tumor progression and metastasis, suppress apoptosis, and activate HER2 [28]. MUC4 interacts directly with HER2, an event that is dependent upon an epidermal growth factor (EGF)-like domain on the ASGP-2 subunit of MUC4 [26]. Through this interaction, it is proposed that MUC4 serves as a ligand for HER2, resulting in increased phosphorylation of HER2 on the residue Tyr1248 [26], which is a major phosphorylation site contributing to the transforming ability of the HER2 oncoprotein [29]. MUC4 does not affect total HER2 receptor expression levels [26, 28]. The JIMT-1 trastuzumab-resistant cell line described by Nagy and colleagues [27] was established from a breast cancer patient showing her2 gene amplification and primary resistance to trastuzumab [30]. Using this model, the authors demonstrated that the level of MUC4 protein was inversely correlated with the trastuzumab binding capacity, and showed that knockdown of MUC4 increased the sensitivity of JIMT-1 cells to trastuzumab [27]. Thus, the authors proposed that elevated MUC4 expression masks the trastuzumab binding epitopes of HER2, resulting in steric hindrance of the interaction between this antibody and its therapeutic target, resulting in drug resistance. Interestingly, the authors also reported that HER2 was unable to interact with other proteins, such as EGFR or HER3, because of epitope masking by MUC4.
Insulin-like growth factor-I receptor signaling
Trastuzumab resistance has been associated with increased signaling from the insulin-like growth factor-I receptor (IGF-IR). Increased expression of IGF-IR was shown to reduce trastuzumab-mediated growth arrest of HER2-overexpressing breast cancer cells [31]. Expression of IGF-binding protein 3, which blocks IGF-I-mediated activation of IGF-IR, restored trastuzumab sensitivity. We recently demonstrated that crosstalk occurs between IGF-IR and HER2, and showed that IGF-IR physically interacts with and phosphorylates HER2 in trastuzumab-resistant cells, but not in trastuzumab-sensitive parental cells [32]. Our results showed that resistant cells exhibited more rapid IGF-I stimulation of downstream PI3K/Akt and MAPK pathways relative to parental cells. Inhibition of IGF-IR signaling, either by antibody blockade or IGF-IR tyrosine kinase inhibition, restored trastuzumab sensitivity in our in vitro resistant model, demonstrating the potential importance of this pathway as a therapeutic target in trastuzumab-resistant breast cancer. Similar to Lu and colleagues [33], we observed downregulation of p27kip1 upon IGF-I stimulation in both parental and resistant cells [32]. Importantly, antisense oligonucleotides [34] and small interfering RNA [35] that reduced p27kip1expression levels also blocked trastuzumab-mediated growth arrest in HER2-overexpressing SKBR3 breast cancer cells. Transfection of p27kip1or pharmacological induction of p27kip1 by the proteasome inhibitor MG132 restored trastuzumab sensitivity in our resistant model [36]. These results suggest that p27kip1 is a critical mediator of trastuzumab response, and that its downregulation may occur subsequent to increased signaling from growth factor receptors such as IGF-IR, promoting resistance to trastuzumab.
PTEN and PI3K signaling
Growth factor receptor tyrosine kinases, such as HER2 and IGF-IR, activate the PI3K signaling pathway. Constitutive PI3K/Akt activity was previously shown to inhibit cell-cycle arrest and apoptosis mediated by trastuzumab [34]. Furthermore, trastuzumab-resistant cells derived from the BT474 HER2-overexpressing breast cancer line demonstrated elevated levels of phosphorylated Akt and Akt kinase activity compared with parental cells [37]. These resistant cells also showed increased sensitivity to LY294002, a small molecule inhibitor of PI3K. Nagata and colleagues [11] provided compelling evidence supporting a role for the PI3K/Akt pathway in trastuzumab resistance. They demonstrated that decreased levels of the PTEN phosphatase resulted in increased PI3K/Akt phosphorylation and signaling and blocked trastuzumab-mediated growth arrest of HER2-overexpressing breast cancer cells. Importantly, they showed that patients with PTEN-deficient HER2-overexpressing breast tumors have a much poorer response to trastuzumab-based therapy. Furthermore, they showed that, in PTEN-deficient cells, PI3K inhibitors rescued trastuzumab resistance in vitro and in vivo. These results suggest that PTEN loss may serve as a predictor of trastuzumab resistance, and that PI3K inhibitors should be explored as potential therapies in patients with trastuzumab-resistant tumors expressing low levels of PTEN protein.
Serum HER2 extracellular domain
The full-length 185 kDa HER2 protein has been reported to be cleaved by matrix metalloproteases into a 110 kDa extracellular domain (ECD), which is released into cell culture media [38–40] or circulating in serum in vivo [41–44], and a 95 kDa amino-terminally truncated membrane-associated fragment with increased kinase activity [45]. Elevated serum levels of HER2 ECD correlate with poor prognosis in patients with advanced breast cancer [41–44, 46]. Of potential importance, trastuzumab blocked HER2 ECD proteolytic cleavage in vitro [47], and patients with elevated pre-treatment ECD levels had higher response rates to trastuzumab [48, 49]. HER2 overexpression in breast cancers correlated with elevated pre-treatment levels of circulating HER2 ECD in patients treated with trastuzumab and paclitaxel, and among these patients, responses correlated with a decline in ECD levels over 12 weeks of therapy versus lower responses in those whose ECD levels remained high post-treatment [50].
Zabrecky and colleagues [40] first described the presence of cleaved ECD in the culture medium of HER2-overexpressing SKBR3 breast cancer cells. The authors showed that HER2-targeted monoclonal antibodies bound to circulating ECD, competing away binding to membrane-bound HER2. Hence, signaling from the receptor form of HER2 continued in the presence of HER2 antibodies, indicating that HER2 ECD promoted resistance to HER2-targeted antibody therapy. However, the predictive role of elevated baseline ECD prior to treatment is not well defined. In one study, elevated HER2 ECD levels predicted favorably for response to trastuzumab and docetaxel [24], but other studies showed limited predictive value in this setting. Interestingly, declining levels of circulating HER2 ECD correlate with improved disease-free survival in several studies [24, 49]. A meta-analysis of 8 clinical trials revealed that patients whose HER2 ECD levels declined by at least 20% in the first few weeks after initiation of trastuzumab-based therapy had improved disease-free and overall survival compared with patients whose HER2 ECD levels did not drop [51]. Hence, circulating ECD of HER2 may be a serum marker useful for predicting response to trastuzumab. In contrast to these studies, a recent study by Anido and colleagues [52] suggests that truncated forms of HER2 are actually the result of alternative initiation of translation from different methionines within the her2 sequence, which are referred to as C-terminal fragments of HER2. The authors present compelling in vivo data showing that trastuzumab does not inhibit growth of mammary xenografts of the T47D breast cancer cell line stably transfected with the truncated form of HER2, but does inhibit growth of T47D HER2 stable transfectant xenografts. Hence, this study suggests that the presence of truncated forms of HER2 may promote resistance to trastuzumab.
Novel therapeutic strategies
Trastuzumab resistance is a major clinical problem that requires concentrated effort to resolve. A clear understanding of HER2 and trastuzumab activity at the molecular and biological levels is needed to fully improve survival of patients whose breast cancers overexpress HER2. As these molecular mechanisms begin to be elucidated, more targeted therapies can be developed to improve response rates in the HER2-overexpressing population and in trastuzumab-refractory patients.
The recombinant humanized HER2 monoclonal antibody pertuzumab (Omnitarg™, 2C4, Genentech) represents a new class of drugs called dimerization inhibitors; these have the potential to block signaling by other HER family receptors, as well as inhibiting signaling in cells that express normal levels of HER2. Pertuzumab sterically blocks dimerization of HER2 with EGFR and HER3, inhibiting signaling from HER2/HER3 and HER2/EGFR heterodimers [53]. Interestingly, we also observed that pertuzumab disrupted interaction between HER2 and IGF-IR in trastuzumab-resistant cells [32]. Trastuzumab and pertuzumab bind to different epitopes in the extracellular domain of HER2, with trastuzumab binding domain IV of the extracellular domain [54] and pertuzumab binding near the junction of domains I, II, and III of the HER2 extracellular domain [55]. Thus, pertuzumab could theoretically be effective in trastuzumab-resistant tumors. However, while combining trastuzumab with pertuzumab produced synergistic apoptosis in HER2-overexpressing trastuzumab-naïve breast cancer cells [56], this agent failed to demonstrate statistically significant differences on the viability of trastuzumab-resistant breast cancer cells [30, 32]. The mechanisms by which trastuzumab-resistant cells develop cross-resistance to alternative HER2-targeted antibodies are unclear, but may reflect aberrations in downstream signaling pathways resulting in resistance to a variety of HER2-targeted agents. Clearly, additional preclinical studies are required to determine the potential efficacy of novel HER2-targeted antibodies in trastuzumab-resistant breast cancers.
Lapatinib (Tykerb™, GSK572016, formerly GW572016; GlaxoSmithKline, Research Triangle Park, NC, USA) is a dual tyrosine kinase inhibitor targeted against both EGFR and HER2. In comparison to other tyrosine kinase inhibitors in clinical trials (for example, gefitinib, erlotinib), interaction of lapatinib with EGFR and HER2 is reversible, similar to other agents, but dissociation is much slower, allowing for prolonged downregulation of receptor tyrosine phosphorylation in tumor cells. Differences in enzyme-inhibitor structures could account for differences in dissociation off-rate, as EGFR is in a closed conformation when lapatinib binds versus a more open conformation when gefitinib binds [57]. However, effects on HER2 appear to be more critical to efficacy of lapatinib than effects on EGFR, and the HER2 status is a determinant of lapatinib activity while EGFR status is apparently not. Pre-clinically, lapatinib induced potent growth arrest and/or apoptosis in EGFR- and HER2-dependent tumor cell lines and xenograft models, and blocked downstream MAPK and Akt activation [58]. In vitro studies demonstrated that the combination of lapatinib with anti-HER2 antibodies enhanced apoptosis of HER2-overexpressing breast cancer cells, and that lapatinib-mediated apoptosis was associated with downregulation of survivin [59]. Interestingly, resistance to lapatinib was recently shown to be mediated by increased signaling from the estrogen receptor (ER) in ER-positive HER2-overexpressing breast cancers, suggesting that co-targeting of ER and HER2 may be beneficial in this population [60].
Important to the issue of trastuzumab resistance, lapatinib was shown to inhibit growth of HER2-overexpressing breast cancer cells maintained long-term on trastuzumab [61]. We have observed that lapatinib induces significant apoptosis in trastuzumab-resistant cells to the same degree as in parental, trastuzumab-sensitive cells. Furthermore, lapatinib appears to have inhibitory effects on IGF-I signaling in the resistant cells, suggesting that its growth inhibitory activity may be due not only to anti-EGFR/HER2 activities but also to IGF-IR inhibition (Nahta R, Yuan LX, Yu D, Esteva FJ, submitted).
Exciting clinical data have strongly positioned lapatinib for FDA approval against HER2-overexpressing breast cancers. The phase I study EGF10004 examined heavily pretreated patients with EGFR-expressing and/or HER2-overexpressing MBC who were randomly assigned to one of five dose cohorts of lapatinib [62]. Four patients with trastuzumab-resistant MBC, two of whom were classified as having inflammatory breast cancer, had partial responses. A recent phase III trial of HER2-overexpressing MBC patients who were heavily pretreated and trastuzumab-refractory demonstrated that combination lapatinib and capecitabine resulted in a doubling of median time to progression and median progression-free survival (both 36.9 weeks) compared with capecitabine alone (median time to progression 19.7 weeks and progression-free survival 17.9 weeks) [63]. Such results are rarely if ever seen in this patient population, and support lapatinib as a promising new agent for patients who have progressed on trastuzumab-based therapy.
IGF-IR inhibition
Based on preclinical evidence suggesting a role for IGF-IR signaling in the development of trastuzumab resistance [31–33], novel IGF-IR-targeted agents have been introduced into pharmaceutical testing and are being assessed in preclinical trastuzumab-resistant models. In vitro studies demonstrated that inhibition of HER2 signaling using trastuzumab, and inhibition of IGF-IR signaling using a dominant negative construct produced synergistic growth inhibition of HER2-overexpressing breast cancer cells [64]. Triple combination treatment of BT474 ER-positive HER2-overxpressing breast cancer cells or MCF7 ER-positive IGF-IR-elevated breast cancer cells with ER, HER2, and IGF-IR antagonists further augmented apoptotic effects of single agents or dual combinations [65]. In addition, our data demonstrate increased apoptosis when lapatinib and the IGF-IR monoclonal antibody alpha IR3 are combined in trastuzumab-resistant cells (Nahta R, Yuan LX, Yu D, Esteva FJ, submitted). Therapeutic strategies that target both the HER2 and IGF-I signaling pathways should be studied further for potential use in cancers that progress on trastuzumab.
PI3K inhibition
Inhibitors of pathways downstream of the HER2 receptor may combat trastuzumab resistance. Perifosine is an Akt inhibitor undergoing clinical testing in patients with solid tumors and hematological malignancies [66, 67]. As most Akt inhibitors have not achieved clinical development due to excessive toxicity in preclinical models, an alternative approach to blocking PI3K/Akt signaling is the use of small molecules that inactivate the kinase mTOR, which functions downstream of Akt. Three mTOR inhibitors being tested in clinical trials for patients with breast cancer and other solid tumors are CCI-779 (temsirolimus; Wyeth-Ayerst, Madison, NJ, USA), RAD001 (everolimus; Novartis, New York, NY, USA), and AP23573 (Ariad; Cambridge, MA, USA) [68, 69]. Based on the results of Nagata and colleagues [11], in which low PTEN-expressing breast tumors were found to have reduced response to trastuzumab, our group launched a clinical trial of trastuzumab in combination with the mTOR inhibitor RAD001 in patients with HER2-overexpressing MBC resistant to trastuzumab-based therapy. Additionally, drug discovery programs are focusing on developing more effective, less toxic, direct inhibitors of the Akt kinase family.
Histone deacetylase inhibitors and trastuzumab
Another class of agents called histone deacetylase inhibitors is being explored in the setting of HER2-overexpressing MBC. Preclinical work demonstrated that the histone deacetylase inhibitor hydroxamic acid analogue, LAQ824, significantly reduced HER2 levels in SKBR3 and BT474 breast cancer cells by promoting proteasome-dependent degradation and reduced transcription of HER2 [70]. These effects on HER2 were associated with induction of p27kip1 and inhibition of Akt and MAPK signaling. In addition, the combination of LAQ824 with trastuzumab induced marked apoptosis in vitro. Another hydroxamate-based histone deacetylase inhibitor called suberoylanilide hydroxamic acid similarly reduced HER2 protein levels [71]. It was found that suberoylanilide hydroxamic acid induced acetylation of the HER2 chaperone protein heat shock protein 90 (hsp90), reducing interaction between the proteins and promoting ubiquitination and degradation of HER2. Suberoylanilide hydroxamic acid and trastuzumab combined resulted in synergistic induction of apoptosis in BT474 and SKBR3 breast cancer cells. These in vitro studies paved the way for clinical trials examining the combination of histone deacetylase inhibitors with trastuzumab.
The clinical problem of trastuzumab resistance is becoming increasingly important as recent studies strongly support a role for trastuzumab not only in the management of metastatic disease but also in the adjuvant setting for HER2-overexpressing breast cancers. Thus, identifying the molecular mechanisms that contribute to trastuzumab resistance is more imperative than ever. Only then can we identify novel therapeutic targets toward the goal of increasing the magnitude and duration of response to trastuzumab-based treatment.
This article is part of a review series on HER2 therapy, edited by Mark Pegram.
Other articles in the series can be found online at http://breast-cancer-research.com/articles/review-series.asp?series=BCR_HER2
antibody-dependent cellular cytotoxicity
extracellular domain
epidermal growth factor
epidermal growth factor receptor
estrogen receptor
Food and Drug Administration
human epidermal growth factor receptor
insulin-like growth factor
insulin-like growth factor-I receptor
mitogen-activated protein kinase
metastatic breast cancer
- mTOR:
mammalian target of rapamycin
phosphatidylinositol 3-kinase
phosphatase and tensin homolog deleted on chromosome ten.
The authors wish to acknowledge funding from the National Cancer Institute (K01CA118174, R Nahta), the Breast Cancer Research Foundation (FJ Esteva), the University Cancer Foundation at the University of Texas MD Anderson Cancer Center (FJ Esteva, R Nahta), the Nellie B Connally Breast Cancer Research Fund, and NIH Cancer Center Support Grant CA-16672 (Media Preparation Facility and Flow Cytometry facilities).
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text:
Imagine there are two agencies left in a pitch for a beer account. Four others have been eliminated including the incumbent.
But the client, as all clients do, asks for one more round of creative. Both agencies are pretty spent. Unbeknownst to each other, each agency decides to crowdsource its final round of creative in hopes of finding something fresh.
Fortunately, the competing shops each choose a different crowdsourcing platform. Agency A chooses to go with Victors and Spoils; Agency B signs on with AdHack. Both platforms assure that they can conduct the process secretly. Victors and Spoils is confident because it has a vetted group of creative talent from all over the world; the company knows much of its community personally and can admit to the "competition" only those who it feels bit the bill.
AdHacks is sure because it has all the legal non-disclosure documentation built into its registration along with a reputation management system that ranks past contributors for adherence to the rules.
The agencies submit their briefs; the briefs are visible only to the participants and not the public. And while anything that ends up on the web can is fair game, both agencies willingly gamble they can keep things contained.
Meanwhile, a young, bored creative team learns about the crowdsourcing request for concepts because the writer on the team is part of the V&S community. At the same time, the art director has previously submitted ideas to AdHack and hears about the call for work from them. The team comes up with a campaign that includes, TV, experiential, and social all wrapped up in a coherent theme. In order to double its chances, the duo decides to enter the same work on both platforms. Why not, right?
Agency A (the one that went with V&AS) loves the work and presents it as part of their final pitch. Agency B (who went with AdHack) thinks the idea is lame, casts it aside and goes with something else. Lo and behold, the crowdsourced campaign is the deciding factor and Agency A prevails.
Starting to sound like the Twilight Zone? Well consider this. The creative team that submitted the work was a junior team at the incumbent agency, which was cut from the pitch in the first round. However, at that agency, the team whose work won wasn't even invited to participate as part of the pitch team; they were deemed too young inexperienced to be beer-pitch-worthy.
Last week, in Boulder, Colorado, I had long conversations with John Winsor of Victors and Spoils and James Sherrett of AdHack. We chatted about the current state of this new tactic, the quality of participating communities and the satisfaction of current clients. Crowdsourcing is still relatively new. No one really knows where it's going, how many clients and agencies will embrace it, or how good the work will be. But one thing we did agree on is that a scenario like the one above could actually happen. I can only hope that I'm not Agency B when it does.
Photo by Michael

subset: commoncrawl


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Amazon nabs the top spot for online cosmetics sales
One of every five beauty purchases online is made via the Amazon marketplace, according to a new report.
Amazon nabs the top spot for online cosmetics sales
One of every five beauty purchases online is made via the Amazon marketplace, according to a new report.
Wal-Mart gives Jet shoppers a taste of its house brands
Sam's Choice and Great Value are among the Wal-Mart brands now available on Jet.com.
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Sponsored by 2013 Social Media 300
This new release offers built-in support for 16 languages.
NEW YORK, Thursday, May 3, 2012 – Emailvision, the international leader in Software as a Service (SaaS) for online relationship marketing, today announced the availability of the newest version of Campaign Commander Enterprise Edition. This release offers innovative capabilities for customer intelligence including the first available geo-marketing analytics solution. Additionally, this release introduces fully integrated multivariate testing for email; enabling marketing teams to test multiple versions of an email campaign and rapidly roll out the highest performing combination.
Featuring drag-and-drop customer data discovery and geo-based heat maps, this new release enables marketers to rapidly explore and analyze millions of records. With a better understanding of their customers by location, behavior, demographics and purchase history marketers can combine these insights to execute smarter marketing campaigns. Having customer intelligence at the heart of campaign development, marketers can increase revenues and profitability without overwhelming their subscribers, fans and followers.
"At Emailvision, we are committed to developing an online marketing solution that empowers marketers with the ability to get more value from their customer data – spending more time understanding customer behavior and characteristics; and less time worrying about how to execute complex campaigns," said Charles Wells, Chief Product Officer for Emailvision. "Our new geo-mapping capabilities, enhanced train of thought analysis and multivariate testing tools make it even easier for marketers to drive complementary upsell, cross-sell and reactivation campaigns."
This new release offers built-in support for 16 languages and Emailvision continues to provide unrivaled global email and SMS delivery rates so marketers can drive successful campaigns anywhere in the world.
"In the past, organizations had to invest significant amounts of budget, time and resource to develop targeted and personalized marketing campaigns using on-premise customer intelligence software. Now, our unique SaaS-based customer intelligence and campaign management platform enables enterprises of all sizes to leverage their fast-growing customer data and turn it into profitable campaigns at a fraction of the cost," said Nick Heys, CEO of Emailvision. "We are focused and committed to building the next-generation SaaS solution for relationship marketing. This release removes the complexity of campaign execution and takes marketing programs to new levels of sophistication."
Every piece of data you collect can help you serve your audience exactly what they ...
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The Supreme Court is surely going to find this question right back on their doorstep next year."


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Recent Comments
- Admin on Texas Laws
- Admin on Texas Laws
- Admin on Texas Laws
- Mike L. on Texas Laws
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Recent Posts
- HOA Foreclosure For $150
- Deputy Accused Of Taking HOA Money
- Can HOA Board Forgive Unpaid Assessments?
- Court Decision Helps Community Organizations
- Abuse Of Power
- HOA Accountability
- Gated HOA Gated Community Streets Responsibility
- Who Pays For HOA BulkHeads
- Homeowner Association Attorney Ethics
- HOAs Adjust To Texas Law Changes
HOA Foreclosure For $150
Deputy Accused Of Taking HOA Money
Some residents of the Trailwood Home Owners Association told WFTV's Myrt Price that they can't believe that someone they trusted, a law enforcement officer and someone who had been their HOA president for seven years, could be accused of something like this.
Read more here: –>HOA Theft
Posted in Homeowner Association News, Theft, Fraud, & Crimes Tagged board, hoa, theft Leave a comment
Can HOA Board Forgive Unpaid Assessments?
Q: Our homeowners association's board of directors forgave homeowners who were two to three years behind on their assessments. This was done without our knowledge, and we found out about it before our annual meeting. Is this legal? This seems unfair to the homeowners who pay their dues every year.
Read the answer here: http://www.charlotteobserver.com/2013/02/15/3855294/can-hoa-board-forgive-unpaid-assessments.html#storylink=cpy
Read more here: –>HOA Financial Responsibility
Posted in HOA Management, Homeowner Association News Tagged board, finance, hoa Leave a comment
Court Decision Helps Community Organizations
Q. I received a legal update via e-blast from a local law firm that specializes in real estate and condo association law. Apparently there is a new court decision that provides relief for banks and third party investors who buy a property at foreclosure sale. As I understood it, a condo or homeowners association will no longer be able to pursue past due maintenance fees if the association foreclosed its lien and owned the property for a period of time. Can you better explain the court decision and what it means for community associations?
Q. We have an owner who has not paid association fees for almost three years. The bank that financed the unit was apparently involved in "robo signing" and the delinquent owner has successfully fought them every step of the way. Does the association have any recourse against the bank, and if so, do you think it would be worth pursuing?
Q. Our condo association has a management company that uses the same vendors for all of their associations. Many of these vendors are handymen who are jacks of all trades (electrical, mold inspections, painting, plumbing, tile, etc.). The management company does not seem to require proper licenses or make sure they have insurance. Consequently, our board thinks these things are unnecessary. What is the association's liability if something goes wrong?
Posted in HOA Management, HOA POA Law, Homeowner Association Q&A's Tagged association, dues, homeowner, law, legislation, question Leave a comment
Abuse Of Power
At Monday night's HOA meeting, residents spoke out against the board.
One man said, "Shame on you. Shame on you board members."
"I mean, it's just wrong," homeowner Judith King told 10News outside the meeting. "It's wrong." Neighbors said Evolfo applied for a city permit to build a backyard "deck" before receiving HOA approval. After getting the permit, the HOA president called an emergency HOA meeting solely for a vote on his "deck." Fellow board members approved construction.
Posted in HOA Boards & Elections, HOA Management Tagged abuse, board, hoa, power Leave a comment
HOA Accountability
Posted in HOA Boards & Elections, HOA Management Tagged association, hoa, homeowner, management, responsible 1 Comment
Gated HOA Gated Community Streets Responsibility
By Robert Lee Long
Citizens say streets in Cross Creek, a private gated community in Hernando, are in need of repair and one of the ways to upgrade their condition is to make them public. One way to achieve improvements and upgrades is to turn the streets over to the city. At issue, however, is the fact that plats of the subdivision will have to be changed, and if the streets are taken into the city, they will have to be accessible to the public.
Leigh Pegram, president of the Cross Creek Homeowners Association, said the group is exploring their options and has retained an attorney. She plans to brief Homeowners Association members on information she received at Tuesday's board meeting at an upcoming meeting of the Homeowners' Association.
City Attorney Kenneth Stockton said Cross Creek is platted and recorded as a private gated subdivision. Stockton is seeking an Attorney General's Opinion on the public access issue. Pegram disagreed slightly, saying the word "private" never appears on the plat. However, at present individuals must have an access code to gain entrance into the subdivision. There are presently two active gates and an emergency gate to allow law enforcement officers and firefighters access to the subdivision.
Posted in HOA Management, HOA POA Law Tagged community, gated, hoa, responsible, streets 1 Comment
Who Pays For HOA BulkHeads
By Gretchen Wenner
One of Oxnard's premier neighborhoods, where boats nose up to million-dollar homes and the ocean beckons just beyond the harbor, has a problem borne of its marine environment: Sea walls are getting old. The reinforced concrete walls that protect Mandalay Bay's 743 homes were built in the late 1960s and early 1970s. They had a projected life span of roughly 40 years — time that's about up.
A group of homeowners is advocating pre-emptive repairs that would cost a fraction of the estimated $118 million needed for total replacement. A recent evaluation found some stretches are at risk of catastrophic failure, but targeted resurfacing could keep the structures standing 25 more years or so.
The challenge is determining who pays for the repairs, expected to cost millions of dollars.
Bill Scarpino, a resident and member of the Channel Islands Waterfront Homeowners Association, thinks the city owns the sea walls and is responsible for maintenance, just as it is for a public street. He has a folder stuffed 4 inches thick with old city resolutions and court rulings that he says prove it.
Posted in HOA Management Tagged bulkhead, financial, hoa, responsibility Leave a comment
Homeowner Association Attorney Ethics
By Jan Bergemann
In a perfect community association world the association attorney would make sure that the interests of all members of the community are represented when acting on behalf of the association. The actions of the attorney would benefit all members of the community – since all are paying the legal bills equally. Board members and owners should be able to rely on an attorney, who acts as the professional the association hired to represent its legal interest.
But since we are not in a perfect community association world, we see lots of problems caused by association attorneys who make it their main objective to protect the members of the board who signed their retainer agreement and who sign the checks – no matter what. It should not be the task of the association attorney to find ways to circumvent the statutes and the governing documents in order to please the board members who may have a private agenda or try to defend their personal egos.
We see frivolous lawsuits filed all the time, filed by overeager association attorneys – just because some board member has something to hide and doesn't like an outspoken owner to challenge his/her "private agenda." These lawsuits are definitely not in the best interest of these associations or the paying members.
Posted in HOA Management, HOA POA Law Tagged association, attorney, ethics, homeowner 2 Comments
HOAs Adjust To Texas Law Changes
By MATTHEW WATKINS
Want to go green by harvesting rainwater and installing solar panels at your house? Your homeowners association can no longer stop you, even if it considers the projects eyesores. Religious symbols under a certain height and flagpoles with United States, Texas or military flags are now also fair game.
And if your homeowners association wants to foreclose on your home for missed dues and unpaid fines, there are new hurdles it must clear. That is because of a series of new laws passed during the 2011 legislative session that have shaken up how the state's numerous and sometimes controversial homeowners associations operate.
The laws cover much more than the regulation of members' yards. Now, all associations must follow open records and meetings laws, meaning they are subject to freedom of information requests, are required to give 72 hours notice before each board meeting and must take meeting minutes.
They now must obtain an expedited court order to foreclose on a house. And they must offer payment plans for their dues and follow new regulations for how they collect and apply payments.
Posted in HOA POA Law Tagged association, homeowner, law, texas 1 Comment
13 Helps Condo Owner Get Action From HOA
By Loni Blandford
Water can cause quite a lot of damage when it leaks, especially if you are living in an apartment. So when it happened at one Valley condo, the owners turned to their Homeowner's Association. But when they couldn't get an answer, they turned to Action News.
"Apparently, there was a leak upstairs," explained Darlene Castello.
Water started leaking into the Las Vegas condo owned by Darlene's parents. It damaged the walls and even the carpet. So Darlene called the Homeowner's Association for help. "I started calling daily. Leaving message after message after message," said Darlene.
Darlene says she knew who she needed to speak with but he wasn't returning her calls. "Nobody's calling back. Let me talk to a supervisor. Well I'm sorry the supervisor is not available would you like to leave a message. I mean that's all I ever got," said Darlene.
Darlene says after three months with no response, she decided to call Action News. Our Call for Action volunteers reached out to HOA for her. To her amazement, it worked almost instantly.
Posted in HOA Management Tagged action, association, condominium, leak, water Leave a comment
Texas Homeowner Association Laws
By Bill Oliver
With more than 60 homeowners associations (HOA), the city of College Station TX is devoting staff time to staying on top of new state laws. Barbara Moore of College Station's neighborhood services office says additional requirements for HOA's will affect how she does her job. Before new laws took affect January 1st, Moore says they worked with recruiting and training new HOA officers. Now, she will be assisting HOA's with complying with new open meetings and records requirements among other things.
Moore says a recent meeting with 80 HOA representatives and members of a HOA trade association generated some surprise from HOA leaders about the increased responsibility caused by new state laws.
Posted in HOA POA Law Tagged association, homeowner, law Leave a comment
Tomball TX Police Connects Homeowner Associations
By Catherine Dominguez
Despite a small turnout, area residents along with the Tomball Police Department are moving forward with an initial email list to get local homeowners association leaders connected. Administrative Sergeant Rebecca Carlisle with the Tomball Police Dept. met with residents March 8 to provide them with information about what they can do to increase security in their communities and discourage crime.
Carlisle said it was important for local communities to establish an electronic system to communicate with each other, including using social media like Facebook and Twitter along with an email blast list. She also said it was critical for HOA officials to enforce HOA regulations, ensure landscaping is maintained and make sure all lights are working in their neighborhood. "This is up to (community members)," Carlisle said.
The meeting was organized by Councilman Mark Stoll, who lives in Spring Pine Estate of Zion Road. After recent reports of two scams in local subdivisions, Stoll decided to put aside his status as a councilman and help organize a community policing system.
Posted in Homeowner Association News Tagged crime, hoa, poa, scam Leave a comment
Legislator 'oops' on HOA Legislation HB-2160
by Kathleen Stinson
Arizona House Bill 2160, authored by Scottsdale Republican state Rep. John Kavanagh and approved by the state House earlier this week, sets new standards for condominium and HOA board elections. It will now go before a Senate committee.
Kavanagh said his bill guarantees secret ballots, prohibits an HOA from including endorsements in official board mailings, prohibits counting ballots before the close of an election, allows for a representative from each candidate to observe the counting, and provides that any identifying information be placed on the outer envelope and not on the ballot itself.
Kavanagh said his bill does not require HOAs to disclose the vote counts to its members "because I never imagined an HOA not announcing the vote numbers.
Posted in HOA POA Law Tagged association, homeowner, legislation Leave a comment
Associa Announces Opening of Texas HOA Collections Service
There was a recent news article that announced that – HOA Collection Services (HCS), an Associa company, launches this week in Texas and California, providing collection services to community associations.
"When community association Boards find collections services necessary, it is paramount to provide efficient, respectful service at a competitive cost," said Paul Reyes, president of HCS.
Associa is the largest Homeowner Association and Property Owner Association companies in the United States and is moving into Canada and Mexico. It is a diversified company with branches in every aspect of HOAs, including homeowner association management, insurance, and now collections. Associa also owns a homeowner shopping enterprise, a political PAC, finance corporation, .
At the same time that John Carona, owner and founder of Associa, was building up the company, he was also building up a political career. He is a Texas state Senator and his company, Associa, also founded a Political PAC – Associa PAC. Senator Carona currently serves as Chairman of the Senate Business and Commerce Committee, Joint Chairman of the Legislative Oversight Board on Windstorm Insurance and as Co-Chairman of the Joint Interim Committee to Study Seacoast Territory Insurance. He also serves as a member of the Senate Select Committee on Redistricting and the Senate Criminal Justice, Education and Jurisprudence committees.
Personal comment begins….. I don't think that legislators, through their private corporation ownership, should be allowed 'PAC ownership'. And, I really question the sanity of allowing legislators to own companies that would benefit from their own legislation, especially when they have a way to funnel their own company funds, through a political PAC, into their political candidate choices. This is just too much 'ownership' of enterprises that can effect every citizen in that geographic area. I believe that this type of activity may be at the core of the 'disgruntled voters' in this country. …. end of personal comment.
What do you think?
Posted in Action Steps, HOA POA Law Tagged association, law, texas 1 Comment
Are All HOA Monies Tax Exempt?
By Gary Poliakoff
A Las Vegas HOA is currently fighting with the IRS over the question of whether $2 million held in the HOA's savings account is subject to a 30% sales tax as corporate surplus.
Associations are generally organized as not-for-profit corporations (some older associations are not incorporated) and therefore must file tax returns like other not-for-profit corporations. Associations are not entitled to tax exempt status like charitable organizations. To be tax-exempt under section 501(c)(3) of the Internal Revenue Code, an organization must be organized and operated exclusively for exempt purposes set forth in the Code. To be tax exempt under IRC 501(c)(4), a homeowners' association must operate for the benefit of the general public, i.e., it must provide a community benefit – not a benefit to the owners or residents. However, homeowners' associations are still taxed on any income or support received that did not constitute dues or assessments paid by its property owner-members for maintenance and improvement of its property.
Posted in HOA Management, HOA POA Law Tagged association, exempt, hoa, homeowner, tax Leave a comment
Big Money To Be Made In Foreclosures
By John Gittelsohn
Private equity firms are jumping into distressed housing as the U.S. government plans to market 200,000 foreclosed homes as rentals to speed up the economic recovery.
GTIS Partners will spend $1 billion by 2016 acquiring single-family homes to manage as rentals, Thomas Shapiro, the fund's founder said. That followed announcements this month that GI Partners, a Menlo Park private equity fund, expects to invest $1 billion, and Los Angeles-based Oaktree Capital Management LP will spend $450 million on similar housing. "It's a massive market," Shapiro said in a telephone interview from New York. "We're starting to see this as a billion dollar opportunity to buy rental housing."
Posted in Association Foreclosure Tagged association, foreclosure, hoa, homeowner Leave a comment
Disturbing New Trend Impacting HOA's
By Donna DiMaggio Berger
Two recent legislative attempts signal a disturbing trend that has the potential to negatively impact Florida's community associations.
The first is this year's construction defect bill, HB 1013, sponsored by Representative Artiles and its Senate companion, SB 1196, sponsored by Senator Bennett. These bills would take away a homeowner's rights to pursue a developer for defects to the driveways, roads, sidewalks. utilities, drainage areas and other so-called "off-site" improvements that are not located on the lot on which a home is constructed or which are located on such a lot but do not contribute to the "habitability" of the home.
Posted in HOA Management, HOA POA Law Tagged association, hoa, homeowner, law Leave a comment
Texas HOA Law Changes
By Jennifer Slewer
A slew of changes are now in effect for the state's homeowners associations, the love-'em-or-hate-'em groups that everyone seems to have an opinion about. The changes grant homeowners more freedoms when it comes to outdoor decorating and installation of environmentally friendly systems. The changes also make it harder for HOAs to foreclose because of unpaid fees.
Now, HOAs won't be able to keep you from displaying the U.S. or Texas flag, or flags of military branches. Free-standing flagpoles 20 feet tall or less will be allowed, too — legislation filed in response to an HOA that sued a Marine veteran for flying the Stars and Stripes on a flagpole.
HOAs also won't be able to keep you from hanging a religious display on your front door, but they can require you to keep it at 25 square inches or less. That legislation was filed after a Jewish couple was threatened with a recurring fine for displaying a mezuzah, a parchment with Hebrew verses enclosed in a case affixed to the doorpost.
Posted in HOA Management, HOA POA Law Tagged association, hoa, homeowner, law 1 Comment
Preparing For HOA Annual Meeting
By Stan Riddle
Over the next few months, a number of homeowner associations will be holding their annual meetings. Of all of the HOA meetings held during the year, this one probably has the most members in attendance due to a number of important issues that are likely on the agenda, such as election of officers.
In an effort to assist HOAs in making this meeting run both effectively and efficiently, the Green Valley Council offers a few suggestions:
Posted in HOA Boards & Elections, HOA Management Tagged association, elections, hoa, homeowner Leave a comment


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Questions? Read our FAQs
Hamilton Chan
Questions? Read our FAQs
Learning to negotiate effectively is one of the most important skills you can acquire in life.
Learn how to negotiate from a graduate of Harvard College and Harvard Law School who was an instructor at the renowned Harvard Law School Program on Negotiation, where he taught alongside Roger Fisher, author of "Getting To Yes." Attendees will engage in a live simulated negotiation, complete with confidential instructions and a partner for negotiating. Following the negotiation simulation, there will be a debriefing and discussion of the most powerful ways to approach a negotiation, following the principles of "Getting To Yes."
Do you have an important negotiation coming up? Are you anxious about the confrontational nature of negotiations? Do you lack a framework and strategy for negotiating, other than to negotiate as hard as possible? Then this class will help provide you a concrete approach for tackling a negotiation head-on, in as effective a way as possible.
We look forward to seeing you in class!
Hamilton Chan Instructor
Hamilton Chan is the CEO of Coaching for Startups. Hamilton graduated phi beta kappa and magna cum laude with highest honors from Harvard College and graduated from Harvard Law School. He worked as an investment banker at JP Morgan in Hong Kong and in New York, performing Mergers & Acquisitions and Corporate Finance work. After graduating from Harvard Law School, Hamilton was a corporate attorney at Munger, Tolles & Olson, where his clients included Berkshire Hathaway and Kobe Bryant. He then worked at MGM as a Business Affairs executive in the Motion Picture Group, before leaving to run his family's commercial printing company, a move that was chronicled in a feature in Los Angeles Magazine. As a sole non-technical founder, Hamilton then launched a tech startup that was funded by $1.75 million of seed capital from Y Combinator, 500 Startups, SV Angel and Rustic Canyon Partners, among others. Hamilton is the Instructor at GA for Business Fundamentals & Tactics, Sales & Business Development Immersive and Negotiation Workshop. After successfully selling his commercial printing business, Hamilton spends his time advising other startup founders as an executive coach, providing them counsel on everything from startup tactics to self-optimization. To learn more about Hamilton, please visit http://www.coachingforstartups.com.
Plans change. We get it. But if you can't make it to a class/workshop, please email us at least 7 days before the scheduled event date. No refunds will be given after this timeframe.
A Conversation with Black Women Entrepreneurs in Celebration of Black History Month
Tuesday, 28 February
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After working up an appetite walking around shopping, our microbrewery/restaurant, with a cachet reminiscent of European bistros, is the perfect place to enjoy a delicious meal. Our menu inspired by French cuisine perfectly complements the beer we brew onsite using only fresh ingredients. Cheers!
Hours: Sunday to Wednesday, 11:30 a.m. to midnight. Thursday, 11:30 a.m. to 1 a.m. Friday and Saturday, 11:30 a.m. to 2 a.m.
Schedule and rates are subject to change without notice. Visit their website or contact them for up-to-date information.
2450, boulevard Laurier
Québec, QC
Borough of Sainte-Foy - Sillery - Cap-Rouge
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French, International
TV and Sport Broadcasting
Free On-Site Indoor Car parking, Free outdoor car parking on site
English, French
Menu available in English, Menu available in French
What do you think of our tourist destination?
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Québec City Tourism would like to know your appreciation of your stay in the Québec City area.
Thank you for your collaboration! To see the contest rules, click here.
For questions or comments, write us at: email@example.com


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Why is the U.S. government bailing out farmers who didn't cover themselves?
By Emily Hutto
Why is the USDA covering for more than a quarter of the nation's farmers and ranchers who didn't cover themselves?
The USDA announced today that it plans to purchase $170 million worth of meat products from American farmers to support food-aid programs. The purchases will be made through the Emergency Surplus Removal Program, which will allow for the USDA to use government funds to purchase products from farmers who have been affected by natural disasters, mainly widespread drought throughout the United States.
"A major factor affecting livestock producers is the value of feed," says an article in the Journal Gazette, "which is currently running high because of the drought."
We've always paid a premium to feed livestock, though. According to PETA.org, more than 70 percent of the grain and cereal that is grown in the United States is fed to animals. The website also reports that it takes 16 pounds of that grain to produce just one pound of edible meat.
Today the USDA also authorized a transfer of $14 million into the Emergency Conservation Program to help farmers and ranchers rehabilitate their land damaged during the droughts. These funds will also support water conservation.
Remember that same pound of meat? It takes 2,400 gallons of water to produce it. (It takes about 25 gallons of water to produce a pound of grain, according to PETA).
Within the last month, says the Journal Gazette, the USDA has opened the Conservation Reserve Program (a government-sponsored program to protect sensitive land) for "emergency haying and grazing." So, in essence, once-protected lands have become victim to agriculture again.
Raising animals for food uses 30 percent of the earth's land mass says a news story by the Food and Agriculture Organization of the United Nations (FAO). More than 260 million acres of United States forest land have been cleared for the grazing of agricultural animals. The Smithsonian Institution will tell you that seven football fields of land is bulldozed worldwide every minute to create more room for farmed animals.
The USDA's goal is an important one – to combat the United States' food shortage by providing greater access to food during natural disaster. If we really want to conquer food shortage, though, the statistics above prove that we're going about it the wrong way.
I'll leave you with one last statistic: The Rain and Hail Insurance Society's 2012 Crop Insurance Update reports that only 69 percent of eligible acres of farmland were insured last year under crop insurance. So why is the USDA covering for more than a quarter of the nation's farmers who didn't cover themselves?


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We are pleased to present to the world a new joint edition of sneakers AFOUR x CIAY - SkyFighter 2 in color Desert storm. In contrast to previous editions summer shoes are made with lightweight lining made of textile and leather. The top is made of genuine suede and textile with a camouflage print "Desert Storm", and the fuselage is decorated with shark jaws.
We are glad to present a limited collection of festival brogues created specifically for concept store Nevalenki
The best models of AFOUR footwear are made by hand with love from materials of the leading European manufacturers
Now you can not only choose your favorite pair of shoes, but also create your own design to order!
Use our capabilities fully - add upgrades, quilted leather, embossing or thermal printing. Make your shoes unique!
What can be more pleasant than giving gifts - only to give opportunities. Treat your loved the opportunity to create shoes of their dreams!
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Pop3 Email Analyzer
This project was successfully completed by codemannz for $30 USD in 5 days.Get free quotes for a project like this
Project Budget$30 - $250 USD
Completed In5 days
Total Bids8
Project Description
Provide PHP scripts which achieve the following purpose.
The application will be run as a CRON schedule job.
There are two SQL tables.
1. Log Table
- Contains a series of log records that we can use to prove that the email addresses were part of an email that we ([url removed, login to view]) were party to.
- [url removed, login to view] means the domain of the pop3 account. We will be using this application for more than one domain.
2. Email Table
- Contains a series of email addresses. No duplicates.
Login into a pop3 account.
For each email in the inbox:
1. Extract all email addresses from the header (to, cc, bcc)
2. For each non [url removed, login to view] email
- Add one records to the Log table
- Log record contains: Sent date, subject and all the email addresses extracted. You can choose the fields and field types. Could all be one text field. We will hardly ever use this file.
- If the email address being processed doesn't exist in the email table add it.
3. Discard the email.
The php code must:
1. Create the tables
2. Allow a user to specify the pop3 account login and password and the domain for [url removed, login to view]
3. Achieve the stated goal.
4. Use meaningful variable and field names
5. Be reasonably documented
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Zebra's Latest Enterprise Tablets Built for Any Environment
Zebra's Latest Enterprise Tablets Built for Any EnvironmentThe ET 50 and ET 55 can be equipped with Windows 8.1 or Android 5.1 OSes, 8.3- or 10.1-inch displays, and connectivity choices depending on user needs.
The Zebra ET50/55 Windows TabletThe Windows 8.1 versions of the ET50 and ET55 Zebra tablets include Intel quad-core 2.4GHz 64-bit processors, 4GB of LPDDR3 RAM and 64GB of onboard eMMC flash storage. All ET50 and ET55 models include a display that's covered with Corning Gorilla Glass 3. All devices with an 8.3-inch display use a 5,900mAh Smart Li-Ion battery, while those with a 10.1-inch display feature an 8,700mAh Smart Li-Ion battery.
The Zebra ET50/55 Android TabletThe Android 5.1 Lollipop versions of the ET50 and ET55 Zebra tablets include Intel quad-core 1.9GHz 64-bit processors, 2GB of LPDDR3 RAM and 32GB of eMMC flash onboard storage.
Choose Windows 8.1 or Android 5.1 LollipopBy giving users the option of having Windows 8.1 or Android 5.1 on their Zebra tablets, companies and workers can get just the right operating system for their needs and internal IT systems, according to Zebra. The Android versions of the devices also include Mobility Extensions (Mx), which add features such as enterprise-class security, device management, data capture capabilities and more.
Ruggedness for Any WorkplaceAll ET50 and ET55 tablets are ruggedized for any work environment, indoors or outdoors. The tablets are dirt-, dust-, water- and temperature-resistant and are built to survive a 3.2-foot drop onto concrete. They are IP65-compliant and can survive a water hose-down at full force.
Connectivity OptionsFor users who need only WiFi connectivity, the ET50 fits the bill with 802.11a/b/g/n support. For users who also require the flexibility of 4G LTE cellular connectivity, the ET55 includes that as well.
Displays Can Be Operated With Gloved HandsBoth tablet models include a capacitive 10-point multitouch display that allows users to operate the display even when wearing gloves. The displays are backlit and feature ambient light sensors and several keypad options.
Accessories for Barcode Scanning and MoreThe ET50/ET55 enterprise tablets can be outfitted with a wide range of accessories that allow them to be tailored for barcode scanning and more, depending on the tasks at hand. Expansion battery chargers and batteries are also available.
Zebra Technologies' latest enterprise-class tablet computers, the ET50 and the ET55, are aimed at a wide variety of business and industrial users in fields from warehousing to delivery and logistics, manufacturing and more. Both the ET50 and the ET55 can be configured with the Windows 8.1 (upgradable to Windows 10) or Android 5.1 Lollipop operating system and can be purchased in 8.3-inch or 10.1-inch display sizes. These are the first Zebra tablets that run Windows 8.1 and allow the devices to be connected to legacy Windows systems. The Android version of the ET50/55 tablet computer comes with Zebra's Mobility Extensions that provide enterprise-class security, device management and data capture capabilities. The ET50 offers WiFi connectivity, while the ET55 also has LTE cellular capabilities for users who need more flexible communications options. Both devices are built to sustain abuse in challenging physical environments and can withstand drops on concrete as well as dust, dirt, humidity and other hazards. Peruse this slide show for more details.


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Could the troubled housing market lead to murder and mayhem? The people behind the film Meeting Evil (based Thomas Berger's 1992 novel of the same name) seem to think so. The film, starring Samuel L. Jackson and Luke Wilson, is set squarely against the backdrop of the U.S.'s fading economy. However, this film is not an exploration of the current financial crisis. It is a B-movie thriller where the good guy can't get away from the menacing bad guy no matter what he does. The film fails to rise above the confines of its generic thriller plot, but it is not without a handful of fun moments and some genuine thrills.
I have to imagine Samuel L. Jackson gets plenty of scripts to read. What attracted him to this dime-a-dozen, straight-to-video fare is beyond me. This film also makes me wonder why Luke Wilson doesn't get better film roles. He showed a lot of promise in films like Bottle Rocket and The Royal Tenenbaums, and he's been in some commercial successful stuff like Old School and Legally Blonde. However, his filmography is filled with films like Vacancy and Bad Seed, just to name a couple, so it's not a huge surprise to see him in this one.
Wilson plays John, a man having just about the worst day of his life, and that's before he even meets the sociopathic killer about to knock on his door. John is a real estate agent who has just lost his job, has a stack of unpaid bills, is about to lose his own house. He has an icy relationship with his wife Joanie (Leslie Bibb). To top it all off, it's his birthday. After his wife leaves to take the kids to the park, John finds himself alone in the house. There's a loud pounding knock at his door. John opens it to find Richie (Jackson) on his doorstep. Richie says his car has stalled and wants John to give him a push to get it started again. It becomes clear rather quickly that Richie means to kill John, but at the last second he changes his mind. Instead he convinces John, who is unaware of the aborted attack, to get in his car.
It's no spoiler to say that Richie is not a nice guy. He seems pretty weird from the get-go. John becomes his unwitting accomplice as Richie terrorizes the town. In simple terms, Richie is evil, while John is good. It's up to John to stop the evil-doing and get his life back. The problem is, John isn't all that good himself. He hates his life, cheats on his wife—neither of them seems to care one iota about their two children. That's actually kind of the point of the movie, but it's never explored. Richie tells John they are a lot alike, but John is still portrayed as an everyman. Given the circumstances, it's hard to sympathize with him or his wife, but the film never gives us any other choice.
Meeting Evil was not without potential. Jackson gives a no-holds-barred performance as the unrepentant Richie. He has plenty of darkly funny lines in the first act of the film. Richie expects common courtesy and he lets people know when he doesn't feel he's received it. If the dark humor had kept going through the entire film, it might have been a better movie. Wilson is a good reactionary actor, and the two play well off each other when they first meet up. Unfortunately the offbeat humor is dropped in favor of genre clichés, leading to the inevitable good guy vs. bad guy showdown. A final twist puts an intriguing spin on the situation, but it's just too little, too late.
The DVD offers no special features. I would have actually been curious to get a little background into the making of this film. I have to wonder if the script was reworked to conform a little more to the standard psycho-killer template, which would explain the shift from campy dark humor to straightforward thriller. Overall it's not a terrible movie, but is probably only worthwhile if you are a fan of Jackson or Wilson.Powered by Sidelines


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|Tim Funk <funk...@joedog.org>
|Re: Multiple requests sharing the same Servlet instance
|Mon, 14 Jun 2004 14:55:44 GMT
Wrong. It is expected that many threads may be executing the service() method of a servlet at the same time. One way to get around this is by making your serlvet implement SingleThreadModel. (ick!) -Tim Keith Hankin wrote: > I am having a problem where one Servlet instance seems to being used by two different threads at the same time. It is my understanding that Servlet instances will not be used by two threads at the same time, so that the service() method would thus only be called by one thread, then it can be called again if the Servlet instance is reused by way of pooling. > > --------------------------------------------------------------------- To unsubscribe, e-mail: email@example.com For additional commands, e-mail: firstname.lastname@example.com
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Target Demo turns 30 today and is celebrating the occasion with a Dairy Queen ice-cream cake (traditional favorite), a dinner involving beef tonight and, at the moment, a ''Firefly'' marathon, courtesy of her birthday-gift DVD. Depending on how long that lasts, it will be followed by the ''Serenity'' DVD, also a birthday goodie. (A later note: The marathon has intrigued TD's mother, so there will probably be more ''Firefly'' viewing in the House of Heldenfels.)
I, meanwhile, have finally caught up with the ''Lazy Sunday'' video, watching it three times this morning and giggling every time. If you have missed it, go here:


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Today's Devotional
Faithful and TrueWhat experiences have shaped your understanding of what it means to be faithful?
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Slow-Roasted Heritage Turkey with Orange and Sage
Heritage turkeys have more dark meat and a gamier, richer flavor than broad-breasted factory birds; try one this holiday with a slow-roasted recipe from Canlis chef Jason Franey. For a complete meal, pair with his Sausage and Sage Un-Stuffing and Cranberry-Orange Jam.
- Servings: 6
Source: The Martha Stewart Show, November 2010
- 1 (14-pound) turkey, such as Wishard Bronze
- Coarse salt and freshly ground pepper
- 3 navel oranges, washed
- 1 bunch fresh sage
- 3 cups (6 sticks) unsalted butter, cut into cubes
One day before roasting turkey, salt cavity. Prick oranges all over with the tines of a fork and stuff inside turkey cavity along with sage. Using a 3-foot-long piece of kitchen twine, loop in half over the neck and pull under the back, crossing twine. Pull twine between legs and breasts and flip bird over; tie drumsticks together tightly. Place turkey on a rimmed baking sheet, breast side up, and refrigerate uncovered overnight.
Heat butter in a large heavy-bottomed saucepan over medium-low heat until melted and bubbling. Skim foam from top and let butter continue to cook until the milk solids sink to the bottom and begin to brown and become fragrant, about 30 minutes. Set a fine mesh sieve lined with a coffee liner over a metal container and strain butter into container. Let cool to room temperature. Refrigerate, covered, until ready to use. Reheat browned butter before using.
Preheat oven to 300 degrees. Fit a roasting pan with a rack and transfer turkey to rack; season with salt and pepper. Let stand 15 minutes.
Brush turkey with some of the browned butter and transfer to oven. Roast, rotating every hour and brushing with browned butter, for 2 hours.
Using an instant-read thermometer, check temperature of turkey by inserting into the largest part of the thigh. Continue cooking turkey until it reaches 140 degrees on instant-read thermometer, 1 to 1 1/2 hours more. Remove turkey from oven and let stand 30 minutes; increase oven temperature to 475 degrees.
Drain fat from roasting pan and clean rack. Place turkey on clean rack and return to oven. Cook, turning frequently, until skin is browned and crispy, 20 to 30 minutes. Remove from oven and let stand 20 minutes before carving. Serve.