Contact: Anna Mikulak amikulak@psychologicalscience.org 202-293-9300 Association for Psychological Science
When financial gain depends on cooperation, we might expect that people would put aside their differences and focus on the bottom line. But new research suggests that people's racial biases make them more likely to leave money on the table when a windfall is not split evenly between groups.
The findings are published in Psychological Science, a journal of the Association for Psychological Science.
"It has been suggested that race bias in economic decisions may not occur in a market where discrimination is costly, but these findings provide the first evidence that this assumption is false," explain psychological scientists Jennifer Kubota and Elizabeth Phelps of New York University. "Our work suggests that after offers are on the table, people perceive the fairness of those offers differently even when they are objectively identical based on race."
The research was inspired by the debt ceiling debates that raged on in the summer of 2011.
"Many members of both the House and Senate seemed willing to incur costs that would hurt their own constituents in order to vote along political lines," say Kubota and Phelps. "The debate led us to wonder: Are people willing to punish members of another group when they perceive their behavior as unfair, even when exacting that punishment comes at a personal cost?"
The researchers decided that an important first step in understanding this phenomenon, given race-based financial disparities in the United States, would be to examine interracial economic decisions.
They had 49 participants of different ethnic and racial backgrounds engage in a so-called "ultimatum game," in which players accept or reject proposed splits of money. Participants were paired off and a "proposer" in each pair was given $10 to split between them. If the other player accepted the offer, the money was doled out accordingly; if the other player rejected the offer, both participants were left empty-handed. The researchers arranged it so that participants were always responding to offers from virtual proposers.
Because of existing cultural associations in the United States that link Black American males with aggression, hostility, and untrustworthiness, the researchers hypothesized that the participants might be more likely to perceive a low financial offer as unfair if it came from a Black rather than White proposer.
Overall, participants were more likely to accept White proposers' offers compared to those from Black proposers. And the data indicated that Black proposers had to offer larger amounts in order for players to accept the deal.
The effect is likely due to specific stereotypes or prejudices associated with Black Americans, given that participants showed a similar pattern of acceptance for offers from other-race proposers (who were neither White nor Black) and from White proposers.
The researchers point out that the financial offers being made in their study were relatively small and that people might be less likely to reject offers based on race when larger financial gains are at stake. Nonetheless, they argue that their findings have broad implications, with relevance to any context in which people punish others for what they consider to be violations of fairness:
"These findings may be especially relevant for legal and economic decisions and serve as an potential example of how people punish unfair or negative behavior in real-life," Kubota and Phelps conclude.
###
For more information about this study, please contact:
Elizabeth A. Phelps at liz.phelps@nyu.edu
Jennifer T. Kubota at jennifer.kubota@nyu.edu
In addition to Phelps and Kubota, co-authors include Jian Li of Peking University, Eyal Bar-David of New York University, and Mahzarin R. Banaji of Harvard University.
The article abstract is available online at: http://pss.sagepub.com/content/early/2013/10/11/0956797613496435.abstract
This work was supported by the National Institutes of Health (Grants MH080756 and AG039283).
The APS journal Psychological Science is the highest ranked empirical journal in psychology. For a copy of the article "The Price of Racial Bias: Intergroup Negotiations in the Ultimatum Game" and access to other Psychological Science research findings, please contact Anna Mikulak at 202-293-9300 or amikulak@psychologicalscience.org.
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The cost of racial bias in economic decisions
Public release date: 17-Oct-2013 [
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Contact: Anna Mikulak amikulak@psychologicalscience.org 202-293-9300 Association for Psychological Science
When financial gain depends on cooperation, we might expect that people would put aside their differences and focus on the bottom line. But new research suggests that people's racial biases make them more likely to leave money on the table when a windfall is not split evenly between groups.
The findings are published in Psychological Science, a journal of the Association for Psychological Science.
"It has been suggested that race bias in economic decisions may not occur in a market where discrimination is costly, but these findings provide the first evidence that this assumption is false," explain psychological scientists Jennifer Kubota and Elizabeth Phelps of New York University. "Our work suggests that after offers are on the table, people perceive the fairness of those offers differently even when they are objectively identical based on race."
The research was inspired by the debt ceiling debates that raged on in the summer of 2011.
"Many members of both the House and Senate seemed willing to incur costs that would hurt their own constituents in order to vote along political lines," say Kubota and Phelps. "The debate led us to wonder: Are people willing to punish members of another group when they perceive their behavior as unfair, even when exacting that punishment comes at a personal cost?"
The researchers decided that an important first step in understanding this phenomenon, given race-based financial disparities in the United States, would be to examine interracial economic decisions.
They had 49 participants of different ethnic and racial backgrounds engage in a so-called "ultimatum game," in which players accept or reject proposed splits of money. Participants were paired off and a "proposer" in each pair was given $10 to split between them. If the other player accepted the offer, the money was doled out accordingly; if the other player rejected the offer, both participants were left empty-handed. The researchers arranged it so that participants were always responding to offers from virtual proposers.
Because of existing cultural associations in the United States that link Black American males with aggression, hostility, and untrustworthiness, the researchers hypothesized that the participants might be more likely to perceive a low financial offer as unfair if it came from a Black rather than White proposer.
Overall, participants were more likely to accept White proposers' offers compared to those from Black proposers. And the data indicated that Black proposers had to offer larger amounts in order for players to accept the deal.
The effect is likely due to specific stereotypes or prejudices associated with Black Americans, given that participants showed a similar pattern of acceptance for offers from other-race proposers (who were neither White nor Black) and from White proposers.
The researchers point out that the financial offers being made in their study were relatively small and that people might be less likely to reject offers based on race when larger financial gains are at stake. Nonetheless, they argue that their findings have broad implications, with relevance to any context in which people punish others for what they consider to be violations of fairness:
"These findings may be especially relevant for legal and economic decisions and serve as an potential example of how people punish unfair or negative behavior in real-life," Kubota and Phelps conclude.
###
For more information about this study, please contact:
Elizabeth A. Phelps at liz.phelps@nyu.edu
Jennifer T. Kubota at jennifer.kubota@nyu.edu
In addition to Phelps and Kubota, co-authors include Jian Li of Peking University, Eyal Bar-David of New York University, and Mahzarin R. Banaji of Harvard University.
The article abstract is available online at: http://pss.sagepub.com/content/early/2013/10/11/0956797613496435.abstract
This work was supported by the National Institutes of Health (Grants MH080756 and AG039283).
The APS journal Psychological Science is the highest ranked empirical journal in psychology. For a copy of the article "The Price of Racial Bias: Intergroup Negotiations in the Ultimatum Game" and access to other Psychological Science research findings, please contact Anna Mikulak at 202-293-9300 or amikulak@psychologicalscience.org.
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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
Potential new drug for some patients with treatment-resistant lung cancer
PUBLIC RELEASE DATE:
20-Oct-2013
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Contact: Lauren Riley lauren.riley@aacr.org 215-446-7155 American Association for Cancer Research
BOSTON The investigational drug AZD9291, a third-generation EGFR inhibitor, showed promise in preclinical studies and provides hope for patients with advanced lung cancers that have become resistant to existing EGFR inhibitors, according to results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19-23.
Mutations in the growth factor gene EGFR are present in about 10 to 15 percent of patients with the most common form of lung cancer, non-small cell lung cancer (NSCLC). Most NSCLCs harboring these EGFR mutations, called activating mutations, respond to the EGFR inhibitor drugs erlotinib and gefitinib. A majority of such cancers, however, develop resistance to these drugs within about nine to 11 months. In many cases, this is due to the cancer cells acquiring a second mutation called EGFR T790M, also known as the "resistance mutation."
"There are no approved therapies to treat lung cancer patients who develop the second mutation in the EGFR that stops the currently available medicines from working," said Susan Galbraith, M.D., Ph.D., head of the Oncology Innovative Medicines Unit at AstraZeneca. "The innovative breakthrough was finding a series of molecules that could target both the activating and resistance mutant forms of EGFR more potently than normal EGFR, which led to development of the new EGFR kinase inhibitor, AZD9291.
"AZD9291 is highly active in preclinical models and is well tolerated in animal models. It inhibits both activating and resistant EGFR mutations while sparing the normal form of EGFR that is present in normal skin and gut cells, thereby reducing the side effects encountered with currently available medicines," she added.
The AstraZeneca scientists first showed that AZD9291 potently inhibited lung cancer cells with mutant EGFR, grown in lab dishes. They then tested the drug on mice bearing lung tumors with activating mutations and mice bearing lung tumors with resistance mutations. AZD9291 showed substantial tumor shrinkage in both groups of mice after 14 days of treatment. After 40 days, the researchers found no visible tumors in these mice, and this effect was sustained for more than 100 days. They also observed similar tumor shrinkage in mice that were genetically modified to develop tumors bearing both the activating and resistance mutations.
When the investigators analyzed blood samples collected from the treated mice, they identified a breakdown product of the parent compound AZD9291, which they called AZ5104, circulating in blood in addition to AZD9291. They then found that AZ5104 is also a potent inhibitor of activating and resistance EGFR mutations, and speculated that this may contribute to the efficacy seen after dosing with AZD9291.
Using data from blood analyses of mice, the researchers then developed a mathematical model to evaluate the dynamics of conversion of AZD9291 to AZ5104 and cumulative tumor-inhibitory effects. These experiments helped them determine the potentially effective doses of AZD9291 for patients with NSCLC harboring both activating and resistance EGFR mutations.
"Findings from preclinical studies have recently been translated to the clinic, where the drug has already demonstrated tumor shrinkage in patients and has been well tolerated, with low rates of side effects," said Galbraith. "The degree of response to treatment with AZD9291 in such a short period of time is very exciting. This new drug has the potential to provide new treatment options for patients in this setting."
###
Galbraith is an employee of AstraZeneca, which sponsored this study.
The 2013 International Conference on Molecular Targets and Cancer Therapeutics is being co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).
This research will be presented at a press conference entitled "Emerging Therapeutics" during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on Sunday, Oct. 20 at 10 a.m. ET in room 202 of the Hynes Convention Center in Boston, Mass. Reporters who cannot attend in person may call in using the following numbers:
U.S./Canada (toll-free): 800-446-2782
International (toll): 847-413-3235
To interview Susan Galbraith, contact Ayesha Bharmal at ayesha.bharmal@astrazeneca.com. For other inquiries, contact Jeremy Moore at jeremy.moore@aacr.org or 215-446-7109.
About the American Association for Cancer Research
Founded in 1907, the American Association for Cancer Research (AACR) is the world's oldest and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer.
For more information about the AACR, visit http://www.AACR.org. Follow the AACR on Twitter: @AACR. Follow the AACR on Facebook: http://www.facebook.com/aacr.org.
About the National Cancer Institute
The National Cancer Institute (NCI) leads the National Cancer Program and the NIH effort to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
About the European Organisation for Research and Treatment of Cancer
The European Organisation for the Research and Treatment of Cancer (EORTC) brings together European cancer clinical research experts from all disciplines for trans-national collaboration. Both multinational and multidisciplinary, the EORTC Network comprises more than 2,500 collaborators from all disciplines involved in cancer treatment and research in more than 300 hospitals in over 30 countries. Through translational and clinical research, the EORTC offers an integrated approach to drug development, drug evaluation programs and medical practices.
EORTC Headquarters, a unique pan European clinical research infrastructure, is based in Brussels, Belgium, from where its various activities are coordinated and run. http://www.eortc.org
Abstract Number: A109
Presenter: Susan Galbraith, M.D., Ph.D.
Title: AZD9291: an irreversible, potent and selective third generation tyrosine kinase inhibitor (TKI) targeting EGFR activating (EGFRm+) and resistance (T790M) mutations in advanced lung adenocarcinoma
Authors: Darren Cross1, Sue Ashton1, Caroline Nebhan2, Cath Eberlein1, M. Raymond V. Finlay1, Gareth Hughes1, Vivien Jacobs1, Martine Mellor1, Monica Red Brewer2, Catherine Meador2, Jonathon Orme1, Paula Spitzler2, Steve Powell1, Amar Rahi1, Paula Taylor1, Richard A. Ward1, Paula Daunt1, Anne Galer1, Teresa Klinowska1, Graham Richmond1, William Pao2. 1AstraZeneca, Macclesfield, United Kingdom; 2Department of Medicine/Division of Hematology-Oncology, Vanderbilt University, Nashville, TN
The first generation EGFR TKIs gefitinib and erlotinib provide significant clinical benefit in patients with advanced lung adenocarcinoma harbouring activating EGFR mutants (EGFRm+), but patients will ultimately develop disease progression due to acquired resistance. Acquisition of the EGFR T790M mutation is the most common mechanism of drug resistance, detected in more than 50% of gefitinib/erlotinib resistant patients. Current therapeutic strategies are limited for advanced lung adenocarcinoma patients with EGFR T790M (EGFRm+/T790M), so this remains a key area of unmet need.
AZD9291 (structure to be disclosed at meeting) is an oral, irreversible, third generation, selective inhibitor of both EGFR activating (EGFRm+) and resistance (EGFRm+/T790M) mutations. The mechanistic and functional activity of AZD9291 was characterised in vitro and in vivo across a number of cell lines harbouring various EGFR-mutations or wild type EGFR. Presented data shows AZD9291 potently inhibits EGFR phosphorylation in EGFRm+ (e.g. PC9; 500nM). Consistently, AZD9291 showed significantly more potent inhibition of proliferation in mutant EGFR cell lines compared to wild-type in vitro. In addition, AZD9291 administered once daily orally at 5mg/kg caused profound regression of tumours across EGFRm+ (PC9; 178% growth inhibition) and EGFRm+/T790M (H1975; 119% growth inhibition) tumour models in vivo, after 14 days dosing. Furthermore 5mg/kg AZD9291 was sufficient to cause significant shrinkage of EGFRm+ and EGFRm+/T790M transgenic mouse lung tumours. Tumour growth inhibition was associated with profound inhibition of EGFR phosphorylation and key downstream signaling pathways such as AKT and ERK. Chronic long-term treatment of PC9 and H1975 xenograft tumours with AZD9291 led to a complete and sustained macroscopic response, with no visible tumours after 40 days dosing, and being maintained beyond 100 days. Furthermore, pre-clinical data also indicates that AZD9291 could target tumours that have acquired resistance to the more recently identified HER2-amplification mechanism, thus potentially extending its benefit in TKI resistant patients.
Taken together, preclinical data demonstrates that AZD9291 is a potent and effective inhibitor of both EGFR activating (EGFRm+) and resistance (EGFRm+/T790M) mutations whilst sparing wild-type EGFR. These data support the further clinical investigation of AZD9291 in advanced EGFR mutant lung adenocarcinoma.
Abstract Number: B94
Presenter: Susan Galbraith, M.D., Ph.D.
Title: Discovery of and first disclosure of the clinical candidate AZD9291, a potent and selective third-generation EGFR inhibitor of both activating and T790M resistant mutations that spares the wild type form of the receptor
Authors: M. Raymond V. Finlay1, Mark Anderton1, Susan Ashton1, Peter G. Ballard1, Rob H. Bradbury1, Sam Butterworth1, Nicola Colclough1, Darren A.E. Cross1, Heather L. McFarland2, Martine J. Mellor1, Richard A. Ward1, Mike J. Waring1. 1AstraZeneca, Oncology Innovative Medicines, Macclesfield, Cheshire, SK10 4TG, United Kingdom; 2AstraZeneca, Global Medicines Development, Macclesfield, Cheshire, SK10 4TG, United Kingdom
Small molecule inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase such as gefitinib and erlotinib have been employed successfully in the treatment of non-small cell lung cancer (NSCLC) patients harboring an activating mutation (EGFRm+). However, resistance to these inhibitors in the form of additional mutations in the kinase domain such as T790M is emerging as a growing clinical issue. This presentation will describe the discovery of AZD9291, an orally bioavailable, irreversible EGFR inhibitor of both the resistance (NCI-H1975, cell phosphorylation IC50 0.5 μM). Wild type EGFR inhibition is believed to drive the observed dose limiting toxicities (such as skin rash and diarrhea) for these first generation therapies in the clinic. New data will be discussed for the first time including the medicinal chemistry program that led to the identification of AZD9291, details of significant in vivo oral activity in pre-clinical xenograft models (including tumor regression in the L858R/T790M double mutant setting at a dose of 5 mpk) and the first disclosure of the candidate drug structure. The pre-clinical findings from this work strongly supported selection of AZD9291 as a clinical candidate, and first dose in man was achieved with AZD9291 in March 2013.
Abstract Number: B212
Presenter: Susan Galbraith, M.D., Ph.D.
Title: Integrating the pre-clinical pharmacokinetic, pharmacodynamics, and efficacy data for AZD9291, an oral, irreversible inhibitor of EGFR activating (EGFRm+) and resistant (EGFRm+/T790M) mutations and an active metabolite to predict the human pharmacokinetics and potential efficacious dose in patients.
Authors: Peter Ballard1, Susan Ashton1, Darren Cross1, Richard Dimelow2, James Yates1. 1AstraZeneca, Macclesfield, Cheshire, United Kingdom; 2Wright-Dose, Altrincham, Cheshire, United Kingdom
Small molecule tyrosine kinase inhibitors gefitinib and erlotinib have demonstrated clinical benefit in advanced NSCLC patients with the EGFR activating mutation but ultimately disease progression develops due to resistant mutations. The most common resistant mutation is EGFR T790M and remains a key area of unmet need.
AZD9291 is an irreversible inhibitor of both the EGFR activating mutant (EGFRm+) and resistance mutation (EGFRm+/T790M), while maintaining a margin to wild type EGFR. AZD9291 has demonstrated impressive efficacy and regressions at low doses in mouse xenograft models for both activating (EGFRm+) and resistant (EGFRm+/T790M) mutant forms of EGFR (PC9 and H1975 cell lines). Analysis of plasma samples from these xenograft studies identified a des-methylated metabolite circulating in addition to AZD9291 with subsequent in vitro studies indicating the metabolite was around five fold more potent than AZD9291.
A program of mouse xenograft studies was undertaken to determine the tumor pEGFR pharmacodynamics (PD) and tumor growth inhibition (TGI) of AZD9291 and metabolite. Mathematical models incorporating an irreversible binding component have been developed to describe the contribution of AZD9291 and metabolite exposure to the pEGFR PD and TGI in the mouse (a PK/PD-TGI model). Pre-clinical drug metabolism and pharmacokinetic data were used to predict the human pharmacokinetics of AZD9291 and formation of the active metabolite. The predicted human exposures of both AZD9291 and metabolite were then used to drive the PK/PD-TGI model to simulate inhibition of pEGFR and inhibition of tumor growth. Assuming that human tumours and biomarkers behave in a similar way to those in mouse xenografts, these simulations suggest that a dose of 7-17 mg of AZD9291 once a day would be efficacious in patients with advanced NSCLC harboring the EGFR activating and T790M resistant mutations.
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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
Potential new drug for some patients with treatment-resistant lung cancer
PUBLIC RELEASE DATE:
20-Oct-2013
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Contact: Lauren Riley lauren.riley@aacr.org 215-446-7155 American Association for Cancer Research
BOSTON The investigational drug AZD9291, a third-generation EGFR inhibitor, showed promise in preclinical studies and provides hope for patients with advanced lung cancers that have become resistant to existing EGFR inhibitors, according to results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19-23.
Mutations in the growth factor gene EGFR are present in about 10 to 15 percent of patients with the most common form of lung cancer, non-small cell lung cancer (NSCLC). Most NSCLCs harboring these EGFR mutations, called activating mutations, respond to the EGFR inhibitor drugs erlotinib and gefitinib. A majority of such cancers, however, develop resistance to these drugs within about nine to 11 months. In many cases, this is due to the cancer cells acquiring a second mutation called EGFR T790M, also known as the "resistance mutation."
"There are no approved therapies to treat lung cancer patients who develop the second mutation in the EGFR that stops the currently available medicines from working," said Susan Galbraith, M.D., Ph.D., head of the Oncology Innovative Medicines Unit at AstraZeneca. "The innovative breakthrough was finding a series of molecules that could target both the activating and resistance mutant forms of EGFR more potently than normal EGFR, which led to development of the new EGFR kinase inhibitor, AZD9291.
"AZD9291 is highly active in preclinical models and is well tolerated in animal models. It inhibits both activating and resistant EGFR mutations while sparing the normal form of EGFR that is present in normal skin and gut cells, thereby reducing the side effects encountered with currently available medicines," she added.
The AstraZeneca scientists first showed that AZD9291 potently inhibited lung cancer cells with mutant EGFR, grown in lab dishes. They then tested the drug on mice bearing lung tumors with activating mutations and mice bearing lung tumors with resistance mutations. AZD9291 showed substantial tumor shrinkage in both groups of mice after 14 days of treatment. After 40 days, the researchers found no visible tumors in these mice, and this effect was sustained for more than 100 days. They also observed similar tumor shrinkage in mice that were genetically modified to develop tumors bearing both the activating and resistance mutations.
When the investigators analyzed blood samples collected from the treated mice, they identified a breakdown product of the parent compound AZD9291, which they called AZ5104, circulating in blood in addition to AZD9291. They then found that AZ5104 is also a potent inhibitor of activating and resistance EGFR mutations, and speculated that this may contribute to the efficacy seen after dosing with AZD9291.
Using data from blood analyses of mice, the researchers then developed a mathematical model to evaluate the dynamics of conversion of AZD9291 to AZ5104 and cumulative tumor-inhibitory effects. These experiments helped them determine the potentially effective doses of AZD9291 for patients with NSCLC harboring both activating and resistance EGFR mutations.
"Findings from preclinical studies have recently been translated to the clinic, where the drug has already demonstrated tumor shrinkage in patients and has been well tolerated, with low rates of side effects," said Galbraith. "The degree of response to treatment with AZD9291 in such a short period of time is very exciting. This new drug has the potential to provide new treatment options for patients in this setting."
###
Galbraith is an employee of AstraZeneca, which sponsored this study.
The 2013 International Conference on Molecular Targets and Cancer Therapeutics is being co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).
This research will be presented at a press conference entitled "Emerging Therapeutics" during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on Sunday, Oct. 20 at 10 a.m. ET in room 202 of the Hynes Convention Center in Boston, Mass. Reporters who cannot attend in person may call in using the following numbers:
U.S./Canada (toll-free): 800-446-2782
International (toll): 847-413-3235
To interview Susan Galbraith, contact Ayesha Bharmal at ayesha.bharmal@astrazeneca.com. For other inquiries, contact Jeremy Moore at jeremy.moore@aacr.org or 215-446-7109.
About the American Association for Cancer Research
Founded in 1907, the American Association for Cancer Research (AACR) is the world's oldest and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer.
For more information about the AACR, visit http://www.AACR.org. Follow the AACR on Twitter: @AACR. Follow the AACR on Facebook: http://www.facebook.com/aacr.org.
About the National Cancer Institute
The National Cancer Institute (NCI) leads the National Cancer Program and the NIH effort to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
About the European Organisation for Research and Treatment of Cancer
The European Organisation for the Research and Treatment of Cancer (EORTC) brings together European cancer clinical research experts from all disciplines for trans-national collaboration. Both multinational and multidisciplinary, the EORTC Network comprises more than 2,500 collaborators from all disciplines involved in cancer treatment and research in more than 300 hospitals in over 30 countries. Through translational and clinical research, the EORTC offers an integrated approach to drug development, drug evaluation programs and medical practices.
EORTC Headquarters, a unique pan European clinical research infrastructure, is based in Brussels, Belgium, from where its various activities are coordinated and run. http://www.eortc.org
Abstract Number: A109
Presenter: Susan Galbraith, M.D., Ph.D.
Title: AZD9291: an irreversible, potent and selective third generation tyrosine kinase inhibitor (TKI) targeting EGFR activating (EGFRm+) and resistance (T790M) mutations in advanced lung adenocarcinoma
Authors: Darren Cross1, Sue Ashton1, Caroline Nebhan2, Cath Eberlein1, M. Raymond V. Finlay1, Gareth Hughes1, Vivien Jacobs1, Martine Mellor1, Monica Red Brewer2, Catherine Meador2, Jonathon Orme1, Paula Spitzler2, Steve Powell1, Amar Rahi1, Paula Taylor1, Richard A. Ward1, Paula Daunt1, Anne Galer1, Teresa Klinowska1, Graham Richmond1, William Pao2. 1AstraZeneca, Macclesfield, United Kingdom; 2Department of Medicine/Division of Hematology-Oncology, Vanderbilt University, Nashville, TN
The first generation EGFR TKIs gefitinib and erlotinib provide significant clinical benefit in patients with advanced lung adenocarcinoma harbouring activating EGFR mutants (EGFRm+), but patients will ultimately develop disease progression due to acquired resistance. Acquisition of the EGFR T790M mutation is the most common mechanism of drug resistance, detected in more than 50% of gefitinib/erlotinib resistant patients. Current therapeutic strategies are limited for advanced lung adenocarcinoma patients with EGFR T790M (EGFRm+/T790M), so this remains a key area of unmet need.
AZD9291 (structure to be disclosed at meeting) is an oral, irreversible, third generation, selective inhibitor of both EGFR activating (EGFRm+) and resistance (EGFRm+/T790M) mutations. The mechanistic and functional activity of AZD9291 was characterised in vitro and in vivo across a number of cell lines harbouring various EGFR-mutations or wild type EGFR. Presented data shows AZD9291 potently inhibits EGFR phosphorylation in EGFRm+ (e.g. PC9; 500nM). Consistently, AZD9291 showed significantly more potent inhibition of proliferation in mutant EGFR cell lines compared to wild-type in vitro. In addition, AZD9291 administered once daily orally at 5mg/kg caused profound regression of tumours across EGFRm+ (PC9; 178% growth inhibition) and EGFRm+/T790M (H1975; 119% growth inhibition) tumour models in vivo, after 14 days dosing. Furthermore 5mg/kg AZD9291 was sufficient to cause significant shrinkage of EGFRm+ and EGFRm+/T790M transgenic mouse lung tumours. Tumour growth inhibition was associated with profound inhibition of EGFR phosphorylation and key downstream signaling pathways such as AKT and ERK. Chronic long-term treatment of PC9 and H1975 xenograft tumours with AZD9291 led to a complete and sustained macroscopic response, with no visible tumours after 40 days dosing, and being maintained beyond 100 days. Furthermore, pre-clinical data also indicates that AZD9291 could target tumours that have acquired resistance to the more recently identified HER2-amplification mechanism, thus potentially extending its benefit in TKI resistant patients.
Taken together, preclinical data demonstrates that AZD9291 is a potent and effective inhibitor of both EGFR activating (EGFRm+) and resistance (EGFRm+/T790M) mutations whilst sparing wild-type EGFR. These data support the further clinical investigation of AZD9291 in advanced EGFR mutant lung adenocarcinoma.
Abstract Number: B94
Presenter: Susan Galbraith, M.D., Ph.D.
Title: Discovery of and first disclosure of the clinical candidate AZD9291, a potent and selective third-generation EGFR inhibitor of both activating and T790M resistant mutations that spares the wild type form of the receptor
Authors: M. Raymond V. Finlay1, Mark Anderton1, Susan Ashton1, Peter G. Ballard1, Rob H. Bradbury1, Sam Butterworth1, Nicola Colclough1, Darren A.E. Cross1, Heather L. McFarland2, Martine J. Mellor1, Richard A. Ward1, Mike J. Waring1. 1AstraZeneca, Oncology Innovative Medicines, Macclesfield, Cheshire, SK10 4TG, United Kingdom; 2AstraZeneca, Global Medicines Development, Macclesfield, Cheshire, SK10 4TG, United Kingdom
Small molecule inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase such as gefitinib and erlotinib have been employed successfully in the treatment of non-small cell lung cancer (NSCLC) patients harboring an activating mutation (EGFRm+). However, resistance to these inhibitors in the form of additional mutations in the kinase domain such as T790M is emerging as a growing clinical issue. This presentation will describe the discovery of AZD9291, an orally bioavailable, irreversible EGFR inhibitor of both the resistance (NCI-H1975, cell phosphorylation IC50 0.5 μM). Wild type EGFR inhibition is believed to drive the observed dose limiting toxicities (such as skin rash and diarrhea) for these first generation therapies in the clinic. New data will be discussed for the first time including the medicinal chemistry program that led to the identification of AZD9291, details of significant in vivo oral activity in pre-clinical xenograft models (including tumor regression in the L858R/T790M double mutant setting at a dose of 5 mpk) and the first disclosure of the candidate drug structure. The pre-clinical findings from this work strongly supported selection of AZD9291 as a clinical candidate, and first dose in man was achieved with AZD9291 in March 2013.
Abstract Number: B212
Presenter: Susan Galbraith, M.D., Ph.D.
Title: Integrating the pre-clinical pharmacokinetic, pharmacodynamics, and efficacy data for AZD9291, an oral, irreversible inhibitor of EGFR activating (EGFRm+) and resistant (EGFRm+/T790M) mutations and an active metabolite to predict the human pharmacokinetics and potential efficacious dose in patients.
Authors: Peter Ballard1, Susan Ashton1, Darren Cross1, Richard Dimelow2, James Yates1. 1AstraZeneca, Macclesfield, Cheshire, United Kingdom; 2Wright-Dose, Altrincham, Cheshire, United Kingdom
Small molecule tyrosine kinase inhibitors gefitinib and erlotinib have demonstrated clinical benefit in advanced NSCLC patients with the EGFR activating mutation but ultimately disease progression develops due to resistant mutations. The most common resistant mutation is EGFR T790M and remains a key area of unmet need.
AZD9291 is an irreversible inhibitor of both the EGFR activating mutant (EGFRm+) and resistance mutation (EGFRm+/T790M), while maintaining a margin to wild type EGFR. AZD9291 has demonstrated impressive efficacy and regressions at low doses in mouse xenograft models for both activating (EGFRm+) and resistant (EGFRm+/T790M) mutant forms of EGFR (PC9 and H1975 cell lines). Analysis of plasma samples from these xenograft studies identified a des-methylated metabolite circulating in addition to AZD9291 with subsequent in vitro studies indicating the metabolite was around five fold more potent than AZD9291.
A program of mouse xenograft studies was undertaken to determine the tumor pEGFR pharmacodynamics (PD) and tumor growth inhibition (TGI) of AZD9291 and metabolite. Mathematical models incorporating an irreversible binding component have been developed to describe the contribution of AZD9291 and metabolite exposure to the pEGFR PD and TGI in the mouse (a PK/PD-TGI model). Pre-clinical drug metabolism and pharmacokinetic data were used to predict the human pharmacokinetics of AZD9291 and formation of the active metabolite. The predicted human exposures of both AZD9291 and metabolite were then used to drive the PK/PD-TGI model to simulate inhibition of pEGFR and inhibition of tumor growth. Assuming that human tumours and biomarkers behave in a similar way to those in mouse xenografts, these simulations suggest that a dose of 7-17 mg of AZD9291 once a day would be efficacious in patients with advanced NSCLC harboring the EGFR activating and T790M resistant mutations.
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Sony’s no stranger to waterproof tech: It’s last smartphone and tablet weren’t afraid of getting dunked in the tub—making them perfect for the accident-prone or Aquaman.
Not content with just one waterproof phone in the U.S., the company announced Tuesday that its other two liquid-friendly Android phones—the Xperia Z1 and Xperia Z Ultra—would also be making their way stateside. The phones have been available internationally for a few months now, but having a few more choices when picking out a smartphone has never been a bad thing.
SonySony’s Xperia Z Ultra is a big phone.
The Ultra comes with a monstrous 6.4-inch HD display, a quad-core processor, and an 8-megapixel camera. This phablet-sized phone ships with Android 4.2 Jelly Bean, but will likely be updated to a more recent version of the OS sometime after its release.
The Z1 has a more reasonably sized 5-inch HD display, but makes up for the difference in size with a 20.7-megapixel camera. The phone will also ship with a quad-core processor and Android 4.2, putting it on par with most of the other Android phones we’ve seen pushed out lately.
Both phones are waterproof and dust-proof, meaning you can rub them in a puddle of mud and have them come away from the encounter unscathed.
Sony
SmartWatch 2
If you prefer your water-proof gizmos on your wrist instead of your pocket, Sony also announced that its SmartWatch 2 would be making its way stateside a little later this year. The watch features NFC and works with “an ever-growing catalog of downloadable apps” from the Google Play Store.
The Xperia Z Ultra and Xperia Z1 will retail for $680 and $670 (off-contract), respectively, while the SmartWatch 2 will set you back a cool $200. No carriers have been announced for either of the two smartphones, but it’s likely we’ll see one of them make their way to T-Mobile or AT&T (judging by the supported bands).
Sony’s made a strong push for water-resilient devices over the past year, and you just have to wonder how long it’ll be before the other big device makers join the party.
If you've ever teased a cat by waving a laser pointer around on the floor and watching it chase the red spot around the floor, you'll know animals can seem pretty dumb. But don't for one second assume that you're a higher form of intelligence.
SundaySky, a company promising to deliver video ads that are customized and updated for each viewer, has raised $20 million in Series C funding.
The round was led by Comcast Ventures, with participation from new investors Liberty Global Ventures and Vintage Investment Partners, as well as existing backers Carmel Ventures, Globespan Capital Partners, and Norwest Venture Partners. Comcast Ventures managing director Andrew Cleland will be joining SundaySky's board of directors. Source: http://feedproxy.google.com/~r/Techcrunch/~3/PUR_j0-n80E/ Related Topics: Texas A&mCameron DouglasBryan Cranstontaylor swift2 Guns
STANFORD, Calif. (AP) — Tyler Gaffney ran for 171 yards and two touchdowns, and No. 13 Stanford smothered Brett Hundley and ninth-ranked UCLA 24-10 on Saturday.
Kevin Hogan threw for 227 yards and a spectacular touchdown to Kodi Whitfield as the Cardinal (6-1, 4-1) regrouped again after losing at Utah last week. Stanford has not lost consecutive games since October 2009.
Stanford hurried Hundley all afternoon to slow down UCLA's up-tempo offense.
Hundley completed 24 of 39 passes for 192 yards, one touchdown and two interceptions to Jordan Richards — the second with a little more than 2 minutes remaining to seal Stanford's victory. UCLA (5-1, 2-1) has not started 6-0 since 2005.
The Cardinal came out on top again in a rematch of last season's Pac-12 title game and showed they're not bowing out of the conference race. Stanford has won six straight over UCLA, including three times in the last year, and 14 in a row against teams from California.
The Bruins entered the game averaging 45.8 points per game. That ranked second in the Pac-12 behind Oregon, which hosts UCLA next week before traveling to Stanford on Nov. 7 in matchups that will likely decide the Pac-12's championship game.
Stanford, which had its 13-game winning streak snapped in Salt Lake City last week, showed just why it has been so tough to keep down the last four years.
The Cardinal outgained UCLA 419 to 266 yards, won the time of possession 37:11 to 22:49 and made big the play when it mattered most again.
With Hundley and UCLA's offense taking the field late with 2:57 remaining, the Cardinal hurried Hundley twice before Richards dove for his second interception after receiver Thomas Duarte fell down. Gaffney capped off a quick Stanford drive with a 4-yard TD run that put the game out of reach.
Devon Cajuste caught seven passes for 109 yards for Stanford before leaving with a right leg injury early in the fourth quarter. UCLA also lost a key player, with inside linebacker Eric Kendricks taken to the hospital for tests on his kidney after making nine tackles in the first half.
It was not immediately clear what caused Kendricks' kidney issue.
The Cardinal controlled the flow from the start but missed opportunities in the first half to ahead big.
Ty Montgomery dropped a deep pass near the goal line on Stanford's first drive. The Cardinal later lost 10 yards on first-and-goal when they fumbled a pitch, and Ishmael Adams intercepted Hogan's pass at UCLA's 6-yard line in the final minute of the half when Cajuste bobbled the ball into his Adams' arms.
But Stanford's scoring erupted with one of the most spectacular plays of the season.
While running to his right on a post route, Whitfield leaped in the air and reached back to make a backhanded catch with his right hand between two defenders. The 30-yard TD reception put Stanford up 10-3 and left most of the crowd "oohing" every time the replay was shown on the video boards.
On UCLA's next drive, Stanford forced a turnover for the 32nd straight game — the second-longest streak in the country — when Richards intercepted Hundley's pass. Richards' return for a touchdown was called back because of a holding penalty.
No matter.
Cajuste caught a leaping 34-yard pass at UCLA's 2 on third down. And three plays later, Gaffney ran for a short TD to put the Cardinal up 17-3 late in the third quarter.
Hundley regrouped to lead UCLA on an 11-play, 75-yard scoring drive. He capped it off with a 3-yard TD pass to Shaquelle Evans that sliced Stanford's lead to 17-10 early in the fourth.
Hundley and the Bruins never looked so smooth again. Ka'imi Fairbairn kicked a tying 38-yard field on the opening drive of the second half for UCLA's only other score.
____
Antonio Gonzalez can be reached at: www.twitter.com/agonzalezAP
The Xbox One may come with its own beefed up audio accessories, but audiophiles waiting on Turtle Beach's XO Ear Force headsets will have to wait: Microsoft won't support them until 2014. According to a statement confirmed by Microsoft, the Xbox One Headset Adapter that enables the use of third ...
The Supreme Court will hear arguments in two cases on Wednesday: Kansas v. Cheever and Kaley v. United States.
Mandel Ngan/AFP/Getty Images
The Supreme Court will hear arguments in two cases on Wednesday: Kansas v. Cheever and Kaley v. United States.
Mandel Ngan/AFP/Getty Images
The U.S. Supreme Court will hear arguments in two cases on Wednesday — one that focuses on the right against self-incrimination and another that looks at when prosecutors can seize defendants' assets.
What Counts As Self-Incrimination?
The first arguments before the court Wednesday come in a murder case that tests whether a court-ordered psychiatric exam can be used to rebut a defendant's claim that he had not formed the necessary intent to kill. The defendant claims that using the examination violated his constitutional right against self-incrimination.
In 2005, Scott Cheever shot and killed a sheriff during the course of an arrest. Cheever, then 24, had been addicted to methamphetamines since he was 17. He claimed that at the time of the killing, he had not slept in nine days, had just injected a near-lethal dose of the drug and was incapable of exercising judgment when the sheriff came to arrest him. In short, he contended that he was incapable of forming the necessary intent to kill — an element that is required to qualify a defendant for the death penalty.
The case took tortuous legal turns, dragging its way through both state and federal court, before Cheever was finally convicted in state court and sentenced to death.
The appeal of that conviction centers on a psychiatric exam that took place at the early stage of the case, prior to trial, and over defense counsel's objection. A federal judge ordered the psychiatric exam when Cheever's lawyer first notified the federal court that the defense intended to argue that Cheever did not have the requisite intent to kill.
For unrelated reasons, the federal prosecution was eventually dropped in favor of a state prosecution. But when the case went to trial in state court, Cheever pressed the same argument. The defense called its own expert witness to testify about the short- and long-term effects of methamphetamine use. That expert testified that Cheever was experiencing paranoid psychosis and could not have exercised any judgment when he killed the sheriff.
In response, the state called the psychiatrist who had conducted the court-ordered examination at the earlier stage of the case. That doctor testified that, while Cheever had antisocial personality disorder and was "impressed and awed" by "outlaws," his mental state at the time was not significantly altered. In short, that the defendant could have intended to kill the sheriff.
The Kansas Supreme Court subsequently voided the conviction. It ruled unanimously that the state had violated Cheever's Fifth Amendment right against self-incrimination by calling the state's psychiatrist to testify.
The state then appealed to the U.S. Supreme Court, where the justices will hear arguments on Wednesday. The state argues that Cheever voluntarily waived his right against self-incrimination by introducing evidence of his mental state. Cheever's attorney counters that presentation of evidence of mental state is not a waiver of the right against self-incrimination.
What Can Prosecutors Seize Before Trial?
The second of the two cases being argued Wednesday tests under what circumstances prosecutors may seize a defendant's assets prior to trial. The defendants in the case claim the seizure of their assets is unconstitutional because it makes it impossible for them to pay their chosen lawyers to conduct a defense.
When the government began investigating Kerri and Brian Kaley for allegedly selling stolen medical supplies, the Kaleys fought back, contending that the medical supplies were not stolen at all. They knew that identical charges in another case had ended in a not-guilty verdict. So, they took out a $500,000 loan on their home and put it into a CD to pay their lawyers for a trial.
Federal prosecutors, however, then sought to freeze all their assets — an action that the Kaleys contend denied them the right to counsel and due process of law.
The couple is asking the Supreme Court to set down rules requiring a pretrial evidentiary hearing prior to allowing the seizure. Prosecutors counter that such a hearing would essentially be a mini-trial, giving defendants two bites at the apple after they are tried.
The case could have a significant impact on both prosecutors and defense lawyers. Groups on the right and the left have filed briefs on behalf of the Kaleys. They say that if the court sides with the Kaleys, it would deprive prosecutors of a heavy weapon used too aggressively and frequently to force guilty pleas on unwilling defendants. On the other hand, prosecutors contend that a decision favoring the Kaleys would encourage white-collar defense lawyers to represent wealthy defendants, regardless of the fact that the lawyers are being paid with their clients' ill-gotten gain.
London (AFP) - South African Graham Ford has been appointed new head coach of Surrey, the English county side confirmed on Monday.
The 52-year-old has signed a three-year deal and will join the club in February when his contract with the Sri Lanka team ends.
He replaces Chris Adams, who was sacked last June after the club were relegated from Division One of the County Championship.
"I am delighted to once again be involved in the English cricketing system," said Ford.
"I have, for a long while, been an admirer of Surrey CCC and see it as a great privilege to be actively involved in such a fine club.
"I look forward to the exciting times ahead!"
Ford will work alongside club board member Alec Stewart, who is to take on the role of director of cricket.
He will also join fellow South African Graeme Smith at the Kia Oval with the long-serving national skipper having been re-signed, as club captain, for 2014.
The move will also see him link up again with England batsman Kevin Pietersen, whom he has known since his school days.
Ford started coaching in 1992 and won domestic honours with Natal before moving up to international level with South Africa in 1999.
He joined Kent in 2005 and later returned to Natal before taking charge of Sri Lanka in January last year.
Mike Myers, famously known for playing the titular spy in the Austin Powers film franchise, is expecting his second child with wife Kelly Tisdale. And it appears every local news anchor across the country chose the same way to announce the good news to their audience. Check out this supercut of media reactions put together byConan O'Brien's late-night team:
WASHINGTON (AP) — The Republicans' clear defeat in the budget-debt brawl has widened the rift between the Grand Old Party and the blossoming tea party movement that helped revive it.
Implored by House Speaker John Boehner to unite and "fight another day" against President Barack Obama and Democrats, Republicans instead intensified attacks on one another, an ominous sign in advance of more difficult policy fights and the 2014 midterm elections.
The tea party movement spawned by the passage of Obama's health care overhaul three years ago put the GOP back in charge of the House and in hot pursuit of the law's repeal. The effort hit a wall this month in the budget and debt fight, but tea partyers promised to keep up the effort.
Whatever the future of the troubled law, Senate Republican Leader Mitch McConnell vowed he would not permit another government shutdown.
"I think we have now fully acquainted our new members with what a losing strategy that is," McConnell said in an interview with The Hill newspaper.
Tea party Sen. Ted Cruz of Texas told ABC News he wouldn't rule out using the tactic again, when the same budget and debt questions come up next year.
"I will continue to do anything I can to stop the train wreck that is Obamacare," Cruz said.
That divide defined the warring Republican factions ahead of the midterm elections, when 35 seats in the Democratic-controlled Senate and all 435 seats in the Republican-dominated House will be on the ballot. In the nearer term, difficult debates over immigration and farm policy loom, along with another round of budget and debt talks.
The animosity only intensified as lawmakers fled Washington this week for a few days' rest.
The Twitterverse crackled with threats, insults and the names of the 27 GOP senators and 87 GOP House members who voted for the leadership's agreement that reopened the government and raised the nation's borrowing limit. Republicans got none of their demands, keeping only the spending cuts they had won in 2011.
Within hours, TeaParty.net tweeted a link to the 114 lawmakers, tagging each as a Republican in name only who should be turned out of office: "Your 2014 #RINO hunting list!"
"We shouldn't have to put up with fake conservatives like Mitch McConnell," read a fundraising letter Thursday from the Tea Party Victory Fund Inc.
Another group, the Senate Conservatives Fund, announced it was endorsing McConnell's GOP opponent, Louisville, Ky., businessman Matt Bevin.
"Mitch McConnell has the support of the entire Washington establishment and he will do anything to hold on to power," the group, which raised nearly $2 million for tea party candidates in last year's elections, announced. "But if people in Kentucky and all across the country rise up and demand something better, we're confident Matt Bevin can win this race."
The same group pivoted to the Mississippi Senate race, where Republican Thad Cochran is weighing whether to seek a seventh term. Cochran voted for the McConnell-Reid deal, so the Senate Conservatives Fund endorsed a primary opponent, state Sen. Chris McDaniel, a private attorney the group says "will fight to stop Obamacare," ''is not part of the Washington establishment" and "has the courage to stand up to the big spenders in both parties."
There were more tea party targets: Republican Sens. Lindsey Graham in South Carolina and Lamar Alexander in Tennessee also are seeking re-election.
To her Facebook friends, vice presidential candidate Sarah Palin posted: "We're going to shake things up in 2014. Rest well tonight, for soon we must focus on important House and Senate races. Let's start with Kentucky — which happens to be awfully close to South Carolina, Tennessee and Mississippi."
Opponents of the tea party strategy to make "Obamacare" the centerpiece of the budget fight seethed over what they said was an exercise in self destruction. Many clamored for Boehner and McConnell, the nation's highest-ranking Republicans, to impose some discipline, pointing to polls that showed public approval of Congress plummeting to historic lows and that most Americans blamed Republicans for the government shutdown.
A Pew Research Center poll released this week showed public favorability for the Tea Party dropped to its lowest level since driving the Republican takeover of the House in the 2010 elections. An AP-Gfk poll showed that 70 percent now hold unfavorable views of the Tea Party.
And yet, House Republican leaders tried again and again to resolve the standoff the tea party's way — by demanding limits on Obamacare in exchange for reopening the government — until they ran of options and accepted the bipartisan deal.
"When your strategy doesn't work, or your tactic doesn't work, you lose credibility in your conference," said Rep. Aaron Schock, R-Ill., referring to the tea partyers' tactics. "Clearly the leadership followed certain members' tactics, certain members' strategies, and they proved not to be all that successful. So I would hope that we learn from the past."
"I do believe the outside groups have really put us in this position," said Rep. Renee Ellmers, R-N.C., referring to the Heritage Foundation's political campaign arm and other organizations demanding fealty to their ideology. Those groups "have worked in conjunction with members of Congress and with Tea Party groups pushing a strategy that was never going to work."
Tea partyers hold a contrary view. Boehner, they say, solidified his standing as the GOP's leader by holding the line against compromise as long as he did. And the standoff, they add, has increased their movement's clout.
"I think it builds credibility, because I think Democrats did not think that we would press this," said Rep. John Fleming, R-La. "And now they know that we will, and that we might do it again."
Audio for this story from Morning Edition will be available at approximately 9:00 a.m. ET.
David Greene talks to Tom Suryan, a crabbing boat captain, about how the federal shutdown is stalling the issuance of quota permits, and thus the start of crab season.
In this Tuesday, Oct. 15, 2013 photo, Carter Howard sits and watches a cartoon during his asthma treatment at his home in Northbrook, Ill. On the days when asthma gives Carter the most trouble, his mother is reminded how doctors at Rush University Medical Center had to stop submitting applications for research grants to study childhood asthma and other diseases and disorders due to the federal government shutdown. (AP Photo/Charles Rex Arbogast)
In this Tuesday, Oct. 15, 2013 photo, Carter Howard sits and watches a cartoon during his asthma treatment at his home in Northbrook, Ill. On the days when asthma gives Carter the most trouble, his mother is reminded how doctors at Rush University Medical Center had to stop submitting applications for research grants to study childhood asthma and other diseases and disorders due to the federal government shutdown. (AP Photo/Charles Rex Arbogast)
In this Tuesday, Oct. 15, 2013 photo, Monique Howard holds Waldo as she caresses her son Carter's head while he sits through his asthma treatment at their Northbrook, Ill., home. On the days when asthma gives Carter the most trouble it reminds her about how doctors at Rush University Medical Center had to stop submitting applications for research grants to study childhood asthma and other diseases and disorders. Hospital officials have said the shutdown could have delayed funding for nearly half a year. (AP Photo/Charles Rex Arbogast)
FILE - In this June 24, 2013 file photo, storm clouds pass over downtown Chicago. The federal government shutdown may have seemed like a frustrating squabble in far-off Washington, but in Chicago, it crept into our lives in small, subtle ways _ from missed vegetable inspections to inaccessible federal websites. (AP Photo/Scott Eisen)
FILE - In this Oct. 2, 2013 file photo, despite signs stating that the national parks are closed, people visit the World War II Memorial in Washington. The federal government shutdown may have seemed like a frustrating squabble in Washington, but it crept into our lives in small, subtle ways _ from missed vegetable inspections to inaccessible federal websites. (AP Photo/Susan Walsh, File)
In this Tuesday, Oct. 15, 2013 photo, Monique Howard, right, holds Waldo as she talks with her son Carter after his asthma treatment at their home in Northbrook, Ill. Howard is worried that federal government shutdown might set research for childhood asthma back five or six months. "It just seems to me like a lot of these studies are going to be scrapped or they will have to restart them," she said. "It is just so frustrating as a parent." (AP Photo/Charles Rex Arbogast)
CHICAGO (AP) — Our food was a little less safe, our workplaces a little more dangerous. The risk of getting sick was a bit higher, our kids' homework tougher to complete.
The federal government shutdown may have seemed like a frustrating squabble in far-off Washington, but it crept into our lives in small, subtle ways — from missed vegetable inspections to inaccessible federal websites.
The "feds" always are there in the background, setting the standards by which we live, providing funds to research cures for our kids' illnesses, watching over our food supply and work environment.
So how did the shutdown alter our daily routines? Here's a look at a day in the life of the 2013 government shutdown.
WAKING UP
That sausage patty on your breakfast plate was safe as ever because meat inspectors — like FBI agents — are considered "essential" and remained at work. But federal workers who inspect just about everything else on your plate — from fresh berries to scrambled eggs — were furloughed.
The Food and Drug Administration, which in fiscal year 2012 conducted more than 21,000 inspections or contracted state agencies to conduct them, put off scores of other inspections at processing plants, dairies and other large food facilities. In all, 976 of the FDA's 1,602 inspectors were sent home.
About 200 planned inspections a week were put off, in addition to more than 8,700 inspections the federal government contracts state officials to perform, according to FDA spokesman Steven Immergut. That included unexpected inspections that keep food processors on their toes.
It worried Yadira Avila, a 34-year-old mother of two buying fruit and vegetables at a Chicago market.
"It's crazy because they (the FDA) sometimes find the bacteria," she said.
The FDA also stopped doing follow-ups on problems it previously detected at, for example, a seafood importer near Los Angeles and a dairy farm in Colorado.
And what about the food that made it to your plate? The federal Centers for Disease Control and Prevention in Atlanta, which furloughed 9,000 of its 13,000 workers, said the shutdown slowed its response to an outbreak of salmonella in chicken that sickened people in 18 states.
OFFICE HOURS
At a warehouse, factory or other worksite, a young minority exposed to racial slurs by his boss had one fewer place to turn for help. Federal officials who oversee compliance with discrimination laws and labor practices weren't working, except in emergencies.
The Equal Employment Opportunity Commission was not issuing right-to-sue letters, so people could not take discrimination cases into federal court, said Peter Siegelman, an expert in workplace discrimination at the University of Connecticut's law school.
Workplaces weren't inspected by the Occupational Safety and Health Administration. One result? Employees could operate dangerous equipment even if not trained or old enough to do so.
"The afternoon before the shutdown we got a complaint of a restaurant where a ... 14-year-old was operating a vertical dough mixer," said James Yochim, assistant director of the U.S. Department of Labor's wage and hour division office in Springfield, Ill. "We (were) not able to get out there and conduct an investigation."
Yochim's office also put on hold an investigation at another restaurant of children reportedly using a meat slicer.
HOME SAFE
Getting around was largely unaffected. Air traffic controllers were on the job, flights still taking off. Trains operated by local agencies delivered millions of commuters to their jobs.
But if something went wrong, such as the mysterious case of a Chicago "ghost train," people were left in the dark.
On the last day of September, an empty Chicago Transit Authority train somehow rumbled down the tracks and crashed into another train, injuring a few dozen passengers. The National Transportation Safety Board dispatched investigators, and they kept working when the shutdown started the next day because they were "essential." But the agency furloughed others whose job is to explain to the public what happened.
So millions of commuters used the transit lines without knowing more about what caused the crash.
The CDC slashed staffing at quarantine stations at 20 airports and entry points, raising chances travelers could enter the country carrying diseases like measles undetected.
In the first week of the shutdown, the number of illnesses detected dropped by 50 percent, CDC spokeswoman Barbara Reynolds said. "Are people suddenly a lot healthier?" she wondered.
STUDY TIME
Children learned the meaning of shutdown when they got home and booted up computers to do homework. From the U.S. Census bureau site to NASA maps, they were greeted by alerts that said government sites were down "due to the shutdown."
Linda Koplin, a math teacher in Oak Park, a Chicago suburb, asked her sixth-grade pupils to use a reliable online source to find the highest and lowest elevations.
"They were able to find all the elevations for the rest of the continents but they couldn't find information for their continent," Koplin said.
It was the same at New Trier High School in Winnetka, Ill., where social studies teacher Robin Forrest said government statistics are more important because of so much dubious information on the web.
"We try to steer our kids toward websites and databases that are legitimate, the same way we would college students," he said.
NIGHT, NIGHT
After hours is when the shutdown arrived at many people's homes.
Monique Howard's 5-year-old son, Carter, has the most trouble with his asthma at night, when his breathing is labored. Her family dreams of a cure, the kind doctors are hunting through federally funded research grants at Rush University Medical Center in Chicago.
During the shutdown, the doctors had to stop submitting grant applications to study childhood asthma and other diseases and disorders. Hospital officials said the shutdown could have delayed funding for nearly half a year.
"I have met some of these doctors who are close to breakthroughs, and if this sets us back five or six months, it just seems to me like a lot of these studies are going to be scrapped or they will have to restart them," Howard said. "It's just so frustrating as a parent."
There was a comedic effect, too. The shutdown might have saved raunchy entertainers from punishment for obscene or offensive language on late-night TV and radio.
The Federal Communications Commission investigates broadcast misbehavior only if viewers or listeners complain. During the shutdown, callers heard a voice with a familiar ring: "The FCC is closed."
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The Xbox One may come with its own beefed up audio accessories, but audiophiles waiting on Turtle Beach's XO Ear Force headsets will have to wait: Microsoft won't support them until 2014. According to a statement confirmed by Microsoft, the Xbox One Headset Adapter that enables the use of third ...
