Cooperative Agreement Grant Research Articles

SWOG S0509: A phase II study of novel oral antiangiogenic agent AZD2171 (NSC-732208) in malignant pleural mesothelioma

7511 Background: Preclinical studies suggest the autocrine growth loop involving VEGF and its receptors is a relevant therapeutic target for malignant pleural mesothelioma (MPM). We evaluated AZD2171, a potent tyrosine kinase inhibitor (TKI) of VEGFR1/2 in MPM. Methods: MPM patients (pts) after platinum-based chemotherapy, with PS 0–2, measurable disease and adequate organ function were treated with oral daily dosing of AZD2171 45 mg. Study endpoints were response rate, progression free survival (PFS), overall survival (OS), frequency/severity of toxicities, and correlation of clinical outcomes with tumor and serum biomarkers. Results: 54 pts were registered between November 2005 and April 2008; 45 pts are eligible for response and 46 for toxicity analysis. Median age was 66.8 yrs; M/F: 37/9. Tumor response by RECIST was seen in 4/45 (9%) of pts; of these responders, 2 pts with bulky disease had 56% and 91% tumor shrinkage, respectively. 15/45 (33%) had SD; 21/45 (47%) had PD; 1/45 (2%) had early death. Thirty-five pts have died. For 46 pts, median PFS is estimated at 3 months; median OS is estimated at 10 months. For 46 pts, frequent grade 1–3 toxicities included anorexia (30%), diarrhea (63%), fatigue (60%), hypertension (67%), and proteinuria (28%). There were 8 grade 4 events: Cognitive disturbance, colitis, confusion, ileal perforation, hypertension, hyponatremia, hypotension, and renal failure. Conclusions: AZD2171 has antitumor activity in MPM, with a DCR (CR/PR/SD) of 42% by RECIST, which has limitations in measuring response in pleural tumors. Notably, 2 pt tumors were exquisitely sensitive to this drug. Toxicities were consistent with those of the anti-angiogenic TKI class of drugs. Studies correlating outcome measures with tumor hypoxia- and angiogenesis-related gene expression and circulating endothelial cells are underway. Based on these data, we are proceeding in SWOG with a study of pemetrexed/cisplatin ± AZD2171 (S0905). This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102, CA38926, CA14028, CA46441, CA105409, CA13612, CA45808, CA20319, CA86780, CA35090, CA67663, CA46282, CA42777, CA76448, CA04919, CA35176, CA63848, CA27057, CA16385. [Table: see text]

Expression of system N protein mRNA, but not system A or L, is upregulated by ileal epithelia of growing beef cattle in response to increased luminal supply of energy but not amino acids

To complete our in vivo study of how basal expression profiles of 20 amino acid (AA) transporter genes respond to increases in luminal supply of substrates or energy in the small intestine, total RNA was extracted from duodenal (D), jejunal (J), and ileal (I) epithelia of 18 ruminally and abomasally catheterized Angus steers (BW ? 260 kg) fed an alfalfa‐cube based diet at 1.3× NEm requirement and infused for 14 to 16 d with either (n = 6) water (basal) or corn starch hydrolysate (20% ME intake) into rumen (increased microbial AA) or abomasum (increased glucose/energy). The effect of infusion treatments on expression of mRNA encoding systems A (ATA1, 2, 3), N (SN1, 2), and L (LAT1, 2) neutral AA transporters was evaluated by real‐time RT‐PCR methodoloy. Basal expression of all mRNA but ATA3 differed (P = 0.06) among D, J, and I: ATA1, D=J>I; ATA2, D=J, D=I, J>I; SN1, D>J=I; SN2, J>D=I; LAT1, D=J>I; LAT2, D=J, J=I, D<I. Increased luminal AA or energy supply did not affect (P > 0.15) the mRNA content of these neutral AA transporters except that expression of SN1 and SN2 mRNA by I was increased (P = 0.08) 57 and 51%, respectively, with increased luminal energy supply. This latter finding suggests that luminal energy supply may limit I expression of SN1 and SN2 mRNA. This study was funded by a USDA‐ARS Special Cooperative Agreement Grant.

Iniciativas en Estados Unidos para investigar el tratamiento del abuso de drogas y la Justicia Penal

Research in the U.S. has consistently shown that drug use and criminal activity are highly related, as evidenced by the growing number of incarcerated substance users in U.S. prisons and jails in the last two decades. The number of incarcerated substance users has led to increased efforts to develop, implement, and test interventions in both institucional programs and community programs at re-entry. In 2002, these efforts facilitated the development of the Criminal Justice Drug Abuse Treatment Studies (CJDATS) cooperative agreement grants funded by the National Institute on Drug Abuse (NIDA). CJDATS has developed twelve research protocols designed to targeted different stages of an offender`s progress from institution to community including assessing current practices, promoting structured re-entry, developing screening and referral instruments, and designing new treatment models. In addition, CJDATS has a vested interest in special populations of offenders (such as women offenders) and unique treatment issues (such as HIV). The success of CJDATS is largely dependent on the partnerships developed at the local, state, and national level with administrators and treatment providers in both correctional settings and in the community

Adiponectin and Coronary Heart Disease: The Strong Heart Study

To the Editor: The adipocyte secreted protein, adiponectin, is of particular interest in metabolic and vascular disease because of its close associations with insulin sensitivity and obesity.1 Lower levels of adiponectin are associated with later development of type 2 diabetes.2 Recent observations from the Health Professionals Follow-Up Study3 suggest that lower adiponectin concentrations might also be associated with incident myocardial infarction, findings in keeping with prior observations in patients with end-stage renal failure.4 We examined prospective relationships of adiponectin to vascular disease in a case–control series selected from the Strong Heart Study (SHS). The SHS is the largest study of cardiovascular disease in American Indians, a group at particular risk of obesity and type 2 diabetes and in whom an increasing incidence of coronary heart disease (CHD) is seen.5 Cases and controls were selected from the SHS cohort.6 The SHS recruited 4549 volunteers of American Indian heritage from 3 geographic areas (Arizona, North and South Dakota, and Oklahoma).6 Volunteers (59% female) were invited to a study examination on three occasions (SH1, 1988 to 1992; SH2, 1993 to 1995; SH3, 1997 to 1999) and remained under continued surveillance for development of vascular disease as described previously.7,8 Because of availability of plasma samples, baseline data for this study were taken from the second examination (SH2), and participants with prevalent cardiovascular disease at SH2 (definite CHD and stroke), …

The Pediatric Emergency Care Applied Research Network (PECARN): Rationale, Development, and First Steps*

Since its formal recognition as a medical specialty, the field of pediatric emergency medicine has made substantial advances with respect to its scope and sophistication. These advances have occurred in clinical practice as well as in the research base to improve clinical practice. There remain, however, many areas in emergency medical services for children (EMSC), in the out-of-hospital as well as the emergency department (ED) and hospital settings, that suffer from a lack of data to guide practice. In an effort to expand the quality and quantity of research in pediatric emergency care, the Pediatric Emergency Care Applied Research Network (PECARN) was created in October 2001. PECARN is the first federally funded national network for research in EMSC. PECARN is the result of Cooperative Agreement grants funded through the Health Resources and Services Administration (HRSA) with the purpose of developing an infrastructure capable of overcoming inherent barriers to pediatric EMSC research. Among these recognized barriers are low incidence rates of serious pediatric emergency events, the need for large numbers of children from varied backgrounds to achieve broadly representative study samples, lack of an infrastructure to test the efficacy of pediatric emergency care, and the need for a mechanism to translate study results into clinical practice. PECARN will serve as a national platform for collaborative research involving the continuum of care within the EMSC system, including out-of-hospital care, patient transport, ED and in-hospital care, and rehabilitation. This article describes the history of EMSC, the need for a national collaborative research network in EMSC, the organization and development of PECARN, and the work plan for the Network.

The Pediatric Emergency Care Applied Research Network (PECARN): rationale, development, and first steps.

Since its formal recognition as a medical specialty, the field of pediatric emergency medicine has made substantial advances with respect to its scope and sophistication. These advances have occurred in clinical practice as well as in the research base to improve clinical practice. There remain, however, many areas in emergency medical services for children (EMSC) in the out-of-hospital, emergency department (ED), and hospital settings that suffer from a lack of data to guide practice. In an effort to expand the quality and quantity of research in pediatric emergency care, the Pediatric Emergency Care Applied Research Network (PECARN) was created in October of 2001. PECARN is the first federally funded national network for research in EMSC and is the result of cooperative agreement grants funded through the Health Resources and Services Administration with the purpose of developing an infrastructure capable of overcoming inherent barriers to EMSC research. Among these recognized barriers are low incidence rates of serious pediatric emergency events, the need for large numbers of children from varied backgrounds to achieve broadly representative study samples, lack of an infrastructure to test the efficacy of pediatric emergency care, and the need for a mechanism to translate study results into clinical practice. PECARN will serve as a national platform for collaborative research involving the continuum of care within the EMSC system, including out-of-hospital care, patient transport, ED and in-hospital care, and rehabilitation. This article describes the history of EMSC, the need for a national collaborative research network in EMSC, the organization and development of PECARN, and the work plan for the network.

The Pediatric Emergency Care Applied Research Network (PECARN): Rationale, Development, and First Steps

Since its formal recognition as a medical specialty, the field of pediatric emergency medicine has made substantial advances with respect to its scope and sophistication. These advances have occurred in clinical practice as well as in the research base to improve clinical practice. There remain, however, many areas in emergency medical services for children (EMSC), in the out-of-hospital as well as the emergency department (ED) and hospital settings, that suffer from a lack of data to guide practice. In an effort to expand the quality and quantity of research in pediatric emergency care, the Pediatric Emergency Care Applied Research Network (PECARN) was created in October 2001. PECARN is the first federally funded national network for research in EMSC. PECARN is the result of Cooperative Agreement grants funded through the Health Resources and Services Administration (HRSA) with the purpose of developing an infrastructure capable of overcoming inherent barriers to pediatric EMSC research. Among these recognized barriers are low incidence rates of serious pediatric emergency events, the need for large numbers of children from varied backgrounds to achieve broadly representative study samples, lack of an infrastructure to test the efficacy of pediatric emergency care, and the need for a mechanism to translate study results into clinical practice. PECARN will serve as a national platform for collaborative research involving the continuum of care within the EMSC system, including out-of-hospital care, patient transport, ED and in-hospital care, and rehabilitation. This article describes the history of EMSC, the need for a national collaborative research network in EMSC, the organization and development of PECARN, and the work plan for the Network.

The New NIH Loan Repayment Program for Pediatric Research and for Clinical Research

In 2000, the United States Congress enacted an eagerly anticipated program to encourage physicians to pursue careers in research by providing educational loan repayments. This program was designed to help alleviate the financial burden associated with pursuing an academic career. Physicians pursuing pediatric research and clinical research who compete successfully in this program may receive up to $35,000 each year toward repayment of their educational loan indebtedness, plus 39% of that amount to cover the tax consequences of this additional income. An aggressive lobbying effort by the pediatric academic community in the last few years culminated in success on October 17, 2000, when Congress passed the Children's Health Act, which contains a provision authorizing the Secretary of the Department of Health and Human Services, acting through the Director of the National Institutes of Health (NIH), to establish a loan repayment program for health professionals conducting pediatric research. In this program, the NIH enters into a contract with a qualified health professional who agrees to conduct pediatric research for at least 2 years in return for the educational loan repayment. If performance is satisfactory, the contract may be extended until most of the educational loans are repaid. After passage of this groundbreaking pediatric research loan repayment program, Congress moved quickly to pass, on November 13, similar legislation authorizing such a program for clinical research in general, not limited to pediatrics. The NIH moved quickly to plan and implement this new authority, building on experience gained in similar loan repayment programs that have existed for several years in the NIH intramural research program. A planning committee produced a proposal for joint implementation of the two programs that was reviewed and cleared to proceed by the Office of Management and Budget (OMB). The program was formally published and announced in the Federal Register (2001;66(173):46643–7) on September 16, 2001, and the acting director of the NIH announced that funds would be provided in fiscal year 2002 to make contractual arrangements with approximately 250 individuals to begin the program. The NIH will select the recipients of these contracts on a competitive peer-reviewed basis, to assure that loan repayments serve the intended purpose of recruiting and retaining high-quality health professionals (mostly physicians) in careers in biomedical research, especially clinical investigation. Applicants must be U.S. citizens, nationals, or permanent residents with doctorate degrees. They must be currently supported by an NIH grant (F32 or T32 training grant; a K series career development award; a first-time RO1, RO3, or R21 research grant; a UO1 cooperative agreement grant; or a first-time director of a subproject of a PO1 or U series grant). Their total educational debt must exceed 20 percent of their annual income. Finally, they must be engaged in pediatric research or clinical research. The NIH expects application forms approved by the OMB to be available around December 1. Forms may be obtained from the Office of Loan Repayment and Scholarship, NIH, 2 Center Drive, Room 2E30, Bethesda, MD 20892-0230, U.S.A., or by e-mail request ([email protected]). Applications will include a personal statement about research career goals, a description of the current research that qualifies the applicant, a research training plan (if applicable), recommendations from three individuals, and a supporting statement from the sponsoring institution. Information on loan indebtedness must also be provided. In the first year of the program, applications will be assigned to the Institute funding the grant that qualifies the applicant for the program. Institute Initial Review Groups (IRG) will provide peer review. The Institute will make funding decisions based on the evaluation of the IRG and on program need and balance. Successful applicants will be offered 2-year contracts, indicating the amount of the loan that will be repaid quarterly by the NIH to the lending institution, in return for a commitment by the applicant to continue to engage in pediatric or clinical research during that time. Performance will be closely monitored, and if research activity ends, the loan repayment will terminate. This program represents a commitment by the U.S. government to increase the number and quality of health professionals engaged in pediatric or clinical research by reducing the often-cited barrier of educational loan debt as a factor that forces young clinicians into clinical practice. The NIH is eager to launch and extend this program, and encourages applications from highly qualified individuals for whom this program can become the means to a career in research.

Adolescents’ Eating Patterns Influence their Nutrient Intakes

Eating patterns established during adolescence shape diet later in life ( (1) Kemm J.R Eating patterns in childhood and adult health. Nutr Health. 1987; 4: 205-215 Google Scholar , (2) Nicklas T.A Farris R.P Smoak C.G Frank G.C Srinivasan S.R Webber L.S Berenson G.S Dietary factors relate to cardiovascular risk factors in early life Bogalusa Heart Study. Arterioscler. 1988; 8: 193-199 Google Scholar ). Compared with younger children, adolescents have more control over their eating habits and more access to food outside the home, experiment more with food choices, deviate more from 3-meal-a-day eating patterns, and are more likely to snack ( (3) Bull N.L Dietary habits, food consumption, and nutrient intake during adolescence. J Adolesc Health. 1992; 13: 384-388 Google Scholar , (4) Court J.M Nutrition and adolescents an overview of concerns in western society. Med J Aust. 1988; 148: S2-S7 Google Scholar , (5) DiPietro L Physical activity, body weight, and adiposity an epidemiologic perspective. Exerc Sport Sci Rev. 1995; 23: 275-303 Google Scholar , (6) Epstein L.H Valoski A.M Vara L.S McCurley J Wisniewski L Kalarchian M.A Klein K.R Effects of decreasing sedentary behavior and increasing activity on weight change in obese children. Health Psychol. 1995; 14: 109-115 Google Scholar , (7) Farthing M.C Current eating patterns of adolescents in the United States. Nutrition Today. 1991; 26: 35-39 Google Scholar , (8) Johnson R.K Johnson D.G Wang M.Q Smiciklas-Wright H Guthrie H.A Characterizing nutrient intakes of adolescents by sociodemographic factors. J Adolesc Health. 1994; 15: 149-154 Google Scholar , (9) Leon G.R et al. Adolescent nutritional and psychological patterns and risk for the development of an eating disorder. Journal of Youth Adolescent. 1989; 18: 273-282 Google Scholar , (10) Siega-Riz A.M Carson T Popkin B Three squares or mostly snacks—what do teens really eat? A sociodemographic study of meal patterns. J Adolesc Health. 1998; 22: 29-36 Google Scholar ). Eating patterns influence nutrient intakes because food choices vary by eating occasion. This paper describes a) the associations of type and number of eating occasions with nutrient intakes, b) the influence of overweight status and prior participation in the intervention or control groups in the Child and Adolescent Trial for Cardiovascular Health (CATCH) on them, and c) patterns and sources of meals and snacks by sex and race/ethnicity among these students. Supported by cooperative agreement grants from the National Heart, Lung, and Blood Institute, National Institutes of Health (U01-HL-39880, U01-HL-39906, U01-HL-39852, U01-HL-39927, U01-HL-39870).

The Pediatric Pharmacology Research Unit Network of the National Institute of Child Health and Human Development

The Pediatric Pharmacology Research Unit (PPRU) Network was established to help address a long-standing problem that was a barrier to optimal health and well-being of children: lack of testing in children of drugs used to treat children. The PPRU Network was developed in 1994 to address the industry concern that there was no satisfactory place to test drugs in children, to provide top quality data that would facilitate pediatric labeling, and to demonstrate that this could be done. The network accomplishes these goals by solicited cooperative agreement grants from leading pediatric pharmacology experts. The network’s developments, accomplishments to date, and plans for the 21st century are covered.