MOLECULAR INTERACTIONS BETWEEN TUMOR CELLS AND BONE Release Date: May 9, 2002 (also see NOT-AR-02-004) RFA: CA-03-013 National Cancer Institute (NCI) ( National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) ( LETTER OF INTENT RECEIPT DATE: October 17, 2002 APPLICATION RECEIPT DATE: November 21, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to become Principal Investigators o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Cancer Institute (NCI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) solicit investigator-initiated applications to promote a better understanding of the pathophysiology of bone metastasis, especially as it relates to tumor cell-bone interactions. The overall goal is to delineate the role of bone microenvironment on tumor cell survival, and colonization. Collaborative interactions between bone biologists, clinical oncologists and cancer biologists are highly encouraged. These studies should contribute towards a better understanding of the molecular events that account for homing of tumor cells to the bone, and generating novel therapeutic reagents. Both the exploratory (R21) and traditional (R01) grant applications will be accepted. RESEARCH OBJECTIVES Background Bone metastases are common in a number of cancers, and they contribute heavily to morbidity and mortality, most prominently in prostate, breast, and multiple myeloma. Current understanding of the molecular underpinnings of bone metastasis is very limited. Recognizing this, the Congress, in the FY2002 NCI Budget, encouraged the NCI "to conduct research to develop a better understanding of the unique role the bone microenvironment plays in metastasis of cancer to bone, in particular breast cancer, prostate cancer and myeloma, including the development of animal models of bone metastasis and identification of novel therapeutic targets and modalities to prevent and treat bone metastasis." The different features of bone metastasis are illustrated by these three cancers but the importance and complexity of the problem is not limited to them. Advanced prostate cancer continues to kill more than 42,000 men per year in the United States, and currently there is there is no curative therapy for advanced prostate cancer. The relationship between prostate cancer and the bone is unique among cancers. Approximately 90% of advanced prostate cancer patients develop clinically significant bone metastasis, causing osteoblastic remodeling of the bone, and contributing to the morbidity and mortality of patients. One third of patients with a prostate specific antigen (PSA) >20 at the time of diagnosis have bone scan evidence of bone metastasis. In addition, RT-PCR studies have identified PSA in bone marrow samples of patients thought to have localized disease and undergoing radical prostatectomy, suggesting that bone marrow metastasis may be an early event, even prior to clinical symptoms and nuclear radiographic positivity. In the case of breast cancer, in 2001 alone, an estimated 192,200 women were diagnosed with invasive breast cancer, with more than 40,200 deaths- 28,000 deaths with breast cancer metastasis to the bone. Both osteoblastic and osteoclastic lesions are seen in patients with bone metastasis. Multiple myeloma (MM) represents 13% of all lymphoid malignancies in the white population and 31% of lymphoid malignancies in the black population and is a severely debilitating, incurable neoplastic disease of B cell origin. The major source of morbidity and mortality associated with MM are osteolytic lesions that form throughout the axial skeleton, resulting from increased osteoclastic bone resorption that occurs adjacent to the myeloma cells and not in areas of normal bone marrow. New bone formation that normally occurs at the sites of bone destruction is also absent. These data suggest that locally acting factors produced by myeloma cells induce extensive bone destruction and block new bone formation. Bisphosphonates, potent inhibitors of bone resorption, significantly reduce skeletal morbidity in patients with advanced breast cancer and can reduce metastasis to bone by human breast cancer cells in an experimental model. Pamidronate, a second generation bisphosphonate, has recently been approved by the FDA for treatment of breast cancer osteolysis. Another inhibitor of bone resorption, the protein osteoprotegerin, is also effective in animal models of bone metastases in breast and prostate cancer, and in reducing bone pain in patients. Although bisphosphonates significantly reduce skeletal morbidity associated with solid tumor metastases to bone, most studies indicate no improvement in survival. Thus, in order to improve therapy and ultimately prevent bone metastases, a precise understanding of the pathophysiology of bone metastases is necessary. It is well recognized that once malignant cells have migrated to the bone, their ability to colonize is facilitated by various growth factors that are secreted by the bone. Recent studies reveal that bone metastases result in increased circulating markers of bone resorption and formation, which may play more important future roles in early diagnosis of bone involvement and in monitoring response to treatment. In addition, there is an active bi- directional response between bone and associated tumor cells, the tumor cells acquire a more aggressive phenotype and accelerated bone turnover occurs in the localized skeletal lesions. Although bone metastasis is of serious clinical relevance, relatively little is known of the important molecular mechanisms involved in the initial tumor cell-bone stroma interactions or in the subsequent colonization and growth of the cancer. Several recent developments suggest that bone metastasis is a research area of great opportunities: (A) The availability of a number of experimental models, obtained by intracardiac or orthotopic injections, to study bone metastasis in prostate, breast and multiple myeloma. In addition, implantation of human bone in SCID mice allows successful homing of prostate cancer and multiple myeloma cells specifically to the human bone. (B) The availability of high through-put technologies and laser capture micro-dissection technology permit evaluation of complex interactions, such as those involved in tumor-bone interactions. (C) Significant advances in basic bone biology research, with development of a repertoire of critical reagents, have provided a large cohort of basic biologists who could enter the field of bone metastasis. Scope Strengthening research programs of relevance to understand tumor host interactions as it relates to bone metastasis is an important area of emphasis for the National Cancer Institute (NCI), the Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The overall objective is to have a better understanding of the unique features of bone and its microenvironment that renders it an attractive site for tumor cells. Areas in which such scientific opportunities exist include, but are not limited to: Tumor Cell- Bone interactions: The identification of the molecular interactions between tumor and bone cells has previously used the candidate gene approach but is ready for the judicious application of gene array technology to identify new targets. Tumor growth does not appear to be a major point of regulation of bone metastases, although growth is the most common parameter assayed in vitro. Microarray identification thus needs to use RNA from metastatic versus non-metastatic cells and be coupled to an efficient system for validating physiological significance of identified candidate genes in animal models. Alternative approaches which address these issues should also be considered. The role played by malignant tumor cells (e.g., breast and prostate cancer) on bone turnover needs to delineated. The relationship between tumor cell adhesion to bone marrow endothelial cells and the subsequent acquisition of motility, migration and invasive phenotype needs to be elucidated. The mechanism by which the turnover of bone, bone matrix proteins and wound healing affect the process of cancer cell dissemination to bone is an area that needs examination. The key transcription factors that are turned on and are required to maintain cancer cell survival in visceral and bone sites need to be identified. One of the interesting aspects of the bone microenvironment-tumor interaction is the difference between mouse and human. The issue of why human tumor cells prefer to colonize human bone but not mouse bone is yet to be addressed. Factors that Promote Bone Metastases: There are several mechanisms that contribute to bone metastases: A) Synthesis, activation, and presentation of extracellular matrix-degrading proteases thought to be critical in enabling metastatic breast cancer cells cross multiple barriers and spread to distant tissue. Studies to identify and determine the functional signature of proteolytic mechanisms, however, are in their early stages, B) The molecules associated with preferential adhesion of invading tumor cells to the bone endothelium, C) Bone-associated cytokines which act as chemoattractants, D) Cytokines, survival factors and anti-apoptotic signals that support the growth and survival of cancer cells in the skeleton. These are areas that need to be actively pursued. Critical Signaling Pathways: The nature of the signaling pathways whereby hormones, growth factors, and adhesion molecules modulate metastasis to the bone is poorly understood. For example, nm23, HER-2/neu, and p53 are several nonprotease genes associated with metastases, but despite intense study, the exact mechanism underlying their association with increased metastatic potential remains obscure. A comprehensive analysis of genetic changes occurring between primary tumor and bone metastases and the development of a tractable system to study bone metastases are needed. Specific Roles of Osteoblasts, Osteocytes, and Osteoclasts: Most research, until now, has focused on osteolytic metastases and suggests that osteolytic factors (such as PTHrP and IL 11) stimulate osteoclasts indirectly by activating the RANK ligand pathway on osteoblastic cells. A role for the osteocyte in metastasis remains unaddressed and needs to be studied. Tumor cell-endothelial cell interactions: The role of angiogenesis in bone metastasis remains largely unexplored. It has been demonstrated that endothelial cells of various organs carry specific cell-surface addresses, which can be modulated by cytokines as well as the stromal and extracellular matrix environment with which they interact. A comparison of gene expression profiles of endothelium derived from normal and tumor tissue revealed a number of genes specifically elevated in tumor-associated endothelium. Many of these tumor endothelial cell markers were expressed in a wide range of tumor types as well as in normal vessels associated with wound healing, corpus luteum formation. Although specific molecular adhesive interactions between circulating tumor cells and bone marrow endothelia have been shown in vitro, their physiological importance in vivo remains to be tested. Considering the special fenestrated anatomy of the marrow microvasculature, the contributions of bone endothelial cells, stromal cells and mature osteoblasts, and the extracellular matrix in promoting tumor cell homing to the bone need to be identified. Identification of critical factors involved in tumor cell survival and colonization in the bone environment need to be identified and their mechanisms delineated. Role of the Immune System: The bone marrow is the primary site of hematopoiesis in the adult. To fulfill this role, the stroma and the cytokine environment of the bone marrow are specialized to support the growth of lymphocytes and other hematopoietic cells. These elements have a variety of direct and indirect effects on bone growth. For example, many immune modulators (IFN, IL-1, -6, -18 and others) have potent effects on osteoclast formation, and RANK ligand is a T cell product. Osteoprotegerin not only neutralizes RANKL but also TRAIL, which stimulates immune cell destruction of breast cancer cells. Very little is known about how such factors relate to other elements of the bone microenvironment, indicating that the role of immune cells in tumor bone interactions has been understudied. Systemic Host Effects: Standard treatment of cancer patients with chemotherapy creates a state of high bone turnover secondary to suppression of sex steroids. High bone turnover may well enhance metastases to bone. This important question can be studied with available animal models. For a number of candidate factors involved in bone metastases, such as endothelin-1, VEGF, and PDGF, effective small molecule inhibitors are already available, such as receptor antagonists for endothelin and receptor kinase inhibitors for VEGF and PDGF. The roles of these molecules in bone turnover are less well understood and the effects of the inhibitors need to be tested in preclinical animal models of normal bone homeostasis. MECHANISM OF SUPPORT This RFA will use NIH R01 and R21 award mechanisms. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing- continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is July 1, 2003. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non- modular research grant applications. FUNDS AVAILABLE NCI and NIDDK intend to commit approximately $4 million in FY 2003 to fund approximately equal numbers of new R21 and R01 grants in response to this RFA. An applicant may request a project period of up to 2 years for an R21 or up to 5 years for an R01 application. While the budgets for R01s are not capped, for the R21 a limit of $100,000 (four budget modules) per year is in place. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of ICs provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Suresh Mohla, Ph.D. Division of Cancer Biology National Cancer Institute 6130 Executive Boulevard, EPN 5038 Bethesda, MD 20892 Telephone: (301) 435-1878 FAX: (301) 480-0864 Email: Mehrdad Tondravi, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institutes of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 451-9871 FAX: (301) 480-3503 Email: o Direct your questions about peer review issues to: Referral Officer National Cancer Institute Division of Extramural Activities 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Telephone: (301) 496-3428 FAX: (301) 402-0275 Email: o Direct your questions about financial or grants management matters to: Bill Wells Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 242 Rockville, MD 20892 Telephone: (301) 496-8796 FAX: 301 496-8606 Email: Florence Danshes Grants Management Branch National Institutes of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Rm 734 Bethesda, MD 20892 Telephone: (301) 594-8861 email: LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NCI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Suresh Mohla, Ph.D. Division of Cancer Biology National Cancer Institute 6130 Executive Boulevard, EPN 5038 Bethesda, MD 20892 SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Blvd., Room 8041, MSC-8329 Rockville, MD 20852 (express courier) Bethesda MD 20892-8329 APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries (i.e. FEDEX, UPS, DHL, etc.) ( This change in practice is effective immediately. This policy is similar to and consistent with the policy for applications addressed to Centers for Scientific Review as published in the NIH Guide Notice APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness by the NCI program staff. Incomplete applications will be returned to the applicant without further consideration. And, if the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities (DEA) at NCI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Those that receive a priority score will undergo a second level review by the appropriate national advisory council or board. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application"s overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? SPECIFIC CRITERIA FOR REVIEW OF R21 APPLICATIONS: R21 applications submitted to this RFA should be considered to be pilot and feasibility studies with a high degree of potential significance and innovation, and for which there may be more risk and no preliminary data. ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: October 17, 2002 Application Receipt Date: November 21, 2002 Peer Review Date: February/March, 2002 Council Review: May 2003 Earliest Anticipated Start Date: July 1, 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (, a complete copy of the updated Guidelines are available at The amended policy incorporates: the use of an NIH definition of clinical research, updated racial and ethnic categories in compliance with the new OMB standards, clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398, and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at A continuing education program in the protection of human participants in research in now available online at: HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at and at Guidance for investigators and institutional review boards regarding research involving human embryonic stem cells, germ cells, and stem cell-derived test articles can be found at Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.396 for NCI and the Catalog of Federal Domestic Assistance No. 93.847 for NIDDK. The program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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