Systems epidemiology and cancer: A review of the National Institutes of Health extramural grant portfolio 2013-2018.

OBJECTIVES: Systems epidemiology approaches may lead to a better understanding of the complex and dynamic multi-level constellation of contributors to cancer risk and outcomes and help target interventions. This grant portfolio analysis aimed to describe the National Institutes of Health (NIH) and the National Cancer Institute (NCI) investments in systems epidemiology and to identify gaps in the cancer systems epidemiology portfolio. METHODS: The analysis examined grants funded (2013-2018) through seven NIH systems science Funding Opportunity Announcements (FOAs) as well as cancer-specific systems epidemiology grants funded by NCI during that same time. Study characteristics were extracted from the grant abstracts and specific aims and coded. RESULTS: Of the 137 grants awarded under the NIH FOAs, 52 (38%) included systems epidemiology. Only five (4%) were focused on cancer systems epidemiology. The NCI-wide search (N = 453 grants) identified 35 grants (8%) that included cancer systems epidemiology in their specific aims. Most of these grants examined epidemiology and surveillance-based questions (60%); fewer addressed clinical care or clinical trials (37%). Fifty-four percent looked at multiple scales within the individual (e.g., cell, tissue, organ), 49% looked beyond the individual (e.g., individual, community, population), and few (9%) included both. Across all grants examined, the systems epidemiology grants primarily focused on discovery or prediction, rather than on impacts of intervention or policy. CONCLUSIONS: The most notable finding was that grants focused on cancer versus other diseases reflected a small percentage of the portfolio, highlighting the need to encourage more cancer systems epidemiology research. Opportunities include encouraging more multiscale research and continuing the support for broad examination of domains in these studies. Finally, the nascent discipline of systems epidemiology could benefit from the creation of standard terminology and definitions to guide future progress.

The Cancer Epidemiology Descriptive Cohort Database: A Tool to Support Population-Based Interdisciplinary Research.

BACKGROUND: We report on the establishment of a web-based Cancer Epidemiology Descriptive Cohort Database (CEDCD). The CEDCD's goals are to enhance awareness of resources, facilitate interdisciplinary research collaborations, and support existing cohorts for the study of cancer-related outcomes. METHODS: Comprehensive descriptive data were collected from large cohorts established to study cancer as primary outcome using a newly developed questionnaire. These included an inventory of baseline and follow-up data, biospecimens, genomics, policies, and protocols. Additional descriptive data extracted from publicly available sources were also collected. This information was entered in a searchable and publicly accessible database. We summarized the descriptive data across cohorts and reported the characteristics of this resource. RESULTS: As of December 2015, the CEDCD includes data from 46 cohorts representing more than 6.5 million individuals (29% ethnic/racial minorities). Overall, 78% of the cohorts have collected blood at least once, 57% at multiple time points, and 46% collected tissue samples. Genotyping has been performed by 67% of the cohorts, while 46% have performed whole-genome or exome sequencing in subsets of enrolled individuals. Information on medical conditions other than cancer has been collected in more than 50% of the cohorts. More than 600,000 incident cancer cases and more than 40,000 prevalent cases are reported, with 24 cancer sites represented. CONCLUSIONS: The CEDCD assembles detailed descriptive information on a large number of cancer cohorts in a searchable database. IMPACT: Information from the CEDCD may assist the interdisciplinary research community by facilitating identification of well-established population resources and large-scale collaborative and integrative research. Cancer Epidemiol Biomarkers Prev; 25(10); 1392-401. ©2016 AACR.

Evolution of the "drivers" of translational cancer epidemiology: analysis of funded grants and the literature.

Concurrently with a workshop sponsored by the National Cancer Institute, we identified key "drivers" for accelerating cancer epidemiology across the translational research continuum in the 21st century: emerging technologies, a multilevel approach, knowledge integration, and team science. To map the evolution of these "drivers" and translational phases (T0-T4) in the past decade, we analyzed cancer epidemiology grants funded by the National Cancer Institute and published literature for 2000, 2005, and 2010. For each year, we evaluated the aims of all new/competing grants and abstracts of randomly selected PubMed articles. Compared with grants based on a single institution, consortium-based grants were more likely to incorporate contemporary technologies (P = 0.012), engage in multilevel analyses (P = 0.010), and incorporate elements of knowledge integration (P = 0.036). Approximately 74% of analyzed grants and publications involved discovery (T0) or characterization (T1) research, suggesting a need for more translational (T2-T4) research. Our evaluation indicated limited research in 1) a multilevel approach that incorporates molecular, individual, social, and environmental determinants and 2) knowledge integration that evaluates the robustness of scientific evidence. Cancer epidemiology is at the cusp of a paradigm shift, and the field will need to accelerate the pace of translating scientific discoveries in order to impart population health benefits. While multi-institutional and technology-driven collaboration is happening, concerted efforts to incorporate other key elements are warranted for the discipline to meet future challenges.

The use of biospecimens in population-based research: a review of the National Cancer Institute's Division of Cancer Control and Population Sciences grant portfolio.

Over the past two decades, researchers have increasingly used human biospecimens to evaluate hypotheses related to disease risk, outcomes and treatment. We conducted an analysis of population-science cancer research grants funded by the National Cancer Institute (NCI) to gain a more comprehensive understanding of biospecimens and common derivatives involved in those studies and identify opportunities for advancing the field. Data available for 1,018 extramural, peer-reviewed grants (active as of July 2012) supported by the Division of Cancer Control and Population Sciences (DCCPS), the NCI Division that supports cancer control and population-science extramural research grants, were analyzed. 455 of the grants were determined to involve biospecimens or derivatives. The most common specimen types included were whole blood (51% of grants), serum or plasma (40%), tissue (39%), and the biospecimen derivative, DNA (66%). While use of biospecimens in molecular epidemiology has become common, biospecimens for behavioral and social research is emerging, as observed in our analysis. Additionally, we found the majority of grants were using already existing biospecimens (63%). Grants that involved use of existing biospecimens resulted in lower costs (studies that used existing serum/plasma biospecimens were 4.2 times less expensive) and more publications per year (1.4 times) than grants collecting new biospecimens. This analysis serves as a first step at understanding the types of biospecimen collections supported by NCI DCCPS. There is room to encourage increased use of archived biospecimens and new collections of rarer specimen and cancer types, as well as for behavioral and social research. To facilitate these efforts, we are working to better catalogue our funded resources and make that data available to the extramural community.

Provocative questions in cancer epidemiology in a time of scientific innovation and budgetary constraints.

In a time of scientific and technological developments and budgetary constraints, the National Cancer Institute's (NCI) Provocative Questions Project offers a novel funding mechanism for cancer epidemiologists. We reviewed the purposes underlying the Provocative Questions Project, present information on the contributions of epidemiologic research to the current Provocative Questions portfolio, and outline opportunities that the cancer epidemiology community might capitalize on to advance a research agenda that spans a translational continuum from scientific discoveries to population health impact.

Safety evaluation of intrathecal substance P-saporin, a targeted neurotoxin, in dogs.

Intrathecal (IT) substance P-Saporin (SP-SAP), a 33-kDa-targeted neurotoxin, produces selective destruction of superficial neurokinin 1 receptor (NK1r)-bearing cells in the spinal dorsal horn. In rats, SP-SAP prevents the formation of hyperalgesia and can reverse established neuropathic pain behavior in rodents. To determine the safety of this therapeutic modality in a large animal model, beagles received bolus IT lumbar injections of vehicle, SP-SAP (1.5, 15, 45, or 150 microg), or a nontargeted preparation of saporin (SAP, 150 microg) for immunohistological analysis of spinal cords. Doses of 15 microg SP-SAP and above produced a significant and equivalent loss of NK1r-bearing cells and dendrites in lumbar laminae II and I compared to vehicle- or SAP-treated animals. Cervical regions in all animals displayed no loss of NK1r immunoreactivity as compared to controls. Total numbers of neurons in the lumbar dorsal horn or alpha-motor neurons in the ventral horn demonstrated no significant changes. No increases in the astrocytic marker glial fibrillary acidic protein were noted following treatment with SP-SAP, suggesting a lack of generalized neurotoxicity. Additional dogs received doses of 1.5-150 microg SP-SAP or SAP and were sacrificed after 28 or 90 days to assess behavioral and physiological parameters. Although some acute motor signs were observed with both SP-SAP and SAP, no long-lasting significant events were noted in any of these animals. These data indicate no adverse toxicity at doses up to 10 times those necessary for producing loss of superficial NK1r-bearing neurons in a large animal model.

Latino populations: a unique opportunity for the study of race, genetics, and social environment in epidemiological research.

Latinos are the largest minority population in the United States. Although usually classified as a single ethnic group by researchers, Latinos are heterogeneous from cultural, socioeconomic, and genetic perspectives. From a cultural and social perspective, Latinos represent a wide variety of national origins and ethnic and cultural groups, with a full spectrum of social class. From a genetic perspective, Latinos are descended from indigenous American, European, and African populations. We review the historical events that led to the formation of contemporary Latino populations and use results from recent genetic and clinical studies to illustrate the unique opportunity Latino groups offer for studying the interaction between racial, genetic, and environmental contributions to disease occurrence and drug response.

Constitutive spinal cyclooxygenase-2 participates in the initiation of tissue injury-induced hyperalgesia.

Inhibitors of the isozyme cyclooxygenase-2 (COX-2) represent an important advance in pain management, although where and when these inhibitors can exert their antihyperalgesic actions are not completely understood. Here we show that unlike many peripheral tissues in which COX-2 is only expressed in physiologically significant levels after tissue injury, in the normal rat lumbar spinal cord, the majority of neurons and radial glia constitutively express high levels of COX-2 protein. Immediately after peripheral tissue injury and before any measurable upregulation of COX-2 protein in peripheral tissue or spinal cord, inhibition of constitutively expressed spinal COX-2 reduced injury-induced activation of primary afferent neurons, activation of spinal neurons, and the mechanical and thermal hyperalgesia that normally occurs after peripheral tissue injury. The present data demonstrate that constitutively expressed spinal COX-2 plays an important role in the initial hyperalgesia that follows peripheral tissue injury. These results suggest that blocking constitutive spinal COX-2 before tissue injury may reduce the initial peripheral and central sensitization that occurs after tissue injury.

Proteomic analysis of the reactive phenotype of astrocytes following endothelin-1 exposure.

Reactive gliosis is an invariant feature of the pathology of central nervous system (CNS) injury and a major determinant of neuronal survival and regeneration. To begin to understand the alterations in astrocyte protein expression that drive glial changes that occur following injury, we used an established model system (endothelin-1 stimulation of hypertrophy) and proteomic analysis to define a discrete set of differentially expressed proteins and post-translational modifications that occur as the astrocytes change from a quiescent to a reactive state. This orchestrated set of changes included proteins involved in cytoskeletal reorganization (caldesmon, calponin, alpha B-crystallin, stathmin, collapsing response mediator protein-2), cell adhesion (vinculin, galectin-1), signal transduction (RACK-1) and astrocyte differentiation (glutamine synthetase). Using proteomic analysis to understand what drives astrocyte expression of these functionally divergent molecules may offer insight into the mechanisms by which astrocytes can exhibit both pro-regenerative and anti-regenerative activities following CNS injury.

Endothelin receptor expression in the normal and injured spinal cord: potential involvement in injury-induced ischemia and gliosis.

The endothelins (ETs) are a family of peptides that exert their biological effects via two distinct receptors, the endothelin A receptor (ET(A)R) and the endothelin B receptor (ET(B)R). To more clearly define the potential actions of ETs following spinal cord injury, we used immunohistochemistry and confocal microscopy to examine the protein expression of ET(A)R and ET(B)R in the normal and injured rat spinal cord. In the normal spinal cord, ET(A)R immunoreactivity (IR) is expressed by vascular smooth muscle cells and a subpopulation of primary afferent nerve fibers. ET(B)R-IR is expressed primarily by radial glia, a small population of gray and white matter astrocytes, ependymal cells, vascular endothelial cells, and to a lesser extent in smooth muscle cells. Fourteen days following compression injury to the spinal cord, there was a significant upregulation in both the immunoexpression and number of astrocytes expressing the ET(B)R in both gray and white matter and a near disappearance of ET(B)R-IR in ependymal cells and ET(A)R-IR in primary afferent fibers. Conversely, the vascular expression of ET(A)R and ET(B)R did not appear to change. As spinal cord injury has been shown to induce an immediate increase in plasma ET levels and a sustained increase in tissue ET levels, ETs would be expected to induce an initial marked vasoconstriction via activation of vascular ET(A)R/ET(B)R and then days later a glial hypertrophy via activation of the ET(B)R expressed by astrocytes. Strategies aimed at blocking vascular ET(A)R/ET(B)R and astrocyte ET(B)Rs following spinal cord injury may reduce the resulting ischemia and astrogliosis and in doing so increase neuronal survival, regeneration, and function.

Different tumors in bone each give rise to a distinct pattern of skeletal destruction, bone cancer-related pain behaviors and neurochemical changes in the central nervous system.

Pain is the most common presenting symptom in patients with bone cancer and bone cancer pain can be both debilitating and difficult to control fully. To begin to understand the mechanisms involved in the generation and maintenance of bone cancer pain, we implanted 3 well-described murine tumor cell lines, 2472 sarcoma, B16 melanoma and C26 colon adenocarcinoma into the femur of immunocompromised C3H-SCID mice. Although each of the tumor cell lines proliferated and completely filled the intramedullary space of the femur within 3 weeks, the location and extent of bone destruction, the type and severity of the pain behaviors and the neurochemical reorganization of the spinal cord was unique to each tumor cell line injected. These data suggest that bone cancer pain is not caused by a single factor such as increased pressure induced by intramedullary tumor growth, but rather that multiple factors are involved in generating and maintaining bone cancer pain.

Endothelin B receptors are expressed by astrocytes and regulate astrocyte hypertrophy in the normal and injured CNS.

The ability of mammalian central nervous system (CNS) neurons to survive and/or regenerate following injury is influenced by surrounding glial cells. To identify the factors that control glial cell function following CNS injury, we have focused on the endothelin B receptor (ET(B)R), which we show is expressed by the majority of astrocytes that are immunoreactive for glial acid fibrillary protein (GFAP) in both the normal and crushed rabbit optic nerve. Optic nerve crush induces a marked increase in ET(B)R and GFAP immunoreactivity (IR) without inducing a significant increase in the number of GFAP-IR astrocytes, suggesting that the crush-induced astrogliosis is due primarily to astrocyte hypertrophy. To define the role that endothelins play in driving this astrogliosis, artificial cerebrospinal fluid (CSF), ET-1 (an ET(A)R and ET(B)R agonist), or Bosentan (a mixed ET(A)R and ET(B)R antagonist) were infused via osmotic minipumps into noninjured and crushed optic nerves for 14 days. Infusion of ET-1 induced a hypertrophy of ET(B)R/GFAP-IR astrocytes in the normal optic nerve, with no additional hypertrophy in the crushed nerve, whereas infusion of Bosentan induced a significant decrease in the hypertrophy of ET(B)R/GFAP-IR astrocytes in the crushed but not in the normal optic nerve. These data suggest that pharmacological blockade of astrocyte ET(B)R receptors following CNS injury modulates glial scar formation and may provide a more permissive substrate for neuronal survival and regeneration.

Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2.

More than half of all chronic cancer pain arises from metastases to bone, and bone cancer pain is one of the most difficult of all persistent pain states to fully control. Several tumor types including sarcomas and breast, prostate, and lung carcinomas grow in or preferentially metastasize to the skeleton where they proliferate, and induce significant bone remodeling, bone destruction, and cancer pain. Many of these tumors express the isoenzyme cycloxygenase-2 (COX-2), which is involved in the synthesis of prostaglandins. To begin to define the role COX-2 plays in driving bone cancer pain, we used an in vivo model where murine osteolytic 2472 sarcoma cells were injected and confined to the intramedullary space of the femur in male C3HHeJ mice. After tumor implantation, mice develop ongoing and movement-evoked bone cancer pain-related behaviors, extensive tumor-induced bone resorption, infiltration of the marrow space by tumor cells, and stereotypic neurochemical alterations in the spinal cord reflective of a persistent pain state. Thus, after injection of tumor cells, bone destruction is first evident at day 6, and pain-related behaviors are maximal at day 14. A selective COX-2 inhibitor was administered either acutely [NS398; 100 mg/kg, i.p.] on day 14 or chronically in chow [MF. tricyclic; 0.015%, p.o.] from day 6 to day 14 after tumor implantation. Acute administration of a selective COX-2 inhibitor attenuated both ongoing and movement-evoked bone cancer pain, whereas chronic inhibition of COX-2 significantly reduced ongoing and movement-evoked pain behaviors, and reduced tumor burden, osteoclastogenesis, and bone destruction by >50%. The present results suggest that chronic administration of a COX-2 inhibitor blocks prostaglandin synthesis at multiple sites, and may have significant clinical utility in the management of bone cancer and bone cancer pain.

Spinal neurons that possess the substance P receptor are required for the development of central sensitization.

In previous studies, we have shown that loss of spinal neurons that possess the substance P receptor (SPR) attenuated pain and hyperalgesia produced by capsaicin, inflammation, and nerve injury. To determine the role of SPR-expressing neurons in modulating pain and hyperalgesia, responses of superficial and deep lumbar spinal dorsal horn neurons evoked by mechanical and heat stimuli and by capsaicin were made after ablation of SPR-expressing neurons using the selective cytotoxin conjugate substance P-saporin (SP-SAP). Morphological analysis and electrophysiological recordings were made after intrathecal infusion of vehicle, saporin alone, or SP-SAP. SP-SAP, but not vehicle or SAP alone, produced an approximately 62% decrease in SPR-expressing neurons in the dorsal horn. Loss of SPR-expressing neurons diminished the responses of remaining neurons to intraplantar injection of capsaicin. Peak responses to 10 microg of capsaicin were approximately 65% lower in animals pretreated with SP-SAP compared with controls. Additionally, sensitization to mechanical and heat stimuli that normally follows capsaicin was rarely observed. Importantly, responses to mechanical and heat stimuli in the absence of capsaicin were not altered after SP-SAP treatment. In addition, nociceptive neurons did not exhibit windup in the SP-SAP-treated group. These results demonstrate that SPR-expressing neurons located in the dorsal horn are a pivotal component of the spinal circuits involved in triggering central sensitization and hyperalgesia. It appears that this relatively small population of neurons can regulate the physiological properties of other nociceptive neurons and drive central sensitization.

Tooth extraction-induced internalization of the substance P receptor in trigeminal nucleus and spinal cord neurons: imaging the neurochemistry of dental pain.

Although pains arising from the craniofacial complex can be severe and debilitating, relatively little is known about the peripheral and central mechanisms that generate and maintain orofacial pain. To better understand the neurons in the trigeminal complex and spinal cord that are activated following nociceptive stimuli to the orofacial complex, we examined substance P (SP) induced internalization of substance P receptors (SPR) in neurons following dental extraction in the rat. Unilateral gingival reflection or surgical extraction of a rat maxillary incisor or molar was performed and tissues harvested at various time points post-extraction. Immunohistochemical analysis of brainstem and cervical spinal cord sections was performed using an anti-SPR antibody and confocal imaging. Both the number and location of neurons showing SPR internalization was dependent on the location and extent of tissue injury. Whereas extraction of the incisor induced internalization of SPR in neurons bilaterally in nucleus caudalis and the spinal cord, extraction of the molar induced strictly unilateral internalization of SPR-expressing neurons in the same brain structures. Minor tissue injury (retraction of the gingiva) activated SPR neurons located in lamina I whereas more extensive and severe tissue injury (incisor or molar extraction) induced extensive SPR internalization in neurons located in both laminae I and III-V. The rostrocaudal extent of the SPR internalization was also correlated with the extent of tissue injury. Thus, following relatively minor tissue injury (gingival reflection) neurons showing SPR internalization were confined to the nucleus caudalis while procedures which cause greater tissue injury (incisor or molar extraction), neurons showing SPR internalization extended from the interpolaris/caudalis transition zone through the C7 spinal level. Defining the population of neurons activated in orofacial pain and whether analgesics modify the activation of these neurons should provide insight into the mechanisms that generate and maintain acute and chronic orofacial pain.

Activation of lamina I spinal cord neurons that express the substance P receptor in visceral nociception and hyperalgesia.

Spinal lamina I neurons expressing the substance P receptor (SPR) have been shown to play a role in the transmission of somatic inflammatory and neuropathic pain. To evaluate their involvement in visceral nociception in both the noninflamed and inflamed colon, we examined the expression and ligand-induced internalization of the SPR in the rat spinal cord after distention of the noninflamed colon and in rats with inflammation induced by intracolonic instillation of zymosan (3 hours). In the noninflamed animal, acute noxious but not non-noxious colorectal distention induced SPR internalization in lamina I neurons at the thoracolumbar (T13) and lumbosacral (S1) spinal levels, whereas SPR internalization was not detected in lamina I neurons at spinal lumbar segment L4. Although zymosan-induced colorectal inflammation alone did not induce SPR internalization in lamina I neurons, there was an increased number of SPR-expressing lamina I neurons showing SPR internalization in segments T12 through S2 of the spinal cord after colorectal distention. These results show that acute noxious visceral stimuli induce activation of spinal lamina I neurons expressing the SPR and, that after visceral inflammation, there is a marked increase in both the number and rostrocaudal extent of lamina I SPR neurons activated in response to both normally non-noxious and noxious distention of the colon.