Focusing on specific treatments or diseases is proposed as a way to increase the efficiency of hospital care. The definition of "focus" or "focused factory", however, lacks clarity. Examples in health care literature relate to very different organizations.Our aim was to explore the application of the focused factory concept in hospital care, including an indication of its performance, resulting in a conceptual framework that can be helpful in further identifying different types of focused factories. Thus contributing to the understanding of the diversity of examples found in the literature.We conducted a cross-case comparison of four multiple-case studies into hospital care. To cover a broad array of focus, different specialty fields were selected. Each study investigated the organizational context, the degree of focus, and the operational performance. Focus was measured using an instrument translated from industry. Data were collected using both qualitative and quantitative methods and included site visits. A descriptive analysis was performed at the case study and cross-case studies level.The operational performance per specialty field varied considerably, even when cases showed comparable degrees of focus. Cross-case comparison showed three focus domains. The product domain considered specialty based focused factories that treated patients for a single-specialty, but did not pursue a specific strategy nor adapted work-designs or layouts. The process domain considered delivery based focused factories that treated multiple groups of patients and often pursued strategies to improve efficiency and timeliness and adapted work-designs and physical layouts to minimize delays. The product-process domain considered procedure based focused factories that treated a single well-defined group of patients offering one type of treatment. The strategic focusing decisions and the design of the care delivery system appeared especially important for delivery and procedure based focused factories.Focus in hospital care relates to limitations on the patient group treated and the range of services offered. Based on these two dimensions, we identified three types of focused factories: specialty based, delivery based, and procedure based. Focus could lead to better operational performance, but only when clear strategic focusing decisions are made. Hospital care is under pressure to increase quality and decrease cost . As a re"a plant established to focus the entire manufacturing system on a limited, concise, manageable set of products, technologies, volumes, and markets precisely defined by the company's strategy, its technology, and its economics" [The focused factory was introduced in manufacturing as: onomics" ,5. Focusonomics" -8. In seonomics" ,10. The onomics" .Both in manufacturing and services, different types of focus are identified. The literature describes focus on products (product lines or markets), processes , and competitive priorities (sometimes described as "order winners") ,11-13. WThe literature on focus in hospital care, however, describes focus as a diffuse mix of treatment characteristics, patient characteristics, specialty characteristics, and organizational aspects ,14-16. EFirst, the diversity of examples and diffuse mix of characteristics shows that the focused factory concept in hospital care is not well understood. Probably the closest thing to a definition of focus in hospital care is offered by Herzlinger, who describes focused factories as (multidisciplinary) organizations based on common objectives (e.g. the treatment of specific patient groups) . HerzlinSecond, evaluating the efficiency of focused factories becomes difficult when there is so much diversity. Conclusions on the operational performance of focused factories are mixed. Several case studies on specialty hospitals and centers for ambulatory surgery report improved efficiencies, higher patient satisfaction, comparable or decreased mortality rates and less adverse outcomes on the hospital level ,18,24,25To understand the diversity in examples of focused factories in hospital care, further studies are required. Similar to manufacturing and services, hospital care delivery systems are influenced by varieties. For example: varieties in; case-mix; the experience and capacities of medical doctors, specialty groups, and other (nursing) staff; and the availability of infrastructure and medical technologies ,33,34. IThis paper aims to explore the application of the focused factory concept in hospital care, including indications of its performance, resulting in a conceptual framework that can be helpful in further identifying different types of focused factories. We performed multiple case studies in four specialty fields, investigating the degrees of focus, the organizational context, and the operational performance. We used the two dimensions of focus from business literature to group cases with similar degrees of focus. Thus we hope to contribute to the understanding of the characteristics of the care delivery system and operations strategy for different types of focus.The study consisted of a cross-case comparison of four, separately performed, multiple-case studies in different specialty fields. Within each specialty field, we performed a comparative multiple case study with embedded units of analysis . This meThe fields for the case studies were selected to correspond with- and reflect the variety of focus examples in the literature ,3,14,17.Using the characteristics and identified fields, we sampled conveniently, primarily selecting hospitals in the Netherlands, but included international good practice cases on medical oncology and cataract care due to the limited number of cases in the Netherlands. We aimed for at least two hospitals and three units of analysis per specialty field. An overview of the cases and units of analysis included is presented in Table We investigated the organizational context by looking at the operations strategy (related to focusing), including the implications for the design of the care delivery system. This design, the organizational structure, is believed to influence organizational outcomes -38. We sThe degree of focus was investigated using a measurement instrument translated from industry. In the literature, only two attempts to measure degrees of focus were found.Mukherjee  used a qThe operational performance was investigated per specialty field, by looking at process indicators; such as utilization, lead times, and the costs of the resources used. The indicators chosen varied per specialty field, depending on the availability of data.Data were collected using both qualitative and quantitative methods. Quantitative data were retrieved from annual reports and, when necessary, provided by the organization. Qualitative data were collected through interviews and observations during site visits. Each study was performed by the authors, or as a master thesis project closely supervised by the authors. Case study protocols per specialty field were used.First, we discussed the similarities and differences between the individual (sub) units' organizational context, degrees of focus, and operational performance per specialty field. We analyzed whether the organizational context and degrees of focus could explain differences in operational performance.Next, we grouped the (sub) units of all four multiple case studies into a framework, based on the degrees of product and process focus. In this cross-case comparison we discussed similarities (and differences) in the organizational context between units in the same group. Replication logic  was usedWe studied the chemotherapy day units (CDU) of three comprehensive cancer centers in the EU and US. An earlier pilot study, comparing complete cancer centers, lead us to conclude this lower level of analysis was required to explain differences. In total, 6 CDUs were studied. The results  total knee implants groups of a general hospital (GH) and an orthopedics center (OC) in the Netherlands. The results  and the comparison of overhead costs favored the general hospital. Only the knee implant patients treated in the joint-care program of the general hospital showed shorter lengths of stay. The differences in the average duration of orthopedics surgery and the length of stay for orthopedics patients are probably caused by the lower complexity of the case-mix of the general hospital. The higher volume of knee surgeries in the orthopedics center probably explains why their average duration of knee surgery is shorter. The limited number of cases does not allow firm conclusions. We could thus not establish a unidirectional relation between focus and efficiency.We studied the cataract care of three eye hospitals, located in the Netherlands (11), the United Kingdom (12), and United States (13). The results , followed by NL (11) and lastly the US (13). As is supported by the results on the number of visits per treatment episode and the use of day-surgery operating rooms over more expensive general operating rooms. The operational performance seemed most influenced by the different operational strategies pursued, aiming for: efficiency (11), timeliness (12), and medical liability (13). These strategies reflected the characteristics of the national reimbursements systems.We studied five hospital-owned centers for low-complex elective surgery in four teaching hospitals in the Netherlands. We investigated the perceived advantages of their care delivery systems. The results  and performed surgical procedures with shorter average duration and lower variation in duration. The Herfindahl-Hirschmann Index (HHI), calculated based on the surgical procedure codes and their volumes, showed reductions in variety by 2 - 4 times compared to the hospital, depending on the specialty. In one case (16) a medical doctor even reported a shorter average duration for one type of surgical procedure, compared to the same procedure performed on the general OR (thought to be caused by the experience of staff). Data were, however, insufficient to compare the exact utilization of the operating rooms, as each case used different definitions to collect data. Although obtaining comparable data proved difficult, observations showed that strategic decisions on the introduction of focus actually led to more efficient processes . We observed short turnover times on the OR and wards. Furthermore, all studied centers used less expensive OR resources compared to a general hospital, as only a limited set of surgical procedures was performed.The results of the four specialty fields did not show a clear relationship between the degrees of focus and the organizational context. Operational performance seemed to depend on focus, strategic choices, and the related organizational context. Units that combined a high degree of focus with clear strategic objectives aimed at efficiency or timeliness, often, showed higher degrees of efficiency or timeliness. When focus scores were similar, variations in efficiency seemed to be related to differences in operating procedures or operations strategy.Combining high degrees of focus with a well-defined operations strategy and work-designs, thus, appeared more important in realizing higher efficiencies than the degree of focus alone. It is of importance, to gain insights in the organizational characteristics of different types of focused factories.We positioned the 18 (sub)units of the four specialty fields into a focus matrix, based on their degrees of focus on product and process  in the organizational context of all units in the same domain  units are found in the product-process domain. These organizations treated a single, specific, group of patients and offered one single (type of) treatment or a single surgical procedure. The majority of the cases pursued strategies aimed at efficiency or timeliness, and consequentially adapted work-designs and the physical layouts. Work-processes were standardized, describing well-defined tasks. Physical layouts enabled more efficient ways of treating patients (such as group rehabilitation) or minimized physical distances. Planning routines differed, but were more or less standardized. Surprisingly, most organizations changed team-compositions frequently. As these organizations treat a single group of patients for a single (type of) treatment, they can be defined as procedure based focused factories.Although the majority of units we studied were procedure based focused factories, we believe that the proposed distinction between different types of focus leads to a better understanding of the relations between focus, operational choices, and the operational performance of an organization. The fit between strategic focusing decisions and the design of the care delivery system appears especially important for delivery and procedure based focused factories.To our knowledge, our analysis, including the development of a measurement instrument, was the first attempt to measure the degree of hospital focus in a structured way. Our approach makes it possible to study and compare types and degrees of focus in different specialty fields.The focus measurement instrument has some drawbacks. Differences between the fields and national healthcare systems make it necessary to adapt the measurement instrument to each specialty field, for instance through defining the ICD code limits. Thus the validity and consistency of the instrument needs further study, especially as we could only include 18 cases. Looking at the difference in focus scores, further studies into the scale and cut-off points that distinguish between different domains of focused factories are needed.The structured case analysis, provided insights in the relations between the degrees of focus, the design of care delivery systems, and the operational performance. We concluded that the applied operations strategy and resulting adaptations to the care delivery system within focused factories explain the differences in performance. This fit between strategic focusing decisions and care delivery design, the operations strategy, appears vital. Although the degree of focus seemed less important in predicting higher efficiencies or timeliness, a higher degree of focus indicates reduced variety. This variety reduction might offer organizations the opportunity to develop a well-focused operations strategy. Further studies into the role of the operations strategy in focused factories are required. Developing a measure of the degree of fit that can be added to the scoring system, seems worthwhile.The proposed framework provides insights in the main characteristics of three types of focused factories. It offers a way for identifying similar types of focused factories, based on product and process foci. We cannot exclude the possibility that not all types of focused factories in hospital care are covered. For instance, diagnostic departments, which might require different focus- and operational choices, were not included in our research. Further studies in other fields are therefore required to validate the framework.A recent study of Schneider et al , coverinOur study shows that focus in hospital care relates to limitations on the patient group treated and the services or treatments offered. Four multiple case studies in the fields of medical oncology, orthopedics, cataract care, and elective surgery showed different scores of focus on product and process.Process focus appeared more often to be related to strategic choices considering the organizational structure and the design of the care delivery system. Product focus appeared to be related to limiting the patient groups treated, having only implicit consequences for the organizational structure. Based on the differences in these degrees of focus, we distinguish three main types of focused factories: specialty based, delivery based and procedure based focused factories.The results suggest that focus can lead to higher productivity and utilization, but only when clear strategic focusing decisions are made. The applied strategic choices and their consequences for the design of the care delivery system seem more important in explaining differences in operational performance than focus scores as such. This might be one of the reasons why studies into the effects of focused factories, including the econometric literature, show such mixed results.No conflicting interests can be indicated. WvH is member of the executive board of one of the involved chemotherapy day units studied in the field of medical oncology.EB co-supervised three case studies, performed one case study, (re)wrote the first draft of the paper, and revised the text. WvL performed one of the case studies and contributed to the text. WvH supervised three case-studies and contributed to- and revised the text. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/10/154/prepubMeasurement instrument focused factories in hospital care. This file presents the measurement instrument used by the researchers to assess the degrees of focus of focused factories in hospital care. Two dimensions are investigated: 1) the degree of product focus, by investigating the volume and variety in patients treated, 1) the degree of process focus, by investigating the volume and variety in specialties involved and services offered. The file can be viewed in Word.Click here for file


Plasmodium falciparum continues to inflict a considerable burden of disease, particularly in sub-Saharan Africa, with infants and young children bearing the greatest morbidity and mortality [Although significant advances have been made in the understanding of parasite and vector biology and the treatment and prevention of malaria, ortality .® , has had a significant impact on the treatment of malaria. A large body of evidence supports consistently high efficacy and safety, demonstrating crucial reliability in vulnerable populations. The efficacy and safety of this ACT have been clearly demonstrated in a clinical development programme spanning 14 years and enrolling approximately 5,000 patients. In trials conducted in different malaria-endemic regions, AL has consistently achieved 28-day PCR-corrected cure rates of >95% in evaluable populations, and has shown a favourable safety and tolerability profile [The introduction of ACT (artemisinin-based combination therapy), especially Coartem profile . The new profile .Studies in Zambia and KwaZulu-Natal have demonstrated the impressive impact that AL can have on malaria morbidity and mortality and transmission, at the same time providing cost savings, as presented in this supplement, when used in combination with other malaria control strategies -11.With the increasing availability of generic forms of ACT, it is important to be aware of quality assurance considerations to be sure that the efficacy and safety of these critical anti-malarials is not compromised. Substandard products may contain lower-than-stated doses, or packaging may not be supportive enough to further understanding and adherence to treatment, which could increase the burden of malaria and promote resistance.Ensuring prompt access to an effective anti-malarial, particularly to remote rural communities in resource-poor countries, is an ongoing challenge. Prescribing health workers and their patients, particularly those who rely on government supplies, continually battle a 'drug is out of stock' syndrome. Rational and implementable anti-malarial drug policies, which are essential decision-support tools in the fight against resistance, are impossible to develop or to implement without an ensured supply of effective, quality assured drugs. Increasingly, community deployment programmes are proving successful in diagnosing and treating malaria patients close to home. The Tigray project, conducted in a remote, rural region of Ethiopia (presented in this supplement ) demonstDiagnostic development represents a potentially powerful strategy to simultaneously improve healthcare delivery and delay emergence of resistance. In the current situation of rapidly evolving malaria epidemiology, accurate diagnosis and appropriate treatment of patients, with both positive and negative results for malaria will be crucial. Informing communities and health care providers that not every fever is malarial in origin and urging them to seek a test before administration of an anti-malarial treatment remains a challenge due to entrenched beliefs and prescribing habits.Novartis has delivered more than 250 million treatments of AL to malaria-endemic countries on a non-profit basis since 2001, saving an estimated 630,000 lives, and has an on-going commitment to serving vulnerable populations. The recent innovation of a dispersible formulation of AL for infants and young children demonstrates a patient-centric approach - the recognition of an unmet medical need followed by a considered response supported by a rigorous clinical development programme. Infants and young children are most vulnerable to malaria, and the delivery of a formulation specifically designed to meet their needs will hopefully represent a significant advance in the successful treatment of this population.Patient-centred care will be vital to encourage adherence to new treatment algorithms developed in response to the changing malaria environment in Africa. The proof of efficacy alone is not sufficient - acceptability to both prescribers and their patients is vital. The provision of effective drugs such as AL and other forms of ACT, in appropriate formulations, will encourage improved adherence to drug regimens. Education and communication programmes to engage both healthcare providers and the community will be essential in a new era of malaria prevention and treatment. Ultimately, healthcare delivery systems are crucial to ensure the effectiveness of the medicine, and there needs to be a concerted effort to improve the healthcare systems in Africa, both publicly and privately.The safety profile of AL in the clinical trials performed so far has remained good. However, there is a need for continued pharmacovigilance to seek any rare untoward effect and the INDEPTH effectiveness and safety studies of anti-malarial drugs in Africa (INESS) will provide the much-needed pharmacovigilance data to supplement the limited spontaneous reporting of adverse events from Africa . The INEThis supplement reviews the contribution made by AL as an ACT to the tremendous progress made in the control of malaria and establishes effective treatment as a cornerstone in the foundation of effective, quality patient care for infants, children and adults with malaria.The author would like to acknowledge that Novartis Pharma AG sponsored this supplement. However, the author does not work for, or represent in any way, Novartis Pharma AG.The author met International Committee of Medical Journal Editors criteria for authorship.


Despite surveillance efforts, unexpected and serious adverse drug reactions (ADRs) repeatedly occur after marketing. The aim of this article is to analyse ADRs reported by available ADR signal detection approaches and to explore which information about new and unexpected ADRs these approaches have detected.We selected three therapeutic cases for the review: antibiotics for systemic use, non-steroidal anti-inflammatory medicines (NSAID) and selective serotonin re-uptake inhibitors (SSRI). These groups are widely used and represent different therapeutic classes of medicines. The ADR studies were identified through literature search in Medline and Embase. The search was conducted in July 2007. For each therapeutic case, we analysed the time of publication, the strengths of the evidence of safety in the different approaches, reported ADRs and whether the studies have produced new information about ADRs compared to the information available at the time of marketing.79 studies were eligible for inclusion in the analysis: 23 antibiotics studies, 35 NSAID studies, 20 SSRI studies. Studies were mainly published from the end of the 1990s and onwards. Although the drugs were launched in different decades, both analytical and observational approaches to ADR studies were similar for all three therapeutic cases: antibiotics, NSAIDs and SSRIs. The studies primarily dealt with analyses of ADRs of the type A and B and to a lesser extent C and D, cf. Rawlins' classification system. The therapeutic cases provided similar results with regard to detecting information about new ADRs despite different time periods and organs attacked. Approaches ranging higher in the evidence hierarchy provided information about risks of already known or expected ADRs, while information about new and previously unknown ADRs was only detected by case reports, the lowest ranking approach in the evidence hierarchy.Although the medicines were launched in different decades, approaches to the ADR studies were similar for all three therapeutic cases: antibiotics, NSAIDs and SSRIs. Both descriptive and analytical designs were applied. Despite the fact that analytical studies rank higher in the evidence hierarchy, only the lower ranking descriptive case reports/spontaneous reports provided information about new and previously undetected ADRs. This review underscores the importance of systems for spontaneous reporting of ADRs. Therefore, spontaneous reporting should be encouraged further and the information in ADR databases should continuously be subjected to systematic analysis. Over thsurprise . Severalsurprise . Informasurprise ,9. The gsurprise ,9. The Rsurprise ,9. Data surprise -12. ThisWe selected three different therapeutic groups of medicines for review. The groups were characterised by different:• Antibiotics for systemic use• Non-steroidal anti-inflammatory drugs (NSAIDs)• Selective serotonin re-uptake inhibitors (SSRIs)Antibiotics were first marketed in the 1940s and NSAIDs in the 1960s, while SSRIs were not launched until the middle of the 1980s .The therapeutic categories present different ADR profiles due to their specific pharmacological characteristics and functions.Studies were identified through Medline from 1966) and Embase (from 1989) using the following MESH terms: serotonin re-uptake inhibitors, anti-inflammatory agents, non-steroidal, anti-bacterial agents, adverse drug reaction reporting systems, pharmacoepidemiology and the key words: adverse drug reactions and information in combination. The literature search was conducted in July 2007 without language restriction. Studies written in non-European languages were later excluded. To be considered relevant for this review, articles had to be empirical in origin and focus on signal detection. Titles and abstracts of the search results were screened and relevant articles identified. The reference lists of included publications were hand-searched for possible additional relevant studies. Non peer-reviewed articles or unpublished observations were not considered. A flow chart of the study selection process for the therapeutic cases is illustrated in figure 966 and EWe developed a taxonomy inspired by general guidelines for pharmacoepidemiological research to analyse the studies systematically . The taxFor each of the three selected therapeutic groups, we analysed the time of publication, the strengths of the evidence in the different approaches, reported ADRs and whether the studies had produced new information about ADRs compared to the information available at the time of marketing.For each included literature reference, the ADRs tested or detected via the various signal detection approaches were classified according to Rawlins' classification system . An overThe explored approaches were classified into analytical or observational approaches according to Strom's definitions . Case-coFor each therapeutic group, we analysed whether there was a connection between time of publication and the applied study design.Evidence-based medicine operates with an evidence hierarchy for evaluating the quality of the various study designs used for therapeutic studies . At the The literature search identified 327 potentially relevant references for all three therapeutic groups, 149 of which were selected from the titles and abstracts and further screened for relevance. Eventually 79 references were included in this analysis. A flow chart of the selection and exclusion process is illustrated in figure Table Tables Case-control studies were carried out on data from various national registers and/or data from spontaneous ADR databases, physicians' databases such as the General Practitioners' database in the UK and Health Insurance Databases ,38,72,73The antibiotic studies were published from 1990 and onwards, most of them from 1995. Cohort studies were published during 1990–1994, while the PEM studies, spontaneous reporting, case reports/case series primarily were published after 1995. The majority of the NSAID studies were published after year 2000. The SSRI studies were published from 1990 to present, most of them from 1995 to 2005. Table ADRs from newer types of antibiotics, such as fluoroquinolones, have been reported much more frequently in the literature than ADRs from the older antibiotics, such as penicillins and macrolides ,33,34,36Studies explored the risk of gastrointestinal -44,50 anStudies explored the risk of extrapyramidal symptoms, withdrawal syndromes and serotonin syndrome with the use of SSRIs, other ADRs investigated were: changes in testosterone and natrium level, alopecia, liver injury and bleeding. ADRs reported only via spontaneous reports are first-trimester exposure on newborns and neonatal withdrawal syndrome, hepatic injury and pancreatitis, suicide, non-puerperal lactation and serotonin syndrome ,86,90-92The approaches produced information about ADR risks compared to placebo or similar drugs as either odds ratios (OR), proportional reporting ratio (PRR) estimates, incidences (IC) and frequencies of ADRs. These parameters are built into the design and based on previous information or hypothesis. The studies were conducted on various patient populations, various medicines within the individual sub-groups, and different types of ADRs, different outcome measures, data sources and time periods. The purpose of the approaches made it possible to adjust the ADR estimate for known confounders and risk factors.The approaches produced information about ADRs as estimates  or as single observations compared to placebo/similar medicines. Case reporting was the only approach that contributed new information about new ADRs in all three therapeutic cases.This review has several main findings:First, analytical approaches ranging higher in the evidence hierarchy provided information about risks of already known or expected ADRs, while information about new and unknown ADRs was detected by case reports only, which range at the lowest level in the evidence hierarchy. Second, the studies primarily dealt with analyses of ADRs of type A and B, and only a few studies analysed type C and D. Third, similar approaches, both analytical and observational, were applied to all therapeutic cases. Fourth, the ADR cases provided similar results with regard to detecting new ADRs despite their connection to different time periods and organs attacked.There is a general lack of standards in the field of ADRs, particularly because many ADRs are not detected until after marketing and the studies are based on selected patient groups, which makes it difficult to generalise the results to other patient groups. As previously argued in the literature, testing specific hypotheses in the analytical approaches makes it difficult to capture information about new and unknown ADRs . DespiteNew ADR signals are often documented by only a small number of case reports, and systematic inclusion of data mining procedures in assessment of new ADR signals would probably contribute to earlier detection and quantification of serious ADR signals ,96. HoweThe objective of this review was to analyse which information signal detection approaches have produced about new ADRs in selected and published therapeutic cases, rather than to perform a systematic review of the entire body of ADR literature covering all therapeutic groups. The choice of widely different therapeutic cases and the similar results obtained across therapeutic cases make us believe that the results qualitatively reflect the general, published experience on ADRs based on signal detection approaches. Findings across therapeutic cases were similar with respect to methodological approaches and time of publication, despite the fact that ADRs differed in nature and affected different organs. Although antibiotics have been marketed since the 1940s, it was not possible to search for literature before the mid-1960s due to the limitations of current databases. Lack of consistency in reporting ADRs, different methodologies used in the studies and their impact on the results are difficult to evaluate in this review.Although the medicines were launched in different decades, approaches to the ADR studies were similar for all three therapeutic cases: antibiotics, NSAIDs and SSRIs. Descriptive as well as analytical designs were applied. Despite the fact that the analytical studies rank higher in the evidence hierarchy, only the descriptive case reports/spontaneous reports provided information about new and previously undetected ADRs. This review underscores the importance of systems for spontaneous reporting of ADRs. Therefore, spontaneous reporting should be encouraged further and the information in ADR databases should continuously be subjected to systematic analysis.The authors declare that they have no competing interests.LA and EHH designed the study, analysed the data and wrote the various drafts of the manuscript. LA did the sampling and literature search. Both authors read and approved the final version of the manuscript.We thank The Danish Medicines Agency and the Hørslev Foundation for their financial support of the study.The pre-publication history for this paper can be accessed here:


The development and maintenance of adequate shared infrastructures is considered a major goal for academic centers promoting translational research programs. Among infrastructures favoring translational research, centralized facilities characterized by shared, multidisciplinary use of expensive laboratory instrumentation, or by complex computer hardware and software and/or by high professional skills are necessary to maintain or improve institutional scientific competitiveness. The success or failure of a shared resource program also depends on the choice of appropriate institutional policies and requires an effective institutional governance regarding decisions on staffing, existence and composition of advisory committees, policies and of defined mechanisms of reporting, budgeting and financial support of each resource. Shared Resources represent a widely diffused model to sustain cancer research; in fact, web sites from an impressive number of research Institutes and Universities in the U.S. contain pages dedicated to the SR that have been established in each Center, making a complete view of the situation impossible. However, a nation-wide overview of how Cancer Centers develop SR programs is available on the web site for NCI-designated Cancer Centers in the U.S., while in Europe, information is available for individual Cancer centers. This article will briefly summarize the institutional policies, the organizational needs, the characteristics, scientific aims, and future developments of SRs necessary to develop effective translational research programs in oncology.In fact, the physical build-up of SRs per se is not sufficient for the successful translation of biomedical research. Appropriate policies to improve the academic culture in collaboration, the availability of educational programs for translational investigators, the existence of administrative facilitations for translational research and an efficient organization supporting clinical trial recruitment and management represent essential tools, providing solutions to overcome existing barriers in the development of translational research in biomedical research centers. In the last few years there has been a tremendous expansion in translational research studies requiring integrated multidisciplinary efforts or special expertise that are not widely available to individual researchers. In fact, single laboratories, clinical divisions, or research groups do not possess sufficient financial funding, space or well-trained personnel to afford such opportunities. Therefore, the development and maintenance of adequate shared infrastructures is considered a major goal for academic centers promoting translational research programs ,2. Among- Institutional, rather than individual, investments offer the opportunity to buy the most technically advanced, high throughput instrumentation to be used by each research group.- Single researchers may have access to new methods or to a multiparametric characterization of tumor models by the use of several technologies contained in the whole set of SRs present in the Institute, an approach that is generally much more cost effective than establishing the technique in each research group laboratory.- Availability to all researchers of highly trained personnel with specialized skills in the technologies present in the Institute.- Given the rapid evolution of biomedical research and technologies, the continuous users' education is an important issue. The availability of highly trained staff in each SR technology permits the provision of an advanced education and training programs to all other investigators.- Quality control programs based on extensive expertise of the users, appropriate setting of the instruments, may lead to superior experimental results because of increased sensitivity, accuracy, and reproducibility.- The presence of highly advanced SRs usually results in an increase of interdisciplinary collaborations and enhancement of translational research programs.- Centralized purchase procedures invariably result in reduction of reagent costs, maintenance of equipment, and personnel expenditure.In order to fulfill the need of new technologies in support of innovative fields within biomedical research, a institution may consider establishing a new SR instead of simply outsourcing its services, based on several aspects: cost effectiveness, turnaround time, flexibility of services offered, commercial availability, and technical quality of the data. All these tasks are equally important since, for example, some technical services may be quite expensive, but commercially unavailable because of the high level of technical expertise required or inconvenience of marketing due to insufficient numbers of researchers who are interested in using particular techniques. On the contrary, outsourcing may be convenient when economically advantageous for the institution or when the half- life of a technology is too short or uncertain to deserve a financial investment. Decisions regarding the technologies to outsource, selection of partners, and the management of such relationships are of crucial importance for institutions aiming at developing competitive research programs. This process may be accomplished through the establishment of criteria, for example through a Decision Support Framework model containing a set of guidelines and procedures useful for Institutional executives to effectively manage decisions on whether to source technologies internally or externally . BiomediThe success or failure of a shared resource program also depends on the choice of appropriate institutional policies. Due to the importance of this issue, policies fostering or disregarding the establishment and appropriate functioning of SRs have been identified both in literature as well as in day-to-day practice in many Institutes . Althoug- The presence and amount of institutional funds that partially share the cost of SR encourage their use by scientists, especially by young researchers who may not yet have fully established laboratory equipment and personnel.- The redistribution of obtained economies to develop new research programs, buy new technologies or hire personnel with higher qualifications supporting cross- sectional institutional research activities reinforces the perception of the importance of having efficient shared infrastructures.- Academic long term commitment for upgrading space, instrumentation, staff training, and financial support; this commitment may be practically realized through the appointment of a qualified Director of all the SR in the institution, who chairs an Advisory Committee that meets regularly to review the information regarding the usage, performance, and customer satisfaction of the SRs and the availability and performance of new technologies present in the market. Based on the Committee's suggestions, the Cancer Center leadership may implement the SR program.- Promote knowledge of the available technologies by including a period of training in SR in educational programs for graduate and post-doctoral students increases their use by more research groups.- Greater emphasis on scientific opportunities and advantages for the entire scientific staff, and scientific excellence may stimulate a positive loop resulting in increased scientific productivity.- Project planning of SRs includes clear guidelines about ownership and access to SRs and about property and scientific use of the data obtained from SR activities; furthermore, the ability to guarantee equitable access to all researchers interested in SR use is mandatory. These are essential ingredients in preventing later misunderstandings and problems.- While the above-mentioned options may improve the successful establishment of SRs, problems may arise when harmful policies are applied. A few examples of harmful policies may be:- Lack of incentives to share resources could result in conflicts and academic staff frustration; institutions lacking an environment that facilitates sharing of productive ideas and resources among investigators from different disciplines may experience requests of unnecessary duplication of instrumentation, staff, and expertise by single researchers and incapacity to access high value technology. Ultimately, this leads to the difficulty in developing successful translational research programs.- Lack of professional opportunities for SR personnel also, negatively affects the presence of high quality SRs. In fact, the success of SR depends upon the attraction of high scientific level staff. The opportunity to develop scientific research of top quality by using sophisticated technologies and the interaction with top level scientists who are part of an academic center's staff, may be key factors in attracting skilled managers and technicians devoted to SR functioning.- Lack of sufficient financial support. The research centers developing an SR program must be aware that the purchase and maintenance of technology equipment is very costly; accordingly, the availability of excellent SR staffs requires salaries and benefits adequate to their professional skills.- Although the establishment of SRs requires substantial financial investments, overemphasis on costs savings rather than on the benefits that inevitably result in productivity and excellence of research programs is probably considered the policy that mostly damages the development of SRs .The appropriate maintenance and development of shared resources requires an effective institutional governance regarding decisions on staffing, existence, and composition of advisory committees, policies, and defined mechanisms of reporting, budgeting, and financial support of each resource.As previously mentioned, the presence of a high quality staff is an essential component in developing a SR system in Cancer Centers and in other research Institutions. Depending on the characteristics of each SR, the staff must be composed of peculiar professional profiles; the responsibilities of the staff encompass several activities, extending beyond technical and educational skills, such as planning and problem solving, communication skills, and the ability to share research programs and experimental results with other scientists. Generally speaking, the role of staff could be:- To prepare a user guide defining general policies, services provided, sample preparation and fees; planning (reservations) and performing experiments.- The use and maintenance of the instrumentation, including troubleshooting problems.- To define and program the acquisition of reagents and supplies for daily operational procedures, according to the SR assigned budget.- To set up new methods and technologies that are strongly requested by research groups in the Cancer Center.- To establish a productive communication with each research group discussing experimental design and results as well as collaborating in preparing grant proposals or scientific manuscripts.- To evaluate new instruments on the market and contribute to the long term strategies of the SR by sending suggestions to the SR committees.SR staff may be constituted by the Director/Medical Director, Administrative Director, the Facility Manager and by a member of technical staff. The Facility Manager provides, in consultation with the SR manager and the users or advisory committees, when present, strategic suggestions to the Board of Directors to establish or modify policy issues, plans and establishes the budget; he/she also proposes acquisition of new instruments and interacts with Cancer Center leadership on program issues. He/she may provide consultation for grant application and preparation of scientific reports. The Manager is usually an internal researcher of the institution who has special expertise in the field devoting a variable percentage of his/her activity to oversee the entire operational aspects of the SR.The Facility Manager is the first point of contact for many prospective users of the facility and is responsible for the daily operations of the SR, including work scheduling, supervision of staff, service and maintenance of the equipment and training programs; she/he assesses each user's research needs, suggests effective experimental approaches and recommends protocols as necessary to obtain the data needed. In addition she/he may be involved in the development of protocols, consultation on experimental design, analysis and interpretation.Depending on the operational needs and on the complexity of the technologies included in the SR, the staff includes a variable number of laboratory technicians, biostatisticians, biomedical engineers, nurses, and data managers. The Facility Manager and the technicians are usually fully devoted to develop SR activities.Committees may also be essential components of the SRs. An appropriate users' committee may be appointed for each SR that periodically evaluates the performance, the utilization, and the costs/productivity of the SR. Furthermore, each committee may assess future needs for technological, financial, and human resources of the SR and prepare a proposal to be evaluated by the SR director and, eventually, by an oversight committee. The overall activity and the strategic value for the Center of all the SRs available may be assessed by a SR Oversight Institutional Committee including core managers, directors of research programs, a director of the administration; this committee interacts with the Directorate of the Institute to discuss the development of an institutional SR program, including the development or discontinuation of individual SRs, the contract of resources, services proposed for the future, and the impact of SR on institutional research programs or the overall impact of SRs on research goals of the Institute.The appointment of an External Advisory Committee may be necessary for SRs requiring very high technology investments or having nation-wide or international usage; this committee could support institutional decisions on the purchase of equipment or on the establishment of relationships with international partners, pharmaceutical, and biotechnological industries.Access policies include the modality of SRs use. Scheduling may be planned on first come-first served basis via web-based systems or paper registries. The involvement of personnel in assisting individual users may vary: assisted use means that users require the assistance of a technician from the SR, this may also signify that users who plan the experiments and/or prepare the samples, while running the instrumentation, rely partially or completely on SR staff. In unassisted use, sample preparation, use of the instrumentation, and interpretation of results relies completely on single investigators and the role of the SR consists in providing efficient instrumentation and in running quality controls. In fact, those users who completed the training and demonstrated the ability to use the equipment without technical support may be certified as independent users, which provides them the opportunity to independently use the equipment, including during off-peak hours. Due to technical complexity, some SRs may function only through assisted use.Usage policies include the fees for each, assisted or unassisted, procedure that are established by the Institution depending on the calculated costs of the SR , on the cost of reagents, on the usage frequency by individual research groups within the Institution or by external users and on the availability of an institutional support budget that may be assigned annually to the functioning of SRs. In the U.S., part of the costs of institutional SRs can be requested through NCI Cancer-Center Support Grants .Policies also include the rules governing intellectual property of experimental results and their relevance for the development of research projects and grants. The degree of involvement by facility staff in planning, execution, and discussion of each project depends on the nature and difficulty of the project and also on the prior expertise of the investigators in that field.SRs are usually maintained by institutional funds and users fees. The latter may support a portion of daily operational costs, while institutional support is mandatory to cover additional costs; in particular, the purchase of new equipment and the development of new technologies. Finally, while each SR functions independently, a very important task is to create a unifying information and tracking system to integrate all the data present in the SRs of each institution. This integration will allow the Cancer Center Board of Directors to efficiently develop annual budgeting issues as well as mid-term strategic plans.Shared resources represent a widely diffuse model to sustain cancer research; in fact, web sites from an impressive number of research Institutes and Universities in the U.S. contain pages dedicated to SRs that have been established in each Center, making a complete view of the situation impossible. However, a nation-wide overview of how Cancer Centers develop SR programs is available for the NCI-designated Cancer Centers in the U.S. . In EuroAccording to the NCI Cancer Center Overview on shared resources, January 2008 update, the majority of Cancer Centers possess at least the following shared resources: Flow Cytometry, Genomics , Proteomics, Animal Facilities , Biostatistics, Bioinformatics, and Clinical Research Office. The type of additional, less represented, Shared Resources is quite heterogeneous and depends on the scientific orientation of each Center . Some of the more diffused or more relevant SRs for translational cancer research programs are included in the following list:- Confocal Microscopy- Flow Cytometry- Genomics or DNA sequencing, microarray, cytogenetics- Proteomics- Pathology- Animal facilities, including imaging, genetically engineered mice- Biobanking/Tumor bank- Bioinformatics- Biostatistics- Pharmacology- Clinical Research OfficeHowever, there is increasing evidence supporting the observation that advances in basic science do not always result in direct benefits for patients by their incorporation in standard medical practices; although the reasons for such failures are multiple and complex, probably one of the most important obstacles is the consistent observation that results obtained in animal models often do not apply to humans ,13. In o- Human immunologic Monitoring- Radiation Resources- Translational researchIn the following paragraphs, the institutional policies, organizational needs, characteristics, scientific aims, and future developments of SRs necessary to develop effective translational research programs in oncology, will be briefly summarized.The high resolution imaging of subcellular components, specific proteins, and other biological molecules represents a very important opportunity in cancer research. Conventional optical microscopy enables a two-dimensional evaluation of biological specimens, while the material is organized in three dimensions. Confocal microscopy permits collection of three-dimensional images from living or fixed cells and tissues by the use of laser scanning technology. This technique has gained popularity in biomedical cancer research  and has The primary characteristics of CM arise from the use of a pinhole to prevent out of focus light that may degrade the image; this system detects only the light within the focal plane, eliminating the background caused by out-of focus light and scatter from images and producing a higher resolution as compared to conventional optical microscopy; in addition, CM permits the acquisition of serial images from living cells on timescales from milliseconds to hours. Biological laser scanning confocal microscopy is almost invariably associated with fluorescent probes that specifically target subcellular components, such as nuclei, mitochondria or the cytoskeleton, even cellular processes, such as apoptosis, enzymatic activities, etc. Therefore, a complete confocal microscopy apparatus consists of the optical microscope and a light emitting source such as lasers; the most commonly used lasers include argon-ion with usable power at 257, 477, and 514 nm and helium neon lasers with usable power at 534, 567, and 612 nm . The sysFlow cytometry is a technique used to measure predefined physical and chemical properties of cells or particles suspended in a stream of fluid. This technique was initially developed to characterize and separate a heterogeneous mixture of cells into distinct populations for phenotyping or functional analysis. The modern flow cytometer consists of a light source, usually a laser, optical detectors, electronics, and a computer to translate signals into data. Although flow cytometry may be considered a mature technique, substantial improvements have been made in the last few years ,21. For Multi-parameter flow cytometry is routinely used in diagnostic laboratories to characterize hematopoietic cells for the diagnosis and classification of hematologic tumors, including the detection of minimal residual disease, of immune system diseases, for measuring in vivo and in vitro specific immune response to infectious agents, cancer vaccines, and autoantigens -28. The Flow cytometers can be equipped with cell sorting devices. These machines can analyze many fluorescence and physical parameters of individual cells and purify those that meet predefined characteristics, i.e. a certain phenotype or DNA content. Current cell sorters are high-speed cell sorters, separating up to 70,000 events per second ,34. ManyGenomic technologies offer important tools to analyze large numbers of gene structures or regulation by identifying DNA mutations and deletions, by assessing the amounts of RNA present in biological specimens, or by epigenetic or karyotypic analyses . In partMolecular cytogenetic aspects are becoming more important for cancer research projects. Traditionally, cytogenetics refers to the study of the description of chromosome structure and alterations that cause diseases . More reAreas of development in the field of genomics include high throughput analysis of the trascriptome based on the sequencing of a technology that may overcome several problems encountered with the use of microarrays ,53, ultrIn some Cancer Centers this resource consists in a standard Pathology laboratory providing routine histology services , expert histopathology evaluations, immunohistochemistry, and in situ hybridization techniques for human and experimental tissue samples. In these cases, the SR is organized as a standard Pathology laboratory, including adequate space, safety hoods, equipment for surgical pathology, automated slide-stainers, optical microscopes, and refrigerating/freezing devices, etc.. Several other Centers have organized facilities with aims and services that are more complex or more research- oriented, such as macromolecular services  or experimental/research pathology and/or molecular pathology core. Experimental/Molecular Pathology cores use advanced, high throughput techniques for the molecular characterization of tumor cells ; in thesA common problem encountered by cancer researchers arises from the heterogeneous nature of tumor tissues that may confound molecular analysis. In order to overcome this problem, a novel technique of laser microdissection has been recently developed and microdissection services are currently offered in several advanced pathology SRs. With this technique, cells of interest may be identified via microscopy and then removed from heterogeneous tissue sections via laser energy . Then, pIn some Institutes, the Tissue Bank facility is included in this SR, but I consider biobanking as a separate entity, one devoted to collection and storage not only of tissues, but also blood, blood products, biological fluids, and nucleic acids as well as maintaining an informatics platform connected with other existing databases .Future developments within this SR may regard the implementation of novel technologies for image analysis of tissues and the development of tissue pharmacodynamic analytical tools that may be of great value in the management of patients included in clinical trials and in evaluation of innovative drug efficacy.Proteomics include the detection, identification, and measurement of proteins and/or peptides, protein modifications (i.e. identification of phosphorylation sites), and the study of protein-protein or protein-DNA interactions and regulation. Proteomic application to cancer provides important information on biomarkers for early detection of tumor development, tumor profiling for diagnostic and staging purposes, and on mapping of cancer signaling pathways aimed at developing new treatments ,64,65. IThe relative expression of proteins in biological samples can also be conducted by non-mass spectrometry, non-microarray based platforms. In general, some techniques that are standard in laboratories, such as ELISA or Western blot, can be considered as proteomic platforms. More recently the Luminex's xMAP technology, an innovative multisphere-based multiplexing system, has been used to measure proteins in biological samples because of several advantages as compared to traditional assays. Some examples of its analytical capabilities that can be performed by using small sample volumes are multiparametric analysis of cytokines, of intracellular signaling pathways, and of protein phosphorylation ,71.Some proteomic SRs include services for the production of synthetic peptides that are used for the generation of specific antibodies, the preparation of peptide vaccines, as bioactive molecules, etc.. Commercially available peptide synthesizers may be purchased to perform peptide synthesis.A current problem in proteomic research is the lack of standards allowing comparisons of the analytic performance in different platforms and/or laboratories. For this reason, future goals of proteomic studies require that researchers with documented expertise, such as those included in Institutional proteomic SRs, develop collaborative protocols that, through identification and validation of common sets of standards, may ultimately permit sharing and comparison of analytical results among various research groups.Animal models are widely used in biomedical research to establish new diagnostic and treatment procedures and study basic mechanisms resulting in the development of several diseases. In particular, investigations in animal models are invaluable in discovering new approaches for diagnosis and treatment of cancer in humans. Animal facilities in various Centers have alternative names, including laboratory animal resource, genetically engineered mouse, transgenic mouse, and animal imaging resource . All theAccording to the NIH guide for the Care and Use of laboratory Animals, animal facilities must be designed considering several factors: in particular, the species, strains, and breed of animals and the goals of the research projects conducted at the Institution. Animal facilities must have adequate space, proper conditions of temperature, humidity, ventilation, and illumination. In addition, facilities must include an Institutional Animal Care and Use Committee and adequately trained personnel caring for animals.Genetically engineered animal SR  may be included in general animal facilities or constitute a separate entity. Genetically engineered mouse models may accurately mimic the pathophysiological and molecular features of human cancers. The purpose of this facility is to provide a service that efficiently produces genetically-engineered mice for basic and translational research, including transgenic and knock-out mice essential to develop animal models for human diseases and study many biological aspects of disease pathogenesis and response to treatments.So as to promote genetic studies on the nature of human cancers, the mouse genome can be modified by the pronuclear integration of exogenous DNA (transgenic mouse), by blastocyst injection of genetically modified ES (embryonic stem) cells (chimeric mouse) or by the excision (knock-out mouse) or alterations (knock-in) of gene functions ,74. ThisFuture developments of genetically engineered animal facilities should take into account that new technologies may be developed to overcome actual limitations of current genetic manipulations of experimental animal models .In vivo imaging consists in the use of non-invasive techniques to monitor the tumor development, progression, and effects of therapeutic interventions; animal facilities using miniaturized conventional imaging techniques, such as CT scan or PET have been developed in several institutions. Animal Imaging is seldom, if ever, included in a separate SR, but it is usually included in integrated services offered by animal facilities. Besides the use of traditional imaging techniques, a new modality, combining in vivo imaging techniques and molecular techniques has been recently developed. Molecular imaging permits the non-invasive visualization of cellular processes at a molecular or genetic level by using imaging probes. It offers the possibility to integrate the detection of molecular alterations with anatomical information specific to each animal or patient, when used in human trials. Animal molecular imaging facilities are particularly useful in those institutions pursuing drug development programs. All of the imaging techniques used in cancer patients have been adapted for use in small animals; the most widely used include magnetic resonance imaging (micro-MRI), x-ray computed tomography (micro-CT), and positron emission tomography (Micro-PET), while single photon emission tomography (SPECT), fluorescence imaging, and ultrasound imaging are less useful in cancer research imaging; excellent literature reviews providing detailed information on animal imaging technologies and techniques are available -77.Micro-MRI provides ultra sensitive (around 100 micron) information on tumor or metastasis localizations and, by using contrast agents, information on tumor vascularity. Micro-MRI Spectroscopy can be used to detect individual targets using magnetically-labeled affinity molecules. Major limitations of micro-MRI are the need of high quality personnel training and the costs of the apparatus .The Micro-CT apparatus is also available in animal SRs; it also has an optimal anatomical resolution (around 50 micron) and can be particularly useful to study discrete anatomical sites, such as lung and bone ,76. It oAlthough the anatomical resolution of Micro-PET in animals is low (in the order of 1–2 mm) the major advantage of this technique is the use of labeled molecules such as fluoro-deoxyglucose  that are rapidly taken up by tumors and measure cellular metabolism and functions. The cellular targets of labeled probes can be metabolites, antigens, or genes expressed in normal or pathological tissues. Micro-PET can be used to track cell trafficking, tissue hypoxia, DNA proliferation, apoptosis, angiogenesis, etc. Although the anatomical resolution of micro-PET is low, other advantages are the requirement of a medium-level personnel training and affordable costs.Advantages and limitations of the use of Micro-PET are similar to those identified in human studies and include the possibility of monitoring molecular events early in the course of the disease or during treatments, while limitations include the limited spatial resolution and the short half life of isotopes .SPECT is a special type of CT scan using radioactive tracers that is able to provide high-resolution images and analysis of multiple biological parameters . SPECT-CUltrasound is a quick and inexpensive technique to screen animals in vivo for tumor development or monitor in vivo interventional procedures , but, duBiobanking is an emerging activity that includes the collection and preservation of biological samples . The collection of human material is situated at the beginning of the chain of translational research and therefore biobanks are actively contributing to advances in translational research by offering opportunities to safely collect and store these samples and link laboratory research to clinical practice, ultimately accelerating the development of personalized medicine ,82. WithLaboratory space and instrumentation requirements include a processing room with thermostatic incubators, biohazard cabinets, centrifuges, and a personal computer with a dedicated software that allows management of archived samples and related information. Additional rooms host storage facilities, like -20°C and -80°C freezers, liquid nitrogen containers, or +4°C freezers that incorporate remote alarm systems to store specimens. The freezing devices must have enough space and temperature conditions to permit their correct functioning (i.e. insufficient space or high temperatures may cause overheating and damage of the cooling systems); liquid nitrogen tanks ideally should be automatically filled from high volume liquid nitrogen reservoirs. Automation procedures may permit great improvement in biobanking throughputs, quality control, and costs. The early phases of the biobanking process already benefit from these procedures, since automated liquid handling and sample dispensing systems are presently available in several laboratories and biobanking facilities ; in the Ideally, the collection of biological specimen process should be linked to the database containing clinical information and a tracking system of stored samples enabling researchers to recover and be aware of the potential development of translational research applications as well as to recover samples needed to develop their projects very rapidly . In thisAlthough remarkable examples of large-scale international studies based on tumor biobanking already exist ,91, futuBioinformatics is an interdisciplinary field that integrates computer science and biostatistics with biomedical sciences . It emerThe Bioinformatics facility requires space to host a high performance computing system for intensive analysis that includes strong data protection security systems. The staff may be composed of computer and bioinformatics specialists with a sufficient background in molecular biology, genetics, physics, or in other biomedical disciplines that constitute part of the research programs in that institution.Future tasks may regard the development of infrastructure that allows more integration between clinical informatics and bioinformatics itself, leading to more effective programs in cancer biology and therapy.Appropriate statistical methods are necessary throughout the entire translational research process, from in vitro studies to interpretation of genomic and proteomic analyses, validation of biomarkers, clinical trail design, analysis and data reporting . The BioThe establishment of this SR requires adequate space and availability of state-of-the-art computers with programming and statistical software with access to institutional databases. Biostatisticians, who may have sufficient expertise in basic research techniques or in clinical trial design/development, essentially compose the staff.Many Cancer Centers recognize that biostatistics collaborations are difficult to define in terms of hourly units and that the free exchange of ideas is essential to ensure a fruitful collaboration between the members of the Center. For these reasons, many Institutions do not apply charge back systems to this facility's services. On the contrary, few other Institutions consider the Biostatistics SR similar to other SR and charge back the services provided to investigators.The discovery of anticancer drugs is undergoing a period of rapid changes -108. In This SR performs standard methods, develops and validates new assays to perform pharmacokinetic, pharmacodynamic, and pharmacogenetic/omic analyses for clinical and preclinical drug development studies . This SRLaboratory instrumentation for this SR includes the most sensitive detectors available for the quantitation of analytical molecules; like triple quadrupole mass spectrometers, ion trap spectrometers that can fragment and analyze the mass of compounds, HPLC systems for the separation and analysis of drugs or drug-derived compounds, and equipment for the preparation and storage of biological samples.Real-time PCR technology, minisequencing reaction by synthesis, high throughput genomic technology platforms, and technologies for proteomic analyses  are particularly important in the development of analytical tools to map genetic loci influencing drug effects or defining the molecular characteristics of drug targets in tumor cells ,112.The Clinical Research Office  is a shared resource dedicated to programs of clinical research and provides administrative, scientific, and educational support to clinical investigators through a dedicated staff. Clinical Trial Protocols are reviewed by an Internal Review Board in the U.S.  and by an Ethics Committee in the E.U. (Directive 2001/20/EC and further implementations), both of which are regulated by specific laws. These Committees are responsible for protection of human subjects involved in clinical trials and provide public assurance of that protection. The clinical trials approved by the Committees can be initiated and processed, usually by the centralized Clinical Research Office -115. ThiNew types of centralized facilities have been recently developed based on complementary innovative approaches. Examples of these types of innovative SRs, are selected in the following:This SR is designed to provide advances testing systems to measure immune function in patients, especially when is necessary to evaluate the effects of therapies in patients enrolled in clinical trials. Although correlates of immune protection in infectious diseases may be hypothesized , a centrRadiation research SRs are built to study the effects of radiations  on cellular processes and on cancerogenesis in small animal models. They may provide ancillary services, like assistance with radiobiological data interpretation or irradiation of cell lines or feeder cells, that may not be available to single research groups because of high purchase prices, radiation safety, and regulatory agencies concerns, as well as expertise in the use of radiation sources. These facilities may be equipped with gamma rays or x-ray irradiators for targeting small macromolecules such as DNA or proteins, microorganisms, mammalian cells or small animals. These SRs may be preferentially located in Radiology or Radiotherapy Departments to facilitate their functioning according to national regulations on radiation safety.The Spatio-Temporal Targeting and Amplification of Radiation Response (STTARR) innovation Center of the University Health Network in Toronto constitutes a remarkable innovative model of radiation research facility . This CeTranslational research SRs are often laboratory facilities designed to support specific research programs including pre-clinical, experimental phases and/or post-clinical analyses in patients enrolled in clinical trials and maintain databases on sample information. As examples, these SRs may include immunological monitoring laboratories or molecular oncology laboratories in institutions that decided not to develop SRs based solely on these individual technologies. Translational research facilities may also offer consultations for the startup of translational research protocols or promote interactions between basic scientists and clinicians to develop interdisciplinary programs; however, at least in US, the strategies relating to development of effective tools that foster interdisciplinary research and training depend on the Center's Director or the Board of Directors rather than research infrastructure.Research infrastructure represents an essential tool in developing successful programs in translational research. Each center needs clear policies on development and on the rules governing the establishment of SRs and the availability of financial resources to set up and maintain these facilities. However, the scientific and economic advantages of an efficient SRs program largely justify the required efforts.The physical build-up of SRs is, however, not sufficient for the successful translation of biomedical research. Appropriate policies to improve the academic culture for collaboration, the availability of educational programs for translational investigators, the existence of administrative facilitations for translational research and an efficient organization supporting clinical trial recruitment and management represent essential tools in providing solutions to overcome existing barriers to the development of translational research in biomedical research centers.The author declares that they have no competing interests.


Pinaceae. The Pinaceae are well represented within the Wealden deposits of southern England, by only one (known) species, Pityites solmsii (Seward) Seward, whereas the macro-fossil record of these deposits is dominated by the extinct conifer family Cheirolepidiaceae, for which no resin chemistry has been reported. By analogy with modern materials, it is probable that the ambers found in these deposits are derived from an extinct member of the Pinaceae, but given the absence of evidence concerning the chemotaxonomy of the Cheirolepidiaceae, this family cannot be excluded a priori as a possible paleobotanical source. These ambers may therefore be assigned to either the Pinaceae or to the Cheirolepidiaceae. These samples are the oldest ambers to date to yield useful chemotaxonomic data.Terpenoid resin is produced by all families and most genera of the order Coniferales (the conifers), and the distribution of terpenes present in most conifer resins is characteristic of the originating family. Analyses of early Cretaceous (Barremian) amber (fossil resin) from the English Wealden, Isle of Wight, southern England, by pyrolysis-gas chromatography-mass spectrometry (Py-GC-MS), indicate a terpene distribution dominated by abietane- and labdane-type terpenes. Similar distributions are observed in some species of the extant family  Cheirolepidiaceae. Alvin et al. [Pseudofrenolopsis parceramosa, creating stands wherein Brachyphyllum obesum grew beneath the canopy. Infrequent examples of other taxa, including species assigned to the Pinaceae, Araucariceae, and Taxodiaceae (now considered part of the Cupressaceae), have also been reported in the Wealden [The Isle of Wight, off the south coast of England, is well known for rich lower Cretaceous (Barremian) fossil beds. In addition to numerous fossil fauna, (the Isle of Wight is widely recognized as one of the most important dinosaur fossil sites in the world), extensive floral remains have also been reported. The paleoenvironment of these deposits has been characterized by Insole and Hutt  as semi-n et al.  further  Wealden ,4,5, altCupressaceae, Araucariaceae, or Taxodiaceae. However, spectroscopic analyses of complex mixtures such as resins provide only a broad "fingerprint" and are, therefore, significantly less reliable than detailed molecular level characterization for chemotaxonomic purposes. The objective of this work was to attempt to determine possible paleobotanical sources of these ambers by using Pyrolysis-gas chromatography-mass spectrometry (Py-GC-MS) analyses.Almost all modern conifers produce resinous exudates. In extant species, these resins are dominated by di- tri- and/or tetracyclic diterpenes. Mono and sesquiterpenoids are also common constituents, and triterpenoids are present in some cases , but thepy = 300 or 480°C to differentiate occluded volatile terpenes and macromolecular materials. Multiple analyses of individual blebs were performed and multiple discrete amber blebs were characterized to ensure that data generated are representative and to exclude the possibility of multiple discrete resins sources. Individual analytes are identified based on comparison of MS data with literature [Samples of amber from the Isle of Wight were obtained by request from the Dinosaur Isle Museum, Isle of Wight. Py-GC-MS analyses of the amber were performed as previously described . Pyrolytterature  and librpy= 480°C) of Isle of Wight amber are illustrated in Figure The results of Py-GC-MS analysis , 18-nor dehydroabietane (9) and lesser amounts of analogous and isomeric products. Small amounts of bicyclic products (5 and 6) and related decarboxylation products (2), characteristic of regular polylabdanoids -15, are py = 300°C is indistinguishable from that observed in Figure The distribution of intact diterpenoids observed in experiments carried out at TPrevious reports of analyses of Cretaceous ambers contain familiar, multi-class terpene distributions ,16,17 anPinaceae [Pinaceae resins are usually predominated by abietanoic acids and lack phenolic diterpenes such as ferruginol or sugiol [Pinaceae resins are also marked by an absence of tetracyclic terpenoids, e.g. kaurane or phyllocladane [Labdanoid- and abietane-type diterpenoids are common constituents of the resins of many extant conifer families but typically occur in conjunction with a variety of other types of diterpenoids. In modern resins, the exclusive presence of labdanoid- and abietane-type diterpenoids is an indicator of the Pinaceae ,18-20. Pr sugiol . These oocladane , also coPinaceae. This assignment is supported by the minor presence of an early pinaceous species (Pityites solmsii (Seward) Seward) within the Wealdon deposits [By analogy with extant resins the observed distribution of diterpenes in these samples suggests a paleobotanical affinity with the deposits .Cheirolepidiace were by far the dominant conifers contributing to these deposits. Phylogenetic relationships between the Cheirolepidiaceae and extant conifer families are uncertain [Cheirolepidiace has been described [Frenelopsis alata has been reported [Frenelopsis. The genera of Cheirolepidiaceae present in the Isle of Wight deposits are reported to be Pseudofrenelopsis and Brachyphyllum. Despite the similarity of the names assigned to these genera (Frenelopsis and Pseudofrenelopsis), these are distinct taxa and therefore, these data do not preclude the possibility that the resin chemistry of the Cheirolepidiaceae genera present in the Isle of Wight deposits may have been similar to the resin chemistry of the extant Pinaceae. Hence, the lack of geochemical data, as well as the dominance of the Cheirolepidiaceae within these deposits, precludes a prioi exclusion of this family as a potential source of these samples. Therefore, in the absence of additional data, the Cheirolepidiaceae must be included as a possible source for the samples characterized in the present study.However, macrofossil evidence indicates that species belonging to the ncertain . To datencertain  and no rescribed . Data dereported , showingPinaceae, the lack of geochemical data for the dominant conifers in the deposits, the Cheirolepidiaceae, precludes the exclusion of this family as a possible source of these samples. It is also not unreasonable to suggest that the Pinaceae may be under represented in the fossil record or that Pityites solmsii (Seward) Seward, the only well represented pinaceous species from the Isle of Wight, may have been a copious resin producer in the environment. Therefore, until clear data concerning the resin chemistry of the Cheirolepidiaceae is presented, the distribution presented here is equivocally assignable to either family. This work has demonstrated the use of resin chemistry in the Early Cretaceous, and these resins are the oldest resins to date to yield useful chemosystematic data.Py-GC-MS analyses of early Cretaceous resin from the Isle of Wight, southern England, indicate that these resins are dominated nearly exclusively by abietane-type and labdanoid-type diterpenes. While this distribution provides a compelling argument for the assignment of these samples to the ensuring that the embedded directory structure is preserved. Once uncompressed, simply open Index.html. Javascript must be enabled in your web browser in order to fully access these files. These files will also be available on line via the Geochemical Transactions web site in the near future.GC-MS data for Isle of Wight amber. Interactive HTML version of data for Figures Click here for file


Low-level exposure to BPA has been shown to cause endocrine disruption in animal experiments, resulting in abnormal development of the prostate and mammary glands, among other adverse outcomes. Interpreting these studies with regard to human health has generated substantial debate, one heightened by growing awareness of the widespread nature of BPA exposure. In this report, researchers describe evidence of substantial exposure to BPA and other potential endocrine disruptors through medical treatment of premature infants EHP 113:1222–1225 (2005)], urine samples were collected from 54 premature infants in neonatal intensive care units at two institutions. The infants required medical interventions such as ventilation, enteral feeding, parenteral feeding, and indwelling catheterization. Some of the medical devices used in these procedures contained the plasticizer di(2-ethylhexyl) phthalate (DEHP), and urine sample analysis revealed that concentrations of DEHP metabolites correlated with the relative intensity  of medical device use—that is, the variety, invasiveness, and duration of the procedure(s) that each infant underwent.In an earlier study by the same group [In the current study, the team used some of those same urine samples to assess exposure to several other potential endocrine disruptors, including BPA, the antimicrobial triclosan, the preservatives methyl paraben and propyl paraben , and benzophenone-3, a sunscreen agent. For each chemical, urinary concentrations of the free (unmetabolized) and total  compounds were measured.The detection of BPA and both parabens in the urine of all the samples analyzed suggested that all the infants had been exposed to those chemicals. Benzophenone-3 was detected in the urine of all but 2 infants, whereas triclosan was detected in only 8 infants. Urinary concentrations of BPA correlated with those of DEHP, suggesting a common pathway of exposure. Of the chemicals assessed in the current study, only BPA correlated significantly with the intensity of medical device use, although the authors have no information about whether or how BPA is used in these devices.The median urinary BPA concentration in these infants was almost 10 times higher than levels reported elsewhere for 6- to 11-year-old children in the general population. The fact that more than 90% of the BPA was conjugated suggests that premature infants are able to metabolize the compound even though metabolic pathways typically do not function at an adult level for some months after birth. The authors suggest that, given concerns over BPA toxicity and the demonstrated exposure, use of BPA-free products may be justified in this developmentally vulnerable population.