Progress and challenges in screening for early detection of ovarian cancer

Ovarian cancer is characterize by few early symptoms, presentation at an advanced stage, and poor survival. As a result, it is the most frequent cause of death from gynecological cancer. During the last decade, a research effort has been directed toward improving outcomes for ovarian cancer by screening for preclinical, early stage disease using both imaging techniques and serum markers. Numerous biomarkers have shown potential in samples from clinically diagnosed ovarian cancer patients, but few have been thoroughly assessed in preclinical disease and screening. The most thoroughly investigated biomarker in ovarian cancer screening is CA125. Prospective studies have demonstrated that both CA125 and transvaginal ultrasound can detect a significant proportion of preclinical ovarian cancers, and refinements in interpretation of results have improved sensitivity and reduced the false-positive rate of screening. There is preliminary evidence that screening can improve survival, but the impact of screening on mortality from ovarian cancer is still unclear. Prospective studies of screening are in progress in both the general population and high-risk population, including the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), a randomized trial involving 200,000 postmenopausal women designed to document the impact of screening on mortality. Recent advances in technology for the study of the serum proteome offer exciting opportunities for the identification of novel biomarkers or patterns of markers that will have greater sensitivity and lead time for preclinical disease than CA125. Considerable interest and controversy has been generated by initial results utilizing surface-enhanced laser desorption/ionization (SELDI) in ovarian cancer. There are challenging issues related to the design of studies to evaluate SELDI and other proteomic technology, as well as the reproducibility, sensitivity, and specificity of this new technology. Large serum banks such as that assembled in UKCTOCS, which contain preclinical samples from patients who later developed ovarian cancer and other disorders, provide a unique resource for carefully designed studies of proteomic technology. There is a sound basis for optimism that further developments in serum proteomic analysis will provide powerful methods for screening in ovarian cancer and many other diseases.     

Impact of NHS walk-in centres on the workload of other local healthcare providers: time series analysis

ObjectivesTo assess the impact of NHS walk-in centres on the workload of local accident and emergency departments, general practices, and out of hours services.DesignTime series analysis in walk-in centre sites with no-treatment control series in matched sites.SettingWalk-in centres and matched control towns without walk-in centres in England.Participants20 accident and emergency departments, 40 general practices, and 14 out of hours services within 3 km of a walk-in centre or the centre of a control town.ResultsA reduction in consultations at emergency departments (–175 (95% confidence interval –387 to 36) consultations per department per month) and general practices (–19.8 (−53.3 to 13.8) consultations per 1000 patients per month) close to walk-in centres became apparent, although these reductions were not statistically significant. Walk-in centres did not have any impact on consultations on out of hours services.ConclusionIt will be necessary to assess the impact of walk-in centres in a larger number of sites and over a prolonged period, to determine whether they reduce the demand on other local NHS providers.

What is already known on this topic

One of the objectives for NHS walk-in centres was to reduce demand on other NHS services, particularly general practitioners'' services and accident and emergency departmentsStudies of walk-in centres in North America have indicated that such centres do not reduce demand on other healthcare servicesStudies of minor injuries units in the United Kingdom (which have some similarities with walk-in centres) indicate that these units substitute mainly for consultations in accident and emergency departments

What this study adds

The data imply that walk-in centres may moderate the increasing demand on general practice and reduce the number of consultations in accident and emergency departmentsThe high level of background variability in consultation rates means that any impact of a walk-in centre is not statistically significantTo draw robust conclusions about the impact of walk-in centres on other health providers will require study of a large number of sites over an extended period of time     

Personal view. Is it reality or an illusion that liquid‐based cytology is better than conventional cervical smears?

Liquid-based cytology (LBC) has been heralded as the way forward for cervical screening, and as the answer to many of its problems. It is already used as a sole method of cell preparation in many private clinics in the UK. It is being used for colposcopy smears in many NHS clinics and is now being piloted for primary screening in three screening centres in England, as well as one in Scotland and one in Wales. LBC has been welcomed as a new technology because it deals with the problem of specimen adequacy at source, removing responsibility for slide preparation and fixation from the clinician or nurse. It provides uniformly well-fixed preparations that are free of inflammatory exudate and blood, and seem easier to screen than conventional smears. There are many articles in the world literature suggesting that LBC is more accurate than conventional screening, and it is thought likely to reduce the number of false negative tests. The main reasons for piloting LBC in the NHS Cervical Screening Programme (NHSCSP) lie in its potential for reducing screening times and for reducing the numbers of repeats for inadequate tests. LBC is expensive in terms of equipment, capital costs, maintenance, consumables, training, technical preparation time, transportation and disposal of liquid media. Its costs could be justified if they were offset by the money saved from reduced screening time and repeat tests, but only if its accuracy in terms of sensitivity and specificity were proven to be equal to or better than conventional cytology. Although that is generally held to be true by the public and medical profession alike, there is very little hard evidence to support it.     

Cervical screening in the UK and laboratory quality control in the context of the 2007 European guidelines

The first part of this article will provide an overview of cervical cancer screening in the UK during the years before, during and after the introduction of a highly successful centrally organised cervical screening programme in 1988: since then the incidence of invasive cervical cancer has fallen by more than 40%. Screening was introduced in a background of opportunistic screening with poor quality control during a period of time when risk of disease was increasing, which will be demonstrated by national registrations of carcinoma in situ as well as invasive cancer. The programme is still facing new challenges and has recently recorded falling screening coverage in younger women, the causes of which have yet to be established. Liquid-based cytology is in the process of being rolled out nationally but high-risk human papillomavirus testing has yet to be introduced into the National Health Service (NHS) programme. Lessons from our experience may be relevant to countries introducing and maintaining organised programmes elsewhere under similar circumstances. The second part of the article will consider laboratory quality control as practiced in the UK and as recommended in the second edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening. These evidence-based guidelines provide recommendations for organising and monitoring quality control as well as for introducing new technology and standardising terminology, which are equally relevant for new and existing programmes. Invasive cancer audit may highlight areas where procedures could be improved in any programme but also can also demonstrate the effectiveness of screening.     

Illuminating the host – How RNAi screens shed light on host-pathogen interactions

Over millions of years pathogens have coevolved with their respective hosts utilizing host cell functions for survival and replication. Despite remarkable progress in developing antibiotics and vaccination strategies in the last century, infectious diseases still remain a severe threat to human health. Meanwhile, genomic research offers a new era of data-generating platforms that will dramatically enhance our knowledge of pathogens and the diseases they cause. Improvements in gene knockdown studies by RNA interference (RNAi) combined with recent developments in instrumentation and image analysis enable the use of high-throughput screening approaches to elucidate host gene functions exploited by pathogens. Although only a few RNAi-based screens focusing on host genes have been reported so far, these studies have already uncovered hundreds of genes not previously known to be involved in pathogen infection. This review describes recent progress in RNAi screening approaches, highlighting both the limitations and the tremendous potential of RNAi-based screens for the identification of essential host cell factors during infection.     

Degradation of sodium polyglyoxylate,a non-persistent metal sequestrant,in laboratory ecosystems

Summary Detergent builders such as zeolites, silicates and most organic polymers present concerns to some because of their environmental persistence. Sodium polyglyoxylate (SPG), on the other hand, is classified as readily biodegradable in a variety of aerobic and anaerobic biodegradation screening tests because it is extensively mineralized. Its persistence, however, is dependent on its rate of chemical hydrolysis to sodium glyoxylate, which is in turn controlled by parameters such as pH, temperature, metal ions and end capping group. The time for SPG's degradation ranges from a few hours at pH 5 to a few weeks at pH 9. Even though SPG is more persistent at alkaline pH values, it is rendered less bioavailable via precipitation/adsorption mechanisms. SPG's removal from and degradation in practically all ecosystems indicates that it will not have a significant impact on the environment with widespread use.     

Is tuberculosis taken seriously in the United Kingdom?

Tuberculosis has been the subject of much concern in recent years. Notifications have increased, inadequacies in surveillance revealed, and policies for BCG immunisation and screening of immigrants questioned. Until recently the disease was given low priority in the United Kingdom. There is no overall strategic framework for tackling tuberculosis, and fears have been expressed about the future of local tuberculosis control programmes in the new market economy of the NHS. An action plan for tuberculosis within the context of a national programme is urgently required. Only then will a major impact on the incidence of the disease be seen.     

Flexible ligand-flexible protein docking in protein kinase systems

Quite a few reviews on molecular docking have already appeared. This mini-review focuses on methods that incorporate protein flexibility in docking rather than those that treat protein targets as rigid molecules. This is still a challenging problem but there are encouraging recent advances. These methods will be reviewed particularly in light of their applications to protein kinases and phosphatases. In addition to obtaining correct docking pose, recent developments on exploring docking pathways are also highlighted.     

Retrospective analysis of census data on general practitioners who qualified in South Asia: who will replace them as they retire?

ObjectivesTo determine the number and geographical distribution of general practitioners in the NHS who qualified medically in South Asia and to project their numbers as they retire.DesignRetrospective analysis of yearly data and projection of future trends.SettingEngland and Wales.SubjectsGeneral practitioners who qualified medically in the countries of Bangladesh, India, Pakistan, and Sri Lanka and who were practising in the NHS on 1 October 1992.Results4192 of 25 333 (16.5%) of all unrestricted general practitioners practising full time on 1 October 1992 qualified in South Asian medical schools. The proportion varied by health authority from 0.007% to 56.5%. Roughly two thirds who were practising in 1992 will have retired by 2007; in some health authorities this will represent a loss of one in four general practitioners. The practices that these doctors will leave seem to be in relatively deprived areas as measured by deprivation payments and a health authority measure of population need.ConclusionMany general practitioners who qualified in South Asian medical schools will retire within the next decade. The impact will vary greatly by health authority. Those health authorities with the greatest number of such doctors are in some of the most deprived areas in the United Kingdom and have experienced the most difficulty in filling vacancies. Various responses will be required by workforce planners to mitigate the impact of these retirements.

Key messages

• Currently, one in six general practitioners practising full time in the NHS qualified medically in a South Asian medical school; two thirds are likely to retire by 2007
• It is unlikely that doctors who qualify in South Asia will be a source of general practice recruitment in the future
• The posts from which South Asian qualifiers are retiring may be more difficult to fill because they are often in practices in areas of higher need
• There is extreme variation in the proportion of total general practitioners who are South Asian qualifiers; flexibility for policy responses should be maintained

     

Signaling protein networks as targets of new antineoplastic drugs

In-depth analysis of molecular regulatory networks in cancer holds the promise of improved knowledge of the pathophysiology of tumor cells so that it will become possible to design a detailed molecular tumor taxonomy. This knowledge will also offer new opportunities for the identification and validation of key molecular tumor targets to be exploited for novel therapeutic approaches. Some signaling proteins have already been identified as such, e.g. c-Myc, Cyclin D1, Bcl-XL, kinases and some nuclear receptors. This has led to the successful development of a few function-modulatory drugs (Glivec, SERM, Iressa), providing proof-of-principle of the validity of this approach. Further developments are likely to derive from "-omic" approaches, aimed at the understanding of signaling networks and of the mechanism of action of newfound lead molecules. High-throughput screening of small drug-like molecules from combinatorial chemical libraries or from microbial extracts will identify novel, "intelligent" drug candidates. An additional medicinal chemistry strategy (via 40-50 unit rosary-bead chains) has the potential to be much more effective than small molecules in interfering with protein-protein interactions. This may lead to considerably higher selectivity and effectiveness compared with historical approaches in drug discovery.     

One fungus, one name promotes progressive plant pathology

The robust and reliable identification of fungi underpins virtually every element of plant pathology, from disease diagnosis to studies of biology, management/control, quarantine and, even more recently, comparative genomics. Most plant diseases are caused by fungi, typically pleomorphic organisms, for which the taxonomy and, in particular, a dual nomenclature system have frustrated and confused practitioners of plant pathology. The emergence of DNA sequencing has revealed cryptic taxa and revolutionized our understanding of relationships in the fungi. The impacts on plant pathology at every level are already immense and will continue to grow rapidly as new DNA sequencing technologies continue to emerge. DNA sequence comparisons, used to resolve a dual nomenclature problem for the first time only 19 years ago, have made it possible to approach a natural classification for the fungi and to abandon the confusing dual nomenclature system. The journey to a one fungus, one name taxonomic reality has been long and arduous, but its time has come. This will inevitably have a positive impact on plant pathology, plant pathologists and future students of this hugely important discipline on which the world depends for food security and plant health in general. This contemporary review highlights the problems of a dual nomenclature, especially its impact on plant pathogenic fungi, and charts the road to a one fungus, one name system that is rapidly drawing near.     

Changes in incidence of and mortality from breast cancer in England and Wales since introduction of screening. United Kingdom Association of Cancer Registries.

OBJECTIVE--To assess the impact of the NHS breast screening programme on the incidence of and mortality from breast cancer. DESIGN--Comparison of age specific incidence and mortality before and after the introduction of screening in the late 1980s. SETTING--England and Wales. SUBJECTS--Women aged over 30 years. RESULTS--In 1992 the age standardised incidence of breast cancer was 40% higher than in 1979. After the introduction of screening in 1988 recorded incidence rates rose steeply in the screened age group (50-64 year olds) but not in others. In 1992 the rates levelled off at about 25% higher than in 1987. Total mortality from breast cancer has increased steadily since the 1950s; the rates increased earlier in the younger age groups. By the mid-1980s rates had begun to fall in the younger age groups; but total mortality was still among the highest in the world. Age standardised mortality in the 55-69 age group changed little during the first three years of screening but then fell steeply and in 1994 was 12% lower than in 1987. CONCLUSIONS--Since the introduction of screening there have been pronounced increases in recorded incidence in the screened age group. Cancer registries have an essential role in assessing screening programmes and cancer services. The steep decrease in mortality in 55-69 year olds which began three years after screening started is unlikely to be due to screening. The widespread adoption of treatment with tamoxifen during this period may be important. With the reduction in mortality already observed and the expected additional benefits from screening, the Health of the Nation target should be achieved.     

Transplantation tolerance: from phenomenon to mechanism

The term "transplantation tolerance" is used for a state when a histoincompatible graft, i.e. one from a genetically different donor, survives in a recipient in which it would have been rejected under normal circumstances. Transplantation tolerance was first experimentally induced in 1953 and since that time the mechanisms underlying this phenomenon have been analysed. Originally, attention was paid to passive mechanisms of transplantation tolerance more recently, active mechanisms of tolerance, have been discovered. The recognition of these regulatory mechanisms and the development of ability to manipulate them has already had and will continue to have increasing impact on aimed the immunoregulation in therapeutic transplantation.     

Protein kinases as targets for anti-parasitic chemotherapy

Parasitic protozoa infecting humans have a staggering impact on public health, especially in the developing world. Furthermore, several protozoan species are major pathogens of domestic animals and have a considerable impact on food production. In many instances, the parasites have developed resistance against available chemotherapeutic agents, making the search for alternative drugs a priority. In line with the current interest in protein kinases inhibitors as potential drugs against a variety of diseases, the possibility that protein kinases may represent targets for novel anti-parasitic agents is being explored. Research into parasite protein kinases has benefited greatly from genome and EST sequencing projects, with the genomes of a few species fully sequenced (notably that of the human malaria parasite Plasmodium falciparum) and several more under way. The overall picture that emerged from research in this area shows that the phylogenetic isolation of parasitic protozoa is reflected by atypical structural and functional properties of many of their protein kinase homologues. Likewise, evidence is emerging, which suggests that the organisation of some otherwise well-conserved signal transduction pathways is divergent in some parasitic species. The differences between protein kinases of a parasite and their homologues in its host cell suggest that specific inhibition of the former can be achieved. The development of anti-parasitic drugs based on protein kinase inhibition is being pursued following two avenues: one consists of screening chemical libraries on recombinant enzymes; several protein kinases from parasitic protozoa are now available for this approach. The second approach relies on the identification of the molecular targets of kinase inhibitors which display anti-parasitic properties. This has led to promising developments in a few instances, in particular regarding PKG as a drug target against Eimeria and Toxoplasma, and purvalanol B, a purine-based CDK inhibitor which appears to affect unexpected targets in several protozoan parasites. The recent resolution of the structure of a Plasmodium protein kinase complexed with small inhibitory molecules opens the way to a rational approach towards the design of anti-parasitic drugs based on kinase inhibition.     

Novel bioactive natural products from bacteria via bioprospecting,genome mining and metabolic engineering

For over seven decades, bacteria served as a valuable source of bioactive natural products some of which were eventually developed into drugs to treat infections, cancer and immune system-related diseases. Traditionally, novel compounds produced by bacteria were discovered via conventional bioprospecting based on isolation of potential producers and screening their extracts in a variety of bioassays. Over time, most of the natural products identifiable by this approach were discovered, and the pipeline for new drugs based on bacterially produced metabolites started to run dry. This mini-review highlights recent developments in bacterial bioprospecting for novel compounds that are based on several out-of-the-box approaches, including the following: (i) targeting bacterial species previously unknown to produce any bioactive natural products, (ii) exploring non-traditional environmental niches and methods for isolation of bacteria and (iii) various types of ‘genome mining’ aimed at unravelling genetic potential of bacteria to produce secondary metabolites. All these approaches have already yielded a number of novel bioactive compounds and, if used wisely, will soon revitalize drug discovery pipeline based on bacterial natural products.     

Systems biology, proteomics, and the future of health care: toward predictive, preventative, and personalized medicine

The emergence of systems biology is bringing forth a new set of challenges for advancing science and technology. Defining ways of studying biological systems on a global level, integrating large and disparate data types, and dealing with the infrastructural changes necessary to carry out systems biology, are just a few of the extraordinary tasks of this growing discipline. Despite these challenges, the impact of systems biology will be far-reaching, and significant progress has already been made. Moving forward, the issue of how to use systems biology to improve the health of individuals must be a priority. It is becoming increasingly apparent that the field of systems biology and one of its important disciplines, proteomics, will have a major role in creating a predictive, preventative, and personalized approach to medicine. In this review, we define systems biology, discuss the current capabilities of proteomics and highlight some of the necessary milestones for moving systems biology and proteomics into mainstream health care.     

DEFINING DYSKARYOSIS – THE BSCC CLASSIFICATION IN 2006

The terminology used for reporting cervical samples in the UK is the BSCC classification, which has evolved over many years. In 2002 the BSCC held a consensus conference to review the BSCC classification, with the intention of providing clearer results for women, improving concordance with other terminologies and facilitating consistency with new scientific developments and technologies. The consensus conference was well attended and robust. In the intervening years there have also been other further advances on morphometry, data on outcomes, data from EQA and other sources. Liquid Based cytology (LBC) has been implemented by the NHS CSP. All of these developments have impacted on the proposed classification, which will be presented in full. The term 'dyskaryosis' will be retained and several of the current reporting categories will be relatively unchanged, though additional information on LBC will be provided.
The major proposed changes are:
(1) A move to a single category of 'High Grade Dyskaryosis' to replace the existing categories of moderate and severe dyskaryosis.
(2) Sub-division of Borderline change into three categories.
Borderline change in glandular cells
Borderline change ?high grade
Borderline change, NOS
(3) The current grades of Mild Dyskaryosis and Borderline change with Koilocytosis to be merged.
Details of these proposals, together with illustrations and the evidence base for change will be presented.     

Prostate cancer: epidemiology, screening, and biomarkers

Carcinoma of the prostate continues to be a major health problem in the United States. Beginning in 1988, a marked increase in detection of prostate cancer occurred due to the development of a test for prostate-specific antigen (PSA). Controversy exists, however, about the value of PSA as a tumor marker. Although it has prognostic significance both before and after definitive therapy for prostate cancer, it is unclear whether routine PSA screening will translate into a survival advantage for patients. Because of its limitations, PSA may not ultimately be a good enough marker to be used as a screening tool. However, molecular biology has led to a rapid rise in the number of potential new prostate tumor markers, which may eventually overcome the weaknesses of PSA. Considerable progress has occurred in the diagnosis and management of prostate cancer: more is understood about the risk factors for the disease, possible ways to prevent it, and new ways to diagnose and monitor it. These developments have already translated into better patient care, while also identifying where further improvements are needed.     

Outcomes of screening to prevent cancer: analysis of cumulative incidence of cervical abnormality and modelling of cases and deaths prevented

ObjectiveTo determine the frequency of different outcomes in women participating in cervical screening.DesignAnalysis of screening records from 348 419 women, and modelling of cases of cervical cancer and deaths with and without screening.SettingCervical screening programme in Bristol.ResultsFor every 10 000 women screened from 1976 to 1996, 1564 had abnormal cytology, 818 were investigated, and 543 had abnormal histology. One hundred and seventy six had persistent abnormality for two years or more. In the absence of screening 80 women would be expected to develop cancer of the cervix by 2011, of whom 25 would die. With screening 10 of these deaths would be avoided. Comparison of cumulative abnormality rates with numbers expected to develop cancer in the absence of screening suggests that at least 80% of high grade dyskaryosis and of high grade dysplasia would not progress to cancer. The lifetime risk of having abnormal cytology detected could be as high as 40% for women born since 1960.ConclusionsScreening is labour and resource intensive. It involves treatment for many women not destined to develop invasive cancer. The increased intervention rate for cervical abnormality in England is due to change in practice, not a cohort effect, and is probably the reason for the marked fall in incidence and mortality during the 1990s. For other cancers there is scope for major iatrogenic harm from screening because of invasive tests and treatments.

What is already known on this topic

Since the mid-1980s incidence of and mortality from cervical cancer in women born since the 1930s in England and Wales has fallen; screening is the most likely explanationFor each death prevented many women have to be screened and many are treated who would not have developed a problem

What this study adds

In the NHS cervical screening programme around 1000 women need to be screened for 35 years to prevent one deathOver 80% of women with high grade cervical intraepithelial neoplasia will not develop invasive cancer, but all need to be treatedFor each death prevented, over 150 women have an abnormal result, over 80 are referred for investigation, and over 50 have treatmentBefore the 1988 relaunch of screening with strict quality standards, for each death prevented there were 57 000 tests and 1955 women had abnormal results     

Valuable products from biotechnology of microalgae

The biotechnology of microalgae has gained considerable importance in recent decades. Applications range from simple biomass production for food and feed to valuable products for ecological applications. For most of these applications, the market is still developing and the biotechnological use of microalgae will extend into new areas. Considering the enormous biodiversity of microalgae and recent developments in genetic engineering, this group of organisms represents one of the most promising sources for new products and applications. With the development of sophisticated culture and screening techniques, microalgal biotechnology can already meet the high demands of both the food and pharmaceutical industries.By continuing the works and ideas of Dr. Gross, that he could not proceed by himself due a tragic fate in the year 2003, we will keep his place in future not only in the research community but also among all colleagues and other persons who knew him.