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     

Growth of Cephalotaxus harringtonia plant-cell cultures

Summary Cell cultures of Cephalotaxus harringtonia were examined to characterize growth kinetics. The requirement for an undefined medium supplement (coconut water) was eliminated by maintaining high cell concentrations in semicontinuous and batch growth. Sucrose fed to batch-cultured cells was completely hydrolyzed and a diauxic growth pattern was observed corresponding to first glucose and then fructose uptake. Examination of increases in cell concentrations on the basis of fresh and dry weight showed that a substantial lag period existed between the initiation of substrate uptake and increases in cell volume. Specific growth rates were highest during periods of glucose uptake, but cell yields were comparable for the two sugars. In contrast, studies with glucose or fructose as the sole carbon source indicated that cell yields were significantly lower with fructose but specific growth rates were comparable for the two sugars.Offprint requests to: P. J. Westgate     

Visualization of planar drug intercalations in B-DNA.

A computerized linked-atom modeling system was developed to examine the stereochemical requirements for intercalation of planar drugs into DNA. All classes of conformational possibilities for extending the polynucleotide backbone were examined for their ability to accommodate insertion of a drug into a base-paired region of DNA compatible with adjacent regions of B-DNA while stacking interactions, steric strain and non-bonded interatomic contacts were optimised. One conformation was found which proved superior to all others in ability to satisfy these criteria: an extension of the backbone by characteristic changes in two torsion angles to trans values, plus a change in one sugar puckering to C3'-endo to relieve strain in an adjacent residue. The turn angle distributed over three polynucleotides for this most general mode of intercalation is 90 degrees, equivalent to a helical unwinding of -18 degrees for B-DNA.     

Atomic coordinates for ferricytochrome c2 of Rhodospirillum rubrum

Atomic coordinates and backbone torsion angles are tabulated for ferricytochrome $\text{c}{}_2$ of $\text{Rhodospirillum rubrum}$.     

Dihydrofolate reductase from Lactobacillus casei. Stereochemistry of NADPH binding.

The NADPH molecule binds to dihydrofolate reductase in an extended conformation. Several of the individual dihedral angles, especially in the adenine mononucleotide portion of the coenzyme, differ from their minimum energy conformations. The ribose phosphate portions of the coenzyme are involved in numerous specific hydrogen-bonded and charge-charge interactions. The adenine ring resides in an apparently nonspecific hydrophobic cleft and the nicotinamide ring is bound within an intricately constructed cavity, one wall of which includes the pyrazine ring of bound methotrexate. Two rather extended loops (residues 10 to 24 and 117 to 135) connecting beta A to alpha B and beta F to beta G, respectively, move 2 to 3 A when NADPH binds to dihydrofolate reductase. No overall structural homology is evident between the dinucleotide binding domains of dihydrofolate reductase on the one hand and the four NAD+-dependent dehydrogenases of known structure on the other. However, binding does occur in both cases at the carboxyl edge of a region of parallel beta sheet flanked by a pair of alpha helices.     

An Integrated Case Study for Evaluating the Impacts of an Oil Refinery Effluent on Aquatic Biota in the Delaware River: Sediment Quality Triad Studies

Triad studies consisting of chemical characterizations in sediment, sediment toxicity testing, and benthic community assessments were used to determine the impacts of Motiva Enterprises oil refinery effluent [primarily polynuclear aromatic hydorcarbons (PAHs)] on aquatic biota in the Delaware River. Triad studies were conducted at 15 near-field, mid-field, and far-field sites near the Refinery in the Delaware River during the spring and summer of 2001 and 2002. Fingerprinting analysis showed that Motiva-related PAHs may be present at four near-field sites. A summary of all Triad data by site for 2001 shows a strong case for contaminant-induced degradation at one near-field site in the discharge canal of the Refinery and two far-field sites as all three lines of evidence suggest impairment. Stressful conditions for benthic communities at the near-field site include elevated temperature conditions and various pesticides (Dieldrin, 4,4′-DDD and 4,4′-DDT). Toxicity at the near-field site may also be related to the presence of pesticides exceeding sediment quality guidelines. Due to exceedances of individual Effects Range Low (ERL) guidelines for two individual PAHs, the Motiva effluent cannot be eliminated as a potential stressor at the near-field site during the summer of 2001. A summary of Triad data for the 15 Delaware River sites sampled in 2002 shows only one mid-field site where all three lines of evidence suggest impairment. Toxicity and benthic community impairment at this mid-field site may be related to PCBs and low molecular weight PAHs. Three individual PAH ERL values were exceeded at three near-field sites in 2002. The source of these PAHs is a combination of both background signature and the Motiva effluent. Multivariate analysis, using a weight of evidence approach, is used to address ecological effects of the Motiva effluent in more detail in Alden et al. (2005) Alden, R W III, Hall, L W JrDauer, D M. 2005. An integrated case study for evaluating the impacts of an oil refinery effluent on aquatic biota in the Delaware River: Integration and analysis of study components. Hum Ecol Risk Assess, 11: 879–936.  [Google Scholar].     

Testing paradigm for prediction of development-limiting barriers and human drug toxicity

The financial investment grows exponentially as a new chemical entity advances through each stage of discovery and development. The opportunity exists for the modern toxicologist to significantly impact expenditures by the early prediction of potential toxicity/side effect barriers to development by aggressive evaluation of development-limiting liabilities early in drug discovery. Improved efficiency in pharmaceutical research and development lies both in leveraging "best in class" technology and integration with pharmacologic activities during hit-to-lead and early lead optimization stages. To meet this challenge, a discovery assay by stage (DABS) paradigm should be adopted. The DABS clearly delineates to discovery project teams the timing and type of assay required for advancement of compounds to each subsequent level of discovery and development. An integrative core pathology function unifying Drug Safety Evaluation, Molecular Technologies and Clinical Research groups that effectively spans all phases of drug discovery and development is encouraged to drive the DABS. The ultimate goal of such improved efficiency being the accurate prediction of toxicity and side effects that would occur in development before commitment of the large prerequisite resource. Good justification of this approach is that every reduction of development attrition by 10% results in an estimated increase in net present value by $100 million.     

Hemorrhage-induced acute lung injury is TLR-4 dependent

Toll-like receptor 4 (TLR-4), initially identified as an LPS receptor, is critical to the signaling of a variety of danger signals, including heat shock protein 60, fibrinogen, and fibronectin. Recent data also suggest that TLR-4 plays a role in determining survival in both endotoxemia and hemorrhagic shock. We hypothesized that a functional TLR-4 would be required for hemorrhage and endotoxin-induced acute lung injury. Hemorrhage- and endotoxin-induced lung TNF-alpha mRNA and protein production, neutrophil accumulation, and protein permeability were dependent on a functional TLR-4. Hemorrhage-induced nuclear factor (NF)-kappaB activation was independent of functional TLR-4, whereas endotoxin-induced activation of NF-kappaB requires a functional TLR-4 for full response. Therefore, we conclude that 1) hemorrhage-induced acute lung injury is TLR-4 dependent and 2) hemorrhage has a different and distinct TLR-4-dependent intracellular activation mechanism compared with endotoxemia.