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PubMed2005

Virtual colonoscopy for colorectal cancer screening: current status.

Computed tomography colonography (CTC) (also known as 'virtual colonoscopy') is a noninvasive method of imaging the colon using helical CT. Although CTC has been shown to be useful for certain clinical indications, it has not yet been endorsed as a colorectal cancer screening test. The purpose of this article is to review the current status of CTC for colorectal cancer screening. CTC is an accurate method to detect colonic polyps and to select patients who would benefit from colonoscopy. The major advantages of CTC over conventional colonography include its relatively low risk and greater tolerance by patients. In this article, the CTC procedure and results of clinical trials are reviewed, as well as potential pitfalls related to CTC performance and interpretation. Finally, radiation dose, the discovery of incidental extracolonic findings with CTC, bowel preparation methods, and computer-aided diagnosis are addressed.

Colonic Neoplasms↗
PubMed1999

Virtual combinatorial syntheses and computational screening of new potential anti-herpes compounds.

The activity of new anti-HSV-1 chemical structures, designed by virtual combinatorial chemical synthesis and selected by a computational screening, is determined by an in vitro assay. A virtual library of phenol esters and anilides was formed from two databases of building blocks: one with carbonyl fragments and the other containing both substituted phenoxy and phenylamino fragments. The library of virtually assembled compounds was computationally screened, and those compounds which were selected by our mathematical model as active ones were finally synthesized and tested. Our antiviral activity model is a "tandem" of four linear functions of topological graph-theoretical descriptors. A given chemical structure was selected as active if it satisfies every discriminant equation in that model. The final result was that five new structures were selected, synthesized, and tested: all of them demonstrated activity, and three showed appreciable anti-HSV-1 activity, with IC(50) values of 0.9 microM. The same model, applied to a database of known compounds, has identified the anti-herpes activity of the following compounds: 3,5-dimethyl-4-nitroisoxazole, nitrofurantoin, 1-(pyrrolidinocarbonylmethyl)piperazine, nebularine, cordycepin, adipic acid, thymidine, alpha-thymidine, inosine, 2, 4-diamino-6-(hydroxymethyl)pteridine, 7-(carboxymethoxy)-4-methylcoumarin, 5-methylcytidine, and others that showed less activity.

Anilides↗
PubMed2006

Digitized pathology: theory and experiences in automated tissue-based virtual diagnosis.

AIMS: To describe the theory and develop an automated virtual slide screening system. Theoretical considerations. Tissue-based diagnosis separates into (a) sampling procedure to allocate the slide area containing diagnostic information, and (b) evaluation of diagnosis from the selected area. Nyquist's theorem broadly applied in acoustics, serves to presetting the sampling accuracy. Tissue-based diagnosis relies on two different information systems: (a) texture, and (b) object information. Texture information can be derived by recursive formulas without image segmentation. Object information requires image segmentation and feature extraction. Both algorithms complete another to a "self-learning" classification system. METHODS: Non-overlapping compartments of the original virtual slide (image) are chosen at random with predefined error-rate (Nyquist's theorem). The standardized image compartments are subject for texture and object analysis. The recursive formula of texture analysis computes median gray values and local noise distribution. Object analysis includes automated measurements of immunohistochemically stained slides. The computations performed at different magnifications (x 2, x 4.5, x 10, x 20, x 40) are subject to multivariate statistically analysis and diagnosis classification. RESULTS: A total of 808 lung cancer cases of diagnoses groups: cohort (1) normal lung (318 cases) - cancer (490 cases); cancer subdivided: cohort (2) small cell lung cancer (10 cases) - non-small cell lung cancer (480 cases); non-small cell lung cancer subdivided: cohort (3) squamous cell carcinoma (318 cases) - adenocarcinoma (194 cases) - large cell carcinoma (70 cases) was analyzed. Cohorts (1) and (2) were classified correctly in 100%, cohort (3) in more than 95%. The selected area can be limited to 10% of the original image without increased error rate. A second approach included 233 breast tissue cases (105 normal, 128 breast carcinomas) and 88 lung tissue cases (58 normal, 38 cancer). Texture analysis revealed a correct classification with only 10 training set cases in >92% for both, breast and lung tissue. CONCLUSIONS: The developed system is a fast and reliable procedure to fulfill all requirements for an automated "pre-screening" of virtual slides in tissue-based diagnosis.

Algorithms↗
PubMed2002

Colorectal cancer screening: the potential role of virtual colonoscopy.

Virtual colonoscopy is a promising new technique that combines rapid spiral CT scanning of the abdomen with advanced computer programs capable of re-creating two- and three-dimensional views of the colon and rectum. Recent studies comparing this method with conventional colonoscopy show that virtual colonoscopy already is more accurate than barium enema X-ray studies for the detection of colorectal polyps, and that it approaches the accuracy of colonoscopy for diagnosing advanced lesions. Before virtual colonoscopy can be promoted for population-based screening for colorectal cancer, a number of issues discussed in this review need to be addressed. These include questions of accuracy, availability, acceptability, and cost-effectiveness.

Colonography, Computed Tomographic↗
PubMed2005

Druggability of SCF ubiquitin ligase-protein interfaces.

The unique mechanism of the SCF ubiquitin ligase poses a challenge to drug discovery. A central enzymatic small molecule-binding active site is not evident in this multisubunit protein enzyme, as is the case with kinases or proteases. Instead, the SCF ligase seems to accomplish ubiquitylation through a series of cooperative movements dependent on the protein interfaces between its components and its substrate. Activity-modulating small molecules, therefore, need to interact with these protein interfaces. The three-dimensional structure of these interfaces may be the key asset in determining their suitability for small molecule binding. Computational tools and a systematic approach described in detail here can assess the "druggability" of an SCF ligase before the investment of effort in high-throughput screening (HTS), structure-based drug design (SBBD), or virtual library screening (VLS).

Binding Sites↗
PubMedDate not supplied

Systematic hybrid LOH: a new method to reduce false positives and negatives during screening of yeast gene deletion libraries.

We have developed a new method, systematic hybrid loss of heterozygosity, to facilitate genomic screens utilizing the yeast gene deletion library. Screening is performed using hybrid diploid strains produced through mating the library haploids with strains from a different genetic background, to minimize the contribution of unpredicted recessive genetic factors present in the individual library strains. We utilize a set of strains where each contains a conditional centromere construct on one of the 16 yeast chromosomes that allows the destabilization and selectable loss of that chromosome. After mating a library gene deletion haploid to such a conditional centromere strain, which corresponds to the chromosome carrying the gene deletion, loss of heterozygosity (LOH) at the gene deletion locus can be generated in these otherwise hybrid diploids. The use of hybrid diploid strains permits complementation of any spurious recessive mutations in the library strain, facilitating attribution of the observed phenotype to the documented gene deletion and dramatically reducing false positive results commonly obtained in library screens. The systematic hybrid LOH method can be applied to virtually any screen utilizing the yeast non-essential gene deletion library and is particularly useful for screens requiring the introduction of a genetic assay into the library strains.

Bacterial Proteins↗
PubMed2005

Colon polyps and cancer.

The role of endoscopy, in particular colonoscopy, clearly is paramount in the screening, diagnosis, and prevention of colorectal cancer. In preparation for writing this "state-of-the-art" review on colon polyps and cancer, a PubMed literature search linking the topic with endoscopy yielded an enormous number of papers published in peer-reviewed journals just in the past 12 months. I have selected a few of these to highlight that I believe are most germane to current issues of risk stratification, screening and surveillance, prevention, and the premalignant potential of different types of adenomas detected by endoscopy. Several of these papers address the advantages and limitations of direct colonoscopy screening for colorectal neoplasia, and discuss the emerging role of virtual colonoscopy screening.

Colonic Neoplasms↗
PubMed2001

Differing attitudes toward virtual and conventional colonoscopy for colorectal cancer screening: surveys among primary care physicians and potential patients.

OBJECTIVES: To investigate attitudes among primary care physicians and potential patients concerning "virtual" and conventional colonoscopy for colorectal cancer screening. METHODS: We sent 1000 questionnaires to primary care physicians by electronic or postal mail and administered 400 to potential patients. Questionnaires contained progressively detailed information about the tests and asked for choices based on information presented. RESULTS: One hundred eight-eight primary care physicians and 323 potential patients were included. Results indicated the following: 76.6% of potential patients and 47.3% of physicians initially preferred virtual colonoscopy because of its noninvasive nature; 23.6% of potential patients and 52.9% of physicians valued the ability of conventional colonoscopy to visualize the mucosa directly; and 67.4% of potential patients and 51.6% of physicians preferred virtual colonoscopy because it does not require sedation. Considering all information, most potential patients preferred virtual to conventional colonoscopy (60.2% vs 25.7%), whereas more physicians preferred conventional to virtual colonoscopy (44.9% vs 30.3%). Additionally, 82.3% of potential patients would comply more with recommendations for colorectal cancer screening, and 61.7% of physicians would refer more patients for screening, if virtual colonoscopy was available. CONCLUSIONS: Potential patients preferred virtual to conventional colonoscopy, whereas physicians favored conventional colonoscopy. Physicians placed more importance on the ability of conventional colonoscopy to visualize the mucosa directly, the opportunity for therapy, and cost. Potential patients were more encouraged than physicians by the availability of virtual colonoscopy for improving participation in colorectal cancer screening.

Colonoscopy↗
PubMed2002

The Internet in dentistry--bringing world class education to your home.

The Internet can provide far greater levels of interactivity and therefore the potential for a greatly improved learning experience when compared with traditional educational media. As an educational medium, interactive streaming video over the internet has the potential to improve standards of dental health and contribute to the development of more universal standards of dental care around the world. The Virtual Auditorium format uses streaming video, audio and presentation of single PowerPoint or dual projection PowerPoint or 35mm slides to allow users to view an entire lecture presentation on their computer screens. The Virtual Auditorium as an alternative means of seeing keynote speakers from major dental meetings, is gaining in popularity and may soon be a standard facility linked to major international conferences.

Education, Dental↗
PubMed1985

The impact of screening on the incidence of cervical cancer in England and Wales.

Age-specific incidence curves for clinical cancer of the cervix in England and Wales show progressive changes over the period 1963-1978; in particular, a large reduction in incidence is seen in the age group 35-54. Since screening on any scale began in the early 1960s, we have investigated how much of this reduction in incidence in the middle age range can be attributed to detection of pre-invasive disease. Data on registrations of in-situ cancer have been used to estimate the patterns that might have been observed in the absence of screening. The results indicate clear cohort effects on incidence, with rising rates in the generations born 1906-1921 and since 1931, with a fall in the decade between. In addition to this, screening has probably led to a substantial reduction in the number of cases of clinical cancer in women aged 35-54, but has had little effect over the age of 60 where virtually no screening has been performed. Below age 35 the observed increase in incidence may be considerably less than it would have been in the absence of screening.

Adult↗
PubMed2003

Colorectal cancer screening and surveillance: clinical guidelines and rationale-Update based on new evidence.

We have updated guidelines for screening for colorectal cancer. The original guidelines were prepared by a panel convened by the U.S. Agency for Health Care Policy and Research and published in 1997 under the sponsorship of a consortium of gastroenterology societies. Since then, much has changed, both in the research rature and in the clinical context. The present report summarizes new developments in this field and suggests how they should change practice. As with the previous version, these guidelines offer screening options and encourage the physician and patient to decide together which is the best approach for them. The guidelines also take into account not only the effectiveness of screening but also the risks, inconvenience, and cost of the various approaches. These guidelines differ from those published in 1997 in several ways: we recommend against rehydrating fecal occult blood tests; the screening interval for double contrast barium enema has been shortened to 5 years; colonoscopy is the preferred test for the diagnostic investigation of patients with findings on screening and for screening patients with a family history of hereditary nonpolyposis colorectal cancer; recommendations for people with a family history of colorectal cancer make greater use of risk stratification; and guidelines for genetic testing are included. Guidelines for surveillance are also included. Follow-up of postpolypectomy patients relies now on colonoscopy, and the first follow-up examination has been lengthened from 3 to 5 years for low-risk patients. If this were adopted nationally, surveillance resources could be shifted to screening and diagnosis. Promising new screening tests (virtual colonoscopy and tests for altered DNA in stool) are in development but are not yet ready for use outside of research studies. Despite a consensus among expert groups on the effectiveness of screening for colorectal cancer, screening rates remain low. Improvement depends on changes in patients' attitudes, physicians' behaviors, insurance coverage, and the surveillance and reminder systems necessary to support screening programs.

Colorectal Neoplasms↗
PubMed2004

PREDICT modeling and in-silico screening for G-protein coupled receptors.

G-protein coupled receptors (GPCRs) are a major group of drug targets for which only one x-ray structure is known (the nondrugable rhodopsin), limiting the application of structure-based drug discovery to GPCRs. In this paper we present the details of PREDICT, a new algorithmic approach for modeling the 3D structure of GPCRs without relying on homology to rhodopsin. PREDICT, which focuses on the transmembrane domain of GPCRs, starts from the primary sequence of the receptor, simultaneously optimizing multiple 'decoy' conformations of the protein in order to find its most stable structure, culminating in a virtual receptor-ligand complex. In this paper we present a comprehensive analysis of three PREDICT models for the dopamine D2, neurokinin NK1, and neuropeptide Y Y1 receptors. A shorter discussion of the CCR3 receptor model is also included. All models were found to be in good agreement with a large body of experimental data. The quality of the PREDICT models, at least for drug discovery purposes, was evaluated by their successful utilization in in-silico screening. Virtual screening using all three PREDICT models yielded enrichment factors 9-fold to 44-fold better than random screening. Namely, the PREDICT models can be used to identify active small-molecule ligands embedded in large compound libraries with an efficiency comparable to that obtained using crystal structures for non-GPCR targets.

Algorithms↗
PubMed2003

Comparative study of several algorithms for flexible ligand docking.

We have performed a comparative assessment of several programs for flexible molecular docking: DOCK 4.0, FlexX 1.8, AutoDock 3.0, GOLD 1.2 and ICM 2.8. This was accomplished using two different studies: docking experiments on a data set of 37 protein-ligand complexes and screening a library containing 10,037 entries against 11 different proteins. The docking accuracy of the methods was judged based on the corresponding rank-one solutions. We have found that the fraction of molecules docked with acceptable accuracy is 0.47, 0.31, 0.35, 0.52 and 0.93 for, respectively, AutoDock, DOCK, FlexX, GOLD and ICM. Thus ICM provided the highest accuracy in ligand docking against these receptors. The results from the other programs are found to be less accurate and of approximately the same quality. A speed comparison demonstrated that FlexX was the fastest and AutoDock was the slowest among the tested docking programs. The database screening was performed using DOCK, FlexX and ICM. ICM was able to identify the original ligands within the top 1% of the total library in 17 cases. The corresponding number for DOCK and FlexX was 7 and 8, respectively. We have estimated that in virtual database screening, 50% of the potentially active compounds will be found among approximately 1.5% of the top scoring solutions found with ICM and among approximately 9% of the top scoring solutions produced by DOCK and FlexX.

Algorithms↗