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PubMed2025

Histology-Based Virtual RNA Inference Identifies Pathways Associated With Metastasis Risk in Colorectal Cancer.

Colorectal cancer (CRC) remains a major health concern, with >150,000 new diagnoses and >50,000 deaths annually in the United States, underscoring an urgent need for improved screening, prognostication, disease management, and therapeutic approaches. The tumor microenvironment (TME)-comprising cancerous and immune cells interacting within the tumor's spatial architecture-plays a critical role in disease progression and treatment outcomes, reinforcing its importance as a prognostic marker for metastasis and recurrence risk. However, traditional methods for TME characterization, such as bulk transcriptomics and multiplex protein assays, lack sufficient spatial resolution. Although spatial transcriptomics (ST) allows for the high-resolution mapping of whole transcriptomes at near-cellular resolution, current ST technologies (eg, Visium and Xenium) are limited by high costs, low throughput, and issues with reproducibility, preventing their widespread application in large-scale molecular epidemiology studies. In this study, we refined and implemented virtual RNA inference (VRI) to derive ST-level molecular information directly from hematoxylin and eosin (H&E)-stained tissue images. Our VRI models were trained on the largest matched CRC ST data set to date, comprising 45 patients and >300,000 Visium spots from primary tumors. Using state-of-the-art deep learning models (UNI, ResNet-50, Vision Transformer, and Vision Mamba), we achieved a median Spearman's correlation coefficient of 0.546 between predicted and measured spot-level expression. As validation, VRI-derived gene signatures linked to specific tissue regions (tumor, interface, submucosa, stroma, serosa, muscularis, and inflammation) showed strong concordance with signatures generated via direct ST, and VRI performed accurately in estimating cell-type proportions spatially from H&E slides. In an expanded CRC cohort controlling for tumor invasiveness and clinical factors, we further identified VRI-derived gene signatures significantly associated with key prognostic outcomes, including metastasis status. Although certain tumor-related pathways are not fully captured by histology alone, our findings highlight the ability of VRI to infer a wide range of "histology-associated" biological pathways at near-cellular resolution without requiring ST profiling. Future efforts will extend this framework to expand TME phenotyping from standard H&E tissue images, with the potential to accelerate translational CRC research at scale.

Humans↗
PubMed1993

The role of receptor binding in drug discovery.

Radioligand receptor binding has been used extensively to identify and characterize a host of receptors and enzymes targeting virtually every therapeutic area. Many drug discovery programs have been based on the utilization of radioligand receptor binding technology to identify lead compounds which interact with receptors likely to be important in neuronal, immunological, gastrointestinal, and cardiovascular function/dysfunction. There are several obvious advantages to using in vitro receptor binding as a first level screen when compared to in vivo pharmacometric screens. Scientifically, the structure activity data generated in binding assays is a direct reflection of the ligand/receptor interaction minus the complications which result from secondary events, bioavailability, and pharmacodynamic issues. Technically, the binding studies require only a small amount of test compound (< or = 1 mg), while whole animal studies routinely need gram quantities. Similarly, only a small amount of tissue is required, compared with the cost of purchase and maintenance of live animals for in vivo screening. Supply and labor costs are drastically reduced due to the limited volume and test tube based technology of receptor binding. For these reasons receptor binding assays have been utilized with considerable success to discover site specific lead compounds in virtually every therapeutic area.

Animals↗
PubMed1996

Outbreak of acute hepatitis C following the use of anti-hepatitis C virus--screened intravenous immunoglobulin therapy.

BACKGROUND & AIMS: Hepatitis C virus (HCV) infection has been associated with intravenous (IV) immunoglobulin (Ig), and plasma donations used to prepare IV Ig are now screened to prevent transmission. Thirty-six patients from the United Kingdom received infusions from a batch of anti-HCV antibody-screened intravenous Ig (Gammagard; Baxter Healthcare Ltd., Thetford, Norfolk, England) that was associated with reports of acute hepatitis C outbreak in Europe. The aim of this study was to document the epidemiology of this outbreak. METHODS: Forty-six patients from the United Kingdom treated with Gammagard (34 exposed and 12 unexposed to the batch) returned epidemiological questionnaires. RESULTS: Eighty-two percent of the exposed patients (28 of 34) became positive for HCV RNA. Eighteen percent of the patients (6 of 34) who had infusions with this batch tested negative for HCV RNA, but 2 of the patients had abnormal liver function and subsequently seroconverted to anti-HCV antibody positive. Twenty-seven percent of the patients (9 of 34) developed jaundice, and 79% (27 of 34) had abnormal liver transferase levels. Virus isolates (n=21), including an isolate from the implicated batch, were genotype 1a and virtually identical by sequence analysis of the NS5 region, consistent with transmission from a single source. CONCLUSIONS: Hepatitis C infection can be transmitted by anti-HCV-screened IV Ig. Careful documentation of IV Ig batch numbers and regular biochemical monitoring is recommended for all IV Ig recipients.

Acute Disease↗
PubMed1998

A new probability formula for surveys to substantiate freedom from disease.

Surveys to substantiate freedom from disease are becoming increasingly important. This is due to the changes in rules governing international trade in animals and animal products, and to an increase in disease eradication and herd-level accreditation schemes. To provide the necessary assurances, these surveys must have a sound theoretical basis. Until now, most surveys have been based on the assumption that the screening test used was perfect (sensitivity and specificity both equal to one), and/or that the study population was infinite. Clearly, these assumptions are virtually always invalid. This paper presents a new formula that calculates the exact probability of detecting diseased animals, and considers both imperfect tests and finite population size. This formula is computationally inconvenient, and an approximation that is simpler to calculate is also presented. The use of these formulae for sample-size calculation and analysis of survey results is discussed. A computer program, 'FreeCalc', implementing the formulae is presented along with examples of sample size calculation for two different scenarios. These formulae and computer program enable the accurate calculation of survey sample-size requirements, and the precise analysis of survey results. As a result, survey costs can be minimised, and survey results will reliably provide the required level of proof.

Animal Diseases↗
PubMed1999

Virtual colonoscopy.

Virtual colonoscopy (VC) is an evolving technique that combines volume scanning and computer visualization methods to enable minimally invasive and effective colorectal cancer screening. Although VC offers significant clinical and public health advantages over conventional endoscopic screening, several issues confront VC's emergence into the medical marketplace.

Colonoscopy↗
PubMed2001

Computer assisted learning. A review.

Since 1980 the amount of medical information has doubled approximately every second year. This implies that oral health students as well as professionals need to manage the flow of information rationally, in order to learn how to undertake evidence-based decision-making for diagnosis and treatment in a given patient situation. Current research indicates that computer connected databases and computer assisted learning (CAL) may enhance learning and provide the clinician with information for decision-making when treating patients. Multimedia for CAL, which combines audio and visual data in an interactive form, has proved to be an effective tool in education. CAL may supplement and reinforce more traditional learning and create opportunities to illustrate clinical situations in an interactive way. CAL has the potential to help students develop skills and knowledge. Students, staff and professionals consider CAL stimulating and motivating. Students easily adapt to CAL although their current computer literacy is still low. New authoring tools make it easier for faculties to develop their own CAL software. In the future we will see more sophisticated software with virtual patients who can communicate and interact with the student in a very realistic way. The software will even "step out" from the screen and help the student with clinical procedures. However, at present CAL should not replace traditional education, but rather be used more as a supplement and for self-directed studies.

Attitude↗
PubMed2003

Use of virtual microscopy for didactic live-audience presentation in anatomic pathology.

Didactic presentations on the topic of anatomic pathology in front of a live audience have been largely dependent on the use of standard 2 x 2 inch projection slides (Kodachromes) of selected still images from the topic at hand. Because of the highly visual nature of the specialty of anatomic pathology, this method has had some serious limitations. With the advent of digital imaging techniques and the availability of new electronic software for the projection of images, new possibilities have become available for didactic presentations in anatomic pathology in front of a large, live audience. We describe a method whereby large digital images or "virtual slides" were produced from digitally scanned whole-mount sections of histologic glass slides and projected using a combination of PowerPoint (Microsoft Corp, Redmond, WA) and virtual microscopy in front of a live audience. To provide a seamless transition between the two presentation formats, the personal computer-based PowerPoint slides were hyperlinked to a browser-based virtual microscope viewer. The presenter, with the use of a mouse, was able to "move" the image of the scanned slide on the screen, to transition seamlessly among various magnifications, and to rapidly select from the whole-mount scanned slide among any areas of interest pertinent to the topic. Thus, the visual experience obtained by the audience simulated that of viewing a glass slide at a multi-headed microscope during a glass slide tutorial. Because this most closely approximates the experience of reviewing glass slides under the microscope for practicing pathologists, the educational experience of the presentation is greatly enhanced by the use of this technique. Also, this method permits making this type of presentation available to a much larger group of individuals in a live audience.

Computer-Assisted Instruction↗
PubMed2002

Colon polyps and cancer.

The superiority of colonoscopy to double-contrast barium enema in detecting neoplasia was finally demonstrated in 2000, but colonoscopic surveillance programs are still based on short-term observations and are mostly inadequate, despite the prospective design of the trials. The evaluation of the diagnostic accuracy of virtual colonoscopy is in progress, but its appropriate place in clinical gastroenterology has not yet been defined. There is now solid evidence that screening with fecal occult blood testing (FOBT) not only reduces the mortality from colorectal cancer, but also that the incidence is substantially reduced after removal of the precursor lesions. Feasibility studies for population screening are ongoing. A once-only sigmoidoscopy will probably not be an optimal method of screening, but may be added to a program with FOBT. Molecular stool screening is attractive, but still experimental. Colonoscopy is not attractive as an initial screening instrument, despite its high diagnostic accuracy, and should only be used for screening high-risk individuals. Genetic methods are playing an increasing role in defining prognostic markers for intestinal neoplasia, and it is recommended that information services should be established for the public. Chemopreventive studies have revealed that dietary fiber supplementation may not reduce the risk of adenomas; the opposite seems to be true for aspirin and non-aspirin NSAIDs, which are active in the early phase of carcinogenesis. New techniques for optimizing diagnostic and therapeutic colonoscopy have been introduced.

Colonic Neoplasms↗
PubMed2007

A comprehensive transposon mutant library of Francisella novicida, a bioweapon surrogate.

Francisella tularensis, the causative agent of tularemia, is one of the most infectious bacterial pathogens known and is a category A select agent. We created a sequence-defined, near-saturation transposon mutant library of F. tularensis novicida, a subspecies that causes a tularemia-like disease in rodents. The library consists of 16,508 unique insertions, an average of >9 insertions per gene, which is a coverage nearly twice that of the greatest previously achieved for any bacterial species. Insertions were recovered in 84% (1,490) of the predicted genes. To achieve high coverage, it was necessary to construct transposons carrying an endogenous Francisella promoter to drive expression of antibiotic resistance. An analysis of genes lacking (or with few) insertions identified nearly 400 candidate essential genes, most of which are likely to be required for growth on rich medium and which represent potential therapeutic targets. To facilitate genome-scale screening using the mutant collection, we assembled a sublibrary made up of two purified mutants per gene. The library provides a resource for virtually complete identification of genes involved in virulence and other nonessential processes.

Alleles↗
PubMed2003

Incidence of fragile X in 5,000 consecutive newborn males.

Fragile X syndrome (FXS) is the commonest cause of inherited mental retardation in males. Even though this affirmation is repeated in virtually all papers referring to FXS, the precise frequency of this syndrome in the general population is unknown. We present a general population screening analyzing an anonymous series of 5,000 consecutive newborn males from the neonatal screening program of the population of Catalonia in Spain. The aim of the study is to determine the incidence of FXS via a simple and economical methodology based on the nonamplification of the fragment containing the CGG repeats of the FRAXA locus in the samples carrying alleles over 52 repeats. From the initial 5,000 samples, 4,920 were in the normal range, 15 gave rise to bands with more than 52 repeats (11 corresponded to intermediate alleles and four premutated alleles). After further studies, two samples were considered to be carriers of full mutations. According to these results, the incidence of FXS affected newborn males is 1 in 2,466, and 1 in 1,233 males is a carrier of the premutation. We can deduce that 1 in 8,333 is an affected female with clinical manifestations and 1 in 411 will be a premutation carrier woman. Upon reviewing the literature, there seems to be variability in the frequencies found by the different groups. Therefore, given that our study is limited to the Catalan population in Spain, these results should be taken as valid for the Catalan region and should only be extrapolated to other populations with caution.

Fragile X Messenger Ribonucleoprotein 1↗
PubMed1992

Inhibitory effect of loratadine and clemastine on histamine release in human skin.

The inhibitory effect of the two H1 antagonists clemastine and loratadine on histamine release in human skin was studied in 15 volunteers. The antihistamines and placebo were administered orally (clemastine 2 mg twice a day, loratadine 10 mg once a day) for 5 days according to a double-blind, crossover design. Clemastine caused a significant sedation in comparison with placebo, whereas there was no difference between loratadine and placebo in this respect. After 5 days' medication, flare reaction was induced by intradermal injection of histamine and the histamine liberator compound 48/80. The antihistamine dosages were approximately equipotent and inhibited the flare response induced by histamine to about the same extent, whereas the flares induced by compound 48/80 were still more inhibited by both drugs. The results indicate that clemastine and loratadine not only inhibit histamine effects at H1 receptor level, but have additional suppressive effects, probably due to inhibition of mast cell degranulation. The simple, virtually noninvasive, in vivo technique described in this paper does not require chemical analysis of the released mediators and could be used to screen 'mast cell stabilizing' effects of various antihistamines.

Adolescent↗
PubMed2006

Improving synthetic efficiency using the computational prediction of biological activity.

A process has been developed whereby libraries of compounds for lead optimization can be synthesized and screened with greater efficiency using computational tools. In this method, analogues of a lead chemical structure are considered in the form of a virtual library. Less than 1/3 of the library is selected as a training set by clustering the compounds and choosing the centroid of each cluster. This training set is then used to generate a model using PLS regression upon the experimental values from that assay using 1D/2D descriptors. The model is applied to the remaining compounds (the test set) for which assay values are predicted and a rank ordering established. An example of this was a set of 169 PDE4 inhibitors. A predictive model was achieved using a training set of 52 compounds. When applied to the remaining 117 compounds this model allowed a rank ordering of these compounds for synthesis and testing. Selecting the top 33 compounds of the test set gives 78% of the compounds with the desired activity (hits) by synthesizing only 50% of the library, including the training set. Selecting the top 59 of the test set gives 97% of the hits from only 67% of the library. This process succeeds by avoiding two principal weaknesses of 2D descriptors: lack of interpretation and lack of extrapolation. Two principal assumptions of QSAR are shown to be unnecessary; removing descriptor redundancy does not improve fit and a predictive r2 greater than 0.5 is not necessary if rank-ordering is desired.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Epigenetic tumor markers in plasma and serum: biology and applications to molecular diagnosis and disease monitoring.

Circulating tumor DNA in plasma and serum has been demonstrated to reflect the biological characteristics of tumors, including the rates of apoptosis and necrosis. Aberrant promoter methylation has increasingly emerged as a fundamental molecular abnormality associated with loss of critical gene functions during carcinogenesis. This epigenetic inheritance has significant biological implications for early tumor initiation and cancer progression or metastasis formation. The promoter-region methylation is crucial in transcriptional silencing of tumor suppressor genes, DNA repair genes, and metastasis inhibitor genes, and is linked to the predisposition of genetic alterations of other cancer-associated genes. Of clinical relevance, epigenetic markers in plasma and serum have recently been established as specific and sensitive biomarkers for early and noninvasive screening, risk assessment, and monitoring of neoplastic diseases. A panel of epigenetic markers may possibly allow the detection of circulating tumor DNA in virtually all patients with different cancer types. Furthermore, the prognostic value of aberrant DNA methylation and therapeutic implications of demethylation of methylated genes could further improve the management of patients with different kinds of cancer.

Biomarkers, Tumor↗
PubMed2006

Concept and development of a computerized positioning of prosthetic teeth for complete dentures.

To date, CAD/CAM technology has made no noteworthy inroads into removable dentures. We want to present a new area of application for this in our study. Models of the maxilla and edentulous mandible were 3D scanned. The software detects and automatically reconstructs the reference structures that are anatomically important for the set-up of artificial teeth, such as the alveolar ridge centerlines and the interalveolar relations between the alveolar ridges. In a further step, the occlusal plane is semiautomatically defined and the front dental arch is designed. After these design features have been determined, artificial teeth are selected from a database and set up automatically. The dental technician can assess the esthetics and function of the suggested dental set-up on the computer screen and make slight corrections if necessary. Summarizing: The interplay of hardware and software components within on integrated solution including conversion of the "virtual" into a real positioning of prosthetic teeth is presented.

Alveolar Process↗
PubMed1982

Pathomorphological findings of a prenatally diagnosed thanatophoric dwarf.

A case of prenatally diagnosed thanatophoric dysplasia is presented. Other syndromes accompanied by chondrodysplastic tetramicromelia were excluded and diagnosis was based on the narrow thorax, secondary pulmonary hypoplasia and macrocephaly detected by ultrasound and on radiological findings of disturbances of bone formation. At the mother's request labour was induced and radiological, anatomic and histological examination of the newborn confirmed the prenatal diagnosis. By electron microscopy, large conspicuous, homogeneous intracytoplasmic, usually single vacuoles were found in virtually every chondrocyte. Attention is focused on the significant hydramnion which led to the suspicion of fetal malformation. The importance of routine ultrasound screening in pregnancy is emphasised, since such malformations can be detected as early as the midtrimester pregnancy. The use of such methods ensures better maternal care.

Adult↗
PubMed2002

Hereditary colorectal cancer: screening and management.

Colorectal cancer (CRC) affects approximately 6% of the US population, with equal distribution between men and women. It is hereditary in a high proportion of cases and is one of the most preventable cancers. Detection and removal of its precursor lesions, the adenomatous polyps, is the foundation of preventive strategies. However, once CRC is diagnosed, surgical resection is the only cure. The likelihood of cure is higher when CRC is diagnosed at an early stage. Dietary and lifestyle modifications have little, if any, impact on CRC. Endoscopy with polypectomy prevents cancer deaths. The most important issues are screening and surveillance by any of the recommended modalities. Remaining concerns include the choice of screening tests, optimal testing intervals, and cost effectiveness. Patients may be stratified by personal and family risk and by the specific strategies used. Newer developments in genetic testing and imaging, including virtual colonoscopy, hold promise for future prevention. Chemoprevention with nonsteroidal anti-inflammatory drugs may have a role in high-risk populations. Colonoscopy is the most effective method of CRC prevention.

Anti-Inflammatory Agents, Non-Steroidal↗