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PubMed2005

In silico identification of breast cancer genes by combined multiple high throughput analyses.

Publicly available human genomic sequence data provide an unprecedented opportunity for researchers to decode the functionality of human genome. Such information is extremely valuable in cancer prevention diagnosis and treatment. Cancer Genome Anatomy Project (CGAP) and Gene Expression Omnibus (GEO) are two bioinformatic infrastructures for studying functional genomics. The goal of this study is to explore the feasibility of incorporating the Internet-available bioinformatic databases to discover human breast cancer-related genes. Several tools including the Gene Finder, Virtual Northern (vNorthern) and SAGE digital gene expression displayer (DGED) were used to analyze differential gene expression between benign and malignant breast tissues. A pilot study was performed using both EST and SAGE vNorthern to analyze the expression of a panel of known genes, including high abundance genes beta-actin and G3PDH, low abundance genes BRCA1 and p53, tissue-specific genes CEA and PSA and two breast cancer-related genes Her2/neu and MUC1. We found a high expression of beta-actin and G3PDH and a low expression of BRCA1 and p53 across different types of tissues as well as a tissue-specific expression of CEA in colon and PSA in prostate. A further analysis of 30 known breast cancer-related genes in breast cancer tissues by vNorthern demonstrated a high expression of oncogenes and low expression of tumor suppressor genes. An open-end analysis of two pools of breast cancer and benign breast tissue libraries by SAGE DGED produced 53 differentially expressed genes according to the screening criteria of a >five-fold difference and p<0.01. Further analysis by EST vNorthern and virtual microarray analysis reduced the candidate genes to six, with four down-regulated genes, ANXA1, CAV1, KRT5 and MMP7, and two up-regulated genes, ERBB2 and G1P3 in breast cancer. These findings were validated by a real-time RT-PCR analysis in eight paired human breast cancer tissue samples. We conclude that the combined multiple high throughput analyses is an effective data mining strategy in cancer gene identification. This approach may improve the usage of public available genomic data through strategic data mining of high throughput analysis.

Blotting, Northern↗
PubMed2002

Cost-effectiveness of screening the average-risk population for colorectal cancer.

This article reviews several of the recent models addressing the cost-effectiveness of colorectal cancer screening in the average-risk individual (Table 1). How can clinicians and policy makers use this information for decision making regarding colorectal cancer screening? The cost-effectiveness ratios reported by themselves do not identify cost-effective practices. They must be placed in a decision context that is expressed in one of two forms. In the first form, an explicit threshold or maximum amount that a policy maker is willing to spend is stated (e.g., $40,000 per LY gained, as has been quoted as an acceptable amount for a prevention program). In the second form of decision context, a list of medical practices and their associated cost-effectiveness ratios, also known as a league table (Table 2) is used as a basis for comparison with the practice under evaluation (e.g., colorectal cancer screening). The practice with the lowest cost-effectiveness ratio is the most cost-effective practice on the list. Practices with lower cost-effectiveness ratios are considered cost-effective compared with those with higher ratios. Table 2 lists incremental cost-effectiveness ratios for common medical practices. The models discussed in this article suggested that colorectal cancer screening using annual FOBT, flexible sigmoidoscopy at 3 or 5 years, the combination of FOBT and flexible sigmoidoscopy, barium enema, colonoscopy, and even virtual colonoscopy had incremental cost-effectiveness ratios ranging from $6300 to $92,900 per LY saved with most of the cost-effectiveness ratio ranging from $10,000 to $40,000 per LY saved. These ratios are similar to the cost of another widely accepted practice, breast cancer screening with annual mammography in women age 50 and older ($22,000 per LY gained). Colorectal cancer screening with any of the modalities discussed is considered less cost-effective than screening for hemochromatosis, which has an incremental cost-effectiveness ratio of $3665 per LY saved. Based on these ratios, however, screening for colorectal cancer is considered cost-effective compared with cervical cancer screening in women age 20 and older with pap smear every 3 years, which has an incremental cost-effectiveness ratio of $250,000 per LY gained. The clinician can use these incremental cost-effectiveness ratios to evaluate the risks and benefits of alternative practices for the individual, and the policy maker with a limited health care budget can use these ratios to set priorities for funding based on the costs and the expected gains in life expectancy for colorectal cancer screening and for alternative health care programs.

Colonoscopy↗
PubMed1997

[Virtual CT colonoscopy. Examination technique, limitations and perspectives].

Virtual CT-colonoscopy is a post-processing method which allows for reconstruction of inner bowel surface structures from helical CT datasets. The reconstructed images simulate the views which are known from fiberoptic endoscopy. Since colorectal cancer is the second main cause of death in USA and Europe today and since recent screening recommendations are often ignored by the public, a non-invasive or minimal-invasive procedure for colonic evaluation would offer some benefits. Virtual CT-colonoscopy generally involves three essential steps: patient preparation with cleansing of the bowel and administration of an air enema, helical CT-examination by using appropriate scan parameters, and interactive 3D rendering of the volume data-set. Although recent studies have demonstrated that polypoid lesions of about 5 mm size are well detectable and although virtual colonoscopy offers many advantages over fiberoptic endoscopy, some technical and clinical limitations must still be noted. Thus, the current inability of virtual colonoscopy to provide texture and color leads to problems in identifying flat lesions; the presence of retained or adherent fecal matter may result to false positive diagnosis and collapsed segments of bowel may cause problems as they cannot subsequently be evaluated during image reconstruction. Virtual endoscopy is still in its infancy and further technical and clinical developments are necessary. Virtual CT-colonoscopy may then prove to be equal or superior to colonoscopy in sensitivity and specificity for polyp detection and be able to reduce the number of unnecessary colonoscopic procedures.

Colonoscopes↗
PubMed2000

A novel mammalian expression screen exploiting green fluorescent protein-based transcription detection in single cells.

The accumulation of DNA sequence information from large-scale genomic and random library sequencing projects is leading to the rapid identification of many putative genes, virtual transcripts and ESTs of unknown function. There is therefore an increasing need for high throughput, sensitive and robust methods for identification and characterisation of genes, and/or their products, based on function. We describe a high throughput functional expression screen based on semi-quantitative analysis of enhanced green fluorescent protein expression in single cells by confocal microscopy. The assay was implemented in a micro-scale format, requiring around 10(4) cells/test. The system was validated by co-transfection of a series of cDNAs encoding pro-inflammatory cytokine intracellular signal mediators with a d2EGFP reporter containing a cytokine responsive promoter. The majority of the test plasmids gave a detectable signal above background at a pool size of 250-500. Replicate tests indicate that the assay is reproducible at this pool size. At this level we demonstrate that large (>10(6) transformants) libraries can be feasibly screened.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Cognitive impairment, physical disability and depressive symptoms in older diabetic patients: the Fremantle Cognition in Diabetes Study.

OBJECTIVE: To determine whether the prevalence of dementia, depression and/or disability in older diabetic subjects warrants an active screening approach by diabetes health care workers. PATIENTS AND METHODS: The initial 223 members of a cohort of 529 eligible diabetic subjects, aged 70 years or over, were screened for cognitive impairment (using the Mini-Mental State Examination (MMSE) and Informant Questionnaire for Cognitive Decline in the Elderly (IQCODE)), physical impairments and depressive symptoms. RESULTS: Virtually all subjects were community-dwelling (99%) and mobile (86%) and relatively few had moderate or severe deficits in activities of daily living (ADL) (17.5%). The prevalences of cognitive impairment and probable dementia estimated from the screening tests were high (range 10.8-17.5%) compared with population studies. Any deficit with ADL was reported by 53% of the subjects and common problems included urinary and faecal incontinence. Scores consistent with clinical depression were reported by 14.2% of the sample but 50.2% of the remainder reported one or more depressive symptoms below the cut-off point for clinical depression. Only 36% of the study subjects were free of deficits in any domain. CONCLUSIONS: Community-living older diabetic subjects have high rates of cognitive impairment, deficits in physical function and depressive symptomatology suggesting that screening programs for functional impairments and depression may be beneficial in health care systems that manage older diabetic patients.

Activities of Daily Living↗
PubMed1997

Screening the monoamine oxidase B gene in 100 male patients with schizophrenia: a cluster of polymorphisms in African-Americans but lack of functionally significant sequence changes.

The monoamine oxidase B (MAO-B) gene was examined in 100 alleles derived from 80 Caucasian, 10 African-American, 5 Asian, and 5 Native American male patients with schizophrenia to identify sequence changes that might be associated with the disease. Approximately 235 kb of genomic sequence, primarily in coding regions, were screened by dideoxy fingerprinting, a modification of single-strand conformational polymorphism (SSCP) analysis that detects virtually 100% of sequence changes [Sarkar et al. (1992): Genomics 13:441-443; Liu and Sommer (1994): PCR Methods Appl 4:97-108]. No sequence changes of likely functional significance were identified, suggesting that mutations affecting the structure of the MAO-B protein are uncommon in the general population and are unlikely to contribute significantly to the genetic predisposition to schizophrenia. Eight polymorphisms were identified in African-Americans and Native Americans, but none were identified among Caucasians. Of the eight observed polymorphisms, a set of five transitions and one microdeletion was identified within approximately 17 kb of genomic sequence in the same 3 African-American individuals, while the remaining 7 African-Americans had a sequence identical to that in Caucasians. The presence of two such haplotypes, without intermediates, is compatible with the hypothesis that germline mutations can occur in clusters, as also suggested by other recent findings.

Black People↗
PubMed2026

Synergistic HMGN1 and VP64 Fusions Potentiate High-Precision and PAM-Flexible Base Editing.

RNA-guided CRISPR-derived base editors (BEs) have revolutionized genome editing by enabling targeted base substitutions. However, their application is frequently constrained by the stringent requirement for PAM sequences and low editing precision (bystander editing). Here, we present a robust strategy to overcome these limitations by coupling SpRY, a near-PAM-less Cas9 variant, with truncated CDA1 cytidine deaminases. While this combination enables precise editing of virtually any cytosine in the genome, it initially exhibited suboptimal efficiency. To address this, we systematically screened a diverse panel of candidate DNA-binding proteins and identified that the synergistic fusion of HMGN1 and VP64 substantially enhances editing activity without compromising precision. Importantly, this enhanced editing efficiency was achieved without markedly increasing off-target effects. Our new BEs demonstrated robust performance not only in yeast but also in rice, suggesting broad applicability in gene therapy, precision breeding, and fundamental research.

Gene Editing↗
PubMed1995

Screening the dopamine D1 receptor gene in 131 schizophrenics and eight alcoholics: identification of polymorphisms but lack of functionally significant sequence changes.

To determine whether mutations in the D1 dopamine receptor (D1 DR) gene are associated with schizophrenia, the coding sequence was examined in 106 Caucasian, 11 African-American, 8 Asian, and 6 Native American patients. Approximately 350 kb of genomic sequence was screened by dideoxy fingerprinting, a method related to single strand conformational polymorphism (SSCP) analysis that detects virtually 100% of sequence changes [Sarkar et al., 1992: Genomics 13:441-443; Liu and Sommer, 1994: PCR Methods and Applications 4:97-108]. One polymorphism was identified in Asians and one in Caucasians, but neither altered the amino acid sequence (Leu66, and Ser421, respectively). In addition, a previously reported polymorphism in the 5' untranslated region of exon 2 at bp -48 was found to be common, with an allele frequency of approximately 40% in Caucasians of Western European descent. Based on the fact that no sequence changes of likely functional significance were identified, these data suggest that mutations affecting the structure of the D1 dopamine receptor protein are uncommon and are unlikely to contribute significantly to the genetic predisposition to schizophrenia. The D1 DR gene also was examined in eight alcoholics, including 3 African-Americans and 1 Native American, but no sequence changes were identified.

Adolescent↗
PubMedDate not supplied

Refractive astigmatism acts predominantly as a source of high spatial frequency image distortion: the associated lineal distortions can be overcome by using a low pass spatial filter!

PURPOSE: Surprisingly, an important characteristic of astigmatism has been overlooked by ophthalmic and clinical scientists. Apparently, refractive astigmatism is due largely to a form of high spatial frequency image distortion. METHODS: Characteristic astigmatic image distortion can be minimized or eliminated by using a low-pass spatial filter (here, a ground glass plate was employed for this purpose). The ground glass is placed a short distance in front of a visual acuity chart, or it may be used with other tests, such as vernier acuity. RESULTS: This test has been performed by us on large numbers of patients and test subjects. A clinician can try this test for himself/herself. Place a +2.00 D.C. (any axis) lens in front of the eye; the usual distortions will be observed. Locate the ground glass plate as described. The usual distortions associated with the conoid of Stürm will not be visible or will be virtually eliminated, although some image blur will remain. CONCLUSIONS: This technique has significance, e.g., in visual screening programs in developing nations, or in assessing patients with media disorders prior to ophthalmic surgery.

Astigmatism↗
PubMed2001

High-sensitivity array analysis of gene expression for the early detection of disseminated breast tumor cells in peripheral blood.

Early detection is an effective means of reducing cancer mortality. Here, we describe a highly sensitive high-throughput screen that can identify panels of markers for the early detection of solid tumor cells disseminated in peripheral blood. The method is a two-step combination of differential display and high-sensitivity cDNA arrays. In a primary screen, differential display identified 170 candidate marker genes differentially expressed between breast tumor cells and normal breast epithelial cells. In a secondary screen, high-sensitivity arrays assessed expression levels of these genes in 48 blood samples, 22 from healthy volunteers and 26 from breast cancer patients. Cluster analysis identified a group of 12 genes that were elevated in the blood of cancer patients. Permutation analysis of individual genes defined five core genes (P < or = 0.05, permax test). As a group, the 12 genes generally distinguished accurately between healthy volunteers and patients with breast cancer. Mean expression levels of the 12 genes were elevated in 77% (10 of 13) untreated invasive cancer patients, whereas cluster analysis correctly classified volunteers and patients (P = 0.0022, Fisher's exact test). Quantitative real-time PCR confirmed array results and indicated that the sensitivity of the assay (1:2 x 10(8) transcripts) was sufficient to detect disseminated solid tumor cells in blood. Expression-based blood assays developed with the screening approach described here have the potential to detect and classify solid tumor cells originating from virtually any primary site in the body.

Breast Neoplasms↗
PubMed1997

A high throughput screening for rarely transcribed differentially expressed genes.

A novel method combining elements of suppression subtractive hybridization with high throughput differential screening permits the efficient and rapid cloning of rarely transcribed differentially expressed genes. The experimental strategy virtually excludes the possibility of isolating false positive clones. The potential of the method is demonstrated by the isolation of 625 differentially expressed cDNAs from the metastatic adenocarcinoma cell line Bsp73-ASML when subtracted from its non-metastatic counterpart Bsp73-1AS. Northern analysis of 72 randomly selected clones demonstrated that 68 were differentially expressed with respect to Bsp73-ASML, indicating a true positive rate of 94%. Additionally, a large proportion of these clones represented rare transcripts as determined by the exposure time required to detect a signal. Sequence data indicated that of the 625 clones obtained, 92 clones scored perfect or near perfect matches with already known genes. Two hundred and eighty one clones scored between 60 and 95% homology to known human and mouse genes, whereas 252 clones scored no match with any sequences in the public databases. The method we describe is ideally suited whenever subtle changes in gene expression profiles need to be determined.

Adenocarcinoma↗
PubMed1982

Improved methods for office fungal culture.

A new screening culture method which can be used as an office fungal culture involves a microculture, where a selective medium (DTM) is used for coating a thin transparent plastic slide. Sampling is performed with a transparent adhesive tape which is pressed on to the surface of the agar and allows daily microscopic examination of the culture. Identification of the fungus is based on its micromorphologic features and possible color change of the substrate. Growth of dermatophytes and candida usually can be detected and registered within 48 hours. The screening method is simple to handle and read and may be monitored by inexperienced personnel with virtually no microbiologic knowledge.

Arthrodermataceae↗
PubMed1987

Low Apgar score as a risk factor for respiratory disturbances in the newborn infant.

The value of the Apgar score as a risk factor for all neonatal respiratory disturbances (RD) was evaluated in a prospective study of an unselected population. All liveborn infants (n = 4656) of mothers living in Gothenburg were screened over one year for signs of respiratory disease. This unselected population could be obtained since virtually all infants in Gothenburg are born in two maternity hospitals, with similar treatment principles, the same equipment standard and neonatal care. A low one minute Apgar score (less than 7) was found to be a powerful risk factor for RD in full term newborns and infants of 33-36 weeks gestation provided that the delivery had been vaginal. In these infants a low Apgar score at five minutes further increased the risk of RD. In immature infants less than 32 weeks and after cesarean section in all gestational ages a low Apgar score did not mean any additional risk of RD. The respiratory component in the Apgar score was not more predictive of RD than any of the others. In most infants with RD, irrespective of Apgar score, there was a few hours interval free from respiratory signs after birth. It has been well shown in other studies that Apgar score is not a reliable index of intrauterine or birth asphyxia. Nevertheless the one-minute score is a powerful predictor of neonatal respiratory difficulties. One explanation might be that Apgar score is correlated with sympathoadrenal activity at birth.(ABSTRACT TRUNCATED AT 250 WORDS)

Apgar Score↗
PubMed2005

[Screening of a hepatic stellate cells subtracted cDNA library of differentially expressed genes in mice with schistosomiasis japonica].

OBJECTIVE: To construct and screen a hepatic stellate cells(HSCs) subtracted cDNA library, in order to seek differentially expressed genes in mice infected with Schistosoma japonicum. METHODS: HSCs were isolated from mouse as targets, and cDNA fragments of normal mouse were compared to those of S. japonicum infected mice to find dif ferentially expressed genes by technique of suppression subtractive hybridization(SSH). Differentially expressed cDNA fragments were then directly inserted into T/A cloning vector to set up the subtractive library. Amplification of the library was carried out with transformation of DH5alpha. A subtracted cDNA library was constructed and then hybridized with forward and backward subtracted probes for differential screening. One hundred positive bacterial clones were randomly selected for se quenching and BLAST analysis. Finally, virtual Northern blot confirmed such differential expression. RESULTS: The amplified library contained more than 400 positive bacterial clones. Random analysis of 100 clones with restriction enzyme digestion showed that all clones contained 200-600 bp inserts. 76 ESTs were obtained with 70 related to fibrosis caused by schistosomiasis or other etiological factors. Other 6 ESTs were not found in PubMed. CONCLUSION: The subtracted cDNA library of differentially expressed genes of HSC in normal mice and schistosome-infected mice was constructed successfully with SSH and T/A cloning techniques.

Animals↗
PubMed1989

Transforming growth factor-alpha in the mammalian brain. Immunohistochemical detection in neurons and characterization of its mRNA.

In this communication, we demonstrate that adult mammalian brain neurons express transforming growth factor-alpha (TGF-alpha). We used the anti-TGF-alpha monoclonal antibody, MF9, to immunohistochemically localize TGF-alpha in human and rat brain. We found specific immunoreactivity in neurons throughout the brain which was not a result of cross-reactivity of MF9 with the neuropeptide, synenkephalin. Northern blot analysis of bovine and rat brain RNA using human and rat TGF-alpha cDNA probes, respectively, revealed a single 4.8-kilobase pair mRNA with approximately equal abundance in the bovine brainstem, cerebellum, hypothalamus, and cerebral cortex. Fetal rat brain had about 2-fold more TGF-alpha mRNA than did adult rat. The brain TGF-alpha cDNA was cloned from a human neonatal brainstem library. Four identical clones were isolated after screening 10(6) recombinant lambda gt11 phage. The sequence of the 894-base pair cDNA was virtually identical with the cDNA isolated from a human renal cell carcinoma. A single alanine codon was deleted in the brain cDNA at an exon-exon junction. The alanine deletion is within the amino-terminal region of the TGF-alpha precursor that is thought to be removed by proteolytic processing of the precursor to the mature growth factor. These studies indicate that the normal mammalian brain neurons express TGF-alpha.

Animals↗
PubMed1995

Medical genetics in Singapore.

This paper is a brief review of the scope of research and clinical work in human genetics in Singapore. Clinical genetics and karyotyping were established in the early sixties. G6PD deficiency was discovered then as the commonest cause of kernicterus in the newborn. Screening of all newborns was instituted. The measures taken have been very successful and kernicterus is virtually unknown since the early 1970s. Numerous G6PD variants have been discovered and characterized. During the 1980s the emphasis shifted to molecular genetics. Work on the molecular genetics of alpha- and beta-thalassemias, Duchenne muscular dystrophy, hemophilia and retinoblastoma have been established, and good progress on diseases such as neurofibromatosis, leukemias, and lymphoid malignancies. The diagnosis of tuberculosis by DNA amplification (PCR) has been successfully implemented. Numerous papers have been published on the molecular genetics of coronary artery disease, as well as in population genetics.

Adult↗
PubMed1995

Oxytocin and the molecular basis of monogamy.

Previous studies in rats have implicated central oxytocin (OT) pathways in the onset of maternal behavior, female sexual receptivity, and the response of the pups to social separation. However, the rat is not ideal for studying effects of OT on attachment as rats fail to form selective, enduring social bonds. To study male-female pair bonds, our laboratory has focused on a microtine rodent, the prairie vole, which is monogamous and highly affiliative. Adult prairie voles form pair bonds after mating (with prolonged, repeated bouts of copulation). As mating releases OT in several species of mammals, we hypothesized that this release was important for pair bond formation in the prairie vole. Central administration of an OT antagonist (but not a V1 antagonist) prevents pair bonding without interfering with the mating behavior. Moreover, central infusion of OT (but not vasopressin, AVP) facilitates pair bonding n the absence of mating. In males, it is AVP (not OT) that appears necessary for pair bond formation. The pattern of OT (and AVP) receptor distribution in the prairie vole brain is entirely distinct from the pattern observed in the closely related non-monogamous montane vole. OT receptors (OTR) in these two species show virtually identical kinetics, specificities, and cDNA sequences (RNA from parturient uterus). In current studies, we are screening genomic libraries from prairie and montane voles to determine if species differences in OTR promoters account for the strikingly different patterns of regional expression in brain. These studies should ultimately provide insight into a neuroendocrine mechanism for pair bond formation.

Animals↗
PubMed1997

Virtual colonoscopy.

A new method for colon examination, virtual colonoscopy, has been created by combining spiral computed tomography and virtual reality computer technology. If virtual colonoscopy proves equal to or superior to traditional colonoscopy in sensitivity and specificity for cancer screening, it would yield significant clinical and public health benefits because of its potential for increased acceptance among patients as well as its considerably lower cost and risks.

Colon↗