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PubMed2001

[Statistical Process Control applied to viral genome screening: experimental approach].

During the National Multicentric Study concerning the introduction of NAT for HCV and HIV-1 viruses in blood donation screening which was supervised by the Medical and Scientific departments of the French Blood Establishment (Etablissement français du sang--EFS), Transcription-Mediated transcription Amplification (TMA) technology (Chiron/Gen Probe) was experimented in the Molecular Biology Laboratory of Montpellier, EFS Pyrénées-Méditerranée. After a preliminary phase of qualification of the material and training of the technicians, routine screening of homologous blood and apheresis donations using this technology was applied for two months. In order to evaluate the different NAT systems, exhaustive daily operations and data were registered. Among these, the luminescence results expressed as RLU of the positive and negative calibrators and the associated internal controls were analysed using Control Charts, Statistical Process Control methods, which allow us to display rapidly process drift and to anticipate the appearance of incidents. This study demonstrated the interest of these quality control methods, mainly used for industrial purposes, to follow and to increase the quality of any transfusion process. it also showed the difficulties of the post-investigations of uncontrolled sources of variations of a process which was experimental. Such tools are in total accordance with the new version of the ISO 9000 norms which are particularly focused on the use of adapted indicators for processes control, and could be extended to other transfusion activities, such as blood collection and component preparation.

Blood Component Removal↗
PubMed2002

A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer.

Aberrant hypermethylation of gene promoters is a major mechanism associated with inactivation of tumor-suppressor genes in cancer. We previously showed this transcriptional silencing to be mediated by both methylation and histone deacetylase activity, with methylation being dominant. Here, we have used cDNA microarray analysis to screen for genes that are epigenetically silenced in human colorectal cancer. By screening over 10,000 genes, we show that our approach can identify a substantial number of genes with promoter hypermethylation in a given cancer; these are distinct from genes with unmethylated promoters, for which increased expression is produced by histone deacetylase inhibition alone. Many of the hypermethylated genes we identified have high potential for roles in tumorigenesis by virtue of their predicted function and chromosome position. We also identified a group of genes that are preferentially hypermethylated in colorectal cancer and gastric cancer. One of these genes, SFRP1, belongs to a gene family; we show that hypermethylation of four genes in this family occurs very frequently in colorectal cancer, providing for (i) a unique potential mechanism for loss of tumor-suppressor gene function and (ii) construction of a molecular marker panel that could detect virtually all colorectal cancer.

Colorectal Neoplasms↗
PubMed2026

Functional genomic screens uncover FERMT2 as a critical regulator of YAP/TAZ-driven tumorigenicity.

YAP and TAZ are transcriptional regulators essential for mechanotransduction, development, and tissue homeostasis, whose dysregulation is implicated in multiple diseases, including cancer. To identify key regulators of YAP/TAZ signaling required for breast cancer cell fitness, we performed CRISPR/Cas9-based loss-of-function genetic screens both in vitro and in vivo. A custom sgRNA library targeting 216 candidate YAP/TAZ modulators was screened across three breast cancer cell lines. Among these, FERMT2, a component of the integrin signaling pathway, consistently emerged as a strong drop-out hit, highlighting its essential role in sustaining YAP/TAZ-dependent fitness. Bioinformatic analysis of large-scale cancer datasets further revealed genetic co-dependency between FERMT2, YAP, and TAZ, particularly in tumors with high YAP/TAZ expression. Functional validation through FERMT2 knockout and silencing demonstrated its requirement for proliferation, anchorage-independent growth, and tumorigenicity in triple-negative breast cancer cells. FERMT2 loss impaired YAP/TAZ nuclear accumulation, reduced the expression of YAP/TAZ target genes, and decreased phosphorylation at key tyrosine residues. Mechanistically, FERMT2 regulates YAP/TAZ independently of the canonical Hippo pathway through integrin-mediated activation of FAK. Consistent with this, glucocorticoid-driven FAK activation restored YAP/TAZ signaling in FERMT2-depleted cells. Partial epistasis analyses also indicate that FERMT2 modulates actin-dependent regulation of YAP/TAZ. Together, these findings identify FERMT2 as a pivotal upstream regulator of YAP/TAZ via FAK signaling, demonstrate that YAP/TAZ are principal effectors of integrin activity, and suggest that FERMT2 may represent a selective vulnerability in cancers with elevated YAP/TAZ signaling.

Humans↗
PubMed2003

Antimicrobial resistance and genomic screening of clinical isolates of thermophilic Campylobacter spp. from south-east Queensland, Australia.

AIM: To screen 90 clinical isolates of thermophilic Campylobacter species for putative resistance to ampicillin, erythromycin and tetracycline and perform numerical analysis to determine isolate relatedness. METHODS AND RESULTS: Disc diffusion, E-test MIC and agar dilution methods were performed. Disc diffusion testing showed 87 (97%) isolates appeared resistant to ampicillin at 10 microg; 14 (16%) resistant to tetracycline at 30 microg; and three (3.4%) resistant to erythromycin at 15 microg. E-test MICs showed a range of 0.5 to >256 mg l(-1) for ampicillin; 16 to >256 mg l(-1) for tetracycline; and >256 mg l(-1) for erythromycin. E-test showed 68% correlation (+/-1 log2 dilution) with agar dilution for ampicillin, 100% for erythromycin and 64% for tetracycline. Disc diffusion testing showed 100% correlation with agar dilution for erythromycin and tetracycline, and 77% for ampicillin. Numerical analyses of restriction endonuclease (RE) fragment profiles suggested a high level of isolate variation. CONCLUSION: The incidence of resistance of thermophilic Campylobacter spp. to erythromycin and tetracycline is low in south-east Queensland. SIGNIFICANCE AND IMPACT OF THE STUDY: Disc diffusion susceptibility testing may be used to screen thermophilic Campylobacter spp. for putative resistance to erythromycin and tetracycline. Agar dilution should be used to determine ampicillin susceptibility.

Ampicillin Resistance↗
PubMed2001

A genome screen of families with multiple cases of prostate cancer: evidence of genetic heterogeneity.

We conducted a genomewide screen for prostate cancer-susceptibility genes on the basis of data from 98 families from the United States and Canada that had three or more verified diagnoses of prostate cancer among first- and second-degree relatives. We found a statistically significant excess of markers for which affected relatives exhibited modest amounts of excess allele-sharing; however, no single chromosomal region contained markers with excess allele-sharing of sufficient magnitude to indicate unequivocal evidence of linkage. Positive linkage signals of nominal statistical significance were found in two regions (5p-q and 12p) that have been identified as weakly positive in other data sets and in region 19p, which has not been identified previously. All these signals were considerably stronger for analyses restricted to families with mean age at onset below the median than for analyses of families with mean age at onset above the median. The data provided little support for any of the putative prostate cancer-susceptibility genes identified in other linkage studies.

Age of Onset↗
PubMed2002

Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis.

It has been known for several years that heterozygous mutations of three members of the fibroblast growth-factor-receptor family of signal-transduction molecules-namely, FGFR1, FGFR2, and FGFR3-contribute significantly to disorders of bone patterning and growth. FGFR3 mutations, which predominantly cause short-limbed bone dysplasia, occur in all three major regions (i.e., extracellular, transmembrane, and intracellular) of the protein. By contrast, most mutations described in FGFR2 localize to just two exons (IIIa and IIIc), encoding the IgIII domain in the extracellular region, resulting in syndromic craniosynostosis including Apert, Crouzon, or Pfeiffer syndromes. Interpretation of this apparent clustering of mutations in FGFR2 has been hampered by the absence of any complete FGFR2-mutation screen. We have now undertaken such a screen in 259 patients with craniosynostosis in whom mutations in other genes (e.g., FGFR1, FGFR3, and TWIST) had been excluded; part of this screen was a cohort-based study, enabling unbiased estimates of the mutation distribution to be obtained. Although the majority (61/62 in the cohort sample) of FGFR2 mutations localized to the IIIa and IIIc exons, we identified mutations in seven additional exons-including six distinct mutations of the tyrosine kinase region and a single mutation of the IgII domain. The majority of patients with atypical mutations had diagnoses of Pfeiffer syndrome or Crouzon syndrome. Overall, FGFR2 mutations were present in 9.8% of patients with craniosynostosis who were included in a prospectively ascertained sample, but no mutations were found in association with isolated fusion of the metopic or sagittal sutures. We conclude that the spectrum of FGFR2 mutations causing craniosynostosis is wider than previously recognized but that, nevertheless, the IgIIIa/IIIc region represents a genuine mutation hotspot.

Acrocephalosyndactylia↗
PubMed2005

Genome screen for twinning rate QTL in four North American Holstein families.

The objective of this study was to identify twinning rate quantitative trait loci (QTL) by typing pooled samples in a preliminary screening followed by interval mapping to test QTL effects. Four elite North American Holstein half-sib sire families with high twinning rate predicted transmitting abilities (PTA) were used in this study. Chromosomes 5, 7, 19 and 23 were not genotyped as these chromosomes were scanned for QTL in these families in a previous study. DNA was extracted from phenotypically extreme sons in each sire family. Two pools were prepared from sons of sires in each phenotypic tail, two each for high and low PTA levels for twinning rates. Each pool contained DNA from 4 to 15% of all sons of the sire depending on family. A total of 268 fluorescently labelled microsatellite markers were tested for heterozygosity in sires. About 135--170 informative markers per family were genotyped using pooled DNA samples. Based on the preliminary evidence for potential twinning rate QTL from pooled typing, interval mapping was performed subsequently on 12 chromosomal regions by family combinations. Evidence of QTL for twinning rate was found in one family on BTA 21 and 29 at a chromosome-wide P<0.05 and on BTA 8, 10 and 14 with a chromosome-wide P<0.01.

Animals↗
PubMed2006

Developmental control of nuclear morphogenesis and anchoring by charleston, identified in a functional genomic screen of Drosophila cellularisation.

Morphogenesis of epithelial tissues relies on the precise developmental control of cell polarity and architecture. In the early Drosophila embryo, the primary epithelium forms during cellularisation, following a tightly controlled genetic programme where specific sets of genes are upregulated. Some of them, for example, control membrane invagination between the nuclei anchored at the apical surface of the syncytium. We used microarrays to describe the global programme of gene expression underlying cellularisation and identified distinct classes of upregulated genes during this process. Fifty-seven genes were then tested functionally by RNAi. We found six genes affecting various aspects of cellular architecture: membrane growth, organelle transport or organisation and junction assembly. We focus here on charleston (char), a new regulator of nuclear morphogenesis and of apical nuclear anchoring. In char-depleted embryos, the nuclei fail to maintain their elongated shape and, instead, become rounded. In addition, together with a disruption of the centrosome-nuclear envelope interaction, the nuclei lose their regular apical anchoring. These nuclear defects perturb the regular columnar organisation of epithelial cells in the embryo. Although microtubules are required for both nuclear morphogenesis and anchoring, char does not control microtubule organisation and association to the nuclear envelope. We show that Char is lipid anchored at the nuclear envelope by a farnesylation group, and localises at the inner nuclear membrane together with Lamin. Our data suggest that Char forms a scaffold that regulates nuclear architecture to constrain nuclei in tight columnar epithelial cells. The upregulation of Char during cellularisation and gastrulation reveals the existence of an as yet unknown developmental control of nuclear morphology and anchoring in embryonic epithelia.

Alkyl and Aryl Transferases↗
PubMed2025

The acceptability of blood spot screening and genome sequencing in newborn screening: a systematic review examining evidence and frameworks.

BACKGROUND: Population-wide newborn blood spot screening programmes are a successful public health intervention used to detect whether the baby is at risk of certain rare conditions, with the aim of earlier diagnosis and provision of optimal care and treatment. Evaluating candidate conditions to include in newborn blood spot and genetic sequencing raises questions regarding acceptability to parents/carers. METHODS: In the context of the possible expansion of the newborn blood spot screening programme in the United Kingdom, this review aimed to systematically review research on the acceptability to parents of newborn blood spot screening and genetic sequencing. A protocol was developed prior to commencing the review and was registered on the PROSPERO database. A team of researchers carried out the review, with checking at all stages carried out by at least two individuals. We included research published after 2013 with participants who were pregnant or a recent parent of a newborn and were resident in a high-income country. We included quantitative and qualitative studies that investigated the acceptability to parents/carers of newborn blood spot screening or genetic sequencing. Quantitative studies were narratively synthesised, and theories/frameworks identified and evaluated. Qualitative studies were analysed for recurring themes, and a meta-synthesis was carried out to compare and contrast these two types of data. We quality appraised included articles using tools appropriate for their study design. RESULTS: Searches were carried out in September to November 2023 and screening identified 25 relevant research articles. Just over half were from North America, with four existing reviews and nine qualitative studies. Domains of acceptability described in the literature were: support for screening; level of anxiety, information and knowledge; consent; views of the procedure; and support after screening. The research indicated consensus support for blood spot screening, and for expanding to some other conditions, although some parental anxiety was reported. Parents/carers mostly perceived that they had received sufficient information, but the timing of this could be improved. While parents indicated interest in genomic screening, studies highlighted the need for clearer consent procedures and greater support for parents following genomic screening than for blood spot screening. Only three included studies reported using any kind of theoretical framework. DISCUSSION: Most parents/carers found newborn blood spot screening programmes to be acceptable and favoured their large-scale implementation. A minority of parents/carers expressed concerns regarding the acceptability of processes underpinning newborn blood spot screening, such as consent, the timing of receiving information and support available after testing. More research is needed regarding the acceptability of newborn genomic sequencing screening programmes, which are less established compared with newborn blood spot screening programmes. LIMITATIONS: The over-representation of studies conducted in the United States has implications for the applicability of findings to other countries where testing is not typically mandatory and health systems differ considerably. Most studies were of cross-sectional design and there was limited representation of people from lower incomes and non-white ethnicity. While the inclusion of studies only in populations of future or very recent parents provided coherence to the findings, unclear reporting of participants may have resulted in under- or overinclusion of some studies. FUNDING: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR159927.

ACCEPTABILITY↗
PubMed2004

High-throughput RNAi in Caenorhabditis elegans: genome-wide screens and functional genomics.

The phenomenon of RNA-mediated interference (RNAi) was first discovered in the nematode Caenorhabditis elegans, in which introduction of double-stranded RNA causes specific inactivation of genes with corresponding sequences. Technical advances in RNAi methodology and the availability of the complete genome sequence have enabled the high-throughput, genome-wide RNAi analysis of this organism. Several groups have used large-scale RNAi to systematically examine every C. elegans gene for knock-down phenotypes, providing basal information to be mined in more detailed studies. Now, in addition to functional genomic RNAi analyses, high-throughput RNAi is also routinely used for rapid, genome-wide screens for genes involved in specific biological processes. The integration of high-throughput RNAi experiments with other large-scale data, such as DNA microarrays and protein-protein interaction maps, enhances the speed and reliability of such screens. The accumulation of RNAi phenotype data dramatically accelerates our understanding of this organism at the genetic level.

Animals↗
PubMed1997

Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances.

Comparative genomic hybridization (CGH) to metaphase chromosomes has been widely used for the genome-wide screening of genomic imbalances in tumor cells. Substitution of the chromosome targets by a matrix consisting of an ordered set of defined nucleic acid target sequences would greatly enhance the resolution and simplify the analysis procedure, both of which are prerequisites for a broad application of CGH as a diagnostic tool. However, hybridization of whole genomic human DNA to immobilized single-copy DNA fragments with complexities below the megabase pair level has been hampered by the low probability of specific binding because of the high probe complexity. We developed a protocol that allows CGH to chips consisting of glass slides with immobilized target DNAs arrayed in small spots. High-copy-number amplifications contained in tumor cells were rapidly scored by use of target DNAs as small as a cosmid. Low-copy-number gains and losses were identified reliably by their ratios by use of chromosome-specific DNA libraries or genomic fragments as small as 75 kb cloned in PI or PAC vectors as targets, thus greatly improving the resolution achievable by chromosomal CGH. The ratios obtained for the same chromosomal imbalance by matrix CGH and by chromosomal CGH corresponded very well. The new matrix CGH protocol provides a basis for the development of automated diagnostic procedures with biochips designed to meet clinical needs.

Chromosome Aberrations↗
PubMed1996

A mass screening device of genome by polymerase chain reaction-restriction fragment-single strand conformation polymorphism analysis.

We have developed a new genome screening method and named it as polymerase chain reaction-restriction fragment-single strand conformation polymorphism (PCR-RF-SSCP) analysis. This method consists of three steps: (1) amplification of long DNA by PCR; (2) digestion of the amplified PCR products by restriction enzyme(s) and labelling the restriction sites; (3) polyacrylamide gel electrophoresis under non-denaturating conditions (SSCP analysis) and under denaturating conditions containing 8M urea. Theoretically, this method enables us to detect even a base substitution, deletion or insertion in up to 22,000 base pairs amplified from genomic DNA by PCR in one analysis. The procedures are very simple, reproducible and require no special apparatus. This method is applicable to any genes already known and we believe that this method is very useful for mass screening of the genome.

Base Sequence↗