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PubMed2000

Typeability of Tn1546-like elements in vancomycin-resistant enterococci using long-range PCRs and specific analysis of polymorphic regions.

Molecular subtyping of the VanA-type resistance element Tn1546 in an international collection of 81 genomically diverse vancomycin-resistant enterococci (VRE) from human, animal, and environmental reservoirs was evaluated by restriction analysis of long-range PCR amplicons (PCR-RFLP), single gene PCRs, Southern blot analysis of genomic digests, and partial DNA sequencing. A dominant Tn1546-RFLP in accordance with Enterococcus faecium BM4147 was detected in 43 of the 49 long-range PCR positive strains from ecologically diverse sources in several European countries and the US. Tn1546-like elements from the 32 (40%) long-range PCR negative strains were typed into 17 different groups by single-gene PCRs and Southern blot analysis of the ORF1, ORF2, vanS-vanH, vanX-vanY, and vanZ regions. All these isolates showed deletions in the ORF1 and/or vanZ primer binding regions explaining the failure of long-range PCR amplification. Enlarged vanS-vanH or vanX-vanY fragments were detected in 7 (22%) and 16 (50%) of the long-range PCR negative strains, respectively. The enlarged vanS-vanH regions of five clinical isolates from the US (n = 2), Ireland (n = 2), and Norway (n = 1) contained identical IS1251-like insertions indicating intercontinental spread of the vanA gene cluster. Intergenic vanS-vanH IS1251 insertions have so far not been reported in European studies. Structural rearrangements of Tn1546-like elements may represent single recombination events that can serve as fingerprints in the molecular examination of vanA gene cluster evolution and transmission. The optimal strategy for such analysis has yet to be determined. Two alternative long-range PCRs with subsequent RFLP analysis were successfully used to type the majority of vanA gene clusters in an ecologically and geographically heterogeneous VRE strain collection, but failed to detect and type a group of variant Tn1546-like elements truncated in the left-end ORF1/ORF2 region. Further subtyping of such variants should specifically target the polymorphic vanS-vanH and vanX-vanY regions.

Base Sequence↗

PubMed2026

An oxidative stress - and immunotherapy-related six-gene signature defines immune subtypes and predicts prognosis and immunotherapy response in hepatocellular carcinoma.

BACKGROUND: Oxidative stress and the tumor immune microenvironment jointly shape hepatocellular carcinoma (HCC) progression and response to immunotherapy, yet integrated biomarkers linking these processes are lacking. METHODS: Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to identify oxidative stress- and immunotherapyrelated differentially expressed genes (OSIRDEGs). Functional enrichment, weighted gene co-expression network analysis (WGCNA) and LASSO-Cox regression were used to construct a prognostic signature. Consensus clustering, TIDE, CIBERSORT and ssGSEA characterized immune phenotypes. Somatic mutation, copy-number and drug-response data were integrated to assess genomic alterations and drug sensitivity. Expression of model genes was validated by qRT-PCR and western blotting in HCC cell lines. RESULTS: We identified 24 OSIRDEGs enriched in cell-cycle and mitotic pathways. WGCNA intersection yielded 18 module genes, from which a six-gene signature (BUB1B, CDKN2A, CENPE, HMMR, PTTG1, SPP1) was derived. The signature robustly stratified patients into high- and low-risk groups with significantly different progression-free and disease-free survival in both TCGA-LIHC and GSE14520. Based on signature expression, two molecular subtypes were defined, exhibiting distinct survival, immune landscapes and predicted immunotherapy responsiveness. Model genes harbored recurrent alterations and showed significant correlations with anticancer agents. All six genes were upregulated at mRNA and protein levels in metastatic HCC cell lines versus normal hepatocytes. CONCLUSIONS: We systematically explored the landscape of OSIRDEGs in HCC, and proposed a validated six-gene signature that refines prognostic stratification, delineates immunerelevant HCC subtypes and highlights candidate biomarkers for therapeutic selection and mechanistic investigation.

Humans↗

PubMedDate not supplied

A cluster of Escherichia coli O157: nonmotile infections associated with recreational exposure to lake water.

OBJECTIVES: To identify cases and determine risk factors for an outbreak of Escherichia coli (E. coli) O157: nonmotile (NM) infections in children attending a summer day care program in California. METHODS: The authors conducted a retrospective cohort study; the cohort comprised first and second graders who attended the day care program during the last week in August 1999. Shiga toxin testing and molecular subtyping using pulsed-field gel electrophoresis were performed on isolates. Lake water, lake bottom sediment samples, and waterfowl feces from the lake environs were cultured for E. coli O157. RESULTS: Three cases of Shiga toxin-producing E. coli O157: NM infections with matching pulsed-field gel electrophoresis patterns and four probable cases were found. Children who swallowed more than a mouthful of water had a higher attack rate than those who swallowed less than a mouthful or none at all (43% vs. 10%, relative risk = 4.43, 95% confidence interval 1.12, 17.50). CONCLUSIONS: E. coli O157: NM infections were associated with swallowing water from a freshwater lake. Potential sources of contamination include feces from humans, cattle, or deer. This outbreak illustrates the value in screening patients with diarrhea for E. coli O157, submitting isolates to public health laboratories, and using molecular techniques to identify related cases. Outbreaks associated with contaminated freshwater could be averted by prevention and early detection of contamination.

California↗

PubMed1995

Biological and molecular characterization of subtype D, G, and A/D recombinant HIV-1 transmissions in Sweden.

HIV-1 can be subdivided into at least nine genetic subtypes (A through H and O), but in Europe and the United States there is an almost complete dominance of subtype B. In this study three Swedish HIV-1 transmission chains of subtypes other than subtype B have been biologically and molecularly characterized. The three index cases were African men. The p17 gag and env V3 regions of the HIV-1 genome were directly sequenced from uncultured lymphocytes. Phylogenetic analyses showed that the HIV-1 variants with each transmission group were genetically closely related, supporting the epidemiological information. The individuals in transmission groups I (n = 3) and II (n = 2) carried subtype G and D virus, respectively. Interestingly, all four individuals in transmission group III displayed a recombinant genotype with subtype D p17 gag sequence and subtype A V3 sequence. The biological phenotype of virus isolates (rapid/high, syncytium-inducing; or slow/low, non-syncytium-inducing) correlated with the clinical stage of the infected individual. The study also suggested that the correlation between biological phenotype and V3 genotype that has been established for subtype B HIV-1 variants may be valid also for other subtypes. This study demonstrates that HIV-1 variants of subtypes other than B, including a subtype A/D recombinant, are being transmitted in Europe.

Adult↗

PubMed2001

Identification of a novel voltage-gated Na+ channel rNa(v)1.5a in the rat hippocampal progenitor stem cell line HiB5.

A conditionally immortalised cell line, HiB5, derived from embryonic hippocampal precursor cells expressed a voltage-gated Na+ channel with electrophysiological characteristics shifted to more negative voltages and a lower sensitivity to tetrodotoxin [concentration required for half-maximal inhibition (IC50) 0.9 microM] compared with endogenous neuronal Na+ channels. The channel activation and steady-state inactivation occurred at very negative potentials with the threshold for activation at -55 mV and half-maximal inactivation at -78.7 mV. The channel was blocked by lamotrigine and sipatrigine voltage and state dependently, with potencies 5-20 times higher (IC50 12 and 1.8 microM at -80 mV respectively) than the corresponding block of endogenous Na+ channels from neurones and cloned rNa(v)1.2a (rBIIA) alpha-subunits. Both compounds slowed the channel's recovery from inactivation. Whereas lamotrigine and sipatrigine had similar effects on the fast inactivated state, the effect of sipatrigine on the slow inactivation state was more pronounced, rendering this compound overall the more effective. The molecular subtype mainly expressed by HiB5 cells was identified using RT-PCR and was a novel splice variant of rNa(v)1.5 (rNa(v)1.5a). It differs from the known rNa(v)1.5 version in that it lacks 53 amino acids in the intracellular loop between domains II and III. rNa(v)1.5a was also detected in mRNA derived from rat whole brain.

Alternative Splicing↗

PubMed2004

Challenges in current drug delivery from the potential application of pharmacogenomics and personalized medicine in clinical practice.

The recent technological achievements in biotechnology and recombinant DNA technology have provided multiple new methods, molecular targets, and DNA-based diagnostics to pharmaceutical research that can be utilized in assays for screening and developing potential biotechnology-based drugs, as well as in biomedicine, health and pharmaceutical care. Furthermore, such advances opened up new opportunities by applying genetic information data in pharmacotherapy and drug delivery, thus ensuring better drug efficacy and safety in clinical practice. Now the concepts of personalized medicine and pharmacogenomics are likely improving the area of pharmacodynamics and pharmacokinetics, since they favor differentiation of the conventional clinical diagnosis and drug selection into separate molecular subtypes of individuals belonging within a group of patients suffering from the same disease. Genetic polymorphisms have already been detected and analyzed in genes encoding drug-metabolizing enzymes, transporters as well as targets (e.g. receptors). The potential of applying genotyping and haplotyping analysis in future pharmaceutical care could eventually lead to pharmacotyping, i.e. individualized drug delivery profiling based on genetic-bioinformatic data in routine patient care. However, the steps towards this direction of drug delivery in clinical practice still have a long way to go to be fully achieved; until then, the critical evaluation of all available clinical data including pharmacodynamic, pharmacokinetic and genomic must be assessed for ensuring drug efficacy and safety. In this way, there has been great progress in elucidating genetic determinants contributing to the observed interindividual differences in drug disposition and effects, thus implementing current drug delivery with molecular genetics and diagnostics.

Drug Delivery Systems↗

PubMed1992

Multiple isolates and characteristics of human T-cell leukemia virus type II.

Human T-cell leukemia (or lymphotropic) virus type II (HTLV-II) was isolated from eight HTLV-seropositive patients, six of whom were also infected with human immunodeficiency virus, by cocultivation of peripheral blood mononuclear cells (PBMCs) with BJAB, a continuous B-cell line. Restriction endonuclease mapping of the proviruses demonstrated consistent differences among isolates, and two distinct physical map patterns were observed. The results suggest the existence of two closely related molecular subtypes of HTLV-II, which are tentatively designated HTLV-IIa and HTLV-IIb. This finding was supported by preliminary nucleotide sequence analysis of the env gene region encoding the transmembrane glycoprotein gp21, which showed consistent differences between the two proposed virus subtypes. Exploitation of differences in restriction endonuclease sites allowed polymerase chain reaction amplification to detect and differentiate the two subtypes in fresh PBMCs of HTLV-seropositive intravenous drug abusers (IVDAs). The results of these studies confirm that HTLV-II infection is the prominent HTLV infection in seropositive IVDAs and also show that infection with both subtypes occurs. The finding of genetic heterogeneity in the HTLV-II group of viruses may have important implications for studies on its role in human disease and will be useful in characterizing the viruses present in newly discovered endemic foci in New World indigenous populations.

Adult↗

PubMed2026

Evaluation of the clinical and mechanistic role of MCM2 expression in the prediction of meningioma recurrence after radiotherapy.

OBJECTIVE: Postoperative radiotherapy is an effective treatment for meningiomas; however, treatment response varies among patients. In addition, practical methods for predicting tumor recurrence after radiotherapy have not been well established. Minichromosome maintenance protein 2 (MCM2), a key regulator of DNA replication licensing, was recently implicated in highly proliferative molecular subtypes of meningioma. In this study, the authors evaluated whether MCM2 immunohistochemical expression predicts response to radiotherapy in patients with meningiomas. METHODS: The authors retrospectively analyzed the records of patients with WHO grade 1-3 meningiomas treated with resection followed by radiotherapy at a single institution between July 2003 and November 2023. The MCM2 labeling index was assessed immunohistochemically, and patients were stratified into MCM2-high and -low groups using a cutoff of 35%. Progression-free survival (PFS) was defined as the interval from the completion of radiation therapy to postoperative radiological tumor recurrence or regrowth. Patients who showed no progression were censored at their last follow-up. PFS was estimated using Kaplan-Meier analysis and subsequently evaluated with Cox proportional hazards models. To further investigate the biological mechanisms associated with MCM2 expression, comprehensive transcriptomic analyses, including gene set enrichment analysis, was performed to elucidate the molecular processes that occur within MCM2-high tumors. RESULTS: The study population included 15 men (42%) and 21 women (58%), with a mean age of 63 years. Ten tumors (28%) were classified as MCM2-high meningiomas and 26 (72%) as MCM2-low meningiomas. High MCM2 expression was significantly associated with WHO grades 2-3 histology and higher Ki-67 labeling indices. During a median follow-up of 2.52 years, tumor progression after radiotherapy occurred in 47% of the patients. High MCM2 expression (HR 8.34, p = 0.03) was significantly associated with shorter PFS and remained an independent predictor of recurrence after adjustment for WHO grade, tumor size, and Ki-67 labeling index. Transcriptomic analyses of MCM2-high tumors revealed upregulation of cell proliferation-related pathways, accompanied by increased signaling through the E2F8-CHEK1 axis associated with radiation resistance and suppression of the TNF-α signaling pathway implicated in radiosensitivity. CONCLUSIONS: In meningiomas, high MCM2 expression is associated with early recurrence following radiotherapy. The study findings suggest that this association is driven by diverse biological mechanisms related to cell cycle regulation and radioresistance. Immunohistochemical assessment of MCM2 expression may serve as a practical and accessible biomarker for risk stratification and may support the future development of individualized postoperative radiotherapy strategies.

Humans↗

PubMed1999

Characterization of a new HLA-B38 allele (B3803) in a Spanish Caucasian individual which is closely related to the Oriental B38021 and B39021 alleles.

The broad HLA-B16 serologic specificity is divided into B38 and B39 splits associated to Bw4 and Bw6, respectively. Differential serologic variants have been defined for several molecular subtypes of B39 and for B38. We found a Spanish Caucasian individual carrying a B16 Bw4-associated antigen which was not recognized by reagents against B16 splits. Sequencing analysis showed a new B16 subtype termed B*3803. HLA class I sequence-based typing (SBT) analysis demonstrated that B*3803 co-segregates with A*2608 and Cw*1203, forming a common Caucasian haplotype. Sequence comparison with B*38 and B*39 subtypes evidences that although B*3803 is close related to B*3802, it only differs from B*39021 by six clustered nucleotide position in the Bw4/Bw6 motif, and strongly suggests that B*3803 could have evolved from, or be the ancestral gene of the Oriental-associated B*3802 and B*39021 alleles. However, more complex patterns of genetic events should be considered due to the Caucasian background of the B*3803 individual an its associated haplotype.

Alleles↗

PubMedDate not supplied

Surveillance for human Salmonella infections in the United States.

Surveillance for human Salmonella infections plays a critical role in understanding and controlling foodborne illness due to Salmonella. Along with its public health partners, the Centers for Disease Control and Prevention (CDC) has several surveillance systems that collect information on Salmonella infections in the United States. The National Salmonella Surveillance System, begun in 1962, receives reports of laboratory-confirmed Salmonella infections through state public health laboratories. Salmonella outbreaks are reported by state and local health departments through the Foodborne Disease Outbreak Reporting System, which became a Web-based, electronic system (eFORS) in 2001. PulseNet facilitates the detection of clusters of Salmonella infections through standardized molecular subtyping (DNA "fingerprinting") of isolates and maintenance of "fingerprint" databases. The National Antimicrobial Resistance Monitoring System for Enteric Bacteria (NARMS) monitors antimicrobial resistance in Salmonella by susceptibility testing of every 20th Salmonella isolate received by state and local public health laboratories. FootNet is an active surveillance system that monitors Salmonella infections in sentinel areas, providing population-based estimates of infection rates. Efforts are underway to electronically link all of the Salmonella surveillance systems at CDC to facilitate optimum use of available data and minimize duplication.

Animals↗

PubMed2026

Bibliometric analysis of retinoblastoma research over the past decade.

BACKGROUND: Retinoblastoma (RB), the most prevalent primary intraocular malignancy in children, has emerged as a model disease for exploring the molecular underpinnings of pediatric cancer. Over the past decade, research in this field has accelerated, propelled by advances in genomics, diagnostic imaging, targeted therapies, and global scientific collaboration. METHODS: This study systematically retrieved RB-related publications from 2015 to 2024 using the Web of Science Core Collection. A total of 4990 articles were included. CiteSpace and VOSviewer were employed to perform bibliometric and visual analyses across multiple dimensions, including countries, institutions, authors, journals, and thematic evolution. RESULTS: The United States and China were identified as the leading contributors, jointly accounting for over 40.55% of all publications. US-based journals led in both publication volume and citation impact, underscoring their global influence. Cluster analysis revealed 4 major research domains: clinical diagnosis, treatment, and prognosis; molecular mechanisms and signaling pathways; gene and protein function studies; and research methodologies and experimental models. CONCLUSION: RB research is transitioning into an era of precision oncology, characterized by molecular subtyping, novel therapeutic targets, and individualized treatment approaches. While diagnostic and therapeutic outcomes have markedly improved in high-income countries, significant disparities persist in low- and middle-income regions due to limited access to early detection and comprehensive care. Future priorities should include the refinement of preclinical models, investigation of drug resistance mechanisms, and promotion of international collaboration to standardize diagnostic and therapeutic strategies. These efforts are critical to improving global outcomes for children with RB.

Retinoblastoma↗

PubMed1999

Restriction fragment length polymorphism analysis of the flaA gene of Campylobacter jejuni for subtyping human, animal and poultry isolates.

233 strains of Campylobacter jejuni were subtyped by PCR-RFLP analysis of the flagellin (flaA) gene by double digestion with EcoRI and PstI (EP flaA-profiling). The strains represented a variety of common Penner heat stable (HS) serotypes and comprised isolates of human, bovine, ovine, chicken and canine origin. FlaA amplicons were obtained directly from DNA in cell lysates of most strains. RFLP analysis showed considerable allelic variation and nine EP flaA-types were identified of which the most common were type 2 (32%), type 3 (20%), type 4 (12%) and type 6 (12%). Other flaA-profiles each represented less than 10% of strains. C. jejuni strains of each serotype generally had one or two specifically associated flaA-types although some were features of several serotypes. Strains with the same flaA-type were found in different hosts. EP flaA-profiles were reproducible, clear and simple to record, and laboratory protocols were rapid and low cost with high throughput capacity. The EP flaA-profiling scheme provided an excellent molecular subtyping method to supplement HS serotyping, and reference strains are recommended to facilitate its use in future epidemiological investigations.

Animals↗

PubMed2006

Frequency, prognostic impact, and subtype association of 8p12, 8q24, 11q13, 12p13, 17q12, and 20q13 amplifications in breast cancers.

BACKGROUND: Oncogene amplification and overexpression occur in tumor cells. Amplification status may provide diagnostic and prognostic information and may lead to new treatment strategies. Chromosomal regions 8p12, 8q24, 11q13, 17q12 and 20q13 are recurrently amplified in breast cancers. METHODS: To assess the frequencies and clinical impact of amplifications, we analyzed 547 invasive breast tumors organized in a tissue microarray (TMA) by fluorescence in situ hybridization (FISH) and calculated correlations with histoclinical features and prognosis. BAC probes were designed for: (i) two 8p12 subregions centered on RAB11FIP1 and FGFR1 loci, respectively; (ii) 11q13 region centered on CCND1; (iii) 12p13 region spanning NOL1; and (iv) three 20q13 subregions centered on MYBL2, ZNF217 and AURKA, respectively. Regions 8q24 and 17q12 were analyzed with MYC and ERBB2 commercial probes, respectively. RESULTS: We observed amplification of 8p12 (amplified at RAB11FIP1 and/or FGFR1) in 22.8%, 8q24 in 6.1%, 11q13 in 19.6%, 12p13 in 4.1%, 17q12 in 9.9%, 20q13Z (amplified at ZNF217 only) in 9.9%, and 20q13Co (co-amplification of two or three 20q13 loci) in 8.5% of cases. The 8q24, 12p13, and 17q12 amplifications were correlated with high grade. The most frequent single amplifications were 8p12 (9.8%), 8q24 (3.3%) and 12p13 (3.3%), 20q13Z and 20q13Co (1.6%) regions. The 17q12 and 11q13 regions were never found amplified alone. The most frequent co-amplification was 8p12/11q13. Amplifications of 8p12 and 17q12 were associated with poor outcome. Amplification of 12p13 was associated with basal molecular subtype. CONCLUSION: Our results establish the frequencies, prognostic impacts and subtype associations of various amplifications and co-amplifications in breast cancers.

Adult↗

PubMed2004

An outbreak of gastroenteritis from a non-chlorinated community water supply.

STUDY OBJECTIVE: To determine the source and the extent of a community wide outbreak of gastroenteritis. DESIGN: A matched case-control study with postal questionnaires. Subtyping of campylobacter strains by pulsed field gel electrophoresis (PFGE). SETTING: A rural municipality with a population of 8600 in southern Finland, August 2000. Two thirds of the population receive non-chlorinated ground water from the municipal water supply. PARTICIPANTS: Cases were randomly selected among residents of the municipality who contacted the municipal health centre because of gastroenteritis and had illness onset between 31 July and 20 August 2000. Community controls were identified from the population registry and matched according to sex, year of birth, and postal code. MAIN RESULTS: Four hundred and sixty three persons contacted the municipal health centre because of gastroenteritis. Campylobacter jejuni was isolated from stool samples of 24 persons. One hundred and thirty seven cases and 388 controls were enrolled in the case-control study. In multivariate analysis, drinking unboiled water from the municipal supply was significantly associated with illness (odds ratio 11.1, 95% confidence interval 1.4 to 90.2). C jejuni was isolated from one tap water sample. The water isolate and all but one of the patient isolates were indistinguishable by PFGE. CONCLUSIONS: Combining epidemiological investigation with molecular subtyping methods provided strong evidence that water was the source of the outbreak. Non-chlorinated small ground water systems may be susceptible to waterborne outbreaks and constitute a risk to rural populations.

Adolescent↗

PubMed1993

Allelic typing of the HLA-DR4 group by polymerase chain reaction--single-strand conformation polymorphism analysis.

The technique of SSCP was applied to the molecular subtyping of the HLA-DR4 group of alleles. SSCPs were defined in 16 cell line DNAs, representing the alleles DRB1*0401-*0411 (except DRB1*0409), using group-specific PCR amplification, nondenaturing polyacrylamide gel electrophoresis, and silver staining. Three sets of gel electrophoresis conditions were necessary to differentiate the 10 alleles tested. The SSCPs defined in the cell line DNAs were validated by analysis of 145 unrelated HLA-DR4-positive individuals previously genotyped for DRB1*04 alleles by sequence-specific oligotyping. This study demonstrates the suitability of the SSCP technique for defining DRB1*04 alleles, particularly when a small number of samples require typing.

Alleles↗

PubMed2025

A comparative genomic analysis of left- and right-sided colon cancer using real-world data from the AACR project GENIE BPC dataset.

Left- and Right-sided colon cancers (LCC and RCC) are increasingly recognized as distinct clinicopathological and molecular subtypes with divergent prognoses and therapeutic responses. Leveraging a large, multi-institutional cohort from the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC) (n = 750; LCC: 363 vs. RCC: 387), we conducted a comprehensive analysis of mutational profiles, tumor mutation burden (TMB), and survival outcomes. Our findings revealed a markedly higher TMB in RCC compared to LCC (6.65 ± 11.3 vs. 3.17 ± 4.35; adjusted P = 3.12×10-32), suggesting greater genomic instability in RCC. After applying functional annotation filters (PolyPhen > 0.85, SIFT < 0.05), RCC tumors were significantly enriched for mutations in BRAF (23.1% vs. 6.7%), KMT2D (8.6% vs. 3.2%), and SMAD4 (13.1% vs. 7.3%), while TP53 mutations predominated in LCC (40.6% vs. 31.8%). Multivariate Cox regression analysis identified RCC as an independent predictor of poorer overall survival (OS) relative to LCC (HR: 1.30, 95% CI: 1.02-1.66, P = 0.033). Notably, KRAS mutations were associated with significantly worse OS in LCC (HR: 1.68, 95% CI: 1.06-2.70, P = 0.027), while BRAF mutations predicted adverse outcomes in RCC (HR: 1.58, 95% CI: 1.05-2.37, P = 0.028). These results underscore the prognostic value of tumor sidedness and specific genetic alterations in colon adenocarcinoma. Our study highlights the need for sidedness-specific molecular profiling to inform precision oncology strategies in colon cancer management.

BRAF↗

PubMed2005

Molecular epidemiology of community- and health care-associated methicillin-resistant Staphylococcus aureus in Manitoba, Canada.

Recently, acquisition of methicillin-resistant Staphylococcus aureus (MRSA) has been increasingly seen in community settings. Beginning in 1995, we have routinely conducted pulsed-field gel electrophoresis (PFGE) of MRSA isolates received at Cadham Provincial Laboratory (CPL) in Manitoba, Canada. Our diverse collection of isolates coupled with molecular subtype information allowed us to assess the extent to which MRSA isolates in general were associated with community acquisition and whether specific PFGE types were more likely to be found in community settings. Forty percent of the MRSA isolates in our analysis were designated community associated (CA), with two of the six most common PFGE types showing a greater likelihood to be CA-MRSA. Overall, CA-MRSA were more likely to show multiple sensitivity to antibiotics and to be associated with younger age groups. Mapping of specific CA-MRSA types over successive 5-year periods showed rapid temporal shifts in prevalence in different parts of the province.

Adult↗

PubMed2006

Expression of full-length p53 and its isoform Deltap53 in breast carcinomas in relation to mutation status and clinical parameters.

BACKGROUND: The tumor suppressor gene p53 (TP53) controls numerous signaling pathways and is frequently mutated in human cancers. Novel p53 isoforms suggest alternative splicing as a regulatory feature of p53 activity. RESULTS: In this study we have analyzed mRNA expression of both wild-type and mutated p53 and its respective Deltap53 isoform in 88 tumor samples from breast cancer in relation to clinical parameters and molecular subgroups. Three-dimensional structure differences for the novel internally deleted p53 isoform Deltap53 have been predicted. We confirmed the expression of Deltap53 mRNA in tumors using quantitative real-time PCR technique. The mRNA expression levels of the two isoforms were strongly correlated in both wild-type and p53-mutated tumors, with the level of the Deltap53 isoform being approximately 1/3 of that of the full-length p53 mRNA. Patients expressing mutated full-length p53 and non-mutated (wild-type) Deltap53, "mutational hybrids", showed a slightly higher frequency of patients with distant metastasis at time of diagnosis compared to other patients with p53 mutations, but otherwise did not differ significantly in any other clinical parameter. Interestingly, the p53 wild-type tumors showed a wide range of mRNA expression of both p53 isoforms. Tumors with mRNA expression levels in the upper or lower quartile were significantly associated with grade and molecular subtypes. In tumors with missense or in frame mutations the mRNA expression levels of both isoforms were significantly elevated, and in tumors with nonsense, frame shift or splice mutations the mRNA levels were significantly reduced compared to those expressing wild-type p53. CONCLUSION: Expression of p53 is accompanied by the functionally different isoform Deltap53 at the mRNA level in cell lines and human breast tumors. Investigations of "mutational hybrid" patients highlighted that wild-type Deltap53 does not compensates for mutated p53, but rather may be associated with a worse prognosis. In tumors, both isoforms show strong correlations in different mutation-dependent mRNA expression patterns.

Alternative Splicing↗