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- Ellegård, Sander, et al.
(författare)
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ERBB2 and PTPN2 gene copy numbers as prognostic factors in HER2-positive metastatic breast cancer treated with trastuzumab
- 2019
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Ingår i: Oncology Letters. - Athens, Greece : Spandidos Publications. - 1792-1074 .- 1792-1082. ; 17:3, s. 3371-3381
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Tidskriftsartikel (refereegranskat)abstract
- Trastuzumab has markedly improved the treatment and long-term prognosis of patients with HER2-positive breast cancer. A frequent clinical challenge in patients with relapsing and/or metastatic disease is de novo or acquired trastuzumab resistance, and to date no predictive biomarkers for palliative trastuzumab have been established. In the present study, the prognostic values of factors involved in the HER2-associated PI3K/Akt signalling pathway were explored. The first 46 consecutive patients treated at the Department of Oncology, Linkoping University Hospital between 2000 and 2007 with trastuzumab for HER2-positive metastatic breast cancer were retrospectively included. The gene copy number variation and protein expression of several components of the PI3K/Akt pathway were assessed in the tumour tissue and biopsy samples using droplet digital polymerase chain reaction and immunohistochemistry. Patients with tumours displaying a high-grade ERBB2 (HER2) amplification level of amp;gt;= 6 copies had a significantly improved overall survival hazard ratio [(HR)=0.4; 95%, confidence interval (CI): 0.2-0.9] and progression-free survival (HR=0.3; 95% CI: 0.1-0.7) compared with patients with tumours harbouring fewer ERBB2 copies. High-grade ERBB2 amplification was significantly associated with the development of central nervous system metastases during palliative treatment. Copy gain (amp;gt;= 3 copies) of the gene encoding the tyrosine phosphatase PTPN2 was associated with a shorter overall survival (HR=2.0; 95% CI: 1.0-4.0) and shorter progression-free survival (HR=2.1; 95% CI: 1.0-4.1). In conclusion, high ERBB2 amplification level is a potential positive prognostic factor in trastuzumab-treated HER2-positive metastatic breast cancer, whereas PTPN2 gain is a potential negative prognostic factor. Further studies are warranted on the role of PTPN2 in HER2 signalling.
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| 2. |
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| 3. |
- Fagerström, Anna, 1980-, et al.
(författare)
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Comparative distribution of extended-spectrum beta-lactamase-producing Escherichia coli from urine infections and environmental waters
- 2019
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Ingår i: PLOS ONE. - : PLOS. - 1932-6203. ; 14:11
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Tidskriftsartikel (refereegranskat)abstract
- Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli have been reported in natural environments, and may be released through wastewater. In this study, the genetic relationship between ESBL-producing E. coli collected from patient urine samples (n = 45, both hospitalized patients and out-patients) and from environmental water (n = 82, from five locations), during the same time period, was investigated. Three independent water samples were collected from the municipal wastewater treatment plant, both incoming water and treated effluent water; the receiving river and lake; and a bird sanctuary near the lake, on two different occasions. The water was filtered and cultured on selective chromID ESBL agar plates in order to detect and isolate ESBL-producing E. coli. Illumina whole genome sequencing was performed on all bacterial isolates (n = 127). Phylogenetic group B2 was more common among the clinical isolates than the environmental isolates (44.4% vs. 17.1%, p < 0.01) due to a significantly higher prevalence of sequence type (ST) 131 (33.3% vs. 13.4%, p < 0.01). ST131 was, however, one of the most prevalent STs among the environmental isolates. There was no significant difference in diversity between the clinical isolates (DI 0.872 (0.790-0.953)) and the environmental isolates (DI 0.947 (0.920-0.969)). The distribution of ESBL genes was similar: blaCTX-M-15 dominated, followed by blaCTX-M-14 and blaCTX-M-27 in both the clinical (60.0%, 8.9%, and 6.7%) and the environmental isolates (62.2%, 12.2%, and 8.5%). Core genome multi-locus sequence typing showed that five environmental isolates, from incoming wastewater, treated wastewater, Svartån river and Hjälmaren lake, were indistinguishable or closely related (≤10 allele differences) to clinical isolates. Isolates of ST131, serotype O25:H4 and fimtype H30, from the environment were as closely related to the clinical isolates as the isolates from different patients were. This study confirms that ESBL-producing E. coli are common in the aquatic environment even in low-endemic regions and suggests that wastewater discharge is an important route for the release of ESBL-producing E. coli into the aquatic environment.
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| 4. |
- Fagerström, Anna, 1980-
(författare)
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Long-term molecular epidemiology of extended-spectrum β-lactamase producing Escherichia coli in a low-endemic setting
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Escherichia coli is a commensal inhabitant in the gastro-intestinal tract of humans and animals but it is also the most common bacterial species causing urinary tract infection, which ranges in severity from distal cystitis to urosepsis and septic shock. During the past decades, the prevalence of antibiotic resistant E. coli has increased worldwide. Extended-spectrum β-lactamases (ESBL) causes resistance to β-lactam antibiotics, the most widely used class of antibiotics. The genes encoding ESBL, bla, are usually carried on conjugative plasmids, which can be transferred between different bacterial lineages and different species. These plasmids frequently also carry resistance genes to additional antibiotic classes, and ESBL-producing E. coli are therefore often multidrug-resistant. The aim of this thesis was to describe the long-term molecular epidemiology of ESBL-producing E. coli in Örebro County during the time when they first started to emerge. In addition, potential transmission to the environment was investigated by performing a comparative analysis on ESBL-producing E. coli isolated from patients and from the aquatic environment in Örebro city. In general, the E. coli population was genetically diverse, but the pandemic lineage ST131, first identified in 2004, appears to have been responsible for the dramatic increase of CTX-M-15-producing E.coli observed during the late 2000s. CTX-M-15 was the most prevalent ESBL-type followed by CTX-M-14 and these genes were mainly found on plasmids belonging to the IncF or IncI1 families. Continuous horizontal transmission of IncI1 ST31 and ST37 plasmids between diverse E. coli lineages have also contributed to the dissemination of blaCTX-M-15 in Örebro County. Extended spectrum β-lactamase-producing E. coli were found to be common in the aquatic environment in Örebro city and E. coli lineages genetically similar to those causing infections in humans were present in environmental waters indicating that transmission of ESBL-producing E. colifrom humans to the aquatic environment likely has occurred.
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| 5. |
- Werner, Anders, et al.
(författare)
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Whole genome sequencing of Clostridioides difficile PCR ribotype 046 suggests transmission between pigs and humans
- 2020
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Ingår i: PLOS ONE. - : PLOS. - 1932-6203. ; 15:12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A zoonotic association has been suggested for several PCR ribotypes (RTs) of Clostridioides difficile. In central parts of Sweden, RT046 was found dominant in neonatal pigs at the same time as a RT046 hospital C. difficile infection (CDI) outbreak occurred in the southern parts of the country.OBJECTIVE: To detect possible transmission of RT046 between pig farms and human CDI cases in Sweden and investigate the diversity of RT046 in the pig population using whole genome sequencing (WGS).METHODS: WGS was performed on 47 C. difficile isolates from pigs (n = 22), the farm environment (n = 7) and human cases of CDI (n = 18). Two different core genome multilocus sequencing typing (cgMLST) schemes were used together with a single nucleotide polymorphisms (SNP) analysis and the results were related to time and location of isolation of the isolates.RESULTS: The pig isolates were closely related (≤6 cgMLST alleles differing in both cgMLST schemes) and conserved over time and were clearly separated from isolates from the human hospital outbreak (≥76 and ≥90 cgMLST alleles differing in the two cgMLST schemes). However, two human isolates were closely related to the pig isolates, suggesting possible transmission. The SNP analysis was not more discriminate than cgMLST.CONCLUSION: No general pattern suggesting zoonotic transmission was apparent between pigs and humans, although contrasting results from two isolates still make transmission possible. Our results support the need for high resolution WGS typing when investigating hospital and environmental transmission of C. difficile.
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| 6. |
- Ziegler, Ingrid, 1976-, et al.
(författare)
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Evaluation of a Commercial Multiplex PCR Assay for Detection of Pathogen DNA in Blood from Patients with Suspected Sepsis
- 2016
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Ingår i: PLOS ONE. - San Francisco, USA : Public Library of Science. - 1932-6203. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- The Magicplex Sepsis Real-time Test (MST) is a commercial multiplex PCR that can detect more than 90 different pathogens in blood, with an analysis time of six hours. The aim of the present study was to evaluate this method for the detection of bloodstream infection (BSI). An EDTA whole blood sample for MST was collected together with blood cultures (BC) from patients with suspected sepsis at the Emergency Department of a university hospital. Among 696 study patients, 322 (46%) patients were positive with at least one method; 128 (18%) were BC positive and 268 (38%) were MST positive. Considering BC to be the gold standard, MST had an overall sensitivity of 47%, specificity of 66%, positive predictive value (PPV) of 23%, and a negative predictive value of 87%. Among the MST positive samples with a negative BC, coagulase-negative staphylococci (CoNS) and species that rarely cause community-acquired BSI were frequently noted. However, the quantification cycle (Cq) values of the MST+/BC- results were often high. We thus hypothesized that the performance of the MST test could be improved if the Cq cut-off level was adjusted downwards. With a lower Cq cut-off value, i.e. 6.0 for Staphylococcus species and 9.0 for all other species, the number of MST positive cases decreased to 83 (12%) and the overall sensitivity decreased to 38%. However, the PPV increased to 59% and the specificity increased to 96%, as many MST positive results for CoNS and bacteria that rarely cause community-acquired BSI turned MST negative. In conclusion, our study shows that with a lower Cq cut-off value, the MST will detect less contaminants and findings with unclear relevance, but to the cost of a lower sensitivity. Consequently, we consider that a positive MST results with a Cq value above the adjusted cut-off should be interpreted with caution, as the result might be clinically irrelevant. In a correspondent way, quantitative results could probably be useful in the interpretation of positive results from other molecular assays for the detection of BSI.
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