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Sökning: WFRF:(Zingmark Carl 1975 )

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1.
  • Bodén, Stina, et al. (författare)
  • C-reactive Protein and Future Risk of Clinical and Molecular Subtypes of Colorectal Cancer
  • 2020
  • Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 29:7, s. 1482-1491
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Inflammation has been implicated in colorectal cancer etiology, but the relationship between C-reactive protein (CRP) and colorectal cancer risk is unclear. We aimed to investigate the association between prediagnostic plasma CRP concentrations and the risk of clinical and molecular colorectal cancer subtypes.Methods: We used prospectively collected samples from 1,010 matched colorectal cancer case-control pairs from two population-based cohorts in Northern Sweden, including 259 with repeated samples. Conditional logistic regression and linear mixed models were used to estimate relative risks of colorectal cancer, including subtypes based on BRAF and KRAS mutations, microsatellite instability status, tumor location, stage, lag time, and (using unconditional logistic regression) body mass index.Results: CRP was not associated with colorectal cancer risk, regardless of clinical or molecular colorectal cancer subtype. For participants with advanced tumors and blood samples <5 years before diagnosis, CRP was associated with higher risk [OR per 1 unit increase in natural logarithm (In) transformed CRP, 1.32; 95% confidence interval (CI), 1.01-1.73]. CRP levels increased over time, but average time trajectories were similar for cases and controls (P-interaction = 0.19).Conclusions: Our results do not support intertumoral heterogeneity as an explanation for previous inconsistent findings regarding the role of CRP in colorectal cancer etiology. The possible association in the subgroup with advanced tumors and shorter follow-up likely reflects undiagnosed cancer at baseline. Impact: Future efforts to establish the putative role of chronic, low-grade inflammation in colorectal cancer development will need to address the complex relationship between systemic inflammatory factors and tumor microenvironment, and might consider larger biomarker panels than CRP alone.
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2.
  • Bodén, Stina, et al. (författare)
  • Plasma concentrations of gut hormones acyl ghrelin and peptide YY and subsequent risk of colorectal cancer and molecular tumor subtypes
  • 2023
  • Ingår i: Cancer Prevention Research. - : American Association for Cancer Research. - 1940-6207 .- 1940-6215. ; 16:2, s. 75-87
  • Tidskriftsartikel (refereegranskat)abstract
    • Obesity and metabolic dysfunction are implicated in colorectal cancer development. Appetite-regulating gut hormones might have a role in colorectal cancer risk. We investigated whether circulating levels of the gut hormones ghrelin (analyzed as acyl ghrelin) and Peptide YY (PYY) were associated with subsequent colorectal cancer risk, including clinical and molecular tumor subtypes. We also provide descriptive data on these hormones in relation to background participant characteristics and metabolic biomarkers. This population-based study included 1,010 matched case-control pairs with a median of 12.3 years of follow-up. Acyl ghrelin and PYY were measured by multiplex immunoassay. Data on KRAS and BRAF mutations and microsatellite instability (MSI) status were available for 704 and 708 cases, respectively. Conditional logistic regression models estimated association to colorectal cancer risk. Partial correlation and linear regression were used to investigate relationships between background and metabolic variables and variation in plasma gut hormone concentrations. Acyl ghrelin was not clearly associated with colorectal cancer risk (multivariable OR per 1 SD increase: 1.11; 95% CI, 1.00-1.23). Positive associations were observed for specific subtypes, in particular BRAF-mutated colorectal cancer and right-sided colon cancer, although with nonsignificant heterogeneity. PYY was not related to colorectal cancer risk (multivariable OR per 1 SD: 1.04; 95% CI, 0.95-1.14) or any tumor subtype. In the control participants, ghrelin was inversely correlated with BMI, and PYY was positively correlated with C-peptide and insulin levels. These findings provide limited support for a possible role for ghrelin in colorectal cancer development, primarily in specific anatomical and molecular tumor subtypes.PREVENTION RELEVANCE: The findings of this study do not support a major role for the metabolic gut hormones ghrelin and PYY in colorectal cancer development but suggest the possibility of an involvement for ghrelin in specific tumor subtypes. Elucidating subtype-specific risk factors and mechanisms of carcinogenesis may have implications for precision prevention.
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3.
  • Conlan, J Wayne, et al. (författare)
  • Differential ability of novel attenuated targeted deletion mutants of Francisella tularensis subspecies tularensis strain SCHU S4 to protect mice against aerosol challenge with virulent bacteria : effects of host background and route of immunization
  • 2010
  • Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 28:7, s. 1824-1831
  • Tidskriftsartikel (refereegranskat)abstract
    • Francisella tularensis subspecies tularensis is a highly virulent facultative intracellular pathogen of humans and a potential biological weapon. A live vaccine strain, F. tularensis LVS, was developed more than 50 years ago by pragmatic attenuation of a strain of the less virulent holarctica subspecies. LVS was demonstrated to be highly effective in human volunteers who were exposed to intradermal challenge with fully virulent subsp. tularensis, but was less effective against aerosol exposure. LVS faces regulatory hurdles that to date have prevented its licensure for general use. Therefore, a better defined and more effective vaccine is being sought. To this end we have created gene deletion mutants in the virulent subsp. tularensis strain and tested them for their ability to elicit a protective immune response against systemic or aerosol challenge with the highly virulent wild-type subsp. tularensis strain, SCHU S4. Both oral and intradermal (ID) primary vaccination routes were assessed in BALB/c and C3H/HeN mice as was oral boosting. One SCHU S4 mutant missing the heat shock gene, clpB, was significantly more attenuated than LVS whereas a double deletion mutant missing genes FTT0918 and capB was as attenuated as LVS. In general mice immunized with SCHU S4DeltaclpB were significantly better protected against aerosol challenge than mice immunized with LVS. A single ID immunization of BALB/c mice with SCHU S4DeltaclpB was at least as effective as any other regimen examined. Mice immunized with SCHU S4Delta0918DeltacapB were generally protected to a similar degree as mice immunized with LVS. A preliminary examination of immune responses to vaccination with LVS, SCHU S4DeltaclpB, or SCHU S4Delta0918DeltacapB provided no obvious correlate to their relative efficacies.
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4.
  • Edin, Sofia, et al. (författare)
  • Opposing roles by KRAS and BRAF mutation on immune cell infiltration in colorectal cancer : possible implications for immunotherapy
  • 2024
  • Ingår i: British Journal of Cancer. - : Springer Nature. - 0007-0920 .- 1532-1827. ; 130
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The immune response has important clinical value in colorectal cancer (CRC) in both prognosis and response to immunotherapy. This study aims to explore tumour immune cell infiltration in relation to clinically well-established molecular markers of CRC.Methods: Multiplex immunohistochemistry and multispectral imaging was used to evaluate tumour infiltration of cytotoxic T cells (CD8+), Th1 cells (T-bet+), T regulatory cells (FoxP3+), B cells (CD20+), and macrophages (CD68+) in a cohort of 257 CRC patients.Results: We found the expected association between higher immune-cell infiltration and microsatellite instability. Also, whereas BRAF-mutated tumours displayed increased immune-cell infiltration compared to BRAF wild-type tumours, the opposite was seen for KRAS-mutated tumours, differences that were most prominent for cytotoxic T cells and Th1 cells. The opposing relationships of BRAF and KRAS mutations with tumour infiltration of cytotoxic T cells was validated in an independent cohort of 608 CRC patients. A positive prognostic importance of cytotoxic T cells was found in wild-type as well as KRAS and BRAF-mutated CRCs in both cohorts.Conclusion: A combined evaluation of MSI status, KRAS and BRAF mutational status, and immune infiltration (cytotoxic T cells) may provide important insights to prognosis and response to immunotherapy in CRC.
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5.
  • Eklöf, Vincy, 1984-, et al. (författare)
  • Cancer-associated fecal microbial markers in colorectal cancer detection
  • 2017
  • Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 141:12, s. 2528-2536
  • Tidskriftsartikel (refereegranskat)abstract
    • Colorectal cancer (CRC) is the second most common cause of cancer death in the western world. An effective screening program leading to early detection of disease would severely reduce the mortality of CRC. Alterations in the gut microbiota have been linked to CRC, but the potential of microbial markers for use in CRC screening has been largely unstudied. We used a nested case-control study of 238 study subjects to explore the use of microbial markers for clbA+ bacteria harboring the pks pathogenicity island, afa-C+ diffusely adherent Escherichia coli harboring the afa-1 operon, and Fusobacterium nucleatum in stool as potential screening markers for CRC. We found that individual markers for clbA+ bacteria and F. nucleatum were more abundant in stool of patients with CRC, and could predict cancer with a relatively high specificity (81.5% and 76.9%, respectively) and with a sensitivity of 56.4% and 69.2%, respectively. In a combined test of clbA+ bacteria and F. nucleatum, CRC was detected with a specificity of 63.1% and a sensitivity of 84.6%. Our findings support a potential value of microbial factors in stool as putative noninvasive biomarkers for CRC detection. We propose that microbial markers may represent an important future screening strategy for CRC, selecting patients with a "high-risk" microbial pattern to other further diagnostic procedures such as colonoscopy.
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6.
  • Kadzhaev, Konstantin, et al. (författare)
  • Identification of genes contributing to the virulence of Francisella tularensis SCHU S4 in a mouse intradermal infection model
  • 2009
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:5, s. e5463-
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Francisella tularensis is a highly virulent human pathogen. The most virulent strains belong to subspecies tularensis and these strains cause a sometimes fatal disease. Despite an intense recent research effort, there is very limited information available that explains the unique features of subspecies tularensis strains that distinguish them from other F. tularensis strains and that explain their high virulence. Here we report the use of targeted mutagenesis to investigate the roles of various genes or pathways for the virulence of strain SCHU S4, the type strain of subspecies tularensis.METHODOLOGY/PRINCIPAL FINDINGS: The virulence of SCHU S4 mutants was assessed by following the outcome of infection after intradermal administration of graded doses of bacteria. By this route, the LD(50) of the SCHU S4 strain is one CFU. The virulence of 20 in-frame deletion mutants and 37 transposon mutants was assessed. A majority of the mutants did not show increased prolonged time to death, among them notably Delta pyrB and Delta recA. Of the remaining, mutations in six unique targets, tolC, rep, FTT0609, FTT1149c, ahpC, and hfq resulted in significantly prolonged time to death and mutations in nine targets, rplA, wbtI, iglB, iglD, purL, purF, ggt, kdtA, and glpX, led to marked attenuation with an LD(50) of > 10(3) CFU. In fact, the latter seven mutants showed very marked attenuation with an LD(50) of > or = 10(7) CFU.CONCLUSIONS/SIGNIFICANCE: The results demonstrate that the characterization of targeted mutants yielded important information about essential virulence determinants that will help to identify the so far little understood extreme virulence of F. tularensis subspecies tularensis.
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7.
  • Kerdreux, Maïwenn, et al. (författare)
  • Porphyromonas gingivalis in colorectal cancer and its association to patient prognosis
  • 2023
  • Ingår i: Journal of Cancer. - : Ivyspring International Publisher. - 1837-9664. ; 14:9, s. 1479-1485
  • Tidskriftsartikel (refereegranskat)abstract
    • Microbiota dysbiosis may affect both the development and progression of colorectal cancer (CRC). Large metagenomic studies have highlighted specific oral bacteria linked to CRC including Porphyromonas gingivalis. Few studies have however analysed the implications of this bacterium in CRC progression and survival. In this study, we investigated the intestinal presence of P. gingivalis by qPCR in both faecal and mucosal samples from two different patient cohorts, including patients with precancerous dysplasia or CRC, as well as controls. P. gingivalis was detected in 2.6-5.3% of CRC patients and significantly different levels of P. gingivalis were found in faeces of CRC patients compared to controls (P = 0.028). Furthermore, an association was found between the presence of P. gingivalis in faeces and tumour tissue (P < 0.001). Our findings further suggested a potential link between mucosal P. gingivalis and tumours of MSI subtype (P = 0.040). Last but not least, patients with faecal P. gingivalis were found to have a significantly decreased cancer-specific survival (P = 0.040). In conclusion, P. gingivalis could be linked to patients with CRC and to a worse patient prognosis. Further studies are needed to elucidate the role of P. gingivalis in CRC pathogenesis.
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8.
  • Li, Xingru, et al. (författare)
  • A Detailed Flow Cytometric Analysis of Immune Activity Profiles in Molecular Subtypes of Colorectal Cancer
  • 2020
  • Ingår i: Cancers. - : MDPI. - 2072-6694. ; 12:11
  • Tidskriftsartikel (refereegranskat)abstract
    • The local anti-tumour immune response has important prognostic value in colorectal cancer (CRC). In the era of immunotherapy, a better understanding of the immune response in molecular subgroups of CRC may lead to significant advances in personalised medicine. On this note, microsatellite instable (MSI) tumours have been characterised by increased immune infiltration, suggesting MSI as a marker for immune inhibitor checkpoint therapy. Here, we used flow cytometry to perform a comprehensive analysis of immune activity profiles in tumour tissues, adjacent non-malignant tissues and blood, from a cohort of 69 CRC patients. We found several signs of immune suppression in tumours compared to adjacent non-malignant tissues, including T cells more often expressing the immune checkpoint molecules programmed cell death protein (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). We further analysed immune cell infiltration in molecular subgroups of CRC. MSI tumours were indeed found to be associated with increased immune infiltration, including increased fractions of PD-1+ T cells. No correlation was, however, found between MSI and the fraction of CTLA-4+ T cells. Interestingly, within the group of patients with microsatellite stable (MSS) tumours, some also presented with increased immune infiltration, including comparably high portions of PD-1+ T cells, but also CTLA-4+ T cells. Furthermore, no correlation was found between PD-1+ and CTLA-4+ T cells, suggesting that different tumours may, to some extent, be regulated by different immune checkpoints. We further evaluated the distribution of immune activity profiles in the consensus molecular subtypes of CRC. In conclusion, our findings suggest that different immune checkpoint inhibitors may be beneficial for selected CRC patients irrespective of MSI status. Improved predictive tools are required to identify these patients.
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9.
  • Li, Xingru, et al. (författare)
  • A modified protein marker panel to identify four consensus molecular subtypes in colorectal cancer using immunohistochemistry
  • 2021
  • Ingår i: Pathology, Research and Practice. - : Elsevier. - 0344-0338 .- 1618-0631. ; 220
  • Tidskriftsartikel (refereegranskat)abstract
    • Colorectal cancer (CRC) is a heterogeneous disease with different genetic and molecular backgrounds, leading to a diverse patient prognosis and treatment response. Four consensus molecular subtypes (CMS 1–4) have recently been proposed based on transcriptome profiling. A clinically practical immunohistochemistry (IHC) based CMS classifier consisting of the four markers FRMD6, ZEB1, HTR2B, and CDX2 was then demonstrated. However, the IHC-CMS classifier did not distinguish between CMS2 and CMS3 tumours. In this study, we have applied the proposed transcriptome based and IHC-based CMS classifiers in a CRC cohort of 65 patients and found a concordance of 77.5 %. Further, we modified the IHC-CMS classifier by analysing the differentially expressed genes between CMS2 and CMS3 tumours using RNA-sequencing data from the TCGA dataset. The result showed that WNT signalling was among the most upregulated pathways in CMS2 tumours, and the expression level of CTNNB1 (encoding β-catenin), a WNT pathway hallmark, was significantly upregulated (P = 1.15 × 10−6). We therefore introduced nuclear β-catenin staining to the IHC-CMS classifier. Using the modified classifier in our cohort, we found a 71.4 % concordance between the IHC and RNA-sequencing based CMS classifiers. Moreover, β-catenin staining could classify 16 out of the 19 CMS2/3 tumours into CMS2 or CMS3, thereby showing an 84.2 % concordance with the RNA-sequencing-based classifier. In conclusion, we evaluated CMS classifiers based on transcriptome and IHC analysis. We present a modified IHC panel that categorizes CRC tumours into the four CMS groups. To our knowledge, this is the first study using IHC to identify all four CMS groups.
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10.
  • Li, Xingru, et al. (författare)
  • Ex Vivo Organoid Cultures Reveal the Importance of the Tumor Microenvironment for Maintenance of Colorectal Cancer Stem Cells
  • 2020
  • Ingår i: Cancers. - : MDPI. - 2072-6694. ; 12:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Colorectal cancer (CRC) is a heterogeneous disease, with varying clinical presentations and patient prognosis. Different molecular subgroups of CRC should be treated differently and therefore, must be better characterized. Organoid culture has recently been suggested as a good model to reflect the heterogeneous nature of CRC. However, organoid cultures cannot be established from all CRC tumors. The study examines which CRC tumors are more likely to generate organoids and thus benefit from ex vivo organoid drug testing. Long-term organoid cultures from 22 out of 40 CRC tumor specimens were established. It was found that organoid cultures were more difficult to establish from tumors characterized as microsatellite instable (MSI), BRAF-mutated, poorly differentiated and/or of a mucinous type. This suggests that patients with such tumors are less likely to benefit from ex vivo organoid drug testing, but it may also suggest biological difference in tumor growth. RNA sequencing analysis of tumor sections revealed that the in vivo maintenance of these non-organoid-forming tumors depends on factors related to inflammation and pathogen exposure. Furthermore, using TCGA data we could show a trend towards a worse prognosis for patients with organoid-forming tumors, suggesting also clinical differences. Results suggest that organoids are more difficult to establish from tumors characterized as MSI, BRAF-mutated, poorly differentiated and/or of a mucinous type. We further suggest that the maintenance of cell growth of these tumors in vivo may be promoted by immune-related factors and other stromal components within the tumor microenvironment.
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