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Sökning: WFRF:(Sjöblom Tobias)

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1.
  • Ali, Muhammad Akhtar, et al. (författare)
  • The transcriptional modulator ZBED6 regulates cell cycle and growth of human colorectal cancer cells
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • The transcription factor ZBED6 is a repressor of IGF2 whose action impacts development, cell proliferation and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Transcriptome analyses revealed enrichment of cell cycle-related processes among differentially expressed genes in both cell lines. Chromatin immunoprecipitation sequencing analyses displayed enrichment of ZBED6 binding at genes upregulated in ZBED6-/- knockout clones. Ten differentially expressed genes were identified as putative direct gene targets and their downregulation by ZBED6 was experimentally validated. Eight of these genes were linked to the Wnt, Hippo, TGF-b, EGFR or PI3K pathways, all involved in colorectal cancer development. Ablation of ZBED6 affected the cell cycle and led to increased growth rate of ZBED6-/- RKO cells. These observations support a role for transcriptional modulation by ZBED6 in cell cycle regulation and growth of colorectal cancers.
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3.
  • Ali, Muhammad Akhtar, et al. (författare)
  • Molecular pathways in tumor progression : from discovery to functional understanding
  • 2009
  • Ingår i: Molecular bioSystems. - : Royal Society of Chemistry (RSC). - 1742-206X .- 1742-2051. ; 5:9, s. 902-908
  • Forskningsöversikt (refereegranskat)abstract
    • The advent of large scale sequencing methods has enabled analyses of the protein-coding parts of cancer genomes to find the mutated genes that cause common human cancers. Unbiased mutation analyses of human tumors originating in the breast, colon, brain, and pancreas have revealed genomic landscapes composed of a few frequently mutated genes alongside a multitude of infrequently mutated genes. These analyses have revealed a stark heterogeneity in the compendium of mutated genes even among tumors of the same tissue origin, and provide evidence for a larger number of driver mutations during tumorigenesis than hitherto presumed. From the multitude of mutated genes, a limited number of central molecular pathways are emerging. Systems biology approaches will be increasingly important to identify and better define these core pathways. Downstream of genetic analyses, scalable methods for prediction and experimental determination of the phenotypes of mutant alleles and pathways will be instrumental for improved mechanistic understanding of cancer as well as future drug discovery efforts.
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4.
  • Ali, Muhammad Akhtar (författare)
  • Understanding Cancer Mutations by Genome Editing
  • 2014
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Mutational analyses of cancer genomes have identified novel candidate cancer genes with hitherto unknown function in cancer. To enable phenotyping of mutations in such genes, we have developed a scalable technology for gene knock-in and knock-out in human somatic cells based on recombination-mediated construct generation and a computational tool to design gene targeting constructs. Using this technology, we have generated somatic cell knock-outs of the putative cancer genes ZBED6 and DIP2C in human colorectal cancer cells. In ZBED6-/- cells complete loss of functional ZBED6 was validated and loss of ZBED6 induced the expression of IGF2. Whole transcriptome and ChIP-seq analyses revealed relative enrichment of ZBED6 binding sites at upregulated genes as compared to downregulated genes. The functional annotation of differentially expressed genes revealed enrichment of genes related to cell cycle and cell proliferation and the transcriptional modulator ZBED6 affected the cell growth and cell cycle of human colorectal cancer cells. In DIP2C-/-cells, transcriptome sequencing revealed 780 differentially expressed genes as compared to their parental cells including the tumour suppressor gene CDKN2A. The DIP2C regulated genes belonged to several cancer related processes such as angiogenesis, cell structure and motility. The DIP2C-/-cells were enlarged and grew slower than their parental cells. To be able to directly compare the phenotypes of mutant KRAS and BRAF in colorectal cancers, we have introduced a KRASG13D allele in RKO BRAFV600E/-/-/ cells. The expression of the mutant KRAS allele was confirmed and anchorage independent growth was restored in KRASG13D cells. The differentially expressed genes both in BRAF and KRAS mutant cells included ERBB, TGFB and histone modification pathways. Together, the isogenic model systems presented here can provide insights to known and novel cancer pathways and can be used for drug discovery.
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5.
  • Alvez, Maria Bueno, et al. (författare)
  • Next generation pan-cancer blood proteome profiling using proximity extension assay
  • 2023
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
  • Tidskriftsartikel (refereegranskat)abstract
    • A comprehensive characterization of blood proteome profiles in cancer patients can contribute to a better understanding of the disease etiology, resulting in earlier diagnosis, risk stratification and better monitoring of the different cancer subtypes. Here, we describe the use of next generation protein profiling to explore the proteome signature in blood across patients representing many of the major cancer types. Plasma profiles of 1463 proteins from more than 1400 cancer patients are measured in minute amounts of blood collected at the time of diagnosis and before treatment. An open access Disease Blood Atlas resource allows the exploration of the individual protein profiles in blood collected from the individual cancer patients. We also present studies in which classification models based on machine learning have been used for the identification of a set of proteins associated with each of the analyzed cancers. The implication for cancer precision medicine of next generation plasma profiling is discussed.
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6.
  • Bergman, Julia, 1983-, et al. (författare)
  • A six marker panel for differential diagnostics of female cancers
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Aim: To present a new immunohistochemistry-based panel for clinical differential diagnostics of breast, ovarian, endometrial and cervical cancer. Background: Diagnostics of metastatic ER-positive tumors can present a clinical challenge. Breast and gynecological cancers are to a varying degree ER+, and can have similar growth patterns. The close proximity of the ovaries, endometrium and cervix also renders difficulties to distinguish between primary gynecological cancer in advanced stages. Material and Methods: As a discovery set for the selection of antibodies, tissue microarray (TMA) blocks containing 60 breast, 60 ovarian, 60 endometrial and 60 cervical tumor samples of predominantly metastatic sources were sectioned and immunohistochemically stained using 43 different primary antibodies, including both well accepted diagnostic markers and novel candidate markers. The results were analyzed for best possible differential diagnostic power to discriminate between these forms of female cancer. Results: By the implementation of a decision tree we were able to define a six-marker panel including antibodies detecting the WT1, ZAG, VIM, CK5, GATA3 and PAX8 proteins. This antibody panel enabled differentiation between breast, ovarian, endometrial and cervical cancer with an accuracy of 80%. The selected markers were then examined in a second cohort of 452 cancer samples comprising 60 breast, 48 ovary, 233 endometrium and 111 cervix patients. A decision tree classifier was used to evaluate the performance of various combinations of these markers in differential diagnosis of the female cancers.  The results suggest that this panel could be used in a clinical setting to achieve a more accurate diagnosis and thus provide a basis for further prospective clinical studies.
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7.
  • Bruzzese, Francesca, et al. (författare)
  • Local and Systemic Protumorigenic Effects of Cancer-Associated Fibroblast-Derived GDF15
  • 2014
  • Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 74:13, s. 3408-3417
  • Tidskriftsartikel (refereegranskat)abstract
    • The tumor stroma is vital to tumor development, progression, and metastasis. Cancer-associated fibroblasts (CAF) are among the abundant cell types in the tumor stroma, but the range of their contributions to cancer pathogenicity has yet to be fully understood. Here, we report a critical role for upregulation of the TGF beta/BMP family member GDF15 (MIC-1) in tumor stroma. GDF15 was found upregulated in situ and in primary cultures of CAF from prostate cancer. Ectopic expression of GDF15 in fibroblasts produced prominent paracrine effects on prostate cancer cell migration, invasion, and tumor growth. Notably, GDF15-expressing fibroblasts exerted systemic in vivo effects on the outgrowth of distant and otherwise indolent prostate cancer cells. Our findings identify tumor stromal cells as a novel source of GDF15 in human prostate cancer and illustrate a systemic mechanism of cancer progression driven by the tumor microenvironment. Further, they provide a functional basis to understand GDF15 as a biomarker of poor prognosis and a candidate therapeutic target in prostate cancer. 
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8.
  • Cano-Cebrian, Maria-Jose, et al. (författare)
  • Chemotherapeutics Combined with Luminal Irritants : Effects on Small-Intestinal Mannitol Permeability and Villus Length in Rats
  • 2022
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Chemotherapy causes intestinal mucositis, which includes villous atrophy and altered mucosal barrier function. However, there is an uncertainty regarding how the reduced small-intestinal surface area affects the mucosal permeability of the small marker probe mannitol (MW 188), and how the mucosa responds to luminal irritants after chemotherapy. The aims in this study were to determine (i) the relationship between chemotherapy-induced villus atrophy and the intestinal permeability of mannitol and (ii) how the mucosa regulate this permeability in response to luminal ethanol and sodium dodecyl sulfate (SDS). This was investigated by treating rats with a single intraperitoneal dose of doxorubicin, irinotecan, or 5-fluorouracil. After 72 h, jejunum was single-pass perfused and mannitol permeability determined at baseline and after 15 min luminal exposure to 15% ethanol or 5 mg/mL SDS. Tissue samples for morphological analyses were sampled from the perfused segment. All three chemotherapeutics caused a similar 30% reduction in villus length. Mannitol permeability increased with irinotecan (1.3-fold) and 5-fluorouracil (2.5-fold) and was reduced with doxorubicin (0.5-fold), suggesting that it is not epithelial surface area alone that regulates intestinal permeability to mannitol. There was no additional increase in mannitol permeability induced by luminal ethanol or SDS in the chemotherapy-treated rats compared to controls, which may be related to the relatively high basal permeability of mannitol compared to other common low-permeability probes. We therefore suggest that future studies should focus on elucidating the complex interplay between chemotherapy in combination with luminal irritants on the intestinal permeability of other probes.
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9.
  • Chen, Lei, 1985-, et al. (författare)
  • Rare Mutation Detection in Blood Plasma Using sRCA Molecule Counting Probes
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Problems in biology and medicine frequently require the ability to observe, evaluate, andcount even extremely rare macromolecules in biological samples. In particular, rare tumorspecific mutations in plasma provide valuable insights in the course of malignant disease andresponses to therapy, but simpler assay techniques are needed. We describe herein a rapidand exquisitely specific means to recognize and magnify detection signals from individualmolecules to easily recorded levels via a process we call super rolling circle amplification(sRCA). We demonstrate the ability of this technique to enumerate tumor-specific sequencevariants in plasma from cancer patients via flow cytometry at very high efficiency, with specificityadequate to detect single nucleotide mutant sequences among 100,000 copies of thenormal sequence in a 3 hr protocol. And the mutation analysis data generated from patientctDNA samples with our sRCA method are in high accordance with the patients’ primary tumorsequencing data.
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10.
  • Conway, Louis P., et al. (författare)
  • Unexpected Acetylation of Endogenous Aliphatic Amines by Arylamine N-Acetyltransferase NAT2
  • 2020
  • Ingår i: Angewandte Chemie International Edition. - : John Wiley & Sons. - 1433-7851 .- 1521-3773. ; 59:34, s. 14342-14346
  • Tidskriftsartikel (refereegranskat)abstract
    • N-Acetyltransferases play critical roles in the deactivation and clearance of xenobiotics, including clinical drugs. NAT2 has been classified as an arylamine N-acetyltransferase that mainly converts aromatic amines, hydroxylamines, and hydrazines. Herein, we demonstrate that the human arylamine N-acetyltransferase NAT2 also acetylates aliphatic endogenous amines. Metabolomic analysis and chemical synthesis revealed increased intracellular concentrations of mono- and diacetylated spermidine in human cell lines expressing the rapid compared to the slow acetylator NAT2 phenotype. The regioselective N8 -acetylation of monoacetylated spermidine by NAT2 answers the long-standing question of the source of diacetylspermidine. We also identified selective acetylation of structurally diverse alkylamine-containing drugs by NAT2, which may contribute to variations in patient responses. The results demonstrate a previously unknown functionality and potential regulatory role for NAT2, and we suggest that this enzyme should be considered for re-classification.
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11.
  • Cunningham, Janet L., et al. (författare)
  • Common pathogenetic mechanism involving human chromosome 18 in familial and sporadic ileal carcinoid tumors
  • 2011
  • Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 50:2, s. 82-94
  • Tidskriftsartikel (refereegranskat)abstract
    • Serotonin producing endocrine carcinoma of small intestine (ileal carcinoid) is a clinically distinct endocrine tumor. It is generally considered as a sporadic disease and its molecular etiology is poorly understood. We report comprehensive clinical and molecular studies of 55 sporadic and familial patients diagnosed with this condition. Nine pedigrees encompassing 23 affected subjects were established, consistent with autosomal dominant mode of inheritance. Familial and sporadic patients demonstrated indistinguishable clinical pictures. Molecular analyses of 61 tumors from 45 individuals, including eight familial and 37 sporadic patients, aimed at determination of global copy number aberrations using BAC and Illumina SNP arrays and gene expression profiling by Affymetrix chips. Chromosome 18 aberrations were identified in both sporadic and in familial tumors; 100% vs. 38%, respectively. Other, less frequent aberrations were also common for both groups. Global expression profiles revealed no differentially expressed genes. Frequent gain of chromosome 7 was exclusively observed in metastases, when patient matched primary tumors and metastases were compared. Notably, the latter aberration correlated with solid growth pattern morphology (P < 0.01), a histopathological feature that has previously been related to worse prognosis. The clinical and molecular similarities identified between sporadic and familial cases suggest a common pathogenetic mechanism involved in tumor initiation. The familial variant of ileal carcinoid represents a previously unrecognized autosomal dominant inherited tumor disease, which we propose to call Familial Ileal Endocrine Carcinoma (FIEC). Our findings indicate the location of a FIEC tumor suppressor gene near the telomere of 18q, involved in development of inherited and sporadic tumors.
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13.
  • Dahlgren, David, et al. (författare)
  • Effect of paracellular permeation enhancers on intestinal permeability of two peptide drugs, enalaprilat and hexarelin, in rats
  • 2021
  • Ingår i: Acta Pharmaceutica Sinica B. - : INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES. - 2211-3835 .- 2211-3843. ; 11:6, s. 1667-1675
  • Tidskriftsartikel (refereegranskat)abstract
    • Transcellular permeation enhancers are known to increase the intestinal permeability of enalaprilat, a 349 Da peptide, but not hexarelin (887 Da). The primary aim of this paper was to investigate if paracellular permeability enhancers affected the intestinal permeation of the two peptides. This was investigated using the rat single-pass intestinal perfusion model with concomitant blood sampling. These luminal compositions included two paracellular permeation enhancers, chitosan (5 mg/mL) and ethylenediaminetetraacetate (EDTA, 1 and 5 mg/mL), as well as low luminal tonicity (100 mOsm) with or without lidocaine. Effects were evaluated by the change in lumen-to-blood permeability of hexarelin and enalaprilat, and the blood-to-lumen clearance of (51)chromium-labeled EDTA (CLCr-EDTA), a clinical marker for mucosal barrier integrity. The two paracellular permeation enhancers increased the mucosal permeability of both peptide drugs to a similar extent. The data in this study suggests that the potential for paracellular permeability enhancers to increase intestinal absorption of hydrophilic peptides with low molecular mass is greater than for those with transcellular mechanism-of-action. Further, the mucosal blood-to-lumen flux of Cr-51-EDTA was increased by the two paracellular permeation enhancers and by luminal hypotonicity. In contrast, luminal hypotonicity did not affect the lumen-to-blood transport of enalaprilat and hexarelin. This suggests that hypotonicity affects paracellular solute transport primarily in the mucosal crypt region, as this area is protected from luminal contents by a constant water flow from the crypts.
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14.
  • Dahlgren, David, et al. (författare)
  • Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat
  • 2020
  • Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 12:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Sufficient colonic absorption is necessary for all systemically acting drugs in dosage forms that release the drug in the large intestine. Preclinically, colonic absorption is often investigated using the rat single-pass intestinal perfusion model. This model can determine intestinal permeability based on luminal drug disappearance, as well as the effect of permeation enhancers on drug permeability. However, it is uncertain how accurate the rat single-pass intestinal perfusion model predicts regional intestinal permeability and absorption in human. There is also a shortage of systematic in vivo investigations of the direct effect of permeation enhancers in the small and large intestine. In this rat single-pass intestinal perfusion study, the jejunal and colonic permeability of two low permeability drugs (atenolol and enalaprilat) and two high-permeability ones (ketoprofen and metoprolol) was determined based on plasma appearance. These values were compared to already available corresponding human data from a study conducted in our lab. The colonic effect of four permeation enhancers-sodium dodecyl sulfate, chitosan, ethylenediaminetetraacetic acid (EDTA), and caprate-on drug permeability and transport of chromium EDTA (an established clinical marker for intestinal barrier integrity) was determined. There was no difference in jejunal and colonic permeability determined from plasma appearance data of any of the four model drugs. This questions the validity of the rat single-pass intestinal perfusion model for predicting human regional intestinal permeability. It was also shown that the effect of permeation enhancers on drug permeability in the colon was similar to previously reported data from the rat jejunum, whereas the transport of chromium EDTA was significantly higher (p < 0.05) in the colon than in jejunum. Therefore, the use of permeation enhancers for increasing colonic drug permeability has greater risks than potential medical rewards, as indicated by the higher permeation of chromium EDTA compared to the drugs.
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15.
  • Ekström, Joakim, 1982-, et al. (författare)
  • Exact Probability Distribution for the ROC Area under Curve
  • 2023
  • Ingår i: Cancers. - : MDPI. - 2072-6694. ; 15:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Simple Summary This contribution allows for the computation of exact p-values and for conducting accurate statistical hypothesis tests of ROC AUC-values. As a result, the development of diagnostic tests is facilitated. This work is illustrated via simulated data and through the development of proteomic blood biomarkers for the early detection of cancer. The Receiver Operating Characteristic (ROC) is a de facto standard for determining the accuracy of in vitro diagnostic (IVD) medical devices, and thus the exactness in its probability distribution is crucial toward accurate statistical inference. We show the exact probability distribution of the ROC AUC-value, hence exact critical values and p-values are readily obtained. Because the exact calculations are computationally intense, we demonstrate a method of geometric interpolation, which is exact in a special case but generally an approximation, vastly increasing computational speeds. The method is illustrated through open access data, demonstrating superiority of 26 composite biomarkers relative to a predicate device. Especially under correction for testing of multiple hypotheses, traditional asymptotic approximations are encumbered by considerable imprecision, adversely affecting IVD device development. The ability to obtain exact p-values will allow more efficient IVD device development.
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16.
  • Enblad, Malin, et al. (författare)
  • Signet Ring Cell Colorectal and Appendiceal Cancer : A Small Signet Ring Cell Component Is Also Associated with Poor Outcome
  • 2023
  • Ingår i: Cancers. - : MDPI. - 2072-6694. ; 15:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Colorectal signet ring cell (SRC) carcinoma with ≥50% SRCs (SRC ≥ 50) has a poor prognosis, but the prognostic role of SRCs < 50% (SRC < 50) is unclear. The aim of this study was to provide a clinicopathological characterization of SRC colorectal and appendiceal tumours and analyse the importance of the SRC component size.Methods: All patients in the Swedish Colorectal Cancer Registry diagnosed with colorectal or appendiceal cancer in 2009–2020 at Uppsala University Hospital, Sweden, were included. The SRCs were verified, and the components estimated by a gastrointestinal pathologist.Results: Of the 2229 colorectal cancers, 51 (2.3%) had SRCs, with a median component size of 30% (interquartile range of 12.5–40) and 10 (0.45%) had SRC ≥ 50. The SRC tumours were primarily localized in the right colon (59%) and appendix (16%). No patients with SRCs had stage I disease, and 26 (51%) had stage IV, of whom, 18 (69%) had peritoneal metastases. The SRC tumours were often high grade with perineural and vascular invasion. The 5-year overall survival (OS) rate for patients with SRC ≥ 50 were 20% (95% confidence interval (CI) 6–70), for SRC < 50, 39% (95% CI 24–61); and for non-SRCs, 55% (95% CI 55–60). Among the patients with SRC < 50 and <50% extracellular mucin, the 5-year OS was 34% (95% CI 19–61), while those with ≥50% extracellular mucin had an OS of 50% (95% CI 25–99). The 5-year recurrence-free survival rates were 51% (95% CI 13–83) for patients with SRC tumours, as compared to 83% (95% CI 77–89) and 81% (95% CI 79–84) for mucinous and non-mucinous adenocarcinoma, respectively.Conclusions: The presence of SRCs was strongly associated with aggressive clinicopathological features, peritoneal metastases, and poor prognosis, also when they make up <50% of a tumour.Simple SummarySignet ring cell (SRC) carcinoma of colorectal and appendiceal cancer is rare but is recognized as the histopathological subtype with the poorest prognosis. However, the prognostic relevance of a SRC component <50% is unclear. The aim of this study was to provide a clinicopathological characterization of all SRC-containing colorectal and appendiceal cancers, including those with <50% SRCs. The results showed that SRCs, both ≥50% and <50%, were associated with aggressive histopathological features, advanced stages, and, particularly, peritoneal metastases. Information about the presence of SRCs in tumour tissue, not only in the case of ≥50% SRCs, should be routinely registered in pathology reports and clinical registers to enable larger studies that can aid our understanding of SRCs in colorectal and appendiceal cancers.
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18.
  • Furuhashi, Masao, et al. (författare)
  • Platelet-derived growth factor production by B16 melanoma cells leads to increased pericyte abundance in tumors and an associated increase in tumor growth rate
  • 2004
  • Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 64:8, s. 2725-2733
  • Tidskriftsartikel (refereegranskat)abstract
    • Platelet-derived growth factor (PDGF) receptor signaling participates in different processes in solid tumors, including autocrine stimulation of tumor cell growth, recruitment of tumor stroma fibroblasts, and stimulation of tumor angiogenesis. In the present study, the B16 mouse melanoma tumor model was used to investigate the functional consequences of paracrine PDGF stimulation of host-derived cells. Production of PDGF-BB or PDGF-DD by tumor cells was associated with an increased tumor growth rate. Characterization of tumors revealed an increase in pericyte abundance in tumors derived from B16 cells producing PDGF-BB or PDGF-DD. The increased tumor growth rate associated with PDGF-DD production was not seen in mice expressing an attenuated PDGF beta-receptor and was thus dependent on host PDGF beta-receptor signaling. The increased pericyte abundance was not associated with an increased tumor vessel density. However, tumor cell apoptosis, but not proliferation, was reduced in tumors displaying PDGF-induced increased pericyte coverage. Our findings thus demonstrate that paracrine PDGF production stimulates pericyte recruitment to tumor vessels and suggest that pericyte abundance influences tumor cell apoptosis and tumor growth.
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19.
  • Gal, Annamaria, et al. (författare)
  • Sustained TGF beta exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis
  • 2008
  • Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 27:9, s. 1218-1230
  • Tidskriftsartikel (refereegranskat)abstract
    • To better understand the dual, tumour-suppressive and tumour-promoting function of transforming growth factor-beta (TGFbeta), we analysed mammary epithelial NMuMG cells in response to short and long-term TGFbeta exposure. NMuMG cells became proliferation-arrested and apoptotic after exposure to TGFbeta for 2-5 days, whereas surviving cells underwent epithelial-mesenchymal transition (EMT). After chronic TGFbeta exposure (2-3 weeks), however, NMuMG cells became resistant to proliferation arrest and apoptosis, showing sustained EMT instead (TD cells). EMT was fully reversed by a pharmacologic TGFbeta-receptor-I kinase inhibitor or withdrawal of TGFbeta for 6-12 days. Interestingly, both cell cycle arresting/proapoptotic (Smads, p38 kinase) and antiapoptotic, proliferation and EMT-promoting signalling pathways (PI3K-PKB/Akt, ERK) were co-suppressed to low, but significant levels. Except for PI3K-Akt, TGFbeta-dependent downregulation of these signalling pathways in transdifferentiated (TD) cells was fully reversed upon TGFbeta withdrawal, together with partial re-induction of proliferation arrest and apoptosis. Co-injection of non-tumorigenic NMuMG cells with tumour-forming CHO cells oversecreting exogenous TGFbeta1 (CHO-TGFbeta1) allowed outgrowth of epithelioid cells in CHO-TGFbeta1 cell-induced tumours. These epithelial islands enhanced CHO-TGFbeta1 tumour cell proliferation, possibly due to chemokines (for example, JE/MCP-1) secreted by NMuMG/TD cells. We conclude that suppression of antiproliferative, proapoptotic TGFbeta signalling in TD cells may permit TGFbeta-dependent proliferation, survival and EMT-enhancing signalling pathways to act at low levels. Thus, TGFbeta may modulate its own signalling to facilitate switching from tumour suppression to tumour progression.
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20.
  • Gazit, Aviv, et al. (författare)
  • Tricyclic quinoxalines as potent kinase inhibitors of PDGFR kinase, Flt3 and Kit
  • 2003
  • Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 11:9, s. 2007-2018
  • Tidskriftsartikel (refereegranskat)abstract
    • Here we report on novel quinoxalines as highly potent and selective inhibitors of the type III receptor tyrosine kinases PDGFR, FLT3, and KIT. These compounds, tricyclic quinoxalines, were generated in order to improve bioavailability over the highly hydrophobic bicyclic quinoxalines. Four of the highly active compounds were characterized in detail and are shown to inhibit PDGFR kinase activity of the isolated receptor as well as in intact cells in the sub-micromolar concentration range. We show that the most active inhibitor (compound 13, AGL 2043) is approximately 15-20 times more potent than its isomer (compound 14, AGL 2044). We therefore compared the three dimensional structures of the two compounds by X-ray crystallography. These compounds are also highly effective in blocking the kinase activity of FLT3, KIT, and the oncogenic protein Tel-PDGFR in intact cells. These compounds are potent inhibitors of the proliferation of pig heart smooth muscle cells. They fully arrest the growth of these cells and the effect is fully reversible. The chemical, biochemical and cellular properties of these compounds as well as the solubility properties make them suitable for development as anti-restenosis and anti-cancer agents.
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21.
  • Glimelius, Bengt, et al. (författare)
  • U-CAN : a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
  • 2018
  • Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 57:2, s. 187-194
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.
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22.
  • Grundberg, Ida, et al. (författare)
  • In situ mutation detection and visualization of intratumor heterogeneity for cancer research and diagnostics
  • 2013
  • Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 4:12, s. 2407-2418
  • Tidskriftsartikel (refereegranskat)abstract
    • Current assays for somatic mutation analysis are based on extracts from tissue sections that often contain morphologically heterogeneous neoplastic regions with variable contents of genetically normal stromal and inflammatory cells, obscuring the results of the assays. We have developed an RNA-based in situ mutation assay that targets oncogenic mutations in a multiplex fashion that resolves the heterogeneity of the tissue sample. Activating oncogenic mutations are targets for a new generation of cancer drugs. For anti-EGFR therapy prediction, we demonstrate reliable in situ detection of KRAS mutations in codon 12 and 13 in colon and lung cancers in three different types of routinely processed tissue materials. High-throughput screening of KRAS mutation status was successfully performed on a tissue microarray. Moreover, we show how the patterns of expressed mutated and wild-type alleles can be studied in situ in tumors with complex combinations of mutated EGFR, KRAS and TP53. This in situ method holds great promise as a tool to investigate the role of somatic mutations during tumor progression and for prediction of response to targeted therapy.
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23.
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24.
  • Gyllensten, Ulf B., et al. (författare)
  • Next Generation Plasma Proteomics Identifies High-Precision Biomarker Candidates for Ovarian Cancer
  • 2022
  • Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Simple Summary Ovarian cancer is the eighth most common cancer among women and has a 5-year survival of only 30-50%. The survival is close to 90% for patients in stage I but only 20% for patients in stage IV. The presently available biomarkers have insufficient sensitivity and specificity for early detection and there is an urgent need to identify novel biomarkers. The aim of our study was to broadly measure protein biomarkers to find tests for the early detection of ovarian cancer. We found that combinations of 4-7 protein biomarkers can provide highly accurate detection of early- and late-stage ovarian cancer compared to benign conditions. The performance of the tests was then validated in a second independent cohort. Background: Ovarian cancer is the eighth most common cancer among women and has a 5-year survival of only 30-50%. The survival is close to 90% for patients in stage I but only 20% for patients in stage IV. The presently available biomarkers have insufficient sensitivity and specificity for early detection and there is an urgent need to identify novel biomarkers. Methods: We employed the Explore PEA technology for high-precision analysis of 1463 plasma proteins and conducted a discovery and replication study using two clinical cohorts of previously untreated patients with benign or malignant ovarian tumours (N = 111 and N = 37). Results: The discovery analysis identified 32 proteins that had significantly higher levels in malignant cases as compared to benign diagnoses, and for 28 of these, the association was replicated in the second cohort. Multivariate modelling identified three highly accurate models based on 4 to 7 proteins each for separating benign tumours from early-stage and/or late-stage ovarian cancers, all with AUCs above 0.96 in the replication cohort. We also developed a model for separating the early-stage from the late-stage achieving an AUC of 0.81 in the replication cohort. These models were based on eleven proteins in total (ALPP, CXCL8, DPY30, IL6, IL12, KRT19, PAEP, TSPAN1, SIGLEC5, VTCN1, and WFDC2), notably without MUCIN-16. The majority of the associated proteins have been connected to ovarian cancer but not identified as potential biomarkers. Conclusions: The results show the ability of using high-precision proteomics for the identification of novel plasma protein biomarker candidates for the early detection of ovarian cancer.
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25.
  • Hammarström, Klara, et al. (författare)
  • A Comprehensive Evaluation of Associations Between Routinely Collected Staging Information and The Response to (Chemo)Radiotherapy in Rectal Cancer
  • 2021
  • Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Simple Summary Rectal cancer patients are often treated with radiotherapy, either alone or combined with chemotherapy, prior to surgery to enable radical surgery on a non-resectable tumor or to lower the recurrence risk. For some patients, the tumor disappears completely after preoperative treatment, while others experience little or no benefit. Accurate prediction of therapy response before treatment is of great importance for a personalized treatment approach and intentional organ preservation. We performed a comprehensive evaluation of the predictive capacity of all routinely collected staging information at diagnosis in a population-based, completely staged patient material of 383 patients representing a real-life clinical situation. Size or stage of the rectal tumor were independent predictors of excellent response irrespective of preoperative treatment, with small/early-stage tumors being significantly more likely to reach a complete response. Levels of the tumor marker carcinoembryonic antigen (CEA) above upper normal limit halved the chance of response. Radiotherapy (RT) or chemoradiotherapy (CRT) are frequently used in rectal cancer, sometimes resulting in complete tumor remission (CR). The predictive capacity of all clinical factors, laboratory values and magnetic resonance imaging parameters performed in routine staging was evaluated to understand what determines an excellent response to RT/CRT. A population-based cohort of 383 patients treated with short-course RT (5 x 5 Gy in one week, scRT), CRT, or scRT with chemotherapy (scRT+CT) and having either had a delay to surgery or been entered into a watch-and-wait program were included. Complete staging according to guidelines was performed and associations between investigated variables and CR rates were analyzed in univariate and multivariate analyses. In total, 17% achieved pathological or clinical CR, more often after scRT+CT and CRT than after scRT (27%, 18% and 8%, respectively, p < 0.001). Factors independently associated with CR included clinical tumor stage, small tumor size (<3 cm), tumor level, and low CEA-value (<3.8 mu g/L). Size or stage of the rectal tumor were associated with excellent response in all therapy groups, with small or early stage tumors being significantly more likely to reach CR (p = 0.01 (scRT), p = 0.01 (CRT) and p = 0.02 (scRT+CT). Elevated level of carcinoembryonic antigen (CEA) halved the chance of response. Extramural vascular invasion (EMVI) and mucinous character may indicate less response to RT alone.
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26.
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27.
  • Hammarström, Klara, et al. (författare)
  • Determining the use of preoperative (chemo)radiotherapy in primary rectal cancer according to national and international guidelines
  • 2019
  • Ingår i: Radiotherapy and Oncology. - : ELSEVIER IRELAND LTD. - 0167-8140 .- 1879-0887. ; 136, s. 106-112
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Pre-operative radiotherapy (RT) or chemoradiotherapy (CRT) is frequently used prior to rectal cancer surgery to improve local control and survival. The treatment is administered according to guidelines, but these recommendations vary significantly between countries. Based on the stage distribution and risk factors of rectal cancers as determined by magnetic resonance imaging (MRI) in an unselected Swedish population, the use of RT/CRT according to 15 selected guidelines is described. Materials and methods: Selected guidelines from different countries and regions were applied to a wellcharacterized unselected population-based material of 686 primary non-metastatic rectal cancers staged by MRI. The fraction of patients assigned to surgery alone or surgery following pre-treatment with (C) RT was determined according to the respective guideline. RT/CRT administered to rectal cancer patients for other reasons, for example, for organ preservation or palliation, was not considered. Results: The fraction of patients with a clear recommendation for pre-treatment with (C) RT varied between 38% and 77% according to the different guidelines. In most guidelines, CRT was recommended to all patients who were not operated directly, and, in others, short-course RT was also recommended to patients with intermediate risk tumours. If only non-resectable or difficult to resect tumours were recommended pre-treatment, as stated in many Japanese publications, 9% would receive CRT followed by a delay to surgery. Conclusions: According to most guidelines, well over 50% of primary non-metastatic rectal cancer patients from a general population, in which screening for colorectal cancer is not practised, are recommended treatment with pre-operative/neo-adjuvant therapy. (C) 2019 Elsevier B. V. All rights reserved. Radiotherapy and Oncology
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28.
  • Hammarström, Klara, et al. (författare)
  • Stage distribution utilizing magnetic resonance imaging in an unselected population of primary rectal cancers
  • 2018
  • Ingår i: European Journal of Surgical Oncology. - : ELSEVIER SCI LTD. - 0748-7983 .- 1532-2157. ; 44:12, s. 1858-1864
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Pre-operative radiotherapy (RT) or chemo-radiotherapy (CRT) are sometimes recommended prior to rectal cancer surgery, but guideline recommendations vary. The aim was to describe stage distribution and other important characteristics required for the treatment decision of patients with primary rectal cancers utilizing magnetic resonance imaging (MRI) in an unselected population. Patients and methods: All 796 histopathologically verified rectal adenocarcinomas diagnosed 2010-2015 in two counties in Sweden (population 630,000 in 2015) were identified. Staging with pelvic MRI unless contraindications were present, treatment and pathology followed Swedish guidelines.Patients and methods: All 796 histopathologically verified rectal adenocarcinomas diagnosed 2010-2015 in two counties in Sweden (population 630,000 in 2015) were identified. Staging with pelvic MRI unless contraindications were present, treatment and pathology followed Swedish guidelines.Results: Twenty-three % of cases (n = 186) had distant metastases at diagnosis, demonstrating more advanced tumor and nodal stages when compared with non-metastatic patients (p < 0.001), and they more often displayed MRI-identified mucinous features and extramural vascular invasion (EMVI) than non-metastatic tumors (p < 0.001 for both). In non-metastatic patients, 8% displayed clinical stage T1 (cT1), 21% cT2, and 53% cT3; one-third of the latter threatened or involved the mesorectal fascia (MRF+). Almost 20% had stage cT4 (4% cT4a, 14% cT4b) of which 50% were considered "non-resectable". EMVI was seen in 33% of cT3M0 tumors and in 48% of cT4M0 tumors.Conclusions: In an unselected population, approximately 80% of primary rectal cancers are referred to as "locally advanced" (stage or cT3-4 or N+), meaning that they, according to many international guidelines, are recommended neo-adjuvant treatment. This study provides a detailed description of the clinical stages and presence of characteristics identifiable on MRI which are of importance when assessing the needs for RT/CRT, when using different guidelines. 
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29.
  • Hammarström, Klara, 1990- (författare)
  • Staging and therapy response in rectal cancer
  • 2023
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Every year, around 2,200 individuals are diagnosed with rectal cancer in Sweden. As a result of better tumour staging using magnetic resonance imaging (MRI), pre-operative radiotherapy (with or without chemotherapy), and improved surgery, outcome has improved substantially during the past few decades. Today less than 5% of patients experience a local recurrence. Treatment response is highly variable, up to 30% of patients have a complete remission (CR) after pre-treatment while others do not benefit from the treatment. The aim of this thesis was to investigate factors associated with CR in rectal cancer as accurate response prediction already at the time of diagnosis could enable a personalized treatment approach. For this purpose, an unselected rectal cancer cohort of approximately 1,200 patients diagnosed between 2010-2018 was built. Paper I provides a description of tumour stages and other MRI characteristics required for the treatment decision in the rectal cancer cohort. In this unselected patient population, most tumours belonged to the risk groups with intermediate or high risk of recurrence and are thus recommended to pre-treatment.In Paper II, the proportions of patients recommended pre-treatment according to different guidelines were investigated to better understand the wide variability in treatment seen worldwide. This study concluded that between 38% and 77% of non-metastatic patients are presently recommended pre-operative treatment according to 15 international guidelines, when strictly applied to our non-selected rectal cancer cohort.   To achieve a more personalized treatment approach and a stricter use of pre-treatment, predictive factors of tumour remission are needed. In Paper III an evaluation of the predictive capacity of all clinical and pathological factors used in the staging of rectal cancer prior to treatment decision was done. In Paper IV a combination of clinical and sequencing data was used in analyses to further assess associations with CR and which factors impact prognosis. Tumour size, stage, tumour marker CEA and treatment were predictive of CR. Moreover, genetic factors such as mutated SMAD4 and SYNE1 were associated with CR but further investigations are needed to determine clinical relevance. Mutated KRAS was an independent predictor of non-CR. BRAF V600E mutation increased the risk of recurrence. 
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30.
  • Handin, Niklas (författare)
  • Proteomics informed investigation of human hepatocytes and liver tissue
  • 2021
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • A successful drug needs to display beneficial absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) profile. It is therefore important to investigate these properties during the drug discovery process. The liver is of particular interest in ADME-Tox studies, as it is highly metabolically active and oral administrated drugs needs to pass the liver before reaching the systemic circulation. However, a dose of a drug that is efficacious and safe for one individual may be inefficacious or toxic, because of inter-individual variability. Therefore, it is important to investigate the ADME-Tox properties in a sufficiently large population. Investigations on ADME-Tox is usually done in in vitro cell models.  Therefore, a variety of models to simulate liver functions have been developed and ranging from subcellular microsomes to complex 3D organoid cultures. This thesis investigates variability of ADME proteins in human liver tissue and in liver cell models.First, mass spectrometry based targeted proteomics was used to quantify ADME relevant proteins from 149 human liver samples. The observed inter-individual protein variability could not solely be explained by genotype. Therefore, a single transporter protein, the bile and drug transporting protein, NTCP, was investigate in detail.  Non-genetic factors, e.g. smoking and alcohol consumption, and epigenetic factors such as DNA methylation, were found to contribute to the observed inter-individual variability of NTCP. Next, hepatocytes (PHH) were isolated from 54 human livers tissues and after which the hepatocytes where cryopreserved. The variable attachment efficiency of cryopreserved hepatocytes where investigated and an apoptosis inhibition protocol for restoration of attachment properties was developed. This protocol was also successfully applied to 3D cultured PHH spheroids resulting in increased ability to form 3D spheroids. The effect of culture conditions on the quality of the 3D cultures was also investigated.  3D PHH spheroids were formed and maintained in different, commonly used culture media. The spheroids were characterized by a variety of functional assays including global proteomics. The proteome analysis showed that while no epithelial to mesenchymal transitions was observed, 3D cultures maintained in fasting glucose and insulin levels resembling the in vivo situation showed a more liver-like phenotype with a high expression of ADME proteins and functional cytochrome P450 metabolism. Transporter kinetics were also investigated in the 3D cultured PHH. Finally, we investigated if global proteomics data from 56 human liver tissues could be deconvoluted to give information about the liver composition. The cell type proportions generated by deconvolution where similar to literature values. Liver samples that displayed deviating cell composition were identified. The deviating liver compositions were in agreement with clinical markers of inflammation in the patient´s blood samples and with altered extracellular matrix protein composition, comparable to that found in liver steatosis.  In conclusion, this thesis have investigated variability in ADME proteins in human liver and in in vitro cultures of human hepatocytes, characterized cofounding factors for in vitro cultured hepatocytes and further extended drug disposition studies in 3D cultured hepatocytes. 
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31.
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32.
  • Hernlund, Emma, et al. (författare)
  • The phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 is effective in inhibiting regrowth of tumour cells after cytotoxic therapy
  • 2012
  • Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 48:3, s. 396-406
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE:Regrowth of tumour cells between cycles of chemotherapy is a significant clinical problem. Treatment strategies where antiproliferative agents are used to inhibit tumour regrowth between chemotherapy cycles are attractive, but such strategies are difficult to test using conventional monolayer culture systems.METHODS:We used the in vitro tumour spheroid model to study regrowth of 3-D colon carcinoma tissue after cytotoxic therapy. Colon carcinoma cells with wild-type or mutant phosphatidyl inositol 3-kinase catalytic subunit (PI3KCA) or KRAS alleles were allowed to form multicellular spheroids and the effects of different pharmacological compounds were studied after sectioning and staining for relevant markers of cell proliferation and apoptosis.RESULTS:Studies using colon cancer cells with gene disruptions suggested that the phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathway was essential for proliferation in 3-D culture. The dual PI3K-mTOR inhibitor NVP-BEZ235, currently in clinical trials, was found to inhibit phosphorylation of the mTOR target 4EBP1 in 3-D cultured cells. The ability of NVP-BEZ235 to inhibit tumour cell proliferation and to induce apoptosis was markedly more pronounced in 3-D cultures compared to monolayer cultures. It was subsequently found that NVP-BEZ235 was effective in inhibiting regrowth of 3-D cultured cells after treatment with two cytotoxic inhibitors of the ubiquitin-proteasome system (UPS), methyl-13-hydroxy-15-oxokaurenoate (MHOK) and bortezomib (Velcade®).CONCLUSIONS:The dual PI3K-mTOR inhibitor NVP-BEZ235 was found to reduce cell proliferation and to induce apoptosis in 3-D cultured colon carcinoma cells, NVP-BEZ235 is a promising candidate for use in sequential treatment modalities together with cytotoxic drugs to reduce the cell mass of solid tumours.
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33.
  • Herrera, Mercedes, et al. (författare)
  • Prognostic Interactions between FAP plus Fibroblasts and CD8a+T Cells in Colon Cancer
  • 2020
  • Ingår i: Cancers. - : MDPI. - 2072-6694. ; 12:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Simple Summary In addition to malignant cells, tumors are composed also of other cell types including immune cells and fibroblasts. These cell types interact with each other and with the malignant cells. Prognosis associations have previously been demonstrated for CD8-positive immune cells. Recent studies suggest that fibroblasts can affect the function of immune cells. The aim of this study was to investigate if the fibroblast composition of tumors affected the prognosis association of CD8 immune cells. This study demonstrated that in colon cancer, CD8 prognosis associations was restricted to the group of tumors with high expression the FAP fibroblast marker. Our findings suggest continued mechanistic studies regarding crosstalk between FAP-positive fibroblasts and the different immune cell types; and also support the investigation of fibroblast/T-cell interactions for therapeutic purposes. Inter-case variations in immune cell and fibroblast composition are associated with prognosis in solid tumors, including colon cancer. A series of experimental studies suggest immune-modulatory roles of marker-defined fibroblast populations, including FAP-positive fibroblasts. These studies imply that the fibroblast status of tumors might affect the prognostic significance of immune-related features. Analyses of a population-based colon cancer cohort demonstrated good prognosis associations of FAP intensity and CD8a density. Notably, a significant prognostic interaction was detected between these markers (p = 0.013 in nonadjusted analyses and p = 0.003 in analyses adjusted for cofounding factors) in a manner where the good prognosis association of CD8 density was restricted to the FAP intensity-high group. This prognostic interaction was also detected in an independent randomized trial-derived colon cancer cohort (p = 0.048 in nonadjusted analyses). In the CD8-high group, FAP intensity was significantly associated with a higher total tumor density of FoxP3-positive immune cells and a higher ratio of epithelial-to-stromal density of CD8a T cells. The study presents findings relevant for the ongoing efforts to improve the prognostic performance of CD8-related markers and should be followed by additional validation studies. Furthermore, findings support, in general, earlier model-derived studies implying fibroblast subsets as clinically relevant modulators of immune surveillance. Finally, the associations between FAP intensity and specific immune features suggest mechanisms of fibroblast-immune crosstalk with therapeutic potential.
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34.
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35.
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36.
  • Iggo, Richard, et al. (författare)
  • Validation of a yeast functional assay for p53 mutations using clonal sequencing
  • 2013
  • Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 231:4, s. 441-448
  • Tidskriftsartikel (refereegranskat)abstract
    • We have previously tested biopsies from 1469 breast tumours with a p53 functional assay in the context of a prospective clinical trial (EORTC 10994/BIG 1-00). The goal of the trial was to determine whether p53 status could be used to select patients who would benefit from inclusion of taxanes in anthracycline-based chemotherapy. The results of the trial were negative. To test whether this was because the functional assay misclassified the tumours, we have reanalysed two groups of biopsies by Sanger sequencing and Roche 454 next generation sequencing (NGS). Comparison of yeast data with pooled cDNA sequencing data in an initial cohort of 69 biopsies showed that conventional sequencing is insensitive when the mutant p53 content is low. A second cohort of 48 biopsies was used to compare directly the yeast assay with Sanger and NGS technology. The mutant sequence was difficult to detect in sequence chromatograms of pooled cDNA, whereas NGS unequivocally identified mutations in every case classified as mutant by the functional assay. The NGS data showed that small deletions, probably caused by PCR splicing, account for most of the unexplained background in the yeast assay. We conclude that mutation detection techniques that test multiple clones, such as the p53 functional assay and NGS, are more reliable than Sanger sequencing of pooled DNA; that the high p53 mutation rate (44%) seen with the yeast assay in the EORTC 10994/BIG 1-00 trial reflects this high sensitivity; and that NGS with Roche 454 technology could be used to identify the p53 mutations in the remaining tumours previously tested in yeast in the EORTC10994/BIG 1-00 trial. 
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37.
  • Imam, Israa, et al. (författare)
  • Neoadjuvant rectal (NAR) score : Value evaluating the efficacy of neoadjuvant therapy and prognostic significance after surgery?
  • 2021
  • Ingår i: Radiotherapy and Oncology. - : Elsevier. - 0167-8140 .- 1879-0887. ; 157, s. 70-77
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: The Neoadjuvant rectal (NAR) score is a new surrogate endpoint to be used in clinical trials for early determination of treatment response to different preoperative therapies. The aim is to further validate the NAR-score, primarily developed using chemoradiotherapy (CRT) with a delay to surgery 6-8 weeks, and explore its value using other schedules. Materials and Methods: The study included all 9978 patients diagnosed with non-metastasized RC in 2007-2015 that had undergone surgery and was registered in the Swedish Colorectal Cancer Registry. The patients of interest had either short-course radiotherapy (scRT)/CRT + delayed surgery, longcourse radiotherapy (RT) + delayed surgery, (C)RT + additional chemotherapy, primary surgery, or scRT + immediate surgery. The scRT/CRT + delayed surgery groups were further divided based on time to surgery. Results: Mean NAR-score differed significantly (p < 0.0001) between different treatments. (C) RT + additional chemotherapy had the lowest mean score of 16.3 and CRT + delayed surgery had 17.7. There was a significant difference (p < 0.05) in overall survival (OS) and time to recurrence (TTR) of patients with a Low NAR-score (<8) compared to those with a High score (>16) for both CRT- and scRT, with a stronger correlation for CRT-patients. C-index for the NAR-score model (0.623) was not superior to when only pathological T- and N-stage was used (0.646). Conclusions: The NAR-score is prognostic, but it is not better than pT- and pN-stage. However, the NARscore can still discriminate between two treatments that have different cell killing effect and may still be of value in clinical trials as an easier method than pT- and N-stage.
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38.
  • Jarvius, Malin, et al. (författare)
  • In situ detection of phosphorylated platelet-derived growth factor receptor beta using a generalized proximity ligation method
  • 2007
  • Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 6:9, s. 1500-1509
  • Tidskriftsartikel (refereegranskat)abstract
    • Improved methods are needed for in situ characterization of post-translational modifications in cell lines and tissues. For example, it is desirable to monitor the phosphorylation status of individual receptor tyrosine kinases in samples from human tumors treated with inhibitors to evaluate therapeutic responses. Unfortunately the leading methods for observing the dynamics of tissue post-translational modifications in situ, immunohistochemistry and immunofluorescence, exhibit limited sensitivity and selectivity. Proximity ligation assay is a novel method that offers improved selectivity through the requirement of dual recognition and increased sensitivity by including DNA amplification as a component of detection of the target molecule. Here we therefore established a generalized in situ proximity ligation assay to investigate phosphorylation of platelet-derived growth factor receptor β (PDGFRβ) in cells stimulated with platelet-derived growth factor BB. Antibodies specific for immunoglobulins from different species, modified by attachment of DNA strands, were used as secondary proximity probes together with a pair of primary antibodies from the corresponding species. Dual recognition of receptors and phosphorylated sites by the primary antibodies in combination with the secondary proximity probes was used to generate circular DNA strands; this was followed by signal amplification by replicating the DNA circles via rolling circle amplification. We detected tyrosine phosphorylated PDGFRβ in human embryonic kidney cells stably overexpressing human influenza hemagglutinin-tagged human PDGFRβ in porcine aortic endothelial cells transfected with the β-receptor, but not in cells transfected with the α-receptor, and also in immortalized human foreskin fibroblasts, BJ hTert, endogenously expressing the PDGFRβ. We furthermore visualized tyrosine phosphorylated PDGFRβ in tissue sections from fresh frozen human scar tissue undergoing wound healing. The method should be of great value to study signal transduction, screen for effects of pharmacological agents, and enhance the diagnostic potential in histopathology.
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39.
  • Jiao, Xiang, et al. (författare)
  • Gene rearrangements in hormone receptor negative breast cancers revealed by mate pair sequencing
  • 2013
  • Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 14
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Chromosomal rearrangements in the form of deletions, insertions, inversions and translocations are frequently observed in breast cancer genomes, and a subset of these rearrangements may play a crucial role in tumorigenesis. To identify novel somatic chromosomal rearrangements, we determined the genome structures of 15 hormone-receptor negative breast tumors by long-insert mate pair massively parallel sequencing. Results: We identified and validated 40 somatic structural alterations, including the recurring fusion between genes DDX10 and SKA3 and translocations involving the EPHA5 gene. Other rearrangements were found to affect genes in pathways involved in epigenetic regulation, mitosis and signal transduction, underscoring their potential role in breast tumorigenesis. RNA interference-mediated suppression of five candidate genes (DDX10, SKA3, EPHA5, CLTC and TNIK) led to inhibition of breast cancer cell growth. Moreover, downregulation of DDX10 in breast cancer cells lead to an increased frequency of apoptotic nuclear morphology. Conclusions: Using whole genome mate pair sequencing and RNA interference assays, we have discovered a number of novel gene rearrangements in breast cancer genomes and identified DDX10, SKA3, EPHA5, CLTC and TNIK as potential cancer genes with impact on the growth and proliferation of breast cancer cells.
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40.
  • Jiao, Xiang (författare)
  • Somatic Mutations in Breast Cancer Genomes : Discovery and Validation of Breast Cancer Genes
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Breast cancer is the most common cancer in women worldwide. However, the genetic alterations that lead to breast cancer are not fully understood. This thesis aims to identify novel genes of potential mechanistic, diagnostic or therapeutic interest in breast cancers by mutational analysis and whole-genome sequencing.In paper I, sequencing of 36 previously identified candidate genes in 96 breast tumors with patient-matched normal DNA determined the somatic mutation prevalence of these candidate genes and identified additional mutations in Notch, NF-κB, PI3K, and Hedgehog pathways as well as in processes mediating DNA methylation, RNA processing and calcium signaling.In paper II, comparison of massively parallel mate-pair sequencing results of a human genome before and after phi29-mediated multiple displacement amplification (MDA) revealed that MDA introduces structural alteration artifacts, with an emphasis on false positive inversions, and impairs the sensitivity to detect true inversions. Therefore, MDA has limited value in sample preparation for whole-genome sequencing for structural alteration detection.In paper III, massively parallel paired-end sequencing identified gene rearrangements in 15 hormone receptor negative breast cancers. Forty validated rearrangements were predicted to directly affect 30 genes, involved in epigenetic regulation, cell mitosis, signalling transduction and glycolytic flux. RNA interference-based assays revealed the potential roles in cell growth of some affected genes, among which DDX10 was implicated to be involved in apoptosis.In paper IV, a method for statistical evaluation of putative translocations detected by massively parallel paired-end sequencing was proposed. In an application of this method to analyse translocations detected by cancer genome deep paired-end sequencing, 76 putative translocations were classified into four categories, with the majority likely to be caused by mismapping due to repetitive regions.Taken together, this thesis provides insights into genes and pathways mutated in sporadic breast cancer genomes, which broaden our understanding of the genetic basis of breast cancer and may ultimately facilitate the diagnosis and treatment of this disease.
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41.
  • Jiao, Xiang, et al. (författare)
  • Somatic mutations in the notch, NF-KB, PIK3CA, and hedgehog pathways in human breast cancers
  • 2012
  • Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 51:5, s. 480-489
  • Tidskriftsartikel (refereegranskat)abstract
    • Exome sequencing of human breast cancers has revealed a substantial number of candidate cancer genes with recurring but infrequent somatic mutations. To determine more accurately their mutation prevalence, we performed a mutation analysis of 36 novel candidate cancer genes in 96 human breast cancers. Somatic mutations with potential impact on protein function were observed in the genes ADAM12, CENTB1, CENTG1, DIP2C, GLI1, GRIN2D, HDLBP, IKBKB, KPNA5, NFKB1, NOTCH1, and OTOF. These findings strengthen the evidence for involvement of the Notch, Hedgehog, NF-KB, and PIK3CA pathways in breast cancer development, and point to novel processes that likely are involved.
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42.
  • Jiao, Xiang, et al. (författare)
  • Structural Alterations from Multiple Displacement Amplification of a Human Genome Revealed by Mate-Pair Sequencing
  • 2011
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:7, s. e22250-
  • Tidskriftsartikel (refereegranskat)abstract
    • Comprehensive identification of the acquired mutations that cause common cancers will require genomic analyses of large sets of tumor samples. Typically, the tissue material available from tumor specimens is limited, which creates a demand for accurate template amplification. We therefore evaluated whether phi29-mediated whole genome amplification introduces false positive structural mutations by massive mate-pair sequencing of a normal human genome before and after such amplification. Multiple displacement amplification led to a decrease in clone coverage and an increase by two orders of magnitude in the prevalence of inversions, but did not increase the prevalence of translocations. While multiple strand displacement amplification may find uses in translocation analyses, it is likely that alternative amplification strategies need to be developed to meet the demands of cancer genomics.
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43.
  • Johansson, Henrik, et al. (författare)
  • Targeted resequencing of candidate genes using Selector Probes
  • 2011
  • Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 39:2, s. e8-
  • Tidskriftsartikel (refereegranskat)abstract
    • Targeted genome enrichment is a powerful tool for making use of the massive throughput of novel DNA-sequencing instruments. We herein present a simple and scalable protocol for multiplex amplification of target regions based on the Selector technique. The updated version exhibits improved coverage and compatibility with next-generation-sequencing (NGS) library-construction procedures for shotgun sequencing with NGS platforms. To demonstrate the performance of the technique, all 501 exons from 28 genes frequently involved in cancer were enriched for and sequenced in specimens derived from cell lines and tumor biopsies. DNA from both fresh frozen and formalin-fixed paraffin-embedded biopsies were analyzed and 94 specificity and 98 coverage of the targeted region was achieved. Reproducibility between replicates was high (R 2=0, 98) and readily enabled detection of copy-number variations. The procedure can be carried out in <24 h and does not require any dedicated instrumentation.
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44.
  • Kahraman, Ali Teymur, et al. (författare)
  • A Simple End-to-End Computer-Aided Detection Pipeline for Trained Deep Learning Models
  • 2024
  • Ingår i: Engineering of Computer-Based Systems : 8th International Conference, ECBS 2023, Proceedings - 8th International Conference, ECBS 2023, Proceedings. - 1611-3349 .- 0302-9743. - 9783031492518 ; 14390 LNCS, s. 259-262
  • Konferensbidrag (refereegranskat)abstract
    • Recently, there has been a significant rise in research and development focused on deep learning (DL) models within healthcare. This trend arises from the availability of extensive medical imaging data and notable advances in graphics processing unit (GPU) computational capabilities. Trained DL models show promise in supporting clinicians with tasks like image segmentation and classification. However, advancement of these models into clinical validation remains limited due to two key factors. Firstly, DL models are trained on off-premises environments by DL experts using Unix-like operating systems (OS). These systems rely on multiple libraries and third-party components, demanding complex installations. Secondly, the absence of a user-friendly graphical interface for model outputs complicates validation by clinicians. Here, we introduce a conceptual Computer-Aided Detection (CAD) pipeline designed to address these two issues and enable non-AI experts, such as clinicians, to use trained DL models offline in Windows OS. The pipeline divides tasks between DL experts and clinicians, where experts handle model development, training, inference mechanisms, Grayscale Softcopy Presentation State (GSPS) objects creation, and containerization for deployment. The clinicians execute a simple script to install necessary software and dependencies. Hence, they can use a universal image viewer to analyze results generated by the models. This paper illustrates the pipeline's effectiveness through a case study on pulmonary embolism detection, showcasing successful deployment on a local workstation by an in-house radiologist. By simplifying model deployment and making it accessible to non-AI experts, this CAD pipeline bridges the gap between technical development and practical application, promising broader healthcare applications.
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45.
  • Kahraman, Ali T., et al. (författare)
  • Automated detection, segmentation and measurement of major vessels and the trachea in CT pulmonary angiography
  • 2023
  • Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13
  • Tidskriftsartikel (refereegranskat)abstract
    • Mediastinal structure measurements are important for the radiologist's review of computed tomography pulmonary angiography (CTPA) examinations. In the reporting process, radiologists make measurements of diameters, volumes, and organ densities for image quality assessment and risk stratification. However, manual measurement of these features is time consuming. Here, we sought to develop a time-saving automated algorithm that can accurately detect, segment and measure mediastinal structures in routine clinical CTPA examinations. In this study, 700 CTPA examinations collected and annotated. Of these, a training set of 180 examinations were used to develop a fully automated deterministic algorithm. On the test set of 520 examinations, two radiologists validated the detection and segmentation performance quantitatively, and ground truth was annotated to validate the measurement performance. External validation was performed in 47 CTPAs from two independent datasets. The system had 86-100% detection and segmentation accuracy in the different tasks. The automatic measurements correlated well to those of the radiologist (Pearson's r 0.68-0.99). Taken together, the fully automated algorithm accurately detected, segmented, and measured mediastinal structures in routine CTPA examinations having an adequate representation of common artifacts and medical conditions.
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46.
  • Karlsson, Henning, et al. (författare)
  • Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
  • 2017
  • Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:18, s. 30217-30234
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The thiosemicarbazone CD 02750 (VLX50) was recently reported as a hit compound in a phenotype-based drug screen in primary cultures of patient tumor cells. We synthesized a copper complex of VLX50, denoted VLX60, and characterized its antitumor and mechanistic properties. Materials and Methods: The cytotoxic effects and mechanistic properties of VLX60 were investigated in monolayer cultures of multiple human cell lines, in tumor cells from patients, in a 3-D spheroid cell culture system and in vivo and were compared with those of VLX50. Results: VLX60 showed ?3-fold higher cytotoxic activity than VLX50 in 2-D cultures and, in contrast to VLX50, retained its activity in the presence of additional iron. VLX60 was effective against non-proliferative spheroids and against tumor xenografts in vivo in a murine model. In contrast to VLX50, gene expression analysis demonstrated that genes associated with oxidative stress were considerably enriched in cells exposed to VLX60 as was induction of reactive oxygen. VLX60 compromised the ubiquitin-proteasome system and was more active in BRAF mutated versus BRAF wild-type colon cancer cells. Conclusions: The cytotoxic effects of the copper thiosemicarbazone VLX60 differ from those of VLX50 and shows interesting features as a potential antitumor drug, notably against BRAF mutated colorectal cancer.
  •  
47.
  • Kashif, Muhammad, et al. (författare)
  • A Pragmatic Definition of Therapeutic Synergy Suitable for Clinically Relevant In Vitro Multicompound Analyses
  • 2014
  • Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 13:7, s. 1964-1976
  • Tidskriftsartikel (refereegranskat)abstract
    • For decades, the standard procedure when screening for candidate anticancer drug combinations has been to search for synergy, defined as any positive deviation from trivial cases like when the drugs are regarded as diluted versions of each other (Loewe additivity), independent actions (Bliss independence), or no interaction terms in a response surface model (no interaction). Here, we show that this kind of conventional synergy analysis may be completely misleading when the goal is to detect if there is a promising in vitro therapeutic window. Motivated by this result, and the fact that a drug combination offering a promising therapeutic window seldom is interesting if one of its constituent drugs can provide the same window alone, the largely overlooked concept of therapeutic synergy (TS) is reintroduced. In vitro TS is said to occur when the largest therapeutic window obtained by the best drug combination cannot be achieved by any single drug within the concentration range studied. Using this definition of TS, we introduce a procedure that enables its use in modern massively parallel experiments supported by a statistical omnibus test for TS designed to avoid the multiple testing problem. Finally, we suggest how one may perform TS analysis, via computational predictions of the reference cell responses, when only the target cell responses are available. In conclusion, the conventional error-prone search for promising drug combinations may be improved by replacing conventional (toxicology-rooted) synergy analysis with an analysis focused on (clinically motivated) TS. 
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48.
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49.
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50.
  • Kiflemariam, Sara (författare)
  • Expression and Mutation Analyses of Candidate Cancer Genes In Situ
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Cancers display heterogeneity in genetic profiles of the individual cancer cells and in the composition of different malignant and non-malignant cell populations. Such intra-tumor heterogeneity plays a role in treatment response and the emergence of resistance to cancer therapies. Approaches that address this complexity and improve stratification of patients for treatment are therefore highly warranted. Thus, the aims of this thesis were to further develop and apply in situ technologies for expression and mutation analyses of candidate cancer genes to gain a deeper understanding of cancer biology and to study intra-tumor heterogeneity.In paper I, we established and validated a procedure for scalable in situ hybridization of large gene sets in human formalin-fixed paraffin-embedded tissues for analysis of gene expression. This method was used in paper II for large-scale expression analysis of the tyrosine kinome and phosphatome, two gene families whose members are frequently mutated in many forms of cancers. Systematic, compartment-specific expression mapping at cell type resolution enabled us to identify several novel vascular markers that have gone unnoticed in bulk transcriptomic analyses. In papers III and IV, we used padlock probes for in situ mutation detection in single cells for studies of genetic intra-tumor heterogeneity. In paper III, multiplex detection and genotyping of oncogenic point mutations was demonstrated in routinely processed tissue materials, whereas in paper IV we further the application by demonstrating multiplex detection of fusion gene transcripts.Collectively, the work presented in this thesis employs in situ-based methods to obtain spatial resolution of gene expression and mutation patterns in normal and cancer tissues, thereby broadening our understanding of the cancer genome.
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