Search results for "digestive"
showing 10 items of 2631 documents
The “unnatural” history of colorectal cancer in Lynch syndrome : lessons from colonoscopy surveillance
2021
Individuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). Regular colonoscopy with polypectomy is recommended to reduce CRC risk in LS individuals. However, recent independent studies demonstrated that a substantial proportion of LS individuals develop CRC despite regular colonoscopy. The reasons for this surprising observation confirmed by large prospective studies are a matter of debate. In this review, we collect existing evidence from clinical, epidemiological and molecular studies and interpret them with regard to the origins and progression of LS-associated CRC. Alon…
Expression of DNA repair proteins hMSH2, hMSH6, hMLH1,O6-methylguanine-DNA methyltransferase and N-methylpurine-DNA glycosylase in melanoma cells wit…
1999
Malignant melanoma is well known for its primary unresponsiveness to chemotherapy. The mechanisms conferring this intrinsic resistance are unclear. In this study, we investigated the role of genes involved in DNA repair in a panel of human melanoma cell variants exhibiting low and high levels of resistance to 4 commonly used drugs in melanoma treatment, i.e., vindesine, etoposide, fotemustine and cisplatin. We show that in melanoma cells exhibiting resistance to cisplatin, etoposide and vindesine, the nuclear content of each of the DNA mismatch repair (MMR) proteins hMLH1, hMSH2 and hMSH6 was reduced by 30–70%. A decreased expression level of up to 80% of mRNAs encoding hMLH1 and hMSH2 was …
Site-Specific Dual-Labeling of a VHH with a Chelator and a Photosensitizer for Nuclear Imaging and Targeted Photodynamic Therapy of EGFR-Positive Tum…
2021
Simple Summary Variable domains of heavy chain only antibodies are small proteins that can be used for tumor imaging and therapy upon conjugation of functional groups. As frequently used random conjugation techniques can decrease binding to the target of interest, site-specific conjugation of these functional groups is preferred. Here, we optimized site-specific conjugation of both a chelator for binding of a radiometal and a photosensitizer to epidermal growth factor receptor (EGFR) binding VHH 7D12. We characterized this dual-labeled VHH for nuclear imaging and targeted photodynamic therapy of EGFR-expressing tumors. Abstract Variable domains of heavy chain only antibodies (VHHs) are valu…
Homozygous mutations in exon 11 of c-KIT in GIST define a group of high risk patients
2010
Gastrointestinal stromal tumors are the most common mesenchymal neoplasms of the gastrointestinal tract. Gain of function mutations of tyrosine kinase receptors, c-KIT, and PDGFRa have been identified in most GIST; c-KIT exon 11 mutations are the most common. The type of c-KIT or PDGFRa mutation indicates tumor responsiveness to imatinib treatment or progression, although GIST with homozygous mutation has been poorly studied. We analyzed 145 GIST at the immunohistopathologic and genetic levels. Formalin-fixed, paraffin-embedded sections were used for our studies. The histological variables included: mitotic count per 50 HPF, necrosis, pleomorphism, and cell type. The immunophenotype was def…
Down-regulation of CYLD as a trigger for NF-κB activation and a mechanism of apoptotic resistance in hepatocellular carcinoma cells
2010
The cylindromatosis gene (CYLD) was identified as a tumor suppressor gene, which is mutated in familial cylindromatosis (Brooke-Spiegler syndrome), an autosomal-dominant predisposition to multiple tumors of the skin appendages. CYLD is a deubiquitinating enzyme acting as a negative regulator of the nuclear factor κB (NF-κB) signaling pathway by removing lysine-63-linked polyubiquitin chains from NF-κB activating proteins. In order to investigate the role of CYLD in apoptotic signaling in human hepatocellular carcinoma (HCC) cells, we first studied the expression levels of CYLD in HCC tissues. CYLD expression was lower in HCC both at protein and mRNA levels compared to the surrounding non-ma…
Acquired resistance of melanoma cells to the antineoplastic agent fotemustine is caused by reactivation of the DNA repair gene mgmt
2001
Acquired resistance to antineoplastic agents is a frequent obstacle in tumor therapy. Malignant melanoma cells are particularly well known for their unresponsiveness to chemotherapy; only about 30% of tumors exhibit a transient clinical response to treatment. In our study, we investigated the molecular mechanism of acquired resistance of melanoma cells (MeWo) to the chloroethylating drug fotemustine. Determination of O6-methylguanine-DNA methyltransferase (MGMT) activity showed that MeWo cells that acquired resistance to fotemustine upon repeated treatment with the drug display high MGMT activity, whereas the parental cell line had no detectable MGMT. The resistant cell lines exhibit cross-…
Efficacy of BET Bromodomain Inhibition in Kras-Mutant Non–Small Cell Lung Cancer
2013
Abstract Purpose: Amplification of MYC is one of the most common genetic alterations in lung cancer, contributing to a myriad of phenotypes associated with growth, invasion, and drug resistance. Murine genetics has established both the centrality of somatic alterations of Kras in lung cancer, as well as the dependency of mutant Kras tumors on MYC function. Unfortunately, drug-like small-molecule inhibitors of KRAS and MYC have yet to be realized. The recent discovery, in hematologic malignancies, that bromodomain and extra-terminal (BET) bromodomain inhibition impairs MYC expression and MYC transcriptional function established the rationale of targeting KRAS-driven non–small cell lung cance…
Epidemiological, clinical and molecular characterization of Lynch‐like syndrome: A population‐based study
2019
Colorectal carcinomas that are mismatch repair (MMR)‐deficient in the absence of MLH1 promoter methylation or germline mutations represent Lynch‐like syndrome (LLS). Double somatic events inactivating MMR genes are involved in the etiology of LLS tumors. Our purpose was to define the clinical and broader molecular hallmarks of LLS tumors and the population incidence of LLS, which remain poorly characterized. We investigated 762 consecutive colorectal carcinomas operated in Central Finland in 2000–2010. LLS cases were identified by a stepwise protocol based on MMR protein expression, MLH1 methylation and MMR gene mutation status. LLS tumors were profiled for CpG Island Methylator Phenotype (…
Inactivation of O(6)-methylguanine-DNA methyltransferase by glucose-conjugated inhibitors.
2001
The DNA-repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a decisive determinant of resistance of tumor cells to methylating and chloroethylating anti-cancer drugs. Therefore, selective inhibition of MGMT in tumors is expected to cause tumor sensitization. Several inhibitors of MGMT have been developed which function in both tumors and normal tissue. To deplete MGMT preferentially in tumors, strategies to target the inhibitor to the tumor tissue need to be developed. Here, we report on the properties of glucose-conjugated MGMT inhibitors that might be useful for tumor targeting since tumor cells frequently over-express glucose transporter. O6-Benzylguanine (O6BG), 8-aza-O6-ben…
The dual PI3K/mTOR inhibitor PKI-587 enhances sensitivity to cetuximab in EGFR-resistant human head and neck cancer models
2014
Background:Cetuximab is the only targeted agent approved for the treatment of head and neck squamous cell carcinomas (HNSCC), but low response rates and disease progression are frequently reported. As the phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways have an important role in the pathogenesis of HNSCC, we investigated their involvement in cetuximab resistance.Methods:Different human squamous cancer cell lines sensitive or resistant to cetuximab were tested for the dual PI3K/mTOR inhibitor PF-05212384 (PKI-587), alone and in combination, both in vitro and in vivo.Results:Treatment with PKI-587 enhances sensitivity to cetuximab in vitro, even in the co…