PURPOSE: The pathologic interactions between tumor and host immune cells within the tumor microenvironment create an immunosuppressive
network that promotes tumor growth and protects the tumor from ...immune attack. In this study, we examined the contribution
of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) on this phenomenon. EXPERIMENTAL DESIGN: Expression of IDO
was analyzed in colorectal cancer cell lines by reverse transcription-PCR and functional enzyme activity was assessed by high-pressure
liquid chromatography. Semiquantitative immunohistochemistry was used to evaluate IDO expression in the tissue samples of
143 patients with colorectal carcinoma, and was then correlated with the number of tumor-infiltrating T cells and clinical
variables. RESULTS: In vitro IDO expression and functional enzyme activity in colorectal cancer cells was found to be strictly
dependent on IFN-gamma stimulation. Immunohistochemical scores revealed IDO-high expression in 56 of 143 (39.2%) tumor specimens,
whereas 87 of 143 (60.8%) cases showed low IDO expression levels. IDO-high expression was associated with a significant reduction
of CD3+ infiltrating T cells (46.02 +/- 7.25) as compared with tissue samples expressing low IDO (19.42 +/- 2.50; P = 0.0003).
Furthermore, IDO-high immunoreactivity significantly correlated with the frequency of liver metastases (P = 0.003). Kaplan-Meier
analysis showed the crossing of survival curves at 45 months. By multivariate Cox's analysis, IDO-high expression emerged
as an independent prognostic variable (<45 months, P = 0.006; >45 months, P = 0.04). CONCLUSION: IDO-high expression by colorectal
tumor cells enables certain cancer subsets to initially avoid immune attack and defeat the invasion of T cells via local tryptophan
depletion and the production of proapoptotic tryptophan catabolites. Thus, IDO significantly contributes to disease progression
and overall survival in patients with colorectal cancer.
Lynch Syndrome: Its Impact on Urothelial Carcinoma Lindner, Andrea Katharina; Schachtner, Gert; Tulchiner, Gennadi ...
International journal of molecular sciences,
01/2021, Letnik:
22, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial cancer (UC). Mismatch repair (MMR) ...deficiency, due to pathogenic variants in
,
,
, and
, and microsatellite instability, are known for development of Lynch syndrome (LS) associated carcinogenesis. UC is the third most common cancer type in LS-associated tumors. The diversity of germline variants in the affected MMR genes and their following subsequent function loss might be responsible for the variation in cancer risk, suggesting an increased risk of developing UC in
mutation carriers. In this review, we will focus on LS-associated UC of the upper urinary tract (UUT) and bladder, their germline profiles, and outcomes compared to sporadic UC, the impact of genetic testing, as well as urological follow-up strategies in LS. In addition, we present a case of metastatic LS-associated UC of the UUT and bladder, achieving complete response during checkpoint inhibition since more than 2 years.
Specific gene promoter DNA methylation is becoming a powerful epigenetic biomarker in cancer diagnostics. Five genes (
,
,
,
, and
) were selected based on their frequently published potential as ...epigenetic markers. Diagnostic promoter methylation assays were generated based on bisulfite-converted DNA pyrosequencing. The methylation patterns of 144 non-small-cell lung cancer (NSCLC) and 7 healthy control formalin-fixed paraffin-embedded (FFPE) samples were analyzed to evaluate the applicability of the putative diagnostic markers. Statistically significant changes in methylation levels are shown for
and
. Furthermore, 12 NSCLC and two benign lung cell lines were characterized for promoter methylation. The in vitro tests involved a comparison of promoter methylation in 2D and 3D cultures, as well as therapeutic tests investigating the impact of
promoter methylation on sensitivity to tyrosine kinase inhibitor (TKI) and DNA methyl-transferase inhibitor (DNMTI) treatments. We conclude that the selected markers have potential and putative impacts as diagnostic or even predictive marker genes, although a closer examination of the resulting protein expression and pathway regulation is needed.
The epithelial glycoprotein Ep-CAM is overexpressed in colon cancer and breast cancer. We assessed the frequency and prognostic significance of Ep-CAM in tissue specimens from 205 patients with ...invasive breast cancer, by immuno-histochemical staining with a monoclonal antibody specific for the Ep-CAM antigen. Ep-CAM overexpression was found in 35·6% of samples and was associated with poor disease-free and overall survival.
Background & Aims: Imbalances of iron homeostasis are accompanied by alterations of intestinal iron absorption. The identification of divalent-metal transporter 1 (DMT1) and ferroportin 1(FP1) has ...improved our understanding of transmembrane iron trafficking. To gain insight into the regulatory properties of these transporters in the duodenum, we studied their expression in patients with hereditary hemochromatosis (HFE-associated and non-HFE-associated), secondary iron overload, and iron deficiency.
Methods: DMT1, FP1 messenger RNA (mRNA), and protein expression were analyzed in duodenal biopsy specimens from patients by means of Taq-Man real-time polymerase chain reaction, Western blotting technique, and immunohistochemistry.
Results: DMT1 and FP1 mRNA levels are positively correlated with each other in all patient groups (P < 0.001). Moreover, DMT1 and FP1 mRNA levels were significantly increased in patients with iron deficiency, HFE and non-HFE hemochromatosis, whereas they were unchanged in patients with secondary iron overload. Alterations in DMT1 and FP1 mRNA levels were paralleled by comparable changes in the duodenal expression of these proteins. In patients with normal iron status or iron deficiency, significant negative correlations between DMT1, FP1 mRNA, and serum iron parameters were found, which were absent in subjects with primary hemochromatosis.
Conclusions: DMT1 and FP1 are centrally involved In iron uptake/transfer in the duodenum and in the adaptive changes of iron homeostasis to iron deficiency and overload.
Since tissue material is often lacking in metastatic prostate cancer (mPCa), there is increasing interest in using liquid biopsies for treatment decision and monitoring therapy responses. The purpose ...of this study was to validate the usefulness of circulating tumor cells (CTCs) and plasma-derived cell-free (cf) RNA as starting material for gene expression analysis through qPCR. CTCs were identified upon prostate-specific membrane antigen and/or cytokeratin positivity after enrichment with ScreenCell (Westford, Massachusetts, USA) filters or the microfluidic ParsortixTM (Guildford, Surrey, United Kingdom) system. Overall, 50% (28/56) of the patients had ≥5 CTCs/7.5 mL of blood. However, CTC count did not correlate with Gleason score, serum PSA, or gene expression. Notably, we observed high expression of CD45 in CTC samples after enrichment, which could be successfully eliminated through picking of single cells. Gene expression in picked CTCs was, however, rather low. In cfRNA from plasma, on the other hand, gene expression levels were higher compared to those found in CTCs. Moreover, we found that PSA was significantly increased in plasma-derived cfRNA of mPCa patients compared to healthy controls. High PSA expression was also associated with poor overall survival, indicating that using cfRNA from plasma could be used as a valuable tool for molecular expression analysis.
Purpose: Gallbladder carcinoma is an aggressive type of cancer that is difficult to cure by conventional procedures. There thus is
a need to identify novel molecular markers for the assessment of ...prognosis and as potential therapeutic targets. This retrospective
study was designed to investigate the prognostic significance of epithelial cell adhesion molecule (Ep-CAM) overexpression
in human gallbladder carcinoma.
Experimental Design: Ep-CAM expression was examined immunohistochemically on paraffin-embedded tissue specimens from 99 patients who underwent
surgical treatment for gallbladder carcinoma in the period between August 1988 and May 1999.
Results: Ep-CAM overexpression was found in 63 (63.6%) of the tumor samples. Kaplan-Meier curves showed that Ep-CAM overexpression
was significantly related to decreased overall survival ( P < 0.01). Overall survival gradually worsened with increasing Ep-CAM scores. Notably, in the subgroup of pT1 tumors ( n = 17), patients without Ep-CAM overexpression had a 5-year overall survival rate of 100% compared with 38% ( P = 0.01) for patients with Ep-CAM-overexpressing tumors. By univariate analysis, no correlation was found with conventional
clinicopathological parameters. Multivariate analysis, including Ep-CAM expression, pT stage, tumor grade, and resection margin
involvement, showed that Ep-CAM overexpression was an independent prognostic marker in gallbladder carcinoma ( P = 0.03; relative risk, 1.8).
Conclusions: These results demonstrate for the first time that Ep-CAM overexpression is an independent prognostic marker in gallbladder
carcinoma and that its prognostic impact should be validated prospectively. Furthermore, the Ep-CAM antigen represents an
attractive target for specific therapies with monoclonal antibodies or specific vaccines in patients with Ep-CAM-overexpressing
gallbladder carcinoma.
Aim of this study was to identify the nitric oxide synthase (NOS) isoform involved in early microcirculatory derangements following solid organ transplantation.
Tetrahydrobiopterin donor treatment ...has been shown to specifically attenuate these derangements following pancreas transplantation, and tetrahydrobiopterin-mediated protective effects to rely on its NOS-cofactor activity, rather than on its antioxidant capacity. However, the NOS-isoform mainly involved in this process has still to be defined.
Using a murine pancreas transplantation model, grafts lacking one of the three NOS-isoforms were compared to grafts from wild-type controls. Donors were treated with either tetrahydrobiopterin or remained untreated. All grafts were subjected to 16 h cold ischemia time and transplanted into wild-type recipients. Following 4 h graft reperfusion, microcirculation was analysed by confocal intravital fluorescence microscopy. Recipient survival was monitored for 50 days.
Transplantation of the pancreas from untreated wild-type donor mice resulted in microcirculatory damage of the transplanted graft and no recipient survived more than 72 h. Transplanting grafts from untreated donor mice lacking either endothelial or inducible NOS led to similar outcomes. In contrast, donor treatment with tetrahydrobiopterin prevented microcirculatory breakdown enabling long-term survival. Sole exception was transplantation of grafts from untreated donor mice lacking neuronal NOS. It resulted in intact microvascular structure and long-term recipient survival, either if donor mice were untreated or treated with tetrahydrobiopterin.
We demonstrate for the first time the crucial involvement of neuronal NOS in early microcirculatory derangements following solid organ transplantation. In this model, protective effects of tetrahydrobiopterin are mediated by targeting this isoform.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Indoleamine 2,3 dioxygenase (IDO) is a negative immune regulator and was found to be a prognostic marker in several tumor entities. In this study, we analysed IDO expression in oral squamous ...cell carcinoma (OSCC) regarding patient’s prognosis. Additionally, expression of IDO like-1 gene (INDOL-1) was analysed. Tumor tissue from 88 patients with OSCC was analysed by immunohistochemistry for IDO expression. The influence of IDO expression on survival was studied by multivariate Cox regression, adjusting for established clinical prognostic parameters. Real time PCR of tumor samples was performed in a subgroup of patients to analyse mRNA expression of IDO and INDOL-1. IDO high-expression was observed in 44.2% of OSCC patients. No significant correlation was found between IDO expression and clinical stage, sex, age, tumor site, tumor size, metastasis or tumor grade. The median overall survival time was 3.1 years for patients with IDO low tumors, compared to 1.36 years for IDO high tumors ( P = .028). Subset analysis of patients receiving adjuvant radio-chemotherapy showed a significant difference ( P = .0046) in overall survival between IDO low tumors (3.35 years) and IDO high tumors (1.26 years). In contrast, the impact of IDO expression on survival time in patients without adjuvant therapy was not significant ( P = .574). Interestingly, INDOL-1 was not expressed in OSCC. IDO high expression represents a significant negative prognostic factor in patients with OSCC, especially in those patients undergoing adjuvant radiochemotherapy. Our data support the suggestion, co-administration of small-molecule IDO inhibitors could represent a promising new strategy to increase the anti-tumor activity of radio-chemotherapy in patients with IDO positive OSCC.
Background/Aims: Severe alcoholic hepatitis (AH) is associated with high mortality. Tumor necrosis factor-alpha (TNFα) has been demonstrated to play an important role in its pathophysiology.
Methods: ...Twelve patients with biopsy-confirmed AH and a Maddrey discriminant factor >32 were treated with a single infusion of the anti-TNF monoclonal antibody Infliximab at a dose of 5
mg/kg body weight. Serial measurements were made for various cytokines using specific enzyme-linked immunoassays (ELISA). In four patients, liver biopsy samples were available pretreatment and on day+28 of therapy.
Results: Ten of the 12 patients are alive at a median of 15 (12–20) months. Two patients died within 30 days from septicemia. Serum bilirubin levels, Maddrey score, neutrophil count and C-reactive protein fell significantly within the first month. There was an early, though not significant, decrease in plasma levels of proinflammatory cytokines (interleukins (IL)-1β, IL-6, IL-8, interferon-gamma), whereas plasma levels of TNFα remained near the sensitivity limit of the assay throughout the treatment course. While TNFα mRNA expression in the liver did not change, expression of IL-8, a cytokine regulated mainly by TNFα, was almost absent on day+28.
Conclusions: Our data suggest that randomized controlled trials of anti-TNF antibody in severe AH are warranted.
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