Abstract Indoleamine 2,3-dioxygenase (IDO) and human leukocyte antigen-G (HLA-G) are two molecules involved in immune tolerance. 3-Hydroxyanthranilic acid is an IDO downstream metabolite that can ...produce an important immune suppression. In dendritic cells, it induces HLA-G cell surface expression and secretion to the medium. The relationship between IDO and HLA-G seems to be dependent on the cell type. In this study we analyzed the effect of the tryptophan metabolite 3-hydroxyanthranilic acid in these two proteins in monocytes and macrophages. This compound decreased IDO activity while increased HLA-G surface expression in macrophages, but not in monocytes. Also, 3-hydroxyanthranilic acid decreased HLA-G1 shedding, but not HLA-G5 secretion by macrophages. These results stress the importance of 3-hydroxyanthranilic acid as a modulator of the immune response.
Although there have been many studies on the p73 gene, some of its functions still remain unclear. There is little research on the relationship between p73 gene transcription and its protein ...expression and the response to certain drugs such as oxaliplatin and cetuximab, which are drugs currently used in colorectal cancer.The purpose of this study was to evaluate the impact of TAp73 expression on oxaliplatin and cetuximab-based chemotherapy in colorectal cancer cell lines with different K-Ras and B-Raf mutational status.
TAp73 was analyzed in three colorectal tumor cell lines HT-29, SW-480 and Caco-2. mRNA TAp73 was determined using Real time PCR; TAp73 protein by immunoblotting and cell viability was analyzed by the MTT method.
We found that mRNA and TAp73 protein were decreased in cells treated with oxaliplatin (in monotherapy or combined with cetuximab) when B-Raf is mutated. This was statistically significant and was also associated with higher cell viability after the treatment.
Here, for the first time we report, that there is a signaling loop between B-Raf activation and p73 function.Low expression of TAp73 in colorectal cancer cell lines with mutated B-Raf may be involved in the lack of response to oxaliplatin in monotherapy or combined with cetuximab.
Mutational analysis of large multiexon genes without prevalent mutations is a laborious undertaking that requires the use of a high‐throughput scanning technique. The Human Genome Project has enabled ...the development of powerful techniques for mutation detection in large multiexon genes. We have transferred heteroduplex analysis (HA) by conformation‐sensitive gel electrophoresis of the two major breast cancer (BC) predisposing genes, BRCA1 and BRCA2, to a multicapillary DNA sequencer in order to increase the throughput of this technique. This new method that we have called heteroduplex analysis by capillary array electrophoresis (HA‐CAE) is based on the use of multiplex‐polymerase chain reaction (PCR), different fluorescent labels and HA in a 16‐capillary DNA sequencer. To date, a total of 114 different DNA sequence variants (19 insertions/deletions and 95 single‐nucleotide substitutions – SNS) of BRCA1 and BRCA2 from 431 unrelated BC families have been successfully detected by HA‐CAE. In addition, we have optimized the multiplex‐PCR conditions for the colorectal cancer genes MLH1 and MSH2 in order to analyze them by HA‐CAE. Both genes have been amplified in 13 multiplex groups, which contain the 35 exons, and their corresponding flanking intronic sequences. MLH1 and MSH2 have been analyzed in nine hereditary nonpolyposis colorectal cancer patients, and we have found six different DNA changes: one complex deletion/insertion mutation in MLH1 exon 19 and another five SNS. Only the complex mutation and one SNS may be classified as cancer‐prone mutations. Our experience has revealed that HA‐CAE is a simple, fast, reproducible and sensitive method to scan the sequences of complex genes.
To evaluate the
KRAS
,
BRAF
,
EGFR
, and
HER2
gene status in colorectal cancer by novel techniques and evaluate whether anti-HER2 therapies could be offered in the treatment of these patients. There ...are conflicting data on the prevalence of
BRAF
mutations and EGFR and HER2 gene amplification in colorectal
KRAS
wild type patients. In our study we tried to evaluate these expressions and their relationship to future treatment assays. Clinical–pathological data and paraffin-embedded specimens were collected from 186 patients who underwent colorectal resections at General Yagüe Hospital in Burgos, Spain.
KRAS
and
BRAF
status was analyzed by real-time PCR in all patients.
EGFR
and
HER2/NEU
gene amplification was detected using fluorescent in situ hybridisation technique (FISH) in 38
KRAS
and
BRAF
wild type patients.
KRAS
mutations were present in 48% of the colorectal cancer patients.
BRAF
mutations were present in 6.25% of the
KRAS
wild type patients.
EGFR
and
HER2
gene amplification was observed in 5.3% and 26.3%, respectively, of
KRAS
and
BRAF
wild type colorectal cancer patients.
HER2
, but not
EGFR
gene amplification, was frequently observed in
KRAS
and
BRAF
wild type colorectal cancer patients. These data indicate that
HER2
amplification could be one of the genes to be considered in the therapeutic management of colorectal cancer.
Introduction
The aim of this study was to compare TOMOX versus FOLFOX4 as first-line treatment of advanced colorectal cancer (CRC).
Materials and methods
191 chemotherapy-naïve patients were ...randomized to receive TOMOX or FOLFOX4. Patients were evaluated every 3 months and chemotherapy was continued until disease progression or unacceptable toxicity. Overall response rate was the primary endpoint.
Results
183 patients were included in the intent-to-treat analysis (92 TOMOX and 91 FOLFOX4). Overall response rate was 45.6 and 36.3 % (
p
= 0.003) for TOMOX and FOLFOX4, respectively. No statistically significant differences were observed in overall survival (15.6 and 17.2 months;
p
= 0.475); progression-free survival (7.7 and 8.7 months;
p
= 0.292), and response duration (6.4 and 7.6 months;
p
= 0.372) for TOMOX and FOLFOX4, respectively. Grades 3 and 4 neutropenia (
p
< 0.0001) and leukopenia (
p
= 0.028) were more common with the FOLFOX4 regimen, while hepatic disorders and asthenia were higher in TOMOX group (
p
= ns). There were two treatment-related deaths in the FOLFOX4 arm and one in the TOMOX arm. Quality of life analysis based on the SF-36 revealed differences between the two regimens for physical and mental composite scores after 6 weeks, and for body pain and emotional role functioning after 6 and 12 weeks; all of these favored the FOLFOX4 arm (
p
≤ 0.05).
Conclusions
TOMOX and FOLFOX4 seem to have similar efficacy and are well tolerated in the first-line treatment for advanced CRC with different profiles of toxicity. The convenient TOMOX regimen may offer an alternative to fluoropyrimidine-based regimens.
This phase II trial investigated the efficacy of an induction regimen of bevacizumab, capecitabine plus oxaliplatin (XELOX) followed by maintenance therapy with bevacizumab plus erlotinib as ...first-line therapy in patients with metastatic colorectal cancer. Patients with metastatic colorectal cancer received intravenous bevacizumab 7.5 mg/kg plus oxaliplatin 130 mg/m(2) on day 1 followed by oral capecitabine 1,000 mg/m(2) twice daily on days 1-14 every 3 weeks for six cycles. In the absence of disease progression, patients then received bevacizumab 7.5 mg/kg every 3 weeks plus oral erlotinib 150 mg once daily. The primary study endpoint was progression-free survival. In the intention-to-treat population (n = 90), the median progression-free survival was 9.2 95% confidence interval (CI): 7.9-11.9 months, and the median overall survival was 25.8 (95% CI: 18.0-30.9) months. In the patient subpopulation who received both induction and maintenance therapy (n = 52), median progression-free survival was 11.1 (95% CI: 9.0-15.7) months, and the median overall survival was 29.5 (95% CI: 23.7-36.7) months. KRAS status did not predict efficacy. The most common grade 3/4 adverse events were diarrhea, asthenia, and neutropenia. XELOX-bevacizumab for 6 cycles followed by bevacizumab-erlotinib maintenance therapy has been shown to be a highly active and well-tolerated first-line regimen in patients with metastatic colorectal cancer.
Abstract
The accurate identification and description of the genes in the human and mouse genomes is a fundamental requirement for high quality analysis of data informing both genome biology and ...clinical genomics. Over the last 15 years, the GENCODE consortium has been producing reference quality gene annotations to provide this foundational resource. The GENCODE consortium includes both experimental and computational biology groups who work together to improve and extend the GENCODE gene annotation. Specifically, we generate primary data, create bioinformatics tools and provide analysis to support the work of expert manual gene annotators and automated gene annotation pipelines. In addition, manual and computational annotation workflows use any and all publicly available data and analysis, along with the research literature to identify and characterise gene loci to the highest standard. GENCODE gene annotations are accessible via the Ensembl and UCSC Genome Browsers, the Ensembl FTP site, Ensembl Biomart, Ensembl Perl and REST APIs as well as https://www.gencodegenes.org.
Summary
Purpose
To determine the efficacy of the addition of gefitinib to raltitrexed in patients with colorectal cancer (CRC) that have progressed after first line chemotherapy. The study also ...sought to explore the safety of the combination and to investigate biomarkers predictive outcome.
Methods
A total of 76 patients were randomized to raltitrexed (3 mg/m
2
i.v.) every 21 days plus either daily gefitinib (250 mg p.o.) or placebo. The primary endpoint of the study was progression free survival (PFS). Tumor tissues were collected to determine the expression of EGFR, pEGFR, pMAPK, and pAkt.
Results
Both groups were well balanced with regard to prognostic factors. Treatment was well tolerated with no increased in toxicity except diarrhea and skin rash in the combination group. There were no differences in PFS between the combination arm 63 days (95% CI: 57–84) compared to the raltitrexed alone arm 72 days (95% CI: 59–132), or overall survival 361 days (95% CI: 283–533 days) versus 291 days (95% CI: 255–539 days) respectively. The objective response rate was 7.9% (3 patients) (CI 95%: 1,66–21,38) versus 5.3% (2 patients) (CI 0,64–17,75), respectively. The biomarker studies were not conclusive.
Conclusion
The combination of raltitrexed and gefitinib was well tolerated although was not associated with improved progression free survival in patients with refractory CRC.
The objective of the work was to study
PIK3CA
mutations in wild type
KRAS
and
BRAF
colorectal cancer. Clinicopathological data and paraffin-embedded specimens were collected on 73 patients who ...underwent colorectal resections at General Yagüe Hospital in Burgos.
KRAS
,
BRAF
and
PIK3CA
status were analyzed by real-time PCR in all patients.
PIK3CA
mutations were present in 8.22% of wild type
KRAS
and
BRAF
colorectal cancers. The most frequent mutation is E545K/D in exon 9 which represents 83.3% of all mutations. By contrast, we did not found any tumour harbouring H1047R mutation in exon 20. Among the patients who undergo a curative resection of colorectal cancer,
PIK3CA
mutation is present in an important percentage of
KRAS
and
BRAF
wild type tumours.
PIK3CA
mutation may be considered as it could be a hypothetic reason to be not responder to anti-EGFR antibodies.
Ensembl 2021 Howe, Kevin L; Achuthan, Premanand; Allen, James ...
Nucleic acids research,
01/2021, Letnik:
49, Številka:
D1
Journal Article
Recenzirano
Odprti dostop
Abstract
The Ensembl project (https://www.ensembl.org) annotates genomes and disseminates genomic data for vertebrate species. We create detailed and comprehensive annotation of gene structures, ...regulatory elements and variants, and enable comparative genomics by inferring the evolutionary history of genes and genomes. Our integrated genomic data are made available in a variety of ways, including genome browsers, search interfaces, specialist tools such as the Ensembl Variant Effect Predictor, download files and programmatic interfaces. Here, we present recent Ensembl developments including two new website portals. Ensembl Rapid Release (http://rapid.ensembl.org) is designed to provide core tools and services for genomes as soon as possible and has been deployed to support large biodiversity sequencing projects. Our SARS-CoV-2 genome browser (https://covid-19.ensembl.org) integrates our own annotation with publicly available genomic data from numerous sources to facilitate the use of genomics in the international scientific response to the COVID-19 pandemic. We also report on other updates to our annotation resources, tools and services. All Ensembl data and software are freely available without restriction.
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