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- Schmoll, H. J., et al.
(author)
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ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making
- 2012
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In: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 23:10, s. 2479-2516
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Journal article (peer-reviewed)abstract
- Colorectal cancer (CRC) is the most common tumour type in both sexes combined in Western countries. Although screening programmes including the implementation of faecal occult blood test and colonoscopy might be able to reduce mortality by removing precursor lesions and by making diagnosis at an earlier stage, the burden of disease and mortality is still high. Improvement of diagnostic and treatment options increased staging accuracy, functional outcome for early stages as well as survival. Although high quality surgery is still the mainstay of curative treatment, the management of CRC must be a multi-modal approach performed by an experienced multi-disciplinary expert team. Optimal choice of the individual treatment modality according to disease localization and extent, tumour biology and patient factors is able to maintain quality of life, enables long-term survival and even cure in selected patients by a combination of chemotherapy and surgery. Treatment decisions must be based on the available evidence, which has been the basis for this consensus conference-based guideline delivering a clear proposal for diagnostic and treatment measures in each stage of rectal and colon cancer and the individual clinical situations. This ESMO guideline is recommended to be used as the basis for treatment and management decisions.
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- Jagannathan, Vidhya, et al.
(author)
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A Mutation in the SUV39H2 Gene in Labrador Retrievers with Hereditary Nasal Parakeratosis (HNPK) Provides Insights into the Epigenetics of Keratinocyte Differentiation
- 2013
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In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 9:10, s. e1003848-
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Journal article (peer-reviewed)abstract
- Hereditary nasal parakeratosis (HNPK), an inherited monogenic autosomal recessive skin disorder, leads to crusts and fissures on the nasal planum of Labrador Retrievers. We performed a genome-wide association study (GWAS) using 13 HNPK cases and 23 controls. We obtained a single strong association signal on chromosome 2 (p(raw) = 4.4x10(-14)). The analysis of shared haplotypes among the 13 cases defined a critical interval of 1.6 Mb with 25 predicted genes. We re-sequenced the genome of one case at 38x coverage and detected 3 non-synonymous variants in the critical interval with respect to the reference genome assembly. We genotyped these variants in larger cohorts of dogs and only one was perfectly associated with the HNPK phenotype in a cohort of more than 500 dogs. This candidate causative variant is a missense variant in the SUV39H2 gene encoding a histone 3 lysine 9 (H3K9) methyltransferase, which mediates chromatin silencing. The variant c.972T>G is predicted to change an evolutionary conserved asparagine into a lysine in the catalytically active domain of the enzyme (p.N324K). We further studied the histopathological alterations in the epidermis in vivo. Our data suggest that the HNPK phenotype is not caused by hyperproliferation, but rather delayed terminal differentiation of keratinocytes. Thus, our data provide evidence that SUV39H2 is involved in the epigenetic regulation of keratinocyte differentiation ensuring proper stratification and tight sealing of the mammalian epidermis.
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- Kaminski, M. F., et al.
(author)
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The NordICC Study : Rationale and design of a randomized trial on colonoscopy screening for colorectal cancer
- 2012
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In: Endoscopy. - : Georg Thieme Verlag KG. - 0013-726X .- 1438-8812. ; 44:7, s. 695-702
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Journal article (peer-reviewed)abstract
- Background and study aim: While colonoscopy screening is widely used in several European countries and the United States, there are no randomized trials to quantify its benefits. The Nordic-European Initiative on Colorectal Cancer (NordICC) is a multinational, randomized controlled trial aiming at investigating the effect of colonoscopy screening on colorectal cancer (CRC) incidence and mortality. This paper describes the rationale and design of the NordICC trial. Study design: Men and women aged 55 to 64 years are drawn from the population registries in the participating countries and randomly assigned to either once-only colonoscopy screening with removal of all detected lesions, or no screening (standard of care in the trial regions). All individuals are followed for 15 years after inclusion using dedicated national registries. The primary end points of the trial are cumulative CRC-specific death and CRC incidence during 15 years of follow-up. Power analysis: We hypothesize a 50% CRC mortality-reducing efficacy of the colonoscopy intervention and predict 50% compliance, yielding a 25% mortality reduction among those invited to screening. For 90% power and a two-sided alpha level of 0.05, using a 2: 1 randomization, 45600 individuals will be randomized to control, and 22800 individuals to the colonoscopy group. Interim analyses of the effect of colonoscopy on CRC incidence and mortality will be performed at 10-year follow-up. Conclusions: The aim of the NordICC trial is to quantify the effectiveness of population-based colonoscopy screening. This will allow development of evidence-based guidelines for CRC screening in the general population.
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- Fenn, Sebastian, et al.
(author)
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Crystal Structure of an Anti-Ang2 CrossFab Demonstrates Complete Structural and Functional Integrity of the Variable Domain
- 2013
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:4
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Journal article (peer-reviewed)abstract
- Bispecific antibodies are considered as a promising class of future biotherapeutic molecules. They comprise binding specificities for two different antigens, which may provide additive or synergistic modes of action. There is a wide variety of design alternatives for such bispecific antibodies, including the "CrossMab" format. CrossMabs contain a domain crossover in one of the antigen-binding (Fab) parts, together with the "knobs-and-holes" approach, to enforce the correct assembly of four different polypeptide chains into an IgG-like bispecific antibody. We determined the crystal structure of a hAng-2-binding Fab in its crossed and uncrossed form and show that CH1-CL-domain crossover does not induce significant perturbations of the structure and has no detectable influence on target binding.
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