Lung Metastases - Diagnostic, Prognostic and Molecular Aspects with Focus on Colorectal Cancer

In Sweden 4200 patients are diagnosed with lung cancer and 6500 patients with colorectal cancer (CRC) annually. The lungs are a common site for metastases. Immunohistochemistry (IHC) is a helpful aid in diagnostics of a pulmonary tumour. Selected patients with metastatic CRC undergo pulmonary metastasectomy and knowledge about which patients benefit from it is important. In this thesis IHC markers to distinguish between primary lung cancer and lung metastases, survival and prognostic factors of CRC patients treated with pulmonary metastasectomy and genetic profiles of paired primary CRC, lung and liver metastases are studied. I: Lung adenocarcinoma (AC) was TTF-1 positive in 89, 93 and 93% of cases with clones 8G7G3/1, SPT24 and SP141 respectively. None of the lung squamous cell carcinoma (SqCC) was positive with clone 8G7G3/1 but 6 and 8% with clone SPT24 and SP141, respectively. Equivalent numbers for CRC lung metastases were 2, 7 and 8%. II: Lung adenocarcinoma (AC) was TTF-1 positive in 90%, napsin A in 84%, and CK7 in 99% of cases. 68% were positive for all three markers and negative for other evaluated markers. None of the lung squamous cell carcinoma (SqCC) was expressed CK5, p40 and p63 in 94-97% of cases, while 64% were positive for all three markers, CK7+/-, and negative for other evaluated markers. CRC lung metastases were CK20+ in 83% and CDX2+ in 99% of cases, while 78% were positive for both and negative for other evaluated markers. III: In total 216 patients with primary tumour in the rectum (57%), left colon (34%) or right colon (9%) underwent pulmonary metastasectomy. The 5-year overall survival was 56%. Age >60 years, >1 lung metastasis, size of metastasis >3 cm, disease-free interval <24 months, N2 status of the primary tumour, low RBM3 expression in the lung metastasis, and no adjuvant chemotherapy following pulmonary metastasectomy were prognostic factors for shorter overall survival. IV: Mutations were most frequent in the TP53, APC and KRAS genes with rates of 81-85%, 70% and 41-48%, respectively in the primary tumours and corresponding lung and liver metastasis. With TST26, identical mutational profile was found in 59% of paired triplet tumours. The concordance was higher between primary tumour and lung metastasis (74%) vs. primary tumour and liver metastasis (63%). For seven (54%) of the 13 KRAS-mutated cases the KRAS mutations were concordant. With TSO500, discordant KRAS mutational profiles could be confirmed, sometimes with discrepancy compared to TST26. There was no significant difference in TMB between primary tumour and metastases

Phenotype and animal domestication : A study of dental variation between domestic, wild, captive, hybrid and insular Sus scrofa

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Acknowledgements We thank the institutions and individuals that provided access to collections, especially the curators of the Museum für Naturkunde, Berlin; Zoologische Staatssammlung, München; Muséum National d’Histoire Naturelle, Paris; Muséum d’Histoire Naturelle, Genève; National Museum of Natural History, Washington; The Field Museum, Chicago and The American Museum of Natural History, New-York. We also thank Jean-Denis Vigne, Nelly Gidaszewski, Vincent Debat and Mathieu Joron for fruitful discussions. This work was supported by a research grant from the Natural Environment Research Council, UK (grant number NE/F003382/1).Peer reviewedPublisher PD

Using traditional biometrical data to distinguish West Palearctic wild boar and domestic pigs in the archaeological record : new methods and standards

Peer reviewedPostprin

Functional analysis of long non-coding RNAs in cancer

For years the functional role of noncoding RNAs was greatly underestimated. Whole genome RNA sequencing projects that unraveled pervasive transcription emitting from large parts of the human genome changed those perspectives and prompted scientists to further look into the involvement of noncoding RNAs (ncRNAs) in development and disease. To date, we have significantly advanced our understanding of ncRNAs, however only a fraction of them has been functionally characterized. The subject of this thesis is to investigate the functional role of long noncoding RNAs (lncRNAs) and their involvement in cancer, particularly in cutaneous malignant melanoma. Previously, the tumor suppressor gene PTEN has been reported to be post-transcriptionally regulated by its pseudogene. In paper I, we investigated an antisense RNA (PTENpg1 asRNA) that is transcribed from the PTEN pseudogene (PTENpg1). We uncovered various PTENpg1 asRNA isoforms and designated two of them as α and β. The role of the PTENpg1 asRNA β isoform is to form an RNA:RNA duplex with the PTENpg1 transcript. This interaction stabilizes and assists the PTENpg1 transcript out to the cytoplasm. On the other hand, the PTENpg1 asRNA α has a very different function, namely mediating epigenetic changes by recruiting EZH2 and DNMT3a to the PTEN promoter. In paper II, we further sought out to understand the recruitment of PTENpg1 asRNA α to the PTEN promoter. We observed promoter-associated/5´UTR transcript emitting from PTEN, which binds and facilitates the recruitment of PTENpg1 asRNA α to the PTEN promoter. In return, PTENpg1 asRNA recruits DNMT3a to the promoter, which leads to epigenetic silencing of PTEN. In paper III we investigated the role of PTENpg1 asRNA in vemurafenib resistance of melanoma. We observed increased PTENpg1 asRNA expression and consequently low PTEN levels caused by enrichment of EZH2 and H3K27me3 at the PTEN promoter. Further, we found that C/EBPβ transcriptionally induced PTENpg1 asRNA in vemurafenib-resistant melanoma cell lines. In addition, manipulation of key components of the PTENpg1 asRNA network caused re-sensitization of the resistant melanoma cells to vemurafenib, and high PTENpg1 asRNA expression was found to correlate with shorter survival in melanoma patients. In paper IV, we investigated the effect of the C/EBPβ antisense (C/EBPβ-AS) transcript on transcriptional regulation of C/EBPβ. We found that C/EBPβ auto-regulates its own and also regulates C/EBPβ-AS expression. In return, C/EBPβ-AS inhibits C/EBPβ positive feedback loop by modulating epigenetic changes at the C/EBPβ promoter in melanoma cell lines. Interestingly, knockdown of C/EBPβ-AS caused re-sensitization to vemurafenib. This thesis highlights the dynamics of lncRNAs in epigenetic silencing and their involvement in cancer and therapy resistance

The assessment and treatment of neurocognition and social cognition in early psychosis

Background: Cognitive impairment is a core feature at all stages of the psychotic illness and significantly predicts functional outcomes. Targeting cognition early is theoretically attractive as a means to reverse the functional impairment before it is fully realized and thus improve the long-term outcome and quality of life of patients with psychotic disorders. Cognitive remediation is an effective treatment of cognitive deficits in schizophrenia, but generalization to everyday functioning remains a challenge. Interventions, such as strategy training combined with computerized training, and socialcognitive training have shown promise in bridging the gap between cognitive gains and functional outcomes. However, relatively little is known about the effects of integrated neuro- and social-cognitive remediation in early psychosis and what may aid in implementing these interventions into standard care for early psychosis. Objectives: The overall aim of this thesis was to assess and treat the neuroand social-cognitive impairment among individuals seeking treatment at an early intervention in psychosis (EIP) service in Iceland. In addition, to examine implementation outcomes of the intervention with regards to attendance, fidelity and acceptability. The specific aims of the first study were to investigate the nature of neuro- and social-cognitive impairment and explore the relationship between social cognition and neurocognition, clinical symptoms, and functional outcome. In addition, we sought to investigate the role of neuro- and social-cognitive domains in predicting variance in informant-reported and self-reported functional outcomes. the specific aims of the second study were to evaluate the effects of a novel integrative neuroand social-cognitive remediation on cognition, clinical symptoms and functional outcome. The specific aims of the third study were to evaluate the long-term effects of the intervention on cognition, clinical symptoms, and functional outcomes. Method: All patients between the ages of 18 and 30, who had experienced their first psychotic episode in the past five years and in seeking treatment at the EIP service between 2015-2017, were offered participation in the first study. A total of 70 patients, 82% of the total patient population receiving care agreed to participate. Cognition, clinical symptoms and functional outcome were assessed, and the results were compared to healthy comparison groups. Participants that performed one half a standard deviation below healthy norms in at least one cognitive domain were offered participation in vi the second study. Participants (n=49) were randomly assigned to either a treatment group (n=25) that received integrated neuro- and social-cognitive remediation in addition to their standard treatment, or a wait-list control group (n=24) that continued their standard treatment. Assessments from the first study were used as baseline assessments in the second study, and both groups were reassessed with the measures at post-treatment. In the third study, all participants that received ICR during the trial (n=37) were reassessed on the same variables 12-months after treatment ended. Implementation outcomes were assessed with attendance data, fidelity checks, and feedback from participants and facilitators. Results: Results suggested that, compared to healthy comparison samples, this group of early psychosis patients demonstrated broad cognitive impairments that were maximal in delayed recall and theory of mind (ToM) (<1SD below the mean). A model including both neuro- and social-cognitive domains predicted variance in informant-reported community functioning, whereas attributional style was the single predictor for self-reported functional outcomes. ICR was associated with improvements on measures of immediate verbal memory, delayed recall, working memory, cognitive flexibility, ToM, and hostile attributional style. No significant between-group differences were found on measures of functional outcomes or clinical symptoms. However, ICR participants demonstrated significant improvements on multiple measures, including cognitive, clinical symptom, and functional outcome measures at post-treatment. Performance at 12- month follow-up was significantly better than performance at baseline for most cognitive measures, and there were further significant increases in performance on processing speed, immediate verbal memory and delayed recall. The intervention had good attendance rates (77.6%), received high treatment satisfaction ratings from participants, and the fidelity to treatment manuals was high (86.6%). Conclusions: The findings of this thesis provide a better understanding of cognitive functioning of early psychosis patients and lend support to the relevance of implementing integrated neuro- and social-cognitive remediation at EIP services. ICR may improve both neuro- and social-cognitive domains and long-term functioning, but further conclusions on the efficacy of the intervention will require replication of the results in a larger randomized controlled trial that includes a control group at the long-term follow-up

A cross-sectional study on nutrient intake and -status in inflammatory bowel disease patients.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Inflammatory bowel disease (IBD) can be associated with nutritional problems. The aim of this study was to investigate diet and nutritional status of IBD patients.A total of 78 participants (35 men and 43 women aged 18-74 years) were included in this cross-sectional study. The majority (80 %) of the participant received infliximab treatment. Participants filled out disease related questionnaires and 31 participants also a 3-day food record. Body composition was measured and blood samples analysed in order to estimate nutritional status.The majority (87 %) claimed that diet affects digestive tract symptoms and 72 % had changed diet accordingly. The most common foods restricted were dairy products (60 %), processed meat (55 %), soft drinks (46 %), alcohol (45 %) and fast food (44 %). Body mass index was mostly in the overweight range but 46 % of the participants had been diagnosed with some nutritional deficiency since IBD diagnosis (most common was iron deficiency: 39 %). Patients who restricted meat products had lower ferritin values (48 ± 39 vs. 95 ± 74 μg/L, P = 0.011). Intake of vitamin D and calcium were not adequate (65 % below recommeded intake for both) and 60 % had poor vitamin D status.IBD patients often change their dietary intake in order to affect digestive tract symptoms. Many patients have a history of nutrient deficiency. Restriction of dairy and meat consumption is common and is negatively associated with intake or status of micronutrients like calcium and iron. Dietary advice by a dietitian and use of potentially helpful dietary supplements is indicated.Science funds of the Landspitali- The National University Hospital of Icelan

On the misidentification of species: sampling error in primates and other mammals using geometric morphometrics in more than 4,000 individuals

An accurate classification is the basis for research in biology. Morphometrics and morphospecies play an important role in modern taxonomy, with geometric morphometrics increasingly applied as a favourite analytical tool. Yet, really large samples are seldom available for modern species and even less common in palaeontology, where morphospecies are often identified, described and compared using just one or a very few specimens. The impact of sampling error and how large a sample must be to mitigate the inaccuracy are important questions for morphometrics and taxonomy. Using more than 4000 crania of adult mammals and taxa representing each of the four placental superorders, we assess the impacts of sampling error on estimates of species means, variances and covariances in Procrustes shape data using resampling experiments. In each group of closely related species (mostly congeneric), we found that a species can be identified fairly accurately even when means are based on relatively small samples, although errors are frequent with fewer specimens and primates more prone to inaccuracies. A precise reconstruction of similarity relationships, in contrast, sometimes requires very large samples (> 100), but this varies widely depending on the study group. Medium-sized samples are necessary to accurately estimate standard errors of mean shapes or intraspecific variance covariance structure, but in this case minimum sample sizes are broadly similar across all groups (≈ 20-50 individuals). Overall, thus, the minimum sample sized required for a study varies across taxa and depends on what is being assessed, but about 25-40 specimens (for each sex, if a species is sexually dimorphic) may be on average an adequate and attainable minimum sample size for estimating the most commonly used shape parameters. As expected, the best predictor of the effects of sampling error is the ratio of between- to within-species variation: the larger the ratio, the smaller the sample size needed to obtain the same level of accuracy. Even though ours is the largest study to date of the uncertainties in estimates of means, variances and covariances in geometric morphometrics, and despite its generally high congruence with previous analyses, we feel it would be premature to generalize. Clearly, there is no a priori answer for what minimum sample size is required for a particular study and no universal recipe to control for sampling error. Exploratory analyses using resampling experiments are thus desirable, easy to perform and yield powerful preliminary clues about the effect of sampling on parameter estimates in comparative studies of morphospecies, and in a variety of other morphometric applications in biology and medicine. Morphospecies descriptions are indeed a small piece of provisional evidence in a much more complex evolutionary puzzle. However, they are crucial in palaeontology, and provide important complimentary evidence in modern integrative taxonomy. Thus, if taxonomy provides the bricks for accurate research in biology, understanding the robustness of these bricks is the first fundamental step to build scientific knowledge on sound, stable and long-lasting foundations

A test for paedomorphism in domestic pig cranial morphology

Domestic animals are often described as paedomorphic, meaning that they retain juvenile characteristics into adulthood. Through a three-dimensional landmark-based geometric morphometric analysis of cranial morphology at three growth stages, we demonstrate that wild boar (n = 138) and domestic pigs (n = 106) (Sus scrofa) follow distinct ontogenetic trajectories. With the exception of the size ratio between facial and neurocranial regions, paedomorphism does not appear to be the primary pattern describing the observed differences between wild and domestic pig cranial morphologies. The cranial phenotype of domestic pigs instead involves developmental innovation during domestication. This result questions the long-standing assumption that domestic animal phenotypes are paedomorphic forms of their wild counterpart