Browsing by Subject "HETEROGENEITY"

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  • DREAM SMC-Het Participants; Salcedo, Adriana; Mustonen, Ville (2020)
    Methods for reconstructing tumor evolution are benchmarked in the DREAM Somatic Mutation Calling Tumour Heterogeneity Challenge. Tumor DNA sequencing data can be interpreted by computational methods that analyze genomic heterogeneity to infer evolutionary dynamics. A growing number of studies have used these approaches to link cancer evolution with clinical progression and response to therapy. Although the inference of tumor phylogenies is rapidly becoming standard practice in cancer genome analyses, standards for evaluating them are lacking. To address this need, we systematically assess methods for reconstructing tumor subclonality. First, we elucidate the main algorithmic problems in subclonal reconstruction and develop quantitative metrics for evaluating them. Then we simulate realistic tumor genomes that harbor all known clonal and subclonal mutation types and processes. Finally, we benchmark 580 tumor reconstructions, varying tumor read depth, tumor type and somatic variant detection. Our analysis provides a baseline for the establishment of gold-standard methods to analyze tumor heterogeneity.
  • Moyano-Galceran, Lidia; Pietila, Elina A.; Turunen, S. Pauliina; Corvigno, Sara; Hjerpe, Elisabet; Bulanova, Daria; Joneborg, Ulrika; Alkasalias, Twana; Miki, Yuichiro; Yashiro, Masakazu; Chernenko, Anastasiya; Jukonen, Joonas; Singh, Madhurendra; Dahlstrand, Hanna; Carlson, Joseph W.; Lehti, Kaisa (2020)
    Metastatic cancers commonly activate adaptive chemotherapy resistance, attributed to both microenvironment-dependent phenotypic plasticity and genetic characteristics of cancer cells. However, the contribution of chemotherapy itself to the non-genetic resistance mechanisms was long neglected. Using high-grade serous ovarian cancer (HGSC) patient material and cell lines, we describe here an unexpectedly robust cisplatin and carboplatin chemotherapy-induced ERK1/2-RSK1/2-EphA2-GPRC5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, pharmacological inhibition or knockdown of RSK1/2 prevented oncogenic EphA2-S897 phosphorylation and EphA2-GPRC5A co-regulation, thereby facilitating a signaling shift to the canonical tumor-suppressive tyrosine phosphorylation and consequent downregulation of EphA2. In combination with platinum, RSK inhibitors effectively sensitized even the most platinum-resistant EphA2(high), GPRC5A(high) cells to the therapy-induced apoptosis. In HGSC patient tumors, this orphan receptor GPRC5A was expressed exclusively in cancer cells and associated with chemotherapy resistance and poor survival. Our results reveal a kinase signaling pathway uniquely activated by platinum to elicit adaptive resistance. They further identify GPRC5A as a marker for abysmal HGSC outcome and putative vulnerability of the chemo-resistant cells to RSK1/2-EphA2-pS897 pathway inhibition.
  • Martinez-Corral, Ines; Zhang, Yan; Petkova, Milena; Ortsater, Henrik; Sjoberg, Sofie; Castillo, Sandra D.; Brouillard, Pascal; Libbrecht, Louis; Saur, Dieter; Graupera, Mariona; Alitalo, Kari; Boon, Laurence; Vikkula, Miikka; Mäkinen, Taija (2020)
    Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic). Cellular mechanisms underlying LM pathology are poorly understood. Here we show that the somatic PIK3CA(H1047R) mutation, resulting in constitutive activation of the p110 alpha PI3K, underlies both macrocystic and microcystic LMs in human. Using a mouse model of PIK3CA(H1047R)-driven LM, we demonstrate that both types of malformations arise due to lymphatic endothelial cell (LEC)-autonomous defects, with the developmental timing of p110 alpha activation determining the LM subtype. In the postnatal vasculature, PIK3CA(H1047R) promotes LEC migration and lymphatic hypersprouting, leading to microcystic LMs that grow progressively in a vascular endothelial growth factor C (VEGF-C)-dependent manner. Combined inhibition of VEGF-C and the PI3K downstream target mTOR using Rapamycin, but neither treatment alone, promotes regression of lesions. The best therapeutic outcome for LM is thus achieved by co-inhibition of the upstream VEGF-C/VEGFR3 and the downstream PI3K/mTOR pathways. Lymphatic malformation (LM) is a debilitating often incurable vascular disease. Using a mouse model of LM driven by a disease-causative PIK3CA mutation, the authors show that vascular growth is dependent on the upstream lymphangiogenic VEGF-C signalling, permitting effective therapeutic intervention.
  • Garcia-Romero, Noemi; Gonzalez-Tejedo, Carmen; Carrion-Navarro, Josefa; Esteban-Rubio, Susana; Rackov, Gorjana; Rodriguez-Fanjul, Vanessa; Oliver-De La Cruz, Jorge; Prat-Acin, Ricardo; Peris-Celda, Maria; Blesa, David; Ramirez-Jimenez, Laura; Sanchez-Gomez, Pilar; Perona, Rosario; Escobedo-Lucea, Carmen; Belda-Iniesta, Cristobal; Ayuso-Sacido, Angel (2016)
    Human gliomas harbour cancer stem cells (CSCs) that evolve along the course of the disease, forming highly heterogeneous subpopulations within the tumour mass. These cells possess self-renewal properties and appear to contribute to tumour initiation, metastasis and resistance to therapy. CSC cultures isolated from surgical samples are considered the best preclinical in vitro model for primary human gliomas. However, it is not yet well characterized to which extent their biological and functional properties change during in vitro passaging in the serum-free culture conditions. Here, we demonstrate that our CSC-enriched cultures harboured from one to several CSC clones from the human glioma sample. When xenotransplanted into mouse brain, these cells generated tumours that reproduced at least three different dissemination patterns found in original tumours. Along the passages in culture, CSCs displayed increased expression of stem cell markers, different ratios of chromosomal instability events, and a varied response to drug treatment. Our findings highlight the need for better characterization of CSC-enriched cultures in the context of their evolution in vitro, in order to uncover their full potential as preclinical models in the studies aimed at identifying molecular biomarkers and developing new therapeutic approaches of human gliomas.
  • Davies, Emma; Dong, Meng; Gutekunst, Matthias; Narhi, Katja; van Zoggel, Hanneke J. A. A.; Blom, Sami; Nagaraj, Ashwini; Metsalu, Tauno; Oswald, Eva; Erkens-Schulze, Sigrun; San Martin, Juan A. Delgado; Turkki, Riku; Wedge, Stephen R.; af Hallstrom, Taija M.; Schueler, Julia; van Weerden, Wytske M.; Verschuren, Emmy W.; Barry, Simon T.; van der Kuip, Heiko; Hickman, John A. (2015)
    Precision-cut slices of in vivo tumours permit interrogation in vitro of heterogeneous cells from solid tumours together with their native microenvironment. They offer a low throughput but high content in vitro experimental platform. Using mouse models as surrogates for three common human solid tumours, we describe a standardised workflow for systematic comparison of tumour slice cultivation methods and a tissue microarray-based method to archive them. Cultivated slices were compared to their in vivo source tissue using immunohistochemical and transcriptional biomarkers, particularly of cellular stress. Mechanical slicing induced minimal stress. Cultivation of tumour slices required organotypic support materials and atmospheric oxygen for maintenance of integrity and was associated with significant temporal and loco-regional changes in protein expression, for example HIF-1 alpha. We recommend adherence to the robust workflow described, with recognition of temporal-spatial changes in protein expression before interrogation of tumour slices by pharmacological or other means.
  • Westra, Harm-Jan; Arends, Danny; Esko, Tonu; Peters, Marjolein J.; Schurmann, Claudia; Schramm, Katharina; Kettunen, Johannes; Yaghootkar, Hanieh; Fairfax, Benjamin P.; Andiappan, Anand Kumar; Li, Yang; Fu, Jingyuan; Karjalainen, Juha; Platteel, Mathieu; Visschedijk, Marijn; Weersma, Rinse K.; Kasela, Silva; Milani, Lili; Tserel, Liina; Peterson, Part; Reinmaa, Eva; Hofman, Albert; Uitterlinden, Andre G.; Rivadeneira, Fernando; Homuth, Georg; Petersmann, Astrid; Lorbeer, Roberto; Prokisch, Holger; Meitinger, Thomas; Herder, Christian; Roden, Michael; Grallert, Harald; Ripatti, Samuli; Perola, Markus; Wood, Andrew R.; Melzer, David; Ferrucci, Luigi; Singleton, Andrew B.; Hernandez, Dena G.; Knight, Julian C.; Melchiotti, Rossella; Lee, Bernett; Poidinger, Michael; Zolezzi, Francesca; Larbi, Anis; Wang, De Yun; van den Berg, Leonard H.; Veldink, Jan H.; Rotzschke, Olaf; Makino, Seiko; Salomaa, Veikko; Strauch, Konstantin; Voelker, Uwe; van Meurs, Joyce B. J.; Metspalu, Andres; Wijmenga, Cisca; Jansen, Ritsert C.; Franke, Lude (2015)
    The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn's disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus.
  • Sveen, Anita; Bruun, Jarle; Eide, Peter W.; Eilertsen, Ina A.; Ramirez, Lorena; Murumägi, Astrid; Arjama, Mariliina; Danielsen, Stine A.; Kryeziu, Kushtrim; Elez, Elena; Tabernero, Josep; Guinney, Justin; Palmer, Hector G.; Nesbakken, Arild; Kallioniemi, Olli; Dienstmann, Rodrigo; Lothe, Ragnhild A. (2018)
    Purpose: Response to standard oncologic treatment is limited in colorectal cancer. The gene expression-based consensus molecular subtypes (CMS) provide a new paradigm for stratified treatment and drug repurposing; however, drug discovery is currently limited by the lack of translation of CMS to preclinical models. Experimental Design: We analyzed CMS in primary colorectal cancers, cell lines, and patient-derived xenografts (PDX). For classification of preclinical models, we developed an optimized classifier enriched for cancer cell-intrinsic gene expression signals, and performed high-throughput in vitro drug screening (n = 459 drugs) to analyze subtype-specific drug sensitivities. Results: The distinct molecular and clinicopathologic characteristics of each CMS group were validated in a single-hospital series of 409 primary colorectal cancers. The new, cancer cell-adapted classifier was found to perform well in primary tumors, and applied to a panel of 148 cell lines and 32 PDXs, these colorectal cancer models were shown to recapitulate the biology of the CMS groups. Drug screening of 33 cell lines demonstrated subtype-dependent response profiles, confirming strong response to EGFR and HER2 inhibitors in the CMS2 epithelial/canonical group, and revealing strong sensitivity to HSP90 inhibitors in cells with the CMS1 microsatellite instability/immune and CMS4 mesenchymal phenotypes. This association was validated in vitro in additional CMS-predicted cell lines. Combination treatment with 5-fluorouracil and luminespib showed potential to alleviate chemoresistance in a CMS4 PDX model, an effect not seen in a chemosensitive CMS2 PDX model. Conclusions: We provide translation of CMS classification to preclinical models and uncover a potential for targeted treatment repurposing in the chemoresistant CMS4 group. (C) 2017 AACR.
  • Athanasiou, Antonios; Veroniki, Areti Angeliki; Efthimiou, Orestis; Kalliala, Ilkka; Naci, Huseyin; Bowden, Sarah; Paraskevaidi, Maria; Martin-Hirsch, Pierre; Bennett, Philip; Paraskevaidis, Evangelos; Salanti, Georgia; Kyrgiou, Maria (2019)
    Introduction Local treatments for cervical intraepithelial neoplasia (CIN) and microinvasive disease remove or ablate a cone-shaped part of the uterine cervix containing the abnormal cells. A trend toward less radical techniques has raised concerns that this may adversely impact the rates of precancerous and cancerous recurrence. However, there has been no strong evidence to support such claims. We hereby describe a protocol of a systematic review and network meta-analysis that will update the evidence and compare all relevant treatments in terms of efficacy and complications. Methods and analysis Literature searches in electronic databases (CENTRAL, MEDLINE, EMBASE) or trial registries will identify published and unpublished randomised controlled trials (RCTs) and cohort studies comparing the efficacy and complications among different excisional and ablative techniques. The excisional techniques include cold knife, laser or Fischer cone, large loop or needle excision of the transformation zone and the ablative radical point diathermy, cryotherapy, cold coagulation or laser ablation. The primary outcome will be residual/recurrent disease defined as abnormal histology or cytology of any grade, while secondary outcomes will include treatment failure rates defined as high-grade histology or cytology, histologically confirmed CIN1+ or histologically confirmed CIN2+, human papillomavirus positivity rates, involved margins rates, bleeding and cervical stenosis rates. We will assess the risk of bias in RCTs and observational studies using tools developed by the Cochrane Collaboration. Two authors will independently assess study eligibility, abstract the data and assess the risk of bias. Random-effects meta-analyses and network meta-analyses will be conducted using the OR for dichotomous outcomes and the mean difference for continuous outcomes. The quality of the evidence for the primary outcome will be assessed using the CINeMA (Confidence In Network Meta-Analysis) tool. Ethics and dissemination Ethical approval is not required. We will disseminate findings to clinicians, policy-makers, patients and the public. PROSPERO registration number CRD42018115508.
  • Athanasiou, Antonios; Veroniki, Areti Angeliki; Efthimiou, Orestis; Kalliala, Ilkka; Naci, Huseyin; Bowden, Sarah; Paraskevaidi, Maria; Martin-Hirsch, Pierre; Bennett, Philip; Paraskevaidis, Evangelos; Salanti, Georgia; Kyrgiou, Maria (2019)
    Introduction There are several local treatment methods for cervical intraepithelial neoplasia that remove or ablate a cone-shaped part of the uterine cervix. There is evidence to suggest that these increase the risk of preterm birth (PTB) and that this is higher for techniques that remove larger parts of the cervix, although the data are conflicting. We present a protocol for a systematic review and network meta-analysis (NMA) that will update the evidence and compare all treatments in terms of fertility and pregnancy complications. Methods and analysis We will search electronic databases (CENTRAL, MEDLINE, EMBASE) from inception till October 2019, in order to identify randomised controlled trials (RCTs) and cohort studies comparing the fertility and pregnancy outcomes among different excisional and ablative treatment techniques and/or to untreated controls. The primary outcome will be PTB ( Ethics and dissemination Ethical approval is not required. Results will be disseminated to academic beneficiaries, medical practitioners, patients and the public.
  • Hagge, Jonas; Abrego, Nerea; Baessler, Claus; Bouget, Christophe; Brin, Antoine; Brustel, Herve; Christensen, Morten; Gossner, Martin M.; Heilmann-Clausen, Jacob; Horak, Akub; Gruppe, Axel; Isacsson, Gunnar; Koehler, Frank; Lachat, Thibault; Larrieu, Laurent; Schlaghamersky, Jiri; Thorn, Simon; Zapponi, Livia; Mueller, Joerg (2019)
    Aim: Beech forests comprise a globally unique temperate forest type in Europe. The dominance of beech in these forests developed during the ongoing post-glacial northward re-colonization, concurrently with intensified forest use by humans. We investigated how these two processes together with climate shaped the patterns of functional diversity of two major species groups involved in wood decomposition and whether functional diversity is determined on the local or regional species pool level. Location: European beech forest distribution range. Taxon: Saproxylic beetles and fungi. Methods: We analysed records of 532,496 saproxylic beetles of 788 species and 8,630 records of 234 saproxylic fungal species based on sets of traits similar to both groups. We tested how space, climate and landscape composition affect trait-based functional diversity on local and regional scales. Using structural equation modelling, we tested whether functional diversity is shaped on the local or regional scale. Results: The response of local functional diversity of both saproxylic beetles and fungi followed a highly congruent pattern of decreasing functional diversity towards the north, with higher elevation and accounted for overall geographical gradients with higher temperature, while increasing with higher precipitation. Structural equation modelling revealed that local functional diversity is determined by community changes operating on the level of the regional species pool. Main conclusions: Our findings suggest that the functional diversity patterns of saproxylic organisms in European beech forests are mainly determined on the regional scale and driven by anthropogenic and biogeographical processes. To conserve the variation and hotspots of functional diversity in beech forests, activities have to focus on a broad spatial and climatic range of sites throughout Europe, including the primeval forests in the east, as started by the UNESCO World Heritage selection of "Ancient and Primeval Beech Forests of the Carpathians and Other Regions of Europe".
  • Anttila, Jani V.; Shubin, Mikhail; Cairns, Johannes; Borse, Florian; Guo, Qingli; Mononen, Tommi; Vazquez-Garcia, Ignacio; Pulkkinen, Otto; Mustonen, Ville (2019)
    A tumour grows when the total division (birth) rate of its cells exceeds their total mortality (death) rate. The capability for uncontrolled growth within the host tissue is acquired via the accumulation of driver mutations which enable the tumour to progress through various hallmarks of cancer. We present a mathematical model of the penultimate stage in such a progression. We assume the tumour has reached the limit of its present growth potential due to cell competition that either results in total birth rate reduction or death rate increase. The tumour can then progress to the final stage by either seeding a metastasis or acquiring a driver mutation. We influence the ensuing evolutionary dynamics by cytotoxic (increasing death rate) or cytostatic (decreasing birth rate) therapy while keeping the effect of the therapy on net growth reduction constant. Comparing the treatments head to head we derive conditions for choosing optimal therapy. We quantify how the choice and the related gain of optimal therapy depends on driver mutation, metastasis, intrinsic cell birth and death rates, and the details of cell competition. We show that detailed understanding of the cell population dynamics could be exploited in choosing the right mode of treatment with substantial therapy gains. Author summary Cells and organisms evolve to better survive in their environments and to adapt to new challenges. Such dynamics manifest in a particularly problematic way with the evolution of drug resistance, which is increasingly recognized as a key challenge for global health. Thus, developing therapy paradigms that factor in evolutionary dynamics is an important goal. Using a minimal mathematical model of a cancer cell population we contrast cytotoxic (increasing death rate) and cytostatic (decreasing birth rate) treatments while keeping the effect of the therapy on the net growth reduction constant. We then quantify how the choice and the related gain of optimal therapy depends on driver mutation, metastasis, intrinsic cell birth and death rates and the details of cell competition. Most importantly, we identify specific cell population dynamics under which a certain treatment could be significantly better than the alternative.
  • Mendelian Randomization Dairy Cons; Huang, Tao; Kähönen, Mika; Mikkilä, Vera; Viikari, Jorma; Raitakari, Olli; Lehtimäki, Terho (2018)
    BACKGROUND: Associations between dairy intake and body mass index (BMI) have been inconsistently observed in epidemiological studies, and the causal relationship remains ill defined. METHODS: We performed Mendelian randomization (MR) analysis using an established dairy intake-associated genetic polymorphism located upstream of the lactase gene (LCT-13910 C/T, rs4988235) as an instrumental variable (IV). Linear regression models were fitted to analyze associations between (a) dairy intake and BMI, (b) rs4988235 and dairy intake, and (c) rs4988235 and BMI in each study. The causal effect of dairy intake on BMI was quantified by IV estimators among 184802 participants from 25 studies. RESULTS: Higher dairy intake was associated with higher BMI (beta = 0.03 kg/m(2) per serving/day; 95% CI, 0.00-0.06; P = 0.04), whereas the LCT genotype with 1 or 2 T allele was significantly associated with 0.20 (95% CI, 0.14-0.25) serving/day higher dairy intake (P = 3.15 x 10(-12)) and 0.12 (95% CI, 0.06-0.17) kg/m(2) higher BMI (P = 2.11 x 10(-5)). MR analysis showed that the genetically determined higher dairy intake was significantly associated with higher BMI (beta = 0.60 kg/m(2) per serving/day; 95% CI, 0.27-0.92; P = 3.0 x 10(-4)). CONCLUSIONS: The present study provides strong evidence to support a causal effect of higher dairy intake on increased BMI among adults. (c) 2017 American Association for Clinical Chemistry
  • Mendelian Randomization Dairy Cons; CHARGE Consortium; Huang, Tao; Kahonen, Mika; Mikkilä, Vera; Havulinna, Aki S.; Viikari, Jorma; Raitakari, Olli; Lehtimäki, Terho; Helminen, Mika; Kanerva, Noora (2019)
    BACKGROUND: Associations between dairy intake and body composition and cardiometabolic traits have been inconsistently observed in epidemiological studies, and the causal relationship remains ill-defined. METHODS: We performed Mendelian randomization analysis using an established genetic variant located upstream of the lactase gene (LCT- 13910 C/T, rs4988235) associated with dairy intake as an instrumental variable (IV). The causal effects of dairy intake on body composition and cardiometabolic traits (lipids, glycemic traits, and inflammatory factors) were quantified by IV estimators among 182041 participants from 18 studies. RESULTS: Each 1 serving/day higher dairy intake was associated with higher lean mass [beta (SE) = 0.117 kg (0.035); P = 0.001], higher hemoglobin A(1c) [0.009% (0.002); P <0.001], lower LDL [-0.014 mmol/L (0.006); P = 0.013], total cholesterol (TC) [-0.012 mmol/L (0.005); P = 0.023], and non-HDL [- 0.012 mmol/L (0.005); P = 0.028]. The LCT- 13910 C/T CT + TT genotype was associated with 0.214 more dairy servings/day (SE = 0.047; P = 0.001), 0.284 cm higher waist circumference (SE = 0.118; P = 0.017), 0.112 kg higher lean mass (SE = 0.027; P = 3.8 X 10(-5)), 0.032 mmol/L lower LDL (SE = 0.009; P = 0.001), and 0.032 mmol/L lower TC (SE = 0.010; P = 0.001). Genetically higher dairy intake was associated with increased lean mass [0.523 kg per serving/day (0.170); P = 0.002] after correction for multiple testing (0.05/18). However, we find that genetically higher dairy intake was not associated with lipids and glycemic traits. CONCLUSIONS: The present study provides evidence to support a potential causal effect of higher dairy intake on increased lean mass among adults. Our findings suggest that the observational associations of dairy intake with lipids and glycemic traits may be the result of confounding. (C) 2019 American Association for Clinical Chemistry
  • Hoekman, David; LeVan, Katherine E.; Ball, George E.; Browne, Robert A.; Davidson, Robert L.; Erwin, Terry L.; Knisley, C. Barry; LaBonte, James R.; Lundgren, Jonathan; Maddison, David R.; Moore, Wendy; Niemelä, Jari; Ober, Karen A.; Pearson, David L.; Spence, John R.; Will, Kipling; Work, Timothy (2017)
    The National Ecological Observatory Network (NEON) will monitor ground beetle populations across a network of broadly distributed sites because beetles are prevalent in food webs, are sensitive to abiotic factors, and have an established role as indicator species of habitat and climatic shifts. We describe the design of ground beetle population sampling in the context of NEON's long-term, continentalscale monitoring program, emphasizing the sampling design, priorities, and collection methods. Freely available NEON ground beetle data and associated field and laboratory samples will increase scientific understanding of how biological communities are responding to land-use and climate change.
  • Gammal, Johanna; Hewitt, Judi; Norkko, Joanna; Norkko, Alf; Thrush, Simon (2020)
    The biodiversity crisis has increased interest in understanding the role of biodiversity for ecosystem functioning. Functional traits are often used to infer ecosystem functions to increase our understanding of these relationships over larger spatial scales. The links between specific traits and ecosystem functioning are, however, not always well established. We investigated how the choice of analyzing either individual species, selected modalities, or trait combinations affected the spatial patterns observed on a sandflat and how this was related to the natural variability in ecosystem functioning. A large dataset of 400 benthic macrofauna samples was used to explore distribution patterns. We hypothesized that (1) if multiple species (redundancy) represent a trait combination or a modality their spatial patterns would be smoothed out, and (2) the lost spatial variability within a trait combination or modality, due to the smoothing effect, would potentially affect their utility for predicting ecosystem functioning (tested on a dataset of 24 samples). We predicted that species would show heterogeneous small spatial patterns, while modalities and trait combinations would show larger and more homogeneous patterns because they would represent a collection of many distributions. If modalities and trait combinations are better predictors of ecosystem functioning than species, then the smoother spatial patterns of modalities and trait combinations would result in a more homogeneous landscape of ecosystem function and the number of species exhibiting specific traits would provide functional redundancy. Our results showed some smoothing of spatial patterns progressing from species through modalities to trait combinations, but generally spatial patterns reflected a few dominant key species. Moreover, some individual modalities and species explained more or equal proportions of the variance in the ecosystem functioning than the combined traits. The findings thus suggest that only some spatial variability is lost when species are combined into modalities and trait combinations and that a homogeneous landscape of ecosystem function is not likely.
  • Birkman, Eva-Maria; Avoranta, Tuulia; Algars, Annika; Korkeila, Eija; Lintunen, Minnamaija; Lahtinen, Laura; Kuopio, Teijo; Ristamäki, Raija; Carpen, Olli; Sundström, Jari (2018)
    Epidermal growth factor receptor (EGFR) gene copy number (GCN) increase is associated with a favorable anti-EGFR antibody treatment response in RAS wild-type metastatic colorectal cancer. However, there are limited and comparative data regarding the EGFR GCN in primary colorectal cancer tumors and corresponding metastases or the effect of anti-EGFR antibody treatment on EGFR GCN in recurrent disease. In addition, little is known about the potential EGFR GCN changes during anti-EGFR therapy in comparison with other treatment regimens. EGFR GCN was analyzed by EGFR immunohistochemistry-guided silver in situ hybridization in primary and corresponding recurrent local or metastatic tumors from 80 colorectal cancer patients. GCN levels were compared between KRAS wild-type patients having received antiEGFR therapy and patients having received other forms of treatment after primary surgery. The EGFR GCN decrease between primary and recurrent tumors was more pronounced among the anti EGFR-treated patients than among patients not treated with anti-EGFR therapy (P=.047). None of the patients experiencing an EGFR GCN increase of at least 1.0 between the primary and recurrent tumors were treated with antiEGFR antibodies. When including only patients with distant metastases, an EGFR GCN decrease of at least 1.0 was more common among the anti EGFR-treated patients than among patients not treated with anti-EGFR therapy (P=.028). Our results suggest that anti-EGFR antibody treatment is associated with EGFR GCN decrease between the primary and recurrent colorectal adenocarcinomas, whereas no GCN change is observed among patients receiving other forms of treatment after primary surgery. (C) 2018 The Authors. Published by Elsevier Inc.
  • He, Siwen; Soininen, Janne; Chen, Kai; Wang, Beixin (2020)
    Metacommunity theory provides a useful framework to describe the underlying factors (e.g., environmental and dispersal-related factors) influencing community structure. The strength of these factors may vary depending on the properties of the region studied (e.g., environmental heterogeneity and spatial location) and considered biological groups. Here, we examined environmental and dispersal-related controls of stream macroinvertebrates and diatoms in three regions in China using the distance-decay relationship analysis. We performed analyses for the whole stream network and separately for two stream network locations (headwater and downstream sites) to test the network position hypothesis (NPH), which states that the strength of environmental and dispersal-related controls varies between headwater and downstream communities. Community dissimilarities were significantly related to environmental distances, but not geographical distances. These results suggest that communities are structured strongly by environmental filtering, but weakly by dispersal-related factors such as dispersal limitation. More importantly, we found that, at the whole network scale, environmental control was the highest in the regions with highest environmental heterogeneity. Results further showed that the influence of environmental control was strong in both headwaters and downstream sites, whereas spatial control was generally weak in all sites. This suggests a lack of consistent support for the NPH in our studied stream networks. Moreover, we found that local-scale variables relative to basin-scale variables better explained community dissimilarities for diatoms than for macroinvertebrates. This indicates that diatoms and macroinvertebrates responded to environment at different scales. Collectively, these results suggest that the importance of drivers behind the metacommunity assembly varied among regions with different level of environmental heterogeneity and between organism groups, potentially indicating context dependency among stream systems and taxa.
  • Skarp, Sini; Xia, Ji-Han; Zhang, Qin; Löija, Marika; Costantini, Alice; Ruddock, Lloyd W.; Mäkitie, Outi; Wei, Gong-Hong; Männikkö, Minna (2020)
    We studied a family with severe primary osteoporosis carrying a heterozygous p.Arg8Phefs*14 deletion in COL1A2, leading to haploinsufficiency. Three affected individuals carried the mutation and presented nearly identical spinal fractures but lacked other typical features of either osteogenesis imperfecta or Ehlers-Danlos syndrome. Although mutations leading to haploinsufficiency in COL1A2 are rare, mutations in COL1A1 that lead to less protein typically result in a milder phenotype. We hypothesized that other genetic factors may contribute to the severe phenotype in this family. We performed whole-exome sequencing in five family members and identified in all three affected individuals a rare nonsense variant (c.1282C > T/p.Arg428*, rs150257846) in ZNF528. We studied the effect of the variant using qPCR and Western blot and its subcellular localization with immunofluorescence. Our results indicate production of a truncated ZNF528 protein that locates in the cell nucleus as per the wild-type protein. ChIP and RNA sequencing analyses on ZNF528 and ZNF528-c.1282C > T indicated that ZNF528 binding sites are linked to pathways and genes regulating bone morphology. Compared with the wild type, ZNF528-c.1282C > T showed a global shift in genomic binding profile and pathway enrichment, possibly contributing to the pathophysiology of primary osteoporosis. We identified five putative target genes for ZNF528 and showed that the expression of these genes is altered in patient cells. In conclusion, the variant leads to expression of truncated ZNF528 and a global change of its genomic occupancy, which in turn may lead to altered expression of target genes. ZNF528 is a novel candidate gene for bone disorders and may function as a transcriptional regulator in pathways affecting bone morphology and contribute to the phenotype of primary osteoporosis in this family together with the COL1A2 deletion. (c) 2020 The Authors.Journal of Bone and Mineral Researchpublished by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
  • Horne, Hisani N.; Chung, Charles C.; Zhang, Han; Yu, Kai; Prokunina-Olsson, Ludmila; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Hopper, John L.; Southey, Melissa C.; Schmidt, Marjanka K.; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A.; Beckmann, Matthias W.; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guenel, Pascal; Truong, Therese; Bojesen, Stig E.; Flyger, Henrik; Benitez, Javier; Gonzalez-Neira, Anna; Anton-Culver, Hoda; Neuhausen, Susan L.; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Hamann, Ute; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Iwata, Hiroji; Dork, Thilo; Bogdanova, Natalia V.; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Chenevix-Trench, Georgia; Wu, Anna H.; den Berg, David Ven; kConFab AOCS Investigators (2016)
    The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Perallelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10(-21)). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P
  • Kyttala, Aija; Moraghebi, Roksana; Valensisi, Cristina; Kettunen, Johannes; Andrus, Colin; Pasumarthy, Kalyan Kumar; Nakanishi, Mahito; Nishimura, Ken; Ohtaka, Manami; Weltner, Jere; Van Handel, Ben; Parkkonen, Olavi; Sinisalo, Juha; Jalanko, Anu; Hawkins, R. David; Woods, Niels-Bjarne; Otonkoski, Timo; Trokovic, Ras (2016)
    Reports on the retention of somatic cell memory in induced pluripotent stem cells (iPSCs) have complicated the selection of the optimal cell type for the generation of iPSC biobanks. To address this issue we compared transcriptomic, epigenetic, and differentiation propensities of genetically matched human iPSCs derived from fibroblasts and blood, two tissues of the most practical relevance for biobanking. Our results show that iPSC lines derived from the same donor are highly similar to each other. However, genetic variation imparts a donor-specific expression and methylation profile in reprogrammed cells that leads to variable functional capacities of iPSC lines. Our results suggest that integration-free, bona fide iPSC lines from fibroblasts and blood can be combined in repositories to form biobanks. Due to the impact of genetic variation on iPSC differentiation, biobanks should contain cells from large numbers of donors.