Articles from BioMed Central


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  • Conenna, Irene; López-Baucells, Adrià; Rocha, Ricardo; Ripperger, Simon; Cabeza, Mar (BioMed Central, 2019)
    Abstract Background Bats are among the most successful desert mammals. Yet, our understanding of their spatio-temporal dynamics in habitat use associated with the seasonal oscillation of resources is still limited. In this study, we have employed state-of-the-art lightweight GPS loggers to track the yellow-winged bat Lavia frons in a desert in northern Kenya to investigate how seasonality in a desert affects the a) spatial and b) temporal dimensions of movements in a low-mobility bat. Methods Bats were tracked during April–May 2017 (rainy season) and January–February 2018 (dry season) using 1-g GPS loggers. Spatial and temporal dimensions of movements were quantified, respectively, as the home range and nightly activity patterns. We tested for differences between seasons to assess responses to seasonal drought. In addition, we quantified home range overlap between neighbouring individuals to investigate whether tracking data will be in accordance with previous reports on territoriality and social monogamy in L. frons. Results We obtained data for 22 bats, 13 during the rainy and 9 during the dry season. Home ranges averaged 5.46 ± 11.04 ha and bats travelled a minimum distance of 99.69 ± 123.42 m/hour. During the dry season, home ranges were larger than in the rainy season, and bats exhibited high activity during most of the night. No apparent association with free water was identified during the dry season. The observed spatial organisation of home ranges supports previous observations that L. frons partitions the space into territories throughout the year. Conclusions Our results suggest that, in low-mobility bats, a potential way to cope with seasonally harsh conditions and resource scarcity in deserts is to cover larger areas and increase time active, suggesting lower cost-efficiency of the foraging activity. Climate change may pose additional pressures on L. frons and other low-mobility species by further reducing food abundances.
  • Cooper, Rory L; Lloyd, Victoria J; Di-Poï, Nicolas; Fletcher, Alexander G; Barrett, Paul M; Fraser, Gareth J (BioMed Central, 2019)
    Abstract Background Vertebrates possess a diverse range of integumentary epithelial appendages, including scales, feathers and hair. These structures share extensive early developmental homology, as they mostly originate from a conserved anatomical placode. In the context of avian epithelial appendages, feathers and scutate scales are known to develop from an anatomical placode. However, our understanding of avian reticulate (footpad) scale development remains unclear. Results Here, we demonstrate that reticulate scales develop from restricted circular domains of thickened epithelium, with localised conserved gene expression in both the epithelium and underlying mesenchyme. These domains constitute either anatomical placodes, or circular initiatory fields (comparable to the avian feather tract). Subsequent patterning of reticulate scales is consistent with reaction–diffusion (RD) simulation, whereby this primary domain subdivides into smaller secondary units, which produce individual scales. In contrast, the footpad scales of a squamate model (the bearded dragon, Pogona vitticeps) develop synchronously across the ventral footpad surface. Conclusions Widely conserved gene signalling underlies the initial development of avian reticulate scales. However, their subsequent patterning is distinct from the footpad scale patterning of a squamate model, and the feather and scutate scale patterning of birds. Therefore, we suggest reticulate scales are a comparatively derived epithelial appendage, patterned through a modified RD system.
  • Katayama, Shintaro; Skoog, Tiina; Söderhäll, Cilla; Einarsdottir, Elisabet; Krjutškov, Kaarel; Kere, Juha (BioMed Central, 2019)
    Abstract Background Standard RNAseq methods using bulk RNA and recent single-cell RNAseq methods use DNA barcodes to identify samples and cells, and the barcoded cDNAs are pooled into a library pool before high throughput sequencing. In cases of single-cell and low-input RNAseq methods, the library is further amplified by PCR after the pooling. Preparation of hundreds or more samples for a large study often requires multiple library pools. However, sometimes correlation between expression profiles among the libraries is low and batch effect biases make integration of data between library pools difficult. Results We investigated 166 technical replicates in 14 RNAseq libraries made using the STRT method. The patterns of the library biases differed by genes, and uneven library yields were associated with library biases. The former bias was corrected using the NBGLM-LBC algorithm, which we present in the current study. The latter bias could not be corrected directly, but could be solved by omitting libraries with particularly low yields. A simulation experiment suggested that the library bias correction using NBGLM-LBC requires a consistent sample layout. The NBGLM-LBC correction method was applied to an expression profile for a cohort study of childhood acute respiratory illness, and the library biases were resolved. Conclusions The R source code for the library bias correction named NBGLM-LBC is available at and . This method is applicable to correct the library biases in various studies that use highly multiplexed sequencing-based profiling methods with a consistent sample layout with samples to be compared (e.g., “cases” and “controls”) equally distributed in each library.
  • Huhtala, Tuulia; Poutiainen, Pekka; Rytkönen, Jussi; Lehtimäki, Kimmo; Parkkari, Teija; Kasanen, Iiris; Airaksinen, Anu J; Koivula, Teija; Sweeney, Patrick; Kontkanen, Outi; Wityak, John; Dominiquez, Celia; Park, Larry C (Springer International Publishing, 2019)
    Abstract Purpose Dopamine receptors are involved in pathophysiology of neuropsychiatric diseases, including Huntington’s disease (HD). PET imaging of dopamine D2 receptors (D2R) in HD patients has demonstrated 40% decrease in D2R binding in striatum, and D2R could be a reliable quantitative target to monitor disease progression. A D2/3R antagonist, [18F] fallypride, is a high-affinity radioligand that has been clinically used to study receptor density and occupancy in neuropsychiatric disorders. Here we report an improved synthesis method for [18F]fallypride. In addition, high molar activity of the ligand has allowed us to apply PET imaging to characterize D2/D3 receptor density in striatum of the recently developed zQ175DN knock-in (KI) mouse model of HD. Methods We longitudinally characterized in vivo [18F] fallypride -PET imaging of D2/D3 receptor densities in striatum of 9 and 12 month old wild type (WT) and heterozygous (HET) zQ175DN KI mouse. Furthermore, we verified the D2/D3 receptor density in striatum with [3H] fallypride autoradiography at 12 months of age. Results We implemented an improved synthesis method for [18F] fallypride to yield high molar activity (MA, 298–360 GBq/μmol) and good reproducibility. In the HET zQ175DN KI mice, we observed a significant longitudinal decrease in binding potential (BPND) (30.2%, p < 0.001, 9 months of age and 51.6%, p < 0.001, 12 months of age) compared to WT littermates. No mass effect was observed when the MA of [18F] fallypride was > 100 GBq/μmol at the time of injection. Furthermore, the decrease of D2/D3 receptor density in striatum in HET zQ175DN KI was consistent using [3H] fallypride autoradiography. Conclusions We observed a significant decrease in D2/D3R receptor densities in the striatum of HET zQ175DN KI mice compared to WT mice at 9 and 12 months of age. These results are in line with clinical findings in HD patients, suggesting [18F] fallypride PET imaging has potential as a quantitative translational approach to monitor disease progression in preclinical studies.
  • Ellilä, Simo; Bromann, Paul; Nyyssönen, Mari; Itävaara, Merja; Koivula, Anu; Paulin, Lars; Kruus, Kristiina (Springer Berlin Heidelberg, 2019)
    Abstract Xylanases are in important class of industrial enzymes that are essential for the complete hydrolysis of lignocellulosic biomass into fermentable sugars. In the present study, we report the cloning of novel xylanases with interesting properties from compost metagenomics libraries. Controlled composting of lignocellulosic materials was used to enrich the microbial population in lignocellulolytic organisms. DNA extracted from the compost samples was used to construct metagenomics libraries, which were screened for xylanase activity. In total, 40 clones exhibiting xylanase activity were identified and the thermostability of the discovered xylanases was assayed directly from the library clones. Five genes, including one belonging to the more rare family GH8, were selected for subcloning and the enzymes were expressed in recombinant form in E. coli. Preliminary characterization of the metagenome-derived xylanases revealed interesting properties of the novel enzymes, such as high thermostability and specific activity, and differences in hydrolysis profiles. One enzyme was found to perform better than a standard Trichoderma reesei xylanase in the hydrolysis of lignocellulose at elevated temperatures.
  • Holm, Matilda; Joenväärä, Sakari; Saraswat, Mayank; Tohmola, Tiialotta; Ristimäki, Ari; Renkonen, Risto; Haglund, Caj (BioMed Central, 2019)
    Abstract Background Colorectal cancer (CRC) is the third most common cancer worldwide, and its incidence is expected to increase to over 2.2 million new cases in 2030. Stage II CRC is classified as localized disease, while stage III CRC has spread to regional lymph nodes. The 5-year survival rate is over 80% for patients with stage II CRC, but less than 60% for patients with stage III CRC. Proteins, especially plasma proteins that are detectable in easily obtained blood samples, that differ between stage II and III CRC could be useful for predicting and monitoring disease progression. CRC displays differences depending on primary tumor location (right colon, left colon, or rectum), and how plasma protein expression changes during CRC progression from stage II to III depending on primary tumor location is not well-characterized. Methods In this study, we have used Ultra Performance Liquid Chromatography-Ultra Definition Mass Spectrometry (UPLC-UDMSE)-based proteomics to analyze plasma samples from 83 patients with stage II or III CRC, followed by statistical and pathway analysis (data are available via ProteomeXchange). The patients were divided into groups according to tumor stage (II or III) and changes in plasma protein expression between stage II and III (localized and regional disease) samples were studied both regardless of primary tumor location and also within each primary tumor location (right colon, left colon, rectum). Results We discovered differences in plasma protein expression within all groups analyzed and identified proteins whose levels changed in one, two, or all three primary tumor locations between stage II and III CRC. Proteins were identified that could separate the groups compared and pathway analysis by IPA discovered altered pathways involved in lipid metabolism and inflammation, among others. Conclusions Plasma protein expression changes significantly as CRC progresses from stage II to III. While the levels of certain plasma proteins changed during cancer progression in only one or two primary tumor locations, the levels of 13 proteins changed in all primary tumor locations and are therefore common to CRC progression.
  • Häkkilä, Matti; Savilaakso, Sini; Johansson, Anna; Sandgren, Terhi; Uusitalo, Anne; Mönkkönen, Mikko; Puttonen, Pasi (BioMed Central, 2019)
    Abstract Background Forest harvesting is the main driver of habitat degradation and biodiversity loss in forests of the boreal zone. To mitigate harmful effects, small-scale habitats with high biodiversity values have been protected within production forests. These include woodland key habitats, and other small-scale habitat patches protected by voluntary conservation action. This article describes a protocol for a systematic review to synthesize the value of small habitat patches left within production landscapes for biodiversity. The topic for this systematic review arose from a discussion with the Finnish forestry sector and was further defined in a stakeholder workshop. Research question: Do small protected habitat patches within production forests provide value for biodiversity conservation in boreal forests? Animal, plant and fungal diversities are addressed as well as the amount of deadwood within the habitat patches as proxy indicators for biodiversity. Methods The literature, both peer-reviewed and grey, will be searched from bibliographical databases, organizational websites and internet search engines in English, Finnish, Swedish and Russian. Article screening will be done at two stages (title/abstract and full-text). The validity of the studies included will be evaluated against validity criteria and studies will be categorized based on their risk of bias. To describe the findings a narrative synthesis will be conducted. If there is enough quantitative data retrieved from the studies, a meta-analysis will be conducted.
  • Doig, Christopher J; Page, Stacey A; McKee, Jessica L; Moore, Ernest E; Abu-Zidan, Fikri M; Carroll, Rosemary; Marshall, John C; Faris, Peter D; Tolonen, Matti; Catena, Fausto; Cocolini, Federico; Sartelli, Massimo; Ansaloni, Luca; Minor, Sam F; Peirera, Bruno M; Diaz, Jose J; Kirkpatrick, Andrew W (BioMed Central, 2019)
    Abstract Background Severe complicated intra-abdominal sepsis (SCIAS) has high mortality, thought due in part to progressive bio-mediator generation, systemic inflammation, and multiple organ failure. Treatment includes early antibiotics and operative source control. At surgery, open abdomen management with negative-peritoneal-pressure therapy (NPPT) has been hypothesized to mitigate MOF and death, although clinical equipoise for this operative approach exists. The Closed or Open after Laparotomy (COOL) study ( ) will prospectively randomize eligible patients intra-operatively to formal abdominal closure or OA with NPTT. We review the ethical basis for conducting research in SCIAS. Main body Research in critically ill incapacitated patients is important to advance care. Conducting research among SCIAS is complicated due to the severity of illness including delirium, need for emergent interventions, diagnostic criteria confirmed only at laparotomy, and obtundation from anaesthesia. In other circumstances involving critically ill patients, clinical experts have worked closely with ethicists to apply principles that balance the rights of patients whilst simultaneously permitting inclusion in research. In Canada, the Tri-Council Policy Statement-2 (TCPS-2) describes six criteria that permit study enrollment and randomization in such situations: (a) serious threat to the prospective participant requires immediate intervention; (b) either no standard efficacious care exists or the research offers realistic possibility of direct benefit; (c) risks are not greater than that involved in standard care or are clearly justified by prospect for direct benefits; (d) prospective participant is unconscious or lacks capacity to understand the complexities of the research; (e) third-party authorization cannot be secured in sufficient time; and (f) no relevant prior directives are known to exist that preclude participation. TCPS-2 criteria are in principle not dissimilar to other (inter)national criteria. The COOL study will use waiver of consent to initiate enrollment and randomization, followed by surrogate or proxy consent, and finally delayed informed consent in subjects that survive and regain capacity. Conclusions A delayed consent mechanism is a practical and ethical solution to challenges in research in SCIAS. The ultimate goal of consent is to balance respect for patient participants and to permit participation in new trials with a reasonable opportunity for improved outcome and minimal risk of harm.
  • Sumasgutner, Petra; Terraube, Julien; Coulon, Aurélie; Villers, Alexandre; Chakarov, Nayden; Kruckenhauser, Luise; Korpimäki, Erkki (BioMed Central, 2019)
    Abstract Background Selecting high-quality habitat and the optimal time to reproduce can increase individual fitness and is a strong evolutionary factor shaping animal populations. However, few studies have investigated the interplay between land cover heterogeneity, limitation in food resources, individual quality and spatial variation in fitness parameters. Here, we explore how individuals of different quality respond to possible mismatches between a cue for prey availability (land cover heterogeneity) and the actual fluctuating prey abundance. Results We analyse timing of breeding and reproductive success in a migratory population of Eurasian kestrels (Falco tinnunculus) breeding in nest-boxes, over a full three-year abundance cycle of main prey (voles), and consider several components of individual quality, including body condition, blood parasite infection, and genetic diversity (n = 448 adults) that act on different time scales. Older individuals, and kestrel parents in higher body condition started egg-laying earlier than younger birds and those in lower body condition. Additionally, egg-laying was initiated earlier during the increase and decrease phases (2011 and 2012) than during the low phase of the vole cycle (2013). Nestling survival (ratio of eggs that fledged successfully) was higher in early nests and in heterogeneous landscapes (i.e., mosaic of different habitat types), which was evident during the increase and decrease phases of the vole cycle, but not during the low vole year. Conclusions We found a strong positive effect of landscape heterogeneity on nestling survival, but only when voles were relatively abundant, whereas a difference in the timing of breeding related to territory landscape heterogeneity was not evident. Therefore, landscape heterogeneity appeared as the main driver of high reproductive performance under favourable food conditions. Our results show that landscape homogenization linked to agricultural intensification disrupts the expected positive effect of vole abundance on reproductive success of kestrels.
  • Räsänen, Minna; Renkonen-Sinisalo, Laura; Mustonen, Harri; Lepistö, Anna (BioMed Central, 2019)
    Abstract Background Neoadjuvant short-course radiotherapy is used to reduce local recurrences in stage III rectal cancer. Radiotherapy is not harmless, and meticulous total mesorectal excision surgery alone has been reported to result in low local recurrence rate in favorable stage III tumors. The aim was to evaluate the effect of short-course (5 × 5 Gy) radiotherapy on the local recurrence risk in patients with pT3N1-2 rectal cancer. Materials and methods This was a retrospective study with 151 consecutive pT3N1-2M0 rectal cancer patients operated on at Helsinki University Hospital, Helsinki, Finland, during January 2005 to June 2014. Short-course radiotherapy was given to 94 patients, and 57 patients were operated on without neoadjuvant radiotherapy. The main outcome measurement was the effect of radiotherapy on local recurrence. Also, the risk factors for local recurrence were analyzed. Results Local recurrence occurred in a total 17 of 151 (11.3%) patients, 8 of 57 (14.0%) in surgery only group compared with 9 of 94 (9.6%) in radiotherapy plus surgery group (p = 0.44). In univariate Cox regression analysis, the risk factors for local recurrence were tumor location under 6 cm from the anal verge (p = 0.01), involved lateral margin (p < 0.001), tumor perforation (p < 0.001), and mucinous histology (p = 0.006). In multivariate analysis, risk factors were tumor location under 6 cm from anal verge (p = 0.03) and involved lateral margin (p = 0.002). Conclusion Neoadjuvant short-course radiotherapy did not affect the local recurrence risk of pT3N1-2M0 rectal cancer. Further studies with larger patient number are needed to evaluate the role of short-course radiotherapy in different T3 subgroups (3a–c) as well as in N1 and N2 cancers in separate.
  • Lallukka, Tea; Mekuria, Gashaw B; Nummi, Tapio; Virtanen, Pekka; Virtanen, Marianna; Hammarström, Anne (BioMed Central, 2019)
    Abstract Background Co-occurrence of mental and somatic symptoms is common, and recent longitudinal studies have identified single trajectories of these symptoms, but it is poorly known whether the symptom trajectories can also co-occur and change across the lifespan. We aimed to examine co-occurring symptoms and their joint trajectories from adolescence to midlife. Methods Longitudinal data were derived from Northern Sweden, where 506 girls and 577 boys aged 16 years participated at baseline in 1981 (99.7% of those initially invited), and have been followed up in four waves until the age of 43. Survey data were collected about depressive, anxiety, and somatic symptoms. Potential joint development of this three-component symptom set was examined with multiple response trajectory analysis, a method that has not been previously used to study co-occurrence of these symptoms. Results We identified a five trajectory solution as the best: “very low” (19%), “low” (31%), “high” (22%), “late sharply increasing” (16%) and a “very high increasing” (12%). In the “late sharply increasing” and “very high increasing” groups the scores tended to increase with age, while in the other groups the levels were more stable. Overall, the results indicated that depressive, anxiety, and somatic symptoms co-exist from adolescence to midlife. Conclusions The multiple response trajectory analysis confirmed high stability in the co-occurrence of depressive, anxiety, and somatic symptoms from adolescence to midlife. Clinicians should consider these findings to detect symptoms in their earliest phase in order to prevent the development of co-occurring high levels of symptoms.
  • Hu, Yaoyue; Leinonen, Taina; van Hedel, Karen; Myrskylä, Mikko; Martikainen, Pekka (BioMed Central, 2019)
    Abstract Background Previous research has shown that certain living arrangements, such as living alone, are associated with worse health at older ages. We assessed the association between living arrangements and hospital care use among middle-aged and older adults, and investigated to what extent observed and unobserved individual characteristics explain this association. Methods Longitudinal Finnish registry data for men and women aged 50–89 years were used for the period 1987–2007. The relationship between living arrangements (based on whether an individual lived with a partner, other adults or alone, and whether they lived with minor/adult children) and heavy hospital care use (i.e., having been in hospital for 8 or more days in a year) was studied. First, we applied logistic regression models and linear probability models controlling for observed time-invariant factors (socioeconomic status measured by education, labour force status, and household income; and marital status), and then individual linear probability models with fixed-effects to further account for unobserved time-invariant individual characteristics in the measurement period. Analyses were done separately for 10 year age-groups. Results In the logistic regression models, men and women who lived alone had higher crude odds of heavy hospital care use than those living only with their partner. These odds ratios were highest for men and women in the youngest age category (50–59 years, 1.72 and 1.36 respectively) and decreased with age. Adjusting for observed time-invariant socioeconomic status attenuated these odds by 14–40%, but adjusting for marital status did not affect the results. Lower odds were observed among adults aged 50–59 years who lived with their partner and (minor or adult) children. But odds were higher for individuals aged 60–79 years who co-resided with their adult children, regardless of whether they lived with a partner. Adjusting for observed time-invariant factors generally did not change these results. After further adjusting for unobserved time-invariant individual characteristics in the individual fixed-effects models, most of these associations largely attenuated or disappeared, particularly for ages 80–89 years. Conclusions The association between living arrangements and higher use of hospital care at middle and older ages is largely explained by socioeconomic disadvantage and unobserved time-invariant individual characteristics.
  • Al-Samadi, Ahmed; Tuomainen, Katja; Kivimäki, Anne; Salem, Abdelhakim; Al-Kubati, Sakhr; Hyytiäinen, Aini; Parikka, Mataleena; Mesimäki, Karri; Wilkman, Tommy; Mäkitie, Antti; Grenman, Reidar; Salo, Tuula (BioMed Central, 2019)
    Abstract Background Currently, in vivo model for personalised cancer drug testing is challenging. A zebrafish larvae xenograft model has been applied in recent years to cancer research, particularly for drug testing purposes, showing promising results in drug testing against patient-derived tumour xenografts. Currently, these xenograft models apply imaging techniques to measure drug efficacy. However, this method carries several limitations, including timely imaging, thereby reducing the available number of tested fish and drugs. Here, we propose a PCR-based fast assay to evaluate drug efficacy in a zebrafish larvae xenograft model. Methods We tested two primary and corresponding metastatic head and neck squamous cell carcinoma (HNSCC) cell lines and patient-derived tongue cancer sample applying zebrafish larvae xenograft model. Cisplatin efficacy was tested using imaging technique and compared the results with PCR-based methods. Drug screening of eight compounds was applied on both cell lines and patient sample using PCR. Results In a head-to-head comparison, all the three techniques (imaging, quantitative PCR, and droplet digital PCR) showed similar reduction of the cancer cells growth after cisplatin treatment. Using the quantitative PCR assay, we demonstrated a dose-dependent response of HNSCC cells to cisplatin. Drug screening results of four HNSCC cell lines and patient sample revealed different drug efficacy between tested cancer cells. Conclusion We introduce a novel, easy, fast and cost-effective PCR-based in vivo zebrafish larvae assay to test the response of cell lines and clinical tumour samples to anti-cancer drugs. This method goes hand-by-hand with the commonly used imaging assay.
  • Husso, Minna; Nissi, Mikko J; Kuivanen, Antti; Halonen, Paavo; Tarkia, Miikka; Teuho, Jarmo; Saunavaara, Virva; Vainio, Pauli; Sipola, Petri; Manninen, Hannu; Ylä-Herttuala, Seppo; Knuuti, Juhani; Töyräs, Juha (BioMed Central, 2019)
    Abstract Background The reliable quantification of myocardial blood flow (MBF) with MRI, necessitates the correction of errors in arterial input function (AIF) caused by the T1 saturation effect. The aim of this study was to compare MBF determined by a traditional dual bolus method against a modified dual bolus approach and to evaluate both methods against PET in a porcine model of myocardial ischemia. Methods Local myocardial ischemia was induced in five pigs, which were subsequently examined with contrast enhanced MRI (gadoteric acid) and PET (O-15 water). In the determination of MBF, the initial high concentration AIF was corrected using the ratio of low and high contrast AIF areas, normalized according to the corresponding heart rates. MBF was determined from the MRI, during stress and at rest, using the dual bolus and the modified dual bolus methods in 24 segments of the myocardium (total of 240 segments, five pigs in stress and rest). Due to image artifacts and technical problems 53% of the segments had to be rejected from further analyses. These two estimates were later compared against respective rest and stress PET-based MBF measurements. Results Values of MBF were determined for 112/240 regions. Correlations for MBF between the modified dual bolus method and PET was rs = 0.84, and between the traditional dual bolus method and PET rs = 0.79. The intraclass correlation was very good (ICC = 0.85) between the modified dual bolus method and PET, but poor between the traditional dual bolus method and PET (ICC = 0.07). Conclusions The modified dual bolus method showed a better agreement with PET than the traditional dual bolus method. The modified dual bolus method was found to be more reliable than the traditional dual bolus method, especially when there was variation in the heart rate. However, the difference between the MBF values estimated with either of the two MRI-based dual-bolus methods and those estimated with the gold-standard PET method were statistically significant.
  • Tiainen, Leena; Korhonen, Emilia A; Leppänen, Veli-Matti; Luukkaala, Tiina; Hämäläinen, Mari; Tanner, Minna; Lahdenperä, Outi; Vihinen, Pia; Jukkola, Arja; Karihtala, Peeter; Aho, Sonja; Moilanen, Eeva; Alitalo, Kari; Kellokumpu-Lehtinen, Pirkko-Liisa (BioMed Central, 2019)
    Abstract Background Angiopoietin growth factors (Angs) regulate angiogenesis and lymphangiogenesis by binding to the endothelial Tie2 receptor. Ang2 expression is elevated in tissue hypoxia and inflammation, which also induce cleavage of the extracellular domain of the orphan Tie1 receptor. Here we have examined if the concentrations of Ang2 and the soluble extracellular domain of Tie1 in patient plasma are associated with the prognosis of patients with metastatic breast cancer. Methods Plasma Tie1 and Ang2 levels were measured in metastatic breast cancer patients treated in a phase II trial with a taxane-bevacizumab combination chemotherapy in the first-line treatment setting. They were analyzed before treatment, after 6 weeks and 6 months of treatment, and at the final study visit. Using the median concentrations as cutoffs, Tie1 and Ang2 data were dichotomized into low and high concentration groups. Additionally, we analyzed Tie1 concentrations in plasma from 10 healthy women participating in a breast cancer primary prevention study. Results Plasma samples were available from 58 (89%) of the 65 patients treated in the trial. The baseline Tie1 levels of the healthy controls were significantly lower than those of the metastatic patients (p < 0.001). The overall survival of the patients with a high baseline Tie1 level was significantly shorter (multivariate HR 3.07, 95% CI 1.39–6.79, p = 0.005). Additionally, the progression-free survival was shorter for patients with a high baseline Tie1 level (multivariate HR 3.78, 95% CI 1.57–9.09, p = 0.003). In contrast, the baseline Ang2 levels had no prognostic impact in a multivariate Cox proportional hazard regression analysis. The combined analysis of baseline Tie1 and Ang2 levels revealed that patients with both high Tie1 and high Ang2 baseline levels had a significantly shorter overall survival than the patients with low baseline levels of both markers (multivariate HR for overall survival 4.32, 95% CI 1.44–12.94, p = 0.009). Conclusions This is the first study to demonstrate the prognostic value of baseline Tie1 plasma concentration in patients with metastatic breast cancer. Combined with the results of the Ang2 analyses, the patients with both high Tie1 and Ang2 levels before treatment had the poorest survival. Trial registration NCT00979641, registration date 19-DEC-2008. The regional Ethics Committee: R08142M, registration date 18-NOV-2008.
  • Chakroborty, Deepankar; Emani, Maheswara R; Klén, Riku; Böckelman, Camilla; Hagström, Jaana; Haglund, Caj; Ristimäki, Ari; Lahesmaa, Riitta; Elo, Laura L (BioMed Central, 2019)
    Abstract Background Prognostic markers specific to a particular cancer type can assist in the evaluation of survival probability of patients and help clinicians to assess the available treatment modalities. Methods Gene expression data was analyzed from three independent colon cancer microarray gene expression data sets (N = 1052). Survival analysis was performed for the three data sets, stratified by the expression level of the LINE-1 type transposase domain containing 1 (L1TD1). Correlation analysis was performed to investigate the role of the interactome of L1TD1 in colon cancer patients. Results We found L1TD1 as a novel positive prognostic marker for colon cancer. Increased expression of L1TD1 associated with longer disease-free survival in all the three data sets. Our results were in contrast to a previous study on medulloblastoma, where high expression of L1TD1 was linked with poor prognosis. Notably, in medulloblastoma L1TD1 was co-expressed with its interaction partners, whereas our analysis revealed lack of co-expression of L1TD1 with its interaction partners in colon cancer. Conclusions Our results identify increased expression of L1TD1 as a prognostic marker predicting longer disease-free survival in colon cancer patients.
  • Sartelli, Massimo; Abu-Zidan, Fikri M; Labricciosa, Francesco M; Kluger, Yoram; Coccolini, Federico; Ansaloni, Luca; Leppäniemi, Ari; Kirkpatrick, Andrew W; Tolonen, Matti; Tranà, Cristian; Regimbeau, Jean-Marc; Hardcastle, Timothy; Koshy, Renol M; Abbas, Ashraf; Aday, Ulaş; Adesunkanmi, A. R K; Ajibade, Adesina; Akhmeteli, Lali; Akın, Emrah; Akkapulu, Nezih; Alotaibi, Alhenouf; Altintoprak, Fatih; Anyfantakis, Dimitrios; Atanasov, Boyko; Augustin, Goran; Azevedo, Constança; Bala, Miklosh; Balalis, Dimitrios; Baraket, Oussama; Baral, Suman; Barkai, Or; Beltran, Marcelo; Bini, Roberto; Bouliaris, Konstantinos; Caballero, Ana B; Calu, Valentin; Catani, Marco; Ceresoli, Marco; Charalampakis, Vasileios; Jusoh, Asri C; Chiarugi, Massimo; Cillara, Nicola; Cuesta, Raquel C; Cobuccio, Luigi; Cocorullo, Gianfranco; Colak, Elif; Conti, Luigi; Cui, Yunfeng; De Simone, Belinda; Delibegovic, Samir; Demetrashvili, Zaza; Demetriades, Demetrios; Dimova, Ana; Dogjani, Agron; Enani, Mushira; Farina, Federica; Ferrara, Francesco; Foghetti, Domitilla; Fontana, Tommaso; Fraga, Gustavo P; Gachabayov, Mahir; Gérard, Grelpois; Ghnnam, Wagih; Maurel, Teresa G; Gkiokas, Georgios; Gomes, Carlos A; Guner, Ali; Gupta, Sanjay; Hecker, Andreas; Hirano, Elcio S; Hodonou, Adrien; Hutan, Martin; Ilaschuk, Igor; Ioannidis, Orestis; Isik, Arda; Ivakhov, Georgy; Jain, Sumita; Jokubauskas, Mantas; Karamarkovic, Aleksandar; Kaushik, Robin; Kenig, Jakub; Khokha, Vladimir; Khokha, Denis; Kim, Jae I; Kong, Victor; Korkolis, Dimitris; Kruger, Vitor F; Kshirsagar, Ashok; Simões, Romeo L; Lanaia, Andrea; Lasithiotakis, Konstantinos; Leão, Pedro; Arellano, Miguel L; Listle, Holger; Litvin, Andrey; Lizarazu Pérez, Aintzane; Lopez-Tomassetti Fernandez, Eudaldo; Lostoridis, Eftychios; Luppi, Davide; Machain V, Gustavo M; Major, Piotr; Manatakis, Dimitrios; Reitz, Marianne M; Marinis, Athanasios; Marrelli, Daniele; Martínez-Pérez, Aleix; Marwah, Sanjay; McFarlane, Michael; Mesic, Mirza; Mesina, Cristian; Michalopoulos, Nickos; Misiakos, Evangelos; Moreira, Felipe G; Mouaqit, Ouadii; Muhtaroglu, Ali; Naidoo, Noel; Negoi, Ionut; Nikitina, Zane; Nikolopoulos, Ioannis; Nita, Gabriela-Elisa; Occhionorelli, Savino; Olaoye, Iyiade; Ordoñez, Carlos A; Ozkan, Zeynep; Pal, Ajay; Palini, Gian M; Papageorgiou, Kyriaki; Papagoras, Dimitris; Pata, Francesco; Pędziwiatr, Michał; Pereira, Jorge; Pereira Junior, Gerson A; Perrone, Gennaro; Pintar, Tadeja; Pisarska, Magdalena; Plehutsa, Oleksandr; Podda, Mauro; Poillucci, Gaetano; Quiodettis, Martha; Rahim, Tuba; Rios-Cruz, Daniel; Rodrigues, Gabriel; Rozov, Dmytry; Sakakushev, Boris; Sall, Ibrahima; Sazhin, Alexander; Semião, Miguel; Sharda, Taanya; Shelat, Vishal; Sinibaldi, Giovanni; Skicko, Dmitrijs; Skrovina, Matej; Stamatiou, Dimitrios; Stella, Marco; Strzałka, Marcin; Sydorchuk, Ruslan; Teixeira Gonsaga, Ricardo A; Tochie, Joel N; Tomadze, Gia; Ugoletti, Lara; Ulrych, Jan; Ümarik, Toomas; Uzunoglu, Mustafa Y; Vasilescu, Alin; Vaz, Osborne; Vereczkei, Andras; Vlad, Nutu; Walędziak, Maciej; Yahya, Ali I; Yalkin, Omer; Yilmaz, Tonguç U; Ünal, Ali E; Yuan, Kuo-Ching; Zachariah, Sanoop K; Žilinskas, Justas; Zizzo, Maurizio; Pattonieri, Vittoria; Baiocchi, Gian L; Catena, Fausto (BioMed Central, 2019)
    Abstract Background Timing and adequacy of peritoneal source control are the most important pillars in the management of patients with acute peritonitis. Therefore, early prognostic evaluation of acute peritonitis is paramount to assess the severity and establish a prompt and appropriate treatment. The objectives of this study were to identify clinical and laboratory predictors for in-hospital mortality in patients with acute peritonitis and to develop a warning score system, based on easily recognizable and assessable variables, globally accepted. Methods This worldwide multicentre observational study included 153 surgical departments across 56 countries over a 4-month study period between February 1, 2018, and May 31, 2018. Results A total of 3137 patients were included, with 1815 (57.9%) men and 1322 (42.1%) women, with a median age of 47 years (interquartile range [IQR] 28–66). The overall in-hospital mortality rate was 8.9%, with a median length of stay of 6 days (IQR 4–10). Using multivariable logistic regression, independent variables associated with in-hospital mortality were identified: age > 80 years, malignancy, severe cardiovascular disease, severe chronic kidney disease, respiratory rate ≥ 22 breaths/min, systolic blood pressure < 100 mmHg, AVPU responsiveness scale (voice and unresponsive), blood oxygen saturation level (SpO2) < 90% in air, platelet count < 50,000 cells/mm3, and lactate > 4 mmol/l. These variables were used to create the PIPAS Severity Score, a bedside early warning score for patients with acute peritonitis. The overall mortality was 2.9% for patients who had scores of 0–1, 22.7% for those who had scores of 2–3, 46.8% for those who had scores of 4–5, and 86.7% for those who have scores of 7–8. Conclusions The simple PIPAS Severity Score can be used on a global level and can help clinicians to identify patients at high risk for treatment failure and mortality.
  • Nordal, Ellen; Rypdal, Veronika; Arnstad, Ellen D; Aalto, Kristiina; Berntson, Lillemor; Ekelund, Maria; Fasth, Anders; Glerup, Mia; Herlin, Troels; Nielsen, Susan; Peltoniemi, Suvi; Zak, Marek; Songstad, Nils T; Rygg, Marite (BioMed Central, 2019)
    Abstract Background The aim of the study was to describe school attendance and participation in physical education in school among children with juvenile idiopathic arthritis (JIA). Methods Consecutive cases of JIA from defined geographical areas of Finland, Sweden and Norway with disease onset in 1997 to 2000 were followed for 8 years in a multi-center cohort study, aimed to be as close to population-based as possible. Clinical characteristics and information on school attendance and participation in physical education (PE) were registered. Results Participation in school and in PE was lowest initially and increased during the disease course. Eight years after disease onset 228/274 (83.2%) of the children reported no school absence due to JIA, while 16.8% reported absence during the last 2 months due to JIA. Full participation in PE was reported by 194/242 (80.2%), partly by 16.9%, and none by 2.9%. Lowest participation in PE was found among children with ERA and the undifferentiated categories. Absence in school and PE was associated with higher disease activity measures at the 8-year visit. School absence > 1 day at baseline predicted use of disease-modifying anti-rheumatic drugs, including biologics (DMARDs) (OR 1.2 (1.1–1.5)), and non-remission off medication (OR 1.4 (1.1–1.7) 8 years after disease onset. Conclusion School absence at baseline predicted adverse long-term outcome. In children and adolescents with JIA participation in school activities is mostly high after 8 years of disease. For the minority with low participation, special attention is warranted to promote their full potential of social interaction and improve long-term outcome.
  • Palanca, Ana; Castelblanco, Esmeralda; Betriu, Àngels; Perpiñán, Hèctor; Soldevila, Berta; Valdivielso, José M; Bermúdez-Lopez, Marcelino; Puig-Jové, Carlos; Puig-Domingo, Manel; Groop, Per-Henrik; Fernández, Elvira; Alonso, Núria; Mauricio, Didac (BioMed Central, 2019)
    Abstract Background Individuals with diabetes have remarkably high rates of cardiovascular morbidity and mortality. However, the incremental cardiovascular risk in diabetes is heterogeneous and has often been related to renal involvement. The purpose of this study was to analyse the prognostic value of subclinical atherosclerosis in determining the incidence of first cardiovascular events (CVEs) in individuals with diabetes and chronic kidney disease (CKD) compared to CKD individuals without diabetes. Methods We included data from individuals with CKD with and without diabetes, free from pre-existing cardiovascular disease, from the NEFRONA cohort. Participants underwent baseline carotid and femoral ultrasound and were followed up for 4 years. All CVEs during follow-up were registered. Bivariate analysis and Fine–Gray competing risk models were used to perform the statistical analysis. Results During the mean follow-up time of 48 months, a total of 203 CVE was registered. 107 CVE occurred among participants without diabetes (19.58 per 1000 person-years) and 96 CVE occurred among participants with diabetes (44.44 per 1000 person-years). Following the competing risk analysis, the variables predicting CVEs in CKD individuals without diabetes were the number of territories with plaque at baseline (HR 1.862, 95% CI [1.432;2.240]), age (HR 1.026, 95% CI [1.003;1.049]) and serum concentrations of 25-OH vitamin D (HR 0.963, 95% CI [0.933;0.094]). The only variable predicting CVEs among CKD participants with diabetes was the number of territories with plaque at baseline (HR 1.782, 95% CI [1.393, 2.278]). For both models, concordance (C) index yielded was over 0.7. Conclusions The burden of subclinical atherosclerosis is the strongest predictor of future CVEs in diabetic individuals with CKD. Early detection of subclinical atherosclerotic burden by multiterritorial vascular ultrasound could improve CVE prediction in this population.
  • Peñate-Medina, Oula; Tower, Robert J; Peñate-Medina, Tuula; Will, Olga; Saris, Per E J; Suojanen, Juho; Sorsa, Timo; Huuskonen, Laura; Hiippala, Kaisa; Satokari, Reetta; Glüer, Claus C; de Vos, Willem M; Reunanen, Justus (BioMed Central, 2019)
    Abstract Background The human gastrointestinal (GI) tract microbiota has been a subject of intense research throughout the 3rd Millennium. Now that a general picture about microbiota composition in health and disease is emerging, questions about factors determining development of microbiotas with specific community structures will be addressed. To this end, usage of murine models for colonization studies remains crucial. Optical in vivo imaging of either bioluminescent or fluorescent bacteria is the basis for non-invasive detection of intestinal colonization of bacteria. Although recent advances in in vivo fluorescence imaging have overcome many limitations encountered in bioluminescent imaging of intestinal bacteria, such as requirement for live cells, high signal attenuation and 2D imaging, the method is still restricted to bacteria for which molecular cloning tools are available. Results Here, we present usage of a lipophilic fluorescent dye together with Katushka far-red fluorescent protein to establish a dual-color in vivo imaging system to monitor GI transit of different bacterial strains, suitable also for strains resistant to genetic labeling. Using this system, we were able to distinguish two different E. coli strains simultaneously and show their unique transit patterns. Combined with fluorescence molecular tomography, these distinct strains could be spatially and temporally resolved and quantified in 3D. Conclusions Developed novel method for labeling microbes and identify their passage both temporally and spatially in vivo makes now possible to monitor all culturable bacterial strains, also those that are resistant to conventional genetic labeling.

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