Articles from BioMed Central

 

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  • Autio, Karoliina P M; Ruotsalainen, Janne J; Anttila, Marjukka O; Niittykoski, Minna; Waris, Matti; Hemminki, Akseli; Vähä-Koskela, Markus J V; Hinkkanen, Ari E (BioMed Central, 2015)
    Abstract Background Dogs suffer from spontaneous tumors which may be amenable to therapies developed for human cancer patients, and dogs may serve as large-animal cancer models. A non-pathogenic Semliki Forest virus vector VA7-EGFP previously showed promise in targeting human tumor xenografts in mice, but the oncolytic capacity of the virus in canine cancer cells and the safety of the virus in higher mammals such as dogs, are not known. We therefore assessed the oncolytic potency of VA7-EGFP against canine cancer cells by infectivity and viability assays in two dog solid tumor cell lines. Furthermore we performed a 3-week safety study in two adult Beagles which received a single intravenous injection of ~2 × 105 plaque forming units of parental A7(74) strain. Results VA7-EGFP was able to replicate in and kill both canine cancer cell lines tested. No adverse events were observed in either of the two virus-injected adult Beagles and no infective virus could be recovered from any of the biological samples collected over the course of the study. Neutralizing antibodies to Semliki Forest virus became detectable in the dogs at 5 days post infection and remained elevated until study termination. Conclusions Based on these results, testing of the oncolytic potential of attenuated Semliki Forest virus in canine cancer patients appears feasible.
  • Tripathi, Sushil; Flobak, Åsmund; Chawla, Konika; Baudot, Anaïs; Bruland, Torunn; Thommesen, Liv; Kuiper, Martin; Lægreid, Astrid (BioMed Central, 2015)
    Abstract Background The gastrointestinal peptide hormones cholecystokinin and gastrin exert their biological functions via cholecystokinin receptors CCK1R and CCK2R respectively. Gastrin, a central regulator of gastric acid secretion, is involved in growth and differentiation of gastric and colonic mucosa, and there is evidence that it is pro-carcinogenic. Cholecystokinin is implicated in digestion, appetite control and body weight regulation, and may play a role in several digestive disorders. Results We performed a detailed analysis of the literature reporting experimental evidence on signaling pathways triggered by CCK1R and CCK2R, in order to create a comprehensive map of gastrin and cholecystokinin-mediated intracellular signaling cascades. The resulting signaling map captures 413 reactions involving 530 molecular species, and incorporates the currently available knowledge into one integrated signaling network. The decomposition of the signaling map into sub-networks revealed 18 modules that represent higher-level structures of the signaling map. These modules allow a more compact mapping of intracellular signaling reactions to known cell behavioral outcomes such as proliferation, migration and apoptosis. The integration of large-scale protein-protein interaction data to this literature-based signaling map in combination with topological analyses allowed us to identify 70 proteins able to increase the compactness of the map. These proteins represent experimentally testable hypotheses for gaining new knowledge on gastrin- and cholecystokinin receptor signaling. The CCKR map is freely available both in a downloadable, machine-readable SBML-compatible format and as a web resource through PAYAO ( http://sblab.celldesigner.org:18080/Payao11/bin/ ). Conclusion We have demonstrated how a literature-based CCKR signaling map together with its protein interaction extensions can be analyzed to generate new hypotheses on molecular mechanisms involved in gastrin- and cholecystokinin-mediated regulation of cellular processes.
  • Valo, Satu; Kaur, Sippy; Ristimäki, Ari; Renkonen-Sinisalo, Laura; Järvinen, Heikki; Mecklin, Jukka-Pekka; Nyström, Minna; Peltomäki, Päivi (BioMed Central, 2015)
    Abstract Background Lynch syndrome (LS) is associated with germline mutations in DNA mismatch repair (MMR) genes. The first “hit” to inactivate one allele of the predisposing MMR gene is present in every cell, contributing to accelerated tumorigenesis. Less information is available of the nature, timing, and order of other molecular “hits” required for tumor development. To this end, MMR protein expression and coordinated promoter methylation were examined in colorectal specimens prospectively collected from LS mutation carriers (n = 55) during colonoscopy surveillance (10/2011–5/2013), supplemented with retrospective specimens. Results Loss of MMR protein corresponding to the gene mutated in the germline increased with dysplasia, with frequency of 0 % in normal mucosa, 50–68 % in low-grade dysplasia adenomas, and 100 % in high-grade dysplasia adenomas and carcinomas. Promoter methylation as a putative “second hit” occurred in 1/56 (2 %) of tumors with silenced MMR protein. A general hypermethylation tendency was evaluated by two gene sets, eight CpG island methylator phenotype (CIMP) genes, and seven candidate tumor suppressor genes linked to colorectal carcinoma (CRC). Hypermethylation followed the same trend as MMR protein loss and was present in some low-grade dysplasia adenomas that still expressed MMR protein suggesting the absence of a “second hit.” To assess prospectively collected normal mucosa for carcinogenic “fields,” the specimen donors were stratified according to age at biopsy (50 years or below vs. above 50 years) and further according to the absence vs. presence of a (previous or concurrent) diagnosis of CRC. In mutation carriers over 50 years old, two markers from the candidate gene panel (SFRP1 and SLC5A8) revealed a significantly elevated average degree of methylation in individuals with CRC diagnosis vs. those without. Conclusions Our findings emphasize the importance and early appearance of epigenetic alterations in LS-associated tumorigenesis. The results serve early detection and assessment of progression of CRC.
  • Grönthal, Thomas; Ollilainen, Matti; Eklund, Marjut; Piiparinen, Heli; Gindonis, Veera; Junnila, Jouni; Saijonmaa-Koulumies, Leena; Liimatainen, Riitta; Rantala, Merja (BioMed Central, 2015)
    Abstract Background Methicillin resistant Staphylococcus pseudintermedius (MRSP) and Staphylococcus aureus (MRSA) are common multi-drug resistant (MDR) bacteria in dogs. In 2012–2013 three dogs of the Guide Dog School of the Finnish Federation of the Visually Impaired were found to be MRSP positive. Guide dogs have regular contact with each other during their first year of life and prolonged contact when in training. Since dogs are placed in different parts of Finland after training, there is a risk for national spread of MDR bacteria. In this study the prevalence of MRSP and MRSA, as well as the risk factors for MRSP were determined in the Finnish guide dog population. MRSP isolates were investigated using molecular methods and compared to the earlier isolates. Results Out of 132 tested dogs 4 were MRSP positive thus giving the prevalence estimate of 3% (95% CI: 1–8%) for MRSP in the target population. MRSA was not detected (prevalence estimate 0%, 95% CI: 0–3%). Risk factors associated with MRSP were being a breeding bitch (OR = 8.4; 95% CI: 1.1–64.1, P = 0.012), the number of veterinary visits (OR = 1.23; 95% CI: 1.0–1.5, P = 0.025) and number of antimicrobial courses (OR = 1.63; 95% CI: 1.0–2.55; P = 0.035). Identified MRSP isolates belonged to five different sequence types (ST45, 71, 402, 403 and 404). All ST71 isolates carried SCCmec II-III, while the SCCmec type of the ST45 and ST402 (a single locus variant of ST45) isolates were non-typeable with the method used. Conclusions MRSP and MRSA had low prevalence in the studied dog population despite the close contact between dogs, and the MRSP population was heterogenic. Antimicrobial therapy and veterinary visits are risk factors for MRSP even among a small case group.
  • Sobral-Leite, Marcelo; Wesseling, Jelle; Smit, Vincent T H B M; Nevanlinna, Heli; van Miltenburg, Martine H; Sanders, Joyce; Hofland, Ingrid; Blows, Fiona M; Coulson, Penny; Patrycja, Gazinska; Schellens, Jan H M; Fagerholm, Rainer; Heikkilä, Päivi; Aittomäki, Kristiina; Blomqvist, Carl; Provenzano, Elena; Ali, Hamid R; Figueroa, Jonine; Sherman, Mark; Lissowska, Jolanta; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Phillips, Kelly-Anne; Couch, Fergus J; Olson, Janet E; Vachon, Celine; Visscher, Daniel; Brenner, Hermann; Butterbach, Katja; Arndt, Volker; Holleczek, Bernd; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John W M; van Deurzen, Carolien H M; van de Water, Bob; Broeks, Annegien; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Easton, Douglas F; Pharoah, Paul D P; García-Closas, Montserrat; de Graauw, Marjo; Schmidt, Marjanka K (BioMed Central, 2015)
    Abstract Background Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model. Results The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05–1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91–1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17–2.45). Conclusions ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.
  • Sobral-Leite, Marcelo; Wesseling, Jelle; Smit, Vincent T H B M; Nevanlinna, Heli; van Miltenburg, Martine H; Sanders, Joyce; Hofland, Ingrid; Blows, Fiona M; Coulson, Penny; Patrycja, Gazinska; Schellens, Jan H M; Fagerholm, Rainer; Heikkilä, Päivi; Aittomäki, Kristiina; Blomqvist, Carl; Provenzano, Elena; Ali, Hamid R; Figueroa, Jonine; Sherman, Mark; Lissowska, Jolanta; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Phillips, Kelly-Anne; Couch, Fergus J; Olson, Janet E; Vachon, Celine; Visscher, Daniel; Brenner, Hermann; Butterbach, Katja; Arndt, Volker; Holleczek, Bernd; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John W M; van Deurzen, Carolien H M; van de Water, Bob; Broeks, Annegien; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Easton, Douglas F; Pharoah, Paul D P; García-Closas, Montserrat; de Graauw, Marjo; Schmidt, Marjanka K (BioMed Central, 2015)
    Abstract Background Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model. Results The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05–1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91–1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17–2.45). Conclusions ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.
  • Virtanen, Jorma I; Vehkalahti, Kimmo I; Vehkalahti, Miira M (BioMed Central, 2015)
    Abstract Background Health behaviors play a major role in the prevention of the most common oral diseases. To investigate health behaviors related to the potential transmission of oral bacteria from mother to child using novel multiple correspondence analysis (MCA). Methods Mothers (n = 313) with children under three years attending two municipal child health clinics in Finland completed a self-administered questionnaire on health knowledge and behaviors such as sharing a spoon with their child, kissing on the lips, and the mothers’ tooth brushing, smoking, age, and level of education. We used MCA to reveal the relationships between the mothers’ behaviors and background factors, along with unconditional, binary, multivariable logistic regression models, odds ratios (OR) and their 95 % confidence intervals (95 %CI). Results Of the mothers, 38 % kissed their child on the lips and 14 % shared a spoon with their child; 11 % believed that oral bacteria cannot be transmitted from mother to child. Two-thirds (68 %) of them reported tooth brushing twice daily, and 80 % were non-smokers. MCA revealed two diverging dimensions of the mothers’ behaviors: a ‘horizontal’ one showing clear evidence of relationships between tooth brushing, smoking, age and education, whereas the ‘vertical’ one revealed the mothers’ habits of kissing the child on the lips and sharing a spoon related to each other. Spoon sharing was related to the kissing on lips (OR 10.3), a higher level of education (OR 3.1), and, inversely, older age (OR 0.1), whereas kissing on lips behavior was inversely related to a higher level of education (OR 0.5). Conclusion The study revealed two diverging dimensions of the mothers’ health behaviors. More emphasis in health education ought to be put to how to avoid bacterial transmission from caregiver to child during feeding.
  • Lienemann, Taru; Kyyhkynen, Aino; Halkilahti, Jani; Haukka, Kaisa; Siitonen, Anja (BioMed Central, 2015)
    Abstract Background Salmonella enterica spp. enterica serotype Typhimurium (STM) is the most common agent of domestically acquired salmonellosis in Finland. Subtyping methods which allow the characterization of STM are essential for effective laboratory-based STM surveillance and for recognition of outbreaks. This study describes the diversity of Finnish STM isolates using phage typing, antimicrobial susceptible testing, pulsed-field gel electrophoresis (PFGE) and multilocus variable-number tandem repeat analysis (MLVA), and compares the discriminatory power and the concordance of these methods. Results A total of 375 sporadic STM isolates were analysed. The isolates were divided into 31 definite phage (DT) types, dominated by DT1 (47 % of the isolates), U277 (9 % of the isolates) and DT104 (8 % of the isolates). Of all the isolates, 62 % were susceptible to all the 12 antimicrobials tested and 11 % were multidrug resistant. Subtyping resulted in 83 different XbaI-PFGE profiles and 111 MLVA types. The three most common XbaI-PFGE profiles (STYM1, STYM7 and STYM8) and one MLVA profile with three single locus variants accounted for 56 % and 49 % of the STM isolates, respectively. The studied isolates showed a genetic similarity of more than 70 % by XbaI-PFGE. In MLVA, 71 % of the isolates lacked STTR6 and 77 % missed STTR10p loci. Nevertheless, the calculated Simpson’s diversity index for XbaI-PFGE was 0.829 (95 % CI 0.792−0.865) and for MLVA 0.867 (95 % CI 0.835−0.898). However, the discriminatory power of the 5-loci MLVA varied among the phage types. The highest concordance of the results was found between XbaI-PFGE and phage typing (adjusted Wallace coefficient was 0.833 and adjusted Rand coefficient was 0.627). Conclusions In general, the calculated discriminatory power was higher for genotyping methods (MLVA and XbaI-PFGE) than for phenotyping methods (phage typing). Overall, comparable diversity indices were calculated for PFGE and MLVA (both DI > 0.8). However, MLVA was phage type dependent providing better discrimination of the most common phage types. Furthermore, 5-loci MLVA was a less laborious method and easier to interpret than XbaI-PFGE. Thus, the laboratory-based surveillance of the Finnish human STM infections has been conducted with a combination of phage typing, antimicrobial susceptibility testing and 5-loci MLVA since January 2014.
  • Pirie, Ailith; Guo, Qi; Kraft, Peter; Canisius, Sander; Eccles, Diana M; Rahman, Nazneen; Nevanlinna, Heli; Chen, Constance; Khan, Sofia; Tyrer, Jonathan; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Michailidou, Kyriaki; Lush, Michael; Dunning, Alison M; Shah, Mitul; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Lambrechts, Dieter; Weltens, Caroline; Leunen, Karin; van Ongeval, Chantal; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Blomqvist, Carl; Aittomäki, Kristiina; Fagerholm, Rainer; Muranen, Taru A; Olsen, Janet E; Hallberg, Emily; Vachon, Celine; Knight, Julia A; Glendon, Gord; Mulligan, Anna M; Broeks, Annegien; Cornelissen, Sten; Haiman, Christopher A; Henderson, Brian E; Schumacher, Frederick; Le Marchand, Loic; Hopper, John L; Tsimiklis, Helen; Apicella, Carmel; Southey, Melissa C; Cross, Simon S; Reed, Malcolm W; Giles, Graham G; Milne, Roger L; McLean, Catriona; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John W; van den Ouweland, Ans M; Marme, Federick; Schneeweiss, Andreas; Yang, Rongxi; Burwinkel, Barbara; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Brenner, Hermann; Butterbach, Katja; Holleczek, Bernd; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Li, Jingmei; Brand, Judith S; Humphreys, Keith; Devilee, Peter; Tollenaar, Robert A; Seynaeve, Caroline; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Ficarazzi, Filomena; Beckmann, Matthias W; Hein, Alexander; Ekici, Arif B; Balleine, Rosemary; Phillips, Kelly-Anne; Benitez, Javier; Zamora, M P; Perez, Jose I A; Menéndez, Primitiva; Jakubowska, Anna; Lubinski, Jan; Gronwald, Jacek; Durda, Katarzyna; Hamann, Ute; Kabisch, Maria; Ulmer, Hans U; Rüdiger, Thomas; Margolin, Sara; Kristensen, Vessela; Nord, Siljie; Evans, D G; Abraham, Jean; Earl, Helena; Poole, Christopher J; Hiller, Louise; Dunn, Janet A; Bowden, Sarah; Yang, Rose; Campa, Daniele; Diver, W R; Gapstur, Susan M; Gaudet, Mia M; Hankinson, Susan; Hoover, Robert N; Hüsing, Anika; Kaaks, Rudolf; Machiela, Mitchell J; Willett, Walter; Barrdahl, Myrto; Canzian, Federico; Chin, Suet-Feung; Caldas, Carlos; Hunter, David J; Lindstrom, Sara; Garcia-Closas, Montserrat; Couch, Fergus J; Chenevix-Trench, Georgia; Mannermaa, Arto; Andrulis, Irene L; Hall, Per; Chang-Claude, Jenny; Easton, Douglas F; Bojesen, Stig E; Cox, Angela; Fasching, Peter A; Pharoah, Paul D; Schmidt, Marjanka K (BioMed Central, 2015)
    Abstract Introduction Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium. Methods A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect. Results Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease. Conclusions Although no variants reached genome-wide significance (P <5 x 10−8), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.
  • Kasteenpohja, Teija; Marttunen, Mauri; Aalto-Setälä, Terhi; Perälä, Jonna; Saarni, Samuli I; Suvisaari, Jaana (BioMed Central, 2015)
    Abstract Background Under-treated depression may be especially harmful in early adulthood. The aims of this study are to describe treatments received for depressive disorders, to define factors associated with treatment adequacy and dropouts from treatment in a Finnish general population sample of young adults. Methods A nationally representative two-stage cluster sample of 1894 Finns aged 19 to 34 years was sent a questionnaire containing several mental health screens. All screen positives and a random sample of screen negatives were invited to participate in a mental health assessment including a SCID interview. Case records from mental health treatments for the same sample were obtained for the final diagnostic assessment. Based on all available information, receiving antidepressant pharmacotherapy for at least two months with at least four visits with any type of physician or at least eight sessions of psychotherapy within 12 months or at least four days of hospitalization were regarded as minimally adequate treatment. Treatment dropout was rated if the treatment strategy was assessed to be adequate according to the case records but the patient discontinued the visits. Results Of participants with depressive disorders (n = 142), 40.9% received minimally adequate treatment. In multiple logistic regression models, substance use disorder and female gender were associated with at least one visit with a physician, while having major depressive disorder was associated with visits with a physician at least 4 times a year. Women had higher odds of having received any psychotherapy and psychotherapy lasting for at least 8 sessions in a year. Low education and a history of suicide attempt were associated with increased odds of treatment dropout. None of the factors explained the final outcome of minimally adequate treatment. Conclusions Treatment adequacy in the present study was better than previously seen, but more efforts are needed to provide adequate treatment for young adults, especially those with low education and suicidality.
  • Ma, Li; Piirainen, Sami; Kulesskaya, Natalia; Rauvala, Heikki; Tian, Li (BioMed Central, 2015)
    Abstract Background Social deficit is one of the core symptoms of neuropsychiatric diseases, in which immune genes play an important role. Although a few immune genes have been shown to regulate social and emotional behaviors, how immune gene network(s) may jointly regulate sociability has not been investigated so far. Methods To decipher the potential immune-mediated mechanisms underlying social behavior, we first studied the brain microarray data of eight inbred mouse strains with known variations in social behavior and retrieved the differentially expressed immune genes. We then made a protein-protein interaction analysis of them to find the major networks and explored the potential association of these genes with the behavior and brain morphology in the mouse phenome database. To validate the expression and function of the candidate immune genes, we selected the C57BL/6 J and DBA/2 J strains among the eight inbred strains, compared their social behaviors in resident-intruder and 3-chambered social tests and the mRNA levels of these genes, and analyzed the correlations of these genes with the social behaviors. Results A group of immune genes were differentially expressed in the brains of these mouse strains. The representative C57BL/6 J and DBA/2 J strains displayed significant differences in social behaviors, DBA/2 J mice being less active in social dominance and social interaction than C57BL/6 J mice. The mRNA levels of H2-d1 in the prefrontal cortex, hippocampus, and hypothalamus and C1qb in the hippocampus of the DBA/2 J strain were significantly down-regulated as compared to those in the C57BL/6 J strain. In contrast, Polr3b in the hippocampus and Tnfsf13b in the prefrontal cortex of the DBA/2 J strain were up-regulated. Furthermore, C1qb, Cx3cl1, H2-d1, H2-k1, Polr3b, and Tnfsf13b were predicted to be associated with various behavioral and brain morphological features across the eight inbred strains. Importantly, the C1qb mRNA level was confirmed to be significantly correlated with the sociability in DBA/2 J but not in C57BL/6 J mice. Conclusions Our study provided evidence on the association of immune gene network(s) with the brain development and behavior in animals and revealed neurobiological functions of novel brain immune genes that may contribute to social deficiency in animal models of neuropsychiatric disorders.
  • Zhang, Yanlei; Ning, Feng; Sun, Jianping; Pang, Zengchang; Wang, Xiaoyong; Kapur, Anil; Sintonen, Harri; Qiao, Qing (BioMed Central, 2015)
    Abstract Background Screening for type 2 diabetes helps detect previously unknown diabetes and identify people with pre-diabetes, but the adverse impact of such screening on individuals labelled as pre-diabetes or classified as normal, is less known. In this study the health-related quality of life (HRQoL), depression and lifestyle changes in a rural Chinese population are assessed three years after a screening program. Methods A total of 647 (39.1%) individuals with pre-diabetes and 1009 (60.9%) individuals with normoglycaemia from a population-based diabetes screening program in 2009 were re-examined in 2012–2013. Changes at the end of 3 years in HRQoL, depression, BMI, weight, frequency of physical activity and vegetable intake were assessed. Results In men with normoglycaemia the mean (SD) 15D scores were 0.974 (0.04) at baseline and 0.973 (0.05) at follow-up; and 0.971 (0.05) and 0.966 (0.06) for men with pre-diabetes. In women the scores were 0.973 (0.05) and 0.963 (0.06) for normoglycaemia and 0.959 (0.06) and 0.954 (0.07) for pre-diabetes, respectively. Compared to baseline, the HRQoL was slightly lower at 3 years in all groups but the change was not considered to be clinically important, and was only statistically significant for women with normoglycaemia (p < 0.05). The depression score was slightly elevated in women, but not in men. No significant changes in BMI were noticed, but weight increased slightly in the normoglycemia group (p < 0.05). Screening had a significant positive impact on physical activity and vegetable intake. Conclusions This population-based diabetes screening program generated long-term positive changes toward a healthy lifestyle as measured by physical activity and vegetable intake for all the participants without adverse effects on the HRQoL and depression.
  • Fortino, Vittorio; Smolander, Olli-Pekka; Auvinen, Petri; Tagliaferri, Roberto; Greco, Dario (BioMed Central, 2014)
    Abstract Background Inferring operon maps is crucial to understanding the regulatory networks of prokaryotic genomes. Recently, RNA-seq based transcriptome studies revealed that in many bacterial species the operon structure vary with the change of environmental conditions. Therefore, new computational solutions that use both static and dynamic data are necessary to create condition specific operon predictions. Results In this work, we propose a novel classification method that integrates RNA-seq based transcriptome profiles with genomic sequence features to accurately identify the operons that are expressed under a measured condition. The classifiers are trained on a small set of confirmed operons and then used to classify the remaining gene pairs of the organism studied. Finally, by linking consecutive gene pairs classified as operons, our computational approach produces condition-dependent operon maps. We evaluated our approach on various RNA-seq expression profiles of the bacteria Haemophilus somni, Porphyromonas gingivalis, Escherichia coli and Salmonella enterica. Our results demonstrate that, using features depending on both transcriptome dynamics and genome sequence characteristics, we can identify operon pairs with high accuracy. Moreover, the combination of DNA sequence and expression data results in more accurate predictions than each one alone. Conclusion We present a computational strategy for the comprehensive analysis of condition-dependent operon maps in prokaryotes. Our method can be used to generate condition specific operon maps of many bacterial organisms for which high-resolution transcriptome data is available.
  • Arnulfo, Gabriele; Narizzano, Massimo; Cardinale, Francesco; Fato, Marco M; Palva, Jaakko M (BioMed Central, 2015)
    Abstract Background Invasive monitoring of brain activity by means of intracerebral electrodes is widely practiced to improve pre-surgical seizure onset zone localization in patients with medically refractory seizures. Stereo-Electroencephalography (SEEG) is mainly used to localize the epileptogenic zone and a precise knowledge of the location of the electrodes is expected to facilitate the recordings interpretation and the planning of resective surgery. However, the localization of intracerebral electrodes on post-implant acquisitions is usually time-consuming (i.e., manual segmentation), it requires advanced 3D visualization tools, and it needs the supervision of trained medical doctors in order to minimize the errors. In this paper we propose an automated segmentation algorithm specifically designed to segment SEEG contacts from a thresholded post-implant Cone-Beam CT volume (0.4 mm, 0.4 mm, 0.8 mm). The algorithm relies on the planned position of target and entry points for each electrode as a first estimation of electrode axis. We implemented the proposed algorithm into DEETO, an open source C++ prototype based on ITK library. Results We tested our implementation on a cohort of 28 subjects in total. The experimental analysis, carried out over a subset of 12 subjects (35 multilead electrodes; 200 contacts) manually segmented by experts, show that the algorithm: (i) is faster than manual segmentation (i.e., less than 1s/subject versus a few hours) (ii) is reliable, with an error of 0.5 mm ± 0.06 mm, and (iii) it accurately maps SEEG implants to their anatomical regions improving the interpretability of electrophysiological traces for both clinical and research studies. Moreover, using the 28-subject cohort we show here that the algorithm is also robust (error < 0.005 mm) against deep-brain displacements (< 12 mm) of the implanted electrode shaft from those planned before surgery. Conclusions Our method represents, to the best of our knowledge, the first automatic algorithm for the segmentation of SEEG electrodes. The method can be used to accurately identify the neuroanatomical loci of SEEG electrode contacts by a non-expert in a fast and reliable manner.
  • Kuchenbaecker, Karoline B; Neuhausen, Susan L; Robson, Mark; Barrowdale, Daniel; McGuffog, Lesley; Mulligan, Anna M; Andrulis, Irene L; Spurdle, Amanda B; Schmidt, Marjanka K; Schmutzler, Rita K; Engel, Christoph; Wappenschmidt, Barbara; Nevanlinna, Heli; Thomassen, Mads; Southey, Melissa; Radice, Paolo; Ramus, Susan J; Domchek, Susan M; Nathanson, Katherine L; Lee, Andrew; Healey, Sue; Nussbaum, Robert L; Rebbeck, Timothy R; Arun, Banu K; James, Paul; Karlan, Beth Y; Lester, Jenny; Cass, Ilana; Registry, Breast C F; Terry, Mary B; Daly, Mary B; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Tihomirova, Laima; Tung, Nadine; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Steele, Linda; v O Hansen, Thomas; Ejlertsen, Bent; Gerdes, Anne-Marie; Nielsen, Finn C; Dennis, Joe; Cunningham, Julie; Hart, Steven; Slager, Susan; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Weitzel, Jeffrey N; Tafur, Isaac; Hander, Mary; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Roversi, Gaia; Scuvera, Giulietta; Bonanni, Bernardo; Mariani, Paolo; Volorio, Sara; Dolcetti, Riccardo; Varesco, Liliana; Papi, Laura; Tibiletti, Maria G; Giannini, Giuseppe; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Hamann, Ute; Donaldson, Alan; Brewer, Carole; Foo, Claire; Evans, D G; Frost, Debra; Eccles, Diana; Douglas, Fiona; Brady, Angela; Cook, Jackie; Tischkowitz, Marc; Adlard, Julian; Barwell, Julian; Ong, Kai-ren; Walker, Lisa; Izatt, Louise; Side, Lucy E; Kennedy, M J; Rogers, Mark T; Porteous, Mary E; Morrison, Patrick J; Platte, Radka; Eeles, Ros; Davidson, Rosemarie; Hodgson, Shirley; Ellis, Steve; Godwin, Andrew K; Rhiem, Kerstin; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hansjoerg; Niederacher, Dieter; Sutter, Christian; Steinemann, Doris; Bogdanova-Markov, Nadja; Kast, Karin; Varon-Mateeva, Raymonda; Wang-Gohrke, Shan; Gehrig, Andrea; Markiefka, Birgid; Buecher, Bruno; Lefol, Cédrick; Stoppa-Lyonnet, Dominique; Rouleau, Etienne; Prieur, Fabienne; Damiola, Francesca; Barjhoux, Laure; Faivre, Laurence; Longy, Michel; Sevenet, Nicolas; Sinilnikova, Olga M; Mazoyer, Sylvie; Bonadona, Valérie; Caux-Moncoutier, Virginie; Isaacs, Claudine; Van Maerken, Tom; Claes, Kathleen; Piedmonte, Marion; Andrews, Lesley; Hays, John; Rodriguez, Gustavo C; Caldes, Trinidad; de la Hoya, Miguel; Khan, Sofia; Hogervorst, Frans B; Aalfs, Cora M; de Lange, JL; Meijers-Heijboer, Hanne E; van der Hout, Annemarie H; Wijnen, Juul T; van Roozendaal, KEP; Mensenkamp, Arjen R; van den Ouweland, Ans M; van Deurzen, Carolien H; van der Luijt, Rob B; Olah, Edith; Diez, Orland; Lazaro, Conxi; Blanco, Ignacio; Teulé, Alex; Menendez, Mireia; Jakubowska, Anna; Lubinski, Jan; Cybulski, Cezary; Gronwald, Jacek; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Arason, Adalgeir; Maugard, Christine; Soucy, Penny; Montagna, Marco; Agata, Simona; Teixeira, Manuel R; Olswold, Curtis; Lindor, Noralane; Pankratz, Vernon S; Hallberg, Emily; Wang, Xianshu; Szabo, Csilla I; Vijai, Joseph; Jacobs, Lauren; Corines, Marina; Lincoln, Anne; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F; Rappaport, Christine; Kaulich, Daphne G; Pfeiler, Georg; Tea, Muy-Kheng; Phelan, Catherine M; Mai, Phuong L; Greene, Mark H; Rennert, Gad; Imyanitov, Evgeny N; Glendon, Gord; Toland, Amanda E; Bojesen, Anders; Pedersen, Inge S; Jensen, Uffe B; Caligo, Maria A; Friedman, Eitan; Berger, Raanan; Laitman, Yael; Rantala, Johanna; Arver, Brita; Loman, Niklas; Borg, Ake; Ehrencrona, Hans; Olopade, Olufunmilayo I; Simard, Jacques; Easton, Douglas F; Chenevix-Trench, Georgia; Offit, Kenneth; Couch, Fergus J; Antoniou, Antonis C (BioMed Central, 2014)
    Abstract Introduction More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10−6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. Conclusions Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.