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ObjectiveTo compare trends, outcomes and risk factors for severe postpartum hemorrhage (PPH) due to uterine atony and retained tissue separately.Study designThis retrospective hospital-based study of severe PPH included deliveries from a 10-year cohort (2008-2017) and a four-year case-control group (2008-2011). Severe PPH was defined as an estimated blood loss of ≥1500 ml or a blood transfusion. Poisson regression was used to estimate the temporal trend in the 10-year cohort. Risk factors were investigated in the case-control group. We performed multinomial regression analysis to investigate associations between pregnancy characteristics and severe PPH caused by uterine atony and by retained tissue compared to controls without severe PPH.ResultsDuring the 10-year study period, 2.7% of all deliveries were complicated by severe PPH. Uterine atony without concurring retained tissue was the cause in 55.4%, while retained tissue was listed as a cause in 32.2% of the cases. Among women who received ≥ four units of blood products, retained tissue caused 42.6% of cases, and severe PPH resulting in a hysterectomy was caused by retained tissue in 61.2% of cases. The rate of severe PPH caused by uterine atony significantly increased during the study period with an estimated annual percentage change of 8.6%, while the increase in severe PPH due to retained tissue was non-significant. Risk factors associated only with uterine atony were multiple pregnancy, macrosomia, Asian ethnicity and operative delivery, while induction of labor, augmentation of labor, use of anticoagulants and assisted reproduction were associated with both uterine atony and retained tissue.ConclusionThe observed increased rate of PPH in the study period was mainly driven by an increase in atonic PPH, while the rate of severe PPH caused by retained tissue remained stable. The proportion caused by retained tissue was highest among the most severe cases of PPH. The reason for the increase in severe PPH due to uterine atony, but not retained tissue was not clear, but we speculate that it may be a combination of increasing risk factors with increased awareness of PPH.

Estimating the trend of new infections was crucial for monitoring risk and for evaluating strategies and interventions during the COVID-19 pandemic. The pandemic revealed the utility of new data sources and highlighted challenges in interpreting surveillance indicators when changes in disease severity, testing practices or reporting occur. Our study aims to estimate the underlying trend in new COVID-19 infections by combining estimates of growth rates from all available surveillance indicators in Norway. We estimated growth rates by using a negative binomial regression method and aligned the growth rates in time to hospital admissions by maximising correlations. Using a meta-analysis framework, we calculated overall growth rates and reproduction numbers including assessments of the heterogeneity between indicators. We find that the estimated growth rates reached a maximum of 25% per day in March 2020, but afterwards they were between -10% and 10% per day. The correlations between the growth rates estimated from different indicators were between 0.5 and 1.0. Growth rates from indicators based on wastewater, panel and cohort data can give up to 14 days earlier signals of trends compared to hospital admissions, while indicators based on positive lab tests can give signals up to 7 days earlier. Combining estimates of growth rates from multiple surveillance indicators provides a useful description of the COVID-19 pandemic in Norway. This is a powerful technique for a holistic understanding of the trends of new COVID-19 infections and the technique can easily be adapted to new data sources and situations.

Objective: To compare trends, outcomes and risk factors for severe postpartum hemorrhage (PPH) due to uterine atony and retained tissue separately. Study design: This retrospective hospital-based study of severe PPH included deliveries from a 10-year cohort (2008–2017) and a four-year case-control group (2008–2011). Severe PPH was defined as an estimated blood loss of ≥1500 ml or a blood transfusion. Poisson regression was used to estimate the temporal trend in the 10-year cohort. Risk factors were investigated in the case-control group. We performed multinomial regression analysis to investigate associations between pregnancy characteristics and severe PPH caused by uterine atony and by retained tissue compared to controls without severe PPH. Results: During the 10-year study period, 2.7% of all deliveries were complicated by severe PPH. Uterine atony without concurring retained tissue was the cause in 55.4%, while retained tissue was listed as a cause in 32.2% of the cases. Among women who received ≥ four units of blood products, retained tissue caused 42.6% of cases, and severe PPH resulting in a hysterectomy was caused by retained tissue in 61.2% of cases. The rate of severe PPH caused by uterine atony significantly increased during the study period with an estimated annual percentage change of 8.6%, while the increase in severe PPH due to retained tissue was non-significant. Risk factors associated only with uterine atony were multiple pregnancy, macrosomia, Asian ethnicity and operative delivery, while induction of labor, augmentation of labor, use of anticoagulants and assisted reproduction were associated with both uterine atony and retained tissue. Conclusion: The observed increased rate of PPH in the study period was mainly driven by an increase in atonic PPH, while the rate of severe PPH caused by retained tissue remained stable. The proportion caused by retained tissue was highest among the most severe cases of PPH. The reason for the increase in severe PPH due to uterine atony, but not retained tissue was not clear, but we speculate that it may be a combination of increasing risk factors with increased awareness of PPH. [ABSTRACT FROM AUTHOR]

Estimating the trend of new infections was crucial for monitoring risk and for evaluating strategies and interventions during the COVID-19 pandemic. The pandemic revealed the utility of new data sources and highlighted challenges in interpreting surveillance indicators when changes in disease severity, testing practices or reporting occur. Our study aims to estimate the underlying trend in new COVID-19 infections by combining estimates of growth rates from all available surveillance indicators in Norway. We estimated growth rates by using a negative binomial regression method and aligned the growth rates in time to hospital admissions by maximising correlations. Using a meta-analysis framework, we calculated overall growth rates and reproduction numbers including assessments of the heterogeneity between indicators. We find that the estimated growth rates reached a maximum of 25% per day in March 2020, but afterwards they were between -10% and 10% per day. The correlations between the growth rates estimated from different indicators were between 0.5 and 1.0. Growth rates from indicators based on wastewater, panel and cohort data can give up to 14 days earlier signals of trends compared to hospital admissions, while indicators based on positive lab tests can give signals up to 7 days earlier. Combining estimates of growth rates from multiple surveillance indicators provides a useful description of the COVID-19 pandemic in Norway. This is a powerful technique for a holistic understanding of the trends of new COVID-19 infections and the technique can easily be adapted to new data sources and situations. [ABSTRACT FROM AUTHOR]

IntroductionBreast cancer is the most common cancer worldwide and the leading cause of cancer related deaths among women. The high incidence and mortality of breast cancer calls for improved prevention, diagnostics, and treatment, including identification of new prognostic and predictive biomarkers for use in precision medicine.Material and methodsWith the aim of compiling a cohort amenable to integrative study designs, we collected detailed epidemiological and clinical data, blood samples, and tumor tissue from a subset of participants from the prospective, population-based Norwegian Women and Cancer (NOWAC) study. These study participants were diagnosed with invasive breast cancer in North Norway before 2013 according to the Cancer Registry of Norway and constitute the Clinical and Multi-omic (CAMO) cohort. Prospectively collected questionnaire data on lifestyle and reproductive factors and blood samples were extracted from the NOWAC study, clinical and histopathological data were manually curated from medical records, and archived tumor tissue collected.ResultsThe lifestyle and reproductive characteristics of the study participants in the CAMO cohort (n = 388) were largely similar to those of the breast cancer patients in NOWAC (n = 10 356). The majority of the cancers in the CAMO cohort were tumor grade 2 and of the luminal A subtype. Approx. 80% were estrogen receptor positive, 13% were HER2 positive, and 12% were triple negative breast cancers. Lymph node metastases were present in 31% at diagnosis. The epidemiological dataset in the CAMO cohort is complemented by mRNA, miRNA, and metabolomics analyses in plasma, as well as miRNA profiling in tumor tissue. Additionally, histological analyses at the level of proteins and miRNAs in tumor tissue are currently ongoing.ConclusionThe CAMO cohort provides data suitable for epidemiological, clinical, molecular, and multi-omics investigations, thereby enabling a systems epidemiology approach to translational breast cancer research.

AimEarlier research has revealed a strong relationship between alcohol use and sickness absence. The aim of this review was to explore and uncover this relationship by looking at differences in type of design (cross-sectional vs. longitudinal), type of data (self-reported vs. registered data), and type of sickness absence (long-term vs. short term).MethodSix databases were searched through June 2020. Observational and experimental studies from 1980 to 2020, in English or Scandinavian languages reporting the results of the association between alcohol consumption and sickness absence among working population were included. Quality assessment, and statistical analysis focusing on differences in the likelihood of sickness absence on subgroup levels were performed on each association, not on each study. Differences in the likelihood of sickness absence were analyzed by means of meta-analysis. PROSPERO registration number: CRD42018112078.ResultsFifty-nine studies (58% longitudinal) including 439,209 employees (min. 43, max. 77,746) from 15 countries were included. Most associations indicating positive and statistically significant results were based on longitudinal data (70%) and confirmed the strong/causal relationship between alcohol use and sickness absence. The meta-analysis included eight studies (ten samples). The increased risk for sickness absence was likely to be found in cross-sectional studies (OR: 8.28, 95% CI: 6.33-10.81), studies using self-reported absence data (OR: 5.16, 95% CI: 3.16-8.45), and those reporting short-term sickness absence (OR: 4.84, 95% CI: 2.73-8.60).ConclusionThis review supports, but also challenges earlier evidence on the association between alcohol use and sickness absence. Certain types of design, data, and types of sickness absence may produce large effects. Hence, to investigate the actual association between alcohol and sickness absence, research should produce and review longitudinal designed studies using registry data and do subgroup analyses that cover and explain variability of this association.

Based on previous large-scale in silico screening several factor Xa inhibitors were proposed to potentially inhibit SARS-CoV-2 Mpro. In addition to their known anticoagulants activity this potential inhibition could have an additional therapeutic effect on patients with COVID-19 disease. In this study we examined the binding of the Apixaban, Betrixaban and Rivaroxaban to the SARS-CoV-2 Mpro with the use of the MicroScale Thermophoresis technique. Our results indicate that the experimentally measured binding affinity is weak and the therapeutic effect due to the SARS-CoV-2 Mpro inhibition is rather negligible.

The benefits of lowering blood pressure (BP) are well established for the prevention of cardiovascular disease. While there are a number of pharmaceuticals available for lowering BP, there is considerable interest in using dietary modifications, lifestyle and behaviour changes as alternative strategies. Kukoamines, caffeic acid derivatives of polyamines present in solanaceous plants, have been reported to reduce BP. We investigated the effect of orally administered synthetic kukoamine A on BP in the Spontaneously Hypertensive Rat (SHR) laboratory animal model of hypertension. Prior to the hypertension study, we determined the safety of the synthetic kukoamine A in a single oral dose (5 or 10 mg kg-1 bodyweight) 14-day observational study in mice. No negative effects of the oral administration of kukoamine A were observed. We subsequently investigated the effect of daily oral doses of kukoamine A (0, 5, 10 mg kg-1 bodyweight) for 35 days using the SHR rat model of hypertension. The normotensive control Wistar Kyoto (WKY) strain was used to provide a baseline for normal BP in rats. We observed no effect of orally administered synthetic kukoamine A on arterial hypertension in this laboratory animal model of hypertension.

BackgroundContinuity of care is particularly important for patients with chronic conditions, such as type 2 diabetes (T2D). Continuity is shown to reduce overall health service utilization among people with diabetes, however, evidence about how it relates to the utilization of outpatient specialist services in Norway is lacking. The aim of this study was to investigate continuity of GP care for people with T2D, and its association with the use of outpatient specialist health care services.MethodsWe used e-mail questionnaire data obtained from members of The Norwegian Diabetes Association in 2018. Eligible for analyses were 494 respondents with T2D and at least one GP visit during the previous year. By descriptive statistics and logistic regressions, we studied usual provider continuity (UPC) and duration of the patient-GP relationship and associations of these measures with somatic outpatient specialist visits. Analyses were adjusted for gender, age, education, self-rated health, and diabetes duration.ResultsMean age was 62.6 years and mean UPC was 0.85 (CI 0.83-0.87). Two thirds of the sample (66.0%) had made all visits to the regular GP during the previous year (full continuity). Among these, 48.1% had made one or more specialist visits during the previous year, compared to 65.2% among those without full continuity. The probability of outpatient specialist visits was significantly lower among participants with full continuity, compared to those without full continuity (Odds Ratio 0.53, Confidence Interval 0.35-0.80). The probability of visiting outpatient specialist services was not associated with duration of the patient-GP relationship.ConclusionsWe conclude that continuity of care, as measured by Usual Provider Continuity, is high and associated with reduced use of somatic outpatient specialist services in people with T2D in Norway. Continuity and its benefits will become increasingly important as the number of older people with diabetes and other chronic diseases increases.

Introduction Maternal cytomegalovirus (CMV) infection in pregnancy may result in vertical transmission of CMV to the child. Long-term effects of congenital CMV infection include visual, cognitive as well as neurological impairment. The aim of this study was to estimate the odds ratios for CMV seropositivity and seroconversion in mothers, with and without delayed language development in 3 year old children, nested within a large cohort. Material and methods The Norwegian Mother, Father and Child Cohort Study (MoBa) is a prospective population-based pregnancy cohort that includes 95 200 mothers and 114 500 children. Blood samples were obtained from mothers during pregnancy weeks 17 or 18 in pregnancy and after birth. We included 300 women from MoBa with children suffering from delayed language development at three years of age, based on validated questionnaires. Within the cohort, 1350 randomly selected women were included as controls to perform a nested case-control study. The cases and controls were tested for CMV IgG antibodies by an enzyme-linked immunosorbent assay. Results Among mothers of cases, 63.2% were CMV-IgG positive in the sample at birth, as compared to 55.9% among controls; OR 1.36, (95% CI; 1.05 to 1.76). Also, among case mothers, 8/118 (6.8%) initially seronegative cases, seroconverted. Among initially seronegative controls, seroconversion occurred in 23/618 (3.7%) mothers. The OR for seroconversion in cases as compared to control mothers was 1.88 (CI; 0.82 to 4.31), thus not statistically significant different. Conclusion This study shows a higher risk of delayed language development at three years of age in children born by mothers seropositive for CMV, compared to children born from seronegative mothers.

The cancer-associated fibroblast (CAF) marker podoplanin (PDPN) is generally correlated with poor clinical outcomes in cancer patients and thus represents a promising therapeutic target. Despite its biomedical relevance, basic aspects of PDPN biology such as its cellular functions and cell surface ligands remain poorly uncharacterized, thus challenging drug development. Here, we utilize a high throughput platform to elucidate the PDPN cell surface interactome, and uncover the neutrophil protein CD177 as a new binding partner. Quantitative proteomics analysis of the CAF phosphoproteome reveals a role for PDPN in cell signaling, growth and actomyosin contractility, among other processes. Moreover, cellular assays demonstrate that CD177 is a functional antagonist, recapitulating the phenotype observed in PDPN-deficient CAFs. In sum, starting from the unbiased elucidation of the PDPN co-receptome, our work provides insights into PDPN functions and reveals the PDPN/CD177 axis as a possible modulator of fibroblast physiology in the tumor microenvironment.

Epithelial ovarian cancer (EOC) has a 5-year relative survival of 50%, partly because markers of early-stage disease are not available in current clinical diagnostics. The aim of the present study was to investigate whether EOC is associated with transcriptional profiles in blood collected up to 7 years before diagnosis. For this, we used RNA-stabilized whole blood, which contains circulating immune cells, from a sample of EOC cases from the population-based Norwegian Women and Cancer (NOWAC) postgenome cohort. We explored case-control differences in gene expression in all EOC (66 case-control pairs), as well as associations between gene expression and metastatic EOC (56 pairs), serous EOC (45 pairs, 44 of which were metastatic), and interval from blood sample collection to diagnosis (≤3 or >3 years; 34 and 31 pairs, respectively). Lastly, we assessed differential expression of genes associated with EOC in published functional genomics studies that used blood samples collected from newly diagnosed women. After adjustment for multiple testing, this nested case-control study revealed no significant case-control differences in gene expression in all EOC (false discovery rate q>0.96). With the exception of a few probes, the log2 fold change values obtained in gene-wise linear models were below ±0.2. P-values were lowest in analyses of metastatic EOC (80% of which were serous EOC). No common transcriptional profile was indicated by interval to diagnosis; when comparing the 100 genes with the lowest p-values in gene-wise tests in samples collected ≤3 and >3 years before EOC diagnosis, no overlap in these genes was observed. Among 86 genes linked to ovarian cancer in previous publications, our data contained expression values for 42, and of these, tests of LIME1, GPR162, STAB1, and SKAP1, resulted in unadjusted p

ObjectiveThis explorative study aimed to assess if there are any time-dependent blood gene expression changes during the first one to eight years after breast cancer diagnosis, which can be linked to the clinical outcome of the disease.Material and methodsA random distribution of follow-up time from breast cancer diagnosis till blood sampling was obtained by a nested, matched case-control design in the Norwegian Women and Cancer Post-genome Cohort. From 2002-5, women were invited to donate blood samples, regardless of any cancer diagnosis. At end of the study period in 2015, any cancer diagnoses in the 50 000 participants were obtained via linkage to the Norwegian Cancer Registry. For each breast cancer patient (n = 415), an age- and storage time-matched control was drawn. The design gave a uniform, random length of follow-up time, independent of cancer stage. Differences in blood gene expression between breast cancer cases and controls were identified using the Bioconductor R-package limma, using a moving window in time, to handle the varying time elapsed from diagnosis to blood sample.ResultsThe number of differentially expressed genes between cases and controls were close to 2,000 in the first year after diagnosis, but fell sharply the second year. During the next years, a transient second increase was observed, but only in women with metastatic disease who later died, both compared to invasive cases that survived (pConclusionThis explorative analysis identified changing trajectories in the years after diagnosis, depending on clinical stage. Hypothetically, this could represent the escape of the metastatic cancer from the immune system.

BackgroundThe aim of this study was to evaluate whether surgeons´ experience and perioperative single-shot antibiotic prophylaxis affect outcome of patients undergoing stapes surgery.Patients and methodsWe retrospectively evaluated audiological outcomes and postoperative complications of 538 consecutive patients who underwent stapes surgery at a single tertiary referral center between 1990 and 2017. Effects of different clinical variables, including single-shot antibiotic prophylaxis and surgeons' experience on outcome were assessed.Results538 patients underwent 667 stapedotomies and postoperative complication rate was 7.5% (n = 50). Air conduction and air-bone gap closure improved significantly after surgery (14.2 ± 14.8 dB, p = 0.001; 14.5 ± 12.8 dB, p = 0.001). Multivariate analysis revealed that 6 years or less of surgical experience was independently associated with a higher incidence of persisting or recurrent conductive hearing loss (p = 0.033, OR 5.13) but perioperative application of antibiotics had no significant effect on outcome.ConclusionFirst, clinical outcome regarding persisting or recurrent conductive hearing loss caused by incus necrosis and prosthesis luxation is linked to surgical performance. This underlines the need for a meticulous training and supervision of less experienced surgeons performing stapes surgery. Second, our results do not support the need for perioperative antibiotic prophylaxis in stapes surgery. Potential standard limitations of retrospective cohort studies (selection bias, confusion bias etc.) could play a role in interpreting our results. However, the probability for these limitations is minimized due to the large patient sample.

Infection with parasitic copepod salmon louse Lepeophtheirus salmonis, represents one of the most important limitations to sustainable Atlantic salmon (Salmo salar L.) farming today in the North Atlantic region. The parasite exerts negative impact on health, growth and welfare of farmed fish as well as impact on wild salmonid populations. It is therefore central to ensure continuous low level of salmon lice with the least possible handling of the salmon and drug use. To address this, vaccination is a cost-effective and environmentally friendly control approach. In this study, efficacy of a vaccine candidate, containing a peptide derived from ribosomal protein P0, was validated post infestation with L. salmonis, at the lab-scale. The sampling results showed good potential of the vaccine candidate when administered intraperitoneally in the host, in reducing the ectoparasite load, through reduction of adult female lice counts and fecundity and with greater presumptive effect in F1 lice generation. The sampling results correlated well with the differential modulation of pro-inflammatory, Th1, Th2 and T regulatory mediators at the transcript level at different lice stages. Overall, the results supports approximately 56% efficacy when administered by intraperitoneal injection. However, additional validation is necessary under large-scale laboratory trial for further application under field conditions.

When non-linear models are fitted to experimental data, parameter estimates can be poorly constrained albeit being identifiable in principle. This means that along certain paths in parameter space, the log-likelihood does not exceed a given statistical threshold but remains bounded. This situation, denoted as practical non-identifiability, can be detected by Monte Carlo sampling or by systematic scanning using the profile likelihood method. In contrast, any method based on a Taylor expansion of the log-likelihood around the optimum, e.g., parameter uncertainty estimation by the Fisher Information Matrix, reveals no information about the boundedness at all. In this work, we present a geometric approach, approximating the original log-likelihood by geodesic coordinates of the model manifold. The Christoffel Symbols in the geodesic equation are fixed to those obtained from second order model sensitivities at the optimum. Based on three exemplary non-linear models we show that the information about the log-likelihood bounds and flat parameter directions can already be contained in this local information. Whereas the unbounded case represented by the Fisher Information Matrix is embedded in the geometric framework as vanishing Christoffel Symbols, non-vanishing constant Christoffel Symbols prove to define prototype non-linear models featuring boundedness and flat parameter directions of the log-likelihood. Finally, we investigate if those models could allow to approximate and replace computationally expensive objective functions originating from non-linear models by a surrogate objective function in parameter estimation problems.

Selective targeting of cancer-associated fibroblasts (CAFs) has been proposed to synergize with immune-checkpoint inhibitors. While the roles of CAFs in cancer development are well described, their immune-regulatory properties remain incompletely understood. This study investigates correlations between CAF and immune-markers in tumor stroma from non-small cell lung cancer (NSCLC) patients, and examines whether a combination of CAF and immune cell scores impact patient prognosis.Tumor specimens from 536 primary operable stage I-III NSCLC patients were organized in tissue microarrays. Expression of protein-markers was evaluated by immunohistochemistry.Fibroblast and stromal markers PDGFRα, PDGFRβ, FAP-1 and vimentin showed weak correlations while αSMA, and Masson's trichrome did not correlate with any of the investigated markers. Hierarchical clustering indicated the existence of different CAF-subsets. No relevant correlations were found between any CAF-marker and the immune-markers CD3, CD4, CD8, CD20, CD68, CD1a, CD56, FoxP3 and CD45RO. High density of fibroblast-activation protein positive mesenchymal cells (CAFFAP) was associated with better prognosis in tumors with high infiltration of CD8 and CD3 T-lymphocytes.The presented data suggest that CAFs, irrespective of identity, have low influence on the degree of tumor infiltration by inflammatory- and/or immune-cells. However, CAFFAP may exert immuno-adjuvant roles in NSCLC, and targeting CAFs should be cautiously considered.

The important process of nutrient uptake in Escherichia coli, in many cases, involves transit of the nutrient through a class of beta-barrel proteins in the outer membrane known as TonB-dependent transporters (TBDTs) and requires interaction with the inner membrane protein TonB. Here we have imaged the mobility of the ferric enterobactin transporter FepA and TonB by tracking them in the membranes of live E. coli with single-molecule resolution at time-scales ranging from milliseconds to seconds. We employed simple simulations to model/analyze the lateral diffusion in the membranes of E.coli, to take into account both the highly curved geometry of the cell and artifactual effects expected due to finite exposure time imaging. We find that both molecules perform confined lateral diffusion in their respective membranes in the absence of ligand with FepA confined to a region [Formula: see text] μm in radius in the outer membrane and TonB confined to a region [Formula: see text] μm in radius in the inner membrane. The diffusion coefficient of these molecules on millisecond time-scales was estimated to be [Formula: see text] μm2/s and [Formula: see text] μm2/s for FepA and TonB, respectively, implying that each molecule is free to diffuse within its domain. Disruption of the inner membrane potential, deletion of ExbB/D from the inner membrane, presence of ligand or antibody to FepA and disruption of the MreB cytoskeleton was all found to further restrict the mobility of both molecules. Results are analyzed in terms of changes in confinement size and interactions between the two proteins.

The tumor proliferation index marker Ki-67 is strongly associated with tumor cell proliferation, growth and progression, and is widely used in routine clinicopathological investigation. Prostate cancer is a complex multifaceted and biologically heterogeneous disease, and overtreatment of localized, low volume indolent tumors, is evident. Here, we aimed to assess Ki-67 expression and related outcomes of 535 patients treated with radical prostatectomy. The percentage of tumor epithelial cells expressing Ki-67 was determined by immunohistochemical assay, both digital image analysis and visual scoring by light microscope were used for quantification. The association of Ki-67 and prostate cancer was evaluated, as well as its prognostic value. There was a positive correlation between high expression of Ki-67 and Gleason score > 7 (p < 0.001) as well as tumor size (≥ 20 mm, p = 0.03). In univariate analyses, a high expression of Ki-67 in tumor epithelium was significantly associated with biochemical failure (BF) (digital scoring, p = 0.014) and (visual scoring, p = 0.004). In the multivariate analyses, a high level of Ki-67 was an independent poor prognostic factor for biochemical failure-free survival (BFFS) (Visual scoring, Ki67, p = 0.012, HR:1.50, CI95% 1.10-2.06). In conclusion, high Ki-67 expression is an independent negative prognostic marker for biochemical failure. Our findings support the role of Ki-67 as a significant, poor prognostic factor for in prostate cancer outcome.

MicroRNAs (miRNAs) are small non-coding RNAs that function as post-transcriptional regulators of gene expression and are dysregulated in cancer. Studies of miRNAs to explore their potential as diagnostic and prognostic markers are of great scientific interest. Here, we investigate the functional properties and expression of the miR-143/145 cluster in breast cancer (BC) in vitro and in vivo. The ER positive MCF7, the HER2 positive SK-BR-3, and the triple negative cell line MDA-MB-231 were used to assess cell proliferation and cell invasion. Expression of miRNA in 108 breast cancers in the Norwegian Women and Cancer Study and 44 benign tissue controls were analyzed by microarray and validated by RT-PCR. Further, in situ hybridization (ISH) was used to study the cellular and subcellular distribution of the miRNAs. In vitro, miR-143 promoted proliferation of MCF7 and MDA-MB-231 cells, whereas miR-145 and the cotransfection of both miRNAs inhibited proliferation in all three cell lines. The cells' invasive capacity was reduced after transfection and cotransfection of the miRNAs. In line with the tumor suppressive functions in vitro, the expression of miR-143 and miR-145 was lower in malignant compared to benign breast tissue, and lower in the more aggressive tumors with higher tumor grade, loss of ER and the basal-like phenotype. ISH revealed miR-143 to be cytoplasmatic and predominantly expressed in luminal cells in benign tissue, whilst miR-145 was nuclear and with strong staining in myoepithelial cells. Both miRNAs were present in malignant epithelial cells and stromal fibroblasts in BC. This study demonstrates that miR-143 and -145 have functional properties and expression patterns typical for tumor suppressors, but the function is influenced by cellular factors such as cell type and miRNA cotransfection. Further, the nuclear functions of miR-145 should be explored for a more complete understanding of the complexity of miRNA regulation and function in BC.

Our main objective was to investigate the association between duration of active labor and severe postpartum hemorrhage. We examined the effect of the total duration of active labor, the effect of each stage of active labor, and the gradient effect of duration of labor on severe postpartum hemorrhage.A case-control study was generated from a source population of all women admitted for delivery at Oslo University Hospital and Drammen Hospital in Buskerud municipality during the time period January 1, 2008 to December 31, 2011. The study population included all cases of severe postpartum hemorrhage (n = 859) and a random sample of controls (n = 1755). Severe postpartum hemorrhage was defined as postpartum blood loss ≥1500 mL or need for blood transfusion. Prolonged labor was defined as duration of active labor >12 hours according to the definition of the World Health Organization. We used logistic multivariable regression in the analysis.We observed a significantly longer mean duration of labor in women who experienced severe postpartum hemorrhage compared to controls (5.4 versus 3.8 hours, p12 hours (adjusted odds ratio = 2.44, 95% confidence interval: 1.69-3.53, p< 0.001).Prolonged active labor (duration >12 hours) was associated with severe postpartum hemorrhage. Increased vigilance seems required when the labor is prolonged to reduce the risk of severe postpartum hemorrhage.

To compare the efficacy of silver in situ hybridization (SISH) and immunohistochemistry (IHC) in detecting MET and IGF1R alterations and to investigate their prevalence and prognostic significance. A possible correlation between MET receptor expression, MET gene alterations and the two most frequent occurring EGFR gene mutations was also investigated.Stage I to IIIA tumors from 326 patients with NSCLC were immunohistochemically tested for protein expression of MET and IGF-1. Their cytoplasmic expression was compared with the gene copy number of the MET and IGF1Rgenes by SISH in paraffin-embedded, formalin-fixed material. Correlations were made with the immunohistochemical expression of two frequent EGFR mutations and clinicopathological variables. Univariate and multivariate survival analyses was used to evaluate the prognostic efficacy of the tested markers.In univariate analyses, high cytoplasmic MET expression showed a significant negative prognostic effect in adenocarcinoma patients (p = 0.026). MET gene to chromosome 7 ratio was a significant positive prognostic marker (p = 0.005), probably only due to the highly negative prognostic significance of chromosome 7 polysomy (p = 0.002). High IGF1R gene copy number was a negative prognostic marker for all NSCLC patients (p = 0.037). In the multivariate analysis, polysomy of chromosome 7 in tumor cells correlated significantly and independently with a poor prognosis (p = 0.011). In patients with adenocarcinoma, a high cytoplasmic MET expression was an independent negative prognostic marker (p = 0.013). In males a high IGF1R gene copy number to chromosome 15 count ratio was significantly and independently correlated to a poor prognosis (p = 0.018).MET protein expression provides superior prognostic information compared with SISH. Polysomy of chromosome 7 is an independent negative prognostic factor in NSCLC patients. This finding has an important implication while examining genes located on chromosome 7 by means of SISH. High IGF1R gene copy number to chromosome 15 count ratio is an independent predictor of inferior survival in male patients with primary NSCLC.

Maternal influenza infection during pregnancy is associated with increased risk of morbidity and mortality. However, the link between the anti-influenza immune responses and health-related risks during infection is not well understood. We have analyzed memory T and NK cell mediated immunity (CMI) responses in pandemic influenza A(H1N1)pdm09 (pdm09) virus infected non-vaccinated pregnant women participating in the Norwegian Influenza Pregnancy Cohort (NorFlu). The cohort includes information on immunization, self-reported health and disease status, and biological samples (plasma and PBMC). Infected cases (N = 75) were defined by having a serum hemagglutination inhibition (HI) titer > = 20 to influenza pdm09 virus at the time of delivery, while controls (N = 75) were randomly selected among non-infected pregnant women (HI titer

Prostate cancer (PC) stratification needs new prognostic tools to reduce overtreatment. Phosphatase of regenerating liver (PRL-3) is a phosphatase found at high levels in several cancer types, where its expression is associated with survival. A recent PC cell line study has shown it to be involved in PC growth and migration.We used a monoclonal antibody to evaluate the expression of PRL-3 in PC tissue of patients in an unselected cohort of 535 prostatectomy patients. We analyzed associations between PRL-3 expression and biochemical failure-free survival (BFFS), clinical failure-free survival (CFFS) and PC death-free survival (PCDFS).Cytoplasmic PRL-3 staining in tumor cells was significantly correlated to expression of molecules in the VEGFR-axis, but not to the clinicopathological variables. High PRL-3 was not significantly associated with survival in the univariate analysis for BFFS (p = 0.131), but significantly associated with CFFS (p = 0.044) and PCDFS (p = 0.041). In multivariate analysis for the various end points, PRL-3 came out as an independent and significant indicator of poor survival for BFFS (HR = 1.53, CI95% 1.10-2.13, p = 0.012), CFFS (HR = 2.41, CI95% 1.17-4.98, p = 0.017) and PCDFS (HR = 3.99, CI95% 1.21-13.1, p = 0.023).PRL-3 is independently associated with all PC endpoints in this study. Since high PRL-3 expression also correlates with poor prognosis in other cancers and functional studies in PC support these findings, PRL-3 emerges as a potential treatment target in PC.

Precursor-B cell receptor (pre-BCR) signaling represents a crucial checkpoint at the pre-B cell stage. Aberrant pre-BCR signaling is considered as a key factor for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) development. BCP-ALL are believed to be arrested at the pre-BCR checkpoint independent of pre-BCR expression. However, the cellular stage at which BCP-ALL are arrested and whether this relates to expression of the pre-BCR components (IGHM, IGLL1 and VPREB1) is still unclear. Here, we show differential protein expression and copy number variation (CNV) patterns of the pre-BCR components in pediatric BCP-ALL. Moreover, analyzing six BCP-ALL data sets (n = 733), we demonstrate that TCF3-PBX1 ALL express high levels of IGHM, IGLL1 and VPREB1, and are arrested at the pre-B stage. By contrast, ETV6-RUNX1 ALL express low levels of IGHM or VPREB1, and are arrested at the pro-B stage. Irrespective of subtype, ALL with high levels of IGHM, IGLL1 and VPREB1 are arrested at the pre-B stage and correlate with good prognosis in high-risk pediatric BCP-ALL (n = 207). Our findings suggest that BCP-ALL are arrested at different cellular stages, which relates to the expression pattern of the pre-BCR components that could serve as prognostic markers for high-risk pediatric BCP-ALL patients.

Here, we investigate induction of immunological tolerance by lentiviral based gene therapy in a mouse model of rheumatoid arthritis, collagen II-induced arthritis (CIA). Targeting the expression of the collagen type II (CII) to antigen presenting cells (APCs) induced antigen-specific tolerance, where only 5% of the mice developed arthritis as compared with 95% of the control mice. In the CII-tolerized mice, the proportion of Tregs as well as mRNA expression of SOCS1 (suppressors of cytokine signaling 1) increased at day 3 after CII immunization. Transfer of B cells or non-B cell APC, as well as T cells, from tolerized to naïve mice all mediated a certain degree of tolerance. Thus, sustainable tolerance is established very early during the course of arthritis and is mediated by both B and non-B cells as APCs. This novel approach for inducing tolerance to disease specific antigens can be used for studying tolerance mechanisms, not only in CIA but also in other autoimmune diseases.

BackgroundProstate cancer is a highly heterogeneous disease and one of the leading causes of mortality in developed countries. Specific prognostic and predictive markers for prostate cancer patients are still lacking. A causal relationship between androgens and the development of prostate cancer is generally considered biologically plausible, but androgens are not the sole effector in the complexity of prostate carcinogenesis. The aim of this study was to evaluate the prognostic significance of progesterone receptor in tumor tissue of T1-3N0 prostate cancer patients undergoing prostatectomy.MethodsTissue microarrays from 535 patients with prostate cancer were constructed. Duplicate cores of tumor cells and tumor stromal tissue from each resected specimen were extracted. Immunohistochemistry was used to evaluate the in-situ expression of progesterone receptor.ResultsIn univariate analyses, high tumor cell density (p = 0.006) and high tumor stromal cell density level (p = 0.045) of progesterone receptor were both significantly associated with tumor progression and clinical failure. In multivariate analysis, progesterone receptor expression in tumor cells was an independent negative prognostic factor for clinical failure (HR: 2.5, 95% CI: 1.2-5.2, p = 0.012).ConclusionHigh progesterone receptor density in tumor cells of the prostate cancer tumor is an independent negative prognostic factor for clinical failure.

BackgroundCancer Associated Fibroblasts (CAFs) are thought to regulate tumor growth and metastasis. Fibroblast Activating Protein 1 (FAP-1) is a marker for fibroblast activation and by many recognized as the main marker of CAFs. Alpha Smooth Muscle Actin (α-SMA) is a general myofibroblast marker, and can be used to identify CAFs. This study investigates the prognostic impact of FAP-1 and α-SMA in non-small cell lung cancer (NSCLC) patients and correlates their expression to 105 proteins investigated in the same cohort.MethodsTumor specimens from 536 NSCLC patients were obtained and tissue micro-arrays were constructed. Immunohistochemistry was used to evaluate the expression of FAP-1 and α-SMA and explore their impact on survival and association with other tumor molecular markers in NSCLC patients.ResultsHigh expression of FAP-1, but not α-SMA, in squamous cell carcinoma (SCC, P = 0.043, HR = 0.63 95% CI 0.40-0.99) was significantly associated with increased disease-specific survival. FAP-1 and α-SMA were not significantly correlated to each other. Analyses of FAP-1 and α-SMA associated with other tumor-related proteins revealed histotype-specific correlation patterns.ConclusionThe presence of FAP-1 expressing CAFs is an indicator of positive outcome for NSCLC-SCC patients. In addition, correlation analyses suggest FAP-1 and α-SMA to label different subsets of fibroblasts and their associations with other tumor-related proteins diverge according to histological subtype.

In non-small cell lung cancer (NSCLC), nodal metastasis is an adverse prognostic factor. Several mediating factors have been implied in the development of nodal metastases and investigated for predictive and prognostic properties in NSCLC. However, study results differ. In this structured review and meta-analysis we explore the published literature on commonly recognized pathways for molecular regulation of lymphatic metastasis in NSCLC.A structured PubMed search was conducted for papers reporting on the expression of known markers of lymhangiogenesis in NSCLC patients. Papers of sufficient quality, presenting survival and/or correlation data were included.High levels of vascular endothelial growth factor C (VEGF-C, HR 1.57 95% CI 1.34-1.84) and high lymphatic vascular density (LVD, HR 1.84 95% CI 1.18-2.87) were significant prognostic markers of poor survival and high expression of VEGF-C, vascular endothelial growth factor receptor 3 (VEGFR3) and LVD was associated with lymph node metastasis in NSCLC.Lymphangiogenic markers are prognosticators of survival and correlate with lymph node metastasis in NSCLC. Their exact role and clinical implications should be further elucidated.

Perturbation of endoplasmic reticulum (ER) homeostasis triggers the ER stress response (also known as Unfolded Protein Response), a hallmark of many pathological disorders. However the connection between ER stress and inflammation remains largely unexplored. Recent data suggest that ER stress controls the activity of inflammasomes, key signaling platforms that mediate innate immune responses. Here we report that expression of NLRP1, a core inflammasome component, is specifically up-regulated during severe ER stress conditions in human cell lines. Both IRE1α and PERK, but not the ATF6 pathway, modulate NLRP1 gene expression. Furthermore, using mutagenesis, chromatin immunoprecipitation and CRISPR-Cas9-mediated genome editing technology, we demonstrate that ATF4 transcription factor directly binds to NLRP1 promoter during ER stress. Although involved in different types of inflammatory responses, XBP-1 splicing was not required for NLRP1 induction. This study provides further evidence that links ER stress with innate.

INTRODUCTION: Monocarboxylate transporters (MCTs) 1-4 are lactate transporters crucial for cancers cells adaption to upregulated glycolysis. Herein, we aimed to explore their prognostic impact on disease-specific survival (DSS) in both cancer and tumor stromal cells in NSCLC. METHODS: Tissue micro arrays (TMAs) were constructed, representing both cancer and stromal tumor tissue from 335 unselected patients diagnosed with stage I-IIIA NSCLC. Immunohistochemistry was used to evaluate the expression of MCT1-4. RESULTS: In univariate analyses; ↓ MCT1 (P = 0.021) and ↑ MCT4 (P = 0.027) expression in cancer cells, and ↑ MCT1 (P = 0.003), ↓ MCT2 (P = 0.006), ↓ MCT3 (P = 0.020) expression in stromal cells correlated significantly with a poor DSS. In multivariate analyses; ↓ MCT1 expression in cancer cells (HR: 1.9, CI 95%: 1.3-2.8, P = 0.001), ↓ MCT2 (HR: 2.4, CI 95%: 1.5-3.9, P

After measles vaccine (MV), all-cause mortality is reduced more than can be explained by the prevention of measles, especially in females.We aimed to study the biological mechanisms underlying the observed non-specific and sex-differential effects of MV on mortality.Within a large randomised trial of MV at 4.5 months of age blood samples were obtained before and six weeks after randomisation to early MV or no early MV. We measured concentrations of cytokines and soluble receptors from plasma (interleukin-1 receptor agonist (IL-1Ra), IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, soluble urokinase-type plasminogen activator receptor), and secreted cytokines (interferon-γ, TNF-α, IL-5, IL-10, IL-13, IL-17) after in vitro challenge with innate agonists and recall antigens. We analysed the effect of MV in multiple imputation regression, overall and stratified by sex. The majority of the infants had previously been enrolled in a randomised trial of neonatal vitamin A. Post hoc we explored the potential effect modification by neonatal vitamin A.Overall, MV versus no MV was associated with higher plasma MCP-1 levels, but the effect was only significant among females. Additionally, MV was associated with increased plasma IL-1Ra. MV had significantly positive effects on plasma IL-1Ra and IL-8 levels in females, but not in males. These effects were strongest in vitamin A supplemented infants. Vitamin A shifted the effect of MV in a pro-inflammatory direction.In this explorative study we found indications of sex-differential effects of MV on several of the plasma biomarkers investigated; in particular MV increased levels in females, most strongly in vitamin A recipients. The findings support that sex and micronutrient supplementation should be taken into account when analysing vaccine effects.clinicaltrials.gov number NCT 00168545.

Receptor tyrosine kinase-like orphan receptors (ROR) 1 and 2 are atypical members of the receptor tyrosine kinase (RTK) family and have been associated with several human diseases. The vertebrate RORs contain an ATP binding domain that deviates from the consensus amino acid sequence, although the impact of this deviation on catalytic activity is not known and the kinase function of these receptors remains controversial. Recently, ROR2 was shown to signal through a Wnt responsive, β-catenin independent pathway and suppress a canonical Wnt/β-catenin signal. In this work we demonstrate that both ROR1 and ROR2 kinase domains are catalytically deficient while CAM-1, the C. elegans homolog of ROR, has an active tyrosine kinase domain, suggesting a divergence in the signaling processes of the ROR family during evolution. In addition, we show that substitution of the non-consensus residues from ROR1 or ROR2 into CAM-1 and MuSK markedly reduce kinase activity, while restoration of the consensus residues in ROR does not restore robust kinase function. We further demonstrate that the membrane-bound extracellular domain alone of either ROR1 or ROR2 is sufficient for suppression of canonical Wnt3a signaling, and that this domain can also enhance Wnt5a suppression of Wnt3a signaling. Based on these data, we conclude that human ROR1 and ROR2 are RTK-like pseudokinases.

Computational prediction of ligand entry and egress paths in proteins has become an emerging topic in computational biology and has proven useful in fields such as protein engineering and drug design. Geometric tunnel prediction programs, such as Caver3.0 and MolAxis, are computationally efficient methods to identify potential ligand entry and egress routes in proteins. Although many geometric tunnel programs are designed to accommodate a single input structure, the increasingly recognized importance of protein flexibility in tunnel formation and behavior has led to the more widespread use of protein ensembles in tunnel prediction. However, there has not yet been an attempt to directly investigate the influence of ensemble size and composition on geometric tunnel prediction. In this study, we compared tunnels found in a single crystal structure to ensembles of various sizes generated using different methods on both the apo and holo forms of cytochrome P450 enzymes CYP119, CYP2C9, and CYP3A4. Several protein structure clustering methods were tested in an attempt to generate smaller ensembles that were capable of reproducing the data from larger ensembles. Ultimately, we found that by including members from both the apo and holo data sets, we could produce ensembles containing less than 15 members that were comparable to apo or holo ensembles containing over 100 members. Furthermore, we found that, in the absence of either apo or holo crystal structure data, pseudo-apo or -holo ensembles (e.g. adding ligand to apo protein throughout MD simulations) could be used to resemble the structural ensembles of the corresponding apo and holo ensembles, respectively. Our findings not only further highlight the importance of including protein flexibility in geometric tunnel prediction, but also suggest that smaller ensembles can be as capable as larger ensembles at capturing many of the protein motions important for tunnel prediction at a lower computational cost.

The expanding roles of PCNA in functional assembly of DNA replication and repair complexes motivated investigation of the structural and dynamic properties guiding specificity of PCNA-protein interactions. A series of biochemical and computational analyses were combined to evaluate the PIP Box recognition features impacting complex formation. The results indicate subtle differences in topological and molecular descriptors distinguishing both affinity and stoichiometry of binding among PCNA-peptide complexes through cooperative effects. These features were validated using peptide mimics of p85α and Akt, two previously unreported PCNA binding partners. This study characterizes for the first time a reverse PIP Box interaction with PCNA. Small molecule ligand binding at the PIP Box interaction site confirmed the adaptive nature of the protein in dictating overall shape and implicates allosterism in transmitting biological effects.

AimmicroRNAs (miRNAs) are involved in various neoplastic diseases, including prostate cancer (PCs). The aim of this study was to investigate the miRNA profile in PC tissue, to assess their association with clinicopathologic data, and to evaluate the potential of miRNAs as diagnostic and prognostic markers.Materials and methodsFrom a cohort of 535 patients submitted to radical prostatectomy (RP), a sample of 30 patients (14 patients with rapid biochemical failure (BF) and 16 patients without BF) with Gleason score 7 were analyzed. A total of 1435 miRNAs were quantified by microarray hybridization, and selected miRNAs with the highest Standard deviation (n = 50) were validated by real-time quantitative PCR (qRT-PCR). In situ hybridization (ISH) was used to evaluate the expression of miR-21.ResultsmiR-21 was the only miR that was significantly up-regulated in the BF group (p = 0.045) miR-21 was up-regulated in patients with BF compared with non-BF group (p = 0.05). In univariate analyses, high stromal expression of miR-21 had predictive impact on biochemical failure-free survival (BFFS) and clinical failure-free survival (CFFS) (p = 0.006 and p = 0.04, respectively). In the multivariate analysis, high stromal expression of miR-21 expression was found to be an independent prognostic factor for BFFS in patients with Gleason score 6 (HR 2.41, CI 95% 1.06-5.49, p = 0.037).ConclusionHigh stromal expression of miR-21 was associated with poor biochemical recurrence-free survival after RP. For patients with Gleason score 6, miR-21 may help predict the risk of future disease progression and thereby help select patients for potential adjuvant treatment or a more stringent follow-up.

The cellular arm of the insect immune response is mediated by the activity of hemocytes. While hemocytes have been well-characterized morphologically and functionally in model insects, few studies have characterized the hemocytes of non-model insects. Further, the role of ontogeny in mediating immune response is not well understood in non-model invertebrate systems. The goals of the current study were to (1) determine the effects of caterpillar size (and age) on hemocyte density in naïve caterpillars and caterpillars challenged with non-pathogenic bacteria, and (2) characterize the hemocyte activity and diversity of cell types present in two forest caterpillars: Euclea delphinii and Lithacodes fasciola (Limacodidae). We found that although early and late instar (small and large size, respectively) naïve caterpillars had similar constitutive hemocyte densities in both species, late instar Lithacodes caterpillars injected with non-pathogenic E. coli produced more than a twofold greater density of hemocytes than those in early instars. We also found that both caterpillar species contained plasmatocytes, granulocytes and oenocytoids, all of which are found in other lepidopteran species, but lacked spherulocytes. Granulocytes and plasmatocytes were found to be strongly phagocytic in both species, but granulocytes exhibited a higher phagocytic activity than plasmatocytes. Our results strongly suggest that for at least one measure of immunological response, the production of hemocytes in response to infection, response magnitudes can increase over ontogeny. While the underlying raison d' être for this improvement remains unclear, these findings may be useful in explaining natural patterns of stage-dependent parasitism and pathogen infection.

CD23, the low affinity receptor for immunoglobulin E (IgE), has been proposed to play a critical role in the regulation of IgE production, based on altered IgE levels in CD23-deficient mice and transgenic mouse models, as well as in mouse strains with mutations in the CD23 gene, e.g. 129 substrains. Here, we have investigated a mouse line termed LxT1 that expresses reduced CD23 surface levels on B cells, and its influence on natural IgE production. Extensive phenotypic analysis showed that CD23 surface expression was reduced in LxT1 compared to the control, without affecting B cell development in general. This CD23(low) surface level in LxT1 mice is not as a result of reduced CD23 mRNA expression levels or intracellular accumulation, but linked to a recessive locus, a 129-derived region spanning 28 Mb on chromosome 8, which includes the CD23 gene. Sequence analysis confirmed five mutations within the CD23 coding region in LxT1 mice, the same as those present in New Zealand Black (NZB) and 129 mice. However, this CD23(low) phenotype was not observed in all 129 substrains despite carrying these same CD23 mutations in the coding region. Moreover, serum IgE levels in LxT1 mice are as low as those in the C57BL/6 (B6) strain, and much lower than those in 129 substrains. These data indicate that the CD23 surface level and serum IgE level are uncoupled and that neither is directly regulated by the mutations within the CD23 coding region. This study suggests that caution should be taken when interpreting the immunological data derived from mice with different genetic background, especially if the gene of interest is thought to influence CD23 surface expression or serum IgE level.

MicroRNAs' dysregulation and profiling have been demonstrated to be clinically relevant in urothelial carcinoma (UC). Urine cytology is commonly used as the mainstay non-invasive test for secondary prevention and follow-up of UC patients. Ancillary tools are needed to support cytopathologists in the diagnosis of low-grade UC. The feasibility and reliability of microRNAs profiling by qRT-PCR analysis (miR-145 and miR-205) in archival routine urine cytology smears (affected by fixation/staining [Papanicolau] and room temperature storage) was tested in a series of 15 non-neoplastic and 10 UC urine specimens. Only samples with >5,000 urothelial cells and with