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Based on classical contagion models we introduce an artificial cyber lab: the digital twin of a complex cyber system in which possible cyber resilience measures may be implemented and tested. Using the lab, in numerical case studies, we identify two classes of measures to control systemic cyber risks: security‐ and topology‐based interventions. We discuss the implications of our findings on selected real‐world cybersecurity measures currently applied in the insurance and regulation practice or under discussion for future cyber risk control. To this end, we provide a brief overview of the current cybersecurity regulation and emphasize the role of insurance companies as private regulators. Moreover, from an insurance point of view, we provide first attempts to design systemic cyber risk obligations and to measure the systemic risk contribution of individual policyholders. [ABSTRACT FROM AUTHOR]

Port connectivity and trading community structure are two fundamental network characteristics that complement one another in explaining the evolution of maritime transport networks. Although port connectivity has been widely studied in the literature, the investigations on trading community structures are rather limited. To better fill this gap, this paper aims to provide a more complete picture of the Global Container Shipping Network (GCSN)'s evolution, based on our earlier works in MEL. In doing so, the GCSN, representing a snapshot of trade at the end of each quarter, from Q3/2011 to Q3/2017, is first constructed. The connectivity of ports and their respective trading communities are then extracted by the Container Port Connectivity Index and the Louvain algorithm, respectively. With our proposed framework, related players would be able to understand the growth of GCSN, as well as the impacts of maritime occurrences on the network of container shipping. Our computational results indicate that port connectivity and trading community structure gradually evolve according to the economic conditions that change over time and the evolution of GCSN could be well explained by these two explanatory variables. In this regard, ports in East Asia consistently dominate others in terms of both inbound and outbound connectivity, led by Shanghai and other major ports of mainland China. Furthermore, the formation of trading communities largely depends on trading patterns—rather than geographical locations—which is evident from the insolvency and mergers of communities in the North American region right after the expansion of the Panama Canal in 2016. [ABSTRACT FROM AUTHOR]

The paper provides a comprehensive overview of modeling and pricing cyber insurance and includes clear and easily understandable explanations of the underlying mathematical concepts. We distinguish three main types of cyber risks: idiosyncratic, systematic, and systemic cyber risks. While for idiosyncratic and systematic cyber risks, classical actuarial and financial mathematics appear to be well-suited, systemic cyber risks require more sophisticated approaches that capture both network and strategic interactions. In the context of pricing cyber insurance policies, issues of interdependence arise for both systematic and systemic cyber risks; classical actuarial valuation needs to be extended to include more complex methods, such as concepts of risk-neutral valuation and (set-valued) monetary risk measures. [ABSTRACT FROM AUTHOR]

Purpose: To compare sociodemographic, health- and exercise-related characteristics of participants vs. decliners, and completers vs. drop-outs, in an exercise intervention trial during cancer treatment. Methods: Patients with newly diagnosed breast, prostate, or colorectal cancer were invited to participate in a 6-month exercise intervention. Background data for all respondents (n = 2051) were collected at baseline by questionnaire and medical records. Additional data were collected using an extended questionnaire, physical activity monitors, and fitness testing for trial participants (n = 577). Moreover, a sub-group of decliners (n = 436) consented to additional data collection by an extended questionnaire. Data were analyzed for between-group differences using independent t-tests and chi2-tests. Results: Trial participants were younger (59 ± 12yrs vs. 64 ± 11yrs, p <.001), more likely to be women (80% vs. 75%, p =.012), and scheduled for chemotherapy treatment (54% vs. 34%, p <.001), compared to decliners (n = 1391). A greater proportion had university education (60% vs 40%, p <.001), reported higher anxiety and fatigue, higher exercise self-efficacy and outcome expectations, and less kinesiophobia at baseline compared to decliners. A greater proportion of trial participants were classified as 'not physically active' at baseline; however, within the group who participated, being "physically active" at baseline was associated with trial completion. Completers (n = 410) also reported less kinesiophobia than drop-outs (n = 167). Conclusion: The recruitment procedures used in comprehensive oncology exercise trials should specifically address barriers for participation among men, patients without university education and older patients. Individualized efforts should be made to enroll patients with low exercise self-efficacy and low outcome expectations of exercise. To retain participants in an ongoing exercise intervention, extra support may be needed for patients with kinesiophobia and those lacking health-enhancing exercise habits at baseline. [ABSTRACT FROM AUTHOR]

To assess treatment response (PSA < 0.2 ng/ml), need for additional therapy and complication rate after robot assisted salvage pelvic lymph node dissection (sPLND) Analysis of outcomes data from radical prostatectomy (RP) patients consecutively operated with robot assisted sPLND due to biochemical recurrence and positron-emission tomography (PET)/computed tomography (CT)-detected nodal recurrence of pelvic lymph nodes. Sixty-nine patients underwent robotic sPLND after a median time of 47 months post- RP. Sixty-four patients (93%) had malignant lymph nodes upon histological assessment of sPLND specimen. Twenty patients (29%) achieved PSA < 0.2 ng/ml 6 weeks postoperatively. After median (IQR) follow-up of 15 months (10–27), fourteen patients (20%) still had PSA < 0.2 ng/ml without additional therapy and forty-one patients (59%) had started additional therapy. No significant predictor for treatment response was found. Postoperative complications occurred in 14 patients (20%). Eleven of these complications were classified as Clavien-Dindo grade 1 Oncological benefit of sPLND as the only salvage procedure seems to be limited, though almost one third of patients achieved treatment response. Clinical trials are needed to determine if sPLND as part of a multimodal treatment may improve outcome. [ABSTRACT FROM AUTHOR]

The demographic shift toward an older population will increase the number of prostate cancer cases. A challenge in the treatment of prostate cancer is to avoid undertreatment of patients at high risk of progression following curative treatment. These men can benefit from early salvage treatment. An explorative cohort consisting of tissue from 16 patients who underwent radical prostatectomy, and were either alive or had died from prostate cancer within 10 years postsurgery, was analyzed by mass spectrometry analysis. Following proteomic and bioinformatic analyses, major vault protein (MVP) was identified as a putative prognostic biomarker. A publicly available tissue proteomics dataset and a retrospective cohort of 368 prostate cancer patients were used for validation. The prognostic value of the MVP was verified by scoring immunohistochemical staining of a tissue microarray. High level of MVP was associated with more than 4-fold higher risk for death from prostate cancer (hazard ratio = 4.41, 95% confidence interval: 1.45–13.38; P = 0.009) in a Cox proportional hazard models, adjusted for Cancer of the Prostate Risk Assessments Post-surgical (CAPRA-S) score and perineural invasion. Decision curve analyses suggested an improved standardized net benefit, ranging from 0.06 to 0.18, of adding MVP onto CAPRA-S score. This observation was confirmed by receiver operator characteristics curve analyses for the CAPRA-S score versus CAPRA-S and MVP score (area under the curve: 0.58 versus 0.73). From these analyses, one can infer that MVP levels in combination with CAPRA-S score might add onto established risk parameters to identify patients with lethal prostate cancer. [ABSTRACT FROM AUTHOR]

We consider the risk sharing problem for capital requirements induced by capital adequacy tests and security markets. The agents involved in the sharing procedure may be heterogeneous in that they apply varying capital adequacy tests and have access to different security markets. We discuss conditions under which there exists a representative agent. Thereafter, we study two frameworks of capital adequacy more closely, namely polyhedral constraints and distribution-based constraints. We prove existence of optimal risk allocations and equilibria within these frameworks and elaborate on their robustness. [ABSTRACT FROM AUTHOR]

This paper explores container port system evolution and port choice from the perspective of a regional or secondary (feeder and short sea) system. Theory predicts that large-scale container port systems tend towards concentration, rationalizing the number of ports, followed by deconcentration. By contrast, regional port systems remain under-researched. Such systems tend to retain their large number of small ports, as the alternative would be serving their long coastlines, small islands and sparse populations by long overland routes or not at all. Norway is a classic feeder and short sea market with a long coastline and dispersed population served by many small ports. The methodology utilizes concentration analysis and semi-structured interviews to explore if the Norwegian system conforms to theories of port concentration and port choice, including issues of regional port governance. Findings show that the Norwegian system demonstrates the same process of concentration and then deconcentration as major port ranges. However, its number of ports has not been rationalized, suggesting that such regional systems may indeed evolve differently to major port ranges. Nevertheless, ongoing discussion of reform in Norway towards regional port governance, similar to other European countries, may eventually result in such rationalization. [ABSTRACT FROM AUTHOR]

We show constructively that every quasi-convex, uniformly continuous function f:C→R with at most one minimum point has a minimum point, where C is a convex compact subset of a finite dimensional normed space. Applications include a result on strictly quasi-convex functions, a supporting hyperplane theorem, and a short proof of the constructive fundamental theorem of approximation theory. [ABSTRACT FROM AUTHOR]

We study the market implications of ambiguity sensitive preferences using the α-maxmin expected utility (α-MEU) model. In the standard Ellsberg framework, we prove that α-MEU preferences are equivalent to either maxmin, maxmax or subjective expected utility (SEU). We show how ambiguity aversion impacts equilibrium asset prices, and revisit the laboratory experimental findings in Bossaerts et al. (Rev Financ Stud 23:1325-1359, 2010). Only when there are three or more ambiguous states, α-MEU, maxmin, maxmax and SEU models induce different portfolio choices. We suggest criteria to discriminate among these models in laboratory experiments and show that ambiguity seeking agents may prevent the existence of market equilibrium. Our results indicate that ambiguity matters for portfolio choice and does not wash out in equilibrium. [ABSTRACT FROM AUTHOR]

In the framework of Bishop's constructive mathematics we introduce co-convexity as a property of subsets B of ${\left\{ {0,1} \right\}^{\rm{*}}}$ , the set of finite binary sequences, and prove that co-convex bars are uniform. Moreover, we establish a canonical correspondence between detachable subsets B of ${\left\{ {0,1} \right\}^{\rm{*}}}$ and uniformly continuous functions f defined on the unit interval such that B is a bar if and only if the corresponding function f is positive-valued, B is a uniform bar if and only if f has positive infimum, and B is co-convex if and only if f satisfies a weak convexity condition. [ABSTRACT FROM AUTHOR]

We provide a characterization in terms of Fatou closedness for weakly closed monotone convex sets in the space of P-quasisure bounded random variables, where P is a (possibly non-dominated) class of probability measures. Applications of our results lie within robust versions the Fundamental Theorem of Asset Pricing or dual representation of convex risk measures. [ABSTRACT FROM AUTHOR]

We consider families of strongly consistent multivariate conditional risk measures. We show that under strong consistency these families admit a decomposition into a conditional aggregation function and a univariate conditional risk measure as introduced Hoffmann et al. (Stoch Process Appl 126(7):2014-2037, 2016). Further, in analogy to the univariate case in Föllmer (Stat Risk Model 31(1):79-103, 2014), we prove that under law-invariance strong consistency implies that multivariate conditional risk measures are necessarily multivariate conditional certainty equivalents. [ABSTRACT FROM AUTHOR]

Background: Robust biomarkers that identify prostate cancer patients with high risk of recurrence will improve personalised cancer care. In this study, we investigated whether tissue metabolites detectable by high-resolution magic angle spinning magnetic resonance spectroscopy (HR-MAS MRS) were associated with recurrence following radical prostatectomy.Methods: We performed a retrospective ex vivo study using HR-MAS MRS on tissue samples from 110 radical prostatectomy specimens obtained from three different Norwegian cohorts collected between 2002 and 2010. At the time of analysis, 50 patients had experienced prostate cancer recurrence. Associations between metabolites, clinicopathological variables, and recurrence-free survival were evaluated using Cox proportional hazards regression modelling, Kaplan-Meier survival analyses and concordance index (C-index).Results: High intratumoural spermine and citrate concentrations were associated with longer recurrence-free survival, whereas high (total-choline+creatine)/spermine (tChoCre/Spm) and higher (total-choline+creatine)/citrate (tChoCre/Cit) ratios were associated with shorter time to recurrence. Spermine concentration and tChoCre/Spm were independently associated with recurrence in multivariate Cox proportional hazards modelling after adjusting for clinically relevant risk factors (C-index: 0.769; HR: 0.72; P=0.016 and C-index: 0.765; HR: 1.43; P=0.014, respectively).Conclusions: Spermine concentration and tChoCre/Spm ratio in prostatectomy specimens were independent prognostic markers of recurrence. These metabolites can be noninvasively measured in vivo and may thus offer predictive value to establish preoperative risk assessment nomograms. [ABSTRACT FROM AUTHOR]

Background:In patients with prostate cancer (PCa), the lack of clear guidelines on the use of radiotherapy after radical prostatectomy (RP) invites unwanted variation of this treatment. We describe the hazard ratios and probabilities related to the use of post-RP radiotherapy. Material and methods:Data were collected from the Cancer Registry of Norway and nine radiotherapy units. All patients were diagnosed with a non-metastatic PCa from January 2004 through June 2011.Adjuvant radiotherapywas defined as pelvic radiotherapy initiated <5 months after RP at a PSA <0.2 ng/ml. All other pelvic radiotherapy series were categorized assalvage radiotherapy, and, combined with adjuvant radiotherapy they were termedpost-RP radiotherapy. Results:Of 6840 prostatectomized patients, 1170 (17%) had undergone post-RP radiotherapy, mainly as salvage radiotherapy. The number of adjuvant radiotherapy series almost tripled from 2009. Based on pre-prostatectomy variables (PSA, Gleason score, and clinical risk group) and findings in the prostatectomy specimens (status of resection margins, pathological tumor category and Gleason’s score), the probability of post-RP radiotherapy ranged respectively from 14% to 73%, and from 4% to 83%. Conclusions:In our study, post-RP radiotherapy was applied in approximately one in six patients. Based on the combination of PCa-specific variables routinely available at the time of diagnosis, a patient’s probability of post-RP radiotherapy can be determinedbeforedecision of primary treatment strategy, followed by probability determination based on histopathological variables emerging from the prostatectomy specimen. [ABSTRACT FROM AUTHOR]

The prognostic value of CpG island methylator phenotype (CIMP) in colorectal cancer remains unsettled. We aimed to assess the prognostic value of this phenotype analyzing a total of 1126 tumor samples obtained from two Norwegian consecutive colorectal cancer series. CIMP status was determined by analyzing the 5-markers CAGNA1G, IGF2, NEUROG1, RUNX3 and SOCS1 by quantitative methylation specific PCR (qMSP). The effect of CIMP on time to recurrence (TTR) and overall survival (OS) were determined by uni- and multivariate analyses. Subgroup analyses were conducted according to MSI and BRAF mutation status, disease stage, and also age at time of diagnosis (<60, 60-74, ≥75 years). Patients with CIMP positive tumors demonstrated significantly shorter TTR and worse OS compared to those with CIMP negative tumors (multivariate hazard ratio [95% CI] 1.86 [1.31-2.63] and 1.89 [1.34-2.65], respectively). In stratified analyses, CIMP tumors showed significantly worse outcome among patients with microsatellite stable (MSS, P < 0.001), and MSS BRAF mutated tumors ( P < 0.001), a finding that persisted in patients with stage II, III or IV disease, and that remained significant in multivariate analysis ( P < 0.01). Consistent results were found for all three age groups. To conclude, CIMP is significantly associated with inferior outcome for colorectal cancer patients, and can stratify the poor prognostic patients with MSS BRAF mutated tumors. [ABSTRACT FROM AUTHOR]

We show constructively that every quasi-convex uniformly continuous function $$f : \mathrm {C}\rightarrow \mathbb {R}^+$$ has positive infimum, where $$\mathrm {C}$$ is a convex compact subset of $$\mathbb {R}^n$$ . This implies a constructive separation theorem for convex sets. [ABSTRACT FROM AUTHOR]

There is a great need to identify new and better prognostic and predictive biomarkers to stratify prostate cancer patients for optimal treatment. The aims of this study were to characterize the expression profile of pre-B cell leukemia homeobox (PBX) transcription factors in prostate cancer with an emphasis on investigating whether PBX3 harbours any prognostic value. The expression profile of PBX3 and PBX1 in prostate tissue was determined by immunohistochemical and immunoblot analysis. Furthermore, the expression of PBX3 transcript variants was analyzed by RT-PCR, NanoString Technologies®, and by analyzing RNA sequence data. The potential of PBX3 to predict prognosis, either at mRNA or protein level, was studied in four independent cohorts. PBX3 was mainly expressed in the nucleus of normal prostate basal cells, while it showed cytosolic expression in prostatic intraepithelial neoplasia and cancer cells. We detected four PBX3 transcript variants in prostate tissue. Competing risk regression analysis revealed that high PBX3 expression was associated with slower progression to castration resistant prostate cancer (sub-hazard ratio (SHR) 0.18, 95% CI: 0.081-0.42, p values < 0.001). PBX3 expression had a high predictive accuracy (area under the curve (AUC) = 0.82) when combined with Gleason score and age. Patients undergoing radical prostatectomy, with high levels of PBX3 mRNA, had improved prostate cancer specific survival compared to patients expressing low levels (SHR 0.21, 95% CI: 0.46-0.93, p values < 0.001, and AUC = 0.75). Our findings strongly indicate that PBX3 has potential as a biomarker, both as part of a larger gene panel and as an immunohistochemical marker, for aggressive prostate cancer. [ABSTRACT FROM AUTHOR]

Objective: The objective of the study was to evaluate the diagnostic accuracy of preoperative magnetic resonance imaging (MRI) for detecting uni- and bilateral extraprostatic disease (T3) in patients with prostate cancer (PCa). Materials and methods: This prospective study included 199 patients with biopsy-proven PCa who underwent MRI prior to radical prostatectomy from December 2009 to July 2012. Extraprostatic extension and seminal vesicle invasion represented T3 disease, and was classified as uni- (right or left) or bilateral. MRI detection of T3 disease was assessed by descriptive statistics and odds ratio (OR). Whole-mount histopathology was used as the reference standard. Results: The overall prevalence of pT3 was 105/199 (53 %), unilateral in 81/105 (77 %) and bilateral in 24/105 (23 %). The sensitivity of MRI for predicting pT3 was 76/105 (72 %), specificity 61/94 (65 %), accuracy 137/199 (69 %), and OR 4.8 (95 % CI 2.7-8.8). A complete match with respect to the laterality of pT3 was found in 52/105 (50 %), and the side-specific accuracy was 113/199 (57 %). When unilateral pT3 was found, MRI falsely suggested contralateral T3 in 4/81 (5 %) and bilateral in 8/81 (10 %). When bilateral pT3 was found, MRI falsely suggested unilateral T3 in 12/24 (50 %). Conclusion: Magnetic resonance imaging (MRI) detected 72 % of all patients with T3 disease, and the accuracy dropped from 69 to 57 % when considering the laterality of T3. Thus far, the MRI technique is not yet adequate to meet the increasing demands of accurate diagnosis of locally advanced disease, and the contemporary MRI staging should be careful. [ABSTRACT FROM AUTHOR]

Objective To examine the performance of T2-weighted ( T2W) and diffusion-weighted ( DW) magnetic resonance imaging ( MRI) for detecting the index tumour in patients with prostate cancer and to examine the agreement between MRI and histology when assessing tumour volume ( TV) and overall tumour burden. Patients and Methods The study included 199 consecutive patients with biopsy confirmed prostate cancer randomised to MRI before radical prostatectomy from December 2009 to July 2012. MRI-detected tumours ( MRTs) were ranked from 1 to 3 according to decreasing volume and were compared with histologically detected tumours ( HTs) ranked from 1 to 3, with HT 1 = index tumour. Whole-mount section histology was used as a reference standard. The TVs of true-positive MRTs ( MRTVs 1-3) were compared with the TVs found by histology ( HTVs 1-3). All tumours were registered on a 30-sector map and by classifying each sector as positive/negative, the rate of true-positive and -negative sectors was calculated. Results The detection rate for the HT 1 (index tumour) was 92%; HT 2, 45%; and HT 3, 37%. The MRTV 1-3 vs the HTV 1-3 were 2.8 mL vs 4.0 mL (index tumour, P < 0.001), 1.0 mL vs 0.9 mL (tumour 2, P = 0.413), and 0.6 mL vs 0.5 mL (tumour 3, P = 0.492). The rate of true-positive and -negative sectors was 50% and 88%, κ = 0.39. Conclusion A combination of T2 W and DW MRI detects the index tumour in 92% of cases, although MRI underestimates both TV and tumour burden compared with histology. [ABSTRACT FROM AUTHOR]

We study, for functions and sets, the relation between law invariance, preserving the convex or uniform order, and dilatation monotonicity based on duality arguments. [ABSTRACT FROM AUTHOR]

Robust biomarkers that can precisely stratify patients according to treatment needs are in great demand. The literature is inconclusive for most reported prognostic markers for colorectal cancer (CRC). Hence, adequately reported studies in large representative series are necessary to determine their clinical potential. We investigated the prognostic value of three Wnt signaling-associated proteins, β-catenin, E-cadherin, and SOX9, in a population-representative single-hospital series of 1290 Norwegian CRC patients by performing immunohistochemical analyses of each marker using the tissue microarray technology. Loss of membranous or cytosolic β-catenin and loss of cytosolic E-cadherin protein expression were significantly associated with reduced 5-year survival in 903 patients who underwent major resection (722 evaluable tissue cores) independently of standard clinicopathological high-risk parameters. Pre-specified subgroup analyses demonstrated particular effect for stage IV patients for β-catenin membrane staining (P=0.018; formal interaction test P=0.025). Among those who underwent complete resection (714 patients, 568 evaluable), 5-year time-to-recurrence analyses were performed, and stage II patients with loss of cytosolic E-cadherin were identified as an independent high-risk sub-group (P=0.020, formal interaction test was not significant). Nuclear β-catenin and SOX9 protein, regardless of intracellular location, were not associated with prognosis. In con-clusion, the protein expression level of membranous or cytosolic β-catenin and E-cadherin predicts CRC patient subgroups with inferior prognosis. [ABSTRACT FROM AUTHOR]

Background:The prognostic impact of an indication of chromosomal instability (CIN) is evaluated in a consecutive series of 952 colorectal cancer patients treated at Aker University Hospital, Norway, during 1993-2003. Microsatellite instability (MSI) in this case series has recently been reported and made it possible to find the co-occurrence and compare the prognostic significance of CIN and MSI.Methods:Data sets for overall survival (OS; n=855) and time to recurrence (TTR; n=579) were studied. To reveal CIN we used automated image cytometry (ICM). Non-diploid histograms were taken as indicative of the presence of CIN. PCR-based measures of MSI in this material have already been described.Results:As with MSI, CIN was found to be an independent predictor of early relapse and death among stage II patients (TTR: n=278: HR 2.19 (95% CI: 1.35-3.55), P=0.002). Of the MSI tumours (16%), 71% were found to be DNA diploid, 21% were DNA tetraploid and 8% were DNA aneuploid. Among microsatellite stable tumours, 24% were DNA diploid, 15% were DNA tetraploid and 61% were DNA aneuploid.Conclusion:For patients presenting with stage II disease, genomic instability as detected by DNA image cytometry has the potential to provide a useful biomarker for relapse and cancer-related death following surgery with curative intent. [ABSTRACT FROM AUTHOR]

We prove the existence of comonotone Pareto optimal allocations satisfying utility constraints when decision makers have probabilistic sophisticated variational preferences and thus representing criteria in the class of law invariant robust utilities. The total endowment is only required to be integrable. [ABSTRACT FROM AUTHOR]

We prove that in a discrete-time market model the lower arbitrage bound of an American contingent claim is itself an arbitrage-free price if and only if it corresponds to the price of the claim optimally exercised under some equivalent martingale measure. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Svindland et al. (2012) A study of Chitosan and c-di-GMP as mucosal adjuvants for intranasal influenza H5N1 vaccine. Influenza and Other Respiratory Viruses 10.1111/irv.12056000(000), 000-000. Background Highly pathogenic avian influenza A/H5N1 virus remains a potential pandemic threat, and it is essential to continue vaccine development against this subtype. A local mucosal immune response in the upper respiratory tract may stop influenza transmission. It is therefore important to develop effective intranasal pandemic influenza vaccines that induce mucosal immunity at the site of viral entry. Objectives We evaluated the humoral and cellular immune responses of two promising mucosal adjuvants (Chitosan and c-di-GMP) for intranasal influenza H5N1 vaccine in a murine model. Furthermore, we evaluated the concept of co-adjuvanting an experimental adjuvant (c-di-GMP) with chitosan. Methods BALB/c mice were intranasally immunised with two doses of subunit NIBRG-14 (H5N1) vaccine (7·5, 1·5 or 0·3 μg haemagglutinin (HA) adjuvanted with chitosan (CSN), c-di-GMP or both adjuvants. Results All adjuvant formulations improved the serum and local antibody responses, with the highest responses observed in the 7·5 μg HA CSN and c-di-GMP-adjuvanted groups. The c-di-GMP provided dose sparing with protective single radial haemolysis (SRH), and haemagglutination inhibition (HI) antibody responses found in the 0·3 μg HA group. CSN elicited a Th2 response, whereas c-di-GMP induced higher frequencies of virus-specific CD4+ T cells producing one or more Th1 cytokines (IFN-γ+, IL-2+, TNF-α+). A combination of the two adjuvants demonstrated effectiveness at 7·5 μg HA and triggered a more balanced Th cytokine profile. Conclusion These data show that combining adjuvants can modulate the Th response and in combination with ongoing studies of adjuvanted intranasal vaccines will dictate the way forward for optimal mucosal influenza vaccines. [ABSTRACT FROM AUTHOR]

Objective. This study aimed to assess the prevalence of positive surgical margins (PSM) and urinary incontinence (UI) in relation to surgeons' annual radical prostatectomy (RP) volume. Material and methods. This national study prospectively assessed 521 preoperatively continent patients with prostate cancer (PCa), scheduled for RP by surgeons with high (>50), medium (20-50) or low annual volume (<20) at 14 urological departments in Norway. Patients responded to UI questions from the Expanded Composite Prostate Cancer Index (EPIC-50) before and 1 year after RP. UI was defined as 'use of pad(s)' and/or 'a moderate or severe urinary leakage problem (ULP)'. Preoperative prediction of PSMs and UI was explored in multivariate regression analyses with the following independent variables: surgeons' annual RP volume, type of hospital (university versus community), patient's health, sociodemographic features and PCa characteristics. Results. Based on histopathological reports, the overall PSM rate was 26%, with differences between the high- (18%), medium- (28%) and low-volume (44%) groups. Increasing PSM rates were predicted by surgeons belonging to the low- and medium-volume categories, prostate-specific antigen> 10 µg/l, Gleason score >7, patient age >65 years and <12 years of education. At 1-year follow-up 40% reported UI, without significant differences between the volume groups. Only 46% of those who used pad(s) experienced ULP. UI was predicted by clinical category ≥T2 and community type of hospital, but not by surgeons' annual RP volume. Conclusions. Preoperative counselling should take into account the relationship between surgeon's annual RP volume and PSM rate and the current knowledge about UI and ULP. [ABSTRACT FROM AUTHOR]

Nutritionally relevant levels of genistein, the predominant isoflavone in soyabean associated with lower risk of prostate cancer (PCa), may modulate the expression of prostate tissue biomarkers associated with cancer prediction and progression. A phase 2 placebo-controlled, randomised, double-blind clinical trial was conducted in forty-seven Norwegian patients before prostatectomy. Intervention was 30 mg genistein or placebo capsules daily for 3–6 weeks. Luminal cells from malignant and benign glands were isolated with laser capture microdissection and the mRNA levels of androgen-related biomarkers (androgen receptor, NK3 homeobox 1, kallikrein-related peptide 4 (KLK4)) and cell cycle-related genes (p21Waf1/Cip1, p27Kip1, p53) were analysed with real-time semiquantitative PCR. Immunohistochemistry of androgen-, cell cycle-, proliferative- (Ki67 nuclear antigen), apoptotic- (B-cell CLL/lymphoma 2 (BCL-2) and BCL-2-associated X protein) and neuroendocrine differentiation-related biomarkers (neuron-specific enolase and cytoplasmic chromogranin A) was performed using tissue microarrays containing normal, Gleason grade 3 and grade 4 prostate tissues. There were no significant effects by genistein intervention on proliferation-, cell cycle-, apoptosis- or neuroendocrine biomarkers. Genistein intervention, however, significantly reduced the mRNA level of KLK4 in tumour cells (P = 0·033) and there was a non-significant reduction in androgen and cell cycle-related biomarkers, except for p27Kip1, whose expression in the nuclear compartment was increased. Genistein intervention modulated the expression of several biomarkers which may be related to PCa prediction and progression. The present study supports genistein as a chemopreventive agent in PCa. Further investigation is warranted in larger and longer-duration studies. [ABSTRACT FROM PUBLISHER]

This article is the first to show that loss of connexin43 (Cx43) expression in colorectal tumors is correlated with significantly shorter relapse-free and overall survival. Cx43 was further found to negatively regulate growth of colon cancer cells, in part by enhancing apoptosis. In addition, Cx43 was found to colocalize with β-catenin and reduce Wnt signaling. The study represents the first evidence that Cx43 acts as a colorectal cancer tumor suppressor and that loss of Cx43 expression during colorectal cancer development is associated with reduced patient survival. The study has important implications for the assessment of Cx43 as a prognostic marker and target in colorectal cancer prevention and therapy. Gap junctions consist of intercellular channels that permit direct transfer of ions and small molecules between adjacent cells. The gap junction channel protein Cx43 plays important roles in cell growth control and differentiation and is frequently dysregulated in human cancers. However, the functional importance and clinical relevance of Cx43 in cancer development has remained elusive. Here, we show that Cx43 is downregulated or aberrantly localized in colon cancer cell lines and colorectal carcinomas, which is associated with loss of gap junction intercellular communication. The in situ protein expression of Cx43 was analyzed in colorectal tumors in a cohort of 674 patients and related to established clinicopathological variables and survival. A subgroup of the patients had weak or no expression of Cx43 in tumors. Loss of Cx43 expression was significantly correlated with shorter relapse-free and overall survival. Loss of Cx43 further identified a high-risk subgroup among stage I and stage II patients with reduced relapse-free and overall survival. Ectopic expression of Cx43 in the colon cancer cell line HT29 was associated with reduced growth in monolayer and soft agar cultures and in tumor xenografts. Cx43 was found to colocalize with β-catenin and negatively regulate the Wnt signaling pathway, and expression of Cx43 was associated with increased levels of apoptosis. Altogether, these data indicate that Cx43 is a colorectal cancer tumor suppressor protein that predicts clinical outcome. [ABSTRACT FROM AUTHOR]

In this paper, we establish a one-to-one correspondence between law-invariant convex risk measures on L∞ and L1. This proves that the canonical model space for the predominant class of law-invariant convex risk measures is L1. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Svindland et al. The mucosal and systemic immune responses elicited by a chitosan-adjuvanted intranasal influenza H5N1 vaccine. Influenza and Other Respiratory Viruses DOI:10.1111/j.1750-2659.2011.00271.x. Background Development of influenza vaccines that induce mucosal immunity has been highlighted by the World Health Organisation as a priority (Vaccine 2005;23:1529). Dose-sparing strategies and an efficient mass-vaccination regime will be paramount to reduce the morbidity and mortality of a future H5N1 pandemic. Objectives This study has investigated the immune response and the dose-sparing potential of a chitosan-adjuvanted intranasal H5N1 (RG-14) subunit (SU) vaccine in a mouse model. Methods Groups of mice were intranasally immunised once or twice with a chitosan (5 mg/ml)-adjuvanted SU vaccine [7·5, 15 or 30 μg haemagglutinin (HA)] or with a non-adjuvanted SU vaccine (30 μg HA). For comparison, another group of mice were intranasally immunised with a whole H5N1 (RG-14) virus (WV) vaccine (15 μg HA), and the control group consisted of unimmunised mice. Results The chitosan-adjuvanted SU vaccine induced an immune response superior to that of the non-adjuvanted SU vaccine. Compared with the non-adjuvanted SU group, the chitosan-adjuvanted SU vaccine elicited higher numbers of influenza-specific antibody-secreting cells (ASCs), higher concentrations of local and systemic antibodies and correspondingly an improved haemagglutination inhibition (HI) and single radial haemolysis (SRH) response against both the homologous vaccine strain and drifted H5 strains. We measured a mixed T-helper 1/T-helper 2 cytokine response in the chitosan-adjuvanted SU groups, and these groups had an increased percentage of virus-specific CD4+ T cells producing two Thelper 1 (Th1) cytokines simultaneously compared with the non-adjuvanted SU group. Overall, the WV vaccine induced higher antibody concentrations in sera and an HI and SRH response similar to that of the chitosan-adjuvanted SU vaccine. Furthermore, the WV vaccine formulation showed a stronger bias towards a T-helper 1 profile than the SU vaccine and elicited the highest frequencies of CD4+ Th1 cells simultaneously secreting three different cytokines (INFγ+, IL2+ and INFα+). As expected, two immunisations gave a better immune response than one in all groups. The control group had very low or not detectable results in the performed immunoassays. Conclusion The cross-clade serum reactivity, improved B- and T-cell responses and dose-sparing potential of chitosan show that a chitosan-adjuvanted intranasal influenza vaccine is a promising candidate vaccine for further preclinical development. [ABSTRACT FROM AUTHOR]

Objective. Laparoscopic radical prostatectomy (LRP) was introduced in the Department of Urology, Oslo University Hospital, in 2002. The aim of this study was to report mid-term oncology results and survival data. Material and methods. From February 2002 to November 2007, 582 consecutive patients with localized prostate cancer underwent LRP. Data were collected prospectively into a database. Results. Mean and median follow-up after LRP was 30.3 months (± 15.5) and 36.0 months (range 3-72). Five patients (1%) were lost during follow-up. Two patients died of prostate cancer during the study period and 10 patients died of other causes. The overall positive surgical margin (PSM) rate was 29% and decreased to 13% for the last 100 patients. The overall PSA progression-free survival (PFS) was 85% at 3 years and 73% at 5 years. Gleason score in the tumour specimen, pT stage and surgical margins were statistical significant independent predictors of biochemical PFS. Conclusion. These oncology results and 5-year PFS data after LRP are in line with other reports. [ABSTRACT FROM AUTHOR]

Avian influenza A H5N1 is a virus with pandemic potential. Mucosal vaccines are attractive as they have the potential to block viruses at the site of entry, thereby preventing both disease and further transmission. The intranasal route is safe for the administration of seasonal live-αttenuated influenza vaccines, but may be less suitable for administration of pandemic vaccines. Research into novel mucosal routes is therefore needed. In this study, a murine model was used to compare sublingual administration with intranasal and intramuscular administration of influenza H5N1 virosomes (2 μg haemagglutinin; HA) in combination with the mucosal adjuvant (39,59)-cyclic dimeric guanylic acid (c-di-GMP). We found that sublingual immunisation effectively induced local and systemic H5N1-specific humoral and cellular immune responses but that the magnitude of response was lower than after intranasal administration. However, both the mucosal routes were superior to intramuscular immunisation for induction of local humoral and systemic cellular immune responses including high frequencies of splenic H5N1-specific multifunctional (IL-2+TNF-α+) CD4+ T cells. The c-di-GMP adjuvanted vaccine elicited systemic haemagglutination inhibition (HI) antibody responses (geometric mean titres ⩾40) both when administered sublingually, intranasally and inramuscularly. In addition, salivary HI antibodies were elicited by mucosal, but not intramuscular vaccination. We conclude that the sublingual route is an attractive alternative for administration of pandemic influenza vaccines. [ABSTRACT FROM AUTHOR]

We study monotone convex functions $ \psi:{L}^0(\Omega,\mathcal{F} ,\mathbb{P})\to (-\infty,\infty]$-additive subgradient. The results are motivated by applications in economic agents' choice theory. [ABSTRACT FROM AUTHOR]