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The DoMore-v1-CRC marker was recently developed using deep learning and conventional haematoxylin and eosin-stained tissue sections, and was observed to outperform established molecular and morphological markers of patient outcome after primary colorectal cancer resection. The aim of the present study was to develop a clinical decision support system based on DoMore-v1-CRC and pathological staging markers to facilitate individualised selection of adjuvant treatment.We estimated cancer-specific survival in subgroups formed by pathological tumour stage (pT4 or pT4), pathological nodal stage (pN0, pN1, or pN2), number of lymph nodes sampled (≤12 or12) if not pN2, and DoMore-v1-CRC classification (good, uncertain, or poor prognosis) in 997 patients with stage II or III colorectal cancer considered to have no residual tumour (R0) from two community-based cohorts in Norway and the UK, and used these data to define three risk groups. An external cohort of 1075 patients with stage II or III R0 colorectal cancer from the QUASAR 2 trial was used for validation; these patients were treated with single-agent capecitabine. The proposed risk stratification system was evaluated using Cox regression analysis. We similarly evaluated a risk stratification system intended to reflect current guidelines and clinical practice. The primary outcome was cancer-specific survival.The new risk stratification system provided a hazard ratio of 10·71 (95% CI 6·39-17·93; p0·0001) for high-risk versus low-risk patients and 3·06 (1·73-5·42; p=0·0001) for intermediate versus low risk in the primary analysis of the validation cohort. Estimated 3-year cancer-specific survival was 97·2% (95% CI 95·1-98·4; n=445 [41%]) for the low-risk group, 94·8% (91·7-96·7; n=339 [32%]) for the intermediate-risk group, and 77·6% (72·1-82·1; n=291 [27%]) for the high-risk group. The guideline-based risk grouping was observed to be less prognostic and informative (the low-risk group comprised only 142 [13%] of the 1075 patients).Integrating DoMore-v1-CRC and pathological staging markers provided a clinical decision support system that risk stratifies more accurately than its constituent elements, and identifies substantially more patients with stage II and III colorectal cancer with similarly good prognosis as the low-risk group in current guidelines. Avoiding adjuvant chemotherapy in these patients might be safe, and could reduce morbidity, mortality, and treatment costs.The Research Council of Norway.

AXIN2 and β-catenin colocalize with GFP-TNKS1 in cytoplasmic degradasomes shortly after addition of G007-LK.

TNKS and β-catenin display similar kinetics upon washout of G007-LK.

GFP-TNKS1 puncta are rapidly induced upon G007-LK-treatment of SW480 cells.

G007-LK-induced degradasomes are rapidly dissolved upon washout of inhibitor.

Stably expressed GFP-TNKS1 localizes to TNKSi-induced degradasomes in SW480 cells.

Endosomal and autophagosomal markers do not colocalize with β-catenin in degradasomes.

Degradasomes target β-catenin for proteasomal degradation.

Correlative light and electron microscopy (CLEM) of G007-LK-induced degradasomes.

G007-LK-treatment in different CRC cell lines.

Degradasomes are highly dynamic complexes in terms of assembly and disassembly.

Fluorescence recovery after photobleaching (FRAP) reveals different dynamic properties of β-catenin and TNKS in G007-LK-induced degradasomes.

Supplementary material and methods and Supplementary figure legends

Supplementary information describing the Nucleotyping method in more detail, including the training and validation results for the calculated Nucleotyping features.

Purpose: Improved prognostic stratification of patients with stage II and III colorectal cancer is warranted for postoperative clinical decision making. This study was conducted to develop a clinically feasible and robust prognostic classifier for these patients independent of adjuvant treatment.Experimental Design: Global gene expression profiles from altogether 387 stage II and III colorectal cancer tissue samples from three independent patient series were included in the study. ColoGuidePro, a seven-gene prognostic classifier, was developed from a selected Norwegian learning series (n = 95; no adjuvant treatment) using lasso-penalized multivariate survival modeling with cross-validation.Results: The expression signature significantly stratified patients in a consecutive Norwegian test series, in which patients were treated according to current standards [HR, 2.9 (1.1–7.5); P = 0.03; n = 77] and an external validation series [HR, 3.7 (2.0–6.8); P < 0.001; n = 215] according to survival. ColoGuidePro was also an independent predictor of prognosis in multivariate models including tumor stage in both series (HR, ≥3.1; P ≤ 0.03). In the validation series, which consisted of patients from other populations (United States and Australia), 5-year relapse-free survival was significantly predicted for stage III patients only (P < 0.001; n = 107). Here, prognostic stratification was independent of adjuvant treatment (P = 0.001).Conclusions: We present ColoGuidePro, a prognostic classifier developed for patients with stage II and III colorectal cancer. The test is suitable for transfer to clinical use and has best prognostic prediction potential for stage III patients. Clin Cancer Res; 18(21); 6001–10. ©2012 AACR.

Supplemental Materials, Figures S1-6, Tables S1-4. Fig. S1. Flow diagram for inclusion of patients in the study. Fig. S2. RNA secondary structure analysis of the 5'UTR RCC2 mutation compared to wild type. Fig. S3. Vector construction overview. Fig. S4. Morphological changes in actin fiber patterns following depletion of RCC2 protein in HCT15 cells. Fig. S5. Subgroup analyses of in situ protein expression of RCC2 for a consecutive CRC series. Fig. S6. Representative electropherograms from fragment analysis of the 5'UTR RCC2 mutation. Table S1. Statistics for relevant parameters for the test series (n = 37). Table S2. Statistics for relevant parameters for the validation series (n = 122). Table S3. Statistics for relevant parameters for the validation series (n = 60, R0 patients). Table S4. Primer and PCR details.

PDF file - 292K, The Supplementary Material contains Supplementary Methods, Supplementary Tables S1 and S2, and Supplementary Figures S1-S4 Table S1. Genes in the prognostic expression signature Table S2. Cox proportional hazards analyses for patients in the learning series Figure S1. Cross-validated partial likelihood and number of active predictors in the learning series as a function of the penalty parameter Figure S2. Expression in the learning series of the genes in the 7-gene prognostic signature. Figure S3. Survival curves for stage III patients in the validation series. Figure S4. Survival curves for stage III patients in the validation series aged 75 years or older

Background: Most endometrial carcinoma patients are diagnosed at an early stage with a good prognosis. However, a relatively low fraction with lethal disease constitutes a substantial number of patients due to the high incidence rate. Preoperative identification of patients with high risk and low risk for poor outcome is necessary to tailor treatment. Nucleotyping refers to characterization of cell nuclei by image cytometry, including the assessment of chromatin structure by nuclear texture analysis. This method is a strong prognostic marker in many cancers but has not been evaluated in preoperative curettage specimens from endometrial carcinoma.Methods: The prognostic impact of changes in chromatin structure quantified with Nucleotyping was evaluated in preoperative curettage specimens from 791 endometrial carcinoma patients prospectively included in the MoMaTEC multicenter trial.Results: Nucleotyping was an independent prognostic marker of disease-specific survival in preoperative curettage specimens among patients with Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage I–II disease (HR=2.9; 95% CI, 1.2–6.5; P = 0.013) and significantly associated with age, FIGO stage, histologic type, histologic grade, myometrial infiltration, lymph node status, curettage histology type, and DNA ploidy.Conclusions: Nucleotyping in preoperative curettage specimens is an independent prognostic marker for disease-specific survival, with potential to supplement existing parameters for risk stratification to tailor treatment.Impact: This is the first study to evaluate the prognostic impact of Nucleotyping in curettage specimens from endometrial carcinoma and shows that this may be a clinically useful prognostic marker in endometrial cancer. External validation is warranted. Cancer Epidemiol Biomarkers Prev; 26(1); 61–67. ©2016 AACR.

Purpose: Colorectal cancer has high incidence and mortality worldwide. Patients with microsatellite instable (MSI) tumors have significantly better prognosis than patients with microsatellite stable (MSS) tumors. Considerable variation in disease outcome remains a challenge within each subgroup, and our purpose was to identify biomarkers that improve prediction of colorectal cancer prognosis.Experimental Design: Mutation analyses of 42 MSI target genes were performed in two independent MSI tumor series (n = 209). Markers that were significantly associated with prognosis in the test series were assessed in the validation series, followed by functional and genetic explorations. The clinical potential was further investigated by immunohistochemistry in a population-based colorectal cancer series (n = 903).Results: We identified the cell-cycle gene regulator of chromosome condensation 2 (RCC2) as a cancer biomarker. We found a mutation in the 5′ UTR region of RCC2 that in univariate and multivariate analyses was significantly associated with improved outcome in the MSI group. This mutation caused reduction of protein expression in dual luciferase gene reporter assays. siRNA knockdown in MSI colon cancer cells (HCT15) caused reduced cell proliferation, cell-cycle arrest, and increased apoptosis. Massive parallel sequencing revealed few RCC2 mutations in MSS tumors. However, weak RCC2 protein expression was significantly associated with poor prognosis, independent of clinical high-risk parameters, and stratifies clinically important patient subgroups with MSS tumors, including elderly patients (>75 years), stage II patients, and those with rectal cancer.Conclusions: Impaired RCC2 affects functional and clinical endpoints of colorectal cancer. High-risk patients with either MSI or MSS tumors can be identified with cost-effective routine RCC2 assays. Clin Cancer Res; 21(16); 3759–70. ©2015 AACR.

Key Points A simplified frailty score predicts survival and toxicity in older patients with DLBCL and can inform treatment-intensity decisions.Full-dose R-CHOP is not superior to R-miniCHOP in older unfit DLBCL patients, whereas older fit patients likely benefit from full-dose R-CHOP., Visual Abstract, Patients with diffuse large B-cell lymphoma (DLBCL) have a median age of 70 years. Yet, empirical knowledge about the treatment of older patients is limited because they are frequently excluded from clinical trials. We aimed to construct a simplified frailty score and examine survival and treatment-related mortality (TRM) according to frailty status and treatment intensity in an older real-world population with DLBCL. All patients aged ≥70 years diagnosed with DLBCL between 2006 and 2016 in southeastern Norway (N = 784) were included retrospectively and divided into training (n = 522) and validation (n = 262) cohorts. We constructed and validated a frailty score based on geriatric assessment variables and examined survival and TRM according to frailty status and treatment. The frailty score identified 3 frailty groups with distinct survival and TRM, independent of established prognostic factors (2-year overall survival [OS]: fit, 82%; unfit, 47%; frail, 14%; P < .001). For fit patients, full-dose R-CHOP (initial dosage >80%) was associated with better survival than attenuated R-CHOP ([R-miniCHOP]; 2-year OS: 86% vs 70%; P = .012), also in adjusted analyses. For unfit and frail patients, full-dose R-CHOP was not superior to R-miniCHOP, whereas an anthracycline-free regimen was associated with poorer survival in adjusted analyses. A simplified frailty score identified unfit and frail patients with a higher risk for death and TRM, which can aid treatment-intensity decisions in older patients with DLBCL. In this study, fit patients benefited from full-dose R-CHOP, whereas unfit and frail patients had no benefit from full-dose R-CHOP over R-miniCHOP. An online calculator for assessment of the frailty score is available at https://wide.shinyapps.io/app-frailty/.

Flertallet av studentene ved landets høyere utdanningsinstitusjoner er kvinner, og det er like mange kvinner som menn som tar doktorgrad. Likevel er over to tredeler av professorene ved landets universiteter og høyskoler menn. Hvordan kan vi forstå denne vedvarende kjønnsubalansen? Hva er det med akademia som gjør at kvinner faller fra på veien opp mot professornivå? Denne boken springer ut av Forskningsrådets BALANSE-program, et initiativ for å bedre kjønnsbalansen i norsk universitets-, høyskole- og instituttsektor. Forfatterne har samlet kunnskap og erfaringer fra prosjektene, og presenterer nye analyser og perspektiver knyttet til kjønn og akademia. Boken løfter frem kjønnsbalanseproblematikken og setter den inn i ulike kontekster. Tekstene inneholder både skråblikk, dilemmaer og nye perspektiver som vil være verdifulle for forskere, studenter og andre som engasjerer seg i spørsmål om kjønn og utdanning.

Previous research has shown an association between moderate workload exercise blood pressure (BP) and coronary disease, whereas maximal exercise BP is associated with stroke. We aimed to investigate the association between the increase in BP during maximal exercise and the long-term risk of stroke in healthy, middle-aged men.Two thousand and fourteen men were included in the Oslo Ischemia Study in the 1970s. In the present study, we examined baseline data of the 1392 participants who remained healthy and performed bicycle exercise tests both at baseline and 7 years later. Cox proportional hazard was used to assess the risk of stroke in participants divided into quartiles based on the difference between resting and maximal workload SBP (ΔSBP) at baseline, adjusting for resting BP, age, smoking, serum cholesterol and physical fitness. Follow-up was until the first ischemic or hemorrhagic stroke through 35 years.There were 195 incident strokes; 174 (89%) were ischemic. In univariate analyses, there were significant positive correlations between age, resting SBP, resting DBP and SBP at moderate and maximal workload, and risk of stroke. In the multivariate analysis, there was a 2.6-fold (P 0.0001) increase in risk of stroke in ΔSBP quartile 4 (ΔSBP 99 mmHg) compared with ΔSBP quartile 2 (ΔSBP 73-85 mmHg), which had the lowest risk of stroke. ΔSBP quartile 1 had a 1.7-fold (P = 0.02) increased risk compared with quartile 2, suggesting a J-shaped association to stroke risk.Stroke risk increased with increasing difference between resting and maximal exercise SBP, independent of BP at rest, suggesting that an exaggerated BP response to physical exercise may be an independent predictor of stroke.

Complex organ development depends on single lumen formation and its expansion during tubulogenesis. This can be achieved by correct mitotic spindle orientation during cell division, combined with luminal fluid filling that generates hydrostatic pressure. Using a human 3D cell culture model, we have identified two regulators of these processes. We find that pleckstrin homology leucine-rich repeat protein phosphatase (PHLPP) 2 regulates mitotic spindle orientation, and thereby midbody positioning and maintenance of a single lumen. Silencing the sole PHLPP family phosphatase in Drosophila melanogaster, phlpp, resulted in defective spindle orientation in Drosophila neuroblasts. Importantly, cystic fibrosis transmembrane conductance regulator (CFTR) is the main channel regulating fluid transport in this system, stimulated by phosphorylation by protein kinase A and inhibited by the AMP-activated protein kinase AMPK. During lumen expansion, CFTR remains open through the action of PHLPP1, which stops activated AMPK from inhibiting ion transport through CFTR. In the absence of PHLPP1, the restraint on AMPK activity is lost and this tips the balance in the favour of channel closing, resulting in the lack of lumen expansion and accumulation of mucus.

The number of publications on deep learning for cancer diagnostics is rapidly increasing, and systems are frequently claimed to perform comparable with or better than clinicians. However, few systems have yet demonstrated real-world medical utility. In this Perspective, we discuss reasons for the moderate progress and describe remedies designed to facilitate transition to the clinic. Recent, presumably influential, deep learning studies in cancer diagnostics, of which the vast majority used images as input to the system, are evaluated to reveal the status of the field. By manipulating real data, we then exemplify that much and varied training data facilitate the generalizability of neural networks and thus the ability to use them clinically. To reduce the risk of biased performance estimation of deep learning systems, we advocate evaluation in external cohorts and strongly advise that the planned analyses, including a predefined primary analysis, are described in a protocol preferentially stored in an online repository. Recommended protocol items should be established for the field, and we present our suggestions.

Blood pressure–lowering drugs have different blood pressure–lowering profiles. We studied if differences in blood pressure mean and variability can explain the differences in risks of cardiovascular events and death among 15 245 high-risk hypertensive patients randomized to valsartan or amlodipine and followed for 4.2 years in the VALUE trial (Valsartan Antihypertensive Long-Term Use Evaluation). We selected patients with ≥3 visits and performed Cox regression analyses, defining mean blood pressure as a time-dependent covariate and visit-to-visit and within-visit blood pressure variability as the SD. Of 14 996 eligible patients, participants in the valsartan group had higher systolic mean blood pressure by 2.2 mm Hg, higher visit-to-visit systolic variability by 1.4 mm Hg, and higher within-visit systolic variability by 0.2 mm Hg ( P values

The mitotic checkpoint protein BUB3, cyclin B1 (CCNB1) and pituitary tumor-transforming 1 (PTTG1) regulates cell division, and are sparsely studied in prostate cancer. Deregulation of these genes can lead to genomic instability, a characteristic of more aggressive tumors. We aimed to determine the expression levels of BUB3, CCNB1, and PTTG1 as potential prognostic markers of recurrence after radical prostatectomy. Protein levels were determined by immunohistochemistry on three formalin-fixed paraffin-embedded tissue sections from each of the 253 patients treated with radical prostatectomy. Immunohistochemistry scores were obtained by automated image analysis for CCNB1 and PTTG1. Recurrence, defined as locoregional recurrence, distant metastasis or death from prostate cancer, was used as endpoint for survival analysis. Tumors having both positive and negative tumor areas for cytoplasmic BUB3 (30%), CCNB1 (28%), or PTTG1 (35%) were considered heterogeneous. Patients with ≥1 positive tumor area had significantly increased risk of disease recurrence in univariable analysis compared with patients where all tumor areas were negative for cytoplasmic BUB3 (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.41-3.36), CCNB1 (HR = 2.98, 95% CI 1.93-4.61) and PTTG1 (HR = 1.91, 95% CI 1.23-2.97). Combining the scores of cytoplasmic BUB3 and CCNB1 improved risk stratification when integrated with the Cancer of the Prostate Risk Assessment post-Surgical (CAPRA-S) score (difference in concordance index = 0.024, 95% CI 0.001-0.05). In analysis of multiple tumor areas, prognostic value was observed for cytoplasmic BUB3, CCNB1, and PTTG1.

Material from the FRONT project shows significant gendered differences in how the working environment and organizational culture are experienced. It is not a single factor that negatively affects women, but a complex process involving many components over time – with different causes and modes of action – together giving an accumulated disadvantage. These processes and their effects are summarized in a model called “Bøygen”, after the creature who creates obstacles and counter-forces to Peer Gynt in Ibsen’s play. The academic version of Bøygen operates partly through an “accumulation” of disadvantage throughout the academic career, and partly through experiences that tend to cause loss of self-confidence and motivation. External resistance and lack of support translates into inner doubt. The Bøygen model is discussed in relation to international research on the effects of barriers to women in academia. The model is the first of three theoretical contributions to the project (Chapters 7, 8 and 9) based on the empirical content in Chapters 1–6.