Prognostic genomic alterations in patients undergoing liver resection for hepatocellular carcinoma.

INTRODUCTION: Genetic mutations and amplifications found in hepatocellular carcinoma (HCC) have a potentially prognostic impact. The aim of this study was to investigate the prognostic value of mutations and amplifications in HCC from patients that were liver resected. METHODS: Patients liver resected for HCC at Copenhagen University Hospital Rigshospitalet between May 2014 and January 2018 were included. DNA from freshly frozen tumour tissue was investigated with TruSight Oncology 500. Mutations and amplifications were correlated with disease-free survival and overall survival using multivariate Cox regression to assess the effect on prognosis. RESULTS: Of the 51 patients included, 88% were male and the median age was 69 years. Most patients had a single tumour (84%) with no vascular invasion (67%) in a non-cirrhotic liver (76% with fibrosis, 24% with cirrhosis). The median follow-up was 37 months. Patients with a MYC amplification (8%) were significantly younger than the remaining patients. Furthermore, they had a significantly shorter overall survival (15 months (95% CI: 0.0-31.6) vs. 59 months (95% CI: 34.4-83.6), p = < 0.001) and disease-free survival (8 months (95% CI: 4.6-11.4) vs. 19 months (95% CI: 12.3-25.7), p = 0.03). However, only overall survival remained statistically significant in the adjusted analysis. Furthermore, all patients with an ARID1A mutation (6%) had microvascular invasion and significantly larger tumours than the patients without ARID1A mutation. CONCLUSION: MYC amplifications had a prognostic influence on survival, whereas ARID1A gene mutations were correlated with microvascular invasion. These may serve as prognostic biomarkers and should be validated in large, independent cohort.

Is punctate palmoplantar keratoderma type 1 associated with malignancy? A systematic review of the literature.

BACKGROUND: An association between punctate palmoplantar keratoderma type 1 (PPPK1) and malignancy has been proposed for decades. Some authors suggest that individuals with PPPK1 should undergo screening for various types of malignancies while others caution that an association is not well-established. In this systematic review, we summarized and evaluated the current evidence for a possible association between PPPK1 and malignancy. METHODS: The review was conducted along PRISMA guidelines. The search used Embase, MEDLINE, Scopus, and the Human Gene Mutation Database up to March 2022. All studies reporting on individuals with the diagnosis of PPPK1 with or without history of malignancy were included. Two authors screened for eligible studies, extracted predefined data, and performed a quality assessment. RESULTS: Of 773 studies identified, 45 were included. Most studies were reports on single families (24 of 45 studies) or multiple families (10 of 45 studies). The number of index cases with PPPK1 across all included studies was 280, and when family members reported with PPPK1 were added, a total of 817 individuals were identified. Overall, 23 studies reported on individuals with PPPK1 with a history of malignancy, whereas 22 studies reported on individuals with PPPK1 without a history of malignancy. Although the extracted data were not considered to be of sufficient quality to synthesize and answer our research question, the review did not confirm an association between PPPK1 and malignancy. CONCLUSION: This review shows that there is a lack of well-designed studies on this topic to conclude whether individuals with PPPK1 have an increased risk of malignancy. Based on the present literature, however, we could not confirm an association between PPPK1 and malignancy and find it highly questionable if patients with PPPK1 should be offered surveillance for malignancies.

Machine learning-based immune phenotypes correlate with STK11/KEAP1 co-mutations and prognosis in resectable NSCLC: a sub-study of the TNM-I trial.

BACKGROUND: We aim to implement an immune cell score model in routine clinical practice for resected non-small-cell lung cancer (NSCLC) patients (NCT03299478). Molecular and genomic features associated with immune phenotypes in NSCLC have not been explored in detail. PATIENTS AND METHODS: We developed a machine learning (ML)-based model to classify tumors into one of three categories: inflamed, altered, and desert, based on the spatial distribution of CD8+ T cells in two prospective (n = 453; TNM-I trial) and retrospective (n = 481) stage I-IIIA NSCLC surgical cohorts. NanoString assays and targeted gene panel sequencing were used to evaluate the association of gene expression and mutations with immune phenotypes. RESULTS: Among the total of 934 patients, 24.4% of tumors were classified as inflamed, 51.3% as altered, and 24.3% as desert. There were significant associations between ML-derived immune phenotypes and adaptive immunity gene expression signatures. We identified a strong association of the nuclear factor-κB pathway and CD8+ T-cell exclusion through a positive enrichment in the desert phenotype. KEAP1 [odds ratio (OR) 0.27, Q = 0.02] and STK11 (OR 0.39, Q = 0.04) were significantly co-mutated in non-inflamed lung adenocarcinoma (LUAD) compared to the inflamed phenotype. In the retrospective cohort, the inflamed phenotype was an independent prognostic factor for prolonged disease-specific survival and time to recurrence (hazard ratio 0.61, P = 0.01 and 0.65, P = 0.02, respectively). CONCLUSIONS: ML-based immune phenotyping by spatial distribution of T cells in resected NSCLC is able to identify patients at greater risk of disease recurrence after surgical resection. LUADs with concurrent KEAP1 and STK11 mutations are enriched for altered and desert immune phenotypes.

Personalized circulating tumor DNA in patients with hepatocellular carcinoma: a pilot study.

BACKGROUND: Mutational analysis of circulating tumor DNA (ctDNA) can potentially be used for early detection of recurrence after resection for hepatocellular carcinoma (HCC). Mutations from tumor may be identified in plasma as an early sign of recurrence. We conducted a pilot study investigating if somatic mutations could be detected in plasma in patients undergoing liver resection for HCC and in patients with advanced non-resectable HCC. METHODS AND RESULTS: We prospectively included patients undergoing curative liver resection for HCC. Tumor tissue was investigated with whole exome sequencing and preoperative blood samples were evaluated for ctDNA using targeted next-generation sequencing (NGS) with TruSight Oncology 500 including 523 cancer-associated genes. Subsequently, the method was evaluated in patients with advanced HCC. We included eight patients curatively resected for HCC, where tumor tissue mutations were identified in seven patients. However, only in one patient tumor specific mutations were found in the preoperative blood sample. In all three patients with advanced HCC, tumor mutations were detected in the blood. CONCLUSIONS: In patients with resectable HCC, ctDNA could not be reliably detected using the applied targeted NGS method. In contrast, ctDNA was detected in all patients with advanced HCC. Small tumors, tumor heterogeneity and limited sequencing coverage may explain the lack of detectable ctDNA.

Correction: Gene expression profiling identifies FYN as an important molecule in tamoxifen resistance and a predictor of early recurrence in patients treated with endocrine therapy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Probiotic or synbiotic alters the gut microbiota and metabolism in a randomised controlled trial of weight management in overweight adults.

The gut microbiota contributes to host energy metabolism, and altered gut microbiota has been associated with obesity-related metabolic disorders. We previously reported that a probiotic alone or together with a prebiotic controls body fat mass in healthy overweight or obese individuals in a randomised, double-blind, placebo controlled clinical study (ClinicalTrials.gov NCT01978691). We now aimed to investigate whether changes in the gut microbiota may be associated with the observed clinical benefits. Faecal and plasma samples were obtained from a protocol compliant subset (n=134) of participants from a larger clinical study where participants were randomised (1:1:1:1) into four groups: (1) placebo, 12 g/d microcrystalline cellulose; (2) Litesse® Ultra™ polydextrose (LU), 12 g/day; (3) Bifidobacterium animalis subsp. lactis 420™ (B420), 1010 cfu/d in 12 g microcrystalline cellulose; (4) LU+B420, 1010 cfu/d of B420 in 12 g/d LU for 6 months of intervention. The faecal microbiota composition and metabolites were assessed as exploratory outcomes at baseline, 2, 4, 6 months, and +1 month post-intervention and correlated to obesity-related clinical outcomes. Lactobacillus and Akkermansia were more abundant with B420 at the end of the intervention. LU+B420 increased Akkermansia, Christensenellaceae and Methanobrevibacter, while Paraprevotella was reduced. Christensenellaceae was consistently increased in the LU and LU+B420 groups across the intervention time points, and correlated negatively to waist-hip ratio and energy intake at baseline, and waist-area body fat mass after 6 months treatment with LU+B420. Functional metagenome predictions indicated alterations in pathways related to cellular processes and metabolism. Plasma bile acids glycocholic acid, glycoursodeoxycholic acid, and taurohyodeoxycholic acid and tauroursodeoxycholic acid were reduced in LU+B420 compared to Placebo. Consumption of B420 and its combination with LU resulted in alterations of the gut microbiota and its metabolism, and may support improved gut barrier function and obesity-related markers.

Correction: Gene expression profiling identifies FYN as an important molecule in tamoxifen resistance and a predictor of early recurrence in patients treated with endocrine therapy.

Since the online publication of the above article, the authors have noted errors in subfigures 1c and 3b. Therefore, new images of the original immmunocytochemistry stainings have been obtained for Fig. 1c, and the Western blots for siRNA-mediated FYN knockdown in Fig. 3b were repeated. The amended versions of Figs. 1c and 3b are now provided.

Do number of days with low back pain and patterns of episodes of pain have similar outcomes in a biopsychosocial prediction model?

PURPOSES: We used two different methods to classify low back pain (LBP) in the general population (1) to assess the overlapping of individuals within the different subgroups in those two classifications, (2) to explore if the associations between LBP and some selected bio-psychosocial factors are similar, regardless which of the two classifications is used. METHOD: During 1 year, 49- or 50-year-old people from the Danish general population were sent fortnightly automated text messages (SMS-Track) asking them if they had any LBP in the past fortnight. Responses for the whole year were then classified into two different ways: (1) In relation to the number of days with LBP in the preceding year (0, 1-30, and >30), (2) In relation to the frequency and duration of episodes of LBP (more or less never pain, episodic, and more or less constant pain). Some bio-psychosocial factors, collected with a questionnaire at baseline 9 years earlier, were entered into regression models to investigate their associations with the subgroups of the two classifications of LBP and the results compared. RESULTS: The percentage of agreement between categories of the two classification systems was above 68 % (Kappa 0.7). Despite the large overlap of persons in the two classification groups, the patterns of associations with the two types of LBP definitions were different in the two classification groups. However, none of the estimates were significantly different when the variables were compared across the two classifications. CONCLUSION: Different classification systems of LBP are capable of bringing forth different findings. This may help explain the lack of consistency between studies on risk factors of LBP.

Back injuries in a cohort of schoolchildren aged 6-12: A 2.5-year prospective study.

The aims of this prospective school cohort study were to describe the epidemiology of diagnosed back pain in childhood, classified as either nontraumatic or traumatic back injury, and to estimate the association with physical activity in different settings. Over 2.5 years, 1240 children aged 6-12 years were surveyed weekly using mobile text messages to ask about the presence or absence of back pain. Pain was clinically diagnosed and injuries were classified using the International Classification of Diseases version 10. Physical activity data were obtained from text messages and accelerometers. Of the 315 back injuries diagnosed, 186 injuries were nontraumatic and 129 were traumatic. The incidence rate ratio was 1.5 for a nontraumatic back injury compared with a traumatic injury. The overall estimated back injury incidence rate was 0.20 per 1000 physical activity units (95% confidence interval 0.18-0.23). The back injury incidence rates were higher for sports when exposure per 1000 physical activity units was taken into consideration and especially children horse-riding had a 40 times higher risk of sustaining a traumatic back injury compared to the risk during non-organized leisure time physical activity. However, the reasonably low injury incidence rates support the recommendations of children continuously being physically active.

A kinase inhibitor screen identifies Mcl-1 and Aurora kinase A as novel treatment targets in antiestrogen-resistant breast cancer cells.

Antiestrogen resistance is a major problem in breast cancer treatment. Therefore, the search for new therapeutic targets and biomarkers for antiestrogen resistance is crucial. In this study, we performed a kinase inhibitor screen on antiestrogen responsive MCF-7 cells and a panel of MCF-7-derived tamoxifen- and fulvestrant-resistant cell lines. Our focus was to identify common and distinct molecular mechanisms involved in tamoxifen- and fulvestrant-resistant cell growth. We identified 18 inhibitors, of which the majority was common for both tamoxifen- and fulvestrant-resistant cell lines. Two compounds, WP1130 and JNJ-7706621, exhibiting prominent preferential growth inhibition of antiestrogen-resistant cell lines, were selected for further studies. WP1130, a deubiquitinase inhibitor, induced caspase-mediated cell death in both tamoxifen- and fulvestrant-resistant cell lines by destabilization of the anti-apoptotic protein Mcl-1. Mcl-1 expression was found upregulated in the antiestrogen-resistant cell lines and depletion of Mcl-1 in resistant cells caused decreased viability. JNJ-7706621, a dual Aurora kinase and cyclin-dependent kinase inhibitor, specifically inhibited growth and caused G2 phase cell cycle arrest of the tamoxifen-resistant cell lines. Knockdown studies showed that Aurora kinase A is essential for growth of the tamoxifen-resistant cells and inhibition of Aurora kinase A resensitized tamoxifen-resistant cells to tamoxifen treatment. Preferential growth inhibition by WP1130 and JNJ-7706621 was also found in T47D-derived tamoxifen-resistant cell lines, pointing at Mcl-1 and Aurora kinase A as potential treatment targets. In addition, tumor samples from 244 estrogen receptor-positive breast cancer patients treated with adjuvant tamoxifen showed that higher expression level of Aurora kinase A was significantly associated with shorter disease-free and overall survival, demonstrating the potential of Aurora kinase A as a biomarker for tamoxifen resistance.

Gene expression profiling identifies FYN as an important molecule in tamoxifen resistance and a predictor of early recurrence in patients treated with endocrine therapy.

To elucidate the molecular mechanisms of tamoxifen resistance in breast cancer, we performed gene array analyses and identified 366 genes with altered expression in four unique tamoxifen-resistant (TamR) cell lines vs the parental tamoxifen-sensitive MCF-7/S0.5 cell line. Most of these genes were functionally linked to cell proliferation, death and control of gene expression, and include FYN, PRKCA, ITPR1, DPYD, DACH1, LYN, GBP1 and PRLR. Treatment with FYN-specific small interfering RNA or a SRC family kinase inhibitor reduced cell growth of TamR cell lines while exerting no significant effect on MCF-7/S0.5 cells. Moreover, overexpression of FYN in parental tamoxifen-sensitive MCF-7/S0.5 cells resulted in reduced sensitivity to tamoxifen treatment, whereas knockdown of FYN in the FYN-overexpressing MCF-7/S0.5 cells restored sensitivity to tamoxifen, demonstrating growth- and survival-promoting function of FYN in MCF-7 cells. FYN knockdown in TamR cells led to reduced phosphorylation of 14-3-3 and Cdc25A, suggesting that FYN, by activation of important cell cycle-associated proteins, may overcome the anti-proliferative effects of tamoxifen. Evaluation of the subcellular localization of FYN in primary breast tumors from two cohorts of endocrine-treated ER+ breast cancer patients, one with advanced disease (N=47) and the other with early disease (N=76), showed that in the former, plasma membrane-associated FYN expression strongly correlated with longer progression-free survival (P<0.0002). Similarly, in early breast cancer patients, membrane-associated expression of FYN in the primary breast tumor was significantly associated with increased metastasis-free (P<0.04) and overall (P<0.004) survival independent of tumor size, grade or lymph node status. Our results indicate that FYN has an important role in tamoxifen resistance, and its subcellular localization in breast tumor cells may be an important novel biomarker of response to endocrine therapy in breast cancer.

Blood sampling and hemolysis affect concentration of plasma metabolites.

Two experiments were carried out to reveal and quantify plasma metabolites that are sensitive to hemolysis and animal stress due to the blood sampling procedure (vein puncture vs. catheter). In Exp. 1, 48 sows were fed 4 diets either once (0800 h) or twice daily (0800 h and 1500 h) in a crossover design and blood was collected after restraint via vein puncture 1, 4, 11, and 23 h after morning feeding. Plasma samples were categorized as without or with minor or major hemolysis [clear (n = 218), yellow (n = 97), or red (n = 37)] upon centrifugation. Plasma NEFA (P < 0.001) was lower in hemolyzed samples but plasma propionate, caproate, isovalerate (P < 0.001), and isobutyrate (P < 0.05) were higher in hemolyzed samples. Plasma glucose and lactate were the only metabolites that were not affected by hemolysis. Interactions with hemolysis and other fixed effects were not found (P > 0.05). In Exp. 2, a subset of samples from 24 sows fed twice daily in Exp. 1 was combined with data obtained from 30 sows sampled using jugular vein catheters. All sows in Exp. 2 were fed twice daily (0800 h and 1500 h) and blood samples collected repeatedly 1, 4, 11, and 23 h after morning feeding (other conditions were similar as in Exp. 1). Plasma isobutyrate (P < 0.001), NEFA (P < 0.01), and acetate (P < 0.05) were lowered and plasma caproate (P < 0.001), glucose (P < 0.01), lactate, and isovalerate (P < 0.05) were elevated in samples obtained via vein puncture as compared to via vein catheters. Plasma insulin, propionate, and butyrate were not sensitive to the blood sampling procedure. In conclusion, blood sampling procedure and hemolysis affect the measured metabolite concentrations and should be considered or accounted for when comparing results within and between experiments.

Feeding motivation and plasma metabolites in pregnant sows fed diets rich in dietary fiber either once or twice daily.

The present study investigated the effects of source and level of dietary fiber (DF) and feeding frequency (once vs. twice daily) on feeding motivation and plasma metabolites at 4 different time points post feeding. Sixty pregnant sows (Sus scrofa, 4 blocks of 15 sows) were allocated to 1 of 5 diets within blocks. Four diets were restricted (approximately 35 MJ ME/d): a barley and wheat control diet (171 g DF/kg DM; 12 g DF/MJ ME), and 3 fiber diets formulated to contain 35% DF by including pectin residue (323 g DF/kg DM; 25 g DF/MJ ME), potato pulp (404 g DF/kg DM; 29 g DF/MJ ME), or sugar beet pulp (367 g DF/kg DM; 25 g DF/MJ ME). The fifth diet was a mixture including an equal amount of the 3 fiber diets offered semi ad libitum (ad libitum access to feed during 6 periods of 1 h starting at 0300, 0600, 1100, 1500, 1800, and 2300; 354 g DF/kg DM; 25 g DF/MJ ME). The experimental period included 2 periods of 4 wk each. Restricted-fed sows were fed once daily (0800 h) during the first period and twice daily (0800 and 1500 h) during the second period, or vice versa. Semi ad libitum fed sows had access to feed 6 times a day in both periods. In each period, the feeding motivation was assessed in an operant conditioning test, and samples of peripheral blood were taken in a balanced design, at 0900, 1200, 1900, and 0700 h, corresponding to 1, 4, 11, and 23 h after feeding for restricted sows fed once daily. No differences in the feeding motivation were found between the 4 restricted diets at any of the time points post feeding, but semi ad libitum fed sows had a decreased feeding motivation (P < 0.001). Among the restricted-fed sows, feeding twice daily resulted in decreased feeding motivation at 1900 h (P < 0.001) and at 0700h (P < 0.05) compared with feeding once daily, but not at 0900 and 1200 h, indicating that feeding twice daily reduced feeding motivation during the night compared with feeding once daily. Among restricted-fed sows, plasma concentrations of short-chain fatty acids (SCFA) were greater in sows fed high-fiber diets compared with the control (P = 0.02). Nonesterified fatty acid was least in sows on the control diet and greatest in sows on the potato diet, whereas sows on the pectin and sugar beet diets were intermediate (P < 0.001). Less diurnal variation in glucose (P < 0.001) was seen in sows on high-fiber diets. In spite of the found effects on plasma metabolites, the applied level of fiber in the diet of restrictedly fed sows did not reduce their feeding motivation irrespective of fiber source.

Financial compensation and vocational recovery: a prospective study of secondary care neck and back patients.

OBJECTIVES: Financial compensation has been shown to be a negative prognostic factor for pain and disability in patients with neck or low back pain. It is unclear whether this association is causal and to what extent it hampers return to work. The objective of this study was to assess the direct influence of a financial compensation process on the ability to remain in regular employment in patients with suspected disc herniation. METHODS: A prospective cohort study with a register-based follow-up at 1, 3, and 5 years after baseline was carried out at two multidisciplinary, non-surgical spine clinics in two public hospitals in Denmark. The study population comprised consecutive patients in regular employment with neck pain radiating to the arm or low back pain radiating to the leg. The exposure variable was any type of claim for financial compensation for the actual low back/leg or neck/arm pain. The outcome measure was receiving income compensation benefits. This information was obtained through national registers. Follow-up points were 1, 3, and 5 years after inclusion. RESULTS: The study included 1243 low back pain patients and 202 neck pain patients. The odds ratio, adjusted for relevant confounders, of receiving income compensation benefits in case of baseline financial claim was approximately 2 for low back/leg pain patients and about 4 for neck/arm pain patients at 1, 3, and 5 years. CONCLUSIONS: In employed patients, a claim for financial compensation for low back or neck pain with radiating pain was found to be independently associated with receipt of income compensation benefits after 1, 3, and 5 years.

High-level physical activity in childhood seems to protect against low back pain in early adolescence.

BACKGROUND: The evidence on the impact of physical activity on back pain in children and adolescents has been contradicting. It has also been shown that the physical activity cannot accurately be estimated in children using questionnaires. PURPOSE: The aim of this study was to establish if physical activity in childhood had any impact on back pain reporting in early adolescence (3 years later), using an objective instrumental measurement of physical activity. STUDY DESIGN: Prospective cohort study. PATIENT SAMPLE: Representative random sample of Danish children from the city of Odense sampled at age 9 years and followed-up at age 12 years. OUTCOME MEASURES: The 1-month period prevalence of back pain (neck pain, mid back pain, and low back pain) was established using a structured interview. METHODS: Physical activity was assessed with the MTI-accelerometer. The accelerometer provides a minute-by-minute measure of the physical activity performed. An overall measure of physical activity and time spent in high activity were studied in relation to back pain using logistic regression. The analyses were performed on the total sample and then stratified on back pain (yes/no) at baseline. RESULTS: High physical activity (HPA) levels seem to protect against future low back pain and appear to actually "treat" and reduce the odds of future mid back pain. When comparing the least active children to the most active children, the least active had a multivariate odds ratio of 3.3 of getting low back pain and 2.7 of getting mid back pain 3 years later. When stratified on back pain at baseline, this effect on mid back pain was especially noticeable in children who had had mid back pain already at baseline, with an odds ratio of 7.2. CONCLUSIONS: HPA in childhood seems to protect against low back pain and mid back pain in early adolescence. Larger prospective studies with repetitive follow-ups and preferably intervention studies should be performed, to see if these findings can be reproduced.

No evidence for presence of bacteria in modic type I changes.

BACKGROUND: Recent studies suggest an association between sciatica and Propionibacterium acnes. "Modic type I changes" in the vertebrae are closely associated with sciatica and lower back pain, and recent studies have questioned the ability of conventional magnetic resonance imaging (MRI) to differentiate between degenerative Modic type I changes and vertebral abnormalities caused by infection. PURPOSE: To test whether bacteria could be cultured from biopsies of Modic type I changes. MATERIAL AND METHODS: Twenty-four consecutive patients with Modic type I changes in lumbar vertebrae had a biopsy taken from the affected vertebra by a strict aseptic procedure. The biopsy was split into two specimens, which were inoculated into thioglycolate agar tubes in the surgical theatre and transported to the microbiology laboratory. In the laboratory, one specimen was streaked onto plates and analyzed for anaerobic and aerobic culture. The other tube was left unopened and incubated directly. Plates and tubes were incubated for 2 weeks and observed for visible growth. RESULTS: None of the biopsies yielded growth of anaerobic bacteria. In one patient, both biopsies yielded growth of Staphylococcus epidermidis, and in another patient coagulase-negative staphylococci were isolated from one biopsy. Both patients received oral antibiotics without convincing effect on symptoms. CONCLUSION: Our results showed no evidence of bacteria in vertebrae with Modic type I changes. The isolation of staphylococci from two patients probably represented contamination.

Poor outcome in patients with spine-related leg or arm pain who are involved in compensation claims: a prospective study of patients in the secondary care sector.

OBJECTIVE: To investigate whether poor outcome after spinal pain episodes is linked with the claim process and, if so, whether this link is independent of other potential risk factors of chronic pain and disability in patients with spine-related leg or arm pain. METHODS: A 1-year prospective outcome study with internal control groups in two Danish secondary care, public, multidisciplinary, non-surgical spine clinics. Patients with low back pain (LBP) radiating to the leg (n = 1243) or with neck and arm pain thought to emanate from the neck (n = 202) were referred to the clinics by their general practitioners. Rheumatologists, physiotherapists, and nurses examined, treated, and informed the patients based on cognitive principles. Follow-up data were collected with a postal questionnaire. Claim, defined as seeking some sort of financial compensation or filing any sort of financial claim, such as workers' compensation, was the main independent variable. Potential confounders examined were: age, sex, social class, smoking, duration and severity of pain and disability. The main outcome measures were: global assessment (main outcome variable), pain, disability, and intake of analgesics. RESULTS: Financial claims were registered by 31% of patients. After adjustment for covariates, the odds ratio for claim and no improvement was calculated to be 4.2 (95% CI 2.8-6.2) for the LBP/leg patients and 17.4 (95% CI 5.1-60.1) for the neck/arm patients. CONCLUSION: A claim for financial compensation is strongly and independently linked with a poor prognosis for Danish patients with pain radiating from the low-back or neck.

The regulatory beta-subunit of protein kinase CK2 regulates cell-cycle progression at the onset of mitosis.

Cell-cycle transition from the G(2) phase into mitosis is regulated by the cyclin-dependent protein kinase 1 (CDK1) in complex with cyclin B. CDK1 activity is controlled by both inhibitory phosphorylation, catalysed by the Myt1 and Wee1 kinases, and activating dephosphorylation, mediated by the CDC25 dual-specificity phosphatase family members. In somatic cells, Wee1 is downregulated by phosphorylation and ubiquitin-mediated degradation to ensure rapid activation of CDK1 at the beginning of M phase. Here, we show that downregulation of the regulatory beta-subunit of protein kinase CK2 by RNA interference results in delayed cell-cycle progression at the onset of mitosis. Knockdown of CK2beta causes stabilization of Wee1 and increased phosphorylation of CDK1 at the inhibitory Tyr15. PLK1-Wee1 association is an essential event in the degradation of Wee1 in unperturbed cell cycle. We have found that CK2beta participates in PLK1-Wee1 complex formation whereas its cellular depletion leads to disruption of PLK1-Wee1 interaction and reduced Wee1 phosphorylation at Ser53 and 121. The data reported here reinforce the notion that CK2beta has functions that are independent of its role as the CK2 regulatory subunit, identifying it as a new component of signaling pathways that regulate cell-cycle progression at the entry of mitosis.

Are smooth pursuit eye movements altered in chronic whiplash-associated disorders? A cross-sectional study.

OBJECTIVE: To evaluate whether smooth pursuit eye movements differed between patients with long-lasting whiplash-associated disorders and controls when using a purely computerized method for the eye movement analysis. DESIGN: Cross-sectional study comparing patients with whiplash-associated disorders and controls who had not been exposed to head or neck trauma and had no notable neck complaints. METHODS: Smooth pursuit eye movements were registered while the subjects were seated with and without rotated cervical spine. SUBJECTS: Thirty-four patients with whiplash-associated disorders with symptoms more than six months after a car collision and 60 controls. RESULTS: Smooth pursuit eye movements were almost identical in patients with chronic whiplash-associated disorders and controls, both when the neck was rotated and in the neutral position. CONCLUSION: Disturbed smooth pursuit eye movements do not appear to be a distinct feature in patients with chronic whiplash-associated disorders. This is in contrast to results of previous studies and may be due to the fact that analyses were performed in a computerized and objective manner. Other possible reasons for the discrepancy to previous studies are discussed.