| 1. |
- Jonsson, Pär, et al.
(författare)
-
Constrained randomization and multivariate effect projections improve information extraction and biomarker pattern discovery in metabolomics studies involving dependent samples
- 2015
-
Ingår i: Metabolomics. - : Springer. - 1573-3882 .- 1573-3890. ; 11:6, s. 1667-1678
-
Tidskriftsartikel (refereegranskat)abstract
- Analytical drift is a major source of bias in mass spectrometry based metabolomics confounding interpretation and biomarker detection. So far, standard protocols for sample and data analysis have not been able to fully resolve this. We present a combined approach for minimizing the influence of analytical drift on multivariate comparisons of matched or dependent samples in mass spectrometry based metabolomics studies. The approach is building on a randomization procedure for sample run order, constrained to independent randomizations between and within dependent sample pairs (e.g. pre/post intervention). This is followed by a novel multivariate statistical analysis strategy allowing paired or dependent analyses of individual effects named OPLS-effect projections (OPLS-EP). We show, using simulated data that OPLS-EP gives improved interpretation over existing methods and that constrained randomization of sample run order in combination with an appropriate dependent statistical test increase the accuracy and sensitivity and decrease the false omission rate in biomarker detection. We verify these findings and prove the strength of the suggested approach in a clinical data set consisting of LC/MS data of blood plasma samples from patients before and after radical prostatectomy. Here OPLS-EP compared to traditional (independent) OPLS-discriminant analysis (OPLS-DA) on constrained randomized data gives a less complex model (3 versus 5 components) as well a higher predictive ability (Q2 = 0.80 versus Q2 = 0.55). We explain this by showing that paired statistical analysis detects 37 unique significant metabolites that were masked for the independent test due to bias, including analytical drift and inter-individual variation.
|
|
| 2. |
- Lindgren, Moa, et al.
(författare)
-
Type IV Collagen in Human Colorectal Liver Metastases—Cellular Origin and a Circulating Biomarker
- 2022
-
Ingår i: Cancers. - : MDPI. - 2072-6694. ; 14:14
-
Tidskriftsartikel (refereegranskat)abstract
- Circulating type IV collagen (cCOL IV) is a potential biomarker for patients with colorectal liver metastases (CLM) who present with elevated levels of COL IV in both CLM tissue and circulation. This study aimed to establish the cellular origin of elevated levels of COL IV and analyze circulating COL IV in CLM patients. The cellular source was established through in situ hybridization, immunohistochemical staining, and morphological evaluation. Cellular expression in vitro was assessed by immunofluorescence. Tissue expression of COL IV-degrading matrix metalloproteinases (MMPs)-2, -7, -9, and -13 was studied with immunohistochemical staining. Plasma levels of COL IV in CLM patients and healthy controls were analyzed with ELISA. This study shows that cancer-associated fibroblasts (CAFs) express COL IV in the stroma of CLM and that COL IV is expressed in vitro by fibroblasts but not by tumor cells. MMP-2, -7, -9, and -13 are expressed in CLM tissue, mainly by hepatocytes and immune cells, and circulating COL IV is significantly elevated in CLM patients compared with healthy controls. Our study shows that stromal cells, not tumor cells, produce COL IV in CLM, and that circulating COL IV is elevated in patients with CLM.
|
|
| 3. |
- Fava, Cristiano, et al.
(författare)
-
Novel mutations in the SLC12A3 gene causing Gitelman's syndrome in Swedes
- 2007
-
Ingår i: DNA Sequence. - : Informa UK Limited. - 1029-2365 .- 1042-5179. ; 18:5, s. 395-399
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Gitelman's syndrome (GS) is an inherited autosomal recessive disorder due to loss of function mutations in the SLC12A3 gene encoding the Na-Cl co-transporter (NCCT), the target of thiazide diuretics. The defective function of the NCCT, which normally is expressed in the apical membrane of the distal convolute tubule in the kidney, leads to mild hypotension, hypokalemia, hyperreninemic hyperaldosteronism, mild metabolic alkalosis, hypomagnesemia and hypocalciuria. Up to now, more than 100 mutations of the SLC12A3 gene have been described in GS patients. METHODS: We have collected 30 patients from Sweden with a clinical diagnosis of GS and undertaken a mutation screening by SSCP and successive sequencing of the 26 exons and intronic boundaries. Both mutations were identified in most (n = 28, 93%) and at least one mutation was identified in all patients. RESULTS: We found 22 different mutations evenly distributed throughout the gene, 11 of which have not been described previously. The new variants include 8 missense mutations (Glu68Lys, His69Asn, Argl45His, Vall53Met, Gly230Asp, Gly342Ala, Val677Leu and Gly867Ser), 1 insertion (c.834_835insG on exon 6) and 2 splice-site mutations (c.2667 + lT>G substitution in splicing donor site after exon 22, c.1569-1G>A substitution in the splicing acceptor site before exon 13). CONCLUSION: In Swedish patients with the clinical features of GS, disease-causing mutations in the SLC12A3 gene were identified in most patients. The spectrum of GS mutations is wide making full mutation screening of the SLC12A3 gene necessary to confirm the diagnosis.
|
|
| 4. |
- Borena, Wegene, et al.
(författare)
-
A prospective study on metabolic risk factors and gallbladder cancer in the metabolic syndrome and cancer (Me-Can) collaborative study
- 2014
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:2, s. e89368-
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:To investigate the association between metabolic risk factors (individually and in combination) and risk of gallbladder cancer (GBC).METHODS:The metabolic syndrome and cancer project (Me-Can) includes cohorts from Norway, Austria, and Sweden with data on 578,700 men and women. We used Cox proportional hazard regression models to calculate relative risks of GBC by body mass index (BMI), blood pressure, and plasma levels of glucose, cholesterol, and triglycerides as continuous standardised variables and their standardised sum of metabolic syndrome (MetS) z-score. The risk estimates were corrected for random error in measurements.RESULTS:During an average follow-up of 12.0 years (SD = 7.8), 184 primary gallbladder cancers were diagnosed. Relative risk of gallbladder cancer per unit increment of z-score adjusted for age, smoking status and BMI (except for BMI itself) and stratified by birth year, sex and sub-cohorts, was for BMI 1.31 (95% confidence interval 1.11, 1.57) and blood glucose 1.76 (1.10, 2.85). Further analysis showed that the effect of BMI on GBC risk is larger among women in the premenopausal age group (1.84 (1.23, 2.78)) compared to those in the postmenopausal age group (1.29 (0.93, 1.79)). For the other metabolic factors no significant association was found (mid blood pressure 0.96 (0.71, 1.31), cholesterol 0.84 (0.66, 1.06) and serum triglycerides 1.16 (0.82, 1.64)). The relative risk per one unit increment of the MetS z-score was 1.37 (1.07, 1.73).CONCLUSION:This study showed that increasing BMI and impaired glucose metabolism pose a possible risk for gallbladder cancer. Beyond the individual factors, the results also showed that the metabolic syndrome as an entity presents a risk constellation for the occurrence of gallbladder cancer.
|
|
| 5. |
- Wirén, Sara, et al.
(författare)
-
Pooled cohort study on height and risk of cancer and cancer death
- 2014
-
Ingår i: Cancer Causes and Control. - : Springer Berlin/Heidelberg. - 0957-5243 .- 1573-7225. ; 25:2, s. 151-159
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To assess the association between height and risk of cancer and cancer death.METHODS: The metabolic syndrome and cancer project is a prospective pooled cohort study of 585,928 participants from seven cohorts in Austria, Norway, and Sweden. Hazard ratios (HRs) and 95 % confidence intervals (CIs) for cancer incidence and death were estimated in height categories and per 5-cm increment for each cancer site using Cox proportional hazards model.RESULTS: During a mean follow-up of 12.7 years (SD = 7.2), 38,862 participants were diagnosed with cancer and 13,547 participants died of cancer. Increased height (per 5-cm increment) was associated with an increased overall cancer risk in women, HR 1.07 (95 % CI 1.06-1.09), and in men, HR 1.04 (95 % CI 1.03-1.06). The highest HR was seen for malignant melanoma in women, HR 1.17 (95 % CI 1.11-1.24), and in men HR 1.12 (95 % CI 1.08-1.19). Height was also associated with increased risk of cancer death in women, HR 1.03 (95 % CI 1.01-1.16), and in men, HR 1.03 (95 % CI 1.01-1.05). The highest HR was observed for breast cancer death in postmenopausal women (>60 years), HR 1.10 (95 % CI 1.00-1.21), and death from renal cell carcinoma in men, HR 1.18 (95 % CI 1.07-1.30). All these associations were independent of body mass index.CONCLUSION: Height was associated with risk of cancer and cancer death indicating that factors related to height such as hormonal and genetic factors stimulate both cancer development and progression.
|
|
| 6. |
- Sundvall, Pär-Daniel, et al.
(författare)
-
Interleukin-6 concentrations in the urine and dipstick analyses were related to bacteriuria but not symptoms in the elderly: a cross sectional study of 421 nursing home residents
- 2014
-
Ingår i: BMC Geriatrics. - : Springer Science and Business Media LLC. - 1471-2318. ; 14
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Up to half the residents of nursing homes for the elderly have asymptomatic bacteriuria (ABU), which should not be treated with antibiotics. A complementary test to discriminate between symptomatic urinary tract infections (UTI) and ABU is needed, as diagnostic uncertainty is likely to generate significant antibiotic overtreatment. Previous studies indicate that Interleukin-6 (IL-6) in the urine might be suitable as such a test. The aim of this study was to investigate the association between laboratory findings of bacteriuria, IL-6 in the urine, dipstick urinalysis and newly onset symptoms among residents of nursing homes. Methods: In this cross sectional study, voided urine specimens for culture, urine dipstick and IL-6 analyses were collected from all residents capable of providing a voided urine sample, regardless of the presence of symptoms. Urine specimens and symptom forms were provided from 421 residents of 22 nursing homes. The following new or increased nonspecific symptoms occurring during the previous month were registered; fatigue, restlessness, confusion, aggressiveness, loss of appetite, frequent falls and not being herself/himself, as well as symptoms from the urinary tract; dysuria, urinary urgency and frequency. Results: Recent onset of nonspecific symptoms was common among elderly residents of nursing homes (85/421). Urine cultures were positive in 32% (135/421), Escherichia coli was by far the most common bacterial finding. Residents without nonspecific symptoms had positive urine cultures as often as those with nonspecific symptoms with a duration of up to one month. Residents with positive urine cultures had higher concentrations of IL-6 in the urine (p < 0.001). However, among residents with positive urine cultures there were no differences in IL-6 concentrations or dipstick findings between those with or without nonspecific symptoms. Conclusions: Nonspecific symptoms among elderly residents of nursing homes are unlikely to be caused by bacteria in the urine. This study could not establish any clinical value of using dipstick urinalysis or IL-6 in the urine to verify if bacteriuria was linked to nonspecific symptoms.
|
|
| 7. |
- Fernebro, Josefin, et al.
(författare)
-
Focus on the tumor periphery in MRI evaluation of soft tissue sarcoma: infiltrative growth signifies poor prognosis
- 2006
-
Ingår i: Sarcoma. - 1357-714X. ; 2006, s. 21251-21251
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose. Infiltrative microscopical peripheral growth of soft tissue sarcomas (STS) has been shown to be of prognostic importance and preoperative risk stratification could individualize neoadjuvant treatment. Patients and methods. We assessed peripheral tumour growth pattern on preoperative MRI from 78 STS. The findings were correlated to histopathology and to outcome. Results. The MRI-based peripheral tumour growth pattern was classified as pushing in 34 tumours, focally infiltrative in 25, and diffusely infiltrative in 19. All tumours with diffuse infiltration on MRI also showed microscopical infiltration, whereas MRI failed to identify infiltration in two-thirds of the microscopically infiltrative tumours. Diffusely infiltrative growth on MRI gave a 2.5 times increased risk of metastases (P = .01) and a 3.7 times higher risk of local recurrence (P = .02). Discussion. Based on this observation we suggest that MRI evaluation of STS should focus on the peripheral tumour growth pattern since it adds prognostic information of value for decisions on neoadjuvant therapies.
|
|
| 8. |
- Häggström, Christel, et al.
(författare)
-
Prostate Cancer, Prostate Cancer Death, and Death from Other Causes, Among Men with Metabolic Aberrations
- 2014
-
Ingår i: Epidemiology. - 1044-3983 .- 1531-5487. ; 25:6, s. 823-828
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Few previous studies of metabolic aberrations and prostate cancer risk have taken into account the fact that men with metabolic aberrations have an increased risk of death from causes other than prostate cancer. The aim of this study was to calculate, in a real-life scenario, the risk of prostate cancer diagnosis, prostate cancer death, and death from other causes.Methods: In the Metabolic Syndrome and Cancer Project, prospective data on body mass index, blood pressure, glucose, cholesterol, and triglycerides were collected from 285,040 men. Risks of prostate cancer diagnosis, prostate cancer death, and death from other causes were calculated by use of competing risk analysis for men with normal (bottom 84%) and high (top 16%) levels of each factor, and a composite score.Results: During a mean follow-up period of 12 years, 5,893 men were diagnosed with prostate cancer, 1,013 died of prostate cancer, and 26,328 died of other causes. After 1996, when prostate-specific antigen testing was introduced, men up to age 80 years with normal metabolic levels had 13% risk of prostate cancer, 2% risk of prostate cancer death, and 30% risk of death from other causes, whereas men with metabolic aberrations had corresponding risks of 11%, 2%, and 44%.Conclusions: In contrast to recent studies using conventional survival analysis, in a real-world scenario taking risk of competing events into account, men with metabolic aberrations had lower risk of prostate cancer diagnosis, similar risk of prostate cancer death, and substantially higher risk of death from other causes compared with men who had normal metabolic levels.
|
|
| 9. |
- Stocks, Tanja, et al.
(författare)
-
Metabolic risk score and cancer risk : pooled analysis of seven cohorts
- 2015
-
Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 44:4, s. 1353-1363
-
Tidskriftsartikel (refereegranskat)abstract
- Background: There are few data on the joint influence of metabolic factors on risk of separate cancers. Methods: We analysed data on body mass index, blood pressure and plasma levels of glucose, total cholesterol and triglycerides from seven European cohorts comprising 564 596 men and women with a mean age of 44 years. We weighted those factors equally into a standardized metabolic risk score [MRS, mean = 0, standard deviation (SD) = 1], with an individual's level indicated as SDs from the sex-and cohort-specific means. Cancer hazard ratios were calculated by Cox regression with age as timescale and with relevant adjustments including smoking status. All statistical tests were two-sided. Results: During a mean follow-up of 12 years, 21 593 men and 14 348 women were diagnosed with cancer. MRS was linearly and positively associated with incident cancer in total and at sites (P<0.05). In men, risk per SD MRS was increased by 43% (95% confidence interval: 27-61) for renal cell cancer, 43% (16-76) for liver cancer, 29% (20-38) for colon cancer, 27% (5-54) for oesophageal cancer, 20% (9-31) for rectal cancer, 19% (4-37) for leukaemias, 15% (1-30) for oral cancer and 10% (2-19) for bladder cancer. In women, risk increases per SD MRS were 56% (42-70) for endometrial cancer, 53% (29-81) for pancreatic cancer, 40% (16-67) for renal cell cancer, 27% (9-47) for cervical cancer and 17% (3-32) for rectal cancer. Conclusion: This largest study to date on the joint influence of metabolic factors on risk of separate cancers showed increased risks for several cancers, in particular renal cell and liver cancer in men and endometrial and pancreatic cancer in women.
|
|
| 10. |
- Sundvall, Pär-Daniel, et al.
(författare)
-
Antimicrobial resistance in urinary pathogens among Swedish nursing home residents remains low: a cross-sectional study comparing antimicrobial resistance from 2003 to 2012
- 2014
-
Ingår i: BMC Geriatrics. - : Springer Science and Business Media LLC. - 1471-2318. ; 14
-
Tidskriftsartikel (refereegranskat)abstract
- Background: There are several risk factors for the colonisation, infection and spreading of antibiotic resistant bacteria among elderly residents of nursing homes. An updated estimate of the native prevalence of antimicrobial resistance in uropathogens among Swedish nursing home residents is needed. Methods: Urine specimens were collected for culture and antimicrobial susceptibility testing against mecillinam, ampicillin, cefadroxil, trimethoprim, nitrofurantoin and quinolones from the residents of 32 and 22 nursing homes, respectively. The residents were capable of providing a voided urine sample in 2003 and 2012. In 2012 urine specimens were also collected from residents with urinary catheters. Any antibiotic treatment during the previous month was registered in 2003 as well as hospitalisation and any antibiotic treatment during the previous six months in 2012. Results: The proportion of positive urine cultures was 32% (207/651) in voided urine specimens in 2003, 35% (147/421) in 2012, and 46% (27/59) in urine samples from catheters in 2012. Escherichia coli (E. coli) was the most commonly occurring bacteria. Resistance rates in E. coli (voided urine specimens) in 2012 were; ampicillin 21%, trimethoprim 12%, mecillinam 7.7%, ciprofloxacin 3.4%, cefadroxil 2.6% and nitrofurantoin 0.85%. There were no significant changes in the average resistance rates in E. coli for antibiotics tested 2003-2012. In 2012, two isolates of E. coli produced extended spectrum beta-lactamase enzymes (ESBL) and one with plasmid mediated AmpC production. Any antibiotic treatment during the previous month increased the risk for resistance in E. coli, adjusted for age and gender; for mecillinam with an odds ratio (OR) of 7.1 (2.4-21; p = 0.00049), ampicillin OR 5.2 (2.4-11; p = 0.000036), nalidixic acid OR 4.6 (1.4-16; p = 0.014) and trimethoprim OR 3.9 (1.6-9.2; p = 0.0023). Hospitalisation during the previous six months increased the risk for antibiotic resistance in E. coli to ampicillin, ciprofloxacin and any antimicrobial tested, adjusted for age, gender and antibiotic treatments during the previous six months. Conclusions: The average rates of antimicrobial resistance were low and did not increase between 2003 and 2012 in E. coli urinary isolates among Swedish nursing home residents. Antibiotic treatment during the previous month and hospitalisation during the previous six months predicted higher resistance rates.
|
|
