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Biomedical subjects

M Nielsen

Publications and source records attributed to M Nielsen.

At least 19 recordsLinked to original sources
PubMed2006

Screening for breast cancer with mammography.

BACKGROUND: A variety of estimates of the benefits and harms of mammographic screening for breast cancer have been published and national policies vary. OBJECTIVES: To assess the effect of screening for breast cancer with mammography on mortality and morbidity. SEARCH STRATEGY: We searched PubMed (June 2005). SELECTION CRITERIA: Randomised trials comparing mammographic screening with no mammographic screening. DATA COLLECTION AND ANALYSIS: Both authors independently extracted data. Study authors were contacted for additional information. MAIN RESULTS: Seven completed and eligible trials involving half a million women were identified. We excluded a biased trial from analysis. Two trials with adequate randomisation did not show a significant reduction in breast cancer mortality, relative risk (RR) 0.93 (95% confidence interval 0.80 to 1.09) at 13 years; four trials with suboptimal randomisation showed a significant reduction in breast cancer mortality, RR 0.75 (0.67 to 0.83) (P = 0.02 for difference between the two estimates). RR for all six trials combined was 0.80 (0.73 to 0.88). The two trials with adequate randomisation did not find an effect of screening on cancer mortality, including breast cancer, RR 1.02 (0.95 to 1.10) after 10 years, or on all-cause mortality, RR 1.00 (0.96 to 1.04) after 13 years. We found that breast cancer mortality was an unreliable outcome that was biased in favour of screening, mainly because of differential misclassification of cause of death. Numbers of lumpectomies and mastectomies were significantly larger in the screened groups, RR 1.31 (1.22 to 1.42) for the two adequately randomised trials; the use of radiotherapy was similarly increased. AUTHORS' CONCLUSIONS: Screening likely reduces breast cancer mortality. Based on all trials, the reduction is 20%, but as the effect is lower in the highest quality trials, a more reasonable estimate is a 15% relative risk reduction. Based on the risk level of women in these trials, the absolute risk reduction was 0.05%. Screening also leads to overdiagnosis and overtreatment, with an estimated 30% increase, or an absolute risk increase of 0.5%. This means that for every 2000 women invited for screening throughout 10 years, one will have her life prolonged. In addition, 10 healthy women, who would not have been diagnosed if there had not been screening, will be diagnosed as breast cancer patients and will be treated unnecessarily. It is thus not clear whether screening does more good than harm. Women invited to screening should be fully informed of both benefits and harms.

Breast Neoplasms↗
PubMed2006

Duodenal carcinoma in MUTYH-associated polyposis.

Bi-allelic germline mutations in the MUTYH gene give rise to multiple adenomas and an increased incidence of colorectal cancer. In addition, duodenal adenomas and other extra-colonic manifestations have been described in MUTYH-associated polyposis (MAP) patients. We describe two patients with bi-allelic MUTYH gene mutations with duodenal carcinoma. The tumour in Patient A was detected during evaluation of non-specific abdominal complaints. Patient B was already diagnosed with tens of adenomas and a colon carcinoma, when a duodenal neoplasm was detected. The identification of somatic G>T mutations in codon 12 of the K-RAS2 gene provides evidence that the duodenal lesions were induced by MUTYH deficiency. Studies in larger series of MAP patients are needed to investigate the risk of upper-gastro-intestinal malignancies and to determine further guidelines for endoscopical surveillance.

Adenomatous Polyposis Coli↗
PubMed2005

[From gene to disease; MutYH-associated polyposis coli (MAP)].

MutYH-associated polyposis coli (MAP) is an autosomal recessive inherited form of polyposis and colorectal carcinoma associated with germline mutations in the MutYH gene on chromosome I. The MutYH protein is a base excision repair glycosylase which is involved in the repair of damage caused by the oxidation ofa guanine leading to 8-oxo-7,8-dihydroguanine. If the MutYH protein is dysfunctional, G:C --> T:A mutations in the APC-gene give rise to polyposis and in 50-60% of cases also colorectal carcinoma. MutYH polyposis differs from familial adenomatous polyposis coli in its mode of transmission, later age of onset, a less florid form of polyposis, and fewer extra colonic manifestations.

Adenomatous Polyposis Coli↗
PubMed2005

Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP).

OBJECTIVE: To investigate the contribution of MYH associated polyposis coli (MAP) among polyposis families in the Netherlands, and the prevalence of colonic and extracolonic manifestations in MAP patients. METHODS: 170 patients with polyposis coli, who previously tested negative for APC mutations, were screened by denaturing gradient gel electrophoresis and direct sequencing to identify MYH germline mutations. RESULTS: Homozygous and compound heterozygous MYH mutations were identified in 40 patients (24%). No difference was found in the percentage of biallelic mutation carriers between patients with 10-99 polyps or 100-1000 polyps (29% in both groups). Colorectal cancer was found in 26 of the 40 patients with MAP (65%) within the age range 21 to 67 years (median 45). Complete endoscopic reports were available for 16 MAP patients and revealed five cases with gastro-duodenal polyps (31%), one of whom also presented with a duodenal carcinoma. Breast cancer occurred in 18% of female MAP patients, significantly more than expected from national statistics (standardised morbidity ratio = 3.75). CONCLUSIONS: Polyp numbers in MAP patients were equally associated with the attenuated and classical polyposis coli phenotypes. Two thirds of the MAP patients had colorectal cancer, 95% of whom were older than 35 years, and one third of a subset of patients had upper gastrointestinal lesions. Endoscopic screening of the whole intestine should be carried out every two years for all MAP patients, starting from age 25-30 years. The frequent occurrence of additional extraintestinal manifestations, such as breast cancer among female MAP patients, should be thoroughly investigated.

Adenomatous Polyposis Coli↗
PubMed2004

Natural image profiles are most likely to be step edges.

We introduce Geometric Texton Theory (GTT), a theory of categorical visual feature classification that arises through consideration of the metamerism that affects families of co-localised linear receptive-field operators. A refinement of GTT that uses maximum likelihood (ML) to resolve this metamerism is presented. We describe a method for discovering the ML element of a metamery class by analysing a database of natural images. We apply the method to the simplest case--the ML element of a canonical metamery class defined by co-registering the location and orientation of profiles from images, and affinely scaling their intensities so that they have identical responses to 1-D, zeroth- and first-order, derivative of Gaussian operators. We find that a step edge is the ML profile. This result is consistent with our proposed theory of feature classification.

Databases, Factual↗
PubMed2004

SARS CTL vaccine candidates; HLA supertype-, genome-wide scanning and biochemical validation.

An effective Severe Acute Respiratory Syndrome (SARS) vaccine is likely to include components that can induce specific cytotoxic T-lymphocyte (CTL) responses. The specificities of such responses are governed by human leukocyte antigen (HLA)-restricted presentation of SARS-derived peptide epitopes. Exact knowledge of how the immune system handles protein antigens would allow for the identification of such linear sequences directly from genomic/proteomic sequence information (Lauemoller et al., Rev Immunogenet 2001: 2: 477-91). The latter was recently established when a causative coronavirus (SARS-CoV) was isolated and full-length sequenced (Marra et al., Science 2003: 300: 1399-404). Here, we have combined advanced bioinformatics and high-throughput immunology to perform an HLA supertype-, genome-wide scan for SARS-specific CTL epitopes. The scan includes all nine human HLA supertypes in total covering >99% of all individuals of all major human populations (Sette & Sidney, Immunogenetics 1999: 50: 201-12). For each HLA supertype, we have selected the 15 top candidates for test in biochemical binding assays. At this time (approximately 6 months after the genome was established), we have tested the majority of the HLA supertypes and identified almost 100 potential vaccine candidates. These should be further validated in SARS survivors and used for vaccine formulation. We suggest that immunobioinformatics may become a fast and valuable tool in rational vaccine design.

Antigen Presentation↗
PubMed2003

Protein expression changes in a cell system of beta-cell maturation reflect an acquired sensitivity to IL-1beta.

AIM/HYPOTHESIS: Type 1 diabetes mellitus (T1DM) is caused by specific destruction of the pancreatic beta cells in the islets of Langerhans. Increased sensitivity to cytokines, in particular to interleukin-1beta (IL-1beta) seems to be an acquired trait during beta-cell maturation. In response to cytokines both protective and deleterious mechanisms are induced in beta cells, and when the deleterious prevail, T1DM develops. The aims of this study were to identify perturbation in protein patterns (PiPP) associated with beta-cell maturation, and compare these changes to previous analyses of IL-1beta exposed rat islets. For this purpose, proteome analyses were carried out using a cell-line, which matures from a glucagon-producing pre-beta-cell phenotype (NHI-glu) to an insulin-producing beta-cell phenotype (NHI-ins). We have previously shown that this maturation is accompanied by acquired sensitivity to the toxic effects of IL-1beta. METHODS: 2D-gel electrophoresis was used to separate the proteins and MALDI-MS and database searches were performed to identify the proteins. RESULTS: During beta-cell maturation 135 protein spots out of 2239 detectable changed expression levels. Of these, 74 were down-regulated, 44 up-regulated, 16 were suppressed and 1 was expressed de novo. Using MALDI-MS, positive identification was obtained for 93 out of the 135 protein-spots revealing 97 different proteins. Of these, 22 proteins were in common with changes identified in previous proteome analysis of perturbation in protein pattern in IL-1beta exposed rat islets. Several of the proteins were present in more than one spot suggesting post-translational modification. CONCLUSION/INTERPRETATION: Several proteins and protein modifications were identified that could be critically involved in beta-cell maturation, insulin-gene expression and the acquired IL-1beta sensitivity.

Animals↗
PubMed2002

Products of random matrices.

We derive analytic expressions for infinite products of random 2 x 2 matrices. The determinant of the target matrix is log-normally distributed, whereas the remainder is a surprisingly complicated function of a parameter characterizing the norm of the matrix and a parameter characterizing its skewness. The distribution may have importance as an uncommitted prior in statistical image analysis.

Journal Article↗
PubMed2002

On-line determination of nitrite in wastewater treatment by use of a biosensor.

A newly developed biosensor for nitrite having a 90% response time of about 1 min was used to monitor nitrite concentration in activated sludge exposed to oxic/anoxic cycles. The NO2- biosensor contains bacteria that reduce NO2-, but not NO3-, to N2O that is subsequently monitored by a built-in electrochemical sensor. Nitrite plus nitrate (NOx-) was simultaneously monitored by a NOx- biosensor. The maximum operational lifetime of the NO2- biosensor was 6 weeks, but much longer lifetimes can be expected as malfunctioning by the 3 sensors used for longer periods was due to either mechanical damage or ineffective internal sterilization during the construction. Insufficiently sterilized sensors became sensitive also to NO3- after some time due to development of NO3(-)-reducing bacterial populations within the sensor. The fraction of NO2- as compared to NO3- in the activated sludge was very dependent on prehistory, actual loading, and aeration. During balanced operation with NH4+ being exhausted during the later parts of the aerobic cycle, NO2- increased in concentration up to about 50 microM during the early part of the aeration cycle until NH4+ became limiting. At that time the NO2- concentration decreased to low levels. Under some operating conditions a peak of NO2- also appeared in the beginning of the anoxic period. NO2- and NO3- were depleted simultaneously during the anoxic period.

Biosensing Techniques↗
PubMed2001

FYVE zinc-finger proteins in the plant model Arabidopsis thaliana: identification of PtdIns3P-binding residues by comparison of classic and variant FYVE domains.

Classic FYVE zinc-finger domains recognize the phosphoinositide signal PtdIns3P and share the basic (R/K)(1)(R/K)HHCR(6) (single-letter amino acid codes) consensus sequence. This domain is present in predicted PtdIns3P 5-kinases and lipases from Arabidopsis thaliana. Other Arabidopsis proteins, named PRAF, consist of a pleckstrin homology (PH) domain, a regulator of chromosome condensation (RCC1) guanine nucleotide exchange factor repeat domain, and a variant FYVE domain containing an Asn residue and a Tyr residue at positions corresponding to the PtdIns3P-interacting His(4) and Arg(6) of the basic motif. Dot-blot and liposome-binding assays were used in vitro to examine the phospholipid-binding ability of isolated PRAF domains. Whereas the PH domain preferentially bound PtdIns(4,5)P(2), the variant FYVE domain showed a weaker charge-dependent binding of phosphoinositides. In contrast, specificity for PtdIns3P was obtained by mutagenic conversion of the variant into a classic FYVE domain (Asn(4),Tyr(6)-->His(4),Arg(6)). Separate substitutions of the variant residues were not sufficient to impose preferential binding of PtdIns3P, suggesting a co-operative effect of these residues in binding. A biochemical function for PRAF was indicated by its ability to catalyse guanine nucleotide exchange on some of the small GTPases of the Rab family, permitting a discussion of the biological roles of plant FYVE proteins and their regulation by phosphoinositides.

Amino Acid Sequence↗
PubMed2001

Does the D(-)/D(+) production asymmetry decrease at large x(F)?

We have applied the meson cloud model to calculate the asymmetries in D and D(s) meson production in high-energy Sigma(-)-nucleus and pi(-)-nucleus collisions. We find a good agreement with recent data. Our results suggest that the asymmetries may decrease at large x(F).

Journal Article↗
PubMed2001

TerplexDNA gene carrier system targeting artery wall cells.

The development of non-viral gene carrier systems becomes more urgent and important due to the major biosafety considerations involved with application of viral vector systems for clinical gene therapy. We recently developed a novel non-viral gene carrier system, termed TerplexDNA, which showed high gene transfer efficiency when compared to the lipofectamine gene delivery system both in HepG2 and A7R5 cell lines in vitro. In present studies, we demonstrated that the TerplexDNA gene carrier system specifically delivered the reporter genes (LacZ and Luciferase) and therapeutic gene (hrVEGF(165) cDNA) into bovine aortic artery wall cells (endothelial cells and smooth muscle cells) by receptor mediated endocytosis. We found that the transfection efficiency to these primary artery wall cells, when mediated by the TerplexDNA system, was dose-dependent, saturable and was significantly inhibited by excess free LDL. The transfection efficiency of the TerplexDNA gene carrier system was approximately 60-fold higher than that of the lipofectamine gene carrier system. The TerplexDNA gene carrier system is a useful and promising tool for artery wall gene transfer.

Animals↗
PubMed2001

Subsurface dimerization in III-V semiconductor (001) surfaces.

We present the atomic structure of the c(8 x 2) reconstructions of InSb-, InAs-, and GaAs-(001) surfaces as determined by surface x-ray diffraction using direct methods. Contrary to common belief, group III dimers are not prominent on the surface, instead subsurface dimerization of group III atoms takes place in the second bilayer, accompanied by a major rearrangement of the surface atoms above the dimers to form linear arrays. By varying the occupancies of four surface sites the (001)-c(8 x 2) reconstructions of III-V semiconductors can be described in a unified model.

Journal Article↗
PubMed2001

Differences in risk factors for local and distant recurrence after breast-conserving therapy or mastectomy for stage I and II breast cancer: pooled results of two large European randomized trials.

PURPOSE: Risk factors for local and distant recurrence after breast-conserving therapy and mastectomy were compared to define guidelines for the decision making between both treatments. PATIENTS AND METHODS: The data of two randomized clinical trials for stage I and II breast cancer patients were pooled. The total number of patients in the study was 1,772, of whom 879 underwent breast conservation, and 893, modified radical mastectomy. Representative slides of the primary tumor were available for histopathologic review in 1,610 cases (91%). RESULTS: There were 79 patients with local recurrence after breast-conservation and 80 after mastectomy, the 10-year rates being 10% (95% confidence interval [CI], 8% to 13%) and 9% (95% CI, 7% to 12%), respectively. Age no more than 35 years (compared with age >60: hazard ratio [HR], 9.24; 95% CI, 3.74 to 22.81) and an extensive intraductal component (HR, 2.52; 95% CI, 1.26 to 5.00) were significantly associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion was predictive of the risk of local recurrence, irrespective of the type of primary treatment (P <.01). Tumor size, nodal status, high histologic grade, and vascular invasion were all highly significant predictors of distant disease after breast-conserving therapy and mastectomy (P <.01). Age no more than 35 years and microscopic involvement of the excision margin were additional independent predictors of distant disease after breast-conserving therapy (P <.01). CONCLUSION: Age no more than 35 years and the presence of an extensive intraductal component are associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion causes a higher risk of local recurrence after mastectomy as well as after breast-conserving therapy and should therefore not be used for deciding between the two treatments.

Adult↗
PubMed2001

STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma.

A characteristic feature of neoplastic transformation is the loss of external control by cytokines and extracellular matrix of cellular differentiation, migration, and mitogenesis. Because suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine-induced signaling, it has been hypothesized that an aberrant SOCS expression plays a role in neoplastic transformation. This study reports on a constitutive SOCS-3 expression in cutaneous T-cell lymphoma (CTCL) cell lines. SOCS-3 protein is constitutively expressed in tumor cell lines (but not in nonmalignant T cells) obtained from affected skin from a patient with mycosis fungoides (MF) and from peripheral blood from a patient with Sezary syndrome (SS). In contrast, constitutive SOCS-3 expression is not found in the leukemic Jurkat T-cell line, the MOLT-4 acute lymphoblastic leukemia cell line, and the monocytic leukemic cell line U937. Expression of SOCS-3 coincides with a constitutive activation of STAT3 in CTCL tumor cells, and stable transfection of CTCL tumor cells with a dominant negative STAT3 strongly inhibits SOCS-3 expression, whereas transfection with wild-type STAT3 does not. Moreover, the reduced SOCS-3 expression in cells transfected with the dominant negative STAT3 is associated with an increased sensitivity to interferon-alpha (IFN-alpha). In conclusion, evidence is provided for a constitutive SOCS-3 expression in cancer cells obtained from patients with CTCL. Moreover, the findings indicate that the aberrant expression of SOCS-3 is mediated by a constitutive activation of STAT3 in CTCL cells and affects the IFN-alpha sensitivity of these cells. (Blood. 2001;97:1056-1062)

Cell Transformation, Neoplastic↗
PubMed2001

Radically altered T cell receptor signaling in glycopeptide-specific T cell hybridoma induced by antigen with minimal differences in the glycan group.

A T cell hybridoma raised against the synthetic glycopeptide T(72)(Tn) was used to study whether the initial TCR signaling events are markedly different when the hybridoma is stimulated with glycopeptides closely related to the cognate glycopeptide antigen. T(72)(Tn) has an alpha-D-GalNAc group O-linked to the central threonine in the decapeptide VITAFTEGLK, and the hybridoma is known to be highly specific for this carbohydrate group. T(72)(Tn)-pulsed APC induced tyrosine phosphorylation of the TCR-zeta 21- and 23-kDa proteins and the downstream p42/44 MAP kinase and strong IL-2 secretion. APC pulsed with T(72)(alpha-D-GlcNAc), which differs from T(72)(Tn) solely by the orientation of a hydroxy group in the carbohydrate structure, completely failed to induce detectable tyrosine phosphorylation and IL-2 secretion. APC pulsed with S(72)(Tn), which differs from T(72)(Tn) by not having a methyl group in the serine amino acid side chain to which the glycan is attached, induced partial tyrosine phosphorylation of the TCR-zeta 21-kDa protein, no tyrosine phosphorylation of the MAP kinases and no IL-2 production. Molecular modeling of the MHC/glycopeptide complex revealed that the dramatic difference between the stimulatory power of T(72)(Tn) and T(72)(alpha-D-GlcNAc) is mainly due to very small differences in the TCR exposed carbohydrate structure.

Cell Line↗
PubMed2001

Immunohistochemical localization of estrogen receptor-alpha in sex ducts and gonads of newborn piglets.

Estrogen receptor-alpha (ER-alpha) expression in piglet uteri has previously been reported from day 15 after birth. Nevertheless, uterine tissue has been reported to be estrogen sensitive from the day of birth. Since estrogen action in the uterine tissue is suggested to be mediated principally by ER-alpha, the present study aimed to evaluate the presence of ER-alpha in uteri of 1- to 2-day-old piglets by means of immunohistochemistry. In addition, sex ducts and gonads of both sexes were examined. The results clearly demonstrate the presence of ER-alpha immunopositive cells in uterine tissue, which explains its estrogen responsiveness. Immunostaining was most intense in the glandular epithelial cells and is suggested to indicate participation of ER-alpha in adenogenesis. In oviducts, almost all epithelial cells were immunostained moderately positive, while the stroma cells were stained comparably more positive. The functional significance of this intensity difference is uncertain but could indicate that part of the estrogen action on the epithelium is mediated through the stroma cells, as is known for the uterus. In ovaries, the surface epithelium and stroma cells were immunostained, whereas germ and granulosa cells were immunonegative. It is speculated that ER-alpha might be involved in yet unknown intraovarian mechanisms. In male sex ducts, immunostaining was virtually confined to the epithelium of efferent ducts. All cells in the epididymis as well as in vas deferens were immunonegative. The unique presence of ER-alpha in efferent ducts corresponds with localization in other species, where it has been shown to be involved in fluid reabsorption. The obtained data on localization of ER-alpha correspond with the present knowledge, obtained in ER-alpha knockout mice, of the biological function of ER-alpha within male and female gonads and sex ducts.

Animals↗