| 1. |
- Kaaks, Rudolf, et al.
(författare)
-
Tumor-associated autoantibodies as early detection markers for ovarian cancer? : A prospective evaluation
- 2018
-
Ingår i: International Journal of Cancer. - : Wiley-Blackwell. - 0020-7136 .- 1097-0215. ; 143:3, s. 515-526
-
Tidskriftsartikel (refereegranskat)abstract
- Immuno-proteomic screening has identified several tumor-associated autoantibodies (AAb) that may have diagnostic capacity for invasive epithelial ovarian cancer, with AAbs to P53 proteins and cancer-testis antigens (CTAGs) as prominent examples. However, the early detection potential of these AAbs has been insufficiently explored in prospective studies. We performed ELISA measurements of AAbs to CTAG1A, CTAG2, P53 and NUDT11 proteins, for 194 patients with ovarian cancer and 705 matched controls from the European EPIC cohort, using serum samples collected up to 36 months prior to diagnosis under usual care. CA125 was measured using electrochemo-luminiscence. Diagnostic discrimination statistics were calculated by strata of lead-time between blood collection and diagnosis. With lead times 6 months, ovarian cancer detection sensitivity at 0.98 specificity (SE98) varied from 0.19 [95% CI 0.08-0.40] for CTAG1A, CTAG2 and NUDT1 to 0.23 [0.10-0.44] for P53 (0.33 [0.11-0.68] for high-grade serous tumors). However, at longer lead-times, the ability of these AAb markers to distinguish future ovarian cancer cases from controls declined rapidly; at lead times >1 year, SE98 estimates were close to zero (all invasive cases, range: 0.01-0.11). Compared to CA125 alone, combined logistic regression scores of AAbs and CA125 did not improve detection sensitivity at equal level of specificity. The added value of these selected AAbs as markers for ovarian cancer beyond CA125 for early detection is therefore limited. What's new? Could autoantibodies against tumor antigens provide an early warning system for ovarian cancer? These authors tested how well certain antibodies detected ovarian cancer. They selected four candidate antibodies, to p53, CTAG1A, CTAG2 and NUDT11 proteins, which appear in elevated levels in cancer patients. None of them performed well as a herald of burgeoning cancer. They did not perform any better than the best currently available biomarker, CA125, and as lead times increased past 6 months prediagnosis, the effectiveness diminished. Surprisingly, elevated antibodies appeared in quite a few of the control samples, suggesting they might not be as cancer-specific as expected.
|
|
| 2. |
- Lundin, Marika, et al.
(författare)
-
Dual topology of the processed hepatitis C virus protein NS4B is influenced by the NS5A protein
- 2006
-
Ingår i: Journal of General Virology. - : Microbiology Society. - 0022-1317 .- 1465-2099. ; 87, s. 3263-3272
-
Tidskriftsartikel (refereegranskat)abstract
- Among the least-known hepatitis C virus proteins is the non-structural protein 4B (NS4B). It localizes to the endoplasmic reticulum (ER) membrane and induces membrane changes, resulting in a membranous web that is reported to be the locale for virus replication. A model was presented previously for the topology of recombinant HCV NS4B of the 1 a genotype based on in vitro data. In this model, the N-terminal tail of a considerable fraction of the NS4B molecules was translocated into the ER lumen via a post-translational process, giving the protein a dual transmembrane topology. It is now reported that translocation of the N terminus also occurs for processed NS4B expressed in cells in the context of the polyprotein. In the presence of NS5A, however, a lower degree of translocation was observed, which may indicate that NS5A influences the topology of NS4B. In vitro expression studies of NS4B from all major genotypes demonstrated that translocation of the N terminus to the ER lumen is conserved across genotypes. This clearly suggests an important function for this feature. Furthermore, when disrupting a previously reported amphipathic helix (AH) in the N terminus of NS4B, translocation was inhibited. As a disrupted AH also abolished the ability of NS4B to rearrange membranes, these data indicate for the first time an association between translocation of the N terminus and membrane rearrangement. Finally, the present experiments also confirm the predicted location of the first luminal loop to be around aa 112.
|
|
| 3. |
- Lundin, Marika
(författare)
-
Topology and membrane rearrangements of the hepatitis C virus protein NS4B
- 2006
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hepatitis C virus (HCV) is a major cause of chronic liver disease and viral hepatitis around the world. Approximately 180 million people or 3% of the world's population are infected with the virus. The infection does only rarely give rise to any acute symptoms, but more than 70% of those infected develop chronic hepatitis with the risk of developing liver cirrhosis and liver cancer. The only treatment available is a combination therapy of pegylated interferon and the broad spectrum antiviral agent ribavirin. All patients cannot be subjected to this treatment however, and of those treated only about 50% (with variations for different genotypes) will clear the virus. A better understanding of HCV and its life cycle is therefore needed to achieve a more efficient and well tolerated therapy against HCV infection. In order to improve the understanding of HCV, we have focused on one of the least known of the viral proteins - the non structural protein 4B (NS4B). NS4B is a relatively small protein (27 KDa) of mostly unknown functions. It is believed however to play an important, but yet unknown part in the viral replication process. By employing fluorescence microscopy we found that NS4B located in the endoplasmic reticulum (ER) membrane, and that it also had the ability to rearrange the membranes into dense aggregates in the cytoplasm. These new structures are called membrane associated foci (MAF) and are believed to be the locale for viral replication. They are assumed to be the same structures, or closely related, as the structure called "membraneous web" found with electron microscopy. In our studies we also found that NS4B is an integral ER membrane protein. By computer predictions and glycosylation mapping we generated a model where the protein initially has four transmembrane segments with the C- and the N-termini in the cytoplasm. After translation and processing from the polyprotein however, the N-terminus of NS4B translocates to the ER lumen, giving the protein a fifth transmembrane segment. In the presence of another viral protein, NS5A, a lower degree of translocation was observed, indicating that NS5A may influence the dual topology of NS4B. Immunoprecipitation showed us that NS4B could homo-oligomerize, and this ability seemed to correlate with induction of MAF structures. Furthermore, we obtained experimental data suggesting that the translocation of the N-terminus may be involved in this process too and in particular an amphipatic helix around aa 40-69. Finally, based on our topology model we created 14 point mutations in the NS4B protein in the subgenomic replicon to assess what portions of NS4B that are important for replication. All mutants except one had negative effects on the replicon establishment efficiency, even changes located to the luminal loops of NS4B (replication occurs on the cytoplasmic side). Neither the polyprotein efficiency nor the ability to induce MAF were affected, supporting a role of NS4B in HCV replication besides providing the necessary environment for viral replication.
|
|
| 4. |
|
|
| 5. |
- Mastropasqua, Francesca, et al.
(författare)
-
Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis.
- 2023
-
Ingår i: Biology open. - : The Company of Biologists. - 2046-6390. ; 12:10
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic variants affecting Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU) have been identified in several neurodevelopmental disorders (NDDs). HNRNPU is widely expressed in the human brain and shows the highest postnatal expression in the cerebellum. Recent studies have investigated the role of HNRNPU in cerebral cortical development, but the effects of HNRNPU deficiency on cerebellar development remain unknown. Here, we describe the molecular and cellular outcomes of HNRNPU locus deficiency during in vitro neural differentiation of patient-derived and isogenic neuroepithelial stem cells with a hindbrain profile. We demonstrate that HNRNPU deficiency leads to chromatin remodeling of A/B compartments, and transcriptional rewiring, partly by impacting exon inclusion during mRNA processing. Genomic regions affected by the chromatin restructuring and host genes of exon usage differences show a strong enrichment for genes implicated in epilepsies, intellectual disability, and autism. Lastly, we show that at the cellular level HNRNPU downregulation leads to an increased fraction of neural progenitors in the maturing neuronal population. We conclude that the HNRNPU locus is involved in delayed commitment of neural progenitors to differentiate in cell types with hindbrain profile.
|
|
