Ubiquitin-specific protease 2 decreases p53-dependent apoptosis in cutaneous T-cell lymphoma

Treatment of advanced cutaneous T-cell lymphomas (CTCL) is challenging because they are resistant to conventional chemotherapy. USP2 has been shown to promote resistance to chemotherapeutic agents in several cancer models. We show here USP2 is expressed in quiescent and activated T-cells and its expression is 50% lower in CTCL cell lines (MyLa2000, SeAx and Hut-78) than in normal T-cells. USP2 is expressed in neoplastic cells in early, plaque-stage mycosis fungoides (MF) and is downregulated in advanced tumor stages. Upon treatment with psoralen with UVA (PUVA) or a p53 activator, nutlin3a, USP2 expression is significantly increased in MyLa2000 (p53(wt/wt)), but not in SeAx (p53(mut)) or Hut-78 (p53−/−). USP2 knockdown decreases MyLa2000 cell viability after PUVA by 50% but not Hut-78, suggesting that the function of USP2 in CTCL cells is p53-dependent. Furthermore, USP2 knockdown results in a decreased Mdm2 expression and upregulation of p53. Taken together, our findings suggest that USP2 stabilizes Mdm2 which antagonizes pro-apoptotic activity of p53 and possibly contributes to therapeutic resistance in CTCL

En analyse af gevinster og omkostninger ved miljømærkning

The overall objective of this project is to analyse how companies perceive the costs and benefits from environmental labelling. The project only covers two labels: - the Nordic ‘Swan’ and the European ‘Flower’. The majority of the companies have to high or some extent achieved their objectives regarding the labels. Moreover, most companies believe that environmental labelling improves image. One third of the companies state that the benefits from labelling exceed the costs they have encountered. However, more than half of the companies do not feel that they have gained important advantages from environmental labelling, e.g. from additional sales and earnings. With regards to the costs, environmental labelling does not necessitate high investments in new technology, recruitments, education etc. In other words, the cost barriers are in general small and most companies are able to defray the costs of environmental labelling. In conclusion, most companies have at least to some extent achieved their goals, whereas the economic impacts from environmental labelling have so far been limited. This does not necessarily imply that environmental labelling is without importance. On the contrary, environmental labels hold a number of potentials that make them attractive to companies. However, the prospects of environmental labelling depend on the values, attitudes and behaviour of all relevant stakeholders. Based on the results from the project, we have listed a number of recommendations for the companies, the customers and the administrators, which might stimulate the future development of environmentally labelled goods and services: * Companies. Even though companies in general do not experience substantial advantages from environmental labelling, the labels might have a number of indirect effects, which might increase the companies’ competitiveness in the long run. For instance, environmental labelling might improve the companies’ image and serve as a door opener for Side 5 Miljømærker og effekter new markets. Furthermore, the costs of environmental labelling are very limited. However, companies also have to realise that environmental labelling is not a panacea, which automatically generates a number of positive impacts. * Customers. It is often concluded that customers care about the environment and are willing to pay a price premium for environmentalfriendly goods and services. However, this is not always the case. The results indicate that the customers’ actual purchasing behaviour is not necessarily in accordance with ‘green’ purchasing policies. For instance, a number of companies have experienced that the public procurement practises are inconsistent with formal policies. Realising that the public sector is the driver of environmental labelling much has to be done in order to improve the public procurement: - e.g. through education, campaigns and political action. * Administrators. In general, companies are not pleased with the fee structure of the labelling schemes. They think it would be fairer to impose the fees on the companies who do not produce eco-labelled products. Moreover, when eco-labels in general do not increase profit of products and services, the fees inevitable become an impediment to the future growth of environmental labelling. In general, there is a need to align the fee structure as well as the administrative procedures to the actual costs and advantages of environmental labelling

The real-world outcomes of multiple myeloma patients treated with daratumumab

Most patients cannot be included in randomized clinical trials. We report real-world outcomes of all Danish patients with multiple myeloma (MM) treated with daratumumab-based regimens until 1 January 2019. METHODS: Information of 635 patients treated with daratumumab was collected retrospectively and included lines of therapy (LOT), hematologic responses according to the International Myeloma Working Group recommendations, time to next treatment (TNT) and the cause of discontinuation of treatment. Baseline characteristics were acquired from the validated Danish Multiple Myeloma Registry (DMMR). RESULTS: Daratumumab was administrated as monotherapy (Da-mono) in 27.7%, in combination with immunomodulatory drugs (Da-IMiD) in 57.3%, in combination with proteasome inhibitors (Da-PI) in 11.2% and in other combinations (Da-other) in 3.8% of patients. The median number of lines of therapy given before daratumumab was 5 for Da-mono, 3 for Da-IMiD, 4 for Da-PI, and 2 for Da-other. In Da-mono, overall response rate (ORR) was 44.9% and median time to next treatment (mTNT) was 4.9 months. In Da-IMiD, ORR was 80.5%, and mTNT was 16.1 months. In Da-PI, OOR was 60.6% and mTNT was 5.3 months. In patients treated with Da-other, OOR was 54,2% and mTNT was 5.6 months. The use of daratumumab in early LOT was associated with longer TNT (p<0.0001). Patients with amplification 1q had outcome comparable to standard risk patients, while patients with t(4;14), t(14;16) or del17p had worse outcome (p = 0.0001). Multivariate analysis indicated that timing of treatment (timing of daratumumab in the sequence of all LOT that the patients received throughout the course of their disease) was the most important factor for outcome (p<0.0001). CONCLUSION: The real-world outcomes of multiple myeloma patients treated with daratumumab are worse than the results of clinical trials. Outcomes achieved with daratumumab were best when daratumumab was used in combination with IMIDs and in early LOT. Patients with high-risk CA had worse outcomes, but patients with amp1q had similar outcomes to standard-risk patients

MicroRNAs in the pathogenesis, diagnosis, prognosis and targeted treatment of cutaneous T-cell lymphomas

Cutaneous T-cell lymphoma (CTCL) represents a heterogeneous group of potentially devastating primary skin malignancies. Despite decades of intense research efforts, the pathogenesis is still not fully understood. In the early stages, both clinical and histopathological diagnosis is often difficult due to the ability of CTCL to masquerade as benign skin inflammatory dermatoses. Due to a lack of reliable biomarkers, it is also difficult to predict which patients will respond to therapy or progress towards severe recalcitrant disease. In this review, we discuss recent discoveries concerning dysregulated microRNA (miR) expression and putative pathological roles of oncogenic and tumor suppressive miRs in CTCL. We also focus on the interplay between miRs, histone deacetylase inhibitors, and oncogenic signaling pathways in malignant T cells as well as the impact of miRs in shaping the inflammatory tumor microenvironment. We highlight the potential use of miRs as diagnostic and prognostic markers, as well as their potential as therapeutic targets. Finally, we propose that the combined use of miR-modulating compounds with epigenetic drugs may provide a novel avenue for boosting the clinical efficacy of existing anti-cancer therapies in CTCL

Deep Visual Proteomics defines single-cell identity and heterogeneity

Peer reviewe

Detailed Long-Term Follow-Up of Patients Who Relapsed After the Nordic Mantle Cell Lymphoma Trials : MCL2 and MCL3

Mantle cell lymphoma (MCL) is an incurable disease with a highly variable clinical course. The prognosis after relapse is generally poor, and no standard of care exists. We investigated the postrelapse outcomes of 149 patients who were initially treated in the Nordic Lymphoma Group trials, MCL2 or MCL3, both representing intensive cytarabine-containing frontline regimens including autologous stem cell transplant. Patients with progression of disease before 24 months (POD24, n = 51, 34%) displayed a median overall survival of 6.6 months compared with 46 months for patients with later POD (n = 98, 66%; P < 0.001). MCL international prognostic index, cell proliferation marker, blastoid morphology, and TP53 mutations showed independent prognostic value irrespective of POD24, and in a combined, exploratory risk score, patients with 0, 1, 2-3, or 4-5 high-risk markers, respectively, displayed a 5-year overall survival of 62%, 39%, 31%, and 0%. By a comparison of median progression-free survival of the different salvage therapies in the relapse setting, bendamustine-rituximab was superior to all other combination chemotherapy regimens; however, it was also associated with longer responses to last line of therapy. Collectively, we confirm the prognostic impact of POD24 and highlight the relevance of other biomarkers, and we emphasize the importance of novel therapies for patients with high-risk features at first POD.Peer reviewe

En ny start

Natur- og Landbrugskommissionen lægger med denne rapport op til at give naturen i Danmark et markant løft. Vi anbefaler også at indføre en helt ny miljøregulering af landbruget til gavn for både erhverv, vandmiljø, natur og klima, så Danmark kan sætte nye standarder for bæredygtig landbrugsproduktion. Og ikke mindst ønsker vi med vores anbefalinger at give et væsentligt bidrag til at skabe ny vækst og udvikling i landbrugserhvervet. Jeg håber, at Natur- og Landbrugskommissionen med vores anbefalinger og vores måde at arbejde på vil bidrage til, at der skabes gode, holdbare løsninger, og at konstruktiv dialog bliver den dominerende arbejdsform i de kommende år, når der skal findes svar på de udfordringer, som natur, miljø og landbrug står over for. Vi må væk fra grøftegravning og mistænkeliggørelse og frem til en mere konstruktiv samtale, der skal bane vejen for flere fælles accepterede og afbalancerede løsninger. Samfundet og de grønne interesser må acceptere, at landbruget som alle andre erhverv skal have lov til at udvikle sig. Ligesom landbruget må anerkende, at det omgivende samfund har brug for en rig natur og et rent miljø. Der er mange muligheder for at finde løsninger, som både kan give udvikling i landbrugserhvervet, beskytte miljøet og skabe mere og rigere natur. Natur, miljø og vækst er ikke nødvendigvis modsætninger, men kan og skal arbejde sammen. Gode løsninger kræver et godt samarbejde mellem de forskellige interesser. Ingen kan få det hele. Alle vil vinde ved at tænke i helheder, balancer og kompromisser. Det kræver lederskab og politisk ansvarlighed. Natur- og Landbrugskommissionen mener at have løst sin opgave på den fastsatte tid og inden for de rammer og vilkår, som regeringen udstak i sit kommissorium i foråret 2012. Kommissionens samlede anbefalinger sikrer en balance mellem hensyn til erhverv, vækst, miljø, klima og natur. Og derfor opfordrer vi til, at anbefalingerne vurderes og anvendes samlet. Vi håber, at vores anbefalinger vil danne grundlag for en konstruktiv, politisk proces i den kommende tid. Nu er det op til regering og Folketing. Jeg vil gerne takke Natur- og Landbrugskommissionens medlemmer for et engageret og konstruktivt arbejde i det forløbne år. Og tak til vores dygtige og flittige sekretariat. Og endelig en meget stor tak til vores følgegruppe og de mange mennesker og organisationer, som har bidraget til vores arbejde med ideer, vurderinger og konkrete forslag i det forløbne, meget intense år. Jeg håber, at det gode samarbejde vil fortsætte under nye former