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- Egg, David, et al.
(författare)
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Therapeutic options for CTLA-4 insufficiency
- 2022
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Ingår i: Journal of Allergy and Clinical Immunology. - : MOSBY-ELSEVIER. - 0091-6749 .- 1097-6825. ; 149:2, s. 736-746
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Tidskriftsartikel (refereegranskat)abstract
- Background: Heterozygous germline mutations in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness. Objective: Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level. Methods: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated. Results: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed. Conclusion: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency.
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- George, Julie, et al.
(författare)
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Comprehensive genomic profiles of small cell lung cancer
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 524:7563, s. 47-U73
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Tidskriftsartikel (refereegranskat)abstract
- We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Dex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
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- Moritz, Juliane, et al.
(författare)
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Hybrid manufacturing of titanium Ti-6Al-4V combining laser metal deposition and cryogenic milling
- 2020
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Ingår i: The International Journal of Advanced Manufacturing Technology. - : Springer. - 0268-3768 .- 1433-3015. ; 107:7-8, s. 2995-3009
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Tidskriftsartikel (refereegranskat)abstract
- Hybrid manufacturing, which, e.g., combines additive manufacturing with conventional machining processes, can be a way of overcoming limitations currently encountered in additive manufacturing. Cryogenic milling might be a viable option for hard-to-cut materials, as it leaves a contamination-free surface and can increase surface quality and tool life compared to conventional cooling concepts. In this study, the influence of cryogenic milling with carbon dioxide on titanium Ti-6Al-4V specimens manufactured with laser metal deposition (LMD) was investigated regarding tool wear and surface integrity in comparison to dry machining and machining with cooling lubricants. Moreover, additional layers of material were deposited on top of conventionally and cryogenically machined surfaces by means of LMD. The interface zone was then examined for defects. The milling process was closely monitored by means of thermal and high-speed imaging. Optical and tactile surface analysis provided evidence that lower roughness values and improved surface qualities could be obtained with cryogenic machining in comparison to dry machining. Moreover, significantly less tool wear was observed when a cryogenic cooling medium was applied. Although the utilization of conventional cooling lubricants resulted in satisfying surface qualities, substantial residual contamination on the milled surface was detected by means of fluorescence analysis. These contaminants are suspected to cause defects when the next layer of material is deposited. This is supported by the fact that pores were found in the weld bead applied on top of the milled specimens by means of LMD. Conversely, cryogenic machining resulted in very clean surfaces due to the residue-free evaporation of the coolant. Hence, a good metallurgical bonding between the weld bead and the milled substrate could be achieved. The results indicate the great potential of cryogenic milling in hybrid manufacturing, especially in terms of intermediate machining, as it provides residue-free surfaces for subsequent material deposition without an additional cleaning step and can significantly prolongate tool life.
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