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| 2. |
- Donia, M., et al.
(författare)
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Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFN gamma Signaling
- 2017
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Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 77:17, s. 4562-4566
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Tidskriftsartikel (refereegranskat)abstract
- Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell-based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFN gamma signaling, led to impaired recognition by tumor-specific CD8(+) T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I-related APM. Loss of target antigens or impaired IFN gamma signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted.
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| 5. |
- Forsberg, Elin, et al.
(författare)
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HER2 CAR-T Cells Eradicate Uveal Melanoma and T-cell Therapy-Resistant Human Melanoma in IL2 Transgenic NOD/SCID IL2 Receptor Knockout Mice
- 2019
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Ingår i: Cancer Research. - 0008-5472. ; 79:5, s. 899-904
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Tidskriftsartikel (refereegranskat)abstract
- Chimeric antigen receptors (CAR) can transmit signals akin to those from activated T-cell receptors when bound to a cell surface target. CAR-expressing T cells against CD19 can cause curative effects in leukemia and lymphoma and is approved for clinical use. However, no CAR-T therapy is currently approved for use in solid tumors. We hypothesize that the resistance of solid tumors to CAR-T can be overcome by similar means as those used to reactivate tumor-infiltrating T lymphocytes (TIL), for example, by cytokines or immune checkpoint blockade. Here we demonstrate that CAR-T cells directed against HER2 can kill uveal and cutaneous melanoma cells in vitro and in vivo. Curative effects in vivo were only observed in xenografts grown in a NOD/SCID IL2 receptor gamma (NOG) knockout mouse strain transgenic for human IL2. The effect was target-specific, as CRISPR/Cas9-mediated disruption of HER2 in the melanoma cells abrogated the killing effect of the CAR-T cells. The CAR-T cells were also able to kill melanoma cells from patients resistant to adoptive T-cell transfer (ACT) of autologous TILs. Thus, CAR-T therapy represents an option for patients that do not respond to immunotherapy with ACT of TIL or immune checkpoint blockade. In addition, our data highlight the use of IL2 transgenic NOG mice as models to prove efficacy of CAR-T-cell products, possibly even in a personalized manner. Significance: These findings demonstrate that a novel humanized mouse model can help clinical translation of CAR-T cells against uveal and cutaneous melanoma that do not respond to TIL therapy or immune checkpoint blockade.
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| 7. |
- Koertge, J., et al.
(författare)
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Vital exhaustion and recurrence of CHD in women with acute myocardial infarction
- 2002
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Ingår i: Psychology, Health & Medicine. - : Informa UK Limited. - 1354-8506 .- 1465-3966. ; 7:2, s. 117-126
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to investigate the prospective impact of vital exhaustion on recurrence after acute myocardial infarction (AMI) in women. Women ≤ 65 years, mean age = 55.30, SD = 7. 63, N = 110, consecutively admitted to a coronary care unit with AMI were examined after three-six months, and followed for five years. Vital exhaustion was assessed using an early version of the Maastricht Questionnaire. A recurrent event was defined as cardiac death, AMI or a revascularization procedure. Forty-five recurrent events were found (in 41% of the study group). One standard deviation (8.4 points) increase of vital exhaustion scores was associated with a 53 % increased risk of a new event and a score above the median was associated with a hazard ratio of 2.24 (95% CI 1.21-4.14). These results remained after adjusting severity of chest pain and significant coronary stenosis. In conclusion, it was found that vital exhaustion is a marker of poor prognosis in women with AMI. The relationship appears to be independent of signs of underlying disease, including severity of chest pain and significant coronary stenosis.
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| 8. |
- Lebègue, Sebastien, et al.
(författare)
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Multiplet effects in the electronic structure of heavy rare-earth metals
- 2006
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Ingår i: JOURNAL OF PHYSICS-CONDENSED MATTER. - : IOP Publishing. - 0953-8984 .- 1361-648X. ; 18, s. 6329-
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Tidskriftsartikel (refereegranskat)abstract
- The spectroscopic properties of elemental terbium, dysprosium, holmium, and erbium are investigated using first-principles calculations taking into account intra-atomic correlation effects. In order to describe the strongly localized f electrons together with the conduction bands, we have used the multiband Hubbard-I approximation to reproduce the multiplet features present in the experimental spectra. A comparison with available experimental data is made and the overall agreement is found to be good.
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| 9. |
- Lebègue, Sebastien, et al.
(författare)
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Multiplet effects in the electronic structure of light rare-earth metals
- 2006
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Ingår i: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 74:4, s. 045114-
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Tidskriftsartikel (refereegranskat)abstract
- The excited-state properties of the light rare-earth elemental metals praseodymium, neodymium, and samarium are studied within the Hubbard-I formalism. This method describes the multiplets of the rare-earth f shell by an exact diagonalization of the two-body part of the Hamiltonian. Subsequently, the rare-earth ion is embedded in the solid environment by incorporation of the atomic self-energy into a solid Green's function, which is calculated using the local density approximation to density functional theory. After describing the method briefly, a systematic comparison with available photoemission experiments is made, and it is found that all main structures of the experimental spectra are reproduced by the approach, with the exception of the features immediately below the Fermi level which are interpreted as a mark of a mechanism different from an atomiclike multiplet transition.
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| 10. |
- Grip, L, et al.
(författare)
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Coronary angioplasty in patients with unstable angina, with special reference to preceding treatment with antithrombin III and heparin
- 1996
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Ingår i: CLINICAL AND APPLIED THROMBOSIS-HEMOSTASIS. - : SAGE Publications. - 1076-0296 .- 1938-2723. ; 2:2, s. 107-115
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Seventy-nine patients undergoing percutane ous transluminal coronary angioplasty (PTCA) for unsta ble angina were analyzed with respect to preceding an tithrombin treatment; group I comprised patients (n = 26) without antecedent antithrombin therapy; group II, pa tients (n = 30) with heparin infusion for ≥24 h, and group III patients (n = 23) with ongoing heparin infusion and given antithrombin III concentrate immediately before the procedure because of plasma antithrombin III <85%. Immediate results were 89% (70 of 79) angiographic suc cess, five (6%) subacute occlusions (two subsequent non-Q wave infarctions), no emergency coronary artery bypass grafting (CABG), and no immediate mortality. There were no differences between the groups. From dis charge to 4 months, one patient died, one had a nonfatal infarction, and 24 (30%) had repeated PTCA or CABG. The cumulative 4-month event rate was 11 of 26 (42%) in group I, 10 of 30 (33%) in group II, and 7 of 23 (30%) in group III (NS). During PTCA, heparin bolus administra tion was guided by activated clotting time (ACT), aiming at>300 s. Baseline ACT was significantly less in patients not treated with heparin (129 ± 34 s in group I vs. 179 ± 38 and 162 ± 29 s in groups II and III, respectively; p < 0.05), but during the procedure, patients from all groups required the same amount of heparin (13,900 ± 4,800, 13,000 ± 6,800, and 13,000 ± 5,700 IU, respectively; NS) to reach similar maximum ACT levels (334 ± 36, 312 ± 32, and 319 ± 44 s, respectively; NS). Patients receiving warfarin ( n = 8) responded with a higher ACT (456 ± 110 s; p < 0.05) on lower doses of heparin (10,000 ± 3,800 IU). In conclusion, patients with unstable angina receiv ing individualized antithrombotic therapy can be success fully treated with PTCA, with an acute complication rate and long-term results comparable with those expected in patients undergoing elective procedures. The value of an tithrombin III substitution must be evaluated in random ized trials. Preprocedural heparin infusion does not re duce the need of extra heparin during the procedure. Key Words: Antithrombin III—Heparin—PTCA (percutane ous transluminal coronary angioplasty)—Unstable angina pectoris.
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