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- Murumagi, A, et al.
(författare)
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Drug response profiles in patient-derived cancer cells across histological subtypes of ovarian cancer: real-time therapy tailoring for a patient with low-grade serous carcinoma
- 2023
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Ingår i: British journal of cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 128:4, s. 678-690
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Tidskriftsartikel (refereegranskat)abstract
- Many efforts are underway to develop novel therapies against the aggressive high-grade serous ovarian cancers (HGSOCs), while our understanding of treatment options for low-grade (LGSOC) or mucinous (MUCOC) of ovarian malignancies is not developing as well. We describe here a functional precision oncology (fPO) strategy in epithelial ovarian cancers (EOC), which involves high-throughput drug testing of patient-derived ovarian cancer cells (PDCs) with a library of 526 oncology drugs, combined with genomic and transcriptomic profiling. HGSOC, LGSOC and MUCOC PDCs had statistically different overall drug response profiles, with LGSOCs responding better to targeted inhibitors than HGSOCs. We identified several subtype-specific drug responses, such as LGSOC PDCs showing high sensitivity to MDM2, ERBB2/EGFR inhibitors, MUCOC PDCs to MEK inhibitors, whereas HGSOCs showed strongest effects with CHK1 inhibitors and SMAC mimetics. We also explored several drug combinations and found that the dual inhibition of MEK and SHP2 was synergistic in MAPK-driven EOCs. We describe a clinical case study, where real-time fPO analysis of samples from a patient with metastatic, chemorefractory LGSOC with a CLU-NRG1 fusion guided clinical therapy selection. fPO-tailored therapy with afatinib, followed by trastuzumab and pertuzumab, successfully reduced tumour burden and blocked disease progression over a five-year period. In summary, fPO is a powerful approach for the identification of systematic drug response differences across EOC subtypes, as well as to highlight patient-specific drug regimens that could help to optimise therapies to individual patients in the future.
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- Raivola, J, et al.
(författare)
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Multiomics characterization implicates PTK7 in ovarian cancer EMT and cell plasticity and offers strategies for therapeutic intervention
- 2022
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 13:8, s. 714-
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Tidskriftsartikel (refereegranskat)abstract
- Most patients with ovarian cancer (OC) are diagnosed at a late stage when there are very few therapeutic options and a poor prognosis. This is due to the lack of clearly defined underlying mechanisms or an oncogenic addiction that can be targeted pharmacologically, unlike other types of cancer. Here, we identified protein tyrosine kinase 7 (PTK7) as a potential new therapeutic target in OC following a multiomics approach using genetic and pharmacological interventions. We performed proteomics analyses upon PTK7 knockdown in OC cells and identified novel downstream effectors such as synuclein-γ (SNCG), SALL2, and PP1γ, and these findings were corroborated in ex vivo primary samples using PTK7 monoclonal antibody cofetuzumab. Our phosphoproteomics analyses demonstrated that PTK7 modulates cell adhesion and Rho-GTPase signaling to sustain epithelial-mesenchymal transition (EMT) and cell plasticity, which was confirmed by high-content image analysis of 3D models. Furthermore, using high-throughput drug sensitivity testing (525 drugs) we show that targeting PTK7 exhibited synergistic activity with chemotherapeutic agent paclitaxel, CHK1/2 inhibitor prexasertib, and PLK1 inhibitor GSK461364, among others, in OC cells and ex vivo primary samples. Taken together, our study provides unique insight into the function of PTK7, which helps to define its role in mediating aberrant Wnt signaling in ovarian cancer.
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- Henein, Michael Y., et al.
(författare)
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Biomarkers predict in-hospital major adverse cardiac events in covid-19 patients : A multicenter international study
- 2021
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Ingår i: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 10:24
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Tidskriftsartikel (refereegranskat)abstract
- Background: The COVID-19 pandemic carries a high burden of morbidity and mortality worldwide. We aimed to identify possible predictors of in-hospital major cardiovascular (CV) events in COVID-19.Methods: We retrospectively included patients hospitalized for COVID-19 from 10 centers. Clinical, biochemical, electrocardiographic, and imaging data at admission and medications were collected. Primary endpoint was a composite of in-hospital CV death, acute heart failure (AHF), acute myocarditis, arrhythmias, acute coronary syndromes (ACS), cardiocirculatory arrest, and pulmonary embolism (PE).Results: Of the 748 patients included, 141(19%) reached the set endpoint: 49 (7%) CV death, 15 (2%) acute myocarditis, 32 (4%) sustained-supraventricular or ventricular arrhythmias, 14 (2%) cardiocirculatory arrest, 8 (1%) ACS, 41 (5%) AHF, and 39 (5%) PE. Patients with CV events had higher age, body temperature, creatinine, high-sensitivity troponin, white blood cells, and platelet counts at admission and were more likely to have systemic hypertension, renal failure (creatinine ≥ 1.25 mg/dL), chronic obstructive pulmonary disease, atrial fibrillation, and cardiomyopathy. On univariate and multivariate analysis, troponin and renal failure were associated with the composite endpoint. Kaplan–Meier analysis showed a clear divergence of in-hospital composite event-free survival stratified according to median troponin value and the presence of renal failure (Log rank p < 0.001).Conclusions: Our findings, derived from a multicenter data collection study, suggest the routine use of biomarkers, such as cardiac troponin and serum creatinine, for in-hospital prediction of CV events in patients with COVID-19.
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- Scribner, Emily D., et al.
(författare)
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Magnesio-lucchesiite, CaMg3Al6(Si6O18)(BO3)3(OH)3O, a new species of the tourmaline supergroup
- 2021
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Ingår i: American Mineralogist. - : Mineralogical Society of America. - 0003-004X .- 1945-3027. ; 106:6, s. 862-871
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Tidskriftsartikel (refereegranskat)abstract
- Magnesio-lucchesiite, ideally CaMg3Al6(Si6O18)(BO3)3(OH)3O, is a new mineral species of the tourmaline supergroup. The holotype material was discovered within a lamprophyre dike that cross-cuts tourmaline-rich metapelites within the exocontact of the O’Grady Batholith, Northwest Territories (Canada). Two additional samples were found at San Piero in Campo, Elba Island, Tuscany (Italy) in hydrothermal veins embedded in meta-serpentinites within the contact aureole of the Monte Capanne intrusion. The studied crystals of magnesio-lucchesiite are black in a hand sample with vitreous luster, conchoidal fracture, an estimated hardness of 7–8, and a calculated density of 3.168 (Canada) and 3.175 g/cm3 (Italy). In plane-polarized light, magnesio-lucchesiite is pleochroic (O = dark brown, E = colorless) and uniaxial (–); its refractive index values are nω = 1.668(3) and nε = 1.644(3) (Canada), and nω = 1.665(5) and nε = 1.645(5) (Italy). Magnesio-lucchesiite is trigonal, space group R3m, Z = 3, with a = 15.9910(3) Å, c = 7.2224(2) Å, V = 1599.42(7) Å3 (Canada) and with a = 15.9270(10) Å, c = 7.1270(5) Å, V = 1565.7(2) Å3 (Italy, sample 1). The crystal structure of magnesio-lucchesiite was refined to R1 = 3.06% using 2953 reflections with Fo > 4σ(Fo) (Canadian sample; 1.96% / 1225 for the Italian sample) The Canadian (holotype) sample has the ordered empirical formula X(Ca0.60Na0.39K0.01)Σ1.00Y(Mg2.02Fe2+0.62Fe3+0.09Ti0.25V0.01Cr0.01)Σ3.00Z(Al5.31Fe3+0.69)Σ6.00[T(Si5.98Al0.02)Σ6.00O18(BO3)3V[(OH)2.59O0.41]Σ3.00W(O0.78F0.22)Σ1.00. The Italian (co-type) material shows a wider chemical variability, with two different samples from the same locality having ordered chemical formulas: X(Ca0.88Na0.12)Σ1.00Y(Mg1.45Fe2+0.40Al0.79Fe3+0.36)Σ3.00ZAl6[T(Si5.05Al0.95)Σ6.00O18](BO3)3V[(OH)2.90O0.10]Σ3.00W(O0.98F0.02)Σ1.00(sample 1) and X(Ca0.71Na0.21o0.08)Σ1.00Y(Mg2.49Fe2+0.41Ti0.10)Σ3.00Z(Al5.44Fe3+0.46Mg0.09V0.01)Σ6.00[T(Si5.87Al0.13)Σ6.00O18](BO3)3V(OH)3W[O0.61(OH)0.39]Σ1.00 (sample 2). Magnesio-lucchesiite is an oxy-species belonging to the calcic group of the tourmaline supergroup. It is related to lucchesiite by the homovalent substitution YFe ↔ YMg, and to feruvite by the homovalent and heterovalent substitutions YFe ↔ YMg and ZAl3+ + WO2– ↔ ZMg2+ + W(OH)1–. The new mineral was approved by the International Mineralogical Association Commission on New Minerals, Nomenclature and Classification (IMA 2019-025). Occurrences of magnesio-lucchesiite show that its presence is not restricted to replacement of mafic minerals only; it may also form in metacarbonate rocks by fluctuations of F and Al during crystallization of common uvitic tourmaline. High miscibility with other tourmaline end-members indicates the large petrogenetic potential of magnesio-lucchesiite in Mg,Al-rich calc-silicate rocks, as well as contact-metamorphic and metasomatic rocks.
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