| 1. |
- Ademuyiwa, Adesoji O., et al.
(författare)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 2. |
- Bokhari, Abdulmalik
(författare)
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Genetic determinants of lung cancer and their application toward therapeutics. The role of ZFP148 transcription factor and anaplastic lymphoma kinase (ALK) fusion proteins in non-small cell lung cancer
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lung cancer causes severe morbidity and mortality in millions of patients globally each year. Anaplastic lymphoma kinase (ALK) mutations facilitate neoplastic growth of lung cancer in adults and neuroblastoma in pediatric patients. However, the ways in which ALK interacts with genetic factors to trigger a variety of signaling pathways remain poorly understood. We investigated the transcription factor Zfp148, which represses activation of tumor suppressor p53, and downstream signaling targets of ALK fusion proteins in patient-derived non-small-cell-lung-cancer (NSCLC) cell lines. In addition, we investigated the efficacy of the United States Food and Drug Administration (FDA)-approved ALK inhibitors brigatinib, alectinib, lorlatinib, crizotinib, and ceritinib as modes of therapy in patients with lung cancer. The cumulative data reported in this thesis shed light on the interplay between ALK mutations and the signaling pathways triggered by ALK in the process of cancer development. Our goal is to understand underlying molecular mechanisms in patient-derived cell lines and to identify drug combinations to treat ALK-driven NSCLC. To increase our understanding of differences between two clinical variants of ALK fusion proteins (EML4-ALK variant 1 and variant 3) in NSCLC, we investigated how these variants influence the activity of downstream signaling. We showed that triapine inhibitors of the RRM2 gene have synergistic effects preventing DNA repair, cell cycle regulation, and ALK activation when given in combination with ALK inhibitors in patients with NSCLC expressing EML4-ALK fusion proteins. SAMMANFATTNING PÅ SVENSKA: Lungcancer orsakar varje år morbiditet och mortalitet hos miljontals människor värden över. Mutationer i Anaplastic lymphoma kinase (ALK) bidrar bland annat till utveckling av lungcancer hos vuxna och barn. Hur ALK samspelar med andra genetiska faktorer för att stimulera en bred repertoar av signaleringsvägar är fortfarande oklart. Vi undersökte transkriptionsfaktorn Zfp148, som inhiberar aktivering av tumörsuppressorn p53, och signaleringsvägar som aktiveras nedströms om ALK-fusionsproteiner i cellinjer som etablerats från patienter med icke-småcellig lungcancer. Vi testade hur effektiva de av amerikanska läkemedelsverket (United States Food and Drug Administration, FDA) godkända ALK-inhibitorerna brigatiniv, alectiniv, lorlatinin, crizotinib och ceritinib är mot icke-småcellig lungcancer. Sammantaget belyser de data som presenteras i avhandlingen samspelet mellan ALK-mutationer och de signaleringsvägar som aktiveras av ALK vid cancerutveckling. Målet är att förstå underliggande molekylära mekanismer i patient-deriverade cellinjer och att identifiera drogkombinationer för behandling av ALK-driven lungcancer. För att bättre förstå skillnaden mellan två kliniska varianter av ALK-fusionsproteiner (EML4-ALK variant 1 och variant 3) undersökte vi hur varianterna påverkar signaleringsvägar nedströms om mutationen. Vi visade att RRM2-hämmaren triapine blockerar DNA reparation, cell cykel–reglering, och ALK-aktivering på ett synergistiskt sätt när den kombineras med ALK-inhibitorer, hos patienter med ickle-småcellig lungcancer som utrycker EML4-ALK fusionsproteiner.
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| 3. |
- Bokhari, Abdulmalik, et al.
(författare)
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Novel human-derived EML4-ALK fusion cell lines identify ribonucleotide reductase RRM2 as a target of activated ALK in NSCLC
- 2022
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Ingår i: Lung Cancer. - : Elsevier BV. - 0169-5002. ; 171, s. 103-114
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Echinoderm microtubule-associated protein-like 4 (EML4)-Anaplastic Lymphoma Kinase (ALK) rearrangements occur in 3% to 7% of lung adenocarcinomas and are targets for treatment with tyrosine kinase inhibitors (TKIs). Here we have developed three novel EML4-ALK-positive patient–derived Non-Small-Cell-Lung-Cancer (NSCLC) cancer cell lines, CUTO8 (variant 1), CUTO9 (variant 1) and CUTO29 (variant 3) and included a fourth ALK-positive cell line YU1077 (variant 3) to study ALK-positive signaling and responses. Variants 1 and 3 are the most common EML4-ALK variants expressed in ALK-positive NSCLC, and currently cell lines representing these EML4-ALK variants are limited. Materials and methods: Resazurin assay was performed to evaluate cell viability. Protein levels were determined using western blotting. RNA sequencing was performed in all four cell lines to identify differentially expressed genes. Whole-genome sequencing was performed to determine the presence of EML4-ALK fusion and ALK tyrosine kinase inhibitor resistance mutations. Results: In this study, we have confirmed expression of the corresponding ALK fusion protein and assessed their sensitivity to a range of ALK tyrosine kinase inhibitors. These patient derived cell lines exhibit differential sensitivity to lorlatinib, brigatinib and alectinib, with EML4-ALK variant 3 containing cell lines exhibiting increased sensitivity to lorlatinib and brigatinib as compared to alectinib. These cell lines were further characterized by whole genome sequencing and RNA-seq analysis that identified the ribonucleotide reductase regulatory subunit 2 (RRM2) as a downstream and potential therapeutic target in ALK-positive NSCLC. Conclusion: We provide a characterization of four novel EML4-ALK-positive NSCLC cell lines, highlighting genomic heterogeneity and differential responses to ALK TKI treatment. The RNA-Seq characterization of ALK-positive NSCLC CUTO8, CUTO9, CUTO29 and YU1077 cell lines reported here, has been compiled in an interactive ShinyApp resource for public data exploration (https://ccgg.ugent.be/shiny/nsclc_rrm2_2022/).
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| 4. |
- Chuang, Tzu-Po, et al.
(författare)
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ALK fusion NSCLC oncogenes promote survival and inhibit NK cell responses via SERPINB4 expression
- 2023
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Ingår i: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 120:8
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Tidskriftsartikel (refereegranskat)abstract
- Anaplastic lymphoma kinase (ALK) fusion variants in Non-Small Cell Lung Cancer (NSCLC) consist of numerous dimerizing fusion partners. Retrospective investigations suggest that treatment benefit in response to ALK tyrosine kinase inhibitors (TKIs) differs dependent on the fusion variant present in the patient tumor. Therefore, under -standing the oncogenic signaling networks driven by different ALK fusion variants is important. To do this, we developed controlled inducible cell models expressing either Echinoderm Microtubule Associated Protein Like 4 (EML4)-ALK-V1, EML4-ALK-V3, Kinesin Family Member 5B (KIF5B)-ALK, or TRK-fused gene (TFG)-ALK and investi-gated their transcriptomic and proteomic responses to ALK activity modulation together with patient-derived ALK-positive NSCLC cell lines. This allowed identification of both common and isoform-specific responses downstream of these four ALK fusions. An inflammatory signature that included upregulation of the Serpin B4 serine protease inhibitor was observed in both ALK fusion inducible and patient-derived cells. We show that Signal transducer and activator of transcription 3 (STAT3), Nuclear Factor Kappa B (NF-kappa B) and Activator protein 1 (AP1) are major transcriptional regulators of SERPINB4 downstream of ALK fusions. Upregulation of SERPINB4promotes survival and inhibits natural killer cell-mediated cytotoxicity, which has potential for therapeutic impact targeting the immune response together with ALK TKIs in NSCLC.
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| 5. |
- Zou, Zhiyuan V., et al.
(författare)
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Genomic profiling of the transcription factor Zfp148 and its impact on the p53 pathway
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Recent data suggest that the transcription factor Zfp148 represses activation of the tumor suppressor p53 in mice and that therapeutic targeting of the human orthologue ZNF148 could activate the p53 pathway without causing detrimental side effects. We have previously shown that Zfp148 deficiency promotes p53-dependent proliferation arrest of mouse embryonic fibroblasts (MEFs), but the underlying mechanism is not clear. Here, we showed that Zfp148 deficiency downregulated cell cycle genes in MEFs in a p53-dependent manner. Proliferation arrest of Zfp148-deficient cells required increased expression of ARF, a potent activator of the p53 pathway. Chromatin immunoprecipitation showed that Zfp148 bound to the ARF promoter, suggesting that Zfp148 represses ARF transcription. However, Zfp148 preferentially bound to promoters of other transcription factors, indicating that deletion of Zfp148 may have pleiotropic effects that activate ARF and p53 indirectly. In line with this, we found no evidence of genetic interaction between TP53 and ZNF148 in CRISPR and siRNA screen data from hundreds of human cancer cell lines. We conclude that Zfp148 deficiency, by increasing ARF transcription, downregulates cell cycle genes and cell proliferation in a p53-dependent manner. However, the lack of genetic interaction between ZNF148 and TP53 in human cancer cells suggests that therapeutic targeting of ZNF148 may not increase p53 activity in humans.
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