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| 3. |
- Ghaddar, N, et al.
(författare)
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The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 4651-
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Tidskriftsartikel (refereegranskat)abstract
- The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a suitable therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a rationale for the implementation of ISR-based regimens in LUAD treatment.
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| 4. |
- Grabner, B, et al.
(författare)
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Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis
- 2015
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6, s. 6285-
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Tidskriftsartikel (refereegranskat)abstract
- STAT3 is considered to play an oncogenic role in several malignancies including lung cancer; consequently, targeting STAT3 is currently proposed as therapeutic intervention. Here we demonstrate that STAT3 plays an unexpected tumour-suppressive role in KRAS mutant lung adenocarcinoma (AC). Indeed, lung tissue-specific inactivation of Stat3 in mice results in increased KrasG12D-driven AC initiation and malignant progression leading to markedly reduced survival. Knockdown of STAT3 in xenografted human AC cells increases tumour growth. Clinically, low STAT3 expression levels correlate with poor survival and advanced malignancy in human lung AC patients with smoking history, which are prone to KRAS mutations. Consistently, KRAS mutant lung tumours exhibit reduced STAT3 levels. Mechanistically, we demonstrate that STAT3 controls NF-κB-induced IL-8 expression by sequestering NF-κB within the cytoplasm, thereby inhibiting IL-8-mediated myeloid tumour infiltration and tumour vascularization and hence tumour progression. These results elucidate a novel STAT3–NF-κB–IL-8 axis in KRAS mutant AC with therapeutic and prognostic relevance.
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- Rao, Shuan, et al.
(författare)
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RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer
- 2017
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Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 31:20, s. 2099-2112
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Tidskriftsartikel (refereegranskat)abstract
- Lung cancer is the leading cause of cancer deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung cancer in women; however, the underlying mechanisms remain unclear. Here we report that the receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is frequently expressed in primary lung tumors, an active RANK pathway correlates with decreased survival, and pharmacologic RANK inhibition reduces tumor growth in patient-derived lung cancer xenografts. Clonal genetic inactivation of KRas(G12D) in mouse lung epithelial cells markedly impairs the progression of KRas(G12D)-driven lung cancer, resulting in a significant survival advantage. Mechanistically, RANK rewires energy homeostasis in human and murine lung cancer cells and promotes expansion of lung cancer stem-like cells, which is blocked by inhibiting mitochondrial respiration. Our data also indicate survival differences in KRas(G12D)-driven lung cancer between male and female mice, and we show that female sex hormones can promote lung cancer progression via the RANK pathway. These data uncover a direct role for RANK in lung cancer and may explain why female sex hormones accelerate lung cancer development. Inhibition of RANK using the approved drug denosumab may be a therapeutic drug candidate for primary lung cancer.
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| 6. |
- Seidler, Y, et al.
(författare)
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KNOWING WHAT TO DO WITH THE DATA - A QUALITATIVE STUDY ON CHALLENGES OF USING SMARTPHONE-BASED EPROS IN RHEUMATOID ARTHRITIS
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 1081-1081
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Using patient-reported outcomes (PROs) has a long tradition in rheumatology, and PRO measurement is included in many composite indices evaluating disease progression and treatment response [1]. However, little is known about patients´ and health professionals´ (HPs) perceptions of using digitally collected PROs, the so-called ePROs, with a personal smartphone app.ObjectivesTo identify main challenges in utilising ePROs for management and treatment of rheumatoid arthritis from patients’ and HPs’ perspectives.MethodsWe interviewed 25 people with rheumatoid arthritis (RA) and 17 HPs (nurses, rheumatologists, and physiotherapists) from Austria and Denmark. We used the RheumaBuddy app as a practical example to illustrate the digital data collection and the feedback that patients would get from entering their self-reported outcomes. Interviews were recorded and transcribed. We applied a qualitative thematic analysis to identify major themes using a procedure of rigorous coding. Analysis was done by two researchers, and conflicts were solved by consensus. Ethical approval was obtained in both countries.ResultsThree main themes emerged: 1) Being simple yet comprehensive; 2) Resources to interpret, use and act upon the collected data; and 3) Being reminded of the disease. Within the first theme, many valued the intuitiveness and simplicity of ePROs, especially when used as a monitoring tool in between clinical visits. HPs were concerned about not to overwhelm the patients with too many questions. On the other hand, the short ePROs asked in the app were not comprehensive enough to capture psychosocial and lifestyle aspects of the disease which were considered important both by patients and HPs. Within the second theme, patients and HPs expressed that ePROs could be the basis for shared decision making. Nevertheless, some patients had clearer ideas on making use of the feedback they could get from their self-reported data than the others. Participants from Denmark, who experienced a higher level of digital health maturity in official institutions, expressed more proactive use of the data than participants from Austria who were on average younger than their Danish counterparts. One patient in Austria even asserted having no idea what to do with the collected data but believed that the “doctor will make good use of it”. HPs in both countries, however, indicated that they needed more resources, skills, and time to make sense of the ePRO data and act accordingly. Under the third theme, patients considered the collection of ePROs to be very important when pain and disease activity were high. HPs, on the other hand, were more concerned that the regular collection of ePROs might constantly remind patients that they are living with the disease.ConclusionThe potential adoption of ePROs in practice depends on both patients and HPs’ motivations and ideas to use the feedback they would get from the collected data. This might be influenced by the level of digital health maturity of a country, as well as available resources. In addition, ePROs need to be intuitive and simple, but at the same time comprehensive and reliable enough so that they can be used for shared decision making. Challenges remain for the ePROs to be used as supporting and empowering tools, and not as reminders of the disease and pain.Table 1.Demographic data of the participants (N=42)DemographicAustriaDenmarkTotalDataPatientHPPatientHPPatientHPN14101172517Women (%)10(71)6(60)7(64)5(71)17(68)11(65)Men (%)4(29)4(40)4(36)2(29)8(32)6(35)AgeMean (Range)54(30-76)41(29-63)65(37-77)47(31-59)60(30-77)44(29-63)References[1]T Stamm, I Parodis, and P Studenic. Patient-reported outcomes with anifrolumab in patients with systemic lupus erythematosus, Lancet Rheumatol, (2022), in Press.AcknowledgementsWe would like to express our particular thank you to all those who have taken part in the interview study and for their valuable inputs.Disclosure of InterestsYuki Seidler: None declared, Tanja Schjødt Jørgensen Speakers bureau: AbbVie, Pfizer, Roche, Novartis, UCB, Biogen and Eli Lilly., Consultant of: AbbVie, Pfizer, Roche, Novartis, UCB, Biogen and Eli Lilly, Paul Studenic: None declared, Helga Radner Speakers bureau: Gilead, Merck Sharp, Pfizer, Abbvie, Consultant of: Gilead, Merck Sharp, Pfizer, Abbvie, Thomas Nygaard: None declared, Nadine Weibrecht: None declared, Nikolas Popper Speakers bureau: Roche, Consultant of: dwh GmbH (as CSO), Lars Erik Kristensen Speakers bureau: Pfizer, AbbVie, Amgen, UCB, Gilead, Biogen, BMS, MSD, Novartis, Eli Lilly, and Janssen pharmaceuticals, Consultant of: Pfizer, AbbVie, Amgen, UCB, Gilead, Biogen, BMS, MSD, Novartis, Eli Lilly, and Janssen pharmaceuticals, Grant/research support from: IIT research grants from Novo, UCB, Eli Lilly; Novartis and Abbvie, Tanita-Christina Wilhelmer: None declared, James Rickmann: None declared, Erika Mosor: None declared, Valentin Ritschl: None declared, Tanja Stamm Speakers bureau: AbbVie, Novartis, Roche, Sanofi, and Takeda., Consultant of: AbbVie and Sanofi Genzyme., Grant/research support from: AbbVie and Roche.
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| 7. |
- Studenic, P, et al.
(författare)
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RHEUMABUDDY4.0 LEADING THE PATH TO A PATIENT-DRIVEN ELECTRONIC SUPPORT AND MONITORING TOOL
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 1801-1802
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The use of health apps has become more popular in recent years, but it is still a small and rather unregulated market. Few apps have been designed in collaboration with patients and these mostly address patient reported symptoms. Some clinical registries have already developed patient apps to complete patient-reported outcome measures (PROMs) on smartphones, which normally would have been collected during an outpatient visit and have shown interchangeability. The next step would be providing a patient app offering possibilities not only of individual disease tracking, but to provide automated peer support, health information and behavioural advice.ObjectivesWe aimed to further develop and validate RheumaBuddy, a health app for patients with rheumatoid arthritis (RA), from a standard monitoring app to an intelligent health app tailored to the needs of the user that provides transparency to all important stakeholders in Rheumatology care.MethodsThis is an international interdisciplinary project between Austrian and Danish partners funded by the EUREKA program. Rheumatologists, health scientists, digital data experts and patients with RA joined forces in a 4 phase-program, running from 2020 to 2023. Phase 1 continues to develop the app in a co-creation approach in several iterations with patients. Phase 2 concerns developing an automated learning algorithm based on user data to identify patient strata and connect these with helpful non-pharmacological interventions. Phase 3 connects healthcare system data on diagnosis, medication prescription, healthcare facility usage with a large clinical RA database. By that we develop patient pathways that correlate high granularity data with system resources to retrieve results on socioeconomic impact. In phase 4 a randomised clinical trial will evaluate the effect of the developed RB4.0 on clinical disease activity and quality of life.ResultsCurrently, RB is regularly being used by more than 3100 patients in 35 countries and 8 languages throughout Europe. The current RheumaBuddy version offers logging of symptoms using Likert scale questions, a joint mannequin to mark painful body parts and a peer-support forum. Additionally, the user can anytime display his/her entries over time in a graphical report and also share data with the healthcare provider. This version is extended with tracking of sleep, working hours and other behaviours. A consultation compass function helps the patient to reflect on goals and issues before the rheumatologist visit.Within this project, we already established a first version of a Recommender System (RS), which computes correlations between user entries (e.g. between a user’s mood and pain), thus providing individual feedback. Through integration of information obtained from the app with claims data and clinical data from a RA registry, patterns can be identified and translated into different case models that concern the impact of common RA symptoms. By mapping these scenarios with evidence based behaviour and lifestyle advice, the “virtual coach” (advanced RS) will be developed and integrated into the RB4.0 system. During continuous data collection on app users, similarities in user behaviour can be identified, and similar entry patterns can be grouped. This will allow users to exchange and learn from each other regarding certain difficult situations (ex. “life-hack”) etc.We are creating a comprehensive system in providing feedback to both clinical and psychosocial aspects of coping and disease management, as well as everyday practicalities for living with a chronic disease. Figure 1 displays these aspects, contributing the empowerment of patients.Figure 1.RB4.0 shall support people living with RA in dealing with disease impactConclusionRheumaBuddy4.0 will provide RA patients the means to improve their quality of life on an individual level, better understand their needs and therapy which could support overcoming barriers of successful shared decision making to achieve better outcomes.Disclosure of InterestsPaul Studenic: None declared, Tanja Stamm Speakers bureau: AbbVie, Novartis, Roche, Sanofi, and Takeda, Consultant of: AbbVie and Sanofi Genzyme, Grant/research support from: AbbVie and Roche, Yuki Seidler: None declared, Andreas Dam Speakers bureau: Gilead, Galapagos, BMS, Roche, Takeda, Merck, Consultant of: Gilead, Galapagos, BMS, Roche, Takeda, Merck, Nadine Weibrecht: None declared, Günther Zauner: None declared, Thomas H Jakobsen: None declared, Rebekka L. Hansen: None declared, Nikolas Popper Speakers bureau: Roche, Consultant of: as CSO of dwh GmbH, Tanita-Christina Wilhelmer: None declared, Helga Radner Speakers bureau: Gilead, Merck Sharp, Pfizer, Abbvie, Consultant of: Gilead, Merck Sharp, Pfizer, Abbvie, Romualdo Ramos: None declared, James Rickmann: None declared, Christoph Urach: None declared, Lars Erik Kristensen Speakers bureau: AbbVie, Pfizer Janssen, Novartis, Galapagos, UCB, Biogen and Eli Lilly, Consultant of: AbbVie, Pfizer, Janssen, Novartis, Galapagos, UCB, Biogen and Eli Lilly, Grant/research support from: IIT grants from UCB, Biogen, Eli Lilly, Novartis, Tanja Schjødt Jørgensen Speakers bureau: AbbVie, Pfizer, Roche, Novartis, UCB, Biogen and Eli Lilly, Consultant of: AbbVie, Pfizer, Roche, Novartis, UCB, Biogen and Eli Lilly
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| 8. |
- Thunnissen, Erik, et al.
(författare)
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The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group
- 2012
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Ingår i: Lung Cancer. - : Elsevier BV. - 1872-8332 .- 0169-5002. ; 76:1, s. 1-18
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Forskningsöversikt (refereegranskat)abstract
- Until recently, the division of pulmonary carcinomas into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was adequate for therapy selection. Due to the emergence of new treatment options subtyping of NSCLC and predictive testing have become mandatory. A practical approach to the new requirements involving interaction between pulmonologist, oncologist and molecular pathology to optimize patient care is described. The diagnosis of lung cancer involves (i) the identification and complete classification of malignancy, (ii) immunohistochemistry is used to predict the likely NSCLC subtype (squamous cell vs. adenocarcinoma), as in small diagnostic samples specific subtyping is frequently on morphological grounds alone not feasible (NSCLC-NOS), (iii) molecular testing. To allow the extended diagnostic and predictive examination (i) tissue sampling should be maximized whenever feasible and deemed clinically safe, reducing the need for re-biopsy for additional studies and (ii) tissue handling, processing and sectioning should be optimized. Complex diagnostic algorithms are emerging, which will require close dialogue and understanding between pulmonologists and others who are closely involved in tissue acquisition, pathologists and oncologists who will ultimately, with the patient, make treatment decisions. Personalized medicine not only means the choice of treatment tailored to the individual patient, but also reflects the need to consider how investigative and diagnostic strategies must also be planned according to individual tumour characteristics. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
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