Дисертації з теми "Response to therapies"
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1
Massó, Vallés Daniel. "Inhibiting Myc and the Myc dependent inflammatory response as cancer therapies." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/458137.
Анотація:
Aquesta tesi s’ha realitzat al Laboratori de Modelització de Teràpies Anti-tumorals en Ratolí dirigit per la Dra. Laura Soucek al Programa de Recerca Preclínica del Vall d’Hebron Institut d’Oncologia (VHIO), i comprèn dos projectes diferenciats centrats en dues de les funcions oncogèniques de Myc.
Pel que fa al primer projecte, hem validat farmacològicament la inhibició dels mastòcits com a estratègia terapèutica contra l’adenocarcinoma ductal de pàncrees (PDAC). Per a fer-ho, hem utilitzat ibrutinib, un inhibidor de la tirosina quinasa de Bruton (BTK) en models de ratolí de PDAC, el tumor de pàncrees més comú i agressiu. El tractament amb ibrutinib inhibeix la desgranulació dels mastòcits, redueix la proliferació i la infiltració leucocitària a l’estroma del tumor i redueix dràsticament la deposició de col·lagen. En models de PDAC fibrosos, tant transgènics com derivats de pacients, ibrutinib allarga la supervivència i és sinèrgic amb la quimioteràpia, demostrant l’aplicabilitat clínica d’aquest fàrmac enfront del càncer de pàncrees. Aquest projecte a portat a la publicació d’un article científic i un editorial (Masso-Valles et al. 2015; Masso-Valles et al. 2016), a més de contribuir a la posada en marxa d’assajos clínics per testar la combinació d’ibrutinib i quimioteràpia en pacients amb PDAC metastàtic (fase 1/2: NCT02562898 i fase 2/3: NCT02436668).
El segon projecte està centrat en la relació entre Myc i la metàstasi. Hem estudiat el potencial d’Omomyc, un mutant dominant negatiu de Myc que ha demostrat una eficàcia extraordinària enfront a tumors primaris en diversos models de ratolí, contra el càncer de mama metastàtic. Hem demostrat que la inhibició de Myc mitjançant Omomyc és una teràpia segura i eficaç contra el càncer de mama, impedint la proliferació cel·lular, l’angiogènesi, la migració i la invasió in vitro, reduint dramàticament el creixement dels tumors primaris i les metàstasis en ratolins immunodeprimits, fins i tot erradicant metàstasis establertes, i impedint gairebé completament la formació de tumors primaris i metàstasis en ratolins immunocompetents. D’aquesta manera, hem demostrat per primera vegada l’aplicabilitat d’Omomyc enfront de les metàstasis, en contra de la noció preestablerta que la inhibició de Myc podria potenciar, enlloc d’inhibir, el procés d’invasió. Finalment, hem validat TMTP1-Omomyc com el primer fàrmac basat en Omomyc administrable directament per al tractament del càncer de mama metastàtic triple negatiu, proporcionant una nova oportunitat terapèutica per als pacients que pateixen aquesta malaltia devastadora i incurable.The work of this thesis was carried out in the Mouse Models of Cancer Therapies Laboratory led by Dr. Laura Soucek in the Preclinical Research Program of the Vall d’Hebron Institute of Oncology (VHIO), and comprises two differentiated parts centered on two oncogenic functions of Myc. In the first project we validated the pharmacological inhibition of mast cells as a therapeutic strategy against pancreatic ductal adenocarcinoma (PDAC). To do so, we made use of the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib in mouse models of PDAC, the most common and aggressive pancreatic tumor. Treatment with ibrutinib inhibited mast cell degranulation, reduced cell proliferation and leukocytic infiltration in the tumor stroma and dramatically reduced collagen deposition. In fibrotic mouse models of PDAC, both genetically-engineered and patient-derived, ibrutinib extended survival and synergized with chemotherapy, demonstrating the clinical applicability of this drug against pancreatic cancer. This project has led to the publication of a research paper and an editorial (Masso-Valles et al. 2015; Masso-Valles et al. 2016), as well as contributing to the initiation of clinical trials combining ibrutinib with chemotherapy in patients with metastatic PDAC (phase 1/2: NCT02562898 and phase 2/3: NCT02436668). The second project is focused on the relationship between Myc and metastasis. We studied de potential of Omomyc, a Myc dominant negative mutant that had shown extraordinary efficacy against primary tumors in multiple mouse models, against metastatic breast cancer. We demonstrated that Myc inhibition by Omomyc is a safe and effective therapy against breast cancer by impairing cell proliferation, angiogenesis, migration and invasion in vitro, dramatically reducing primary tumor and metastatic growth in immunocompromised mice, even eradicating established metastases, and preventing primary tumor and metastatic formation almost completely in immunocompetent mice. Thus, we have demonstrated for the first time the applicability of Omomyc against metastasis, challenging the pre-established notion that Myc inhibition could potentiate, rather than inhibit, invasion. Finally, we have validated TMTP1-Omomyc as the first direct-deliverable Omomyc-based drug for the treatment of metastatic triple negative breast cancer, providing a new therapeutic opportunity for patients suffering from this dreadful and incurable disease.
2
FATIMA, RIZWAN NARJIS. "Targeting the integrated stress response (ISR) as a therapeutic option for chronic lymphocytic leukemia." Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/25009.
Анотація:
The mechanisms behind development of drug resistance in B-Chronic lymphocytic leukemia (CLL) are unclear and need research to find better treatment options. BCR signalling lead to activation of MEK/ERK, PI3K/AKT pathways and reduced apoptosis through BCL2 pathway. Studies have shown that integrated stress response (ISR) also stimulates oncogenic signalling.
This thesis was aimed at understanding the mechanisms of action of some novel drugs that can inhibit CLL proliferation by targeting the BCR and ISR pathways in presence of an in vitro CLL tumor microenvironment (TME).
We have shown induction of CLL-specific apoptosis by a novel imipridone, ONC-212, by targeting specific proteins of ISR, together with inhibition of BCL2 and MAPK/ERK pathways.
In the following chapter, the effects of another imipridone, TR57, were investigated in combination with BCL2 inhibitor, venetoclax. We exhibited synergistic effect of this combination on normal and high risk primary CLL. Studies on TP53 deficient CLL cell line and patient cells with 17p deletion / TP53 mutations showed similar results indicating the efficacy of this combination is independent of TP53 status. We showed upregulation of ATF4, TRAIL, and down-regulation of HSP90, HSP60, Grp78 proteins in cells treated with TR57 alone and in combination with venetoclax. Our study suggests targeting both BCL2 and ISR has therapeutic potential for the treatment of high risk or relapsed/refractory CLL.
The next chapter focuses on a stress regulatory enzyme HYPE. HYPE modifies proteins with AMP in a post translational modification, ‘AMPylation’. We ablated the HYPE gene in the OSU-CLL cell line using CRISPR-Cas9 to study the role of AMPylation in mediating the effects of fludarabine. HYPE KO cells showed more sensitivity to fludarabine compared to WT CLL cells.
We also performed a global proteome analysis (using TMT labelled mass spectrometry) of CLL cell lines in presence and absence of the TP53 gene after treating them with a chemotherapeutic drug, fludarabine. Less downregulation of apoptotic inducing DNA licencing factors in TP53 KO cells compared with WT cells understand fludarabine resistance in CLL.
In conclusion, this thesis highlights how the integrated stress response could be targeted for the treatment of relapsed/refractory, drug resistant and high risk CLL disease
3
Nji, Akindeh Mbuh. "Modeling response and delayance to parasite clearance time to artemisinin combination therapies(ACT)." Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-168213.
4
Randall, Adrian Joseph. "A systems approach to uncovering the adaptive response of cancer to targeted therapies." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/72967.
Анотація:
Thesis (S.M.)--Massachusetts Institute of Technology, Computational and Systems Biology Program, 2012.Cataloged from PDF version of thesis.
Includes bibliographical references (p. 47-53).
Tyrosine kinase inhibitors have significant promise in the fight to develop agents that can target cancer in a tumor-specific manner. A number of drugs have been and are currently in development to inhibit specific kinases that can mediate uncontrolled proliferation; however, an unfortunate eventuality for most patients receiving these treatments is the development of resistance that renders these drugs almost completely ineffective. While a number of mechanisms can evolve within a tumor to mitigate effects of kinase inhibitors, we sought to uncover what changes are occurring in the tyrosine phosphorylation network at both short timescales (minutes to 72 hours) and long timescales (120 hours+) that can be playing a role in helping a tumor become resistant to driver-kinase inhibition. It is our hypothesis that specific feedback networks are able to detect and overcome driver kinase inhibition through activation of potential other pathways, which can go on to mediate a longer term resistance phenotype. In order to probe dynamics in the tyrosine phosphorylation network, we employed mass spectrometry to analyze peptides derived from six non-small cell lung cancer cell lines that we classify as either EGFR+ or EML4-ALK+. From both mass spectrometry data and growth assays, we identified an unintuitive boost in signaling and growth in response to low inhibitor concentrations, suggestive of a cellular mechanism that is adaptive to driver kinase inhibition. Studies of EML4-ALK driven H3122 cells showed that this short-term response is not the same as the known long-term resistance mechanism to ALK inhibition, leading support to the notion that the short-term "adaptive response" may be a novel type of mechanism to aid tumor adaptation to targeted therapies. In an effort to better probe signaling events occurring downstream of the phosphotyrosine network, a new pull down technique for mass spectrometry using 14-3-3 protein against phosphoserine and phosphothreonine peptides is described. The results of these studies open up many potential avenues for further exploration into the immediate and long-term signaling response of cancer to targeted therapies.
by Adrian Joseph Randall.
S.M.
5
Breen, Michael Scott. "TISSUE RESPONSE TO INTERVENTIONAL MRI-GUIDED THERMAL ABLATION THERAPY." Case Western Reserve University School of Graduate Studies / OhioLINK, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=case1080938405.
6
Reddy, Papari Prashanth. "Non-motor symptoms in advanced Parkinson's : the natural history and response to advanced therapies." Thesis, King's College London (University of London), 2015. http://kclpure.kcl.ac.uk/portal/en/theses/nonmotor-symptoms-in-advanced-parkinsons(b82ce682-b4f0-424d-9c7e-9f293b11bc18).html.
Анотація:
Background and Method Non-motor symptoms (NMS) are a key determinant of health related quality of life (HrQoL) in Parkinson’s disease (PD) (Martinez-Martin et al., 2011) and are present in virtually every PD patient. Many aspects of NMS are treatable by dopaminergic drugs (Chaudhuri and Schapira, 2009) and treating NMS remains a key unmet need. (Chaudhuri et al., 2011) Currently treatment choices in advanced PD are Apomorphine (Apo), intra-jejunal levodopa infusion (IJLI) and Deep brain stimulation of the subthalamic nucleus (DBS-STN) and are solely recommended based on motor symptoms. This thesis addresses a range of comparative multicentre, international collaborative studies of real life dopaminergic therapies in PD with a focus on non-motor effects. Non-motor effect has been measured using the validated PD non-motor symptoms scale (NMSS). (Chaudhuri et al., 2007) The largest real life worldwide study with a long-term longitudinal follow-up design addresses a key unmet need with over 40 patients in each arm. Using regression analysis and comparative measures, effects on motor function, quality of life were compared and contrasted with non-motor effects. A patient reported outcome tool was developed using the same cohort of patients. Results and Conclusion This project has shown the beneficial effects of Apo, IJLI and DBS-STN therapies on aspects of NMS in advanced Parkinson’s that translate to a robust improvement in the HrQoL. For the first time we show that there are differences between Apo, a dopamine agonist based therapy versus IJLI (a levodopa therapy) on aspects of NMS and this would need to be explored further. The effects could be explained by a central dopaminergic effect and effective treatment of NMS arising from non-motor fluctuations. (Storch et al., 2013) Choice of advanced therapies in PD should therefore take into account their non-motor effects and patient expectations along with improvement of motor symptoms.
7
Fenton, Audrey C. "The role of oncogenic kras as a determinant of response to EGER?HER2 targeted therapies." Thesis, Queen's University Belfast, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534743.
8
Cramer, Megan L. "Novel signaling pathways in skeletal muscle: Modifiers of disease and the immune response to therapies." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1531790292235549.
9
McNally, Jonathan P. "The rational targeting of the DNA damage response pathway for the selective elimination of encephalitogenic T cells." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1428652709.
10
Beshir, Kahlid Bushra. "Genetic polymorphisms in 'Plasmodium falciparum' associated with reduced response to artemisinin combination therapies in Western Kenya." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558359.
11
Tousignant, Kaylyn Davis. "Investigation of metabolic rewiring in prostate cancer cells during the adaptive response to androgen-targeted therapies." Thesis, Queensland University of Technology, 2020. https://eprints.qut.edu.au/180822/1/Kaylyn_Tousignant_Thesis.pdf.
Анотація:
The development of therapy resistance is a major obstacle in the successful treatment of advanced prostate cancer. This thesis investigated mechanisms that help drive therapy resistance and discovered that prostate cancer cells can utilise different metabolic pathways in order to become resistant to current therapies. This project also explores new therapeutic strategies to use in combination with current treatments to help fight disease progression and improve outcomes for men with prostate cancer.
12
Savic, Sinisa. "The role of dysregulated unfolded protein response and resistance to apoptosis in the pathogenesis of rheumatoid arthritis and non- response to anti-TNF therapies." Thesis, University of Leeds, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534440.
13
Hu, Qiuhua. "Investigating prostate tumour vasculature and oxygenation status in response to androgen-targeted therapies using photoacoustic-ultrasound imaging." Thesis, Queensland University of Technology, 2022. https://eprints.qut.edu.au/228679/8/Qiuhua_Hu_Thesis.pdf.
Анотація:
This project provides a holistic view of changes in the prostate cancer microenvironment in response to androgen targeted therapies. Oxygen saturation and total haemoglobin were monitored using the ultrasound and photoacoustic imaging capabilities of the VEVO LAZR system (FUJIFILM Visual Sonics Inc) and compared with measuring hypoxic and vascular markers using conventional protein and gene expression techniques. Understanding the effects of castration and enzalutamide on the vasculature and oxygenation status of prostate cancer subcutaneous xenografts has the potential to reveal novel mechanisms of therapy resistance and may improve the prediction of patient therapy responses.
14
Nji, Akindeh Mbuh [Verfasser], and Ulrich [Akademischer Betreuer] Mansmann. "Modeling response and delayance to parasite clearance time to artemisinin combination therapies (ACT) / Akindeh Mbuh Nji. Betreuer: Ulrich Mansmann." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/1049393309/34.
15
Hecker, Michael [Verfasser], Reinhard [Akademischer Betreuer] Guthke, Raimund W. [Akademischer Betreuer] Kinne, and Ronald [Akademischer Betreuer] Westra. "Integrative Modeling of Transcriptional Regulation in Response to Autoimmune Desease Therapies / Michael Hecker. Gutachter: Reinhard Guthke ; Raimund W. Kinne ; Ronald Westra." Jena : Thüringer Universitäts- und Landesbibliothek Jena, 2011. http://d-nb.info/1016367775/34.
16
Giovanni, Nuciforo Paolo. "Quantitative analysis of HER family proteins using mass spectrometry as a predictive tool of response to anti-HER therapies in breast cancer." Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/395203.
Анотація:
Introducción: La expresión desregulada y la actividad de los miembros de la familia HER es frecuente en el cáncer de mama (CM). Hasta el 25% de CM sobreexpresan HER2. Los altos niveles de este oncogén, casi invariablemente como consecuencia de la amplificación genómica, conllevan una enfermedad agresiva y es una importante diana terapéutica. Los anticuerpos monoclonales y las pequeñas moléculas inhibidoras de quinasa son las principales estrategias dirigidas contra HER2 en CM. Aunque el tratamiento con trastuzumab se asocia con importantes beneficios en términos de supervivencia, un número significativo de pacientes con CM HER2-positivo no se benefician de ella o se vuelven resistentes. Otros fármacos anti-HER2 (por ejemplo, lapatinib, pertuzumab y T-DM1) han sido aprobados para el tratamiento de CM metastásico HER2-positivo después de la progresión a trastuzumab. Estos nuevos fármacos anti-HER2 están siendo probados en el tratamiento adyuvante, solo o en regímenes de anticuerpos duales sin quimioterapia concomitante o secuencial. Identificar qué pacientes con CM tienen más probabilidades de beneficiarse de una u otra forma de terapia dirigida anti-HER es crucial. Los métodos actuales para la determinación del estado de HER2 (IHC y FISH) son semicuantitativos, sufren de problemas de reproducibilidad, y no predicen la respuesta al trastuzumab. El objetivo principal de este proyecto fue investigar si el análisis cuantitativo de la proteína HER2 por espectrometría de masas (MS) puede mejorar la predicción actual de respuesta o resistencia a los medicamentos dirigidos contra HER.
Métodos: Hemos cuantificado mediante MS los niveles de proteína HER2 en muestras de tejido, fijados en formol e incluidos en parafina que habían sido clasificadas como negativas (HER2 0, 1+), equívoca (2+) o positiva (3+) por inmunohistoquímica (IHC). Las curvas ROC (Característica Operativa del Receptor) se construyeron mediante el cálculo de la sensibilidad y especificidad de cantidades crecientes de HER2 (por MS) en la predicción de positividad de HER2 (por IHC/ISH combinado) y de beneficio en la supervivencia después de tratamiento con anti-HER2. El análisis de supervivencia se llevo a cabo con el método de Kaplan-Meier y las curvas se compararon mediante el test del Log-Rank. Para el análisis multivariable se utilizó la regresión de Cox ajustado por el estado de los receptores hormonales, el estadío del tumor, los ganglios linfáticos y los niveles de HER2 por MS. Los resultados se consideraron significativos cuando los valores de p (p) fueron menos de 0,05.
Resultados: Los niveles absolutos de HER2 (amol/μg) se correlacionaron significativamente con HER2 por IHC y el estado de la amplificación por ISH (p <0,0001). Dentro de la categoría de IHC-positivos (3+), se observó un amplio rango dinámico de la expresión de la proteína HER2 (de 163,7 a 17,446.7 amol/μg). Utilizando el punto de corte de 740 amol/μg, la tasa de correlación entre HER2 por MS y estándar IHC/ISH fue del 94% (p <0,0001). Los casos discordantes (MS-negativo/ISH-positivo) mostraron un patrón de amplificación característica conocida como “doble minutes” (DM). Los pacientes con niveles de HER2 por MS por encima de 2200 amol/μg (super-expressors) tuvieron un tiempo de supervivencia libre de enfermedad (DFS) y una supervivencia global (OS) mas largas después de tratamiento adyuvante y un OS mas largo en línea metastásica. Ni HER2/CEP17 ni tampoco HER2 GCN fueron predictivos de DFS después de tratamiento adyuvante.
Conclusión: Una cuantificación precisa de la proteína HER2 se puede lograr utilizando la MS y puede llevarse a cabo en muestras de tejido FFPE clínica de los pacientes con CM. La medición cuantitativa de HER2 por MS se correlaciona con la expresión de la proteína por IHC, pero proporciona un rango dinámico más amplio, destacando así la resolución limitada de la IHC diagnóstica. No todos los tumores ISH-positivos muestran expresión alta de la proteína HER2 a pesar de ser IHC 3+. Los tumores amplificados en DM tienen niveles de la proteína HER2 significativamente más bajos en comparación con aquellos con patrón de “homegenously stained regions”. La MS es superior a IHC e ISH en predecir la supervivencia después del tratamiento con terapia anti-HER2. Los pacientes cuyos tumores expresan la proteína HER2 a niveles de > 2200 mg amol/μg obtienen un beneficio más grande tras el tratamiento con la terapia anti-HER2 que los pacientes con bajos niveles de expresión de HER2.Introduction: Dysregulated expression and activity of HER family members is frequent in breast cancer (BC). Up to 25% of BC overexpress HER2. High levels of this oncogene, almost invariably as a consequence of genomic amplification, drives aggressive disease and is an important therapeutic target. Monoclonal antibodies and small molecules kinase inhibitors are the main strategies to target HER2 in BC. Although trastuzumab treatment is associated with considerable benefits in terms survival outcomes, a significant number of patients with HER2-positive BC do not benefit from it or become resistant. Other HER2-targeted drugs (eg, lapatinib, pertuzumab, and T-DM1) have been approved for the treatment of HER2-positive metastatic BC after progression on trastuzumab. These new HER2-targeted drugs are now being tested in the adjuvant setting, alone or in dual antibody regimens without concomitant or sequential chemotherapy. Identifying which patients with BC are most likely to benefit from one or another form of anti-HER targeted therapy is crucial. Current standard methods for the determination of HER2 status (IHC and FISH) are semiquantitative, suffers from reproducibility issues, and do not predict response to trastuzumab. In the present study we sought to investigate if quantitative analysis of HER2 by mass spectrometry (MS) may improve current prediction of response or resistance to HER-targeting drugs. Methods: Using selected reaction monitoring MS, we quantified HER2 protein levels in formalin-fixed, paraffin-embedded tissue samples that had been classified as negative (HER2 0, 1+), equivocal (2+) or positive (3+) by immunohistochemistry (IHC). Receiver operating characteristic (ROC) curves were constructed by computing the sensitivity and specificity of increasing quantities of HER2 (by MS) in predicting HER2 positivity (by combined IHC/ISH) and of survival benefit after anti- HER2 therapy. Survival was modeled using the Kaplan-Meier curves and the p-value obtained by the log-rank test. Multivariate survival analysis was performed using the Cox proportional hazards model adjusted for hormone receptor status, tumor stage, lymph node status and HER2 SRM levels. Results were considered significant when p-values (p) were less than 0.05. Results: Absolute HER2 amol/μg levels were significantly correlated with both HER2 IHC and amplification status by ISH (p<.0001). Within IHC-positive (3+), a wide dynamic range of HER2 protein expression (from 163.7 to 17,446.7 amol/μg) was present. A HER2 threshold of 740 amol/μg showed an agreement rate of 94% with IHC and ISH standard HER2 testing (p<0.0001). Discordant cases (MS-negative/ISH-positive) showed a characteristic amplification pattern known as double minutes (DM). Patients showing HER2 levels by MS above the threshold of 2200 amol/mg (super-expressors) had a significant longer disease-free survival (DFS) and overall survival (OS) in an adjuvant setting and longer OS in a metastatic setting. Neither HER2/CEP17 ratio nor HER2 GCN was predictive of longer DFS or OS in the adjuvant setting. Conclusion: Accurate HER2 protein quantification can be achieved using MS and can be conducted in FFPE clinical tissue samples from BC patients. Quantitative HER2 measurement by MS correlates with protein expression by IHC but provides a wider dynamic range, thus highlighting the limited resolution of diagnostic IHC. Not all ISH-positive tumors show high HER2 protein expression despite being IHC 3+. Tumors amplified in DM show significantly lower HER2 protein levels compared to those with HSR pattern. MS is superior to IHC and ISH in predicting outcome after treatment with anti-HER2 therapy. Patients whose tumors express HER2 protein level >2200 amol/mg benefit more from anti-HER2 therapy than patients with lower HER2 expression levels.
17
Ma, Yuting. "The crosstalk between dying tumor cells and immune effectors within tumor microenvironment elicited by anti-cancer therapies dictates the therapeutic outcome." Phd thesis, Université Paris Sud - Paris XI, 2011. http://tel.archives-ouvertes.fr/tel-00636891.
Анотація:
Besides exerting cytostatic or cytotoxic effects on tumor cells, some anti-cancer therapies (anthracyclines, oxaliplatin, X-Rays) could trigger an immunogenic cell death modality, releasing danger signals to alert immune system. We have shown that tumor-specific IFN- producing CD8+ T cells (Tc1) are mandatory for the success of chemotherapy to prevent tumor outgrowth. Priming of Tc1 response depends on IL-1β secretion by DC confronted with anthracycline-treated tumor cells releasing ATP. To identify the inflammatory components which link innate and cognate immune responses, we analyzed the influence of immunogenic chemotherapy on tumor microenvironment. We found an upregulated Th1- and Th17-related gene expression pattern in growth-retarded tumor after anthracycline treatment. By interfering with IFN- or IL-17A pathways, therapeutic effect of doxorubicin and oxaliplatin was abolished and dying tumor cell-based vaccine lost its efficacy to protect mice from live tumor cell rechallenge. Interestingly, we discovered that distinct subsets of T lymphocytes (V4+ and V6+) colonized tumors shortly after chemotherapy, where they proliferated and became the dominant IL-17 producers within tumor beds. In three tumor models treated with chemotherapy or radiotherapy, a strong correlation between the presence of IL-17-producing T ( T17) and IFN--producing CD8+ TIL (Tc1) was discovered. IL-17A signaling acts as upstream of IFN- since defect in IL-17RA led to complete loss of antigen specific Tc1 priming. The contribution of T17 cells (V4+ and V6+) to chemotherapy is critical as V4/6-/- mice showed reduced sensitivity to chemotherapy and vaccination. Also, tumor infiltrating T17 and Tc1 cells were reduced to basal level in this strain. IL-1β/IL-1R, but not IL-23/IL-23R, is pivotal for IL-17 production by T cells and the success of chemotherapy. Importantly, adoptive transfer of T cells could restore the efficacy of chemotherapy in IL-17A-/- mice and ameliorate the effect of chemotherapy in wild type host, provided that they retain the expression of IL-1R and IL-17A. Our research suggest a DC (IL-1β) → T cells (IL-17) → Tc1 (IFN-) immune axis triggered by chemotherapy-induced dying tumor cells, which is critical for the favorable therapeutic response. To boost the immune system, we try to combine immunogenic chemotherapy with tumor vaccine in the presence of TLR3 agonist Poly (A:U). This sequential combined therapy, which we named VCT, could significantly retard tumor growth or even completely eradicate tumor and establish long-term protection against rechallenge in highly tumorigenic models. To dissect the effect of Poly (A:U) on immune system and that on TLR3 expressing-tumor cells, we performed VCT treatment in nude mice, TRIF-/- mice and with TRIF-silencing tumors. Interestingly, our results suggested that anti-tumor effect of VCT required T cells and intact TRIF signaling pathway at the level of the host and that of tumor cells. Poly (A:U) treatment could induce high level of CCL5 and CXCL10 production from tumor cells both in vitro and in vivo, which could negatively and positively influence the therapeutic outcome. By uncoupling the effect of CCL5 from that of CXCL10, the VCT treatment can be ameliorated. Our study emphasizes that both tumor and host derived inflammatory factors participate in regulating anti-tumor response. We also highlight that therapeutic application of TLR agonists can be optimized through regulating the profile of chemokines and their downstream signaling events.
18
Rudalska, Ramona [Verfasser], and Christiane [Akademischer Betreuer] Ritter. "Multiplex in vitro and in vivo RNAi screening to identify treatment response modifiers of targeted therapies in HCC / Ramona Rudalska ; Betreuer: Christiane Ritter." Braunschweig : Technische Universität Braunschweig, 2014. http://d-nb.info/1175820806/34.
19
Bates, Victoria. "The role of hypoxia-regulated glucose transporters and glucose metabolism in the response to hypoxia-linked therapies and as an indicator of prognosis in solid tumours." Thesis, Liverpool John Moores University, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531361.
20
Yuting, Ma. "The crosstalk between dying tumor cells and immune effectors within tumor microenvironment elicited by anti-cancer therapies dictates the therapeutic outcome." Thesis, Paris 11, 2011. http://www.theses.fr/2011PA11T033/document.
Анотація:
En dehors des effets cytostatiques ou cytotoxiques sur les cellules tumorales, certaines thérapies anti-cancéreuses peuvent déclencher la mort cellulaire immunogénique, libérant les signaux de danger pour alerter le système immunitaire. Les cellules T CD8+ T (Tc1) productrices d’IFN- et spécifiques de la tumeur sont nécessaires pour le succès de la chimiothérapie et la diminution de la croissance tumorale. L’amorçage d’une réponse bénéfique Tc1 dépend de la sécrétion d'IL-1β par les cellules dendritiques confrontées à des cellules tumorales traitées avec de l’anthracycline libérant de l’ATP. Pour identifier les composants inflammatoires qui lient les réponses immunitaires innées et adaptatives, nous avons analysé l'influence de la chimiothérapie immunogène sur le microenvironnement de la tumeur. Nous avons identifié une up-régulation de gènes associés à la réponse Th1 et Th17 dans un modèle de tumeur répondant au traitement par les anthracyclines par un retard de croissance. En interférant avec les voies IFN- ou l'IL-17A, l'effet thérapeutique de la doxorubicine et l'oxaliplatine a été aboli et le vaccin à base de cellules tumorales mortes ne protège plus les souris de la réintroduction de cellules tumorales vivantes. Nous avons également découvert que des sous-populations distinctes de lymphocytes T (V4+ et V6+) colonisent des tumeurs peu de temps après la chimiothérapie, où ils ont proliféré et sont devenus producteurs majeurs de l’IL-17 au sein de la tumeur. Nous avons constaté une forte corrélation entre la présence de lymphocytes T producteurs d’IL-17 ( T17) et de TIL CD8+ (Tc1) dans trois modèles différents de tumeurs traitées par la chimiothérapie ou la radiothérapie. IL-17A agit sur la signalisation en amont de l'IFN- puisqu’un défaut d’expression d’IL-17RA conduit à la perte complète de la production des Tc1 spécifiques de l’antigène. La contribution des cellules T17 (V4+ et V6+) dans l’effet bénéfique de la chimiothérapie est essentielle puisque les souris V4/6-/-. L’axe IL-1β/IL-1R, mais pas IL-23/IL-23R, est essentielle pour la production d'IL-17 par les cellules T et l’effet bénéfique de la chimiothérapie. Le transfert adoptif de lymphocytes T peut rétablir l'efficacité de la chimiothérapie dans le modèle de souris IL-17A-/- et améliorer l'effet de la chimiothérapie chez la souris wt, s'ils conservent l'expression de l'IL-1R et de l'IL-17A. Nos résultats suggèrent l’existence d’un axe fonctionnel: DC (IL-1β) → cellules T (IL-17) → Tc1 (IFN-), déclenché par la chimiothérapie induisant la mort des cellules tumorales, phénomène essentiel pour une réponse thérapeutique favorable. Pour renforcer la réponse immunitaire, nous essayons de combiner la chimiothérapie « immunogène » avec le vaccin anti-tumoral en présence d’adjuvants (poly (A:U), l'agoniste de TLR3).Ce type de thérapie séquentielle combinée, appelé VCT, pourrait retarder considérablement la croissance des tumeurs, voire l’éradiquer complètement et établir une protection spécifique à long terme. Pour décortiquer l'effet de la poly (A:U) sur le système immunitaire et sur les cellules tumorales exprimant le TLR3, nous avons effectué un traitement VCT chez la souris nude, TRIF-/- et les souris présentant une diminution de l’expression de TRIF au niveau des cellules tumorales. Ainsi l'effet anti-tumoral de VCT requiert les lymphocytes T et la voie de signalisation TRIF intacte au niveau de l'hôte et des cellules tumorales. Le traitement poly (A:U) peut induire un niveau élevé de production de certaines chimiokines associées à la réponse de type Th1 (CCL5 et CXCL10 ) par les cellules tumorales in vitro et in vivo, ce qui peut influencer négativement et positivement les résultats thérapeutiques. Le découplage de l’action de CCL5 et de XCL10, pourrait améliorer le traitement par la VCT. Notre étude souligne ainsi le rôle des facteurs inflammatoires dérivés de la tumeur et de l’hôte dans la régulation de la réponse immunitaire anti-tumoraleBesides exerting cytostatic or cytotoxic effects on tumor cells, some anti-cancer therapies (anthracyclines, oxaliplatin, X-Rays) could trigger an immunogenic cell death modality, releasing danger signals to alert immune system. We have shown that tumor-specific IFN- producing CD8+ T cells (Tc1) are mandatory for the success of chemotherapy to prevent tumor outgrowth. Priming of Tc1 response depends on IL-1β secretion by DC confronted with anthracycline-treated tumor cells releasing ATP. To identify the inflammatory components which link innate and cognate immune responses, we analyzed the influence of immunogenic chemotherapy on tumor microenvironment. We found an upregulated Th1- and Th17-related gene expression pattern in growth-retarded tumor after anthracycline treatment. By interfering with IFN- or IL-17A pathways, therapeutic effect of doxorubicin and oxaliplatin was abolished and dying tumor cell-based vaccine lost its efficacy to protect mice from live tumor cell rechallenge. Interestingly, we discovered that distinct subsets of T lymphocytes (V4+ and V6+) colonized tumors shortly after chemotherapy, where they proliferated and became the dominant IL-17 producers within tumor beds. In three tumor models treated with chemotherapy or radiotherapy, a strong correlation between the presence of IL-17-producing T ( T17) and IFN--producing CD8+ TIL (Tc1) was discovered. IL-17A signaling acts as upstream of IFN- since defect in IL-17RA led to complete loss of antigen specific Tc1 priming. The contribution of T17 cells (V4+ and V6+) to chemotherapy is critical as V4/6-/- mice showed reduced sensitivity to chemotherapy and vaccination. Also, tumor infiltrating T17 and Tc1 cells were reduced to basal level in this strain. IL-1β/IL-1R, but not IL-23/IL-23R, is pivotal for IL-17 production by T cells and the success of chemotherapy. Importantly, adoptive transfer of T cells could restore the efficacy of chemotherapy in IL-17A-/- mice and ameliorate the effect of chemotherapy in wild type host, provided that they retain the expression of IL-1R and IL-17A. Our research suggest a DC (IL-1β) → T cells (IL-17) → Tc1 (IFN-) immune axis triggered by chemotherapy-induced dying tumor cells, which is critical for the favorable therapeutic response. To boost the immune system, we try to combine immunogenic chemotherapy with tumor vaccine in the presence of TLR3 agonist Poly (A:U). This sequential combined therapy, which we named VCT, could significantly retard tumor growth or even completely eradicate tumor and establish long-term protection against rechallenge in highly tumorigenic models. To dissect the effect of Poly (A:U) on immune system and that on TLR3 expressing-tumor cells, we performed VCT treatment in nude mice, TRIF-/- mice and with TRIF-silencing tumors. Interestingly, our results suggested that anti-tumor effect of VCT required T cells and intact TRIF signaling pathway at the level of the host and that of tumor cells. Poly (A:U) treatment could induce high level of CCL5 and CXCL10 production from tumor cells both in vitro and in vivo, which could negatively and positively influence the therapeutic outcome. By uncoupling the effect of CCL5 from that of CXCL10, the VCT treatment can be ameliorated. Our study emphasizes that both tumor and host derived inflammatory factors participate in regulating anti-tumor response. We also highlight that therapeutic application of TLR agonists can be optimized through regulating the profile of chemokines and their downstream signaling events
21
Paredes, Raisa, Fritner Véliz, and Aldo Lucchetti. "Comparison of the Virological Response According to the Antiretroviral Regimens in Peruvian HIV Patients Who Presented the M184V Mutation in Two National Hospitals during the Years 2008 to 2019." Mary Ann Liebert Inc, 2021. http://hdl.handle.net/10757/655814.
Анотація:
El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado.Introduction: In patients with HIV in antiretroviral treatment (ART) and virological failure to the first-line regimen, establishing a therapeutic regimen after having identified the M184V mutation, which confers ART resistance, represents a dilemma. Objective: To compare the virological response of the therapeutic regimens prescribed to patients with HIV who presented the M184V mutation in two national hospitals in Lima, Peru, during the years 2008 to 2019, and to determine the risk factors associated with poor virological response. Methods: A retrospective cohort study was developed based on the information of the HIV program participants with the M184V mutation. Results: A total of 175 participants were eligible for the study. The male sex predominated (75.4%), the current median age was 41 years [interquartile range (IQR) 35.84-47.47], and the time on ART was 89 months (IQR 57.7-124.53). The median initial viral load (VL) was 4.5 log10 copies/mL (IQR 3.97-5.09) and the time between genotyping and the change of therapy was 2 months (IQR 0-3.56). The most used antiretroviral regimen was protease inhibitor plus two nucleoside reverse transcriptase inhibitors (55.4%). With the protease inhibitor plus integrase inhibitor (PI + INI) ART, 69% less risk of poor virological response was obtained [p = .019 (confidence interval 95% 0.117-0.825)]. Conclusions: In patients with HIV and the M184V mutation, the PI + INI ART has shown a greater decrease in control VL and, thus, a good virological response. The risk factors associated with a poor virological response were the delay between genotyping and change of therapy, high levels of initial VL, and poor adherence among the participants.
Revisión por pares
22
Lion, Maëva. "Biomarqueurs prédictifs de la réponse aux traitements par thérapies ciblées dans le cancer du sein." Thesis, Université de Lorraine, 2015. http://www.theses.fr/2015LORR0287.
Анотація:
Le cancer du sein est le cancer le plus fréquemment diagnostiqué chez la femme et constitue un véritable problème de santé publique. Les progrès de la biologie moléculaire ont permis la caractérisation des principales voies de signalisation et ont mis en évidence l'implication majeure de la signalisation cellulaire dans les processus de cancérogenèse. Des cibles moléculaires ont ainsi été identifiées et ont permis le développement de thérapeutiques dites ciblées, telles que les anticorps monoclonaux ou encore les inhibiteurs de kinase. Malgré ces avancées considérables qui ont permis l'amélioration de la prise en charge des patientes, on constate l'apparition de résistances aux traitements. Ce travail avait pour objectifs d'identifier de nouveaux biomarqueurs et de déterminer leur signification clinique, leur intérêt théranostique ainsi que leur impact sur la réponse aux traitements. Dans un premier temps nous avons étudié les mutations activatrices du gène PIK3CA. Ces mutations sont retrouvées dans 25% des cancers du sein et sont impliquées dans la résistance au trastuzumab, aux anti-œstrogènes et aux inhibiteurs de mTOR. 149 échantillons de tumeurs de sein infiltrantes ont été analysés par une technique de PCR-HRM (High Resolution Melting) et 118 échantillons par une technique de PCR-ARMS (Amplification Refractory Mutation System). Les résultats des 2 techniques étaient concordants (k=0,845 ; p<0,001) et une relation entre mutations du gène PIK3CA et grade SBR a été mise en évidence, les tumeurs de grade SBR III étant moins fréquemment mutées que les autres (p=0.025 en HRM et p=0.009 en ARMS). Dans un second temps, notre travail a consisté en l'exploration fonctionnelle des voies de signalisation PI3K/AKT/mTOR, RAS/RAF/MAPKinases et P38MAPKinase. Pour cela nous avons analysé le niveau d'expression des phosphoprotéines p-AKT, p-GSK3ß, p-S6 kinase, p-MEK1, p-ERK1/2, p-P90RSK, p-IGF1R ainsi que p-P38MAPK par immuno-analyse multiplexe. Cette partie a comporté 3 études. Une première étude rétrospective sur 45 échantillons de tumeurs mammaires invasives congelées a mis en évidence des niveaux d'expression de P38 et de p-P38 plus élevés dans les tumeurs RE+. La deuxième étude était une étude prospective visant à déterminer des biomarqueurs de réponse à l'association trastuzumab-évérolimus chez des patientes présentant un cancer du sein précoce traitées en préopératoire. Cette étude a révélé une augmentation statistiquement significative du niveau d'expression de p-MEK1 (p=0.012), p-ERK1/2 (p=0.003) et p-P38MAPK (p<0.001) dans le bras de traitement associant l'évérolimus au trastuzumab qui pourrait s'expliquer par la suppression par l'évérolimus d’une boucle de rétrocontrôle négatif contrôlant l'activation de la voie RAS/RAF/MAPKinases. Dans le bras de traitement évaluant le trastuzumab seul, aucune variation du niveau d'expression des phosphoprotéines n'a été mise en évidence, y compris en aval du récepteur HER2, ce qui soulève l'hypothèse d'un mécanisme d'action prédominant immunologique du trastuzumab. La troisième étude qui comparait l'impact du trastuzumab in vitro et en situation clinique confirme la différence des mécanismes d'action mis en jeu en fonction des conditions cellulaires et cliniques. Dans son ensemble, ce travail a mis en évidence que la détermination du statut mutationnel du gène PIK3CA et du niveau d’expression des phosphoprotéines pourrait être utile à une meilleure caractérisation moléculaire des cancers du sein et à l’optimisation de la personnalisation des prescriptions de thérapies cibléesBreast cancer is the most frequently diagnosed cancer in women and is a real public health problem.Advances in molecular biology have allowed the characterization of the major signaling pathways and revealed their major implication in carcinogenesis processes. Molecular targets have been identified and have enabled the development of targeted therapies, such as monoclonal antibodies, or kinase inhibitors. Despite these considerable advances that have improved the care of patients, emerging of resistance to treatments has been observed. The aim of this work was to identify new tumor biomarkers and determine their clinical significance, their theranostic interest and their impact on the response to targeted therapies. Initially, we studied the activating mutations of the PIK3CA gene. These mutations are found in 25% of breast cancers and are involved in resistance to trastuzumab, antiestrogens and mTOR inhibitors. We analyzed 149 invasive breast tumor samples for PIK3CA gene mutations by PCR-HRM (High Resolution Melting) and 118 by PCR-ARMS (Amplification Refractory Mutation System). The results achieved with the 2 techniques were consistent (k = 0.845; p <0.001) and a relationship between PIK3CA mutations and grade SBR was highlighted with a lower occurrence of mutations in SBR grade III tumors (p=0.025 in HRM and p=0.009 in ARMS). Secondly, we investigated the functional alteration of PI3K/AKT/mTOR, RAS/RAF/MAPKinases and P38MAPKinase signaling pathways. We have analyzed the expression level of phosphoproteins p-AKT, p-GSK3ß, p-S6 kinase, p-MEK1, p-ERK1 / 2, p-P90RSK, p-IGF1R and p-p38MAPK by multiplex immunoanalysis. This part includes 3 studies. The first study was a retrospective study of 45 frozen samples of invasive breast tumors in which we observed that the level of expression of P38 and p-P38 was higher in the ER + tumors. The second study was a prospective study to identify biomarkers of response to trastuzumab-everolimus association in patients with early breast cancer treated preoperatively. This study showed a statistically significant increase of the expression level of p-MEK1 (p = 0.012), p-ERK1/2 (p = 0.003) and p-p38MAPK (p<0.001) in arm treated by trastuzumab associated with everolimus. It could be explained by the repression of a negative feedback loop involving S6K, PI3K and RAS by everolimus, leading to the activation of RAS/RAF/MAPKinases signaling pathway. In the control arm investigating trastuzumab alone, no significant variations of the level of expression of phosphoproteins was demonstrated, raising the hypothesis of the implementation of a predominant immunological mechanism of action for Trastuzumab. The third study that compared effect of trastuzumab in vitro and in clinical setting confirms that trastuzumab has different modes of action when evaluated in cells and in clinical conditions. As a whole, this work showed that determining the mutation status of PIK3CA and the expression level of phosphoproteins could be useful to refine the molecular characterization of breast cancers and optimize the criteria used to personalize the prescription of targeted therapies
23
Chhouri, Houssein. "Analysis by DNA barcoding of the heterogeneous response to anticancer drugs by different subpopulations of lung cancer cells." Electronic Thesis or Diss., Normandie, 2022. http://www.theses.fr/2022NORMR037.
Анотація:
Le cancer est une maladie évolutive, caractérisée par l’existence d’un mélange complexe de plusieurs sous-populations cellulaires qui peuvent évoluer en réponse aux conditions environnementales. Cette hétérogénéité intratumorale a des conséquences extrêmement importantes, non seulement sur la progression tumorale, les métastases, mais aussi sur l’efficacité des traitements. Le cancer bronchique non à petites cellules (CBNPC) avec mutations activatrices de l’Epidermal Growth Factor Receptor (EGFR) est traité avec des inhibiteurs spécifiques de ce récepteur. Malheureusement, après une réponse favorable de plusieurs mois, ces tumeurs presque invariablement développent une résistance à ces médicaments. Au cours des traitements, des sous-populations de cellules résistantes ou tolérantes sont sélectionnées et vont émerger pour conduire à une rechute de la tumeur.Dans cette étude, nous avons utilisé une approche d’étiquetage cellulaire pour marquer plusieurs milliers de populations de cellules PC9 de CBNPC avec des codes-barres génétiques et suivre leur évolution clonale en réponse aux thérapies anticancéreuses. Nos résultats ont révélé que certains clones présentent une réponse spécifique et prédéterminée en fonction du traitement, ce qui indique que le phénotype tolérant ou encore hautement sensible représente une propriété intrinsèque de certaines cellules qui préexistent au sein de la population cellulaire initiale. Nous avons également montré que chaque type de médicament anticancéreux exerce un effet caractéristique sur l'architecture clonale de la population cellulaire, ce qui entraîne un profil de code-barres spécifique qui peut être utilisé comme signature pour comparer différents composés et étudier leurs mécanismes d'action. Nous avons généré une collection de profils de codes-barres à partir de 87 composés connus, agissant sur des processus cellulaires différents, et les avons utilisés pour identifier le mécanisme d'action d’une nouvelle molécule capable d'inhiber spécifiquement la croissance des cellules de CBNPC.Dans la dernière partie de la thèse, grâce à la technologie CRISPR/Cas9, nous avons développé Barcode-Tracker, une nouvelle stratégie pour identifier et isoler des clones d'intérêt à partir d’une population de cellules tumorales, basée sur la reconnaissance d'un code-barres génétique spécifique. Contrairement à d'autres approches, Barcode-Tracker n'utilise pas d’inhibiteur pour sélectioner des cellules, et peut être utilisé pour purifier les clones selon leur capacité intrinsèque à se comporter d'une manière particulière en présence d'un traitement, imitant ainsi la réponse d'une tumeur naïve. Avec une meilleure compréhension de la manière dont le traitement anticancéreux peut affecter l’évolution tumorale, ces études devraient permettre une amélioration des stratégies thérapeutiques pour les patients atteints de CBNPCCancer is a dynamic disease, characterized by the co-existence of multiple subpopulations of tumor cells that can evolve in response to environmental changes. This intratumor heterogeneity has dramatic consequences, not only for cancer progression and metastatic spread, but also for treatment. Specific tyrosine kinase inhibitors are effective against non-small cell lung cancers harboring activating mutations of the epidermal growth factor receptor (EGFR), but the response is not durable, and cure remains elusive because of the inevitable development of acquired resistance. During therapeutic intervention, small subpopulations of resistant or tolerant cells are selected by virtue of their higher fitness, ultimately resulting in tumor relapse.In this study, we used cellular barcoding to label several thousand populations of PC9 NSCLC cells and monitor their clonal dynamics in response to anti-cancer therapies. Our results revealed that some clones display a specific and predetermined response to treatment, indicating that cells that are primed to behave as tolerant or highly sensitive pre-exist in the original mass population. We extended these findings and showed that each type of anti-cancer drugs exerts a characteristic effect on the clonal architecture of the cell population, resulting in a specific barcode pattern that can be used as a signature to compare different compounds and investigate their mechanism of action. We have generated barcode profiles from 87 drugs targeting various pathways and used it to predict the mechanism of action of a new compound that can specifically inhibit NSCLC cell growth.In the last part of the thesis, we took advantage of CRISPR/Cas9 technology to devise Barcode-Tracker, a new strategy to identify and isolate clones of interest from a mass population based on the recognition of a specific genetic barcode. Contrary to other approaches, Barcode-Tracker doesn’t involve drug selection of the cells and it can be used to sort clones according to their intrinsic capacity to behave in a particular manner in the presence of treatment, thus mimicking the response of a therapy-naïve tumor. By providing a better understanding of how treatment can shape clonal evolution, our studies should help to improve therapeutic strategies for NSCLC patients
24
Hopper, Sophie. "The therapist experience of client non-response." Thesis, University of Leeds, 2015. http://etheses.whiterose.ac.uk/10725/.
Анотація:
This study aimed to explore the therapist subjective experience of client non-response, how they made sense of their experience and how they managed the experience. A total of seven therapists were recruited and interviewed using a semi-structured interview format, designed for the purposes of the study. The resulting transcribed interviews were analysed using interpretative-phenomenological analysis. Fifteen super-ordinate themes were found and organised across four discrete, but interacting stages; ‘starting out’, ‘when therapy fails to progress’, trying to end’ and ‘it’s over’. The over-arching theme of ‘the destruction of hope’ encompasses the experiential and time-ordered themes. The therapist experience was marked by challenging feelings of anxiety, helplessness, inadequacy, anger and guilt. Feelings of loss were also apparent, specifically regarding the omnipotence of therapy and the therapist’s identity as a healer. The novel findings are discussed in the context of the extant evidence concerned with the therapist experience of non-response, the distinct contribution made by the current findings and the identified methodological limitations of the research approach.
25
Landström, Birgitta, and Helene Stedmon. "Patientsuicid - : Terapeuters upplevelser och påverkan ur ett systemiskt perspektiv." Thesis, Umeå universitet, Psykoterapi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-118499.
Анотація:
I yrket som terapeut är ämnet suicid ständigt närvarande. När professionella terapeuter hamnar i kris blir reaktionen lika stark som hos andra människor. Vår utgångspunkt var att patientsuicid är en händelse som inte hanteras optimalt i arbetsorganisationen, vilket leder till psykiska, fysiska och sociala konsekvenser för terapeuten, både på arbetsplatsen och i privatlivet. Syftet med studien är att öka kunskapen inom psykoterapiområdet om vad som händer vid ett patientsuicid, bli medveten som terapeut, enskild individ och organisation hur ett patientsuicid påverkar ur ett systemiskt perspektiv. Organisationens förbättrade förmåga att hantera ett patientsuicid bör kunna få positiv betydelse för terapeuten då kunskapen ökar om hur terapeut och system samverkar. Studien grundar sig på sex terapeuters upplevelser av patientsuicid. I resultatet framkommer vad dessa terapeuter upplevt, samt deras synpunkter på vad som skulle kunna förbättras vid framtida patientsuicid. Ett fynd vi gjort är att det bör finnas en flexibilitet i organisationen för individuella bedömningar vad gäller behov av stöd till drabbade terapeuter. Sättet på vilket terapeuter meddelas om patientsuicid, samt av vem, får olika effekter på terapeuten. Organisationen kan utvecklas vad gäller bemötandet av den terapeut som drabbas av patientsuicid. Ytterligare ett viktigt fynd och förbättringsområde är rutiner kring hantering av kontakt med anhöriga.
26
Sterner, Irit. "Client responses to therapist statements as behavioural requests." Thesis, University of Ottawa (Canada), 1990. http://hdl.handle.net/10393/5690.
Анотація:
Psychotherapists' statements may be conceptualized and described in different ways, depending on which aspects of the statements are highlighted. Traditionally, therapist statements have been described in terms of techniques that serve, for example, interpretative, reflective, or supportive functions. From a psycholinguistic or an interactional communications perspective, therapist statements may also be understood as inviting or instructing the client (directly or indirectly) to respond in a particular manner and to carry out given behaviours. Accordingly, the primary purposes of the present research were (1) to examine therapist statements as potentially containing requests for verbal behaviour, and (2) to test hypotheses regarding clients' responses to these antecedent behavioural requests. The data consisted of 12 sessions; two sessions from the beginning, middle, and end of two therapy cases, one Gestalt and the other psychodynamic. Raters identified therapist statements that contained requests for verbal behaviour and specified the nature of these requests. The requests were then organized into a general set of categories for each therapist. A second team of raters ascertained the goodness of fit between the therapist statements and the categories to which they had been assigned. A third team of judges rated the clients' responses to the therapists' antecedent requests on a four-point scale of conformity. The results indicated that a large proportion of therapist statements contained requests for verbal behaviour (66.3%). While some requests were communicated explicitly as such, others were implicit in the therapists' statements. Some categories of requested verbal behaviour were common to both therapists while others appeared to be unique to a particular therapeutic approach. Both therapists invited certain categories of verbal behaviour more often than others. The findings also showed that the level of client conformity to the therapists' antecedent requests was high in general (82% of client responses in the Gestalt case, 98% in the psychodynamic case), and that this high level was relatively stable and consistent across sessions. In the Gestalt case, the degree of conformity was found to vary depending on the type of verbal behaviour requested by the therapist. Nevertheless, a high level of conformity was reflected in all the categories in one case, and most of the categories in the other case. Contrary to expectations, the findings did not show (1) a strong upsurge in client opposition corresponding to particular stages of therapy, or (2) stage differences in the extent of conformity or type of opposition. The findings of this investigation are discussed in terms of their implications for clinical practice and future research.
27
Laura, Bergantini. "Immune modulatory effects of novel monoclonal antibodies target therapies in severe eosinophilic asthma patients." Doctoral thesis, Università di Siena, 2020. http://hdl.handle.net/11365/1120137.
Анотація:
New anti IL-5 antibodies, mepolizumab and benralizumab, have recently been approved for severe asthma, sharing the same inclusion criteria. To contribute on biomarkers research leading to the personalized choice, we investigated L-selectin, KL-6 and lymphocyte subsets as bioindicators of airways hyper-responsiveness and remodelling and to phenotype patients according to their answer to the treatment. L‐selectin mediates leukocyte rolling of lung endothelium and its expression on T cells is increased in asthma patients. Regulatory T cells (Tregs) suppress inflammation by secreting a wide variety of cytokines that inhibit T cell proliferation.
A cohort of 28 patients affected by severe eosinophilic asthma were treated with anti IL-5 drugs: 20 with Mepolizumab and 8 with Benralizumab. Lymphocytes subsets, Regulatory T cells and CD4+CD62L+ cells were analyzed through flow cytometry, Serum L-selectin quantification was performed by bead-based multiplex analysis, while KL-6 was analyzed through CLEIA.
Clinical, functional and immunological data at baseline (T0), after one month (T1) and 6 months of therapy were collected in a database. All treated patients showed variations in FEV1, FEV1/FVC ratio and peripheral eosinophils for both drugs. Mepolizumab treated patients also showed significant differences between T0 and T1 in CD8+ and NK-T like cells percentages and a significant increase in L-selectin concentrations. Stratifying the cohort of our patients in “early responders and partial responders at T0 they showed significant differences in peripheral eosinophils, sL-selectin, and KL-6, while no differences were found at T0 between “early responders” and “partial responders” patients treated with Benralizumab. In a subgroup of 14 mepolizumab treated patients, immunological data showed an increase in Tregs and CD4+CD62L+ at T1. Soluble L-selectin concentrations were lower at T1. CD45+ and CD62L+ cell features differed significantly in early and partial responders before and after therapy. The FEV1/FVC ratio showed an indirect correlation with L-selectin levels (r=-0.6, p=0.03), peripheral eosinophilia (r=-0.7, p=0.01). This real-life study provides new insights for the personalized approach to severe asthma therapy. Although preliminary, the results indicate that besides to peripheral eosinophils, other molecules are useful as biomarkers of early response that can also involving in the pathogenesis of severe asthma. Mepolizumab therapy was found to modulate immune response, restoring immune balance in patients with SEA. L-selectin and Tregs were also proposed as biomarkers of response to mepolizumab treatment.
28
Cyr, Yolande. "Self-disclosure by marital therapists and consequent spouse responses." Thesis, University of Ottawa (Canada), 1987. http://hdl.handle.net/10393/5152.
29
Bancroft, Courtney. "Trainee therapist responses to the discussion of trauma in therapy." Thesis, Pepperdine University, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=3643872.
Анотація:
Responses to disclosures/discussions of trauma can have lasting impacts on survivors who choose to share their experiences and historically have been categorized as positive, negative, and/or neutral responses with corresponding effects on the survivor. Literature recommends the use of tenets and techniques reminiscent of therapeutic common factors (e.g., listening skills, empathy, support, validation, creating a safe environment and strong therapeutic alliance) when responding to trauma. However, existing research focuses on reactions to survivors' disclosures outside of therapy and there is little research focusing on therapists' responses. Specifically, there are no studies that investigate how therapists or trainees are actually responding in psychotherapy sessions (e.g., frequency and rate of such responses).
Accordingly, the purpose of the present study was to qualitatively explore the responses of student therapists in psychotherapy sessions with trauma survivors. A sample of 5 therapist-participants from university-based community counseling centers were selected and transcribed videotaped sessions in which client- and trainee therapist-participants discussed trauma were analyzed using a qualitative and deductive content analysis. A coding system was created to categorize responses based on extant literature. Results indicated that trainee therapist-participants responded in all proposed categories (positive: validating, supportive, empathic; negative: invalidating, unsupportive, unempathetic; and neutral: clarifying questions, and reflection/summary statements). Of these, neutral responses tended to occur more frequently than positive or negative responses. Overall, positive responses followed as next most frequent and negative responses as least frequent. Other findings included that in 2 of the 5 individual sessions, negative responses were more frequent than positive responses; empathic responses were the least frequent code across all 10 coding categories; and 2 sessions had 0 recorded empathic responses. Finally, there were numerous missed opportunities for positive responding throughout the sessions.
It is hoped that this study will raise awareness around the importance of therapeutic responses to trauma survivors' discussions in psychotherapy sessions and provide insight as to how trainee therapists might apply their existing competencies to respond to clients in positive ways. Findings have implications for both future studies and clinical training practices, for example in graduate programs for trainee therapists, an area of study that is currently under-researched.
30
Höglund, Andreas. "Regulation of DNA damage responses by the Myc oncogene : implications for future anti-cancer therapies." Doctoral thesis, Umeå universitet, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet), 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-44284.
Анотація:
Myc is a transcription factor frequently found deregulated in human cancer. Cells with deregulated expression of Myc carry a selective advantage against its neighbours due to the fact that Myc-mediated transcription governs crucial cellular events such as proliferation and growth. In addition, Myc has been implicated in several other aspects of tumour biology like cellular immortality, the formation of new blood vessels and the colonization of distant tissues through the process of metastasis. Therapy aimed at disrupting essential pathways regulated by Myc is important because of the many different types of cancers that depend on continued signalling along these pathways. This thesis describes new treatment opportunities for cancers with a high Myc signature. In Paper Ι, we describe a new role for the DNA methyltransferase inhibitor Decitabine in the treatment of Myc transformed tumours cells. We show that the therapeutic potential of Decitabine in the treatment of Burkitt Lymphoma relies not only on its ability to cause reactivation of silenced genes such as pro-apoptotic PUMA, but also on the DNA damage that this drug induces. In vivo, Decitabine delays disease progression of transplanted lymphoma cells. In Paper ΙΙ, we identify the DNA damage checkpoint kinase Chk1 as a therapeutic target in Myc overexpressing cancers. We show that targeting Chk1 with shRNA or with a novel small molecule inhibitor cause a delay in disease progression of transplanted lymphoma cells in vivo. In Paper ΙΙΙ, the Chk1-related kinase Chk2 is evaluated as a therapeutic target in Myc overexpressing cancers. Myc overexpressing cells are not dependent on Chk2 but we show that Chk2 abrogation using shRNA causes polyploidization and protection against DNA damage. However, Chk2-targeted therapy elicits a synergistic lethal response in combination with inhibition of the DNA repair associated protein PARP. In conclusion, this thesis shows the potential of targeting the DNA damage machinery and the functional hubs important for maintenance of genomic stability in tumours with a deregulated expression of Myc.
31
Muller, Ilaria. "Autoimmune responses to thyroid/breast shared antigens to develop novel and specific therapies and diagnostics." Thesis, Cardiff University, 2016. http://orca.cf.ac.uk/91002/.
Анотація:
An association between breast cancer (BC) and thyroid autoimmunity (TA) has been frequently observed and several small-scale studies correlated the presence of thyroid peroxidase (TPO) autoantibodies (TPOAb) with an improved BC outcome. The presence of an immune response to shared thyroid/breast antigens has been hypothesized: both tissues express the sodium iodide symporter (NIS) and have a peroxidase activity: TPO in thyroid and lactoperoxidase (LPO) in breast. I have identified 3 possibilities: i) BC patients with TPOAb may also have autoantibodies to NIS (NISAb) ii) BC may express TPO iii) TPOAb may cross-react with LPO in BC. This thesis aimed to identify the TA/BC shared antigen(s) and also investigated the prognostic role of TPOAb in a large cohort of BC patients. The presence of NISAb was investigated by flow cytometry using CHO cells stably transfected with human NIS. No positive response was obtained in 42 patients with BC and/or TA, therefore NIS is unlikely to be an antigen. TPO transcripts (RT-PCR, QPCR, LongRange PCR) and protein (western blot, immunohistochemistry, immunofluorescence) were detected in BC tissues but at levels 104 times less than in thyroid tissue. TPO was also expressed in adipose tissue and different cancers. Some potentially BC specific TPO isoforms were identified. The observational large-scale study conducted on 1974 women affected with BC did not reveal any evidence for a significant impact of TPOAb and/or thyroid function on BC prognosis. In conclusion, BC and thyroid tissues share similar properties and could be common targets of TA, with TPO being the most likely common antigen; further studies are needed to clarify the role of tissue-specific TPO isoforms. The roles of TPOAb and thyroid function on BC prognosis have to be reconsidered, maybe focusing on different TA aspects (e.g. goitre, different autoantibodies).
32
Byng-Maddick, Rachel. "Differential effects of anti-TNF therapies for inflammatory arthritides on immune responses to Mycobacterium tuberculosis." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10043230/.
Анотація:
Tumour necrosis factor (TNF) antagonists have revolutionised the management of rheumatoid arthritis (RA) and other inflammatory diseases. This success is partly tempered by substantially increased risk of granulomatous infectious diseases, particularly tuberculosis (TB). In this thesis I sought new insights into the mechanisms by which TNF blockade leads to an increased incidence of TB. In a new analysis of data collected by the British Society of Rheumatology Biologics Registry, I confirmed that anti-TNF therapy leads to reactivation of latent TB infection, rather than increasing the risk of new TB infection, consistent with published literature. I derived and validated four separate context-specific transcriptional modules representing TNF inducible gene expression in macrophages, keratinocytes and whole blood. I used these modules to quantify TNF bioactivity in clinical samples from RA patients responding to anti TNF therapies or treated with methotrexate only. As expected, anti-TNF therapy was associated with attenuated expression of the TNF modules in whole blood following ex vivo stimulation. However, anti-TNF therapy had no effect on TNF module expression and therefore TNF function, at the site of acute cell mediated immune responses in vivo, modelled by the tuberculin skin test. These data are consistent with a model in which anti-TNF therapies do not reach sufficient concentration within tissues to block TNF responses in an acute inflammatory challenge. Rather, my data suggest that anti TNF therapies mediate their therapeutic and adverse effects by regulating TNF activity at foci of chronic inflammation or by alternative non-canonical pathways. Finally I tested the hypothesis that anti-TNF therapy may inhibit cellular restriction of mycobacteria in human macrophage cultures. Using an in vitro model of human monocyte-derived macrophages, I established a new method to quantify fluorescent mycobacterial load both inside and outside cells, and showed that TNF blockade in this model did not have a significant impact on mycobacterial growth.
33
Querbach, Julia [Verfasser]. "EEG-Response-Prädiktion der medikamentösen antidepressiven Therapie mittels affektiver Stimuli bei unipolarer Major Depression / Julia Querbach." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2020. http://d-nb.info/1218076364/34.
34
Leicht, Christina [Verfasser], and Arndt [Akademischer Betreuer] Hartmann. "Untersuchung molekularer Therapie-Response-Marker bei lokal fortgeschrittenen Harnblasenkarzinomen mit adjuvanter Chemotherapie / Christina Leicht. Betreuer: Arndt Hartmann." Regensburg : Universitätsbibliothek Regensburg, 2012. http://d-nb.info/1025386175/34.
35
Pachmayr, Eva Maria [Verfasser]. "Prädiktion der Therapie-Response im Patienten-abgeleiteten Maus-Xenograft-Modell bei peritoneal metastasiertem kolorektalem Karzinom / Eva Maria Pachmayr." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2019. http://d-nb.info/120204168X/34.
36
Pachmayr, Eva [Verfasser]. "Prädiktion der Therapie-Response im Patienten-abgeleiteten Maus-Xenograft-Modell bei peritoneal metastasiertem kolorektalem Karzinom / Eva Maria Pachmayr." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2019. http://d-nb.info/120204168X/34.
37
Klingner, Maria Brigitte. "Untersuchung zur Vorhersagbarkeit des Therapieansprechens unter anti-TNF-Therapie bei Patienten mit Rheumatoider Arthritis." Doctoral thesis, Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-146837.
Анотація:
Die Rheumatoide Arthritis (RA) ist eine der häufigsten Autoimmunerkrankungen des Menschen. Sie ist durch einen chronischen Verlauf mit Allgemeinsymptomen und erosiven Gelenkentzündungen gekennzeichnet. Die klinischen Beschwerden reichen von Morgensteifigkeit der Gelenke bis zu deren Funktionsverlust mit Deformationen. Extraartikuläre Manifestationen, vor allem das kardiovaskuläre System betreffend, erschweren den Krankheitsverlauf und verkürzen die Lebenserwartung.
In der Pathogenese der RA steht die Synovitis, die Entzündung der Gelenkinnenhaut, im Mittelpunkt. Die Ansammlung von Lymphozyten und Monozyten in der Synovialmembran und sezernierte proinflammatorische Zytokine bewirken eine Aufrechterhaltung des Entzündungsgeschehens. Das hauptsächlich von Monozyten produzierte Zytokin Tumornekrosefaktor (TNF) spielt eine entscheidende Rolle in diesem Immunprozess. TNF stimuliert Fibroblasten zur Sezernierung destruktiver Enzyme und regt zur Produktion weiterer, proinflammatorischer Botenstoffe an. Klassischerweise wirkt TNF in seiner löslichen Form und bindet an TNF-Rezeptoren auf nahezu allen Körperzellen. Ein weiterer Wirkmechanismus ist die retrograde Signaltransduktion über membranständiges TNF (tmTNF). Die Funktion von tmTNF, als Rezeptor Signale in die tmTNF-tragende Zelle zu vermitteln, wird als Reverse Signaling bezeichnet. Es ist bekannt, dass Reverse Signaling via tmTNF in Monozyten von RA-Patienten Apoptose auslöst und in weiteren komplexen Immunprozessen involviert ist.
Die Bedeutung von TNF für die Rheumatoide Arthritis wird nicht zuletzt dadurch unterstrichen, dass die anti-TNF-Therapie einen sehr wirksamen Therapieansatz darstellt. Die Behandlung führt bei ca. zwei Drittel der Patienten zu einer Reduktion der entzündlichen und schmerzhaften Gelenkschwellung und zu einem Sistieren der Gelenkdestruktion. Es ist jedoch bekannt, dass ein Teil der Patienten schlecht auf die Therapie anspricht. Das dadurch verzögerte Erreichen eines guten Therapieerfolgs führt zu einer Verlängerung des Leidens und zu unnötigen, zum Teil schwerwiegenden Nebenwirkungen. Gesundheitsökonomisch ist dies ebenfalls kritisch zu sehen, da mit hohen Behandlungskosten zu rechnen ist. Eine Vorhersage des Therapieansprechens ist jedoch aktuell nicht möglich.
Ziel dieser Studie war es, einen prädiktiven Marker für das anti-TNF-Therapieansprechen bei Patienten mit RA zu finden. Dabei galt der Bedeutung des Reverse Signaling via tmTNF großes Interesse.
In der Studie wurden 20 Patienten mit Rheumatoider Arthritis vor und während einer Therapie mit dem TNF-Antagonist Etanercept insgesamt 24 Wochen betreut. Die Erhebung klinischer Daten, wie die Anzahl der druckschmerzhaften und geschwollenen Gelenke, die Einschätzung der Krankheitsaktivität durch den Patienten auf einer visuellen Analogskala (VAS) und die Untersuchung der Entzündungsaktivität mit CRP und BSG, erfolgte einmalig vor und alle vier Wochen unter Therapie. Zur Einschätzung der Krankheitsaktivität wurde der Disease Activity Score (DAS) genutzt. Das Therapieansprechen wurde entsprechend einer Klassifikation und der Veränderung der einzelnen klinischen Parameter im Therapieverlauf gewertet. Auf der Suche nach einem prädiktiven Faktor wurden ebenfalls einmalig vor und alle vier Wochen während der Therapie mit Etanercept laborchemische Experimente durchgeführt. Dazu wurden aus dem Blut der RA-Patienten die Monozyten mit Hilfe einer Dichtegradientenzentrifugation und einer Magnetseparation isoliert. Diese wurden hinsichtlich ihrer Expression von tmTNF sowie TNFR1 und TNFR2 nach Inkubation mit entsprechenden Antikörpern durchflusszytometrisch untersucht. Weiterhin wurden die RA-Monozyten mit Etanercept bzw. einer Negativkontrolle inkubiert. Im Anschluss wurde die Apoptose der Monozyten mittels Durchflusszytometrie und Färbung mit Propidiumiodid bzw. Annexin V quantifiziert.
Entsprechend den EULAR-Kriterien kam es bei 10 Patienten (53%) zu einem guten, bei 7 Patienten (37%) zu einem mittleren und bei 2 Patienten (10%) zu einem schlechten Ansprechen. Aufgrund der klinischer Beurteilung erfolgte eine Einteilung in zwei Gruppen, sodass unter den Patienten 10 Responder (53%) und 9 (47%) Non-Responder waren.
Die Monozyten der RA-Patienten exprimierten tmTNF mit einer mittleren Fluoreszenzintensität (MFI) von 14,23 ± 3,04. Es wurde eine MFI für TNFR1 mit 31,84 ± 12,99 und für TNFR2 mit 30,02 ± 8,9 gemessen.
Die Inkubation der RA-Monozyten mit Etanercept bzw. mit der Negativkontrolle ergab unterschiedliche Resultate innerhalb der Patientengruppe. Dabei wurde die Apoptose der Monozyten in Spontanapoptose (Negativkontrolle) und in Reverse Signaling induzierte Apoptose eingeteilt. Vor Beginn der anti-TNF-Therapie zeigte ein Teil der Patienten eine niedrige Spontanapoptose und eine erhöhte Reverse Signaling induzierte Apoptose. Die Monozyten der anderen RA-Patienten zeigten umgekehrt eine hohe Spontanapoptose und eine niedrige Reverse Signaling induzierte Apoptose. Im Folgenden wurde der Einfluss der Etanercept-Therapie auf die Apoptose der Monozyten untersucht. Es wurde ein Anstieg der niedrigen Spontanapoptose bzw. Reverse Signaling induzierte Apoptose und ein Abfall der hohen Spontanapoptose bzw. Reverse Signaling induzierte Apoptose gesehen.
Bezieht man in die Analyse das Therapieansprechen mit ein, so ergibt sich für Responder eine initial hohe Spontanapoptose, die unter Therapie signifikant sinkt. Non-Responder hingegen haben vor Therapie eine niedrige Spontanapoptose, die unter einer Therapie mit Etanercept ansteigt. Für den Verlauf der Reverse Signaling induzierte Apoptose unter der anti-TNF-Therapie gab es keine signifikanten Unterschiede hinsichtlich des Therapieansprechens.
Im Fisher-Exact-Test zeigte sich eine deutliche Tendenz (p=0,07), dass Patienten mit niedriger Spontanapoptose bzw. hoher Reverse Signaling induzierter Apoptose zu Studienbeginn schlecht auf die Therapie ansprechen. Dieses Ergebnis konnte mit Einzelparametern verifiziert werden.
Die Studie kam zu dem Schluss, dass RA-Patienten, deren Monozyten eine niedrige Reverse Signaling induzierte Apoptose bzw. eine hohe Spontanapoptose aufwiesen, besser auf eine anti-TNF-Therapie mit Etanercept ansprachen. Dieses Ergebnis kann hilfreich für die Entwicklung einer entscheidenden Diagnostik vor Therapieeinstellung sein und leistet einen Beitrag für die Vorhersage des Therapieansprechens.
38
Kluge, Regine, Lidia Chavdarova, Martha Hoffmann, Carsten Kobe, Bogdan Malkowski, Françoise Montravers, Lars Kurch, et al. "Inter-reader reliability of early FDG-PET/CT response assessment using the Deauville Scale after 2 cycles of intensive chemotherapy (OEPA) in Hodgkin’s Lymphoma." Universitätsbibliothek Leipzig, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-204087.
Анотація:
Purpose: The five point Deauville (D) scale is widely used to assess interim PET metabolic response to chemotherapy in Hodgkin lymphoma (HL) patients. An International Validation Study reported good concordance among reviewers in ABVD treated advanced stage HL patients for the binary discrimination between score D1,2,3 and score D4,5. Inter-reader reliability of the whole scale is not well characterised. Methods: Five international expert readers scored 100 interim PET/CT scans from paediatric HL patients. Scans were acquired in 51 European hospitals after two courses of OEPA chemotherapy
(according to the EuroNet-PHL-C1 study). Images were interpreted in direct comparison with staging PET/CTs. Results: The probability that two random readers concord on the five point D score of a random case
is only 42% (global kappa = 0.24). Aggregating to a three point scale D1,2 vs. D3 vs. D4,5 improves concordance to 60% (kappa = 0.34). Concordance if one of two readers assigns a given score is 70% for score D1,2 only 36% for score D3 and 64% for D4,5. Concordance
for the binary decisions D1,2 vs. D3,4,5 is 67% and 86% for D1,2,3 vs D4,5 (kappa = 0.36 resp. 0.56). If one reader assigns D1,2,3 concordance probability is 92%, but only 64% if D4,5 is called. Discrepancies occur mainly in mediastinum, neck and skeleton. Conclusion: Inter-reader reliability of the five point D-scale is poor in this interobserver analysis of paediatric patients who underwent OEPA. Inter-reader variability is maximal in cases assigned to D2 or D3. The binary distinction D1,2,3 versus D4,5 is the most reliable criterion for clinical decision making.
39
Richard, Matthias. "Die Konzeptualisierung und Validierung von Therapie-Response und seine Bedeutung für die Behandlungsplanung in einem verlaufsorientierten Qualitätsmanagement am Beispiel von Essstörungen." [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=961906766.
40
Düsterwald, Jan Ole [Verfasser], Achim [Gutachter] Mumme, and Letterio [Gutachter] Barbera. "Überprüfung der perioperativen Response und Evaluation einer standardisierten Optimierung der antithrombozytären Therapie bei gefäßchirurgischen Patienten / Jan Ole Düsterwald ; Gutachter: Achim Mumme, Letterio Barbera." Bochum : Ruhr-Universität Bochum, 2017. http://d-nb.info/1129452093/34.
41
Hansen, Brian P. "Sudden Gains: A Pluralistic Approach to the Patient and Therapist Experience." BYU ScholarsArchive, 2013. https://scholarsarchive.byu.edu/etd/4290.
Анотація:
Qualitative and quantitative research methods were used to study instances of sudden gains within the case load of a private practice practitioner. Five clients whose progress was marked by such changes were contrasted with the views of five clients whose progress was marked by significant setbacks. Results from the quantitative analyses indicated that clients who experienced sudden gains during therapy tended to retain their therapeutic gains over a 2-year time period. In contrast, individuals who experienced setbacks in therapy generally continued to be distressed at the 2-year reassessment. Clients who experienced sudden gains were more distressed prior to treatment and were more satisfied with their experience looking back. A stronger working alliance was found amongst those who experienced sudden gains, although there was no difference between the groups' ratings regarding the strength of the therapeutic bond. Qualitative results suggested that therapy was helpful in bringing about many changes in clients' lives, but clients who experienced sudden gains generally recalled more positive aspects of therapy, demonstrated greater utilization of therapeutic techniques, endorsed more long-term changes, accepted more responsibility for their treatment outcomes, and were less likely to react negatively to therapeutic techniques. Clients who experienced setbacks in therapy were generally less optimistic about the future, felt that they had regressed since termination, and demonstrated more resistance to therapeutic techniques.
42
Rakotomalala-Andrianasolo, Andria. "Développement et caractérisation de modèles cellulaires pour l'étude du rôle de l'oncohistone H3.3 K27M dans le phénotype agressif et la réponse aux thérapies des gliomes pédiatriques diffus de la ligne médiane." Electronic Thesis or Diss., Université de Lille (2022-....), 2024. http://www.theses.fr/2024ULILS015.
Анотація:
Le traitement des DMG altérés H3 K27, n’ayant pas connu d’amélioration au cours de ces 50 dernières années, figure parmi les plus grands défis de la neuro-oncologie pédiatrique. En 2012, a été découverte une mutation spécifique de l’histone 3 (oncohistone), dite H3.3 K27M, présentant une prévalence très élevée (70-80% des cas) dans les DMG. Bien que l’impact épigénétique de cette mutation ait été décrit, des études demeurent nécessaires afin de mieux comprendre son rôle dans le phénotype agressif et la réponse aux thérapies des cellules DMG. Afin d’étudier précisément l’impact de la mutation H3.3 K27M sur le phénotype des cellules de DMG,nous avons développé et caractérisé des modèles cellulaires isogéniques complémentaires de gliome pédiatrique de haut grade induits et invalidés pour l’oncohistone. À l’aide de ces modèles, nous souhaitions élucider l’impact de H3.3 K27M sur la biologie des cellules de DMG et leur réponse aux traitements anti-cancéreux, notamment la radiothérapie, unique traitement de référence actuel pour la prise en charge des DMG. Par la caractérisation de nos lignées cellulaires de gliomes pédiatriques sustentoriels induites pourH3.3 K27M, nous avons montré que l’oncohistone impacte la réponse aux radiations ionisantes et à certaines thérapies ciblées de manière dépendante du contexte cellulaire.Sur la base de ce constat, nous avons pris le parti de caractériser les impacts biologiques de l’oncohistone dans un contexte cellulaire plus pertinent de DMG. En ce sens, nous avons établi des modèles cellulaires knock-out pour H3.3 K27M et les avons caractérisés comparativement à leurs lignées cellulaires parentales mutées. Par des caractérisations omiques (transcriptomique et protéomique) et du métabolisme cellulaire de ces modèles, nous avons notamment identifié un impact de la mutation H3.3 K27M sur le métabolisme lipidique des cellules DMG. De surcroit, dans des modèles de sphéroïdes 3D, cette modification du métabolisme lipidique associée à l’oncohistone semblait conditionnée par des facteurs du microenvironnement encore à l’étude.D’autre part, une approche fonctionnelle par criblage pharmacologique nous a permis d’identifier des dépendances à certaines voies de réparation des dommages à l’ADN spécifiquement associées à la mutationH3.3 K27M. De plus, la caractérisation radiobiologique de nos modèles, actuellement en cours, indique une radiosensibilité associée à H3.3 K27M, corrélant avec une diminution de l’efficacité de réparation de l’ADN postirradiation. Au-delà de cet impact sur la réparation des dommages à l’ADN, notre criblage pharmacologique a également révélé une sensibilité exacerbée à certains composés de la famille des glycosides cardiaques induite par H3.3 K27M. Ce résultat apparaît particulièrement intéressant au regard de nos données transcriptomiques montrant un enrichissement en gènes impliqués dans les cardiomyopathies et l’homéostasie ionique parmi les gènes différentiellement exprimés en présence de l’oncohistone. Dans ce contexte, nous avons entrepris l’étude des processus moléculaires et biologiques sous-jacents à cette différence de sensibilité gouvernée parH3.3 K27M.In fine, nous avons utilisé nos modèles cellulaires isogéniques pour montrer que l’oncohistoneH3.3 K27M entraîne des modifications du métabolisme lipidique des cellules de DMG. Ces changements métaboliques pourraient rendre les cellules de DMG altérés H3 K27 plus susceptibles au déclenchement de certaines voies de morts cellulaires (e.g. ferroptose) et affecter la réponse à certaines thérapies. De plus, H3.3K27M semble induire des sensibilités spécifiques, notamment à la radiothérapie et aux glycosides cardiaques [...]H3K27-altered DMG treatment is one of the most significant challenges in pediatric neuro-oncology,with no improvement in patient survival over the past 50 years. In 2012, it was shown that DMGs harbor a specific histone 3 mutation (oncohistone) called H3.3 K27M with a very high prevalence (70-80% of cases). Although theH3.3 K27M impact on the epigenetic landscape has been well described, studies are needed to understand betterits role in DMG cells’ aggressiveness and response to therapies.To study the H3.3 K27M mutation impact on DMG cell phenotypes precisely, we developed andcharacterized pediatric high-grade glioma isogenic cellular models induced and knock-out for the oncohistone.Using these models, we aimed to decipher the oncohistone impact on DMG cell biology and response to anticancertherapies, including radiation therapy, the only current standard of care for DMGs. Characterization of our H3.3 K27M-induced pediatric supratentorial glioma cell lines reveals that the oncohistone affects the response to ionizing radiations and specific targeted therapies in a cellular context-dependentway. Based on these results, we settled to characterize oncohistone biological impacts in a more relevant cellular context of DMG. In that sense, we established H3.3 K27M knock-out cellular models and characterized them regarding their parental DMG H3.3 K27M mutated cell lines. Through omic (transcriptomic and proteomic)and cell metabolism characterizations of these models, we notably showed the H3.3 K27M mutation impact on DMG cells’ lipid metabolism. In 3D spheroid models, this H3.3 K27M-induced lipid metabolism rewiring appeared conditioned by microenvironment factors still under investigation.On the other hand, a functional pharmacological screen identified H3.3 K27M-driven dependencies tospecific DNA repair pathways. In addition, ongoing radiobiological characterization of our models indicates anH3.3 K27M-associated radiosensitivity correlating with a decrease in DNA repair efficiency following ionizingradiations. Beyond this DNA repair impact, our pharmacological screen also revealed an H3.3 K27M-relatedsensitivity to cardiac glycoside drugs. This result makes sense with our transcriptomic data showing enrichmentin genes involved in cardiomyopathies and ion homeostasis among differentially expressed genes with theoncohistone. In this context, we began unraveling the molecular and biological processes underlying thisH3.3 K27M-driven effect.Finally, we used our isogenic cellular models to show that the H3.3 K27M oncohistone drives lipidmetabolism modifications. These metabolic changes could prime H3K27-altered DMG cells to specific regulatedcell death pathways (e.g., ferroptosis) and affect the response to certain therapies. Moreover, the H3.3 K27Mseems to drive specific sensitivities, notably to radiation therapy and cardiac glycoside drugs. Understanding the underlying molecular mechanisms governing these H3.3 K27M-associated Achille heels could highlight newinsights into the oncohistone role in DMG cells and provide rationales for developing new therapeutic strategies
43
Daheim, Mathias Stefan Moritz [Verfasser]. "Ausnutzung molekularer Defekte in der DNA damage response ATM-mutierter Zellen durch gezielte Therapie einer starken non-oncogene addiction von PRKDC / Mathias Stefan Moritz Daheim." Köln : Deutsche Zentralbibliothek für Medizin, 2014. http://d-nb.info/1049199340/34.
44
Meyrath, David [Verfasser], and Knut [Akademischer Betreuer] Schnell. "Response einer Therapie mit Olanzapin bei schizophrenen Psychosen in Abhängigkeit von vorangegangenem Cannabiskonsum und dessen Impact auf das endogene Cannabinoidsystem / David Meyrath ; Betreuer: Knut Schnell." Heidelberg : Universitätsbibliothek Heidelberg, 2019. http://d-nb.info/1177043769/34.
45
Saiger, David [Verfasser]. "Lithiumtherapie und Nierenfunktion bei Patienten mit Bipolarer Störung : Einfluss der Therapiedauer auf die glomeruläre Filtrationsrate im Kontext von somatischer Komorbidität und Therapie-Response / David Saiger." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2017. http://d-nb.info/1140486802/34.
46
Hope, Roslyn. "Professionalism, evidence and power : key themes influencing the management of a mental health programme in the National Health Service in England." Thesis, University of Hertfordshire, 2012. http://hdl.handle.net/2299/13903.
Анотація:
This thesis critically examines a national programme in mental health which has been driven by the implementation of National Institute of Health and Clinical Excellence (NICE) guidance. Assumptions which underpin research method, drawn from the natural sciences, are critiqued in terms of their adequacy in accounting for human relating and expert therapeutic practice. The work of Dreyfus and Dreyfus (1986) is problematized in how they account for proficiency and expertise as intuition and the leap that they make from calculative to deliberative rationality. An alternative source of understanding, based on non-linear causality and complex responsive processes, is developed, building on the work of Stacey (2001, 2005, 2007). The ineffability of expert practice (or clinical judgement) is contrasted with competence based, rule governed practice, which necessarily underpins the early stages of learning. It is argued that because research practices undertaken in randomised controlled trials (RCTs) must be describable, measurable and focussed on predictable outcomes, then these cannot account for expert practice, therefore the assertion that the Improving Access to Psychological Therapies programme (IAPT) is wholly based on research based, evidence based therapies, cannot be substantiated. The work explores professionalism and specifically considers the role of psychiatrists, psychologists and psychological therapists in mental health and in increasing access to psychological therapies. The role of managers and managerialism are explored, specifically how the NHS has sought to manage 3 professional staff and multi-disciplinary teams in adopting corporate and new ways of working (NWW). This includes the importance of and difficulty in countering professional identity using competence based approaches. The performance management processes in the NHS are recognised as an equally relevant source of evidence (to that of NICE), despite there being a poor (traditional) evidence base for it (Stacey, 2010; Seddon, 2008). Power relating in human relationships is identified as immanent, using the context of a management group, and it is argued that Foucault’s concept of disciplinary power (1994) can account for what is considered to be knowledge and truth, drawing on specialist expertise based on science and research, with a forceful potential for rendering others silent as well as pervasively self-silencing, in processes of inclusion and exclusion (Elias, 1978). It is argued that these on-going processes of relating influence policy decisions at national and local levels and how these policies are implemented in practice. The inevitability of unpredictable outcomes is highlighted, despite strong centralised programme management along with the provision of an explicit blueprint for implementation.
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Waiczies, Sonia. "Modulation of human antigen-specific T-cell response therapeutic implications for multiple sclerosis /." Doctoral thesis, [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=969681844.
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Henke, Henning. "Löslicher Interleukin-2-Rezeptor-[alpha] [Interleukin-2-Rezeptor-alpha] als möglicher prognostischer Marker des virologischen Ansprechens einer Therapie mit PEG-Interferon-a-2b und Ribavirin bei Patienten mit chronischer Hepatitis C, die auf eine vorangegangene Therapie mit Interferon-alpha und Ribavirin nicht angesprochen haben (Non-Responder)." [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=966445570.
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Müller, Christine-Susanne. "Course of clinical response during primary systemic therapy with a dose-dense 4 cycles regime of adriamycin and docetaxel in patients with operable cancer of the breast Zeitlicher Verlauf der Klinischen Response während der Primären Systemischen Therapie des Operablen Mamma-Karzinoms mit einem Dosis Dichten Therapieregime aus 4 Zyklen Adriamycin und Docetaxel /." [S.l. : s.n.], 2005. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB12168001.
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Sitaru, Ana Gabriela. "Modulation der T-Zell-Reaktivität durch MHC-Klasse-I Peptide und ihre Varianten Perspektiven für eine antigen-spezifische Therapie in der Transplantation = Modulation of the T cell response with MHC class I peptides and their analogues /." Doctoral thesis, [S.l.] : [s.n.], 2003. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-4561.
Анотація:
Transplantation is now firmly established as a therapeutic approach to extend and improve the life of patients in the final stages of organ failure. It has been demonstrated that transplantation between genetically non-identical individuals leads to the activation of the recipient’s alloimmune response as a major determinant of transplant outcome. T cell recognition of foreign MHC molecules plays a key role in initiating and sustaining allograft rejection. To prevent the risk of rejection, patients are given immunosuppressive drugs, which are non-specific and have major side-effects (infections, malignancies). It has been shown that the alloreactive T cells specifically recognize donor MHC-derived peptides. This implies that it may be possible to develop antigen-specific strategies in order to modulate the alloimmune response by peptide analogues and specifically altered peptide ligands. The purpose of this study was to explore the potential of “recipient-adapted” analogues from the dominant MHC class I peptide to modulate the alloimmune response. Beside the significant role of donor dominant determinants in the rejection process, we tested seven 13-to-24-mer peptides from the Wistar-Furth MHC class I molecule (WF, RT1.Au) for their possible immunogenicity in a fully MHC-mismatched WF to Lewis (LEW, RT1l) rat strain combination. Secondly, the immunodominant allopeptide was selected to generate analogues in order to investigate their modulatory capacity. All peptides were tested in vitro in a standard proliferation assay and in vivo using a heterotopic heart transplantation model. Our findings show that five peptides (P1-P5) were able to induce specific T cell proliferation in LEW responders. Furthermore, we found a hierarchical distribution of the determinants: peptide P1 as a good candidate for the immunodominant determinant, while P2, P3, P4, and P5 as subdominant epitopes and the other two peptides, P6 and P7, as non-immunogenic determinants of WF MHC class I molecule. Furthermore, the dominance of P1 was confirmed by the strong proliferation induced after immunization with a mixture of peptides in the presence of P1. This hierarchical distribution of the proliferative response correlated with the cytokine production. Peptide P1, comprising only 3 allogeneic amino acids (L5, L9, and T10) induced the strongest T cell proliferation and produced high levels of cytokines, especially IL-2 and IFN-g. In addition, the immunodominance of peptide P1 was confirmed by the significant reduction in the allograft survival time in comparison to the non-immunized control animals. Since the TCR Vß repertoire of rejected graft-infiltrating cells in rejected allografts was similar to the profile observed after in vitro restimulation of P1-primed T cells, we concluded that peptide P1 is able to activate the alloreactive T cell population. Our results demonstrate the particular role of the dominant peptide P1 (residues 1-19) in the allograft rejection in WF to LEW rat strain combination. In the second set of experiments, we investigated the fine specificity of the dominant peptide P1-activated T cells using peptide analogues from P1. The “recipient-adapted” analogues were designed by changing the allogeneic RT1.Au amino acids (L5, L9, T10) one-by-one with the correspondent syngeneic RT1.Al amino acids (M5, D9, I10) in the sequence of peptide P1. The six peptide analogues (A1.1-A1.6) consisting of either one or two allogeneic amino acids were able to induce a specific T cell proliferative response and cytokine production. Analogue A1.5 with only one allogeneic amino acid (L5) was of particular interest because it induced a low T cell proliferation and high cytokine levels, especially IL-4 and IL-10. In addition, immunization with A1.5 did not influence the allograft survival time in comparison to the non-immunized LEW recipients. A1.5 was the only analogue able to down-regulate the proliferation of P1-primed T cells. Our results reveal that A1.5 is an MHC competitor as confirmed by the in vitro MHC competition assay and the inhibition of the negative effect of P1 on the allograft survival time when recipients were immunized with a mixture of P1 and A1.5. These findings suggest that it is possible to design peptide analogues, such as A1.5, which do not stimulate the dominant peptide P1-specific T cell population and even more, are able to block its presentation in the MHC molecule. In all, the results indicate that the specific suppression of indirect allorecognition can be achieved by using peptide analogues of the dominant allopeptideUrsache der Transplantatabstoßung ist in erster Linie die genetische Differenz im Haupthistokompatibilitätskomplex (MHC) zwischen Transplantatspender und Empfänger. Dabei stellen die aus den Fremd-MHC-Molekülen durch empfänger-eigene antigenpräsentierende Zellen prozessierten MHC-Peptide einen wichtigen Stimulus zur Aktivierung alloreaktiver T-Lymphozyten des Transplantat empfängers dar. Für die Transplantation bedeutsam ist, dass sowohl diese, als auch synthetische MHC-Peptide, wenn sie die genetische Differenz zwischen einer bestimmten Spender-Empfänger-Kombination repräsentieren, die Alloimmunantwort induzieren und damit die Abstoßung fördern. Das Ziel dieser Arbeit war, dass bereits in zahlreichen Experimentalmodellen für Autoimmunerkrankungen erfolgreiche Konzept der antigenspezifischen Immuntherapie mit Peptidvarianten oder altered peptide ligands auf die Transplantation zu übertragen. Anders als bei Autoimmunerkrankungen basiert die Alloimmunantwort aber nicht auf ein einyelnes Peptidantigen und darüber hinaus beeinflußt die jeweilige Spender-Empfänger-Kombination sehr stark dieses Peptidantigen-Repertoire. Um die Frage zu klären, welche der potentiellen MHC-Peptidantigene in der Alloimmunaktivierung dominieren, wurden Untersuchungen im Nagermodell für die allogene Spender-Empfänger-Kombination Wistar-Furth (WF, RT1u) und Lewis (LEW, RT1l) durchgeführt. Für die Transplantation wird erwartet, dass solche gezielt hergestellten Peptidvarianten sowohl die Aktivierung alloreaktiver T-Lymphozyten als auch weitere Funktionen, wie z. B. die Produktion von Cytokinen, hemmen. Dieser antigenspezifische, und wahrscheinlich auch nebenwirkungsfreie Therapieansatz könnte möglicherweise zur langfristigen Erhaltung der Transplantatfunktion führen. Durch Vergleich der Sequenzen für das MHC-Klasse-I Molekül beider Ratten-Stämme wurden für die a1 und a2 Domäne - dies ist der extrazelluläre, für die Bindung von Peptiden unterschiedlichster Herkunft verantwortliche Bereich des Moleküls - insgesamt 34 Positionen identifiziert, in denen beide Stämme unterschiedliche Aminosäuren aufweisen. Diese Differenzen werden von sieben synthetischen, mit den entsprechenden Bereichen des Spender MHC-Klasse-I Moleküls identischen MHC-Peptiden repräsentiert, welche zwischen 13 und 24 Aminosäuren lang sind. Die immunstimulierende Wirkung dieser Peptide (P1 bis P7) wurde im Proliferationsassay und im Transplantationsmodell bestimmt. Ausschließlich das Peptid mit der Bezeichnung P1 induzierte mit über 20.000 cpm die stärkste, mit einen Th1-dominierten Cytokinmuster (IL-2 und IFN-g) einhergehende T-Zellproliferation. Lewis-Empfänger, die vor der Transplantation mit diesem Peptid immunisiert wurden, stießen ihre von WF-Spendern stammenden heterotopen Herztransplantate beschleunigt ab. Von sieben potentiellen Peptidantigenen induzierte somit ausschließlich Peptid P1 eine dominante Alloimmunaktivierung und erscheint als Peptidantigen zur Herstellung von Peptidvarianten prädestiniert. P1 weicht in drei Aminosäurepositionen von der entsprechenden Sequenz der Lewis-Ratte ab. Durch sequentiellen Austausch dieser drei in der WF-Sequenz befindlichen allogenen Aminosäuren durch die entsprechenden syngenen Aminosäuren in der LEW-Sequenz führte zu sechs Peptidvarianten. Diese Empfänger-angepassten Varianten A1.1 bis A1.6 wurden anschließend auf ihre Fähigkeit untersucht, eine peptidspezifische T-Zellproliferation zu inhibieren, die möglicherweise mit einer protektiven Wirkung auf die Transplantatfunktion einhergeht. Von diesen Peptidvarianten induzierte nur Variante A1.5, sie besitzt noch eine allogene Aminosäure an Position 5, eine reduzierte T-Zellproliferation von 11.450 cpm, die mit einem Th2-dominierten Cytokinmuster (IL-4 und IL-10) korreliert. Zusätzlich hemmte A1.5 die Proliferation der P1-spezifischen T-Lymphozyten. Im Gegensatz zum Ausgangs-peptid P1 beeinflußte A1.5 nicht die Abstoßung heterotoper Herztransplantate und konnte, wurde es in Kombination mit P1 appliziert, die P1-induzierte Transplantatabstoßung verzögern. Um diese immunmodulatorische Fähigkeit der Variante A1.5 weiter zu untersuchen, wurde das Peptid in einem T-Zellrezeptor-Modulationsassay sowie in einem MHC-Kompetitionsassay getestet. Die Ergebnisse zeigten, dass A1.5 nicht die T-Zellproliferation über den T-Zellrezeptor inhibiert, sondern über die verstärkte Bindung an das MHC-Klasse-II Molekül, wodurch das Peptid P1 wahrscheinlich aus der Bindungstasche verdrängt wird. Dieses Ergebnis wurde von weiteren in vivo Daten unterstützt. Wurden beide Peptide getrennt und nicht im Gemisch appliziert, konnte A1.5 die abstoßungsinduzierende Wirkung von P1 nicht mehr kompensieren, und das Transplantat wurde zum gleichen Zeitpunkt nach Transplantation abgestoßen wie in P1-immunisierten Tieren