The development of checkpoint immunotherapy has been a paradigm shift in the treatment of cancer, leading to dramatic improvement in treatment outcomes across a broad range of tumor types. Nevertheless, our current understanding of the tumor immune microenvironment and mediators of resistance to therapy are limited. The recent development of high-throughput single-cell RNA-Sequencing (scRNA-Seq) technology has opened up an unprecedented window into the transcriptional states of distinct tumor-infiltrating immune and stromal cells. However, even this technology has its biological limitations, with very high levels of data dropout induced by low total mRNA molecules and capture efficiency. This thesis explores the application of a transcriptional regulatory protein activity inference approach to single-cell data in order to resolve gene dropout and more deeply characterize upstream drivers of cell state within the micro-environment of several distinct tumor types. To this end, algorithms for inference of protein activity, drug sensitivity, and cell-cell interaction have been adapted to scRNA-Seq data, along with an approach for querying enrichment of single-cell-derived population marker gene sets patient-by-patient in larger bulk-RNA-Seq cohorts. By applying these tools systematically, we have identified distinct cellular sub-populations associated with clinical outcome in different tumor types, including a novel population of C1Q+/TREM2+/APOE+ macrophages associated with post-surgical tumor recurrence in clear cell renal carcinoma, a sub-population of fibroblasts associated with improved response to immunotherapy in head and neck squamous cell carcinoma, tumor cell subpopulations with distinct inferred drug sensitivities in cholangiocarcinoma and prostate cancer, as well as tumor-specific regulatory T-cells (Tregs), active as a mechanism of immunotherapy resistance across a range of tumor types. In ongoing clinical trials from both primary and metastatic prostate cancer as well as clear cell renal carcinoma, we are able to assess which of these populations are enriched in non-responders to checkpoint immunotherapy. The proteomic master regulators of each of these single-cell types have direct utility as potential biomarkers for treatment response, but they may also be therapeutically modulated as novel targets for combination immunotherapy, potentially improving treatment response rates and treatment outcomes in future clinical trials. Finally, this thesis also presents a discovery-to-validation platform to accelerate micro-environment-directed drug repurposing in the context of immunotherapy resistance and rapid CRISPRko validation of novel therapeutic targets. This platform has been developed specifically to validate newly identified master regulators of tumor-specific immunosuppressive regulatory T-cells (Tregs), resulting in discovery of low-dose gemcitabine as a tumor-specific Treg-modulating drug synergistic with anti-PD1 checkpoint immunotherapy and TRPS1 as a proteomic master regulator with clinically significant effect on tumor Treg-infiltrating and tumor growth rate. However, the platform itself may be readily extended in future work to prioritize agents against immunosuppressive macrophage and fibroblast populations for clinical development and trials. As we have discovered, different cancers have different populations of cells driving therapy response and resistance. Taken together, the analytical and validation tools presented in this thesis represent an opportunity to tailor future immuno-therapies at the single-cell level to particular tumor types and to individual patients.

Photodynamic therapy (PDT) has shown to be a promising technique to treat various forms of malignant neoplasia. The photodynamic eradication of the tumor cells is achieved by applying a photosensitizer either locally or systemically and following local activation through irradiation of the tumor mass with light of a specific wavelength after a certain time of incubation. Due to preferential accumulation of the photosensitizer in tumor cells, this procedure allows a selective inactivation of the malignant tumor while sparing the surrounding tissue to the greatest extent. These features and requirements make the PDT an attractive therapeutic option for the treatment of retinoblastoma, especially when surgical enucleation is a curative option. This extreme solution is still in use in case of tumours that are resistant to conventional chemotherapy or handled too late due to poor access to medical care in less advanced country. In this study we initially conducted in-vitro investigations of the new cationic water-soluble photo sensitizer tetrahydroporphyrin-tetratosylat (THPTS) regarding its photodynamic effect on human Rb-1 and Y79 retinoblastoma cells. We were able to show, that neither the incubation with THPTS without following illumination, nor the sole illumination showed a considerable effect on the proliferation of the retinoblastoma cells, whereas the incubation with THPTS combined with following illumination led to a maximal cytotoxic effect on the tumor cells. Moreover the phototoxicity was lower in normal primary cells from retinal pigmented epithelium demonstrating a higher phototoxic effect of THPTS in cancer cells than in this normal retinal cell type. The results at hand form an encouraging foundation for further in-vivo studies on the therapeutic potential of this promising photosensitizer for the eyeball and vision preserving as well as potentially curative therapy of retinoblastoma.

Bakgrund: En stor andel individer drabbas årligen av cancer i Sverige. Vanliga behandlingsformer är cytostatika och strålning. Effekten av behandlingarna har många orala biverkningar, vilket kan påverka drabbade individers liv negativt. Syfte:Var att beskriva patienters upplevelse av munhälsa vid cytostatika- och strålbehandling mot cancer. Metod: Studien genomfördes som en allmän litteraturstudie och grundades på åtta resultatartiklar som bearbetats med hjälp av innehållsanalys där resultat har granskats, sammanställts och skapat kategorier.Resultat: Patienter upplevde orala komplikationer relaterat till cytostatika- och eller strålbehandling samt stor påverkan på det sociala livet. Det framkom även upplevelse av bristande information om hantering av orala biverkningar. Resultatet delas in i tre kategorier; Patienters upplevda munhälsa vid cytostatika- och strålbehandling, Information om vikten av munhygien vid cytostatika- och strålbehandling och Patienters upplevelse av utanförskap kopplat till nedsatt munhälsa. Konklusion: Att drabbas av orala komplikationer vid cancerbehandling påverkar patienters hela livssituation både fysiskt och psykiskt. För att tillgodose patienters välbefinnande är det av vikt att inte bara fokusera på att bota från sjukdom utan även lindra biverkningar under behandling. En ökad medvetenheten om hur orala biverkningar påverkar patienter som genomgått cancerbehandling är av stor vikt ur ett omvårdnadsperspektiv. / Background: Individuals suffer from cancer annually in Sweden. Common treatments are chemotherapy and radiation. The effect of the treatments has oral side effects, which can negatively affect the lives of individuals. Purpose: To describe patients' experience of oral health in chemotherapy and radiotherapy. Method: The study was conducted as a general literature study based on eight result articles. Content analysis were used. Results have been reviewed and compiled creating categories. Results: Patients experienced oral complications related to chemotherapy and radiotherapy as well as impact on social life. There was also experience of a lack of information on the management of oral side effects. The result is divided into three categories; Patients' perceived oral health during chemotherapy and radiotherapy, Information about the importance of oral hygiene during chemotherapy and radiotherapy and Patient's experience of exclusion linked to impaired oral health.Conclusion: Experiencing oral complications related to cancer treatment affects patients' life situation both physically and mentally. To ensure the well-being of patients, it is important not only to focus on curing from disease, but also to relieve side effects during treatment. Raising awareness of how oral side effects affect patients undergoing cancer treatment is of great importance from a nursing perspective.

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Bakgrund I majoriteten av länderna världen över klassas livmoderhalscancer som den näst vanligaste eller den vanligaste cancerdiagnosen hos kvinnor. Sjukdomen som till största del orsakas av ihållande infektioner med humant papillomvirus (HPV) kan bilda cellförändringar som senare utvecklar cancertumörer i livmoderhalsen. Aggressiva behandlingsformer i olika kombinationer sätts in och ger vanligen en rad olika biverkningar som påverkar kvinnorna på olika sätt. Ett sjukdomslidande är ett lidande som orsakas av sjukdomen i sig samt dess behandlingar. Kvinnor som får livmoderhalscancer har därav en ökad tendens till att uppleva ett lidande.  Syfte Syftet med studien var att belysa kvinnors erfarenheter och upplevelser av att leva med livmoderhalscancer.  Metod En icke-systematisk litteraturöversikt tillämpades och författarna baserade resultatet på 15 vetenskapliga artiklar med kvantitativ samt kvalitativ design. Via databaserna Public Medline (PubMed) samt Cumulative Index to Nursing & Allied Health literature (CINAHL) inhämtades artiklarna med hjälp av olika sökkombinationer. Artiklarna som inkluderades i studien kvalitetsgranskades utifrån bedömningsunderlaget framtaget av Sophiahemmet högskola. Därefter genomfördes en integrerad dataanalys där artiklarna till resultatdelen sorterades in i kategorier och underkategorier, genom detta utformades fyra huvudrubriker med tillhörande underrubriker.  Resultat I litteraturöversiktens resultat beskrivs hur kvinnor upplever livmoderhalscancer. I resultatet framkommer det att beskedet om diagnosen, genomförandet av behandling samt dess biverkningar påverkat majoriteten av kvinnornas fysiska, psykiska och sexuella förmåga. I resultatet framkommer det även att majoriteten av kvinnorna som lever med sjukdomen upplever en förändrad vardag med anledning av detta.  Slutsats Litteraturöversiktens resultat visar sammanfattningsvis att upplevelsen av livmoderhalscancer är varierande hos kvinnor, framför allt på grund av val av behandlingsmetod. Det framgår i resultatet att lidandet hos kvinnor är tydligt inom flertalet områden. Kvinnor upplever fysiska och psykiska hinder i livet både under och efter att ha diagnostiserats med livmoderhalscancer. / Background In the majority of countries around the world, cervical cancer is classified as the second most common or the most common cancer diagnosis in women. The disease, which is largely caused by persistent infections with human papillomavirus (HPV), can form cell changes that later develop cancerous tumors in the cervix. Aggressive forms of treatment in different combinations are used and usually cause a number of different side effects that affect women in different ways. The suffering of illness is a suffering caused by the disease itself and its treatments. Women who get cervical cancer therefore have an increased tendency to experience suffering.  Aim The purpose of this study was to illustrate women's experiences of living with cervical cancer.  Method A non-systematic literature overview was applied and the authors based their results from 15 scientific articles with quantitative and qualitative design. The articles are collected from the databases Public Medline (PubMed) and Cumulative Index to Nursing & Allies Health Literature (CINAHL), using different search combinations. The articles included in the study has been quality audited based on the assessment data produced by Sophiahemmet Högskola. Thereafter, an integrated data analysis was carried out where the articles were sorted into categories, and under categories, through this, four main headings with associated subheadings were designed.  Results In the result of the literature overview, it is described how women experience cervical cancer. The results show that the information about the diagnosis, the implementation of treatment and its side effects affected the majority of the women's physical, mental and sexual abilities. The results also show that the majority of women living with the disease experience a changed everyday life due to this.  Conclusions In summary, the result of the literature overview show that the experience of cervical cancer varies in women, mainly due to the choice of treatment method. The results show a clear suffering of women and in many areas. Women experience physical and mental barriers in life both during and after being diagnosed with cervical cancer.

SAMMANFATTNING Bakgrund: Ungdomar och unga vuxna under cancerbehandling är i behov av specialanpassad och ålderslämplig vård då deras åldersgrupp genomgår unika livsutvecklande milstolpar i övergången från barndom till att bli vuxen som påverkas av cancersjukdomen. En störd livsutveckling kan resultera med långsiktiga negativa konsekvenser som kan påverka ungdomar och unga vuxna även efter avslutad behandling.   Syfte: Att undersöka ungdomar och unga vuxnas upplevelser av sin psykosociala situation under cancerbehandling.   Metod: Litteraturstudie med systematisk ansats med beskrivande design. Litteratursökningen använde MEDLINE, CINAHL, och PsycINFO. Resultatet baserades på elva kvalitativa studier samt en kvantitativ studie med kvalitativ bearbetning av ett fritextsvar publicerade mellan år 2014–2020.   Resultat: Ungdomar och unga vuxna värderade bibehållandet av ett normalt liv och strävade efter att uppnå detta med olika strategier. Självständighet och känslan för den egna identiteten kunde störas. Stöttning från anhöriga, närstående, cancerdrabbade jämnåriga, och vårdpersonal var av betydelse men inte alltid tillräckligt. Upprymdhet upplevdes över att avsluta cancerbehandlingen men också en oro inför framtiden efteråt.   Slutsats: Rapporterade upplevelser av psykosociala påfrestningar under cancerbehandlingen leder till slutsatsen att kunskap om hur dessa utmaningar kan bemötas på ett specialanpassat och ålderslämpligt vis är bristfällig. En vidare fördjupad förståelse för ungdomar och unga vuxnas psykosociala upplevelser under cancerbehandling från ytterligare forskning kan potentiellt förbättra sjukvårdens möjlighet till att erbjuda adekvat vård.   Nyckelord: Ungdomar och unga vuxna (AYA), Cancerbehandling, Psykosocial, Erfarenheter. / ABSTRACT Background: Adolescents and young adults undergoing cancer treatment are in need of specially adapted and age appropriate care since their age group undergoes unique life-developing milestones in the transition period between childhood and adulthood that may be affected by cancer. A disrupted life development may result in long-term negative consequences that may affect adolescents and young adults even after the end of cancer treatment.   Aim: This study aimed to examine adolescents and young adults’ experiences of their psychosocial situation during cancer treatment.   Method: Literature review with descriptive design. The literature search used MEDLINE, CINAHL, and PsycINFO. The result was based on eleven qualitative studies and a quantitative study with qualitative processing of a free text answer published between 2014-2020.   Result: Adolescents and young adults valued the maintenance of a normal life and strived to achieve this with different strategies. Independence and the feeling for one's own identity could be disturbed. Support from family, friends, cancer-stricken peers, and healthcare staff was of importance, but not always enough. Exaltation was experienced over ending the cancer treatment but also a concern for the future afterwards.   Conclusion: Reported experiences of psychosocial stress during cancer treatment lead to the conclusion that knowledge of how these challenges can be met in a specially adapted and age-appropriate way is deficient. A further in-depth understanding of adolescents and young adults' psychosocial experiences during cancer treatment from further research may potentially improve healthcare's ability to offer adequate care.   Keywords: Adolescents and Young Adults (AYA), Cancer Treatment, Psychosocial, Experiences.

Triple-negative breast cancers (TNBCs) are highly refractive to current treatment strategies, and new multi-targeted treatments need to be elucidated. Combination therapy that includes targeting the murine double minute 2 (Mdm2) signaling axis offers a promising approach. Protein-protein interaction inhibitors such as Nutlin-3a block the binding of key signaling molecules such as p53, p73α, and E2F1 to the hydrophobic pocket of Mdm2 and can lead to activation of cell-death signaling pathways. Since clinical trials for TNBC are evaluating the DNA damaging agent carboplatin, the objective of this thesis was to evaluate the therapeutic potential and mechanism of action of combination carboplatin and Nutlin-3a to treat TNBC. In TNBC cell lines with a mutant p53 background, we determined if modulation of Mdm2 function in the context of carboplatin-mediated DNA damage resulted in a synergistic inhibition of cell growth. Several ratios of carboplatin:Nutlin-3a were strongly synergistic in increasing cell death, with combination indices of 0.5 and lower. Mechanistic studies indicated that drug sensitivity and Mdm2 expression were dependent on p73. Mdm2 localized to a larger degree in the chromatin fraction isolated from cells treated with the combination treatment consistent with observations by others that Mdm2 binds to the Mre11/Rad50/Nbs1 complex, inhibits the DNA damage response, and increases drug sensitivity. In vivo efficacy experiments were conducted in the TMD231 orthotopic mammary fat pad model in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. For assessment of baseline tumor burden and randomization, fluorescent imaging of E2-Crimson expressing TMD231 cells was performed. Following Nutlin-3a and carboplatin combination treatment, there was a statistically significant reduction in primary tumor volume as well as lung metastases with significantly increased probability of survival compared to Vehicle and single drug treatments (p<0.001). While there was a decrease in bone-marrow cellularity, this did not lead to bone-marrow aplasia, and body weights recovered to normal levels within 7 days post-treatment. The present studies demonstrate the promise of Mdm2 as a therapeutic target in combination with conventional therapy, increase our understanding of how to potentiate DNA damage in cancers, and may lead to new clinical therapies for triple-negative primary and metastatic breast cancer.

Användningen av per oral cancerbehandling har ökat de senaste åren. Per oral cancerbehandling är inte automatiskt förknippat med samma strikta riktlinjer som vid intravenös behandling, däremot så är biverkningsprofilen med allvarliga och ibland livshotande tillstånd i stort sett densamma. Forskning har visat att följsamheten till den per orala cancerbehandlingen varierar, ibland är låg och inte är bättre än andra kroniskt sjuka gruppers följsamhet. Patienten sköter till stor del behandlingen själv. Konsekvenserna av detta kan vara ett försämrat behandlingsresultat, risk för över resp. underdosering och oförutsägbara biverkningar. Mätning av följsamhet är komplext och det finns ingen standardiserad metod.                              Syftet med denna studie var att belysa faktorer som påverkar patienters följsamhet till läkemedelsordinationer med per oral cancerbehandling. Metoden var en en forskningsöversikt. Sökorden som användes var; oral administration, antineoplastic agents, patient compliance, nursing care, medication adherence, treatment compliance och drug administration methods. De databaser som söktes igenom var PubMed, Cinahl och PsykInfo (Ovid). Totalt så inkluderades 15 artiklar i resultatet. Resultatet visade att förekomst av biverkningar och svårighet att hantera dessa kunde hindra följsamhet. Ett samband mellan följsamhet och chansen till att behandlingen var verksam hittades. Andra faktorer som framkom var att yngre patienter kunde löpa högre risk för att inte följa ordinationen, följsamheten var till viss del lägre bland yngre patienter. Enstaka studier fann ett samband mellan var behandlingen gavs (universitetssjukhus eller andra vårdinrättningar) och socioekonomisk status. Utbildning kunde öka följsamheten enligt en studie. En studie visade att psykologisk hälsa hos patienten kunde påverka följsamheten. Slutsatsen var att följsamhet till per oral cancerbehandling beror på flera olika faktorer. Förekomst av biverkningar, patientens uppfattning om prognos och ålder kan påverka följsamheten. Socioekonomisk status, var behandlingen ges och psykologisk hälsa är faktorer som kan påverka följsamheten och behöver studeras vidare. Informationen måste vara individuell och samtal kring följsamhet kan vara av betydelse. Hantering av biverkningar och information kring konsekvenserna av en låg följsamhet behöver utvecklas. Vårdpersonalen behöver utbildas i vad som kan påverka följsamhet och vara lyhörda för eventuella missuppfattningar kring behandlingens effekt. Vikten av följsamhet bör tas upp av både läkare och sjuksköterskor och gärna tillsammans med anhöriga.

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