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Tumors are mutated abnormal groups of cells that develop at any stage of life in any part of the body. Mammilla tumors appear in chest tissue that contain malignant cells in the terminal ductal-lobular unit, where the risk of the development of a mammilla tumor increases with age with a probability of 14.7%. Previous reviews have only focused on radiotherapy and digital mammography, while this review is, to the best of the author´s knowledge, the first review that encompasses the tomosynthesis and presumptive magnetic resonance using digital mammography. The aim of the meta-analysis was to determine the extent in which mass-testing of mammilla tumor metastasis can lead to its mitigation in adult females of all age-groups. The research question was the following: To what extent can mammilla tumor metastasis be mitigated by mass-testing of adult females of all age-groups? As part of the meta-analysis, a literature review was conducted using a selection of keywords in search queries on Pubmed, Libsearch and Academic Search Elite. In conclusion, mass-testing of mammilla tumor metastasis does not lead to a mitigation in adult females of all age-groups, since there was not a statistical significance of pooled value as indicated by the forest plot and the funnel plot indicated that the publication bias had some effect and the Mann-Whitney U-test also indicated that there was not a significance difference. Future research may consist of whether adult females within the age-range of 60-80 benefit from the test.

<p>2022-03-22</p>

<p>2022-03-21</p>

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No description available.

Cancer is among the most common causes of human deaths globally. Because of limitations and adverse effects of conventional cancer treatments, the need for new treatments is imminent. A rapidly expanding field in cancer therapy is cancer immunotherapy, which aims to, in one way or another, aid the patient’s own immune system in its battle against the tumor cells. A type of cancer immunotherapy is oncolytic virotherapy which utilizes viruses that either have a natural inclination to infect and replicate inside tumor cells or have been engineered to specially replicate in tumor cells causing oncolysis. An example of an oncolytic virus is the Lokon Oncolytic Adenovirus (LOAd). This virus specifically replicates inside cancer cells and is based on adenovirus serotype 5 but with a serotype 35 fiber, causing it to infect via the cluster of differentiation 46 receptor, which is ubiquitously expressed on somatic and tumor cells. A notable virus with the LOAd backbone, that is being evaluated in several clinical trials, is LOAd703, which is armed with the immunostimulatory transgenes 4-1BB ligand and a trimerized cluster of differentiation 40 ligands. In this project, I describe the development and evaluation of Ad703+, a cell killing adenovirus carrying the transgenes of LOAd703 as well as a novel cytotoxic transgene that never has been used in oncolytic virotherapy previously. This virus was developed using the AdEasy system, which is a replication-deficient virus platform based on adenovirus serotype 5. This virus enters cells using the human coxsackie and adenovirus receptor, which is homologous to the murine equivalent.  The ability to express the immunostimulatory transgenes and the cell killing ability of Ad703+ was evaluated in two different human cell lines, HEK293 which allows the replication of Ad703+, and the lung cancer model A549. Ad703+ was shown to express the immunostimulatory transgenes in both of the cell lines, but in a replication-dependent manner. Ad703+ was also shown to exhibit cell killing ability in a replication-independent manner on par with other oncolytic viruses.  The ability of Ad703+ to trigger cell death in a replication-independent manner opens up for the possible application in pre-clinical in vivo studies using mice due to its theoretical ability to infect murine cells and simulate viral oncolysis.

Glioblastoma is the most malignant form of gliomas and is a highly infiltrative while non-metastatic tumor of the central nervous system. Patients with glioblastoma have a poor prognosis of 15 months median survival after diagnosis. Promising results were reported in recent clinical trial regarding glioblastoma treatment with chimeric antigen receptor (CAR) T therapy. The lab has previously developed five novel scFvs targeting IL13R⍺2, a tumor-associated antigen in glioblastoma, and integrated them into the second-generation CAR. We named them, 10CAR, 27CAR, 55CAR, 75CAR and 117CAR. The ex vivo cytotoxicity and proliferation assay demonstrated that the 117CAR T construct has the best functionality, while 27CAR T construct has a poor functionality compared to the rest of the constructs. FACS analysis was performed to check the CAR expression in different constructs. 27CAR T cells showed the lowest surface CAR expression and 117CAR T cells displayed the highest out of five constructs. 27CAR T cells were also activated more without stimulation compared to other constructs. We selected out 27CAR and 117CAR T cells for the further investigation to understand the attribution of the discrepancy between 27CAR and 117CAR T cells.   We observed a larger cellular size for 27CAR T cells compared to the rest constructs in flowcytometry analysis, which is usually associated with activation. IFN-γ production of all constructs without target cells stimulation were detected to examine the activation state of different constructs. We observed the highest IFN-γ production in 27CAR T cells without stimulation. These results together indicate that a potent antigen-independent activation or, in other words, tonic signaling is present in 27CAR T cell. The tonic signaling further leads to an early exhaustive phenotype of 27CAR T cells, that is not present in 117CAR T cells. Removing the endodomain of CAR rescued the antigen-independent activation and early exhaustion of 27CAR T cells. The surface and total CAR expression of 27CAR and 117CAR T cells were determined by flowcytometry. 27CAR T cells presented a lower expression of both surface and total CAR. A significantly lower percentage of total CAR on the surface indicates the internalization of CARs in 27CAR T cells. Removing the intracellular domain of 27CAR did not restore the surface expression of CAR. 27CAR and 117CAR differ in four CDRs of scFv, CDR1, 2,3 in the heavy chain and CDR3 in the light chain. We replaced all the amino acids differing between these two constructs with alanine in a CDR-by-CDR manner and obtained five alanine substitution constructs. We then analyzed the CAR expression in Jurkat cells, and we found that the trafficking of CAR to the surface was significantly improved by mutating the CDR2 in the heavy chain or CDR3 in the light chain. Moreover, when the two CDRs were replaced simultaneously, almost all transduced cells expressed CAR, as was the case of cells transduced with 117CAR.   To summarize, the tonic signaling induced by higher tendency of clustering of 27scFv results in the antigen-independent activation and early exhaustion of 27CAR T cells. By removing the endodomain of 27CAR, we abrogated the phenomenon. Further, CDR2 in heavy and CDR3 in light chain in 27scFv are responsible for the impaired trafficking of CAR to the surface.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2007. / Härtill 5 uppsatser.

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