Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 121-136).

Background. Head and neck cancers (HNC) are among the most common malignancies worldwide, and about 90–92% of oral neoplasias are oral squamous cell carcinomas (OSCC). Alcohol and tobacco consumption have been recognized as the main risk factors for OSCC development. Oncogenic viruses, such as human papillomavirus (HPV) or Epstein-Barr virus (EBV), as well as genetic alterations may also contribute to tumour formation.  Aims. To study the prevalence of HPV, EBV, Herpes simplex type-1 (HSV-1), and HPV-16 and their integration status as well as the molecular mechanisms that can serve as a basis for the development of OSCC. Results. In Paper I we reported a statistically significant increase in the prevalence of HPV-16 in oral epithelial dysplasia (OED) and OSCC samples compared to controls. A statistically significant increase was also seen in integrated HPV-16 compared to episomal viral forms when comparing OED and OSCC samples. Paper II reported the detection of HSV-1 in 54% of healthy samples, in 36% of oral leukoplakia samples, and 52% of OSCC samples. However, these differences were not statistically significant. In Paper III we reported a statistically significant increase in the detection of HPV-positive samples when comparing nested polymerase chain reaction (PCR) with single-PCR results in OSCC and fresh oral mucosa. Paper IV reported that the highest prevalence of HPV (65%) was seen in Sudan, while an HSV-1 prevalence of 55% and an EBV prevalence of 80% were seen in the UK. Finally, Paper V reported that the mRNA levels of Bcl-2, keratin 1, keratin 13, and p53 were significantly lower and that the level of survivin was significantly higher in the OSCC samples of the toombak users than in their paired control samples. Significant downregulation in keratin 1 and keratin 13 expression levels was found in the OSCC samples of the non-toombak users relative to their normal control samples. Conclusion. HPV-16 integration was increased in oral epithelial dysplasia and OSCC compared to normal oral mucosa. Nested PCR is a more accurate method of establishing HPV prevalence in samples containing low copy numbers of HPV DNA. HPV and EBV may be a risk factor in OSCC development. Our findings confirmed the role of survivin in OSCC carcinogenesis and survivin might be interesting as a biomarker to be monitored. The results presented here provide both clinical and biological insights that will bring us closer to the goal of managing this disease and improving treatment and outcomes for future patients.

Indiana University-Purdue University Indianapolis (IUPUI) / Giant axonal neuropathy (GAN) is a rare genetic disease that causes progressive damage to the nervous system. Neurons in GAN patients develop an abnormal organization of cytoskeletal proteins called intermediate filaments (IFs), which normally provide strength and support for the overall cell structure. The irregular IF structure in GAN patient neurons leads to a progressive loss of motor skills in children and subsequent death in adolescence. GAN is caused by reduced levels of the gigaxonin (Giga) protein. Giga functions to control the degradation of other cellular proteins, and the loss of Giga in GAN cells results in significantly elevated levels of the galectin-1 (Gal-1) protein. Gal-1 stabilizes the active form of the Ras signaling protein, which functions as a molecular switch to regulate the phosphorylation and subsequent organization of IFs. The connection between these pathways led us to propose that Giga regulates IF phosphorylation and structure by modulating Ras signaling through the degradation of Gal-1. Using GAN patient cells, we demonstrated that restoring Giga reduced Gal-1 protein levels, decreased IF phosphorylation, and reestablished normal IF organization. Similar effects of reduced IF phosphorylation and improved IF structure were also obtained in GAN cells by directly decreasing the protein levels of either Gal-1, or downstream Ras signaling proteins. Taken together, these results demonstrate that the loss of Giga induces Gal-1 mediated activation of Ras signaling, thereby leading to the increased IF phosphorylation and abnormal IF structure observed in GAN cells. Identification of aberrant Ras signaling is significant because it is the first to specify a mechanism by which the loss of Giga leads to the development of GAN and provides targets for novel drug therapies for the treatment of this currently immedicable genetic disease.

Diss. (sammanfattning) Umeå : Umeå universitet, 2010.

Several lines of evidence support an autoimmune basis for alopecia areata (AA), a common putative autoimmune hair loss disorder. However, definitive support is lacking largely because the identity of hair follicle (HF) autoantigen(s) involved in its pathogenesis remains unknown. Here, we isolated AA-reactive HF-specific antigens from normal human scalp anagen HF extracts by immunoprecipitation using serum antibodies from 10 AA patients. Samples were analyzed by LC-MALDI-TOF/TOF mass spectrometry, which indicated strong reactivity to the hair growth phase-specific structural protein trichohyalin in all AA sera. Keratin 16 (K16) was also identified as another potential AA-relevant target HF antigen. Double immunofluorescence studies using AA (and control sera) together with a monoclonal antibody to trichohyalin revealed that AA sera contained immunoreactivity that colocalized with trichohyalin in the growth phase-specific inner root sheath of HF. Furthermore, a partial colocalization of AA serum reactivity with anti-K16 antibody was observed in the outer root sheath of the HF. In summary, this study supports the involvement of an immune response to anagen-specific HFs antigens in AA and specifically suggests that an immune response to trichohyalin and K16 may have a role in the pathogenesis of the enigmatic disorder.