Purpose: Atypical glandular cells (AGC) are often associated with clinically significant lesions,... more Purpose: Atypical glandular cells (AGC) are often associated with clinically significant lesions, but the interpretation of AGC and the associated lesions on Pap smears remains challenging, even for experienced cytopathologists. The frequency and histologic follow–up of AGC regardless of gland cell type were investigated. Methods: A retrospective review was conducted involving 199,265 cervicovaginal smears which were examined in the Department of Pathology and Cytology of Celje General Hospital between 1 January 2003 and 31 December 2008. We investigated the frequency of AGC on conventional Pap smears and evaluated the follow–up and correlation between cytology results and subsequent biopsy diagnoses over a 6–year period. The data were processed using the statistics program, SPSS. Statistical significance was set at a p<0.05. Results: Between 1 January 2003 and 31 December 2008, a total of 745 women had AGC, representing 0.4% of all Pap smear results. One hundred seventy–two wome...
Biopharmaceuticals are becoming one of the most promising drugs on the market mainly due to their... more Biopharmaceuticals are becoming one of the most promising drugs on the market mainly due to their successful treatment of a vast array of serious diseases, such as cancers, immune disorders, and infections. Structurally, biopharmaceuticals are proteins and it is important to mention that more than 60 % of biopharmaceuticals are glycosylated. Glycosylation is one of the most common posttranslational modifications. It is also the most demanding and the most complex posttranslational modification. The research showed that glycosylation can significantly impact on the safety, efficiency, and quality of the therapeutic glycoproteins. In the first part of the introduction of the present thesis, the development of the therapeutic glycoproteins and their classification were reviewed. Glycosylation process and nomenclature were also discussed. The second part of the introduction revealed current issues in the field of the production and the characterization of the therapeutic glycoproteins. ...
Objectives Infliximab, trastuzumab and bevacizumab are among the most frequently prescribed thera... more Objectives Infliximab, trastuzumab and bevacizumab are among the most frequently prescribed therapeutic proteins, and like most other therapeutic proteins, are glycosylated. As differences in glycosylation may significantly change the safety and efficacy of therapeutic glycoproteins, it is extremely important to control N-glycosylation consistency. In the first part of this study, the batch-to-batch consistency of the N-glycosylation of infliximab, trastuzumab and bevacizumab was analysed. In the second part, the consistency of the N-glycosylation of bevacizumab stored in polycarbonate syringes (for offlabel drug use) for 3 months was examined. Methods N-glycans were (i) enzymatically released using peptide-N-glycosidase F, (ii) reduced, and (iii) analysed using hydrophilic interaction liquid chromatography coupled with high-resolution mass spectrometry. Mass spectrometry data were interpreted using principal component analysis combined with twoway analysis of variance and Tukey post hoc tests. The biological activity of infliximab and trastuzumab was examined using enzyme-linked immunosorbent assays. Results The results of both studies make important contributions to the field of hospital pharmacy. All batches of the studied therapeutic glycoproteins (infliximab, trastuzumab and bevacizumab) varied considerably (especially in galactosylation), while the N-glycosylation of bevacizumab remained unchanged during 3-month storage. Conclusions Threshold values for batch-to-batch N-glycosylation variations should be established and batch-to-batch glycosylation consistency should be regularly tested. In our study, samples with significantly different N-glycosylation profiles showed no significant variations in biological activity, suggesting that the differences are probably not therapeutically significant.
Therapeutic proteins are among the top selling drugs in the pharmaceutical industry. More than 60... more Therapeutic proteins are among the top selling drugs in the pharmaceutical industry. More than 60 % of the approved therapeutic proteins are glycosylated. Nowadays, it is well accepted that changes in glycosylation may affect the safety and the efficacy of the therapeutic proteins. For this reason, it is important to char-Keywords Therapeutic glycoproteins. N-Glycans. Principal component analysis (PCA). Soft independent modelling by class analogy (SIMCA). High-resolution mass spectrometry (HRMS). Hydrophilic interaction liquid chromatography (HILIC)
Biopharmaceuticals have emerged as the new class of blockbuster drugs in the pharmaceutical indus... more Biopharmaceuticals have emerged as the new class of blockbuster drugs in the pharmaceutical industry. More than 60% of the approved biopharmaceuticals are glycosylated. Glycosylation has an effect on the efficacy and the safety of therapeutic glycoproteins. N-glycosylation characterization of therapeutic glycoproteins is a regulatory requirement. Biosimilar releases are increasing and demonstration of comparability poses challenges for N-glycosylation characterization.
Purpose: Atypical glandular cells (AGC) are often associated with clinically significant lesions,... more Purpose: Atypical glandular cells (AGC) are often associated with clinically significant lesions, but the interpretation of AGC and the associated lesions on Pap smears remains challenging, even for experienced cytopathologists. The frequency and histologic follow–up of AGC regardless of gland cell type were investigated. Methods: A retrospective review was conducted involving 199,265 cervicovaginal smears which were examined in the Department of Pathology and Cytology of Celje General Hospital between 1 January 2003 and 31 December 2008. We investigated the frequency of AGC on conventional Pap smears and evaluated the follow–up and correlation between cytology results and subsequent biopsy diagnoses over a 6–year period. The data were processed using the statistics program, SPSS. Statistical significance was set at a p<0.05. Results: Between 1 January 2003 and 31 December 2008, a total of 745 women had AGC, representing 0.4% of all Pap smear results. One hundred seventy–two wome...
Biopharmaceuticals are becoming one of the most promising drugs on the market mainly due to their... more Biopharmaceuticals are becoming one of the most promising drugs on the market mainly due to their successful treatment of a vast array of serious diseases, such as cancers, immune disorders, and infections. Structurally, biopharmaceuticals are proteins and it is important to mention that more than 60 % of biopharmaceuticals are glycosylated. Glycosylation is one of the most common posttranslational modifications. It is also the most demanding and the most complex posttranslational modification. The research showed that glycosylation can significantly impact on the safety, efficiency, and quality of the therapeutic glycoproteins. In the first part of the introduction of the present thesis, the development of the therapeutic glycoproteins and their classification were reviewed. Glycosylation process and nomenclature were also discussed. The second part of the introduction revealed current issues in the field of the production and the characterization of the therapeutic glycoproteins. ...
Objectives Infliximab, trastuzumab and bevacizumab are among the most frequently prescribed thera... more Objectives Infliximab, trastuzumab and bevacizumab are among the most frequently prescribed therapeutic proteins, and like most other therapeutic proteins, are glycosylated. As differences in glycosylation may significantly change the safety and efficacy of therapeutic glycoproteins, it is extremely important to control N-glycosylation consistency. In the first part of this study, the batch-to-batch consistency of the N-glycosylation of infliximab, trastuzumab and bevacizumab was analysed. In the second part, the consistency of the N-glycosylation of bevacizumab stored in polycarbonate syringes (for offlabel drug use) for 3 months was examined. Methods N-glycans were (i) enzymatically released using peptide-N-glycosidase F, (ii) reduced, and (iii) analysed using hydrophilic interaction liquid chromatography coupled with high-resolution mass spectrometry. Mass spectrometry data were interpreted using principal component analysis combined with twoway analysis of variance and Tukey post hoc tests. The biological activity of infliximab and trastuzumab was examined using enzyme-linked immunosorbent assays. Results The results of both studies make important contributions to the field of hospital pharmacy. All batches of the studied therapeutic glycoproteins (infliximab, trastuzumab and bevacizumab) varied considerably (especially in galactosylation), while the N-glycosylation of bevacizumab remained unchanged during 3-month storage. Conclusions Threshold values for batch-to-batch N-glycosylation variations should be established and batch-to-batch glycosylation consistency should be regularly tested. In our study, samples with significantly different N-glycosylation profiles showed no significant variations in biological activity, suggesting that the differences are probably not therapeutically significant.
Therapeutic proteins are among the top selling drugs in the pharmaceutical industry. More than 60... more Therapeutic proteins are among the top selling drugs in the pharmaceutical industry. More than 60 % of the approved therapeutic proteins are glycosylated. Nowadays, it is well accepted that changes in glycosylation may affect the safety and the efficacy of the therapeutic proteins. For this reason, it is important to char-Keywords Therapeutic glycoproteins. N-Glycans. Principal component analysis (PCA). Soft independent modelling by class analogy (SIMCA). High-resolution mass spectrometry (HRMS). Hydrophilic interaction liquid chromatography (HILIC)
Biopharmaceuticals have emerged as the new class of blockbuster drugs in the pharmaceutical indus... more Biopharmaceuticals have emerged as the new class of blockbuster drugs in the pharmaceutical industry. More than 60% of the approved biopharmaceuticals are glycosylated. Glycosylation has an effect on the efficacy and the safety of therapeutic glycoproteins. N-glycosylation characterization of therapeutic glycoproteins is a regulatory requirement. Biosimilar releases are increasing and demonstration of comparability poses challenges for N-glycosylation characterization.
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