Ivana Knezevic - Academia.edu (original) (raw)

Papers by Ivana Knezevic

Филолог – часопис за језик књижевност и културу, 2019

The lexical level of language is the most prominent representative of each field of science indiv... more The lexical level of language is the most prominent representative of each field of science individually. The paper discusses the use of Grecisms in theological papers of academic or strictly scientific substyle. The analysis was carried out on the corpus of works of eminent authors in Serbian and in English, and in the case where there are appropriate translations, a comparative analysis was made.

Филолог – часопис за језик књижевност и културу, 2017

ABCDEFGD HDIJIKFC EBLEFC MBINFCB EB DEOJDPIC F PMQPIC RDAF *S<5 3' ?5TUVWXYZ \V]^_ Z Z` ^abVc dZ ... more ABCDEFGD HDIJIKFC EBLEFC MBINFCB EB DEOJDPIC F PMQPIC RDAF *S<5 3' ?5TUVWXYZ \V]^_ Z Z` ^abVc dZ dêb^f Zg e ZhVg W Vg e ]YZXie j\de kVbZ Z g Vc Ye \VbZie c V \V]^_ ZhV ]\W f Zl ^abVc dZ YVW ie m noe jZpZXY^c d he d^]^b^f Zg e Z iV\Vide \V a^fc b^_ c i^f o^YVqV ^c dV_rV c _g d\Vf ZYV c pe \W h^\p^b^f Zg e k V f be ] V c e k Zhe sW ĉ dVbf k Z W iV\Vide \Zc dZXYĝ W od\e aZ Vhe YZjVm t \V]W iĝ Z

Biologicals, 2015

Biotherapeutic products (BTPs) are the fastest growing medicines in the pharmaceutical market. De... more Biotherapeutic products (BTPs) are the fastest growing medicines in the pharmaceutical market. Despite their clinical success, the immunogenicity of BTPs continues to be a major concern. Assessment of immunogenicity as well as appropriate interpretation of immunogenicity data is therefore, of critical importance for defining safety profile of these products for the purpose of their licensure and use. In the past decade, much progress has been made towards how immunogenicity should be studied. This article reflects the content of the brief presentation on principles of methods used for immunogenicity assessment and their merits and limitations given at the first World Health Organization (WHO) implementation workshop on rDNA derived biotherapeutic products held in the Republic of Korea in May 2014 to support the case studies on immunogenicity presented and discussed during the workshop. The purpose of this article is to provide an overview of the methods used for assessing immunogenicity of biotherapeutic products (BTPs) and the most important considerations in interpreting results in the context of regulatory overview of these products.

Biologicals, 2015

Monoclonal antibodies are large molecules with complex structure and functions. They have a wide ... more Monoclonal antibodies are large molecules with complex structure and functions. They have a wide application for treatment of a broad range of chronic diseases and represent the largest class of biotherapeutic products. Given that biotherapeutic products may induce unwanted humoral and/or cellular immune responses in recipients, it is essential to investigate the immunogenicity of a product prior to licensure. The immune response is influenced by many factors and data generated in the pre-licensure studies are usually somewhat difficult for regulatory review. The knowledge and expertise required for this requires a thorough understanding of animal and human immunology as well as specific product characteristics, including mechanism of action, antibody assays and assessment of results in a given clinical context. The appropriate interpretation of immunogenicity data is of critical importance for defining the safety profile of a monoclonal antibody. Two case studies described in this paper were prepared to mimic a real situation in which regulators need to evaluate immunogenicity studies conducted by manufacturers of monoclonal antibody products. The specific objective of the case studies was to illustrate assessment of unwanted immunogenicity and the important factors that need to be considered in this context. Regulators and manufacturers who attended the World Health Organization (WHO) implementation workshop on Evaluation of Biotherapeutic Products, held in Seoul, Republic of Korea, in May 2014, participated in the case studies and provided valuable input. This article outlines the main aspects of immunogenicity discussed in these case studies and a summary of the lessons learned at this occasion.

Biologicals, 2015

In 2010, the WHO guidance document for the evaluation of cell substrates for producing biological... more In 2010, the WHO guidance document for the evaluation of cell substrates for producing biologicals was replaced with updated recommendations and in May 2013 an implementation workshop on the new recommendations was held in Beijing, China. As part of this workshop, a survey of the use and evaluation of cell substrates for producing biologicals was undertaken and the information obtained was updated in June 2014. The purpose of survey was to capture the status of national requirements related to cell substrates in various countries with particular emphasis on whether or not the updated WHO recommendations had been, or were to be, incorporated into national requirements. This paper reports the outcome of the survey and is based on information provided by regulators in eleven countries. Since the publication of the updated WHO recommendations, several activities such as the implementation workshop and publications have been undertaken by the WHO. The aim of these activities, including the publication of this article, is to contribute to the implementation of WHO recommendations so as to reduce regulatory gaps between national requirements and globally agreed expectations.

Vaccine, 2010

In May 2009, a group of international experts on dengue, vaccine quality and clinical evaluation ... more In May 2009, a group of international experts on dengue, vaccine quality and clinical evaluation met together (i) to review disease, vaccine pipeline, quality issues in manufacturing, issues of environmental risk assessment, nonclinical and clinical evaluation of live recombinant dengue vaccines and (ii) to initiate revising WHO guidelines for the production and quality control of candidate tetravalent dengue vaccines (live). This report summarizes an exchange of views on scientific and technical issues related to the quality, safety and efficacy of candidate dengue vaccines. Recognizing live dengue vaccines are the major vaccines in the clinical pipeline, the Working Group agreed (i) to focus on live dengue vaccines in the revision of the WHO guidelines and (ii) to add new guidelines on nonclinical and clinical evaluation, and environmental risk assessment for live dengue vaccines in the revision.

Vaccine, 2008

Current methods for the identification of BCG vaccine in quality control settings involve acid-fa... more Current methods for the identification of BCG vaccine in quality control settings involve acid-fast staining with microscopic examination. However, this method is unable to distinguish the many different substrains of BCG, or to differentiate BCG strains from virulent members of the Mycobacterium tuberculosis complex. A multiplex PCR (mPCR) which uses six target regions in mycobacteria has been developed to identify specific sub-strains of BCG. This study reports the findings from an international collaborative study to assess the accuracy, robustness and reproducibility of this mPCR method to differentiate BCG sub-strains. The method was found to fulfil these criteria successfully and was able to distinguish BCG sub-strains in vaccine preparations. The majority of the participants in the study generated the expected PCR product profiles indicating the method is also robust.

Vaccine, 2002

To analyze the current global situation with respect to vaccine quality and to monitor progress i... more To analyze the current global situation with respect to vaccine quality and to monitor progress in attaining it, it is first necessary to define what this means. While acknowledging that manufacturers are responsible for the quality of the vaccines they produce, World Health Organization (WHO) proposes a definition for "vaccines of assured quality" which depends on the existence of a competent and fully functional regulatory authority as assessed by an external expert team using widely agreed indicators to regulate the product. A vaccine of assured quality is defined as one that consistently meets appropriate levels of purity, potency, safety and efficacy as judged through an independent review system competent to take an evidence-based decision on the product for a specified population in a specific context. Such a review system would make use of all available information, such as licensing dossiers, surveillance of field performance, lot-by-lot scrutiny, appropriate laboratory testing, cGMP inspection of manufacturers, and evaluation of clinical trials, generally assumed by a fully functional regulatory authority. This definition implies that, faced with the same risk/benefit, any competent group would come to the same decision. The definition also indicates clear pathways to improve vaccine quality by strengthening national regulatory authorities and WHO is actively engaged in this task. By insisting on competent regulatory oversight, while recognizing the role of risk analysis in the selection of vaccines for use, WHO strongly reiterates the need for a single standard of quality. Only vaccine of assured quality should be considered for use in national immunization programs on the basis of the risk/benefit ratio for the particular population.

Vaccine, 2010

The current World Health Organization Requirements for BCG vaccine are in need of revision to add... more The current World Health Organization Requirements for BCG vaccine are in need of revision to address the diversity of sub-strains used for production, potential improvements of quality control assays for lot release, and the establishment of sub-strain specific Reference Reagents. A consultation meeting was organized to discuss issues regarding the standardization and evaluation of BCG vaccines in the forum of regulators, BCG vaccine manufacturers, developers of selected new live tuberculosis (TB) vaccines and researchers. The development of new recombinant BCG and live attenuated TB vaccines and the characterisation of different BCG sub-strains using state-of-the-art technologies were also reviewed. The objective of the meeting was to revise and update the current recommendations focused on the scope, terminology, manufacturing issues, and the incorporation of new reference reagents and new quality control tests.

Journal of Molecular and Cellular Cardiology, 2011

Journal of Biological Chemistry, 2012

Postnatal cardiac remodeling is characterized by a marked decrease in the insulin-like growth fac... more Postnatal cardiac remodeling is characterized by a marked decrease in the insulin-like growth factor 1 (IGF1) and IGF1 receptor (IGF1R) expression. The underlying mechanism remains unexplored. This study examined the role of microRNAs in postnatal cardiac remodeling. By expression profiling, we observed a 10-fold increase in miR-378 expression in 1-week-old neonatal mouse hearts compared with 16-day-old fetal hearts. There was also a 4-6-fold induction in expression of miR-378 in older (10 months) compared with younger (1 month) hearts. Interestingly, tissue distribution analysis identified miR-378 to be highly abundant in heart and skeletal muscles. In the heart, specific expression was observed in cardiac myocytes, which was inducible by a variety of stressors. Overexpression of miR-378 enhanced apoptosis of cardiomyocytes by direct targeting of IGF1R and reduced signaling in Akt cascade. The inhibition of miR-378 by its anti-miR protected cardiomyocytes against H(2)O(2) and hypoxia reoxygenation-induced cell death by promoting IGF1R expression and downstream Akt signaling cascade. Additionally, our data show that miR-378 expression is inhibited by IGF1 in cardiomyocytes. In tissues such as fibroblasts and fetal hearts, where IGF1 levels are high, we found either absent or significantly low miR-378 levels, suggesting an inverse relationship between these two factors. Our study identifies miR-378 as a new cardioabundant microRNA that targets IGF1R. We also demonstrate the existence of a negative feedback loop between miR-378, IGF1R, and IGF1 that is associated with postnatal cardiac remodeling and with the regulation of cardiomyocyte survival during stress.

Biophysical Journal, 2011

Airway smooth muscles (ASM) contraction is primarily mediated by M2 and M3 muscarinic acetylcholi... more Airway smooth muscles (ASM) contraction is primarily mediated by M2 and M3 muscarinic acetylcholine receptors. We and others have shown that one of the functions of large conductance Ca 2þ -and voltage-activated (BK) potassium channel and the accessory b1 subunit is to moderate ASM excitationcontraction coupling by opposing cholinergic evoked depolarization and reducing activation of L-type voltage-dependent calcium channels. Here, we have employed airway contraction studies, and a mouse knockout of the BK channel b1 subunit to investigate fuctional consequences specifically downstream of M2 signaling. Our results indicate that effects of BK channels are downstream of M2 signaling since M2 receptor antagonist (100 nM AF-DX 116) eliminates the enhanced contraction of b1 KO trachea. We found that the mechanism of M2 antagonist evoked relaxation of b1 KO is a reduction of excitation-contraction coupling since pretreatment with L-type Ca 2þ channels blocker Nifedipine or with low extracellular potassium solution that hyperpolarizes membrane potential occludes effect of M2 antagonist. M2 mediated membrane depolarization and the role of BK/b1 in controlling ASM membrane potentials were directly confirmed using sharp electrode recording of membrane voltage. In summary, these results indicate that the important role of BK/b1 during M2 activation is to oppose membrane depolarization and thereby attenuating Ca 2þ -influx through voltage dependent Ca 2þ -channels. Blocking M2 signaling largely made BK channels superfluous to control of ASM contraction.

Biologicals, 2008

This report reflects the discussion and conclusions of an informal consultation held on 19e20 Apr... more This report reflects the discussion and conclusions of an informal consultation held on 19e20 April 2007 at the World Health Organization concerning the regulatory evaluation of therapeutic biological medicinal products. The objectives of this meeting were to discuss the current status of so-called ''similar'' biological medicinal products (biosimilars) and to review regulatory pathways and challenges in evaluating the quality, safety and efficacy of these products. Biosimilars are products that are subject to licensing with a reduced data package due to a proven 'similarity' to the licensed reference product.

Филолог – часопис за језик књижевност и културу, 2019

The lexical level of language is the most prominent representative of each field of science indiv... more The lexical level of language is the most prominent representative of each field of science individually. The paper discusses the use of Grecisms in theological papers of academic or strictly scientific substyle. The analysis was carried out on the corpus of works of eminent authors in Serbian and in English, and in the case where there are appropriate translations, a comparative analysis was made.

Филолог – часопис за језик књижевност и културу, 2017

ABCDEFGD HDIJIKFC EBLEFC MBINFCB EB DEOJDPIC F PMQPIC RDAF *S<5 3' ?5TUVWXYZ \V]^_ Z Z` ^abVc dZ ... more ABCDEFGD HDIJIKFC EBLEFC MBINFCB EB DEOJDPIC F PMQPIC RDAF *S<5 3' ?5TUVWXYZ \V]^_ Z Z` ^abVc dZ dêb^f Zg e ZhVg W Vg e ]YZXie j\de kVbZ Z g Vc Ye \VbZie c V \V]^_ ZhV ]\W f Zl ^abVc dZ YVW ie m noe jZpZXY^c d he d^]^b^f Zg e Z iV\Vide \V a^fc b^_ c i^f o^YVqV ^c dV_rV c _g d\Vf ZYV c pe \W h^\p^b^f Zg e k V f be ] V c e k Zhe sW ĉ dVbf k Z W iV\Vide \Zc dZXYĝ W od\e aZ Vhe YZjVm t \V]W iĝ Z

Biologicals, 2015

Biotherapeutic products (BTPs) are the fastest growing medicines in the pharmaceutical market. De... more Biotherapeutic products (BTPs) are the fastest growing medicines in the pharmaceutical market. Despite their clinical success, the immunogenicity of BTPs continues to be a major concern. Assessment of immunogenicity as well as appropriate interpretation of immunogenicity data is therefore, of critical importance for defining safety profile of these products for the purpose of their licensure and use. In the past decade, much progress has been made towards how immunogenicity should be studied. This article reflects the content of the brief presentation on principles of methods used for immunogenicity assessment and their merits and limitations given at the first World Health Organization (WHO) implementation workshop on rDNA derived biotherapeutic products held in the Republic of Korea in May 2014 to support the case studies on immunogenicity presented and discussed during the workshop. The purpose of this article is to provide an overview of the methods used for assessing immunogenicity of biotherapeutic products (BTPs) and the most important considerations in interpreting results in the context of regulatory overview of these products.

Biologicals, 2015

Monoclonal antibodies are large molecules with complex structure and functions. They have a wide ... more Monoclonal antibodies are large molecules with complex structure and functions. They have a wide application for treatment of a broad range of chronic diseases and represent the largest class of biotherapeutic products. Given that biotherapeutic products may induce unwanted humoral and/or cellular immune responses in recipients, it is essential to investigate the immunogenicity of a product prior to licensure. The immune response is influenced by many factors and data generated in the pre-licensure studies are usually somewhat difficult for regulatory review. The knowledge and expertise required for this requires a thorough understanding of animal and human immunology as well as specific product characteristics, including mechanism of action, antibody assays and assessment of results in a given clinical context. The appropriate interpretation of immunogenicity data is of critical importance for defining the safety profile of a monoclonal antibody. Two case studies described in this paper were prepared to mimic a real situation in which regulators need to evaluate immunogenicity studies conducted by manufacturers of monoclonal antibody products. The specific objective of the case studies was to illustrate assessment of unwanted immunogenicity and the important factors that need to be considered in this context. Regulators and manufacturers who attended the World Health Organization (WHO) implementation workshop on Evaluation of Biotherapeutic Products, held in Seoul, Republic of Korea, in May 2014, participated in the case studies and provided valuable input. This article outlines the main aspects of immunogenicity discussed in these case studies and a summary of the lessons learned at this occasion.

Biologicals, 2015

In 2010, the WHO guidance document for the evaluation of cell substrates for producing biological... more In 2010, the WHO guidance document for the evaluation of cell substrates for producing biologicals was replaced with updated recommendations and in May 2013 an implementation workshop on the new recommendations was held in Beijing, China. As part of this workshop, a survey of the use and evaluation of cell substrates for producing biologicals was undertaken and the information obtained was updated in June 2014. The purpose of survey was to capture the status of national requirements related to cell substrates in various countries with particular emphasis on whether or not the updated WHO recommendations had been, or were to be, incorporated into national requirements. This paper reports the outcome of the survey and is based on information provided by regulators in eleven countries. Since the publication of the updated WHO recommendations, several activities such as the implementation workshop and publications have been undertaken by the WHO. The aim of these activities, including the publication of this article, is to contribute to the implementation of WHO recommendations so as to reduce regulatory gaps between national requirements and globally agreed expectations.

Vaccine, 2010

In May 2009, a group of international experts on dengue, vaccine quality and clinical evaluation ... more In May 2009, a group of international experts on dengue, vaccine quality and clinical evaluation met together (i) to review disease, vaccine pipeline, quality issues in manufacturing, issues of environmental risk assessment, nonclinical and clinical evaluation of live recombinant dengue vaccines and (ii) to initiate revising WHO guidelines for the production and quality control of candidate tetravalent dengue vaccines (live). This report summarizes an exchange of views on scientific and technical issues related to the quality, safety and efficacy of candidate dengue vaccines. Recognizing live dengue vaccines are the major vaccines in the clinical pipeline, the Working Group agreed (i) to focus on live dengue vaccines in the revision of the WHO guidelines and (ii) to add new guidelines on nonclinical and clinical evaluation, and environmental risk assessment for live dengue vaccines in the revision.

Vaccine, 2008

Current methods for the identification of BCG vaccine in quality control settings involve acid-fa... more Current methods for the identification of BCG vaccine in quality control settings involve acid-fast staining with microscopic examination. However, this method is unable to distinguish the many different substrains of BCG, or to differentiate BCG strains from virulent members of the Mycobacterium tuberculosis complex. A multiplex PCR (mPCR) which uses six target regions in mycobacteria has been developed to identify specific sub-strains of BCG. This study reports the findings from an international collaborative study to assess the accuracy, robustness and reproducibility of this mPCR method to differentiate BCG sub-strains. The method was found to fulfil these criteria successfully and was able to distinguish BCG sub-strains in vaccine preparations. The majority of the participants in the study generated the expected PCR product profiles indicating the method is also robust.

Vaccine, 2002

To analyze the current global situation with respect to vaccine quality and to monitor progress i... more To analyze the current global situation with respect to vaccine quality and to monitor progress in attaining it, it is first necessary to define what this means. While acknowledging that manufacturers are responsible for the quality of the vaccines they produce, World Health Organization (WHO) proposes a definition for "vaccines of assured quality" which depends on the existence of a competent and fully functional regulatory authority as assessed by an external expert team using widely agreed indicators to regulate the product. A vaccine of assured quality is defined as one that consistently meets appropriate levels of purity, potency, safety and efficacy as judged through an independent review system competent to take an evidence-based decision on the product for a specified population in a specific context. Such a review system would make use of all available information, such as licensing dossiers, surveillance of field performance, lot-by-lot scrutiny, appropriate laboratory testing, cGMP inspection of manufacturers, and evaluation of clinical trials, generally assumed by a fully functional regulatory authority. This definition implies that, faced with the same risk/benefit, any competent group would come to the same decision. The definition also indicates clear pathways to improve vaccine quality by strengthening national regulatory authorities and WHO is actively engaged in this task. By insisting on competent regulatory oversight, while recognizing the role of risk analysis in the selection of vaccines for use, WHO strongly reiterates the need for a single standard of quality. Only vaccine of assured quality should be considered for use in national immunization programs on the basis of the risk/benefit ratio for the particular population.

Vaccine, 2010

The current World Health Organization Requirements for BCG vaccine are in need of revision to add... more The current World Health Organization Requirements for BCG vaccine are in need of revision to address the diversity of sub-strains used for production, potential improvements of quality control assays for lot release, and the establishment of sub-strain specific Reference Reagents. A consultation meeting was organized to discuss issues regarding the standardization and evaluation of BCG vaccines in the forum of regulators, BCG vaccine manufacturers, developers of selected new live tuberculosis (TB) vaccines and researchers. The development of new recombinant BCG and live attenuated TB vaccines and the characterisation of different BCG sub-strains using state-of-the-art technologies were also reviewed. The objective of the meeting was to revise and update the current recommendations focused on the scope, terminology, manufacturing issues, and the incorporation of new reference reagents and new quality control tests.

Journal of Molecular and Cellular Cardiology, 2011

Journal of Biological Chemistry, 2012

Postnatal cardiac remodeling is characterized by a marked decrease in the insulin-like growth fac... more Postnatal cardiac remodeling is characterized by a marked decrease in the insulin-like growth factor 1 (IGF1) and IGF1 receptor (IGF1R) expression. The underlying mechanism remains unexplored. This study examined the role of microRNAs in postnatal cardiac remodeling. By expression profiling, we observed a 10-fold increase in miR-378 expression in 1-week-old neonatal mouse hearts compared with 16-day-old fetal hearts. There was also a 4-6-fold induction in expression of miR-378 in older (10 months) compared with younger (1 month) hearts. Interestingly, tissue distribution analysis identified miR-378 to be highly abundant in heart and skeletal muscles. In the heart, specific expression was observed in cardiac myocytes, which was inducible by a variety of stressors. Overexpression of miR-378 enhanced apoptosis of cardiomyocytes by direct targeting of IGF1R and reduced signaling in Akt cascade. The inhibition of miR-378 by its anti-miR protected cardiomyocytes against H(2)O(2) and hypoxia reoxygenation-induced cell death by promoting IGF1R expression and downstream Akt signaling cascade. Additionally, our data show that miR-378 expression is inhibited by IGF1 in cardiomyocytes. In tissues such as fibroblasts and fetal hearts, where IGF1 levels are high, we found either absent or significantly low miR-378 levels, suggesting an inverse relationship between these two factors. Our study identifies miR-378 as a new cardioabundant microRNA that targets IGF1R. We also demonstrate the existence of a negative feedback loop between miR-378, IGF1R, and IGF1 that is associated with postnatal cardiac remodeling and with the regulation of cardiomyocyte survival during stress.

Biophysical Journal, 2011

Airway smooth muscles (ASM) contraction is primarily mediated by M2 and M3 muscarinic acetylcholi... more Airway smooth muscles (ASM) contraction is primarily mediated by M2 and M3 muscarinic acetylcholine receptors. We and others have shown that one of the functions of large conductance Ca 2þ -and voltage-activated (BK) potassium channel and the accessory b1 subunit is to moderate ASM excitationcontraction coupling by opposing cholinergic evoked depolarization and reducing activation of L-type voltage-dependent calcium channels. Here, we have employed airway contraction studies, and a mouse knockout of the BK channel b1 subunit to investigate fuctional consequences specifically downstream of M2 signaling. Our results indicate that effects of BK channels are downstream of M2 signaling since M2 receptor antagonist (100 nM AF-DX 116) eliminates the enhanced contraction of b1 KO trachea. We found that the mechanism of M2 antagonist evoked relaxation of b1 KO is a reduction of excitation-contraction coupling since pretreatment with L-type Ca 2þ channels blocker Nifedipine or with low extracellular potassium solution that hyperpolarizes membrane potential occludes effect of M2 antagonist. M2 mediated membrane depolarization and the role of BK/b1 in controlling ASM membrane potentials were directly confirmed using sharp electrode recording of membrane voltage. In summary, these results indicate that the important role of BK/b1 during M2 activation is to oppose membrane depolarization and thereby attenuating Ca 2þ -influx through voltage dependent Ca 2þ -channels. Blocking M2 signaling largely made BK channels superfluous to control of ASM contraction.

Biologicals, 2008

This report reflects the discussion and conclusions of an informal consultation held on 19e20 Apr... more This report reflects the discussion and conclusions of an informal consultation held on 19e20 April 2007 at the World Health Organization concerning the regulatory evaluation of therapeutic biological medicinal products. The objectives of this meeting were to discuss the current status of so-called ''similar'' biological medicinal products (biosimilars) and to review regulatory pathways and challenges in evaluating the quality, safety and efficacy of these products. Biosimilars are products that are subject to licensing with a reduced data package due to a proven 'similarity' to the licensed reference product.