Pub Date : 2016-01-01DOI: 10.1016/j.nhtm.2016.01.001
Edited by Selvamani Palanisamy , Latha Subbiah , Ruckmani Kandasamy
{"title":"Scientific Abstracts presented at the 5th International Convention of Association of Pharmacy Professionals: Redesigning Pharmacy Education and Regulations for Translational Drug Research in India, hosted at Anna University, Centre for Excellence in Nanobio Translational Research, Bharathidasan Institute of Technology Campus, Tiruchirappalli, Tamil Nadu, India, 22nd–23rd January, 2016.","authors":"Edited by Selvamani Palanisamy , Latha Subbiah , Ruckmani Kandasamy","doi":"10.1016/j.nhtm.2016.01.001","DOIUrl":"https://doi.org/10.1016/j.nhtm.2016.01.001","url":null,"abstract":"","PeriodicalId":90660,"journal":{"name":"New horizons in translational medicine","volume":"3 1","pages":"Pages 30-61"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nhtm.2016.01.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"137440853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-01DOI: 10.1016/j.nhtm.2016.04.002
Neethu Hari, Ananthakrishnan Jayakumaran Nair
Nowadays, Chitosan has attained more attention due to its potential applications in food, agriculture and pharmaceutics. The cationic nature of chitosan enhances the film forming capacity of this polymer. However, films made only from chitosan lack water resistance and have reduced mechanical properties. The functional properties of chitosan films can be improved when chitosan films are combined with other film forming materials. The objective of this study was to prepare chitosan based antimicrobial films by the incorporation of streptomycin loaded starch Nanocrystals. Different properties of this film such as swelling nature, moisture content, degradation nature and the antimicrobial activity of modified chitosan films were investigated. Drug releasing efficacy of the film was also studied. The addition of streptomycin loaded Starch nanocrystals in chitosan-gelatin film increased crystallinity of the film, lowered the swelling nature of the film to a controlled manner. Moreover the Modified chitosan based antimicrobial film showed almost 90% of Escherichia coli inhibition and 80% of Bacillus subtilis inhibition and also the film showed a sustained release (60%) of streptomycin for 10 days.
Focal point
•
Benchside
Synthesis of streptomycin loaded starch nanoparticles (SS-NPs) using nanoprecipitation method and the development of novel chitosan based antimicrobial film by the incorporation of streptomycin loaded starch nanoparticles using solvent casting technique
•
Bedside
Development of potential multifunctional antimicrobial film for medical, pharmaceutical and food based applications due to its excellent film forming ability, biocompatibility, biodegradability and antimicrobial property
•
Industry
The designed unique antimicrobial film, if finely tuned, can be used both in biomedical fields for developing scaffolds in tissue engineering, wound dressing material, capsule material for sustained drug release and immobilization of enzyme and food industry as packaging material
•
Government
Financial investment and support from government would help to develop new novel translational tools which contribute for better health care and also help to reduces disease burden
•
Regulatory
Stringent regulatory principles limit the clinical trials essential for validation of biomaterials which might have turned in to a highly beneficial multifunctional product such as antimicrobial film potentially useful both in biomedical and food industry.
{"title":"Development and characterization of chitosan-based antimicrobial films incorporated with streptomycin loaded starch nanoparticles","authors":"Neethu Hari, Ananthakrishnan Jayakumaran Nair","doi":"10.1016/j.nhtm.2016.04.002","DOIUrl":"10.1016/j.nhtm.2016.04.002","url":null,"abstract":"<div><p><span><span>Nowadays, Chitosan has attained more attention due to its potential applications in food, agriculture and pharmaceutics. The cationic nature of chitosan enhances the film forming capacity of this polymer. However, films made only from chitosan lack water resistance and have reduced mechanical properties. The functional properties of chitosan films can be improved when chitosan films are combined with other film forming materials. The objective of this study was to prepare chitosan based antimicrobial films by the incorporation of streptomycin loaded starch </span>Nanocrystals<span>. Different properties of this film such as swelling nature, moisture content, degradation nature and the antimicrobial activity<span> of modified chitosan films were investigated. Drug releasing efficacy of the film was also studied. The addition of streptomycin loaded Starch nanocrystals in chitosan-gelatin film increased crystallinity of the film, lowered the swelling nature of the film to a controlled manner. Moreover the Modified chitosan based antimicrobial film showed almost 90% of </span></span></span><em>Escherichia coli</em> inhibition and 80% of <span><em>Bacillus subtilis</em></span><span> inhibition and also the film showed a sustained release (60%) of streptomycin for 10 days.</span></p></div><div><h3>Focal point</h3><p></p><ul><li><span>•</span><span><p>Benchside</p><p>Synthesis of streptomycin loaded starch nanoparticles (SS-NPs) using nanoprecipitation method and the development of novel chitosan based antimicrobial film by the incorporation of streptomycin loaded starch nanoparticles using solvent casting technique</p></span></li><li><span>•</span><span><p>Bedside</p><p><span>Development of potential multifunctional antimicrobial film for medical, pharmaceutical and food based applications due to its excellent film forming ability, biocompatibility, </span>biodegradability and antimicrobial property</p></span></li><li><span>•</span><span><p>Industry</p><p>The designed unique antimicrobial film, if finely tuned, can be used both in biomedical fields for developing scaffolds in tissue engineering<span>, wound dressing material, capsule material for sustained drug release and immobilization of enzyme and food industry as packaging material</span></p></span></li><li><span>•</span><span><p>Government</p><p>Financial investment and support from government would help to develop new novel translational tools which contribute for better health care<span> and also help to reduces disease burden</span></p></span></li><li><span>•</span><span><p>Regulatory</p></span></li></ul><p>Stringent regulatory principles limit the clinical trials essential for validation of biomaterials which might have turned in to a highly beneficial multifunctional product such as antimicrobial film potentially useful both in biomedical and food industry.</p></div>","PeriodicalId":90660,"journal":{"name":"New horizons in translational medicine","volume":"3 1","pages":"Pages 22-29"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nhtm.2016.04.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79848886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-01DOI: 10.1016/j.nhtm.2016.03.001
R. Bhome , H.A. Al Saihati , R.W. Goh , M.D. Bullock , J.N. Primrose , G.J. Thomas , A.E. Sayan , A.H. Mirnezami
Solid tumours comprise, not only malignant cells but also a variety of stromal cells and extracellular matrix proteins. These components interact via an array of signalling pathways to create an adaptable network that may act to promote or suppress cancer progression. To date, the majority of anti-tumour chemotherapeutic agents have principally sought to target the cancer cell. Consequently, resistance develops because of clonal evolution, as a result of selection pressure during tumour expansion. The concept of activating or inhibiting other cell types within the tumour microenvironment is relatively novel and has the advantage of targeting cells which are genetically stable and less likely to develop resistance. This review outlines key players in the stromal tumour microenvironment and discusses potential targeting strategies that may offer therapeutic benefit.
Focal points:
•
Benchside
○ The tumour stroma consists of mesenchymal, immune and vascular cells housed in an extracellular matrix. Stromal cells and extracellular matrix proteins represent genetically stable targets which can be exploited in cancer treatment. Numerous in vitro and animal studies support the concept of stromal-directed treatment.
•
Bedside
○ Several therapeutic strategies have been developed or repurposed to target the stroma. The anti-angiogenic agent bevacizumab was one of the first specific stromal-targeting agents to be licensed for cancer treatment over a decade ago. More recently, immune modulation of the stroma has become a hugely successful strategy, with novel drugs such as checkpoint inhibitors set to revolutionise cancer treatment.
•
Governments
○ Funding bodies should continue to acknowledge the pivotal role that the stroma plays in cancer progression, in parallel with cancer cell itself. Undoubtedly, the most successful treatment regimens of the future will address both the “seed” and the “soil”.
{"title":"Translational aspects in targeting the stromal tumour microenvironment: From bench to bedside","authors":"R. Bhome , H.A. Al Saihati , R.W. Goh , M.D. Bullock , J.N. Primrose , G.J. Thomas , A.E. Sayan , A.H. Mirnezami","doi":"10.1016/j.nhtm.2016.03.001","DOIUrl":"10.1016/j.nhtm.2016.03.001","url":null,"abstract":"<div><p>Solid tumours comprise, not only malignant cells but also a variety of stromal cells and extracellular matrix proteins. These components interact via an array of signalling pathways to create an adaptable network that may act to promote or suppress cancer progression. To date, the majority of anti-tumour chemotherapeutic agents have principally sought to target the cancer cell. Consequently, resistance develops because of clonal evolution, as a result of selection pressure during tumour expansion. The concept of activating or inhibiting other cell types within the tumour microenvironment is relatively novel and has the advantage of targeting cells which are genetically stable and less likely to develop resistance. This review outlines key players in the stromal tumour microenvironment and discusses potential targeting strategies that may offer therapeutic benefit.</p></div><div><h3><strong>Focal points:</strong></h3><p></p><ul><li><span>•</span><span><p>Benchside</p><p>○ The tumour stroma consists of mesenchymal, immune and vascular cells housed in an extracellular matrix. Stromal cells and extracellular matrix proteins represent genetically stable targets which can be exploited in cancer treatment. Numerous <em>in vitro</em> and animal studies support the concept of stromal-directed treatment.</p></span></li><li><span>•</span><span><p>Bedside</p><p>○ Several therapeutic strategies have been developed or repurposed to target the stroma. The anti-angiogenic agent bevacizumab was one of the first specific stromal-targeting agents to be licensed for cancer treatment over a decade ago. More recently, immune modulation of the stroma has become a hugely successful strategy, with novel drugs such as checkpoint inhibitors set to revolutionise cancer treatment.</p></span></li><li><span>•</span><span><p>Governments</p><p>○ Funding bodies should continue to acknowledge the pivotal role that the stroma plays in cancer progression, in parallel with cancer cell itself. Undoubtedly, the most successful treatment regimens of the future will address both the “seed” and the “soil”.</p></span></li></ul></div>","PeriodicalId":90660,"journal":{"name":"New horizons in translational medicine","volume":"3 1","pages":"Pages 9-21"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nhtm.2016.03.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34556017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-01DOI: 10.1016/j.nhtm.2016.04.001
Stainsloss Isabella, Sankaran Mirunalini
Breast cancer is the second most prevalent cancer among women and its incidence is amplifying alarmingly. Since genetic factors are believed to account for only 10% of the reported cases, remaining the environmental factors, including diet are thought to play a significant role in predisposing breast cancer. Many bioactive compounds have been reported for their anticancer potential. One among the bioactive compound 3, 3′-Diindolylmethane (DIM) is a phytochemical possess a wide array of pharmacological activities such as anti-proliferative and anti-oxidant properties. Its properties such as poor water solubility and low bioavailability have hampered its clinical development.
Therefore, it is a great interest to study whether the nano formulation for DIM with chitosan for its enhanced potential, the present study was aimed to evaluate the chemotherapeutic potential of 3, 3′- Diindolylmethane encapsulated chitosan nanoparticles (DIM@CS-NP) on 7,12-Dimethylbenz(a)anthracene (DMBA) induced mammary carcinoma in rats. DMBA was induced in a single subcutaneous injection of 25mg/ kg body weight to each rat. In the present study, we investigated the altered activities of lipid peroxidation, enzymatic antioxidants (SOD, CAT, GPx) and non- enzymatic antioxidant (GSH) in plasma, liver and mammary tissue, supported by histopathological study of mammary tissues. We evaluated the changes in the body weight of control and experimental animals. There was a significant decrease in the final body weight of tumor bearing animals, when compared to control animals. Also, we observed a diminished cellular antioxidant status and the elevated oxidant levels in plasma, liver, mammary tissues of DMBA induced rats. However, administration of DIM@CS-NP significantly increased the mean final body weight when compared with DMBA induced animals. Oral supplementation of different doses of DIM@CS-NP (0.5, 1, 2 mg/kg BW), significantly renovated the activities of cellular antioxidants and ultimately diminished the levels of lipid peroxidation, which pointed towards suppression of preneoplastic lesions, thereby reduced the cancer risk, and significant improvement in the levels of enzymatic (SOD, CAT, GPx) and non- enzymatic antioxidant (GSH) in the plasma, liver and mammary tissue. Based on the above finding we conclude the nano formulation of DIM provides a novel therapeutic regime for mammary cancer.
Focal points:
•
Benchside
○
Oxidants, antioxidant status and histopathological examination of mammary tumor tissue are necessary to determine the chemotherapeutic potential of DIM@CS-NP on experimental induced rat mammary carcinoma.
•
Bedside
○
Ingestion of DIM@CS-NP may reduce the severity of D
{"title":"Chemotherapeutic effect of 3, 3′-Diindolylmethane encapsulated chitosan nanoparticles on 7, 12-Dimethylbenz (a) anthracene induced mammary cancer – A dose dependent study","authors":"Stainsloss Isabella, Sankaran Mirunalini","doi":"10.1016/j.nhtm.2016.04.001","DOIUrl":"10.1016/j.nhtm.2016.04.001","url":null,"abstract":"<div><p><span>Breast cancer is the second most prevalent cancer among women and its incidence is amplifying alarmingly. Since genetic factors are believed to account for only 10% of the reported cases, remaining the </span>environmental factors<span>, including diet are thought to play a significant role in predisposing breast cancer. Many bioactive compounds have been reported for their anticancer potential. One among the bioactive compound 3, 3′-Diindolylmethane (DIM) is a phytochemical possess a wide array of pharmacological activities such as anti-proliferative and anti-oxidant properties. Its properties such as poor water solubility and low bioavailability have hampered its clinical development.</span></p><p><span>Therefore, it is a great interest to study whether the nano formulation for DIM with chitosan for its enhanced potential, the present study was aimed to evaluate the chemotherapeutic potential of 3, 3′- Diindolylmethane encapsulated chitosan nanoparticles<span> (DIM@CS-NP) on 7,12-Dimethylbenz(a)anthracene (DMBA) induced mammary carcinoma<span> in rats. DMBA was induced in a single subcutaneous injection of 25</span></span></span> <span>mg/ kg body weight to each rat. In the present study, we investigated the altered activities of lipid peroxidation<span>, enzymatic antioxidants (SOD, CAT, GPx) and non- enzymatic antioxidant (GSH) in plasma, liver and mammary tissue, supported by histopathological study of mammary tissues. We evaluated the changes in the body weight of control and experimental animals. There was a significant decrease in the final body weight of tumor bearing animals, when compared to control animals. Also, we observed a diminished cellular antioxidant status and the elevated oxidant levels in plasma, liver, mammary tissues of DMBA induced rats. However, administration of DIM@CS-NP significantly increased the mean final body weight when compared with DMBA induced animals. Oral supplementation of different doses of DIM@CS-NP (0.5, 1, 2 mg/kg BW), significantly renovated the activities of cellular antioxidants and ultimately diminished the levels of lipid peroxidation, which pointed towards suppression of preneoplastic lesions, thereby reduced the cancer risk, and significant improvement in the levels of enzymatic (SOD, CAT, GPx) and non- enzymatic antioxidant (GSH) in the plasma, liver and mammary tissue. Based on the above finding we conclude the nano formulation of DIM provides a novel therapeutic regime for mammary cancer.</span></span></p><p><strong>Focal points:</strong></p><p></p><ul><li><span>•</span><span><p>Benchside</p><ul><li><span>○</span><span><p>Oxidants, antioxidant status and histopathological examination of mammary tumor tissue are necessary to determine the chemotherapeutic potential of DIM@CS-NP on experimental induced rat mammary carcinoma.</p></span></li></ul></span></li><li><span>•</span><span><p>Bedside</p><ul><li><span>○</span><span><p><span>Ingestion of DIM@CS-NP may reduce the severity of D","PeriodicalId":90660,"journal":{"name":"New horizons in translational medicine","volume":"3 1","pages":"Pages 1-8"},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nhtm.2016.04.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87636049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-09-01DOI: 10.1016/j.nhtm.2015.09.001
Trevor A. Hall, Robert D. Steiner , Hollis Wright, Beth Wilmot, Jean-Baptiste Roullet , Meaghan Peters, Michael Harris
Objective
Research has uncovered potential links between lipid and sterol metabolism and autism spectrum disorder (ASD). We worked to characterize genetic sequence variants in lipid/sterol related genes in children affected with ASD to investigate the association between lipid/sterol gene sequence variation and neurodevelopmental phenotype that could identify new etiologies for ASD and eventually aid to focus intervention strategies.
Design and methods
Children with confirmed ASD were recruited from a regional academic health center. Participants included 24 children (20 male and 4 female) between the ages of 40 to 81 months (M=60 months). Several neurodevelopmental measures were administered which provided an assessment of neurodevelopmental functional status. We applied our exome sequencing workflow to perform alignment to the Human Reference Sequence (build 37) base calling for every base pair in the reads that align to the reference sequence QC evaluation of the annotation of all genetic variants different from the reference sequence using dbSNP and the 1000 Genomes databases. We investigated whether novel variants identified were related to neurodevelopmental functioning.
Results and conclusions
Variants occurred in 355 total genomic positions, 53 of which were not previously annotated as variant positions in either dbSNP or the 1000 Genomes Project׳s variant annotation. Of these 355 variants, 169 were nonsynonymous (31 were novel). The total number of variants observed in the exons of captured regions of an individual participant ranged from 88 to 117; novel variants ranged from four to 10 per participant, while nonsynonymous variants ranged from 36 and 51 per participant. The total number of nonsynonymous variants per subject was significantly associated with neurodevelopmental function. Further, several genes involved in sterol and lipid metabolism including NPC1, DHCR24 and others that when mutated cause diseases with ASD characteristics, were associated with ASD in Network analysis. Altogether, the findings suggest that nonsynonymous variants in lipid/sterol related genes may be a biological marker of neurodevelopment status in ASD. Results support an association between lipid and sterol metabolism and ASD and suggest the need for further research attempting to elucidate the mechanisms behind the association and the etiology and neurodevelopmental effects of ASD.
Focal points
•
Bedside
Understanding the association between genetics and metabolism and ASD will contribute to the scientific understanding of complex neurodevelopmental disorders. Continued study into the association between lipid and sterol genes and ASD may lead to new novel and effective treatment options for ASD.
{"title":"Lipid and sterol gene sequence variation in autism and correlates with neurodevelopmental status: A pilot study","authors":"Trevor A. Hall, Robert D. Steiner , Hollis Wright, Beth Wilmot, Jean-Baptiste Roullet , Meaghan Peters, Michael Harris","doi":"10.1016/j.nhtm.2015.09.001","DOIUrl":"10.1016/j.nhtm.2015.09.001","url":null,"abstract":"<div><h3>Objective</h3><p>Research has uncovered potential links between lipid and sterol metabolism and autism spectrum disorder (ASD). We worked to characterize genetic sequence variants in lipid/sterol related genes in children affected with ASD to investigate the association between lipid/sterol gene sequence variation and neurodevelopmental phenotype that could identify new etiologies for ASD and eventually aid to focus intervention strategies.</p></div><div><h3>Design and methods</h3><p>Children with confirmed ASD were recruited from a regional academic health center. Participants included 24 children (20 male and 4 female) between the ages of 40 to 81 months (<em>M</em><span>=60 months). Several neurodevelopmental measures were administered which provided an assessment of neurodevelopmental functional status. We applied our exome sequencing workflow to perform alignment to the Human Reference Sequence (build 37) base calling for every base pair in the reads that align to the reference sequence QC evaluation of the annotation of all genetic variants different from the reference sequence using dbSNP and the 1000 Genomes databases. We investigated whether novel variants identified were related to neurodevelopmental functioning.</span></p></div><div><h3>Results and conclusions</h3><p>Variants occurred in 355 total genomic positions, 53 of which were not previously annotated as variant positions in either dbSNP or the 1000 Genomes Project׳s variant annotation. Of these 355 variants, 169 were nonsynonymous (31 were novel). The total number of variants observed in the exons of captured regions of an individual participant ranged from 88 to 117; novel variants ranged from four to 10 per participant, while nonsynonymous variants ranged from 36 and 51 per participant. The total number of nonsynonymous variants per subject was significantly associated with neurodevelopmental function. Further, several genes involved in sterol and lipid metabolism<span> including NPC1, DHCR24 and others that when mutated cause diseases with ASD characteristics, were associated with ASD in Network analysis. Altogether, the findings suggest that nonsynonymous variants in lipid/sterol related genes may be a biological marker of neurodevelopment status in ASD. Results support an association between lipid and sterol metabolism and ASD and suggest the need for further research attempting to elucidate the mechanisms behind the association and the etiology and neurodevelopmental effects of ASD.</span></p></div><div><h3>Focal points</h3><p></p><ul><li><span>•</span><span><p>Bedside</p></span></li></ul><p>Understanding the association between genetics and metabolism and ASD will contribute to the scientific understanding of complex neurodevelopmental disorders. Continued study into the association between lipid and sterol genes and ASD may lead to new novel and effective treatment options for ASD.</p><p></p><ul><li><span>•</span><span><p>Benchside</p></span></li></ul><p>A large","PeriodicalId":90660,"journal":{"name":"New horizons in translational medicine","volume":"2 6","pages":"Pages 137-146"},"PeriodicalIF":0.0,"publicationDate":"2015-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nhtm.2015.09.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87816672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Niemann–Pick diseases are a group of rare autosomal recessive disorders caused by an inherited deficiency of lysosomal storage with similar clinical presentations. At least three different Niemann–Pick (NP) diseases have been described, with NPA and NPB occurring as a result of a deficiency of the acid sphingomyelinase (ASM) enzyme, while NPC as a disorder that cause misregulation in cholesterol and lipids turnover, causing their accumulation in various tissues, including brain. The resulting phenotypic spectrum ranges from a severe infantile type with neurologic degeneration and death, usually by 3 years of age (NPA), to a non-neurologic adult onset form compatible with survival into adulthood (NPB) and a neurovisceral disorder with symptoms that occur at different times and progress independently (NPC).
Here, we report on an Italian child born from non-consanguineous healthy parents, with a negative family history, who developed infantile spasms at the age of 5 months and clinical signs of potential storage disease. The genetic screening, performed by means of whole exome sequencing, revealed compound heterozygous mutations in the Sphingomyelin Phosphodiesterase 1 gene (SMPD1), comprising both a homozygous polymorphism (p.V36A) in exon 1 and a new frameshift heterozygous deletion (c.1187delT) in exon 3 generating a premature stop (TAA) at codon 424 (p.L395fsX29).
This result appears to corroborate the phenotypic heterogeneity of the symptoms and suggests a correlation between the presence of a truncated SMPD1 polypeptide and the very early onset of the disease.
Focal points
•
Benchside: The comprehension of genotype–phenotype correlations in patients affected by Niemann–Pick disease will accelerate the accuracy of the diagnosis and permit to ameliorate patient follow-up.
•
Bedside: The coexistence of a homozygous polymorphism and of a new heterozygous frameshift deletion in exon 3 of the SMPD1 gene reveals the presence of infantile spasms, not previously related to mutations in SMPD1 gene. Elucidating the mechanisms associated to this altered gene product could open novel approaches in therapy.
{"title":"Infantile spasms in early-onset Niemann–Pick disease with a novel compound heterozygous mutations in SMPD1 gene","authors":"Massimiliano Chetta , Anna Guacci , Francesca Rizzo , Giovanna Marchese , Francesca Felicia Operto , Alessandro Weisz , Giangennaro Coppola","doi":"10.1016/j.nhtm.2015.11.001","DOIUrl":"10.1016/j.nhtm.2015.11.001","url":null,"abstract":"<div><p>Niemann–Pick diseases are a group of rare autosomal recessive disorders<span><span><span> caused by an inherited deficiency of lysosomal storage with similar clinical presentations. At least three different Niemann–Pick (NP) diseases have been described, with NPA and NPB occurring as a result of a deficiency of the </span>acid sphingomyelinase (ASM) enzyme, while NPC as a disorder that cause misregulation in cholesterol and </span>lipids turnover, causing their accumulation in various tissues, including brain. The resulting phenotypic spectrum ranges from a severe infantile type with neurologic degeneration and death, usually by 3 years of age (NPA), to a non-neurologic adult onset form compatible with survival into adulthood (NPB) and a neurovisceral disorder with symptoms that occur at different times and progress independently (NPC).</span></p><p><span><span>Here, we report on an Italian child born from non-consanguineous healthy parents, with a negative family history, who developed infantile spasms at the age of 5 months and clinical signs of potential storage disease. The genetic screening, performed by means of </span>whole exome sequencing, revealed compound heterozygous mutations in the Sphingomyelin Phosphodiesterase 1 gene (</span><em>SMPD1</em>), comprising both a homozygous polymorphism (p.V36A) in exon 1 and a new frameshift heterozygous deletion (c.1187delT) in exon 3 generating a premature stop (TAA) at codon 424 (p.L395fsX29).</p><p>This result appears to corroborate the phenotypic heterogeneity of the symptoms and suggests a correlation between the presence of a truncated <em>SMPD1</em><span> polypeptide and the very early onset of the disease.</span></p><p><strong>Focal points</strong></p><p></p><ul><li><span>•</span><span><p><strong>Benchside</strong><span>: The comprehension of genotype–phenotype correlations in patients affected by Niemann–Pick disease will accelerate the accuracy of the diagnosis and permit to ameliorate patient follow-up.</span></p></span></li><li><span>•</span><span><p><strong>Bedside</strong>: The coexistence of a homozygous polymorphism and of a new heterozygous frameshift deletion in exon 3 of the SMPD1 gene reveals the presence of infantile spasms, not previously related to mutations in SMPD1 gene. Elucidating the mechanisms associated to this altered gene product could open novel approaches in therapy.</p></span></li></ul></div>","PeriodicalId":90660,"journal":{"name":"New horizons in translational medicine","volume":"2 6","pages":"Pages 155-158"},"PeriodicalIF":0.0,"publicationDate":"2015-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nhtm.2015.11.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80569047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human cytomegalovirus is a paradigm for studies of viral strategies of immune evasion. In particular, the virus has developed multiple mechanisms for evasion of immune surveillance by lymphocytes expressing the activating receptor NKG2D. The human genome encodes several ligands able to bind NKG2D and in this article we review and discuss what is known about the various viral proteins and micro RNAs that act to minimise the recognition of the infected cell by modulation of the expression and trafficking of the different NKG2D ligand molecules.
Focal points
•
The activating receptor NKG2D is important in the immune response to HCMV.
•
HCMV has developed multiple strategies to evade immunosurveillance by cytotoxic lymphocytes expressing NKG2D.
•
A better understanding of immune evasion by HCMV will likely be relevant for the development of better vaccination strategies.
{"title":"Viral strategies to modulate NKG2D-ligand expression in Human Cytomegalovirus infection","authors":"Hugh Reyburn , Gloria Esteso , Omodele Ashiru , Mar Vales-Gomez","doi":"10.1016/j.nhtm.2015.11.002","DOIUrl":"10.1016/j.nhtm.2015.11.002","url":null,"abstract":"<div><p>Human cytomegalovirus<span><span><span> is a paradigm for studies of viral strategies of immune evasion. In particular, the virus has developed multiple mechanisms for evasion of </span>immune surveillance<span><span> by lymphocytes expressing the activating receptor NKG2D. The </span>human genome encodes several ligands able to bind NKG2D and in this article we review and discuss what is known about the various </span></span>viral proteins<span> and micro RNAs that act to minimise the recognition of the infected cell by modulation of the expression and trafficking of the different NKG2D ligand molecules.</span></span></p></div><div><h3><strong>Focal points</strong></h3><p></p><ul><li><span>•</span><span><p>The activating receptor NKG2D is important in the immune response to HCMV.</p></span></li><li><span>•</span><span><p>HCMV has developed multiple strategies to evade immunosurveillance by cytotoxic lymphocytes expressing NKG2D.</p></span></li><li><span>•</span><span><p>A better understanding of immune evasion by HCMV will likely be relevant for the development of better vaccination strategies.</p></span></li></ul></div>","PeriodicalId":90660,"journal":{"name":"New horizons in translational medicine","volume":"2 6","pages":"Pages 159-166"},"PeriodicalIF":0.0,"publicationDate":"2015-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nhtm.2015.11.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83640805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We synthesized and tested for biological activity eleven new PEGylated hGH derivatives. To this aim we used different strategies. A first group of PEGylable Cys derivatives was prepared by mutating into Cys single specific aminoacid residues located either in the connecting loop between helices 1 and 2 (Ile36 and Phe44) or in the connecting loop between helices 3 and 4 (Ile138 and Phe146). A second group of mutants was synthetized by inserting new Cys close to the aforementioned positions. Other PEGylable mutants were prepared by inserting a Gly4–Cys chain either at the N- or at the C-terminus of the hGH molecule. Finally, a Cys residue of the second hGH disulfide bond (Cys182–Cys189) was made available for PEGylation by mutating its companion Cys to open up the disulfide bridge. All these mutants were tested for their ability to affect Nb2 cell proliferation in vitro and showed different effects. Two mutations (Phe44Cys and +Cys47) severely impaired and two (Ile138Cys and Phe146Cys) increased hGH bioactivity. The mutation Cys189Ser was functionally silent whereas the remaining mutations caused a 15–50% decrease in activity. 20 kDa-pegylation caused a dramatic decrease in bioactivity in all mutants. The r-hGH-(Ile138Cys)–Cys138–PEG derivative showed the highest activity (15% of wild-type unpegylated hGH) and was selected for pharmacockinetic studies in vivo. It showed a fivefold longer half-life and was significantly more effective than wild-type hGH in causing weight gain when given subcutaneously twice a week to hypophysectomized rats.
In conclusion, even when it is directed to residues supposed to have a marginal role in the activity of this hormone, 20 kDa pegylation has detrimental effect on hGH bioactivity. These effects may be counterbalanced by the increase in half-life as it happens in pegylated Ile138Cys–hGH that could represent a promising new long-acting hGH derivative.
Focal points:
•
Bedside: Current therapy of GH deficiency still has the important limitation of being delivered by daily subcutaneous injections and this reduces the compliance of the small pediatric patients. There is, therefore interest in developing long-acting GH derivative such as the new ones that we present here.
•
Benchside: By investigating the effect of Cys substitutions at aminoacidic positions that had not been investigated in previous studies, we obtained evidence that Ile138 and Phe146 have a role in GH bioactivity in vitro.
•
Industry: The mono-pegylated hGH mutant described in this work represents a promising candidate for human clinical pharmacology studies as long-acting derivative of h-GH.
{"title":"Preclinical characterization of eleven new Cys-PEGylated hGH mutants","authors":"Fabio Selis , Stefano Genovese , Barbara Salis , Rodolfo Schrepfer , Valeriana Sblendorio , Mauro Cataldi , Giancarlo Tonon , Gaetano Orsini","doi":"10.1016/j.nhtm.2015.12.002","DOIUrl":"10.1016/j.nhtm.2015.12.002","url":null,"abstract":"<div><p><span>We synthesized and tested for biological activity eleven new PEGylated hGH derivatives. To this aim we used different strategies. A first group of PEGylable Cys derivatives was prepared by mutating into Cys single specific aminoacid residues located either in the connecting loop between helices 1 and 2 (Ile36 and Phe44) or in the connecting loop between helices 3 and 4 (Ile138 and Phe146). A second group of mutants was synthetized by inserting new Cys close to the aforementioned positions. Other PEGylable mutants were prepared by inserting a Gly</span><sub>4</sub><span>–Cys chain either at the N- or at the C-terminus of the hGH molecule. Finally, a Cys residue of the second hGH disulfide<span><span> bond (Cys182–Cys189) was made available for PEGylation by mutating its companion Cys to open up the disulfide bridge. All these mutants were tested for their ability to affect Nb2 </span>cell proliferation in vitro and showed different effects. Two mutations (Phe44Cys and +Cys47) severely impaired and two (Ile138Cys and Phe146Cys) increased hGH bioactivity. The mutation Cys189Ser was functionally silent whereas the remaining mutations caused a 15–50% decrease in activity. 20</span></span> <!-->kDa-pegylation caused a dramatic decrease in bioactivity in all mutants. The r-hGH-(Ile138Cys)–Cys<sup>138</sup>–PEG derivative showed the highest activity (15% of wild-type unpegylated hGH) and was selected for pharmacockinetic studies in vivo. It showed a fivefold longer half-life and was significantly more effective than wild-type hGH in causing weight gain when given subcutaneously twice a week to hypophysectomized rats.</p><p>In conclusion, even when it is directed to residues supposed to have a marginal role in the activity of this hormone, 20<!--> <!-->kDa pegylation has detrimental effect on hGH bioactivity. These effects may be counterbalanced by the increase in half-life as it happens in pegylated Ile138Cys–hGH that could represent a promising new long-acting hGH derivative.</p><p><strong>Focal points:</strong></p><p></p><ul><li><span>•</span><span><p><em>Bedside</em><span><span>: Current therapy of GH deficiency still has the important limitation of being delivered by daily </span>subcutaneous injections and this reduces the compliance of the small pediatric patients. There is, therefore interest in developing long-acting GH derivative such as the new ones that we present here.</span></p></span></li></ul><p></p><ul><li><span>•</span><span><p><em>Benchside</em>: By investigating the effect of Cys substitutions at aminoacidic positions that had not been investigated in previous studies, we obtained evidence that Ile138 and Phe146 have a role in GH bioactivity in vitro.</p></span></li></ul><p></p><ul><li><span>•</span><span><p><em>Industry</em>: The mono-pegylated hGH mutant described in this work represents a promising candidate for human clinical pharmacology studies as long-acting derivative of h-GH.</p></span></li></ul><p></p><ul><li><s","PeriodicalId":90660,"journal":{"name":"New horizons in translational medicine","volume":"2 6","pages":"Pages 147-154"},"PeriodicalIF":0.0,"publicationDate":"2015-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nhtm.2015.12.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75146837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-09-01DOI: 10.1016/j.nhtm.2015.09.002
Jimstan Periselneris, Ricardo J. José, Jeremy Brown
Streptococcus pneumoniae is a common cause of infectious morbidity and mortality, causing otitis media, pneumonia, septicaemia, and meningitis. The host inflammatory response is required for clearance of bacteria, but excessive inflammation can mediate bystander tissue damage. The host response is complex; involving initial recognition by pattern recognition receptors, clearance by tissue macrophages and the institution of an inflammatory response. This is orchestrated by the synthesis of a range of cytokines and chemokines that mediate both local and distant inflammatory effects. This causes neutrophil recruitment, upregulation of mucosal immunity, an acute phase response, and eventually the generation of antibodies. Currently, apart from antibiotic initiation, the use of adjuncts is limited to steroids in meningitis, with less evidence for their use in pneumonia. Some antibiotics used in recommended treatment regimens have immunomodulatory effects which may explain their beneficial effects above and beyond their antibacterial functions. By understanding the role of inflammation in pathogenesis better, more targeted approaches are being developed to limit excessive inflammation. Pathways being evaluated include inhibition of chemokines, inhibition of coagulation pathways that crosstalk with inflammatory signalling, and possibly the repurposing of statins to take of advantage of their immunomodulatory effects. All these approaches much strike the balance of reducing excessive inflammation while allowing enough phagocyte recruitment to enable effective bacterial clearance.
Focal Points
•
Bedside: Targeted inhibition of inflammatory pathways may be a useful adjuvant to antibiotic therapy of S. pneumoniae pneumonia and meningitis, to ameliorate host induced tissue damage. Nuance approaches may yield more benefit than broad brush immunosuppression, such as with corticosteroids.
•
Benchside: The dissection of the complex interaction of pathways downstream of S. pneumoniae recognition will allow targeting of specific components of the inflammatory response. This will allow enough inflammation to control bacterial replication, but limit bystander tissue damage.
•
Industry: Several drugs have been trialled for use in sepsis and pneumonia trials to control excessive inflammation that may be effective against S. pneumoniae induced disease. By identifying more effective targets, and identifying the cause of infection early, there is the potential to develop drugs that have therapeutic benefit.
{"title":"Targeting Inflammatory Responses to Streptococcus pneumoniae","authors":"Jimstan Periselneris, Ricardo J. José, Jeremy Brown","doi":"10.1016/j.nhtm.2015.09.002","DOIUrl":"10.1016/j.nhtm.2015.09.002","url":null,"abstract":"<div><p><span><em>Streptococcus pneumoniae</em></span><span><span> is a common cause of infectious morbidity and mortality, causing otitis media, pneumonia, septicaemia<span><span>, and meningitis. The host inflammatory response is required for clearance of bacteria, but excessive inflammation can mediate bystander tissue damage. The host response is complex; involving initial recognition by pattern recognition receptors, clearance by tissue macrophages and the institution of an inflammatory response. This is orchestrated by the synthesis of a range of cytokines and </span>chemokines<span><span> that mediate both local and distant inflammatory effects. This causes neutrophil<span> recruitment, upregulation of mucosal immunity<span>, an acute phase response, and eventually the generation of antibodies. Currently, apart from antibiotic initiation, the use of adjuncts is limited to steroids in meningitis, with less evidence for their use in pneumonia. Some antibiotics used in recommended </span></span></span>treatment<span> regimens have immunomodulatory effects which may explain their beneficial effects above and beyond their antibacterial functions. By understanding the role of inflammation in pathogenesis better, more targeted approaches are being developed to limit excessive inflammation. Pathways being evaluated include inhibition of chemokines, inhibition of coagulation pathways that crosstalk with inflammatory signalling, and possibly the repurposing of statins to take of advantage of their immunomodulatory effects. All these approaches much strike the balance of reducing excessive inflammation while allowing enough phagocyte recruitment to enable effective </span></span></span></span>bacterial clearance.</span></p></div><div><h3>Focal Points</h3><p></p><ul><li><span>•</span><span><p>Bedside: Targeted inhibition of inflammatory pathways may be a useful adjuvant to antibiotic therapy of <span><em>S. pneumoniae</em></span><span> pneumonia and meningitis, to ameliorate host induced tissue damage. Nuance approaches may yield more benefit than broad brush immunosuppression, such as with corticosteroids.</span></p></span></li></ul><p></p><ul><li><span>•</span><span><p>Benchside: The dissection of the complex interaction of pathways downstream of <em>S. pneumoniae</em> recognition will allow targeting of specific components of the inflammatory response. This will allow enough inflammation to control bacterial replication, but limit bystander tissue damage.</p></span></li></ul><p></p><ul><li><span>•</span><span><p><span>Industry: Several drugs have been trialled for use in sepsis and pneumonia trials to control excessive inflammation that may be effective against </span><em>S. pneumoniae</em> induced disease. By identifying more effective targets, and identifying the cause of infection early, there is the potential to develop drugs that have therapeutic benefit.</p></span></li></ul></div>","PeriodicalId":90660,"journal":{"name":"New horizons in translational medicine","volume":"2 6","pages":"Pages 167-174"},"PeriodicalIF":0.0,"publicationDate":"2015-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nhtm.2015.09.002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77366236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-09-01DOI: 10.1016/j.nhtm.2015.12.001
{"title":"Abstracts: 3rd Annual Congress of the European Society for Translational Medicine (EUSTM-2015) 1-4 September, 2015, Vienna, Austria.","authors":"","doi":"10.1016/j.nhtm.2015.12.001","DOIUrl":"10.1016/j.nhtm.2015.12.001","url":null,"abstract":"","PeriodicalId":90660,"journal":{"name":"New horizons in translational medicine","volume":"2 6","pages":"Pages 175-194"},"PeriodicalIF":0.0,"publicationDate":"2015-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.nhtm.2015.12.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89824635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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