vascular and 5% gastro-intestinal involvement. 37 patients (31%) were out of work with 44 patient... more vascular and 5% gastro-intestinal involvement. 37 patients (31%) were out of work with 44 patients (37%) claiming employment related benefits. With regard to individual clinical manifestations, ocular disease had a statistically significant increased risk for being out of work when assessed alone with OR 2.84 (95% CI 1.13, 7.13) but lost statistical significance when analysed in the multivariate model: OR 2.45 (95% CI 0.70, 8.60). With regard to cumulative clinical manifestations, patients with four or more clinical manifestations of BS had a statistically significant increased risk of being out of work with OR 5.57 (95% CI 1.33, 23.27) in comparison to patients with two manifestations in the multivariate model. Conclusions: This study has highlighted the significant burden of BS on work outcomes in this UK cohort. In particular, four or more cumulative BS manifestations were independently associated with being out of work in this young cohort. Further work is required to identify whether education or intervention in the workplace can help prevent disease related job loss in BS.
Emerging machine learning (ML) technologies have the potential to significantly improve the resea... more Emerging machine learning (ML) technologies have the potential to significantly improve the research and treatment of rare diseases, which constitute a vast set of diseases that affect a small proportion of the total population. Artificial Intelligence (AI) algorithms can help to quickly identify patterns and associations that would be difficult or impossible for human analysts to detect. Predictive modeling techniques, such as deep learning, have been used to forecast the progression of rare diseases, enabling the development of more targeted treatments. Moreover, AI has also shown promise in the field of drug development for rare diseases with the identification of subpopulations of patients who may be most likely to respond to a particular drug. This review aims to highlight the achievements of AI algorithms in the study of rare diseases in the past decade and advise researchers on which methods have proven to be most effective. The review will focus on specific rare diseases, as...
It has been recently suggested that amino acid replacements with Gly can modify the shape of prot... more It has been recently suggested that amino acid replacements with Gly can modify the shape of protein surfaces and, hence, protein dynamics and functions. We have browsed ClinVar, the database of all the reported variants of clinical relevance, to identify all the proteins having missense X/Gly mutations that determine Mendelian disorders. We have found 959 benign and 875 pathogenic X/Gly substitutions. Pathogenicity origins were initially searched in the distribution profiles of replaced amino acids. These profiles indicate that Mendelian disorders including Gly-replacements arise mainly from substitutions of amino acids bearing bulky hydrophobic side chains, thus reducing protein core stability. In the case mutated proteins were structurally defined, we could give a deeper insight into pathogenicity mechanisms, checking whether Gly-mutations altered protein shapes, modifying water surface dynamics and, hence, the physiological protein-protein interaction processes. In several cases...
The transmembrane glycoprotein CD93 has been identified as a potential new target to inhibit tumo... more The transmembrane glycoprotein CD93 has been identified as a potential new target to inhibit tumor angiogenesis. Recently, Multimerin-2 (MMRN2), a pan-endothelial extracellular matrix protein, has been identified as a ligand for CD93, but the interaction mechanism between these two proteins is yet to be studied. In this article, we aim to investigate the structural and functional effects of induced mutations on the binding domain of CD93 to MMRN2. Starting from experimental data, we assessed how specific mutations in the C-type lectin-like domain (CTLD) affect the binding interaction profile. We described a four-step workflow in order to predict the effects of variations on the inter-residue interaction network at the PPI, based on evolutionary information, complex network metrics, and energetic affinity. We showed that the application of computational approaches, combined with experimental data, allowed us to gain more in-depth molecular insights into the CD93–MMRN2 interaction, of...
In this review, we focus on bioinformatic oncology as an integrative discipline that incorporates... more In this review, we focus on bioinformatic oncology as an integrative discipline that incorporates knowledge from the mathematical, physical, and computational fields to further the biomedical understanding of cancer. Before providing a deeper insight into the bioinformatics approach and utilities involved in oncology, we must understand what is a system biology framework and the genetic connection, because of the high heterogenicity of the backgrounds of people approaching precision medicine. In fact, it is essential to providing general theoretical information on genomics, epigenomics, and transcriptomics to understand the phases of multi-omics approach. We consider how to create a multi-omics model. In the last section, we describe the new frontiers and future perspectives of this field.
Additional file 1. In Additional file 1 a more detailed description of QoL scores is provided. Mo... more Additional file 1. In Additional file 1 a more detailed description of QoL scores is provided. Moreover, informational layers, data and features included in ApreciseKUre are collected and listed.
Alternative strategies for developing antiviral drugs are needed, as vaccines could not be the fi... more Alternative strategies for developing antiviral drugs are needed, as vaccines could not be the final answer against the present SARS CoV-2 outbreak, due to the still existing ambiguities in the immunological response to the virus. Thus, SARS CoV-2 enzymes have been thoroughly investigated to develop their inhibitors as antiviral drugs. We have searched the latter antiviral drugs among those small molecules that can interfere with the trimeric assembly of the S glycoprotein. We have systematically explored the trimer interfaces in the search of pockets that can be suitable for ligand binding. Virtual screening of FDA-approved drug library confirmed that concave moieties of S glycoprotein protomer interfaces can act as binding sites of small molecules. Interfering with S glycoprotein quaternary assembly, these small molecules would represent an alternative family of antiviral drugs.
IEEE/ACM Transactions on Computational Biology and Bioinformatics, 2020
With a structural bioinformatic approach, we have explored amino acid compositions at PISA define... more With a structural bioinformatic approach, we have explored amino acid compositions at PISA defined interfaces between small molecules and proteins that are contained in an optimized subset of 11,351 PDB files. The use of a series of restrictions, to prevent redundancy and biases from interactions between amino acids with charged side chains and ions, yielded a final data set of 45,230 protein-small molecule interfaces. We have compared occurrences of natural amino acids in surface exposed regions and binding sites for all the proteins of our data set. From our structural bioinformatic survey, the most relevant signal arose from the unexpected Gly abundance at enzyme catalytic sites. This finding suggested that Gly must have a fundamental role in stabilizing concave protein surface moieties. Subsequently, we have tried to predict the effect of in silico Gly mutations in hen egg white lysozyme to optimize those conditions that can reshape the protein surface with the appearance of new pockets. Replacing amino acids having bulky side chains with Gly in specific protein regions seems a feasible way for designing proteins with additional surface pockets, which can alter protein surface dynamics, therefore, representing controllable switches for protein activity.
Alkaptonuria (AKU, OMIM: 203500) is an autosomal recessive disorder caused by mutations in the Ho... more Alkaptonuria (AKU, OMIM: 203500) is an autosomal recessive disorder caused by mutations in the Homogentisate 1,2-dioxygenase (HGD) gene. A lack of standardized data, information and methodologies to assess disease severity and progression represents a common complication in ultra-rare disorders like AKU. This is the reason why we developed a comprehensive tool, called ApreciseKUre, able to collect AKU patients deriving data, to analyse the complex network among genotypic and phenotypic information and to get new insight in such multi-systemic disease. By taking advantage of the dataset, containing the highest number of AKU patient ever considered, it is possible to apply more sophisticated computational methods (such as machine learning) to achieve a first AKU patient stratification based on phenotypic and genotypic data in a typical precision medicine perspective. Thanks to our sufficiently populated and organized dataset, it is possible, for the first time, to extensively explore ...
Alkaptonuria (AKU) is a rare metabolic disease of historical and medical interest. Despite the id... more Alkaptonuria (AKU) is a rare metabolic disease of historical and medical interest. Despite the identification of gene and protein defects leading to the accumulation of homogentisic acid (HGA), little is known on how HGA is transformed into an ochronotic pigment (the hallmark of the disease) leading to a range of clinical manifestations. Major obstacles in tackling the pathological features of AKU are the rarity of biological samples, the invasiveness of sampling techniques and the intrinsic difficulties of studying the pigmented tissues. This review provides an overview of the in vitro and ex vivo cell and tissue models that were recently developed and characterized to fill the above-mentioned gaps in the knowledge of AKU.
Introduction Voltage-dependent calcium channels (VSCC) is involved in important biological functi... more Introduction Voltage-dependent calcium channels (VSCC) is involved in important biological function as calcium ion transmembrane transport and cardiac contraction. VSCC is a multi-pass membrane protein, made up from α-1, α-2, β and δ subunits. α-1 subunit regulates the entry of ion calcium. Voltage-dependent L-type calcium channel subunit alpha-1C (Cav1.2 α1C subunit channel) is an isoform of VSCC, and is characterized from an high-voltage activation. Previous study have shown that class of molecules as benzothiazepines (Tikhonov D. et al, 2008), are able to block the alpha-1C subunit. Recent works have demonstrated that molecules belonged at the flavonoid class are able to inhibit or to raise channel activity (Saponara S. et al, 2011). In this work, we reported the sensing- residues that could play a key role in Cav1.2 α1C activity. Furthermore, we proposed a potential mechanism of action inside Cav1.2 α1C binding-site with differences between inhibitors and stimulants. Our work ha...
MOTIVATION Alkaptonuria (AKU) is a rare and genetic disease which causes discoloration of bone (a... more MOTIVATION Alkaptonuria (AKU) is a rare and genetic disease which causes discoloration of bone (a process called ‘ochronosis’) and induces early-onset osteoarthritis. AKU data have not been organized yet and the disease has no approved biomarkers. The ability to collect, integrate and analyze relevant data streams is the core for developing a “Precision Medicine Ecosystem” AKU-dedicated in which biological resources are shared between researchers, clinicians and patients. Computational modeling can be a useful guide to generate an exhaustive and dynamic picture of the individual and to identify the molecular interactions between biomarkers on which progressive diseases are based. METHODS It has been built a new integrated interactive database thanks to MySQL, the most frequently chosen for use in web applications. In addition, data are statistically analyzed by R software (www.r-project.org) based on Pearson’s correlation coefficient andPvalue. For a biological interpretation of sta...
Alkaptonuria (AKU) is a disease caused by a deficient homogentisate 1,2‐dioxygenase activity lead... more Alkaptonuria (AKU) is a disease caused by a deficient homogentisate 1,2‐dioxygenase activity leading to systemic accumulation of homogentisic acid (HGA), that forms a melanin‐like polymer that progressively deposits onto connective tissues causing a pigmentation called “ochronosis” and tissue degeneration. The effects of AKU and ochronotic pigment on the biomechanical properties of articular cartilage need further investigation. To this aim, AKU cartilage was studied using thermal (thermogravimetry and differential scanning calorimetry) and rheological analysis. We found that AKU cartilage had a doubled mesopore radius compared to healthy cartilage. Since the mesoporous structure is the main responsible for maintaining a correct hydrostatic pressure and tissue homoeostasis, drastic changes of thermal and rheological parameters were found in AKU. In particular, AKU tissue lost its capability to enhance chondrocytes metabolism (decreased heat capacity) and hence the production of prot...
Cancer research and treatment : official journal of Korean Cancer Association, Jan 26, 2017
Lung cancer is strongly associated to tobacco smoking. However, global statistics estimate that i... more Lung cancer is strongly associated to tobacco smoking. However, global statistics estimate that in females the proportion of lung cancer cases that is unrelated to tobacco smoking reaches fifty percent, making questionable the etiology of the disease. A never-smoker female with primary EGFR/KRAS/ALK-negative squamous cell carcinoma of the lung and their normal sibs were subjected to a novel integrative "omic" approach using a pedigree-based model for discovering genetic factors leading to cancer in the absence of well-known environmental trigger. A first-step whole-exome sequencing on tumor and normal tissue did not identify mutations in known driver genes. Building on the idea of a germline oligogenic origin of lung cancer, we performed whole-exome sequencing of DNA from patients' peripheral blood and their unaffected sibs. Finally, RNA-sequencing analysis in tumoral and matched non-tumoral tissues was carried out in order to investigate the clonal profile and the pat...
To characterize the role of cAMP-dependent protein kinase (PKA) in regulating vascular Ca(2+) cur... more To characterize the role of cAMP-dependent protein kinase (PKA) in regulating vascular Ca(2+) current through Cav1.2 channels [ICa1.2], we have documented a marked capacity of the isoquinoline H-89, widely used as a PKA inhibitor, to reduce current amplitude. We hypothesized that the ICa1.2 inhibitory activity of H-89 was mediated by mechanisms unrelated to PKA inhibition. To support this, an in-depth analysis of H-89 vascular effects on both ICa1.2 and contractility was undertaken by performing whole-cell patch-clamp recordings and functional experiments in rat tail main artery single myocytes and rings, respectively. H-89 inhibited ICa1.2 with a pIC50 (M) value of about 5.5, even under conditions where PKA activity was either abolished by both the PKA antagonists KT5720 and protein kinase inhibitor fragment 6-22 amide or enhanced by the PKA stimulators 6-Bnz-cAMP and 8-Br-cAMP. Inhibition of ICa1.2 by H-89 appeared almost irreversible upon washout, was charge carrier- and voltage-...
BMC medical informatics and decision making, Jan 14, 2017
Alkaptonuria (AKU; OMIM:203500) is a classic Mendelian genetic disorder described by Garrod alrea... more Alkaptonuria (AKU; OMIM:203500) is a classic Mendelian genetic disorder described by Garrod already in 1902. It causes urine to turn black upon exposure to air and also leads to ochronosis as well as early osteoarthritis. Our objective is the implementation of a Precision Medicine (PM) approach to AKU. We present here a novel ApreciseKUre database facilitating the collection, integration and analysis of patient data in order to create an AKU-dedicated "PM Ecosystem" in which genetic, biochemical and clinical resources can be shared among registered researchers. In order to exploit the ApreciseKUre database, we developed an analytic method based on Pearson's correlation coefficient and P value that generates as refreshable correlation matrix. A complete statistical analysis is obtained by associating every pair of parameters to examine the dependence between multiple variables at the same time. Employing this analytic approach, we showed that some clinically used biomar...
vascular and 5% gastro-intestinal involvement. 37 patients (31%) were out of work with 44 patient... more vascular and 5% gastro-intestinal involvement. 37 patients (31%) were out of work with 44 patients (37%) claiming employment related benefits. With regard to individual clinical manifestations, ocular disease had a statistically significant increased risk for being out of work when assessed alone with OR 2.84 (95% CI 1.13, 7.13) but lost statistical significance when analysed in the multivariate model: OR 2.45 (95% CI 0.70, 8.60). With regard to cumulative clinical manifestations, patients with four or more clinical manifestations of BS had a statistically significant increased risk of being out of work with OR 5.57 (95% CI 1.33, 23.27) in comparison to patients with two manifestations in the multivariate model. Conclusions: This study has highlighted the significant burden of BS on work outcomes in this UK cohort. In particular, four or more cumulative BS manifestations were independently associated with being out of work in this young cohort. Further work is required to identify whether education or intervention in the workplace can help prevent disease related job loss in BS.
Emerging machine learning (ML) technologies have the potential to significantly improve the resea... more Emerging machine learning (ML) technologies have the potential to significantly improve the research and treatment of rare diseases, which constitute a vast set of diseases that affect a small proportion of the total population. Artificial Intelligence (AI) algorithms can help to quickly identify patterns and associations that would be difficult or impossible for human analysts to detect. Predictive modeling techniques, such as deep learning, have been used to forecast the progression of rare diseases, enabling the development of more targeted treatments. Moreover, AI has also shown promise in the field of drug development for rare diseases with the identification of subpopulations of patients who may be most likely to respond to a particular drug. This review aims to highlight the achievements of AI algorithms in the study of rare diseases in the past decade and advise researchers on which methods have proven to be most effective. The review will focus on specific rare diseases, as...
It has been recently suggested that amino acid replacements with Gly can modify the shape of prot... more It has been recently suggested that amino acid replacements with Gly can modify the shape of protein surfaces and, hence, protein dynamics and functions. We have browsed ClinVar, the database of all the reported variants of clinical relevance, to identify all the proteins having missense X/Gly mutations that determine Mendelian disorders. We have found 959 benign and 875 pathogenic X/Gly substitutions. Pathogenicity origins were initially searched in the distribution profiles of replaced amino acids. These profiles indicate that Mendelian disorders including Gly-replacements arise mainly from substitutions of amino acids bearing bulky hydrophobic side chains, thus reducing protein core stability. In the case mutated proteins were structurally defined, we could give a deeper insight into pathogenicity mechanisms, checking whether Gly-mutations altered protein shapes, modifying water surface dynamics and, hence, the physiological protein-protein interaction processes. In several cases...
The transmembrane glycoprotein CD93 has been identified as a potential new target to inhibit tumo... more The transmembrane glycoprotein CD93 has been identified as a potential new target to inhibit tumor angiogenesis. Recently, Multimerin-2 (MMRN2), a pan-endothelial extracellular matrix protein, has been identified as a ligand for CD93, but the interaction mechanism between these two proteins is yet to be studied. In this article, we aim to investigate the structural and functional effects of induced mutations on the binding domain of CD93 to MMRN2. Starting from experimental data, we assessed how specific mutations in the C-type lectin-like domain (CTLD) affect the binding interaction profile. We described a four-step workflow in order to predict the effects of variations on the inter-residue interaction network at the PPI, based on evolutionary information, complex network metrics, and energetic affinity. We showed that the application of computational approaches, combined with experimental data, allowed us to gain more in-depth molecular insights into the CD93–MMRN2 interaction, of...
In this review, we focus on bioinformatic oncology as an integrative discipline that incorporates... more In this review, we focus on bioinformatic oncology as an integrative discipline that incorporates knowledge from the mathematical, physical, and computational fields to further the biomedical understanding of cancer. Before providing a deeper insight into the bioinformatics approach and utilities involved in oncology, we must understand what is a system biology framework and the genetic connection, because of the high heterogenicity of the backgrounds of people approaching precision medicine. In fact, it is essential to providing general theoretical information on genomics, epigenomics, and transcriptomics to understand the phases of multi-omics approach. We consider how to create a multi-omics model. In the last section, we describe the new frontiers and future perspectives of this field.
Additional file 1. In Additional file 1 a more detailed description of QoL scores is provided. Mo... more Additional file 1. In Additional file 1 a more detailed description of QoL scores is provided. Moreover, informational layers, data and features included in ApreciseKUre are collected and listed.
Alternative strategies for developing antiviral drugs are needed, as vaccines could not be the fi... more Alternative strategies for developing antiviral drugs are needed, as vaccines could not be the final answer against the present SARS CoV-2 outbreak, due to the still existing ambiguities in the immunological response to the virus. Thus, SARS CoV-2 enzymes have been thoroughly investigated to develop their inhibitors as antiviral drugs. We have searched the latter antiviral drugs among those small molecules that can interfere with the trimeric assembly of the S glycoprotein. We have systematically explored the trimer interfaces in the search of pockets that can be suitable for ligand binding. Virtual screening of FDA-approved drug library confirmed that concave moieties of S glycoprotein protomer interfaces can act as binding sites of small molecules. Interfering with S glycoprotein quaternary assembly, these small molecules would represent an alternative family of antiviral drugs.
IEEE/ACM Transactions on Computational Biology and Bioinformatics, 2020
With a structural bioinformatic approach, we have explored amino acid compositions at PISA define... more With a structural bioinformatic approach, we have explored amino acid compositions at PISA defined interfaces between small molecules and proteins that are contained in an optimized subset of 11,351 PDB files. The use of a series of restrictions, to prevent redundancy and biases from interactions between amino acids with charged side chains and ions, yielded a final data set of 45,230 protein-small molecule interfaces. We have compared occurrences of natural amino acids in surface exposed regions and binding sites for all the proteins of our data set. From our structural bioinformatic survey, the most relevant signal arose from the unexpected Gly abundance at enzyme catalytic sites. This finding suggested that Gly must have a fundamental role in stabilizing concave protein surface moieties. Subsequently, we have tried to predict the effect of in silico Gly mutations in hen egg white lysozyme to optimize those conditions that can reshape the protein surface with the appearance of new pockets. Replacing amino acids having bulky side chains with Gly in specific protein regions seems a feasible way for designing proteins with additional surface pockets, which can alter protein surface dynamics, therefore, representing controllable switches for protein activity.
Alkaptonuria (AKU, OMIM: 203500) is an autosomal recessive disorder caused by mutations in the Ho... more Alkaptonuria (AKU, OMIM: 203500) is an autosomal recessive disorder caused by mutations in the Homogentisate 1,2-dioxygenase (HGD) gene. A lack of standardized data, information and methodologies to assess disease severity and progression represents a common complication in ultra-rare disorders like AKU. This is the reason why we developed a comprehensive tool, called ApreciseKUre, able to collect AKU patients deriving data, to analyse the complex network among genotypic and phenotypic information and to get new insight in such multi-systemic disease. By taking advantage of the dataset, containing the highest number of AKU patient ever considered, it is possible to apply more sophisticated computational methods (such as machine learning) to achieve a first AKU patient stratification based on phenotypic and genotypic data in a typical precision medicine perspective. Thanks to our sufficiently populated and organized dataset, it is possible, for the first time, to extensively explore ...
Alkaptonuria (AKU) is a rare metabolic disease of historical and medical interest. Despite the id... more Alkaptonuria (AKU) is a rare metabolic disease of historical and medical interest. Despite the identification of gene and protein defects leading to the accumulation of homogentisic acid (HGA), little is known on how HGA is transformed into an ochronotic pigment (the hallmark of the disease) leading to a range of clinical manifestations. Major obstacles in tackling the pathological features of AKU are the rarity of biological samples, the invasiveness of sampling techniques and the intrinsic difficulties of studying the pigmented tissues. This review provides an overview of the in vitro and ex vivo cell and tissue models that were recently developed and characterized to fill the above-mentioned gaps in the knowledge of AKU.
Introduction Voltage-dependent calcium channels (VSCC) is involved in important biological functi... more Introduction Voltage-dependent calcium channels (VSCC) is involved in important biological function as calcium ion transmembrane transport and cardiac contraction. VSCC is a multi-pass membrane protein, made up from α-1, α-2, β and δ subunits. α-1 subunit regulates the entry of ion calcium. Voltage-dependent L-type calcium channel subunit alpha-1C (Cav1.2 α1C subunit channel) is an isoform of VSCC, and is characterized from an high-voltage activation. Previous study have shown that class of molecules as benzothiazepines (Tikhonov D. et al, 2008), are able to block the alpha-1C subunit. Recent works have demonstrated that molecules belonged at the flavonoid class are able to inhibit or to raise channel activity (Saponara S. et al, 2011). In this work, we reported the sensing- residues that could play a key role in Cav1.2 α1C activity. Furthermore, we proposed a potential mechanism of action inside Cav1.2 α1C binding-site with differences between inhibitors and stimulants. Our work ha...
MOTIVATION Alkaptonuria (AKU) is a rare and genetic disease which causes discoloration of bone (a... more MOTIVATION Alkaptonuria (AKU) is a rare and genetic disease which causes discoloration of bone (a process called ‘ochronosis’) and induces early-onset osteoarthritis. AKU data have not been organized yet and the disease has no approved biomarkers. The ability to collect, integrate and analyze relevant data streams is the core for developing a “Precision Medicine Ecosystem” AKU-dedicated in which biological resources are shared between researchers, clinicians and patients. Computational modeling can be a useful guide to generate an exhaustive and dynamic picture of the individual and to identify the molecular interactions between biomarkers on which progressive diseases are based. METHODS It has been built a new integrated interactive database thanks to MySQL, the most frequently chosen for use in web applications. In addition, data are statistically analyzed by R software (www.r-project.org) based on Pearson’s correlation coefficient andPvalue. For a biological interpretation of sta...
Alkaptonuria (AKU) is a disease caused by a deficient homogentisate 1,2‐dioxygenase activity lead... more Alkaptonuria (AKU) is a disease caused by a deficient homogentisate 1,2‐dioxygenase activity leading to systemic accumulation of homogentisic acid (HGA), that forms a melanin‐like polymer that progressively deposits onto connective tissues causing a pigmentation called “ochronosis” and tissue degeneration. The effects of AKU and ochronotic pigment on the biomechanical properties of articular cartilage need further investigation. To this aim, AKU cartilage was studied using thermal (thermogravimetry and differential scanning calorimetry) and rheological analysis. We found that AKU cartilage had a doubled mesopore radius compared to healthy cartilage. Since the mesoporous structure is the main responsible for maintaining a correct hydrostatic pressure and tissue homoeostasis, drastic changes of thermal and rheological parameters were found in AKU. In particular, AKU tissue lost its capability to enhance chondrocytes metabolism (decreased heat capacity) and hence the production of prot...
Cancer research and treatment : official journal of Korean Cancer Association, Jan 26, 2017
Lung cancer is strongly associated to tobacco smoking. However, global statistics estimate that i... more Lung cancer is strongly associated to tobacco smoking. However, global statistics estimate that in females the proportion of lung cancer cases that is unrelated to tobacco smoking reaches fifty percent, making questionable the etiology of the disease. A never-smoker female with primary EGFR/KRAS/ALK-negative squamous cell carcinoma of the lung and their normal sibs were subjected to a novel integrative "omic" approach using a pedigree-based model for discovering genetic factors leading to cancer in the absence of well-known environmental trigger. A first-step whole-exome sequencing on tumor and normal tissue did not identify mutations in known driver genes. Building on the idea of a germline oligogenic origin of lung cancer, we performed whole-exome sequencing of DNA from patients' peripheral blood and their unaffected sibs. Finally, RNA-sequencing analysis in tumoral and matched non-tumoral tissues was carried out in order to investigate the clonal profile and the pat...
To characterize the role of cAMP-dependent protein kinase (PKA) in regulating vascular Ca(2+) cur... more To characterize the role of cAMP-dependent protein kinase (PKA) in regulating vascular Ca(2+) current through Cav1.2 channels [ICa1.2], we have documented a marked capacity of the isoquinoline H-89, widely used as a PKA inhibitor, to reduce current amplitude. We hypothesized that the ICa1.2 inhibitory activity of H-89 was mediated by mechanisms unrelated to PKA inhibition. To support this, an in-depth analysis of H-89 vascular effects on both ICa1.2 and contractility was undertaken by performing whole-cell patch-clamp recordings and functional experiments in rat tail main artery single myocytes and rings, respectively. H-89 inhibited ICa1.2 with a pIC50 (M) value of about 5.5, even under conditions where PKA activity was either abolished by both the PKA antagonists KT5720 and protein kinase inhibitor fragment 6-22 amide or enhanced by the PKA stimulators 6-Bnz-cAMP and 8-Br-cAMP. Inhibition of ICa1.2 by H-89 appeared almost irreversible upon washout, was charge carrier- and voltage-...
BMC medical informatics and decision making, Jan 14, 2017
Alkaptonuria (AKU; OMIM:203500) is a classic Mendelian genetic disorder described by Garrod alrea... more Alkaptonuria (AKU; OMIM:203500) is a classic Mendelian genetic disorder described by Garrod already in 1902. It causes urine to turn black upon exposure to air and also leads to ochronosis as well as early osteoarthritis. Our objective is the implementation of a Precision Medicine (PM) approach to AKU. We present here a novel ApreciseKUre database facilitating the collection, integration and analysis of patient data in order to create an AKU-dedicated "PM Ecosystem" in which genetic, biochemical and clinical resources can be shared among registered researchers. In order to exploit the ApreciseKUre database, we developed an analytic method based on Pearson's correlation coefficient and P value that generates as refreshable correlation matrix. A complete statistical analysis is obtained by associating every pair of parameters to examine the dependence between multiple variables at the same time. Employing this analytic approach, we showed that some clinically used biomar...
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Papers by Ottavia Spiga