To date, the 5-year overall survival rate of 60% for early-stage non-small cell lung cancer (NSCL... more To date, the 5-year overall survival rate of 60% for early-stage non-small cell lung cancer (NSCLC) is still unsatisfactory. Therefore, reliable prognostic factors are needed. Growing evidence shows that cancer progression may depend on an interconnection between cancer cells and the surrounding tumor microenvironment; hence, circulating molecules may represent promising markers of cancer recurrence. In order to identify a prognostic score, we performed in-depth high-throughput analyses of plasma circulating markers, including exosomal microRNAs (Exo-miR) and peptides, in 67 radically resected NSCLCs. The miRnome profile selected the Exo-miR-130a-3p as the most overexpressed in relapsed patients. Peptidome analysis identified four progressively more degraded forms of fibrinopeptide A (FpA), which were depleted in progressing patients. Notably, stepwise Cox regression analysis selected Exo-miR-130a-3p and the greatest FpA (2-16) to build a score predictive of recurrence, where high-r...
Cancer is a complex and heterogeneous disease and is still one of the leading causes of morbidity... more Cancer is a complex and heterogeneous disease and is still one of the leading causes of morbidity and mortality worldwide, mostly as the population ages. Despite the encouraging advances made over the years in chemotherapy, the development of new compounds for cancer treatments is an urgent priority. In recent years, the design and chemical synthesis of several innovative hybrid molecules, which bring different pharmacophores on the same scaffold, have attracted the interest of many researchers. Following this strategy, we designed and synthetized a series of new hybrid compounds that contain three pharmacophores, namely trimethoxybenzene, thiazolidinedione and thiazole, and tested their anticancer properties on two breast cancer (MCF-7 and MDA-MB-231) cell lines and one melanoma (A2058) cell line. The most active compounds were particularly effective against the MCF-7 cells and did not affect the viability of the normal MCF-10A cells. Docking simulations indicated the human Topoiso...
Chemotherapy is commonly used for cancer treatment, however the lack of selectivity on healthy ce... more Chemotherapy is commonly used for cancer treatment, however the lack of selectivity on healthy cells and the development of resistance phenomena are the major issues. A better understanding of cancer genetics helped the development of new targeted anticancer treatments, which permit drug delivery with high specificity and lower toxicity. Moreover, the multi-target drug design concept represents the current trend for future drug research and development. Starting from good results previously obtained by our research group on the resveratrol (RSV) phenylacetamide derivative 2, which displayed an interesting anti-inflammatory and anti-proliferative activity towards the breast cancer cells MCF-7 and MDA-MB-231, we identified other features, as the ability to perturb the cytoskeleton dynamics and interfere with the migration and metastatic processes. In vitro and in silico studies demonstrate that the derivative 2 is a tubulin and actin polymerization inhibitor and an actin depolymerizat...
Triple-negative breast cancer (TNBC) constitutes a heterogeneous group of malignancies that are o... more Triple-negative breast cancer (TNBC) constitutes a heterogeneous group of malignancies that are often aggressive and associated with a poor prognosis. The development of new TNBC treatment strategies has become an urgent clinical need. Diagnosis and subtyping of TNBC are essential to establish alternative treatments and targeted therapies for every TNBC patient. Chemotherapy, particularly with anthracycline and taxanes, remains the backbone for medical management for both early and metastatic TNBC. More recently, immune checkpoint inhibitors and targeted therapy have revolutionized cancer treatment. Included in the different strategies studied for TNBC treatment is drug repurposing. Despite the numerous medications available, numerous studies in medicinal chemistry are still aimed at the synthesis of new compounds in order to find new antiproliferative agents capable of treating TNBC. Additionally, some supplemental micronutrients, nutraceuticals and functional foods can potentially...
Over the past decade, metal complexes based on N-heterocyclic carbenes (NHCs) have attracted grea... more Over the past decade, metal complexes based on N-heterocyclic carbenes (NHCs) have attracted great attention due to their wide and exciting applications in material sciences and medicinal chemistry. In particular, the gold-based complexes are the focus of research efforts for the development of new anticancer compounds. Literature data and recent results, obtained by our research group, reported the design, the synthesis and the good anticancer activity of some silver and gold complexes with NHC ligands. In particular, some of these complexes were active towards some breast cancer cell lines. Considering this evidence, here we report some new Au-NHC complexes prepared in order to improve solubility and biological activity. Among them, the compounds 1 and 6 showed an interesting anticancer activity towards the breast cancer MDA-MB-231 and MCF-7 cell lines, respectively. In addition, in vitro and in silico studies demonstrated that they were able to inhibit the activity of the human t...
Background. 46,XX disorders of sex development are rare. Approximately, 90% of XX males are SRY-p... more Background. 46,XX disorders of sex development are rare. Approximately, 90% of XX males are SRY-positive, while testicular development in the absence of SRY takes place in a minority. Methods: A boy with 46,XX karyotype (SRY-negative; absence of SOX9 duplications) was investigated by targeted Next Generation Sequencing (NGS), Multiplex ligation-dependent probe amplification (MLPA), and Comparative Genomic Hybridization array (CGH-array). Results: The boy had normal male phenotype and normal prepubertal values of testicular hormones. He presented a heterozygous duplication of 49.626 bp, encompassing exons 2 and 3 of DMRT1. The result was arr[GRCh37] 9p24.3(845893_895518)x3. Since both breakpoints are harbored in the intronic regions, the duplication does not stop or shift the coding frame. Additional known pathogenic or uncertain variants in pro-testis gene cascade were not identified. Conclusions: This study report a boy with 46,XX testicular disorder of sex differentiation, showing...
Background: Cancer tissue is characterized by low oxygen availability triggering neo angiogenesis... more Background: Cancer tissue is characterized by low oxygen availability triggering neo angiogenesis and metastatisation. Accordingly, oxidation is a possible strategy for counteracting cancer progression and relapses. Previous studies used ozone gas, administered by invasive methods, both in experimental animals and clinical studies, transiently decreasing cancer growth. This study evaluated the effect of ozonized oils (administered either topically or orally) on cancer, exploring triggered molecular mechanisms. Methods: In vitro, in lung and glioblastoma cancer cells, ozonized oils having a high ozonide content suppressed cancer cell viability by triggering mitochondrial damage, intracellular calcium release, and apoptosis. In vivo, a total of 115 cancer patients (age 58 ± 14 years; 44 males, 71 females) were treated with ozonized oil as complementary therapy in addition to standard chemo/radio therapeutic regimens for up to 4 years. Results: Cancer diagnoses were brain glioblastoma,...
Chemotherapy is used for the treatment of all stages of breast cancer, including the metastatic s... more Chemotherapy is used for the treatment of all stages of breast cancer, including the metastatic stage of the disease. Treatment regimens are generally tailored for each patient′s particular situation. However, chemotherapeutic agents are the leading cause of serious drug‐related adverse effects; moreover, drug resistance often occurs. In this study, we designed and synthesized a new series of N‐alkylcarbazoles derived from ellipticine, an alkaloid with a carbazole skeleton initially used in the treatment of metastatic breast cancer and later dismissed because of poor aqueous solubility and severe side effects. After evaluating the binding modes of our class of newly synthesized compounds with human topoisomerase II (hTopo II), we performed hTopo II decatenation assays, identifying compound 4 f (2‐(4‐((3‐chloro‐9H‐carbazol‐9‐yl)pentyl)piperazin‐1‐yl)‐N,N,N‐trimethylethanammonium iodide) as a good inhibitor. Moreover, 4 f and 4 g (2‐(4‐((3‐chloro‐9H‐carbazol‐9‐yl)hexyl)piperazin‐1‐yl)‐N,N,N‐trimethylethanammonium iodide) showed a good anti‐proliferative activity toward breast cancer cells, causing apoptosis by activation of the caspase pathway. Interestingly, the activity of these two compounds on triple‐negative MDA‐MB‐231 cells, which tend to be highly metastatic and aggressive, is strictly connected to the observed inhibition of hTopo II.
A multiscale scheme is proposed and validated for Triton X-100 (TX-100), which is a detergent wid... more A multiscale scheme is proposed and validated for Triton X-100 (TX-100), which is a detergent widely employed in biology. The hybrid particle field formulation of the model allows simulations of large-scale systems. The coarse-grained (CG) model, accurately validated in a wide range of concentrations, shows a critical micelle concentration, shape transition in isotropic micellar phase, and appearance of hexagonal ordered phase in the experimental ranges reported in the literature. The fine resolution of the proposed CG model allows one to obtain, by a suitable reverse mapping procedure, atomistic models of micellar assemblies and of the hexagonal phase. In particular, atomistic models of the micelles give structures in good agreement with experimental pair distance distribution functions and hydrodynamic measurements. The picture emerging by detailed analysis of simulated systems is quite complex. Polydisperse mixtures of spherical-, oblate-, and prolate-shaped aggregates have been found. The shape and the micelle behavior are mainly dictated by the aggregation number (Nagg). Micelles with low Nagg values (∼40) are spherical, while those with high Nagg values (∼140 or larger) are characterized by prolate ellipsoidal shapes. For intermediate Nagg values (∼70), fluxional micelles alternating between oblate and prolate shapes are found. The proposed model opens the way to investigations of several mechanisms involving TX-100 assembly in protein and membrane biophysics.
The structure of AcP from the hyperthermophilic archaeon Sulfolobus solfataricus has been determi... more The structure of AcP from the hyperthermophilic archaeon Sulfolobus solfataricus has been determined by (1)H-NMR spectroscopy and X-ray crystallography. Solution and crystal structures (1.27 A resolution, R-factor 13.7%) were obtained on the full-length protein and on an N-truncated form lacking the first 12 residues, respectively. The overall Sso AcP fold, starting at residue 13, displays the same betaalphabetabetaalphabeta topology previously described for other members of the AcP family from mesophilic sources. The unstructured N-terminal tail may be crucial for the unusual aggregation mechanism of Sso AcP previously reported. Sso AcP catalytic activity is reduced at room temperature but rises at its working temperature to values comparable to those displayed by its mesophilic counterparts at 25-37 degrees C. Such a reduced activity can result from protein rigidity and from the active site stiffening due the presence of a salt bridge between the C-terminal carboxylate and the act...
Niemann-Pick C, the autosomal recessive neuro-visceral disease resulting from a failure of choles... more Niemann-Pick C, the autosomal recessive neuro-visceral disease resulting from a failure of cholesterol trafficking within the endosomal-lysosomal pathway, is due to mutations in NPC1 or NPC2 genes. We characterized 34 unrelated patients including 32 patients with mutations in NPC1 gene and two patients in NPC2 gene. Overall, 33 distinct genotypes were encountered. Among the 21 unpublished NPC1 alleles, 15 were due to point mutations resulting in 13 codon replacements (p.C100S, p.P237L, p.R389L, p.L472H, p.Y634C, p.S636F, p.V780G, p.Q921P, p.Y1019C, p.R1077Q, p.L1102F, p.A1187V, and p.L1191F) and in two premature stop codons (p.R934X and p.Q447X); a new mutant carried two in cis mutations, p.[L648H;M1142T] and four other NPC1 alleles were small deletions/insertions leading both to frame shifts and premature protein truncations (p.C31WfsX26, p.F284LfsX26, p.E1188fsX54, and p.T1205NfsX53). Finally, the new intronic c.464-2A>C change at the 3' acceptor splice site of intron 4 af...
To date, the 5-year overall survival rate of 60% for early-stage non-small cell lung cancer (NSCL... more To date, the 5-year overall survival rate of 60% for early-stage non-small cell lung cancer (NSCLC) is still unsatisfactory. Therefore, reliable prognostic factors are needed. Growing evidence shows that cancer progression may depend on an interconnection between cancer cells and the surrounding tumor microenvironment; hence, circulating molecules may represent promising markers of cancer recurrence. In order to identify a prognostic score, we performed in-depth high-throughput analyses of plasma circulating markers, including exosomal microRNAs (Exo-miR) and peptides, in 67 radically resected NSCLCs. The miRnome profile selected the Exo-miR-130a-3p as the most overexpressed in relapsed patients. Peptidome analysis identified four progressively more degraded forms of fibrinopeptide A (FpA), which were depleted in progressing patients. Notably, stepwise Cox regression analysis selected Exo-miR-130a-3p and the greatest FpA (2-16) to build a score predictive of recurrence, where high-r...
Cancer is a complex and heterogeneous disease and is still one of the leading causes of morbidity... more Cancer is a complex and heterogeneous disease and is still one of the leading causes of morbidity and mortality worldwide, mostly as the population ages. Despite the encouraging advances made over the years in chemotherapy, the development of new compounds for cancer treatments is an urgent priority. In recent years, the design and chemical synthesis of several innovative hybrid molecules, which bring different pharmacophores on the same scaffold, have attracted the interest of many researchers. Following this strategy, we designed and synthetized a series of new hybrid compounds that contain three pharmacophores, namely trimethoxybenzene, thiazolidinedione and thiazole, and tested their anticancer properties on two breast cancer (MCF-7 and MDA-MB-231) cell lines and one melanoma (A2058) cell line. The most active compounds were particularly effective against the MCF-7 cells and did not affect the viability of the normal MCF-10A cells. Docking simulations indicated the human Topoiso...
Chemotherapy is commonly used for cancer treatment, however the lack of selectivity on healthy ce... more Chemotherapy is commonly used for cancer treatment, however the lack of selectivity on healthy cells and the development of resistance phenomena are the major issues. A better understanding of cancer genetics helped the development of new targeted anticancer treatments, which permit drug delivery with high specificity and lower toxicity. Moreover, the multi-target drug design concept represents the current trend for future drug research and development. Starting from good results previously obtained by our research group on the resveratrol (RSV) phenylacetamide derivative 2, which displayed an interesting anti-inflammatory and anti-proliferative activity towards the breast cancer cells MCF-7 and MDA-MB-231, we identified other features, as the ability to perturb the cytoskeleton dynamics and interfere with the migration and metastatic processes. In vitro and in silico studies demonstrate that the derivative 2 is a tubulin and actin polymerization inhibitor and an actin depolymerizat...
Triple-negative breast cancer (TNBC) constitutes a heterogeneous group of malignancies that are o... more Triple-negative breast cancer (TNBC) constitutes a heterogeneous group of malignancies that are often aggressive and associated with a poor prognosis. The development of new TNBC treatment strategies has become an urgent clinical need. Diagnosis and subtyping of TNBC are essential to establish alternative treatments and targeted therapies for every TNBC patient. Chemotherapy, particularly with anthracycline and taxanes, remains the backbone for medical management for both early and metastatic TNBC. More recently, immune checkpoint inhibitors and targeted therapy have revolutionized cancer treatment. Included in the different strategies studied for TNBC treatment is drug repurposing. Despite the numerous medications available, numerous studies in medicinal chemistry are still aimed at the synthesis of new compounds in order to find new antiproliferative agents capable of treating TNBC. Additionally, some supplemental micronutrients, nutraceuticals and functional foods can potentially...
Over the past decade, metal complexes based on N-heterocyclic carbenes (NHCs) have attracted grea... more Over the past decade, metal complexes based on N-heterocyclic carbenes (NHCs) have attracted great attention due to their wide and exciting applications in material sciences and medicinal chemistry. In particular, the gold-based complexes are the focus of research efforts for the development of new anticancer compounds. Literature data and recent results, obtained by our research group, reported the design, the synthesis and the good anticancer activity of some silver and gold complexes with NHC ligands. In particular, some of these complexes were active towards some breast cancer cell lines. Considering this evidence, here we report some new Au-NHC complexes prepared in order to improve solubility and biological activity. Among them, the compounds 1 and 6 showed an interesting anticancer activity towards the breast cancer MDA-MB-231 and MCF-7 cell lines, respectively. In addition, in vitro and in silico studies demonstrated that they were able to inhibit the activity of the human t...
Background. 46,XX disorders of sex development are rare. Approximately, 90% of XX males are SRY-p... more Background. 46,XX disorders of sex development are rare. Approximately, 90% of XX males are SRY-positive, while testicular development in the absence of SRY takes place in a minority. Methods: A boy with 46,XX karyotype (SRY-negative; absence of SOX9 duplications) was investigated by targeted Next Generation Sequencing (NGS), Multiplex ligation-dependent probe amplification (MLPA), and Comparative Genomic Hybridization array (CGH-array). Results: The boy had normal male phenotype and normal prepubertal values of testicular hormones. He presented a heterozygous duplication of 49.626 bp, encompassing exons 2 and 3 of DMRT1. The result was arr[GRCh37] 9p24.3(845893_895518)x3. Since both breakpoints are harbored in the intronic regions, the duplication does not stop or shift the coding frame. Additional known pathogenic or uncertain variants in pro-testis gene cascade were not identified. Conclusions: This study report a boy with 46,XX testicular disorder of sex differentiation, showing...
Background: Cancer tissue is characterized by low oxygen availability triggering neo angiogenesis... more Background: Cancer tissue is characterized by low oxygen availability triggering neo angiogenesis and metastatisation. Accordingly, oxidation is a possible strategy for counteracting cancer progression and relapses. Previous studies used ozone gas, administered by invasive methods, both in experimental animals and clinical studies, transiently decreasing cancer growth. This study evaluated the effect of ozonized oils (administered either topically or orally) on cancer, exploring triggered molecular mechanisms. Methods: In vitro, in lung and glioblastoma cancer cells, ozonized oils having a high ozonide content suppressed cancer cell viability by triggering mitochondrial damage, intracellular calcium release, and apoptosis. In vivo, a total of 115 cancer patients (age 58 ± 14 years; 44 males, 71 females) were treated with ozonized oil as complementary therapy in addition to standard chemo/radio therapeutic regimens for up to 4 years. Results: Cancer diagnoses were brain glioblastoma,...
Chemotherapy is used for the treatment of all stages of breast cancer, including the metastatic s... more Chemotherapy is used for the treatment of all stages of breast cancer, including the metastatic stage of the disease. Treatment regimens are generally tailored for each patient′s particular situation. However, chemotherapeutic agents are the leading cause of serious drug‐related adverse effects; moreover, drug resistance often occurs. In this study, we designed and synthesized a new series of N‐alkylcarbazoles derived from ellipticine, an alkaloid with a carbazole skeleton initially used in the treatment of metastatic breast cancer and later dismissed because of poor aqueous solubility and severe side effects. After evaluating the binding modes of our class of newly synthesized compounds with human topoisomerase II (hTopo II), we performed hTopo II decatenation assays, identifying compound 4 f (2‐(4‐((3‐chloro‐9H‐carbazol‐9‐yl)pentyl)piperazin‐1‐yl)‐N,N,N‐trimethylethanammonium iodide) as a good inhibitor. Moreover, 4 f and 4 g (2‐(4‐((3‐chloro‐9H‐carbazol‐9‐yl)hexyl)piperazin‐1‐yl)‐N,N,N‐trimethylethanammonium iodide) showed a good anti‐proliferative activity toward breast cancer cells, causing apoptosis by activation of the caspase pathway. Interestingly, the activity of these two compounds on triple‐negative MDA‐MB‐231 cells, which tend to be highly metastatic and aggressive, is strictly connected to the observed inhibition of hTopo II.
A multiscale scheme is proposed and validated for Triton X-100 (TX-100), which is a detergent wid... more A multiscale scheme is proposed and validated for Triton X-100 (TX-100), which is a detergent widely employed in biology. The hybrid particle field formulation of the model allows simulations of large-scale systems. The coarse-grained (CG) model, accurately validated in a wide range of concentrations, shows a critical micelle concentration, shape transition in isotropic micellar phase, and appearance of hexagonal ordered phase in the experimental ranges reported in the literature. The fine resolution of the proposed CG model allows one to obtain, by a suitable reverse mapping procedure, atomistic models of micellar assemblies and of the hexagonal phase. In particular, atomistic models of the micelles give structures in good agreement with experimental pair distance distribution functions and hydrodynamic measurements. The picture emerging by detailed analysis of simulated systems is quite complex. Polydisperse mixtures of spherical-, oblate-, and prolate-shaped aggregates have been found. The shape and the micelle behavior are mainly dictated by the aggregation number (Nagg). Micelles with low Nagg values (∼40) are spherical, while those with high Nagg values (∼140 or larger) are characterized by prolate ellipsoidal shapes. For intermediate Nagg values (∼70), fluxional micelles alternating between oblate and prolate shapes are found. The proposed model opens the way to investigations of several mechanisms involving TX-100 assembly in protein and membrane biophysics.
The structure of AcP from the hyperthermophilic archaeon Sulfolobus solfataricus has been determi... more The structure of AcP from the hyperthermophilic archaeon Sulfolobus solfataricus has been determined by (1)H-NMR spectroscopy and X-ray crystallography. Solution and crystal structures (1.27 A resolution, R-factor 13.7%) were obtained on the full-length protein and on an N-truncated form lacking the first 12 residues, respectively. The overall Sso AcP fold, starting at residue 13, displays the same betaalphabetabetaalphabeta topology previously described for other members of the AcP family from mesophilic sources. The unstructured N-terminal tail may be crucial for the unusual aggregation mechanism of Sso AcP previously reported. Sso AcP catalytic activity is reduced at room temperature but rises at its working temperature to values comparable to those displayed by its mesophilic counterparts at 25-37 degrees C. Such a reduced activity can result from protein rigidity and from the active site stiffening due the presence of a salt bridge between the C-terminal carboxylate and the act...
Niemann-Pick C, the autosomal recessive neuro-visceral disease resulting from a failure of choles... more Niemann-Pick C, the autosomal recessive neuro-visceral disease resulting from a failure of cholesterol trafficking within the endosomal-lysosomal pathway, is due to mutations in NPC1 or NPC2 genes. We characterized 34 unrelated patients including 32 patients with mutations in NPC1 gene and two patients in NPC2 gene. Overall, 33 distinct genotypes were encountered. Among the 21 unpublished NPC1 alleles, 15 were due to point mutations resulting in 13 codon replacements (p.C100S, p.P237L, p.R389L, p.L472H, p.Y634C, p.S636F, p.V780G, p.Q921P, p.Y1019C, p.R1077Q, p.L1102F, p.A1187V, and p.L1191F) and in two premature stop codons (p.R934X and p.Q447X); a new mutant carried two in cis mutations, p.[L648H;M1142T] and four other NPC1 alleles were small deletions/insertions leading both to frame shifts and premature protein truncations (p.C31WfsX26, p.F284LfsX26, p.E1188fsX54, and p.T1205NfsX53). Finally, the new intronic c.464-2A>C change at the 3' acceptor splice site of intron 4 af...
Uploads
Papers by Camillo Rosano