Publications by authors named "Claudia Fusco"

26 Publications

  • Page 1 of 1

Fragment-Based Design of a Potent MAT2a Inhibitor and Evaluation in an MTAP Null Xenograft Model.

J Med Chem 2021 05 26;64(10):6814-6826. Epub 2021 Apr 26.

Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom.

MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite -adenosylmethionine (SAM) from methionine and ATP. Tumors bearing the co-deletion of p16 and MTAP genes have been shown to be sensitive to MAT2a inhibition, making it an attractive target for treatment of MTAP-deleted cancers. A fragment-based lead generation campaign identified weak but efficient hits binding in a known allosteric site. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a merging and growing strategy into an arylquinazolinone series of potent MAT2a inhibitors. The selected tool compound reduced SAM-dependent methylation events in cells and inhibited proliferation of MTAP-null cells . studies showed that was able to induce antitumor response in an MTAP knockout HCT116 xenograft model.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00067DOI Listing
May 2021

Comparative analysis of antigen and molecular tests for the detection of Sars-CoV-2 and related variants: A study on 4266 samples.

Int J Infect Dis 2021 Apr 18;108:187-189. Epub 2021 Apr 18.

Department of Biomedicine and Prevention, Tor Vergata University, 00133 Rome, Italy; Genomic Medicine Laboratory UILDM, IRCCS Santa Lucia Foundation, 00179 Rome, Italy. Electronic address:

Objectives: The present study compared the performance of the Lumipulse G Sars-CoV-2 Ag kit with the TaqPath COVID-19 RT-PCR CE IVD kit.

Methods: The study was conducted on 4266 naso-oropharyngeal swabs. Samples were subjected to antigen RT-PCR tests for the detection of Sars-CoV-2 and related variants. Statistical analyses were conducted in R software.

Results: We found 503 positives (including 138 H69-V70 deletion carriers) and 3763 negatives by RT-PCR, whereas 538 positives and 3728 negatives were obtained by antigen testing. We achieved empirical and binormal AU-ROCs of 0.920 and 0.990, accuracy of 0.960, sensitivity of 0.866, specificity of 0.973, positive and negative predictive values of 0.810 and 0.980. We obtained a positive correlation between viral loads and antigen levels (R = 0.81), finding a complete concordance for high viral loads (log copies/mL > 5.4). Antigen levels > 222 pg/mL were found to be reliable in assigning positive samples (p < 0.01). Concerning variant carriers, antigen test detected them with the same accuracy as other positive samples.

Conclusions: Molecular and antigen tests should be evaluated regarding the prevalence of the area. In case of low prevalence, antigen testing can be employed as a first-line screening for the timely identification of affected individuals with high viral load, also if carriers of Sars-CoV-2 variants.
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http://dx.doi.org/10.1016/j.ijid.2021.04.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053214PMC
April 2021

The switch-like expression of heme-regulated kinase 1 mediates neuronal proteostasis following proteasome inhibition.

Elife 2020 04 24;9. Epub 2020 Apr 24.

Max Planck Institute for Brain Research, Frankfurt am Main, Germany.

We examined the feedback between the major protein degradation pathway, the ubiquitin-proteasome system (UPS), and protein synthesis in rat and mouse neurons. When protein degradation was inhibited, we observed a coordinate dramatic reduction in nascent protein synthesis in neuronal cell bodies and dendrites. The mechanism for translation inhibition involved the phosphorylation of eIF2α, surprisingly mediated by eIF2α kinase 1, or heme-regulated kinase inhibitor (HRI). Under basal conditions, neuronal expression of HRI is barely detectable. Following proteasome inhibition, HRI protein levels increase owing to stabilization of HRI and enhanced translation, likely via the increased availability of tRNAs for its rare codons. Once expressed, HRI is constitutively active in neurons because endogenous heme levels are so low; HRI activity results in eIF2α phosphorylation and the resulting inhibition of translation. These data demonstrate a novel role for neuronal HRI that senses and responds to compromised function of the proteasome to restore proteostasis.
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http://dx.doi.org/10.7554/eLife.52714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224698PMC
April 2020

Design and Synthesis of 56 Shape-Diverse 3D Fragments.

Chemistry 2020 Jul 8;26(41):8969-8975. Epub 2020 Jul 8.

Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK.

Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2D molecules. Herein, we describe a workflow for the design and synthesis of 56 3D disubstituted pyrrolidine and piperidine fragments that occupy under-represented areas of fragment space (as demonstrated by a principal moments of inertia (PMI) analysis). A key, and unique, underpinning design feature of this fragment collection is that assessment of fragment shape and conformational diversity (by considering conformations up to 1.5 kcal mol above the energy of the global minimum energy conformer) is carried out prior to synthesis and is also used to select targets for synthesis. The 3D fragments were designed to contain suitable synthetic handles for future fragment elaboration. Finally, by comparing our 3D fragments with six commercial libraries, it is clear that our collection has high three-dimensionality and shape diversity.
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http://dx.doi.org/10.1002/chem.202001123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496344PMC
July 2020

Acute effects of two different initial heart rates on testing the repeated sprint ability in elite women soccer players.

J Sports Med Phys Fitness 2020 Apr 5;60(4):527-535. Epub 2020 Feb 5.

Interdepartmental Center of Science and Culture of Sport, Faculty of Medicine and Surgery, Tor Vergata University, Rome, Italy.

Background: Repeated sprint ability (RSA) in women's soccer is crucial to ensure high level of performance during the game. The aim of this study is to investigate the acute effects of two different initial heart rates intensities on fatigue when testing the RSA.

Methods: Since there are many kinds of pre-match warming-ups, the heart rate reached at the end of two different warm-up protocols (~90 vs. ≈60% HRmax) as an indicator of internal load has been selected and the respective RSA performances were compared. RSA tests were performed by 19 elite women soccer players (age: 22.5±3.3 years, height 163.9±7.3 cm, body mass 54.3±6.4 kg, BMI 20.6±1.5 kg/m2) with two sets of ten shuttle-sprints (15+15 m) with a 1:3 exercise to rest ratio, in different days (randomized order) with different initial HR% (60% and 90% HRmax). In order to compare the different sprint performances a Fatigue Index (FI%) was computed; the blood lactate concentrations (BLa-) were measured before and after testing, to compare metabolic energy.

Results: Significant differences among trials within each set (P<0.01) were found, as evidence of fatigue. Differences between sets were not found, (Factorial ANOVA 2x10; P>0.05). Although the BLa- after warm-up was higher between 90% vs. 60% HRmax (P<0.05), at the completion of RSA tests (after 3 minutes) the differences were considerably low and not significant (P>0.05).

Conclusions: This study shows that, contrary to male soccer, the initial heart rates, induced by different modes of warming-up, do not affect the overall performance while testing RSA in women's soccer players.
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http://dx.doi.org/10.23736/S0022-4707.19.10311-8DOI Listing
April 2020

When the Injury's Healing Process Meets the Needs of a Top-Level Volleyball Player: A Nonconventional Treatment of a Mallet Fracture Reinjury.

Am J Phys Med Rehabil 2019 02;98(2):e10-e12

From the Department of Rehabilitation (DC, MZ, CF), and Orthopaedics and Traumatology Unit (MB), Foligno Hospital, Foligno, Italy; and Department of Physical and Rehabilitation Medicine, Hacettepe University Medical School, Ankara, Turkey (LÖ).

Managing top-level athlete's recovery after an injury is very complicated because it requires a challenging combination of clinical and social/professional aspects with the need to return as soon as possible to sports play. Herein, we report a top-level volleyball player for whom a finger splint combined with a custom made thermoplastic protection was used for the conservative management of a Mallet fracture reinjury. This way our player continued training and competitions in contrast to conventional rehabilitation protocols, which suggest to avoid new traumas until the healing phase is completed. After 8 wks, we obtained the fracture healing and a complete functional recovery without major medical complications. From our results, we suggest that novel treatment strategies or modification of conventional rehabilitation protocols are worth consideration for the management of high-level sports players' injuries. However, new clinical studies with a larger sample can compare these results with those resulting from both surgical procedures and from immobilization and rest as well.
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http://dx.doi.org/10.1097/PHM.0000000000000984DOI Listing
February 2019

Second-generation CK2α inhibitors targeting the αD pocket.

Chem Sci 2018 Mar 20;9(11):3041-3049. Epub 2018 Feb 20.

Department of Chemistry , University of Cambridge , CB2 1EW , Cambridge , UK . Email:

CK2 is a critical cell cycle regulator that also promotes various anti-apoptotic mechanisms. Development of ATP-non-competitive inhibitors of CK2 is a very attractive strategy considering that the ATP binding site is highly conserved among other kinases. We have previously utilised a pocket outside the active site to develop a novel CK2 inhibitor, . Whilst bound to this new pocket it was also interacting with the ATP site: herein, we describe an example of a CK2α inhibitor that binds completely outside the active site. This second generation αD-site binding inhibitor, compound (IC = 7 μM, GI = 10.0 ± 3.6 μM), has numerous advantages over the previously reported , including a reduction in the number of rotatable bonds, the absence of amide groups susceptible to the action of proteases and improved cellular permeability. Unlike with , there was no need to facilitate cellular uptake by making a prodrug. Moreover, displayed no drop off between its ability to inhibit the kinase (IC) and the ability to inhibit cell proliferation (GI).
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http://dx.doi.org/10.1039/c7sc05122kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916021PMC
March 2018

A fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066.

Bioorg Med Chem 2017 07 30;25(13):3471-3482. Epub 2017 Apr 30.

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address:

Recently we reported the discovery of a potent and selective CK2α inhibitor CAM4066. This compound inhibits CK2 activity by exploiting a pocket located outside the ATP binding site (αD pocket). Here we describe in detail the journey that led to the discovery of CAM4066 using the challenging fragment linking strategy. Specifically, we aimed to develop inhibitors by linking a high-affinity fragment anchored in the αD site to a weakly binding warhead fragment occupying the ATP site. Moreover, we describe the remarkable impact that molecular modelling had on the development of this novel chemical tool. The work described herein shows potential for the development of a novel class of CK2 inhibitors.
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http://dx.doi.org/10.1016/j.bmc.2017.04.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587527PMC
July 2017

Specific inhibition of CK2α from an anchor outside the active site.

Chem Sci 2016 Nov 12;7(11):6839-6845. Epub 2016 Jul 12.

Department of Biochemistry , University of Cambridge , 80 Tennis Court Road , Cambridge CB2 1GA , UK . Email:

The development of selective inhibitors of protein kinases is challenging because of the significant conservation of the ATP binding site. Here, we describe a new mechanism by which the protein kinase CK2α can be selectively inhibited using features outside the ATP site. We have identified a new binding site for small molecules on CK2α adjacent to the ATP site and behind the αD loop, termed the αD pocket. An elaborated fragment anchored in this site has been linked with a low affinity fragment binding in the ATP site, creating a novel and selective inhibitor (CAM4066) that binds CK2α with a of 320 nM and shows significantly improved selectivity compared to other CK2α inhibitors. CAM4066 shows target engagement in several cell lines and similar potency to clinical trial candidate CX4945. Our data demonstrate that targeting a poorly conserved, cryptic pocket allows inhibition of CK2α a novel mechanism, enabling the development of a new generation of selective CK2α inhibitors.
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http://dx.doi.org/10.1039/c6sc02335eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355960PMC
November 2016

Acetylated tubulin is essential for touch sensation in mice.

Elife 2016 12 13;5. Epub 2016 Dec 13.

EMBL Mouse Biology Unit, Monterotondo, Italy.

At its most fundamental level, touch sensation requires the translation of mechanical energy into mechanosensitive ion channel opening, thereby generating electro-chemical signals. Our understanding of this process, especially how the cytoskeleton influences it, remains unknown. Here we demonstrate that mice lacking the α-tubulin acetyltransferase Atat1 in sensory neurons display profound deficits in their ability to detect mechanical stimuli. We show that all cutaneous afferent subtypes, including nociceptors have strongly reduced mechanosensitivity upon Atat1 deletion, and that consequently, mice are largely insensitive to mechanical touch and pain. We establish that this broad loss of mechanosensitivity is dependent upon the acetyltransferase activity of Atat1, which when absent leads to a decrease in cellular elasticity. By mimicking α-tubulin acetylation genetically, we show both cellular rigidity and mechanosensitivity can be restored in Atat1 deficient sensory neurons. Hence, our results indicate that by influencing cellular stiffness, α-tubulin acetylation sets the force required for touch.
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http://dx.doi.org/10.7554/eLife.20813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5158137PMC
December 2016

Tennis is not dangerous for the spine during growth: results of a cross-sectional study.

Eur Spine J 2016 09 26;25(9):2938-44. Epub 2016 Feb 26.

Physical and Rehabilitation Medicine, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Purpose: Tennis is widely practiced by adolescents in many countries. Many spinal deformity experts consider this activity, together with other asymmetrical sports, as risk factors for scoliosis development even though scientific data are missing. The aim of the present study was to verify the prevalence of spinal deformities and LBP in adolescent competitive tennis players compared to healthy controls.

Methods: We designed a cross-sectional study. A convenience sample of 102 adolescent tennis players (52 girls) was compared to 203 scholars (102 girls) of the same age (12 years). We used a questionnaire to collect data on LBP and we measured the ATR to screen for spinal deformities and the plumb line distances for kyphosis (C7 and C7 + L3) and lordosis (L3).

Results: We found similar spinal deformities in both groups: ATR female: 3.2° ± 1° (tennis) versus 2.8° ± 1° (school), NS; ATR males: 2.8° ± 1° (tennis) versus 2.6° ± 1° (school), p < 0.05. No differences were found for kyphosis and lordosis. Low back pain prevalence was similar for both groups, but a significant difference was found for limitation of usual activity, which was higher for tennis players than controls.

Conclusion: The correlation between tennis, an asymmetric sport, and spinal deformities that has been postulated by many experts was not confirmed by our data. There was no correlation between tennis and LBP, even if there were some differences among groups for limitations of the daily activities. Adolescent competitive tennis showed to be a safe sport without an increased risk of spinal deformities and LBP.
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http://dx.doi.org/10.1007/s00586-016-4452-1DOI Listing
September 2016

Low rate of surgery in juvenile idiopathic scoliosis treated with a complete and tailored conservative approach: end-growth results from a retrospective cohort.

Scoliosis 2014 18;9:12. Epub 2014 Aug 18.

Physical and Rehabilitation Medicine, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy ; IRCCS Don Gnocchi Foundation, Milan, Italy.

Background Context: The main distinctive aspect of Juvenile Idiopathic Scoliosis (JIS) with respect to Adolescent Idiopathic Scoliosis (AIS) is the high risk of severe deformity and surgery. Approximately 70% of curves in patients with JIS progress and ultimately require surgery. There are presently very few studies with long-term follow-up of JIS and even fewer looking specifically at bracing Purpose To verify the effectiveness of a complete conservative treatment, including bracing and exercises, for JIS.

Study Design/setting: Retrospective cohort observational study nested in a clinical prospective database of consecutive outpatients. Patient Sample Inclusion criteria: JIS, no previous treatment, all consecutive radiographies available from treatment start to end of growth (Risser sign 3). We found 30 patients, 27 females, 10 JIS type 1; mean age at first diagnosis was 7.8 +/-1.5 and mean treatment lasted 5.8 years. Cobb degrees 24.4+/-10 degrees, with 7 cases >30 degrees, and 2 > 45degrees. Outcome Measures Physiological measures. Radiographic and clinical data.

Methods: Treatment (exercises alone, or elastic-rigid-highly rigid braces plus exercises) was tailored and continuously changed according to Cobb degrees, individual preferences, anthropometric characteristics, pubertal spurt, remaining growth, rotation, hump, lumbar curve take-off, and imbalance. The SOSORT Guidelines for patients' management have been followed. Funding and Conflict of Interest: no.

Results: 33.3% (95% Confidence Interval 16.4-50.2%) of patients worsened over the years. At the end of growth, 6.6% (0-15.5%) had surgical deformities (>45degrees). We observed a good correction in the first years of treatment until pubertal growth spurt, when progression was usually noted and treatment changed increasing corrective forces (hours or rigidity of bracing). 23 cases were followed up until they had two consecutive radiographies showing Risser sign 5 and showed stability.

Conclusions: Conservative treatment initiated already in childhood may favorably change the natural history of JIS with the aim of reaching a curve as far as possible from surgical thresholds. Observation, physical exercises, braces can be useful tools in the hand of physicians, but they must be carefully utilized by a deep knowledge of JIS.
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http://dx.doi.org/10.1186/1748-7161-9-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149041PMC
September 2014

Asymmetric catalysis on the nanoscale: the organocatalytic approach to helicenes.

Angew Chem Int Ed Engl 2014 May 15;53(20):5202-5. Epub 2014 Apr 15.

Max-Planck-Institut für Kohlenforschung, Kaiser Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany).

The first asymmetric organocatalytic synthesis of helicenes is reported. A novel SPINOL-derived phosphoric acid, bearing extended π-substituents, catalyzes the asymmetric synthesis of helicenes through an enantioselective Fischer indole reaction. A variety of azahelicenes and diazahelicenes could be obtained with good to excellent yields and enantioselectivities.
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http://dx.doi.org/10.1002/anie.201400474DOI Listing
May 2014

Musculoskeletal problems in pediatric acute leukemia.

J Pediatr Orthop B 2013 May;22(3):264-9

aDepartment of Paediatrics, Paediatric Oncology Service bDepartment of Orthopaedics, Second University of Naples, Italy.

Acute leukemia (AL) in children can mimic several orthopedic pathologies at presentation, with a variable delay in the correct diagnosis. This is a major problem, which may result in fractures, loss of mobility, and deformity, with resultant adverse effects on quality of life. Here, we studied the clinical and radiological musculoskeletal manifestations in children with AL. We reviewed 328 children [208 boys (62%), median age 7.2 years] with acute lymphoblastic (279, 85%) or myeloid (49, 15%) leukemia, treated between January 1982 and December 2003 by the Paediatric Oncology Service, Second University of Naples. The group was further divided into two groups: group 1 included 255 patients (78%, 163 boys) without skeletal morbidity at diagnosis, and group 2 included 73 patients (22%, 41 boys) with musculoskeletal symptoms. This group was further subdivided into group 2A (56 patients), which included children with symptoms related to the appendicular skeleton, and group 2B (17 patients), which included children with symptoms related to the axial skeleton. Moreover, we also reported the long-term complications of therapy, such as osteonecrosis of the weight-bearing joints. In group 2A, 44 children presented only pain, seven septic arthritis-type symptoms, and five osteomyelitis-type symptoms. Joint compression was in the tibia-tarsus (21 patients), knee (16), coxofemoral (12), and elbow (seven). In group 2B, 11 patients presented with vertebral collapses. The remaining six patients complained of localized pain in the lumbar-sacral area, with limited flexor and extensor muscle capacity. Fifty-five (75.3%) patients showed radiographic abnormalities: osteoporosis in 22 patients (40%), pathological fractures in 11 (20%), osteolysis in 10 (18.1%), osteosclerosis in five (9%), periosteal reactions in four (7.2%), and metaphyseal bands in three (5.4%). Four (1.2%) patients in total showed avascular necrosis (4.3% when only high-risk patients were considered). At presentation, 22% of our children had at least one musculoskeletal manifestation and 75.3% showed one radiographic change. Our study highlights the importance of including AL in the differential diagnosis of musculoskeletal manifestations. Four cases of avascular necrosis confirm the need for regular check-ups, both orthopedic and nonorthopedic, particularly in adolescent girls, to prevent permanent disability.
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http://dx.doi.org/10.1097/BPB.0b013e32835d731cDOI Listing
May 2013

Enantioselective α-hydroxylation of β-ketoamides.

Org Biomol Chem 2013 Feb 7;11(6):896-9. Epub 2013 Jan 7.

Dipartimento di Chimica, Università di Salerno, Via Ponte don Melillo, 84084 Fisciano, Italy.

The first enantioselective α-hydroxylation reaction of α-substituted β-ketoamides has been developed by using the commercially available hydroquinine/TBHP system. The tertiary alcohols are obtained in good to high yield and up to 83% ee, which can be improved by a single crystallization.
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http://dx.doi.org/10.1039/c2ob27283kDOI Listing
February 2013

Noncovalent organocatalytic synthesis of enantioenriched terminal aziridines with a quaternary stereogenic center.

Org Lett 2012 Aug 2;14(16):4078-81. Epub 2012 Aug 2.

Dipartimento di Chimica e Biologia, Università di Salerno, Via Ponte don Melillo, 84084 Fisciano, Italy.

A high-yielding and enantioselective access to novel N-Boc terminal aziridines, bearing a quaternary stereogenic center, has been developed via an aza-Michael initiated ring-closure (aza-MIRC) reaction of α-acyl acrylates with an N-tosyloxy tert-butyl carbamate catalyzed by a chiral amino thiourea. The feasibility of the aziridine regioselective ring-opening to valuable α,α-disubstituted α-amino acid esters has been demonstrated.
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http://dx.doi.org/10.1021/ol3017066DOI Listing
August 2012

Hexafluorobenzene: a powerful solvent for a noncovalent stereoselective organocatalytic Michael addition reaction.

Chem Commun (Camb) 2012 Feb 21;48(11):1650-2. Epub 2011 Dec 21.

Dipartimento di Chimica e Biologia, Via Ponte don Melillo, 84084, Fisciano, Italy.

A dramatic enhancement of the diastereo- and enantioselectivity in the nitro-Michael addition reaction organocatalysed by a commercially available α,α-L-diaryl prolinol was disclosed when performing the reaction in unconventional hexafluorobenzene as a medium. DFT calculations were performed to clarify the origin of stereoselectivity and the role of C(6)F(6).
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http://dx.doi.org/10.1039/c2cc17488jDOI Listing
February 2012

Methotrexate toxicity and efficacy during the consolidation phase in paediatric acute lymphoblastic leukaemia and MTHFR polymorphisms as pharmacogenetic determinants.

Cancer Chemother Pharmacol 2011 Nov 18;68(5):1339-46. Epub 2011 May 18.

Pediatric Department, Second University of Naples, Naples, Italy.

Purpose: Folate-metabolizing single-nucleotide polymorphisms (SNPs) are emerging as important pharmacogenetic prognostic determinants of the response to chemotherapy. With high doses of methotrexate (MTX) in the consolidation phase, methylenetetrahydrofolate reductase (MTHFR) polymorphisms could be potential modulators of the therapeutic response to antifolate chemotherapeutics in identifying a possible correlation with the outcome. This study aims to analyse the potential role of the MTHFR C677T and A1298C genetic variants in modulating the clinical toxicity and efficacy of high doses of MTX in a cohort of paediatric ALL patients (n = 151) treated with AIEOP protocols.

Methods: This work includes DNA extraction by slides and RFLP-PCR.

Results: The first observation relative to early toxicities (haematological and non-haematological), after the first doses of MTX in all protocols, was an association between the 677T and 1298C carriers and global toxicity. We found that in the 2 g/m(2) MTX group, patients harbouring 677TT homozygously exhibited a substantial 12-fold risk of developing toxicity. In this study, we demonstrate that the MTHFR 677TT variant is associated with an increased risk of relapse when compared to other genotypes. The Kaplan-Meier analysis showed that the 677TT variant had a lower 7-year DFS(disease-free survival) probability compared to the 677C carrier genotype (log-rank test P = 0.003) and OS (overall survival) and also confirms the lower probability of survival for patients with the 677TT variant (log-rank test, P = 0.006).

Conclusions: Our study provides further evidence of the critical role played by folate pathway enzymes in the outcome of ALL, possibly through the interference of MTX.
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http://dx.doi.org/10.1007/s00280-011-1665-1DOI Listing
November 2011

Idiopathic scoliosis patients with curves more than 45 Cobb degrees refusing surgery can be effectively treated through bracing with curve improvements.

Spine J 2011 May 2;11(5):369-80. Epub 2011 Feb 2.

Rehabilitation Department, Italian Scientific Spine Institute, Via Bellarmino 13/1, Milan, Italy.

Background Context: It is a broad consensus today that scoliosis curves cannot be improved through bracing, and the Scoliosis Research Society (SRS) methodological criteria for bracing have the avoidance of progression as their only objective. Consequently, in curves more than 45°, fusion is considered as basically the only possible treatment.

Purpose: The purpose of the study was to verify in a series of patients who utterly refused surgery if it was possible to achieve improvements of scoliosis of more than 45° through a complete conservative treatment (bracing and exercises).

Study Design/setting: Retrospective cohort from a prospective database.

Patient Sample: Out of 1,148 idiopathic scoliosis (IS) patients at the end of treatment, the sample comprised 28 subjects older than 10 years, still growing, with at least one curve above 45°, who had continually refused fusion. The group comprised 24 females and four males, including 14 in which previous brace treatments had failed; at the start of treatment, the age was 14.2±1.8 years and Cobb degrees in the curve were 49.4° (range, 45°-58°). Subgroups considered were gender, bone age, type of scoliosis, treatment used, and previous failed treatment.

Outcome Measures: Self-report measurement: SRS-22; physiological measures: Cobb degrees, Bunnell angle of trunk rotation (ATR), aesthetic index (AI), and sagittal plumb line distances.

Methods: The methods comprised full-time treatment (23 or 24 hours per day) for 1 year with Risser cast, Lyon, or Sforzesco brace; weaning of 1 to 2 hours every 6 months; with strategies to maximize compliance through the Society on Scoliosis Orthopaedic and Rehabilitation Treatment (SOSORT) management criteria applied and specific scientific exercises approach to scoliosis exercises (SEAS) performed.

Results: Reported compliance in the 4.10±1.2 treatment years was 94%, with satisfaction regarding treatment and excellent results at the SRS-22. Two patients (7%) remained above 50° Cobb but six patients (21%) finished between 30° and 35° Cobb and 12 patients (43%) finished between 36° and 40° Cobb. Improvements have been found in 71% of patients and a 5° Cobb progression in one patient. Statistically, we found highly significant reductions of the main (-9.25°), average (-6.6°), thoracic (-7.8°), and lumbar (-15.9°) curves. Statistically significant improvements have been found for the AI and ATR, with a general decrease in plumb line distances.

Conclusions: Bracing can be successfully used in patients who do not want to undergo operations for IS with curves ranging between 45° and 60° Cobb, given sufficient clinical expertise to apply good braces and achieve great compliance. Future studies could demonstrate the percentages at which this result can be achieved.
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http://dx.doi.org/10.1016/j.spinee.2010.12.001DOI Listing
May 2011

The SPoRT concept of bracing for idiopathic scoliosis.

Physiother Theory Pract 2011 Jan;27(1):54-60

ISICO (Italian Scientific Spine Institute), Milan, Italy.

The SPoRT (acronym: Symmetrical, Patient-oriented, Rigid, Three-dimensional, active) concept of bracing is a new way to build braces based on our 20 years of experience and the biomechanical principles of scoliosis correction, inclusive of the Sibilla and Sforzesco braces. The concept always requires a custom brace, which is made according to the patient's individual requirements. New technologies such as CAD-CAM can be applied, and often for better results, without the customary use of prebuilt forms whose measurements are stored in databases. Once the initial draft brace is completed, a final test must be made on the patient to modify and adapt it, depending on his or her real interaction between the body and the brace. The results that are today available on the SPoRT concept relate to the Sforzesco brace and are necessarily short-term, because the first treated patients are now reaching the fourth-year follow-up examination and haven't yet completed their treatments. On the basis of the initial evaluations, we can state that the Sforzesco brace is more effective than the Lyon brace after 6 months of treatment and that the Sforzesco brace is equally effective as the Risser Plast brace.
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http://dx.doi.org/10.3109/09593985.2010.503988DOI Listing
January 2011

Organocatalytic stereoselective epoxidation of trisubstituted acrylonitriles.

J Org Chem 2011 Jan 22;76(2):676-9. Epub 2010 Dec 22.

Dipartimento di Chimica, Università di Salerno, Via Ponte don Melillo, 84084, Fisciano, Italy.

The first diastereospecific and enantioselective epoxidation of trans-2-aroyl-3-arylacrylonitriles by means of the commercially available diaryl L-prolinol/tert-butyl hydroperoxide system has been developed. These diversely functionalized epoxides were obtained in excellent yield (up to 99%), complete diastereoselectivity for the trans-isomer, and good enantioselectivity (up to 84% ee). Highly enantioenriched epoxides can be easily obtained after a single crystallization (ee > 90%).
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http://dx.doi.org/10.1021/jo102020aDOI Listing
January 2011

Kaposiform hemangioendothelioma of the kidney: an unusual presentation of a rare vascular neoplasm.

J Pediatr Hematol Oncol 2010 Jul;32(5):e195-8

Pediatric Department, Pediatric Oncology Service, Second University of Naples, Naples, Italy.

Kaposiform hemangioendothelioma (KHE) is a rare, locally aggressive, vascular spindle-cell proliferation, with resemblance to Kaposi sarcoma. Usually, this tumor occurs in the skin and the retroperitoneum. We described a girl with a kidney localization and extension into the inferior vena cava and even into the right atrium. The case presented here is unique in 2 ways. First, kidney involvement of KHE has never been described in the literature until now. Second, and most remarkably, extensive tumor thrombosis suggests surgical excision even with cardiopulmonary bypass. The KHE of the kidney is a rare tumor but should be taken into account in the differential diagnosis with other pediatric renal neoplasms.
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http://dx.doi.org/10.1097/MPH.0b013e3181e15c9eDOI Listing
July 2010

Effectiveness of complete conservative treatment for adolescent idiopathic scoliosis (bracing and exercises) based on SOSORT management criteria: results according to the SRS criteria for bracing studies - SOSORT Award 2009 Winner.

Scoliosis 2009 Sep 4;4:19. Epub 2009 Sep 4.

ISICO (Italian Scientific Spine Institute), Via Roberto Bellarmino 13/1, 20141 Milan, Italy.

Background: The SRS criteria give the methodological reference framework for the presentation of bracing results, while the SOSORT criteria give the clinical reference framework for an appropriate bracing treatment. The two have not been combined in a study until now. Our aim was to verify the efficacy of a complete, conservative treatment of Adolescent Idiopathic Scoliosis (AIS)according to the best methodological and management criteria defined in the literature.

Methods: Study Design. Retrospective study. Population. We included all AIS patients respecting the SRS inclusion criteria (age 10 years or older; Risser test 0-2; Cobb degrees 25-40 degrees ; no prior treatment; less than one year post-menarchal) who had reached the end of treatment since our institute database start in 2003. Thus we had 44 females and four males, with an age of 12.8 +/- 1.6 at the commencement of the study. Methods. According to individual needs, two patients have been treated with Risser casts followed by Lyon brace, 40 with Lyon or SPoRT braces (14 for 23 hours per day, 23 for 21 h/d, and seven for 18 h/d at start), and two with exercises only (1 male, 1 female): these were excluded from further analysis. Outcome criteria. SRS (unchanged; worsened 6 degrees or more; over 45 degrees at the end of treatment; surgically treated; two years' follow-up); clinical (ATR, Aesthetic Index, plumbline distances); radiographic (Cobb degrees); and ISICO (optimal; minimal). Statistics. Paired ANOVA and t-test, Tukey-Kramer and chi-square test.

Results: Median reported compliance during the 4.2 +/- 1.4 treatment years was 90% (range 5-106%). No patient progressed beyond 45 degrees , nor was any patient fused, and this remained true at the two-year follow-up for the 85% that reached it. Only two patients (4%) worsened, both with single thoracic curve, 25-30 degrees Cobb and Risser 0 at the start. We found statistically significant reductions of the scoliosis curvatures (-7.1 degrees ): thoracic (-7.3 degrees ), thoracolumbar (-8.4 degrees ) and lumbar (-7.8 degrees ), but not double major. Statistically significant improvements have also been found for aesthetics and ATR.

Conclusion: Respecting also SOSORT management criteria and thus increasing compliance, the results of conservative treatment were much better than what had previously been reported in the literature using SRS criteria only.
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http://dx.doi.org/10.1186/1748-7161-4-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3224944PMC
September 2009

How to improve aesthetics in patients with Adolescent Idiopathic Scoliosis (AIS): a SPoRT brace treatment according to SOSORT management criteria.

Scoliosis 2009 Sep 1;4:18. Epub 2009 Sep 1.

ISICO, Milan, Italy.

Background: Aesthetics is a main goal of both conservative and surgical treatments in adolescent idiopathic scoliosis (AIS). Previously, we developed and validated a clinical scale - the Aesthetic Index (AI)--in order to measure aesthetic impairment and changes during treatment.

Aim: To verify the efficacy of bracing on aesthetics in AIS.

Study Design: Prospective Cohort Study.

Population: Thirty-four consecutive patients, age 13.2 +/- 3.7, initial Cobb Angle 32 +/- 12 degrees , ATR 10 +/- 4 degrees Bunnel, 11 males.

Methods: Patients with AI scores of at least 5/6 were included. Each of them had a brace prescription (18 to 23 hours per day), according to the SPoRT concept. AI was measured again after six months and at the end of treatment, and then the pre- and post-treatment scores compared. The Wilcoxon test was performed.

Results: Twenty-nine patients out of the 34 included completed the treatment and had six-month and final results; four patients were lost during the treatment, and one was fused. At baseline, median AI was 6 (95% IC 5-6) but the score decreased to 3 (95% IC 0-5; p < 0.05) after six months with brace, and this value was maintained in the 29 who completed the treatment (95% IC 1-6; p < 0.05 with respect to the baseline).

Conclusion: Aesthetics can be improved in a clinically significant way when the brace treatment is performed according to the SPoRT concept and by following the SOSORT management criteria. This is a relevant result for patients and a major goal of scoliosis treatment, be it conservative or surgical. The use of a more sensitive tool like TRACE could more easily detect the clinical changes; nevertheless, AI proved sensible enough that its use in everyday clinical practice can be suggested.
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http://dx.doi.org/10.1186/1748-7161-4-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743641PMC
September 2009

Specific exercises performed in the period of brace weaning can avoid loss of correction in Adolescent Idiopathic Scoliosis (AIS) patients: Winner of SOSORT's 2008 Award for Best Clinical Paper.

Scoliosis 2009 Apr 7;4. Epub 2009 Apr 7.

ISICO Milano, Milan, Italy.

Background: Exercises are frequently performed in order to improve the efficacy of bracing and avoid its collateral effects. Very frequently there is a loss of correction during brace weaning in AIS treatment.

Aim: To verify the efficacy of exercises in reducing correction loss during brace weaning.

Study Design: Retrospective controlled study.

Population: Sixty-eight consecutive patients (eight males), age 15 +/- 1 and Cobb angle 22 +/- 8 degrees at start of brace weaning.

Methods: The start of brace weaning was defined as the first visit in which the wearing of brace for less than 18/24 hours was prescribed (according to our protocol, at Risser 3). Patients were divided into two groups according to whether or not exercises were performed: (1) EX (exercises), included 39 patients and was further divided into two sub-groups: SEAS (who performed exercises according to our institute's protocol, 14 patients) and OTH (other exercises, 25 patients) and (2) CON (controls, 29 patients) that was divided into two other sub-groups: DIS (discontinuous exercises, 19 patients) and NO (no exercises, 10 patients). Complete brace weaning was defined as the first visit in which the brace was no longer prescribed (ringapophysis closure or Risser 5, according to our protocol). ANOVA and Chi Square tests were performed.

Results: There was no difference between groups at baseline. However, at the end of treatment, 2.7 years after the start of the weaning process, Cobb angle increased significantly in both the DIS and NO groups (3.9 degrees and 3.1 degrees Cobb, respectively). The SEAS and OTH groups did not change. Comparing single groups, OTH (with respect to DIS) had a significant difference (P < 0.05).

Conclusion: Exercises can help reduce the correction loss in brace weaning for AIS.
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http://dx.doi.org/10.1186/1748-7161-4-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2672077PMC
April 2009

3-DEMO classification of scoliosis: a useful understanding of the 3(rd) dimension of the deformity.

Stud Health Technol Inform 2008 ;135:139-53

ISICO (Italian Scientific Spine Institute), Via Carlo Crivelli 20, 20122 Milan, Italy.

The third-dimension of scoliosis represent a great challenge for clinicians used to think in two dimensions due to the classical radiographic representation of the deformity. This caused problems in everyday clinical approaches, and led to the development of new bidimensional classifications (King, Lenke) who tried in different ways to face these problems, mainly in a surgical perspective. Recently, some three-dimensional classifications have been proposed, all developed in laboratory by bioengineers. In this paper we present the existing classifications of scoliosis, both bi-dimensional and three-dimensional and we thoroughly discuss the 3-DEMO (3-D Easy Morphological) that has been first presented years ago, and recently thoroughly published; this classification has been developed by clinicians with the main aim of being understandable and easily applicable to everyday clinical life.
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June 2008