Pegvaliase therapy for phenylketonuria: Real-world case series and clinical insights.

OBJECTIVE: The aim of this study is to present a series of case studies on the real-life use of pegvaliase in Italy in managing patients affected by phenylketonuria (PKU) and provide practical insight and support to healthcare professionals currently approaching and facing this novel enzyme substitution therapy. METHODS: A panel of 11 PKU experts from seven leading Italian treatment centers attended online virtual meetings with the aim of reviewing their clinical and practical experiences with pegvaliase based on occurred cases. In selecting the cases, specific consideration was given to the nationwide representation of the centers involved and to the number of patients with PKU managed. Cases were thoroughly reviewed, with comprehensive discussions enabling the identification of key take-home messages regarding pegvaliase therapy. RESULTS: The panel discussed 18 cases, 11 males and 7 females (age range 17-43 years). At the last follow-up (up to 111 weeks after pegvaliase initiation), 11 out of 18 patients (61%) reached Phe levels below 600 µmol/l. Outcomes varied significantly across cases. All cases underscore the potential of pegvaliase in reducing Phe levels, enhancing the quality of life, and promoting social skills and independence. Additionally, the cases highlight the challenges associated with pegvaliase therapy, including managing adverse events and ensuring patient motivation and adherence. CONCLUSION: This is the first report about the Italian experience of managing patients affected by PKU with pegvaliase. Given the limited real-world data on the use of pegvaliase in PKU management, this case series offers valuable insights into the practical implementation and management of pegvaliase therapy in this Country. Continued research and data collection will be crucial to confirm and progress with this treatment. Despite potential challenges, pegvaliase therapy represents a substantial promise in managing PKU in Italy. Patient education, personalized treatment approaches, and careful monitoring are important to ensure optimal patient outcomes.

Management of patients with phenylketonuria (PKU) under enzyme replacement therapy: An Italian model (expert opinion).

Objective: Phenylketonuria (PKU) is a metabolic disorder necessitating lifelong management to prevent severe neurological impairments. This paper synthesises clinical practices from Italian specialist centres to delineate a unified approach for administering pegvaliase, a novel enzyme replacement therapy for PKU. Methods: Virtual meetings convened in September 2022, gathering a steering committee (SC) of experts from five Italian centres specialising in PKU. The SC reviewed, and discussed clinical practices, and formulated recommendations for pegvaliase treatment. Results: The SC outlined a comprehensive treatment roadmap for PKU management with pegvaliase, emphasising the importance of multidisciplinary care teams, patient selection, pre-treatment evaluation, and education. Recommendations include initial hospital-based pegvaliase administration, regular monitoring of phenylalanine and tyrosine levels, dietary adjustments, and management of adverse events. A consensus was reached on the need for a digital database to manage treatment plans and enhance communication between healthcare professionals and patients. Conclusion: The expert panel's consensus highlights the complexity of PKU management and the necessity for a coordinated, patient-centred approach. The recommendations aim to standardise care across Italian centres and provide a framework for integrating pegvaliase therapy into clinical practice, potentially informing international guidelines. Further research is warranted to evaluate the long-term impact of these practices on patient outcomes and quality of life.

The role of unidentified bright objects in the neurocognitive profile of neurofibromatosis type 1 children: a volumetric MRI analysis.

PURPOSE: Cognitive impairment is described in 80% of Neurofibromatosis type 1 (NF1) patients. Brain focal areas of T2w increased signal intensity on MRI, the so-called Unidentified Bright Objects (UBOs) have been hypothesized to be related to cognitive dysfunction, although conflicting results are available in literature. Here, we investigated the possible relation between UBOs' volume, cognitive impairment, and language disability in NF1 patients. MATERIAL AND METHODS: In this retrospective study, clinical and MRI data of 21 NF1 patients (M/F = 12/9; mean age 10.1 ± 4.5) were evaluated. Brain intellectual functioning and language abilities were assessed with specific scales, while the analyzed MRI sequences included axial 2D-T2-weighted and FLAIR sequences. These images were used independently for UBOs segmentation with a semiautomatic approach and obtained volumes were normalized for biparietal diameters to take into account for brain volume. Possible differences in terms of normalized UBOs volumes were probed between cognitively affected and preserved patients, as well as between subjects with or without language impairment. RESULTS: Patients cognitively affected were not different in terms of UBOs volume compared to those preserved (p = 0.35 and p = 0.30, for T2-weighted and FLAIR images, respectively). Similarly, no differences were found between patients with and without language impairment (p = 0.47 and p = 0.40, for the two sequences). CONCLUSIONS: The relation between UBOs and cognition in children with NF1 has been already investigated in literature, although leading to conflicting results. Our study expands the current knowledge, showing a lack of correlation between UBOs volume and both cognitive impairment and language disability in NF1 patients.

Serious Games in the new era of digital-health interventions: A narrative review of their therapeutic applications to manage neurobehavior in neurodevelopmental disorders.

Children and adolescents with neurodevelopmental disorders generally show adaptive, cognitive and motor skills impairments associated with behavioral problems, i.e., alterations in attention, anxiety and stress regulation, emotional and social relationships, which strongly limit their quality of life. This narrative review aims at providing a critical overview of the current knowledge in the field of serious games (SGs), known as digital instructional interactive videogames, applied to neurodevelopmental disorders. Indeed, a growing number of studies is drawing attention to SGs as innovative and promising interventions in managing neurobehavioral and cognitive disturbs in children with neurodevelopmental disorders. Accordingly, we provide a literature overview of the current evidence regarding the actions and the effects of SGs. In addition, we describe neurobehavioral alterations occurring in some specific neurodevelopmental disorders for which a possible therapeutic use of SGs has been suggested. Finally, we discuss findings obtained in clinical trials using SGs as digital therapeutics in neurodevelopment disorders and suggest new directions and hypotheses for future studies to bridge the gaps between clinical research and clinical practice.

Postnatal microcephaly and retinal involvement expand the phenotype of RPL10-related disorder.

Hemizygous missense variants in the RPL10 gene encoding a ribosomal unit are responsible for an X-linked syndrome presenting with intellectual disability (ID), autism spectrum disorder, epilepsy, dysmorphic features, and multiple congenital anomalies. Among 15 individuals with RPL10-related disorder reported so far, only one patient had retinitis pigmentosa and microcephaly was observed in approximately half of the cases. By exome sequencing, three Italian and one Spanish male children, from three independent families, were found to carry the same hemizygous novel missense variant p.(Arg32Leu) in RPL10, inherited by their unaffected mother in all cases. The variant, not reported in gnomAD, is located in the 28S rRNA binding region, affecting an evolutionary conserved residue and predicted to disrupt the salt-bridge between Arg32 and Asp28. In addition to features consistent with RPL10-related disorder, all four boys had retinal degeneration and postnatal microcephaly. Pathogenic variants in genes responsible for inherited retinal degenerations were ruled out in all the probands. A novel missense RPL10 variant was detected in four probands with a recurrent phenotype including ID, dysmorphic features, progressive postnatal microcephaly, and retinal anomalies. The presented individuals suggest that retinopathy and postnatal microcephaly are clinical clues of RPL10-related disorder, and at least the retinal defect might be more specific for the p.(Arg32Leu) RPL10 variant, suggesting a specific genotype/phenotype correlation.

Can early physical therapy positively affect the onset of independent walking in infants with Down syndrome? A retrospective cohort study.

BACKGROUND: The development of both gross and fine motor skills in a child with Down syndrome is generally delayed. The most seriously affected stage is the achievement of independent walking ability, which influences the onset of all following motor and cognitive skills. The study objectives were: 1) to assess the time taken to achieve independent walking ability in a cohort of children with Down syndrome; 2) to examine differences in walking onset by patient characteristics; and 3) to verify the effect of early physical therapy (neurodevelopmental treatment based on Bobath Concept practiced within the first months of life) in the achievement of that skill. METHODS: A retrospective study was carried out on a cohort of 86 children with Down Syndrome. The knowledge of the exact age of walking onset and information about comorbidities and rehabilitation practiced since birth were the eligibility criteria. RESULTS: The average age at which walking began in the sample was 26 months (standard deviation=9.66). Some patient characteristics proved to be related negatively to the walking onset: gender male, trisomy 21, improved joint ligamentous laxity. When practiced, early physical therapy was able to contrast the delay in walking. CONCLUSIONS: NDT-Bobath is a well-known and valid instrument for a child with Down syndrome to attain his highest possible psychomotor functioning level. This study pointed out for the first time ever its capability to contrast the delay on walking onset, which can influence positively the development of the following motor and cognitive skills.

Obstructive Sleep Apnoea in Children with Down Syndrome: A Multidisciplinary Approach.

A comprehensive evaluation of obstructive sleep apnoea (OSA) may allow for the development of more efficient management of Down syndrome (DS). We aimed to evaluate the effect of a multidisciplinary approach to DS with OSA. A total of 48 DS children aged 4−12 years were prospectively investigated with nasal endoscopy, orthodontic examination, and overnight polygraphy (PG); the Italian Child Sleep Habits Questionnaire (CSHQ-IT) was filled out by the mothers. The total CSHQ-IT score was 63 (96% of children reporting sleep problems). The major ear, nose, and throat characteristics were enlarged palatine tonsils (62%), adenoid tonsils (85%), and chronic rhinosinusitis (85%). DS children showed orthognathic profile in 68% of cases, class I relationship in 63%, and cross-bite in 51%. PG revealed OSA in 67% of cases (37% mild, 63% moderate−severe). The oxygen desaturation index (ODI) was higher in the group with OSA (5.2) than with non-OSA (1.3; p < 0.001). The ODI was higher (p = 0.001) and SpO2 lower (p = 0.03) in children with moderate−severe OSA than with mild OSA. The apnoea−hypopnea index (AHI) and percentage time with SpO2 < 90% were higher in DS children with grade III than with grade I or II adenoids (5 vs. 1, p = 0.04, and 1.2 vs. 0.1, p = 0.01, respectively). No significant correlations were found between PG and the total CSHQ-IT score or orthodontic data. However, children showing associated cross-bite, grade III adenoids and size 3 or 4 palatine tonsils showed higher AHI and ODI than those without (p = 0.01 and p = 0.04, respectively). A coordinated multidisciplinary approach with overnight PG is a valuable tool when developing diagnostic protocols for OSA in DS.

Beneficial Effects of Slow-Release Large Neutral Amino Acids after a Phenylalanine Oral Load in Patients with Phenylketonuria.

The mainstay of phenylketonuria treatment is a low protein diet, supplemented with phenylalanine (Phe)-free protein substitutes and micronutrients. Adhering to this diet is challenging, and even patients with good metabolic control who follow the dietary prescriptions in everyday life ignore the recommendations occasionally. The present study explores the ability of slow-release large neutral amino acids (srLNAAs) to prevent Phe increase following a Phe dietary load. Fourteen phenylketonuric patients aged ≥13 years were enrolled in a 6-week protocol. Oral acute Phe loads of 250 and 500 mg were added to the evening meal together with srLNAAs (0.5 gr/kg). Phe and tyrosine were dosed before dinner, 2h-after dinner, and after the overnight fast. After oral Phe loads, mean plasma Phe remained stable and below 600 µmol/L. No Phe peaks were registered. Tyrosine levels significantly increased, and Phe/Tyrosine ratio decreased. No adverse events were registered. In conclusion, a single oral administration of srLNAAs at the dose of 0.5 gr/kg is effective in maintaining stable plasma Phe during acute oral loads with Phe-containing food and may be added to the dietetic scheme in situations in which patients with generally good adherence to diet foresee a higher than prescribed Phe intake due to their commitments.

Linguistic adaptation and psychometric evaluation of Italian version of children's sleep habits questionnaire.

BACKGROUND: The Children's Sleep Habits Questionnaire (CSHQ) is a parent-report questionnaire used to examine sleep behavior in children. Linguistic adaptation of CSHQ into several languages and/or psychometric analysis of reliability have been published. MAIN TEXT: Our aim was to translate the original 33-items CSHQ from English to Italian and to examine its reliability for use in 4-10 years-old children of Italy. After translation and back-translation procedure of the original CSHQ, the Italian CSHQ (CSHQ-IT) was administered to 69 mothers of healthy children. Reliability of CSHQ-IT was examined by the internal consistency of the scale (using the Cronbach's alpha coefficient), and by the test-retest analysis obtained by asking mothers who had completed the CSHQ-IT at baseline to re-complete it after a two-week interval (measured with the Lin's Concordance Correlation Coefficient, CCC). The CSHQ-IT showed adequate internal consistency (Cronbach's alpha = 0.81 for the total scale). The total CSHQ-IT score showed a strong correlation in retests (CCC 0.87; 95% Confidence Interval, 0.80; 0.92). CONCLUSION: CSHQ-IT is a valuable tool for evaluating sleep behavior in children 4-10 years-old in Italy. Future research should be implemented to provide definitive validity of CSHQ-IT in children with sleep-disordered breathing.

Expanding the neurological and behavioral phenotype of White-Sutton syndrome: a case report.

BACKGROUND: White-Sutton (WHSUS) is a recently recognized syndrome caused by mutations of the POGZ gene. Approximately 70 patients have been reported to date. Intellectual disability, hypotonia, behavioral abnormalities, autism, and typical facial dysmorphisms are recognized as WHSUS features; however, still few patients receive a comprehensive psychometric, behavioral and neurological examination. In this report, we describe the pediatric, dysmorphological, neurological, psychometric and behavioral phenotype in a new WHSUS patient due to a novel heterozygous POGZ mutation, highlighting the distinctive epileptic phenotype and the cognitive pattern. CASE PRESENTATION: The patient, an 8 years-old girl, presented history of hypotonia, motor and speech delay, and distinctive facial features. The diagnosis of WHSUS followed the identification of the de novo variant p.Asp828GlyfsTer36 (c.2482dupG) in the POGZ gene. The patient showed a distinctive neurological phenotype with the occurrence of both paroxysmal not-epileptic events in the first 6 months of age and EEG abnormalities without evidence of clinical seizures after the first year of age. Psychological and behavioral testing highlighted moderate intellectual and communication deficit, mild autism spectrum and visual-motor integration deficit. CONCLUSIONS: This is the first described case of WHSUS with a co-existence of paroxysmal not-epileptic events and abnormal EEG without seizures in the same patient. Together with the available literature data, this observation suggests that paroxysmal not-epileptic events could be more frequent than expected and that this feature belongs to the WHSUS phenotypic spectrum. Autism is a known comorbidity of WHSUS but is still poorly investigated. Specific clinical testing could help detect also mild autistic phenotypes and better define autism prevalence in POGZ-related syndrome. Special attention should be given to symptoms such as stereotypies, social withdrawal, and hyperactivity that, when present, should be considered as possible signs of autism symptoms. The dissection of the neurological and behavioral phenotype is crucial for individualized therapies tailored to patient's needs.

Epigallocatechin-3-Gallate Plus Omega-3 Restores the Mitochondrial Complex I and F0F1-ATP Synthase Activities in PBMCs of Young Children with Down Syndrome: A Pilot Study of Safety and Efficacy.

Down syndrome (DS) is a major genetic cause of intellectual disability. DS pathogenesis has not been fully elucidated, and no specific pharmacological therapy is available. DYRK1A overexpression, oxidative stress and mitochondrial dysfunction were described in trisomy 21. Epigallocatechin-3-gallate (EGCG) is a multimodal nutraceutical with antioxidant properties. EGCG inhibits DYRK1A overexpression and corrects DS mitochondrial dysfunction in vitro. The present study explores safety profiles in DS children aged 1-8 years treated with EGCG (10 mg/kg/die, suspended in omega-3, per os, in fasting conditions, for 6 months) and EGCG efficacy in restoring mitochondrial complex I and F0F1-ATP synthase (complex V) deficiency, assessed on PBMCs. The Griffiths Mental Developmental Scales-Extended Revised (GMDS-ER) was used for developmental profiling. Results show that decaffeinated EGCG (>90%) plus omega-3 is safe in DS children and effective in reverting the deficit of mitochondrial complex I and V activities. Decline of plasma folates was observed in 21% of EGCG-treated patients and should be carefully monitored. GMDS-ER scores did not show differences between the treated group compared to the DS control group. In conclusion, EGCG plus omega-3 can be safely administered under medical supervision in DS children aged 1-8 years to normalize mitochondria respiratory chain complex activities, while results on the improvement of developmental performance are still inconclusive.

Large Neutral Amino Acids (LNAAs) Supplementation Improves Neuropsychological Performances in Adult Patients with Phenylketonuria.

Phenylketonuria is an inborn error of phenylalanine (Phe) metabolism diagnosed by newborn screening and treated early with diet. Although diet prevents intellectual disability, patients often show impairment of executive functions, working memory, sustained attention, and cognitive flexibility. Large neutral amino acids (LNAAs) have been proposed as a dietary supplement for PKU adults. Few studies show that LNAAs may help in improving metabolic control as well as cognitive functions. In this study, 10 adult PKU patients with poor metabolic control were treated for 12 months with LNAAs (MovisCom, 0.8-1 g/kg/day) and underwent Phe and Tyrosine (Tyr) monitoring monthly. Neuropsychological assessment was performed at T0, T+3, and T+12 months by using the American Psychological General Well-Being Index, the Wisconsin Card Sorting Test, the Test of Attentional Performance, and the 9-Hole Peg Test. No change in plasma Phe levels was observed during LNAAs supplementation, while Tyr levels significantly improved during LNAAs supplementation (p = 0.03). Psychometric tests showed an improvement of distress and well-being rates, of executive functions, attention, and vigilance, whereas no difference was noted regarding hand dexterity. This study adds evidence of the advantage of LNAAs supplementation in improving cognitive functions and well-being in patients with PKU with poor metabolic control.

Prospective evaluation of autoimmune and non-autoimmune subclinical hypothyroidism in Down syndrome children.

OBJECTIVE: To evaluate the prevalence and natural course of autoimmune and non-autoimmune subclinical hypothyroidism (SH) in Down syndrome (DS) children and adolescents. DESIGN: Prospective multicenter study. METHODS: For the study, 101 DS patients with SH (TSH 5-10 mIU/L; FT4 12-22 pmol/L), aged 2-17 years at SH diagnosis were enrolled. Annual monitoring of TSH, FT4, BMI, height, and L-thyroxine dose was recorded for 5 years. Thyroid autoimmunity was tested at diagnosis and at the end of follow-up. RESULTS: Thirty-seven out of 101 patients displayed autoantibody positivity (group A); the remaining 64 were classified as non-autoimmune SH (group B). Group A was characterized by higher median age at SH diagnosis and by more frequent family history of thyroid disease (6.6 vs 4.7 years, P = 0.001; 32.4% vs 7.8%, P = 0.001 respectively), whereas congenital heart defects were more common in group B (65.6% vs 43.2%, P = 0.028). Gender, median BMI (SDS), height (SDS), FT4, and TSH were similar in both groups. At the end of follow-up: 35.1% of group A patients developed overt hypothyroidism (OH) vs 17.2% of group B (P = 0.041); 31.25% of group B vs 10.8% of group A became biochemically euthyroid (P = 0.02); and 37.8% of group A vs 51.5% of group B still had SH condition (P = 0.183). Logistic regression suggested autoimmunity (OR = 3.2) and baseline TSH values (OR = 1.13) as predictive factors of the evolution from SH to OH. CONCLUSIONS: In DS children, non-autoimmune SH showed higher prevalence and earlier onset. The risk of thyroid function deterioration over time seems to be influenced by thyroid autoimmunity and higher baseline TSH values.

The contribution of the citrate pathway to oxidative stress in Down syndrome.

Inflammatory conditions and oxidative stress have a crucial role in Down syndrome (DS). Emerging studies have also reported an altered lipid profile in the early stages of DS. Our previous works demonstrate that citrate pathway activation is required for oxygen radical production during inflammation. Here, we find up-regulation of the citrate pathway and down-regulation of carnitine/acylcarnitine carrier and carnitine palmitoyl-transferase 1 genes in cells from children with DS. Interestingly, when the citrate pathway is inhibited, we observe a reduction in oxygen radicals as well as in lipid peroxidation levels. Our preliminary findings provide evidence for a citrate pathway dysregulation, which could be related to some phenotypic traits of people with DS.

B-cell receptor-guided delivery of peptide-siRNA complex for B-cell lymphoma therapy.

BACKGROUND: Despite the clinical response of conventional anticancer therapy, including chemotherapeutic treatments, radiation therapy and corticosteroids, tumorigenic B-cell lymphomas show an incomplete response to clinical practices that result in a minimal residual disease (MRD) where few residual neoplastic cells undetected in vivo, replenish the cancer cell reservoir. This scenario, which is also shared with other cancer diseases, requires the development of strategies to advance in novel, selective targeting toward the tumorigenic cells that survive to the anticancer agents. METHODS: Here, we have taken advantage of the therapeutic properties of an idiotype specific peptide (pA20-36) that bind specifically to murine B-lymphoma cells in the setting of an anti cancer strategy, based on the selected delivery of electrostatic-based complex, peptide-siRNA. To this end, two engineered, arginine rich, peptides that included the pA20-36 targeting sequence were designed to bind fluorescent-labelled siRNA. One peptide presented 9 Arg at the C-terminal of pA20-36 whereas the other included 5 Arg at the N- and C-terminus, respectively. RESULTS: Compared to the control and random peptide-siRNA complexes, both pA20-36-siRNA complexes were endowed with the selective delivering of fluorescent-labelled siRNA toward the A20 murine B-cell lymphoma, as evaluated by cytofluorimetry and confocal microscopy, whereas fluorescent-labelled siRNA alone was not internalized in the selected cells. Compared to peptide controls, the use of the modified pA20-36 peptides complexed with siRNA anti-GAPDH and anti-Bcl2 showed a down-regulation in the expression levels of the corresponding genes. CONCLUSIONS: Peptide-siRNA complex can be suitable tool for both selective peptide-driven cell targeting and gene silencing. In this setting, the improvement of this strategy is expected to provide a safe and non-invasive approach for the delivery of therapeutic molecules.

Long-term follow-up of patients with phenylketonuria treated with tetrahydrobiopterin: a seven years experience.

BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive disorder caused by the deficiency of phenylalanine hydroxylase that catalyzes the conversion of phenylalanine to tyrosine, using tetrahydrobiopterin (BH4) as coenzyme. Besides dietary phenylalanine restriction, new therapeutic options are emerging, such as the treatment with BH4 in subgroups of PKU patients responding to a loading test with BH4. METHODS: A no-profit open-label interventional trial with long-term oral BH4 therapy, sponsored by the Italian Medicines Agency (AIFA), was performed in a group of 17 PKU patients resulted as BH4 responders among 46 subjects analyzed for BH4-responsiveness (prot. FARM5MATC7). We report on efficacy and safety data of BH4 therapy and analyze factors predicting BH4-responsiveness and long-term response to BH4. A BH4-withdrawal test was used as a proof of the efficacy of long-term therapy with BH4. RESULTS: Forty-four percent of the patients responded to the 48 h-long loading test with BH4. All the phenotypic classes were represented. Genotype was the best predictor of responsiveness, along with lower phenylalanine levels at diagnosis, higher tolerance and lower phenylalanine/tyrosine ratio before the test. In BH4 responder patients, long-term BH4 therapy resulted safe and effective in increasing tolerance while maintaining a good metabolic control. The BH4 withdrawal test, performed in a subset of patients, showed that improved tolerance was directly dependent on BH4 assumption. Tolerance to phenylalanine was re-evaluated in 43.5% of patients and was longitudinally analyzed in 5 patients. CONCLUSIONS: Long-term treatment with BH4 is safe and effective in increasing tolerance to phenylalanine. There is real need to assess the actual tolerance to phenylalanine in PKU patients to ameliorate quality of life, improve nutritional status, avoiding unnecessarily restricted diets, and interpret the effects of new therapies for PKU.

Aberrant glycosylation as biomarker for cancer: focus on CD43.

Glycosylation is a posttranslational modification of proteins playing a major role in cell signalling, immune recognition, and cell-cell interaction because of their glycan branches conferring structure variability and binding specificity to lectin ligands. Aberrant expression of glycan structures as well as occurrence of truncated structures, precursors, or novel structures of glycan may affect ligand-receptor interactions and thus interfere with regulation of cell adhesion, migration, and proliferation. Indeed, aberrant glycosylation represents a hallmark of cancer, reflecting cancer-specific changes in glycan biosynthesis pathways such as the altered expression of glycosyltransferases and glycosidases. Most studies have been carried out to identify changes in serum glycan structures. In most cancers, fucosylation and sialylation are significantly modified. Thus, aberrations in glycan structures can be used as targets to improve existing serum cancer biomarkers. The ability to distinguish differences in the glycosylation of proteins between cancer and control patients emphasizes glycobiology as a promising field for potential biomarker identification. In this review, we discuss the aberrant protein glycosylation associated with human cancer and the identification of protein glycoforms as cancer biomarkers. In particular, we will focus on the aberrant CD43 glycosylation as cancer biomarker and the potential to exploit the UN1 monoclonal antibody (UN1 mAb) to identify aberrant CD43 glycoforms.

FKBP51 increases the tumour-promoter potential of TGF-beta.

BACKGROUND: FKBP51 (FKBP5 Official Symbol) is a large molecular weight component of the family of FK506 binding proteins (FKBP). In recent years, research studies from our laboratory highlighted functions for FKBP51 in the control of apoptosis and melanoma progression. FKBP51 expression correlated with the invasiveness and aggressiveness of melanoma. Since a role for TGF-ß in the enhanced tumorigenic potential of melanoma cells is widely described, we hypothesized a cooperative effect between FKBP51 and TGF-ß in melanoma progression. METHODS: SAN and A375 melanoma cell lines were utilized for this study. Balb/c IL2γ NOD SCID served to assess the ability to colonize organs and metastasize of different cell lines, which was evaluated by in vivo imaging. Realtime PCR and western blot served for measurement of mRNA and protein expression, respectively. RESULTS: By comparing the metastatic potential of two melanoma cell lines, namely A375 and SAN, we confirmed that an increased capability to colonize murine organs was associated with increased levels of FKBP51. A375 melanoma cell line expressed FKBP51 mRNA levels 30-fold higher in comparison to the SAN mRNA level and appeared more aggressive than SAN melanoma cell line in an experimental metastasis model. In addition, A375 expressed, more abundantly than SAN, the TGF-ß and the pro angiogenic TGF-ß receptor type III (TßRIII) factors. FKBP51 silencing produced a reduction of TGF-ß and TßRIII gene expression in A375 cell line, in accordance with previous studies. We found that the inducing effect of TGF-ß on Sparc and Vimentin expression was impaired in condition of FKBP51 depletion, suggesting that FKBP51 is an important cofactor in the TGF-ß signal. Such a hypothesis was supported by co immunoprecipitation assays, showing that FKBP51 interacted with either Smad2,3 and p300. In normal melanocytes, FKBP51 potentiated the effect of TGF-ß on N-cadherin expression and conferred a mesenchymal-like morphology to such round-shaped cells. CONCLUSIONS: Overall, our findings show that FKBP51 enhances some pro oncogenic functions of TGF-ß, suggesting that FKBP51-overexpression may help melanoma to take advantage of the tumor promoting activities of the cytokine.