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Natural and synthetic retinoids have proved to be effective in the treatment and prevention of various human cancers. In the present study, we investigated the effect of retinoids on Epstein-Barr virus (EBV)-infected lymphoblastoid cell lines (LCLs), since these cells closely resemble those that give rise to EBV-related lymphoproliferative disorders in the immunosuppressed host. All six compounds tested inhibited LCL proliferation with no significant direct cytotoxicity, but 9-cis-retinoic acid (RA), 13-cis-RA, and all-trans-RA (ATRA) were markedly more efficacious than Ro40-8757, Ro13-6298, and etretinate. The antiproliferative action of the three most effective compounds was confirmed in a large panel of LCLs, thus appearing as a generalized phenomenon in these cells. LCL growth was irreversibly inhibited even after 2 days of treatment at drug concentrations corresponding to therapeutically achievable plasma levels. Retinoid-treated cells showed a marked downregulation of CD71 and a decreased S-phase compartment with a parallel accumulation in Gzero/ G1 phases. These cell cycle perturbations were associated with the upregulation of p27 Kip1, a nuclear protein that controls entrance and progression through the cell cycle by inhibiting several cyclin/cyclin-dependent kinase complexes. Unlike what is observed in other systems, the antiproliferative effect exerted by retinoids on LCLs was not due to the acquisition of a terminally differentiated status. In fact, retinoid-induced modifications of cell morphology, phenotype (downregulation of CD19, HLA-DR, and s-Ig, and increased expression of CD38 and c-Ig), and IgM production were late events, highly heterogeneous, and often slightly relevant, being therefore only partially indicative of a drug-related differentiative process. Moreover, EBV-encoded EBV nuclear antigen-2 and latent membrane protein-1 proteins were inconstantly downregulated by retinoids, indicating that their growth-inhibitory effect is not mediated by a direct modulation of viral latent antigen expression. The strong antiproliferative activity exerted by retinoids in our experimental model indicates that these compounds may represent a useful tool in the medical management of EBV-related lymphoproliferative disorders of immunosuppressed patients.

Sjögren's syndrome (SS) has been indicated as an ideal human model to investigate B cell lymphomagenesis. Our aim was to investigate similarities or differences in cytokine expression in both prelymphomatous and frank B cell lymphomatous SS lesions, as well as in SS related lesions versus SS unrelated malignant B cell non-Hodgkin's lymphomas.The mRNA expression of interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-6, IL-6R, IL-9, IL-10, IL-12, tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), and transforming growth factor beta (TGF-beta) was analyzed by a sensitive reverse transcriptase polymerase chain reaction technique in 10 SS tissue samples from 10 consecutive patients [7 nonmalignant parotid myoepithelial sialadenitis (MESA) lesions with evidence of B cell clonal expansion, and 3 B cell non-Hodgkin's lymphomas] as well as a series of 11 SS unrelated B cell non-Hodgkin's lymphomas.IL-1, IL-2, IL-3, IL-6, IL-6R, IL-10, IL-12, IFN-gamma, TNF-alpha, and TGF-beta mRNA was expressed in all or in the vast majority of the samples analyzed. IL-4 mRNA was detected in 2/3 SS related and in 3/11 SS unrelated non-Hodgkin's lymphomas, while SS related MESA samples were characterized by an IL-4 negative pattern and lacked IL-3 or IFN-gamma expression in 3/7 cases and in 2/7 cases, respectively.Many cytokines may be involved in the evolution of prelymphomatous to definite B cell malignant lesions in SS, as well as in the development of SS unrelated B cell non-Hodgkin's lymphomas. A putative pathobiological role of the IL-12/IL-4 balance, in the presence of cytokines that may sustain B cell proliferation (i.e., IL-3, IL-6, IL-10), may represent a major point for future research. Finally, our data reinforce the view of SS as a human model of B cell lymphomagenesis.

Studies have analyzed T cell receptor (TCR)-Vbeta in benign, minor salivary or lacrimal gland, or kidney lesions in Sjögren's syndrome (SS). We investigated SS related lymphoproliferative lesions.By "family" reverse transcriptase polymerase chain reaction, we studied the expression of 20 different TCR-Vbeta families in parotid lymphoproliferative lesions and peripheral blood lymphocytes (PBL) from 7 patients with primary SS, in PBL from 6 primary SS patients with no associated lymphoproliferative disorder, and in activated PBL from 2 healthy controls. T cell clonal expansion was investigated in 10 Vbeta families (i.e., the most expanded ones and those previously implicated in SS pathogenesis) by single strand conformation polymorphism (SSCP) analysis. Frozen sections from parotid gland specimens were tested by immunohistochemistry for the expansion of selected Vbeta families. Viral infection within the parotid lesions and serum autoantibody response were also studied.An unrestricted Vbeta pattern was observed. The most widely expressed Vbeta family in parotid lesions was Vbeta2, and Vbeta immunohistochemistry results were concordant with Vbeta mRNA findings. A similar pattern was observed in PBL, although the Vbeta2 family was expressed at lower levels. The parotid/PBL ratio was occasionally1.8-2.0 (indicative of local Vbeta overexpression) in different Vbeta families. T cell expansion proved to be largely polyclonal by SSCP analysis, and scattered T cell clonotypes were detected within different Vbeta families, with a different pattern from patient to patient.Our observations in SS related lymphoproliferative lesions largely reflect previous evidence in fully benign lesions. The pathogenetic events involved in autoimmune benign lesions in SS may then persist and play a role in SS related lymphoproliferative disorders. The link between the observed TCR-Vbeta repertoire and specific local triggering (auto)antigens remains to be elucidated.

Background Monosomy 1p36 is the most common terminal deletion syndrome with an autosomal dominant pattern of inheritance. This syndrome is defined by an extremely wide spectrum of characteristics; however, developmental delay and intellectual disability of various degree are present in all patients and about the 90% of patients have a severe intellectual disability. Dental agenesis or other dental anomalies have not been described in previous reports. Case presentation We report the case of two little sisters born from healthy and non-consanguineous parents, presenting with dental anomalies and one of them with epilepsy, dilated cardiomyopathy with left-ventricular non-compaction, strabismus, history of poor growth, hypotonia and mild language delay. Patients were evaluated in several departments (genetic, child neuropsychiatric, cardiology, odontostomatology, ophthalmology, otorhinolaryngology) of Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy. They underwent investigations such as electrocardiogram, echocardiogram, dental orthopantomography X-Ray and Computed Tomography, electroencephalograms, abdomen ultrasound, blood tests, IQ tests, genetic analysis. They both have an Intelligence Quotient greater than 70 and a negative neurologic exam. Each sister carries the same 1p36 deletion of about 2.3 Mb. Genetic analysis of the parents’ blood samples (Single Nucleotide Polymorphism- array, karyotype and Fluorescent In Situ Hybridization) did not reveal any deletion, translocation or inversion and confirmed the paternity. A third sib of the probands does not carry the 1p36 deletion or other quantitative alterations. Conclusion This report describes a new trait linked to monosomy 1p36, namely a mild intellectual outcome associated with significant dental anomalies. Our finding suggests that 1p36 deletion syndrome may present with a mild cognitive impairment or even with a normal intellectual development: this is very important for the genetic counselling, especially in a prenatal setting. Moreover, we report the third study with recurrent 1p36 deletion syndrome in two siblings, likely due to germline mosaicism. Finally, we believe that the dental anomalies should be investigated in 1p36 deletion syndrome and that the spectrum of the condition could be broader than we assume.

Stathmin is a p53-target gene, frequently overexpressed in late stages of human cancer progression. Type II High Grade Epithelial Ovarian Carcinomas (HG-EOC) represents the only clear exception to this observation. Here, we show that stathmin expression is necessary for the survival of HG-EOC cells carrying a p53 mutant (p53(MUT) ) gene. At molecular level, stathmin favours the binding and the phosphorylation of p53(MUT) by DNA-PKCS , eventually modulating p53(MUT) stability and transcriptional activity. Inhibition of stathmin or DNA-PKCS impaired p53(MUT) -dependent transcription of several M phase regulators, resulting in M phase failure and EOC cell death, both in vitro and in vivo. In primary human EOC a strong correlation exists between stathmin, DNA-PKCS , p53(MUT) overexpression and its transcriptional targets, further strengthening the relevance of the new pathway here described. Overall our data support the hypothesis that the expression of stathmin and p53 could be useful for the identification of high risk patients that will benefit from a therapy specifically acting on mitotic cancer cells.