Normal Thymic Tissue Research Articles

Focal adhesion kinase is overexpressed in thymic epithelial tumors and may serve as an independent prognostic biomarker.

Focal adhesion kinase (FAK) has long been considered to be a key regulator of growth factor receptor- and integrin-mediated signals, with pivotal roles in tumor cells through its kinase activity and scaffolding function. Increased FAK expression and activity has been observed in tumors of various origins and is often associated with a poor prognosis. However, there have been no studies on the aberrant expression of FAK in thymic epithelial tumors to date. The aim of the present study was to evaluate FAK expression in thymic epithelial tumors and to explore the prognostic significance of FAK. FAK expression was investigated in 100 formalin-fixed, paraffin-embedded human thymic epithelial tumor (TET) specimens using immunohistochemical analysis with FAK-specific monoclonal antibody 4.47, and the associations between FAK expression and clinicopathological parameters (including sex, age, tumor size, myasthenia gravis, World Health Organization classification and Masaoka-Koga stage) were analyzed. FAK was significantly overexpressed in TETs compared with in normal thymus tissues (P<0.001). Additionally, FAK overexpression was significantly associated with advanced tumor stages (stages III or IV; P<0.001) and highly aggressive TET subtypes (type B2 and B3 thymomas and thymic carcinomas; P<0.001). Furthermore, FAK overexpression was significantly associated with a worse 10-year overall survival, as determined by univariate analysis (P<0.001). Multivariate analysis revealed that FAK overexpression was an independent prognostic factor for patients with TETs (P=0.034). The results of the present study suggest that FAK serves an important role in the tumorigenesis and progression of TETs. Therefore, FAK may serve as a prognostic biomarker and is a potential therapeutic target for the treatment of TETs.

Wnt4 overexpression promotes thymoma development through a JNK-mediated planar cell polarity-like pathway.

Thymoma is the most common neoplasm of the anterosuperior mediastinum. Activation of the Wnt signaling pathway has a role in a variety of human cancers. The present objective was to examine c-Jun N-terminal kinase (JNK) mRNA and protein expression in thymoma cells undergoing apoptosis subsequent to downregulation of Wnt4. Wnt4 and JNK mRNA and protein expression was analyzed by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry, respectively, in 15 thymoma tissues and 6 thymus cyst tissues. Thymoma cells were cultured and transfected with shRNA plasmids targeting the Wnt4 gene. Wnt4 and JNK protein expression was detected by western blot analysis. Apoptosis was analyzed using Wright-Giemsa staining, Hoechst-33342/propidium iodine double staining and flow cytometry. The results showed that Wnt4 and JNK mRNA and protein expression were significantly increased in thymoma compared with normal thymus tissue. Subsequent to transfection, thymoma Wnt4 and JNK mRNA and protein expression were significantly decreased in shRNA-treated groups, with the strongest inhibition being 52.37%. Characteristic apoptotic morphological changes were observed and apoptosis increased. Overall, the present concluded that Wnt4 has an important role in thymoma development, which appears to be activated through a JNK mediated planar cell polarity-like pathway.

Thymic hyperplasia causing right ventricular outflow tract compression following treatment for oesophageal rupture in an Arabian colt

SummaryTrue thymic hyperplasia has been reported sporadically in the human literature as an immunological rebound phenomenon following immunosuppressive treatment or disease. There are limited accounts in domestic species, mainly following vaccination, and thymic hyperplasia has not been a recognised condition in the horse to date. This report details a case of true thymic hyperplasia in a 10‐week‐old Arabian colt diagnosed by histopathology of core biopsy samples. The colt developed pulmonary stenosis caused by compression due to a space occupying lesion in the cranial mediastinum following a 3‐month history of hospitalisation for treatment of traumatic oesophageal rupture with perioesophageal abscess formation. Diagnostic imaging of the cranial mediastinum was indicative of a thymic mass, and histopathology confirmed the mass was normal (hyperplastic) thymic tissue. The colt was treated with a tapering dose of corticosteroids, which led to involution of the hyperplastic tissue and resolution of pulmonary artery compression. Thymic hyperplasia may be an unrecognised sequela to chronic inflammation in horses and was only identified in this case when the size was sufficient to compress right cardiac outflow.

Analysis of the expression level and methylation of tumor protein p53, phosphatase and tensin homolog and mutS homolog 2 in N-methyl-N-nitrosourea-induced thymic lymphoma in C57BL/6 mice.

Tumorigenesis is often caused by somatic mutation or epigenetic changes in genes that regulate aspects of cell death, proliferation and survival. Although the functions of multiple tumor suppressor genes have been well studied in isolation, how these genes cooperate during the progression of a single tumor remains unclear in numerous cases. The present study used N-methyl-N-nitrosourea (MNU), one of the most potent mutagenic nitrosourea compounds, to induce thymic lymphoma in C57BL/6J mice. Subsequently, the protein expression levels of phosphatase and tensin homolog (PTEN), transformation protein 53 and mutS homolog 2 (MSH2) were evaluated concomitantly in the thymus, liver, kidney and spleen of MNU-treated mice by western blotting. To determine whether changes in expression level were due to aberrant epigenetic regulation, the present study further examined the methylation status of each gene by MassARRAY analysis. During the tumorigenesis process of an MNU-induced single thymic lymphoma, the expression level of PTEN was revealed to be reduced in thymic lymphoma samples but not in normal or non-tumor thymus tissue samples. Furthermore, a marked reduction of P53 expression levels were demonstrated in thymic lymphomas and spleens with a metastatic tumor. Conversely, MSH2 upregulation was identified only in liver, kidney, and spleen samples that were infiltrated by thymic lymphoma cells. Furthermore, the present study revealed that a number of 5'-C-phosphate-G-3' sites located in the promoter of aberrantly expressed genes had significantly altered methylation statuses. These results improve the understanding of the course of mutagen-induced cancer, and highlight that epigenetic regulation may serve an important function in cancer.

Thymus ectopique : une cause rare de tuméfaction cervicale chez le nourrisson

Ectopic cervical thymus (ECT) is a rare embryological abnormality in children. It can be revealed by a compressive neck mass mistaken for a malignant tumor. Through a new case of ECT, we review the embryopathogenesis, diagnostic difficulties and therapeutic features. A 19-month-old girl presented a right cervical mass that quickly increased in size, causing intermittent dyspnea. The physical examination objectified a 6-cm, soft and compressible, painless right cervical tumefaction, extending from the mastoid area to the ipsilateral supraclavicular fossa. The diagnosis suggested based on CT was a cervicomediastinal cystic lymphangioma. The diagnoses discussed based on MRI were a collection of necrotic lymphadenopathy, rhabdomyosarcoma or neurofibroma debris. The mass was surgically excised through a laterocervical incision. A whitish multilobular tissular mass was found, adherent to the neurovascular axis of the neck. Pathological examination concluded in normal ectopic thymus tissue. The postoperative course was uneventful. Although ECT is a rare benign anomaly, it should be considered as a possible cause of a neck mass in children. Surgery is the curative treatment. Before surgery, the presence of a mediastinal thymus must be confirmed to avoid the risk of a total thymectomy in children. MRI is helpful in delineating thymic ectopia compared to the mediastinal thymus.

Thymic Epithelial Tumors phenotype relies on miR-145-5p epigenetic regulation

BackgroundThymoma and thymic carcinoma are the most frequent subtypes of thymic epithelial tumors (TETs). A relevant advance in TET management could derive from a deeper molecular characterization of these neoplasms. We previously identified a set of microRNA (miRNAs) differentially expressed in TETs and normal thymic tissues and among the most significantly deregulated we described the down-regulation of miR-145-5p in TET. Here we describe the mRNAs diversely regulated in TETs and analyze the correlation between these and the miRNAs previously identified, focusing in particular on miR-145-5p. Then, we examine the functional role of miR-145-5p in TETs and its epigenetic transcriptional regulation.MethodsmRNAs expression profiling of a cohort of fresh frozen TETs and normal tissues was performed by microarray analysis. MiR-145-5p role in TETs was evaluated in vitro, modulating its expression in a Thymic Carcinoma (TC1889) cell line. Epigenetic transcriptional regulation of miR-145-5p was examined by treating the TC1889 cell line with the HDAC inhibitor Valproic Acid (VPA).ResultsStarting from the identification of a 69-gene signature of miR-145-5p putative target mRNAs, whose expression was inversely correlated to that of miR-145-5p, we followed the expression of some of them in vitro upon overexpression of miR-145-5p; we observed that this resulted in the down-regulation of the target genes, impacting on TETs cancerous phenotype. We also found that VPA treatment of TC1889 cells led to miR-145-5p up-regulation and concomitant down-regulation of miR-145-5p target genes and exhibited antitumor effects, as indicated by the induction of cell cycle arrest and by the reduction of cell viability, colony forming ability and migration capability. The importance of miR-145-5p up-regulation mediated by VPA is evidenced by the fact that hampering miR-145-5p activity by a LNA inhibitor reduced the impact of VPA treatment on cell viability and colony forming ability of TET cells. Finally, we observed that VPA was also able to enhance the response of TET cells to cisplatin and erlotinib.ConclusionsAltogether our results suggest that the epigenetic regulation of miR-145-5p expression, as well as the modulation of its functional targets, could be relevant players in tumor progression and treatment response in TETs.

Pathological Findings in Myasthenia Gravis Patients with Thymic Hyperplasia and Thymoma.

Thymectomy is routinely carried out in patients with myasthenia gravis (MG) and thymomas. However, there is still a dispute as to whether MG patients with thymic hyperplasia should undergo thymectomy. We aimed to investigate the pathological findings in the thymus in patients with co-existing MG and thymic hyperplasia or thymomas treated with thymectomy, as well as effects of immunosuppression. Thirty-three patients with MG were selected and grouped accordingly: patients with no thymic abnormalities, patients with thymic hyperplasia, and patients with thymomas. All patients were treated with methylprednisolone alongside immunosuppression. A separate cohort of 24 MG patients with thymic hyperplasia or thymomas and treated with thymectomy were selected. As controls, 5 patients with thymomas or thymic carcinoma without MG were selected. Expression of CD5, extracellular regulated protein kinases1/2 mitogen activated protein kinase (ERK1/2MAPKs) and CD95 ligand (FasL) in the thymus was examined. Methylprednisolone and immunosuppressive therapy are highly effective in MG patients with normal thymus tissue and MG patients with thymic hyperplasia compared to MG patients with thymomas alone. CD5 expression was highest in MG patients with thymic hyperplasia, correlating with expression of ERK1/2MAPKs. FasL expression was similar across all groups. Thymomas may be distinguished from thymic hyperplasia by expression of CD5 and ERK1/2MAPKs. Thymectomy is the preferred treatment for MG patients with thymomas but may not be necessary in MG patients with thymic hyperplasia who are treated with immunosuppressive therapy.

CD4+ FoxP3+ T regulatory cell subsets in myasthenia gravis patients

Although myasthenia gravis (MG) is a classic autoantibody-mediated disease, T cells are centrally involved in its pathogenesis. In recent years a number of studies have analyzed the role of CD4+ FoxP3+ regulatory T cells (Treg) in the disease with contradictory results. Here, the generation of Treg was significantly reduced in thymoma as compared to thymic hyperplasia and normal thymus tissue (p=0.0002). In the peripheral blood, Treg subsets classified according to CD49d, HELIOS and CD45RA expression changed after thymectomy and in the long-term course of immunosuppression. Compared to healthy volunteers the frequency of CD45RA+FoxP3low Treg was reduced in MG patients in general (p=0.037) and in particular in patients without immunosuppression (p=0.036). In our study, thymectomy and immunosuppressive treatment were associated with changes in Treg subpopulations. The reduced frequency of CD45RA+FoxP3low Treg we observed in MG patients might play a role in MG pathogenesis.

Resolution of primary hyperparathyroidism following surgical removal of cervical thymus

Recent research has emphasized the capacity of thymus cells of producing parathyroid hormone (PTH) if adequately stimulated, and have investigated the role of the so-called “thymic PTH”, produced by the medullary thymic epithelial cells (m-TECs). To the best of our knowledge, only a single case of well-documented PTH secretion from a thymoma causing primary hyperparathyroidism (PHTP) has been reported in the literature so far. We report here the case of a female patient with PHTP who underwent neck exploration for a suspected parathyroid adenoma. After surgery, a normalization of serum PTH concentration was observed, but the histological examination of the surgically excised mass revealed exclusively normal thymus tissue. The present case provides additional evidence of PHTP caused by an ectopic thymus.

Mimics of Neck Lesions in Post Treatment Neck Surveillance

This talk highlights the possible mimics seen in a busy oncology centre during a follow up imaging, especially ultrasound (US) of the neck. Various innocuous findings may be mistaken for recurrent or residual disease causing confusion due to inexperience or an apparent lack of knowledge. All the findings, which may lead to an erroneous diagnosis, have been divided into the following categories. Thyroid and salivary gland abnormalities, nodal, vascular, neurogenic, cartilaginous, bony and soft tissue abnormalities. These include several conditions which mimic metastatic nodes, extra capsular nodal spread, residual lesions of thyroid bed, parathyroid adenomas and a few specific lesions such as Kutteners tumor of submandibular gland. Post operative or foreign body granulomas may mimic soft tissue recurrences or laryngeal neoplasm. In two cases parasitic pathology was identified causing concern for neoplasm. Calcified, necrotic or non necrotic tuberculous lymph nodes also form an important subset due to its high incidence in some countries. Normal thymic and tonsillar tissue also adds to the confusion. These various normal and abnormal findings in Head and Neck cancer follow-up need to be understood by radiologists of various levels of expertise in busy imaging departments.

Elevated Level Expression of MiR-223 Is Associated with Worse Prognosis in Childhood T-Cell Lymphoblastic Lymphoma

Background: No stratification criteria have been established so far for treatment of childhood lymphoblastic T-cell lymphoma (T-LBL). Probability of event-free survival is about 75%, however survival in relapsed patients is very poor. Activating NOTCH1 mutations were reported to be associated with favorable prognosis and it has been demonstrated that in T-cell acute lymphoblastic leukemia miR-223 up-regulates NOTCH1 through negative modulation of FBXW7. We recently identified a miRNA expression profile specific for pediatric T-LBL [Mussolin et al, Leukemia 2014], suggesting that few miRNAs, including miR-223, may play a major role in T-LBL pathogenesis. The prognostic relevance of miR-223 and its correlation with NOTCH1/FBXW7 mutational status and protein expression is still unknown in T-LBL.Objectives: This study aimed to analyze miR-223 expression in a large series of pediatric T-LBL cases and to investigate its relevance in improving risk stratification. In addition, we aimed to the identification of miR-223 direct target genes that could be involved in T-LBL tumourigenesis.Methods: All patients were treated according to international EURO-LB-02 protocol. MiRNA measurements were performed using the TaqMan MicroRNA Assays (Applied Biosystems). Mutational hot spots of NOTCH1 and FBXW7 were amplified using standard polymerase chain reaction conditions and PCR products were sequenced on an ABI-3500 Genetic Analyzer. The expression of NOTCH1 protein was analyzed by Western blotting. Clonogenicity assays in soft agar were performed in the T-LBL cell line SUPT-1 upon transient transfection of miR-223 mimics and in the Jurkat cell line upon inhibition of miR-223.Results: The study was conducted in 65 T-LBL tumor biopsies that were diagnostic specimens obtained from patients for whom complete clinical data were available. NOTCH1 was found mutated in 51% (33/65) of the patients and associated with favorable prognosis (p=0.022), whereas FBXW7 was found mutated in 18% (12/65) of the cases. Interestingly, within NOTCH1 wild-type patients most of cases (65%) displayed active NOTCH1 protein. With respect to miRNA expression, miR-223 was up-regulated up to 400 times in T-LBL compared to normal thymus tissue. Importantly, high miR-223 expression (> median value) was associated with worse prognosis (p=0.006) and, when we combined miR-223 expression levels and NOTCH1 mutational statusas prognostic markers, we observed that miR-223 outweighs the prognostic value of NOTCH1: progression-free survival (PFS) of patients carrying wild-type NOTCH1(NOTCH1WT) and elevated miR-223 was 63% (+10%) vs 80% (+13%) for patients NOTCH1WTwith low miR-223 (p=0.006). In contrast, patients with mutated NOTCH1 (NOTCH1mut) and elevated miR-223 showed a significant inferior PFS compare to those with NOTCH1mutand low level of miR-223 (72%+14 vs 100%). In order to investigate the biological effect of miR-223, we tested whether expression/deletion of miR-223 would affect the clonogenic properties of SUPT-1 and Jurkat cells by measuring their ability to form colonies in soft agar. Interestingly, miR-223 over-expression in SUPT-1 was sufficient to significantly increase the formation of colonies in soft agar, whereas miR-223 abrogation in Jurkat cell line was sufficient to reduce it. Based on miRNA-target predictions, we found salt-inducible kinase 1 (SIK-1) protein an interesting candidate target of miR-223. Transient transfection of miR-223 mimics in SUPT-1 cells showed downregulation of SIK-1 protein at different time-points (24, 48, 72 hrs). SIK-1 is involved in prevention of metastasis in adult solid tumors and we found a significantly different expression level of SIK-1 protein in T-LBL cases based on miR-223 expression level. Of note, all relapsed patients displayed at diagnosis high level of miR-223 and very low level of SIK-1.Conclusions: Our data suggest that miR-223 has a prognostic value in T-LBL patients that appears to outweigh the prognostic value of NOTCH-1 mutational status. In addition, our data suggest that SIK-1 may be a target of miR-223 contributing to a more aggressive tumor phenotype. DisclosuresNo relevant conflicts of interest to declare.

Minimally invasive mediastinal surgery.

In the past, mediastinal surgery was associated with the necessity of a maximum exposure, which was accomplished through various approaches. In the early 1990s, many surgical fields, including thoracic surgery, observed the development of minimally invasive techniques. These included video-assisted thoracic surgery (VATS), which confers clear advantages over an open approach, such as less trauma, short hospital stay, increased cosmetic results and preservation of lung function. However, VATS is associated with several disadvantages. For this reason, it is not routinely performed for resection of mediastinal mass lesions, especially those located in the anterior mediastinum, a tiny and remote space that contains vital structures at risk of injury. Robotic systems can overcome the limits of VATS, offering three-dimensional (3D) vision and wristed instrumentations, and are being increasingly used. With regards to thymectomy for myasthenia gravis (MG), unilateral and bilateral VATS approaches have demonstrated good long-term neurologic results with low complication rates. Nevertheless, some authors still advocate the necessity of maximum exposure, especially when considering the distribution of normal and ectopic thymic tissue. In recent studies, the robotic approach has shown to provide similar neurological outcomes when compared to transsternal and VATS approaches, and is associated with a low morbidity. Importantly, through a unilateral robotic technique, it is possible to dissect and remove at least the same amount of mediastinal fat tissue. Preliminary results on early-stage thymomatous disease indicated that minimally invasive approaches are safe and feasible, with a low rate of pleural recurrence, underlining the necessity of a "no-touch" technique. However, especially for thymomatous disease characterized by an indolent nature, further studies with long follow-up period are necessary in order to assess oncologic and neurologic results through minimally invasive approaches. Furthermore, increased robotic experience and studies, including randomized controlled trials, are needed to validate the findings of the current literature.

Oral 1.04. MicroRNA networks: novel key regulators in thymic epithelial tumors

Thymic epithelial tumors (TET) are the most frequent human primary mediastinal tumors. For invasive and/or relapsing cases no effective treatment regimens have been definied, as relevant pathways are still not known. A biological characterization of the relevant molecules related to the pathogenesis and progression of neoplastic tissue in TET is strongly needed. MicroRNAs (miRNAs) constitute a large group of negative gene regulators playing an important role in carcinogenesis in several tumor systems. Mature miRNAs are single-stranded RNA molecules of 20- to 23-nucleotide (nt) length controlling gene expression in many cellular processes. We recently identified a group of mature miRNAs differentially expressed in tumor versus normal thymic tissues by microarray analysis of 54 formalin-fixed paraffin embedded (FFPE) thymic tumors and 12 normal counterparts. In particular, we found 56 miRNAs that were up-regulated and 31 down-regulated in thymic tumors. We found that a subgroup of these miRNAs was also differentially expressed among the different tumor histotypes. Finally, by bioinformatics analysis we identified molecular pathways whose members are putatively targeted by TET-associated miRNAs and that could impact on TET biology. We performed an Affimetrix-based study on a series of fresh frozen thymoma and normal thymic samples from our series. A deeper characterization of the identified pathways involved in TET carcinogenesis by the identification of the key molecular interactions is in progress. Our preliminary data support a key regulator role of mature miRNA in TET.

Video-assisted transcervical thymectomy for myasthenia gravis.

A 49-year-old female presents with ptosis, diplopia and dysphagia and is diagnosed with myasthenia gravis by electromyography (Figure 1). The patient reports some improvement of her symptoms with pyridostigmine, but due to increasing symptoms, she has been placed on prednisone and mycophenolate mofetil. She is otherwise healthy and takes no other medications. Computed tomography imaging shows normal thymic tissue with no thymoma. She is referred by her neurologist for consideration of thymectomy to treat her myasthenia gravis.

Circulating miR-21-5p and miR-148a-3p as emerging non-invasive biomarkers in thymic epithelial tumors

ABSTRACTThymic epithelial cells give rise to both thymoma and thymic carcinoma. A crucial advance in thymic epithelial tumors (TET) management may derive from the identification of novel molecular biomarkers able to improve diagnosis, prognosis and treatment planning.In a previous study, we identified microRNAs that were differentially expressed in tumor vs normal thymic tissues. Among the microRNAs resulted up-regulated in TET tissues, we evaluated miR-21-5p, miR-148a-3p, miR-141-3p, miR-34b-5p, miR-34c-5p, miR-455-5p as blood plasma circulating non-invasive biomarkers for TET management.We firstly report that the expression levels of specific onco-miRNAs, that we found upregulated in the blood plasma collected from TET patients at surgery, resulted significantly reduced in follow-up samples.This pilot study suggests that circulating miR-21-5p and miR-148a-3p could represent novel non-invasive biomarkers to evaluate the efficacy of therapy and the prognosis of TET.

Slug overexpression is associated with poor prognosis in thymoma patients.

Slug, a member of the Snail family of transcriptional factors, is a newly identified suppressive transcriptional factor of E-cadherin. The present study investigated the expression pattern of Slug in thymomas to evaluate its clinical significance. Immunohistochemistry was used to investigate the expression pattern of the Slug protein in archived tissue sections from 100 thymoma and 60 histologically normal thymus tissue samples. The associations between Slug expression and clinicopathological factors, such as prognosis, were analyzed. Positive expression of Slug was detected in a greater proportion of thymoma samples [51/100 (51%) patients, P<0.001] compared with normal thymus tissues [9/60 (15%) cases]. Of the 100 patients with thymoma, 42 (42%) displayed high levels of Slug expression (high-level group) and 58 (58%) displayed low levels of Slug expression (low-level group). The 10-year survival rate was improved for patients in the low-level group when compared with those in the high-level group (P=0.002). A multivariate analysis using the Cox proportional hazards regression model demonstrated that Slug overexpression was not an independent prognostic factor. In conclusion, the present study demonstrated that Slug overexpression was associated with poor prognosis in patients with thymoma. Therefore, Slug may be a potential diagnostic biomarker and a predictor of poor prognosis in thymoma patients.

Cytoplasm estrogen receptor β5 as an improved prognostic factor in thymoma and thymic carcinoma progression

A number of previous studies have reported that sex steroid hormones, including estrogens, are involved in the regulation of the thymic function. The aim of the present study was to investigate the expression of estrogen receptor β5 (ERβ5) in thymic tumors and the correlation between ERβ5 expression and thymoma biological characteristics. The expression levels of ERβ5 in thymic epithelial tumors was evaluated in 103 patents using immunohistochemical staining and reverse transcription-quantitative polymerase chain reaction. In addition, an indirect immunofluorescence assay was performed to evaluate the ERβ5 expression levels in the TC1889 and T1682 cell lines. The survival outcome was estimated using Kaplan-Meier plots. The results indicated that ERβ5 expression was mainly located in the thymic tumor cell cytoplasm (87.37%; 90/103 cases) and overexpression was observed in thymic tumors compared with normal thymic tissues (P=0.001). Using the Kruskal-Wallis test, a statistically significant association was observed between cytoplasmic ERβ5 (cERβ5) expression and thymic tumor subtypes (P=0.024) and stages (P=0.003 and R=-0.376). The Kaplan-Meier plots revealed that cERβ5 expression was significantly associated with improved overall and progression-free survival (P=0.008 and P=0.004, respectively). The present study suggested that overexpression of cERβ5 may indicate an improved prognosis and may be involved in the underlying mechanism through which estrogen inhibits thymoma and thymic carcinoma development.

Association of B-cell activating factor receptor deficiency with the P21R polymorphism and common variable immunodeficiency

Association of B-cell activating factor receptor deficiency with the P21R polymorphism and common variable immunodeficiency

Cyclin-dependent kinase inhibitors, p16 and p27, demonstrate different expression patterns in thymoma and thymic carcinoma.

The role of cell cycle inhibitors in tumorigenesis has been proven in various neoplasms; however, their roles in thymic tumors are still unclear. We examined the expression of cell cycle inhibitors such as those of the Cip/Kip family (p21, p27, and p57) and the INK-4/ARF family (p16 and p14) in thymoma and thymic carcinoma. Samples from 41 thymoma and 14 thymic carcinoma patients, and 34 normal thymic tissue samples were prepared for the study. Immunohistochemical analysis using antibodies to p21, p27, p57, p16, and p14 was carried out, and the positivity for these inhibitors in each group was estimated in terms of their subcellular location and percentage of cells showing positive staining. Nuclear p27 showed a stepwise decrease (p < 0.0001), and the cytoplasmic p27 showed a stepwise increase (p < 0.0001) in expression level with the increase in malignancy. p16 in both the nucleus and cytoplasm showed a stepwise increase (p < 0.0001) in expression level with the increase in malignancy. However, as for p21, p57, and p14, there was almost no nuclear or cytoplasmic expression in each group. Our findings suggest that low nuclear and high cytoplasmic p27 expression levels, and high nuclear and cytoplasmic p16 expression levels may correlate with the increase in thymic malignancy.

MicroRNA expression profiling of thymic epithelial tumors

BackgroundThymic epithelial tumors (TET) are the most frequent human primary mediastinal tumors in adults. A deep biological characterization of the processes at the basis of the transformed phenotype could strongly improve our understanding of the morphological and clinical heterogeneity of these diseases. MicroRNAs (miRNAs) are non-coding RNAs involved in post-transcriptional regulation and their altered expression accounts for the pathogenesis of several tumors. ObjectivesThe aim of this study was to identify the miRNAs that are differentially expressed in tumor vs normal thymic tissues or among the different tumor histotypes and that could impact on the biology of TET. Materials and methodsmicroRNAs expression profiling was performed by microarray analysis of formalin-fixed paraffin embedded (FFPE) tissue from 54 thymic tumor samples and 12 normal counterparts, derived from two patient cohorts. Results and conclusionWe identified groups of miRNAs differentially expressed between: (i) TET and normal thymic tissues, (ii) thymomas and thymic carcinomas, (iii) histotype groups. Moreover, we identified putative molecular pathways targeted by these differentially expressed miRNAs that could be involved in thymic carcinogenesis and in the maintenance and spreading of this tumor.