Disconnected interacting protein 2 homolog A (DIP2A) is highly expressed in nervous system and respiratory system of developing embryos. However, genes regulated by Dip2a in developing brain and lung have not been systematically studied. Transcriptome of brain and lung in embryonic 19.5 day (E19.5) were compared between wild type and Dip2a-/- mice. An average of 50 million reads per sample was mapped to the reference sequence. A total of 214 DEGs were detected in brain (82 up and 132 down) and 1900 DEGs in lung (1259 up and 641 down). GO enrichment analysis indicated that DEGs in both Brain and Lung were mainly enriched in biological processes 'DNA-templated transcription and Transcription from RNA polymerase II promoter', 'multicellular organism development', 'cell differentiation' and 'apoptotic process'. In addition, COG classification showed that both were mostly involved in 'Replication, Recombination, and Repair', 'Signal transduction and mechanism', 'Translation, Ribosomal structure and Biogenesis' and 'Transcription'. KEGG enrichment analysis showed that brain was mainly enriched in 'Thyroid cancer' pathway whereas lung in 'Complement and Coagulation Cascades' pathway. Transcription factor (TF) annotation analysis identified Zinc finger domain containing (ZF) proteins were mostly regulated in lung and brain. Interestingly, study identified genes Skor2, Gpr3711, Runx1, Erbb3, Frmd7, Fut10, Sox11, Hapln1, Tfap2c and Plxnb3 from brain that play important roles in neuronal cell maturation, differentiation, and survival; genes Hoxa5, Eya1, Errfi1, Sox11, Shh, Igf1, Ccbe1, Crh, Fgf9, Lama5, Pdgfra, Ptn, Rbp4 and Wnt7a from lung are important in lung development. Expression levels of the candidate genes were validated by qRT-PCR. Genome wide transcriptional analysis using wild type and Dip2a knockout mice in brain and lung at embryonic day 19.5 (E19.5) provided a genetic basis of molecular function of these genes.

Acute lymphoblastic leukemia is marked by aberrant transcriptional features that alter cell differentiation, self-renewal, and proliferative features. We sought to identify the transcription factors exhibiting altered and subtype-specific expression patterns in B-ALL and report here that SOX11, a developmental and neuronal transcription factor, is aberrantly expressed in the ETV6-RUNX1 and TCF3-PBX1 subtypes of acute B-cell leukemias. We show that a high expression of SOX11 leads to alterations of gene expression that are typically associated with cell adhesion, migration, and differentiation. A high expression is associated with DNA hypomethylation at the SOX11 locus and a favorable outcome. The results indicate that SOX11 expression marks a group of patients with good outcomes and thereby prompts further study of its use as a biomarker.

Purpose: Our purpose is to report a patient with primary unilateral ciliary body marginal zone lymphoma who initially presented with hemorrhagic hypopyon. Methods: Retrospective review of the clinical, imaging, and immunohistopathological features of the case was performed. Results: A 59-year-old man was referred with right anterior uveitis of unknown etiology which was unresponsive to systemic treatment. Slit-lamp biomicroscopy showed normotensive hemorrhagic hypopyon in that eye. Anterior segment ultrasound biomicroscopy revealed an iridociliary mass lesion. Because an anterior chamber paracentesis was noncontributory, a diagnostic cyclectomy was performed. Histopathological evaluation showed that the neoplastic cells were positive for CD20, lambda light chain, and BCL 2. BCL 6, CD10, CD5, SOX11, kappa, and Cyclin D1 stains were negative. The final diagnosis was extranodal marginal zone lymphoma of the ciliary body. Conclusions: Although rare, ciliary lymphoma may be a cause of intractable anterior uveitis. Repeat biopsies could be carried out when there is a high level of clinical suspicion.

Keywords: Ciliary body; hyphema; lymphoma; pseudohypopyon.

The role of DNA methylation in β-cell neogenesis is poorly understood. We report that during the process of induced cell reprogramming, methylation content of the Ngn3 and Sox11 genes are diminished. These findings emphasise DNA methylation is a barrier in β-cell regeneration in adulthood, a well described pathophysiological phenomenon of major significance in explaining β-cell deficiency in diabetes in the adult pancreas.

Mesenchymal stem cell (MSC) transplantation is an effective periodontal regenerative therapy. MSCs are multipotent, have self-renewal ability, and can differentiate into periodontal cells. However, senescence is inevitable for MSCs. In vitro, cell senescence can be induced by long-term culture with/without cell passage. However, the regulatory mechanism of MSC senescence remains unclear. Undifferentiated MSC-specific transcription factors can regulate MSC function. Herein, we identified the regulatory transcription factors involved in MSC senescence and elucidated their mechanisms of action. We cultured human MSCs (hMSCs) with repetitive cell passages to induce cell senescence and evaluated the mRNA and protein expression of cell senescence-related genes. Additionally, we silenced the cell senescence-induced transcription factors, GATA binding protein 6 (GATA6) and SRY-box 11 (SOX11), and investigated senescence-related signaling pathways. With repeated passages, the number of senescent cells increased, while the cell proliferation capacity decreased; GATA6 mRNA expression was upregulated and that of SOX11 was downregulated. Repetitive cell passages decreased Wnt and bone morphogenetic protein (BMP) signaling pathway-related gene expression. Silencing of GATA6 and SOX11 regulated Wnt and BMP signaling pathway-related genes and affected cell senescence-related genes; moreover, SOX11 silencing regulated GATA6 expression. Hence, we identified them as pair of regulatory transcription factors for cell senescence in hMSCs via the Wnt and BMP signaling pathways.

Keywords: BMP; Cell senescence; GATA6; Mesenchymal stem cells; SOX11; Wnt.

Background Ventilator-induced lung injury (VILI) is the most common complication in the mechanical ventilation in clinic. The pathogenesis of VILI has not been well understood. The SRY related High Mobility Group box group-F family member 11(Sox11) is a protein associated with lung development. The focal adhesion kinase(FAK) is a cytoplasmic tyrosine kinase and is regulated by Sox11. The present study, therefore, was undertaken to explore the potential role of Sox11 and FAK in VILI. Methods High volume mechanical ventilation(HMV) was used to establish mouse VILI model under anesthesia. The lung injury was evaluated by analyzing the lung weight, bronchoalveolar lavage fluid, histopathological changes and apoptosis of the lung. The Sox11 and FAK expressions in the lung were investigated by real-time qPCR, western blot and immunohistochemistry analysis. Results HMV induced VILI simultaneously companied with decreased expressions of Sox11 and FAK in alveolar epithelial and interstitial cells either in gene and protein levels. Transfection of Sox11 plasmid significantly upregulated expressions of Sox11 and FAK in gene and protein levels in the lung and particularly effectively alleviated VILI. Furthermore, FAK antagonism by PF562271(FAK antagonist) blocked the alleviating effect of Sox11 plasmid transfection on the VILI. Conclusion The dysregulation in the Sox11 and FAK after HMV play an important role in the pathogenesis of VILI, and facilitating the activity of Sox11and FAK might be an effective target and potential option in the prevention and treatment of VILI in clinic.

OBJECTIVE

The present study aimed to identify novel useful clinical biomarker at early stages and to elucidate the molecular background of carcinogenesis in human pancreatic ductal adenocarcinomas (PDACs).

METHODS

Proteomes of dissected PDACs and adjacent nontumor pancreatic tissues from formalin-fixed and paraffin-embedded sections from 10 patients were analyzed using QSTAR Elite liquid chromatography-tandem mass spectrometry, ProteinPilot Software, and Ingenuity Pathway Analysis. Expression of potential biomarker candidates was validated immunohistochemically in 50 PDAC patients, followed by survival analyses and statistical comparison of protein expression with clinicopathologic variables.

RESULTS

Eight hundred five proteins displaying significant quantitative changes were identified in human PDACs by liquid chromatography-tandem mass spectrometry. Based on altered expression of downstream molecules, Ingenuity Pathway Analysis predicted up-regulation and/or activation of nuclear factor β-catenin, SOX11, enolase 1, NFE2L2, SP1, SMAD1, SMAD2, SMAD3, SMAD4, HIF-1, and others. From proteome analysis, paraneoplastic Ma antigen-like 1 was selected as a potential biomarker of human PDAC. Furthermore, paraneoplastic neuronal Ma antigen-like 1 immunohistochemical evaluation in 50 PDAC patients revealed that its positive expression was significantly associated with the better overall survival (log-rank test; P = 0.009) and histological differentiation of PDACs (well, moderate, and poor; P = 0.027) as compared with patients with negative expression.

CONCLUSIONS

Paraneoplastic Ma antigen-like 1 is suggested as a novel potential clinically useful prognostic biomarker for patients with PDAC.

Members of the Sox gene family play crucial roles during reproduction and development, but their genome-wide identification has not yet been performed in large yellow croaker, Larimichthys crocea. In this study, a total of 26 members of the Sox gene family were identified from the genome of large yellow croaker and classified into seven subgroups based on the conserved HMG-box domain they contain. Among the identified Sox gene family members, eight belonged to the SoxB subgroup (five in B1 and three in B2), four belonged to the SoxC subgroup, four belonged to the SoxD subgroup, six belonged to the SoxE subgroup, three belonged to the SoxF subgroup, and one belonged to the SoxK subgroup. During evolution, members of the SoxE subgroup (Sox8, Sox9, Sox10), Sox1, Sox4, Sox6, and Sox11 evolved into two copies, which may be a result of teleost-specific whole-genome duplication. Sox genes were distributed unevenly across 15 chromosomes. The number of introns in large yellow croaker Sox genes varied from 0 to 14. Results of the expression profile during embryogenesis revealed that most of the members of the Sox gene family had lower expression, except several Sox genes, and expression patterns also differed among each Sox gene group and duplicated gene. This study systematically characterized and analyzed the Sox gene family in large yellow croaker and provided new insights into its function during embryogenesis.

Background: Severe congenital ophthalmological malformations and glaucoma might be an important occasional feature in patients with Coffin-Siris syndrome (CSS), especially Coffin-Siris syndrome 9 (CSS9, OMIM #615866) caused by SOX11 mutation. Recently, primary (open-angle) glaucoma was described in two children with the most common form of Coffin-Siris syndrome, CSS1 (OMIM #135900) by ARID1B (AT-rich interaction domain-containing protein 1B) gene mutation. In this article, we present the first report of glaucoma with Coffin-Siris syndrome 9 as well as the first report of secondary glaucoma with any form of Coffin-Siris syndrome. These findings indicate that secondary glaucoma is an occasional finding in patients with Coffin-Siris syndrome.

Case presentation: A child with secondary childhood glaucoma and additional ocular manifestations was evaluated and treated at the childhood glaucoma centre in Mainz, Germany. Examination under general anaesthesia revealed ocular anterior segment dysgenesis (ASD) (Peters type iridocorneal dysgenesis) in combination with congenital limbal stem cell deficiency (LSCD), aniridia, and cataract. The patient also had multiple other congenital anomalies and severe developmental delay. To explain his combination of anomalies, molecular genetic analysis from peripheral blood was performed in late 2018 and early 2019. Following normal findings with a panel diagnostic of 18 genes associated with congenital glaucoma, whole exome sequencing was performed and revealed a novel likely pathogenic heterozygous variant c.251G>T, p.(Gly84Val) in the SOX11 gene (SRY-related HMG-box gene 11). The variant had occurred de novo. Thus, the multiple congenital anomalies and developmental delay of the patient represented Coffin-Siris syndrome 9 (CSS9, OMIM #615866).

Conclusions: When eye diseases occur in combination with other systemic features, genetic analysis can be seminal. Results indicate that glaucoma is an occasional feature of patients with Coffin-Siris syndrome. As early treatment may improve the visual outcome of patients with glaucoma, we suggest that patients with Coffin-Siris syndrome should receive specific ophthalmological screening.

Keywords: Aniridia; Anterior segment dysgenesis; Case report; Coffin-Siris syndrome; Coffin-Siris syndrome 9; Peters anomaly; SOX11 gene; Secondary childhood glaucoma.

Objective: To explore the expression and prognostic significance of miR-223 in patients with mantle cell lymphoma (MCL) and to investigate the possible mechanism. Methods: Twenty-one newly diagnosed MCL patients with bone marrow involvement were enrolled in the present study, 20 healthy donors as normal control. The expression level of miR-223 and SOX11 mRNA was determined by RQ-PCR. CCK-8 and flow cytometer assays were used to analyze cell proliferation, cell cycle and apoptosis of the constructed miR-223 overexpressing MCL cell line, Granta519 cells. SOX11 protein expression level was determined by Western blot. The target gene of miR-223 was confirmed by dual luciferase reporter assay. Results: ①Of the 21 newly diagnosed MCL patients, 15 were male and 6 female, the median age was 58 (37-72) years. The expression level of miR-223 was significantly down regulated in MCL patients compared with that of healthy donors (14.7±10.5 vs 1 244.1±1 935.2, P<0.001). The lower expression of miR-223 was inversely correlated with high-risk mantle international prognostic index (P=0.001), elevated LDH (P=0.001), ECOG score ≥2 (P=0.035). ②Using the median relative expression level of miR-223 as the cutoff value, 21 MCL patients were divided into high-expression group (n=10) and low-expression group (n=11) and found that the high-expression group had a significantly superior OS (median OS: 36 vs 12 months, P=0.021). ③In vitro results showed that compared with the control group, the proliferation of miR-223 overexpressed Granta519 cells was inhibited (the most significant reduction on 96h, P<0.001), manifested by lower proportion of cells in G2/M phase (P<0.001) and increased apoptosis (P<0.001), and the expression level of SOX11 protein in Granta519 cells was significantly lower than that of the control group. ④miR-223 could inhibited the 3' untranslated region of SOX11, and the expression level of miR-223 was significantly negatively correlated with mRNA level of SOX11 in MCL patients (r=-0.81, P<0.001). Conclusions: The expression of miR-223 was repressed in MCL and was associated with poor clinical outcomes, which may be probably attributed to its direct targeting SOX11.

Cyclin D1 protein expression in lymphocytes is classically associated with mantle cell lymphoma. Although increasingly recognized in other lymphoproliferative disorders, cyclin D1 expression and CCND1 gene abnormalities have not been well studied in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Using a double stain for CD20/cyclin D1, we quantified cyclin D1 expression in 10 cases of NLPHL and correlated those findings with SOX11 expression, CCND1 gene abnormalities, and clinical data. For comparison, we examined 5 cases of T cell-/histiocyte-rich large B-cell lymphoma (THRLBCL). All cases of NLPHL stained for cyclin D1 showed at least rare positivity in lymphocyte-predominant (LP) cells. In 4 cases, at least 20% of LP cells were positive for CD20/cyclin D1. Neither SOX11 expression nor CCND1 gene rearrangement was found in any of the cases, but fluorescence in situ hybridization showed a proportion of the large cells with 3 to 4 copies of nonfused IGH and CCND1 signals or 3 intact CCND1 break-apart signals. Further study with CCND1/CEP11 showed polysomy in 6 of 9 cases with cyclin D1 expression and 5 of 16 NLPHL not examined for cyclin D1. Two of 5 cases of THRLBCL showed rare positive staining for CD20/cyclin D1; 1 case showed polysomy with CCND1/CEP11. Results show that cyclin D1 may be expressed in LP cells without SOX11 expression or CCND1 translocation. Polysomy with increased copies of CCND1 may account for cyclin D1 expression in some cases. Cyclin D1 expression is not useful for distinguishing NLPHL from THRLBCL and has no apparent clinical significance in NLPHL.

The main cause of death in mantle cell lymphoma (MCL) patients is relapse due to undetermined minimal residual disease (MRD) and therefore monitoring MRD is crucial for making the best treatment decisions. The gold standard method for MRD analysis is the quantitative polymerase chain reaction. The most commonly used molecular markers for measuring MRD in MCL are: t(11;14)(q13;p32) translocation or CCND1 expression and IGH rearrangement. Such markers can, however, be found in other B cell non-Hodgkin lymphomas. Recent studies demonstrate that SOX11 expression is highly specific for MCL and could be used as a marker for measuring MRD. Moreover, evidence shows that SOX11 level could be predictive for overall survival (OS) and progression-free survival (PFS). We have measured MRD level in follow-up samples from 27 patients diagnosed with MCL using the molecular markers: t(11;14), IGH rearrangement and SOX11 expression. We compared all markers by their sensitivity, utility and quantitative range. We also examined the predictive value of SOX11 expression for OS and PFS. SOX11 expression was found to have better specificity, quantitative range and utility than the t(11;14). The predictive value of SOX11 expression was confirmed. At diagnosis, patients with high SOX11 expression had shorter PFS than patients with low SOX11 expression (p = 0.04*); differences between OS being statistically insignificant. To our best knowledge this is a first study comparing SOX11 with t(11;14) and IGH rearrangement as markers of MRD level. Moreover, in this study we confirmed that SOX11 is useful in cases when other molecular markers cannot be used.

In this issue of Neuron, Welsbie et al. (2017) and Norsworthy et al. (2017) implicate the transcription factor Sox11 as a key player after optic nerve injury-in DLK signaling of RGC cell death, and in RGC regeneration and survival but only in certain RGCs.

Objective: Investigate the expression of SRY-related HMG box 11 (SOX11) and paired box domain 5 (PAX5) in patients with mantle cell lymphoma (MCL) and analyze the relationship between them and their clinical significance.

Methods: Seventy-six formalin-fixed paraffin-embedded (FFPE) samples of patients who were diagnosed with MCL from January 2012 to August 2017 were collected．Fifty-six FFPE samples from patients with diffuse large B cell lymphoma (DLBCL), thirty-eight FFPE samples from patients with follicular lymphoma (FL) and nine FFPE samples from patients with Burkitt's lymphoma (BL) were used as control groups. Real-time quantitative PCR (qRT-PCR) and immunohistochemistry were used to detect the mRNA and protein expressions of SOX11 and PAX5. The association between expressions of SOX11 and PAX5 in patients with MCL was analyzed. On the basis of the median H score of SOX11 and PAX5 protein expressions in patients with MCL, they were divided into high and low expression group, and the relationship between the different groups and patients' clinical characteristics and prognosis were analyzed.

Results: The different mRNA expression levels of SOXPAXP<0.01). The mRNA expression levels of SOXPAXP<0.01). However, the differences of those between MCL and BL were not significant ( P>0.05). The expression level of SOX11 protein was also higher than those of the control groups ( P<0.000 1). However, there was no significant difference in PAX5 protein expression level between the MCL group and the control group, nor the expression levels of SOX11 and PAX5 genes and proteins among the control groups ( P>0.05). By analyzing the samples from patients with MCL, we observed a positive relevance between SOX11 and PAX5 both in mRNA expression level ( r _s=0.714, P<0.000 1) and protein expression level ( G=0.407, P=0.01). There was no difference in clinical characteristics and overall survival between the high and low expression group.

Conclusion: In MCL, there was a positive relevance between the expressions of SOX11 and PAX5. The expression of SOX11 or PAX5 alone has no significant effect on the prognostic stratification of MCL patients.

Keywords: Mantle cell lymphoma; PAX5; Prognosis; SOX11.

SOX transcription factors play an irreplaceable role in biological developmental processes. Sox genes have been identified in a wide variety of species; however, their identification and functional analysis in the genome of the Chinese soft-shell turtle (Pelodiscus sinensis) have not been performed. In the present study, the Chinese soft-shell turtle genome was found to contain 17 Sox genes, which were categorized into seven groups according to their phylogenetic relationships. Gene structure and protein motif analysis of the Sox genes showed that within the same phylogenetic group, their exon-intron number and motif structure of the Sox family were relatively conserved, but diverged in the comparison between different groups. Sexual dimorphism expression analysis for the Sox genes displayed that Sox8 and Sox9 were upregulated in the testis, while Sox3, Sox7, Sox11, and Sox13 were upregulated in the ovary. A correlation network analysis of SOX transcription factors with their target genes analysis showed that Sox3 correlated negatively with Sox9 and gata4. Sox11 and Sox7 correlated negatively with gata4. Sox8 and Sox9 correlated positively with gata4. Therefore, the genome-wide identification and functional analysis of the Sox gene family will be useful to further reveal the functions of Sox genes in the Chinese soft-shell turtle.

The apoptotic cascade is an orchestrated event, whose final stages are mediated by effector caspases. Regulatory binding proteins have been identified for caspases such as caspase-3, -7, -8, and -9. Many of these proteins belong to the inhibitor of apoptosis (IAP) family. By contrast, caspase-6 is not believed to be influenced by IAPs, and little is known about its regulation. We therefore performed a yeast-two-hybrid screen using a constitutively inactive form of caspase-6 for bait in order to identify novel regulators of caspase-6 activity. Sox11 was identified as a potential caspase-6 interacting protein. Sox11 was capable of dramatically reducing caspase-6 activity, as well as preventing caspase-6 self- cleavage. Several regions, including amino acids 117-214 and 362-395 within sox11 as well as a nuclear localization signal (NLS) all contributed to the reduction in caspase-6 activity. Furthermore, sox11 was also capable of decreasing other effector caspase activity but not initiator caspases -8 and -9. The ability of sox11 to reduce effector caspase activity was also reflected in its capacity to reduce cell death following toxic insult. Interestingly, other sox proteins also had the ability to reduce caspase-6 activity but to a lesser extent than sox11.

The t(11;14)(q13;q32) translocation is the most common chromosomal translocation in plasma cell myeloma (PCM), but the cytogenetic and immunophenotypic features of PCM with t(11;14)(q13;q32) remain to be fully elucidated. To address the issue, we retrospectively analyzed 21 newly diagnosed PCM patients with the t(11;14)(q13;q32) translocation in our institute. CD20 is a B-cell-specific transmembrane protein that is the topic of much focus as a potential target in immunotherapy. We observed a low incidence of CD20 expression (2 of 21 patients, 11%), although the expression of CD20 was previously reported to be associated with t(11;14)(q13;q32). PAX5 is an essential transcriptional factor involved in B-cell development and commitment, and is down-regulated upon plasma cell differentiation. We observed one patient (6%) with expression of PAX5. The expression of CD19, CD56, and CD138 was detected in one (0.7%), nine (60%), and 13 patients (87%), respectively. Cyclin D1, CD38, and BCL2 were detected in all patients; on the other hand, neither BCL6 nor SOX11 was detected in any of the evaluated patients. Abnormalities of chromosome 13 were detected in six patients (38%), but deletion of TP53 was not observed in any of the evaluated patients. Our results suggest the absence of BCL6 and SOX11 expression, and infrequent expression of CD20, PAX5, and CD56 in PCM with t(11;14)(q13;q32), in contrast to the findings of earlier reports.

Interstitial deletions within the chromosomal region 2q24.2 have already been linked to intellectual disability (ID) in the past. In most cases the described patients showed a syndromic form of ID associated with large deletions containing multiple genes. Here we describe a family with two siblings with mild non-syndromic ID. They shared the same 564 kb deletion in the chromosomal region 2q24.2 containing only the TANK gene, which was inherited from the similarly affected father, thus suggesting haploinsufficiency of TANK as a novel cause of non-syndromic ID. TANK encodes the TRAF family member-associated NF-kappa-B activator (OMIM #603893), which is expressed in many tissues. It functions as an adapter protein that interacts with the NF-kappa-B pathway and SOX11, an essential transcription factor in regeneration, survival and differentiation of the neuronal system. TANK has not been linked to ID or other human diseases before. To further elucidate the role of TANK in non-syndromic ID, we screened a cohort of 288 TANK deletion negative non-syndromic mental retardation patients for TANK mutations without identifying any pathogenic variant.

Follicular lymphoma is composed of clonal germinal center B cells. It shows a follicular pattern lacking mantle zones, with a network of interfollicular dendritic cells. Transformation to more aggressive lymphomas is documented, but the only connections to mantle cell lymphoma are described cases of composite lymphoma consisting of these 2 entities. We discuss here a case of a lymph node harboring CD20, CD10, BCL2, BCL6, cyclin D1, CD5, Ki67, and SOX11 with CD21, showing an almost intact network of dendritic cells in one part of a lymph node, and CD20, CD5, SOX11, BCL6, cyclin D1, CD10, Ki67, and CD21 cells restricted to the mantle area in another part of the same lymph node. Both parts of the lymph node had BCL2 rearrangement, a lack of t(11:14)(q13;q32), the presence of SOX11 expression, and the same clonal band. The described case suggests heterogenous development of small cell lymphomas and indicates the possibility of differentiation regression.