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Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1BCSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive webbased survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1BID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features., We are grateful for the assistance of Pepijn Cox in setting up the website www.arid1bgene.com. This study has made use of data generated by the Human Disease Genes website series, www.humandiseasegenes.com. This work was financially supported by grants from the Netherlands Organisation for Health Research and Development (917-86-319 to B.B.A.d.V., 912-12-109 to B.B.A.d.V.)

Idiopathic pulmonary fibrosis (IPF) is the most common and most deadly form of interstitial lung disease. Osteopontin (OPN), a matricellular protein with proinflammatory and profibrotic properties, plays a major role in several fibrotic diseases, including IPF; OPN is highly upregulated in patients' lung samples. In this study, we knocked down OPN in a bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model using small interfering RNA (siRNA) to determine whether the use of OPN siRNA is an effective therapeutic strategy for IPF. We found that fibrosing areas were significantly smaller in specimens from OPN siRNA-treated mice. The number of alveolar macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage fluid was also reduced in OPN siRNA-treated mice. Regarding the expression of epithelial-mesenchymal transition (EMT)-related proteins, the administration of OPN-siRNA to BLM-treated mice upregulated E-cadherin expression and downregulated vimentin expression. Moreover, in vitro, we incubated the human alveolar adenocarcinoma cell line A549 with transforming growth factor (TGF)-beta 1 and subsequently transfected the cells with OPN siRNA. We found a significant upregulation of Col1A1, fibronectin, and vimentin after TGF-beta 1 stimulation in A549 cells. In contrast, a downregulation of Col1A1, fibronectin, and vimentin mRNA levels was observed in TGF-beta 1-stimulated OPN knockdown A549 cells. Therefore, the downregulation of OPN effectively reduced pulmonary fibrotic and EMT changes both in vitro and in vivo. Altogether, our results indicate that OPN siRNA exerts a protective effect on BLM-induced PF in mice. Our results provide a basis for the development of novel targeted therapeutic strategies for IPF.

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.

Coffin-Siris syndrome (CSS) (MIM 135900) is characterized by developmental delay, severe speech impairment, distinctive facial features, hypertrichosis, aplasia or hypoplasia of the distal phalanx or nail of the fifth digit and agenesis of the corpus callosum. Recently, it was shown that mutations in the ARID1B gene are the main cause of CSS, accounting for 76% of identified mutations. Here, we report a 15 year-old female patient who was admitted to our clinic with seizures, speech problems, dysmorphic features, bilaterally big, large thumb, cafe-au-lait (CAL) spots, obesity and hyperinsulinism. First, the patient was thought to have an association of neurofibromatosis and Rubinstein Taybi syndrome. Because of the large size of the NF1 gene for neurofibromatosis and CREBBP gene for Rubinstein Taybi syndrome, whole exome sequence analysis (WES) was conducted and a novel ARID1B mutation was identified. The proband WES test identified a novel heterozygous frameshift mutation c.3394_3395insTA in exon 13 of ARID1B (NM_017519.2) predicting a premature stop codon p.(Tyr1132Leufs*67). Sanger sequencing confirmed the heterozygous c.3394_3395insTA mutation in the proband and that it was not present in her parents indicating de novo mutation. Further investigation and new cases will help to understand this phenomenon better.

Reported here are twins, both of whom have a 1q21.3 microdeletion and who exhibit key features common to previously reported cases such as microcephaly and developmental delay. However, some clinical findings and deleted genes differed from those in previously reported cases. The karyotype was normal 46, XX for both of the twins. Array comparative genomic hybridization (CGH) identified a 2.6 Mb deletion on chromosome 1q21.3 (chr1: 153,514,121-156,171,335 bp) in case 1 and a 1.6 Mb deletion on chromosome 1q21.3 (chr1: 154,748,365-156,358,923 bp) in case 2. The deleted region includes DPM3, MUC1, GBA, PKLR, RIT1, and LAMTOR2 in both siblings. To the extent known, this is the second report of a 1q21.3 microdeletion in a family with mental retardation, developmental delay, seizures, and some dysmorphic features, thus expanding the phenotypic spectrum.

Breast cancer is the most common cause of cancer in women in the United States and the Western world. The important question is what can be done to limit the human suffering associated with cancer and to reduce the burden on society? One solution is early detection. Early diagnosis of breast cancer before symptoms emerge is the most effective prevention of breast cancer.

Rhinologic diseases have a very high prevalence worldwide. It is known now that many rhinologic diseases have a strong genetic background. Some formidable challenges still remain for these diseases. However, research in the field of genetics has made much progress over the last decade and is expected to advance even further in the near future, as increasingly powerful analytical tools are being developed to unlock the complexities of genetic diseases. Information on the genetics of allergic diseases is important not only for analyzing the molecular basis of these diseases but also for investigating new drugs. Today, there is a huge effort to understand the molecular basis of disease and to find new therapies.

Cancer stem cells (CSC) are thought to be a sub-population of cancer cells, which are the main tumorigenic cells in the tumors. Although chemoradiotherapy may kill the majority of rapidly dividing cells, CSC-like cell populations may be left behind due to their low turnover and infrequent cell cycling. In 2007, Prince et al. reported the presence of head and neck cancer stem cells for the first time. In the current study, UTTSCC74A and UTTSCC74B head and neck cancer cell lines as material derived from the primary tumor and their lymph node metastasis, respectively, were used. FACS was used for isolation of cancer stem cells using antibodies against CD44 and ALDH1. However we could not get specific response from CD44 antigen ie can not isolate cancer stem cell. However ALDH1 antibody selection gave us isolation of cancer stem cells from both of UTTSCC74A and B cell lines though much less cancer stem cells existed in UTTSCC74B cell line. The cells were first cultured in normal DMEM with 10% FBS under the condition of 5% CO2. Then the cells were changed into stem cell medium and cultured. Cancer stem cells were isolated using antibody against ALDH1 and these cells were cultured in stem cell medium and its characteristics were confirmed through sphere formation as well as immunofluorescence staining with antibody against ALDH1 and control antibody against DAPI. Expressions of sox-2, oct-4 and klf-4 were confirmed. After characterization of cancer stem cell from head and neck cancer cell line was confirmed, microarray analysis were performed using Gene Chip PrimeView Human expression Array (U133-HG133/ 47,000 transcript). Each group of ALDH1+ (cancer stem) and - cells isolated from each of UTTSCC74A and UTTSCC74B cell lines were exposed to microarray analysis. RNA extraction and cDNA construction from each sub group were prepared for microarray analysis. Comparison of UTTSCC74A ALDH1+ and - provided increased expression of 2037 and decreased expression in 2263 genes in various ratios. Similarly comparison of UTTSCC74B ALDH1+ and - provided increased expression of 6349 and decreased expression in 5322 genes in various ratios. 26 genes with most up and down regulation were selected and confirmation was done through real-time RT-PCR designing custom primers. Similar results were taken as in microarray analysis. From these 26 genes with confirmation of their expressions, 5 up regulated and 5 downregulated genes were selected for further analysis. We currently prepare expression plasmids of these genes and continue their in vitro functional analysis. Thus, the identification of the cancer-stem cell related signalling pathways in head and neck cancer stem cell would provide valuable information for a better understanding of cancer stem cell properties, molecular mechanisms of carcinogenesis, invasion and metastasis in this cancer type. By this way, effective therapeutic options targeting CSCs may be developed. Citation Format: Mehmet Gunduz, Omer Faruk Hatipoglu, Esra Gunduz, Elif Nihan Cetin, Eyyup Uctepe, Sadık Cigdem, Reidar Grenman, Muradiye Acar. Characterization of cancer stem cell properties and identification of invasion as well as metastatic process in head and neck cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1399. doi:10.1158/1538-7445.AM2015-1399

Chronic myeloproliferative disorders such as polycythemia vera (PV), essential thrombocytosis (ET), and idiopathic myelofibrosis arise from clonal proliferation of neoplastic stem cells in the bone marrow. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that have potential to degrade all types of extracellular matrix (ECM) and also play a role in remodeling of the ECM. It is known that MMPs play a role in bone marrow remodeling. The primary goal of our study is to explore the relationship between chronic myeloproliferative diseases and some of MMP gene polymorphisms. The demonstration of a relationship will help to understand whether these polymorphisms may be a potential early diagnosis marker of the diseases. Patients were selected from outpatient clinics of Turgut Ozal University Hospital, Ankara, Turkey, between December 2010 and May 2011. Twenty-eight patients that previously diagnosed and followed-up with PV, 17 with secondary polycythemia (SP), and 12 with ET were enrolled in the study, along with a control group of 22 healthy people. DNA was isolated from peripheral blood. Using polymerase chain reaction–restriction fragment length polymorphism method, MMP2 and MMP9 gene polymorphisms were analyzed with agarose gel electrophoresis. There was a statistically significant difference between the study groups and the control group in terms of Gln279Arg polymorphisms rates of MMP9. The highest MMP9 Gln279Arg polymorphism rate was observed in the ET group. But nobody from the control group had polymorphic MMP9. There was no statistically significant difference between the groups in terms of MMP2-735 C > T polymorphism rates. In conclusion, MMP9 gene Gln279Arg polymorphism was associated with ET, SP, and PV diseases. Hence, we believe that these gene polymorphisms may play a role in the mechanism of bone marrow fibrosis and may be a factor that increases the risk of thrombosis. Illumination of the molecular basis of the relationship between MMP-thrombosis and MMP-fibrosis provides a better understanding of the pathophysiology of PV and ET diseases and will allow new approaches to diagnosis and treatment.