Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

Background:Amino-acid transporters are necessary for the tumour cell growth and survival, and have a crucial role in the development and invasiveness of cancer cells. But, it remains unclear about the prognostic significance of L-type amino-acid transporter 1 (LAT1), system ASC amino-acid transporter-2 (ASCT2), and xCT expression in patients with tongue cancer. We conducted the clinicopathological study to investigate the protein expression of these amino-acid transporters in tongue cancer.Methods:Eighty-five patients with surgically resected tongue cancer were evaluated. Tumour sections were stained by immunohistochemistry for LAT1, ASCT2, xCT, 4F2hc/CD98hc (4F2hc), Ki-67, and microvessel density (MVD) determined by CD34, and p53.Results:L-type amino-acid transporter 1 and 4F2hc were highly expressed in 61% (52 out of 85) and 45% (38 out of 47), respectively. ASC amino-acid transporter-2 and xCT were positively expressed in 59% (50 out of 85) and 21% (18 out of 85), respectively. The expression of both LAT1 and ASCT2 was significantly associated with disease staging, lymph-node metastasis, lymphatic permeation, 4F2hc expression and cell proliferation (Ki-67). xCT expression indicated a significant association with advanced stage and tumour factor. By univariate analysis, disease staging, lymphatic permeation, vascular invasion, LAT1, ASCT2, 4F2hc, and Ki-67 had a significant relationship with overall survival. Multivariate analysis confirmed that LAT1 was an independent prognostic factor for predicting poor prognosis.Conclusions:L-type amino-acid transporter 1 and ASCT2 can serve as a significant prognostic factor for predicting worse outcome after surgical treatment and may have an important role in the development and aggressiveness of tongue cancer.

The prepositus hypoglossi nucleus (PHN) is thought to be a neural structure involved in transforming eye or head velocity signals into eye position signals for horizontal eye movements. In this study, we investigated the relationship between electrophysiological membrane properties and expression patterns of cellular markers for excitatory and inhibitory neurons by whole-cell patch clamp recordings followed by reverse transcription polymerase chain reaction (RT-PCR) analysis in rat brainstem slices. Three types of voltage response properties, namely afterhyperpolarization (AHP), firing pattern, and response to hyperpolarizing current pulses, were characterized in each neuron. Following RT-PCR analysis, we identified PHN neurons as either glutamatergic (n = 22) or GABAergic (n = 43), although a small number of cholinergic (n = 2) and glycinergic neurons (n = 1) were also identified. Both glutamatergic and GABAergic neurons showed a wide variety of membrane properties; however, we found several characteristic relationships between neuronal type and membrane properties. Most neurons exhibiting (i) AHP without a slow component, (ii) a firing pattern with a delay in the generation of the first spike, (iii) a firing pattern with a transient burst and (iv) a firing pattern with a prolonged initial interspike interval were GABAergic. On the other hand, glutamatergic neurons were primarily characterized by a low firing rate. These results indicate that there is a close relationship between specific electrophysiological membrane properties and expression of chemical markers in some types of glutamatergic and GABAergic PHN neurons.

Recent progression in the understanding of stem cell biology has greatly facilitated the identification and characterization of cancer stem cells (CSCs). Moreover, evidence has accumulated indicating that conventional cancer treatments are potentially ineffective against CSCs. Histone deacetylase inhibitors (HDACi) have multiple biologic effects consequent to alterations in the patterns of acetylation of histones and are a promising new group of anticancer agents. In this study, we investigated the effects of two HDACi, suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), on two CD44+ cancer stem-like cell lines from squamous cell carcinoma of the head and neck (SCCHN) cultured in serumfree medium containing epidermal growth factor and basic fibroblast growth factor. Histone deacetylase inhibitors inhibited the growth of SCCHN cell lines in a dose-dependent manner as measured by MTS assays. Moreover, HDACi induced cell cycle arrest and apoptosis in these SCCHN cell lines. Interestingly, the expression of cancer stem cell markers, CD44 and ABCG2, on SCCHN cell lines was decreased by HDACi treatment. In addition, HDACi decreased mRNA expression levels of stemness-related genes and suppressed the epithelial-mesencymal transition phenotype of CSCs. As expected, the combination of HDACi and chemotherapeutic agents, including cisplatin and docetaxel, had a synergistic effect on SCCHN cell lines. Taken together, our data indicate that HDACi not only inhibit the growth of SCCHN cell lines by inducing apoptosis and cell cycle arrest, but also alter the cancer stem cell phenotype in SCCHN, raising the possibility that HDACi may have therapeutic potential for cancer stem cells of SCCHN. (Cancer Sci 2013; 104: 1468-1475 E vidence has accumulated indicating that only a minority of cancer cells with stem cell properties, cancer stem cells (CSCs), are responsible for the maintenance and growth of tumors.(1-3) These CSC subpopulations show a capacity for high tumorigenicity, self-renewal, and differentiation. To date, human CSCs have been identified, purified, and characterized in a variety of tumors. (4)(5)(6)(7)(8) In squamous cell carcinoma of the head and neck (SCCHN), since Prince et al.(9) first demonstrated that the purified CD44+ population possessed the properties of CSCs, various cell surface markers, including CD133 and ALDH1, have been identified for the isolation of CSCs. (10)(11)(12) Moreover, numerous studies have demonstrated that conventional cancer treatments are potentially ineffective against CSCs, which are subsequently responsible for tumor relapse and distant metastases.(13-15) Therefore, the development of novel therapeutic strategies to overcome treatment resistance of CSCs is urgently needed.Recent studies have demonstrated that not only genetic but also epigenetic changes, including DNA methylation and histone modifications, play an essential role in cancer development. (16,17) Of histone modifications, acetylation and deacetylation affect the chromatin structure and gene expression, and ...

Salivary gland swelling is a commonly encountered clinical symptom, but the establishment of a diagnosis is occasionally difficult. Here, we present two sialodochitis fibrinosa patients with recurring bilateral parotid swelling. In both patients, secretion of mucous plugs containing numerous eosinophils was observed from Stensen's ducts. As expected, the level of interleukin-5 in the saliva was much higher than that in the serum. One patient had no medical history of allergic disease; the other had allergic rhinitis which had never been associated with parotid gland swelling. Microbiological examination was unable to isolate significant bacterial specimens from the mucous plugs. Thus, although allergy and/or bacterial infection are reportedly implicated as causes of sialodochitis fibrinosa, there may exist other possibilities for its pathogenesis. Interleukin-5 seems to play a crucial role in the pathogenesis of sialodochitis fibrinosa.

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