Immunolocalization of notch signaling protein molecules in a maxillary chondrosarcoma and its recurrent tumor

<p>Abstract</p> <p>Background</p> <p>Notch receptors are critical determinants of cell fate in a variety of organisms. Notch signaling is involved in the chondrogenic specification of neural crest cells. Aberrant Notch activity has been implicated in numerous human diseases including cancers; however its role in chondrogenic tumors has not been clarified.</p> <p>Method</p> <p>Tissue samples from a case of primary chondrosarcoma of the maxilla and its recurrent tumor were examined immunohistochemically for Notch1-4 and their ligands (Jagged1, Jagged2 and Delta1) expression.</p> <p>Results</p> <p>Both primary and recurrent tumors were histopathologically diagnosed as conventional hyaline chondrosarcoma (WHO Grade I). Hypercellular tumor areas strongly expressed Notch3 and Jagged1 in spindle and pleomorphic cells suggesting up-regulation of these protein molecules at sites of tumor proliferation. Expression patterns were distinct with some overlap. Differentiated malignant and atypical chondrocytes demonstrated variable expression levels of Jagged1, and weak to absent staining for Notch1, 4 and Delta1. Protein immunolocalization was largely membranous and cytoplasmic, sometimes outlining the lacunae of malignant chondrocytes. Hyaline cartilage demonstrated a diffuse or granular precipitation of Jagged1 suggesting presence of soluble Jagged1 activity at sites of abnormal chondrogenesis. No immunoreactivity for the other Notch members was observed. Calcified cartilage was consistently Notch-negative indicating down-regulation of Notch with cartilage maturation. Stromal components namely endothelial cells and fibroblasts variably expressed Notch1, 3 and Jagged1 but were mildly or non-reactive for the other members.</p> <p>Conclusions</p> <p>Results indicate that Notch signaling pathway may participate in cellular differentiation and proliferation in chondrosarcoma. Findings implicate Notch3 and Jagged1 as key molecules that influence the differentiation and maturation of cells of chondrogenic lineage.</p

Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.

Congenital muscular dystrophies display a wide phenotypic and genetic heterogeneity. The combination of clinical, biochemical, and molecular genetic findings must be considered to obtain the precise diagnosis and provide appropriate genetic counselling. Here we report five individuals from four families presenting with variable clinical features including muscular dystrophy with a reduction in dystroglycan glycosylation, short stature, intellectual disability, and cataracts, overlapping both the dystroglycanopathies and Marinesco-Sjögren syndrome. Whole-exome sequencing revealed homozygous missense and compound heterozygous mutations in INPP5K in the affected members of each family. INPP5K encodes the inositol polyphosphate-5-phosphatase K, also known as SKIP (skeletal muscle and kidney enriched inositol phosphatase), which is highly expressed in the brain and muscle. INPP5K localizes to both the endoplasmic reticulum and to actin ruffles in the cytoplasm. It has been shown to regulate myoblast differentiation and has also been implicated in protein processing through its interaction with the ER chaperone HSPA5/BiP. We show that morpholino-mediated inpp5k loss of function in the zebrafish results in shortened body axis, microphthalmia with disorganized lens, microcephaly, reduced touch-evoked motility, and highly disorganized myofibers. Altogether these data demonstrate that mutations in INPP5K cause a congenital muscular dystrophy syndrome with short stature, cataracts, and intellectual disability

Contributions of lean mass and fat mass to bone mineral density: a study in postmenopausal women

<p>Abstract</p> <p>Background</p> <p>The relative contribution of lean and fat to the determination of bone mineral density (BMD) in postmenopausal women is a contentious issue. The present study was undertaken to test the hypothesis that lean mass is a better determinant of BMD than fat mass.</p> <p>Methods</p> <p>This cross-sectional study involved 210 postmenopausal women of Vietnamese background, aged between 50 and 85 years, who were randomly sampled from various districts in Ho Chi Minh City (Vietnam). Whole body scans, femoral neck, and lumbar spine BMD were measured by DXA (QDR 4500, Hologic Inc., Waltham, MA). Lean mass (LM) and fat mass (FM) were derived from the whole body scan. Furthermore, lean mass index (LMi) and fat mass index (FMi) were calculated as ratio of LM or FM to body height in metre squared (m²).</p> <p>Results</p> <p>In multiple linear regression analysis, both LM and FM were independent and significant predictors of BMD at the spine and femoral neck. Age, lean mass and fat mass collectively explained 33% variance of lumbar spine and 38% variance of femoral neck BMD. Replacing LM and FM by LMi and LMi did not alter the result. In both analyses, the influence of LM or LMi was greater than FM and FMi. Simulation analysis suggested that a study with 1000 individuals has a 78% chance of finding the significant effects of both LM and FM, and a 22% chance of finding LM alone significant, and zero chance of finding the effect of fat mass alone.</p> <p>Conclusions</p> <p>These data suggest that both lean mass and fat mass are important determinants of BMD. For a given body size -- measured either by lean mass or height --women with greater fat mass have greater BMD.</p

Base-Induced Chemiluminescent Decomposition of Bicyclic Dioxetanes Bearing a (Benzothiazol-2-yl)-3-hydroxyphenyl Group: A Radiationless Pathway Leading to Marked Decline of Chemiluminescence Efficiency

Charge-transfer-induced decomposition (CTID) of bicyclic dioxetanes <b>1b</b>–<b>d</b> bearing a 3-hydroxylphenyl moiety substituted with a benzothiazol-2-yl group at the 2-, 6-, or 5-position was investigated, and their chemiluminescence properties were compared to each other, based on those for a 4-benzothiazolyl analogue <b>1a</b>. Dioxetanes <b>1c</b> and <b>1d</b> underwent CTID to give the corresponding oxido anions of keto esters <b>8c</b> or <b>8d</b> in the singlet excited state with high efficiencies similarly to the case of <b>1a</b>. On the other hand, <b>1b</b> showed chemiluminescence with quite low efficiency, though it gave exclusively keto ester <b>2b</b>. The marked decline of chemiluminescence efficiency for <b>1b</b> was attributed to <b>1b</b> mainly being decomposed to <b>8b</b> through a radiationless pathway, in which intramolecular nucleophilic attack of nitrogen in the benzothiazolyl group to dioxetane O–O took place to give cyclic intermediate <i>cis</i>-<b>11</b>

Base-Induced Chemiluminescent Decomposition of Bicyclic Dioxetanes Bearing a (Benzothiazol-2-yl)-3-hydroxyphenyl Group: A Radiationless Pathway Leading to Marked Decline of Chemiluminescence Efficiency

Charge-transfer-induced decomposition (CTID) of bicyclic dioxetanes <b>1b</b>–<b>d</b> bearing a 3-hydroxylphenyl moiety substituted with a benzothiazol-2-yl group at the 2-, 6-, or 5-position was investigated, and their chemiluminescence properties were compared to each other, based on those for a 4-benzothiazolyl analogue <b>1a</b>. Dioxetanes <b>1c</b> and <b>1d</b> underwent CTID to give the corresponding oxido anions of keto esters <b>8c</b> or <b>8d</b> in the singlet excited state with high efficiencies similarly to the case of <b>1a</b>. On the other hand, <b>1b</b> showed chemiluminescence with quite low efficiency, though it gave exclusively keto ester <b>2b</b>. The marked decline of chemiluminescence efficiency for <b>1b</b> was attributed to <b>1b</b> mainly being decomposed to <b>8b</b> through a radiationless pathway, in which intramolecular nucleophilic attack of nitrogen in the benzothiazolyl group to dioxetane O–O took place to give cyclic intermediate <i>cis</i>-<b>11</b>

Base-Induced Chemiluminescent Decomposition of Bicyclic Dioxetanes Bearing a (Benzothiazol-2-yl)-3-hydroxyphenyl Group: A Radiationless Pathway Leading to Marked Decline of Chemiluminescence Efficiency

Charge-transfer-induced decomposition (CTID) of bicyclic dioxetanes <b>1b</b>–<b>d</b> bearing a 3-hydroxylphenyl moiety substituted with a benzothiazol-2-yl group at the 2-, 6-, or 5-position was investigated, and their chemiluminescence properties were compared to each other, based on those for a 4-benzothiazolyl analogue <b>1a</b>. Dioxetanes <b>1c</b> and <b>1d</b> underwent CTID to give the corresponding oxido anions of keto esters <b>8c</b> or <b>8d</b> in the singlet excited state with high efficiencies similarly to the case of <b>1a</b>. On the other hand, <b>1b</b> showed chemiluminescence with quite low efficiency, though it gave exclusively keto ester <b>2b</b>. The marked decline of chemiluminescence efficiency for <b>1b</b> was attributed to <b>1b</b> mainly being decomposed to <b>8b</b> through a radiationless pathway, in which intramolecular nucleophilic attack of nitrogen in the benzothiazolyl group to dioxetane O–O took place to give cyclic intermediate <i>cis</i>-<b>11</b>