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PubMed2002

Mandibular asymmetry and antigonial notching in individuals with unilateral cleft lip and palate.

OBJECTIVE: To determine whether asymmetric antigonial notching is associated with the development of mandibular and lower facial asymmetry in individuals with unilateral cleft lip and palate (UCLP). DESIGN: Retrospective mixed-longitudinal investigation including UCLP and nonaffected orthodontic patients. PARTICIPANTS: All (24) available patients with UCLP treated in our clinic with complete longitudinal records, and 72 skeletal maturation matched noncleft orthodontic patients that served as controls. Subject records included hand-wrist, panoramic, frontal, and 45 degrees oblique cephalometric radiographs. MAIN OUTCOME MEASURES: The development of mandibular asymmetry, measured on oblique cephalometric radiographs, as well as lower facial asymmetry, measured on frontal cephalometric radiographs, was monitored in individuals with UCLP in relation to antigonial notching asymmetry, assessed on panoramic and oblique cephalometric radiographs. RESULTS: First, no statistical differences were found in antigonial notching asymmetry between patients with UCLP and noncleft controls. Second, antigonial notching asymmetry, observed on panoramic and oblique cephalometric radiographs, significantly correlated with the attendant development of mandibular and lower facial asymmetry in individuals with UCLP. Third, the development of mandibular and lower facial asymmetry at pubertal and postpubertal growth spurt stages significantly correlated with antigonial notching asymmetry, measured on panoramic radiographs, at prepubertal and pubertal growth spurt stages, respectively. CONCLUSIONS: The degree of antigonial notching noted on panoramic radiographs can be used as an early indicator of developing mandibular and lower facial asymmetry in individuals with UCLP.

Adolescent↗
PubMed2000

Toward the rational design of cell fate modifiers: notch signaling as a target for novel biopharmaceuticals.

Recent advances in our understanding of highly conserved mechanisms that control cell fate determination are paving the way towards rationally designed biologics that modulate specific cell fate decisions. Cell fate decisions leading to proliferation, differentiation or apoptosis are crucial elements in the pathogenesis of countless human diseases. Biopharmaceuticals designed to regulate such processes in specific cell types in vivo or ex vivo have vast potential applications in oncology, stem cell technology, immunomodulation and neuropathology. One of the most conserved mechanisms controlling cell fate determination is based upon Notch-ligand interactions and subsequent signaling events. Recent studies have shown that this mechanism regulates cell differentiation, proliferation and apoptosis in a wide variety of cell maturation processes and in neoplastic cells. These observations identify the Notch signaling network as a promising drug target for numerous indications. In this review, we describe: 1) potential drug targets in the Notch signaling network; 2) the Notch agonists and antagonists developed so far, including recombinant proteins, antibody-based agents, synthetic peptides, antisense oligonucleotides and gene therapy approaches, as well as possible strategies to design novel Notch-targeting biopharmaceuticals; 3) the possible clinical applications of such biopharmaceuticals and 4) a model strategy for the selection and developement of a Notch-targeting biopharmaceutical.

Animals↗
PubMed2002

The Notch ligand Jagged-1 is able to induce maturation of monocyte-derived human dendritic cells.

Notch receptors play a key role in several cellular processes including differentiation, proliferation, and apoptosis. This study investigated whether the activation of Notch signaling would affect the maturation of dendritic cells (DCs). Direct stimulation of Notch signaling in DCs with a peptide ligand induced DC maturation, similar to LPS: DCs up-regulated maturation markers, produced IL-12, lost endocytosis capacity, and became able to activate allogeneic T cells. Furthermore, coculture of DCs with cells expressing Notch ligand Jagged-1 induced up-regulation of maturation markers, IL-12 production, T cell proliferative responses, and IFN-gamma production. Our data suggest that activation of Notch by Jagged-1 plays an important role in maturation of human DCs. Additionally, they reveal a novel role for Notch signaling in cell maturation events distal to the cell fate decision fork. These data may have important medical implications, since they provide new reagents to induce DC activity, which may be beneficial as adjuvants in situations where an immune response needs to be elicited, such as tumor immunotherapy.

Amino Acid Sequence↗
PubMed2006

Evidence for a role for notch signaling in the cytokine-dependent survival of activated T cells.

Peripheral T cell homeostasis results from a balance between factors promoting survival and those that trigger deletion of Ag-reactive cells. The cytokine IL-2 promotes T cell survival whereas reactive oxygen species (ROS) sensitize T cells to apoptosis. Two pathways of activated T cell apoptosis-one triggered by Fas ligand and the other by cytokine deprivation-depend on ROS, with the latter also regulated by members of the Bcl-2 family. Notch family proteins regulate several cell-fate decisions in metazoans. Ectopic expression of the Notch1 intracellular domain (NICD) in T cells inhibits Fas-induced apoptosis. The underlying mechanism is not known and the role, if any, of Notch in regulating apoptosis triggered by cytokine deprivation or neglect has not been examined. In this study, we use a Notch1/Fc chimera; a blocking Ab to Notch1 and chemical inhibitors of gamma-secretase to investigate the role of Notch signaling in activated T cells of murine origin. We show that perturbing Notch signaling in activated CD4+/CD8+ T cells maintained in IL-2 results in the accumulation of ROS, reduced Akt/protein kinase B activity, and expression of the antiapoptotic protein Bcl-xL, culminating in apoptosis. A broad-spectrum redox scavenger inhibits apoptosis but T cells expressing mutant Fas ligand are sensitive to apoptosis. Activated T cells isolated on the basis of Notch expression (Notch+) are enriched for Bcl-xL expression and demonstrate reduced susceptibility to apoptosis triggered by neglect or oxidative stress. Furthermore, enforced expression of NICD protects activated T cells from apoptosis triggered by cytokine deprivation. Taken together, these data implicate Notch1 signaling in the cytokine-dependent survival of activated T cells.

Animals↗
PubMed1975

Occurrence and regression of initial and terminal notching of the QRS complex in the electrocardiograms of patients with acute myocardial infarction.

The occurrence of initial and terminal notching in the QRS complex of the electrocardiogram was studied in a series of 158 male patients surviving acute myocardial infarction during hospital admission and at follow-up examinations 6-8 weeks, 5 and 12 months after the infarction. In 115 men with their first myocardial infarction signifiant initial notching was found in the acute stage in 30% and significant terminal notching in 32%. One year later these percentages were 14 and 9, respectively. In patients with reinfarction the prevalence of notching was even higher. Inital notches were most often associated with anterior and terminal notches with inferoposterio infarction.

Acute Disease↗
PubMed2003

The significance of the neurovascular structures passing through the spinoglenoid notch.

OBJECTIVE: To define the detailed anatomy of the neurovascular bundle at the spinoglenoid notch and to report the dimensions of these structures in cadavers. METHODS: In the present study, the external diameters of suprascapular artery, vein and nerve were measured at the spinoglenoid notch region in 18 formalin fixed cadavers (36 shoulders) by using a caliper. The study was carried out in the dissection laboratory of Anatomy Departments of Hacettepe University, Ankara University, Ankara and Mersin University, Mersin, Turkey, between 2002 and 2003. RESULTS: The average external diameter for the suprascapular vein was 2.6 mm, artery was 2.2 mm and nerve was 2.2 mm. The spinoglenoid notch was roofed by the spinoglenoid ligament and appeared as a fibroosseous foramen in all cadavers. We found that the vascular structures (suprascapular artery and vein) occupied 68.5% and the suprascapular nerve occupied 31.5% of this foramen. CONCLUSION: Although the diameters of the vascular structures at the spinoglenoid notch measured by magnetic resonance imaging have been reported, to our knowledge, external diameters of these structures at the spinoglenoid notch have not been described in cadavers. We believe that detailed anatomy of suprascapular neurovascular bundle at the spinoglenoid notch should be appreciated for better understanding of risk factors possibly causing the suprascapular nerve entrapment syndrome, specially for those who are involved in violent overhead sports activities such as volleyball and baseball.

Adult↗
PubMed2003

Interobserver reliability and intraobserver reproducibility in suprascapular notch typing.

The size and shape of the suprascapular notch may be a factor in suprascapular nerve entrapment. The suprascapular notches of 623 scapulae were digitally photographed and used to determine notch type and area. Three researchers used to different classification systems for suprascapular notch typing. These systems were compared for interobserver reliability and intraobserver reproducibility using the kappa test. The mean kappa value for the classification used by Rengachary and colleagues was 0.468 and for the classification used by Ticker and associates was 0.531 for the inferior border of the notch and 0.736 for the superior border of the notch. The classification system used by Ticker and associates was more reliable and reproducible and produced both a superior and an inferior classification, making it possibly more clinically relevant than the classification system used by Rengachary and colleagues.

Adolescent↗
PubMed2004

The Notch ligand, Delta-1, reduces TNF-alpha-induced growth suppression and apoptosis by decreasing activation of caspases in U937 cells.

The Notch signaling pathway plays an important role in the regulation of self-renewal and differentiation of hematopoietic progenitors. Tumor necrosis factor (TNF)-alpha induces apoptosis through activation of caspase pathway. A monoblastic leukemia cell line, U937, undergoes apoptosis following stimulation with TNF-alpha. We found that Notch activation induced by a recombinant Notch ligand, Delta-1, reduced the TNF-alpha-induced growth suppression and apoptosis in U937 cells. As the molecular mechanism involved, we showed Delta-1 stimulation partially suppressed the sequential activation of caspase-8, caspase-3, and, PARP induced by TNF-alpha. The TNF-alpha-induced activation of c-Jun N-terminal kinase (JNK), p38, and NF-kappaB was not affected by Delta-1 stimulation. The cells needed to be exposed to Delta-1 prior to TNF-alpha stimulation to reduce the suppressive effect of TNF-alpha. Therefore, we thought that Delta-1 stimulation might reduce the expression of TNF-receptor (R) 1 and proteins to modulate the activation of caspases such as FLIP and XIAP. However, Delta-1 stimulation did not affect their expression. The precise mechanism by which Notch signaling suppresses caspase activation has yet to be determined. This is the first report to show the relationship between Notch activation and TNF-R1 signaling. The findings suggest possible mechanisms by which Notch activation supports cell survival.

Apoptosis↗
PubMed2006

[Anatomical names of skeletal notches--analysis and classification of Latin names, and comparison with corresponding Japanese names--].

For better understanding of the structures comprising the human body and in view of possible need for future revision, Latin anatomical names (Nomina Anatomica, 3rd edition) of the skeletal notches were analyzed and classified, and compared with the corresponding Japanese anatomical names. The words following Incisura indicated: 1) the structure to which the notch belongs; 2) location of the notch; 3) the structure of which the notch is a component; 4) the bone or osseous structure with which the notch is connected; or 5) non-osseous structure attached to the notch. Analysis of Latin names and comparison with Japanese names clarified some characteristics of both names and revealed some problems in them.

Bone and Bones↗
PubMed1991

Anacrotic "notch" on the upstroke of external carotid curve may indicate a critically high systolic pulmonary arterial pressure value.

Acute respiratory failure is followed by decreased left ventricular performance probably due to the right ventricle dilatation induced by pulmonary hypertension and intraventricular septal shift to the left. An anacrotic notch on the upstroke slope of the carotid curve was detected in 22 of 36 hemodynamic studies with simultaneous ECG, PCG and external pulse carotid curve recording in 7 burned patients with acute respiratory failure. Comparing the values (x +/- SEM) obtained in group with notch and in group without notch, PAPs, PAPm, PVRI were higher (56 +/- 2.30 mmHg; 32 +/- 0.99 mm Hg; 543 +/- 56.8 dyn x s/cm5/m2 versus 32 +/- 1.08 mm Hg; 20 +/- 0.9 mm Hg; 173 +/- 14.7 dyn x s/cm5/m2) and CI and LVSWI were lower (2.6 +/- 0.17 l/min/m2; 25.8 +/- 2.41 g x m/m2; versus 3.8 +/- 0.26 l/min/m2; 38.3 +/- 2.82 g x m/m2) in group with notch. As it is shown by 11 paired measurements where the notch disappeared immediately after starting vasodilator therapy PAPs, PAPm, PVRI decreased (from 54 +/- 3.1, 35 +/- 0.8 mm Hg, 498 +/- 64.1 dyn x s/cm5/m2 to 35 +/- 0.8, 21 +/- 1.1 mmHg, 189 +/- 18.4 dyn x s/cm5/m2 respectively) and heart performance improved. Since the left ventricle contractility (characterized by EF, PCWP, ICT) was normal in both groups, our findings suggest that critically high PAPs values (over 40 mmHg) cause a septal bulging at the beginning of the systole which in turn narrows the left ventricle outflow tract. Regarding to the clinical importance of the deteriorated biventricular function at the critically high PAPs evidenced by notch phenomenon on carotid curve but measurable only by indwelling pulmonary arterial catheterization always being a source of infection, the noninvasive parameters as independent variables were entered into canonical discriminant analysis. The ratio of the correctly classified cases was 89%.

Acute Disease↗
PubMedDate not supplied

The "notch" sign: meniscal contour deformities as indicators of tear in MR imaging of the knee.

Conventional magnetic resonance (MR) criteria for meniscal tearing emphasize intrameniscal signal and its communication with the articular surface. In this retrospective study, the value of a focal contour deformity of the meniscal articular surface, termed a "notch," as an additional MR sign of meniscal tearing was assessed. One hundred fifty-four menisci were evaluated. Twenty-three of 24 notches correlated with the site of tear at arthroscopy. Seven notches improved the reading confidence from possible to definite tear; in eight notches, the diagnosis of tear would otherwise not have been considered. Five tears occurred without intrameniscal signal, four following recent trauma. The notch sign improved the sensitivity from 79.8 to 87.8%. Notches are useful additional signs of meniscal tearing, increasing the confidence of a reading when occurring near grade 1 or 2 meniscal signal, and are the only MR sign present in some tears.

False Negative Reactions↗
PubMed1999

Arbiter of differentiation and death: Notch signaling meets apoptosis.

Notch-ligand interactions are a highly conserved mechanism that regulates cell fate decisions. Over the past few years, numerous observations have shown that this mechanism operates to regulate cell differentiation in an enormous variety of developmental and cell maturation processes. Recent studies indicate that in addition to cell differentiation, Notch signaling has direct effects on proliferation and programmed cell death. The picture emerging from these findings suggests that, depending on cellular and developmental context, Notch signaling may function as a general "arbiter" of cell fate, regulating differentiation potential, rate of proliferation, and apoptotic cell death. In this review, we briefly summarize the current knowledge of the structure and function of Notch receptors and discuss the recent evidence that Notch signaling regulates apoptotic cell death. The possible mechanisms of this effect and its potential implications for developmental biology, immunobiology, neuropathology, and tumor biology are discussed.

Alzheimer Disease↗
PubMed2000

Linking Notch signaling, chromatin remodeling, and T-cell leukemogenesis.

Intercellular communication that controls the developmental fate of multipotent cells is commonly mediated by the Notch family of transmembrane receptors. Specific transmembrane ligands activate Notch receptors on neighboring cells inducing the proteolytic liberation and nuclear translocation of the intracellular domain of Notch (N(IC)). Nuclear N(IC) associates with a transcriptional repressor known as C-promoter binding factor/RBP-J kappa, suppressor of hairless, or LAG-1, converting it from a repressor into an activator. Through physical interactions with chromatin remodeling enzymes and potentially with components of the transcriptional machinery, N(IC) activates target genes that mediate cell fate decisions. As Notch1 is disrupted via a chromosomal translocation in a subset of human T-cell leukemia, leading to a truncated polypeptide resembling N(IC), deregulated chromatin remodeling and transcription may fuel uncontrolled cell proliferation in this hematopoietic malignancy. This review summarizes the mechanics of Notch signaling and focuses on prospective molecular mechanisms for how constitutively active Notch might derail nuclear processes as an initiating step in T-cell leukemogenesis. J. Cell. Biochem. Suppl. 35:46-53, 2000.

Animals↗
PubMed2001

Oh no, Notch again!

The Notch receptor signaling pathway is important for morphogenesis and development of many organs and tissues in most if not all multicellular species. The classical view holds that Notch signaling keeps cells in an undifferentiated state. Recently, however, this notion has been challenged in the nervous system by two sets of observations: Notch plays an active role in the differentiation of glial cells,(1-4) and Notch influences the length and organisation of neuronal processes.(5-7) In this review, we analyse these recent data and discuss how Notch signaling may be able to perform such quite different tasks during nervous system development. BioEssays 23:3-7, 2001.

Animals↗
PubMed2006

Eyeing tumorigenesis: Notch signaling and epigenetic silencing of Rb in Drosophila.

Notch signaling plays an essential role in the processes of embryogenesis and cellular differentiation, and it is believed that the oncogenic effects of dysregulated Notch signaling are an anomalous reflection of the normal functions of this cascade. Nonetheless, the cellular events associated with oncogenic Notch signaling have thus far remained elusive. In a recent report, Ferres-Marco et al. described how they used the Drosophila eye as a model system and found that elevated Notch signaling in combination with activation of components of the Polycomb complex of transcriptional repressors led to metastatic growth of tumors through epigenetic silencing of the Rbf gene. Rbf is the Drosophila homologue of the retinoblastoma tumor-suppressor gene (Rb), thus it represents a novel link between Notch signaling, tumor growth and metastasis.

Animals↗
PubMed2003

Notch-associated gene expression in embryonic and adult taste papillae and taste buds suggests a role in taste cell lineage decisions.

The Notch signaling pathway is involved in cell fate decisions during development. To explore the role of this signaling cascade in the taste system, we investigated the expression patterns of Notch signaling genes in fetal and adult mouse tongues using in situ hybridization. Three of the four murine Notch receptors, their ligands, Delta-like 1 (Dll-1), Jagged1, and Jagged2, as well as three transcription factors, Hes1, Hes6, and Mash1, are expressed in the embryonic taste epithelium. Expression is first detected in the circumvallate papilla at embryonic day E14.5, when Notch1, Jagged1, and Jagged2 are expressed broadly in the papilla and general lingual epithelium. In contrast, Mash1 and Hes6 are restricted to only a few epithelial cells in the apical region of the developing papilla. By E18.5, many of the genes now exhibit a bimodal expression pattern in the papillary epithelium: apically and dorsally they are expressed in sparse clusters of cells, while more ventrally expression typically occurs throughout the lower regions of the trenches. The extent of papilla innervation was compared with Mash1 and Hes6 expression. At E14.5, when Hes6 and Mash1 are already expressed in small numbers of epithelial cells, PGP9.5 immunoreactive fibers have not yet invaded the epithelium, consistent with the specification of taste bud primordia prior to nerve contact. All of the genes examined (except Notch2) are also expressed in subsets of cells within circumvallate taste buds in adult mice, although Notch1 is restricted to basal cells adjacent to taste buds. The onset of embryonic Notch associated gene expression after the morphological differentiation of the circumvallate papilla argues that this signaling cascade may specify taste receptor cell lineages within an already specified taste papilla. Similarly, Notch gene expression in adult taste buds suggests continued roles in cell lineage determination and cell turnover.

Animals↗
PubMed2002

Isolation and characterization of Xenopus Hey-1: a downstream mediator of Notch signaling.

Regulation of Notch signaling likely occurs, at least in part, at the level of basic helix-loop-helix (bHLH) transcription factors that function downstream of Suppressor of Hairless (Su(H)) in the Notch pathway. To begin to characterize modulation of Notch signaling during organogenesis, we examined the bHLH transcription factor, XHey-1 (hairy related-1) in early Xenopus laevis embryos. XHey-1 is expressed in numerous tissues during early development including the somites, head, embryonic kidneys, and heart. Importantly, the expression of XHey-1 was significantly altered in response to perturbation of Notch signaling by means of inducible constructs that served to either activate or suppress Notch signaling through Su(H) in a temporally controlled manner.

Animals↗
PubMed2005

Interactions between the Notch, EGFR, and decapentaplegic signaling pathways regulate vein differentiation during Drosophila pupal wing development.

The formation of longitudinal veins in the Drosophila wing involves cell interactions mediated by the conserved signaling pathways Decapentaplegic (Dpp), Notch, and epidermal growth factor receptor (EGFR). Interactions between Notch and EGFR taking place in the wing disc divide each vein into a central domain, where EGFR is active, and two boundary domains where Notch is active. The expression of decapentaplegic (dpp) is activated in the veins during pupal development, and we have generated Gal4 drivers using the regulatory region that drives dpp expression at this stage. By using these drivers, we studied the relationships between the Notch, EGFR, and Dpp signaling pathways that occur during pupal development. Our results indicate that the interactions between EGFR and Notch initiated in the imaginal disc are maintained throughout pupal development and contribute to determine the places where dpp is expressed. Once dpp expression is initiated, Dpp and EGFR activities in the provein maintain each other and, in cooperation, determine vein cell differentiation.

Animals↗