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PubMedDate not supplied

Clinical evaluation and treatment of spinoglenoid notch ganglion cysts.

Spinoglenoid notch cysts were identified by magnetic resonance imaging in 73 patients. Posterosuperior labral tears were identified in 65 patients who had spinoglenoid notch cysts. Patient follow-up was available on 88% of patients at a mean of 20.5 months after treatment. There were 52 men and 11 women, with a mean age of 39 years (range, 19-76 years). All patients reported shoulder pain. Infraspinatus atrophy occurred in 25 patients, weakness with external rotation in 43, and posterior shoulder tenderness in 30. Nineteen patients underwent nonoperative management of the cyst (group I). Eleven underwent attempted needle aspiration of the cyst (group II). Six had isolated arthroscopic treatment of a labral defect with no cyst excision (group III). Twenty-seven were treated with surgical cyst excision with the cyst and superior labral tear fixed arthroscopically or with an open approach in various combinations (group IV). Of the patients, 53% were satisfied in group I, 64% in group II, 67% in group III, and 97% in group IV.

Adult↗
PubMed2003

The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gamma-secretase.

Notch signaling is involved in numerous cell fate decisions in invertebrates and vertebrates. The Notch receptor is a type I transmembrane (TM) protein that undergoes two proteolytic steps after ligand binding, first by an ADAM (a distintegrin and metalloprotease) in the extracellular region, followed by gamma-secretase-mediated cleavage inside the TM domain. We demonstrate here that the murine ligand Delta1 (Dll1) undergoes the same sequence of cleavages, in an apparently signal-independent manner. Identification of the ADAM-mediated shedding site localized 10 aa N-terminal to the TM domain has enabled us to generate a noncleavable mutant. Kuzbanian/ADAM10 is involved in this processing event, but other proteases can probably substitute for it. We then show that Dll1 is part of a high-molecular-weight complex containing presenilin1 and undergoes further cleavage by a gamma-secretase-like activity, therefore releasing the intracellular domain that localizes in part to the nucleus. Using the shedding-resistant mutant, we demonstrate that this gamma-secretase cleavage depends on prior ectodomain shedding. Therefore Dll1 is a substrate for regulated intramembrane proteolysis, and its intracellular region possibly fulfills a specific function in the nucleus.

Amino Acid Sequence↗
PubMed2003

Gleevec inhibits beta-amyloid production but not Notch cleavage.

Amyloid-beta (Abeta) peptides, consisting mainly of 40 and 42 aa (Abeta40 and Abeta42, respectively), are metabolites of the amyloid precursor protein and are believed to be major pathological determinants of Alzheimer's disease. The proteolytic cleavages that form the Abeta N and C termini are catalyzed by beta-secretase and gamma-secretase, respectively. Here we demonstrate that gamma-secretase generation of Abeta in an N2a cell-free system is ATP dependent. In addition, the Abl kinase inhibitor imatinib mesylate (Gleevec, or STI571), which targets the ATP-binding site of Abl and several other tyrosine kinases, potently reduces Abeta production in the N2a cell-free system and in intact N2a cells. Both STI571 and a related compound, inhibitor 2, also reduce Abeta production in rat primary neuronal cultures and in vivo in guinea pig brain. STI571 does not inhibit the gamma-secretase-catalyzed S3 cleavage of Notch-1. Furthermore, production of Abeta and its inhibition by STI571 were demonstrated to occur to similar extents in both Abl-/- and WT mouse fibroblasts, indicating that the effect of STI571 on Abeta production does not involve Abl kinase. The efficacy of STI571 in reducing Abeta without affecting Notch-1 cleavage may prove useful as a basis for developing novel therapies for Alzheimer's disease.

Amyloid Precursor Protein Secretases↗
PubMed2001

Presenilin, Notch, and the genesis and treatment of Alzheimer's disease.

Elucidation of the proteolytic processing of the amyloid beta-protein precursor (APP) has revealed that one of the two proteases (gamma-secretase) that cleave APP to release amyloid beta-protein (Abeta) is likely to be presenilin. Presenilin also mediates the gamma-secretase-like cleavage of Notch receptors to enable signaling by their cytoplasmic domains. Therefore, APP and Notch may be the first identified substrates of a unique intramembranous aspartyl protease that has presenilin as its active-site component. In view of the evidence for a central role of cerebral build-up of Abeta in the pathogenesis of Alzheimer's disease, this disorder appears to have arisen in the human population as a late-life consequence of the conservation of a critical developmental pathway.

Alzheimer Disease↗
PubMed1998

Identity of the beta-globin locus control region binding protein HS2NF5 as the mammalian homolog of the notch-regulated transcription factor suppressor of hairless.

Previously, we characterized a DNA-binding protein, HS2NF5, that bound tightly to a conserved region within hypersensitive site 2 (HS2) of the human beta-globin locus control region (LCR) (Lam, L. T. , and Bresnick, E. H. (1996) J. Biol. Chem. 271, 32421-32429). The beta-globin LCR controls the chromatin structure, transcription, and replication of the beta-globin genes. We have now purified HS2NF5 to near-homogeneity from fetal bovine thymus. Two polypeptides of 56 and 61 kDa copurified with the DNA binding activity. The two proteins bound to the LCR recognition site with an affinity (3.1 nM) and specificity similar to mouse erythroleukemia cell HS2NF5. The amino acid sequences of tryptic peptides of purified HS2NF5 revealed it to be identical to the murine homolog of the suppressor of hairless transcription factor, also known as recombination signal binding protein Jkappa or C promoter binding factor 1 (CBF1). The CBF1 site within HS2 resides near sites for hematopoietic regulators such as GATA-1, NF-E2, and TAL1. An additional conserved, high affinity CBF1 site was localized within HS4 of the LCR. As CBF1 is a downstream target of the Notch signaling pathway, we propose that Notch may modulate LCR activity during hematopoiesis.

Amino Acid Sequence↗
PubMed2001

Carhart notch effect in otosclerotic ears measured by electric bone-conduction audiometry.

The Carhart notch is an elevation in the middle-frequency bone-conduction threshold of an ear with clinical otosclerosis. The study population consisted of 138 patients with clinical otosclerosis. Conventional air-conduction (AC) and bone-conduction (BC) and electric bone-conduction (EBC, with Audimax 500 audiometer) thresholds were measured 2 weeks before and 7 months after stapes surgery. The EBC thresholds were converted from mA values to dB SPL to compare the results obtained with the different methods. The mean differences in the BC thresholds before and after the operation were 3.2 dB (95% CI 1.9-4.6) at 1 kHz and 7.6 dB (95% CI 6.1-9.1) at 2 kHz. The mean differences in the EBC thresholds were 5.4 dB (95% CI 3.8-6.9) at 1 kHz and 5.3 dB (95% CI 3.4-7.1) at 2 kHz. Thus, both methods showed a distinct Carhart notch effect.

Audiometry, Pure-Tone↗
PubMed2005

Dermoid cyst at the suprasternal notch: an adult case.

We present a case of a 39-year-old Japanese man with a two-year history of a mass in his suprasternal notch. Histopathologically the diagnosis was confirmed as a dermoid cyst; the cyst wall was almost normal with an epidermal structure consisting of sebaceous and apocrine glands and on the inside there were keratin materials and hair shafts. A dermoid cyst at the suprasternal notch is rare, and in an adult is the first as far as we know.

Adult↗
PubMed1978

Role of membrane permeabilities (calcium, chloride, and potassium) in the genesis of the notch observed on simian and prosimian cardiac action potentials.

The effect of temperature reduction on monkey ventricular action potentials has been studied. Under this condition the genesis of a notch separating the AP spike from the AP plateau has been related either to a conduction phenomenon or to a delay in the activation of the slow inward current. It is observed that the development of a notch at the beginning of the plateau depends both on the presence of a large outward, repolarising current, carried by chloride and/or potassium ions, and on the presence of a slow inward calcium current large enough to depolarise the membrane as the chloride current deactivates.

Action Potentials↗
PubMed2001

Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation.

The role of Notch signaling in growth/differentiation control of mammalian epithelial cells is still poorly defined. We show that keratinocyte-specific deletion of the Notch1 gene results in marked epidermal hyperplasia and deregulated expression of multiple differentiation markers. In differentiating primary keratinocytes in vitro endogenous Notch1 is required for induction of p21WAF1/Cip1 expression, and activated Notch1 causes growth suppression by inducing p21WAF1/Cip1 expression. Activated Notch1 also induces expression of 'early' differentiation markers, while suppressing the late markers. Induction of p21WAF1/Cip1 expression and early differentiation markers occur through two different mechanisms. The RBP-Jkappa protein binds directly to the endogenous p21 promoter and p21 expression is induced specifically by activated Notch1 through RBP-Jkappa-dependent transcription. Expression of early differentiation markers is RBP-Jkappa-independent and can be induced by both activated Notch1 and Notch2, as well as the highly conserved ankyrin repeat domain of the Notch1 cytoplasmic region. Thus, Notch signaling triggers two distinct pathways leading to keratinocyte growth arrest and differentiation.

Animals↗
PubMed1975

Negative complementation at the notch locus of Drosophila melanogaster.

Four Abruptex alleles (AxE1, AxE2, Ax9B2, and Ax16172) have been mapped within the Notch locus. Based on their visible phenotypes and their interactions with one another and with N mutations, the Ax alleles can be divided into two groups. Heterozygous combinations of members of the same group are intermediate in phenotype compared to the respective homozygotes, whereas heterozygotes of Ax alleles from different groups exhibit negative heterosis, being much less viable and more extremely mutant than either homozygote. It is suggested that the Notch locus is a multi-functional regulator ("integrator") gene, whose product possesses both "repressor" and "activator" functions for the processes it regulates.

Animals↗
PubMed1991

The auditory brain stem response recorded with 60 Hz notch filters.

Line-frequency (60 Hz in the USA) interference is a common source of contamination during recording of the auditory brain stem response (ABR). Notch filters are undeniably effective in eliminating this artifact, but concerns have been expressed as to their effect on the ABR itself. Theoretical considerations suggest that the degree of distortion should be minimal if the filter is sufficiently sharp and the stimulus rate has no multiples very close to 60 Hz. Responses simultaneously recorded through three notch filters of varying sharpness confirmed this: Latency was virtually unaffected with any filter or stimulus rate, and distortion was minimal when a sharply tuned filter was used in conjunction with a stimulus rate of 23.3 Hz, whose nearest harmonic to 60 is 69.9 Hz.

Acoustics↗
PubMed1990

Magnetic resonance imaging of Kernohan's notch.

Compression of the cerebral peduncle against the tentorial incisura contralateral to a supratentorial mass, the so-called Kernohan's notch, can be a cause of false localizing motor signs. The authors present a case of Kernohan's notch secondary to a traumatic extradural hematoma. The patient developed an oculomotor palsy and a dense motor deficit ipsilateral to the extra-axial hematoma. Magnetic resonance imaging in the postoperative period clearly showed the midbrain lesion. The motor deficit and 3rd nerve palsy subsequently resolved.

Adult↗
PubMed2002

Kernohan's notch phenomenon: a case study.

In a patient suffering from brain herniation due to a right-sided subdural hematoma, a neurological examination should show left-sided deficits, known as localizing signs, and a decreased level of consciousness. However, false localizing signs may be present, attributed to pressure on Kernohan's notch. A case study demonstrates these false localizing signs, known as Kernohan's notch phenomenon.

Adult↗
PubMed2006

Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation.

Notch signaling promotes commitment of keratinocytes to differentiation and suppresses tumorigenesis. p63, a p53 family member, has been implicated in establishment of the keratinocyte cell fate and/or maintenance of epithelial self-renewal. Here we show that p63 expression is suppressed by Notch1 activation in both mouse and human keratinocytes through a mechanism independent of cell cycle withdrawal and requiring down-modulation of selected interferon-responsive genes, including IRF7 and/or IRF3. In turn, elevated p63 expression counteracts the ability of Notch1 to restrict growth and promote differentiation. p63 functions as a selective modulator of Notch1-dependent transcription and function, with the Hes-1 gene as one of its direct negative targets. Thus, a complex cross-talk between Notch and p63 is involved in the balance between keratinocyte self-renewal and differentiation.

Animals↗
PubMed1992

Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands.

Expression of the int-3 locus is activated in mouse mammary tumors as a consequence of insertional mutagenesis by the mouse mammary tumor virus (MMTV). Integration of the MMTV provirus into the int-3 locus promotes the transcription and translation of flanking cellular int-3 sequences sharing significant homology with the intracellular domain of the neurogenic Notch gene of Drosophila, and with the yeast cell cycle regulatory genes cdc10 and SWI6. To determine the in vivo consequences of activated int-3 expression, transgenic mice were generated harboring a genomic tumor DNA fragment consisting of the MMTV LTR and the flanking cellular int-3 sequences. All six int-3 founder transgenic mice and the progeny of one established line exhibited similar dramatic phenotypic abnormalities in tissues in which the transgene was expressed. Focal and often multiple poorly differentiated mammary and salivary adenocarcinomas appeared in the majority of transgenic mice between 2 and 7 months of age. Significantly, mammary glands were arrested in development and were lactation deficient in all female int-3 mice. The salivary glands, glands of the nasal mucosa and maxillary sinus, the extraorbital lacrimal glands, and the Harderian glands of juvenile and adult transgenic mice all contained proliferating immature ductule cells and were incompletely differentiated. In addition, all male int-3 transgenic mice were sterile, apparently the result of severe hyperplasia of the epididymis. These findings demonstrate in vivo that expression of the activated Notch-related int-3 gene causes deregulation of normal developmental controls and hyperproliferation of glandular epithelia.

Adenocarcinoma↗
PubMed2006

Notch controls proliferation and differentiation of stem cells in a dose-dependent manner.

Self-renewal and differentiation of CNS stem cells are regulated by still poorly understood cell-cell interactions. Notch is a well-known cell surface protein that can promote both cell cycle progression and mitotic arrest but the molecular mechanism controlling these opposite effects is unknown. Here we demonstrate that, in CNS stem cells, the level of active Notch1 determines the cellular response. Specifically, low levels of the active form of Notch1 promote proliferation whereas high levels lead to growth arrest. Here we provide the first evidence that Notch effects on proliferation and differentiation are a function of dose, and propose a hypothesis on how oncogenes may also act as tumor suppressors.

Animals↗
PubMed2005

Analysis of transmembrane domain mutants is consistent with sequential cleavage of Notch by gamma-secretase.

gamma-Secretase is a lipid-embedded, intramembrane-cleaving aspartyl protease that cleaves its substrates twice within their transmembrane domains (TMD): once near the cytosolic leaflet (at S3/epsilon) and again in the middle of the TMD (at S4/gamma). To address whether this unusual process occurs in two independent or interdependent steps, we investigated how mutations at the S3/epsilon site in Notch1-based substrates impact proteolysis. We demonstrate that such mutations greatly inhibit not only gamma-secretase-mediated cleavage at S3 but also at S4, independent of their impact on NICD stability. These results, together with our previous observations, suggest that hydrolysis at the center of the Notch transmembrane domain (S4/gamma) is dependent on the S3/epsilon cleavage. Notch (and perhaps all gamma-secretase substrates) may be cleaved by sequential proteolysis starting at S3.

Amyloid Precursor Protein Secretases↗
PubMed1999

Development of noncarious cervical notch lesions in vitro.

PURPOSE: The initiation and progression of noncarious cervical notch lesions (NCCL) continues to perplex clinicians worldwide and poses a considerable restorative challenge. The purpose of this brief communication is to report what is believed to be the first in vitro production of notch-shaped lesions in the cervical third of premolar teeth. MATERIALS AND METHODS: The lesions, were produced by axial loading of selected permanent premolar teeth in a 10% aqueous solution of sulfuric acid over a period of 5 days, followed by immersion in water for 7 days. RESULTS: Results revealed macroscopic and microscopic features similar to those observed in noncarious cervical lesions in vivo. The lesions were incidental findings while the authors were studying stress corrosion of enamel at low pH. Although much remains to be investigated regarding the etiology and pathogenesis of NCCL, axial loading and a corrosive environment may be implicated in these processes. The artificial lesions arose in clinically sound teeth, suggesting that there is no simple clinical examination to identify teeth at risk from NCCL. CLINICAL SIGNIFICANCE: The relationship between the development of NCCL and applied stress indicates that occlusal factors may play the most significant role in the initiation and progression of NCCL.

Bicuspid↗