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PubMed2001

Notch receptor expression in adult human liver: a possible role in bile duct formation and hepatic neovascularization.

Notch signaling is an evolutionarily conserved mechanism, used to regulate cell fate decisions. Four Notch receptors have been identified in man (Notch-1 to -4). In this study, semiquantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry were used to examine the expression pattern of Notch receptor genes in whole adult human liver and isolated liver cell preparations. All 4 receptors were expressed in the adult liver, with no significant differences in the levels of Notch-1, -2, and -4 messenger RNA (mRNA) between normal and diseased liver. However, Notch-3 expression appeared to be increased in diseased tissue. The distribution of Notch-1 and -4 in normal tissue was similar, with Notch-1 also detectable at low levels in the sinusoidal endothelium. Notch-2 expression was more widely distributed, and detectable in hepatocytes, medium-sized bile ducts, and the sinusoidal endothelium. Notch-3 expression was seen on hepatocytes, with weaker expression detectable in portal veins, hepatic arteries, and the sinusoids. In normal liver tissue Notch-1, -2, and -3 were found to be coexpressed on bile duct epithelium; however, with the exception of Notch-3 in primary sclerosing cholangitis (PSC) livers, expression was absent on proliferating ductules in all disease states examined. Interestingly, the expression of Notch-2 and -3 was associated with numerous small vessels within the portal tract septa of diseased tissue. The absence of Notch receptor expression on proliferating bile ductules and its presence on neovessels suggests that Notch signaling may be important for normal bile duct formation and the aberrant neovascularization seen in diseased liver tissue.

Adult↗
PubMed2003

An O-fucose site in the ligand binding domain inhibits Notch activation.

Two glycosyltransferases that transfer sugars to EGF domains, OFUT1 and Fringe, regulate Notch signaling. However, sites of O-fucosylation on Notch that influence Notch activation have not been previously identified. Moreover, the influences of OFUT1 and Fringe on Notch activation can be positive or negative, depending on their levels of expression and on whether Delta or Serrate is signaling to Notch. Here, we describe the consequences of eliminating individual, highly conserved sites of O-fucose attachment to Notch. Our results indicate that glycosylation of an EGF domain proposed to be essential for ligand binding, EGF12, is crucial to the inhibition of Serrate-to-Notch signaling by Fringe. Expression of an EGF12 mutant of Notch (N-EGF12f) allows Notch activation by Serrate even in the presence of Fringe. By contrast, elimination of three other highly conserved sites of O-fucosylation does not have detectable effects. Binding assays with a soluble Notch extracellular domain fusion protein and ligand-expressing cells indicate that the NEGF12f mutation can influence Notch activation by preventing Fringe from blocking Notch-Serrate binding. The N-EGF12f mutant can substitute for endogenous Notch during embryonic neurogenesis, but not at the dorsoventral boundary of the wing. Thus, inhibition of Notch-Serrate binding by O-fucosylation of EGF12 might be needed in certain contexts to allow efficient Notch signaling.

Amino Acid Sequence↗
PubMed1995

Complementary and combinatorial patterns of Notch gene family expression during early mouse development.

The Drosophila Notch gene encodes a transmembrane receptor involved in the regulation of cell fate. It exerts its effect by lateral specification, inductive signaling and is also important for cell adhesion and axonal pathfinding. In this report we analyse the expression of the three mammalian Notch homologues during early mouse development by in situ hybridization. The Notch 1, 2 and 3 genes show dynamic and complex expression patterns, in particular during gastrulation and somitogenesis and in early nervous system formation. During gastrulation, the Notch genes are expressed in non-overlapping, successive patterns. Notch 3 is widely expressed in both ectoderm and mesoderm. Notch 2 is then expressed in the node, notochord and neural groove while Notch 1 becomes highly expressed in presomitic mesoderm. As somitogenesis begins, Notch 2 expression is activated in newly forming somites while Notch 3 is activated in mature somites. Various neural crest cell populations and ectodermal placode cells can be defined by expression of specific combinations of Notch genes. All three Notch genes are expressed within cells of the dorsal neural tube at E9.5, although neural crest cells that have begun migrating all show distinct patterns of Notch expression. Finally, Notch 1 expression is observed not only in placodes, but also in cells migrating from placodes to the site of the ganglia anlagen. This expression pattern may be analogous to Notch expression in the peripheral nervous system of Drosophila, suggesting that mammalian Notch genes may also be involved in axonal pathfinding.

Animals↗
PubMed1991

Notched-noise measures of frequency selectivity in adults and children using fixed-masker-level and fixed-signal-level presentation.

Three experiments were performed to examine the development of frequency selectivity and to attempt to separate peripheral versus central contributions to frequency selectivity. In Experiment 1, frequency selectivity was examined in 4-year-old children, 6-year-old children, and adults, using a fixed-masker-level, notched-noise masking method. Thresholds were determined in a no-notch condition and in conditions in which the notchwidth was 0.3 times the center frequency (0.3 x fc) or 0.6 x fc. The results for the adults and 6-year-olds were similar, but the notched-noise functions of the 4-year-old listeners were relatively shallow. These results were consistent with an interpretation that frequency selectivity is relatively poor in 4-year-old listeners; however, the results of the 4-year-old listeners might also be accounted for in terms of poor processing efficiency. For example, the children may require a relatively high level of signal-related excitation in order for detection to occur. If the growth of excitation is steeper in the no-notch condition than in notched-noise conditions, then thresholds in the notched-noise conditions might be elevated because of poor processing efficiency rather than poor frequency selectivity. This interpretation is consonant with past data showing that the growth of loudness of partially masked signals steepens as a function of increasing masker level: The masker level at the output of the auditory filter centered on the signal frequency would be less for the notched-noise masker than for the masker having no notch. In Experiment 2 the growth of loudness was examined for three adult listeners in the no-notch condition and the 0.6 x fc notched noise. Results showed a steeper growth of loudness in the no-notch case. In Experiment 3, a notched-noise measure of frequency selectivity was used in which the signal level was fixed at 15 dB SL and the masker level was varied adaptively. In this method the noise level at the output of the auditory filter centered on the signal should theoretically be constant over the different notch conditions. Adult and 4-year-old listeners were tested. The notched-noise functions were similar between the adult and 4-year-old listeners. This result supports an interpretation that the shallow notched-noise, fixed-masker-level functions of 4-year-old children may be due to poor processing efficiency rather than to poor peripheral frequency selectivity.

Adult↗
PubMedDate not supplied

Analysis of the intercondylar notch by computed tomography.

The purposes of this study were to document the dimensions and configuration of the intercondylar notch in the normal knee; to compare normal knee intercondylar notches to those of knees with unilateral and bilateral ACL tears to determine if there is a relationship between intercondylar notch stenosis and ACL tears; and to determine if generalized ligamentous laxity is associated with intercondylar notch stenosis and ACL tears. Three groups were compared: Group I, bilateral ACL tears; Group II, unilateral tears; and Group III, normal knees. Notch dimensions were computer-generated from CT scans. All patients were examined for ligamentous laxity. Statistically significant differences were found between normal and ACL-injured knees in regard to opening notch angle, ratio of notch width at two-thirds of the notch length to condylar width, and ratio of maximum notch width to condylar width, suggesting a significant association between anterior outlet stenosis and unilateral and bilateral ACL tears. The shapes of the notches were determined from tracings of the distal CT scan. Shapes ranged from inverted U to cresting wave. Narrow notches tended to be waveshaped, but more study is needed in this area. Notch-plasty is recommended for those with documented stenosis. The ratio of maximum notch width at two-thirds of the notch height to maximum condyle width should not be much less than 0.2, and the opening notch angle should be at least 50 degrees.

Adult↗
PubMedDate not supplied

Intercondylar notch size and anterior cruciate ligament injuries in athletes. A prospective study.

Published reports agree that there is a strong association between intercondylar notch stenosis and anterior cruciate ligament injuries. In a previously published retrospective study on bilateral anterior cruciate ligament injuries and associated intercondylar notch stenosis, we formulated the notch width index to measure and compare intercondylar notch width. The purpose of this prospective study was to establish a normal range for the notch width index and to correlate intercondylar notch size and anterior cruciate ligament injuries. We gathered data on 902 high school athletes, including range of motion, thigh girth, ligament stability and intercondylar notch width using the notch width index. The population was then followed prospectively and anterior cruciate ligament injuries were recorded and correlated with notch width index in a blind manner. Two-year results showed that the overall anterior cruciate ligament injury rate was 3%. The normal intercondylar notch ratio was 0.231 +/- 0.044. Intercondylar notch width index for men was larger than that for women. Athletes sustaining noncontact anterior cruciate ligament tears have statistically significant intercondylar notch stenosis (notch width index, 0.189). Ten of 14 athletes with noncontact anterior cruciate ligament injuries had a notch width index that was at least 1 SD below the mean. Athletes with contact anterior cruciate ligament injuries had a mean of 0.233. We conclude that athletes with a stenotic intercondylar notch are at significantly greater risk for sustaining noncontact anterior cruciate ligament injury.

Adolescent↗
PubMed2002

The tentorial notch: anatomical variation, morphometric analysis, and classification in 100 human autopsy cases.

OBJECT: Variations in the structure of the tentorial notch may influence the degree of brainstem distortion in transtentorial herniation, concussion, and acceleration-deceleration injuries. The authors examined the anatomical relationships of the mesencephalon, cerebellum, and oculomotor nerves to the dimensions of the tentorial aperture. On the basis of numerical data collected from this study, the authors have developed the first classification system of the tentorial notch and present new neuroanatomical observations pertaining to the subarachnoid third cranial nerve and the brainstem. METHODS: The mesencephalon was sectioned at the level of the tentorial edge in 100 human autopsy cases (specimens from 23 female and 77 male cadavers with a mean age at time of death of 42.5 years [range 18-80 years]). The following measurements were determined: 1) anterior notch width, the width of the tentorial notch in the axial plane through the posterior aspect of the dorsum sellae; 2) maximum notch width (MNW), the maximum width of the notch in the axial plane; 3) notch length (NL), the length of the tentorial notch from the superoposterior edge of the dorsum sellae to the apex of the notch; 4) posterior tentorial length, the shortest distance between the apex of the notch and the most anterior part of the confluence of the sinuses; 5) interpedunculoclival (IC) distance, the distance from the interpeduncular fossa to the superoposterior edge of the dorsum sellae; 6) apicotectal (AT) distance, the distance from the tectum in the median plane to a perpendicular line dropped from the apex of the tentorial notch to the cerebellum; 7) cisternal third nerve distance, the distance covered by the cisternal portion of the third cranial nerve; and 8) inter-third nerve angle, the angle between the two third cranial nerves. The quartile distribution technique was applied to all measurements. Mean values are presented as the means +/- standard deviations. Quartile groups defined by NL (mean 57.7 +/- 5.6 mm) were labeled long, short, and midrange, and those defined by MNW (mean 29.6 +/- 3 mm) were labeled wide, narrow, and midrange. Combining these groups into a matrix formation resulted in the classification of the tentorial notch into the following eight types: 1) narrow (15% of specimens); 2) wide (12% of specimens); 3) short (8% of specimens); 4) long (15% of specimens); 5) typical (24% of specimens); 6) large (9% of specimens); 7) small (10% of specimens); and 8) mixed (7% of specimens). The IC distance (mean 20.4 +/- 3.2 mm) was used to characterize brainstem position as prefixed (28% of specimens), postfixed (36% of specimens), or midposition (36% of specimens). The IC distance was correlated with the left and right cisternal third nerve distances (means 26.7 +/- 2.9 mm and 26.1 +/- 3.2 mm, respectively) and the inter-third nerve angle (mean 57.3 +/- 7.3 degrees). The exposed cerebellar parenchyma within the notch, the relationship between the brainstem and tentorial edge, and the brainstem position varied considerably among individuals. The cisternal third nerve distance, its trajectory, and its anatomical relation to the skull base also varied widely. Two anatomically distinct segments of the subarachnoid third cranial nerves were characterized with respect to the skull base as suspended and supported segments. CONCLUSIONS: The authors present a new classification system for the tentorial aperture to help explain variations in herniation syndromes in patients with otherwise similar intracranial pathological conditions, and responses to concussive and acceleration-deceleration injuries. The authors present observations not previously described regarding the position of the brainstem within the tentorial aperture and the cisternal portion of the third cranial nerves. A significant statistical correlation was discovered among specific morphometric parameters of the tentorial notch, brainstem, and oculomotor nerves. These findings may have neurosurgical implications in clinical situations that cause brainstem distortion. Additionally, this analysis provides baseline data for interpreting magnetic resonance and computerized tomography images of the tentorial notch and its regional anatomy.

Adolescent↗
PubMed2001

The Advanced Glaucoma Intervention Study (AGIS): 10. Variability among academic glaucoma subspecialists in assessing optic disc notching.

PURPOSE: An analysis of data from the Advanced Glaucoma Intervention Study (AGIS) has found eyes reported to have partial optic disc rim notching (not to the edge) at baseline to have less risk of subsequent visual field loss than eyes with no notching. Because this is counterintuitive and because classification of notching had not been defined in the AGIS protocol, we have assessed AGIS ophthalmologists interobserver and intraobserver agreement on notching. METHODS: Fourteen glaucoma subspecialists classified notching in 26 pairs of stereoscopic disc photographs of eyes with mild to severe glaucomatous optic neuropathy. They classified images as showing either no notching, notching not to the edge, or notching to the edge. Several hours later, 10 of them classified the same images a second time. RESULTS: In an analysis of interobserver agreement, of 26 stereoscopic images, a plurality of ophthalmologists classified notching as absent in 9 (35%), as present but not to the edge in 7 (27%), and as present and not to the edge in 10 (38%). All 14 ophthalmologists (100%) agreed on the classification of 7 (27%) of the images, and 13 of the 14 ophthalmologists (93%) agreed on the classification of 4 additional images (15%). Of these 11 images with at least 93% agreement, notching was reported as absent in 3 (27%) and to the edge in 8 (73%). In the remaining 15 images, there was substantial disagreement about whether notching was present and, if so, whether it was to the edge. In an analysis of intraobserver agreement, none of the 10 ophthalmologists who completed the viewing a second time classified all eyes exactly the same as the first time, though 5 ophthalmologists made 4 or fewer reclassifications. Overall, 80% of the original classifications were reproduced on second reading. Of the initial classifications that were not reproduced, slightly more than half were first classified as having notching not to the edge. CONCLUSION: Without definitions or examples of optic disc rim notching, the glaucoma subspecialists had relatively high intraobserver agreement but were likely to disagree with each other in characterizing the degree of disc rim notching. We recommend development of a standard photographic classification of disc rim notching. The classification should be tested for inter- and intra-observer agreement.

Academic Medical Centers↗
PubMedDate not supplied

Expression of Notch pathway components in spermatogonia and Sertoli cells of neonatal mice.

Members of the Notch gene family have been shown to play an important role in the control of cell fate in many developmental systems. We hypothesized that the fate of the male germ line stem cells may also be mediated through the Notch signaling pathway. We therefore sought to determine whether the components of the Notch pathway are expressed in the mouse testis. Western blot analysis revealed the expression of three Notch receptors (Notch 1, Notch 2, and Notch 3), Notch ligands (Jagged 1, Jagged 2, and Delta 1), and presenilin 1 (PS1) in neonatal mouse testis. We then examined their cellular localization by immunohistochemical analysis of cocultures of spermatogonia and Sertoli cells. The 3 Notch receptors were found to be expressed in spermatogonia. Sertoli cells expressed only Notch 2 receptor. Among the Notch ligands, Delta 1 and Jagged 1 were localized exclusively in spermatogonia and Sertoli cells, respectively. PS1 was apparent in both spermatogonia and Sertoli cells. The presence of Notch receptors and Notch ligands in spermatogonia and Sertoli cells indicates that these cells are capable of responding to and eliciting Notch signaling during the process of spermatogenesis. Key words: Cell fate, delta, jagged, presenilin, spermatogenesis.

Animals↗
PubMed2004

Drosophila Nedd4 regulates endocytosis of notch and suppresses its ligand-independent activation.

BACKGROUND: Ligand-induced proteolytic cleavage and internalization of the plasma membrane receptor Notch leads to its activation. Ligand-independent, steady-state internalization of Notch, however, does not lead to activation. The mechanism by which downstream effectors discriminate between these bipartite modes of Notch internalization is not understood. Nedd4 is a HECT domain-containing E3 ubiquitin ligase that targets transmembrane receptors containing the PPSY motif for endocytosis. Deltex is a positive Notch signaling regulator that encodes a putative ubiquitin ligase of the ring finger type. RESULTS: We used the Drosophila system to show that Notch is ubiquitinated and destabilized by Nedd4 in a manner requiring the PPSY motif in the Notch intracellular domain. Loss of Nedd4 function dominantly suppresses the Notch and Deltex mutant phenotypes, and its hyperactivation attenuates Notch activity. In tissue culture cells, the dominant-negative form of Nedd4 blocks steady-state Notch internalization and activates Notch signaling independently of ligand binding. This effect was further potentiated by Deltex. Nedd4 destines Deltex for degradation in a Notch-dependent manner. CONCLUSIONS: Nedd4 antagonizes Notch signaling by promoting degradation of Notch and Deltex. This Nedd4 function may be important for protecting unstimulated cells from sporadic activation of Notch signaling.

Animals↗
PubMed2004

Identification of two binding regions for the suppressor of hairless protein within the intracellular domain of Drosophila notch.

Notch is a phylogenetically conserved transmembrane receptor that is required for many aspects of animal development. Upon ligand stimulation, a fragment of Notch is released proteolytically and enters the nucleus to form a complex with the DNA-binding protein CSL (CBF1/Suppressor of Hairless/Lag1) and activate transcription of Notch-CSL target genes. The physical structure of the Notch-CSL complex remains unclear, however, clouding the interpretation of previous efforts to correlate Notch structure and function. We have, therefore, characterized the binding of Drosophila CSL (called Suppressor of Hairless, or Su(H)) to the intracellular domain of Drosophila Notch both in vitro and in vivo. We report the identification of two Su(H) binding regions in Notch. The first is in the juxtamembrane region (the "RAM" domain). The second is just C-terminal to the Notch ankyrin repeats, overlapping or identical to two previously proposed nuclear localization sequences, in a domain we term PPD (potential phosphorylated domain). The ankyrin repeats themselves do not bind to Su(H); however, they substantially enhance binding of Su(H) to the more C-terminal region. Consistent with this picture, removal of either the Ram or PPD binding sites, separately, modestly reduces Notch activity in vivo, whereas removal of both renders Notch severely defective. These results clarify the relationship between Notch and CSL, help to explain the importance of the ankyrin repeats in Notch signaling, and reconcile many apparently contradictory results from previous Notch structure/function studies. Moreover, they suggest a second function for the Notch nuclear localization sequence elements.

Amino Acid Sequence↗
PubMed2004

Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells.

INTRODUCTION: Notch signaling has been implicated in the regulation of cell-fate decisions such as self-renewal of adult stem cells and differentiation of progenitor cells along a particular lineage. Moreover, depending on the cellular and developmental context, the Notch pathway acts as a regulator of cell survival and cell proliferation. Abnormal expression of Notch receptors has been found in different types of epithelial metaplastic lesions and neoplastic lesions, suggesting that Notch may act as a proto-oncogene. The vertebrate Notch1 and Notch4 homologs are involved in normal development of the mammary gland, and mutated forms of these genes are associated with development of mouse mammary tumors. METHODS: In order to determine the role of Notch signaling in mammary cell-fate determination, we have utilized a newly described in vitro system in which mammary stem/progenitor cells can be cultured in suspension as nonadherent 'mammospheres'. Notch signaling was activated using exogenous ligands, or was inhibited using previously characterized Notch signaling antagonists. RESULTS: Utilizing this system, we demonstrate that Notch signaling can act on mammary stem cells to promote self-renewal and on early progenitor cells to promote their proliferation, as demonstrated by a 10-fold increase in secondary mammosphere formation upon addition of a Notch-activating DSL peptide. In addition to acting on stem cells, Notch signaling is also able to act on multipotent progenitor cells, facilitating myoepithelial lineage-specific commitment and proliferation. Stimulation of this pathway also promotes branching morphogenesis in three-dimensional Matrigel cultures. These effects are completely inhibited by a Notch4 blocking antibody or a gamma secretase inhibitor that blocks Notch processing. In contrast to the effects of Notch signaling on mammary stem/progenitor cells, modulation of this pathway has no discernable effect on fully committed, differentiated, mammary epithelial cells. CONCLUSION: These studies suggest that Notch signaling plays a critical role in normal human mammary development by acting on both stem cells and progenitor cells, affecting self-renewal and lineage-specific differentiation. Based on these findings we propose that abnormal Notch signaling may contribute to mammary carcinogenesis by deregulating the self-renewal of normal mammary stem cells.

Cell Differentiation↗
PubMed2004

Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas.

Notch signaling regulates cell fate decisions in a variety of adult and embryonic tissues, and represents a characteristic feature of exocrine pancreatic cancer. In developing mouse pancreas, targeted inactivation of Notch pathway components has defined a role for Notch in regulating early endocrine differentiation, but has been less informative with respect to a possible role for Notch in regulating subsequent exocrine differentiation events. Here, we show that activated Notch and Notch target genes actively repress completion of an acinar cell differentiation program in developing mouse and zebrafish pancreas. In developing mouse pancreas, the Notch target gene Hes1 is co-expressed with Ptf1-P48 in exocrine precursor cells, but not in differentiated amylase-positive acinar cells. Using lentiviral delivery systems to induce ectopic Notch pathway activation in explant cultures of E10.5 mouse dorsal pancreatic buds, we found that both Hes1 and Notch1-IC repress acinar cell differentiation, but not Ptf1-P48 expression, in a cell-autonomous manner. Ectopic Notch activation also delays acinar cell differentiation in developing zebrafish pancreas. Further evidence of a role for endogenous Notch in regulating exocrine pancreatic differentiation was provided by examination of zebrafish embryos with homozygous mindbomb mutations, in which Notch signaling is disrupted. mindbomb-deficient embryos display accelerated differentiation of exocrine pancreas relative to wild-type clutchmate controls. A similar phenotype was induced by expression of a dominant-negative Suppressor of Hairless [Su(H)] construct, confirming that Notch actively represses acinar cell differentiation during zebrafish pancreatic development. Using transient transfection assays involving a Ptf1-responsive reporter gene, we further demonstrate that Notch and Notch/Su(H) target genes directly inhibit Ptf1 activity, independent of changes in expression of Ptf1 component proteins. These results define a normal inhibitory role for Notch in the regulation of exocrine pancreatic differentiation.

Adenoviridae↗
PubMed2006

Correlation of intercondylar notch cross sections to the ACL size: a high resolution MR tomographic in vivo analysis.

INTRODUCTION: To correlate cross sections of the intercondylar notch to cross sections of the anterior cruciate ligament (ACL) and to analyze gender-related differences in notch and ACL morphometry with an attempt to explain the observation that a small intercondylar notch and the female gender predispose to a rupture of the ACL. MATERIAL AND METHODS: High resolution MR imaging was performed on a 1.5 T magnet using a dedicated extremity-coil in ten left and ten right knee joints of 20 volunteers (10 male, 10 female, mean age 25 years) with no history of knee abnormalities. Continuous axial T2-weighted MR images perpendicular to the longitudinal axis of the ACL were acquired. Cross-sectional areas of the ACL midsubstance at the contact area to the posterior cruciate ligament were measured. For imaging and evaluation of the osseous limits of the intercondylar notch a 3D-dataset of the knee was acquired. Anterior, middle and posterior planes of the intercondylar notch were calculated and analyzed for measurement of the notch area AN and notch width index NWI. The ratio of the ACL cross-sectional area of the ACL and the cross-sectional area of the notch was defined as the ACL notch index (ANI) and used as a standardized tool for evaluation. For statistical evaluation, linear regression analysis was performed. Mean values between male and female were compared using a t test. In addition, five matched pairs of male and female volunteers of same height were analyzed. RESULTS: Mean cross-sectional size of the ACL at the crossing with the PCL was 54.4 +/- 20.4 mm2. Regression analysis showed a significant correlation (P < 0.05) of the ACL cross-sectional area to the notch areas on all three planes and NWI, respectively. Comparison between the sexes revealed that female participants had significantly smaller cross-sectional areas of the ACL, the notch areas, the NWI and ANI. This difference was found for both the complete study group and the matched pairs of same height. CONCLUSIONS: The smaller the intercondylar notch the smaller the cross-sectional area of the ACL midsubstance. In addition to the impingement of the ACL at the anterior and posterior roof of the notch, a biomechanically weaker ACL may be the reason for disposition to an ACL rupture in patients with a small intercondylar notch. Women have a thinner ACL midsubstance than men of the same height which may be one of the critical etiologic factors that predispose women to an ACL rupture.

Anterior Cruciate Ligament↗
PubMed1996

Dimensional differences in the craniofacial morphologies of groups with deep and shallow mandibular antegonial notching.

Certain craniofacial characteristics were identified on the lateral cephalograms of 40 untreated subjects with shallow mandibular antegonial notches and 40 subjects with deep notches. Subjects with shallow notches demonstrated more on the morphological characteristics usually associated with horizontal mandibular growth patterns than did subjects with deep notches, and their mandibles were positioned more protrusively. In general, the mandibles of the shallow notch subjects proved to be longer than mandibles of the deep notch subjects. On average, mandibles with deep notches showed greater gonial angles, deeper posterior ramus notch depths, and larger occlusal plane inclinations. The total anterior facial height of shallow notch subjects was much smaller than that of the deep notch subjects. The maxillae in deep notch subjects were more retrusive in relation to the cranial base when compared with the shallow notch subjects. A discriminant analysis was used to determine which combinations of variables were most consistently related to either deep or shallow mandibular antegonial notches. Eighty percent (80%) of the cases were classified correctly as deep or shallow notch cases by means of this discriminant function.

Adolescent↗
PubMed2005

The Notch signaling pathway is related to neurovascular progression of pancreatic cancer.

OBJECTIVE: To analyze the potential role of the Notch signaling pathway in pancreatic cancer angiogenesis and invasion. BACKGROUND: Angiogenesis, pain, and early neuroinvasion are clinical features of pancreatic cancer. Blood vessels and nerves develop together and use common routes through the organism. The Notch pathway (Notch-1/4, Jagged-1/2, Delta-1) appears crucial in this process. The current study analyzed the Notch pathway in pancreatic cancer and characterized its angiogenic and invasive effects. METHODS: Five PaCa cell lines were cultured for the in vitro experiments. Real-time quantitative RT-PCR was done to quantify mRNA expression in 31 human PaCa specimens, and immunohistochemistry was used to localize protein expression within tumor specimens. Activation of the Notch signaling was done by transfection of PaCa cells with a constitutive active Notch-1 mutant (Notch-IC). Overexpression of Jagged and Delta was achieved by transfection of full-length cDNA. Spheroid assays were used to study angiogenesis and ELISAs to measure VEGF, bFGF, and angiogenin expression. Matrigel invasion assays were used to analyze tumor cell invasion. RESULTS: Notch-3 and Notch-4 mRNA were significantly (P < 0.001) overexpressed in PaCa. Immunohistochemistry revealed protein accumulation of Notch-1 as well. All ligands were significantly up-regulated. A positive immunosignal of ligands was seen in nerves, blood vessels, and ductal tumor cells. Transfection of PaCa cells with the constitutive active Notch-IC mutant and with Jagged-1 revealed increased levels for VEGF. Concomitantly, recombinant Jagged-1 increased sprouting of endothelial cells in the spheroid assay. CONCLUSION: The Notch pathway most likely regulates neurovascular development in pancreatic cancer. Activation of this signaling pathway by constitutive Notch-1 mutants and by Jagged-1 causes an angiogenic and invasive tumor phenotype. Specific blockade of Notch signaling may therefore be beneficial for patients with pancreatic cancer.

Disease Progression↗
PubMed2006

Notch-1 regulates pulmonary neuroendocrine cell differentiation in cell lines and in transgenic mice.

The notch gene family encodes transmembrane receptors that regulate cell differentiation by interacting with surface ligands on adjacent cells. Previously, we demonstrated that tumor necrosis factor-alpha (TNF) induces neuroendocrine (NE) cell differentiation in H82, but not H526, undifferentiated small cell lung carcinoma lines. We now test the hypothesis that TNF mediates NE cell differentiation in part by altering Notch gene expression. First, using RT-PCR, we determined that TNF treatment of H82, but not H526, transiently decreases notch-1 mRNA in parallel with induction of gene expression for the NE-specific marker DOPA decarboxylase (DDC). Second, we treated H82 and H526 with notch-1 antisense vs. sense oligodeoxynucleotides. Using quantitative RT-PCR and Western analyses we demonstrate that DDC mRNA and protein are increased in H82 by notch-1 antisense, whereas notch-1 mRNA and activated Notch-1 protein are decreased. mRNA for Hes1, a transcription factor downstream from activated Notch, is also decreased by Notch-1 antisense in H82 but not H526. After 7 days of Notch-1 antisense treatment, neural cell adhesion molecule (NCAM) immunoreactivity is induced in H82 but not H526. Third, we generated transgenic mice bearing notch-1 driven by the neural/NE-specific calcitonin promoter, which express activated Notch-1 in developing lung epithelium. Newborn NotchCal mouse lungs have high levels of hes1 mRNA, reflecting increased activated Notch, compared with wild-type. NotchCal lungs have decreased CGRP-positive NE cells, decreased protein gene product 9.5 (PGP9.5)-positive NE cells, and decreased gastrin-releasing peptide (GRP), CGRP, and DDC mRNA levels compared with normal littermates. Cumulatively, these observations provide further support for a role for Notch-1 signaling in regulating pulmonary NE cell differentiation.

Animals↗
PubMed2001

The relationship of femoral intercondylar notch width to height, weight, and sex in patients with intact anterior cruciate ligaments.

Intercondylar notch width, femoral bicondylar width, height, and weight of patients with intact anterior cruciate ligaments were measured to determine whether intercondylar notch width was related to body size. A 45 degrees weight-bearing posteroanterior radiograph was obtained for 315 men and 163 women. Notch width and bicondylar width was measured at one-half notch height. Mean notch width for men was statistically significantly wider than for women (17.1 mm versus 14.7 mm, respectively; P<.01). There was no statistically significant correlation between height and notch width for men (r=-0.0019; P=.97) or women (r=0.1308; P=.10). No significant correlation existed between weight and notch width for men (r=-0.0311; P=.58) or women (r=0.0523; P=.51). Analysis of variance showed height and weight were not significant covariates in notch width for either men (P=.44) or women (P=.91). Women of the same height and weight as men had significantly narrower notches (P<.01). There was a statistically significant correlation between wider femoral bicondylar widths and higher weight for men (r=0.694; P<.01) and women (r=0.821; P<.01). Similarly, there was a statistically significant correlation between wider femoral bicondylar widths and increased height for men (r=0.670; P<.01) and women (r=0.785; P<.01). These data demonstrate height and weight are poor predictors of intercondylar notch width. Therefore, one cannot assume body size is a predictor of notch width. Furthermore, because mean notch width does not increase with increasing height and weight, the notch width index calculation cannot accurately reflect the size of the intercondylar notch.

Adolescent↗