Are chin and symphysis morphology facial type-dependent? A computed tomography-based study.

INTRODUCTION: The chin is a major determinant of the facial profile; hence, it plays a major role in orthodontics and orthognathic surgery. It is thus essential to follow and better understand its expression in different facial types. The major objectives of the current study were to characterize morphometrically the chin and symphysis and reveal their association with different facial types. METHODS: Computed tomography scans of the head and neck of 311 adults (163 males, 148 females; age range, 18-95 years) were classified into 3 facial types: short, average, and long. Height, width, projection, inclination, thickness, and area were measured on the chin and symphysis. RESULTS: The majority of the population (70%) manifested an average facial type; the other 30% were almost equally distributed between short and long facial types. The long facial type was more common among females and the short facial type among males. Chin projection, area, and size were significantly greater in short-faced patients. Chin width in males was similar for all facial types, whereas, in females, chin width was the widest in the short facial type and the narrowest in the long facial type. Symphysis height was significantly greater in long-faced patients in both sexes. The mandibular incisors' inclination relative to the mandibular plane was not significantly associated with the chin or symphysis morphology. CONCLUSIONS: Chin and symphysis morphology is facial type-dependent. Orthodontists and maxillofacial surgeons should be aware of the complex relationship between facial types and chin/symphysis size and shape when planning treatment.

Post-Orthodontic Lower Incisors Recessions: Combined Periodontic and Orthodontic Approach.

The bonded lingual retainer (BLR) is considered a favorable choice for retaining lower incisors' alignment post-orthodontic treatment; however, it may cause some unwanted effects such as inadvertent tooth movement and torque changes. These often result in gingival recession (Miller class III-type) with exposure of the root surface, which compromises the esthetics and hinders the comfort of the patient. Fifteen post-orthodontic patients presenting Miller class III-type recessions with BLR were examined. Two protocols were used: the first included the removal of the BLR prior to surgery and the second included only a surgical approach. All patients underwent the same surgery of a modified tunnel double papilla procedure for root coverage. The gingival recession was measured using a dental probe before, and three to six months post-surgery. The average improvement in recession depth was significantly greater (p = 0.008) for the protocol that included removal of the BLR (4.0 ± 0.83 mm) with an improvement of 87.2% as compared to the second protocol that showed an improvement of 43.8% (1.88 ± 1.29 mm). Removing the BLR prior to surgery is beneficial for predictable root coverage in post-orthodontic Miller class III recessions.

Upper Lip Horizontal Line: Characteristics of a Dynamic Facial Line.

Background: Upper lip appearance received major attention with the introduction of diverse treatment modalities, including lip augmentation, rhinoplasty surgery, and dental treatment designed to support the upper lip. Our objectives were to define the prevalence and characteristics of the upper lip horizontal line (ULHL), which is a dynamic line appearing during a smile, in relation to gender, malocclusions, aging, and facial morphology. Methods: First, the prevalence and gender distribution of ULHL was examined from standardized en-face imaging at full smile of 643 randomly selected patients. Second, cephalometric and dental cast model analyses were made for 97 consecutive patients divided into three age groups. Results: ULHL appears in 13.8% of the population examined, and prevailed significantly more in females (78%). The prevalence of ULHL was not related to age nor to malocclusion. Patients presenting ULHL showed shorter upper lip and deeper lip sulcus. The skeletal pattern showed longer mid-face, shorter lower facial height and greater prevalence of a gummy smile. Conclusions: Female patients with short upper lip, concavity of the upper lip, and gummy smile are more likely to exhibit ULHL. The ULHL is not age-related and can be identified in children and young adults. Therefore, it should be considered when selecting diverse treatment modalities involving the upper lip.

The cancer paradigms of mammalian regeneration: can mammals regenerate as amphibians?

Regeneration in mammals is restricted to distinct tissues and occurs mainly by expansion and maturation of resident stem cells. During regeneration, even subtle mutations in the proliferating cells may cause a detrimental effect by eliciting abnormal differentiation or malignant transformation. Indeed, cancer in mammals has been shown to arise through deregulation of stem cells maturation, which often leads to a differentiation block and cell transformation. In contrast, lower organisms such as amphibians retain a remarkable regenerative capacity in various organs, which occurs via de- and re-differentiation of mature cells. Interestingly, regenerating amphibian cells are highly resistant to oncogenic transformation. Therapeutic approaches to improve mammalian regeneration mainly include stem-cell transplantations; but, these have proved unsuccessful in non-regenerating organs such as the heart. A recently developed approach is to induce de-differentiation of mature cardiomyocytes using factors that trigger their re-entry into the cell cycle. This novel approach raises numerous questions regarding the balance between transformation and regeneration induced by de-differentiation of mature mammalian somatic cells. Can this balance be controlled artificially? Do de-differentiated cells acquire the protection mechanisms seen in regenerating cells of lower organisms? Is this model unique to the cardiac tissue, which rarely develops tumors? This review describes regeneration processes in both mammals and lower organisms and, particularly, the ability of regenerating cells to avoid transformation. By comparing the characteristics of mammalian embryonic and somatic cells, we discuss therapeutic strategies of using various cell populations for regeneration. Finally, we describe a novel cardiac regeneration approach and its implications for regenerative medicine.

ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation.

The murine neonatal heart can regenerate after injury through cardiomyocyte (CM) proliferation, although this capacity markedly diminishes after the first week of life. Neuregulin-1 (NRG1) administration has been proposed as a strategy to promote cardiac regeneration. Here, using loss- and gain-of-function genetic tools, we explore the role of the NRG1 co-receptor ERBB2 in cardiac regeneration. NRG1-induced CM proliferation diminished one week after birth owing to a reduction in ERBB2 expression. CM-specific Erbb2 knockout revealed that ERBB2 is required for CM proliferation at embryonic/neonatal stages. Induction of a constitutively active ERBB2 (caERBB2) in neonatal, juvenile and adult CMs resulted in cardiomegaly, characterized by extensive CM hypertrophy, dedifferentiation and proliferation, differentially mediated by ERK, AKT and GSK3ß/ß-catenin signalling pathways. Transient induction of caERBB2 following myocardial infarction triggered CM dedifferentiation and proliferation followed by redifferentiation and regeneration. Thus, ERBB2 is both necessary for CM proliferation and sufficient to reactivate postnatal CM proliferative and regenerative potentials.

A possible case of cherubism in a 17th-century Korean mummy.

Cherubism is a benign fibro-osseous disease of childhood limited specifically to the maxilla and mandible. The progressive replacement of the jaw bones with expansile multilocular cystic lesions causes eventual prominence of the lower face, and hence the classic "cherubic" phenotype reflecting variable extents of jaw hypertrophy. Histologically, this condition has been characterized as replacement of the normal bone matrix with multicystic pockets of fibrous stroma and osteoclastic giant cells. Because of radiographic features common to both, primarily the presence of multiloculated lucencies with heterogeneous "ground-glass" sclerosis on CT imaging, cherubism was long mistaken for a craniofacial subtype of fibrous dysplasia. In 1999, however, the distinct genetic basis for cherubism was mapped to chromosome 4p16.3 and the SH-3 binding protein SH3BP2. But while there are already three suspected cases of fibrous dysplasia amongst archaeological populations, no definitive cases of cherubism have yet been reported in historical populations. In the current study we describe micro- and macro-structural changes in the face of a 17th century Joseon Dynasty Korean mummy which may coincide with the clinic-pathologic and radiologic features of cherubism.

Socioeconomic and physical characteristics of individuals with degenerative lumbar spinal stenosis.

STUDY DESIGN: A descriptive study of the association between demographic factors, and physical characteristics, and degenerative lumbar spinal stenosis (DLSS). OBJECTIVE: To shed light on the association between socioeconomic parameters, physical characteristics, and DLSS. SUMMARY OF BACKGROUND DATA: Lumbar spinal stenosis is a prevalent and disabling condition in the aging population. DLSS is considered to be the most common type and is essentially associated with disc disease, facet joint arthrosis, ligamentum flavum thickening, and osteophyte formation. Although there is ample information regarding the association between body mass index, cardiovascular disorders, smoking habits, and disc disease, very little is known about their association with DLSS. Data on the association of body physique (e.g., height and weight) and DLSS are limited. METHODS: Two sample populations were studied. The first included 165 individuals with DLSS (mean age, 64 ± 9.9 yr) and the second 180 individuals without spinal stenosis related symptoms (mean age, 62.5 ± 12.6 yr). An evaluation of the cross-sectional area of the dural sac and degenerative listhesis for all participants was performed using computed tomographic lumbar spine images, obtained by Philips EBW station (Brilliance 64, Philips Medical System, Cleveland, OH). All participants were interviewed to obtain demographic, physical, and health data. Independent t test, Mann-Whitney and χ tests were used to determine the association between parametric and nonparametric variables and DLSS. Logistic regression analysis was carried out to reveal predicting variables for DLSS. RESULTS: Females with stenosis were significantly heavier and shorter than their counterparts in the control group. We also noticed that they delivered babies more often than those in the control group. Prevalence of individuals experiencing diabetes mellitus was significantly higher in the males with stenosis than control group. In the stenosis group, the frequencies of individuals engaged in heavy manual labor (males) and housekeeping (females) were significantly higher than that of their counterparts in the control group. CONCLUSION: Heavy manual labor and diabetes mellitus in males and housekeeping (females) play major roles in the genesis of DLSS.

p53 coordinates cranial neural crest cell growth and epithelial-mesenchymal transition/delamination processes.

Neural crest development involves epithelial-mesenchymal transition (EMT), during which epithelial cells are converted into individual migratory cells. Notably, the same signaling pathways regulate EMT function during both development and tumor metastasis. p53 plays multiple roles in the prevention of tumor development; however, its precise roles during embryogenesis are less clear. We have investigated the role of p53 in early cranial neural crest (CNC) development in chick and mouse embryos. In the mouse, p53 knockout embryos displayed broad craniofacial defects in skeletal, neuronal and muscle tissues. In the chick, p53 is expressed in CNC progenitors and its expression decreases with their delamination from the neural tube. Stabilization of p53 protein using a pharmacological inhibitor of its negative regulator, MDM2, resulted in reduced SNAIL2 (SLUG) and ETS1 expression, fewer migrating CNC cells and in craniofacial defects. By contrast, electroporation of a dominant-negative p53 construct increased PAX7(+) SOX9(+) CNC progenitors and EMT/delamination of CNC from the neural tube, although the migration of these cells to the periphery was impaired. Investigating the underlying molecular mechanisms revealed that p53 coordinates CNC cell growth and EMT/delamination processes by affecting cell cycle gene expression and proliferation at discrete developmental stages; disruption of these processes can lead to craniofacial defects.

SPATA18, a spermatogenesis-associated gene, is a novel transcriptional target of p53 and p63.

The transcription factor p53 functions not only to suppress tumorigenesis but also to maintain normal development and homeostasis. Although p53 was implicated in different aspects of fertility, including spermatogenesis and implantation, the mechanism underlying p53 involvement in spermatogenesis is poorly resolved. In this study we describe the identification of a spermatogenesis-associated gene, SPATA18, as a novel p53 transcriptional target and show that SPATA18 transcription is induced by p53 in a variety of cell types of both human and mouse origin. p53 binds a consensus DNA motif that resides within the first intron of SPATA18. We describe the spatiotemporal expression patterns of SPATA18 in mouse seminiferous tubules and suggest that SPATA18 transcription is regulated in vivo by p53. We also demonstrate the induction of SPATA18 by p63 and suggest that p63 can compensate for the loss of p53 activity in vivo. Our data not only enrich the known collection of p53 targets but may also provide insights on spermatogenesis defects that are associated with p53 deficiency.

Mutant p53 facilitates somatic cell reprogramming and augments the malignant potential of reprogrammed cells.

p53 deficiency enhances the efficiency of somatic cell reprogramming to a pluripotent state. As p53 is usually mutated in human tumors and many mutated forms of p53 gain novel activities, we studied the influence of mutant p53 (mut-p53) on somatic cell reprogramming. Our data indicate a novel gain of function (GOF) property for mut-p53, which markedly enhanced the efficiency of the reprogramming process compared with p53 deficiency. Importantly, this novel activity of mut-p53 induced alterations in the characteristics of the reprogrammed cells. Although p53 knockout (KO) cells reprogrammed with only Oct4 and Sox2 maintained their pluripotent capacity in vivo, reprogrammed cells expressing mutant p53 lost this capability and gave rise to malignant tumors. This novel GOF of mut-p53 is not attributed to its effect on proliferation, as both p53 KO and mut-p53 cells displayed similar proliferation rates. In addition, we demonstrate an oncogenic activity of Klf4, as its overexpression in either p53 KO or mut-p53 cells induced aggressive tumors. Overall, our data show that reprogrammed cells with the capacity to differentiate into the three germ layers in vitro can form malignant tumors, suggesting that in genetically unstable cells, such as those in which p53 is mutated, reprogramming may result in the generation of cells with malignant tumor-forming potential.

p53-dependent transcriptional regulation of EDA2R and its involvement in chemotherapy-induced hair loss.

The p53 tumor suppressor coordinates a multitude of cellular and organismal processes and exerts its activities mainly by activation of gene transcription. Here we describe the transcriptional activation of ectodysplasin A2 receptor (EDA2R) by p53 in a variety of cell types and tissues. We demonstrate that treatment of cancer cells with the ligand EDA-A2, known to specifically activate EDA2R, results in p53-dependent cell death. Moreover, we show that EDA2R is transactivated by p53 during chemotherapy-induced hair-loss, although its presence is not necessary for this process. These data shed new light on the role of EDA2R in exerting p53 function.

p53 is balancing development, differentiation and de-differentiation to assure cancer prevention.

Many of the roles played by the tumor suppressor p53 in restraining cancer initiation and progression are well established. These include the ability of p53 to induce cell-cycle arrest, DNA repair, senescence and apoptosis. In addition, during the 30 years of p53 research, numerous studies have implicated p53 in the regulation of differentiation and developmental pathways. Here, we summarize the data on these relatively less-characterized functions of p53, including its involvement in embryogenesis and various differentiation programs, as well as its function in restraining de-differentiation of mature somatic cells. Besides the well-known functions of p53 as a cell-cycle regulator and a mediator of apoptosis, both coincide with differentiation processes, p53 was shown to exert its effects on various differentiation programs via direct regulation of specific key factors controlling these programs. The complex regulation by p53, which acts to suppress or to induce differentiation, is mainly the result of the specific cell type and fate. We argue that regulation of differentiation is pivotal for the tumor-suppressive activity of p53, which act to maintain the proper cellular state, preventing improper maturation or reprogramming. This conclusion is further supporting the notion that aberrant differentiation is associated with malignant transformation.

Cloned myogenic cells can transdifferentiate in vivo into neuron-like cells.

BACKGROUND: The question of whether intact somatic cells committed to a specific differentiation fate, can be reprogrammed in vivo by exposing them to a different host microenvironment is a matter of controversy. Many reports on transdifferentiation could be explained by fusion with host cells or reflect intrinsic heterogeneity of the donor cell population. METHODOLOGY/PRINCIPAL FINDINGS: We have tested the capacity of cloned populations of mouse and human muscle progenitor cells, committed to the myogenic pathway, to transdifferentiate to neurons, following their inoculation into the developing brain of newborn mice. Both cell types migrated into various brain regions, and a fraction of them gained a neuronal morphology and expressed neuronal or glial markers. Likewise, inoculated cloned human myogenic cells expressed a human specific neurofilament protein. Brain injected donor cells that expressed a YFP transgene controlled by a neuronal specific promoter, were isolated by FACS. The isolated cells had a wild-type diploid DNA content. CONCLUSIONS: These and other results indicate a genuine transdifferentiation phenomenon induced by the host brain microenvironment and not by fusion with host cells. The results may potentially be relevant to the prospect of autologous cell therapy approach for CNS diseases.

Transplanted myogenic progenitor cells express neuronal markers in the CNS and ameliorate disease in experimental autoimmune encephalomyelitis.

This study explores the potential of non-neural progenitor cells for CNS cell therapy. Muscle progenitor cells (MPCs), transplanted either intraventricularly or intraperitonealy, incorporated into the CNS of EAE-induced but not of naïve mice. Some of the migrating MPCs expressed the neuronal marker beta-III-Tubulin and gained neuronal morphology. Co-treatment of transplanted mice with the immunomodulatory agent glatiramer acetate (GA, Copaxone) resulted in improved MPCs incorporation and differentiation towards the neuronal pathway. The therapeutic potential of myogenic progenitor cells was demonstrated by amelioration of clinical symptoms and reduced mortality in EAE mice, as well as by expression of IL-10, TGF-beta, and the neurotrophin-BDNF.

p53 plays a role in mesenchymal differentiation programs, in a cell fate dependent manner.

BACKGROUND: The tumor suppressor p53 is an important regulator that controls various cellular networks, including cell differentiation. Interestingly, some studies suggest that p53 facilitates cell differentiation, whereas others claim that it suppresses differentiation. Therefore, it is critical to evaluate whether this inconsistency represents an authentic differential p53 activity manifested in the various differentiation programs. METHODOLOGY/PRINCIPAL FINDINGS: To clarify this important issue, we conducted a comparative study of several mesenchymal differentiation programs. The effects of p53 knockdown or enhanced activity were analyzed in mouse and human mesenchymal cells, representing various stages of several differentiation programs. We found that p53 down-regulated the expression of master differentiation-inducing transcription factors, thereby inhibiting osteogenic, adipogenic and smooth muscle differentiation of multiple mesenchymal cell types. In contrast, p53 is essential for skeletal muscle differentiation and osteogenic re-programming of skeletal muscle committed cells. CONCLUSIONS: These comparative studies suggest that, depending on the specific cell type and the specific differentiation program, p53 may exert a positive or a negative effect, and thus can be referred as a "guardian of differentiation" at large.

Regeneration and transdifferentiation potential of muscle-derived stem cells propagated as myospheres.

We have isolated from mouse skeletal muscle a subpopulation of slow adherent myogenic cells that can proliferate for at least several months as suspended clusters of cells (myospheres). In the appropriate conditions, the myospheres adhere to the plate, spread out, and form a monolayer of MyoD(+) cells. Unlike previously described myogenic cell lines, most of the myosphere cells differentiate, without cell fusion, into thin mononucleated contractile fibers, which express myogenin and skeletal muscle myosin heavy chain. The presence of Pax-7 in a significant proportion of these cells suggests that they originate from satellite cells. The addition of leukemia inhibitory factor to the growth medium of the myospheres enhances proliferation and dramatically increases the proportion of cells expressing Sca-1, which is expressed by several types of stem cells. The capacity of myosphere cells to transdifferentiate to other mesodermal cell lineages was examined. Exposure of cloned myosphere cells to bone morphogenetic protein resulted in suppression of myogenic differentiation and induction of osteogenic markers such as alkaline phosphatase and osteocalcin. These cells also sporadically differentiated to adipocytes. Myosphere cells could not, so far, be induced to transdifferentiate to hematopoietic cells. When inoculated into injured muscle, myosphere-derived cells participated in regeneration, forming multinucleated cross-striated mature fibers. This suggests a potential medical application.

Proapoptotic BID is an ATM effector in the DNA-damage response.

The "BH3-only" proapoptotic BCL-2 family members are sentinels of intracellular damage. Here, we demonstrated that the BH3-only BID protein partially localizes to the nucleus in healthy cells, is important for apoptosis induced by DNA damage, and is phosphorylated following induction of double-strand breaks in DNA. We also found that BID phosphorylation is mediated by the ATM kinase and occurs in mouse BID on two ATM consensus sites. Interestingly, BID-/- cells failed to accumulate in the S phase of the cell cycle following treatment with the topoisomerase II poison etoposide; reintroducing wild-type BID restored accumulation. In contrast, introducing a nonphosphorylatable BID mutant did not restore accumulation in the S phase and resulted in an increase in cellular sensitivity to etoposide-induced apoptosis. These results implicate BID as an ATM effector and raise the possibility that proapoptotic BID may also play a prosurvival role important for S phase arrest.

BID-D59A is a potent inducer of apoptosis in primary embryonic fibroblasts.

The proapoptotic activity of BID seems to solely depend upon its cleavage to truncated tBID. Here we demonstrate that expression of a caspase-8 non-cleavable (nc) BID-D59A mutant or expression of wild type (wt) BID induces apoptosis in Bid -/-, caspase-8 -/-, and wt primary MEFs. Western blot analysis indicated that no cleavage products appeared in cells expressing ncBID. ncBID was as effective as wtBID in inducing cytochrome c release, caspase activation, and apoptosis. ncBID and wtBID (nc/wtBID) were much less effective than tBID in localizing to mitochondria and in inducing cytochrome c release, but only slightly less effective in inducing apoptosis. Studies with Apaf-1- and caspase-9-deficient primary MEFs indicated that both proteins were essential for nc/wtBID and for tBID-induced apoptosis. Most importantly, expression of non-apoptotic levels of either ncBID or wtBID in Bid -/- MEFs induced a similar and significant enhancement in apoptosis in response to a variety of death signals, which was accompanied by enhanced localization of BID to mitochondria and cytochrome c release. Thus, these results implicate full-length BID as an active player in the mitochondria during apoptosis.