Measuring the outcomes of lateral ridge augmentation using cone-beam computed tomography.

OBJECTIVES: Lateral ridge augmentation (LRA) is a surgical technique to gain bone prior to implant placement. Performing cone-beam computed tomography (CBCT) pre- and post-surgery allows for quantitative comparison of the buccal-lingual width and the vertical height of the edentulous ridges. This study used CBCT images to evaluate the bone regeneration following surgery. METHODS: A total of 30 cases from adult patients who underwent LRA and had high-quality CBCT images taken pre- and post-surgery from the same CBCT scanner were available for the retrospective study. Study data included linear measurements of the bone ridge width and height obtained from the middle of the edentulous ridge and a volumetric measurement of bone growth at the edentulous site observed on the CBCT scan. RESULTS: The reliability of the measurements was excellent as indicated by Intra-Class Coefficient values of 0.974 or higher. There was a significant mean bone increase from pre-surgery compared to post-surgery for both the linear and volumetric measurements. The linear bone gain ranged from 1.5 to 2.5 mm and volumetric gain from 250 to 750 mm3 . However, two patients did not gain any bone. Multivariate regression showed the strongest predictors of bone gain post-surgery were the pre-surgery bone volume and a surgical site being in the mandible. For maxillary surgical sites, particularly anterior areas, the LRA surgeries were the least successful. CONCLUSIONS: LRA before implant placement helped to increase bone for the majority of patients, particularly for surgical sites in the mandible. The quantitative analyses in the CBCT images showed excellent intra-examiner agreement.

Connecting the dots towards precision orthodontics.

Precision orthodontics entails the use of personalized clinical, biological, social and environmental knowledge of each patient for deep individualized clinical phenotyping and diagnosis combined with the delivery of care using advanced customized devices, technologies and biologics. From its historical origins as a mechanotherapy and materials driven profession, the most recent advances in orthodontics in the past three decades have been propelled by technological innovations including volumetric and surface 3D imaging and printing, advances in software that facilitate the derivation of diagnostic details, enhanced personalization of treatment plans and fabrication of custom appliances. Still, the use of these diagnostic and therapeutic technologies is largely phenotype driven, focusing mainly on facial/skeletal morphology and tooth positions. Future advances in orthodontics will involve comprehensive understanding of an individual's biology through omics, a field of biology that involves large-scale rapid analyses of DNA, mRNA, proteins and other biological regulators from a cell, tissue or organism. Such understanding will define individual biological attributes that will impact diagnosis, treatment decisions, risk assessment and prognostics of therapy. Equally important are the advances in artificial intelligence (AI) and machine learning, and its applications in orthodontics. AI is already being used to perform validation of approaches for diagnostic purposes such as landmark identification, cephalometric tracings, diagnosis of pathologies and facial phenotyping from radiographs and/or photographs. Other areas for future discoveries and utilization of AI will include clinical decision support, precision orthodontics, payer decisions and risk prediction. The synergies between deep 3D phenotyping and advances in materials, omics and AI will propel the technological and omics era towards achieving the goal of delivering optimized and predictable precision orthodontics.

Morphological integration in inferior alveolar canal and mandibular shapes.

OBJECTIVE: During embryogenesis of mandible, the initial ossification centre begins at the bifurcation of the inferior alveolar (IA) and the mental nerves. Additionally, in congenital anomalies like craniofacial microsomia (CFM), the IA canal is completely absent on the microsomic side. These observations led us to hypothesise that there may be a morphological integration between these structures - the IA nerve and the mandibular shapes. Therefore, the primary objective of this study was to test for morphological integration between these structures and the secondary objective was to determine if there were shape variations in these structures among skeletal Classes I, II and III subjects. SETTING AND SAMPLE POPULATION: The sample size of the study is 80 full-head cone-beam computed tomography (CBCT) scans (age 16-56 years). METHODS: We retrieved CBCT scans from our archived database using specific inclusion/exclusion criteria. In the de-identified CBCT scans, traditional coordinate landmarks and sliding semi-landmarks were placed on the mandible and the IA canal (proxy for IA nerve). Using geometric morphometric analyses, we tested integration between the IA canal and the mandibular shapes. We used Procrustes ANOVA to test for overall shape variations among the three skeletal classes (Classes I, II and III). RESULTS: The IA canal and posterior/inferior border of mandible showed strong integration (r-PLS = .845, P = .001). Similar strong integration was also observed between the IA canal and the overall shape of the mandible (r-PLS = .866, P = .001). Additionally, there was a statistically significant variation in overall shape between skeletal Class I and Class II (P = .008) and Class II and Class III (P = .001). CONCLUSIONS: The strong integration between two structures suggests that the IA nerve may play a role in establishing mandibular shape early in development. We posit this may be important in driving mandibular defects seen in CFM, which warrants further investigation.

Applications, functions, and accuracy of artificial intelligence in restorative dentistry: A literature review.

OBJECTIVE: The applications of artificial intelligence (AI) are increasing in restorative dentistry; however, the AI performance is unclear for dental professionals. The purpose of this narrative review was to evaluate the applications, functions, and accuracy of AI in diverse aspects of restorative dentistry including caries detection, tooth preparation margin detection, tooth restoration design, metal structure casting, dental restoration/implant detection, removable partial denture design, and tooth shade determination. OVERVIEW: An electronic search was performed on Medline/PubMed, Embase, Web of Science, Cochrane, Scopus, and Google Scholar databases. English-language articles, published from January 1, 2000, to March 1, 2022, relevant to the aforementioned aspects were selected using the key terms of artificial intelligence, machine learning, deep learning, artificial neural networks, convolutional neural networks, clustering, soft computing, automated planning, computational learning, computer vision, and automated reasoning as inclusion criteria. A manual search was also performed. Therefore, 157 articles were included, reviewed, and discussed. CONCLUSIONS: Based on the current literature, the AI models have shown promising performance in the mentioned aspects when being compared with traditional approaches in terms of accuracy; however, as these models are still in development, more studies are required to validate their accuracy and apply them to routine clinical practice. CLINICAL SIGNIFICANCE: AI with its specific functions has shown successful applications with acceptable accuracy in diverse aspects of restorative dentistry. The understanding of these functions may lead to novel applications with optimal accuracy for AI in restorative dentistry.

Embryonic inhibition of colony-stimulating factor 1 receptor impacts craniofacial morphogenesis.

OBJECTIVES: Colony-stimulating factor-1 receptor (CSF1R) is vital for the recruitment of monocytes, and their proliferation and differentiation into functional osteoclasts. Mouse studies, where CSF1R and its cognate ligand are absent, have significant craniofacial phenotypes, but these have not been studied in detail. MATERIALS AND METHODS: Pregnant CD1 mice were fed diets laced with CSF1R inhibitor-PLX5622 starting at embryonic day 3.5 (E3.5) up to birth. Pups were collected at E18.5 to study CSF1R expression using immunofluorescence. Additional pups were studied at postnatal day 21 (P21) and P28 using microcomputed tomography (µCT) and Geometric Morphometrics, to evaluate craniofacial form. RESULTS: CSF1R-positive cells were present throughout the developing craniofacial region, including the jaw bones, surrounding teeth, tongue, nasal cavities, brain, cranial vault and base regions. Animals exposed to the CSF1R inhibitor in utero had severe depletion of CSF1R-positive cells at E18.5 and had significant differences in craniofacial form (size and shape) at postnatal timepoints. Centroid sizes for the mandibular and cranio-maxillary regions were significantly smaller in CSF1R-inhibited animals. Proportionally, these animals had a domed skull, with taller and wider cranial vaults and shortening of their midfacial regions. Mandibles were smaller vertically and anterio-posteriorly, with proportionally wider inter-condylar distances. CONCLUSIONS: Embryonic inhibition of CSF1R impacts postnatal craniofacial morphogenesis, with significant influences on the mandibular and cranioskeletal size and shape. These data indicate that CSF1R plays a role in early cranio-skeletal patterning, likely through osteoclast depletion.

A retrospective study of incidental findings occurring in a consecutive case series of lateral cephalograms of 12- to 20-year-old patients referred for routine orthodontic treatment.

Purpose: Lateral cephalograms of orthodontic patients may contain incidental findings that could potentially lead to harm. Materials and Methods: The lateral cephalograms of 1765 consecutive 12- to 20-year-old patients, being considered for routine orthodontic treatment, were retrospectively reviewed. These patients were considered normal, because no abnormalities were found either in their medical history or on their clinical examination. Results: The overall prevalence of incidental findings was 18.8%, of which 10.3% were ponticulus posticus and 4.2% were bridging of the sella turcica. Although occipital spurs and ponticulus posticus were more prevalent in males, the size of the sella turcicas did not differ between sexes. Of the 1156 patients completing treatment about 2 years later, only one lateral cephalogram displayed progression of the ponticulus posticus in that time. Conclusion: The prevalence of incidental findings on lateral cephalograms of otherwise normal orthodontic 12- to 20-year-old patients was almost a fifth, of which ponticulus posticus, vertebral fusion, and enlarged parietal foramina were clinically significant.

Craniofacial form differences between obese and nonobese children.

INTRODUCTION: Current evidence suggests that obesity is correlated with differences in craniofacial form in children and adolescents. Here, we sought to test this hypothesis by evaluating the craniofacial form of obese and nonobese preorthodontic patients, using 2D cephalometric data combined with cephalometric and geometric morphometric approaches. METHODS: Height, weight, age, and lateral cephalometric radiographs were gathered from patients aged 7-16 years before beginning orthodontic treatment at the University of British Columbia. Based on their body mass index, 24 obese patients were age, sex, and Angle classification of malocclusion matched with nonobese controls. Cephalometric radiographs were annotated, and coordinates of landmarks were used to obtain linear and angular cephalometric measurements. Geometric morphometric analyses were performed to determine overall craniofacial form differences between cohorts. Dental maturation index scores and cervical vertebral maturation scores were recorded as an indicator of skeletal maturation. RESULTS: Cephalometric analysis revealed that the maxillary length and gonial angle are the only marginally larger metrics in obese subjects than in control subjects. However, principal component and discriminant analyses (geometric morphometrics) confirmed that the overall craniofacial form of obese patients differs statistically from that of control patients. Obese patients tend to be slightly mandibular prognathic and brachycephalic. Dental maturation index scores were statistically higher in the obese group than in the control group, with no statistical difference in cervical vertebral maturation scores. CONCLUSIONS: Our data reveals a subtle but significant difference in cranial skeletal morphology between obese and nonobese children and adolescents, suggesting a correlation between craniofacial form and physiological/metabolic phenotypes of subjects. It is likely that with continued growth, these differences may increase. Recording body mass index as part of the orthodontic records for patients may help in supporting the assessment of craniofacial form.

A 3D analysis of growth trajectory and integration during early human prenatal facial growth.

Significant shape changes in the human facial skeleton occur in the early prenatal period, and understanding this process is critical for studying a myriad of congenital facial anomalies. However, quantifying and visualizing human fetal facial growth has been challenging. Here, we applied quantitative geometric morphometrics (GM) to high-resolution magnetic resonance images of human embryo and fetuses, to comprehensively analyze facial growth. We utilized non-linear growth estimation and GM methods to assess integrated epigenetic growth between masticatory muscles and associated bones. Our results show that the growth trajectory of the human face in the early prenatal period follows a curved line with three flexion points. Significant antero-posterior development occurs early, resulting in a shift from a mandibular prognathic to relatively orthognathic appearance, followed by expansion in the lateral direction. Furthermore, during this time, the development of the zygoma and the mandibular ramus is closely integrated with the masseter muscle.

Analysis of facial skeletal asymmetry during foetal development using µCT imaging.

OBJECTIVES: Asymmetry has been noted in the human craniofacial region in several pathological conditional and growth abnormalities, often with a directional predilection. Physiological asymmetry has also been reported in normal adults and adolescents, with certain regions of the cranioskeleton, such as the mandible, displaying prevalent asymmetry. However, the timing at which such asymmetries arise has not been evaluated. The objectives of this study were to assess the degree of asymmetry in facial bones during the foetal stages of human development. MATERIAL AND METHODS: Twenty-one preserved conceptuses from the Congenital Anomaly Research Center at Kyoto University, between ages 15 and 20 weeks of gestation, were studied using high-resolution µCT imaging. Asymmetry analysis was performed on digitally segmented facial bone pairs, using geometric morphometric (GM) approaches as well as adapted deformation-based asymmetry (DBA) methods. RESULTS: GM analysis revealed that the developing facial bones display statistically significant fluctuating and directional asymmetry. DBA methods suggest that the magnitude of asymmetry in facial bones is low and does not appear to be correlated to the estimate of overall size of conceptus. Additionally, the patterns of asymmetry are highly variable between individual specimens. CONCLUSIONS: The developing foetal facial skeleton displays variable patterns of low magnitude asymmetry. GM and DBA methods offer unique advantages to assess facial asymmetry quantitatively and qualitatively.

Reliability of upper airway assessment using CBCT.

Background: Upper airway analysis is an often-cited use of CBCT imaging by orthodontists; however, the reliability of airway measurements using this technology is not fully established. Objective: To determine the intra-examiner and inter-examiner reliability of the complete process of volumetric and cross-sectional area assessments of the upper airway using CBCT imaging. Materials and Methods: Six examiners of varying levels of education and clinical experience performed the steps necessary for airway analysis, including manual orientation, slice and threshold selection and measured nasopharyngeal, oropharyngeal, hypopharyngeal and total upper pharyngeal airway volumes in addition to minimum cross-sectional area on the CBCT images of 10 patients. All measurements were repeated after 4-weeks. Intra- and inter-examiner reliability was calculated using ICC and 95% CI. Results: Threshold selection showed poor intra- and poor inter-examiner reliability, whereas minimum cross-sectional area showed moderate intra- and poor inter-examiner reliability. Intra-examiner reliability of volumetric measurements varied based on the region assessed with ICC ranging from 0.747 to 0.976, and was worst for hypopharynx and best for the oropharynx. Inter-examiner reliability of volume measurements was generally lower, with ICC ranging from 0.175 to 0.945, and was worst for nasopharynx and best for the oropharynx. Conclusions: This study, for the first time, assessed the reliability of upper airway analysis with CBCT when all steps of image processing and measurement are performed by each examiner. Reliability improved with examiner experience, though was generally low for the hypopharynx and nasopharynx volumes and overall minimal cross-sectional area. The oropharyngeal volume was the only parameter to have excellent intra- and inter-examiner reliability.

Depletion of embryonic microglia using the CSF1R inhibitor PLX5622 has adverse sex-specific effects on mice, including accelerated weight gain, hyperactivity and anxiolytic-like behaviour.

Microglia are the resident immune cells in the central nervous system (CNS). Originally thought to be primarily responsible for disposing of cellular debris and responding to neural insults, emerging research now shows that microglia are highly dynamic cells involved in a variety of neurodevelopmental processes. The hypothalamus is a brain region critical for maintaining homeostatic processes such as energy balance, thirst, food intake, reproduction, and circadian rhythms. Given that microglia colonize the embryonic brain alongside key steps of hypothalamic development, here we tested whether microglia are required for the proper establishment of this brain region. The Colony-stimulating factor-1 receptor (Csf1r) is expressed by microglia, macrophages and osteoclasts, and is required for their proliferation, differentiation, and survival. Therefore, to eliminate microglia from the fetal brain, we treated pregnant dams with the CSF1R inhibitor PLX5622. We showed that approximately 99% of microglia were eliminated by embryonic day 15.5 (E15.5) after pregnant dams were placed on a PLX5622 diet starting at E3.5. Following microglia depletion, we observed elevated numbers of apoptotic cells accumulating throughout the developing hypothalamus. Once the PLX5622 diet was removed, microglia repopulated the postnatal brain within 7 days and did not appear to repopulate from Nestin+ precursors. Embryonic microglia depletion also resulted in a decreased litter size, as well as an increase in the number of pups that died within the first two postnatal days of life. In pups that survived, the elimination of microglia in the fetal brain resulted in a decrease in the number of Pro-opiomelanocortin (POMC) neurons and a concomitant accelerated weight gain starting at postnatal day 5 (P5), suggesting that microglia could be important for the development of cell types key to hypothalamic satiety centers. Moreover, surviving PLX5622 exposed animals displayed craniofacial and dental abnormalities, perhaps due to non-CNS effects of PLX5622 on macrophages and/or osteoclasts. Finally, depletion of microglia during embryogenesis had long-term sex-specific effects on behaviour, including the development of hyperactivity and anxiolytic-like behaviour in juvenile and adult female mice, respectively. Together, these data demonstrate an important role for microglia during the development of the embryonic hypothalamus, and perhaps the CNS more broadly.

Genetic Disorders of Dental Development: Tales from the Bony Crypt.

PURPOSE OF REVIEW: The ebb and flow of genetic influence relative to the understanding of craniofacial and dental disorders has evolved into a tacit acceptance of the current genetic paradigm. This review explores the science behind craniofacial and dental disorders through the lens of recent past and current findings and using tooth agenesis as a model of advances in craniofacial genetics. RECENT FINDINGS: Contemporary studies of craniofacial biology takes advantage of the technological resources stemming from the genomic and post-genomic eras. Emerging data highlights the role of key genes and the epigenetic landscape controlling these genes, in causing dentofacial abnormalities. We also report here a novel Glu78FS MSX1 mutation in one family segregating an autosomal dominant form of severe tooth agenesis as an illustration of an evolving theme, i.e., different mutations in the same gene can result in a spectrum of dentofacial phenotypic severity. The future of clinical therapeutics will benefit from advances in genetics and molecular biology that refine the genotype-phenotype correlation. Indeed, the past century suggests a continued convergence of genetic science in the practice of clinical dentistry.

Postnatal Ontogeny of the Cranial Base and Craniofacial Skeleton in Male C57BL/6J Mice: A Reference Standard for Quantitative Analysis.

Growth of the craniofacial skeleton is a complex process controlled by both genetic and epigenetic factors, perturbations of which can lead to varying degrees of dysmorphology. Mouse models that recapitulate clinical craniofacial phenotypes are instrumental in studying the morphogenetic progression of diseases as well as uncovering their genetic and molecular bases. Commonly encountered phenotypes in these models include defects in the cranial base synchondroses, calvarial sutures, mandible or the midface, or any combination thereof, with the concurrent presence of altered overall craniofacial growth. However, the literature lacks an adequate normative timeline of developmental events and growth trends that shape the mouse craniofacial skeleton. In this report, we analyzed the postnatal craniofacial ontogeny (from postnatal day 7 [P7] through to P112) of male mice from the most widely used inbred mouse strain, C57BL/6J, using high-resolution microcomputed tomography (µCT) in combination with classic morphometric approaches. We also evaluated cranial base synchondroses at the histological level, and compared it to µCT-generated data to assess the timing and pattern of closure of these structures. Our data underscore the complex and unique growth patterns of individual bones and cranial regions and highlight the need to include younger animals in studies aimed at analyzing craniofacial growth processes. Furthermore, these data serve as a reference standard for future quantitative work.

Characterization of recombinant lysyl oxidase propeptide.

Lysyl oxidase enzyme activity is critical for the biosynthesis of mature and functional collagens and elastin. In addition, lysyl oxidase has tumor suppressor activity that has been shown to depend on the propeptide region (LOX-PP) derived from pro-lysyl oxidase (Pro-LOX) and not on lysyl oxidase enzyme activity. Pro-LOX is secreted as a 50 kDa proenzyme and then undergoes biosynthetic proteolytic processing to active approximately 30 kDa LOX enzyme and LOX-PP. The present study reports the efficient recombinant expression and purification of rat LOX-PP. Moreover, using enzymatic deglycosylation and DTT derivatization combined with mass spectrometry technologies, it is shown for the first time that rLOX-PP and naturally occurring LOX-PP contain both N- and O-linked carbohydrates. Structure predictions furthermore suggest that LOX-PP is a mostly disordered protein, which was experimentally confirmed in circular dichroism studies. Due to its high isoelectric point and its disordered structure, we propose that LOX-PP can associate with extracellular and intracellular binding partners to affect its known biological activities as a tumor suppressor and inhibitor of cell proliferation.

Lysyl oxidase propeptide inhibits FGF-2-induced signaling and proliferation of osteoblasts.

Pro-lysyl oxidase is secreted as a 50-kDa proenzyme and is then cleaved to a 30-kDa mature enzyme (lysyl oxidase (LOX)) and an 18-kDa propeptide (lysyl oxidase propeptide (LOX-PP)). The presence of LOX-PP in the cell layers of phenotypically normal osteoblast cultures led us to investigate the effects of LOX-PP on osteoblast differentiation. Data indicate that LOX-PP inhibits terminal mineralization in primary calvaria osteoblast cultures when added at early stages of differentiation, with no effects seen when present at later stages. LOX-PP was found to inhibit serum- and FGF-2-stimulated DNA synthesis and FGF-2-stimulated cell growth. Enzyme-linked immunosorbent assay and Western blot analyses show that LOX-PP inhibits FGF-2-induced ERK1/2 phosphorylation, signaling events that mediate the FGF-2-induced proliferative response. LOX-PP inhibits FGF-2-stimulated phosphorylation of FRS2alpha and FGF-2-stimulated DNA synthesis, even after inhibition of sulfation of heparan sulfate proteoglycans. These data point to a LOX-PP target at or near the level of fibroblast growth factor receptor binding or activation. Ligand binding assays on osteoblast cell layers with (125)I-FGF-2 demonstrate a concentration-dependent inhibition of FGF-2 binding to osteoblasts by LOX-PP. In vitro binding assays with recombinant fibroblast growth factor receptor protein revealed that LOX-PP inhibits FGF-2 binding in an uncompetitive manner. We propose a working model for the respective roles of LOX enzyme and LOX-PP in osteoblast phenotype development in which LOX-PP may act to inhibit the proliferative response possibly to allow cells to exit from the cell cycle and progress to the next stages of differentiation.

A loss-of-function polymorphism in the propeptide domain of the LOX gene and breast cancer.

The lysyl oxidase (LOX) gene reverted Ras transformation of NIH 3T3 fibroblasts and tumor formation by gastric cancer cells, which frequently carry mutant RAS genes. The secreted lysyl oxidase proenzyme is processed to a propeptide (LOX-PP) and a functional enzyme (LOX). Unexpectedly, the tumor suppressor activity mapped to the LOX-PP domain, which inhibited tumor formation and the invasive phenotype of NF639 breast cancer cells driven by human epidermal growth factor receptor-2/neu, which signals via Ras. A single-nucleotide polymorphism, G473A (rs1800449), resulting in an Arg158Gln substitution in a highly conserved region within LOX-PP, occurs with an average 473A allele carrier frequency of 24.6% in the HapMap database, but was present in many breast cancer cell lines examined. Here, we show that the Arg-to-Gln substitution profoundly impairs the ability of LOX-PP to inhibit the invasive phenotype and tumor formation of NF639 cells in a xenograft model. LOX-PP Gln displayed attenuated ability to oppose the effects of LOX, which promoted a more invasive phenotype. In a case-control study of African American women, a potential association of the Gln-encoding A allele was seen with increased risk of estrogen receptor (ER)-alpha-negative invasive breast cancer in African American women. Consistently, LOX gene expression was higher in ER-negative versus ER-positive primary breast cancers, and LOX-PP Gln was unable to inhibit invasion by ER-negative cell lines. Thus, these findings identify for the first time genetic polymorphism as a mechanism of impaired tumor suppressor function of LOX-PP and suggest that it may play an etiologic role in ER-negative breast cancer.

The lysyl oxidase pro-peptide attenuates fibronectin-mediated activation of focal adhesion kinase and p130Cas in breast cancer cells.

The lysyl oxidase (LOX) gene encodes an enzyme (LOX) critical for extracellular matrix maturation. The LOX gene has also been shown to inhibit the transforming activity of Ras oncogene signaling. In particular, the pro-peptide domain (LOX-PP) released from the secreted precursor protein (Pro-LOX) was found to inhibit the transformed phenotype of breast, lung, and pancreatic cancer cells. However, the mechanisms of action of LOX-PP remained to be determined. Here, the ability of LOX-PP to attenuate the integrin signaling pathway, which leads to phosphorylation of focal adhesion kinase (FAK), and the activation of its downstream target p130Cas, was determined. In NF639 breast cancer cells driven by Her-2/neu, which signals via Ras, ectopic Pro-LOX and LOX-PP expression inhibited fibronectin-stimulated protein tyrosine phosphorylation. Importantly, phosphorylation of FAK on Tyr-397 and Tyr-576, and p130Cas were substantially reduced. The amount of endogenous p130Cas in the Triton X-100-insoluble protein fraction, and fibronectin-activated haptotaxis were decreased. Interestingly, expression of mature LOX enzyme enhanced fibronectin-stimulated integrin signaling. Of note, treatment with recombinant LOX-PP selectively reduced fibronectin-mediated haptotaxis of NF639, MDA-MB-231, and Hs578T breast cancer cells. Thus, evidence is provided that one mechanism of action of LOX-PP tumor suppression is to block fibronectin-stimulated signaling and cell migration.