Presentation and Outcome of Patients with Multiple Myeloma (MM), Single Centre Experience from Windsor Essex Regional Cancer Centre.

Introduction: Outcomes for patients with multiple myeloma has significantly improved through the years. This is mainly related to the use of novel agents. Methods: This is a retrospective study that reviewed presentation and outcome of 139 patients with multiple myeloma at the Windsor Essex Regional Cancer Centre from Jan. 1, 2015 to Dec. 31, 2019. Median age was 71 years and most patients had higher risk disease (65.5% either R ISS stage II or III). 30% had high risk FISH for myeloma including del.17P, t (4:14), t (14:16) and Gain (1q21). In terms of presentation, 38.8% had anemia (hemoglobin <100g/L), 18.7% had hypercalcemia, 74.1% had skeletal lytic lesions, 38.8% had pathologic fracture and 17.3% had plasmacytoma. Results: Almost all (92%) of the patients were treated using at least one novel agent (proteasome inhibitor or immunomodulators [ImiDs]). Cyclophosphamide, bortezomib, and dexamethasone (CyBorD) was the most used treatment regimen (48.9%) followed by bortezomib, melphalan and prednisone (BMP) at 28.8% and lenalidomide, dexamethasone (LenDex) at 14.4%. With respect to response to therapy, 51.8% had at least Very good partial response (VGPR), while 9.4% had progressive disease. 33% had autologous stem cell transplant. After a median follow up of 2.4 years, median overall survival was 3.7 years. 2 years overall survival and relapse-free survival were 70% and 83%, respectively. Discussion: Our study showed comparable outcome for patients with multiple myeloma despite older age and higher risk disease. Outcome is expected to improve with the introduction of more novel agents.

Blood pH Analysis in Combination with Molecular Medical Tools in Relation to COVID-19 Symptoms.

The global outbreak of SARS-CoV-2/COVID-19 provided the stage to accumulate an enormous biomedical data set and an opportunity as well as a challenge to test new concepts and strategies to combat the pandemic. New research and molecular medical protocols may be deployed in different scientific fields, e.g., glycobiology, nanopharmacology, or nanomedicine. We correlated clinical biomedical data derived from patients in intensive care units with structural biology and biophysical data from NMR and/or CAMM (computer-aided molecular modeling). Consequently, new diagnostic and therapeutic approaches against SARS-CoV-2 were evaluated. Specifically, we tested the suitability of incretin mimetics with one or two pH-sensitive amino acid residues as potential drugs to prevent or cure long-COVID symptoms. Blood pH values in correlation with temperature alterations in patient bodies were of clinical importance. The effects of biophysical parameters such as temperature and pH value variation in relation to physical-chemical membrane properties (e.g., glycosylation state, affinity of certain amino acid sequences to sialic acids as well as other carbohydrate residues and lipid structures) provided helpful hints in identifying a potential Achilles heel against long COVID. In silico CAMM methods and in vitro NMR experiments (including 31P NMR measurements) were applied to analyze the structural behavior of incretin mimetics and SARS-CoV fusion peptides interacting with dodecylphosphocholine (DPC) micelles. These supramolecular complexes were analyzed under physiological conditions by 1H and 31P NMR techniques. We were able to observe characteristic interaction states of incretin mimetics, SARS-CoV fusion peptides and DPC membranes. Novel interaction profiles (indicated, e.g., by 31P NMR signal splitting) were detected. Furthermore, we evaluated GM1 gangliosides and sialic acid-coated silica nanoparticles in complex with DPC micelles in order to create a simple virus host cell membrane model. This is a first step in exploring the structure-function relationship between the SARS-CoV-2 spike protein and incretin mimetics with conserved pH-sensitive histidine residues in their carbohydrate recognition domains as found in galectins. The applied methods were effective in identifying peptide sequences as well as certain carbohydrate moieties with the potential to protect the blood-brain barrier (BBB). These clinically relevant observations on low blood pH values in fatal COVID-19 cases open routes for new therapeutic approaches, especially against long-COVID symptoms.

Effects of onabotulinumtoxin A in patients concurrently diagnosed with chronic migraine encephalalgia and temporomandibular disorders: A retrospective case series.

OBJECTIVE: Chronic migraine encephalalgia (CME) with concomitant temporomandibular disorder (TMD) is a serious illness with limited effective treatment options. This study explores the effectiveness of onabotulinumtoxinA (BtxA) as an adjunct therapeutic to TMJ arthroscopy in the relief of CME. METHODS: A retrospective cohort study of patients receiving TMJ arthroscopy, with or without BtxA injections for CME, was conducted. Variables assessed include pain using a visual analog scale (VAS), maximal incisal opening (MIO), muscle soreness, and headache frequency and duration. RESULTS: Sixty patients (44 BtxA, 16 Control), consisting of 56 (93.3%) females, met inclusion criteria. A significant reduction in pain is reported with patients receiving BtxA (p < 0.0001) on VAS as compared to Control group. BtxA treatment also significantly reduced headache frequency and duration (p < 0.05). CONCLUSION: These results support the use of adjunctive BtxA treatment with arthroscopy for the treatment of CME in the context of TMD.

Efficacy of Chondroprotective Food Supplements Based on Collagen Hydrolysate and Compounds Isolated from Marine Organisms.

Osteoarthritis belongs to the most common joint diseases in humans and animals and shows increased incidence in older patients. The bioactivities of collagen hydrolysates, sulfated glucosamine and a special fatty acid enriched dog-food were tested in a dog patient study of 52 dogs as potential therapeutic treatment options in early osteoarthritis. Biophysical, biochemical, cell biological and molecular modeling methods support that these well-defined substances may act as effective nutraceuticals. Importantly, the applied collagen hydrolysates as well as sulfated glucosamine residues from marine organisms were strongly supported by both an animal model and molecular modeling of intermolecular interactions. Molecular modeling of predicted interaction dynamics was evaluated for the receptor proteins MMP-3 and ADAMTS-5. These proteins play a prominent role in the maintenance of cartilage health as well as innate and adapted immunity. Nutraceutical data were generated in a veterinary clinical study focusing on mobility and agility. Specifically, key clinical parameter (MMP-3 and TIMP-1) were obtained from blood probes of German shepherd dogs with early osteoarthritis symptoms fed with collagen hydrolysates. Collagen hydrolysate, a chondroprotective food supplement was examined by high resolution NMR experiments. Molecular modeling simulations were used to further characterize the interaction potency of collagen fragments and glucosamines with protein receptor structures. Potential beneficial effects of collagen hydrolysates, sulfated glycans (i.e., sulfated glucosamine from crabs and mussels) and lipids, especially, eicosapentaenoic acid (extracted from fish oil) on biochemical and physiological processes are discussed here in the context of human and veterinary medicine.

True Unilateral Mandibular Cherubism: A Literature Review and Case Report.

Cherubism is a self-limiting fibro-osseous disorder that is classically characterized by bilateral mandibular swelling in the first or second decade of life. Three cases of unilateral cherubism have been described in the literature; however, bilateral involvement did not eventually develop in only 1 case. Histopathologic variation and genetic heterogeneity complicate the diagnosis and treatment of a unilateral benign giant cell lesion of the jaws. Our case report presents a 13-year-old male patient with unilateral posterior mandibular swelling that proved to be histologically and clinically consistent with unilateral cherubism. Involution of the unilateral lesion with no bilateral involvement occurred during 8 years of serial examination.

Xenopus pitx3 target genes lhx1 and xnr5 are identified using a novel three-fluor flow cytometry-based analysis of promoter activation and repression.

BACKGROUND: Pitx3 plays a well understood role in directing development of lens, muscle fiber, and dopaminergic neurons; however, in Xenopus laevis, it may also play a role in early gastrulation and somitogenesis. Potential downstream targets of pitx3 possess multiple binding motifs that would not be readily accessible by conventional promoter analysis. RESULTS: We isolated and characterized pitx3 target genes lhx1 and xnr5 using a novel three-fluor flow cytometry tool that was designed to dissect promoters with multiple binding sites for the same transcription factor. This approach was calibrated using a known pitx3 target gene, Tyrosine hydroxylase. CONCLUSIONS: We demonstrate how flow cytometry can be used to detect gene regulatory changes with exquisite precision on a cell-by-cell basis, and establish that in HEK293 cells, pitx3 directly activates lhx1 and represses xnr5. Developmental Dynamics 246:657-669, 2017. © 2017 Wiley Periodicals, Inc.

Treatment of Osteomyelitis: A Case for Disruption of the Affected Adjacent Periosteum.

PURPOSE: To evaluate the response of mandibular osteomyelitis treated by surgical decortication with disruption of the affected adjacent periosteum in concert with long-term targeted antibiotic therapy. The hypothesis is that, by removing the buccal cortical plate and disrupting the hypertrophically inflamed adjacent periosteum, the medullary bone will be brought in contact with bleeding tissue and circulating immunologic factors and antibiotics, which will promote definitive resolution. PATIENTS AND METHODS: A retrospective review was conducted of 7 patient charts with associated radiographs from November 2010 to August 2016 treated by the first author at the University of Tennessee Medical Center (Knoxville, TN). Patients with chronic suppurative or nonsuppurative osteomyelitis of the mandible without condylar involvement or pathologic fracture were selected and treated with decortication with periosteal disruption in combination with long-term targeted antibiotic therapy. RESULTS: Seven patients (3 women and 4 men; mean age, 60 yr) underwent decortication with periosteal disruption of the affected area and received at least 6 weeks of targeted intravenous antibiotics. Computed tomography was performed preoperatively and a repeat study was performed after completion of antibiotics. In each case, post-treatment imaging showed definitive resolution after treatment with decortication in concert with disruption of the inflamed hypertrophic periosteum and intravenous antibiotics. CONCLUSION: Debridement of the infected cortical bone with restoration of the blood supply through disruption of the adjacent periosteum provided definitive resolution of mandibular osteomyelitis in the 7 patients treated. The hypothesis is that disruption of the affected adjacent periosteum reintroduces an immune-mediated response in concert with improved antibiotic delivery to and penetrance of the diseased mandible, aiding in definitive resolution. Decortication with periosteal disruption allows for preservation of the inferior alveolar nerve, maintains mandibular integrity, and obviates reconstructive surgery. Decortication with disruption of the adjacent periosteum, when combined with targeted antimicrobial therapy, produced definitive resolution of osteomyelitis as shown by postoperative imaging. It is the authors' assertion that not only decortication, but also disruption of the adjacent periosteum in combination with targeted antibiotic therapy should be considered a valid and principal therapeutic option for the surgical treatment of osteomyelitis of the mandible.

Improving the Medical Curriculum in Predoctoral Dental Education: Recommendations From the American Association of Oral and Maxillofacial Surgeons Committee on Predoctoral Education and Training.

Dental procedures are often performed on patients who present with some level of medical fragility. In many dental schools, the exercise of taking a medical history is all too often a transcription of information to the dental chart, with little emphasis on the presurgical risk assessment and the development of a treatment plan appropriate to the medical status of the dental patient. Changes in dentistry, driven by an increasingly medically complex population of dental patients, combined with treatment advances rooted in the biomedical sciences necessitate the adaptation of our dental education to include a stronger background in systemic health. Many predoctoral educators in the American Association of Oral and Maxillofacial Surgeons (AAOMS) have expressed concern about the medical preparedness of our dental students; therefore, the AAOMS and its Committee on Predoctoral Education and Training have provided recommendations for improving the medical curriculum in predoctoral dental education, including a strengthening of training in clinical medicine and biomedical sciences, with specific recommendations for improved training of our dental students and dental faculty.

Concurrence of Gemination and Fusion in Maxillary Central Incisors: A Case Report.

This case reports the concurrence of gemination and fusion affecting the maxillary central incisors of a twelve-year-old patient and the collaboration of the pediatric dentist, endodontist, orthodontist and oral and maxillofacial surgeon. Developmental dental anomalies can occur in both primary and permanent dentitions as a result of conjoining defects. Double teeth, or cases of gemination or fusion, are not exceedingly rare, but the presence of both anomalies in a single patient is a rarity. Gemination is the division of a single tooth bud, resulting in a large single tooth with a bifid crown and common root and root canal. Fusion is the union of two separate tooth buds, resulting in a joined tooth with confluence of dentin and separate root canals. Labial apexogenesis with MTA, composite resin placement, re-contouring and orthodontic care allowed proper alignment with long-term monitoring of growth and development for possible incisor replacement.

Study of model systems to test the potential function of Artemia group 1 late embryogenesis abundant (LEA) proteins.

Embryos of the brine shrimp, Artemia franciscana, are genetically programmed to develop either ovoviparously or oviparously depending on environmental conditions. Shortly upon their release from the female, oviparous embryos enter diapause during which time they undergo major metabolic rate depression while simultaneously synthesize proteins that permit them to tolerate a wide range of stressful environmental events including prolonged periods of desiccation, freezing, and anoxia. Among the known stress-related proteins that accumulate in embryos entering diapause are the late embryogenesis abundant (LEA) proteins. This large group of intrinsically disordered proteins has been proposed to act as molecular shields or chaperones of macromolecules which are otherwise intolerant to harsh conditions associated with diapause. In this research, we used two model systems to study the potential function of the group 1 LEA proteins from Artemia. Expression of the Artemia group 1 gene (AfrLEA-1) in Escherichia coli inhibited growth in proportion to the number of 20-mer amino acid motifs expressed. As well, clones of E. coli, transformed with the AfrLEA-1 gene, expressed multiple bands of LEA proteins, either intrinsically or upon induction with isopropyl-ß-thiogalactoside (IPTG), in a vector-specific manner. Expression of AfrLEA-1 in E. coli did not overcome the inhibitory effects of high concentrations of NaCl and KCl but modulated growth inhibition resulting from high concentrations of sorbitol in the growth medium. In contrast, expression of the AfrLEA-1 gene in Saccharomyces cerevisiae did not alter the growth kinetics or permit yeast to tolerate high concentrations of NaCl, KCl, or sorbitol. However, expression of AfrLEA-1 in yeast improved its tolerance to drying (desiccation) and freezing. Under our experimental conditions, both E. coli and S. cerevisiae appear to be potentially suitable hosts to study the function of Artemia group 1 LEA proteins under environmentally stressful conditions.

A 5-Year Retrospective Review of Primary Palatoplasty Cases Utilizing an Acellular Collagen Interpositional Graft.

PURPOSE: Multiple palatoplasty techniques have been developed, but a technique involving a partial 2-layer soft tissue closure of the posterior hard palate and nasal floor and a 3-layer soft tissue closure of the soft palate with reorientation of the levator and tensor veli muscles across the midline has been the gold standard for cleft repair. This report describes a series of primary palatoplasties reconstructed with a middle layer of acellular collagen membrane that aided in maintaining closure between the oral and nasal cavities without the development of an oronasal fistula. MATERIALS AND METHODS: An acellular collagen membrane was placed between the muscular layer and the oral mucosa during primary palatoplasty. Six patients with primary cleft palatoplasty were identified and followed for 1 year (patient 1, a 10-month-old boy; patient 2, a 12-month-old girl; patient 3, a 12-month-old girl; patient 4, a 6-year-old boy; patient 5, a 12-month-old girl; and patient 6, an 18-month-old girl). RESULTS: At 1 year, no oronasal fistulas had developed where augmentation with the acellular collagen membrane was used. CONCLUSIONS: The use of an acellular collagen graft to aid in the 3-layer closure of primary palatoplasty surgery is a very effective strategy in primary and secondary healing and in preventing oronasal fistulation. The risk associated with the use of acellular collagen membranes appears nonexistent.

Contemporary update on the treatment of dog bite: injuries to the oral and maxillofacial region.

PURPOSE: The purpose of the present retrospective record review was to evaluate the patient demographics, treatment rendered, and long-term outcomes of patients injured in dog bite attacks to the oral and maxillofacial region. MATERIALS AND METHODS: In the present study, a retrospective medical record review was conducted of patients treated by the oral and maxillofacial surgery department at the University of Tennessee Medical Center who had presented with injuries to the head, neck, and face region from dog bite attacks from February 1, 2006 to October 31, 2013. Each patient included had to have had at least 1 follow-up visit. The data obtained from the patients' medical records included patient demographics, event details, injuries sustained, and treatment rendered and analyzed. RESULTS: The medical records from 20 patients were included and reviewed. More than one half (60%) of the patients were younger than 12 years old. The dog was owned by the patient or a relative in 58% of the cases. The children sustained injuries requiring hospital admission and repair in an operating room setting more often than did the adults. Pit bulls were more frequently associated with injuries than other breeds (9 of 20). CONCLUSIONS: Our patients required a total of 28 hospital inpatient days, 29 total procedures, and follow-up treatment for up to 2 years. Our review has shown the complexity of soft tissue injury treatment and the significant financial impact associated with dog bite injuries owing to the multiple hospital admissions, surgical revisions, and lengthy follow-up period required.

The deregulated promoter methylation of the Polo-like kinases as a potential biomarker in hematological malignancies.

Deregulation of Polo-like kinase (PLK) transcription via promoter methylation results in perturbations at the protein level, which has been associated with oncogenesis. Our objective was to further characterize the methylation profile for PLK1-4 in bone marrow aspirates displaying blood neoplasms as well as in cells grown in vitro. Clinically, we have determined that more than 70% of lymphoma and myelodysplastic syndrome (MDS)/leukemia bone marrow extracts display a hypermethylated PLK4 promoter region in comparison to the normal. Decreased PLK4 protein expression due to promoter hypermethylation was negatively correlated with JAK2 overexpression, a common occurrence in hematological malignancies. In vitro examination of the PLKs under biologically relevant condition of 5% O2 revealed that the highly conserved PLKs respond to lower oxygen tension at both the DNA and the protein level. These findings suggest that PLK promoter methylation status correlates with disease and tumorigenesis in blood neoplasms and could serve as a biomarker.

p53-Dependent and cell specific epigenetic regulation of the polo-like kinases under oxidative stress.

The polo-like kinase (PLKs) family, consisting of five known members, are key regulators of important cell cycle processes, which include mitotic entry, centrosome duplication, spindle assembly, and cytokinesis. The PLKs have been implicated in a variety of cancers, such as hepatocellular carcinoma (HCC), with PLK1 typically overexpressed and PLKs 2-5 often downregulated. Altered expression of the PLKs in malignancy is often correlated with aberrant promoter methylation. Epigenetic marks are dynamic and can be modified in response to external environmental stimuli. The aim of our study was to determine if oxidative stress, a common feature of solid tumours, would induce changes to the promoter methylation of the PLKs resulting in changes in expression. We examined the promoter methylation status via MSP and subsequent expression levels of the PLK family members under exposure to hypoxic conditions or reactive oxygen species (ROS). Interestingly, murine embryonic fibroblasts exposed to hypoxia and ROS displayed significant hypermethylation of Plk1 and Plk4 promoter regions post treatment. Corresponding proteins were also depleted by 40% after treatment. We also examined the HCC-derived cell lines HepG2 and Hep3B and found that for PLK1 and PLK4, the increase in hypermethylation was correlated with the presence of functional p53. In p53 wild-type cells, HepG2, both PLK1 and PLK4 were repressed with treatment, while in the p53 null cell line, Hep3B, PLK4 protein was elevated in the presence of hypoxia and ROS. This was also the case for ROS-treated, p53 null, osteosarcoma cells, Saos-2, where the PLK4 promoter became hypomethylated and protein levels were elevated. Our data supports a model in which the PLKs are susceptible to epigenetic changes induced by microenvironmental cues and these modifications may be p53-dependent. This has important implications in HCC and other cancers, where epigenetic alterations of the PLKs could contribute to tumourigenesis and disease progression.

Case report of spontaneous hemorrhage in a sublingual arteriovenous malformation causing an emergent airway obstruction.

The literature is devoid of articles on spontaneous orofacial hemorrhage with hematoma formation without an underlying condition. Rupture of an arteriovenous malformation (AVM) is possibly the rarest form of spontaneous hemorrhage and life-threatening hematoma formation. This pathology is widely known because of its occurrence in the central nervous system, but it can appear in any location. AVM is not generally thought to be an inherited disorder, except in the context of a specific hereditary syndrome. AVMs can be seen using computerized tomographic angiography, but distraction angiography is the gold standard for diagnosis and treatment decision making. Surgery is the mainstay of treatment; however, endovascular embolization has become an important adjunct to surgical intervention. With shrinkage of the lesion or definitive treatment with coils, particles, or glue. Other important considerations in the choice of treatment are the patient's age, lesion size and location, and prior history of hemorrhage.

Synovial chondromatosis of the temporomandibular joint: a case report and literature review.

Synovial chondromatosis (SC) is a pathologic condition in which mesenchymal tissue rests in a given synovial membrane undergo a metaplastic process, ultimately producing and secreting cartilaginous bodies into the joint space. It is more commonly discussed in the orthopedic literature, since the axial skeleton is the most frequently affected. Although rare, it does occur within the temporomandibular joint (TMJ), with approximately 100 cases previously being described. Within the TMJ, its presentation can be variable, though most cases will show it to be unilateral with fixed and/or loose cartilaginous bodies confined to the superior joint space. Clinically, patients may present with symptoms similar to that of an internal derangement disorder, including pain, clicking, tenderness, functional limitations, and swelling. A thorough history and physical examination, along with proper radiographic examination, are paramount in properly diagnosing SC. Treatment options consist of arthroscopy, arthrotomy with synovectomy, excision of cartilaginous bodies, and possible discectomy. In the current paper, the authors describe the presentation, diagnosis, and surgical management of a SC case involving the right TMJ in a 31-year-old Caucasian female.

The dual-specificity phosphatase hYVH1 (DUSP12) is a novel modulator of cellular DNA content.

The dual-specificity phosphatase hYVH1 (DUSP12) is an evolutionary conserved phosphatase that also contains a unique zinc-binding domain. Recent evidence suggests that this enzyme plays a role in cell survival and ribosome biogenesis. Here, we report that hYVH1 expression also affects cell cycle progression. Overexpression of hYVH1 caused a significant increase in polyploidy and in the G 2/M cell population, with a subsequent decrease in the G 0/G 1 population. Phosphatase activity is dispensable, while the zinc-binding domain is necessary and sufficient for hYVH1-mediated cell cycle changes. In agreement with this, siRNA-mediated silencing of hYVH1 expression resulted in a dramatic increase in the G 0/G 1 population and susceptibility to cellular senescence. Additionally, mass spectrometry-based methods identified novel hYVH1 phosphorylation sites, including a C-terminal modification at position Ser ( 335) in the zinc-binding domain. Interestingly, phosphorylation at Ser335 regulates subcellular targeting of hYVH1 and augments the hYVH1 G 2/M phenotype. Collectively we demonstrate that hYVH1 is a novel modulator of cell cycle progression; a function mainly mediated by its C-terminal zinc-binding domain.

Aberrant methylation of Polo-like kinase CpG islands in Plk4 heterozygous mice.

BACKGROUND: Hepatocellular carcinoma (HCC), one of the most common cancers world-wide occurs twice as often in men compared to women. Predisposing conditions such as alcoholism, chronic viral hepatitis, aflatoxin B1 ingestion, and cirrhosis all contribute to the development of HCC. METHODS: We used a combination of methylation specific PCR and bisulfite sequencing, qReal-Time PCR (qPCR), and Western blot analysis to examine epigenetic changes for the Polo-like kinases (Plks) during the development of hepatocellular carcinoma (HCC) in Plk4 heterozygous mice and murine embryonic fibroblasts (MEFs). RESULTS: Here we report that the promoter methylation of Plk4 CpG islands increases with age, was more prevalent in males and that Plk4 epigenetic modification and subsequent downregulation of expression was associated with the development of HCC in Plk4 mutant mice. Interestingly, the opposite occurs with another Plk family member, Plk1 which was typically hypermethylated in normal liver tissue but became hypomethylated and upregulated in liver tumours. Furthermore, upon alcohol exposure murine embryonic fibroblasts exhibited increased Plk4 hypermethylation and downregulation along with increased centrosome numbers and multinucleation. CONCLUSIONS: These results suggest that aberrant Plk methylation is correlated with the development of HCC in mice.

Gene expression patterns in heterozygous Plk4 murine embryonic fibroblasts.

BACKGROUND: The polo-like kinases (Plks) are a group of serine/threonine kinases which have roles in many aspects of cellular function including the regulation of mitotic activity and cellular stress responses. This study focuses on Plk4, the most divergent member of the Plk family, which is necessary for proper cellular proliferation. More specifically, alterations in Plk4 levels cause significantly adverse mitotic defects including abnormal centrosome duplication and aberrant mitotic spindle formation. We sought to clarify the effect of reduced Plk4 levels on the cell by examining transcript profiles of Plk4 wild-type and heterozygous mouse embryonic fibroblasts (MEFs). Subsequently, the levels of several key proteins involved in the DNA damage response were examined. RESULTS: 143 genes were found to be significantly up-regulated in the heterozygous MEFs compared to their wild-type counterparts, while conversely, 9 genes were down-regulated. Numerous genes with increased transcript levels in heterozygous MEFs were identified to be involved in p53-dependent pathways. Furthermore, examination of the promoter regions of all up- and down-regulated genes revealed that the majority contained putative p53 responsive elements. An analysis of transcript levels in MEFs after exposure to either ionizing or ultraviolet radiation revealed a significant change between wild type and heterozygous MEFS for Plk4 transcript levels upon only UV exposure. Furthermore, changes in protein levels of several important cell check-point and apoptosis regulators were examined, including p53, Chk1, Chk2, Cdc25C and p21. In heterozygous MEFs, p53, p21 and Chk2 protein levels were at significantly higher levels. Furthermore, p53 activity was increased 5 fold in the Plk4 heterozygous MEFs. CONCLUSION: Global transcript profiles and levels of key proteins involved in cellular proliferation and DNA damage pathways were examined in wild-type and Plk4 heterozygous MEFs. It was determined that Plk4 haploinsufficiency leads to changes in the levels of RNA accumulation for a number of key cellular genes as well as changes in protein levels for several important cell cycle/DNA damage proteins. We propose a model in which reduced Plk4 levels invoke an increase in p53 levels that leads to the aforementioned changes in global transcription profiles.