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Robert West, Jonathan Pollack and colleagues identify mutations in either the Hedgehog pathway gene SMO or the MAPK gene BRAF in 24 of the 28 ameloblastoma samples studied. They found 9 of 11 SMO mutations were found in maxillary ameloblastomas, whereas 9 of 13 BRAF mutations were found in mandibular cases. Here we report the discovery of oncogenic mutations in the Hedgehog and mitogen-activated protein kinase (MAPK) pathways in over 80% of ameloblastomas, locally destructive odontogenic tumors of the jaw, by genomic analysis of archival material. Mutations in SMO (encoding Smoothened, SMO) are common in ameloblastomas of the maxilla, whereas BRAF mutations are predominant in tumors of the mandible. We show that a frequently occurring SMO alteration encoding p.Leu412Phe is an activating mutation and that its effect on Hedgehog-pathway activity can be inhibited by arsenic trioxide (ATO), an anti-leukemia drug approved by the US Food and Drug Administration (FDA) that is currently in clinical trials for its Hedgehog-inhibitory activity. In a similar manner, ameloblastoma cells harboring an activating BRAF mutation encoding p.Val600Glu are sensitive to the BRAF inhibitor vemurafenib. Our findings establish a new paradigm for the diagnostic classification and treatment of ameloblastomas.

PurposeBisphosphonates reduce bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We describe risk factors for BRONJ and compare BRONJ provoked by infection or trauma with spontaneous lesions, which carry a better prognosis.MethodsSWOG 0307 randomized women with stage I–III breast cancer to receive zoledronic acid (ZA), clodronate (CL), or ibandronate (IB) for 3 years, implemented BRONJ prevention guidelines, and collected information about dental health and development of BRONJ. All statistical tests were two-sided.ResultsOf 6018 women, 48 developed BRONJ. Infection was present in 21 (43.8%). Median time to BRONJ was 2.1 years for ZA, 2.0 years for IB, and 3.4 years for clodronate (p = 0.04). BRONJ was associated with bisphosphonate type (28/2231 (1.26%) for ZA, 8/2235 (0.36%) for CL, 12/1552 (0.77%) for IB), dental calculus (OR 2.03), gingivitis (OR 2.11), moderate/severe periodontal disease (OR 2.87), and periodontitis > 4 mm (OR 2.20) (p < 0.05). Of 57 lesions, BRONJ occurred spontaneously in 20 (35.1%) and was provoked by dental extraction in 20 (35.1%), periodontal disease in 14 (24.6%), denture trauma in 6 (10.5%), and dental surgery in 2 (3.5%). Spontaneous BRONJ occurred more frequently at the mylohyoid ridge. There were no differences in dental disease, infection, or bisphosphonate type between spontaneous and provoked BRONJ.ConclusionZA and worse dental health were associated with increased incidence of BRONJ, with a trend toward additive risk when combined. BRONJ incidence was lower than in similar studies, with prevention strategies likely linked to this.Clinical trial numberNCT00127205Registration dateJuly 2005

Determining long-term trends in chronic pain prevalence is critical for evaluating and shaping U.S. health policies, but little research has examined such trends. This study (1) provides estimates of pain trends among U.S. adults across major population groups; (2) tests whether sociodemographic disparities in pain have widened or narrowed over time; and (3) examines socioeconomic, behavioral, psychological, and medical correlates of pain trends. Regression and decomposition analyses of joint, low back, neck, facial/jaw pain, and headache/migraine using the 2002–2018 National Health Interview Survey for adults aged 25–84 (N = 441,707) as sess the trends and their correlates. We find extensive escalation of pain prevalence in allpopulation subgroups: over all, reports of pain in at least one site increased by 10%, representing an additional 10.5 million adults experiencing pain. Socioeconomic disparities in pain are widening over time, and psychological distress and health behaviors are among the salient correlates of the trends. This study thus comprehensively documents rising pain prevalence among Americans across the adult life span and highlights socioeconomic, behavioral, and psychological factors as important correlates of the trends. Chronic pain is an important dimension of population health, and demographic research should include it when study ing health and health disparities.

This study aimed to evaluate the ability of ω-3 to modulate the tissue response in rats with MRONJ, focusing on histopathological and immunohistochemical parameters. Forty Wistar rats were subjected to bilateral ovariectomy and, three months later, the medication regimen with ZOL (100μg/kg; groups ZOL and ZOL-ω3) of vehicle (VEH and VEH-ω3) was initiated. Following 3 weeks of ZOL or VEH, experimental periodontitis was induced around the mandibular left first molars of all animals. Then, 14 days later (one day before tooth extraction), daily dietary supplementation with ω-3 was given to animals belonging to groups VEH-ω3 or ZOL-ω3. Euthanasia was performed 21 days after tooth extraction. Histologic, histometric (newly-formed bone tissue [NFBT] and non-vital bone tissue [NVBT]), and immunohistochemical (TNF-α, α-SMA, ALP, IL-1β, VEGF, OCN, and TRAP) analyses were performed. Dietary supplementation with ω-3 reduced the amount of NVBT and controlled the intensity and extension of the inflammatory infiltrate in ZOL-ω3, as compared with ZOL. Osteoclast and osteoblast activity were not statistically different between groups ZOL and ZOL-ω3. The structure of the epithelium and the underlining connective tissue were improved by the supplementation with ω-3 in animals under ZOL therapy. Oral supplementation with omega-3 controlled the inflammation and reduced the amount of non-vital bone at the tooth extraction site of ovariectomized rats treated with ZOL and attenuating the severity of MRONJ.

Background This study aims to investigate the clinical characteristics, imaging features, treatment, and prognostic factors of jaw Langerhans cell histiocytosis (JLCH), providing valuable insights for its clinical diagnosis and management. Method This study retrospectively analyzed the clinical and follow-up data of JLCH patients treated between January 2010 and January 2024. Data collected included gender, age, symptoms, imaging findings, treatment strategies, and outcomes. Univariate and multivariate Cox regression analyses were performed using SAS software to identify factors affecting treatment outcomes, with P  ≤ 0.05 considered statistically significant. Results A total of 68 patients (50 males, 18 females; median age 13.5 years) were included. Forty percent of patients were under 10 years old, and 71% had mandibular involvement. Disease classification included 49 cases of single-system unifocal (SS-s) disease, 10 cases of single-system multifocal (SS-m) disease, and 9 cases of multi-system (MS) disease. Common symptoms included jaw or tooth pain (28 cases), facial swelling (22), gingival ulceration (10), and loose teeth (9). Imaging revealed periodontal disease-like (7), cyst-like (17), and osteomyelitis-like (44) lesions. Univariate and multivariate Cox regression analyses identified that female patients had a lower risk of progression (P = 0.014, HR 0.071), while SS-m (P = 0.019, HR 4.992) and MS patients (P = 0.030, HR 4.182) exhibited higher progression risks compared to SS-s patients. Cyst-like (P = 0.001, HR 0.054) and osteomyelitis-like lesions (P < 0.001, HR 0.023) were associated with lower progression risks compared to alveolar lesions. Conclusion JLCH can affect individuals of all ages, though it is more common in children. Factors such as gender, lesion multiplicity, and lesion type (alveolar) are significant in predicting disease progression. Complete surgical resection combined with radiotherapy offers the highest likelihood of cure for SS-type JLCH.

Abstract Context Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a heritable form of primary hyperparathyroidism caused by germline inactivating mutations in CDC73 encoding parafibromin and is associated with an increased risk of parathyroid cancer. There is little evidence to guide the management of patients with the disease. Objective (1) Characterize the natural history of HPT-JT, (2) correlate genotype and histology of parathyroid tumors with parafibromin immunostaining, (3) understand molecular changes downstream to CDC73 loss. Design Retrospective study of patients with HPT-JT syndrome (genetically confirmed or affected first-degree relatives). Independent review of uterine tumor from 2 patients and staining for parafibromin on parathyroid tumors from 19 patients (13 adenomas, 6 carcinomas) was performed. RNA-sequencing was performed in 21 parathyroid samples (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas, and 7 sporadic carcinomas with wild-type CDC73). Results We identified 68 patients from 29 kindreds with HPT-JT with median age at last follow-up of 39 [interquartile range, 29-53] years. A total of 55/68 (81%) developed primary hyperparathyroidism; 17/55 (31%) had parathyroid carcinoma. Twelve of 32 (38%) females developed uterine tumors. Of the 11 patients who had surgical resection for uterine tumors, 12/24 (50%) tumors were rare mixed epithelial mesenchymal polypoid lesions. Four of 68 patients (6%) developed solid kidney tumors; 3/4 had a CDC73 variant at p.M1 residue. Parafibromin staining of parathyroid tumors did not correlate with tumor histology or genotype. RNA-sequencing showed a significant association of HPT-JT-related parathyroid tumors with transmembrane receptor protein tyrosine kinase signaling pathway, mesodermal commitment pathway, and cell-cell adhesion. Conclusions Multiple, recurrent atypical adenomyomatous uterine polyps appear to be enriched in women with HPT-JT and appear characteristic of the disease. Patients with CDC73 variants at p.M1 residue appear predisposed to kidney tumors. Clinical Trial number NCT04969926

Key Points Clefts of the lip and/or palate (CLP) are common birth defects of complex aetiology. CLP affects approximately 1 in 700 live births, with wide variability across geographic origin, racial and ethnic groups, as well as environmental exposures and socioeconomic status. CLP can occur in syndromic or non-syndromic forms. This Review focuses on the latter. Although twin studies and familial clustering studies have provided compelling evidence for a genetic component to non-syndromic CLP, few pedigrees show clear-cut Mendelian inheritance and many cases appear to be sporadic. Accurate phenotyping is crucial to understanding both the epidemiology and aetiology of any congenital malformation because the power to detect effects is weakened when heterogeneous groups are treated as a single entity. To date, genetic approaches to non-syndromic CLP have included: linkage analysis using large, multiplex families or smaller but inbred families, or analysis of affected relative pairs; association studies using case–parent trios or case–control samples; identification of chromosomal anomalies or micro-deletions in cases; and direct sequencing of affected individuals. Genome-wide association studies have provided recent major advances in our understanding of genes and pathways that have a role in the aetiology of CLP. There is remarkable heterogeneity by ancestry in the relative contributions by genes found with common variants contributing to CLP. There is evidence that environmental factors have a role in CLP risk and interactions of the environment with certain genetic variants have been identified. The next critical phase of statistical analyses will be to examine the heterogeneity underlying the aetiology of oral clefts and to investigate the gene–gene and gene–environment interactions that control risk. Integration of genetic and environmental risk using epigenetics, systems biology, gene expression and epidemiology will be required to generate a synthesis that will both better characterize aetiologies and eventually lead to improvements in prevention and clinical care. Clefts of the lip and/or palate are common and have a complex genetic and environmental basis. Recent work on these birth defects illustrates the value of combining genome-wide association studies, animal models and improved clinical phenotyping. Future work may also address gene–environment interactions. Clefts of the lip and/or palate (CLP) are common birth defects of complex aetiology. CLP can occur in isolation or as part of a broad range of chromosomal, Mendelian or teratogenic syndromes. Although there has been marked progress in identifying genetic and environmental triggers for syndromic CLP, the aetiology of the more common non-syndromic (isolated) forms remains poorly characterized. Recently, using a combination of epidemiology, careful phenotyping, genome-wide association studies and analysis of animal models, several distinct genetic and environmental risk factors have been identified and confirmed for non-syndromic CLP. These findings have advanced our understanding of developmental biology and created new opportunities for clinical translational research.

Objectives. We examined school days missed for routine dental care versus dental pain or infection to determine the relationship between children's oral health status and school attendance and performance. Methods. We used 2008 data from the North Carolina Child Health Assessment and Monitoring Program. The study sample, weighted to reflect the state's population, included 2183 schoolchildren. Variables assessed included school absences and performance, oral health status, parental education, health insurance coverage, race, and gender. Results. Children with poor oral health status were nearly 3 times more likely (odds ratio = 3.89; 95% confidence interval = 1.96, 7.75) than were their counterparts to miss school as a result of dental pain. Absences caused by pain were associated with poorer school performance (P < .05), but absences for routine care were not. Mediation analyses revealed that oral health status was associated with performance independent of absence for pain. Conclusions. Children with poorer oral health status were more likely to experience dental pain, miss school, and perform poorly in school. These findings suggest that improving children's oral health status may be a vehicle to enhancing their educational experience.

This paper outlines the burden of oral diseases worldwide and describes the influence of major sociobehavioural risk factors in oral health. Despite great improvements in the oral health of populations in several countries, global problems still persist. The burden of oral disease is particularly high for the disadvantaged and poor population groups in both developing and developed countries. Oral diseases such as dental caries, periodontal disease, tooth loss, oral mucosal lesions and oropharyngeal cancers, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS)-related oral disease and orodental trauma are major public health problems worldwide and poor oral health has a profound effect on general health and quality of life. The diversity in oral disease patterns and development trends across countries and regions reflects distinct risk profiles and the establishment of preventive oral health care programmes. The important role of sociobehavioural and environmental factors in oral health and disease has been shown in a large number of socioepidemiological surveys. In addition to poor living conditions, the major risk factors relate to unhealthy lifestyles (i.e. poor diet, nutrition and oral hygiene and use of tobacco and alcohol), and limited availability and accessibility of oral health services. Several oral diseases are linked to noncommunicable chronic diseases primarily because of common risk factors. Moreover, general diseases often have oral manifestations (e.g. diabetes or HIV/AIDS). Worldwide strengthening of public health programmes through the implementation of effective measures for the prevention of oral disease and promotion of oral health is urgently needed. The challenges of improving oral health are particularly great in developing countries.