A specialized metabolic pathway partitions citrate in hydroxyapatite to impact mineralization of bones and teeth.

Citrate is a critical metabolic substrate and key regulator of energy metabolism in mammalian cells. It has been known for decades that the skeleton contains most (>85%) of the body's citrate, but the question of why and how this metabolite should be partitioned in bone has received singularly little attention. Here, we show that osteoblasts use a specialized metabolic pathway to regulate uptake, endogenous production, and the deposition of citrate into bone. Osteoblasts express high levels of the membranous Na+-dependent citrate transporter solute carrier family 13 member 5 (Slc13a5) gene. Inhibition or genetic disruption of Slc13a5 reduced osteogenic citrate uptake and disrupted mineral nodule formation. Bones from mice lacking Slc13a5 globally, or selectively in osteoblasts, showed equivalent reductions in cortical thickness, with similarly compromised mechanical strength. Surprisingly, citrate content in mineral from Slc13a5-/- osteoblasts was increased fourfold relative to controls, suggesting the engagement of compensatory mechanisms to augment endogenous citrate production. Indeed, through the coordinated functioning of the apical membrane citrate transporter SLC13A5 and a mitochondrial zinc transporter protein (ZIP1; encoded by Slc39a1), a mediator of citrate efflux from the tricarboxylic acid cycle, SLC13A5 mediates citrate entry from blood and its activity exerts homeostatic control of cytoplasmic citrate. Intriguingly, Slc13a5-deficient mice also exhibited defective tooth enamel and dentin formation, a clinical feature, which we show is recapitulated in primary teeth from children with SLC13A5 mutations. Together, our results reveal the components of an osteoblast metabolic pathway, which affects bone strength by regulating citrate deposition into mineral hydroxyapatite.

Impact of high-fat diet on cognitive behavior and central and systemic inflammation with aging and sex differences in mice.

Aging and age-related diseases are associated with cellular stress, metabolic imbalance, oxidative stress, and neuroinflammation, accompanied by cognitive impairment. Lifestyle factors such as diet, sleep fragmentation, and stress can potentiate damaging cellular cascades and lead to an acceleration of brain aging and cognitive impairment. High-fat diet (HFD) has been associated with obesity, metabolic disorders like diabetes, and cardiovascular disease. HFD also induces neuroinflammation, impairs learning and memory, and may increase anxiety-like behavior. Effects of a HFD may also vary between sexes. The interaction between Age- and Sex- and Diet-related changes in neuroinflammation and cognitive function is an important and poorly understood area of research. This study was designed to examine the effects of HFD on neuroinflammation, behavior, and neurodegeneration in mice in the context of aging or sex differences. In a series of studies, young (2-3 months) or old (12-13 months) C57BL/6J male mice or young male and female C57Bl/6J mice were fed either a standard diet (SD) or a HFD for 5-6 months. Behavior was assessed in Activity Chamber, Y-maze, Novel Place Recognition, Novel Object Recognition, Elevated Plus Maze, Open Field, Morris Water Maze, and Fear Conditioning. Post-mortem analyses assessed a panel of inflammatory markers in the plasma and hippocampus. Additionally, proteomic analysis of the hypothalamus, neurodegeneration, neuroinflammation in the locus coeruleus, and neuroinflammation in the hippocampus were assessed in a subset of young and aged male mice. We show that HFD increased body weight and decreased locomotor activity across groups compared to control mice fed a SD. HFD altered anxiety-related exploratory behavior. HFD impaired spatial learning and recall in young male mice and impaired recall in cued fear conditioning in young and aged male mice, with no effects on spatial learning or fear conditioning in young female mice. Effects of Age and Sex were observed on neuroinflammatory cytokines, with only limited effects of HFD. HFD had a more significant impact on systemic inflammation in plasma across age and sex. Aged male mice had induction of microglial immunoreactivity in both the locus coeruleus (LC) and hippocampus an effect that HFD exacerbated in the hippocampal CA1 region. Proteomic analysis of the hypothalamus revealed changes in pathways related to metabolism and neurodegeneration with both aging and HFD in male mice. Our findings suggest that HFD induces widespread systemic inflammation and limited neuroinflammation. In addition, HFD alters exploratory behavior in male and female mice, and impairs learning and memory in male mice. These results provide valuable insight into the impact of diet on cognition and aging pathophysiology.

Infigratinib, a selective FGFR1-3 tyrosine kinase inhibitor, alters dentoalveolar development at high doses.

BACKGROUND: Fibroblast growth factor receptor-3 (FGFR3) gain-of-function mutations are linked to achondroplasia. Infigratinib, a FGFR1-3 tyrosine kinase inhibitor, improves skeletal growth in an achondroplasia mouse model. FGFs and their receptors have critical roles in developing teeth, yet effects of infigratinib on tooth development have not been assessed. Dentoalveolar and craniofacial phenotype of Wistar rats dosed with low (0.1 mg/kg) and high (1.0 mg/kg) dose infigratinib were evaluated using micro-computed tomography, histology, and immunohistochemistry. RESULTS: Mandibular third molars were reduced in size and exhibited aberrant crown and root morphology in 100% of female rats and 80% of male rats at high doses. FGFR3 and FGF18 immunolocalization and extracellular matrix protein expression were unaffected, but cathepsin K (CTSK) was altered by infigratinib. Cranial vault bones exhibited alterations in dimension, volume, and density that were more pronounced in females. In both sexes, interfrontal sutures were significantly more patent with high dose vs vehicle. CONCLUSIONS: High dose infigratinib administered to rats during early stages affects dental and craniofacial development. Changes in CTSK from infigratinib in female rats suggest FGFR roles in bone homeostasis. While dental and craniofacial disruptions are not expected at therapeutic doses, our findings confirm the importance of dental monitoring in clinical studies.

Sentinel lymph node biopsy status improves adjuvant therapy decision-making in patients with clinical stage IIB/C melanoma: A population-based analysis.

BACKGROUND: Given the results of the recent KEYNOTE-716 trial, the performance of sentinel lymph node (SLN) biopsy for patients with clinical stage IIB/C melanoma has been questioned. OBJECTIVE: Determine the utility of SLN status in guiding the recommendations for adjuvant therapy. METHODS: Patients with clinical stage IIB/C cutaneous melanoma who underwent wide local excision and SLN biopsy between 2004 and 2011 were identified from the Surveillance, Epidemiology, and End Results database. Two prognostic models, with and without SLN status, were developed predicting risk of melanoma-specific death (MSD). The primary outcome was net benefit at treatment thresholds of 20% to 40% risk of 5-year MSD. RESULTS: For the 4391 patients included, the 5-year MSD rate was 46%. The model estimating 5-year MSD risk that included SLN status provided greater net benefit at treatment thresholds from 30% to 78% compared to the model without SLN status. The added net benefit for the SLN biopsy-containing model persisted in subgroup analysis of patients in different age groups and with various T stages. LIMITATIONS: Retrospective study. CONCLUSIONS: A prognostic model with SLN status estimating patient risk for 5-year MSD provides superior net benefit compared to a model with primary tumor staging factors alone for threshold mortality rates ≥30%.

The diverse landscape of dermatologic toxicities of non-immune checkpoint inhibitor monoclonal antibody-based cancer therapy.

BACKGROUND: Since their first approval 25 years ago, monoclonal antibodies (mAbs) have become important targeted cancer therapeutics. However, dermatologic toxicities associated with non-immune checkpoint inhibitor (non-ICI) mAbs may complicate the course of cancer treatment. Data on the incidence and types of these reactions are limited. METHODS: A comprehensive review was conducted on dermatologic toxicities associated with different classes of non-ICI mAbs approved for treatment of solid tumors and hematologic malignancies. The review included prospective Phase 1, 2, and 3 clinical trials; retrospective literature reviews; systematic reviews/meta-analyses; and case series/reports. RESULTS: Dermatologic toxicities were associated with several types of non-ICI mAbs. Inflammatory reactions were the most common dermatologic toxicities, manifesting as maculopapular, urticarial, papulopustular/acneiform, and lichenoid/interface cutaneous adverse events (cAEs) with non-ICI mAbs. Immunobullous reactions were rare and a subset of non-ICI mAbs were associated with the development of vitiligo cAEs. CONCLUSION: Dermatologic toxicities of non-ICI mAbs are diverse and mostly limited to inflammatory reactions. Awareness of the spectrum of the histopathologic patterns of cAE from non-ICI mAbs therapy is critical in the era of oncodermatology and oncodermatopathology.

Local Recurrence Rates After Excision of Desmoplastic Melanoma: A Systematic Review and Meta-Analysis.

BACKGROUND: Few prospective studies have evaluated local recurrence rates (LRR) after excision of desmoplastic melanoma (DM); however, several retrospective studies have reported high LRR. OBJECTIVE: To determine LRR after excision of DM and evaluate factors affecting LRR. MATERIALS AND METHODS: Systematic review of the PubMed, Embase, and Web of Science databases was performed to identify studies reporting local recurrence after excision of DM with conventional wide local excision (WLE), Mohs micrographic surgery (MMS), or staged excision (SE). Meta-analysis was performed to calculate summary LRR and pooled risk ratios (RR). RESULTS: Literature search identified 4 studies evaluating MMS or SE (total n = 61 DM). 53 studies assessed WLE ( n = 3,080) and were analyzed quantitatively. The overall LRR after WLE of DM was 21% (95% CI, 0.16-0.28; n = 2,308). Local recurrence rate was higher with positive/unknown histologic excision margins (49%, 95% CI, 0.25-0.74; n = 91) versus negative histologic margins (11%, 95% CI, 0.07-0.17; n = 1,075; [ p < .01]). Neurotropism was also associated with increased LRR (RR, 1.79; 95% CI, 1.34-2.38, p < .01; n = 644). CONCLUSION: DM has high LRR after WLE. Local recurrence risk was greatest with positive excision margins, indicating the importance of achieving negative microscopic margins. Greater study of MMS and SE for DM is required.

A 4D Theoretical Framework for Measuring Topic-Specific Influence on Twitter: Development and Usability Study on Dietary Sodium Tweets.

BACKGROUND: Social media has emerged as a prominent approach for health education and promotion. However, it is challenging to understand how to best promote health-related information on social media platforms such as Twitter. Despite commercial tools and prior studies attempting to analyze influence, there is a gap to fill in developing a publicly accessible and consolidated framework to measure influence and analyze dissemination strategies. OBJECTIVE: We aimed to develop a theoretical framework to measure topic-specific user influence on Twitter and to examine its usability by analyzing dietary sodium tweets to support public health agencies in improving their dissemination strategies. METHODS: We designed a consolidated framework for measuring influence that can capture topic-specific tweeting behaviors. The core of the framework is a summary indicator of influence decomposable into 4 dimensions: activity, priority, originality, and popularity. These measures can be easily visualized and efficiently computed for any Twitter account without the need for private access. We demonstrated the proposed methods by using a case study on dietary sodium tweets with sampled stakeholders and then compared the framework with a traditional measure of influence. RESULTS: More than half a million dietary sodium tweets from 2006 to 2022 were retrieved for 16 US domestic and international stakeholders in 4 categories, that is, public agencies, academic institutions, professional associations, and experts. We discovered that World Health Organization, American Heart Association, Food and Agriculture Organization of the United Nations (UN-FAO), and World Action on Salt (WASH) were the top 4 sodium influencers in the sample. Each had different strengths and weaknesses in their dissemination strategies, and 2 stakeholders with similar overall influence, that is, UN-FAO and WASH, could have significantly different tweeting patterns. In addition, we identified exemplars in each dimension of influence. Regarding tweeting activity, a dedicated expert published more sodium tweets than any organization in the sample in the past 16 years. In terms of priority, WASH had more than half of its tweets dedicated to sodium. UN-FAO had both the highest proportion of original sodium tweets and posted the most popular sodium tweets among all sampled stakeholders. Regardless of excellence in 1 dimension, the 4 most influential stakeholders excelled in at least 2 out of 4 dimensions of influence. CONCLUSIONS: Our findings demonstrate that our method not only aligned with a traditional measure of influence but also advanced influence analysis by analyzing the 4 dimensions that contribute to topic-specific influence. This consolidated framework provides quantifiable measures for public health entities to understand their bottleneck of influence and refine their social media campaign strategies. Our framework can be applied to improve the dissemination of other health topics as well as assist policy makers and public campaign experts to maximize population impact.

Is orofacial granulomatosis a distinct clinical disorder?

Orofacial granulomatosis is a rare disorder that is heterogeneously defined in the published literature. Herein, we describe a patient with orofacial granulomatosis with clinical and histologic evidence, discuss differential diagnoses, and offer clinical pearls for diagnosing and assessing this disorder. Our case provides support that orofacial granulomatosis is a distinct disorder as opposed to a sequela of other systemic granulomatous diseases. This information will aid dermatologists in decision making and diagnosing the disorder.

Between a rock and a hard place: Regulation of mineralization in the periodontium.

The periodontium supports and attaches teeth via mineralized and nonmineralized tissues. It consists of two, unique mineralized tissues, cementum and alveolar bone. In between these tissues, lies an unmineralized, fibrous periodontal ligament (PDL), which distributes occlusal forces, nourishes and invests teeth, and harbors progenitor cells for dentoalveolar repair. Many unanswered questions remain regarding periodontal biology. This review will focus on recent research providing insights into one enduring mystery: the precise regulation of the hard-soft tissue borders in the periodontium which define the interfaces of the cementum-PDL-alveolar bone structure. We will focus on advances in understanding the molecular mechanisms that maintain the unmineralized PDL "between a rock and a hard place" by regulating the mineralization of cementum and alveolar bone.

Prognostic Significance of Primary Tumor-Infiltrating Lymphocytes in a Contemporary Melanoma Cohort.

BACKGROUND: The prognostic impact of tumor-infiltrating lymphocytes (TILs) on outcomes and treatment efficacy for patients with melanoma in the contemporary era remains poorly characterized. METHODS: Consecutive patients who underwent wide excision and sentinel lymph node biopsy for cutaneous melanoma 1 mm thick or thicker at a single institution were identified (2006-2019). The patients were stratified based on primary tumor TIL status as brisk (bTILs), non-brisk (nbTILs), or absent (aTILs). Associations between patient factors and outcomes were analyzed using multivariable analysis. RESULTS: Of the 1017 patients evaluated, 846 (83.2 %) had primary TILs [nbTILs (n = 759, 89.7 %) and bTILs (n = 87, 10.3 %)]. In the multivariable analysis, the patients with any type of TILs had higher rates of regression [odds ratio (OR), 1.86; p = 0.016], lower rates of acral lentiginous histology (OR, 0.22; p < 0.001), and lower rates of SLN positivity (OR, 0.64; p = 0.042) than those without TILs. The multivariable analysis found no association between disease-specific survival and bTILs [hazard ratio (HR), 1.04; p = 0.927] or nbTILs (HR, 0.89; p = 0.683). An association was found between bTILs and recurrence-free survival (RFS) advantage [bTILs (HR 0.46; p = 0.047), nbTILs (HR 0.71; p = 0.088)], with 5-year RFS rates of 84 % for bTILs, 71.8 % for nbTILs, and 68.4 % for aTILs (p = 0.044). For the 114 immune checkpoint blockade (ICB)-naïve patients who experienced a recurrence treated with ICB therapy, no association was observed between progression-free survival and bTILs (HR, 0.64; p = 0.482) or nbTILs (HR, 0.58; p = 0.176). CONCLUSIONS: The prognostic significance of primary TILs in the contemporary melanoma era appears complex. Further studies characterizing the phenotype of TILs and their association with regional metastasis and responsiveness to ICB therapy are warranted.

Association of type II diabetes mellitus with characteristics and outcomes for patients undergoing sentinel lymph node biopsy for cutaneous melanoma.

BACKGROUND AND OBJECTIVES: Type II diabetes mellitus (T2DM) can lead to an immunosuppressed state, but whether T2DM is associated with worse outcomes for patients with melanoma has not been well studied. METHODS: Consecutive patients diagnosed with clinical stage I-II cutaneous melanoma who underwent sentinel lymph node biopsy at a single institution (2007-2016) were identified. Melanoma characteristics and recurrence/survival outcomes were compared between patients with and without T2DM at the time of melanoma diagnosis. RESULTS: Of 1128 patients evaluated, 111 (9.8%) had T2DM (n = 94 [84.7%] non-insulin dependent [NID-T2DM]; n = 17 [15.3%] insulin dependent [ID-T2DM]). T2DM patients were more likely to be older (odds ratio [OR] 1.04, p < 0.001), male (OR 2.15, p = 0.003), have tumors >1.0 mm (OR 1.88, p = 0.023), and have microsatellitosis (OR 2.29, p = 0.030). Five-year cumulative incidence of melanoma recurrence was significantly higher for patients with ID-T2DM (46.7% ID-T2DM vs. 25.7% NID-T2DM vs. 17.1% no T2DM, p < 0.001), and on multivariable analysis, ID-T2DM was independently associated with melanoma recurrence (hazard ratio 2.57, p = 0.015). No difference in 5-year disease-specific survival was observed between groups. CONCLUSIONS: ID-T2DM appears to be associated with more advanced melanoma and increased risk for melanoma recurrence. Further study as to whether this reflects differences in tumor biology or host factors is warranted.

Sentinel lymph node biopsy in patients with clinical stage IIB/C cutaneous melanoma: A national cohort study.

BACKGROUND: Approval of adjuvant anti-programmed cell death protein 1 therapy for pathologic stage IIB/C cutaneous melanoma has led some to question the role of sentinel lymph node (SLN) biopsy in the clinical stage IIB/C disease. OBJECTIVE: To determine the prognostic significance of SLN staging on disease-specific survival (DSS) for clinical stage IIB/C primary cutaneous melanoma in the preimmunotherapy era. METHODS: A retrospective cohort study was performed evaluating patients who underwent excision of clinical stage IIB/C cutaneous melanoma using the Surveillance, Epidemiology, and End Results database (2004-2011). Patients who did and did not undergo SLN biopsy were compared using propensity matching, and among those who underwent SLN biopsy, matched patients were further stratified by SLN status (SLN positive [SLN+] or SLN negative [SLN-]). RESULTS: Of the 8562 patients evaluated, 6021 (70.3%) underwent SLN biopsy. SLN positivity was associated with significantly reduced 5-year DSS among matched patients who underwent SLN biopsy (47.1% SLN+ vs 75.5% SLN-; P < .001). Five-year DSS remained significantly different across matched T-stages: T3b (54.2% SLN+ vs 64.8% SLN-; P = .004), T4a (55.5% SLN+ vs 71.6% SLN-; P = .001), and T4b (38.6% SLN+ vs 60.9% SLN-; P < .001). LIMITATIONS: Retrospective study. CONCLUSION: For patients with clinical stage IIB/C cutaneous melanoma, SLN status provides essential prognostic information.

Lichen-planus-pemphigoides-like reaction to PD-1 checkpoint blockade.

BACKGROUND: Programmed cell death protein (PD-1) and programmed death-ligand 1 (PD-L1) inhibition checkpoint blockade leads to various cutaneous adverse reactions, including bullous pemphigoid and lichen-planus-like reactions. However, lichen planus pemphigoides (LPP), manifesting histopathologic features of both lichen planus and bullous pemphigoid, has more rarely been associated with immunotherapy. METHODS: The clinical and histopathologic findings of three patients were examined, and a review of cases of LPP and bullous lichen planus secondary to PD-1 inhibitor therapy was performed. RESULTS: Three patients (two with advanced non-small-cell lung adenocarcinoma and the third with metastatic breast cancer) presented with both lichenoid eruptions and bullae. Biopsy of the lesions revealed lichenoid tissue reactions in all three patients. Together with the histopathologic findings, direct immunofluorescence (DIF) showing linear C3 and IgG deposition and positive enzyme-linked immunosorbent assay (ELISA) showing BP180 positivity supported a diagnosis of LPP in two patients. The third patient in our series also showed confirmatory ELISA testing supporting LPP. CONCLUSIONS: Lichen planus pemphigoides is a distinct cutaneous toxicity to checkpoint inhibitor therapy illustrates a possible pathogenic mechanism and the importance of dermatopathology recognition to render an accurate diagnosis.

Diverse landscape of dermatologic toxicities from small-molecule inhibitor cancer therapy.

BACKGROUND: Advances in molecular biology and genetics have contributed to breakthrough treatments directed at specific pathways associated with the development of cancer. Small-molecule inhibitors (Nibs) aimed at a variety of cellular pathways have been efficacious; however, they are associated with significant dermatologic toxicities. METHODS: We conducted a comprehensive review of dermatologic toxicities associated with Nibs categorized into the following five groups: (a) mitogen-activated protein kinase; (b) growth factor/multi-tyrosine kinase; (c) cell division/DNA repair; (d) signaling associated with myeloproliferative neoplasms; and (e) other signaling pathways. Prospective phase I, II, or III clinical trials, retrospective literature reviews, systematic reviews/meta-analyses, and case reviews/reports were included for analysis. RESULTS: Dermatologic toxicities reviewed were associated with every class of Nibs and ranged from mild to severe or life-threatening adverse skin reactions. Inflammatory reactions manifesting as maculopapular, papulopustular/acneiform, and eczematous lesions were frequent types of dermatologic toxicities seen with Nibs. Squamous cell carcinoma with keratoacanthoma-like features was associated with a subset of Nibs. Substantial overlap in dermatologic toxicities was found between Nibs. CONCLUSIONS: Dermatologic toxicities from Nibs are diverse and may overlap between classes of Nibs. Recognition of the various types of toxicities from Nibs is critical for patient care in the era of "oncodermatology/dermatopathology."

Optimizing Detection of Lymphatic Invasion in Primary Cutaneous Melanoma With the Use of D2-40 and a Paired Melanocytic Marker.

ABSTRACT: Dual immunohistochemical (IHC) staining with D2-40 and S100 improves detection of lymphatic invasion (LI) in primary cutaneous melanoma. However, limited data exist evaluating this technique using other melanocytic markers, and thus, the optimal marker for detection of LI is unestablished. To address this knowledge gap, a case-control study was performed comparing melanoma specimens from 22 patients with known lymphatic spread (LS) with a control group of 11 patients without LS. Specimens underwent dual IHC staining with D2-40 and MART-1, SOX-10, and S100 to evaluate for LI. Receiver operating characteristic analysis was used to estimate each stain's accuracy for detection of LI. The LS group was more likely to be ≥65 years (P = 0.04), have a tumor thickness of ≥1 mm (P < 0.01), and have ulcerated tumors (P = 0.02). Detection of LI with D2-40/MART-1 significantly correlated with LS (P = 0.03), and the D2-40/MART-1 stain was most accurate for LI based on receiver operating characteristic curve analysis (area under the curve [AUC] 0.705) in comparison with D2-40/SOX-10 (AUC 0.575) and D2-40/S100 (AUC 0.633). These findings suggest that MART-1 may be the optimal melanocytic marker to combine with D2-40 for detection of LI in melanoma. Further studies are needed to determine the utility of routinely performing these stains for histopathologic analysis of melanoma.

Association of the Affordable Care Act's Medicaid expansion with the diagnosis and treatment of clinically localized melanoma: A National Cancer Database study.

BACKGROUND: The Affordable Care Act's Medicaid expansion is associated with earlier diagnosis and improved care among lower socioeconomic status populations with cancer, but its impact on melanoma is undefined. OBJECTIVE: To determine the association of Medicaid expansion with stage of diagnosis and use of sentinel lymph node biopsy in nonelderly adult patients with newly diagnosed clinically localized melanoma. METHODS: Quasi-experimental, difference-in-differences retrospective cohort analysis using data from the National Cancer Database from 2010 to 2017. Patients from expansion versus nonexpansion states and diagnosed before (2010-2013) versus after (2014-2017) expansion were identified. RESULTS: Of 83,322 patients, 46.6% were female, and the median age was 55 years (interquartile range, 49-60). After risk adjustment, Medicaid expansion was associated with a decrease in the diagnosis of T1b stage or higher melanoma (odds ratio [OR], 0.93; 95% confidence interval [CI], 0.88-0.98; P = .011) and decrease in uninsured status (OR, 0.61; 95% CI, 0.52-0.72; P < .001) but was not associated with a difference in sentinel lymph node biopsy performance when indicated (OR, 1.06; 95% CI, 0.95-1.20; P = .29). LIMITATIONS: Retrospective study using a national database. CONCLUSION: In this study of patients with clinically localized melanoma, Medicaid expansion was associated with a decrease in the diagnosis of later T-stage tumors.

Dental and craniofacial defects in the Crtap-/- mouse model of osteogenesis imperfecta type VII.

BACKGROUND: Inactivating mutations in the gene for cartilage-associated protein (CRTAP) cause osteogenesis imperfecta type VII in humans, with a phenotype that can include craniofacial defects. Dental and craniofacial manifestations have not been a focus of case reports to date. We analyzed the craniofacial and dental phenotype of Crtap-/- mice by skull measurements, micro-computed tomography (micro-CT), histology, and immunohistochemistry. RESULTS: Crtap-/- mice exhibited a brachycephalic skull shape with fusion of the nasofrontal suture and facial bones, resulting in mid-face retrusion and a class III dental malocclusion. Loss of CRTAP also resulted in decreased dentin volume and decreased cellular cementum volume, though acellular cementum thickness was increased. Periodontal dysfunction was revealed by decreased alveolar bone volume and mineral density, increased periodontal ligament (PDL) space, ectopic calcification within the PDL, bone-tooth ankylosis, altered immunostaining of extracellular matrix proteins in bone and PDL, increased pSMAD5, and more numerous osteoclasts on alveolar bone surfaces. CONCLUSIONS: Crtap-/- mice serve as a useful model of the dental and craniofacial abnormalities seen in individuals with osteogenesis imperfecta type VII.

Salience-Driven Value Construction for Adaptive Choice under Risk.

Decisions we face in real life are inherently risky and can result in one of many possible outcomes. However, most of what we know about choice under risk is based on studies that use options with only two possible outcomes (simple gambles), so it remains unclear how the brain constructs reward values for more complex risky options faced in real life. To address this question, we combined experimental and modeling approaches to examine choice between pairs of simple gambles and pairs of three-outcome gambles in male and female human subjects. We found that subjects evaluated individual outcomes of three-outcome gambles by multiplying functions of reward magnitude and probability. To construct the overall value of each gamble, however, most subjects differentially weighted possible outcomes based on either reward magnitude or probability. These results reveal a novel dissociation between how reward information is processed when evaluating complex gambles: valuation of each outcome is based on a combination of reward information whereas weighting of possible outcomes mainly relies on a single piece of reward information. We show that differential weighting of possible outcomes could enable subjects to make decisions more easily and quickly. Together, our findings reveal a plausible mechanism for how salience, in terms of possible reward magnitude or probability, can influence the construction of subjective values for complex gambles. They also point to separable neural mechanisms for how reward value controls choice and attention to allow for more adaptive decision making under risk.SIGNIFICANCE STATEMENT Real-life decisions are inherently risky and can result in one of many possible outcomes, but how does the brain integrate information from all these outcomes to make decisions? To address this question, we examined choice between pairs of gambles with multiple outcomes using various computational models. We found that subjects evaluated individual outcomes by multiplying functions of reward magnitude and probability. To construct the overall value of each gamble, however, they differentially weighted possible outcomes based on either reward magnitude or probability. By doing so, they were able to make decisions more easily and quickly. Our findings illustrate how salience, in terms of possible reward magnitude or probability, can influence the construction of subjective values for more adaptive choice.

OPG-Fc treatment partially rescues low bone mass phenotype in mature Bgn/Fmod deficient mice but is deleterious to the young mouse skeleton.

Biglycan (Bgn) and Fibromodulin (Fmod) are small leucine rich proteoglycans (SLRPs) which are abundant in the extra-cellular matrix (ECM) of mineralized tissues. We have previously generated a Bgn/Fmod double knock-out (DKO) mouse model and found it has a 3-fold increase in osteoclastogenesis compared with Wild type (WT) controls, resulting in a markedly low bone mass (LBM) phenotype. To try and rescue/repair the LBM phenotype of Bgn/Fmod DKO mice by suppressing osteoclast formation and activity, 3- and 26-week-old Bgn/Fmod DKO mice and age/gender matched WT controls were treated with OPG-Fc for 6 weeks after which bone parameters were evaluated using DEXA, micro-computed tomography (µCT) and serum biomarkers analyses. In the appendicular skeleton, OPG-Fc treatment improved some morphometric and geometric parameters in both the trabecular and cortical compartments in Bgn/Fmod DKO female and male mice, especially in the repair module. For many of the skeletal parameters analyzed, the Bgn/Fmod DKO mice were more responsive to the treatment than their WT controls. In addition, we found that OPG-Fc treatment was not able to prevent or ameliorate the formation of ectopic ossification, which are common lesions seen in aged joints and are one of the phenotypical hallmarks of our Bgn/Fmod DKO model. Analysis of skull bones, specifically the occipital bone, showed the treatment recovered some parameters of LBM phenotype in the craniofacial skeleton, more so in the younger rescue module. Using OPG-Fc as treatment alleviated, yet did not completely restore, the severe osteopenia and mineralized tissue structural abnormalities that Bgn/Fmod DKO mice suffer from.

Insights into dental mineralization from three heritable mineralization disorders.

Teeth are comprised of three unique mineralized tissues, enamel, dentin, and cementum, that are susceptible to developmental defects similar to those affecting bone. X-linked hypophosphatemia (XLH), caused by PHEX mutations, leads to increased fibroblast growth factor 23 (FGF23)-driven hypophosphatemia and local extracellular matrix disturbances. Hypophosphatasia (HPP), caused by ALPL mutations, results in increased levels of inorganic pyrophosphate (PPi), a mineralization inhibitor. Generalized arterial calcification in infancy (GACI), caused by ENPP1 mutations, results in vascular calcification due to decreased PPi, later compounded by FGF23-driven hypophosphatemia. In this perspective, we compare and contrast dental defects in primary teeth associated with XLH, HPP, and GACI, briefly reviewing genetic and biochemical features of these disorders and findings of clinical and preclinical studies to date, including some of our own recent observations. The distinct dental defects associated with the three heritable mineralization disorders reflect unique processes of the respective dental hard tissues, revealing insights into their development and clues about pathological mechanisms underlying such disorders.