MDA-9/Syntenin in the tumor and microenvironment defines prostate cancer bone metastasis.

Bone metastasis is a frequent and incurable consequence of advanced prostate cancer (PC). An interplay between disseminated tumor cells and heterogeneous bone resident cells in the metastatic niche initiates this process. Melanoma differentiation associated gene-9 (mda-9/Syntenin/syndecan binding protein) is a prometastatic gene expressed in multiple organs, including bone marrow-derived mesenchymal stromal cells (BM-MSCs), under both physiological and pathological conditions. We demonstrate that PDGF-AA secreted by tumor cells induces CXCL5 expression in BM-MSCs by suppressing MDA-9-dependent YAP/MST signaling. CXCL5-derived tumor cell proliferation and immune suppression are consequences of the MDA-9/CXCL5 signaling axis, promoting PC disease progression. mda-9 knockout tumor cells express less PDGF-AA and do not develop bone metastases. Our data document a previously undefined role of MDA-9/Syntenin in the tumor and microenvironment in regulating PC bone metastasis. This study provides a framework for translational strategies to ameliorate health complications and morbidity associated with advanced PC.

Menopause-Associated Changes in Mandibular Bone Microarchitecture Are Site-Specific.

BACKGROUND: There are conflicting reports on the effects of decreased estrogen levels on mandibular bone microarchitecture. Whether these effects are consistent throughout the mandible is unclear and may have important implications for treatment planning. PURPOSE: The goal of this study was to evaluate trabecular and cortical bone microstructure in the mandibular condyle and the mandibular basal bone and compare these sites between premenopausal and postmenopausal women. STUDY DESIGN, SETTING, SAMPLE: Participants were recruited for a cross-sectional cohort study at Columbia University Irving Medical Center. Each participant had cone-beam computed tomography taken of their mandibular condyles and the basal bone. Exclusion criteria for the population included a) current chemotherapy or immunotherapy; b) history of bisphosphonate or other osteoporosis therapy; and c) currently pregnant, nursing, or on hormonal birth control. INDEPENDENT VARIABLE: The predictor variables are menopausal status (before or after menopause) and mandibular region of interest (condyle/basal bone). MAIN OUTCOME VARIABLE: Parameters of interest included the following indicators of bone quality: trabecular bone volume fraction, trabecular thickness, trabecular number, trabecular separation, cortical bone volume fraction, cortical thickness, and cortical porosity. COVARIATES: Covariates included demographic variables such as age, estrogen levels, and ethnicity. ANALYSES: Quantitative microstructure analyses were conducted on cone-beam computed tomography images, and differences between groups for continuous measures (including age) were assessed with an unpaired t-test, and demographic variables were assessed by χ2. Statistical significance was recorded at P < .05. RESULTS: The premenopausal and postmenopausal groups each had 31 participants, with the following average age: premenopausal = 43.9 ± 6.9 versus postmenopausal = 57.5 ± 7.6 years old; P < .001, and estrogen levels: premenopausal = 91.77 ± 80.13 pg/ml versus postmenopausal = 41.44 ± 61.62 pg/ml; P < .01). Postmenopausal women had significantly greater condylar trabecular separation (0.61 ± 0.18 vs 0.47 ± 0.11 mm; P < .001) and lower trabecular number (1.03 ± 0.18 vs 1.21 ± 0.19 mm-1; P < .001) compared to premenopausal women. There were no significant differences in the basal bone microarchitectural parameters between the menopausal groups. CONCLUSION AND RELEVANCE: Menopause is associated with mandibular condylar trabecular bone loss but has minimal effects on the mandibular basal bone. This may have important ramifications for treatment planning in advanced-age individuals.

Postmenopausal women with HIV have increased tooth loss.

BACKGROUND: With effective antiretroviral therapy, people with HIV (PWH) are living longer and aging; the majority of PWH in the United States are now over the age of 50 and in women have gone through the menopause transition. Menopause potentiates skeletal bone loss at the spine, hip, and radius in PWH. The alveolar bone which surronds the teeth is different than long bones because it is derived from the neural crest. However, few studies have assessed the oral health and alveolar bone in middle aged and older women with HIV. Therefore, the objective of this study was to evaluate periodontal disease and alveolar bone microarchitecture in postmenopausal women with HIV. METHODS: 135 self-reported postmenopausal women were recruited (59 HIV-, 76 HIV + on combination antiretroviral therapy with virological suppression) from a single academic center. The following parameters were measured: cytokine levels (IFN-γ, TNF-α, IL-1ß, IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17 A, OPG, and RANKL) in gingival crevicular fluid, bleeding on probing, probing depth, clinical attachment loss, number of teeth present, alveolar crestal height, and alveolar bone microarchitecture. RESULTS: The mean age of participants was 57.04+/-6.25 years and a greater proportion of women with HIV were black/African American (HIV + 68.42%, HIV- 23.73%; p < 0.001). There was no significant difference in bleeding on probing (p = 0.17) and attachment loss (p = 0.39) between women who were HIV infected vs. HIV uninfected. Women with HIV had significantly higher RANKL expression in Gingival Crevicular Fluid (HIV + 3.80+/-3.19 pg/ul, HIV- 1.29+/-2.14 pg/ul ; p < 0.001), fewer teeth present (HIV + 17.75+/-7.62, HIV- 22.79+/-5.70; p < 0.001), ), lower trabecular number (HIV + 0.08+/-0.01, HIV- 0.09+/-0.02; p = 0.004) and greater trabecular separation (HIV + 9.23+/-3.11, HIV- 7.99+/-3.23; p = 0.04) compared to women without HIV that remained significant in multivariate logistic regression analysis in a sub-cohort after adjusting for age, race/ethnicity, smoking status, and diabetes. CONCLUSION: Postmenopausal women with HIV have deterioration of the alveolar trabecular bone microarchitecture that may contribute to greater tooth loss.

Evaluation of the mandibular condylar bone microarchitecture in people living with HIV.

OBJECTIVES: People living with HIV (PLWH) have been shown to have lower bone density at the spine, hip, and radius. However, whether a similar bone phenotype is seen in craniofacial bones is not known. The goal of this study was to evaluate the bone microarchitecture of the mandibular condyle in PLWH. METHODS: We recruited 212 participants, which included 88 HIV-negative participants and 124 PLWH on combination antiretroviral therapy with virological suppression from a single academic center. Each participant filled out a validated temporomandibular disorder (TMD) pain screening questionnaire and had cone beam computed tomography (CBCT) of their mandibular condyles. Qualitative radiographic evidence of temporomandibular joint disorders-osteoarthritis (TMJD-OA) assessment and quantitative microarchitecture analysis of their mandibular condylar bones were conducted. RESULTS: There was no statistically significant difference in either self-reported TMD or in radiographic evidence of TMJD-OA in PLWH compared with HIV-negative controls. Linear regression analysis revealed that positive HIV status remained significantly associated with increased trabecular thickness, decreased cortical porosity, and increased cortical bone volume fraction after adjusting for race, diabetes, sex, and age. CONCLUSION: PLWH have increased mandibular condylar trabecular bone thickness and cortical bone volume fraction compared with HIV-negative controls.

Infection Risk of COVID-19 in Dentistry Remains Unknown: A Preliminary Systematic Review.

COVID-19 is a novel viral respiratory disease caused by a member of the coronavirus family, SARS-CoV-2, and has been declared as a pandemic on March 2020. Dental practitioners are routinely exposed to infectious bodily excretions, for example, saliva, blood, and respiratory excretions. Therefore, they are in the first line of SARS-CoV-2 infection-prone health care providers. The purposes of the current review are to trace documented cases of COVID-19 transmission inside dental settings worldwide and to explore the clinical management of these cases. METHODS: We searched MEDLINE and Google Scholar for all possible reported cases of COVID-19 transmission in dental practice as of December 1, 2019, until May 13, 2020. Multiple terms and combinations were used, including "coronavirus," "COVID-19," "SARS-CoV-2," "dental," "dentistry," "transmission," and "nosocomial." Articles that were not written in English were excluded. RESULTS: A total of 78 articles were found from December 29, 2019, until May 13, 2020. Of these, 31 articles discussed the risks related to dental practice and recommended infection management protocols for dental health care personnel. Of these articles, only 1 had reported data on transmission of COVID-19 in dental practice. Two possible transmissions of COVID-19 to dental personnel were reported in China before its recognition as an epidemic. CONCLUSIONS: Although it seems that there are almost no reported cases of infection by SARS-CoV-2 during dental treatments, occupational or nosocomial transmission could not be ruled out. Hence, further prospective assessment of COVID-19 transmission is urgently required, and careful and protective measurements are necessary to avoid infection during dental practice.

Men with HIV Have Increased Alveolar Bone Loss.

Background: Periodontal health in men with HIV remains understudied, despite suggestions of associations between HIV infection and gingival pocketing, periodontal attachment loss, and gingival inflammation. As antiretroviral therapy (ART) has improved the quality of life for people living with HIV (PLWH), aging-related risk factors and comorbidities, including periodontitis, have emerged. This study aims to assess alveolar bone height, gingival crevicular fluid (GCF) cytokines, and periodontal disease activity in men with and without HIV. Methods: Ninety-three men (50 HIV+, 43 HIV‒) aged 35-70 years were recruited from Columbia University Irving Medical Center clinics. Periodontal examination, GCF collection, and intraoral radiographs were conducted. Results: While no significant differences were observed in bleeding on probing, clinical attachment loss and pocket depths, men with HIV exhibited significantly greater alveolar crestal height on radiographs compared to men without HIV (HIV + 3.41+/-1.35 mm, HIV- 2.64+/-1.01 mm; p = 0.004), reflecting greater alveolar bone loss. GCF IL6 levels showed a trend towards elevation in men with HIV (HIV + 0.349+/-0.407 pg/ml, HIV- 0.220+/-0.228 pg/ml; p = 0.059). Conclusions: Men with HIV demonstrate increased alveolar bone loss compared to those without HIV, possibly mediated by elevated IL6 levels. These results underscore the importance of comprehensive oral health management in PLWH and highlight the need for further research understanding the mechanisms linking HIV infection, cytokine dysregulation, and periodontal health.

Bone marrow stromal cells generate an osteoinductive microenvironment when cultured on titanium-aluminum-vanadium substrates with biomimetic multiscale surface roughness.

Osseointegration of titanium-based implants possessing complex macroscale/microscale/mesoscale/nanoscale (multiscale) topographies support a direct and functional connection with native bone tissue by promoting recruitment, attachment and osteoblastic differentiation of bone marrow stromal cells (MSCs). Recent studies show that the MSCs on these surfaces produce factors, including bone morphogenetic protein 2 (BMP2) that can cause MSCs not on the surface to undergo osteoblast differentiation, suggesting they may produce an osteogenic environmentin vivo. This study examined if soluble factors produced by MSCs in contact with titanium-aluminum-vanadium (Ti6Al4V) implants possessing a complex multiscale biomimetic topography are able to induce osteogenesis ectopically. Ti6Al4V disks were grit-blasted and acid-etched to create surfaces possessing macroscale and microscale roughness (MM), micro/meso/nanoscale topography (MN), and macro/micro/meso/nanoscale topography (MMNTM). Polyether-ether-ketone (PEEK) disks were also fabricated by machining to medical-grade specifications. Surface properties were assessed by scanning electron microscopy, contact angle, optical profilometry, and x-ray photoelectron spectroscopy. MSCs were cultured in growth media (GM). Proteins and local factors in their conditioned media (CM) were measured on days 4, 8, 10 and 14: osteocalcin, osteopontin, osteoprotegerin, BMP2, BMP4, and cytokines interleukins 6, 4 and 10 (IL6, IL4, and IL10). CM was collected from D14 MSCs on MMNTMand tissue culture polystyrene (TCPS) and lyophilized. Gel capsules containing active demineralized bone matrix (DBM), heat-inactivated DBM (iDBM), and iDBM + MMN-GM were implanted bilaterally in the gastrocnemius of athymic nude mice (N= 8 capsules/group). Controls included iDBM + GM; iDBM + TCPS-CM from D5 to D10 MSCs; iDBM + MMN-CM from D5 to D10; and iDBM + rhBMP2 (R&D Systems) at a concentration similar to D5-D10 production of MSCs on MMNTMsurfaces. Legs were harvested at 35D. Bone formation was assessed by micro computed tomography and histomorphometry (hematoxylin and eosin staining) with the histology scored according to ASTM 2529-13. DNA was greatest on PEEK at all time points; DNA was lowest on MN at early time points, but increased with time. Cells on PEEK exhibited small changes in differentiation with reduced production of BMP2. Osteoblast differentiation was greatest on the MN and MMNTM, reflecting increased production of BMP2 and BMP4. Pro-regenerative cytokines IL4 and IL10 were increased on Ti-based surfaces; IL6 was reduced compared to PEEK. None of the media from TCPS cultures was osteoinductive. However, MMN-CM exhibited increased bone formation compared to iDBM and iDBM + rhBMP2. Furthermore, exogenous rhBMP2 alone, at the concentration found in MMN-CM collected from D5 to D10 cultures, failed to induce new bone, indicating that other factors in the CM play a critical role in that osteoinductive microenvironment. MSCs cultured on MMNTMTi6Al4V surfaces differentiate and produce an increase in local factors, including BMP2, and the CM from these cultures can induce ectopic bone formation compared to control groups, indicating that the increased bone formation arises from the local response by MSCs to a biomimetic, multiscale surface topography.

Hydrophilic implants generated using a low-cost dielectric barrier discharge plasma device at the time of placement exhibit increased osseointegration in an animal pre-clinical study: An effect that is sex-dependent.

OBJECTIVES: Increased wettability of titanium and titanium alloy surfaces due to processing and storage methods increases osteoprogenitor cell differentiation and osseointegration compared to microroughness alone. Implants that are exposed to air have a hydrophobic surface due to adsorption of atmospheric hydrocarbons, which can limit overall implant success. Dielectric barrier discharge plasma (DBD) is one method to increase surface hydrophilicity. Although current DBD methods yield a hydrophilic surface, adsorbed hydrocarbons rapidly restore hydrophobicity. We demonstrated that application of DBD to implants previously packaged in a vacuum, generates a hydrophilic surface that supports osteoblastic differentiation in vitro and this can be done immediately prior to use. In the present study, we tested the hypothesis that DBD treatment to alter surface wettability at the time of implant placement will improve osseointegration in vivo. MATERIALS AND METHODS: Twenty male and sixteen female rabbits were used in a preclinical trans-axial femur model of osseointegration. Control and DBD treatment implants were inserted randomized per hind limb in each rabbit (1 implant/hind-limb). At 6 weeks post-surgery, bone-to-implant contact, adjacent bone volume, and torque to failure were assessed by micro-CT, calcified histology, and mechanical testing. RESULTS: DBD plasma treatment of vacuum-sealed implants increased surface wettability and did not change surface chemistry or roughness. Peak torque and torsional energy, and bone-to-implant contact increased with DBD treatment in males. In contrast, female rabbits showed increased osseointegration equal to DBD treated male implants regardless of DBD plasma treatment. CONCLUSION: DBD treatment is an effective method to enhance osseointegration by increasing surface wettability; however, this response is sex dependent. In healthy female patients, DBD treatment may not be necessary but in older patients or patients with compromised bone, this treatment could be an effective measure to ensure implant success.

Interpretation of spatial language in a map navigation task.

We have developed components of an automated system that understands and follows navigational instructions. The system has prior knowledge of the geometry and landmarks of specific maps. This knowledge is exploited to infer complex paths through maps based on natural language descriptions. The approach is based on an analysis of verbal commands in terms of elementary semantic units that are composed to generate a probability distribution over possible spatial paths in a map. An integration mechanism based on dynamic programming guides this language-to-path translation process, ensuring that resulting paths satisfy continuity and smoothness criteria. In the current implementation, parsing of text into semantic units is performed manually. Composition and interpretation of semantic units into spatial paths is performed automatically. In the evaluations, we show that the system accurately predicts the speakers' intended meanings for a range of instructions. This paper provides building blocks for a complete system that, when combined with robust parsing technologies, could lead to a fully automatic spatial language interpretation system.

Clinical accuracy outcomes of splinted and nonsplinted implant impression methods in dental residency settings.

OBJECTIVE: The splint technique of implant-supported restorations is a popular impression method; however, in-vivo studies showing the advantage of this method are scarce. The objective was to compare radiographic fit of the metal frameworks fabricated according to splinted or nonsplinted impression techniques. The null hypothesis was that splinting techniques would result in more accurate impressions. METHOD AND MATERIALS: A retrospective analysis was performed on 71 patients who had undergone multi-implant-supported rehabilitation in the years of 2012 to 2013. The treatment was carried out by three senior dentists or by residents in the department of Oral Rehabilitation at the Hebrew University Hadassah Medical Center. Each senior and the residents under his guidance treated patients consistently by only one different impression method: (1) no splint; (2) splinted transfers with pattern resin over dental floss scaffold; (3) splinting of transfers to impression tray with pattern resin. Orthoradial radiographs were used to determine if the metal framework fit the implant abutments. RESULTS: In total, 81 impressions and 285 implants were included in the study; 56 impressions were done by seniors and 25 by residents. There was no difference in success between the three methods when done by seniors (P = .76). The fixation to tray method was found to be significantly unsuccessful in the hands of residents (P = .01). CONCLUSION: Because the splint methods were not found to be more accurate, splinting the transfers might be an unnecessary step. Splinting of transfers to the impression tray is not recommended for inexperienced dentists.

Statistical reconstruction algorithms for continuous wave electron spin resonance imaging.

Electron spin resonance imaging (ESRI) is an important branch of ESR that deals with heterogeneous samples ranging from semiconductor materials to small live animals and even humans. ESRI can produce either spatial images (providing information about the spatially dependent radical concentration) or spectral-spatial images, where an extra dimension is added to describe the absorption spectrum of the sample (which can also be spatially dependent). The mapping of oxygen in biological samples, often referred to as oximetry, is a prime example of an ESRI application. ESRI suffers frequently from a low signal-to-noise ratio (SNR), which results in long acquisition times and poor image quality. A broader use of ESRI is hampered by this slow acquisition, which can also be an obstacle for many biological applications where conditions may change relatively quickly over time. The objective of this work is to develop an image reconstruction scheme for continuous wave (CW) ESRI that would make it possible to reduce the data acquisition time without degrading the reconstruction quality. This is achieved by adapting the so-called "statistical reconstruction" method, recently developed for other medical imaging modalities, to the specific case of CW ESRI. Our new algorithm accounts for unique ESRI aspects such as field modulation, spectral-spatial imaging, and possible limitation on the gradient magnitude (the so-called "limited angle" problem). The reconstruction method shows improved SNR and contrast recovery vs. commonly used back-projection-based methods, for a variety of simulated synthetic samples as well as in actual CW ESRI experiments.

High-sensitivity Q-band electron spin resonance imaging system with submicron resolution.

A pulsed electron spin resonance (ESR) microimaging system operating at the Q-band frequency range is presented. The system includes a pulsed ESR spectrometer, gradient drivers, and a unique high-sensitivity imaging probe. The pulsed gradient drivers are capable of producing peak currents ranging from ∼9 A for short 150 ns pulses up to more than 94 A for long 1400 ns gradient pulses. Under optimal conditions, the imaging probe provides spin sensitivity of ∼1.6 × 10(8) spins∕√Hz or ∼2.7 × 10(6) spins for 1 h of acquisition. This combination of high gradients and high spin sensitivity enables the acquisition of ESR images with a resolution down to ∼440 nm for a high spin concentration solid sample (∼10(8) spins∕µm(3)) and ∼6.7 µm for a low spin concentration liquid sample (∼6 × 10(5) spins/µm(3)). Potential applications of this system range from the imaging of point defects in crystals and semiconductors to measurements of oxygen concentration in biological samples.