Nine Degree-of-Freedom Kinematic Modeling of the Upper-Limb Complex for Constrained Workspace Evaluation.

The design of rehabilitation devices for patients experiencing musculoskeletal disorders (MSDs) requires a great deal of attention. This article aims to develop a comprehensive model of the upper-limb complex to guide the design of robotic rehabilitation devices that prioritize patient safety, while targeting effective rehabilitative treatment. A 9 degree-of-freedom kinematic model of the upper-limb complex is derived to assess the workspace of a constrained arm as an evaluation method of such devices. Through a novel differential inverse kinematic method accounting for constraints on all joints1820, the model determines the workspaces in which a patient is able to perform rehabilitative tasks and those regions where the patient needs assistance due to joint range limitations resulting from an MSD. Constraints are imposed on each joint by mapping the joint angles to saturation functions, whose joint-space derivative near the physical limitation angles approaches zero. The model Jacobian is reevaluated based on the nonlinearly mapped joint angles, providing a means of compensating for redundancy while guaranteeing feasible inverse kinematic solutions. The method is validated in three scenarios with different constraints on the elbow and palm orientations. By measuring the lengths of arm segments and the range of motion for each joint, the total workspace of a patient experiencing an upper-limb MSD can be compared to a preinjured state. This method determines the locations in which a rehabilitation device must provide assistance to facilitate movement within reachable space that is limited by any joint restrictions resulting from MSDs.

Silencing matrix metalloproteinase-13 (Mmp-13) reduces inflammatory bone resorption associated with LPS-induced periodontal disease in vivo.

OBJECTIVES: The aim of this study was to evaluate the effect of specific inhibition of MMP-13 on inflammation and inflammatory bone resorption in a murine model of lipopolysaccharide (LPS)-induced periodontitis. MATERIALS AND METHODS: Periodontitis was induced in mice by micro-injections of LPS into the gingival tissues adjacent to the palatal surfaces of maxillary molars twice a week for 15 days. Matrix metalloproteinase-13 (Mmp-13) shRNA or a specific biochemical inhibitor were also injected into the same sites in alternating days with the LPS injections. Efficacy of shRNA-mediated silencing of Mmp-13 was verified by quantitative real-time polymerase chain reaction (qPCR) and immunoblot. Bone resorption was assessed by microcomputed tomography (uCT). Histological sections stained with hematoxylin/eosin (H/E) were used in the stereometric analysis of the inflammatory infiltrate. Gingival tissues were used to evaluate expression of Mmp-13, Il-6, Tnf-α, Ptgs2, and Rankl (qPCR). Protein levels of TGF-ß and IL-10 in the tissues were determined by enzyme-linked immunosorbent assays (ELISA) or by MMP-13 and p38 immunoblot. RESULTS: Silencing Mmp-13 expression reduced bone resorption significantly. Expression of Mmp-13, Il-6, and Tnf-α, as well as the protein levels of IL-6 and TNF-α, was reduced in the animals treated with adenovirus-delivered shRNA; however, these effects were not associated with modulation of p38 MAPK signaling. Interestingly, inhibition Mmp-13 did not affect the severity of inflammatory infiltrate. CONCLUSIONS: Site-specific inhibition of MMP-13 reduced bone resorption and production of inflammatory mediators associated with periodontal disease. CLINICAL RELEVANCE: The results suggest that site-specific inhibition of MMP-13 may be an interesting strategy to modulate inflammation and reduce bone resorption in osteolytic inflammatory diseases.

Local application of curcumin-loaded nanoparticles as an adjunct to scaling and root planing in periodontitis: Randomized, placebo-controlled, double-blind split-mouth clinical trial.

OBJECTIVE: Assess a single local application of curcumin-loaded nanoparticles as an adjunct to scaling and root planing (SRP) in nonsurgical periodontal treatment (NPT). MATERIALS AND METHODS: Twenty healthy subjects with periodontitis received SRP+PLGA/PLA nanoparticles loaded with 50 µg of curcumin (N-Curc) or SRP+empty nanoparticles. Probing pocket depth (PPD), clinical attachment level (CAL), and bleeding on probing (BOP) were monitored at baseline, 30, 90, and 180 days. IL-1α, IL-6, TNFα, and IL-10 in the gingival crevicular fluid (GCF) were assessed by ELISA, and counts of 40 bacterial species were determined by DNA hybridization at baseline, 3, 7, and 15 days post-therapy. RESULTS: PPD, CAL, and BOP were similarly and significantly improved in both experimental groups. There was no difference in GCF cytokine levels between experimental groups, although IL-6 was decreased at 3 days only in the N-Curc group. NPT reduced counts of red complex bacterial species in both groups. Veillonella Parvula counts increased significantly only in N-Curc group at 7 days, whereas Aggregatibacter actinomycetemcomitans counts increased significantly only in the control group from day 3 to day 15. CONCLUSION: We conclude that a single local administration of nanoencapsulated curcumin in periodontally diseased sites had no additive benefits to NPT. CLINICAL RELEVANCE: Our results showed that a single local application of curcumin-loaded nanoparticles associated with nonsurgical periodontal therapy did not improve clinical outcomes. Hence, our findings do not support the use of curcumin as an adjunct to nonsurgical periodontal therapy.

Systemic administration of curcumin or piperine enhances the periodontal repair: a preliminary study in rats.

OBJECTIVES: Studies have documented the anti-inflammatory effects of spices, which may be related to treatment of chronic diseases. The purpose of this study was to evaluate the influence of curcumin and piperine and their association on experimental periodontal repair in rats. MATERIALS AND METHODS: Periodontitis was induced via the installation of a ligature around the first molar. After 15 days, the ligatures were removed, and the rats were separated into groups (12 animals per group): (i) curcumin, (ii) piperine, (iii) curcumin+piperine, (iv) corn oil vehicle, and (v) control group (animals had ligature-induced periodontitis but were not treated). The compounds were administered daily, for 15 days by oral gavage. Animals were euthanized at 5 and 15 days, and hemimaxillae and gingival tissues were harvested. Bone repair was assessed by µCT (microcomputer tomography). Histological sections were stained with hematoxylin/eosin (H/E) for the assessment of cellular infiltrate or picrosirius red for quantification of collagen content, and subjected to immunohistochemistry for detecting NF-ĸB. Gingival tissues were used to evaluate levels of TGF-ß and IL-10 (ELISA). RESULTS: Curcumin and piperine increased the TGF-ß level, significantly improved the collagen repair, and decreased the cellularity and activation of NF-ĸB in the periodontal tissues, but only curcumin caused a significant increase in early bone repair. CONCLUSION: Curcumin and piperine promoted a substantive effect on tissue repair; however, there was not synergistic effect of compounds administered in combination. CLINICAL RELEVANCE: Curcumin and piperine stimulates the tissue repair and may be potential candidates for the treatment of periodontal disease.

Linkage of Periodontitis and Rheumatoid Arthritis: Current Evidence and Potential Biological Interactions.

The association between rheumatoid arthritis (RA) and periodontal disease (PD) has been the focus of numerous investigations driven by their common pathological features. RA is an autoimmune disease characterized by chronic inflammation, the production of anti-citrullinated proteins antibodies (ACPA) leading to synovial joint inflammation and destruction. PD is a chronic inflammatory condition associated with a dysbiotic microbial biofilm affecting the supporting tissues around the teeth leading to the destruction of mineralized and non-mineralized connective tissues. Chronic inflammation associated with both RA and PD is similar in the predominant adaptive immune phenotype, in the imbalance between pro- and anti-inflammatory cytokines and in the role of smoking and genetic background as risk factors. Structural damage that occurs in consequence of chronic inflammation is the ultimate cause of loss of function and disability observed with the progression of RA and PD. Interestingly, the periodontal pathogen Porphyromonas gingivalis has been implicated in the generation of ACPA in RA patients, suggesting a direct biological intersection between PD and RA. However, more studies are warranted to confirm this link, elucidate potential mechanisms involved, and ascertain temporal associations between RA and PD. This review is mainly focused on recent clinical and translational research intends to discuss and provide an overview of the relationship between RA and PD, exploring the similarities in the immune-pathological aspects and the possible mechanisms linking the development and progression of both diseases. In addition, the current available treatments targeting both RA and PD were revised.

The Role of Forkhead Box 1 (FOXO1) in the Immune System: Dendritic Cells, T Cells, B Cells, and Hematopoietic Stem Cells.

Forkhead box-O (FOXO) transcription factors have a fundamental role in the development and differentiation of immune cells. FOXO1 and FOXO3 are FOXO members that are structurally similar and bind to the same conserved consensus DNA sequences to induce transcription. FOXO1 has been studied in detail in the activation of dendritic cells (DCs), where it plays an important role through the regulation of target genes such as ICAM-1, CCR7, and the integrin αvß3. FOXO1 is activated by bacteria challenge in DCs and promotes DC bacterial phagocytosis, migration, homing to lymph nodes, DC stimulation of CD4+ T cells and resting B cells, and antibody production. Deletion of FOXO1 in DCs enhances susceptibility to bacteria-induced periodontal disease. FOXO1 and FOXO3 maintain naive T cell quiescence and survival. FOXO1 and FOXO3 enhance the formation of regulatory T cells and inhibit the formation of T-helper 1 (Th1) and Th17 cells. FOXO1 promotes differentiation, proliferation, survival, immunoglobulin gene rearrangement, and class switching in B cells, but FOXO3 has little effect. Both FOXO1 and FOXO3 are important in the maintenance of hematopoietic stem cells by protecting them from oxidative stress. This review examines FOXO1/FOXO3 in the adaptive immune response, key target genes, and FOXO inhibition by the phosphoinositide 3-kinase/AKT pathway.

NOD1 in the modulation of host-microbe interactions and inflammatory bone resorption in the periodontal disease model.

Periodontitis is a chronic inflammatory condition characterized by destruction of non-mineralized and mineralized connective tissues. It is initiated and maintained by a dysbiosis of the bacterial biofilm adjacent to teeth with increased prevalence of Gram-negative microorganisms. Nucleotide-binding oligomerization domain containing 1 (NOD1) is a member of the Nod-like receptors (NLRs) family of proteins that participate in the activation of the innate immune system, in response to invading bacteria or to bacterial antigens present in the cytoplasm. The specific activating ligand for NOD1 is a bacterial peptidoglycan derived primarily from Gram-negative bacteria. This study assessed the role of NOD1 in inflammation-mediated tissue destruction in the context of host-microbe interactions. We used mice with whole-genome deletion of the NOD1 gene in a microbe-induced periodontitis model using direct injections of heat-killed Gram-negative or Gram-negative/Gram-positive bacteria on the gingival tissues. In vitro experiments using primary bone-marrow-derived macrophages from wild-type and NOD1 knockout mice provide insight into the role of NOD1 on the macrophage response to Gram-negative and Gram-negative/Gram-positive bacteria. Microcomputed tomography analysis indicated that deletion of NOD1 significantly aggravated bone resorption induced by Gram-negative bacteria, accompanied by an increase in the numbers of osteoclasts. This effect was significantly attenuated by the association with Gram-positive bacteria. In vitro, quantitative PCR arrays indicated that stimulation of macrophages with heat-killed Gram-negative bacteria induced the same biological processes in wild-type and NOD1-deficient cells; however, expression of pro-inflammatory mediators was increased in NOD1-deficient cells. These results suggest a bone-sparing role for NOD1 in this model.

Clopidogrel enhances periodontal repair in rats through decreased inflammation.

AIM: We hypothesized that platelet inactivation induced by drugs might interfere with periodontal repair in experimental periodontitis by suppressing the release of biological mediators from platelets at the site of injury. MATERIAL AND METHODS: Sixty rats were randomly assigned to six groups (n = 10) and ligatures were placed around lower first molars of three groups. The other three groups were used as negative controls. Ligatures were removed after 10 days of periodontitis induction and all groups were submitted to treatment with aspirin (Asp) (30 mg/kg), clopidogrel (Clop) (75 mg/kg) or NaCl 0.9% intra-gastrically once daily for 3 days. Periodontal tissue was assessed by the measurement of CXCL12, CXCL4, CCL5 and platelet-derived growth factor (PDGF) by enzyme-linked immunosorbent assay; histomorphometrical analysis of polymorphonuclear (PMN) infiltration, attachment loss, bone loss and osteoclast numbers and quantification of blood vessels by imunnohistochemistry. RESULTS: During periodontal repair and treatment with NaCl 0.9%, CCL5 was decreased and CXCL12 increased when compared with negative control groups. Asp and Clop did not affect CCL5 expression, decreased CXCL12 but only Clop decreased CXCL4 and PDGF content compared with saline-treated animals. Clop increased blood vessel number, reduced PMN count and decreased attachment and bone loss, also decreased osteoclast number in animals submitted or not to periodontal repair. CONCLUSION: Systemic administration of Clop for 3 days improved the repair process associated with experimental periodontal disease, suggesting that it may have therapeutic value under situations where tissues undergo a transition from inflammation to repair.

Biomechanical loading modulates proinflammatory and bone resorptive mediators in bacterial-stimulated PDL cells.

The present study aimed to evaluate in vitro whether biomechanical loading modulates proinflammatory and bone remodeling mediators production by periodontal ligament (PDL) cells in the presence of bacterial challenge. Cells were seeded on BioFlex culture plates and exposed to Fusobacterium nucleatum ATCC 25586 and/or cyclic tensile strain (CTS) of low (CTSL) and high (CTSH) magnitudes for 1 and 3 days. Synthesis of cyclooxygenase-2 (COX2) and prostaglandin E2 (PGE2) was evaluated by ELISA. Gene expression and protein secretion of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) were evaluated by quantitative RT-PCR and ELISA, respectively. F. nucleatum increased the production of COX2 and PGE2, which was further increased by CTS. F. nucleatum-induced increase of PGE2 synthesis was significantly (P < 0.05) increased when CTSH was applied at 1 and 3 days. In addition, CTSH inhibited the F. nucleatum-induced upregulation of OPG at 1 and 3 days, thereby increasing the RANKL/OPG ratio. OPG and RANKL mRNA results correlated with the protein results. In summary, our findings provide original evidence that CTS can enhance bacterial-induced syntheses of molecules associated with inflammation and bone resorption by PDL cells. Therefore, biomechanical, such as orthodontic or occlusal, loading may enhance the bacterial-induced inflammation and destruction in periodontitis.

A novel chemically modified curcumin reduces severity of experimental periodontal disease in rats: initial observations.

Tetracycline-based matrix metalloproteinase- (MMP-) inhibitors are currently approved for two inflammatory diseases, periodontitis and rosacea. The current study addresses the therapeutic potential of a novel pleiotropic MMP-inhibitor not based on an antibiotic. To induce experimental periodontitis, endotoxin (LPS) was repeatedly injected into the gingiva of rats on one side of the maxilla; the contralateral (control) side received saline injections. Two groups of rats were treated by daily oral intubation with a chemically modified curcumin, CMC 2.24, for two weeks; the control groups received vehicle alone. After sacrifice, gingiva, blood, and maxilla were collected, the jaws were defleshed, and periodontal (alveolar) bone loss was quantified morphometrically and by µ-CT scan. The gingivae were pooled per experimental group, extracted, and analyzed for MMPs (gelatin zymography; western blot) and for cytokines (e.g., IL-1ß; ELISA); serum and plasma samples were analyzed for cytokines and MMP-8. The LPS-induced pathologically excessive bone loss was reduced to normal levels based on either morphometric (P = 0.003) or µ-CT (P = 0.008) analysis. A similar response was seen for MMPs and cytokines in the gingiva and blood. This initial study, on a novel triketonic zinc-binding CMC, indicates potential efficacy on inflammatory mediators and alveolar bone loss in experimental periodontitis and warrants future therapeutic and pharmacokinetic investigations.

Improved bioimpedance spectroscopy tissue classification through data augmentation from generative adversarial networks.

Bioimpedance spectroscopy is a tissue classification technique with many clinical applications. Similarly to other data-driven methods, it requires large amounts of data to accurately distinguish similar classes of tissue. Classifiers trained on small datasets typically suffer from over-fitting and lack the ability to generalise to previously unseen data. However, a large in or ex vivo spectral database is difficult to attain. Data collection is usually limited to studies that occur infrequently, and publicly available data is often not available. A solution to this problem is to artificially increase the training dataset by creating modified, yet accurate, copies of the original dataset. The most common techniques in spectral classification are to add noise to copies of the original data, over-sample it, or randomly interpolate pairs of the original data. However, simply perturbing or interpolating the data does not guarantee that the new dataset captures the key features of the original data needed for accurate classification. This study proposes a novel way to augment bioimpedance spectral data. It uses generative adversarial networks (GAN)-a model in which two neural networks (NN) compete with each other: while one NN artificially manufactures data that could be mistaken for real data, the role of the second NN is to identify which data it receives has been artificially created. The first NN then interactively adapts its output until the second NN can no longer flag artificially created data. The result is a new dataset that truly represents the features of the original data. In this study, three GAN architectures are used, i.e., the vanilla GAN, the deep convolutional GAN, and the Wasserstein GAN. Then, the generated data is used to train five classification methods, and their results are compared to a baseline that only uses the original data. The results from a dataset of 13 different tissue classes show that the deep convolutional GAN is most statistically similar to the original data and improves classification accuracy by 15% when compared to the same model trained only on the original data. The Wasserstein-GAN architecture also provides significant improvements of up to 24% better accuracy.

SOCS3 expression correlates with severity of inflammation, expression of proinflammatory cytokines, and activation of STAT3 and p38 MAPK in LPS-induced inflammation in vivo.

SOCS3 is an inducible endogenous negative regulator of JAK/STAT pathway, which is relevant in inflammatory conditions. We used a model of LPS-induced periodontal disease in rats to correlate SOCS3 expression with the inflammatory status. In vitro we used a murine macrophage cell line to assess the physical interaction between SOCS3 and STAT3 by coimmunoprecipitation. 30 ug of LPS from Escherichia coli were injected in the gingival tissues on the palatal aspect of first molars of the animals 3x/week for up to 4 weeks. Control animals were injected with the vehicle (PBS). The rats were sacrificed at 7, 15, and 30 days. Inflammation and gene expression were assessed by stereometric analysis, immunohistochemistry, RT-qPCR, and western blot. LPS injections increased inflammation, paralleled by an upregulation of SOCS3, of the proinflammatory cytokines IL-1 ß , IL-6, and TNF- α and increased phosphorylation of STAT3 and p38 MAPK. SOCS3 expression accompanied the severity of inflammation and the expression of proinflammatory cytokines, as well as the activation status of STAT3 and p38 MAPK. LPS stimulation in a macrophage cell line in vitro induced transient STAT3 activation, which was inversely correlated with a dynamic physical interaction with SOCS3, suggesting that this may be a mechanism for SOCS3 regulatory function.

Improved Configurations for 3D Acoustoelectric Tomography With a Minimal Number of Electrodes.

OBJECTIVE: Acoustoelectric tomography (AET) is a hybrid imaging technique combining ultrasound and electrical impedance tomography (EIT). It exploits the acoustoelectric effect (AAE): an US wave propagating through the medium induces a local change in conductivity, depending on the acoustoelectric properties of the medium. Typically, AET image reconstruction is limited to 2D and most cases employ a large number of surface electrodes. METHODS: This article investigates the detectability of contrasts in AET. We characterize the AEE signal as a function of the medium conductivity and electrode placement, using a novel 3D analytical model of the AET forward problem. The proposed model is compared to a finite element method simulation. RESULTS: In a cylindrical geometry with an inclusion contrast of 5 times the background and two pairs of electrodes, the maximum, minimum, and mean suppression of the AEE signal are 68.5%, 3.12%, and 49.0%, respectively, over a random scan of electrode positions. The proposed model is compared to a finite element method simulation and the minimum mesh sizes required successfully model the signal is estimated. CONCLUSION: We show that the coupling of AAE and EIT leads to a suppressed signal and the magnitude of the reduction is a function of geometry of the medium, contrast and electrode locations. SIGNIFICANCE: This model can aid in the reconstruction of AET images involving a minimum number of electrodes to determine the optimal electrode placement.

Expression of interferon-γ, interferon-α and related genes in individuals with Down syndrome and periodontitis.

BACKGROUND: Recently, attenuation of anti-inflammatory and increase of pro-inflammatory mediators was demonstrated in individuals with Down syndrome (DS) in comparison with euploid patients during periodontal disease (PD), suggesting a shift to a more aggressive inflammation in DS. AIM: To determine the influence of DS in the modulation of interferons (IFNs) signaling pathway in PD. MATERIALS AND METHODS: Clinical periodontal assessment was performed and gingival tissue samples obtained from a total of 51 subjects, including 19 DS individuals with PD, 20 euploid individuals with PD and 12 euploid individuals without PD. Expression levels of interferon-gamma (IFNG) and interferon-alpha (IFNA), and their receptors IFNGR1, IFNGR2, IFNAR1 and IFNAR2, the signaling intermediates Janus kinase 1 (JAK1), signal transducer and activator of transcription 1 (STAT1) and interferon regulatory factor 1 (IRF1) were determined using real time quantitative polymerase chain reaction (qPCR). RESULTS: Clinical signs of periodontal disease were markedly more severe in DS and euploid patients with PD in comparison to euploid and periodontally healthy patients. There was no difference on mRNA levels of IFNA, IFNG, INFGR2, IFNAR1 and IFNAR2 between DS and euploid individuals, even though some of these genes are located on chromosome 21. STAT1 and IRF1 mRNA levels were significantly lower in DS patients in comparison with euploid individuals with PD. In euploid individuals, PD was associated with an increased expression of IFNGR1, IFNGR2, IFNAR1, STAT1 and IRF1. CONCLUSIONS: Reduced expression of STAT1 and IRF1 genes indicate an impaired activation of IFNs signaling in individuals with DS and PD. Expression of IFNA, IFNG and IFN receptors was not altered in DS patients, indicating that indirect mechanisms are involved in the reduced activation of IFN signaling.

Development of a tissue discrimination electrode embedded surgical needle using vibro-tactile feedback derived from electric impedance spectroscopy.

Some tumours may not be detected by ultrasound during biopsy, but recent evidence has shown that different tissues can be discerned by electric impedance. This paper explores the application of vibrotactile feedback in an electrode embedded needle to help classify tissue during fine-needle aspiration biopsy from bioimpedance measurements. The process uses electric impedance spectroscopy from 10 Hz to 349 kHz to fit the double-dispersion Cole model through the Newton-Raphson algorithm. A Naive Bayes classifier is then used on the equivalent circuit parameters to estimate the tissue at the needle tip. The method is validated through a series of experiments and user trials. The results show that the vibrotactile feedback is able to help the operator in determining the tissue the needle is in, suggesting that this may prove to be a useful supplement to the standard procedure used today. Graphical Abstract This paper explores the application of vibrotactile feedback for an electrode embedded needle to help classify tissue from electric impedance measurements. The data is fit to an equivalent circuit using Newton- Raphon's method. A Naive Bayes classifier is trained and later used in an experiment to estimate the tissue at the needle tip and provide an assigned vibrotacticle feedback to the user.

Galanin mediates tumor-induced immunosuppression in head and neck squamous cell carcinoma.

PURPOSE: Galanin receptor 2 (GALR2) plays a significant role in the progression of head and neck squamous cell carcinomas (HNSCC). Since there is virtually no information on immunomodulation mediated by its ligand in the tumor microenvironment, we assessed the effects of galanin on peripheral blood mononuclear cells (PBMCs). METHODS: After verification of GALR2 expression and it activity in PBMCs we evaluated the effect of galanin and conditioned media from HNSCC cell lines silenced for galanin or antibody-depleted, on proliferation, apoptosis, cytokine expression and activation/differentiation of immune cells. RESULTS: We found that galanin alone and as a component of the HNSCC secretome decreased HNSCC cell proliferation and expression of pro-inflammatory cytokines (IFNγ, IL-12, IL-17A, IL-1α, IL-6 and TNF-α), whilst increasing apoptosis and expression of pro-tumoral cytokines/growth factors (IL-10, IL-4, PDGF and GM-CSF). T cell activation (using CD69 as activation marker) and anti-tumoral phenotypes in CD4+ T cells (Th1 and Th17) were found to be suppressed. In vivo, tumor growth was found to be increased in the presence of galanin-stimulated PBMCs. Data from The Cancer Genome Atlas (TCGA) revealed that high expression of galanin was associated with a reduced overall survival of patients with HNSCC. CONCLUSION: Our data indicate that galanin secreted by HNSCC cells exhibits immune-suppressive and pro-tumoral effects.

Influence of tumor cell-derived TGF-ß on macrophage phenotype and macrophage-mediated tumor cell invasion.

In oral squamous cell carcinoma (OSCC), macrophages are the most abundant immune cell type in the tumor microenvironment (TME). Macrophage infiltration is inversely proportional to prognosis and disease survival, particularly when these tumor-associated macrophages (TAM) assume an M2-like phenotype. This phenotype is determined by cues from the microenvironment, especially tumor cell-secreted molecules, and is associated with increased production of extracellular-matrix-degrading enzymes, angiogenic molecules and immunosuppressing cytokines. This study investigates, in vitro and in vivo, the relative contribution of OSCC cell-secreted transforming growth factor beta (TGF-ß) on the phenotype of macrophages and on macrophage-facilitated tumor invasion. TCGA database shows a positive correlation between high expression of TGFB1 and macrophage infiltrate in Head and neck squamous cell carcinoma (HNSCC). THP-1 derived-macrophages were exposed to the secretome of two OSCC cell lines using two strategies to block the effects of neoplastic cell-secreted TGF-ß: pre-treatment with a TGF-ß receptor type I kinase inhibitor (LY364947) and antibody-mediated depletion. RT-qPCR, ELISA and flow cytometry determined macrophage phenotype after exposure to conditioned medium (CM) from H-314 (TGF-ßhigh) or SCC-9 (TGF-ßlow) cell lines. The influence of TGF-ß on macrophage-mediated tumor cell invasion (myogel and CAM assays) and chemotaxis (Boyden chamber) was assessed using co-cultures of macrophages and OSCC cells in which macrophages were pre-conditioned with the secretome of OSCC cells in the presence and absence of LY364947. Blocking the effects of TGF-ß skewed macrophages to the M1 end of the phenotype by differential effects depending on the strategy for inhibiting the influence of TGF-ß and on the neoplastic cell secretome. In vitro and in vivo invasion of H-314 cell line was reduced by inhibiting TGFBR1 signaling in macrophages, whereas SCC-9 cell invasion was not affected. SCC-9/macrophage reciprocal chemotaxis were enhanced by inhibiting TGFBR1 signaling in macrophages, whereas only macrophage chemotaxis to H314 products was inhibited by inhibiting TGFBR1. In summary, blocking the effects of OSCC cell-secreted TGF-ß in macrophages attenuates M2-like phenotypical traits of macrophages and can impact invasion and chemotaxis of tumor cells differentially.

Silencing mitogen-activated protein kinase-activated protein kinase-2 arrests inflammatory bone loss.

p38 mitogen-activated protein kinases (MAPKs) are critical for innate immune signaling and subsequent cytokine expression in periodontal inflammation and bone destruction. In fact, previous studies show that systemic p38 MAPK inhibitors block periodontal disease progression. However, development of p38 MAPK inhibitors with favorable toxicological profiles is difficult. Here, we report our findings regarding the contribution of the downstream p38 MAPK substrate, mitogen-activated protein kinase-activated protein kinase 2 (MK2 or MAPKAPK-2), in immune response modulation in an experimental model of pathogen-derived lipopolysaccharide (LPS)-induced periodontal bone loss. To determine whether small interfering RNA (siRNA) technology has intraoral applications, we initially validated MK2 siRNA specificity. Then, gingival tissue surrounding maxillary molars of rats was injected with MK2 siRNA or scrambled siRNA at the palatal regions of bone loss. Intraoral tissues treated with MK2 siRNA had significantly less MK2 mRNA expression compared with scrambled siRNA-treated tissues. MK2 siRNA delivery arrested LPS-induced inflammatory bone loss, decreased inflammatory infiltrate, and decreased osteoclastogenesis. This proof-of-concept study suggests a novel target using an intraoral RNA interference strategy to control periodontal inflammation.

Electrical Impedance Tomography for Robot-Aided Internal Radiation Therapy.

High dose rate brachytherapy (HDR) is an internal based radiation treatment for prostate cancer. The treatment can deliver radiation to the site of dominant tumor growth within the prostate. Imaging methods to delineate the dominant tumor are imperative to ensure the maximum success of HDR. This paper investigates the feasibility of using electrical impedance tomography (EIT) as the main imaging modality during robot-aided internal radiation therapy. A procedure utilizing brachytherapy needles in order to perform EIT for the purpose of robot-aided prostate cancer imaging is proposed. It is known that cancerous tissue exhibits different conductivity than healthy tissue. Using this information, it is hypothesized that a conductivity map of the tissue can be used to locate and delineate cancerous nodules via EIT. Multiple experiments were conducted using eight brachytherapy needle electrodes. Observations indicate that the imaging procedure is able to observe differences in tissue conductivity in a setting that approximates transperineal HDR and confirm that brachytherapy needles can be used as electrodes for this purpose. The needles can access the tissue at a specific depth that traditional EIT surface electrodes cannot. The results indicate the feasibility of using brachytherapy needles for EIT for the purpose internal radiation therapy.

Sonographic Diagnosis of COVID-19: A Review of Image Processing for Lung Ultrasound.

The sustained increase in new cases of COVID-19 across the world and potential for subsequent outbreaks call for new tools to assist health professionals with early diagnosis and patient monitoring. Growing evidence around the world is showing that lung ultrasound examination can detect manifestations of COVID-19 infection. Ultrasound imaging has several characteristics that make it ideally suited for routine use: small hand-held systems can be contained inside a protective sheath, making it easier to disinfect than X-ray or computed tomography equipment; lung ultrasound allows triage of patients in long term care homes, tents or other areas outside of the hospital where other imaging modalities are not available; and it can determine lung involvement during the early phases of the disease and monitor affected patients at bedside on a daily basis. However, some challenges still remain with routine use of lung ultrasound. Namely, current examination practices and image interpretation are quite challenging, especially for unspecialized personnel. This paper reviews how lung ultrasound (LUS) imaging can be used for COVID-19 diagnosis and explores different image processing methods that have the potential to detect manifestations of COVID-19 in LUS images. Then, the paper reviews how general lung ultrasound examinations are performed before addressing how COVID-19 manifests itself in the images. This will provide the basis to study contemporary methods for both segmentation and classification of lung ultrasound images. The paper concludes with a discussion regarding practical considerations of lung ultrasound image processing use and draws parallels between different methods to allow researchers to decide which particular method may be best considering their needs. With the deficit of trained sonographers who are working to diagnose the thousands of people afflicted by COVID-19, a partially or totally automated lung ultrasound detection and diagnosis tool would be a major asset to fight the pandemic at the front lines.