Publications by authors named "Carlos Rossa"

74 Publications

Electrical Impedance Tomography for Robot-Aided Internal Radiation Therapy.

Front Bioeng Biotechnol 2021 21;9:698038. Epub 2021 Jun 21.

Faculty of Engineering and Applied Science, Ontario Tech University, Oshawa, ON, Canada.

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.
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http://dx.doi.org/10.3389/fbioe.2021.698038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256893PMC
June 2021

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

Front Big Data 2021 9;4:612561. Epub 2021 Mar 9.

Faculty of Engineering and Applied Science, Ontario Tech University, Oshawa, ON, Canada.

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.
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http://dx.doi.org/10.3389/fdata.2021.612561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968725PMC
March 2021

Evaluation of a Virtual Reality Percutaneous Nephrolithotomy (PCNL) Surgical Simulator.

Front Robot AI 2019 14;6:145. Epub 2020 Jan 14.

Faculty of Engineering and Applied Science, Ontario Tech University, Oshawa, ON, Canada.

Percutaneous Nephrolithotomy is the standard surgical procedure used to remove large kidney stones. PCNL procedures have a steep learning curve; a physician needs to complete between 36 and 60 procedures, to achieve clinical proficiency. Marion Surgical K181 is a virtual reality surgical simulator, which emulates the PCNL procedures without compromising the well-being of patients. The simulator uses a VR headset to place a user in a realistic and immersive operating theater, and haptic force-feedback robots to render physical interactions between surgical tools and the virtual patient. The simulator has two modules for two different aspects of PCNL kidney stone removal procedure: kidney access module where the user must insert a needle into the kidney of the patient, and a kidney stone removal module where the user removes the individual stones from the organ. In this paper, we present user trials to validate the face and construct validity of the simulator. The results, based on the data gathered from 4 groups of users independently, indicate that Marion's surgical simulator is a useful tool for teaching and practicing PCNL procedures. The kidney stone removal module of the simulator has proven construct validity by identifying the skill level of different users based on their tool path. We plan to continue evaluating the simulator with a larger sample of users to reinforce our findings.
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http://dx.doi.org/10.3389/frobt.2019.00145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805868PMC
January 2020

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

Clin Oral Investig 2021 May 2;25(5):3161-3172. Epub 2020 Nov 2.

Department of Diagnosis and Surgery, School of Dentistry at Araraquara-State University of São Paulo UNESP, Rua Humaita, 1680, Centro, Araraquara, SP, 14801-903, Brazil.

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-β 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.
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http://dx.doi.org/10.1007/s00784-020-03644-3DOI Listing
May 2021

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.

Clin Oral Investig 2021 May 30;25(5):3217-3227. Epub 2020 Oct 30.

Department of Diagnosis and Surgery, School of Dentistry at Araraquara, Sao Paulo State University (UNESP), Araraquara, SP, Brazil.

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.
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http://dx.doi.org/10.1007/s00784-020-03652-3DOI Listing
May 2021

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

J Biomech Eng 2021 Feb;143(2)

Faculty of Applied Science and Engineering, Ontario Tech University, Oshawa, ON L1G 0C5, Canada.

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.
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http://dx.doi.org/10.1115/1.4048573DOI Listing
February 2021

Validation in a Brazilian population of gene markers of periodontitis previously investigated by GWAS and bioinformatic studies.

J Periodontol 2021 05 2;92(5):689-703. Epub 2020 Oct 2.

Department of Morphology, Genetics, Orthodontics and Pediatric Dentistry, School of Dentistry at Araraquara, São Paulo State University - UNESP, Araraquara, São Paulo, Brazil.

Background: Bioinformatic tools and genome-wide association studies (GWAS) have led to comprehensive identification of single nucleotide polymorphisms (SNPs) associated with periodontitis in diverse populations. Here we aimed to detect and validate the association of seven SNPs as genetic markers of susceptibility to periodontitis in a Brazilian population.

Methods: This case-control study assessed complete periodontal parameters of 714 subjects with periodontal status classified as healthy/mild periodontitis (n = 356) and moderate/severe periodontitis (n = 358). Genotyping for rs187238, rs352140, rs1360573, rs2521634, rs3811046, rs3826782, and rs7762544 SNPs were evaluated. Genetic-phenotype associations, and sex or smoking effects of SNPs on periodontitis were tested using multiple logistic regressions adjusted for covariates.

Results: The rs2521634-AA (close to NPY gene) presented increased risk for severe periodontitis (OR = 2.34; 95% CI = 1.19-4.59). The rs3811046-GG (IL37 gene) demonstrated increased risk for moderate periodontitis (OR = 2.58; 95% CI = 1.28-5.18). Higher risk for moderate periodontitis was found in male with rs7762544-AG close to NCR2 gene. The rs352140-TT in the TLR9 gene proved to be associated with lower risk to severe periodontitis in men. The rs2521634-AA was associated with higher percentage of interproximal probing pocket depth (P = .004).

Conclusions: This is the first evidence of validation in a Brazilian population of genetic markers of periodontitis previously investigated by GWAS and bioinformatics studies. SNPs in the NPY, IL37, and NCR2 genes were associated with susceptibility to moderate or severe periodontitis; whereas the TLR9 marker was associated with lower chance to develop severe periodontitis. Those SNPs had sex- and smoking-habit-specific effects on periodontitis; reinforcing the genetic profile predisposing to periodontitis.
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http://dx.doi.org/10.1002/JPER.20-0126DOI Listing
May 2021

Smoking reduces cathelicidin LL-37 and human neutrophil peptide 1-3 levels in the gingival crevicular fluid of patients with periodontitis.

J Periodontol 2021 04 3;92(4):562-570. Epub 2020 Sep 3.

Department of Oral Diagnosis and Surgery, São Paulo State University (Unesp), School of Dentistry, Araraquara, São Paulo, Brazil.

Background: Antimicrobial peptides are components of innate immune response that have a key role on susceptibility and resistance of the oral cavity to diseases. This study aimed to investigate the influence of smoking on cathelicidin LL-37 and human neutrophil peptides 1 through 3 (HNP 1-3) levels in the gingival crevicular fluid (GCF) of patients with periodontitis. The relationship between levels of these peptides with the periodontal status and selected inflammatory mediators levels in smokers and non-smokers was also evaluated.

Methods: Forty patients with periodontitis, 20 smokers and 20 non-smokers were recruited. After a full periodontal clinical assessment, GCF samples were collected from healthy (n = 5) and diseased (n = 5) sites of each patient. Peptides and inflammatory mediators in the GCF were quantitated by sandwich ELISAs and Multiplex assay, respectively.

Results: Diseased sites had significantly (P <0.05) higher levels of LL-37 and lower levels of HNP 1-3 than healthy sites in both smokers and non-smokers. Diseased sites of smokers presented significantly lower levels of LL-37 and HNP 1-3 when compared with diseased sites of non-smokers. Concentration of LL-37 was directly correlated with the presence of proinflammatory mediators matrix metalloproteinase (MMP)-8 and interleukin (IL)-1β and inversely correlated with concentration of IL-10. HNP 1-3 concentration was positively correlated with IL-10 and negatively correlated with concentrations of MMP-8 and IL-1β.

Conclusions: Smoking was associated with reduced levels of LL-37 and HNP 1-3 in GCF of patients with periodontitis. LL-37 had a distinct expression pattern from HNP 1-3: LL-37 was upregulated in diseased sites, and HNP 1-3 was increased in periodontally healthy sites.1.
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http://dx.doi.org/10.1002/JPER.20-0098DOI Listing
April 2021

Perillyl alcohol has antibacterial effects and reduces ROS production in macrophages.

J Appl Oral Sci 2020 27;28:e20190519. Epub 2020 Apr 27.

Programa de Pós-Graduação em Odontologia, Universidade Federal da Paraíba, João Pessoa, Paraíba, Brasil.

Natural products have emerged as a rich source of bioactive compounds for adjunctive treatments of many infectious and inflammatory conditions, including periodontitis. Among the monoterpenes with significant biological properties, there is the perillyl alcohol (POH), which can be found in several essential oils and has shown immunomodulatory properties in recent studies, which may be interesting in the treatment of non-neoplastic inflammatory disorders. Objective To determine the antibacterial and immune modulatory activities of the POH. Methodology The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of the POH for two significant Gram-negative periodontal pathogens were determined by macrodilution and subculture, respectively. Cell proliferation and cytotoxicity in RAW 264.7 macrophages were determined by Trypan Blue and mitochondrial enzymatic activity assay. The modulation of reactive oxygen species (ROS) was analyzed by flow cytometry and expression of TNF and arginase-1 by real-time PCR. Results The POH was effective against P. gingivalis (ATCC 33277) and F. nucleatum (ATCC 25586) with MIC= MBC=1600 μM. No cytotoxicity up to 100 µM was observed on macrophages. The cell proliferation was inhibited from 48 hours at 100 μM (p<0.05) and 250 μM (p<0.01). The POH increased ROS production at both 10 μM and 100 μM (p<0.05) in unstimulated cells. The PMA-induced ROS production was not affected by POH, whereas 100 μM significantly reduced lipopolysaccharide-induced (LPS-induced) ROS. The expression of TNF was not affected by POH in unstimulated cells or in cells polarized to M1 phenotype, whereas both concentrations of POH reduced (p<0.05) the expression of arginase-1 in M2-polarized macrophages. Conclusion The POH has antibacterial activity against periodontal pathogens and reduced proliferation of murine macrophages without significant cytotoxicity at concentrations up to 100 μM. In addition, the POH reduced the LPS-induced ROS and the expression of arginase-1 in M2-polarized macrophages.
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http://dx.doi.org/10.1590/1678-7757-2019-0519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185983PMC
May 2020

Design and Control of a 3 Degree-of-Freedom Parallel Passive Haptic Device.

IEEE Trans Haptics 2020 Oct-Dec;13(4):720-732. Epub 2020 Dec 25.

Teleoperated robotic surgery and surgical simulation provide surgeons with tools that can improve the health outcomes of their patients. The limiting factor in many of these systems, however, is the lack of a haptic system that can render high impedance without compromising transparency or stability. To address this issue, we constructed a 3-Degree-of-Freedom haptic device using brakes as actuators. A novel controller is also proposed to increase the range of forces the device can generate and eliminate stiction. The device uses a modified Delta kinematic structure making it light and rigid. Since brakes are intrinsically stable, the device safely generates a wide range of impedance making it well suited for many surgical applications. The novel controller attempts to minimize the sum of forces acting perpendicular to the virtual surface eliminating un-smooth force output and stiction characteristic to passive devices, while increasing the range of displayable forces. The controller was validated using six testing scenarios where it rendered contact with frictionless surfaces. When using the controller, the device rendered the desired surface without stiction. Since the controller successfully rendered complex geometry, it can also work in other applications, such as robotic surgery and surgical simulation.
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http://dx.doi.org/10.1109/TOH.2020.2983037DOI Listing
December 2020

Impact of Kinematic Structure on the Force Displayability of Planar Passive Haptic Devices.

IEEE Trans Haptics 2020 Jan-Mar;13(1):219-225. Epub 2020 Jan 31.

Haptic devices containing passive actuators, such as controllable brakes or dampers, are an attractive alternative to their motor-driven counterparts due to intrinsic stability and improved impedance bandwidth. Passive actuators cannot generate energy and, therefore, the output force can only oppose the applied velocity. In the same way the kinematic structure of traditional manipulators is designed to maximize dexterity and manipulability, one must consider adapting the device topology to optimize force displayability when designing passive actuators. This article introduces a set of metrics to evaluate and compare the performance of 2-degree-of-freedom (DOF) serial and parallel passive haptic devices. These metrics consider the impact of the kinematic structure on the force displayability according to the directions of the device velocity and desired force. Applying these metrics to nine manipulators revealed that: 1.) serial manipulators can generate passive forces in all directions equally regardless of the link length ratio; 2.) the base link length of five-bar parallel manipulators strongly influences passive force displayability; 3.) five-bar parallel manipulators with the base link length of zero can generate the widest range of passive forces when all links have the same length. The novel performance metrics presented in this paper can aid in the design of 2-DOF passive haptic devices.
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http://dx.doi.org/10.1109/TOH.2020.2970906DOI Listing
November 2020

NLRC4 inflammasome has a protective role on inflammatory bone resorption in a murine model of periodontal disease.

Immunobiology 2020 01 30;225(1):151855. Epub 2019 Nov 30.

Department of Diagnosis and Surgery, UNESP-State University of Sao Paulo, School of Dentistry at Araraquara, Araraquara, SP, Brazil. Electronic address:

There is virtually no information on the role of NLRC4 inflammasome on bone resorption and inflammation associated with periodontitis. Bacterial-associated experimental periodontitis was induced in wild-type (WT) and Nlrc4-KO C57BL/6 mice. 3 μL of a 1 × 10 UFC/mL PBS suspension of heat-killed Gram-negative bacteria were injected (3x/week for 4 weeks) directly into the gingival tissues of WT and Nlrc4-KO mice (n = 6/genotype). Control animals were injected bilaterally (3x/week for 4 weeks) in the same sites with the same volume of the PBS vehicle. Alveolar bone resorption was quantified by μCT. Inflammatory infiltrate in the gingival tissues was assessed qualitatively in H&E-stained slides and by the detection of a pan-leukocyte marker (CD45) and a neutrophil marker (Ly6G) using immunofluorescence. Modulation of Rankl, Mmp-13, Tnf-a, Il-6 and Il-10 expression in the gingival tissues was determined by RT-qPCR. Osteoclastogenesis was assessed in vivo by biochemical staining for TRAP. The relevance of NLRC4 for RANKL-induced osteoclastic differentiation and activity was investigated in vitro using bone marrow-derived macrophages from WT and Nlrc4-KO mice. Bone resorption was significantly greater in Nlrc4-KO mice; however there were no differences between WT and Nlrc4-KO mice on osteoclast numbers and on the inflammatory infiltrate. In vitro, osteoclast activity was significantly enhanced in Nlrc4-deficient macrophages; whereas RANKL-induced differentiation was not affected. Expression of the selected candidate genes was also similarly increased by the induction of experimental periodontal disease, except for the expression of Tnf-alpha and Il-10, which was already significantly higher in the gingival tissues of Nlrc4-KO mice. We conclude that NLRC4 inflammasome has a protective role on inflammatory bone resorption in this experimental model. Furthermore, the bone-sparing effect may be related with the modulation of osteoclast activity.
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http://dx.doi.org/10.1016/j.imbio.2019.10.004DOI Listing
January 2020

Severe magnesium deficiency compromises systemic bone mineral density and aggravates inflammatory bone resorption.

J Nutr Biochem 2020 03 26;77:108301. Epub 2019 Nov 26.

Department of Diagnosis and Surgery, Sao Paulo State University, School of Dentistry at Araraquara-UNESP, Araraquara, 14801-930, Sao Paulo, Brazil.

We sought to evaluate the effects of magnesium (Mg) intake deficiency on bone metabolism in rats with induced periodontal disease (PD). Holtzman rats were randomly divided into two groups: Control - animals fed a standard diet and test - animals fed a diet with 90% Mg deficiency. After 60 days on the diets, all animals received ligature on the lower left first molars to induce PD. Animals were euthanized after 30 days following ligature placement. Blood and urine were collected for determination of serum concentrations of Mg, calcium, osteocalcin (OCN), alkaline phosphatase and parathyroid hormone (PTH) by enzyme-linked immunosorbent assay, and the urinary concentration of deoxypyridinoline (DPD). Systemic bone mineral density (BMD), bone volume and architectural bone parameters were evaluated by micro-CT in L4 lumbar vertebrae and mandible. Tartrate-resistant acid phosphatase staining and immunohistochemical (IHC) analysis of inducible nitric oxide synthase (iNOS), Runt-related transcription factor 2 (RUNX2), CD86, CD80, proliferating cell nuclear antigen, vascular endothelial growth factor, OCN and osteopontin were investigated. Reverse-transcription polymerase chain reaction was employed to assess mRNA expression of receptor-activator of nuclear factor-kB ligand, osteoprotegerin (OPG) and interleukin (IL)-6. Mg deficiency was associated with higher concentrations of PTH and DPD, and significant decrease on both systemic and mandibular BMD, as well as greater severity of alveolar and trabecular bone loss. Significant increase in osteoclasts was observed in the test group with PD. IHC analysis showed significant increase in the expression of iNOS and decreased expression of OCN and RUNX2. Increased IL-6 mRNA and decreased OPG mRNA expressions were evidenced in the test group with PD. Mg deficiency caused systemic effects indicative of altered bone metabolism in the vertebrae and affected both immune and stromal cells, aggravating inflammatory bone resorption in the ligature-induced model of periodontitis.
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http://dx.doi.org/10.1016/j.jnutbio.2019.108301DOI Listing
March 2020

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

Int J Mol Sci 2019 Sep 13;20(18). Epub 2019 Sep 13.

Department of Rheumatology, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands.

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 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.
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http://dx.doi.org/10.3390/ijms20184541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769683PMC
September 2019

Non-murine models to investigate tumor-immune interactions in head and neck cancer.

Oncogene 2019 06 14;38(25):4902-4914. Epub 2019 Mar 14.

Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.

The immune response has important roles in the biology of solid tumors, including oncogenesis, tumor growth, invasion and metastasis, and response to treatment. Improved understanding of tumor-immune system interactions has provided promising therapeutic options that are based on the rescue and enhancement of the anti-tumoral host response. Immune-based treatments have been approved for clinical use in various types of cancer, including head and neck cancer (HNC); other strategies involving combination therapies are currently in development. These novel therapies were developed based on knowledge derived from in vitro, in silico, and in vivo pre-clinical studies. However, clinical trials seldom replicate the efficacy observed in pre-clinical animal studies. This lack of correlation between pre-clinical studies and clinical trials may be related to limitations of the models used; which highlights the relevance of considering immune-related aspects of different pre-clinical models. Murine models are the most frequently used pre-clinical models of HNC and are discussed elsewhere. Non-murine models have characteristics that offer unique opportunities for the study of HNC etiology, therapeutic strategies, and tumor-immune system interactions. The current review focuses on immune-related aspects of non-murine models, including dog, cat, pig, zebrafish, and frog, that could be used to investigate tumor-immune interactions in HNC.
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http://dx.doi.org/10.1038/s41388-019-0776-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586515PMC
June 2019

Analysing eucalypt expansion in Portugal as a fire-regime modifier.

Sci Total Environ 2019 May 16;666:79-88. Epub 2019 Feb 16.

Centro de Investigação e de Tecnologias Agroambientais e Biológicas (CITAB), Universidade de Trás-os-Montes e Alto Douro, Quinta dos Prados, 5001-801 Vila Real, Portugal.

Eucalypts, especially blue gum (Eucalyptus globulus), have been extensively planted in Portugal and nowadays dominate most of its forest landscapes. Large-scale forestation programs can intensify fire activity, and blue gum plantations are often viewed as highly flammable due to the nature and structure of the fuel complex. The role of eucalypt plantations in the fire regime of Mediterranean climate regions is increasingly debated following the recent catastrophic wildfires in Portugal and elsewhere. In this study we examined the effects of eucalypt forestation on burned area (BA), fire size, and fire severity in Portugal. This was based on fire and vegetation mapping and statistics, fire weather data, satellite imagery, and national forest inventory data. Eucalypt BA comprised an average of 12.5% of total BA (1980-2017) and did not increase over time and with eucalypt expansion. Eucalypt metrics did not explain interannual BA variability after accounting for the effects of other variables. Forest fires started within eucalypt stands were the least likely to become large, and large fire size was irresponsive to forest composition. Likewise, forest type was a generally minor influence in mega-fire severity and accounted for just 1.4-8.6% of surface fuel-hazard metrics variation. In general, large-scale conversion of maritime pine to eucalypt stands (1970-2015) implied lower fuel accumulation. Fire activity results are consistent with fuel hazard results and express trade-offs between short-rotation forestry and fire behaviour in blue gum stands, with high spotting potential versus modest crown fire likelihood. We found no support for the contention of a modified fire regime as a result of eucalypt forestation in Portugal, but the rising undermanaged and abandoned blue gum estate, especially after large-fire seasons, is a concern for the future. However, it remains to be determined whether post-fire eucalypt regrowth is a higher fire threat than native vegetation in the same context.
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http://dx.doi.org/10.1016/j.scitotenv.2019.02.237DOI Listing
May 2019

Immune-relevant aspects of murine models of head and neck cancer.

Oncogene 2019 05 29;38(21):3973-3988. Epub 2019 Jan 29.

Department of Periodontics and Oral Medicine, School of Dentistry, Ann Arbor, MI, 48109, USA.

Head and neck cancers (HNCs) cause significant mortality and morbidity. There have been few advances in therapeutic management of HNC in the past 4 to 5 decades, which support the need for studies focusing on HNC biology. In recent years, increased recognition of the relevance of the host response in cancer progression has led to novel therapeutic strategies and putative biomarkers of tumor aggressiveness. However, tumor-immune interactions are highly complex and vary with cancer type. Pre-clinical, in vivo models represent an important and necessary step in understanding biological processes involved in development, progression and treatment of HNC. Rodents (mice, rats, hamsters) are the most frequently used animal models in HNC research. The relevance and utility of information generated by studies in murine models is unquestionable, but it is also limited in application to tumor-immune interactions. In this review, we present information regarding the immune-specific characteristics of the murine models most commonly used in HNC research, including immunocompromised and immunocompetent animals. The particular characteristics of xenograft, chemically induced, syngeneic, transgenic, and humanized models are discussed in order to provide context and insight for researchers interested in the in vivo study of tumor-immune interactions in HNC.
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http://dx.doi.org/10.1038/s41388-019-0686-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533118PMC
May 2019

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

Clin Oral Investig 2019 Aug 29;23(8):3297-3306. Epub 2018 Nov 29.

Department of Diagnosis and Surgery, School of Dentistry at Araraquara - Univ Estadual Paulista (UNESP), Rua Humaita, 1680 - Centro, Araraquara, SP, 14801-903, Brazil.

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-β and IL-10 (ELISA).

Results: Curcumin and piperine increased the TGF-β 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.
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http://dx.doi.org/10.1007/s00784-018-2755-9DOI Listing
August 2019

Dose-response assessment of chemically modified curcumin in experimental periodontitis.

J Periodontol 2019 05 20;90(5):535-545. Epub 2018 Dec 20.

Department of Diagnosis and Surgery, School of Dentistry at Araraquara, UNESP, Araraquara, Brazil.

Background: CMC2.24, a novel tri-ketonic chemically modified compound based on natural di-ketonic curcumin, has been shown to reduce bone loss and inflammatory mediators in experimental periodontitis, however, a potential dose-response relationship was not determined. The purpose of this study was to assess the effects of different doses of CMC2.24 on inflammation and bone resorption in vivo and also to describe on the effects of CMC2.24 on macrophage response.

Methods: CMC2.24 was administered daily to animals for 28 days by oral gavage, at the following doses: 0 (control), 1, 3, 10, and 30 mg/kg of body weight. Experimental periodontitis was induced by injections of lipopolysaccharide (LPS) into the gingival tissues. Outcomes assessed were bone resorption, detection of tartrate-resistant acid phosphatase, and determination of gene expression. In vitro, macrophages (RAW264.7) were treated with different concentrations of CMC2.24: 1, 3, 10, and 30 μM and then subjected to different activation stimuli. Gene expression, phagocytic activity, production of reactive oxygen species (ROS) and cytokine production were evaluated.

Results: CMC2.24 inhibited bone resorption, osteoclastogenesis, and tumor necrosis factor (TNF)-α expression in vivo. These beneficial responses reached maximum levels at a dose of 1 mg/kg, i.e. no dose-dependent effect. In vitro, CMC2.24 reduced the production of TNF-α and interleukin-10, inhibited phagocytic activity and stimulated production of ROS. A dose-dependent effect was observed only for ROS production.

Conclusion: Low doses of CMC2.24 (1 mg/kg/day) administered orally were sufficient to significantly inhibit alveolar bone resorption associated with the experimental periodontal disease; whereas in vitro macrophage inflammatory gene expression and phagocytosis were reduced, whereas production of ROS was stimulated.
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http://dx.doi.org/10.1002/JPER.18-0392DOI Listing
May 2019

Robotic-Assisted Needle Steering Around Anatomical Obstacles Using Notched Steerable Needles.

IEEE J Biomed Health Inform 2018 11 6;22(6):1917-1928. Epub 2017 Dec 6.

Robotic-assisted needle steering can enhance the accuracy of needle-based interventions. Application of current needle steering techniques are restricted by the limited deflection curvature of needles. Here, a novel steerable needle with improved curvature is developed and used with an online motion planner to steer the needle along curved paths inside tissue. The needle is developed by carving series of small notches on the shaft of a standard needle. The notches decrease the needle flexural stiffness, allowing the needle to follow tightly curved paths with small radius of curvature. In this paper, first, a finite element model of the notched needle deflection in tissue is presented. Next, the model is used to estimate the optimal location for the notches on needle's shaft for achieving a desired curvature. Finally, an ultrasound-guided motion planner for needle steering inside tissue is developed and used to demonstrate the capability of the notched needle in achieving high curvature and maneuvering around obstacles in tissue. We simulated a clinical scenario in brachytherapy, where the target is obstructed by the pubic bone and cannot be reached using regular needles. Experimental results show that the target can be reached using the notched needle with a mean accuracy of 1.2 mm. Thus, the proposed needle enables future research on needle steering toward deeper or more difficult-to-reach targets.
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http://dx.doi.org/10.1109/JBHI.2017.2780192DOI Listing
November 2018

Long-term testosterone depletion attenuates inflammatory bone resorption in the ligature-induced periodontal disease model.

J Periodontol 2018 04;89(4):466-475

Department of Physiology and Pathology, Araraquara School of Dentistry, University of São Paulo State, UNESP, Araraquara, SP, Brazil.

Background: Testosterone is known to affect bone in physiological and pathological conditions. The purpose of this study is to evaluate the role of testosterone in experimental periodontal disease in rats.

Methods: In this study we used a ligature model of periodontal disease in rats submitted to orchiectomy (OCX, testosterone depletion) with and without testosterone replacement therapy (TR). Control animals were sham-operated and retained physiological testosterone levels. Sixty-two days after orchiectomy and sham operations, ligatures were placed around the lower first molars for 2 weeks to induce experimental periodontal disease. Negative control animals received no ligatures. The outcomes assessed in the periodontal tissues were: inflammatory cytokine expression by enzyme-linked immunosorbent assay (ELISA), stereometric analysis of the inflammatory process and quantitation of inflammatory bone resorption by microcomputed tomography (μ-CT).

Results: The OCX+TR group showed the greatest increase in fibroblastic cells and blood vessels with reduced inflammatory cell numbers in the gingival tissue with induction of periodontal disease. There were no significant differences between OCX and Sham-operated groups in all the stereometric parameters assessed. Ligature placement induced inflammatory bone resorption, which was significantly attenuated in OCX animals. Experimental periodontitis induced a significant increase in interleukin (IL)-1β, but the lowest levels were observed in the periodontitis/OCX group. IL-6 levels were not affected by OCX, but were significantly reduced in OCX+TR animals.

Conclusion: The findings of the present study suggest that testosterone depletion attenuates inflammatory bone resorption in ligature-induced periodontitis, which may be partly mediated via decreased production of IL-1β.
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http://dx.doi.org/10.1002/JPER.17-0457DOI Listing
April 2018

Differential effects of natural Curcumin and chemically modified curcumin on inflammation and bone resorption in model of experimental periodontitis.

Arch Oral Biol 2018 Jul 10;91:42-50. Epub 2018 Apr 10.

Department of Restorative Dentistry School of Dentistry of Riberão Preto University of São Paulo Riberão Preto SP Brazil. Electronic address:

Objective: The purpose of this study was to compare the effects of the oral administration of natural curcumin and a chemically modified curcumin (CMC2.24) on osteoclast-mediated bone resorption, apoptosis, and inflammation in a murine model of experimental periodontal disease.

Design: Fifty male rats were distributed among the following treatment groups: (i) 2% carboxymethylcellulose, (ii) CMC2.24 30 mg/kg body weight, (iii) Curcumin 100 mg/kg body weight and (iv) no treatment. Compounds were administered daily by oral intubation over a 15-day period of time. Periodontal disease was induced by injections of LPS (lipopolysaccharide) into the gingival tissues three times per week. Contralateral sides were injected with the same volume of PBS (phosphate buffered saline) vehicle. After 15 days, hemimaxillae and gingival tissues were harvested. Bone resorption was assessed by μCT (microcomputer tomography). Formalin-fixed, paraffin embedded histological sections were stained with haematoxylin/eosin (H/E) for the assessment of cellular infiltrate or subjected to immunohistochemistry for detecting TRAP (tartrate-resistant acid phosphatase)-positive cells and caspase-3. Apoptosis was assessed in the gingival tissues by DNA fragmentation.

Results: CMC2.24 and curcumin caused a significant reduction of the inflammatory cell infiltrate, however μCT analysis showed that only CMC2.24 reduced bone resorption and the number of TRAP-positive multinucleated cells (osteoclasts). Curcumin, but not CMC2.24, significantly reduced the number of apoptotic cells in the gingival tissues and of osteocytes in the alveolar bone crest.

Conclusions: The results suggest that CMC2.24 and curcumin inhibit inflammation by different mechanisms, but only CMC2.24 was capable of reducing alveolar bone resorption in the LPS-induced model of periodontitis.
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http://dx.doi.org/10.1016/j.archoralbio.2018.04.007DOI Listing
July 2018

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

Crit Rev Immunol 2017 ;37(1):1-13

Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.

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 αvβ3. 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.
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http://dx.doi.org/10.1615/CritRevImmunol.2017019636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085137PMC
April 2019

Topical application of bFGF on acid-conditioned and non-conditioned dentin: effect on cell proliferation and gene expression in cells relevant for periodontal regeneration.

J Appl Oral Sci 2017 Nov-Dec;25(6):689-699

Univ Estadual Paulista - UNESP, Faculdade de Odontologia de Araraquara, Departmento de Diagnóstico e Cirurgia, Araraquara, SP, Brasil.

Material And Methods: Periodontal regeneration is still a challenge in terms of predictability and magnitude of effect. In this study we assess the biological effects of combining chemical root conditioning and biological mediators on three relevant cell types for periodontal regeneration. Bovine dentin slices were conditioned with 25% citric acid followed by topical application of basic fibroblast growth factor (bFGF, 10 and 50 ng). We used ELISA to assess the dynamics of bFGF release from the dentin surface and RT-qPCR to study the expression of Runx2, Col1a1, Bglap and fibronectin by periodontal ligament (PDL) fibroblasts, cementoblasts and bone marrow stromal cells (BMSC) grown onto these dentin slices. We also assessed the effects of topical application of bFGF on cell proliferation by quantification of genomic DNA.

Results: Acid conditioning significantly increased the release of bFGF from dentin slices. Overall, bFGF application significantly (p<0.05) increased cell proliferation, except for BMSC grown on non-conditioned dentin slices. Dentin substrate discretely increased expression of Col1a1 in all cell types. Expression of Runx2, Col1a1 and Fn was either unaffected or inhibited by bFGF application in all cell types. We could not detect expression of the target genes on BMSC grown onto conditioned dentin.

Conclusion: Acid conditioning of dentin improves the release of topically-applied bFGF. Topical application of bFGF had a stimulatory effect on proliferation of PDL fibroblasts, cementoblasts and BMSC, but did not affect expression of Runx2, Col1a1, Bglap and fibronectin by these cells.
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http://dx.doi.org/10.1590/1678-7757-2017-0051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701540PMC
February 2018

Suppressor of cytokine signaling 1 expression during LPS-induced inflammation and bone loss in rats.

Braz Oral Res 2017 Sep 28;31:e75. Epub 2017 Sep 28.

Universidade Estadual Paulista - UNESP, School of Dentistry at Araraquara, Department of Diagnosis and Surgery, Araraquara, SP, Brazil.

This study aimed to characterize the dynamics of suppressor of cytokine signaling (SOCS1) expression in a rat model of lipopolysaccharide-induced periodontitis. Wistar rats in the experimental groups were injected three times/week with LPS from Escherichia coli on the palatal aspect of the first molars, and control animals were injected with vehicle (phosphate-buffered saline). Animals were sacrificed 7, 15, and 30 days after the first injection to analyze inflammation (stereometric analysis), bone loss (macroscopic analysis), gene expression (qRT-PCR), and protein expression/activation (Western blotting). The severity of inflammation and bone loss associated with LPS-induced periodontitis increased from day 7 to day 15, and it was sustained through day 30. Significant (p < 0.05) increases in SOCS1, RANKL, OPG, and IFN-γ gene expression were observed in the experimental group versus the control group at day 15. SOCS1 protein expression and STAT1 and NF-κB activation were increased throughout the 30-day experimental period. Gingival tissues affected by experimental periodontitis express SOCS1, indicating that this protein may potentially downregulate signaling events involved in inflammatory reactions and bone loss and thus may play a relevant role in the development and progression of periodontal disease.
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http://dx.doi.org/10.1590/1807-3107BOR-2017.vol31.0075DOI Listing
September 2017

Phototoxicity in a laryngeal cancer cell line enhanced by a targeting amphiphilic chlorin photosensitizer.

Photodiagnosis Photodyn Ther 2017 Sep 14;19:355-362. Epub 2017 Jul 14.

Programa de Pós-Graduação Interunidades Bioengenharia EESC/FMRP/IQSC, Universidade de São Paulo, São Carlos, SP, Brazil; Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil. Electronic address:

Background: Photodynamic therapy (PDT) has been established in several countries as an alternative therapy for the treatment of various malignancies. This therapy involves the incorporation of a photosensitizer (PS) that is activated by visible light and form reactive oxygen species leading to target cell death by apoptosis or necrosis. Previously, our group has demonstrated that CHL-T (semi-synthesized from chlorophyll a and containing a linked solubilizing group TRISMA) presented a pronounced potential to induce death in HeLa cell line after PDT. In the present study, besides confirm the high cytotoxicity in another cell line, we have further investigated the cell death mechanisms caused by CHL-T as a photosensitizer in laryngeal carcinoma cells.

Methods: Cells were exposed to different concentrations of three photosensitizers, namely, hypericin (HY), unmodified chlorin (CHL) and a synthesized amphiphilic chlorin derivative (CHL-T). PSs accumulation and localization were accessed by fluorescence assays. Photosensitization was induced at 6Jcm using red LEDs (630±10nm). Viability was assessed by mitochondrial function (MTT); whereas apoptosis/necrosis was evaluated by fluorescence microscopy and flow cytometry. Expression of pro-apoptotic p53 protein was studied by Western blot.

Results And Conclusions: All PS showed similar localization profile in the HEp-2 cells. The use of CHL-T increased the percentage of apoptotic cells and also p53 expression in comparison with the use of HY and CHL as photosensitizers. This study shows a significant effect of CHLT associated with red light (630±10nm and 18mWcm) irradiation on a cancer cell line, indicating the potential of this amphiphilic chlorin in enhancing the therapeutic effectiveness of Photodynamic Therapy (PDT).
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http://dx.doi.org/10.1016/j.pdpdt.2017.07.003DOI Listing
September 2017

A Chemically Modified Curcumin (CMC 2.24) Inhibits Nuclear Factor κB Activation and Inflammatory Bone Loss in Murine Models of LPS-Induced Experimental Periodontitis and Diabetes-Associated Natural Periodontitis.

Inflammation 2017 Aug;40(4):1436-1449

Department of Oral Biology and Pathology, School of Dental Medicine, SUNY at Stony Brook, Stony Brook, NY, USA.

The purpose of this study was to assess the effect of a novel chemically modified curcumin (CMC 2.24) on NF-κB and MAPK signaling and inflammatory cytokine production in two experimental models of periodontal disease in rats. Experimental model I: Periodontitis was induced by repeated injections of LPS into the gingiva (3×/week, 3 weeks); control rats received vehicle injections. CMC 2.24, or the vehicle, was administered by daily oral gavage for 4 weeks. Experimental model II: Diabetes was induced in adult male rats by streptozotocin injection; periodontal breakdown then results as a complication of uncontrolled hyperglycemia. Non-diabetic rats served as controls. CMC 2.24, or the vehicle, was administered by oral gavage daily for 3 weeks to the diabetics. Hemimaxillae and gingival tissues were harvested, and bone loss was assessed radiographically. Gingival tissues were pooled according to the experimental conditions and processed for the analysis of matrix metalloproteinases (MMPs) and bone-resorptive cytokines. Activation of p38 MAPK and NF-κB signaling pathways was assessed by western blot. Both LPS and diabetes induced an inflammatory process in the gingival tissues associated with excessive alveolar bone resorption and increased activation of p65 (NF-κB) and p38 MAPK. In both models, the administration of CMC 2.24 produced a marked reduction of inflammatory cytokines and MMPs in the gingival tissues, decreased bone loss, and decreased activation of p65 (NF-κB) and p38 MAPK. Inhibition of these cell signaling pathways by this novel tri-ketonic curcuminoid (natural curcumin is di-ketonic) may play a role in its therapeutic efficacy in locally and systemically associated periodontitis.
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http://dx.doi.org/10.1007/s10753-017-0587-4DOI Listing
August 2017

Functional Haplotypes in Interleukin 4 Gene Associated with Periodontitis.

PLoS One 2017 23;12(1):e0169870. Epub 2017 Jan 23.

Department of Morphology, School of Dentistry at Araraquara, UNESP- Univ Estadual Paulista, Araraquara, São Paulo, Brazil.

Chronic periodontitis (CP) is an infectious inflammatory disease that affects tooth-supporting structures and in which dental plaque bacteria, immune mechanisms and genetic predisposition play important roles. Interleukin 4 (IL-4) is a key anti-inflammatory cytokine with relevant action in imbalances in inflamed periodontal tissue. Individuals carrying the TCI/CCI genotype (S-haplotype) of the IL-4 gene are 5 times more susceptible to CP, whereas the CTI/TTD genotype (P-haplotype) confers protection against CP. Compared with the S-haplotype, subjects with the P-haplotype produce higher levels of the IL-4 protein after non-surgical periodontal therapy. The present in vitro study aimed to investigate the functionality of IL-4 haplotypes in immune cells to obtain insight into the influence of these genetic variations in regulating immune responses to CP-associated bacteria. Peripheral blood was collected from 6 subjects carrying each haplotype, and their immune cells were challenged with periodontopathogens to compare responses of the different haplotypes with regard to gene expression, protein secretion and the immunophenotype of T helper responses. We found higher IL-4 mRNA and protein levels in the P-haplotype, which also presented higher levels of anti-inflammatory cytokines. In contrast, cells from S-haplotype subjects responded with higher levels of pro-inflammatory cytokines. S-haplotype individuals exhibited significantly greater polarization toward the Th1 phenotype, whereas the P-haplotype was associated with an attenuated response to periodontopathogens, with suggestive skewing toward Th2/M2 phenotypes. In conclusion, IL-4 genetic variations associated with susceptibility to or protection against chronic periodontitis are directly associated with influencing the response of immune cells to periodontopathogens.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169870PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256924PMC
August 2017

A Hand-Held Assistant for Semiautomated Percutaneous Needle Steering.

IEEE Trans Biomed Eng 2017 03 19;64(3):637-648. Epub 2016 May 19.

Objective: Permanent prostate brachytherapy is an effective and popular treatment modality for prostate cancer in which long needles are inserted into the prostate. Challenges associated with manual needle insertion such as needle deflection limit this procedure to primarily treat the entire prostate gland even for patients with localized cancer. In this paper, we present a new semiautomated hand-held needle steering assistant designed to help surgeons improve needle placement accuracy.

Methods: Regular clinical brachytherapy needles are connected to a compact device that the surgeon holds. As the surgeon inserts the needle, the device rotates the needle base on a measured and calculated basis in order to produce a desired trajectory of the needle tip. A novel needle-tissue interaction model and a steering algorithm calculate such control actions based on ultrasound images of the needle in tissue. The assistant can also apply controlled longitudinal microvibrations to the needle that reduce needle-tissue friction.

Results: Experimental validation of the proposed system in phantom and ex-vivo biological tissue report an average needle targeting accuracy of 0.33 mm over 72 needle insertions in 12 different experimental scenarios.

Conclusion: We introduce a new framework for needle steering in prostate brachytherapy in which the surgeon remains in charge of the needle insertion. The device weighs 160 g, making it easy to incorporate with current insertion techniques.

Significance: Expected benefits of the proposed system include more precise needle targeting accuracy, which can result in improved focal treatment of prostate cancer.
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http://dx.doi.org/10.1109/TBME.2016.2565690DOI Listing
March 2017

A data-driven soft sensor for needle deflection in heterogeneous tissue using just-in-time modelling.

Med Biol Eng Comput 2017 Aug 10;55(8):1401-1414. Epub 2016 Dec 10.

Department of Electrical and Computer Engineering, University of Alberta, Edmonton, AB, T6G 2V4, Canada.

Global modelling has traditionally been the approach taken to estimate needle deflection in soft tissue. In this paper, we propose a new method based on local data-driven modelling of needle deflection. External measurement of needle-tissue interactions is collected from several insertions in ex vivo tissue to form a cloud of data. Inputs to the system are the needle insertion depth, axial rotations, and the forces and torques measured at the needle base by a force sensor. When a new insertion is performed, the just-in-time learning method estimates the model outputs given the current inputs to the needle-tissue system and the historical database. The query is compared to every observation in the database and is given weights according to some similarity criteria. Only a subset of historical data that is most relevant to the query is selected and a local linear model is fit to the selected points to estimate the query output. The model outputs the 3D deflection of the needle tip and the needle insertion force. The proposed approach is validated in ex vivo multilayered biological tissue in different needle insertion scenarios. Experimental results in five different case studies indicate an accuracy in predicting needle deflection of 0.81 and 1.24 mm in the horizontal and vertical lanes, respectively, and an accuracy of 0.5 N in predicting the needle insertion force over 216 needle insertions.
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http://dx.doi.org/10.1007/s11517-016-1599-1DOI Listing
August 2017
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