Histological evaluation of nonsurgical periodontal treatment with and without the use of sodium hypochlorite / amino acids and cross-linked hyaluronic acid gels in dogs.

OBJECTIVES: To evaluate periodontal wound healing following scaling and root planing (SRP) in conjunction with the application of sodium hypochlorite/amino acids and cross-linked hyaluronic acid (xHyA) gels in dogs. MATERIALS AND METHODS: In four beagle dogs, 2-wall intrabony defects were created and metal strips were placed around the teeth. Clinical parameters were measured 4 weeks after plaque accumulation. The experimental root surfaces were subjected to SRP with either the subgingival application of a sodium hypochlorite/amino acid gel and a xHyA gel (test group) or SRP alone (control group) using a split-mouth design. Clinical parameters were re-evaluated at 6 weeks. The animals were sacrificed at 8 weeks for histological analysis. RESULTS: The test group showed significant improvements in all clinical parameters compared to the control group. Histologically, the test group exhibited statistically significantly greater new bone formation [i.e., length of newly formed bone, new bone area] compared with the control group (p < 0.05). Furthermore, statistically significantly greater formation of new attachment [i.e., linear length of new cementum adjacently to newly formed bone with inserting collagen fibers] and new cementum was detected in the test group compared with the control group at 8 weeks (p < 0.05 and p < 0.01, respectively). CONCLUSION: The adjunctive subgingival application of sodium hypochlorite/amino acid and xHyA gels to SRP offers an innovative novel approach to enhance periodontal wound healing/regeneration. CLINICAL RELEVANCE: The present findings have for the first-time shown histologic evidence for periodontal regeneration in support of this novel treatment modality.

The development of non-resorbable bone allografts: Biological background and clinical perspectives.

Bone grafts are typically categorized into four categories: autografts, allografts, xenografts, and synthetic alloplasts. While it was originally thought that all bone grafts should be slowly resorbed and replaced with native bone over time, accumulating evidence has in fact suggested that the use of nonresorbable xenografts is favored for certain clinical indications. Thus, many clinicians take advantage of the nonresorbable properties/features of xenografts for various clinical indications, such as contour augmentation, sinus grafting, and guided bone regeneration, which are often combined with allografts (e.g., human freeze-dried bone allografts [FDBAs] and human demineralized freeze-dried bone allografts [DFDBAs]). Thus, many clinicians have advocated different 50/50 or 70/30 ratios of allograft/xenograft combination approaches for various grafting procedures. Interestingly, many clinicians believe that one of the main reasons for the nonresorbability or low substitution rates of xenografts has to do with their foreign animal origin. Recent research has indicated that the sintering technique and heating conducted during their processing changes the dissolution rate of hydroxyapatite, leading to a state in which osteoclasts are no longer able to resorb (dissolve) the sintered bone. While many clinicians often combine nonresorbable xenografts with the bone-inducing properties of allografts for a variety of bone augmentation procedures, clinicians are forced to use two separate products owing to their origins (the FDA/CE does not allow the mixture of allografts with xenografts within the same dish/bottle). This has led to significant progress in understanding the dissolution rates of xenografts at various sintering temperature changes, which has since led to the breakthrough development of nonresorbable bone allografts sintered at similar temperatures to nonresorbable xenografts. The advantage of the nonresorbable bone allograft is that they can now be combined with standard allografts to create a single mixture combining the advantages of both allografts and xenografts while allowing the purchase and use of a single product. This review article presents the concept with evidence derived from a 52-week monkey study that demonstrated little to no resorption along with in vitro data supporting this novel technology as a "next-generation" biomaterial with optimized bone grafting material properties.

Cross-linked hyaluronic acid gel with or without a collagen matrix in the treatment of class III furcation defects: A histologic and histomorphometric study in dogs.

AIM: To histologically evaluate the effects of cross-linked hyaluronic acid (xHyA) with or without a collagen matrix (CM) on periodontal wound healing/regeneration in class III furcation defects in dogs. MATERIALS AND METHODS: Class III furcation defects were surgically created in the mandibular premolars in six beagle dogs. The defects were randomly treated as follows: open flap debridement (OFD) + CM (CM), OFD + xHyA (xHyA), OFD + xHyA + CM (xHyA/CM) and OFD alone (OFD). At 10 weeks, the animals were euthanized for histological evaluation. RESULTS: The newly formed bone areas in the xHyA (4.04 ± 1.51 mm2 ) and xHyA/CM (4.32 ± 1.14 mm2 ) groups were larger than those in the OFD (3.25 ± 0.81 mm2 ) and CM (3.31 ± 2.26 mm2 ) groups. The xHyA (6.25 ± 1.45 mm) and xHyA/CM (6.40 ± 1.35 mm) groups yielded statistically significantly (p < .05) greater formation of new connective tissue attachment (i.e., new cementum, with inserting connective tissue fibres) compared with the OFD (1.47 ± 0.85 mm) group. No significant differences were observed in any of the histomorphometric parameters between the xHyA and xHyA/CM groups. Complete furcation closure was not observed in any of the four treatment modalities. CONCLUSIONS: Within their limits, the present results suggest that the use of xHyA with or without CM positively influences periodontal wound healing in surgically created, acute-type class III furcation defects.

Periodontitis promotes the expression of gingival transmembrane serine protease 2 (TMPRSS2), a priming protease for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

OBJECTIVES: The oral cavity is one of the main entry sites for SARS-CoV-2. Gingival keratinocytes express transmembrane serine protease 2 (TMPRSS2), responsible for priming the SARS-CoV-2 spike protein. We investigated whether periodontitis increased the expression of TMPRSS2. METHODS: To investigate gene expression in periodontitis, we analyzed the expression of specific genes from (1) the Gene Expression Omnibus (GEO) dataset of 247 human gingival tissues and (2) an experimentally-induced periodontitis mouse model. Human gingival tissues with or without periodontitis were immunohistochemically stained using an anti-TMPRSS2 antibody. Analysis of the TMPRSS2 promoter was performed using a ChIP-Atlas dataset. TMPRSS2 expression was detected in cultured human keratinocytes using quantitative reverse transcription (qRT)-PCR and Western blot analysis. RESULTS: GEO dataset analysis and an experimentally-induced periodontitis model revealed increased expression of TMPRSS2 in periodontitis gingiva. The keratinocyte cell membrane in periodontitis gingiva was strongly immunohistochemically stained for TMPRSS2. Using ChIP-Atlas and GEO datasets, we screened for transcription factors that bind to the TMPRSS2 promoter region. We found one candidate, estrogen receptor 1 (ESR1), highly expressed in periodontitis gingiva. Analysis of the GEO dataset revealed a correlation between ESR1 and TMPRSS2 expression in gingival tissues. An ESR1 ligand induced TMPRSS2 expression in cultured keratinocytes. CONCLUSIONS: Periodontitis increases TMPRSS2 expression in the cell membrane of gingival keratinocytes.

Discrepancies in pathological diagnosis of endometrial stromal sarcoma: a multi-institutional retrospective study from the Japanese clinical oncology group.

Endometrial stromal sarcoma (ESS) is a rare uterine malignancy that requires accurate pathological diagnosis for proper treatment. This study aimed to clarify the discrepancies in the pathological diagnosis of ESS and obtain practical clues to improve diagnostic accuracy. Between 2002 and 2015, 148 patients with low-grade ESS (LGESS), high-grade ESS (HGESS), undifferentiated endometrial sarcoma (UES), or undifferentiated uterine sarcoma (UUS) diagnosed at 31 institutions were included. We performed immunohistochemistry, real-time polymerase chain reaction for JAZF1-SUZ12 and YWHAE-NUTM2A/B, and break-apart fluorescent in situ hybridization for JAZF1, PHF1, and YWHAE. Central pathology review (CPR) was performed by six pathologists. After CPR, LGESS, HGESS, UES/UUS, and other diagnoses were confirmed in 72, 25, 16, and 31 cases, respectively. Diagnostic discrepancies were observed in 19.6% (18/92) of LGESS and 34% (18/53) of HGESS or UUS/UES. Adenosarcomas, endometrial carcinomas, carcinosarcomas, and leiomyosarcomas were common diagnostic pitfalls. JAZF1-SUZ12 transcript, PHF1 split signal, and YWHAE-NUTM2A/B transcript were mutually exclusively detected in 23 LGESS, 3 LGESS, and 1 LGESS plus 3 HGESS, respectively. JAZF1-SUZ12 and YWHAE-NUTM2A/B transcripts were detected only in cases with CPR diagnosis of LGESS or HGESS. The CPR diagnosis of LGESS, HGESS, and UUS was a significant prognosticator, and patients with LGESS depicted a favorable prognosis, while those with UUS showed the worst prognosis. Pathological diagnosis of ESS is often challenging and certain tumors should be carefully considered. The accurate pathological diagnosis with the aid of molecular testing is essential for prognostic prediction and treatment selection.

Comparison of periodontal wound healing/regeneration by recombinant human fibroblast growth factor-2 combined with ß-tricalcium phosphate, carbonate apatite, or deproteinized bovine bone mineral in a canine one-wall intra-bony defect model.

AIM: To evaluate periodontal wound healing/regeneration of one-wall intra-bony defects treated with recombinant human fibroblast growth factor-2 (rhFGF-2) and beta-tricalcium phosphate (ß-TCP), carbonate apatite (CO3 Ap), or deproteinized bovine bone mineral (DBBM) in dogs. MATERIALS AND METHODS: The stability of rhFGF-2 adsorbed onto the bone substitutes was evaluated by Enzyme-Linked Immunosorbent Assay (ELISA). One-wall intra-bony defects (5 × 5 × 5 mm) created in five adult male beagle dogs were treated with rhFGF-2 alone (rhFGF-2), rhFGF-2 with ß-TCP (rhFGF-2/ß-TCP), rhFGF-2 with CO3 Ap (rhFGF-2/CO3 Ap), or rhFGF-2 with DBBM (rhFGF-2/DBBM). Histological outcomes (e.g., linear length of new cementum adjacent to the newly formed bone with inserting collagen fibres [NA] as the primary outcome) were evaluated at 10 weeks post surgery. RESULTS: Significantly higher amount of rhFGF-2 was adsorbed onto CO3 Ap compared with ß-TCP. Among the treatment groups, the rhFGF-2/DBBM group showed the highest amount of periodontal tissue regeneration. The rhFGF-2/DBBM group showed significantly greater formation of NA (3.22 ± 0.40 mm) compared with rhFGF-2 (1.17 ± 1.00 mm, p < .01) group. Additionally, new bone area in the rhFGF-2/DBBM group (9.78 ± 2.30 mm2 ) was significantly higher than that in the rhFGF-2 (5.08 ± 1.26 mm2 , p < .01), rhFGF-2/ß-TCP (5.91 ± 1.27 mm2 , p < .05), and rhFGF-2/CO3 Ap (6.51 ± 1.49 mm2 , p < .05) groups. Slight ankylosis was found in the rhFGF-2/ß-TCP (1/9 sites), rhFGF-2/CO3 Ap (3/10 sites), and rhFGF-2/DBBM (1/9 sites) groups. CONCLUSIONS: Within their limitations, the present data indicate that DBBM seems to be a suitable carrier for rhFGF-2 and that rhFGF-2/DBBM treatment promotes favourable periodontal regeneration compared with rhFGF-2, rhFGF-2/ß-TCP, and rhFGF-2/CO3 Ap treatments in one-wall intra-bony defects.

Histological Evaluation of Gingival and Intrabony Periodontal Defects Treated with Platelet-rich Fibrin Using Different Protocols: A Canine Study.

PURPOSE: To histologically compare the effects of platelet-rich fibrin (PRF) produced using different protocols on periodontal wound healing/regeneration in periodontal defects in dogs. MATERIALS AND METHODS: Dehiscence-type gingival recession and two-wall intrabony defects were created bilaterally in the maxillary canines and mandibular premolars, respectively, in four beagle dogs. The recession defects were randomly treated with coronally advanced flap (CAF) alone, CAF and PRF produced via fixed-angle centrifugation (F-PRF; Leukocyte and PRF (L-PRF) protocol) or CAF and PRF produced via horizontal centrifugation (H-PRF). After 2 weeks, the two-wall intrabony defects were randomly treated as follows: open flap debridement (OFD), OFD + F-PRF, OFD + H-PRF and OFD + heated albumin with PRF using bio-heat technologies (Alb-PRF). Eight weeks after the 2nd reconstructive surgery, the animals were euthanised for histological evaluation. RESULTS: In the PRF-applied defects, new bone and new cementum formation occurred to varying degrees regardless of the protocols used to produce PRF. Particularly in the two-wall intrabony defects, new bone formation extended from the host bone toward the coronal region of the defects in the H-PRF applied sites compared with those in the OFD, F-PRF and Alb-PRF groups, and the H-PRF group showed the greatest amount of newly formed cementum. CONCLUSION: PRF induced periodontal regeneration in gingival recession and two-wall intrabony defects in dogs. Further studies are needed to determine the optimal protocol for obtaining predictable periodontal regeneration in periodontal defects in humans.

Characteristics and outcomes of women with adenocarcinoma versus squamous cell carcinoma of the vulva: A Japanese Gynecologic Oncology Group study.

OBJECTIVE: Studies on vulvar adenocarcinoma are lacking. Thus, we aimed to compare the characteristics and survival outcomes between vulvar adenocarcinoma and squamous cell carcinoma (SCC). METHODS: This was a preplanned sub-analysis of a previously organized nationwide retrospective observational study in Japan conducted between 2001 and 2010 (JGOG-1075S). Surgically treated women with stage I-IV vulvar invasive adenocarcinoma were compared to those with SCC. Multivariable analysis was performed to identify patient and tumor characteristics related to adenocarcinoma. Inverse probability of treatment weighting was used to balance the background differences, and a Cox proportional hazards regression model was fitted to estimate the effect of the histological type on survival. RESULTS: Forty-eight women with adenocarcinoma were compared with 537 women with SCC. On multivariable analysis, women with adenocarcinoma were younger (median age, 64.5 vs. 70 years, adjusted odds ratio [OR] per age 0.975, 95% confidence interval [CI] 0.955-0.995, P = 0.016) and had higher positive surgical margin rates (31.2% vs. 18.4%, adjusted OR 2.376, 95% CI 1.188-4.754, P = 0.014) than those with SCC. However, according to the weighted model, the survival outcomes were comparable (hazard ratio for progression-free survival, 1.088, 95% CI 0.740-1.601, P = 0.667 and hazard ratio for overall survival, 1.008, 95% CI 0.646-1.573, P = 0.973). Similar associations were observed when the cohort was stratified by age (≤70 or >70 years), stage (I-II or III-IV), and surgical margin (negative or positive) (all, P > 0.05). CONCLUSION: Vulvar adenocarcinoma is characterized by a younger age at diagnosis and higher positive surgical margin rates than SCC, but the survival outcomes are comparable.

Evaluation of rapid drug safety communication materials for patients in Japan.

Since 2011, pharmaceutical companies in Japan have been required to issue two types of documents regarding severe adverse drug reactions reported post-marketing, namely the Rapid Safety Communication Materials for Patients and the Related Materials. However, the adequacy of these documents has not yet been systematically assessed. The aim of this study was to evaluate the adequacy of these two types of materials. The Rapid Safety Communications for Patients were obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) website. The Related Materials were obtained from pharmaceutical companies or the PMDA website. Three assessors independently scored the Rapid Safety Communication for Patients and the Related Materials using the Centers for Disease Control and Prevention Clear Communication Index (CCI). In addition, the contents and descriptions of the materials were analyzed. In total, 13 materials for seven drugs were assessed. Almost all materials contained the "main message" and "call to action". However, the average CCI scores for the Rapid Safety Communication for Patients and Related Materials for Patients were 68.8 and 74.3 (out of 100), respectively. Further, none of the evaluated materials were scored above the CCI threshold score (i.e., ≥ 90%). Descriptions regarding "language", "state of science", and "risk" were not adequate. In particular, the terminology used in materials seemed difficult for patients to understand. In conclusion, the Japanese Rapid Communication Materials for Patients require improvement. Furthermore, a system for evaluating these materials prior to publication should be established.

Effect of interleukin-1ß on bone morphogenetic protein-9-induced osteoblastic differentiation of human periodontal ligament fibroblasts.

Bone morphogenetic protein-9 (BMP-9) has been shown to potently induce osteoblastic differentiation of periodontal ligament fibroblasts (PDLFs) and may be a candidate therapeutic agent for periodontal tissue healing/regeneration, but the effect of the inflammatory environment of periodontitis on such approaches is unclear. We investigated whether interleukin-1ß (IL-1ß) affected BMP-9-mediated osteoblastic differentiation of human (h) PDLFs. IL-1ß suppressed BMP-9-induced osteogenic differentiation of hPDLFs, as evidenced by reduced alkaline phosphatase (ALP) activity and mineralization, and the downregulated expression of BMP-9-mediated bone-related genes, RUNX2, SP7, IBSP, and SPP1. In hPDLFs, with or without BMP-9, IL-1ß increased the protein expression of activin A, a BMP-9 antagonist, and decreased follistatin protein, an antagonist of activin A. Similarly, IL-1ß upregulated the expression of the activin A gene and downregulated that of the follistatin gene. Notably, follistatin re-established BMP-9-induced ALP activity suppressed by IL-1ß. Activin A inhibited the expression of BMP-9-responsive genes and BMP-9-induced ALP activity, while follistatin re-established them. Finally, extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and nuclear factor-kappa B (NF-κB) inhibition significantly blocked IL-1ß-induced activin A gene expression. Our data indicate that IL-1ß inhibits BMP-9-induced osteoblastic differentiation of hPDLFs, possibly by promoting activin A production via the ERK1/2, p38, and NF-κB pathways.

Prospective Longitudinal Changes in the Periodontal Inflamed Surface Area Following Active Periodontal Treatment for Chronic Periodontitis.

Periodontal disease is a chronic inflammatory disease of the periodontal tissue. The periodontal inflamed surface area (PISA) is a proposed index for quantifying the inflammatory burden resulting from periodontitis lesions. This study aimed to investigate longitudinal changes in the periodontal status as evaluated by the PISA following the active periodontal treatment. To elucidate the prognostic factors of PISA, mixed-effect modeling was performed for clinical parameters, tooth-type, and levels of periodontal pathogens as independent variables. One-hundred-twenty-five patients with chronic periodontitis who completed the active periodontal treatment were followed-up for 24 months, with evaluations conducted at 6-month intervals. Five-times repeated measures of mean PISA values were 130+/-173, 161+/-276, 184+/-320, 175+/-417, and 209+/-469 mm2. Changes in clinical parameters and salivary and subgingival periodontal pathogens were analyzed by mixed-effect modeling. Plaque index, clinical attachment level, and salivary levels of Porphyromonas gingivalis were associated with changes in PISA at the patient- and tooth-level. Subgingival levels of P. gingivalis and Prevotella intermedia were associated with changes in PISA at the sample site. For most patients, changes in PISA were within 10% of baseline during the 24-month follow-up. However, an increase in the number of bleeding sites in a tooth with a deep periodontal pocket increased the PISA value exponentially.

Enhanced bone formation of calvarial bone defects by low-intensity pulsed ultrasound and recombinant human bone morphogenetic protein-9: a preliminary experimental study in rats.

OBJECTIVES: The aim of this study was to evaluate the combined effects of recombinant human bone morphogenetic protein - 9 (rhBMP-9) loaded onto absorbable collagen sponges (ACS) and low-intensity pulsed ultrasound (LIPUS) on bone formation in rat calvarial defects. MATERIALS AND METHODS: Circular calvarial defects were surgically created in 18 Wistar rats, which were divided into LIPUS-applied (+) and LIPUS-non-applied (-) groups. The 36 defects in each group received ACS implantation (ACS group), ACS with rhBMP-9 (rhBMP-9/ACS group), or surgical control (control group), yielding the following six groups: ACS (+/-), rhBMP-9/ACS (+/-), and control (+/-). The LIPUS-applied groups received daily LIPUS exposure starting immediately after surgery. At 4 weeks, animals were sacrificed and their defects were investigated histologically and by microcomputed tomography. RESULTS: Postoperative clinical healing was uneventful at all sites. More new bone was observed in the LIPUS-applied groups compared with the LIPUS-non-applied groups. Newly formed bone area (NBA)/total defect area (TA) in the ACS (+) group (46.49 ± 7.56%) was significantly greater than that observed in the ACS (-) (34.31 ± 5.68%) and control (-) (31.13 ± 6.74%) groups (p < 0.05). The rhBMP-9/ACS (+) group exhibited significantly greater bone volume, NBA, and NBA/TA than the rhBMP-9/ACS (-) group (2.46 ± 0.65 mm3 vs. 1.76 ± 0.44 mm3, 1.25 ± 0.31 mm2 vs. 0.88 ± 0.22 mm2, and 62.80 ± 11.87% vs. 42.66 ± 7.03%, respectively) (p < 0.05). Furthermore, the rhBMP-9/ ACS (+) group showed the highest level of bone formation among all groups. CONCLUSION: Within their limits, it can be concluded that LIPUS had osteopromotive potential and enhanced rhBMP-9-induced bone formation in calvarial defects of rats. CLINICAL RELEVANCE: The use of rhBMP-9 with LIPUS stimulation can be a potential bone regenerative therapy for craniofacial/peri-implant bone defects.

Estimation of the Periodontal Inflamed Surface Area by Simple Oral Examination.

The periodontal inflamed surface area (PISA) is a useful index for clinical and epidemiological assessments, since it can represent the inflammation status of patients in one contentious variable. However, calculation of the PISA is difficult, requiring six point probing depth measurements with or without bleeding on probing on 28 teeth, followed by data input in a calculation program. More simple methods are essential for screening periodontal disease or in epidemiological studies. In this study, we tried to establish a convenient partial examination method to estimate PISA. Cross-sectional data of 254 subjects who completed active periodontal therapy were analyzed. Teeth that represent the PISA value were selected by an item response theory approach. The maxillary second molar, first premolar, and lateral incisor and the mandibular second molar and lateral incisor were selected. The sum of the PISAs of these teeth was significantly correlated with the patient's PISA (R2 = 0.938). More simply, the sum of the maximum values of probing pocket depth with bleeding for these teeth were also significantly correlated with the patient's PISA (R2 = 0.6457). The simple model presented in this study may be useful to estimate PISA.

Periodontal wound healing/regeneration of two-wall intrabony defects following reconstructive surgery with cross-linked hyaluronic acid-gel with or without a collagen matrix: a preclinical study in dogs.

OBJECTIVES: In-vitro data have shown that cross-linked hyaluronic acid (HA) enhances the proliferative and migratory properties of cells involved in periodontal wound healing/regeneration, stabilizes the blood clot, reduces the inflammatory response, and facilitates angiogenesis. The aim of this study was to histologically evaluate the effects of cross-linked HA alone or combined with a collagen matrix (CM) on the periodontal wound healing/regeneration in intrabony defects. METHOD AND MATERIALS: Two-wall intrabony defects (5 mm wide, 5 mm deep) were surgically created at the distal and mesial aspects of mandibular premolars in six beagle dogs. The 24 defects were randomly treated as follows: open flap debridement (OFD) + HA, OFD + CM, OFD + HA + CM (HA/CM), and OFD alone (control). At 2 months, the animals were euthanized for histologic evaluation. RESULTS: The HA (2.43 ±â€¯1.25 mm) and HA/CM (2.60 ±â€¯0.99 mm) groups yielded statistically significantly (P < .05) greater formation of new attachment (ie, linear length of new cementum adjacent to newly formed bone, with inserting collagen fibers) compared with the OFD (0.55 ± 0.99 mm) group. Among the four treatment groups, the HA/CM group demonstrated the highest amount of regenerated tissues, although no statistically significant differences in any of the histometric parameters were observed between the HA and HA/CM groups. CONCLUSION: Within their limits, it can be concluded that cross-linked HA alone or combined with CM promotes periodontal wound healing/regeneration in two-wall intrabony defects in dogs.

Healing of buccal gingival recessions following treatment with coronally advanced flap alone or combined with a cross-linked hyaluronic acid gel. An experimental study in dogs.

AIM: To clinically and histologically evaluate in dogs the healing of gingival recessions treated with coronally advanced flap (CAF) with or without cross-linked hyaluronic acid (HA). MATERIALS AND METHODS: Gingival recession defects were surgically created on the vestibular side of both maxillary canines in 8 dogs. After 8 weeks of plaque accumulation, the 16 chronic defects were randomly treated with either CAF alone or CAF and HA-gel (CAF/HA). Clinical and histological outcomes were evaluated at 10 weeks post-surgically. RESULTS: Compared to baseline, the clinical measurements at 10 weeks revealed a statistically significant decrease in gingival recession for both CAF (p < 0.01) and CAF/HA (p < 0.001) groups. Statistically significant differences were found in clinical attachment level (p < 0.05) and width of gingival recession (p < 0.01) favouring the CAF/HA group. Bone formation was statistically significantly greater in the CAF/HA group than in the CAF group (1.84 ± 1.16 mm vs., 0.72 ± 0.62 mm, respectively, p < 0.05). Formation of cementum and connective tissue attachment were statistically significantly higher in the CAF/HA group compared with the CAF group (i.e. 4.31 ± 1.78 mm versus 2.40 ± 1.35 mm and 1.69 ± 0.98 mm versus 0.74 ± 0.68 mm, respectively (p < 0.05)). CONCLUSIONS: The present data have for the first time provided histologic evidence for periodontal regeneration of gingival recession defects following treatment with CAF and HA. CLINICAL RELEVANCE: The use of HA in conjunction with CAF may represent a novel modality for treating gingival recession defects.

Phase 2 single-arm study on the efficacy and safety of niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer.

OBJECTIVE: To evaluate the efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer. METHODS: This Phase 2 open-label, single-arm study enrolled Japanese women with homologous recombination deficiency-positive relapsed, high-grade serous ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of therapy. The starting dose of niraparib was 300 mg administered once daily in continuous 28-day cycles until objective progressive disease, unacceptable toxicity, consent withdrawal or discontinuation. The primary endpoint, objective response rate (ORR), was assessed by the investigator using RECIST version 1.1. Safety evaluations included the incidence of treatment-emergent adverse events (TEAEs), including serious TEAEs. RESULTS: Twenty women were enrolled and the confirmed ORR in the full analysis set (FAS) was 35.0% (7/20), consisting of 1 complete response and 6 partial responses. Disease control rate in the FAS was 90.0%. The most frequently reported TEAEs (>50%) were anemia, nausea, and platelet count decreased. One patient (5.0%) had TEAEs leading to discontinuation of niraparib whereas reductions or interruptions were reported in 14 (70.0%) and 15 (75.0%) patients, respectively. The median dose intensity (202.9 mg daily) corresponded to a relative dose intensity of 67.6%. CONCLUSION: Efficacy and safety of niraparib in heavily pretreated Japanese women was comparable to that seen in an equivalent population of non-Japanese women. No new safety signals were identified. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759600.

Optimal Examination Sites for Periodontal Disease Evaluation: Applying the Item Response Theory Graded Response Model.

Periodontal examination data have a complex structure. For epidemiological studies, mass screenings, and public health use, a simple index that represents the periodontal condition is necessary. Periodontal indices for partial examination of selected teeth have been developed. However, the selected teeth vary between indices, and a justification for the selection of examination teeth has not been presented. We applied a graded response model based on the item response theory to select optimal examination teeth and sites that represent periodontal conditions. Data were obtained from 254 patients who participated in a multicenter follow-up study. Baseline data were obtained from initial follow-up. Optimal examination sites were selected using item information calculated by graded response modeling. Twelve sites-maxillary 2nd premolar (palatal-medial), 1st premolar (palatal-distal), canine (palatal-medial), lateral incisor (palatal-central), central incisor (palatal-distal) and mandibular 1st premolar (lingual, medial)-were selected. Mean values for clinical attachment level, probing pocket depth, and bleeding on probing by full mouth examinations were used for objective variables. Measuring the clinical parameters of these sites can predict the results of full mouth examination. For calculating the periodontal index by partial oral examination, a justification for the selection of examination sites is essential. This study presents an evidence-based partial examination methodology and its modeling.

Periodontal tissue regeneration after low-intensity pulsed ultrasound stimulation with or without intra-marrow perforation in two-wall intra-bony defects-A pilot study in dogs.

AIM: To evaluate the effects of low-intensity pulsed ultrasound (LIPUS) with/without intra-marrow perforation (IMP) on periodontal healing in two-wall intra-bony defects in dogs. MATERIALS AND METHODS: Two-wall intra-bony defects (5 mm wide, 5 mm deep) were created at the distal and mesial aspects of mandibular premolars in four beagle dogs (four defects per dog). The 16 defects were divided into four treatment groups: IMP, LIPUS, IMP + LIPUS (IMP/LIPUS) and control (open flap debridement). The LIPUS and IMP/LIPUS sites received daily LIPUS exposure for 3 weeks starting 1 week after surgery. The animals were euthanized 4 weeks after surgery for histologic evaluation. RESULTS: There was significantly greater new bone formation at LIPUS (2.93 ± 0.74 mm) and IMP/LIPUS (3.18 ± 0.52 mm) sites than at control sites (1.65 ± 0.46 mm). New bone area at LIPUS (6.36 ± 2.28 mm2 ) and IMP/LIPUS (6.13 ± 1.25 mm2 ) sites was significantly greater than that at control sites (2.15 ± 1.75 mm2 ). New cementum length at LIPUS sites (4.09 ± 0.75 mm) was significantly greater than that at control (2.29 ± 1.02 mm) and IMP (2.41 ± 0.41 mm) sites. No significant difference was observed between LIPUS and IMP/LIPUS sites in any histomorphometric parameter. CONCLUSIONS: These findings suggest that LIPUS effectively promotes periodontal regeneration in two-wall intra-bony defects in dogs.

BMP9 prevents induction of osteopontin in JNK-inactivated osteoblasts via Hey1-Id4 interaction.

Osteopontin (OPN) is an osteoblast-derived secretory protein that plays a role in bone remodeling, osteoblast responsiveness, and inflammation. We recently found that osteoblast differentiation is type-specific, with conditions of JNK inactivation inducing osteoblasts that preferentially express OPN (OPN-type). Since OPN-type osteoblasts highly express osteogenesis-inhibiting proteins and Rankl, an important inducer of osteoclastogenesis, an increased appearance of OPN-type osteoblasts may be associated with inefficient and poor-quality bone regeneration. However, whether specific osteogenic inducers can modulate OPN-type osteoblast differentiation is completely unknown. Here, we demonstrate that bone morphogenic protein 9 (BMP9) prevents induction of OPN-type osteoblast differentiation under conditions of JNK inhibition. Although JNK inactivation suppressed both BMP2- and BMP9-induced matrix mineralization and osteocalcin expression, the expression of Rankl and specific cytokines such as Gpha2, Esm1, and Sfrp1 under similar conditions was increased in all cells except those treated with BMP9. Increased expression of Id4, a critical transcriptional regulator of OPN-type osteoblast differentiation, was similarly prevented only in BMP9-treated cells. We also found that BMP9 specifically induces the expression of Hey1, a bHLH transcriptional repressor, and that Id4 inhibits the suppressive effects of Hey1 on Opn promoter activity by forming Id4-Hey1 complexes in osteoblasts. Using site-direct mutagenesis, ChIP, and immunoprecipitation, we elucidated that BMP9-induced overexpression of Hey1 can overcome the effects of Id4 and suppress OPN expression. We further found that p38 activation and JNK inactivation are involved in BMP9-induced Hey1 expression. Collectively, these data suggest that BMP9 is a unique osteogenic inducer that regulates OPN-type osteoblast differentiation.