Enhanced wound healing using a 3D printed VEGF-mimicking peptide incorporated hydrogel patch in a pig model.

There is a need for effective wound healing through rapid wound closure, reduction of scar formation, and acceleration of angiogenesis. Hydrogel is widely used in tissue engineering, but it is not an ideal solution because of its low vascularization capability and poor mechanical properties. In this study, gelatin methacrylate (GelMA) was tested as a viable option with tunable physical properties. GelMA hydrogel incorporating a vascular endothelial growth factor (VEGF) mimicking peptide was successfully printed using a three-dimensional (3D) bio-printer owing to the shear-thinning properties of hydrogel inks. The 3D structure of the hydrogel patch had high porosity and water absorption properties. Furthermore, the bioactive characterization was confirmed by cell culture with mouse fibroblasts cell lines (NIH 3T3) and human umbilical vein endothelial cells. VEGF peptide, which is slowly released from hydrogel patches, can promote cell viability, proliferation, and tubular structure formation. In addition, a pig skin wound model was used to evaluate the wound-healing efficacy of GelMA-VEGF hydrogel patches; the results suggest that the GelMA-VEGF hydrogel patch can be used for wound dressing.

Effects of anti-resorptive drugs on implant survival and peri-implantitis in patients with existing osseointegrated dental implants: a retrospective cohort study.

The effect of anti-resorptive drug (ARD) usage among patients with successful dental implant osseointegration is controversial. This study showed an increased risk of implant failure in ARD users. Risk factors included pre-existing marginal bone loss, overdenture, diabetes, and a short interval between implant placement and ARD administration. INTRODUCTION: This retrospective study aimed to determine whether anti-resorptive drug (ARD) usage increased risk of implant failure among patients with successful implant osseointegration. Additionally, the study investigated risk factors that affected implant survival rate in ARD users. METHODS: Eighty ARD users with 344 implants who had more than 12 months of follow-up from the initiation of ARD treatment during the period between 2008 and 2017 were included, along with 80 non-ARD users from the same period. The primary outcome was dental implant survival. Kaplan-Meier survival curves and Cox proportional hazard models were used for survival analysis. RESULTS: Average follow-up was 85.3 months. Implant survival rates were 89.83% in ARD users and 96.03% in non-ARD users. In the univariate Cox proportional hazard model, risk of implant failure was significantly higher in patients with pre-existing marginal bone loss (MBL), diabetes, and concurrent bone augmentation. However, risk of implant failure was significantly lower when the interval between implant placement and ARD administration was < 36 months. Compared with overdenture, single crown and fixed splinted users had lower risk of implant failure. In multivariate analysis, variables including pre-existing MBL, diabetes, < 36-month interval between implant placement and ARD treatment, and usage of fixed splinted prosthesis were significantly associated with increased risk of implant failure. CONCLUSIONS: ARD administration after implant osseointegration was correlated with a reduced implant survival rate. Pre-existing MBL, diabetes, type of final prosthesis, and the interval between implant placement and initiation of ARD administration influenced risk of implant failure.

Three-dimensional changes of proximal segments in facial asymmetry patients after bilateral vertical ramus osteotomy.

The intraoral vertical ramus osteotomy (IVRO) is a useful technique for mandibular setback surgery. However, there is a tendency for lateral flaring of the proximal segments on the non-deviation side after the correction of mandibular asymmetry with this technique. The purpose of this retrospective study was to evaluate the positional changes of the proximal segments after IVRO setback in skeletal class III patients with asymmetry, using preoperative and postoperative computed tomography scan data, and to apply the results in clinical practice. A total of 28 skeletal class III patients with asymmetry who underwent bimaxillary orthognathic surgery were included. A three-dimensional cone beam computed tomography scan was obtained preoperative, at 1month postoperative, and at 1year postoperative. At 1month after the surgery, the proximal segments showed an outward rotation, lateral flaring, and anterior rotation of the condylar head. All postsurgical directional changes had returned to the preoperative state at 1year postoperative, and there was no statistically significant difference in postoperative angulation changes between the two sides. The results showed no statistical differences in the positional changes of the proximal segments between the deviation and non-deviation sides. This study reaffirms the benefits of the IVRO for a minimal bony interference between the proximal and distal segments in three dimensions, including mandibular asymmetry cases.

Pharmacokinetics of K117 and K127, two novel antidote candidates to treat Tabun poisoning.

AIMS: K117 and K127 are bis-pyridinium aldoximes but K117 is a bis-pyridinium bis-aldoxime while K127 has only one single aldoxime in addition to its amide substituent. Is there any difference in pharmacokinetics in these compounds that otherwise have the same chemical structure? Both K117 and K127 are developed as antidotes in acetylcholinesterase and butyrylcholinesterase poisoning in terrorist attacks or intoxication with other organophosphorous compounds. Their distributions have been scouted in the bodies of rats. MAIN METHODS: White male Wistar rats were intramuscularly injected. The animals were sacrificed, tissue samples were homogenized, and either K117 or K127 concentrations were determined using reversed-phase high-performance liquid chromatography. KEY FINDINGS: Both K117 and K127 were present in all tissues that were analyzed including blood (serum), the brains, cerebrospinal fluid, the eyes, livers, kidneys, lungs and testes. Their pharmacokinetics and body distributions are similar. SIGNIFICANCE: Either K117 or K127 meets the essential requirements for antidotes. Dose dependence and kinetics of their distribution were compared to that of other pyridinium aldoximes.

Condylectomy as the treatment for active unilateral condylar hyperplasia of the mandible and severe facial asymmetry: retrospective review over 18 years.

Unilateral condylar hyperplasia (UCH) of the mandible is a disorder affecting the condyle size, resulting in facial asymmetry. This study was a retrospective review of 27 patients with UCH who underwent condylectomy between 2000 and 2017 at Yonsei University Dental Hospital. Patient demographic characteristics were summarized. UCH was divided into three subtypes: hemimandibular elongation (HE, n=15), hemimandibular hyperplasia (HH, n=4), and osteochondroma (OC, n=8). Of the 27 patients, only one with the HE type and five (18.5%) with the OC type complained of joint pain. Bone scans of all patients showed higher uptake on the UCH side. Lip and maxillary canting was prominent in the HH and HE types. Five patients (18.5%) underwent condylectomy alone, 13 (48.1%) underwent condylectomy with orthodontic treatment, and nine (33.3%) underwent adjunctive jaw surgery with orthodontic treatment. The treatment modalities varied according to the subtype. In all OC type patients, removal of the hyperplastic condyle treated the facial asymmetry. Additional post-surgical orthodontic treatment was necessary in only three cases (37.5%). All HH type patients required mandibuloplasty. All patients showed a stable occlusal outcome without relapse and an improvement in subjective symptoms, despite a decrease in mouth opening of 2.2mm. These findings might be useful in treatment planning for UCH patients.

Hard and soft tissue changes and long-term stability after vertical height reduction genioplasty using biodegradable fixation.

The aim of this work was to analyse the stability of vertical height reduction genioplasty using biodegradable material, as well as to determine vertical changes of hard and soft tissues during this procedure. Forty patients underwent vertical height reduction genioplasty using two types of biodegradable fixation (Biosorb FX® or OSTEOTRANS-MX®), combined with mandibular setback surgery. We assessed lateral cephalographs over time (pre-operation; immediately post-operation; 3 months, 6 months and 12 months post-operation). We found a mean vertical difference of 0.22mm (standard deviation (SD)=0.49mm) at the menton point immediately post-operation, compared with 12 months post-operation. And there was no statistical significance(P>0.05). The chin hard tissue remained stable from the immediate post-operation period to 1 year post-operation, and the chin soft tissue remained stable from 3 months to 1 year post-operation. The regression equation describing the replacement of hard tissue with soft tissue change, between pre-operation and 12 months post-operation is y=0.590x+0.885 (R2=0.300, P<0.001). We confirm that the use of biodegradable fixation is a stable method, in terms of skeletal tissues, and a relatively stable method, in terms of soft tissues. In vertical height reduction genioplasty, soft tissue does not reflect 100% of the vertical tissue reduction in hard tissues. This data may influence establishment of surgical treatment objectives.

Systematic review with meta-analysis: the efficacy of vonoprazan-based triple therapy on Helicobacter pylori eradication.

BACKGROUND: In order to increase eradication rates, vonoprazan, a novel potassium-competitive acid blocker, has been used in Helicobacter pylori eradication therapy. AIM: To summarise the results of the efficacy of vonoprazan-based triple therapy, helping clinicians to better understand the benefit of vonoprazan in the treatment of H. pylori infection. METHODS: We conducted a systematic literature search on MEDLINE, EMBASE, and the Cochrane Library using the primary keywords "vonoprazan," "takecab", "TAK-438," "potassium," "competitive," "potassium-competitive," "Helicobacter," and "pylori." Studies were included if they evaluated the eradication rate between the vonoprazan-based and proton pump inhibitor (PPI)-based triple therapies. RESULTS: Ten studies and 10 644 patients were evaluated. The crude H. pylori eradication rate determined by intention-to-treat analysis was 87.9% and 72.8% in the vonoprazan-based triple therapy and PPI-based triple therapy respectively. The eradication rate of the vonoprazan-based triple therapy was superior to that of the PPI-based triple therapy (pooled risk ratio [RR] [95% confidence interval (CI)]=1.19 [1.15-1.24]) In addition, there was no significant difference in dropout rate due to adverse event between the regimens (pooled RR of the vonoprazan-based triple therapy [95% CI]=0.69 [0.23-2.03]). The incidence of any adverse events also did not differ between the regimens (pooled RR [95% CI]=1.02 [0.78-1.34]). CONCLUSIONS: The vonoprazan-based triple therapy showed superior efficacy in terms of H. pylori eradication as compared to the PPI-based triple therapy. In addition, the vonoprazan-based triple therapy showed comparable tolerability and incidence of adverse events.

Mandibular step osteotomy using CAD/CAM-derived surgical splint: case report.

Mandibular step osteotomy is a useful technique for large mandibular setbacks. We report a case of a patient who had a mandibular step osteotomy using a CAD/CAM-derived wafer for mandibular setback with reduction of the arch.

Periorbital melasma: Hierarchical cluster analysis of clinical features in Asian patients.

BACKGROUND: Studies have shown melasma lesions to be distributed across the face in centrofacial, malar, and mandibular patterns. Meanwhile, however, melasma lesions of the periorbital area have yet to be thoroughly described. METHODS: We analyzed normal and ultraviolet light-exposed photographs of patients with melasma. The periorbital melasma lesions were measured according to anatomical reference points and a hierarchical cluster analysis was performed. RESULTS: The periorbital melasma lesions showed clinical features of fine and homogenous melasma pigmentation, involving both the upper and lower eyelids that extended to other anatomical sites with a darker and coarser appearance. The hierarchical cluster analysis indicated that patients with periorbital melasma can be categorized into two clusters according to the surface anatomy of the face. Significant differences between cluster 1 and cluster 2 were found in lateral distance and inferolateral distance, but not in medial distance and superior distance. Comparing the two clusters, patients in cluster 2 were found to be significantly older and more commonly accompanied by melasma lesions of the temple and medial cheek. CONCLUSION: Our hierarchical cluster analysis of periorbital melasma lesions demonstrated that Asian patients with periorbital melasma can be categorized into two clusters according to the surface anatomy of the face.

Calling the patient's own name facilitates recovery from general anaesthesia: a randomised double-blind trial.

People can hear and pay attention to familiar terms such as their own name better than general terms, referred to as the cocktail party effect. We performed a prospective, randomised, double-blind trial to investigate whether calling the patient's name compared with a general term facilitated a patient's response and recovery from general anaesthesia. We enrolled women having breast cancer surgery with general anaesthesia using propofol and remifentanil. Patients were randomly allocated into two groups depending on whether the patient's name or a general term was called, followed by the verbal command - 'open your eyes!' - during emergence from anaesthesia; this pre-recorded sentence was played to the patient using headphones. Fifty patients were allocated to the name group and 51 to the control group. Our primary outcome was the time from discontinuation of anaesthesia until eye opening. The mean (SD) time was 337 (154) s in the name group and 404 (170) s in the control group (p = 0.041). The time to i-gel® removal was 385 (152) vs. 454 (173) s (p = 0.036), the time until achieving a bispectral index of 60 was 174 (133) vs. 205 (160) s (p = 0.3), and the length of stay in the postanaesthesia care unit was 43.8 (3.4) vs. 47.3 (7.1) min (p = 0.005), respectively. In conclusion, using the patient's name may be an easy and effective method to facilitate recovery from general anaesthesia.

Inhibition of breast cancer invasion by TIS21/BTG2/Pc3-Akt1-Sp1-Nox4 pathway targeting actin nucleators, mDia genes.

The mammalian homolog of Drosophila diaphanous (mDia), actin nucleator, has been known to participate in the process of invasion and metastasis of cancer cells via regulating a number of actin-related biological processes. We have previously reported that tumor suppressor TIS21(/BTG2/Pc3) (TIS21) inhibits invadopodia formation by downregulating reactive oxygen species (ROS) in MDA-MB-231 cells. We herein report that TIS21(/BTG2/Pc3) downregulates diaphanous-related formin (DRF) expression via reducing NADPH oxidase 4 (Nox4)-derived ROS generation by Akt1 activation and subsequently impairs invasion activity of the highly invasive breast cancer cells. Knockdown of Akt1 by RNA interference recovered the TIS21(/BTG2/Pc3)-inhibited F-actin remodeling and ROS generation by recovering Nox4 expression. Furthermore, Sp1-mediated Nox4 transcription was downregulated by TIS21(/BTG2/Pc3)-Akt1 signals, leading to the inhibition of cancer cell invasion via F-actin remodeling by mDia genes. To our best knowledge, this is the first study to show that TIS21(/BTG2/Pc3)-Akt1 inhibited Sp1-Nox4-ROS cascade, subsequently reducing invasion activity via inhibition of mDia family genes.

Conversion of cell-survival activity of Akt into apoptotic death of cancer cells by two mutations on the BIM BH3 domain.

Survival and proliferation of cancer cells are often associated with hyperactivity of the serine/threonine kinase, Akt. Herein, we show that prosurvival activity of Akt can be converted into prodeath activity by embedding an Akt recognition sequence in the apoptogenic BH3 domain of human BIM. The recognition sequence was created by introducing two mutations, I155R and E158S, into the core region of the BIM BH3 domain. Although a 21-mer BIM BH3 peptide containing these two mutations bound weakly to BCL-XL and BCL-2, this peptide with phosphorylation of Ser158 bound to these proteins with a dissociation constant of <10 nM. The crystal structure of the phosphorylated peptide bound to BCL-XL revealed that the phospho-Ser158 makes favorable interactions with two BCL-XL residues, which cannot be formed with unphosphorylated Ser158. Remarkably, the designed peptide showed a cytotoxic effect on PTEN-null PC3 tumor cells whose Akt activity is aberrantly high. The cell-killing activity disappeared when the cellular Akt activity was lowered by ectopic PTEN expression. Thus, these results lay a foundation for developing a peptide or protein agent that is dormant in normal cells but is transformed into a potent apoptogenic molecule upon phosphorylation by hyperactivity of Akt in cancer cells.

Evaluation of lymph node status after neoadjuvant chemotherapy in breast cancer patients: comparison of diagnostic performance of ultrasound, MRI and ¹8F-FDG PET/CT.

OBJECTIVE: To evaluate the diagnostic performance of ultrasound, MRI and fluorine-18 fludeoxyglucose positron emission tomography (¹8F-FDG PET)/CT for the diagnosis of metastatic axillary lymph node (ALN) after neoadjuvant chemotherapy (NAC) and to find out histopathological factors affecting the diagnostic performance of these imaging modalities. METHODS: From January 2012 to November 2014, 191 consecutive patients with breast cancer who underwent NAC before surgery were retrospectively reviewed. We included 139 patients with ALN metastasis that was confirmed on fine needle aspiration or core needle biopsy at initial diagnosis. RESULTS: After NAC, 39 (28%) patients showed negative conversion of ALN on surgical specimens of sentinel lymph node (LN) or ALN. The sensitivity of ultrasound, MRI and PET/CT was 50% (48/96), 72% (70/97) and 22% (16/73), respectively. The specificity of ultrasound, MRI and PET/CT was 77% (30/39), 54% (21/39) and 85% (22/26), respectively. The Az value of combination of ultrasound and PET/CT was the highest (0.634) followed by ultrasound (0.626) and combination of ultrasound, MRI and PET/CT (0.617). The size of tumour deposit in LN and oestrogen receptor was significantly associated with the diagnostic performance of ultrasound (p < 0.001 and p = 0.009, respectively) and MRI (p = 0.045 and p = 0.036, respectively). The percentage diameter decrease, size of tumour deposit in LN, progesterone receptor, HER2 and histological grade were significantly associated with the diagnostic performance of PET/CT (p = 0.023, p = 0.002, p = 0.036, p = 0.044 and p = 0.008, respectively). On multivariate logistic regression analysis, size of tumour deposit within LN was identified as being independently associated with diagnostic performance of ultrasound [odds ratio, 13.07; 95% confidence interval (CI), 2.95-57.96] and PET/CT (odds ratio, 6.47; 95% CI, 1.407-29.737). CONCLUSION: Combination of three imaging modalities showed the highest sensitivity, and PET/CT showed the highest specificity for the evaluation of ALN metastasis after NAC. Ultrasound alone or combination of ultrasound and PET/CT showed the highest positive-predictive value. The size of tumour deposit within ALN was significantly associated with diagnostic performance of ultrasound and PET/CT. ADVANCES IN KNOWLEDGE: This study is about the diagnostic performance of ultrasound, MRI, PET/CT and combination of each imaging modality for the evaluation of metastatic ALN after NAC. Of many histopathological factors, only the size of tumour deposit within ALN was an independent factor associated with the diagnostic performance of ultrasound and PET/CT.

Loss of presenilin 2 is associated with increased iPLA2 activity and lung tumor development.

Presenilins are the enzymatic components of γ-secretase complex that cleaves amyloid precursor protein, Notch and ß-catenin, which has critical roles in the development of Alzheimer's disease and cancer cell growth. Therefore, in the present study, we studied the effects and mechanisms of PS2 knockout on lung cancer development and possible mechanisms as a key regulator of lung tumor development. We compared carcinogen-induced tumor growth between PS2 knockout mice and wild-type mice. PS2 knockout mice showed increased urethane (1 mg/g)-induced lung tumor incidence when compared with that of wild-type mice with decreased activity of γ-secretase in the lung tumor tissues. Consequently, iPLA2 activities in lung tumor tissues of PS2 knockout mice were much higher than in tumor tissues of wild-type mice. Furthermore, knockdown of PS2 using PS2 siRNA decreased γ-secretase activity with increased iPLA2 activity in the lung cancer cells (A549 and NCI-H460), leading to increased lung cancer cell growth. PS2 knockout mice and PS2 knockdown lung cancer cells showed increased DNA-binding activities of nuclear factor kappa-beta, signal transducer and activator of transcription 3 (STAT3) and AP-1 which are critical transcriptional factors of iPLA2 than those of PS2 wild-type mice and control lung cancer cells. Taken together, these results suggest that the loss of PS2 could have a critical role in lung tumor development through the upregulation of iPLA2 activity by reducing γ-secretase.

Prostate cancer bone metastases acquire resistance to androgen deprivation via WNT5A-mediated BMP-6 induction.

BACKGROUND: Androgen ablation is the first-line therapy for patients with metastatic prostate cancer (CaP). However, castration resistance will eventually emerge. In the present study, we have investigated the role of bone morphogenetic protein-6 (BMP-6) in the development of castration-resistant prostate cancer (CRPC) in the context of bone metastases. METHODS: We initially investigated the clinical course of 158 men with advanced CaP who were treated with primary androgen deprivation therapy. To elucidate the underlying mechanism of CRPC in the context of bone metastases, we examined the impact of bone stromal cells on CaP in the absence of androgens using a co-culture model. RESULTS: In the 158 patients, we found that the median time to prostate-specific antigen progression was significantly shorter when bone metastases were present (14 months (95% CI, 10.2-17.8 months) vs 57 months (95% CI, 19.4-94.6 months)). These results suggest that bone-tumour interactions may accelerate castration resistance. Consistent with this hypothesis, in vitro co-cultures demonstrated that CaP cells proliferated under an androgen-depleted condition when incubated with bone stromal cells. Mechanistically, gene expression analysis using quantitative polymerase chain reaction arrays showed a dramatic induction of BMP-6 by CaP cell lines in the presence of bone stromal cells. Further studies revealed that WNT5A derived from bone stromal cells induced the expression of BMP-6 by CaP cells; BMP-6 in turn stimulated cellular proliferation of CaP cells in an androgen-deprived media via a physical interaction between Smad5 and ß-catenin. Intracellularly, WNT5A increased BMP-6 expression via protein kinase C/NF-κB pathway in CaP cell lines. CONCLUSIONS: These observations suggest that bone-CaP interaction leads to castration resistance via WNT5A/BMP-6 loop.

Effect of palonosetron on the QTc interval in patients undergoing sevoflurane anaesthesia.

BACKGROUND: Palonosetron is a recently introduced 5-HT3 receptor antagonist for postoperative nausea and vomiting. Detailed standardized evaluation of corrected QT (QTc) interval change by palonosetron under sevoflurane anaesthesia is lacking. We evaluated QTc intervals in patients who are undergoing surgery with sevoflurane anaesthesia and receive palonosetron. METHODS: Our study included 100 patients who were undergoing elective surgery under sevoflurane anaesthesia. The patients were randomly assigned to two groups: those who received an i.v. injection of palonosetron 0.075 mg immediately before induction of anaesthesia (pre-surgery group, n=50) and those who received it after surgery in the recovery room (post-surgery group, n=50). QTc intervals were measured before operation, intraoperatively (baseline, immediately after tracheal intubation, and at 2, 10, 15, 30, 60, and 90 min after administration of palonosetron or placebo), and after operation (before and at 3, and 10 min after administration of palonosetron or placebo). QTc intervals were calculated using Fridericia's, Bazett's, or Hodges formulas. RESULTS: The perioperative QTc intervals were significantly increased from the baseline values, but were not affected by the pre- or post-surgical timing of palonosetron administration. CONCLUSIONS: There was no significant difference in the QTc intervals during the perioperative period, whether 0.075 mg of palonosetron is administered before or after sevoflurane anaesthesia. Palonosetron may be safe in terms of QTc intervals during sevoflurane anaesthesia. Clinical trial registration ClinicalTrials.gov: NCT01650961.