Differentiation between Chondrosarcoma and Synovial Chondromatosis of the Temporomandibular Joint Using CT and MR Imaging.

BACKGROUND AND PURPOSE: Chondrosarcoma and synovial chondromatosis of the temporomandibular joint share overlapping clinical and histopathologic features. We aimed to identify CT and MR imaging features to differentiate chondrosarcoma from synovial chondromatosis of the temporomandibular joint. MATERIALS AND METHODS: The CT and MR images of 12 and 35 patients with histopathologically confirmed chondrosarcoma and synovial chondromatosis of the temporomandibular joint, respectively, were retrospectively reviewed. Imaging features including lesion size, center, enhancement, destruction/sclerosis of surrounding bone, infiltration into the tendon of the lateral pterygoid muscle, calcification, periosteal reaction, and osteophyte formation were assessed. A comparison between chondrosarcoma and synovial chondromatosis was performed with a Student t test for quantitative variables and the Fisher exact test or linear-by-linear association test for qualitative variables. Receiver operating characteristic analysis was performed to determine the diagnostic performance for differentiation of chondrosarcoma and synovial chondromatosis based on a composite score obtained by assigning 1 point for each of 9 imaging features. RESULTS: High-risk imaging features for chondrosarcoma were the following: lesion centered on the mandibular condyle, destruction of the mandibular condyle, no destruction/sclerosis of the articular eminence/glenoid fossa, infiltration into the tendon of the lateral pterygoid muscle, absent or stippled calcification, periosteal reaction, internal enhancement, and size of ≥30.5 mm. The best cutoff value to discriminate chondrosarcoma from synovial chondromatosis was the presence of any 4 of these high-risk imaging features, with an area under the curve of 0.986 and an accuracy of 95.8%. CONCLUSIONS: CT and MR imaging features can distinguish chondrosarcoma from synovial chondromatosis of the temporomandibular joint with improved diagnostic performance when a subcombination of 9 imaging features is used.

Safety and efficacy of trastuzumab biosimilar plus irinotecan or gemcitabine in patients with previously treated HER2 (ERBB2)-positive non-breast/non-gastric solid tumors: a phase II basket trial with circulating tumor DNA analysis.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) (ERBB2)-directed agents are standard treatments for patients with HER2-positive breast and gastric cancer. Herein, we report the results of an open-label, single-center, phase II basket trial to investigate the efficacy and safety of trastuzumab biosimilar (Samfenet®) plus treatment of physician's choice for patients with previously treated HER2-positive advanced solid tumors, along with biomarker analysis employing circulating tumor DNA (ctDNA) sequencing. METHODS: Patients with HER2-positive unresectable or metastatic non-breast, non-gastric solid tumors who failed at least one prior treatment were included in this study conducted at Asan Medical Center, Seoul, Korea. Patients received trastuzumab combined with irinotecan or gemcitabine at the treating physicians' discretion. The primary endpoint was the objective response rate as per RECIST version 1.1. Plasma samples were collected at baseline and at the time of disease progression for ctDNA analysis. RESULTS: Twenty-three patients were screened from 31 December 2019 to 17 September 2021, and 20 were enrolled in this study. Their median age was 64 years (30-84 years), and 13 patients (65.0%) were male. The most common primary tumor was hepatobiliary cancer (seven patients, 35.0%), followed by colorectal cancer (six patients, 30.0%). Among 18 patients with an available response evaluation, the objective response rate was 11.1% (95% confidence interval 3.1% to 32.8%). ERBB2 amplification was detected from ctDNA analysis of baseline plasma samples in 85% of patients (n = 17), and the ERBB2 copy number from ctDNA analysis showed a significant correlation with the results from tissue sequencing. Among 16 patients with post-progression ctDNA analysis, 7 (43.8%) developed new alterations. None of the patients discontinued the study due to adverse events. CONCLUSIONS: Trastuzumab plus irinotecan or gemcitabine was safe and feasible for patients with previously treated HER2-positive advanced solid tumors with modest efficacy outcomes, and ctDNA analysis was useful for detecting HER2 amplification.

Preoperative Chemoradiotherapy With Capecitabine With or Without Temozolomide in Patients With Locally Advanced Rectal Cancer: A Prospective, Randomised Phase II Study Stratified by O6-Methylguanine DNA Methyltransferase Status: KCSG-CO17-02.

AIMS: To evaluate the clinical efficacy of adding temozolomide (TMZ) to preoperative capecitabine (CAP)-based chemoradiotherapy in patients with locally advanced rectal cancer (LARC) and validate O6-methylguanine DNA methyltransferase (MGMT) methylation status as a predictive marker for TMZ combined regimens. MATERIALS AND METHODS: LARC patients with clinical stage II (cT3-4N0) or III (cTanyN+) disease were enrolled. They were stratified into unmethylated MGMT (uMGMT) and methylated MGMT (mMGMT) groups by methylation-specific polymerase chain reaction before randomisation and were then randomly assigned (1:1) to one of four treatment arms: uMGMT/CAP (arm A), uMGMT/TMZ + CAP (arm B), mMGMT/CAP (arm C) and mMGMT/TMZ + CAP (arm D). The primary end point was the pathological complete response (pCR) rate. RESULTS: Between November 2017 and July 2020, 64 patients were randomised. Slow accrual caused early study termination. After excluding four ineligible patients, 60 were included in the full analysis set. The pCR rate was 15.0% (9/60), 0%, 14.3%, 18.8% and 26.7% for the entire cohort, arms A, B, C and D, respectively (P = 0.0498 between arms A and D). The pCR rate was 9.7% in the CAP group (arms A + C), 20.7% in the TMZ + CAP group (arms B + D), 6.9% in the uMGMT group (arms A + B) and 22.6% in the mMGMT group (arms C + D). Grade 1-2 nausea or vomiting was significantly more frequent in the TMZ + CAP treatment groups (arms B + D) than in the CAP treatment groups (arms A + C, P < 0.001) with no difference in grade 3 adverse events. There were no grade 4 or 5 adverse events. CONCLUSION: The addition of TMZ to CAP-based chemoradiotherapy tended to improve pCR rates, particularly in those with mMGMT LARC. MGMT status may warrant further investigation as a predictive biomarker for chemotherapeutic agents and radiotherapy.

Pemetrexed plus cisplatin in patients with previously treated advanced sarcoma: a multicenter, single-arm, phase II trial.

BACKGROUND: Patients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. We assessed the efficacy and tolerability of pemetrexed and cisplatin combination therapy in patients with refractory bone and soft tissue sarcoma (STS). PATIENTS AND METHODS: Patients were included in this multicenter, phase II study (ClinicalTrials.gov identifier NCT03809637) if they progressed after receiving one or more chemotherapy regimens containing an anthracycline and/or ifosfamide. Pemetrexed was first administered intravenously, followed by cisplatin, over a cycle of 21 days, for a maximum of six cycles. The primary endpoint was a progression-free rate (PFR) at 3 months (3-month PFR). RESULTS: From January 2017 to September 2019, we enrolled 37 patients; of these, 73% had previously undergone three or more rounds of chemotherapy. Five patients (13.5%) exhibited objective responses, including two patients (2/6, 33.3%) with malignant peripheral nerve sheath tumors, one patient (1/4, 25%) with synovial sarcoma, one patient (1/4, 25%) with undifferentiated pleomorphic sarcoma, and one patient (1/4, 25%) with angiosarcoma. The median progression-free survival was 2.6 months, and the 3-month PFR was 45.9% (n = 17). None of the four patients with osteosarcoma exhibited objective responses or were progression free at 3 months. The most frequent treatment-related grade 3-4 toxicities included neutropenia (16.2%), anemia (13.5%), thrombocytopenia (13.5%), and fatigue (8.1%). Among 26 patients (70.3%) available for immunohistochemical assessments, patients in the low-excision repair cross-complementation group 1 (ERCC1) and low-thymidylate synthase expression groups showed a tendency for longer overall survival. CONCLUSIONS: Combination therapy with pemetrexed and cisplatin was associated with clinically meaningful and sustained responses among patients with advanced and refractory STS. The combination therapy met its predefined primary study endpoint.

Imaging features of synovial chondromatosis of the temporomandibular joint: a report of 34 cases.

AIM: To investigate the imaging features of synovial chondromatosis of the temporomandibular joint (TMJ), which is a rare benign arthropathy with cartilaginous proliferation. MATERIALS AND METHODS: Computed tomography and magnetic resonance imaging examinations of 34 patients with histopathologically confirmed primary synovial chondromatosis of the TMJ were reviewed retrospectively. Imaging features including the lesion epicentre, destruction/sclerosis of surrounding bone, calcification, periosteal reaction, osteophyte, lesion size, and joint space dimensions were assessed. RESULTS: Thirty-one of thirty-four patients (91.2%) showed the superior joint space as the lesion epicentre. For the mandibular condyle, more than one-third of patients (14/34; 41.2%) showed no destruction, and more than half of patients (19/34; 55.9%) showed no sclerosis. Conversely, >70% of patients showed destruction and sclerosis of the articular eminence/glenoid fossa, while >80% of patients (28/34; 82.4%) presented with various calcifications, including the ring-and-arc (9/34; 26.5%) and popcorn (13/34; 38.2%) types. The mean joint space on the affected side was significantly larger than that of the unaffected side (p<0.001). More than three-fourths of patients (76.9%) experienced no interval increase in lesion size during an average of 1.6 years of follow-up. CONCLUSION: Synovial chondromatosis of the TMJ demonstrated several imaging features, including the lesion centre being located in the superior joint space, resultant articular eminence/glenoid fossa-oriented bone changes, ring-and-arc and popcorn calcification, joint space widening, and self-limiting growth. These imaging features may be helpful in differentiating synovial chondromatosis from other lesions of the TMJ.

Prenylflavonoids isolated from Macaranga tanarius stimulate odontoblast differentiation of human dental pulp stem cells and tooth root formation via the mitogen-activated protein kinase and protein kinase B pathways.

AIM: To identify odontogenesis-promoting compounds and examine the molecular mechanism underlying enhanced odontoblast differentiation and tooth formation. METHODOLOGY: Five different nymphaeols, nymphaeol B (NB), isonymphaeol B (INB), nymphaeol A (NA), 3'-geranyl-naringenin (GN) and nymphaeol C (NC) were isolated from the fruit of Macaranga tanarius. The cytotoxic effect of nymphaeols on human DPSCs was observed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effect of nymphaeols on odontoblast differentiation was analysed with Alizarin Red S staining and odontoblast marker expression was assessed using real-time polymerase chain reaction and Western blot analysis. The molecular mechanism was investigated with Western blot analysis. In order to examine the effect of INB on dentine formation in the developing tooth germ, INB-soaked beads were placed under the tooth bud explants in the collagen gel; thereafter, the tooth bud explant-bead complexes were implanted into the sub-renal capsules for 3 weeks. Tooth root formation was analysed using micro-computed tomography and histological analysis. Data are presented as mean ± standard error (SEM) values of three independent experiments, and results are compared using a two-tailed Student's t-test. The data were considered to have statistical significance when the P-value was less than 0.05. RESULTS: Three of the compounds, NB, INB, and GN, did not exert a cytotoxic effect on human DPSCs. However, INB was most effective in promoting the deposition of calcium minerals in vitro (P < 0.001) and induced the expression of odontogenic marker genes (P < 0.05). Moreover, this compound strongly induced the phosphorylation of mitogen-activated protein (MAP) kinases and protein kinase B (AKT) (P < 0.05). The inhibition of p38 MAP, c-Jun N-terminal kinase (JNK), and AKT substantially suppressed the INB-induced odontoblast differentiation (P < 0.001). In addition, isonymphaeol B significantly induced the formation of dentine and elongation of the tooth root in vivo (P < 0.05). CONCLUSIONS: Prenylflavonoids, including INB, exerted stimulatory effects on odontoblast differentiation and tooth root and dentine formation via the MAP kinase and AKT signalling pathways. These results suggest that nymphaeols could stimulate the repair processes for dentine defects or injuries.

Imaging features of chondrosarcoma of the temporomandibular joint: report of nine cases and literature review.

AIM: To investigate the imaging features of chondrosarcoma of the temporomandibular joint (TMJ) and review the literature. MATERIALS AND METHODS: Computed tomography (CT), magnetic resonance imaging (MRI), and integrated positron-emission tomography (PET)/CT images of nine patients with histopathologically confirmed chondrosarcoma of the TMJ were reviewed retrospectively. Imaging features regarding the direction of lesion growth, bone destruction, infiltration into the tendon of the lateral pterygoid muscle (LPM) in the pterygoid fovea, enhancement pattern, calcification, periosteal reaction, markedly hyperintense T2 signal area, and qualitative PET signal intensity were evaluated. RESULTS: Seven of nine patients (77.8%) presented with lesion growth that was outward from the medulla of the mandibular condyle. Infiltration into the tendon of LPM in the pterygoid fovea was observed in all cases, and 77.8% (7/9) of them demonstrated >50% infiltration. All the lesions showed a mixed peripheral and internal enhancement, and revealed a markedly hyperintense T2 signal intensity area, which showed no enhancement. Although five of nine cases demonstrated higher FDG uptake compared with that of the liver, the other four cases showed less FDG uptake than that of the liver. CONCLUSION: Chondrosarcoma of the TMJ demonstrated several imaging features, including outward growth from the mandibular condyle, resultant infiltration into the tendon of LPM in the pterygoid fovea, various patterns of internal enhancement, and a markedly hyperintense T2 signal intensity area. These imaging features may be helpful to differentiate chondrosarcoma from other lesions of the TMJ.

Anti-inflammatory character of Phelligridin D modulates periodontal regeneration in lipopolysaccharide-induced human periodontal ligament cells.

BACKGROUND AND OBJECTIVE: Phelligridin D is a hispidin analogue from the mushroom Phellinus baumii that is widely used as a food source in East Asia. This study tested phelligridin D for the anti-inflammatory effect and mechanism in lipopolysaccharide (LPS)-induced human periodontal ligament cells (HPDLCs). The objective of this study was to clarify whether the anti-inflammatory function of phelligridin D affects periodontal regeneration for supporting the HPDLCs of teeth. MATERIAL AND METHODS: Primary HPDLCs were isolated from healthy teeth and then cultured. The anti-inflammatory function, mechanism and differentiation molecules were verified with reactive oxygen species generation and western blot analysis in LPS-induced HPDLCs. RESULTS: HPDLCs showed increased inflammatory molecules (intracellular adhesion molecule-1 and vascular cell adhesion molecule-1) and decreased osteogenic proteins (bone morphogenetic protein-7, Osterix and runt-related transcription factor 2) by LPS treatment. Phelligridin D decreased inflammatory molecules and increased osteogenic molecules via downregulation of the extracellular signal-regulated kinase and c-jun N-terminal kinases pathway among the mitogen-activated protein kinase, followed by blocking of nuclear factor kappa-B translocation from cytosol to nucleus. In addition, phelligridin D showed antioxidant properties by reducing reactive oxygen species activity. Finally, the anti-inflammatory and antioxidant function of phelligridin D promoted the periodontal differentiation of HPDLCs. CONCLUSION: These results suggest that phelligridin D supports teeth on the alveolar bone against outside stress, and may be used as an anti-inflammatory compound for the prevention of periodontitis or periodontal regenerative related disease.

Anti-inflammatory and antioxidant properties of Schisandrin C promote mitochondrial biogenesis in human dental pulp cells.

AIM: To examine the properties of Schisandrin C as an anti-inflammatory and antioxidant compound, and whether its characteristics promote mitochondrial biogenesis in human dental pulp cells (HDPCs). METHODOLOGY: HDPCs were extracted from fresh third molars and cultured for experiments. Reactive oxidative stress (ROS) and nitric oxide (NO) formation were analysed by a Muse cell analyser. Western blotting and gelatin zymography were used to identify the presence of antioxidants, as well as anti-inflammatory and mitochondrial biogenesis with specific antibody. An unpaired Student's t-test was used for statistical analysis. RESULTS: Schisandrin C inhibited lipopolysaccharide-stimulated inflammatory molecules; interleukin 1 beta, tumour necrosis factor alpha, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, matrix metalloproteinase-2 and -9, NO production, ROS formation, nuclear factor kappa B translocation (P < 0.05) through the mitogen-activated protein kinase pathway. Schisandrin C increased the expression of superoxide dismutase enzymes as well as haem oxygenase-1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha through the phosphorylated-protein kinase B (p-Akt) and nuclear factor erythroid 2-related factor-2 pathways (P < 0.05). The anti-inflammatory and antioxidant properties of Schisandrin C promoted mitochondrial biogenesis. CONCLUSIONS: Schisandrin C has the potential to reduce inflammation and oxidation and to promote mitochondrial biogenesis. Therefore, Schisandrin C may be considered for use as an anti-inflammatory compound for oral inflammation through mitochondrial biogenesis.

Adipochemokines induced by ultraviolet irradiation contribute to impaired fat metabolism in subcutaneous fat cells.

BACKGROUND: Adipose tissue is now appreciated as the pivotal regulator of metabolic and endocrine functions. Subcutaneous (SC) fat, in contrast to visceral fat, may protect against metabolic syndrome and systemic inflammation. We demonstrated that chronic as well as acute ultraviolet (UV) irradiation to the skin induces loss of underlying SC fat. UV-irradiated SC fat may produce chemokines or cytokines that modulate lipid homeostasis and secretion of adipokines. OBJECTIVES: To elucidate UV-induced specific adipochemokines implicated in UV-induced modulation of SC fat. METHODS: Primary cultured adipocytes were treated with conditioned medium from UV- or sham-irradiated skin cells. Young and older healthy participants provided SC fat from sun-exposed and sun-protected skin. Sun-protected skin from other participants was irradiated with UV. Differentially expressed adipochemokines were screened by cytokine array, and confirmed in vitro and in vivo. The functions of select adipochemokines involved in lipid metabolism were examined via short interfering RNA-mediated knockdown of cognate receptors. RESULTS: Specific adipochemokines, including C-X-C motif chemokine (CXCL) family members such as CXCL5/ENA-78, and C-C motif chemokine (CCL) family members such as CCL20/MIP-3α and CCL5/RANTES, were greatly induced in SC fat by UV exposure. They could impair triglyceride synthesis via downregulation of lipogenic enzymes and sterol regulatory element-binding protein-1 through their respective cognate receptors, CXC chemokine receptor type (CXC-R)2, C-C chemokine receptor type (CCR)-6, and CCR-5. In addition, UV irradiation induced infiltration of adipose tissue macrophages responsible for the secretion of several chemokines into SC fat. CONCLUSIONS: These UV-induced adipochemokines may be implicated in the reduction of lipogenesis in SC fat, leading to impairment of fat homeostasis and associated comorbidities such as obesity.

A comparison between McGrath MAC videolaryngoscopy and Macintosh laryngoscopy in children.

BACKGROUND: This prospective, randomised, controlled study was performed to evaluate the usefulness of the McGrath VL compared with Macintosh laryngoscopy in children with expected normal airway during endotracheal intubation, by comparing the time to intubation and difficulty of intubation. METHODS: Eighty-four patients aged 1-10 years who underwent endotracheal intubation for elective surgery were randomly assigned to the McGrath group (n = 42) or the Macintosh group (n = 42). Anaesthesia was induced with 2.5-3.0 mg/kg of propofol and sevoflurane 5-8 vol%. Orotracheal intubation was performed 2 min after injection of rocuronium 0.6 mg/kg with McGrath VL or Macintosh laryngoscope; the primary outcome was the time to intubation. The Cormack and Lehane glottic grade, intubation difficulty score (IDS), and success rate on intubation were assessed. Haemodynamic changes were also recorded. RESULTS: As the primary outcome, median time to intubation [interquartile range] did not differ between the McGrath group and the Macintosh group (25.0 [22.8-28.3] s vs. 26.0 [24.0-29.0] s, P = 0.301). The incidence of grade I glottic view was significantly higher in the McGrath group than in the Macintosh group (95% vs. 74%, P = 0.013). Median IDS was lower in the McGrath group than in the Macintosh group (0 [0-0] vs. 0 [0-1], P = 0.018). There were no significant differences in success rate on intubation or haemodynamics between the two groups. CONCLUSIONS: McGrath VL provides better laryngeal views and lower IDS but similar intubation times and success rates compared with the Macintosh laryngoscope in children with normal airway.

MAP2K1 Mutation in Colorectal Cancer Patients: Therapeutic Challenge Using Patient-Derived Tumor Cell Lines.

BACKGROUND: The MAP2K1 K57T mutation is known to be a potential mechanism of primary and secondary resistance to EGFR inhibitors in metastatic colorectal cancer (CRC) and has also been reported to promote resistance to BRAF and MEK inhibitors. It is important to overcome therapeutic resistance to EGFR inhibitors to improve the treatment outcomes of metastatic CRC. METHODS: We established patient-derived tumor cells (PDCs) from metastatic lesions that newly appeared during treatment with a BRAF inhibitor (LGX-818) plus an EGFR inhibitor (cetuximab) in a patient with BRAF-mutant CRC. To investigate therapeutic options to overcome acquired resistance due to MAP2K1 mutation in BRAF-mutant CRC, we performed cell viability assays using the PDCs. RESULTS: We tested whether the PDCs were resistant to an EGFR inhibitor (cetuximab) and a BRAF inhibitor (sorafenib) as these cells were established at the time of resistance to the EGFR plus BRAF inhibitors. Moreover, the anti-tumor effect of AZD6244 (MEK inhibitor) was evaluated because PDCs harbored a MAP2K1 mutation at the time of resistance to the EGFR plus BRAF inhibitors. MTT proliferation assays showed that monotherapy with cetuximab, sorafenib, or AZD6244 did not suppress cell viability. We next tested viability of the PDCs to combination treatment with cetuximab plus AZD6244 and sorafenib plus AZD6244. Proliferation of PDCs was significantly inhibited by sorafenib and AZD6244, but not by cetuximab plus AZD6244. Investigation of the combined effect of sorafenib and AZD6244 using the calculated combination index (CI) showed synergistic effects of sorafenib and AZD6244 in combination therapy applied to PDCs with the MAP2K1 K57T mutation. CONCLUSION: Our results suggest that combination treatment with BRAF and MEK inhibitors might be a novel treatment strategy for MAP2K1 K57T-mutant CRC. This finding will be helpful to guide treatment of patients with CRC that is resistant to EGFR inhibitors.

Core-shell nanoparticle arrays double the strength of steel.

Manipulating structure, defects and composition of a material at the atomic scale for enhancing its physical or mechanical properties is referred to as nanostructuring. Here, by combining advanced microscopy techniques, we unveil how formation of highly regular nano-arrays of nanoparticles doubles the strength of an Fe-based alloy, doped with Ti, Mo, and V, from 500 MPa to 1 GPa, upon prolonged heat treatment. The nanoparticles form at moving heterophase interfaces during cooling from the high-temperature face-centered cubic austenite to the body-centered cubic ferrite phase. We observe MoC and TiC nanoparticles at early precipitation stages as well as core-shell nanoparticles with a Ti-C rich core and a Mo-V rich shell at later precipitation stages. The core-shell structure hampers particle coarsening, enhancing the material's strength. Designing such highly organized metallic core-shell nanoparticle arrays provides a new pathway for developing a wide range of stable nano-architectured engineering metallic alloys with drastically enhanced properties.

The effect of optimal space allowance on growth performance and physiological responses of pigs at different stages of growth.

This study was conducted to determine the optimal space allowance for maximizing the growth performance of pigs at each of the following five growth stages (based on BW ranges): stage 1, 11 to 25 kg BW; stage 2, 25 to 45 kg BW; stage 3, 45 to 65 kg BW; stage 4, 65 to 85 kg BW; and stage 5, 85 to 110 kg BW. A total of 1590 crossbred (Landrace×Yorkshire×Duroc) pigs were assigned to one of four treatments at each growth stage, with three replicates each. Pen areas at each growth stage were 6, 11, 16, 19.5 and 20 m2 for stages 1 to 5, respectively. Space allowances for the four treatments at each growth stage were modified by varying the number of pigs per pen (22, 25, 28 and 31 pigs in T1, T2, T3 and T4, respectively). Blood samples were collected on the final day of each growth stage. The average daily gain (ADG) decreased significantly with decreased space allowances at all growth stages, except at stage 2. Average daily feed intake (ADFI) was not significantly affected by space allowances at stages 1 to 4; however, at stage 5, there was a linear effect of space allowance on ADFI. Thus, the feed conversion ratio showed results similar to those for ADG. Serum cortisol concentrations, indicating the level of stress response, increased as space allowances decreased. The highest serum cortisol concentrations were observed in T3 at stages 2 to 5. Serum tumor necrosis factor-α levels were significantly higher in association with a small space allowance than with at large space allowance at stages 2, 4 and 5. Serum interleukin-1ß levels also increased in a significant linear manner at every growth stage in pigs reared at a low space allowance, except at stage 4 (P=0.068). This study found that limited space allowance decreases the growth performance of pigs and induces stress and inflammatory responses. We confirmed that no significant effect of space allowance on growth performance and serum cortisol concentrations are observed between T1 and T2 across all growth stages. We suggest that the optimal space allowances for pigs according to their BW are as follows: 0.24, 0.44, 0.64, 0.78 and 0.80 m2/pig for BWs of 11 to 25, 25 to 45, 45 to 65, 65 to 85 and 85 to 115 kg, respectively.

Foxp3 is a key downstream regulator of p53-mediated cellular senescence.

The downstream events and target genes of p53 in the process of senescence are not fully understood. Here, we report a novel function of the forkhead transcription factor Foxp3, which is a key player in mediating T-cell inhibitory functions, in p53-mediated cellular senescence. The overexpression of Foxp3 in mouse embryonic fibroblasts (MEFs) accelerates senescence, whereas Foxp3 knockdown leads to escape from p53-mediated senescence in p53-expressing MEFs. Consistent with these results, Foxp3 expression resulted in the induction of senescence in epithelial cancer cells, including MCF7 and HCT116 cells. Foxp3 overexpression also increased the intracellular levels of reactive oxygen species (ROS). The ROS inhibitor N-acetyl-l-cysteine rescued cells from Foxp3-expression-induced senescence. Furthermore, the elevated ROS levels that accompanied Foxp3 overexpression were paralleled by an increase in p21 expression. Knockdown of p21 in Foxp3-expressing MEFs abrogated the Foxp3-dependent increase in ROS levels, indicating that Foxp3 acts through the induction of p21 and the subsequent ROS elevation to trigger senescence. Collectively, these results suggest that Foxp3 is a downstream target of p53 that is sufficient to induce p21 expression, ROS production and p53-mediated senescence.

Fyn is a redox sensor involved in solar ultraviolet light-induced signal transduction in skin carcinogenesis.

Solar ultraviolet (UV) light is a major etiological factor in skin carcinogenesis, with solar UV-stimulated signal transduction inducing pathological changes and skin damage. The primary sensor of solar UV-induced cellular signaling has not been identified. We use an experimental system of solar simulated light (SSL) to mimic solar UV and we demonstrate that Fyn is a primary redox sensor involved in SSL-induced signal transduction. Reactive oxygen species (ROS) generated by SSL exposure directly oxidize Cys488 of Fyn, resulting in increased Fyn kinase activity. Fyn oxidation was increased in mouse skin after SSL exposure and Fyn-knockout mice formed larger and more tumors compared with Fyn wild-type mice when exposed to SSL for an extended period of time. Murine embryonic fibroblasts (MEFs) lacking Fyn and cells in which Fyn expression was knocked down were resistant to SSL-induced apoptosis. Furthermore, cells expressing mutant Fyn (C448A) were resistant to SSL-induced apoptosis. These findings suggest that Fyn acts as a regulatory nexus between solar UV, ROS and signal transduction during skin carcinogenesis.

Single-Stage Coil Embolization of Multiple Intracranial Aneurysms: Technical Feasibility and Clinical Outcomes.

PURPOSE: Not infrequently, intracranial aneurysms may be multifocal. However, strategies conferring open surgical access to opposite sides of the brain are limited. Given the recent advances in protection devices and coiling technique, a study of single-stage coil embolization in patients with multiple intracranial aneurysms was undertaken, assessing procedural safety and efficacy. METHODS: Data prospectively accrued between January 2010 and September 2013 were systematically reviewed, assessing clinical and morphologic outcomes of single-stage coil embolization in 172 patients with multiple aneurysms (≥ 2 aneurysms each; total, 371 aneurysms). RESULTS: Internal carotid artery (n = 132) was the most common site, with progressively fewer aneurysms found elsewhere (middle cerebral artery, 103; anterior communicating artery, 41; posterior communicating artery, 38). In 26 patients, one-stage embolization of three or more aneurysms took place (25 patients with three each; 1 patient with four). Stents were applied in 109 aneurysms, and in 33 lesions, balloons were used. Occlusion was achieved in 326 aneurysms (87.9 %) through coil embolization, and attempted coiling rarely failed (3 of 371, 0.8 %). Mean procedural time was 111.5 ± 37.8 min. Although procedure-related adverse events included three instances of treatment failure, asymptomatic thrombi in four patients, and aneurysmal leakage in one patient, procedural morbidity was low (1 of 172, 0.6 %), and no procedure-related deaths occurred. Postembolization follow-up of 303 aneurysms at > 6 months (mean, 15.4 ± 9.8 months) showed complete occlusion in the vast majority (275 of 303, 90.8 %), with comparatively fewer instances of minor (19 of 303, 6.3 %) and major (9 of 303, 3.0 %) recanalization. Four patients experienced delayed cerebral infarction, but only one suffered permanent neurologic deficit (Glasgow outcome scale 4). CONCLUSION: Single-stage coil embolization of multiple unruptured intracranial aneurysms is technically feasible. The time required for such procedures and the rate of complications observed seem acceptable.

Ucma, a direct transcriptional target of Runx2 and Osterix, promotes osteoblast differentiation and nodule formation.

OBJECTIVE: Runt-related transcription factor 2 (Runx2) and Osterix (Osx) are the master transcription factors in bone formation. Nonetheless, genes acting downstream of both Runx2 and Osx have yet to be fully characterized. Here, we investigate the downstream targets of both Runx2 and Osx in osteoblasts. MATERIALS AND METHODS: DNA microarray analysis was conducted on calvarial RNA from wild-type, Runx2 heterozygous, Osx heterozygous, and Runx2/Osx double heterozygous embryos. Expression and transcriptional responses of the selected target gene were analyzed in MC3T3-E1 osteoblastic cells. RESULTS: The expression of unique cartilage matrix-associated protein (Ucma) was decreased in Runx2/Osx double heterozygous embryos. In contrast, Ucma expression was increased in osteoblasts overexpressing both Runx2 and Osx. Ucma expression was initiated mid-way through osteoblast differentiation and continued throughout the differentiation process. Transcriptional activity of the Ucma promoter was increased upon transfection of the cells with both Runx2 and Osx. Runx2-and Osx-mediated activation of the Ucma promoter was directly regulated by Runx2-and/or Sp1-binding sites within its promoter. During osteoblast differentiation, the formation of mineralized nodules in Ucma-overexpressing stable clones occurred earlier and was more enhanced than that in the mock-transfected control. Mineralized nodule formation was strongly augmented in the cells cultured in a medium containing secretory Ucma proteins. CONCLUSION: Ucma is a novel downstream gene regulated by both Runx2 and Osx and it stimulates osteoblast differentiation and nodule formation.

Effect of mycophenolic acid on proliferation of dermal papilla cells and induction of anagen hair follicles.

BACKGROUND: Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil, has anti-inflammatory effects, and is widely used as an immunomodulatory agent. However, the beneficial effect of MPA in hair-loss disorders is not fully understood. AIM: To investigate the direct effect of MPA on dermal papilla cells (DPCs), and to examine the hair growth-stimulating effects of MPA topically applied to mouse skin. METHODS: Cultured DPCs were treated with various concentrations of MPA and analysed by MTT assay. Expressions of hair growth-related genes, including Wnt/ß-catenin pathway-related genes and cellular apoptosis-regulating genes, such as Bcl-2, Bax and caspase-9, were examined using reverse transcription (RT)-PCR and western blotting. The Wnt/extracellular signal-regulated kinase (ERK) pathway was analysed by western blotting. The effect of topically applied MPA on anagen hair follicle induction after microneedle (MN) treatment with or without minoxidil (MXD) was evaluated by histopathological examination and RT-PCR. RESULTS: MPA showed a promoting effect on DPC proliferation, which was associated with increased Axin2 transcription levels. In addition, phospho-ERK protein was detected in the MPA-treated DPCs. An increased Bcl-2/Bax transcript ratio contributed to cellular proliferation, and this was maintained in the MPA-treated environment. Topically applied MPA promoted anagen hair follicle induction in mice. The effect of MPA on hair follicles was compatible with that of MXD, and this effect was accelerated by MN treatment. CONCLUSIONS: MPA promotes proliferation of DPCs and induction of anagen hair follicles in mice. This finding raises the possibility that MPA could be used as a treatment option for hair-loss disorders.