Sumoylation of histone deacetylase 1 regulates MyoD signaling during myogenesis

Sumoylation, the conjugation of a small ubiquitin-like modifier (SUMO) protein to a target, has diverse cellular effects. However, the functional roles of the SUMO modification during myogenesis have not been fully elucidated. Here, we report that basal sumoylation of histone deacetylase 1 (HDAC1) enhances the deacetylation of MyoD in undifferentiated myoblasts, whereas further sumoylation of HDAC1 contributes to switching its binding partners from MyoD to Rb to induce myocyte differentiation. Differentiation in C2C12 skeletal myoblasts induced new immunoblot bands above HDAC1 that were gradually enhanced during differentiation. Using SUMO inhibitors and sumoylation assays, we showed that the upper band was caused by sumoylation of HDAC1 during differentiation. Basal deacetylase activity was not altered in the SUMO modification-resistant mutant HDAC1 K444/476R (HDAC1 2R). Either differentiation or transfection of SUMO1 increased HDAC1 activity that was attenuated in HDAC1 2R. Furthermore, HDAC1 2R failed to deacetylate MyoD. Binding of HDAC1 to MyoD was attenuated by K444/476R. Binding of HDAC1 to MyoD was gradually reduced after 2 days of differentiation. Transfection of SUMO1 induced dissociation of HDAC1 from MyoD but potentiated its binding to Rb. SUMO1 transfection further attenuated HDAC1-induced inhibition of muscle creatine kinase luciferase activity that was reversed in HDAC1 2R. HDAC1 2R failed to inhibit myogenesis and muscle gene expression. In conclusion, HDAC1 sumoylation plays a dual role in MyoD signaling: enhancement of HDAC1 deacetylation of MyoD in the basally sumoylated state of undifferentiated myoblasts and dissociation of HDAC1 from MyoD during myogenesis.

Evaluation of Local Flow Conditions in Jailed Side Branch Lesions Using Computational Fluid Dynamics

BACKGROUND AND OBJECTIVES: Lesions of vascular bifurcation and their treatment outcomes have been evaluated by anatomical and physiological methods, such as intravascular ultrasound and fractional flow reserve (FFR). However, local changes in flow dynamics in lesions of bifurcation have not been well evaluated. This study aimed at evaluating changes in the local flow patterns of bifurcation lesions. MATERIALS AND METHODS: Eight (n=8) representative simulation-models were constructed: 1 normal bifurcation, 5 main-branch (MB) stenting models with various side-branch (SB) stenoses (ostial or non-ostial 75% diameter stenosis with 1- or 2-cm lesion lengths, ostial 75% diameter stenosis caused by carina shift), and 2 post-kissing models (no or 50% SB residual stenosis). Pressure, velocity, and wall shear stress (WSS) profiles around the bifurcation sites were investigated using computational fluid dynamics. RESULTS: Post-stenting models revealed significant pressure drop in the SB (FFR<0.75), excluding the carina shift model (FFR=0.89). In the post-kissing models, there was no significant pressure drop. All post-stenting models revealed eccentric low velocity flow patterns and areas of low WSS, primarily in the lateral wall on distal MB. Post-kissing angioplasty improved pressure drop in the SB but resulted in alteration of flow distribution in the MB. In the carina shift model, kissing ballooning resulted in deteriorated local flow conditions due to increased area of low velocity and WSS. CONCLUSION: This study suggests that the most commonly used bifurcation intervention strategy may cause local flow disturbances, which may partially explain high restenosis and event rates in patients with bifurcation lesions.

Evaluation of Local Flow Conditions in Jailed Side Branch Lesions Using Computational Fluid Dynamics

BACKGROUND AND OBJECTIVES: Lesions of vascular bifurcation and their treatment outcomes have been evaluated by anatomical and physiological methods, such as intravascular ultrasound and fractional flow reserve (FFR). However, local changes in flow dynamics in lesions of bifurcation have not been well evaluated. This study aimed at evaluating changes in the local flow patterns of bifurcation lesions. MATERIALS AND METHODS: Eight (n=8) representative simulation-models were constructed: 1 normal bifurcation, 5 main-branch (MB) stenting models with various side-branch (SB) stenoses (ostial or non-ostial 75% diameter stenosis with 1- or 2-cm lesion lengths, ostial 75% diameter stenosis caused by carina shift), and 2 post-kissing models (no or 50% SB residual stenosis). Pressure, velocity, and wall shear stress (WSS) profiles around the bifurcation sites were investigated using computational fluid dynamics. RESULTS: Post-stenting models revealed significant pressure drop in the SB (FFR<0.75), excluding the carina shift model (FFR=0.89). In the post-kissing models, there was no significant pressure drop. All post-stenting models revealed eccentric low velocity flow patterns and areas of low WSS, primarily in the lateral wall on distal MB. Post-kissing angioplasty improved pressure drop in the SB but resulted in alteration of flow distribution in the MB. In the carina shift model, kissing ballooning resulted in deteriorated local flow conditions due to increased area of low velocity and WSS. CONCLUSION: This study suggests that the most commonly used bifurcation intervention strategy may cause local flow disturbances, which may partially explain high restenosis and event rates in patients with bifurcation lesions.

Differential Expressions of Genes in Colorectal Cancer with Liver Metastasis by using a cDNA Microarray Chip: A Pilot Study

PURPOSE: Liver metastasis is the most common type of failure in the treatment of colorectal cancer. The identification of differential expressions of genes in colorectal cancer and liver metastasis is important to differentiate the genetic mechanism of carcinogenesis and liver metastasis from that of a normal mucosa. The aim of this study is to find candidate genes playing roles in liver metastasis of colorectal cancer by using cDNA microarray. METHODS: We screened a group of genes differentially expressed in a normal mucosa and in cancer and liver metastasis by using a 4.7 K cDNA microarray chip in 8 patients with far advanced colorectal cancer from Jan 2003 to May 2004 at Kyungpook National University Hospital. RESULTS: A comparison of mRNA expressions of genes in normal mucosa vs. cancer, normal mucosa vs. liver metastasis, and cancer vs. liver metastasis, 76 and 27 known and unknown genes were significantly over-expressed in cancer and liver metastasis, respectively. Also 62 and 26 genes were down- regulated in cancer and liver metastasis. Among those genes, TIMP-1, SRY-box9, Rattus norvegicus fibronectin 1, mitotic check point regulator, etc. were constantly up- regulated in cancer or metastasis, and hsgk, etc. were down-regulated in cancer or liver metastasis. CONSLUSIONS: The cDNA microarray chip technique could be a useful for robust screening of candidate genes involved in carcinogenesis or metastasis of colorectal cancer.

Development and Assessment Individual Maximum Permissible Dose Method of I-131 Therapy in High Risk Patients with Differentiated Papillary Thyroid Cancer / 대한핵의학회잡지

PURPOSE: Radioiodine (I-131) therapy is an effective modality to reduce both recurrence and mortality rates in differentiated thyroid cancer. Whether higher doses shows higher therapeutic responses was still debatable. The purpose of this study was to validate curve-fitting (CF) method measuring maximum permissible dose (MPD) by a biological dosimetry using metaphase analysis of peripheral blood lymphocytes. MATERIALS AND METHODS: Therapeutic effects of MPD was evaluated in 58 patients (49 females and 9 males, mean age 50+/-11 years) of papillary thyroid cancer. Among them 43 patients were treated with or =9.25 GBq. The former was defined as low-dose group, and the latter high-dose group. Therapeutic response was defined as complete response when complete disappearance of lesions on follow-up I-131 scan and undetectable serum thyroglobulin levels were found. Statistical comparison between groups were done using chi-square test. P value less than 0.05 was regarded as statistically significant. RESULTS: MPD measured by CF method using tracer and therapeutic doses were 13.3+/-1.9 and 13.8+/-2.1 GBq, respectively (p=0.20). They showed a significant correlation (r=0.8, p< 0.0001). Exposed doses to blood measured by CF and biological methods were 1.54+/-0.03 and 1.78+/-0.03 Gy (p=0.01). They also showed a significant correlation (r=0.86, p=0.01). High-dose group showed a significantly higher rate of complete response (12/15, 80%) as compared to the low-dose group (22/43, 51.2%) (p=0.05). While occurrence of side effects was not different between two groups (40% vs. 30.2%, p=0.46). CONCLUSION: Measurement of MPD using CF method is reliable, and the high-dose I-131 therapy using MPD gains significantly higher therapeutic effects as compared with low-dose therapy.

Lateral Orbital Wall Fracture: New Classification and Clinical Importance

The purpose of this study is to propose a new fracture classification of lateral orbital wall, to emphasize the clinical significance of lateral orbital wall fractures, and to suggest appropriate surgical approach according to our classification. This study is based on a treatment of forty-seven patients with lateral orbital wall fractures, and medical records and radiologic studies were reviewed retrospectively. A clinical classification was based on radiographs obtained. Grade I fracture is a fracture of the frontal process of the zygoma at the zygomatico-sphenoidal suture line. Grade I fractures are further divided into 2 subgroups: Grade IA-compressed; Grade IBa-laterally displaced fracture; Grade IBb-medially displaced fracture. Grade II fractures are fractures that extend to the orbital plate of the greater wing of the sphenoid. These fractures are further divided: Grade IIA-compressed; and Grade IIB-displaced fracture. In Grade III fractures, the entire greater wing of the sphenoid is impacted toward the orbital apex with possible intrusion into the middle cranial fossa. The most common type of fracture was Grade IBa (51%) and the least common type was Grade IIA (4%). All Grade II and Grade III fractures had major ophthalmic problems. Nineteen of 47cases (40%) developed ophthalmic problems such as proptosis (23%), diplopia (21%), restricted extraocular muscle movement (15%), displacement of eye globe (15%), optic nerve injury (4%), and globe rupture(4%). Postsurgical sequelae included proptosis (4%), diplopia (4%), restricted extraocular muscle movement (6%) and blindness (6%). Our classification can be applied to all types of lateral orbital wall fractures. Our data and analysis demonstrate that Grade II/III fractures have a significant of major and sometimes devastating ophthalmic injuries. These findings, we believe, mandate that all patients with clinically suspected lateral wall fractures obtain a thorough ophthalmologic examination and complete facial CT scans. This classification may be helpful for the diagnosis and treatment of lateral orbital wall fracture.

Appropriate Selection of Free Flap Donor Sites for Functional Reconstruction of Intraoral Defect

As the oral cavity plays a vital role in swallowing, speech articulation and intelligibility, a variety of surgical techniques have been devised to reconstruct the intraoral defect which remains after ablative surgery. The ideal method of intraoral reconstruction has not yet been established, but microvascular free flaps have rapidly become the "gold standard" compared to other techniques, and nowadays interest is focused on the improvement of detailed function following reconstruction. The purposes of this study are to understand the main goal of reconstruction and to suggest the appropriate donor sites of free flap depending on the location and size of defects. From July 1988 to December 1999, 42 patients underwent intraoral reconstruction with various kinds of free flaps in accordance with the location nd size of defects. We divided the location of intraoral defects into tongue, mouth floor, buccal mucosa, and palate, retromolar trigone, pharyngeal wall according to the anatomical structures. We tried to select the most appropriate donor tissue for the requisites of defect area. After partial glossectomy, we used free jejunal patch flap as a first choice. Free lateral arm flap has been used to reconstruct the defect of hemi-glossectomy, and free rectus abdominis flap for the defect of total glossectomy. For the reconstructions of mouth floor and buccal mucosa, transversely designed and two skin paddles free radial forearm flaps have been used as a first choice. For the defects of palate, retromolar trigone or pharyngeal wall, free jejunal patch flap has been a first choice. The postoperative courses of these cases are uneventful. There was no orocutaneous fistula during follow up periods. The patients could recover their intelligible speech, deglutition and mastication. We conclude that appropriate selection of free flap donor site for intraoral reconstruction depending on the location and size of defects can improve detailed function and aesthetics, and enhance the rehabilitation and remaining quality of life.

The Bone Forming Effect of Sodium Fluoride During The Distraction Osteogenesis on Membranous Bone: An Experimental Study in the Mandibles of Rabbits

The purpose of this study was to improve bone formation and shorten the period involved in distraction osteogenesis using sodium fluoride (NaF). This has been used in managing osteoporosis for several decades. This study was carried out on 40 New Zealand white rabbits. Twenty animals were used for a control group (no medication) and 20 for the experimental group. NaF 1 mg/kg/day was administered to each experimental animal via drinking water beginning 4 weeks prior to surgery and continued until sacrifice for examination. A distraction device was applied to the left mandible along a plane perpendicular to the direction of osteotomy. After a 5-day latent period, the mandibles were lengthened at 1 mm per 24 hours for 10 days. Five rabbits from each group were sacrificed on the 1st day, 2nd week, 4th week and 8th week of the consolidation period. After lengthening, all the rabbits developed a severe cross-bite. By the 4th week, cortical continuity was seen. Bone densities at the site of bony lengthening were measured by quantitative computer tomography (QCT) and dual X-ray absorptiometry (DXA). The results were as follows: the measurements of the experimental group were significantly higher than of the control group by the 1st day of the consolidation period (p>0.05) and insignificantly higher after the 2nd week. Histologically, in the experimental group, there were more osteoblasts, increased and thickened trabeculae and more mature lamellar bones than in the control group. This study showed that osteogenesis of the experimental group was significantly higher during and immediately after distraction. Our study suggested that the use of NaF could improve bone formation and decrease the period of distraction osteogenesis if a safe dose and method of fluoride administration can be determined for growing humans.

Clinical application of hydroxyapatite(surgibone(r))

No abstract available.