Suppression of neointimal hyperplasia induced by arteriovenous anastomosis and balloon injury in rats by multimeric tumor necrosis factor-related apoptosis-inducing ligand.

Excessive blood vessel wall thickening, known as intimal hyperplasia, can result from injury or inflammation and increase the risk of vascular diseases. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plays key roles in tumor surveillance, autoimmune diseases, and apoptosis; however, its role in vascular stenosis remains controversial. Treatment with recombinant isoleucine zipper hexamerization domain soluble TRAIL (ILz(6):TRAIL) significantly inhibited the progression of neointimal hyperplasia (NH) induced by anastomosis of the carotid artery and jugular vein dose dependently, and adenovirus expressing secretable ILz(6):TRAIL also inhibited NH induced by balloon injury in the femoral artery of rats. This study demonstrated the preventive and partial regressive effects of ILz(6):TRAIL on anastomosis of the carotid artery and jugular vein- or balloon-induced NH.

Inverse regulation of serum osteoprotegerin and tumor necrosis factor-related apoptosis-inducing ligand levels in patients with leg lesional vascular calcification: An observational study.

We hypothesized that circulating osteoprotegerin (OPG) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) levels could be associated with vascular calcification, which is predominant in diabetes.The study included 71 Korean participants (36 with diabetes and 35 without diabetes), who were sub-grouped according to the results of the ankle-brachial index (ABI) and/or X-ray computed tomography scan (CT scan). Serum OPG and TRAIL levels were assayed using the respective enzyme-linked immunosorbent assay kits. Statistical significance was analyzed using Student's t test between the 2 groups or analysis of variance (ANOVA) among the 4 groups.Serum OPG was up-regulated in the participants with diabetes, with peripheral arterial disease (PAD), and/or with vascular calcification. TRAIL down-regulation was more strictly controlled than OPG up-regulation; it was significantly downregulated in the participants with PAD and vascular calcification, but not in the participants with diabetes. Serum OPG and TRAIL were regulated in the participants with femoral, popliteal, and peroneal artery calcification but not in the participants with aortic calcification.OPG up-regulation and TRAIL down-regulation were found to be associated with leg lesional vascular calcification; therefore, the average OPG/TRAIL ratio was significantly increased by 3.2-fold in the leg lesional vascular calcification group.

The regulation of combined treatment-induced cell death with recombinant TRAIL and bortezomib through TRAIL signaling in TRAIL-resistant cells.

BACKGROUND: Multiple trials have attempted to demonstrate the effective induction of cell death in TRAIL-resistant cancer cells, including using a combined treatment of recombinant TRAIL and various proteasome inhibitors. These studies have yielded limited success, as the mechanism of cell death is currently unidentified. Understanding this mechanism's driving forces may facilitate the induction of cell death in TRAIL-resistant cancer cells. METHODS: Three kinds of recombinant soluble TRAIL proteins were treated into TRAIL-resistant cells and TRAIL-susceptible cells, with or without bortezomib, to compare their respective abilities to induce cell death. Recombinant TRAIL was treated with bortezomib to investigate whether this combination treatment could induce tumor regression in a mouse syngeneic tumor model. To understand the mechanism of combined treatment-induced cell death, cells were analyzed by flow cytometry and the effects of various cell death inhibitors on cell death rates were examined. RESULTS: ILz:rhTRAIL, a recombinant human TRAIL containing isoleucine zipper hexamerization domain, showed the highest cell death inducing ability both in single treatment and in combination treatment with bortezomib. In both TRAIL-resistant and TRAIL-susceptible cells treated with the combination treatment, an increase in cell death rates was dependent upon both the dose of TRAIL and its intrinsic properties. When a syngeneic mouse tumor model was treated with the combination of ILz:rhTRAIL and bortezomib, significant tumor regression was seen as a result of the effective induction of cancer cell death. The combination treatment-induced cell death was both inhibited by TRAIL blocking antibody and caspase-dependent. However, it was not inhibited by various ER stress inhibitors and autophagy inhibitors. CONCLUSIONS: The combination treatment with ILz:rhTRAIL and bortezomib was able to induce cell death in both TRAIL-susceptible and TRAIL-resistant cancer cells through the intracellular TRAIL signaling pathway. The efficiency of cell death was dependent on the properties of TRAIL under the environment provided by bortezomib. The combination treatment-induced cell death was not regulated by bortezomib-induced ER stress response or by autophagy.

Hybrid treatment of multilevel revascularization in patients with peripheral arterial disease - a multi-centre study in Korea.

BACKGROUND: Endovascular treatment is an alternative first-line management for peripheral artery disease (PAD). Hybrid treatment (HT) is defined as a combined treatment for patients with PAD using endovascular and open surgery, simultaneously performed in an operating room. The results of HT are reportedly good for multilevel revascularization (MR) in patients with chronic limb ischaemia, and even in older high-risk patients. The goal of this study was to examine the clinical and haemodynamic outcomes of HT in patients who need MR. PATIENTS AND METHODS: Nine university hospitals in Korea participated in this multicentre study. A total of 134 patients with multilevel PAD underwent HT and MR. Patients were enrolled from July 2014 to June 2015 and were followed for 18 months. RESULTS: The mean age of the patients was 68.8 ± 9.93 years and 88.1 % were men. Patients with Rutherford category 2 to 3 and 4 to 6 comprised 59.0 % and 42.0 % of the group, respectively. The technical success rate was 100 %. The primary patency rates at 12 and 18 months were 77.6 % and 63.9 %, respectively. The primary-assisted patency rates at 12 and 18 months were both 90.0 %. The pre-operative mean ankle brachial index (0.43 ± 0.23) increased to 0.87 ± 0.23 at six months post-operatively (t-test, p < 0.05). The amputation free survival rate was 97.1 %. CONCLUSIONS: Although outcomes of multilevel PAD are reportedly poor when endovascular treatment alone is used, we have shown that HT is a feasible alternative modality for patients with multilevel PAD, with satisfactory amputation-free survival and freedom from re-intervention rates.

Erratum to: Potentiation of TRAIL killing activity by multimerization through isoleucine zipper hexamerization motif.

The BMB Reports would like to correct in the ACKNOWLEDGEMENTS of BMB Rep. 49(5), 282-287 titled "Potentiation of TRAIL killing activity by multimerization through isoleucine zipper hexamerization motif."

Diagnosis and Treatment of Lower Extremity Deep Vein Thrombosis: Korean Practice Guidelines.

Lower extremity deep vein thrombosis is a serious medical condition that can result in death or major disability due to pulmonary embolism or post-thrombotic syndrome. Appropriate diagnosis and treatment are required to improve symptoms and salvage the affected limb. Early thrombus clearance rapidly resolves symptoms related to venous obstruction, restores valve function and reduces the incidence of post-thrombotic syndrome. Recently, endovascular treatment has been established as a standard method for early thrombus removal. However, there are a variety of views regarding the indications and procedures among medical institutions and operators. Therefore, we intend to provide evidence-based guidelines for diagnosis and treatment of lower extremity deep vein thrombosis by multidisciplinary consensus. These guidelines are the result of a close collaboration between interventional radiologists and vascular surgeons. The goals of these guidelines are to improve treatment, to serve as a guide to the clinician, and consequently to contribute to public health care.

Potentiation of TRAIL killing activity by multimerization through isoleucine zipper hexamerization motif.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a homo-trimeric cytotoxic ligand. Several studies have demonstrated that incorporation of artificial trimerization motifs into the TRAIL protein leads to the enhancement of biological activity. Here, we show that linkage of the isoleucine zipper hexamerization motif to the N-terminus of TRAIL, referred as ILz(6):TRAIL, leads to multimerization of its trimeric form, which has higher cytotoxic activity compared to its native state. Size exclusion chromatography of ILz(6):TRAIL revealed possible existence of various forms such as trimeric, hexameric, and multimeric (possibly containing one-, two-, and multi-units of trimeric TRAIL, respectively). Increased number of multimerized ILz(6):TRAIL units corresponded with enhanced cytotoxic activity. Further, a high degree of ILz(6):TRAIL multimerization triggered rapid signaling events such as activation of caspases, tBid generation, and chromatin condensation. Taken together, these results indicate that multimerization of TRAIL significantly enhances its cytotoxic activity. [BMB Reports 2016; 49(5): 282-287].

Anatomical Features and Early Outcomes of Endovascular Repair of Abdominal Aortic Aneurysm from a Korean Multicenter Registry.

PURPOSE: To introduce a nation-based endovascular aneurysm repair (EVAR) registry in South Korea and to analyze the anatomical features and early clinical outcomes of abdominal aortic aneurysms (AAA) in patients who underwent EVAR. MATERIALS AND METHODS: The Korean EVAR registry (KER) was a template-based online registry developed and established in 2009. The KER recruited 389 patients who underwent EVAR from 13 medical centers in South Korea from January 2010 to June 2010. We retrospectively reviewed the anatomic features and 30-day clinical outcomes. RESULTS: Initial deployment without open conversion was achieved in all cases and procedure-related 30-day mortality rate was 1.9%. Anatomic features showed the following variables: proximal aortic neck angle 48.8±25.7° (mean±standard deviation), vertical neck length 35.0±17.2 mm, aneurysmal sac diameter 57.2±14.2 mm, common iliac artery (CIA) involvement in 218 (56.3%) patients, and median right CIA length 34.9 mm. Two hundred and nineteen (56.3%) patients showed neck calcification, 98 patients (25.2%) had neck thrombus, and the inferior mesenteric arteries of 91 patients (23.4%) were occluded. CONCLUSION: Anatomical features of AAA in patients from the KER were characterized as having angulated proximal neck, tortuous iliac artery, and a higher rate of CIA involvement. Long-term follow-up and ongoing studies are required.

Analysis of Intermediate Term Results of Short Vein Bypass Graft in the Patient with Critical Limb Ischemia.

PURPOSE: Since the introduction of short vein bypass (SVB), many have reported its feasibility when long vein bypass (LVB) cannot be performed due to limited vein conduit. However, the presence of inflow-vessel disease may affect graft patency and thus require endovascular treatment prior to surgery. Our study aims to analyze the results between SVB and LVB. MATERIALS AND METHODS: From 2009 to 2013, 27 bypass procedures were reviewed retrospectively. Outcomes such as patency rate, postoperative ankle brachial index (ABI) and limb salvage rate between SVB and LVB were compared. Wound healing time and primary patency rate were analyzed and the former was also analyzed according to the respective angiosome and revascularization type. RESULTS: There were 11 males and 16 females and the mean age was 66.6±12.3 years. Twenty four patients had TransAtlantic Inter-Society Consensus (TASC) D and 3 patients had TASC C lesions below knee. The 1-year cumulative patency rate between SVB and LVB were 63% and 66%, P=0.627. The limb salvage rate (100% vs. 73%; P=0.280) and postoperative ABI (0.592 vs. 0.508; P=0.620) were higher in the SVB group than in the LVB group, although the differences were not significant. There was no difference in wound healing time by angiosomal revascularization type. In situ vein graft showed higher patency rate than reversed greater saphenous vein (75% vs. 61%; P=0.00). CONCLUSION: The results of SVB were similar to those of LVB. SVB is feasible in the setting of limited conduit availability, in combination with endovascular treatment in the presence of proximal lesions.

Clinical Implications of Methylenetetrahydrofolate Reductase Mutations and Plasma Homocysteine Levels in Patients with Thromboembolic Occlusion.

PURPOSE: Hyperhomocysteinemia has been identified as an independent risk factor in arterial and venous thrombosis. Mutations in genes encoding methylenetetrahydrofolate reductase (MTHFR), involved in the metabolism of homocysteine, may account for reduced enzyme activity and elevated plasma homocysteine levels. In this study, we investigated the interrelation of MTHFR C677T genotype and level of homocysteine in patients with arterial and venous thrombosis. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 146 patients who were diagnosed as having arterial and venous thrombosis. We excluded patients diagnosed with atrial fibrillation. We examined routinely the plasma concentration of total homocysteine level and MTHFR C677T polymorphism for evaluation of thrombotic tendency in all patients. Screening processes of MTHFR C677T polymorphism were performed by real-time polymerase chain reaction. RESULTS: Investigated groups consisted of thrombotic arterial occlusion in 48 patients and venous occlusion in 63 patients. The distribution of the three genotypes was as follows: homozygous normal (CC) genotype in 29 (26.1%), heterozygous (CT) genotype in 57 (51.4%), and homozygous mutant (TT) genotype in 25 (22.5%) patients. There were no significant differences among individuals between each genotype group for baseline characteristics. Plasma concentration of homocysteine in patients with the TT genotype was significantly increased compared to the CC genotype (P<0.05). CONCLUSION: We observed a significant interaction between TT genotypes and homocysteine levels in our results. The results might reflect the complex interaction between candidate genes and external factors responsible for thrombosis.

Minimal killing unit of the mitochondrial targeting domain of Noxa.

Noxa is a key player in p53-induced cell death via mitochondrial dysfunction, and the mitochondrial-targeting domain (MTD) of Noxa is responsible for the translocation of Noxa to mitochondria and for the induction of necrotic cell death. The purpose of this study was to define the minimal killing unit of MTD in vitro and in vivo. It was found that the peptides R8:MTD(10), R8:MTD(9), and R8:MTD(8) can kill various human tumor cells (HCT116, HeLa, MCF-7, BJAB), but that R8:MTD(7) abolishes the killing activity of MTD mainly because of the loss of mitochondrial targeting activity. We find it interesting that R8:MTD(8) was found to kill tumor cells but showed a limited killing activity on normal peritoneal macrophages. Furthermore, R8:MTD(10), R8:MTD(9), and R8:MTD(8) limitedly suppressed tumor growth when injected i.v. into BalB/C mice bearing CT26 cell-derived tumors. These results indicate that MTD(8) is the minimal killing unit of MTD.

MUDENG is cleaved by caspase-3 during TRAIL-induced cell death.

MUDENG, also known as AP5M1, was originally identified as an adaptin domain-containing gene that induced cell death in lymphoma cell lines. However, little is known of the mechanism responsible for MUDENG-mediated cell death. In this study, we investigated MUDENG changes during TRAIL-induced cell death. We found that MUDENG is rapidly processed in response to TRAIL in Jurkat and BJAB cells with time line similar to that of caspase activation. Caspase-3-mediated MUDENG cleavage was confirmed by an in vitro cleavage assay using recombinant active caspase proteins. Caspase cleavage sites (D276 and D290) were located in the adaptin domain of MUDENG, and cleaved MUDENG showed the reduced killing activity. These results suggest that the adaptin domain plays a key role in MUDENG-mediated cell death.

Octamer-binding transcription factor-1 gene is upregulated in primary varicose veins.

While the pathogenesis of varicose veins is assumed to be multifactorial, including the aging process, the etiology, especially in the very young, is strongly linked to genetics and is believed to be associated with improper development and regulation of venous tissue maturation. The aim of this study was to identify the genes whose expression is different in primary varicose veins compared to normal veins in the legs. To test this hypothesis, the differentially expressed gene technique was performed on a large-scale screen of mRNA from varicose and normal veins. Transcriptional products corresponding to cDNA were compared between the two vein types, and one gene showed the greatest differential expression between the samples in all sets of experiments, confirmed by reverse-transcriptase polymerase chain reaction. Octamer-binding transcription factor-1 gene (Oct-1) was upregulated in primary varicose veins. Therefore, we suggest that Oct-1 may play an important role in the development of primary lower extremity varicose veins.

Minimally invasive video-assisted kidney transplantation (MIVAKT).

BACKGROUND: Minimally invasive surgery has been applied to nearly all fields of surgery due to its advantages such as reduced morbidity, a better cosmetic outcome, and early recovery. The recent advances in its technique have allowed us to use modified minimally invasive surgery technique in the field of kidney transplantation. MATERIALS AND METHODS: From January 2004 to March 2006, minimally invasive video-assisted kidney transplantation was carried out in 20 patients. Many clinical variables were compared with the conventional method. The operative procedure began with a 7 to 8 cm skin incision. A laparoscopic balloon dissector was used to create the retroperitoneal space for the placement of the grafted kidney. Vascular anastomosis and ureteroneocystostomy were performed under direct vision and with video-assisted TV monitoring. RESULTS: The average length of the wound was 7.8 cm and it was placed below the belt line. The average operating time was 186 min. Less analgesic was given compared with conventional methods. There was one postoperative complication, a mild lymphocele. All patients showed normalized serum creatinine levels within 4 d. All grafted kidneys showed normal findings on the postoperative ultrasound and renal scans. CONCLUSIONS: Minimally invasive video-assisted kidney transplantation is technically feasible and may offer benefits in terms of better cosmetic outcomes, less pain, and quicker recuperation than conventional kidney transplantation.

Surgical treatment of cholelithiasis and choledocholithiasis in a 2-month-old premature and low birth weight infant.

Detection rates of cholelithiasis and choledocholithiasis in infants and children have increased since the introduction of ultrasonography, and surgical treatment is gradually tending to increase. However, for cholelithiasis and choledocholithiasis, controversies over etiology, diagnostic means, operation time, and operating method remain. Using ultrasonogram and magnetic resonance cholangiopancreatography (MRCP), we diagnosed cholelithiasis and choledocholithiasis in a premature and low birth weight infant who was admitted to the hospital with complaints of obstructive jaundice and alcoholic feces. We report the successful treatment of this infant by cholecystectomy and T-tube drainage.