The limitations of medical management of symptomatic intracranial arterial stenosis (ICS) have prompted development of new strategies, including endovascular treatment. However, stenting of symptomatic ICS remains investigational. Here, we have reported and analyzed a series of 19 endovascular procedures involving placement of a Wingspan stent.
We conducted a retrospective review of a series of ICS in which patients were treated with percutaneous transarterial balloon angioplasty and stent placement (PTAS). Patients included in the study were diagnosed as symptomatic ICS between May 2010 and September 2011.
Nineteen patients (median age, 65 years; 12 males, seven women) were treated with the Wingspan stent system for symptomatic ICS ranging from 50% to 99%. The technical success rate was 100%. The location of ICS included the internal carotid (n = 5; 1 petrous, 3 cavernous, and 1 clinoid segments), vertebral (n = 1; V4 segment), basilar (n = 1), and middle cerebral (n = 12; 9 M1, 3 M2) arteries. There was no occurrence of procedure-related mortality. Periprocedural morbidity occurred in two cases (10.5%), including carotid-cavernous fistula (n = 1) and subarachnoid hemorrhage (n = 1). No ipsilateral stroke was recorded beyond 30 days during a mean follow-up period of 13.2 months (range 9-19 months). Restenosis (> 50%) was observed in one patient (6.3%), who was asymptomatic, on follow-up imaging.
Wingspan stent for symptomatic ICS can be performed with a high rate of technical success and acceptable periprocedural morbidity rates. Our initial experience indicates that this procedure represents a viable treatment option for this patient population.
Intracranial stenosis; Angioplasty; Stent implantation; Wingspan stent
Dual origin and fenestration of the vertebral artery (VA) are very rare anomalies. Understanding of these variations, however, is important because they can be misdiagnosed as a VA dissection. A 42-year-old woman presented with motor weakness and sensory disturbance of the right upper extremity. Radiologic evaluations showed ectatic change in the right VA and an arteriovenous fistula between the right VA and the vertebral vein. We decided on endovascular occlusion of the proximal right VA and its fistulous portion. During the endovascular procedure, we had misunderstood the dual origin and fenestration of the VA as a dissection. Thus, failure to recognize these anomalies might result in unnecessary anticoagulation or therapeutic intervention. Clinicians should be alert to such VA variations when making a diagnosis and when planning any intervention or surgery involving the proximal VA.
Dissection; Dual origin; Fenestration; Vertebral artery
The purpose of this report is to describe our surgical experiences in the treatment of cerebral decompression with in situ floating resin cranioplasty. We included in this retrospective study 7 patients who underwent in situ floating resin cranioplasty for cerebral decompression between December 2006 and March 2008. Of these patients, 3 patients had traumatic brain injury, 3 cerebral infarction, and one subarachnoid hemorrhage due to aneurysmal rupture. In situ floating resin cranioplasty for cerebral decompression can reduce complications related to the absence of a bone flap and allow reconstruction by secondary cranioplasty without difficulty. Furthermore, it provides cerebral protection and selectively eliminates the need for secondary cranioplasty in elderly patients or patients who have experienced unfavorable outcome.
Decompressive craniectomy; Floating; Resin cranioplasty
Although the number of studies using tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) for the treatment of high-risk pediatric solid tumors has been increasing, documentation of hematologic recovery after tandem HDCT/autoSCT is very limited. For this reason, we retrospectively analyzed the hematologic recovery of 236 children with high-risk solid tumors who underwent tandem HDCT/autoSCT. The median numbers of CD34+ cells transplanted during the first and second HDCT/autoSCT were 4.3 × 106/kg (range 0.6-220.2) and 4.1 × 106/kg (range 0.9-157.6), respectively (P = 0.664). While there was no difference in neutrophil recovery between the first and second HDCT/autoSCT, platelet and RBC recoveries were significantly delayed in the second HDCT/autoSCT (P < 0.001 and P < 0.001, respectively). Delayed recovery in the second HDCT/autoSCT was more prominent when the number of transplanted CD34+ cells was lower, especially if it was < 2 × 106/kg. A lower CD34+ cell count was also associated with increased RBC transfusion requirements and a higher serum ferritin level after tandem HDCT/autoSCT. More CD34+ cells need to be transplanted during the second HDCT/autoSCT in order to achieve the same hematologic recovery as the first HDCT/autoSCT.
High-Dose Chemotherapy; Autologous Stem Cell Transplantation; CD34+ Cells; Hematologic Recovery; Iron Overload
The -D- phenotype is a rare Rh phenotype that strongly expresses D antigen without C, c, E, or e antigens. In -D- phenotype individuals, anti-Rh17 (Hro) is commonly found if there is a history of pregnancy or transfusion with red blood cells (RBCs) that express C, c, E, or e antigens. We report the first case of a -D- phenotype patient with multiple Rh antibodies including anti-Rh17 who had a history of two occasions of transfusion with eight random donor platelet concentrates two and six years ago. We found that a trivial amount of RBCs in the platelet components was able to trigger sensitization to RBC antigens, especially the highly immunogenic and clinically significant Rh antigens, including C, c, E, e or CcEe polypeptides. To avoid unnecessary sensitization and to minimize the risk of hemolytic transfusion reactions in patients with this rare Rh phenotype, a modified strategy for pretransfusion screenings needs to be discussed in the field of transfusion medicine.
Rh-Hr blood group system; Rh isoimmunization; Platelet transfusion
Reactive oxygen species (ROS) contribute to the development of a number of neuronal diseases including ischemia. DJ-1, also known to PARK7, plays an important role in transcriptional regulation, acting as molecular chaperone and antioxidant. In the present study, we investigated whether DJ-1 protein shows a protective effect against oxidative stress-induced neuronal cell death in vitro and in ischemic animal models in vivo. To explore DJ-1 protein's potential role in protecting against ischemic cell death, we constructed cell permeable Tat-DJ-1 fusion proteins. Tat-DJ-1 protein efficiently transduced into neuronal cells in a dose- and time-dependent manner. Transduced Tat-DJ-1 protein increased cell survival against hydrogen peroxide (H2O2) toxicity and also reduced intracellular ROS. In addition, Tat-DJ-1 protein inhibited DNA fragmentation induced by H2O2. Furthermore, in animal models, immunohistochemical analysis revealed that Tat-DJ-1 protein prevented neuronal cell death induced by transient forebrain ischemia in the CA1 region of the hippocampus. These results demonstrate that transduced Tat-DJ-1 protein protects against cell death in vitro and in vivo, suggesting that the transduction of Tat-DJ-1 may be useful as a therapeutic agent for ischemic injuries related to oxidative stress.
brain ischemia; CA1 region, hippocampal; cell survival; neurons; PARK7 protein, human; reactive oxygen species; toxicity
Patients with severe spontaneous cerebellar hemorrhage typically undergo treatment with suboccipital craniectomy and hematoma evacuation. However, this is a stressful procedure for patients due to the long operating time and operation-induced tissue damage. In addition, the durotomy can result in pseudomeningocele. We investigated the efficacy of stereotactic or navigation-guided burr hole aspiration surgery as a treatment for spontaneous hypertensive cerebellar hemorrhage (SHCH).
Between January 2002 and December 2011, 26 patients with SHCH underwent surgery using the stereotactic or navigation-guided burr hole aspiration and catheter insertion technique in our institution.
Mean hematoma volume was 21.8 ± 5.8 cc at admission and 13.1 ± 5.4 cc immediately following surgery. Preoperative Glasgow Coma Scale (GCS) score was 12.5 ± 1.3 and postoperative GCS score was 13.1 ± 1.2. Seven days after surgery, the mean hematoma volume was 4.3 ± 5.6 cc, and there was no occurrence of surgery-related complications during the six-month follow-up period. The mean operation time for catheter insertion was 43.1 ± 8.9 min, and a mean 31.3 ± 6.0 min was also added for extra-ventricular drainage. The mean Glasgow Outcome Scale (GOS) score after six months was 4.6 ± 1.0.
Stereotactic burr hole aspiration surgery for treatment of SHCH is less time-consuming and invasive than other interventions, and resulted in no surgery-related complications. Therefore, we suggest that this surgical method could be a safe and effective treatment option for selected patients with SHCH.
Cerebellar hemorrhage; Aspiration; Stereotactic; Navigation; Outcome
DNA barcoding has been widely used in species identification and biodiversity research. A short fragment of the mitochondrial cytochrome c oxidase subunit I (COI) sequence serves as a DNA bio-barcode. We collected DNA barcodes, based on COI sequences from 156 species (529 sequences) of fish, insects, and shellfish. We present results on phylogenetic relationships to assess biodiversity the in the Korean peninsula. Average GC% contents of the 68 fish species (46.9%), the 59 shellfish species (38.0%), and the 29 insect species (33.2%) are reported. Using the Kimura 2 parameter in all possible pairwise comparisons, the average interspecific distances were compared with the average intraspecific distances in fish (3.22 vs. 0.41), insects (2.06 vs. 0.25), and shellfish (3.58 vs. 0.14). Our results confirm that distance-based DNA barcoding provides sufficient information to identify and delineate fish, insect, and shellfish species by means of all possible pairwise comparisons. These results also confirm that the development of an effective molecular barcode identification system is possible. All DNA barcode sequences collected from our study will be useful for the interpretation of species-level identification and community-level patterns in fish, insects, and shellfish in Korea, although at the species level, the rate of correct identification in a diversified environment might be low.
cytochrome c oxidase subunit I; mitochondrial DNA; molecular taxonomy; taxonomic DNA barcoding
Sparganum (plerocercoid of Spirometra erinacei) is a parasite that possesses the remarkable ability to survive by successfully modifying its physiology and morphology to suit various hosts and can be found in various tissues, even the nervous system. However, surprisingly little is known about the molecular function of genes that are expressed during the course of the parasite life cycle. To begin to decipher the molecular processes underlying gene function, we constructed a database of expressed sequence tags (ESTs) generated from sparganum.
SpiroESTdb is a web-based information resource that is built upon the annotation and curation of 5,655 ESTs data. SpiroESTdb provides an integrated platform for expressed sequence data, expression dynamics, functional genes, genetic markers including single nucleotide polymorphisms and tandem repeats, gene ontology and KEGG pathway information. Moreover, SpiroESTdb supports easy access to gene pages, such as (i) curation and query forms, (ii) in silico expression profiling and (iii) BLAST search tools. Comprehensive descriptions of the sparganum content of all sequenced data are available, including summary reports. The contents of SpiroESTdb can be viewed and downloaded from the web (http://pathod.cdc.go.kr/spiroestdb).
This integrative web-based database of sequence data, functional annotations and expression profiling data will serve as a useful tool to help understand and expand the characterization of parasitic infections. It can also be used to identify potential industrial drug targets and vaccine candidate genes.
Sparganum; Plerocercoid; Spirometra erinacei; Expressed sequence tags (ESTs); Database
NF-κB is a multifunctional transcription factor involved in diverse biological processes. It has been well documented that NF-κB can be activated in response to various stimuli. While signal-inducible NF-κB activation mechanisms have been extensively characterized, exogenous signal-independent intrinsic NF-κB activation processes remain poorly understood. Here we show that IκB kinase β (IKKβ) can be intrinsically activated in the nucleus by a homeobox protein termed Nkx3.2 in the absence of exogenous IKK-activating signals. We found that ubiquitin chain-dependent, but persistent, interactions between Nkx3.2 and NEMO (also known as IKKγ) can give rise to constitutive IKKβ activation in the nucleus. Once the Nkx3.2-NEMO-IKKβ complex is formed in the nucleus, IKKβ-induced Nkx3.2 phosphorylation at Ser148 and Ser168 allows βTrCP to be engaged to cause IκB-α ubiquitination independent of IκB-α phosphorylation at Ser32 and Ser36. Taken together, our results provide a novel molecular explanation as to how an intracellular factor such as Nkx3.2 can accomplish persistent nuclear IKK activation to enable intrinsic and constitutive degradation of IκB in the nucleus in the absence of exogenous NF-κB-activating signals, which, in turn, plays a role in chondrocyte viability maintenance.
Chlorogenic acid (CGA) possesses various biological activities such as anti-oxidant, anti-inflammatory, and anti-diabetic activities. In the present study, we examined the effect of CGA on the transduction efficiency of PEP-1-ribosomal protein S3 (PEP-1-rpS3) into cells and brain tissues, and its neuroprotective potential against ischemia/reperfusion. We found that, in the presence of CGA, the transduction efficiency of PEP-1-rpS3 into astrocytes and the CA1 region of the hippocampus was enhanced, compared to its transduction in the absence of CGA. Also, cell viability data demonstrated that the sample treated with CGA + PEP-1-rpS3 exhibited improved cell viability against hydrogen peroxide (H2O2)-induced toxicity more significantly than the sample treated with PEP-1-rpS3 alone. Also, in a gerbil ischemia model, data demonstrated that following the ischemic insult, the group treated with PEP-1-rpS3 + CGA showed markedly enhanced protection of neuron cells in CA1 region of hippocampus, compared to those treated with CGA or PEP-1-rpS3 alone. Taken together, these results suggest that CGA may improve the transduction efficiency of protein transduction domain (PTD) fusion proteins into target cells or tissues, thereby enhancing their therapeutic potential against various diseases.
chlorogenic acid; PEP-1-ribosomal protein S3; protein transduction; ischemic insult
The main treatment for acute arterial ischemic stroke is intravenous or intra-arterial thrombolysis within a particular time window. Endovascular mechanical embolectomy is another treatment option in the case of major artery occlusion. Endovascular mechanical embolectomy is a useful technique for restoring blood flow in patients with large-vessel occlusion, and especially in those who are contraindicated for thrombolytics or in whom thrombolytic therapy has failed.
We report herein two cases of emergency microsurgical embolectomy for the treatment of acute middle cerebral artery and internal carotid artery occlusion as an alternative treatment for major artery occlusion.
Emergency microsurgical mechanical embolectomy may be an alternative treatment option for restoring blood flow in selected patients with large-vessel acute ischemic stroke.
acute ischemic stroke; large-vessel occlusion; microsurgical embolectomy; alternative treatment
Clonorchis sinensis is the causative agent of the life-threatening disease endemic to China, Korea, and Vietnam. It is estimated that about 15 million people are infected with this fluke. C. sinensis provokes inflammation, epithelial hyperplasia, and periductal fibrosis in bile ducts, and may cause cholangiocarcinoma in chronically infected individuals. Accumulation of a large amount of biological information about the adult stage of this liver fluke in recent years has advanced our understanding of the pathological interplay between this parasite and its hosts. However, no developmental gene expression profiles of C. sinensis have been published. In this study, we generated gene expression profiles of three developmental stages of C. sinensis by analyzing expressed sequence tags (ESTs). Complementary DNA libraries were constructed from the adult, metacercaria, and egg developmental stages of C. sinensis. A total of 52,745 ESTs were generated and assembled into 12,830 C. sinensis assembled EST sequences, and then these assemblies were further categorized into groups according to biological functions and developmental stages. Most of the genes that were differentially expressed in the different stages were consistent with the biological and physical features of the particular developmental stage; high energy metabolism, motility and reproduction genes were differentially expressed in adults, minimal metabolism and final host adaptation genes were differentially expressed in metacercariae, and embryonic genes were differentially expressed in eggs. The higher expression of glucose transporters, proteases, and antioxidant enzymes in the adults accounts for active uptake of nutrients and defense against host immune attacks. The types of ion channels present in C. sinensis are consistent with its parasitic nature and phylogenetic placement in the tree of life. We anticipate that the transcriptomic information on essential regulators of development, bile chemotaxis, and physico-metabolic pathways in C. sinensis that presented in this study will guide further studies to identify novel drug targets and diagnostic antigens.
Clonorchis sinensis is a significant pathogen that causes clonorchiasis, which is endemic to East Asian countries. This fluke provokes acute inflammation and chronic hyperplasic changes in the biliary tracts. C. sinensis promotes cholangiocarcinoma, and has been classified as a Group 1 biological carcinogen, alongside Opisthorchis viverrini, by the World Health Organization. Recently, transcriptomes for adult liver flukes have been reported with the molecular functionalities predicted on the bases of their transcriptomic data sets. We generated the developmental C. sinensis transcriptome for three different developmental stages, revealing that most functional genes were differentially expressed in each developmental stage; only a small proportion of the expressed genes were shared between the three stages. The developmental transcriptome describes the gene expression landscapes of C. sinensis adults, metacercariae, and eggs, and provides insight into how this fluke adapts to the distinctly different environments provided by its various hosts. We anticipate that the transcriptome will contribute significantly to the identification of intervention points along the developmental stages and allow the exploitation of novel potential targets for diagnostic, drug, and vaccine development purposes.
The extracellular signal-regulated kinase 1/2 (ERK) pathway, part of the mitogen-activated protein kinase (MAPK) family, is well-known for its role in cell differentiation and proliferation. In the context of osteoclastogenesis, macrophage colony stimulating factor (M-CSF) is an upstream activator of ERK, which signals for the survival of osteoclast precursors prior to their differentiation into multinucleated osteoclasts. In addition, many recent studies have revealed the involvement of ERK in promoting osteolysis. In this study, we extended these existing findings linking ERK and osteolysis by identifying the ERK pathway as the primary pathway for osteolysis in osteoclasts and macrophages. We also elucidated the pro-inflammatory capacity of osteoblasts using the ERK pathway. Moreover, the ERK inhibitor, PD98059, inhibited the inflammatory reaction propagated by all three cell types at both a local and systemic level. The importance of ERK signaling in previously known cell types mediating inflammatory osteolysis as well as the discovery of osteoblastic innate immunity involving ERK signaling enhances our understanding of inflammatory osteolysis and supports further future investigation of targeted therapies against the ERK pathway for treating osteolytic diseases.
Extracellular signal-regulated kinase (ERK) signaling; osteoblasts; Macrophage-colony stimulating factor (M-CSF); inflammatory osteolysis; lipopolysaccharide (LPS)
A family of calcium-dependent protein kinases (CDPKs) is a unique enzyme which plays crucial roles in intracellular calcium signaling in plants, algae, and protozoa. CDPKs of malaria parasites are known to be key regulators for stage-specific cellular responses to calcium, a widespread secondary messenger that controls the progression of the parasite. In our study, we identified a gene encoding Plasmodium vivax CDPK4 (PvCDPK4) and characterized its molecular property and cellular localization. PvCDPK4 was a typical CDPK which had well-conserved N-terminal kinase domain and C-terminal calmodulin-like structure with 4 EF hand motifs for calcium-binding. The recombinant protein of EF hand domain of PvCDPK4 was expressed in E. coli and a 34 kDa product was obtained. Immunofluorescence assay by confocal laser microscopy revealed that the protein was expressed at the mature schizont of P. vivax. The expression of PvCDPK4-EF in schizont suggests that it may participate in the proliferation or egress process in the life cycle of this parasite.
Plasmodium vivax; calcium-dependent protein kinase; schizont; EF-hand motif
FK506 binding proteins (FKBPs) and cyclophilins (CYPs) are abundant and ubiquitous proteins belonging to the peptidyl-prolyl cis/trans isomerase (PPIase) superfamily, which regulate much of metabolism through a chaperone or an isomerization of proline residues during protein folding. They are collectively referred to as immunophilin (IMM), being present in almost all cellular organs. In particular, a number of IMMs relate to environmental stresses.
FKBP and CYP proteins in rice (Oryza sativa cv. Japonica) were identified and classified, and given the appropriate name for each IMM, considering the ortholog-relation with Arabidopsis and Chlamydomonas or molecular weight of the proteins. 29 FKBP and 27 CYP genes can putatively be identified in rice; among them, a number of genes can be putatively classified as orthologs of Arabidopsis IMMs. However, some genes were novel, did not match with those of Arabidopsis and Chlamydomonas, and several genes were paralogs by genetic duplication. Among 56 IMMs in rice, a significant number are regulated by salt and/or desiccation stress. In addition, their expression levels responding to the water-stress have been analyzed in different tissues, and some subcellular IMMs located by means of tagging with GFP protein.
Like other green photosynthetic organisms such as Arabidopsis (23 FKBPs and 29 CYPs) and Chlamydomonas (23 FKBs and 26 CYNs), rice has the highest number of IMM genes among organisms reported so far, suggesting that the numbers relate closely to photosynthesis. Classification of the putative FKBPs and CYPs in rice provides the information about their evolutional/functional significance when comparisons are drawn with the relatively well studied genera, Arabidopsis and Chlamydomonas. In addition, many of the genes upregulated by water stress offer the possibility of manipulating the stress responses in rice.
In order to confirm the roles of creatine (Cr) in epilepsy, we investigated the anti-convulsive effects of Cr, creatine transporter (CRT) and creatine kinases (CKs) against chemical-induced acute seizure activity and chronic epileptic seizure activity.
Two hr after pilocarpine (PILO)-seizure induction, ubiquitous mitochondrial CK (uMtCK) immunoreactivity was unaltered as compared to control level. However, brain-type cytoplasm CK (BCK) immunoreactivity was decreased to 70% of control level. CRT immunoreactivity was decreased to 60% of control level. Following Cr or Tat-CK treatment, uMtCK or CRT immunoreactivity was unaffected, while BCK immunoreactivity in Cr treated group was increased to 3.6-fold of control levels. β-Guanidinopropionic acid (GPA, a competitive CRT inhibitor) reduced BCK and CRT expression. In addition, Cr and tat-BCK treatment delayed the beginning of seizure activity after PILO injection. However, GPA treatment induced spontaneous seizure activity without PILO treatment. In chronic epilepsy rats, both uMtCK and CRT immunoreactivities were reduced in the hippocampus. In contrast, BCK immunoreactivity was similar to that observed in control animals. Cr-, GPA and tat-BCK treatment could not change EEG.
Cr/CK circuit may play an important role in sustaining or exacerbating acute seizure activity, but not chronic epileptic discharge.
Partial thrombosis of giant aneurysms is not uncommon however, complete angiographic occlusion occurs less frequently. In the case of non-giant aneurysms, complete thrombosis and recanalization has been rarely reported. A 31-year-old man presented to the emergency department with sudden bursting headache. Brain computed tomography (CT) revealed diffuse subarachnoid hemorrhage on the left side. Both CT angiography (CTA) and digital subtraction angiography showed suspicion of small left anterior choroidal artery aneurysm. We performed surgical exploration. In the operation field, anterior choroidal artery aneurysm of 2 × 2 mm with broad neck and friable appearance was observed. Because we could not clip without sacrificing the anterior choroidal artery, we performed wrapping only. Follow up CTA after 7 months demonstrated 4 mm right internal carotid artery bifurcation aneurysm. The patient underwent aneurismal neck clipping. During the operation, 9 × 13 mm sized thrombosed aneurysm was detected and completely clipped. We initially thought this aneurysm to be a de novo aneurysm however, it was an aneurysm that had recanalized from a completely thrombosed aneurysm. This case report provides an insight into the potential for complete thrombosis and recanalization of non-giant aneurysms.
Cerebral aneurysm; Thrombosis; Recanalization
Transfusion-related acute lung injury (TRALI) is a serious adverse transfusion reaction that is presented as acute hypoxemia and non-cardiogenic pulmonary edema, which develops during or within 6 hr of transfusion. Major pathogenesis of TRALI is known to be related with anti-HLA class I, anti-HLA class II, or anti-HNA in donor's plasma. However, anti-HLA or anti-HNA in recipient against transfused donor's leukocyte antigens also cause TRALI in minor pathogenesis and which comprises about 10% of TRALI. Published reports of TRALI are relatively rare in Korea. In our cases, both patients presented with dyspnea and hypoxemia during transfusion of packed red blood cells and showed findings of bilateral pulmonary infiltrations at chest radiography. Findings of patients' anti-HLA antibodies and recipients' HLA concordance indicate that minor pathogenesis may be not as infrequent as we'd expected before. In addition, second case showed that anti-HLA class II antibodies could be responsible for immunopathogenic mechanisms, alone.
Adverse Transfusion Reaction; Transfusion-Related Acute Lung Injury (TRALI); Anti-HLA Antibody
High-dose interleukin-2 (IL-2) induces durable therapeutic responses in a small subset of patients with metastatic melanoma and renal cell carcinoma, but simple pretreatment predictors of response have not been identified.
Patients and Methods
To identify predictive biomarkers of clinical response, sera from patients treated with high-dose IL-2 were collected for analysis using a customized, multiplex antibody-targeted protein array platform that surveyed expression of soluble factors associated with tumor immunobiology. Soluble factors associated with clinical responses were analyzed using a multivariate permutation test, and survival outcomes were determined using Kaplan-Meier and log-rank tests.
A training set from 10 patients identified 68 potentially relevant soluble factors that were then tested in an independent validation set of 49 patients. Class comparison revealed a cluster of 11 biomarkers that were associated with therapeutic outcome. Vascular endothelial growth factor (VEGF) and fibronectin were identified as independent predictors of response. In particular, high levels of these proteins were correlated with lack of clinical response and decreased overall survival.
Serum VEGF and fibronectin are easily measured pretreatment biomarkers that could serve to exclude patients unlikely to respond to IL-2 therapy.
The ankyrin repeat and suppressor of cytokine signalling (SOCS) box proteins (Asbs) are a large protein family implicated in diverse biological processes including regulation of proliferation and differentiation. The SOCS box of Asb proteins is important in a ubiquitination-mediated proteolysis pathway. Here, we aimed to evaluate expression and function of human Asb-9 (ASB9).
We found that a variant of ASB9 that lacks the SOCS box (ASB9ΔSOCS) was naturally detected in human cell lines but not in peripheral blood mononuclear cells or normal hepatocytes. We also identified ubiquitous mitochondrial creatine kinase (uMtCK) as a new target of ASB9 in human embryonic kidney 293 (HEK293) cells. The ankyrin repeat domains of ASB9 can associate with the substrate binding site of uMtCK in a SOCS box-independent manner. The overexpression of ASB9, but not ASB9ΔSOCS, induces ubiquitination of uMtCK. ASB9 and ASB9ΔSOCS can interact and colocalise with uMtCK in the mitochondria. However, only expression of ASB9 induced abnormal mitochondrial structure and a decrease of mitochondrial membrane potential. Furthermore, the creatine kinase activities and cell growth were significantly reduced by ASB9 but not by ASB9ΔSOCS.
ASB9 interacts with the creatine kinase system and negatively regulates cell growth. The differential expression and function of ASB9 and ASB9ΔSOCS may be a key factor in the growth of human cell lines and primary cells.
High-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) was applied to improve the prognosis of patients with high-risk stage 3 neuroblastoma. From January 1997 to December 2006, 28 patients were newly diagnosed as stage 3 neuroblastoma. Nine of 11 patients with N-myc amplification and 5 of 17 patients without N-myc amplification (poor response in 2 patients, persistent residual tumor in 2 and relapse in 1) underwent single or tandem HDCT/ASCR. Patients without high-risk features received conventional treatment modalities only. While 8 of 9 patients underwent single HDCT/ASCR and the remaining one patient underwent tandem HDCT/ASCR during the early study period, all 5 patients underwent tandem HDCT/ASCR during the late period. Toxicities associated with HDCT/ASCR were tolerable and there was no treatment-related mortality. While the tumor relapsed in two of eight patients in single HDCT/ASCR group, all six patients in tandem HDCT/ASCR group remained relapse free. The 5-yr event-free survival (EFS) from diagnosis, in patients with N-myc amplification, was 71.6±14.0%. In addition, 12 of 14 patients who underwent HDCT/ASCR remained event free resulting in an 85.1±9.7% 5-yr EFS after the first HDCT/ASCR. The present study demonstrates that HDCT/ASCR may improve the survival of patients with high-risk stage 3 neuroblastoma.
Neuroblastoma; High-dose Chemotherapy; Autologous Stem Cell Rescue; Prognosis; N-myc