API5 induces cisplatin resistance through FGFR signaling in human cancer cells

Most tumors frequently undergo initial treatment with a chemotherapeutic agent but ultimately develop resistance, which limits the success of chemotherapies. As cisplatin exerts a high therapeutic effect in a variety of cancer types, it is often used in diverse strategies, such as neoadjuvant, adjuvant and combination chemotherapies. However, cisplatin resistance has often manifested regardless of cancer type, and it represents an unmet clinical need. Since we found that API5 expression was positively correlated with chemotherapy resistance in several specimens from patients with cervical cancer, we decided to investigate whether API5 is involved in the development of resistance after chemotherapy and to explore whether targeting API5 or its downstream effectors can reverse chemo-resistance. For this purpose, cisplatin-resistant cells (CaSki P3 CR) were established using three rounds of in vivo selection with cisplatin in a xenografted mouse. In the CaSki P3 CR cells, we observed that API5 acted as a chemo-resistant factor by rendering cancer cells resistant to cisplatin-induced apoptosis. Mechanistic investigations revealed that API5 mediated chemo-resistance by activating FGFR1 signaling, which led to Bim degradation. Importantly, FGFR1 inhibition using either an siRNA or a specific inhibitor disrupted cisplatin resistance in various types of API5(high) cancer cells in an in vitro cell culture system as well as in an in vivo xenograft model. Thus, our results demonstrated that API5 promotes chemo-resistance and that targeting either API5 or its downstream FGFR1 effectors can sensitize chemo-refractory cancers.

Experimental Murine Fascioliasis Derives Early Immune Suppression with Increased Levels of TGF-beta and IL-4

In fascioliasis, T-helper 2 (Th2) responses predominate, while little is known regarding early immune phenomenon. We herein analyzed early immunophenotype changes of BALB/c, C57BL/6, and C3H/He mice experimentally infected with 5 Fasciola hepatica metacercariae. A remarkable expansion of CD19+ B cells was observed as early as week 1 post-infection while CD4+/CD8+ T cells were down-regulated. Accumulation of Mac1+ cells with time after infection correlated well with splenomegaly of all mice strains tested. The expression of tumor necrosis factor (TNF)-alpha mRNA in splenocytes significantly decreased while that of IL-4 up-regulated. IL-1beta expression was down-modulated in BALB/c and C57BL/6 mice, but not in C3H/He. Serum levels of transforming growth factor (TGF)-beta were considerably elevated in all mice during 3 weeks of infection period. These collective results suggest that experimental murine fascioliasis might derive immune suppression with elevated levels of TGF-beta and IL-4 during the early stages of infection.

Kinesin Superfamily KIF1A Protein Binds to Synaptotagmin XI / 대한해부학회지

The kinesin proteins (KIFs) make up a large superfamily of molecular motors that transport cargo such as vesicles, protein complexes, and organelles. KIF1A is a monomeric motor that conveys synaptic vesicle precursors and plays an important role in neuronal function. Here, we used the yeast two-hybrid system to identify the neuronal protein (s) that interacts with the tail region of KIF1A and found a specific interaction with synaptotagmin XI. The amino acid residues between 830 and 1300 of KIF1A are required for the interaction with synaptotagmin XI. KIF1A also bound to the tail region of synaptotagmin IV but not to other synaptotagmin in the yeast two-hybrid assay. KIF1A interacted with GST-synaptotagim XI fusion proteins, but not with GST alone. An antibody to synaptotagmin XI specifically co-mmunoprecipitated KIF1A associated with synaptotagimin from mouse brain extracts. These results suggest that KIF1A motor protein transports of synaptotagmin XI-containing synaptic vesicle precursors along microtubule.

A seroepidemiological survey of Taenia solium cysticercosis in Nabo, Guangxi Zhuang Autonomous Region, China

We have observed the seropositive rate of Taenia solium cysticercosis in residents at Nabo Village, Tiandong County, Guangxi Zhuang Autonomous Region, China by enzyme linked immunosorbent assay. The village had been found to be a relatively high endemic area of porcine cysticercosis among roaming pigs. Of 202 persons examined four males aged 15, 25, 35 and 41 year-old exhibited absorbance (abs) at 0.18, 0.20, 0.35 and 0.55, respectively. In addition, two females whose ages were 35 and 39 years revealed specific antibody levels of abs 0.26 and 0.41 in their sera. Overall positive rate among the people was 2.97%. All of these persons agreed that they had ingested the pork infected with T. solium metacestode (TsM), while history of proglottid discharge was not noticed from all of them. Three males and one female complained of intermittent headache. Our findings reinforced not only that the prevalence of cysticercosis might be related with roaming pigs infected with TsM but also that behavioral and environmental practices in local community constituted risk factors for transmission of the infection.

Migration of a Slipped Aneurysmal Clip from the Intracranium into the Spinal Canal: Case Report

Very rarely, clips used for the ligation of intracranial aneurysms become detached and subsequently migrate into the spinal canal, causing lumbar pain or radiculopathy by compressing nerve roots or inducing inflammatory processes in their newly established location. However, it is easy to overlook the migration of the clip, because there may be either no noticeable symptoms, or a herniated disk may be mistakenly diagnosed as being the source of the present symptoms. Herein, the authors report a case in which an aneurysmal clip migrated into the spinal cord.

Efficacy of Percutaneous Transluminal Angioplasty for Treating Non-Maturing Brescia-Cimino Fistulas

PURPOSE: We wished to report our experiences for the treatment of non-maturing Brescia-Cimino fistulas by using percutaneous transluminal angioplasty (PTA). MATERIALS AND METHODS: From January 1997 and December 2003, we treated 22 patients with non-maturing Brescia-Cimino fistulas by using percutaneous transluminal angioplasty (PTA). A retrospective analysis was performed on the findings of the fistulograms, techniques and success rate of the PTA, and the patency rate. RESULTS: Seventeen segmental stenoses and 5 segmental occlusions of the cephalic veins were identified. Sixteen stenoses and 2 occlusions were located at the cephalic vein adjacent to the anastomosis site, and 3 occlusions and 1 stenosis are seen at the proximal vein near the elbow joint. In addition to venous stenosis, a focal arterial stenosis at the anastomosis site and two accompanying accessory veins that might hamper the maturation of main cephalic vein was seen in each of two patients, respectively, and the simultaneous occlusion of the left innominate vein as well as occlusion of the cephalic vein was noted in one patient. The initial success rate of the PTA procedures was 95.5% (21/22). The overall success rate including the 11 additional PTAs that were performed during follow-up was 96.9% (32/33). No major complication were noted to have occurred. The primary and secondary patency rates were 72% (16/22) and 95% (21/22) at 3 months, and 50% (11/22) and 77% (17/22) at 6 months, respectively. CONCLUSION: PTA is an effective and safe method for treating non-maturing Brescia-Cimino fistulas.

Cloning of a pore-forming subunit of ATP-sensitive potassium channel from Clonorchis sinensis

A complete cDNA sequence encoding a pore-forming subunit (Kir6.2) of ATP-senstive potassium channel in the adult worm, Clonorchis sinensis, termed CsKir6.2, was isolated from an adult cDNA library. The cDNA contained a single open-reading frame of 333 amino acids, which has a structural motif (a GFG-motif) of the putative pore-forming loop of the Kir6.2. Peculiarly, the CsKir6.2 shows a lack-sequence structure, which deleted 57 amino acids were deleted from its N-terminus. The predicted amino acid sequence revealed a highly conserved sequence as other known other Kir6.2 subunits. The mRNA was weekly expressed in the adult worm.

Evaluation of LG Malaria Anti-PvTM for Diagnosis of Plasmodium vivax Malaria in the Republic of Korea / 대한임상병리학회지

BACKGROUND: In the Republic of Korea, Plasmodium vivax malaria, which had disappeared since 1984, re-emerged in 1993. Currently, malaria is becoming a serious public health problem in the Republic of Korea. The diagnosis of malaria has relied on microscopic examination such as thin and thick blood smears. However, even for expert microscopists, this test is a laborious and time-consuming procedure. Therefore, the development of a reliable, easy, and convenient diagnostic test is crucial. Recently, the LG malaria anti-PvTM enzyme-linked immunosorbent assay (ELISA) kit for the detection of a specific antibody against the merozoite surface protein (MSP) of P. vivax was developed. The aim of this study was to evaluate the diagnostic kit for P. vivax malaria in the Republic of Korea. METHODS: To determine the usefulness of the LG malaria anti-PvTM as a diagnostic kit for vivax malaria, a total of 59 serum samples from patients with P. vivax malaria were tested. The patients were diagnosed microscopically and the parasitemia index of their blood was calculated. Sera from 203 uninfected healthy blood donors, which were microscopically negative for Plasmodium vivax, were used as negative controls. RESULTS: The sensitivity and specificity of the LG malaria anti-PvTM were 98.31% (58/59) and 98.03% (199/203), respectively. The false-positive and false-negative rates were 1.97% (4/203) and 1.69% (1/59), respectively. CONCLUSIONS: The diagnostic kit, LG malaria anti-PvTM, might be a useful tool for diagnosis and screening of P. vivax malaria in Korea.

Analysis of polymorphic regions of Plasmodium vivax Duffy binding protein of Korean isolates

The present study was designed to investigate polymorphism in Duffy binding protein (DBP) gene of Plasmodium vivax isolates of Korea. Thirty samples were obtained from P. vivax patients in Yonchon-gun, Kyonggi-do in 1998. The PCR products of the samples were subjected to sequencing and hybridization analyses of the regions II and IV of P. vivax DBP gene. Two genotypes, SK-1 and SK-2, were identified on the basis of amino acid substitution and deletion. The genotype of 10 isolates was SK-1 and that of 20 isolates was SK-2. Most of the predicted amino acids in the region II of DBP gene were conserved between the Korean isolates and Belem strain except for 4-5 amino acid substitutions. In the region IV of DBP, a 6-bp insert that was shown in the Sal-1 allele type was found in SK-1, and a 27-bp insert that was shown in the Papua New Guinea allele type was found in SK-2. In conclusion, the present findings suggest that two genotypes of P. vivax coexist in the endemic area of Korea.

Measurement of Anti-GAD65 Autoantibodies in Patients with Type 1 Diabetes Mellitus with / without Autoimmune Thyroid Diseases (Immunoblotting followed by Immunoprecipitation) / 대한내분비학회지

BACKGROUND: Type 1 diabetes mellitus is frequently associated with other autoimmune diseases. The broad concept of polyendocrinopathies takes into consideration that patients affected by at least one endocrine disease may have another autoimmune disorder or express specific autoantibodies. Anti-glutamic acid decarboxylase autoantibodies, now recognized as one of the major serological markers for type 1 diabetes has been reported to be higher in type 1 diabetes patients with autoimmune thyroid diseases (ATD) than in those without ATD. The objective of the present study was to evaluate the prevalences of GAD65 antibodies applying a newly developed assay(anti-GAD65) in type 1 diabetes patients with and without ATD. METHODS: We developed a new anti-GAD65 assay after mammalian expression of a recombinant GAD65 antigen. Since the detection of anti-GAD65 is rather complicated and insensitive due to inherent antigenic difference of antibody recognition in conventional assays, we applied this new approach in measuring anti-GAD autoantibodies and compared the result with ICA and anti-GAD measurement using the purified porcine GAD (anti-GAD) in 109 cases of type 1 diabetes, 29 of whom had concomitant ATD (mean age at diagnosis: 7.9 yr, mean duration of type 1 diabetes: 4.5 yrs). RESULTS: The overall prevalence of anti-GAD65 antibodies was 65% (71 of 109) in patients with Korean type 1 diabetes. Prevalences and titers of anti-GAD65 had not changed much after controlling for the duration and the status of concomitant ATD. In contrast, the prevalence of anti-GAD was 56%(61 of 109), while that of ICA(+) WAS 36% in type 1 diabetes patients. We found significant, but not strong association of anti-GAD65 either with anti-GAD(r=0.4, p<0.01) or with ICA(r=0.6, p< 0.001). CONCLUSION: From this, we could assess that autoantibodies are present at comparable sensitivity and specificity in Korean type 1 diabetes patients. This anti-GAD65 assay, another immunologic marker for type 1 diabetes might also confer disease susceptibility among Koreans, but no increase in the prevalence or in the titer in patients with ATD may suggest that this marker is unlikely to give much benefit, for the detection of the overlapping disease of type 1 diabetes and ATD.

Incidence of Lipoprotein Lipase Gene Polymorphism and Correlation with Severity of Coronary Artery Disease in Korean

BACKGROUND: Lipoprotein lipase(LPL) is a key enzyme in the metabolism of serum triglyceride(TG) which is utilized in the peripheral tissue as free fatty acid and stored in adipose tissue. LPL gene consists of 10 exons which encode 475 amino acids and more than 9 LPL gene polymorphisms have been reported. LPL gene polymorphism is related to lipids level and the severity of atherosclerosis in coronary artery disease. In Korea, LPL polymorphism has not been reported yet. The purpose of this study is to konw the incidences of LPL gene polymorphism and it's relationship with blood lipids level and the severity of atherosclerosis. METHODS: Subjects were divided into three groups; normal controls(n=50), coronary artery disease(CAD, n=51) and cerebrovascular disease(CVD, n=52). The PCR- amplified genomic DNA from peripheral white blood cell was analyzed with restriction fragment length polymorphism(RFLP) by two different restriction enzymes(Pvu II, Hind III). RESULTS: Total cholesterol(TC) was higher in CVD than in controls and CAD (203+/-60mg/dl vs 188+/-37, 167+/-42, p<0.01). Triglyceride(TG) was also elevated in CAD(166+/-65mg/dl vs 122+/-62 in controls, p<0.05). HDL cholesterol(HDL-C) was higher in controls than in CVD and CAD(49+/-9mg/dl vs 36+/-10, 44+/-9, p<0.05). The incidence of Hind III RFLP and Pvu II RFLP was not different among groups. There was no correlation between LPL gene RFLP and lipid profile. There was no correlation between LPL gene RFLP and severity of coronary arterial stenosis. The incidence of Hind III RFLP (-/-) homozygotes was lower in Korean than in other country(5% vs 7-10%). The incidence of Pvu II RFLP (-/-) homozygotes was lower in Korean than in other country(10.3% vs 18-29%). CONCLUSIONS: The LPL gene mutations in intron 6 and 8 have no direct effects on the lipid profiles and the severity of coronary artery disease. Although LPL is a key enzyme in TG metabolism, two mutations in this study could not change the activity of LPL, nor were a marker linked to other site of mutation(s). The mutation(s) in exon which encode amino acid for enzyme activity should be detected to dissect the pathphysiologic mechanism in the atherogenesis.

Positivity of Chlamydia Pneumoniae Antibody and It's Significance in Atherosclerosis

BACKGROUND: The relationship between infection of microorganism and atherosclerosis has been studied because the pathophysiology after infection is similar to those of cell injury and/or lipid theory. Although there are many reports which described the relationships between the infection of chalamydia pneumoniae and the atherosclerosis. In Korea, even the prevalence of chlamydia infection has not been studied yet. This study was purposed on the prevalence of chlamydia infection and it's correlation to atherosclerosis. METHODS: 235 subjects were enrolled and age and sex adjusted subjects were divided into two groups, normal controls (n=43), atherosclerosis (AS, n=90) group:coronary artery disease (CAD, n=61) and cerebrovascular disease (CVD, n=29). Serum total cholesterol (TC), triglyceride (TG), HDL-cholesterol (HDL-C) were measured, LDL-cholesterol (LDL-C) was calculated. Serum IgG chlamydia antibody were measured by ELISA method. RESULTS: TG was significantly higher in AS (162.51+/-100.04 mg/dL vs 122.91+/-63.31 mg/dL, mean+/-SD, p=0.019), and HDL-C was significantly higher in controls (47.30+/-9.88 mg/dL vs 39.38+/-8.29 mg/dL, p0.01). Levels of LDL-C and TC were not statistical significant. Serum IgG chlamydia antibody was positive in 29.8% (70/235), 30% (27/90) in AS group and 28% in controls and there was no statistical significance between groups (p=0.804). CONCLUSION: In conclusion, there was no significant differences in positivity of IgG chlamydia antibody in AS compared with that of controls. Overall positivity of chlamydia antibody was lower in Korea than in other country. It is still controversial whether Chlamydia pneumoniae is a primary etiologic agent of atherosclerosis or not. This study could not demonstrate the relationship between chlamydia infection and atherosclerosis in Korea. The effectiveness and indications of antichlamydial antibiotics for prevention of cardiovascular complications in atherosclerosis and overall chlamydia infection in general population will be needed in large scale trials.

A Case of Supraaortic Ridge and Subaortic Membrane Manifestated as Aortic Regurgitation

Supraaortic stenosis is a localized or diffuse congenital narrowing of the ascending aorta at the levels of superior margin of the sinus of Valsalva, just above coronary arteries. Hemodynamically, it is a usually manifestated as aortic stenosis especially when it combined with subaortic membrane. And there is no case report of supraaortic stenosis combined with subaortic membrane which has aortic valvular reurgitation due to secondary change of dilated sinus of Valsalva by supraaortic ridge. We have experienced a case of aortic regurgitation associated with supraaortic ridge combined with subvalvular aortic membrane.