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2.  Surveillance for nosocomial pathogens in our ICU 
Critical Care  2014;18(Suppl 1):P350.
doi:10.1186/cc13540
PMCID: PMC4069497
3.  A novel strategy inducing autophagic cell death in Burkitt's lymphoma cells with anti-CD19-targeted liposomal rapamycin 
Blood Cancer Journal  2014;4(2):e180-.
Relapsed or refractory Burkitt's lymphoma often has a poor prognosis in spite of intensive chemotherapy that induces apoptotic and/or necrotic death of lymphoma cells. Rapamycin (Rap) brings about autophagy, and could be another treatment. Further, anti-CD19-targeted liposomal delivery may enable Rap to kill lymphoma cells specifically. Rap was encapsulated by anionic liposome and conjugated with anti-CD19 antibody (CD19-GL-Rap) or anti-CD2 antibody (CD2-GL-Rap) as a control. A fluorescent probe Cy5.5 was also liposomized in the same way (CD19 or CD2-GL-Cy5.5) to examine the efficacy of anti-CD19-targeted liposomal delivery into CD19-positive Burkitt's lymphoma cell line, SKW6.4. CD19-GL-Cy5.5 was more effectively uptaken into SKW6.4 cells than CD2-GL-Cy5.5 in vitro. When the cells were inoculated subcutaneously into nonobese diabetic/severe combined immunodeficiency mice, intravenously administered CD19-GL-Cy5.5 made the subcutaneous tumor fluorescent, while CD2-GL-Cy5.5 did not. Further, CD19-GL-Rap had a greater cytocidal effect on not only SKW6.4 cells but also Burkitt's lymphoma cells derived from patients than CD2-GL-Rap in vitro. The specific toxicity of CD19-GL-Rap was cancelled by neutralizing anti-CD19 antibody. The survival period of mice treated with intravenous CD19-GL-Rap was significantly longer than that of mice treated with CD2-GL-Rap after intraperitoneal inoculation of SKW6.4 cells. Anti-CD19-targeted liposomal Rap could be a promising lymphoma cell-specific treatment inducing autophagic cell death.
doi:10.1038/bcj.2014.2
PMCID: PMC3944660  PMID: 24510029
CD19; liposome; rapamycin; Burkitt's lymphoma
4.  PDK1 inhibition is a novel therapeutic target in multiple myeloma 
British Journal of Cancer  2012;108(1):170-178.
Background:
Cancer cells utilise the glycolytic pathway even when adequate oxygen is present, a phenomenon known as the Warburg effect. We examined whether this system is operative in multiple myeloma (MM) cells and whether glycolysis inhibition is a potential therapeutic modality.
Methods:
The MM cells were purified from 59 patients using CD138-immunomagnetic beads. The expression levels of genes associated with glycolysis, c-MYC, GLUT1, LDHA, HIF1A and pyruvate dehydrogenase kinase-1 (PDK1) were determined by real-time PCR. Glucose consumption and lactate production by MM cell lines were analysed. Oxamate, an LDH inhibitor, and dichloroacetate (DCA), a PDK1 inhibitor, were employed. Inhibition of PDK1 expression was achieved using a siRNA.
Results:
High LDHA expression was found to be an indicator of poor prognosis. It was also positively correlated with the expression of PDK1, c-MYC and GLUT1. Greater glucose consumption and lactate production in MM cells was associated with higher LDHA expression. All the glycolysis inhibitors (oxamate, DCA and PDK1 siRNA) induced apoptosis in MM cells. DCA combined with bortezomib showed additive cytotoxic effects.
Conclusion:
The present data suggest that the Warburg effect is operative in MM cells. As PDK1 is not overexpressed in normal tissues, PDK1 inhibition could serve as a novel therapeutic approach.
doi:10.1038/bjc.2012.527
PMCID: PMC3553526  PMID: 23321518
multiple myeloma; glycolysis; PDK1; apoptosis
5.  Stromal cells expressing hedgehog-interacting protein regulate the proliferation of myeloid neoplasms 
Blood Cancer Journal  2012;2(9):e87-.
Aberrant reactivation of hedgehog (Hh) signaling has been described in a wide variety of human cancers including cancer stem cells. However, involvement of the Hh-signaling system in the bone marrow (BM) microenvironment during the development of myeloid neoplasms is unknown. In this study, we assessed the expression of Hh-related genes in primary human CD34+ cells, CD34+ blastic cells and BM stromal cells. Both Indian Hh (Ihh) and its signal transducer, smoothened (SMO), were expressed in CD34+ acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)-derived cells. However, Ihh expression was relatively low in BM stromal cells. Remarkably, expression of the intrinsic Hh-signaling inhibitor, human Hh-interacting protein (HHIP) in AML/MDS-derived stromal cells was markedly lower than in healthy donor-derived stromal cells. Moreover, HHIP expression levels in BM stromal cells highly correlated with their supporting activity for SMO+ leukemic cells. Knockdown of HHIP gene in stromal cells increased their supporting activity although control cells marginally supported SMO+ leukemic cell proliferation. The demethylating agent, 5-aza-2′-deoxycytidine rescued HHIP expression via demethylation of HHIP gene and reduced the leukemic cell-supporting activity of AML/MDS-derived stromal cells. This indicates that suppression of stromal HHIP could be associated with the proliferation of AML/MDS cells.
doi:10.1038/bcj.2012.36
PMCID: PMC3461706  PMID: 22961059
acute myeloid leukemia (AML); myelodysplastic syndrome (MDS); human hedgehog-interacting protein (HHIP); stromal cells
6.  Secreted Frizzled-related protein-1 is a negative regulator of androgen receptor activity in prostate cancer 
British Journal of Cancer  2009;100(7):1165-1174.
Secreted Frizzled-related protein-1 (sFRP1) associates with Wnt proteins and its loss can lead to activation of Wnt/β-catenin signalling. It is frequently downregulated in cancer, including prostate cancer, but its function in prostate cancer is unclear because it can increase proliferation of prostate epithelial cells. We investigated the function of sFRP1 in androgen-dependent prostate cancer and found that sFRP1 inhibited androgen receptor (AR) transcriptional activity. In addition, sFRP1 inhibited the proliferation of androgen-dependent LNCaP cells but not of an androgen-independent subline LNCaP-r, suggesting a role in androgen-dependent growth. The inhibition of AR by sFRP1 was unaffected by co-expression of Wnt3a, stabilised β-catenin or β-catenin shRNA, suggesting it does not involve Wnt/β-catenin signalling. Wnt5a also inhibited AR and expression of Wnt5a and sFRP1 together did not further inhibit AR, suggesting that Wnt5a and sFRP1 activate the same signal(s) to inhibit AR. However, sFRP1 inhibition of AR was unaffected by inhibitors of kinases involved in Wnt/Ca2+ and Wnt/planar cell polarity non-canonical Wnt signalling. Interestingly, the cysteine-rich domain of sFRP1 interacted with Frizzled receptors expressed in prostate cancer cells, suggesting that sFRP1/Frizzled complexes activate a signal that leads to repression of AR. Taken together, these observations highlight the function of β-catenin-independent Wnt signalling in the control of AR activity and provide one explanation for sFRP1 downregulation in prostate cancer.
doi:10.1038/sj.bjc.6604976
PMCID: PMC2669996  PMID: 19277043
sFRP1; prostate cancer; Wnt signal; Frizzled; Wnt5a
7.  Hepatitis C virus core protein promotes proliferation of human hepatoma cells through enhancement of transforming growth factor α expression via activation of nuclear factor‐κB 
Gut  2006;55(12):1801-1808.
Background
Hepatitis C virus (HCV) infection is a major cause of human hepatocellular carcinoma (HCC). The precise mechanism of hepatocarcinogenesis in humans by HCV is currently unclear. It was recently shown, however, that transgenic mice with the HCV core gene often develop HCC, suggesting tumorigenic activity of the HCV core protein. Further, the HCV core protein expressed in HepG2 cells transfected with the core gene was shown to stimulate proliferation of transfectants through activation of nuclear factor‐κB (NF‐κB). The downstream target molecule(s) of NF‐κB activated by the HCV core protein to evoke cell proliferation is not yet identified. Transforming growth factor (TGF) α, which is often overexpressed in various tumour tissues such as HCC, has been shown to stimulate hepatocyte proliferation through activation of the mitogen‐activated protein kinase or extracellular signal‐related protein kinase (MAPK/ERK) cascade.
Aims
To explore the possibility that TGFα might be a target molecule for NF‐κB activated by the HCV core, and that TGFα participates in the growth promotion of the core transfectants in an autocrine manner, activating the MAPK/ERK pathway.
Methods
A HCV core expression vector was transfected into human hepatoma Huh‐7, HepG2 and Hep3B cells. NF‐κB activity was examined by an electrophoretic mobility shift assay. TGFα transcription was assessed by a luciferase reporter assay. TGFα protein was determined by immunoblot and ELISA. MAPK/ERK activity was examined by an in vitro kinase assay. Cell proliferation was assessed by a water‐soluble tetrazolium salt‐1 assay.
Results
In the HCV core transfectants, NF‐κB bound to the κB site in the TGFα proximal promoter region, resulting in an increase in TGFα transcription. Immunoblot as well as ELISA showed increased TGFα expression in the HCV core transfectants. SN50, a specific inhibitory peptide for NF‐κB, cancelled HCV core‐induced TGFα expression. HCV core protein increased cell proliferation as well as ERK activity of the HCV core transfectants as compared with the mock transfectants. The growth‐promoting activity and activation of ERK by the HCV core protein were negated by treatment with anti‐TGFα antibodies.
Conclusions
These results suggest that the HCV core protein promotes proliferation of human hepatoma cells by activation of the MAPK/ERK pathway through up regulation of TGFα transcription via activation of NF‐κB. Our finding provides a new insight into the mechanism of hepatocarcinogenesis by HCV infection.
doi:10.1136/gut.2005.070417
PMCID: PMC1856483  PMID: 16581947
8.  MT1-MMP regulates urothelial cell invasion via transcriptional regulation of Dickkopf-3 
British Journal of Cancer  2008;99(4):663-669.
Membrane type-1 matrix metalloproteinase (MT1-MMP) is a zinc-binding endopeptidase, which plays a crucial role in tumour growth, invasion and metastasis. We have shown previously that MT1-MMP has higher expression levels in the human urothelial cell carcinoma (UCC) tissue. We show here that siRNA against MT1-MMP blocks invasion in UCC cell lines. Invasion is also blocked by broad-spectrum protease and MMP inhibitors including tissue inhibitor of metalloproteinase-1 and -2. Membrane type-1-MMP can also regulate transcription. We have used expression arrays to identify genes that are differentially transcribed when siRNA is used to suppress MT1-MMP expression. Upon MT1-MMP knockdown, Dickkopf-3 (DKK3) expression was highly upregulated. The stability of DKK3 mRNA was unaffected under these conditions, suggesting transcriptional regulation of DKK3 by MT1-MMP. Dickkopf-3 has been previously shown to inhibit invasion. We confirm that the overexpression of DKK3 leads to decreased invasive potential as well as delayed wound healing. We show for the first time that the effects of MT1-MMP on cell invasion are mediated in part through changes in DKK3 gene transcription.
doi:10.1038/sj.bjc.6604513
PMCID: PMC2527828  PMID: 18665176
MT1-MMP; invasion; DKK3; urothelial cell carcinoma; transcription
9.  Treatment of Vertebro-Basilar Dissecting Aneurysms Using Intravascular Stents 
Interventional Neuroradiology  2006;12(Suppl 1):137-144.
Summary
Endovascular surgery is an established primary therapeutic modality for dissecting aneurysms at vertebro-basilar arteries. Intravascular stents can be used to treat the dissecting aneurysms for which simple obliteration procedures cannot be used. In such cases, stent implantation alone or a combination of stents and coils need to be selected properly by taking into consideration the site and shape of dissections.
In this report, three patterns of stent application are described and their method of selection is discussed.
PMCID: PMC3387941  PMID: 20569619
dissecting aneurysm, stent, coil, vertebral artery, basilar artery
10.  Pars plana vitrectomy assisted by triamcinolone acetonide for refractory uveitis: a case series study 
The British Journal of Ophthalmology  2003;87(8):1010-1014.
Aim: To examine the outcome of a triamcinolone acetonide (TA) assisted pars plana vitrectomy (PPV) for refractory uveitis.
Methods: Six patients suffering from proliferative vitreoretinopathy (PVR) with refractory uveitis underwent a TA assisted PPV. The patients consisted of one with Vogt-Koyanagi-Harada disease, one with acute retinal necrosis, one with Behçet’s disease, and three with sarcoidosis. TA was inoculated into the vitreous cavity to visualise the vitreous. In four of six patients, 4 mg of TA were intentionally left in the vitreous cavity to reduce the degree of postoperative inflammation.
Results: The vitreous body was clearly seen using TA during surgery, which greatly helped us to perform a posterior hyaloid resection safely and thoroughly. As we previously observed in other disease, TA allowed us to visualise the transparent vitreous and thus was helpful in removing the vitreous cortex from the retina completely in uveitis. One patient (Behçet’s disease, in whom TA was intentionally left) showed an elevated intraocular pressure (IOP) transiently after surgery which was controllable by topical eye drops. The remaining TA diminished day by day and had almost completely disappeared within a month from operation.
Conclusion: TA improved the visibility of the hyaloid and the safety of the surgical procedures and no serious complications were observed after TA assisted PPV in uveitis. Although the long term effects are still unknown, this method appears to be potentially useful as an improved treatment for PVR associated with refractory uveitis.
PMCID: PMC1771810  PMID: 12881346
triamcinolone; vitrectomy; uveitis
11.  ST segment elevation in the right precordial leads following administration of class Ic antiarrhythmic drugs 
Heart  2001;85(1):e3.
Electrocardiographic changes were evaluated retrospectively in five patients without previous episodes of syncope or ventricular fibrillation who developed abnormal ST segment elevation mimicking the Brugada syndrome in leads V1-V3 after the administration of class Ic antiarrhythmic drugs. Pilsicainide (four patients) or flecainide (one patient) were administered orally for the treatment of symptomatic paroxysmal atrial fibrillation or premature atrial contractions. The QRS duration, QTc, and JT intervals on 12 lead surface ECG before administration of these drugs were all within normal range. After administration of the drugs, coved-type ST segment elevation in the right precordial leads was observed with mild QRS prolongation, but there were no apparent changes in JT intervals. No serious arrhythmias were observed during the follow up periods. Since ST segment elevation with mild QRS prolongation was observed with both pilsicainide and flecainide, strong sodium channel blocking effects in the depolarisation may have been the main factors responsible for the ECG changes. As the relation between ST segment elevation and the incidence of serious arrhythmias has not yet been sufficiently clarified, electrocardiographic changes should be closely monitored whenever class Ic drugs are given.


Keywords: class Ic antiarrhythmic drugs; Brugada syndrome; ST segment elevation
doi:10.1136/heart.85.1.e3
PMCID: PMC1729593  PMID: 11119481
12.  Apoptosis and p53 status predict the efficacy of postoperative administration of UFT in non-small cell lung cancer 
British Journal of Cancer  2001;84(2):263-269.
To examine whether efficacy of postoperative oral administration of UFT, a 5-fluorouracil derivative chemotherapeutic agent, may be influenced by incidence of apoptosis (apoptosis index) or apoptosis-related gene status (p53 and bcl-2) of the tumour, a total of 162 patients with pathologic stage I non-small cell lung cancer were retrospectively reviewed. UFT was administrated postoperatively to 44 patients (UFT group), and not to the other 118 patients (Control group). For all patients, 5-year survival rate of the UFT group (79.9%) seemed higher than that of the Control group (69.8%), although without significant difference (P = 0.054). For patients with higher apoptotic index, 5-year survival rate of the UFT group (83.3%) was significantly higher than that of the Control group (67.6%, P = 0.039); for patients with lower apoptotic index, however, there was no difference in the prognosis between these two groups. Similarly, UFT was effective for patients without p53 aberrant expression (5-year survival rates: 95.2% for the UFT group and 74.3% for the Control group, P = 0.022), whereas not effective for patients with p53 aberrant expression. Bcl-2 status did not influence the efficacy of UFT. In conclusion, apoptotic index and p53 status are useful factors to predict the efficacy of postoperative adjuvant therapy using UFT. © 2001 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2000.1579
PMCID: PMC2363717  PMID: 11161386
p53; bcl-2; apoptosis; adjuvant therapy; 5-fluorouracil; UFT
13.  Acute myelitis with hyperIgEaemia and mite antigen specific IgE: atopic myelitis 
An occurrence of acute localised myelitis was recently seen in four adult patients with atopic dermatitis who had hyperIgEaemia and mite antigen specific IgE. The total and mite antigen specific IgE was therefore studied in serum samples from 19 consecutive patients with acute localised myelitis of unknown aetiology, 56patients with clinically definite multiple sclerosis, and 40 healthy controls. The total IgE concentration was significantly higher in acute localised myelitis (median=360 U/ml) than in multiple sclerosis (median=52 U/ml, p<0.0001) and the controls (median=85 U/ml, p=0.0002). The specific IgE to Dermatophagoides pteronyssinus was found more often in patients with acute localised myelitis (95%) than in patients with multiple sclerosis (34%, p<0.0001) and the controls (35%, p<0.0001) and the specific IgE to Dermatophagoides farinae was similar (acute localised myelitis 79%, multiple sclerosis 29% (p<0.0001), controls 30%, (p=0.0003). Atopic dermatitis coexisted more commonly in patients with acute localised myelitis (37%) than in patients with multiple sclerosis (0%, p<0.0001) and the controls (7.5%, p=0.0089). Therefore, acute localised myelitis with hyperIgEaemia, in which atopy to mite antigens seems to exist, may be a distinct subtype of allergic myelitis—that is, atopic myelitis.


PMCID: PMC2170101  PMID: 9598690
14.  Increased number of IgE positive Langerhans cells in the conjunctiva of patients with atopic dermatitis 
AIM—To determine the role of Langerhans cells (LCs) found to bear IgE in patients with atopic dermatitis (AD) by evaluating the surface distribution of these cells in the conjunctival epithelium and epidermis of skin lesions in patients with AD.
METHODS—The double labelling method was used to evaluate IgE positive cells that were positive for anti-CD1a or anti-CD23 antibody in an epithelial sheet of the conjunctival limbus. Specimens of conjunctiva were obtained from 12 men, six of whom had AD and ocular complications. Five patients without atopic disease served as controls, plus one additional patient with asthma but no AD. A similar study was conducted using epidermal sheets obtained from two patients with AD and from one without AD.
RESULTS—The number of CD1a+ cells present in the conjunctival epithelium of the patients with AD significantly exceeded that of the patients without AD. Most CD1a+ cells in the conjunctival epithelium and epidermis from the patients with AD bore IgE on their surfaces. Few such cells from patients without AD bore IgE. No CD23+ cells were found in the patients with or without AD.
CONCLUSIONS—The presence of an increased number of LCs bearing IgE on their surfaces in the conjunctival epithelium of patients with AD suggests that these cells may be involved in eliciting the hypersensitivity reaction and participate in ocular inflammation.


PMCID: PMC1722197  PMID: 9227207
15.  Mutational analysis of human immunodeficiency virus type 1 (HIV-1) accessory genes: requirement of a site in the nef gene for HIV-1 replication in activated CD4+ T cells in vitro and in vivo. 
Journal of Virology  1997;71(11):8456-8466.
Human immunodeficiency virus type 1 (HIV-1) accessory genes including nef, vif, and vpr are important factors that determine the replication and pathogenesis of HIV-1. The state of activation is also important for the replication of HIV-1. We evaluated the properties of nef-, vif-, and vpr-minus macrophage-tropic HIV-1(JR) CSF in primary CD4+ Th1- or Th2-like cell cultures which had been activated through CD3 molecules in the presence of interleukin-2 (IL-2) and IL-12 (Th1-like culture) or IL-4 (Th2-like culture), respectively. In activated Th1- or Th2-like cultures, replication of nef-minus HIV-1(JR-CSF) was markedly lower than that of wild-type HIV-1. Subsequent analysis by site-directed mutagenesis showed that (i) the presence of an acidic amino acid-rich domain (amino acid residues 72 to 75) in the Nef protein was critical for the enhancement of viral DNA synthesis, resulting in increased virus growth rate, and (ii) prolines that form part of Src homology 3 binding domain were not essential for viral replication. We also confirmed the importance of sites by using an HIV-1-infected animal model, the hu-PBL-SCID mouse system, representing HIV-1 replication and pathogenesis in activated CD4+ T cells in vivo. These results indicate that Nef accelerates viral replication in activated CD4+ T cells.
PMCID: PMC192308  PMID: 9343202
16.  Primary human immunodeficiency virus type 1 viremia and central nervous system invasion in a novel hu-PBL-immunodeficient mouse strain. 
Journal of Virology  1997;71(3):2417-2424.
We established four new mouse strains with defective T and B cells as well as defects in innate immunological reactions using an NK cell depletion antibody and showed that all mutant mouse strains efficiently received human peripheral blood leukocyte (PBL) engraftment (hu-PBL-scid mice). Higher levels of human immunodeficiency virus type 1 (HIV-1) replication were observed in these new hu-PBL-scid mice than in conventional hu-PBL-C.B-17-scid mice. In one particular strain, hu-PBL-NOD-scid mice, high levels of HIV-1 viremia (more than 10(6) 50% infectious doses per ml) were detected after infection with HIV-1. The plasma viral load was about 100 to 1,000 times higher than that observed in other hu-PBL-scid mice infected with HIV-1. Although high-level viremia did not correlate with the total amount of HIV-1 RNA in cells from infected mice, high levels of free virions were detected only in hu-PBL-NOD-scid mice. HIV-1 viremia induced systemic HIV-1 infection involving the liver, lungs, and brain. PCR in situ hybridization confirmed that HIV-1-infected cells invaded the brain tissue of the hu-PBL-NOD-scid mice. Our results suggest that the genetic background, including innate immunity, is critical in the development of primary HIV-1 viremia and subsequent central nervous system invasion with HIV-1. The hu-PBL-NOD-scid mouse represents a useful model for the study of the pathogenesis of HIV-1 in vivo, especially brain involvement, and therapy of primary HIV-1 viremia.
PMCID: PMC191352  PMID: 9032379
17.  Chronic hypertrophic cranial pachymeningitis associated with HTLV-I infection. 
Two patients presenting with recurrent multiple cranial neuropathy showed diffuse thickening and gadolinium enhancement of the dura mater on brain MRI. Both had anti-HTLV-I antibodies in serum. A quantitative polymerase chain reaction study of the peripheral blood disclosed that the HTLV-I proviral DNA loads increased considerably in one case and moderately in the other. Both showed a spontaneous proliferation of peripheral blood lymphocytes as well as an increase in helper/inducer T cells. Neither had any other underlying infections or autoimmune diseases. Thus it is possible that hypertrophic pachymeningitis developed as a result of multiorgan involvement of HTLV-I infection in these patients.
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PMCID: PMC486083  PMID: 7561926

Results 1-17 (17)