bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure-dependent activation of endoplasmic reticulum stress-mediated apoptosis in pancreatic cancer by 1,1-bis(3′-indoly)-1-(p-substituted phenyl)methanes
Authors: Lei Ping , Abdelrahim Maen , Cho Sung Dae , Liu Xingi , Safe Stephen
Published: October 2008

1,1-Bis(3′-indoly)-1-(p-substituted phenyl)methanes (C-DIM) exhibit structure-dependent activation of peroxisome proliferator–activated receptor γ and nerve growth factor–induced Bα (Nur77) and induce receptor-dependent and receptor-independent apoptosis in cancer cells and tumors. In this study, we investigated the activation of apoptosis in pancreatic cancer cells by p-bromo (DIM-C-pPhBr) and p-fluoro (DIM-C-pPhF) and structurally related analogues that do not activate either peroxisome proliferator–activated receptor γ or Nur77. The ortho, meta, and para-bromo and -fluoro isomers all activated endoplasmic reticulum (ER) stress-dependent apoptosis in pancreatic cancer cells; however, methylation of the indole N group significantly decreased activity, suggesting that a free N was important for activation of ER stress. Both DIM-C-pPhBr and DIM-C-pPhF resembled the classic ER stress inducer thapsigargin in pancreatic cancer cells and activated ER stress markers, such as glucose-related protein 78 and the c-Jun NH2 kinase pathway, resulting in the induction of CCAAT/enhancer-binding protein homologous protein, death receptor 5, and the extrinsic apoptotic pathway. Moreover, DIM-C-pPhBr also inhibited tumor growth in an orthotopic model for pancreatic cancer, demonstrating the clinical potential for this C-DIM compound in pancreatic cancer chemotherapy. [Mol Cancer Ther 2008;7(10):3363–72]
Fibroblast growth factor receptor-mediated signals contribute to the malignant phenotype of non-small cell lung cancer cells: therapeutic implications and synergism with epidermal growth factor receptor inhibition
Authors: Fischer Hendrik , Taylor Ninon , Allerstorfer Sigrid , Grusch Michael , Sonvilla Gudrun , Holzmann Klaus , Setinek Ulrike , Elbling Leonilla , Cantonati Heidelinde , Grasl-Kraupp Bettina , Gauglhofer Christine , Marian Brigitte , Micksche Michael , Berger Walter
Published: October 2008

Fibroblast growth factors (FGF) and their high-affinity receptors (FGFR) represent an extensive cellular growth and survival system. Aim of this study was to evaluate the contribution of FGF/FGFR-mediated signals to the malignant growth of non-small cell lung cancer (NSCLC) and to assess their potential as targets for therapeutic interventions. Multiple FGFR mRNA splice variants were coexpressed in NSCLC cells (n = 16) with predominance of FGFR1. Accordingly, both expression of a dominant-negative FGFR1 (dnFGFR1) IIIc-green fluorescent protein fusion protein and application of FGFR small-molecule inhibitors (SU5402 and PD166866) significantly reduced growth, survival, clonogenicity, and migratory potential of the majority of NSCLC cell lines. Moreover, dnFGFR1 expression completely blocked or at least significantly attenuated s.c. tumor formation of NSCLC cells in severe combined immunodeficient mice. Xenograft tumors expressing dnFGFR1 exhibited significantly reduced size and mitosis rate, enhanced cell death, and decreased tissue invasion. When FGFR inhibitors were combined with chemotherapy, antagonistic to synergistic in vitro anticancer activities were obtained depending on the application schedule. In contrast, simultaneous blockage of FGFR- and epidermal growth factor receptor-mediated signals exerted synergistic effects. In summary, FGFR-mediated signals in cooperation with those transmitted by epidermal growth factor receptor are involved in growth and survival of human NSCLC cells and should be considered as targets for combined therapeutic approaches. [Mol Cancer Ther 2008;7(10):3408–19]
Identification and characterization of small-molecule inhibitors of hepsin
Authors: Chevillet John R. , Park Gemma J. , Bedalov Antonio , Simon Julian A. , Vasioukhin Valeri I.
Published: October 2008

Hepsin is a type II transmembrane serine protease overexpressed in the majority of human prostate cancers. We recently demonstrated that hepsin promotes prostate cancer progression and metastasis and thus represents a potential therapeutic target. Here we report the identification of novel small-molecule inhibitors of hepsin catalytic activity. We utilized purified human hepsin for high-throughput screening of established drug and chemical diversity libraries and identified sixteen inhibitory compounds with IC50 values against hepsin ranging from 0.23-2.31 μM and relative selectivity of up to 86-fold or greater. Two compounds are orally administered drugs established for human use. Four compounds attenuated hepsin-dependent pericellular serine protease activity in a dose dependent manner with limited or no cytotoxicity to a range of cell types. These compounds may be used as leads to develop even more potent and specific inhibitors of hepsin to prevent prostate cancer progression and metastasis. [Mol Cancer Ther 2008;7(10):3343–51]
Expression of the fat-1 gene diminishes prostate cancer growth in vivo through enhancing apoptosis and inhibiting GSK-3β phosphorylation
Authors: Lu Yi , Nie Daibang , Witt William T. , Chen Qiuyan , Shen Miaoda , Xie Haiyang , Lai Liangxue , Dai Yifan , Zhang Jian
Published: October 2008

Epidemiologic studies inclusively indicate that “unhealthy” dietary fat intake is one of the potential risk factors for cancer. In dietary fat, there are two types of polyunsaturated fatty acids (PUFA), ω-3 (n-3) and ω-6 (n-6). Numerous studies support that the ratio of n-6/n-3 affects tumorigenesis. It was reported that adenoviral transfer of the fat-1 gene, which converts n-6 to n-3, into breast and lung cancer cells had an antitumor effect in vitro. However, the effects of the fat-1 gene expression on tumor growth in vivo have not been studied and the mechanisms remain unclear. Accordingly, prostate cancer DU145 and PC3 cells were transfected with either the fat-1 gene or a control vector. The cells that expressed the fat-1 gene had a lower n-6/n-3 PUFA ratio compared with the cells that expressed the control vector. The fat-1 gene expression significantly inhibited prostate cancer cell proliferation and invasion in vitro. The fat-1 and control vector-transfected prostate cancer cells were s.c. implanted into severe combined immunodeficient mice for 6 weeks. The fat-1 gene expression significantly diminished tumor growth in vivo, but the control vector had no effect. Finally, we evaluated signaling pathways that may be important for fat-1 gene function. Administration of n-3 PUFA induced caspase-3-mediated prostate cancer cell apoptosis in vitro. The fat-1 gene expression inhibited prostate cancer cell proliferation via reduction of GSK-3β phosphorylation and subsequent down-regulation of both β-catenin and cyclin D1. These results suggest that fat-1 gene transfer directly into tumor cells could be used as a novel therapeutic approach. [Mol Cancer Ther 2008;7(10):3203–11]
15-deoxy-Δ12,14-prostaglandin J2 up-regulates death receptor 5 gene expression in HCT116 cells: involvement of reactive oxygen species and C/EBP homologous transcription factor gene transcription
Authors: Su Rong-Ying , Chi Kwan-Hwa , Huang Duen-Yi , Tai Ming-Hui , Lin Wan-Wan
Published: October 2008

Although 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2) was reported to up-regulate death receptor 5 (DR5) protein expression and sensitize TRAIL-induced cytotoxicity, its action mechanism remains unclear. Using HCT116 colon cancer cells, we found that sensitization of TRAIL-induced cytotoxicity by 15dPGJ2 resulted from up-regulation of DR5 via gene transcription but was not associated with PPAR-γ activation. Moreover, 15dPGJ2 induced GRP78, XBP1, and C/EBP homologous transcription factor (CHOP) expression in HCT116 cells, confirming that 15dPGJ2 is an endoplasmic reticulum stress inducer. Knockdown of the CHOP gene by siRNA attenuated DR5 up-regulation and the sensitized cytotoxicity in colon cancer HCT116 and SW480. With deletion plasmids of DR5 promoters, we found that the CHOP-binding site was involved in activating the DR5 gene by 15dPGJ2. A mechanistic study showed the contributions of reactive oxygen species (ROS) and intracellular calcium in CHOP and DR5 gene up-regulation. 15dPGJ2 was also found to induce DR5 in two prostate cancer cell lines, LNCaP and PC3. Although in LNCaP DR5 up-regulation was accompanied by CHOP expression by 15dPGJ2, no significant increase in CHOP expression or DR5 promoter activity was observed in PC3 cells. Intriguingly, 15dPGJ2 induced ROS and calcium production in PC3 cells. This inability to induce CHOP was not due to the p53-null in PC3 cells, as similar extents of increase in CHOP protein were found due to 15dPGJ2 in both wild-type and p53-null HCT116 cells. In summary, the effect of up-regulation of DR5 by 15dPGJ2 in colon cancer cells is independent of PPAR-γ and p53 but relies on CHOP induction through gene transcription involving ROS and calcium. [Mol Cancer Ther 2008;7(10):3429–40]
Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer
Authors: Song Dongweon , Chaerkady Raghothama , Tan Aik Choon , García-García Elena , Nalli Anuradha , Suárez-Gauthier Ana , López-Ríos Fernando , Zhang Xian Feng , Solomon Anna , Tong Jeffrey , Read Margaret , Fritz Christian , Jimeno Antonio , Pandey Akhilesh , Hidalgo Manuel
Published: October 2008

Targeting Hsp90 is an attractive strategy for anticancer therapy because the diversity and relevance of biological processes are regulated by these proteins in most cancers. However, the role and mode of action of Hsp90 inhibitors in pancreatic cancer has not been studied. This study aimed to assess the antitumor activity of the Hsp90 inhibitor, IPI-504, in pancreatic cancer and to determine the biological effects of the agent. In vitro, we show that pharmacologic inhibition of Hsp90 by IPI-504 exerts antiproliferative effects in a panel of pancreatic cancer cells in a dose- and time-dependent manner. In pancreatic cancer xenografts obtained directly from patients with pancreas cancer, the agent resulted in a marked suppression of tumor growth. Although known Hsp90 client proteins were significantly modulated in IPI-504-treated cell line, no consistent alteration of these proteins was observed in vivo other than induction of Hsp70 expression in the treated xenografted tumors. Using a proteomic profiling analysis with isotope tags for relative and absolute quantitation labeling technique, we have identified 20 down-regulated proteins and 42 up-regulated proteins on IPI-504 treatment.tumor growth Identical changes were observed in the expression of the genes coding for these proteins in a subset of proteins including HSPA1B, LGALS3, CALM1, FAM84B, FDPS, GOLPH2, HBA1, HIST1H1C, HLA-B, and MARCKS. The majority of these proteins belong to the functional class of intracellular signal transduction, immune response, cell growth and maintenance, transport, and metabolism. In summary, we show that IPI-504 has potent antitumor activity in pancreatic cancer and identify potential pharmacologic targets using a proteomics and gene expression profiling. [Mol Cancer Ther 2008;7(10):3275–84]
Curcumin suppresses constitutive activation of nuclear factor-κB and requires functional Bax to induce apoptosis in Burkitt's lymphoma cell lines
Authors: Hussain Azhar R. , Ahmed Maqbool , Al-Jomah Naif A. , Khan Asma S. , Manogaran Pulicat , Sultana Mehar , Abubaker Jehad , Platanias Leonidas C. , Al-Kuraya Khawla S. , Uddin Shahab
Published: October 2008

We provide evidence that curcumin, a natural compound isolated from rhizomes of plant Curcuma longa, induces apoptosis in several Burkitt's lymphoma cell lines expressing Bax protein (AS283A, KK124, and Pa682PB), whereas it has no effects in cell lines with no Bax expression (BML895 and CA46). Our data show that curcumin treatment results in down-regulation of constitutive activation of nuclear factor-κB (NF-κB) via generation of reactive oxygen species where it causes conformational changes in Bax protein leading to loss of mitochondrial membrane potential and release of cytochrome c to the cytosol. This leads to activation of caspase-9, caspase-3, and poly(ADP)-ribose polymerase cleavage leading to caspase-dependent apoptosis. In addition, curcumin treatment of Burkitt's lymphoma cell lines also causes up-regulation of DR5; however, this up-regulation does not result in apoptosis. Importantly, cotreatment with curcumin and TRAIL induces apoptosis in Bax-deficient cell lines. Taken together, our findings suggest that curcumin is able to induce apoptosis in Bax-positive cell lines, whereas combinations with TRAIL result in apoptosis in Bax-negative cell lines. These findings also raise the possibility that incorporation of curcumin in treatment regimens may provide a novel approach for the treatment of Burkitt's lymphomas and provide the molecular basis for such future translational efforts. [Mol Cancer Ther 2008;7(10):3318–29]
Polymeric nanogels containing the triphosphate form of cytotoxic nucleoside analogues show antitumor activity against breast and colorectal cancer cell lines
Authors: Galmarini Carlos M. , Warren Galya , Kohli Ekta , Zeman Arin , Mitin Anton , Vinogradov Serguei V.
Published: October 2008

The therapeutic efficiency of anticancer nucleoside analogues (NA) strongly depends on their intracellular accumulation and conversion into 5′-triphosphates. Because active NATP cannot be directly administrated due to instability, we present here a strategy of nanoencapsulation of these active drugs for efficient delivery to tumors. Stable lyophilized formulations of 5′-triphosphates of cytarabine (araCTP), gemcitabine (dFdCTP), and floxuridine (FdUTP) encapsulated in biodegradable PEG-cl-PEI or F127-cl-PEI nanogel networks (NGC and NGM, respectively) were prepared by a self-assembly procedure. Cellular penetration, in vitro cytotoxicity, and drug-induced cell cycle perturbations of these nanoformulations were analyzed in breast and colorectal cancer cell lines. Cellular accumulation and NATP release from nanogel was studied by confocal microscopy and direct high-performance liquid chromatography analysis of cellular lysates. Antiproliferative effect of dFdCTP nanoformulations was evaluated in human breast carcinoma MCF7 xenograft animal model. Nanoencapsulated araCTP, dFdCTP, and FdUTP showed similar to NA cytotoxicity and cell cycle perturbations. Nanogels without drugs showed very low cytotoxicity, although NGM was more toxic than NGC. Treatment by NATP nanoformulations induced fast increase of free intracellular drug concentration. In human breast carcinoma MCF7 xenograft animal model, i.v. dFdCTP-nanogel was equally effective in inhibiting tumor growth at four times lower administered drug dose compared with free gemcitabine. Active triphosphates of NA encapsulated in nanogels exhibit similar cytotoxicity and cell cycle perturbations in vitro and faster cell accumulation and equal tumor growth-inhibitory activity in vivo at much lower dose compared with parental drugs, illustrating their therapeutic potential for cancer chemotherapy. [Mol Cancer Ther 2008;7(10):3373–80]
Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function
Authors: Basak Shashwati , Pookot Deepa , Noonan Emily J. , Dahiya Rajvir
Published: October 2008

Androgen receptor (AR) is a ligand-activated transcription factor belonging to the steroid hormone receptor family and is very important for the development and progression of prostate cancer. The soy isoflavone genistein has been shown previously to down-regulate AR in androgen-dependent prostate cancer cell lines such as LNCaP. However, the mechanism(s) by which AR is down-regulated by genistein is still not known fully. We show a new mechanism by which genistein inhibits AR protein levels. We show that genistein-treated LNCaP cells exhibit increased ubiquitination of AR, suggesting that AR protein is down-regulated via a proteasome-mediated pathway. AR is normally stabilized by the chaperone activity of the heat shock protein Hsp90. The increased ubiquitination of AR after genistein treatment is attributed to decreased Hsp90 chaperone activity as assessed by its increased functionally inactive acetylated form. Consistent with this result, we find that HDAC6, which is a Hsp90 deacetylase, is inhibited by the antiestrogenic activity of genistein. Hence, in this study, we elucidate a novel mechanism of AR down-regulation by genistein through inhibition of HDAC6-Hsp90 cochaperone function required to stabilize AR protein. Our results suggest that genistein could be used as a potential chemopreventive agent for prostate cancers along with known inhibitors of HDAC6 and Hsp90. [Mol Cancer Ther 2008;7(10):3195–202]
Loss of prostaglandin D2 synthase: a key molecular event in the transition of a low-grade astrocytoma to an anaplastic astrocytoma
Authors: Payne Cathy A. , Maleki Sanaz , Messina Marinella , O'Sullivan Maree G. , Stone Glenn , Hall Nathan R. , Parkinson Jonathon F. , Wheeler Helen R. , Cook Raymond J. , Biggs Michael T. , Little Nicholas S. , Teo Charles , Robinson Bruce G. , McDonald Kerrie L.
Published: October 2008

Reduction in the mRNA and protein expression of lipocalin-like prostaglandin D2 (PGD2) synthase (PGDS), the main arachidonic acid metabolite produced in neurons and glial cells of the central nervous system, is a significant biological event involved in the malignant progression of astrocytomas and is predictive of poor survival. In vitro, the addition of the main PGDS metabolite, PGD2, to A172 glioblastoma cells devoid of PGDS resulted in antiproliferative activity and cell death. In vitro PGD2 substitution also enhanced the efficacy of cyclo-oxygenase-2 inhibitors. This finding has exciting implications for early interventional efforts for the grade 2 and 3 astrocytomas. [Mol Cancer Ther 2008;7(10):3420–8]
A genomic approach to identify molecular pathways associated with chemotherapy resistance
Authors: Riedel Richard F. , Porrello Alessandro , Pontzer Emily , Chenette Emily J. , Hsu David S. , Balakumaran Bala , Potti Anil , Nevins Joseph , Febbo Phillip G.
Published: October 2008

Resistance to chemotherapy in cancer is common. As gene expression profiling has been shown to anticipate chemotherapeutic resistance, we sought to identify cellular pathways associated with resistance to facilitate effective combination therapy. Gene set enrichment analysis was used to associate pathways with resistance in two data sets: the NCI-60 cancer cell lines deemed sensitive and resistant to specific chemotherapeutic agents (Adriamycin, cyclophosphamide, docetaxel, etoposide, 5-fluorouracil, paclitaxel, and topotecan) and a series of 40 lung cancer cell lines for which sensitivity to cisplatin and docetaxel was determined. Candidate pathways were further screened in silico using the Connectivity Map. The lead candidate pathway was functionally validated in vitro. Gene set enrichment analysis associated the matrix metalloproteinase, p53, methionine metabolism, and free pathways with cytotoxic resistance in the NCI-60 cell lines across multiple agents, but no gene set was common to all drugs. Analysis of the lung cancer cell lines identified the bcl-2 pathway to be associated with cisplatin resistance and the AKT pathway enriched in cisplatin- and docetaxel-resistant cell lines. Results from Connectivity Map supported an association between phosphatidylinositol 3-kinase/AKT and docetaxel resistance but did not support the association with cisplatin. Targeted inhibition of the phosphatidylinositol 3-kinase/AKT pathway with LY294002, in combination with docetaxel, resulted in a synergistic effect in previously docetaxel-resistant cell lines but not with cisplatin. These results support the use of a genomic approach to identify drug-specific targets associated with the development of chemotherapy resistance and underscore the importance of disease context in identifying these pathways. [Mol Cancer Ther 2008;7(10):3141–9]
Decreased Oxidative Stress Index of Urine in Patients with Urinary Tract Infection
Authors: Ciftci Halil , Verit Ayhan , Yeni Ercan , Savas Murat
Published: October 2008

Aim: To investigate the oxidative and antioxidative status of urine and serum of patients with urinary tract infection (UTI) and to compare them with those of controls. Materials and Methods: The antioxidative status of urine and serum were evaluated by measuring total antioxidant capacity (TAC) and plasma vitamin C concentration. The oxidative status of the samples was assessed by measuring the total peroxide and the oxidative stress index (OSI) levels. The means of the parameters were compared and the relationships among them were determined. Results: Total peroxide and OSI levels were found to be lower and TAC was found to be higher in the urine of patients with UTI. On the contrary, while the plasma vitamin C concentration and TAC of serum was lower, the total peroxide and OSI levels were higher in patients than controls. There was a negative correlation between serum TAC and urine TAC values. There was also a positive correlation between plasma vitamin C concentration and serum TAC levels. Conclusion: The urine of the patients with UTI have higher TAC and lower total peroxide and OSI levels. However, lower TAC and plasma vitamin C concentration and higher total peroxide and OSI levels were observed in UTI. This condition may be a factor which facilitates the development of the infection or is secondary to UTI.
Ectopic Adrenal Cortex Tissue: An Incidental Finding during Inguinoscrotal Operations in Pediatric Patients
Authors: Ketata Sabeur , Ketata Hafedh , Sahnoun Ahmad , FakhFakh Hamadi , Bahloul Ali , Mhiri Mohamed Nabil
Published: October 2008

Objective: The aim of the present study was to assess the occurrence of ectopic remnants of adrenal cortex tissue encountered in pediatric patients who underwent groin surgical explorations. Materials and Methods: We studied 1,862 patients with groin surgical explorations during a period of 12 consecutive years (1995–2006). Nodules resembling ectopic adrenal tissue were removed and the histopathological examination was performed using hematoxylin and eosin staining. Results: We found ectopic adrenal cortex tissue along the spermatic cord in 31 patients in 1,862 groin surgical explorations, an overall incidence of 1.66%. None were found in females. Of the 31 cases, 20 were diagnosed as having undescended testes, 8 communicating hydrocele, and 3 inguinal hernia. Median age at diagnosis was 6.5 years (range 2–14). The nodules were found located along the spermatic cord, in the apex of the hernial sac, and between the testis and epididymis. Macroscopically, the nodules were round to oval in shape, 2–6 mm in diameter, and bright yellow to orange in color. Microscopically, they had three well-defined layers of adrenal cortex, with predominance of the zona fasciculata, surrounded by a fibrous capsule and none contained any medulla. Conclusion: Ectopic adrenal cortical tissue is a benign lesion. Although a routine search for this lesion is not indicated, it should be resected for histological analysis and differential diagnosis when it is found during a surgical procedure in this area.
Induction of Pulmonary Thromboembolism by Neutrophil Elastase in Collagen-Induced Arthritis Mice and Effect of Recombinant Human Soluble Thrombomodulin
Authors: Matsuoka Toshiaki , Jin Enjing , Tachihara Akitoshi , Ghazizadeh Mohammad , Nakajima Atsuo , Yoshino Shinichi , Katayama Yasuo , Kawanami Oichi
Published: October 2008

We previously reported that during total knee arthroplasty in rheumatoid arthritis (RA) patients, the use of tourniquet might promote local release of neutrophil elastase (NE) from neutrophils, which may contribute to the development of pulmonary thromboembolism (PTE) and tissue injury. The aim of this study was to develop PTE by the use of NE in a mouse model of collagen-induced arthritis (CIA) and investigate the relationship between thrombus and endothelial cells as well as the effect of recombinant human soluble thrombomodulin (rhs-TM) in reducing the risk of PTE. Male DBA/1J mice were injected intracutaneously at several sites with an emulsion containing bovine collagen and later a booster shot to produce CIA mice. Subsequently, NE was injected intravenously 2 times a day for 3 days and after a further 4 days, mice were sacrificed. A group of mice received rhs-TM injections prior to NE injections. We divided the mice into four groups of normal, CIA control, CIA + NE, and CIA + rhs-TM + NE mice and evaluated thrombus formation status. All CIA + NE mice developed PTE. In contrast, no thrombosis was found in normal control, CIA control and CIA + rhs-TM + NE mice. Plasma thrombin level, fibrinogen expression and neutrophil count were increased in CIA + NE mice. Double staining for anticoagulant TM and procoagulant von Willebrand factor (vWF) in pulmonary endothelial cells in normal mice showed a TM-dominant expression while in both CIA control and CIA + NE mice a vWF-dominant expression compatible with coagulant status was observed. Injection of rhs-TM into CIA + NE mice resulted in a phenotypic conversion of endothelial cells from vWF-dominant to TM-dominant expression and a reduction in fibrinogen deposition. These findings demonstrate that by repeated use of NE in CIA mice, it is feasible to produce PTE and to study its pathogenesis and that rhs-TM reduces the risk of PTE. We suggest that in surgical operations of upper and lower extremities in RA patients, the use of a tourniquet should be avoided as it may trigger NE release.
The Use of Autogenous Sclera as Wrapping Material in Hydroxyapatite Implantation
Authors: Yoon Jin Sook , Lew Helen , Kook Koung Hoon , Lee Sang Yeul
Published: October 2008

Purpose: To report postoperative results and effectiveness using autogenous sclera as a wrapping material for hydroxyapatite orbital implant. Methods: A chart review of 78 patients (78 eyes) undergoing primary enucleation or a secondary procedure using autogenous sclera as a wrapping material from March 1997 to October 2004 was undertaken. Primary enucleation was performed in 54 eyes and secondary implantation in 24. In severely constricted eyes or eviscerated eyes with small implants, the sclera was unfolded and used for wrapping only on the anterior surface of the implant. Results: The average size of implants was 19.7 mm in diameter, and all the 78 implants were over 18 mm. During an average postoperative follow-up of 18 months, complications such as implant exposure, infection or extrusion did not occur in any case. Conclusion: This study shows that autogenous sclera is a safe, effective wrapping material for hydroxyapatite orbital implants with no serious complications.
Pars Plana Vitrectomy with Internal Limiting Membrane Peeling Compared with Intravitreal Triamcinolone Injection in the Treatment of Diabetic Macular Edema
Authors: Kim Yong Min , Chung Eun Jee , Byeon Suk Ho , Lee Sung Chul , Kwon Oh Woong , Koh Hyoung Jun
Published: October 2008

Aim: To compare the efficacy of pars plana vitrectomy (PPV) with internal limiting membrane (ILM) removal and intravitreal triamcinolone acetonide (IVTA) injection in patients with diabetic macular edema (DME). Methods: This study was a retrospective, comparative, interventional case study examining 14 patients (15 eyes in total) who underwent PPV and ILM removal (vitrectomy group), and 14 patients (14 eyes in total) who were treated with an IVTA injection (triamcinolone group). Main outcome measures were visual acuity and central macular thickness at 1, 3 and 6 months postoperatively. Results: Patients in the vitrectomy group had significantly decreased central macular thicknesses at 1, 3 and 6 months postoperatively (p = 0.001, p = 0.001 and p = 0.002, respectively). The improvement in visual acuity was not significant at 1 month, but it gradually became statistically significant at 3 and 6 months after surgery (p = 0.031 and p = 0.015, respectively). Compared with the triamcinolone group, the vitrectomy group showed a better visual acuity at 6 months after surgery (p = 0.025). Conclusions: PPV combined with ILM removal is a good therapeutic option for improving visual acuity and decreasing macular thickness in DME, and this treatment has a better long-term efficacy than a single IVTA injection.
Mechanism of Cd-Induced Inhibition of Na-Glucose Cotransporter in Rabbit Proximal Tubule Cells: Roles of Luminal pH and Membrane-Bound Carbonic Anhydrase
Authors: Tsuruoka Shuichi , Swenson Erik R. , Fujimura Akio , Imai Masashi
Published: October 2008

Background/Aims: We have previously reported that a complex of cadmium-metallothionein (Cd-MT) directly affects the apical Na-glucose cotransporter on the luminal side in proximal tubules, suggesting that Cd-MT is more toxic than CdCl2 in causing tubulopathy. To find the potential mechanisms, we evaluated the effect of luminal pH alteration and carbonic anhydrase (CA) inhibition on Cd-MT-induced reduction of glucose-dependent transmural voltage in rabbit S2 segments perfused in vitro. Methods: Before and after the addition of Cd-MT (1 µg Cd/ml) to the lumen, the deflections of transmural voltage upon the elimination of glucose from the perfusate (ΔVtglu) were measured as a parameter of activity of the Na-glucose cotransporter. Results: During perfusion with a control solution of pH 7.4, the ΔVtglu significantly decreased after addition of Cd-MT for 10 min. A reduction in pH to 6.8 significantly shortened the time needed to reduce the ΔVtglu to <5 min, whereas an increase of pH to 7.7 significantly prolonged the time to >20 min. Furthermore, simultaneous addition of acetazolamide with control perfusate prevented the reduction. P-Fluorobenzyl-aminobenzolamide (pFB-ABZ), a membrane-impermeable CA inhibitor, added to the lumen also completely prevented the reduction in ΔVtglu. In rabbits with chronic Cd exposure, acetazolamide prevented the glucosuria. Conclusion: Cd-MT-induced inhibition of Na-glucose cotransporter activity in the S2 segment strongly depends on luminal pH, and that an increase in pH by inhibition of luminal membrane-bound CA is useful to prevent renal Cd toxicity.
Second Eye Cataract Surgery in the Diabetes Patient? Quality of Life Gains and Speed of Visual and Functional Rehabilitation
Authors: Mozaffarieh Maneli , Heinzl Harald , Sacu Stefan , Wedrich Andreas
Published: October 2008

Purpose: To assess gains in quality of life (QOL) and visual acuity (VA), and to evaluate speed of visual and functional rehabilitation in diabetes patients with different stages of retinopathy (DR) after phacoemulsification in either one or both eyes. Methods: This prospective longitudinal study comprised 102 patients having either (1) first eye, or (2) first and subsequent second eye cataract surgery. One surgeon performed all surgeries. In both groups, the following subset of patients was compared: those with no apparent retinopathy (no DR), those with mild nonproliferative DR (NPDR), those with severe NPDR, and those with proliferative DR. VA and questionnaire (VF-14) responses were recorded prior to and 1, 3, 6, 8 and 12 months after surgery. Results: Patients with no DR and mild NPDR showed a significantly more rapid speed of visual and functional rehabilitation compared to patients with severe NPDR and proliferative DR. Maximum visual and functional results for these patients were observed 1 month after surgery, and values were significantly higher in comparison to other patients (p values <0.0001). Patients with no DR and mild NPDR who had second eye surgery demonstrated significant improvements (VA, QOL) and sustainment of the improved functional status achieved after first eye surgery (p < 0.001). Conclusions: Patients with no DR and mild NPDR show greater significant improvements in QOL and VA, and a more rapid speed of visual and functional rehabilitation in comparison to patients with more advanced DR. Functional gains are sustained at 1 year after surgery, if second eye surgery is performed.
Values for Macular Perimetry Using the MP-1 Microperimeter in Normal Subjects
Authors: Shah Vinay A. , Chalam K.V.
Published: October 2008

Purpose: To establish values for the fixation pattern and macular sensitivity to light in healthy subjects using the MP-1 microperimeter (Nideck Technologies, Vigonza, Italy). Method: A prospective study of 37 healthy subjects (age: 19–71 years), approved by the institutional review board. Full-threshold microperimetry of the central 12° of the retina (the macula) was performed prospectively, utilizing 16 points with the MP-1. The fixation stability was simultaneously recorded during microperimetry testing. The relationship between the fixation pattern and light sensitivity with age was calculated using linear regression analysis. Results: Microperimetry was performed on 66 eyes. Total mean sensitivity was 18.33 dB (range: 13.0–19 dB). Mean macular sensitivities at 2°, 4° and 6° as measured by the MP-1 were 18.4 ± 2.0, 18.2 ± 2.3 and 18.2 ± 2.1 dB, respectively. The linear regression analysis revealed a 0.019240, 0.0248 and 0.0285 dB per year age-related decline in mean macular sensitivity at 2°, 4° and 6° from the center of the macula, respectively. The total mean fixation stability values within 2° and 4° were 86 and 96%, respectively. The linear regression analysis also revealed a 0.344% and 0.122% per year decline in age-related fixation stability within 2° and 4°, respectively. There were no statistically significant differences between the median retinal sensitivity or fixation stability values for sex or race in the study. Conclusions: The MP-1 may be a reliable tool to measure macular sensitivity. Among normal healthy subjects, there was a linear decline in light sensitivity with increasing age.
Effect of Fat Embolism with Triolein Emulsion on Blood-Retinal Barrier
Authors: Lee Ji Eun , Jea Seung Youn , Oum Boo Sup , Kim Hak Jin , Ohn Young Hoon
Published: October 2008

Background: Triolein emulsion is under investigation for supplemental use to open the blood-brain barrier during chemotherapy. The effects of triolein emulsion on the blood-retinal barrier (BRB) were investigated. Methods: Fat emboli were induced in 20 cats by injecting triolein emulsion through the carotid artery. At 30 min, 4, 12 and 48 h after embolization, electroretinography (ERG) and fluorescein angiography (FA) were performed. The eyeballs were enucleated for transmission electron-microscopic study. Results: FA revealed multiple leaking points at 30 min, and prominent diffuse leakage at 4 h when scotopic b-waves showed significant differences between the study and control eyes. Multiple focal disruptions of the blood vessels by fat vacuoles were found with electron microscopic study. ERG improved at 12 and 48 h, and the BRB appeared to be recovered on FA and electron microscopic studies after 48 h. Conclusion: An experimental embolism with triolein emulsion disrupted the blood retinal barrier. Delayed maximal change was observed, and it could be implicated in the latent interval of clinical fat embolism syndrome.
Fetal Hydrops and Other Variables Associated with the Fetal Hematocrit Decrease after the First Intrauterine Transfusion for Red Cell Alloimmunization
Authors: Lobato Gustavo , Soncini Cristina Silveira
Published: October 2008

Objective: To evaluate the influence of fetal hydrops and other variables on fetal hematocrit (Hct) decrease after the first intrauterine transfusion (IUT) in alloimmunized pregnancies. Methods: From 1996 to 2006, the data of all alloimmunized pregnancies submitted to IUT were assessed. Exclusion criteria included: fetuses submitted to intraperitoneal transfusion; pregnancies complicated by other fetal abnormalities; pregnancies submitted to only one IUT, and cases in which posttransfusion or pretransfusion blood samples were not obtained. Linear regression models were implemented to assess the relationship between the rate of Hct fall after the first IUT and the following variables: fetal hydrops; antibody titer; gestational age at the first IUT; number of days between the first and second IUT; pretransfusion and posttransfusion fetal Hct values. Results: Fifty fetuses fulfilled the study criteria. The fetal Hct decrease after the first IUT was 1.21 (range 0.18–2.3) %/day. The variables independently associated with the fetal Hct drop after the first IUT were the fetal hydrops (p = 0.000), the pretransfusion fetal Hct (p = 0.001) and the posttransfusion fetal Hct (p = 0.016). Conclusion: Fetal hydrops, pretransfusion fetal Hct and posttransfusion fetal Hct seem to influence the fetal Hct decrease between the first and second IUT. These findings may be helpful for estimating the rate of fetal Hct drop and programming the following IUT.
Predictive Value of the Clock Drawing Test
Authors: Peters Ruth , Pinto Elisabete M.
Published: October 2008

Background/Aims: The Clock Drawing Test (CDT) assesses cognition focusing on executive function and praxis in contrast to the more language-based Mini-Mental State Exam. The CDT may allow early identification of cognitive decline. Methods: A systematic review of the literature was used to identify studies that had used the CDT to predict future cognitive impairment. Results: Five studies were found with the CDT as a predictor. The data were too disparate for meta-analytic techniques. Conclusion: The CDT may be a useful tool to identify decline before more traditional screening tests; however, further studies are needed as the data are sparse and heterogeneous.
Frequency and Prognostic Value of Cognitive Disorders in Stroke Patients
Authors: Leśniak Marcin , Bak Thomas , Czepiel Wojciech , Seniów Joanna , Członkowska Anna
Published: October 2008

Background: Stroke is one of the most common diseases to cause cognitive disorders in adults. Aims: To assess the frequency of cognitive deficits in stroke patients and to evaluate the prognostic value of cognitive syndromes for functional recovery. Methods: 200 consecutive patients were examined using a clinical screening battery for cognitive assessment in the second week after their first-ever stroke. 80 were re-examined after a 1-year follow-up. Results: In the post-acute stage, 78% patients were impaired in one or more cognitive domains. The most frequently affected cognitive abilities were attention (48.5%), language (27%), short-term memory (24.5%) and executive functions (18.5%). At the 1-year follow-up, attention deficits were still the most frequent symptom. In contrast, executive dysfunction, aphasia, and long-term memory disorder were significantly less frequent than in the post-acute period. Logistic regression analysis showed that older age, lower score on the Barthel Index, and the presence of executive dysfunction on initial examination were significant predictors of a poor functional outcome at the 1-year follow-up examination. Conclusions: Cognitive-behavioral syndromes are frequent and often chronic consequences of stroke. Executive deficits proved to be the most robust cognitive predictor of poor functional recovery after stroke.
Transient Bevacizumab (Avastin)-Induced Alterations in Rat Eyes
Authors: Sancho-Tello María , Johnsen-Soriano Siv , Muriach María , Bosch-Morell Francisco , Díaz-Llopis Manuel , Palacios-Pozo Elena , Navea Amparo , Romero Francisco Javier
Published: October 2008

Aims: To study the histopathological, biochemical and functional effects of intravitreal bevacizumab on the rat eye, with special emphasis on its immediate pro-inflammatory features eventually associated with cellular oxidative burden. Methods: Histopathological evaluation was performed 24 h, 1 and 4 weeks after bevacizumab (75 μg/rat eye) or saline intravitreal injection, as well as biochemical analysis of oxidative stress-related markers and electroretinograms. Results: Bevacizumab induces a transient inflammatory reaction together with a modification of the b-wave amplitude and latency of the electroretinogram. No changes were observed in any of the oxidative stress markers studied at any time after injection. Conclusion: Intravitreal bevacizumab injection per se generates an immediate, transient and mild inflammation of the rat eye, which is not associated with oxidative stress in ocular tissues.
Exogenous Superoxide Dismutase Prevents Peroxynitrite-Induced Apoptosis in Non-Heart-Beating Donor Livers
Authors: Song S.W. , Tolba R.H. , Yonezawa K. , Manekeller S. , Minor T.
Published: October 2008

Objective: To investigate the role of oxygen free radicals in the induction of apoptosis in non-heart-beating donor (NHBD) livers, and if superoxide dismutase (SOD) ameliorates these alterations. Methods: Rat livers were perfused via the portal vein with histidine/tryptophan/α-ketoglutarate solution from heart-beating donors (HBD) or 60-min warm ischemia from NHBD, with or without the addition of SOD. After 24 h, cold storage livers were evaluated by isolated reperfusion. Results: NHBD showed significantly higher enzyme leakage and elevated portal venous pressure (PVP) versus HBD. Bile and total adenine nucleotides (TAN) were significantly decreased. Apoptosis was prominent in sinusoidal lining cells, coupled with strong nitrotyrosine staining (NTR). The concentrations of nitric oxide and lipoperoxides were largely increased. SOD medication reduced hepatic enzyme release by 30% and lipoperoxides by nearly 50%. Apoptosis and NTR were significantly decreased, and PVP was strikingly reduced to normal values. A 3-fold enhancement in bile production and 1.5-fold increase in TAN of the liver tissue were also observed. Conclusion: NHBD livers are prone to severe reoxygenation injury promoted by oxygen free radicals, massive nitrite oxide production and peroxynitrite-induced apoptosis within the sinusoids. Antioxidant medication with SOD should be considered as a useful means of preserving NHBD livers.
Imaging Appetite-Regulating Pathways in the Central Nervous System Using Manganese-Enhanced Magnetic Resonance Imaging
Authors: Parkinson James R.C. , Chaudhri Owais B. , Bell Jimmy D.
Published: October 2008

The global increase in obesity has led to a redoubling of efforts directed at understanding the control of energy homeostasis. Insight into the mechanisms which govern appetite regulation is central to understanding the pathophysiology of obesity and the design of effective therapeutic interventions. Exploitation of hormonal satiety signals secreted by the gut requires greater insight into their interaction with central nervous system (CNS) circuits of appetite control. Manganese-enhanced magnetic resonance imaging is a novel technique, recently adapted to investigate the effects of gut peptides on CNS appetite circuits. Using manganese ion accumulation as a marker of neuronal activity, changes in signal intensity in key appetite centres within the hypothalamus following peripheral injection of gut hormones have been demonstrated. Manganese-enhanced magnetic resonance imaging offers several advantages over methodologies currently used for the study of gut hormone interactions with the CNS and has the potential for application in fields beyond appetite regulation.
Antioxidant SOD Mimetic Prevents NADPH Oxidase-Induced Oxidative Stress and Renal Damage in the Early Stage of Experimental Diabetes and Hypertension
Authors: Peixoto Elisa B.M.I. , Pessoa Bruno S. , Biswas Subrata K. , Lopes de Faria Jose B.
Published: October 2008

Aims: The presence of hypertension increases renal oxidative stress by increasing NADPH oxidase-dependent superoxide production and by decreasing antioxidant defense in the early stage of experimental diabetes mellitus (DM). In the present study, we investigated whether the administration of an antioxidant mimetic of the superoxide dismutase (SOD) (tempol) corrects the oxidative imbalance and oxidative stress-induced renal injury in the presence of DM and hypertension. Methods: DM was induced in spontaneously hypertensive rats (SHR) by streptozotocin at 4 weeks of age. The diabetic rats either did or did not receive tempol for 20 days. Oxidative-stress parameters and indices of renal injury were evaluated. Results: Tempol reestablished the imbalance in redox status induced by DM. It elevated the expression of renal antioxidant extracellular SOD, p < 0.0001; decreased (p = 0.049) the production of renal NADPH-dependent superoxide production, and diminished (p = 0.016) a marker of oxidative stress-induced DNA damage, 8-hydroxy-2′-deoxyguanosine. Reduction of oxidative stress markers was associated with reduction in renal damage parameters associated with DN. DM-induced albuminuria and elevation in renal expression of collagen IV were reduced to the level observed in control rats. Conclusion: We conclude that an imbalance in renal redox status is associated with markers of renal injury in the early stage of DM and hypertension. Antioxidant treatment reestablished the redox status and prevented oxidative stress-induced renal damage.
CD147, MMP-1, MMP-2 and MMP-9 Protein Expression as Significant Prognostic Factors in Human Prostate Cancer
Authors: Zhong Wei-de , Han Zhao-dong , He Hui-chan , Bi Xue-cheng , Dai Qi-shan , Zhu Gang , Ye Yong-kang , Liang Yu-xiang , Qin Wei-jun , Zhang Ze , Zeng Guo-hua , Chen Zhi-nan
Published: October 2008

Aim: CD147 and MMPs have been demonstrated to be involved in tumor invasion and angiogenesis. The aim of this study was to analyze the clinicopathological significance of CD147, MMP-1, MMP-2 and MMP-9 expression in human prostate cancer (PCa) and to evaluate their involvement in the progression of PCa. Methods: CD147, MMP-1, MMP-2 and MMP-9 expression was assessed in paraffin-embedded specimens collected from 62 cases of PCa and 15 cases of benign prostatic hyperplasia (BPH) by immunohistochemistry. Spearman’s correlation was applied to determine possible relationships between CD147, MMP-1, MMP-2 and MMP-9 expression and PCa. The association of CD147 and MMP-2 protein expression with the clinicopathological characteristics and the prognosis of PCa was subsequently assessed. Results: CD147was expressed in 51/62 (82.3%) PCa patients and in 2/15 (13.3%) BPH cases. MMP-1, MMP-2 and MMP-9 expression was significantly higher in PCa tissue than in BPH tissue. Using Spearman analysis, a significant positive correlation between CD147 and MMP-1, MMP-2 and MMP-9 expression was found (p <0.05). CD147 and MMP-2 expression was correlated with TMN grade and Gleason score. Patients with concurrent expression of CD147+ and MMP-2+ had the lowest survival (p <0.01). Conclusion: The results suggest that concurrent expression of CD147 and MMP may be an important characteristic of PCa which may help in the prediction of PCa progression.